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Computerized advice on drug dosage to improve prescribing practice

  1. Florence Gillaizeau1,
  2. Ellis Chan2,
  3. Ludovic Trinquart1,
  4. Isabelle Colombet3,
  5. RT Walton4,
  6. Myriam Rège-Walther5,
  7. Bernard Burnand5,
  8. Pierre Durieux6,*

Editorial Group: Cochrane Effective Practice and Organisation of Care Group

Published Online: 12 NOV 2013

Assessed as up-to-date: 12 DEC 2012

DOI: 10.1002/14651858.CD002894.pub3


How to Cite

Gillaizeau F, Chan E, Trinquart L, Colombet I, Walton RT, Rège-Walther M, Burnand B, Durieux P. Computerized advice on drug dosage to improve prescribing practice. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD002894. DOI: 10.1002/14651858.CD002894.pub3.

Author Information

  1. 1

    Hôpital Hôtel-Dieu, French Cochrane Center, Paris, France

  2. 2

    Hôpital Hôtel-Dieu, Centre d'Epidémiologie Clinique, Paris, France

  3. 3

    Georges Pompidou European Hospital, Paris Descartes University, INSERM U872 eq20, Medical Informatics Department, Paris, France

  4. 4

    Barts and the London Medical School, Centre for Health Sciences, London, UK

  5. 5

    Lausanne University Hospital, Cochrane Switzerland, Institute of Social and Preventive Medicine, Lausanne, Switzerland

  6. 6

    Georges Pompidou European Hospital, Paris Descartes University, INSERM U872 eq 22, Department of Public Health and Medical Informatics, Paris, France

*Pierre Durieux, Department of Public Health and Medical Informatics, Georges Pompidou European Hospital, Paris Descartes University, INSERM U872 eq 22, 20 rue Leblanc, Paris, 75015, France. pierre.durieux@egp.aphp.fr. pierdurieux@gmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 12 NOV 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Ageno 1998

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Episode of care
Power calculation: Not reported


ParticipantsProfession: Mixed (physicians + nurses)

Level of training: Accredited/licensed

Clinical specialty: Other, anticoagulant clinic

Country: Canada (Ontario)

Centre: 1 general hospital (Hamilton General Hospital)

Location of care: Outpatient care

Participants: 101 outpatients on long-term oral anticoagulant therapy after mechanical heart valve replacement


InterventionsClinical problem: Long-term warfarin therapy
Intervention: Prediction rules, computer-assisted group (n = 50) vs. control group (n = 51)
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: User-initiated
Type of intervention: Direct intervention
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Proportion of doses adjustments (potential unit of analysis error)

Serum concentrations and therapeutic range: None

Physiological parameters: None (percentage of days in range with an INR of 2.5-3.5 according to the Duxburry method (reported as time spent in days per 100 patient-days of treatment), % of INRs > 5: reported, % of INRs < 2: reported, mean INR values: no dispersion data, % of INRs in range (2.3-3.7): not included, % of days in range (2.5-3.5): not included, % of days in range (2.3-3.7): not included)

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: None

Improvement: None


Notes- The author confirm that none of the participants was included in both studies Ageno 1998 and Ageno 2000

- Therapeutic INR range: "Warfarin is administered with a therapeutic INR range of 2.5 to 3.5, according to the 1995 American College of Chest Physicians recommendations"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandom sequence generation not specified

Allocation concealment (selection bias)Unclear risk"Consecutive patients who were discharged from the Hamilton General Hospital (Ontario, Canada) after mechanical heart valve replacement were randomized to be controlled by the computerized system or standard manual monitoring by trained personnel". No further information provided

Baseline outcome measurements similarLow riskNo baseline measure of outcome

Baseline characteristics similarUnclear riskParticipant randomization. "The two groups were similar with respect to age and gender." No further information provided.

Providers were 2 physicians and 3 registered nurses, all with several years of experience in the management of people on oral anticoagulants

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot clearly specified in the paper

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Ageno 2000

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Other (dose, INR, participant)
Power calculation: Not reported


ParticipantsProfession: Mixed (physicians + nurses)
Level of training: Accredited/licensed
Clinical specialty: General/family practice

Country: Canada (Ontario)

Centre: 1 general hospital (Hamilton General Hospital)

Location of care: Inpatient care
Participants: 101 participants who required oral anticoagulation (heart valve replacement, treatment of venous thromboembolism, atrial fibrillation, prophylaxis for deep vein thrombosis, acute myocardial infarction and vascular surgery)


InterventionsClinical problem: Warfarin adjustment in hospitalized people
Intervention: Computer-based control of oral anticoagulation (n = 50 participants) vs. standard manual dosing (n = 51 participants). The computerized induction treatment module (DAWN AC INDUCTION) calculated the daily dosage of warfarin based on algorithms that could be set at every centre according to the local clinical practice
Computer advice: Given in real time
CDSS integration in CPOE: Not reported
Starter: Not reported
Type of intervention: Direct intervention
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Proportion of doses adjustments (potential unit of analysis error) (daily dose of warfarin: no dispersion data)

Serum concentrations and therapeutic range: None

Physiological parameters: None (% of INRs > 5: reported, mean INR values: no dispersion data, % of participants with at least 1 INR > upper limit of therapeutic range: not included)

Time to achieve therapeutic control: None

Clinical events: Minor bleeding (major bleeding: not included)

Healthcare costs: None

Improvement: None


Notes- There were different indications for oral anticoagulation: "heart valve replacement (n:74), treatment of venous thromboembolism (n:16), atrial fibrillation (n:5), prophylaxis for deep vein thrombosis (n:4), acute myocardial infarction (n:1), and vascular surgery (n:1)"

- The author confirm that none of the participants was included in both studies Ageno 1998 and Ageno 2000

- Therapeutic INR range: "Because of a higher risk of bleeding during the early days of treatment due to the presence of pacing wires which are usually removed between the fifth and seventh post operative day, the initial therapeutic INR for participants following heart valve replacement ranges between 1.5 to 2.6. After the wires are removed, the therapeutic INR is 2.5 to 3.5 for mechanical valves, and 2.0 to 3.0 for bioprosthetic valves. For all other indications, the therapeutic INR ranges between 2.0 and 3.0. In the algorithm set in the computer, we defined a low therapeutic regime for the first 5 days of treatment for all the participants following heart valve replacement"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandom sequence generation not specified

Allocation concealment (selection bias)Unclear risk"Consecutive patients who were hospitalized at the Hamilton General Hospital (Ontario, Canada) and who required oral anticoagulation were randomized to control by the computerized system or standard manual dosing until the seventh day of treatment or until discharge, whichever happened first". No further information provided

Baseline outcome measurements similarLow riskNo baseline measure of outcome

Baseline characteristics similarLow riskParticipant randomization. "The two groups were similar with respect to age (64.6 manual group; 63.3 computer group), whereas the proportion of males was higher in the computer group (64%) than in the manual group (53%) [...] The proportion of participants following heart valve replacement was 78% in the computer group and 69% in the manual group.[...] The mean INR was 2.09 in the computer group, and 2.07 in the manual group"

Providers were trained nurses or physicians (supposed to be the same providers at baseline and during intervention)

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot clearly specified in the paper

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskOutcomes included bleeding events. Minor and major bleeding events were not clearly defined

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Anderson 2007

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Done


ParticipantsProfession: Mixed (physicians + pharmacists)
Level of training: Not reported
Clinical specialty: Not reported

Country: USA (Salt Lake City)

Centre: 1 general urban hospital and surgical centre (LDS Hospital, Intermountain's outstanding heart network in the Salt Lake Valley)

Location of care: Inpatient care
Participants: 206 participants being initiated on oral anticoagulation. 200 participants analyzed


InterventionsClinical problem: Warfarin initiation
Intervention: Pharmacogenetic-guided dosing (n = 101) versus standard empirical dosing (n = 99). Pharmacogenetic-arm dosing was determined with a regression equation included CYP2C9 (*1, *2, *3) and VKORC1 (C1173T) genotypes, age, weight and sex. Standard dosing followed the 10-mg warfarin nomogram of Kovacs et al.
Computer advice: Given in real time
CDSS integration in CPOE: Not reported
Starter: User-initiated
Type of intervention: Direct intervention
Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: Dose adjustments per participant

Serum concentrations and therapeutic range: None

Physiological parameters: Time (%) within therapeutic range (% of out-of-range INRs: not included, Number of INR measurements: not included, % participants reaching therapeutic INR on days 5 and 8: not included)

Time to achieve therapeutic control: None (time to first supratherapeutic INR: not included)

Clinical events: % participants with adverse events (clinical plus INR ≥ 4), % participants with serious adverse events (clinical only)

Healthcare costs: None

Improvement: None


Notes- Therapeutic INR range: "Although the target INR range was 2 to 3, we prospectively defined an out-of-range INR value, for purposes of end-point analysis and for clinical dose adjustment, as 1.8 or 3.2 to allow for measurement error and to avoid problems inherent in overcorrection"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomization (in permuted blocks of 5) to the pharmacogenetic or standard arm"

Allocation concealment (selection bias)Low risk"The randomization arm assignment was blinded to patients and clinicians/investigators and known only to a designated research assistant and pharmacist"

Baseline outcome measurements similarLow riskNot applicable (initiation of warfarin therapy)

Baseline characteristics similarHigh risk"Clinical characteristics were balanced except for older age and greater prevalence of hypertension in pharmacogenetic patients." The results on primary endpoint were unchanged by further adjustment for differences in age and hypertension

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo apparent missing data

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective. "An independent Data and Safety Monitoring Committee tracked unblinded safety data. A separate independent Clinical Events Committee adjudicated key clinical adverse events blinded to study arm"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants were randomized. "The randomization arm assignment was blinded to patients and clinicians/investigators and known only to a designated research assistant and pharmacist"

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Anderson 2008

Methods


Participants


Interventions


Outcomes


Notes- Same study as Anderson 2007

Asberg 2010

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Other (blood sample, participant)
Power calculation: Not done "In this pilot study, the number of subjects needed to be included was empirically based"


ParticipantsProfession: Physicians
Level of training: Accredited/licensed
Clinical specialty: Nephrology
Country: Norway (Oslo)
Centre: 1 university hospital
Location of care: Mixed (nephrology and standard clinical follow-up)
Participants: 40 adult kidney transplant recipients on CsA, prednisolone and mycophenolate were included 2 weeks after transplantation (discharge from the surgical department) and followed for at least 8 weeks (standard clinical follow-up)


InterventionsClinical problem: CsA in early post-transplant phase
Intervention: Computer dosing of CsA doses (n = 20 participants) vs. standard practice (n = 20 participants). Individual CsA doses were calculated by a population pharmacokinetic model and suggested to the physician
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: User-initiated
Type of intervention: Indirect intervention
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Daily CsA dose

Serum concentrations and therapeutic range: None (% participants with a deviation from the targeted blood concentration > 50% on at least 1 occasion: not included)

Physiological parameters: Glomerular filtration rate (renal function) (mL/min) (% of blood concentrations within the therapeutic window for an individual: reported, 2-hour plasma glucose (mmol/L): not included)

Time to achieve therapeutic control: None

Clinical events: Proportion of participants with cytomegalovirus infections

Healthcare costs: None

Improvement: Proportion of participants without biopsy-confirmed rejections


Notes"The attending physician specified individual therapeutic C2 windows based on clinical evaluation of patient characteristics and risk factors. The standard protocol at our center is 900-1100 µg/L for the first month of transplant, followed by 700-900 µg/L up to month 3 in a normal risk patient; high-risk patients start with a therapeutic window of 1200-1600 µg/L followed by appropriate tapering"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandom sequence generation not specified

Allocation concealment (selection bias)Unclear risk"A single center randomized prospective trial in adult kidney transplant recipients on CsA-based immunosuppression was performed." No further information provided

Baseline outcome measurements similarLow risk"There was no significant differences between the number of samples collected in the 2 groups (P=0.12) or in the percentage of C2 values obtained in each group (MAP-BE: 82%, CONTR: 78%, P=0.39)." No further information provided

Baseline characteristics similarUnclear riskParticipant randomization. "There was no relevant demographic differences between groups"

Providers were physicians (supposed to be the same providers at baseline and during intervention)

Incomplete outcome data (attrition bias)
All outcomes
Low risk"There was no significant differences between the number of samples collected in the 2 groups (P=0.12)"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Augstein 2007

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Done. "Using a one-sided test at a 5% level of statistical significance, the trial was designed to have an 85% statistical power to detect a difference of 0.5% in change in A1C ( A1C) from baseline to end of trial between the CGMS and CGMS/KADIS group, with an assumed SD of 0.6"


ParticipantsProfession: Physicians
Level of training: Not reported
Clinical specialty: General/family practice, diabetes specialty
Country: Germany
Centre: 5 outpatient centres (3 general and 2 diabetes specialist practices)
Location of care: Outpatient care
Participants: 49 insulin-treated outpatients. 46 subjects completed the study (3 subjects had incomplete first CGMS monitoring and were excluded)


InterventionsClinical problem: Insulin in people with diabetes
Intervention: CGMS + KADIS (n = 24 participants) vs. CGMS (n = 25 participants). CGMS provides information about glycaemic control by glucose readings every 5 min and was used as the source of glucose data. All participants were educated to use CGMS monitors and the CGMS data were downloaded and transferred to the centre (Institute of Diabetes) for analysis. Depending on the group to which the participant belonged, physicians received either CGMS data alone or CGMS data plus KADIS decision support report. KADIS is based on a mathematical model that describes the glucose/insulin metabolism in type 1 diabetes in the form of a coupled differential equation
Computer advice: Not reported
CDSS integration in CPOE: No
Starter: User-initiated
Type of intervention: Not reported
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Insulin (IU/day)

Serum concentrations and therapeutic range: None

Physiological parameters: Mean sensor glucose (mmol/L), A1C (%) (duration of hypoglycaemic excursions (h/day): not included, duration of hyperglycaemic excursions (h/day): not included, Bread Exchange Unit: not included)

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: None

Improvement: None


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients with even random numbers, derived from a random number table, were assigned for the CGMS and patients with uneven random numbers for the CGMS/KADIS group"

Allocation concealment (selection bias)Unclear riskRandom number table. No further information provided

Baseline outcome measurements similarLow risk"Both study groups included type 1 and type 2 diabetic subjects in equal proportions. There were no significant differences in age, sex, diabetes duration, BMI [body mass index], or insulin application between groups (Table 1)"

Baseline characteristics similarLow riskParticipant randomization. "The two groups were similar with respect to age (64.6 manual group; 63.3 computer group), whereas the proportion of males was higher in the computer group (64%) than in the manual group (53%) [...] The proportion of participants following heart valve replacement was 78% in the computer group and 69% in the manual group.[...] The mean INR was 2.09 in the computer group, and 2.07 in the manual group"

Providers were trained nurses or physicians (supposed to be the same providers at baseline and during intervention)

Incomplete outcome data (attrition bias)
All outcomes
High risk"Of the 49 subjects found eligible, 46 (24 in the CGMS and 22 in the CGMS/KADIS group) completed the study. Three subjects had incomplete first CGMS monitoring (one in the CGMS and two in the CGMS/KADIS group) and were excluded"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Begg 1989

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Physicians
Level of training: Not reported
Clinical specialty: Not reported
Country: New Zealand

Centre: 1 general hospital (Christchurch Hospital)

Location of care: Inpatient care
Participants: 50 hospital inpatients (ICU excluded)


InterventionsClinical problem: Aminoglycoside
Intervention: Pharmacokinetic model, computer-assisted group (n = 24) vs. control group (n = 26)

Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Not reported
Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: Aminoglycoside (mg/day)

Serum concentrations and therapeutic range: Aminoglycoside peak plasma concentration after 2 days (mg/L), % participants within drug therapeutic range (plasma peak concentrations of 6-10 mg/L and trough concentrations of 1-2 mg/L at 2 days), % participants with plasma peak concentrations of 6-10 mg/L at 2 days (peak concentration criterion alone) (peak concentrations after 5 days: not included, through concentrations: not included, number of dose alterations: not included)

Physiological parameters: None

Time to achieve therapeutic control: None

Clinical events: Death, nephrotoxicity (increase in creatinine clearance)

Healthcare costs: None

Improvement: None


Notes"Patients in the intensive care unit were excluded, since they formed the basis of a similar study with a different control group being conducted concurrently"

Hickling K, Begg E, Moore ML (1989): 32 adult patients in intensive care unit at Christchurch Hospital (New Zealand) who required gentamicin or tobramycin therapy for serious life threatening infections, other than those receiving haemodialysis for renal acute failure


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Computer generated randomisation procedure"

Allocation concealment (selection bias)Low risk"Computer generated randomisation procedure"

Baseline outcome measurements similarLow riskNo information provided

Baseline characteristics similarLow risk"There were no major differences between the groups in their demographic features (Table 1)"

Incomplete outcome data (attrition bias)
All outcomes
High riskNumber of participants randomized: 50 (24 in the computer-assisted group, 26 in the control group)

Number of participants analyzed: 45 ("for the remaining patients aminoglycoside therapy was discontinued before analysis of plasma concentration"). Peak concentrations were available for 33 participants at 2 days, and 26 participants at 5 days. Trough concentrations were available for 32 participants at 2 days, and 26 participants at 5 days

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Blaha 2009

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Mixed (physicians + nurses)
Level of training: Not reported
Clinical specialty: Surgical ICU
Country: Czech Republic (Prague)

Centre: 1 university hospital (Charles University and General University Hospital)

Location of care: Inpatient care
Participants: 120 adults admitted to the postoperative ICU after elective cardiac surgery were randomly assigned into the Matias protocol based on the absolute glucose value (n = 40), the Bath protocol based on the relative glucose change (n = 40), or the computer-based model predictive control algorithm with variable sampling rate (eMPC) (n = 40)


InterventionsClinical problem: Insulin in critically ill people (cardiac surgery patients)
Intervention: Matias protocol based on the absolute glucose value (n = 40 participants) versus computer-based model predictive control algorithm with variable sampling rate (eMPC) (n = 40 participants). The eMPC is an enhanced version of the model predictive control algorithm (MPC), a model of the glucoregulatory system. Glucose concentration, insulin dosage, and carbohydrate content of enteral and parenteral input are the input variables for the eMPC. The insulin infusion rate and the time of the next glucose sample are the outputs. Group with the Bath protocol based on the relative glucose change (n = 40) was excluded since most of standard protocols use the absolute glucose value and this protocol had not been used in the Charles University and General University Hospital before the study
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: User-initiated
Type of intervention: Direct intervention

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: None

Physiological parameters: % of time within the target range for blood glucose during the study or the first 48 h (80-110 mg/dL or 4.4-6.1 mmol/L), mean blood glucose (mmol/L)

Time to achieve therapeutic control: Time to target range (hours), mean sampling interval (hours)

Clinical events: Proportion of participants with severe hypoglycaemic episodes (blood glucose level < 2.3 mmol/L)

Healthcare costs: None

Improvement: None


Notes- "The target glucose range was 4.4 – 6.1 mmol/l, which has been demonstrated to reduce mortality and morbidity". "severe hypoglycemic episodes (blood glucose <2.3 mmol/l)"

- The study is part of CLINICIP (Closed Loop Insulin Infusion for Critically Ill Patients; www.clinicip.org), an integrated project funded by the European Community


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandom sequence generation not specified

Allocation concealment (selection bias)Unclear riskNo information provided

Baseline outcome measurements similarLow riskNo significant differences on blood glucose at study start or number of participants with history of diabetes (Table 1)

Baseline characteristics similarLow riskNo significant differences on baseline characteristics (Table 1)

Incomplete outcome data (attrition bias)
All outcomes
Low risk"Because the duration of the ICU stay and the total monitoring time differed among patients, only data for up to 48 h were used for the comparison of the protocols. Forty-eight hours of ICU stay were accomplished in 109 of 120 patients included in the study"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMain outcomes were objective. Hypoglycaemic episodes are clearly defined

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Burton 1991

MethodsDesign: RCT
Unit of allocation: House staff team (a random number table was used to determine which of the house staff teams would be assigned to the intervention group. At the end of each 4 months, during the study, intervention groups were changed to control and vice versa to ensure equal allocation of participant types and infections to each group)
Unit of analysis: Participant (cluster was not taken into account in the analysis)
Power calculation: Not reported


ParticipantsProfession: Physicians
Level of training: Accredited/licensed
Clinical specialty: Not reported
Country: USA (Dallas)

Centre: 1 Veterans Administration Medical Center (680-bed tertiary care - affiliated institution)
Location of care: Inpatient care
Participants: 147 participants treated with aminoglycosides


InterventionsClinical problem: Aminoglycoside
Intervention: Dose advice based on Bayesian pharmacokinetic model (n = 72) vs. usual care (n = 75)
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Not reported

Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: Beginning aminoglycoside dose (mg/day), Ending aminoglycoside dose (mg/day)

Serum concentrations and therapeutic range: Aminoglycoside peak serum concentration (mg/L), toxic drug level (% participants within peak concentration > 4 mg/L) (maximum trough concentration: not included, % participants within trough concentrations ≥ 2 mg/L: not included)

Physiological parameters: None

Time to achieve therapeutic control: None

Clinical events: Nephrotoxicity (rise in serum creatinine level of 0.5 mg/dL if the initial value was ≤ 1.5 mg/dL or a 30% rise in the serum creatinine value), death

Healthcare costs: Length of stay

Improvement: % of participants cured (afebrile for 4 consecutive days and without: recurrence of fever, leukocytosis, recurrence of infection, use of another effective antibiotic within 48 hours of stopping aminoglycoside)


Notes"All initial and revised dosages in the intervention group were targeted to obtain peak and trough serum concentrations within the recognized therapeutic range of 5 to 10 mg/L for peak concentrations and less than 2 mg/L for through concentrations of gentamicin and tobramycin. The therapeutic range for amikacin was 20 to 30 mg/L for peak concentrations and less than 5 mg/L for through serum concentrations"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Random number table to determine which 9 of the 17 house staff teams would be assigned as control groups"

Allocation concealment (selection bias)Low risk"Random number table to determine which 9 of the 17 house staff teams would be assigned as control groups"

Baseline outcome measurements similarLow riskNo information provided

Baseline characteristics similarLow risk"As shown in Table II, there were no significant differences in any of the patient characteristics between subjects in the control versus the intervention group." "In a similar manner, there were no significant differences in the clinical diagnosis between patients in each group (Table I)"

Incomplete outcome data (attrition bias)
All outcomes
High riskNumber of participants randomized: 147 (72 in intervention group and 75 in the control group)

Number of participants analyzed: 136 for number of participants cured (68 in each groups), 143 for toxic drug levels (70 in intervention group and 73 in the control group)

"Intervention patients were excluded from the study if recommended dosing was not implemented within 48 hours of the first dose of aminoglycoside"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective. Nephrotoxicity and % of participants cured were clearly defined in the methods section

Blinding of participants and personnel (performance bias)
All outcomes
High riskTeams were randomized in 1 site. At the end of each 4 months during the study, intervention groups were changed to control and vice versa

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of bias

Carter 1987

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Mixed (physicians + pharmacists)
Level of training: Not reported
Clinical specialty: Not reported
Country: USA

Centre: 1 Veterans Administration Medical Center
Location of care: Inpatient care
Participants: 65 adult inpatients receiving warfarin sodium


InterventionsClinical problem: Initiation of warfarin therapy
Intervention: Pharmacokinetic concepts, analogue-computer program (n = 31) vs. empiric dosing (n = 34)

Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Indirect intervention

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Warfarin stabilization dosage (mg/day) (for the 39 participants who achieved stable prothrombin ratios before discharge)

Serum concentrations and therapeutic range: None

Physiological parameters: None

Time to achieve therapeutic control: Time to stabilization (for the 39 participants who achieved stable prothrombin ratios before discharge)

Clinical events: None

Healthcare costs: None

Improvement: None


Notes"A prothrombin time (PT) ratio (patient PT divided by control PT) between 1,3 and 2,5 was considered to be in therapeutic range"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"The patients were randomly assigned to one of the three groups for warfarin dosage prediction". No further information provided

Allocation concealment (selection bias)Unclear risk"The patients were randomly assigned to one of the three groups for warfarin dosage prediction". No further information provided

Baseline outcome measurements similarLow riskNot applicable (initiation of warfarin therapy)

Baseline characteristics similarHigh riskDemographic data only available for the subgroup of participants who achieved stable prothrombin ratios before discharge (54/101 participants)

Incomplete outcome data (attrition bias)
All outcomes
High riskNumber of participants randomized: 101

Number of participants analyzed: 87 (31 in the analogue-computer group, 22 in the linear-regression group, 34 in the empiric-dosing group)

"Fourteen randomized patients (3 analog computer, 7 linear regression, 4 empiric dosing) were removed from the study because they did not receive an initial warfarin dosage of 10 mg for three days or because the drug was discontinued before day 5"

"33 patients were discharged before they met the stated criteria for a stable PT [prothrombin]"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Casner 1993

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not done


ParticipantsProfession: Physicians
Level of training: Not reported
Clinical specialty: Not reported
Country: USA (El Paso, Texas)

Centre: 1 general hospital

Location of care: Inpatient care
Participants: 35 participants with diagnoses of asthma or obstructive pulmonary disease


InterventionsClinical problem: Theophylline maintenance for asthma
Intervention: Suggestion based on linear 1 compartment model (n = 17) vs. usual care (n = 18)

Computer advice: Given in real time
CDSS integration in CPOE: Yes
Starter: User-initiated
Type of intervention: Direct intervention

Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: Serum theophylline (mg/L) (at the 3rd level (C3) after adjustment and prior to discontinuation of infusion)

Physiological parameters: None (PH and partial pressure of carbon dioxide (PCO2) measurements: not included)

Time to achieve therapeutic control: None

Clinical events: Proportion of participants with theophylline toxicity (nausea, vomiting, tremor, tachycardia and seizures)

Healthcare costs: Length of stay

Improvement: None


Notes"Physicians adjusting theophylline infusions were instructed to attain a therapeutic goal of 15mg/L theophylline level and to base this empirically on the C1 and C2 levels that had been obtained"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Each patient was randomized to one of two groups as determined by a computer-derived randomization list"

Allocation concealment (selection bias)Low risk"Each patient was randomized to one of two groups as determined by a computer-derived randomization list"

Baseline outcome measurements similarLow riskNot appropriate (theophylline maintenance for asthma)

Baseline characteristics similarLow risk"There were no significant differences between the kinetic group in age or height, although there was a significant difference in actual body weight (85.5 versus 69.0 kg; p<0.05), but the ideal weights of both groups was not significantly different (55.7 versus 54.1 kg). Theophilline infusion doses were based on ideal body weight"

Table 1: 54.7 versus 54.1 kg

Incomplete outcome data (attrition bias)
All outcomes
High risk"Twelve patients were withdrawn from study because of incomplete data collection (i.e., either C1, C2, or C3 was missing or inadequate time interval between levels), which left 35 patients for analysis"

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective. Theophylline toxicity was defined

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Chertow 2001

MethodsDesign: NRCT (alternating time series design with 4 consecutive 2-month period)
Unit of allocation: Participant
Unit of analysis: Episode of care
Power calculation: Not reported


ParticipantsProfession: Physicians
Level of training: Not reported
Clinical specialty: Other mixed
Country: USA (Boston, Massachusetts)

Centre: 1 urban tertiary care academic medical centre (Brigham and Women's Hospital, 720 beds)
Location of care: Inpatient care
Participants: 17,828 inpatients with renal insufficiency


InterventionsClinical problem: Renal insufficiency
Intervention: CDSS periods (n = 7887 participants) vs. control periods (n = 9941 participants)

Computer advice: Given in real time
CDSS integration in CPOE: Yes
Starter: System-initiated
Type of intervention: Direct intervention

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: Proportion of appropriate orders (potential unit of analysis error)

Physiological parameters: None

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: Length of stay

Improvement: None


Notes"The BICS order entry application provides the physician with a range of possible dose amounts for that medication (dose list) along with 1 dose that is highlighted as the default or recommended dose amount." "An expert panel [...] selected those medications that were renally cleared and/or nephrotoxic" "To smooth dose recommendations, renal insufficiency was divided into 3 categories: mild (estimated creatinine clearance, 50-80 mL/min [0,84-1,34 mL/s]), moderate (estimated creatinine clearance, 16-49 mL/min [0,27-0,82 mL/s]), and advanced (estimated creatinine clearance, d15 mL/min [d0,25 mL/s])" "A selection was considered appropriate if the dose amount or frequency interval did not exceed the parameters set forth by the expert panel"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High risk"The study periods consisted of 4 alternating 8-week blocks of intervention and control subperiods"

Allocation concealment (selection bias)High risk"The study periods consisted of 4 alternating 8-week blocks of intervention and control subperiods"

Baseline outcome measurements similarLow riskNot appropriate

Baseline characteristics similarUnclear riskMean age of participants and sex "were not significantly different across periods". The mean Diagnosis Related Group (DRG) weight "was higher during control periods"

"The number of admissions and the hospital census were higher during the control periods"

Incomplete outcome data (attrition bias)
All outcomes
Low riskA log was kept of all instances

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskAlternating 8-week blocks of intervention and control subperiods

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasUnclear risk"The Cockcroft-Gault formula may overestimate renal function when the serum creatinine is increasing, and underestimate renal function when the serum creatinine is decreasing"

Claes 2005

MethodsDesign: RCT
Unit of allocation: GP practice
Unit of analysis: Participant (cluster was taken into account in statistical analysis)
Power calculation: Done


ParticipantsProfession: Mixed (GP + pathologists)
Level of training: Accredited/licensed
Clinical specialty: General/family practice + laboratory medicine
Country: Belgium

Centre: 96 GPs regrouped in 66 GP practices, for whom the clinical laboratory of the Medical Centre for GPs in Tessenderlo determined the INRs on venous blood
Location of care: Community-based care
Participants: 834 participants on oral anticoagulation were included (out of 936 participants eligible). 91 participants who underwent a surgical intervention with an interruption of the anticoagulation during the study period were excluded from the analysis


InterventionsClinical problem: Oral anticoagulation therapy at steady state (anticoagulation therapy for at least 28 days)
Intervention: Multifaceted education and DAWN AC computer advice (n = 15 GP practices, n = 201 participants) vs. multifaceted education (n = 17 GP practices, n = 170 participants). The Grol's multifaceted education: summary of the guidelines printed on the cover of a folder containing the anticoagulation files; information booklets on anticoagulation for their patients; website with guidelines, study design, and general information; newsletter sent every 2 months to inform the GPs on the study progress and requested them to send the anticoagulation files for control

Computer advice: Not reported (the pathologist reviewed the computer-generated advice and faxed it the same afternoon to the GP)
CDSS integration in CPOE: No (advice faxed)

Starter: User-initiated
Type of intervention: Indirect intervention (the pathologist reviewed the computer-generated advice and faxed it to the GP)

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None (% of participants with treatment changes: reported, median number of tests per participant and per month: reported)

Serum concentrations and therapeutic range: None

Physiological parameters: None (mean % of time in range (0.5 INT-units from target): reported, mean % of time in range (0.75 INT-units from target): not included, % of participants with at least 1 INR > 5: reported, % of participants with at least 1 INR < 2: reported)

Time to achieve therapeutic control: None

Clinical events: Number of bleeding events (minor + major) per patient-years, number of thromboembolic events per patient-years

Healthcare costs: See Claes 2006

Improvement: None


Notes- The practices were randomized into 4 groups: multifaceted education (group A), multifaceted education + feedback on the performance
of the practice (group B), multifaceted education + a CoaguChek device to determine the INR on the spot using capillary blood (group C), multifaceted education + DAWN AC computer advice that generated a recommended dosing scheme and the time to next visit (group D). Only groups A and D were retained for the review

- The target range were defined as within 0.5 INR-units and 0.75 INR-units from the chosen target INR of 2.5 or 3.5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The 66 GP-practices were divided into four different groups using a stratified block randomization. Six different strata of GP-practices were defined depending on the number of anticoagulated patients (5 patients, 6-14 patients, 15 patients) and the type of practice (single-handed GP or group practice). These six strata (numbered containers with cards) were divided blindly over the four intervention groups by a university staff member as follows: out of the first container a card was drawn and placed in box A, the next card in box B, C, D, A, B, etc. The same procedure was followed for the other five boxes"

Allocation concealment (selection bias)Low riskUnit of allocation: GP practice

Baseline outcome measurements similarLow risk"The 6 months retrospective analysis showed that the patients of the practices assigned to groups A, B, C, and D were 55, 49, 46, and 44% of time within 0.5 INR-units from target, respectively. There was no significant difference among the four groups in the per cent within 0.5 INR-units from target (P = 0.50) or within 0.75 INR-units from target (P = 0.70)"

Baseline characteristics similarHigh riskBaseline characteristics were not reported for GP practices, GPs or participants. Number of participants per group were not provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber of participants per group were not provided

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
Low riskGP practices were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Claes 2006

MethodsDesign: RCT
Unit of allocation: GP practice
Unit of analysis: Participant (cluster was taken into account in statistical analysis)
Power calculation: Done


ParticipantsProfession: Mixed (GP + pathologists)
Level of training: Accredited/licensed
Clinical specialty: General/family practice + laboratory medicine
Country: Belgium

Centre: 96 GPs regrouped in 66 GP practices, for whom the clinical laboratory of the Medical Centre for GPs in Tessenderlo determined the INRs on venous blood
Location of care: Community-based care
Participants: 834 participants on oral anticoagulation were included (out of 936 participants eligible). 91 participants who underwent a surgical intervention with an interruption of the anticoagulation during the study period were excluded from the analysis


InterventionsClinical problem: Oral anticoagulation therapy at steady state (anticoagulation therapy for at least 28 days)
Intervention: Multifaceted education and DAWN AC computer advice (n = 15 GP practices, n = 201 participants) vs. multifaceted education (n = 17 GP practices, n = 170 participants). The Grol's multifaceted education: summary of the guidelines printed on the cover of a folder containing the anticoagulation files; information booklets on anticoagulation for their participants; website with guidelines, study design, and general information; newsletter sent every 2 months to inform the GPs on the study progress and request them to send the anticoagulation files for checking

Computer advice: Not reported (The pathologist reviewed the computer-generated advice and faxed it the same afternoon to the GP)
CDSS integration in CPOE: No (advice faxed)

Starter: User-initiated
Type of intervention: Indirect intervention (the pathologist reviewed the computer-generated advice and faxed it to the GP)

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: See Claes 2005

Serum concentrations and therapeutic range: See Claes 2005

Physiological parameters: See Claes 2005

Time to achieve therapeutic control: See Claes 2005

Clinical events: See Claes 2005

Healthcare costs: None ((monthly cost per participant (in EUR): reported, incremental cost-effectiveness ratio (ICER): reported)

Improvement: See Claes 2005


Notes- This is a cost-effectiveness analysis conducted as a part of the Belgian Improvement Study on Oral Anticoagulation Therapy (BISOAT) study reported by Claes et al. (see Claes 2005)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"The 66 GP-practices were divided into four different groups using a stratified block randomization. Six different strata of GP-practices were defined depending on the number of anticoagulated patients (5 patients, 6-14 patients, 15 patients) and the type of practice (single-handed GP or group practice). These six strata (numbered containers with cards) were divided blindly over the four intervention groups by a university staff member as follows: out of the first container a card was drawn and placed in box A, the next card in box B, C, D, A, B, etc. The same procedure was followed for the other five boxes"

Allocation concealment (selection bias)Low riskUnit of allocation: GP practice

Baseline outcome measurements similarLow risk"The 6 months retrospective analysis showed that the patients of the practices assigned to groups A, B, C, and D were 55, 49, 46, and 44% of time within 0.5 INR-units from target, respectively. There was no significant difference among the four groups in the per cent within 0.5 INR-units from target (P = 0.50) or within 0.75 INR-units from target (P = 0.70)"

Baseline characteristics similarHigh riskBaseline characteristics were not reported for GP practices, GPs or participants. Number of participants per group were not provided

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber of participants per group were not provided

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
Low riskGP practices were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Cordingley 2009

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Nurses
Level of training: Not reported
Clinical specialty: ICU
Country: UK (London), Belgium (Leuven)
Centre: 1 large specialist heart and lung hospital affiliated with the university and NHS Foundation Trust (Royal Brompton Hospital (RBH)), 1 university hospital (University Hospital Gasthuisberg (KUL))
Location of care: Inpatient care
Participants: 34 critically ill patients admitted to ICU with hyperglycaemia (glucose > 120 mg/dL)


InterventionsClinical problem: Insulin in critically ill patients with hyperglycaemia
Intervention: eMPC algorithm (n = 16 participants) vs. standard care (n = 18 participants). The eMPC algorithm calculates the time of the next glucose sample and the optimum insulin infusion rate expected to achieve the target glucose concentration
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Direct intervention
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: None

Physiological parameters: % of time in target glucose range (hyperglycaemia index (area of the glucose-time concentration curve above 110 mg/dL (6.1 mmol/L) divided by the time of the study): not included (data differed between text, table 3, table 4 and table 5 and the author had not replied by January 2012), blood glucose: not included (sample mean), time-weighted mean glucose concentration (mg/dL) (area under the glucose-time curve for each participant divided by the elapsed time): not included)

Time to achieve therapeutic control: Time to establish glucose control (Ttarget) (time from study entry until the plasma glucose concentration was in the target range of 80-110 mg/dL (4.4-6.1 mmol/L)) (minutes), mean sampling interval (hours)

Clinical events: Proportion of participants with plasma glucose concentrations < 60 mg/dL, proportion of participants with plasma glucose concentrations < 40 mg/dL

Healthcare costs: None

Improvement: None


Notes- "At KUL nursing staff (each taking care of 2 patients) aimed to maintain plasma glucose in the range 80-110 mg/dL (4.4-6.1 mmol/L) using a paper-based guideline that allows intuitive decisions to be taken. At RBH, nurses (each taking care of 1 patient) used a written dynamic insulin infusion protocol targeting a plasma glucose concentration of 72-108 mg/dL (4-6 mmol/L)"

- The study is part of CLINICIP (Closed Loop Insulin Infusion for Critically Ill Patients; www.clinicip.org), an integrated project funded by the European Community


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients entered into the trial were randomized [...]". No further information provided

Allocation concealment (selection bias)Unclear risk"Patients entered into the trial were randomized [...]". No further information provided

Baseline outcome measurements similarLow risk"Glucose concentration at study entry was similar in both groups (Table 3)"

Baseline characteristics similarLow riskNo significant differences on main characteristics (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Low risk18 participants vs 16 participants. No apparent missing data

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasHigh riskAn erratum had been published because there were some inconsistencies in the text and tables; we found other inconsistencies in tables, full text, and abstract; the author was contacted (had not replied by January 2012).

Destache 1990

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Done


ParticipantsProfession: Mixed (physicians + clinical pharmacists)
Level of training: Mixed
Clinical specialty: Internal medicine, surgery ICU
Country: USA (Omaha, Nebraska)

Centre: 1 tertiary care facility (Saint Joseph Hospital)

Location of care: Inpatient care
Participants: 145 participants treated with aminoglycosides for infection


InterventionsClinical problem: Aminoglycoside
Intervention: Participants whose doctors accepted recommendations based on a 1 compartment Bayesian pharmacokinetic model (n = 75) vs. those of doctors who did not (n = 70)
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Indirect intervention

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Number of doses adjustments (potential unit of analysis error) (number of serum aminoglycoside concentrations drawn/participant: not included)

Serum concentrations and therapeutic range: proportion of participants with first peak aminoglycoside serum concentrations "adequate" 0.5 h after infusion

Physiological parameters: None

Time to achieve therapeutic control: None (time for elevated temperature to decrease to < 99.8 °F (37.7 °C): not included, time for elevated heart rate to decrease to < 90 beats/min: not included, time for respiratory rate to decrease to < 24/min: not included)

Clinical events: Death, nephrotoxicity (≥ 0.5 mg/dL rise in serum creatinine)

Healthcare costs: Length of hospital stay (h), direct cost per participant (USD)

Improvement: None


Notes"First peak concentrations were categorized as "adequate" (>=5.0 mcg/ml and >=20.0 mcg/ml for amikacin [an aminoglycoside]), "low" (<5.0 mcg/ml and <20.0 mcg/ml for amikacin), or not drawn"

"The target trough therapeutic ranges are concentrations of <2.0 mcg/ml for gentamicin and tobramycin and 5-10 mcg/ml for amikacin"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomization assignments were determined by a table of random numbers"

Allocation concealment (selection bias)Low risk"Assignments were individually placed in sealed envelopes"

Baseline outcome measurements similarLow riskNot appropriate

Baseline characteristics similarLow riskNo significant differences except for weight (table 3)

Incomplete outcome data (attrition bias)
All outcomes
High riskMany participants excluded from analysis: 20 of the 90 participants from the control group (monitored by other clinical pharmacists), 35 of the 110 participants from the computer advice group (recommendations were not always followed)

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective. Nephrotoxicity was clearly defined in the methods section

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Fitzmaurice 2000

MethodsDesign: RCT
Unit of allocation: Primary care practice and participant (2 control populations: participants individually randomized as controls in the intervention practices and all participants in the control practices, which allow an estimate of the Hawthorn effect)
Unit of analysis: Participant, INR (cluster was taken into account in statistical analysis)
Power calculation: Done


ParticipantsProfession: Mixed (physicians + nurses)
Level of training: Not reported
Clinical specialty: General/family practice
Country: UK (Birmingham)

Centre: 12 practices

Location of care: Community-based care
Participants: 224 outpatients with cardiovascular disease


InterventionsClinical problem: Warfarin adjustment for long-term therapy
Intervention: CDSS group (n = 122) vs. routine care (n = 102)

Computer advice: Given in real time
CDSS integration in CPOE: Not reported
Starter: User-initiated
Type of intervention: Direct intervention

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: None

Physiological parameters: Proportion of INR measurements within therapeutic range (unit of analysis error)

Time to achieve therapeutic control: None

Clinical events: Death, number of haemorrhagic events (epistaxis) per patient-years, number of thrombotic events per patient-years

Healthcare costs: None

Improvement: None


NotesThere were 2 levels of randomization. Practices were randomly tagged as intervention or control practices. Then, in intervention practices, participants were individually randomized to intervention or control. We did not analyze 'control practices' because of a potential unit of analysis error

"Dosing recommendations made by the CDSS were based on the current INR in relation to individual therapeutic range, based on the British Society of Haematology guidelines, with the 2 main ranges being 2.0 to 3.0 and 3.0 to 4.5"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPractices were randomly selected by means of random numbers from a list of 21 practices that had expressed interest in the study

Allocation concealment (selection bias)Low riskPractices were randomly selected by means of random numbers from a list of 21 practices that had expressed interest in the study

Baseline outcome measurements similarLow riskNot appropriate

Baseline characteristics similarLow riskNo apparent differences (table 2)

Incomplete outcome data (attrition bias)
All outcomes
High risk224 participants were recruited. 40 participants discontinued the study before 12 months, including 11 participants randomized to intervention who returned to hospital care

Only participants with 3 or more INR results (n = 202) were included in the analysis of proportion of time spent in the target INR range

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskMain outcomes were objective. Monitoring for haemorrhagic and thrombotic events is not clearly defined

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPractices were randomized and participants individually randomized as controls in the intervention practices (intrapractice controls) and all participants in the control practices (interpractice controls)

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Gonzalez 1989

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not done


ParticipantsProfession: Physicians
Level of training: Not reported
Clinical specialty: Not reported
Country: USA (Virginia, Richmond)

Centre: 1 emergency department (Medical College of Virginia)

Location of care: Inpatient care
Participants: 82 participants with asthma treated with aminophylline


InterventionsClinical problem: Theophylline
Intervention: Bayesian 1 compartment pharmacokinetic model (n = 37) vs. population-based guidelines (n = 30)

Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: System-initiated
Type of intervention: Not reported

Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: Theophylline loading dose (mg/kg), theophylline maintenance dose (mg/kg/h)

Serum concentrations and therapeutic range: Theophylline concentration (4 hours post load) (mg/L) (theophylline concentration at 1 and 2 hours post load: not included)

Physiological parameters: None

Time to achieve therapeutic control: None

Clinical events: Proportion of participants with adverse reactions (including nausea and vomiting)

Healthcare costs: None

Improvement: None


Notes"Patients in group 1 received an IV bolus of aminophylline to achieve a serum theophylline concentration of 10 to 20 mg/L"

"Patients in group 2 received and IV aminophylline bolus followed by a maintenance infusion to achieve a serum theophylline concentration of 15 mg/L"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"A random-numbers table was used to pre-assign 82 patients to either group 1 or group 2"

Allocation concealment (selection bias)Low risk"A random-numbers table was used to pre-assign 82 patients to either group 1 or group 2"

Baseline outcome measurements similarLow riskNot appropriate

Baseline characteristics similarUnclear riskNo apparent differences on patient demographics (table 2). No further information provided

Incomplete outcome data (attrition bias)
All outcomes
High risk"Fifteen patients were excluded because of protocol violations (three left the ED against medical advice; 12 had insufficient blood level data)"

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskMain outcomes were objective. Adverse events are not clearly defined

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Hickling 1989

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Not reported
Level of training: Not reported
Clinical specialty: Other (intensive care)
Country: New Zealand

Centre: 1 general hospital (Christchurch Hospital)

Location of care: Inpatient care
Participants: 32 ICU patients who required aminoglycoside therapy for serious life threatening infections


InterventionsClinical problem: aminoglycoside (gentamicin or tobramycin)
Intervention: Pharmacokinetic model, computer-assisted group (n = 15) vs. control group (n = 17)
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Not reported

Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: Aminoglycoside mean peak concentration at 48-72 h, % participants within drug therapeutic range after 2 days (peak plasma concentrations 6-10 mg/L measured 1 h after the start of the infusion, and peak trough concentrations 1-2 mg/L within 30 min of the next dose), % participants achieving peak plasma concentrations at 48-72 h > 6 mg/L (peak concentration criterion alone) (proportion of participants achieving peak plasma concentrations at 48-72 h > 5 mg/L: not included, proportion of participants achieving peak plasma concentrations at 48-72 h > 7 mg/L: not included)

Physiological parameters: None

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: None

Improvement: None


Notes"The program was designed to predict the dose and dose interval required to achieve any desired peak and trough concentration. For the purpose of the study the specific target concentrations were a peak of 8 mg/l and a trough of 1.5 mg/l"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation was carried out by computer using a random number generator"

Allocation concealment (selection bias)Low risk"Randomisation was carried out by computer using a random number generator"

Baseline outcome measurements similarLow riskNot appropriate

Baseline characteristics similarHigh riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
High risk4 participants (out of 32) were excluded because a dose change was made on clinical grounds before the 4th dose of aminoglycoside

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Hovorka 2007

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Physicians
Level of training: Not reported
Clinical specialty: Other (Department of Cardiovascular Surgery)
Country: Czech Republic (Prague)

Centre: 1 university hospital (Charles University and General University Hospital)

Location of care: Inpatient care
Participants: 60 adults admitted for major elective cardiac surgery


InterventionsClinical problem: Insulin in critically ill patients (cardiac surgery patients)
Intervention: Laptop-based algorithm eMPC (n = 30 participants) vs. standard protocol treatment (n = 30 participants). The eMPC is an enhanced version of the model predictive control algorithm (MPC), a model of the glucoregulatory system. Glucose concentration, insulin dosage, and carbohydrate content of enteral and parenteral input are the input variables for the eMPC. The insulin infusion rate and the time of the next glucose sample are the outputs
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: User-initiated
Type of intervention: Direct intervention

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Total Insulin dose (insulin units/24 h)

Serum concentrations and therapeutic range: None

Physiological parameters: % of time within the target range for blood glucose in the first 24 h (80-110 mg/dL or 4.4-6.1 mmol/L), blood glucose levels at ICU (mmol/L) (blood glucose levels at operating theatre: not included, time (h) above the target range for blood glucose in the first 24 h (>110 mg/dL): not included, time (h) under the target range for blood glucose in the first 24 h (>110 mg/dL): not included)

Time to achieve therapeutic control: Mean sampling interval (hours)

Clinical events: Proportion of participants with hypoglycaemic episodes (blood glucose level < 2.9 mmol/L)

Healthcare costs: None

Improvement: None


Notes- "The target range for blood glucose levels, as defined by the study protocol, was 4.4–6.1 mmol/liter, which has reduced mortality and morbidity in post-cardiac surgery patients." "Severe hypoglycemia was defined as blood glucose less than 2.9 mmol/liter"

- The authors were contacted and confirmed that none of the participants from Kremen 2007 was included in Hovorka 2007

- The study is part of CLINICIP (Closed Loop Insulin Infusion for Critically Ill Patients; www.clinicip.org), an integrated project funded by the European Community


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandom sequence generation not specified

Allocation concealment (selection bias)Unclear riskNo information provided

Baseline outcome measurements similarLow riskNo significant differences on blood glucose at study start or number of participants treated with diabetes before study start (table 1)

Baseline characteristics similarLow riskNo significant differences on baseline characteristics (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe number of glucose values used for calculation varied in each hour (figure 2) but the blood glucose was measured in 1- to 4-h intervals as requested by each algorithm during surgery and postoperatively over 24 h

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMain outcomes were objective. Hypoglycaemic episodes are clearly defined

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Hurley 1986

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Physicians
Level of training: Accredited/licensed
Clinical specialty: Other (emergency)
Country: Australia (Victoria)

Centre: 1 community hospital (Preston and Northcote Community Hospital (PANCH))

Location of care: Inpatient care
Participants: 91 participants admitted to hospital with asthma


InterventionsClinical problem: Theophylline
Intervention: Doctors given estimate of theophylline clearance based on 1 compartment linear pharmacokinetic model (n = 48) vs. usual care based on theophylline levels (n = 43). Computer gave advice on dose each day based on estimates of theophylline clearance

Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: System-initiated
Type of intervention: Not reported

Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: Initial and maintenance daily dose of theophylline (mg/day)

Serum concentrations and therapeutic range: serum concentration at day 2 (μg/mL), proportions of participants with serum trough concentrations in the therapeutic range, proportions of participants with serum concentrations in the toxic range

Physiological parameters: None

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: Death, length of stay

Improvement: None


Notes"Ideally theophylline serum concentrations should be within a relatively narrow therapeutic range of 10 to 20 µg/ml"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details

Allocation concealment (selection bias)Unclear riskNo details

Baseline outcome measurements similarLow riskNot appropriate

Baseline characteristics similarLow riskNo apparent differences (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Low risk96 participants enrolled, 91 participants analyzed (1 participant because of intolerance to aminophylline, 1 because of lack of cooperation, 3 because of previous enrolment in the trial)

Loading doses were available for 72 participants, infusion rate at day 1 for 91 participants, infusion rate at day 2 for 74 participants. Missing values were equally distributed and unlikely to overturn the study results

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Jowett 2009

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: INR
Power calculation: Done


ParticipantsProfession: Physicians
Level of training: Accredited/licensed
Clinical specialty: Not reported
Country: Europe, Israel, Australia
Centre: 32 centres in 13 countries (Europe: 29, Israel: 2, Australia: 1)
Location of care: Outpatient care
Participants: 13,219 anticoagulation patients randomized at each centre into manual-dosed or computer-assistant dosed arm (DAWN AC or PARMA 5). 13,052 participants analyzed (167 participants without INR results): 2631 for the DAWN AC study and 10,421 for the PARMA 5 study


InterventionsClinical problem: Oral anticoagulation (warfarin, nicoumalone (acenocoumarol), phenprocoumon)
Intervention: Computer-assisted dosage program (PARMA5 (n = 5290 participants)) versus manual dosage (n = 5131 participants). Computer-assisted dosage program (DAWN AC (n = 1315 participants)) versus Manual dosage (n = 1316 participants). Recruitment was restricted to new patients initiated oral anticoagulation. 2 subroutines: induction and steady-state monitoring; the aim of the dosage algorithm was to maintain the INR value as close as possible to the mean target INR and to provide the next appointment date

Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: System-initiated
Type of intervention: Not reported
Calculated dose given as a recommendation: No


OutcomesDose of drug administered to the participant: See Poller 2008 PARMA 5 and Poller 2009 DAWN AC

Serum concentrations and therapeutic range: See Poller 2008 PARMA 5 and Poller 2009 DAWN AC

Physiological parameters: See Poller 2008 PARMA 5 and Poller 2009 DAWN AC

Time to achieve therapeutic control: See Poller 2008 PARMA 5 and Poller 2009 DAWN AC

Clinical events: See Poller 2008 PARMA 5 and Poller 2009 DAWN AC

Healthcare costs: None (total cost per participant (Euros, base 2006) for all INR visits during the time period of the study (4.5 years) (dosing cost (staff time and the software for computer dosing), clinical event cost): reported)

Improvement: See Poller 2008 PARMA 5 and Poller 2009 DAWN AC


Notes- This is a cost-effectiveness analysis conducted as a part of the European Action on Anticoagulation's (EEA) randomized multicentre study of computer-assisted oral anticoagulant dosage vs. manual dosing reported by Poller et al (see Poller 2008 PARMA 5 and Poller 2009 DAWN AC)

- Costs were available for 28/32 clinics. There was no distinct results for PARMA 5 and DAWN AC systems


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskNo information provided

Baseline outcome measurements similarLow riskNot applicable

Baseline characteristics similarLow riskNo apparent differences on baseline characteristics of the 13,052 participants (see table 1 of Poller 2008 PARMA 5 and Poller 2009 DAWN AC)

Incomplete outcome data (attrition bias)
All outcomes
Low riskBoth cost and outcome data were available for 6218/6447 in manual-dosed group and 6366/6605 in computer-assisted dosage group

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMain outcomes were objective. Events were adjudicated by a committee

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Kremen 2007

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Physicians
Level of training: Not reported
Clinical specialty: Other (Department of Cardiovascular Surgery ICU)
Country: Czech Republic (Prague)

Centre: 1 university hospital (Charles University and General University Hospital)

Location of care: Inpatient care
Participants: 20 adults who underwent a planned-cardiac surgery (coronary artery bypass or valve replacement) with glycaemia higher than 6.7 mmol/L at the time of admission to ICU


InterventionsClinical problem: Insulin in critically ill patients (cardiac surgery patients) with hyperglycaemia
Intervention: Laptop-based algorithm MPC (n = 10 participants) vs. routine blood glucose management protocol (n = 10 participants). The MPC is a model representing the glucoregulatory system. Glucose concentration, insulin dosage, and carbohydrate intake are the input variables for the MPC. The insulin infusion rate is the output parameter and was adjusted hourly as suggested by the algorithm
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: User-initiated
Type of intervention: Not reported
Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: Total Insulin dose (insulin units/48 h)

Serum concentrations and therapeutic range: None

Physiological parameters: Mean blood glucose (mmol/L) (Time (h) within the target range for blood glucose in the first 24 h (80-110 mg/dL or 4.4-6.1 mmol/L): reported, duration of hyperglycaemia (> 8.3 mmol/L) (h): not included)

Time to achieve therapeutic control: Time to establish glucose control (Ttarget) (time from study entry until the plasma glucose concentration was in the target range of 80-110 mg/dL (4.4-6.1 mmol/L)) (min), time to target range (hours)

Clinical events: Proportion of participants with hypoglycaemic episodes (blood glucose level < 2.9 mmol/L)

Healthcare costs: None

Improvement: None


Notes- "The target range for blood glucose levels, as defined by the study protocol, was 4.4–6.1 mmol/liter, which has reduced mortality and morbidity in post-cardiac surgery patients." "Severe hypoglycemia was defined as blood glucose less than 2.9 mmol/liter"

- The authors were contacted and confirmed that none of the participants from Kremen 2007 was included in Hovorka 2007

- The study is part of CLINICIP (Closed Loop Insulin Infusion for Critically Ill Patients; www.clinicip.org), an integrated project funded by the European Community


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandom sequence generation not specified

Allocation concealment (selection bias)Unclear riskNo information provided

Baseline outcome measurements similarLow riskNo significant differences on blood glucose at study start (table 2)

Baseline characteristics similarHigh risk5 men/5 women in MPC group, 9 men/1 women in standard group (table 2)

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe blood glucose was measured in 1- to 2-h intervals as requested by each algorithm during surgery and postoperatively over 48 h

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMain outcomes were objective. Hypoglycaemic episodes are clearly defined

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Unclear riskPilot study. Outcomes were not defined in the methods section

Other biasUnclear riskPilot study with 10 participants in each groups. Article in Czech language. Authors were contacted but had not replied by February 2012

Le Meur 2007

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Done


ParticipantsProfession: Physicians
Level of training: Accredited/licensed
Clinical specialty: Nephrology
Country: France
Centre: 11 centres
Location of care: Inpatient care
Participants: 137 renal allograft recipients receiving basiliximab, CsA, MMF and corticosteroids. 130 participants analyzed


InterventionsClinical problem: MMF dosing in renal transplant patients
Intervention: Concentration-controlled (CC) regimen (n = 65 participants) vs. fixed-dose (FD) MMF (n = 65 participants). In the CC group, MMF dose adjustments were calculated by a computer program to reach an MPA AUC target of 40 mg.h/L and were proposed to the physician. In the FD group, MMF dose adjustments were based on clinical experience
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Direct intervention
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None (MMF dose: not included (fixed dose in control group))

Serum concentrations and therapeutic range: None (serum creatinine level (μmol/L): not included)

Physiological parameters: None (% participants within therapeutic range at day 14 (MPA AUC > 30 mg.h/L): reported)

Time to achieve therapeutic control: None

Clinical events: Death, proportion of participants with cytomegalovirus infections, proportion of participants with adverse events (anaemia, leukopenia, gastrointestinal adverse effects, infections)

Healthcare costs: None

Improvement: Proportion of participants without treatment failure (a composite of death, graft loss, acute rejection and MMF discontinuation), proportion of participants without biopsy-confirmed rejections


NotesPrimary outcome: Treatment failure (a composite of death, graft loss, acute rejection and MMF discontinuation)
"In the CC group, MMF dose adjustments were calculated by a computer program (available at www.chu-limoges.fr/stp/stpacces.htm, June 21, 2007) to reach an MPA AUC target of 40 mg.h /L. The minimum dose change was 250 mg twice a day. Each dose adjustment of at least 250 mg twice a day that was able to result in an AUC closer to 40 mg.h /L was proposed by the program to the physician"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Within the first 3 days posttransplant, patients were randomized by an interactive voice response system administered by a private company; randomization was balanced within centers in blocks of 4 patients, and patients were enrolled and assigned to one of the two groups by physicians at each center"

Allocation concealment (selection bias)Low risk"Within the first 3 days posttransplant, patients were randomized by an interactive voice response system administered by a private company; randomization was balanced within centers in blocks of 4 patients, and patients were enrolled and assigned to one of the two groups by physicians at each center"

Baseline outcome measurements similarLow riskNot applicable

Baseline characteristics similarHigh risk"The sex ratio differed between groups in that there were a larger percentage of males in the CC-treated group (Table 1)"

Incomplete outcome data (attrition bias)
All outcomes
Low risk"There were seven withdrawals (CC, n = 5; FD, n = 2) due to death, primary non functioning graft or because MMF was not administered." In most of tables, only percentages are reported and according to the first decimal of percentages, there were missing data in the denominator. However, missing values were unlikely to overturn the study results

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Acute rejection was diagnosed by renal biopsy except in patients with contraindications and were graded according to the Banff classification, in which case diagnosis was based on clinical and laboratory criteria (in particular, any unexplained increase in serum creatinine)." No committee reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Le Meur 2007 extract

Methods


Participants


Interventions


Outcomes


NotesText extracted from original article Le Meur 2007

Leehey 1993

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Mixed (physicians + pharmacists)
Level of training: Not reported
Clinical specialty: Not applicable
Country: USA (Hines, Illinois)
Centre: 1 Veterans Affairs Hospital
Location of care: Inpatient care
Participants: 324 participants receiving aminoglycosides for suspected or confirmed infection were enrolled and randomly assigned to 1 of 3 groups: usual physician-directed dosing (group 1), pharmacist-assisted dosing (group 2), or pharmacist-directed dosing (group 3). 81 participants were dropped from the study because they received < 72 h of therapy, leaving 243 study participants (73 in group 1, 90 in group 2, 80 in group 3)


InterventionsClinical problem: Aminoglycoside in participants with suspected or confirmed infection
Intervention: Pharmacist-directed dosing (group 3, n = 80) vs. usual physician-directed dosing (group 1, n = 73). Participants randomized to group 1 (customary dosing) had no intervention from study personnel other than the placement of an order in the hospital chart for the determination of serum creatinine levels post-therapy. In participants randomized to group 3 (pharmacist-directed dosing), all orders for aminoglycoside dosing were written by a pharmacist (with countersignature by 1 of the 2 study physicians) specially trained in the Bayesian dosing methods used in the study). Group 2 (pharmacist-assisted dosing) was excluded: dosing and monitoring recommendations were written by a pharmacist in the progress note section of the hospital chart, and the physicians caring for the participant were notified of these suggestions (the pharmacist served as a consultant)
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Indirect intervention
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Mean total aminoglycoside doses (mg) (duration of therapy: not included)

Serum concentrations and therapeutic range: Mean peak serum aminoglycoside levels (µg/mL) (mean serum trough concentrations (µg/mL): reported)

Physiological parameters: None

Time to achieve therapeutic control: None

Clinical events: Need for dialysis, nephrotoxicity

Healthcare costs: None

Improvement: Proportion of participants with response to treatment


NotesNephrotoxicity was defined as a ≥ 100% increase in serum creatinine concentration with at least a 44 µmol/L (0.5 mg/dL) increment in this value


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskNo information provided

Baseline outcome measurements similarLow riskNot appropriate

Baseline characteristics similarHigh riskSex gender not reported. There were differences on use of contrast media and the presence of lung disease

Incomplete outcome data (attrition bias)
All outcomes
Low risk81 participants were dropped from the study because they received < 72 h of therapy, leaving 243 study participants (73 in group 1, 90 in group 2, 80 in group 3). Incomplete data were unlikely to overturn the study results

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Study data were reviewed by one of the authors who was blinded as to group assignment"

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Lesourd 2002

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Physicians
Level of training: Not reported
Clinical specialty: Obstetrics and gynaecology
Country: France (Toulouse, Rouen, Paris)

Centre: 3 centres (private and university teaching hospitals)
Location of care: Outpatient care
Participants: 164 women undergoing ovarian stimulation to treat infertility


InterventionsClinical problem: Ovarian stimulation by gonadotropins
Intervention: CDSS group (n = 82) vs. control group (n = 82)
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Direct intervention

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Number of follicle-stimulating hormone units administered

Serum concentrations and therapeutic range: None

Physiological parameters: None

Time to achieve therapeutic control: None

Clinical events: None (cancelled cycles of ovarian stimulation: not included)

Healthcare costs: None

Improvement: Proportion of participants with clinical pregnancies (ongoing pregnancies: not included, mean number of follicles ≥ 18 mm: not included)


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskNo information provided

Baseline outcome measurements similarLow riskNot applicable

Baseline characteristics similarHigh riskParticipants in the group with the decision by software were younger than in the group with the decision by clinicians (31.7 ± 4.5 years versus 33.1 ± 4.2 years, P value < 0.05 (table 2))

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMain outcomes (pregnancies) are objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasUnclear riskFew results reported (1 sentence in the results). Not enough information to evaluate the bias of the study

Manotti 2001

MethodsDesign: NRCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Done


ParticipantsProfession: Physicians
Level of training: Accredited/licensed
Clinical specialty: Not reported
Country: Italy

Centre: 5 anticoagulant clinics, all federated with the FCSA (Italian Federation of Anticoagulation Clinics)

Location of care: Outpatient care
Participants: 335 participants on oral anticoagulants


InterventionsClinical problem: initiation of oral anticoagulant therapy (warfarin and acenocoumarol)
Intervention: Computer-aided dosing (n = 145) vs. manual dosing (n = 190)

Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: System-initiated
Type of intervention: Direct intervention

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None (maintenance dose (mg/week): not included (number of appointments, available only for warfarin))

Serum concentrations and therapeutic range: None

Physiological parameters: None (% of participants reaching a stable state of anticoagulation (3 INR measurements within therapeutic range): reported)

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: None

Improvement: None


Notes"The use of only two separate therapeutic ranges was suggested:
Low Intensity = INR 2.0 to 3.0; target value 2.5. People with deep venous thrombosis/pulmonary embolism, atrial fibrillation, heart valve disease, biological valve prosthesis.
High Intensity = INR 3.0 to 4.5 ; target value 3.5. People with a mechanical heart valve prosthesis, coronary or other arterial disease"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients were randomized into two arms." No further information provided

Allocation concealment (selection bias)Unclear risk"Patients were randomized into two arms." No further information provided

Baseline outcome measurements similarLow riskNot applicable (initiation of oral anticoagulant therapy)

Baseline characteristics similarLow riskNo apparent differences (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskData were provided with patient-years. No details for follow-up

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Mihajlovic 2003

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Not reported
Level of training: Not reported
Clinical specialty: Psychiatry
Country: Serbia
Centre: 1 psychiatric clinic of a clinical hospital centre (Clinical Hospital Center Kragujevac)
Location of care: Not reported
Participants: 60 participants with major depressive disorder (according to ICD-10)


InterventionsClinical problem: Amitriptyline in the treatment of major depressive episode
Intervention: Computer-aided dosing of amitriptyline (n = 30 participants) vs. usual dose regimen (n = 30 participants). The individualization of amitriptyline dose was calculated using the modified Bayesian method (on the basis of therapeutic steady-state concentration of 80 ng/mL, participant's sex, weight, age, creatinine plasma concentration, albumin plasma concentration and volume of the liquid on the 'third space')
Computer advice: Not reported
CDSS integration in CPOE: Not reported
Starter: Not reported
Type of intervention: Not reported
Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: Drug daily doses of amitriptyline + nortriptyline at day 14 (mg) (at day 28, day 42, day 56: not included)

Serum concentrations and therapeutic range: None

Physiological parameters: Steady-state plasma concentration of amitriptyline + nortriptyline at J14 (during the treatment course) (at day 28, day 42, day 56: not included)

Time to achieve therapeutic control: None

Clinical events: Proportion of participants with adverse effects of amitriptyline per days of research at day 14 (at day 28, day 42, day 56: not included)

Healthcare costs: None

Improvement: Hamilton Depression Rating scale scores at day 28 (at day 14, day 42, day 56: not included, Clinical Global Impression scale: not included)


NotesAmong the 60 participants included in the study, 15 were also included in Jankovic 1999 (excluded study)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Random table, in blocks of 10"

Allocation concealment (selection bias)Unclear risk"Random table, in blocks of 10". No further information provided

Baseline outcome measurements similarLow riskNot appropriate

Baseline characteristics similarLow risk"In general, the demographic characteristics of the patients were similar in the experimental and control groups (table 1)"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated. Denominator not reported in tables

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskMain outcomes were objective. Hamilton scale is an hetero-questionnaire

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasHigh riskSelection bias/opportunistic series:

- Mihajlovic 2003: 60 participants admitted during 1997

- Mihajlovic 2010: Safety analysis of the study reported by Mihajlovic 2003

All 15 participants from the Jankovic study were included in the Mihajlovic study (confirmed by the author S. Jankovic)

Mihajlovic 2010

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Not reported
Level of training: Not reported
Clinical specialty: Psychiatry
Country: Serbia
Centre: 1 psychiatric clinic of a clinical hospital centre (Clinical Hospital Center Kragujevac)
Location of care: Not reported
Participants: 60 participants with major depressive disorder (according to ICD-10).


InterventionsClinical problem: Amitriptyline in the treatment of major depressive episode
Intervention: Computer-aided dosing of amitriptyline (n = 30 participants) vs. usual dose regimen (n = 30 participants). The individualization of amitriptyline dose was calculated using the modified Bayesian method (on the basis of therapeutic steady-state concentration of 80 ng/mL, participant's sex, weight, age creatinine plasma concentration, albumin plasma concentration and volume of the liquid on the 'third space')
Computer advice: Not reported
CDSS integration in CPOE: Not reported
Starter: Not reported
Type of intervention: Not reported
Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: See Mihajlovic 2003

Serum concentrations and therapeutic range: See Mihajlovic 2003

Physiological parameters: See Mihajlovic 2003

Time to achieve therapeutic control: See Mihajlovic 2003

Clinical events: None

Healthcare costs: See Mihajlovic 2003

Improvement: See Mihajlovic 2003


NotesThis is a safety analysis conducted as a part of the randomized multicentre study of computer-aided dosing of amitriptyline vs. usual dose regimen reported by Mihajlovic et al. (see Mihajlovic 2003)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Random table, in blocks of 10"

Allocation concealment (selection bias)Unclear risk"Random table, in blocks of 10". No further information provided

Baseline outcome measurements similarLow riskNot appropriate

Baseline characteristics similarUnclear risk"In general, the demographic characteristics of the patients were similar in the experimental and control groups"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated. Denominator not reported in tables

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskMain outcomes were objective. Clinical Global Impression Scale is an hetero-questionnaire

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskParticipants were randomized

Selective reporting (reporting bias)Unclear riskAll relevant outcomes were reported in the results section

Other biasUnclear riskSelection bias/Opportunistic series:

- Mihajlovic 2003: 60 participants admitted during 1997

- Mihajlovic 2010: Safety analysis of the study reported by Mihajlovic 2003

All 15 participants from the Jankovic study were included in the Mihajlovic study (confirmed by the author S. Jankovic)

Mitra 2005

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant, dose of treatment
Power calculation: Not done


ParticipantsProfession: Physicians
Level of training: Not reported
Clinical specialty: Rehabilitation
Country: USA
Centre: 1 free-standing, 288-bed, academic rehabilitation centre
Location of care: Inpatient care
Participants: 280 hospitalized rehabilitation patients who were prescribed warfarin for anticoagulation


InterventionsClinical problem: Warfarin (Coumadin) to maintain hospitalized rehabilitation patients within a therapeutic INR (2.0-3.0)
Intervention: Computer-aided dosing of warfarin (n = 14 participants) vs. physician dosing (n = 16 participants). The computer-generated program (DAWN AC) gave instructions to the physicians for warfarin dosing and for timing and frequency of blood draws
Computer advice: Given in real time
CDSS integration in CPOE: Not reported
Starter: Not reported
Type of intervention: Not reported
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: None

Physiological parameters: None (time spent in days per 100 patient-days of treatment: reported)

Time to achieve therapeutic control: None

Clinical events: Proportion of participants with thromboembolism (pulmonary embolism, deep vein thrombosis) (number of blood draws: not included)

Healthcare costs: Length of stay (days)

Improvement: None


Notes"The goal of both groups was to maintain patients within a target INR of 2.0 - 3.0"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Subjects were randomized using a random number table into one of two groups: group P (physician dosing) or group C (computer dosing)"

Allocation concealment (selection bias)Unclear risk"Subjects were randomized using a random number table into one of two groups: group P (physician dosing) or group C (computer dosing)." No further information provided

Baseline outcome measurements similarLow riskNot applicable

Baseline characteristics similarHigh risk"A larger percentage of patients in group C had a history of atrial fibrillation (28% vs. 6%), and group P had a larger proportion of patients with a history of DVT [deep vein thrombosis] (50% vs. 7%)"

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"The total number of data points (INR values) was 1014, excluding 36 days during which the INR score could not be imputed." The original group of 32 patients was reduced to 30 through loss of data sheets. It is unclear if missing values could overturn the study results

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskPulmonary embolism, deep vein thrombosis: No committee reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Mungall 1994

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Done


ParticipantsProfession: Mixed physicians + pharmacists)
Level of training: Not reported
Clinical specialty: Other (coronary care unit)
Country: USA (Michigan)

Centre: 2 medical centres (McLaren Regional Medical Center, Midland Regional Medical Center)

Location of care: Inpatient care
Participants: 51 participants needing anticoagulation with heparin after myocardial infarction


InterventionsClinical problem: Heparin adjustment
Intervention: Bayesian computer-generated starting doses (n = 25) vs. doctors using nomogram (n = 26)

Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Indirect intervention (dosage determined by pharmacy using)

Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: mean heparin dose (units/h)

Serum concentrations and therapeutic range: None

Physiological parameters: None (activated partial thromboplastin time ratio (compared with baseline activated partial thromboplastin time before heparin therapy): not included, number of activated partial thromboplastin time measurements per day of therapy: not included)

Time to achieve therapeutic control: None

Clinical events: Proportion of participants with clinical adverse events (recurrent chest pain, recurrent chest pain and readministration of thromboplastin, development of congestive heart failure, thrombotic stroke, arterial embolization, pulmonary embolus, transient ischaemic attack), proportion of participants with bleeding events

Healthcare costs: None

Improvement: None


Notes- The therapeutic range was 1.2-2.5 times the participant's baseline activated partial thromboplastin time


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskNo information provided

Baseline outcome measurements similarLow riskNot applicable

Baseline characteristics similarLow riskNo significant differences on main characteristics (table II)

Incomplete outcome data (attrition bias)
All outcomes
Low riskMean length of stay was 8 days. According to denominator in tables, there were no missing data

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMain outcomes were objective. Bleeding and clinical events are clearly defined

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Pachler 2008

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported (non-inferiority trial but no margin addressed)


ParticipantsProfession: Nurses
Level of training: Not reported
Clinical specialty: ICU
Country: Austria (Graz)
Centre: 1 x 9-bed medical ICU in a tertiary teaching hospital
Location of care: Inpatient care
Participants: 50 mechanically ventilated medical ICU patients


InterventionsClinical problem: Insulin in critically ill patients with hyperglycaemia
Intervention: Laptop-based algorithm eMPC (n = 25 participants) vs. routine nurse-based protocol (n = 25 participants). The eMPC is an enhanced version of the MPC, a model of the glucoregulatory system. Glucose concentration, insulin dosage and carbohydrate content of enteral and parenteral input are the input variables for the eMPC. The insulin infusion rate and the time of the next glucose sample are the outputs
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: User-initiated
Type of intervention: Direct intervention
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Insulin (IU/h) (change of insulin rate (number of times in 72 h): reported, carbohydrate administration (g/h): not included)

Serum concentrations and therapeutic range: None

Physiological parameters: Hyperglycaemia index (mmol/L) (blood glucose (mmol/L): not included (unit of analysis error))

Time to achieve therapeutic control: Mean sampling interval (hours)

Clinical events: Proportion of participants with hypoglycaemic episodes (blood glucose levels lower than 2.2 mM)

Healthcare costs: None

Improvement: None


Notes- Hyperglycaemic index was used as primary endpoint for the assessment of glucose control. The hyperglycaemic index developed by Vogelzang et al. is defined as the AUC above the upper limit of normal (glucose level 6.1 mmol/L, modified from the original 6.0 mmol/L) divided by the total length of stay (time in study)

- Non-inferiority trial analyzed like superiority trial

- The study is part of CLINICIP (Closed Loop Insulin Infusion for Critically Ill Patients; www.clinicip.org), an integrated project funded by the European Community


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants fulfilling the inclusion criterion were randomly assigned using serially numbered, sealed envelopes to either the intervention group (BG control by the eMPC) or the control group (routine BG management protocol)

Allocation concealment (selection bias)Low riskParticipants fulfilling the inclusion criterion were randomly assigned using serially numbered, sealed envelopes to either the intervention group (BG control by the eMPC) or the control group (routine BG management protocol)

Baseline outcome measurements similarLow riskNo significant differences on blood glucose at study start or number of participants treated with insulin before study start (table 1)

Baseline characteristics similarLow riskNo significant differences on baseline characteristics (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated. Denominator not reported in tables. The treatment was discontinued ahead of schedule in 2 participants of the control group and in 5 participants assigned to the eMPC group. It is not clear if these participants were excluded from analysis

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMain outcomes were objective. Hypoglycaemic episodes are clearly defined

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Plank 2006

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant, time under treatment
Power calculation: Not reported


ParticipantsProfession: Not reported
Level of training: Not reported
Clinical specialty: ICU
Country: Europe (Austria, Czech Republic, UK)
Centre: 3 ICUs across Europe (Graz, Prague, London)
Location of care: Inpatient care
Participants: 60 participants undergoing cardiac surgery with postsurgery hyperglycaemia (glucose > 120 mg/dL)


InterventionsClinical problem: Insulin in critically ill patients with hyperglycaemia
Intervention: Laptop-based algorithm MPC (n = 30 participants) vs. routine blood glucose management protocol (n = 30 participants). The MPC is a model representing the glucoregulatory system. Glucose concentration, insulin dosage and carbohydrate intake are the input variables for the MPC. The insulin infusion rate is the output parameter and was adjusted hourly as suggested by the algorithm
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: User-initiated
Type of intervention: Indirect intervention
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Insulin dosages used for the first 24 h (insulin units/24 h)

Serum concentrations and therapeutic range: None

Physiological parameters: % of time within the target range for blood glucose in the first 24 h (80-110 mg/dL or 4.4-6.1 mmol/L), mean glucose levels (mg/dL) (% of time above the target range for blood glucose in the first 24 h (> 110 mg/dL): not included, % of time between 54 and 79 mg/dL for blood glucose in the first 24 h (2.9 to < 4.4 mmol/L): not included)

Time to achieve therapeutic control: Mean sampling interval (h)

Clinical events: Proportion of participants with hypoglycaemic episodes (blood glucose level < 54 mg/dL or < 3 mmol/L)

Healthcare costs: None

Improvement: None


Notes- "The target range for blood glucose levels, as defined by the study protocol, was 80-110 mg/dl (4.4-6.1 mmol/l), which has been demonstrated to reduce mortality and morbidity in postcardiac surgery patients. The MPC algorithm and the routine care management protocol in Graz are aiming for exactly the same target range, while in Prague a slightly higher level for the upper limit (81-117 mg/dl [4.5-6.5 mmol/l]) and in London a slightly lower level for the lower limit (72-108 mg/dl [46 mmol/l]) is implemented in the routine glucose protocol. Likewise, small differences in the definition of hypoglycemia can be found among the routine management protocols (London: 54 mg/dl [3.0 mmol/l], Graz: 60 mg/dl [3.3 mmol/l], and Prague: 63 mg/dl [3.5 mmol/l]). For the study protocol, blood glucose levels 54 mg/dl (3.0 mmol/l) were defined as hypoglycemic events"

- The author was contacted and confirmed that the algorithm gave advice to the ICU personnel (nurses and physicians), who input the glucose values and changed the infusion rate

- The study is part of CLINICIP (Closed Loop Insulin Infusion for Critically Ill Patients; www.clinicip.org), an integrated project funded by the European Community


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"60 patients were randomized by individual centers in blocks of 10"

Allocation concealment (selection bias)Unclear risk"60 patients were randomized by individual centers in blocks of 10". No further information provided

Baseline outcome measurements similarUnclear riskBlood glucose at entry was reported by ICU (Graz, Prague, London) but not across study groups (table 1)

Baseline characteristics similarHigh riskBaseline characteristics of participants were reported by ICU (Graz, Prague, London) but not across study groups (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated. Denominator not reported in tables

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMain outcomes were objective. Hypoglycaemic episodes are clearly defined

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Poller 1998 pop1

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Episode of care
Power calculation: Not reported


ParticipantsProfession: Physicians
Level of training: Accredited/licensed
Clinical specialty: Not applicable
Country: Europe (Manchester (UK), London (UK), Oslo (Norway), Esbjerg (Denmark), Gaia (Portugal))

Centre: 5 centres

Location of care: Outpatient care
Participants: 79 inpatients needing anticoagulant therapy (stabilized patients)


InterventionsClinical problem: Warfarin therapy maintenance
Intervention: Computer-generated-dose group (n = 39) or traditional-dose group (n = 40)

Computer advice: Not reported
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Not reported

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None (proportion of doses adjustments: unknown denominator)

Serum concentrations and therapeutic range: None

Physiological parameters: Proportion of time spent within target (INR)

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: None

Improvement: None


NotesThe proportion of time within target INR range was determined according to the Rosendaal method

"The program has two main modules - the induction module for starting warfarin therapy over the first 4 days to reach a dose within 1 mg of eventual maintenance dose, and the maintenance module (version 4 only was used) for finely tuning the dose to the therapeutic range and sustaining it"

"The INR target ranges were decided by the individual centre, based on one of: the guidelines on oral anticoagulation of the British Society of Haematology, the Leuven Group, and the ACCP Consensus. Three different ranges of INR resulted; 2.0-3.0, 3.0-4.5, and 2.5-3.5"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation was done according to computer-generated order at each centre"

Allocation concealment (selection bias)Low risk"Randomisation was done according to computer-generated order at each centre"

Baseline outcome measurements similarLow riskNot appropriate (warfarin therapy maintenance)

Baseline characteristics similarHigh riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk285 randomized, 254 analyzed (16 excluded vs. 15)

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Poller 1998 pop2

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Episode of care
Power calculation: Not reported


ParticipantsProfession: Physicians
Level of training: Accredited/licensed
Clinical specialty: Not applicable

Country: Europe (Manchester (UK), London (UK), Oslo (Norway), Esbjerg (Denmark), Gaia (Portugal))

Centre: 5 centres

Location of care: Outpatient care
Participants: 175 outpatients needing anticoagulant therapy (in the stabilization period)


InterventionsClinical problem: Warfarin therapy stabilization
Intervention: Computer-generated-dose group (n = 83) or traditional-dose group (n = 92)

Computer advice: Not reported
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Not reported

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None (proportion of doses adjustments: unknown denominator)

Serum concentrations and therapeutic range: None

Physiological parameters: Proportion of time spent within target (INR)

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: None

Improvement: None


NotesThe proportion of time within target INR range was determined according to the Rosendaal method

"The program has two main modules - the induction module for starting warfarin therapy over the first 4 days to reach a dose within 1 mg of eventual maintenance dose, and the maintenance module (version 4 only was used) for finely tuning the dose to the therapeutic range and sustaining it"

"The INR target ranges were decided by the individual centre, based on one of: the guidelines on oral anticoagulation of the British Society of Haematology, the Leuven Group, and the ACCP Consensus. Three different ranges of INR resulted; 2.0-3.0, 3.0-4.5, and 2.5-3.5"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation was done according to computer-generated order at each centre"

Allocation concealment (selection bias)Low risk"Randomisation was done according to computer-generated order at each centre"

Baseline outcome measurements similarLow riskNot appropriate (Warfarin therapy maintenance)

Baseline characteristics similarHigh riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk285 randomized, 254 analyzed (16 excluded versus 15)

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Poller 2002

Methods


Participants


Interventions


Outcomes


Notes- Same data as Poller 1998 pop1; Poller 1998 pop2

Poller 2003

Methods


Participants


Interventions


Outcomes


Notes- Abstract corresponding to the Protocol of the study published in 2008 (Poller 2008)

Poller 2008

Methods


Participants


Interventions


Outcomes


Notes- Clinical endpoint report from the European Action on Anticoagulation (EAA), which gave the combined results using 2 currently marked computer-assisted dosage programs (DAWN AC and PARMA 5). The subgroup analyses were included (Poller 2009 DAWN AC, Poller 2008 PARMA 5)

Poller 2008 PARMA 5

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: INR
Power calculation: Done


ParticipantsProfession: Physicians
Level of training: Accredited/licensed
Clinical specialty: Not reported
Country: Europe, Israel, Australia
Centre: 32 centres in 13 countries (Europe: 29, Israel: 2, Australia: 1)
Location of care: Outpatient care
Participants: 13,219 anticoagulation patients randomized at each centre into manual-dosed or computer-assistant dosed arm (DAWN AC or PARMA 5). 13,052 participants analyzed (167 participants without INR results): 2631 for the DAWN AC study and 10,421 for the PARMA 5 study


InterventionsClinical problem: Oral anticoagulation (warfarin, nicoumalone (acenocoumarol), phenprocoumon)
Intervention: Computer-assisted dosage program (PARMA5 (n = 5290 participants)) versus manual dosage (n = 5131 participants). Recruitment was restricted to new patients initiated oral anticoagulation. 2 subroutines: induction and steady state monitoring; the aim of the dosage algorithm was to maintain the INR value as close as possible to the mean target INR and to provide the next appointment date
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: System-initiated
Type of intervention: Not reported
Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: None

Physiological parameters: Time in target INR range (INR: not included)

Time to achieve therapeutic control: None

Clinical events: Death, number of bleeding events (major + minor) (events per 100 patient-years), number of thrombotic events (events per 100 patient-years) (number of events (minor bleeding events, major bleeding events, thrombotic events, deaths): not included)

Healthcare costs: None

Improvement: None


Notes- Time in target INR range = proportion of time for which participants were maintained within the locally decided target INR ranges

- This report is a subgroup analysis of the previous clinical endpoint report from the European Action on Anticoagulation (EAA) (Poller 2008b), which gave the combined results using 2 currently marked computer-assisted dosage programs (DAWN AC and PARMA 5 ) (Poller 2009 DAWN AC, Poller 2008 PARMA 5)

- There were some incoherences between the number of events adjudicated in Poller 2008b (table 2) and the sum of number of events in Poller 2008 PARMA 5 (table II) and in Poller 2009 DAWN AC (table 2). The author confirmed the numbers in Poller 2008b and Poller 2008 PARMA 5 and corrected those in Poller 2009 DAWN AC


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskNo information provided

Baseline outcome measurements similarLow riskNot applicable

Baseline characteristics similarLow riskNo apparent differences on baseline characteristics of the 10,421 participants (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Low risk44/5175 in manual-dosed group and 87/5377 in computer-assisted dosage group did not receive allocated intervention

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMain outcomes were objective. Events were adjudicated by a committee

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Poller 2009 DAWN AC

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: INR
Power calculation: Done


ParticipantsProfession: Physicians
Level of training: Accredited/licensed
Clinical specialty: Not reported
Country: Europe, Israel, Australia
Centre: 32 centres in 13 countries (Europe: 29, Israel: 2, Australia: 1)
Location of care: Outpatient care
Participants: 13,219 anticoagulation patients randomized at each centre into manual-dosed or computer-assistant dosed arm (DAWN AC or PARMA 5). 13,052 participants analyzed (167 participants without INR results): 2631 for the DAWN AC study and 10,421 for the PARMA 5 study


InterventionsClinical problem: Oral anticoagulation (warfarin, nicoumalone (acenocoumarol), phenprocoumon)
Intervention: Computer-assisted dosage program (DAWN AC (n = 1315 participants)) versus manual dosage (n = 1316 participants). Recruitment was restricted to new patients initiated oral anticoagulation. 2 modules: induction and maintenance; the time to the next test was set by the program using a table of variables
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: System-initiated
Type of intervention: Not reported
Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: None

Physiological parameters: Time in target INR range (INR: not included)

Time to achieve therapeutic control: None

Clinical events: Death, number of bleeding events (major + minor) (events per 100 patient-years), number of thrombotic events (events per 100 patient-years) (number of events (minor bleeding events, major bleeding events, thrombotic events, deaths): not included)

Healthcare costs: None

Improvement: None


Notes- Time in target INR range = proportion of time for which participants were maintained within the locally decided target INR ranges

- This report is a subgroup analysis of the previous clinical endpoint report from the European Action on Anticoagulation (EAA) (Poller 2008b), which gave the combined results using 2 currently marked computer-assisted dosage programs (DAWN AC and PARMA 5 ) (Poller 2009 DAWN AC, Poller 2008 PARMA 5)

- There were some incoherences between the number of events adjudicated in Poller 2008b (table 2) and the sum of number of events in Poller 2008 PARMA 5 (table II) and in Poller 2009 DAWN AC (table 2). The author confirmed the numbers in Poller 2008b and Poller 2008 PARMA 5 and corrected those in Poller 2009 DAWN AC


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskNo information provided

Baseline outcome measurements similarLow riskNot applicable

Baseline characteristics similarLow riskNo apparent differences on baseline characteristics of the 2631 participants (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Low risk12/1328 in manual-dosed group and 24/1339 in computer-assisted dosage group were excluded because no INR results were reported

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMain outcomes were objective. Events were adjudicated by a committee

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Poller 2009 erratum

Methods


Participants


Interventions


Outcomes


Notes- Erratum from original article Poller 2009 DAWN AC

Rodman 1984

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not done


ParticipantsProfession: Not reported
Level of training: Not reported
Clinical specialty: Not reported
Country: USA

Centre: 1 medical centre (University of Southern California Medical Center)

Location of care: Inpatient care
Participants: 20 participants admitted to medical ICU or coronary care unit needing lignocaine therapy


InterventionsClinical problem: Lidocaine therapy
Intervention: Advice on initial therapy using individualized linear 2 compartment pharmacokinetic model (n = 9) vs. usual care (n = 11)
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: User-initiated
Type of intervention: Not reported

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: mean first hour infusion rate (μg/kg/min), mean final infusion rate (μg/kg/min), mean overall infusion rate

Serum concentrations and therapeutic range: serum concentrations (lidocaine)

Physiological parameters: None

Time to achieve therapeutic control: None

Clinical events: proportion of participants with adverse reactions (monitoring of rhythm, intermittent hard-copy rhythm strips, serial electrocardiographs, daily measurements of electrolyte and cardiac enzyme levels, liver function tests)

Healthcare costs: None

Improvement: None


NotesObjective: "To achieve and maintain plasma concentrations in the approximate middle of the usual therapeutic range of 1.5 to 5.0 µg/mL"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details

Allocation concealment (selection bias)Low riskSealed envelope

Baseline outcome measurements similarLow riskNot appropriate

Baseline characteristics similarHigh riskThere were 6/9 men in the computer-assisted therapy group and 11//11 in the conventional lidocaine therapy group

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMain outcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Unclear riskOutcomes were not defined in the methods section

Other biasUnclear riskOnly 20 participants were included

Rousseau 2010

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Done


ParticipantsProfession: Physicians
Level of training: Accredited/licensed
Clinical specialty: Nephrology
Country: France
Centre: 11 centres
Location of care: Inpatient care
Participants: 137 renal allograft recipients receiving basiliximab, CsA, MMF and corticosteroids. 130 participants analyzed


InterventionsClinical problem: MMF dosing in renal transplant patients
Intervention: Concentration-controlled (CC) regimen (n = 65 participants) vs. fixed-dose (FD) MMF (n = 65 participants). In the CC group, MMF dose adjustments were calculated by a computer program to reach an MPA AUC target of 40 mg.h/L and were proposed to the physician. In the FD group, MMF dose adjustments were based on clinical experience
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Direct intervention
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: See Le Meur 2007

Serum concentrations and therapeutic range: See Le Meur 2007

Physiological parameters: See Le Meur 2007

Time to achieve therapeutic control: See Le Meur 2007

Clinical events: See Le Meur 2007

Healthcare costs: Cost per participant during the first year of transplantation based on diagnosis-related groups reimbursements (EUR, base 2007) (hospital stays, drugs, biological tests and medical transportation)

Improvement: See Le Meur 2007


NotesThis is a cost-effectiveness analysis conducted as a part of the APOMYGRE randomized multicentre study of concentration-controlled dosing regimen of MMF vs. fixed-dose reported by Le Meur et al. (see Le Meur 2007)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Within the first 3 days posttransplant, patients were randomized by an interactive voice response system administered by a private company; randomization was balanced within centers in blocks of 4 patients, and patients were enrolled and assigned to one of the two groups by physicians at each center"

Allocation concealment (selection bias)Low risk"Within the first 3 days posttransplant, patients were randomized by an interactive voice response system administered by a private company; randomization was balanced within centers in blocks of 4 patients, and patients were enrolled and assigned to one of the two groups by physicians at each center"

Baseline outcome measurements similarLow riskNot applicable

Baseline characteristics similarHigh risk"The sex ratio differed between groups in that there were a larger percentage of males in the CC-treated group (table 1)"

Incomplete outcome data (attrition bias)
All outcomes
Low risk"There were seven withdrawals (CC, n = 5; FD, n = 2) due to death, primary non functioning graft or because MMF was not administered." In most of tables, only percentages were reported and according to the first decimal of percentages, there were missing data in the denominator. However, missing values were unlikely to overturn the study results

Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"Acute rejection was diagnosed by renal biopsy except in patients with contraindications and were graded according to the Banff classification, in which case diagnosis was based on clinical and laboratory criteria (in particular, any unexplained increase in serum creatinine)." No committee reported

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Saager 2008

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Done


ParticipantsProfession: Mixed (trained healthcare professionals)
Level of training: Not reported
Clinical specialty: Not reported
Country: USA
Centre: 1 large academic medical centre
Location of care: Inpatient care
Participants: 40 participants with diabetes mellitus scheduled for cardiac surgery (cardiothoracic ICU)


InterventionsClinical problem: Insulin in people with diabetes undergoing cardiac surgery
Intervention: Computer-guided glucose management system (n = 20 participants) vs. standard paper-based insulin protocol (n = 20 participants). The computer system (EndoTool Glucose Management System (MD Scientific)) used the previous 4 dose responses to recommend the insulin dose, glucose determination frequency, and a 50% dextrose dose (when appropriate) for hypoglycaemia
Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: System-initiated
Type of intervention: Direct intervention
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: None

Physiological parameters: Mean blood glucose (mg/dL) in ICU (available in operating room: not included, time in blood glucose range in operating room: reported, time in blood glucose range in ICU: reported)

Time to achieve therapeutic control: None

Clinical events: Proportion of participants with side effects (hypoglycaemia: < 60 mg/dL at any time) in ICU (available in operating room: not included)

Healthcare costs: None

Improvement: None


Notes"The standard paper-based ICU insulin protocol was developed at this institution with the goal of targeting blood sugar concentrations between 90 and 150 mg/dL"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details

Allocation concealment (selection bias)Unclear riskNo details

Baseline outcome measurements similarLow riskNo significant differences on baseline characteristics (table 1)

Baseline characteristics similarLow riskNo significant differences on blood glucose (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Sato 2011

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant, blood glucose measurements
Power calculation: Done


ParticipantsProfession: Anaesthesiologists
Level of training: Not reported
Clinical specialty: Other (anaesthesiology/cardiology)
Country: Canada (Montreal)
Centre: 1 university hospital (Royal Victoria Hospital, McGill University Health Centre)
Location of care: Inpatient care
Participants: 42 participants without diabetes undergoing elective cardiac surgery were randomized. 36 participants were analyzed. All studies were conducted by 6 anaesthesiologists, each anaesthesiologist was assigned to 3 manual and 3 GINCS studies in random order


InterventionsClinical problem: Glucose and insulin administration in cardiac surgical patients
Intervention: GIN Computer Software (GINCS) (n = 18) versus manual control group (n = 18). The computer program uses an algorithm based on the original clamp equation (DeFronzo et al.) and modified for its use during cardiac surgery requiring extracorporeal circulation. It takes account of the characteristic of glucose dynamics during cardiac surgery and CPB, including plasma glucose fluctuation, alterations in glucose utilization, transfusion of blood products, and rewarming of the patients
Computer advice: Given in real time
CDSS integration in CPOE: Not reported
Starter: Not reported
Type of intervention: Direct intervention
Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: mean amount of insulin infused (IU) (mean amount of glucose administered (g): reported)

Serum concentrations and therapeutic range: None

Physiological parameters: Mean blood glucose (mmol/L), % of participants with all measurements within the target range for blood glucose (4-6 mmol/L) (% of time within the target range for blood glucose (4-6 mmol/L) (unit of analysis error): reported, % of time below the target range for blood glucose (4-6 mmol/L) (unit of analysis error): not included, % of time above the target range for blood glucose (4-6 mmol/L) (unit of analysis error): not included, time (min) within the target range for blood glucose (4-6 mmol/L): not included, time (min) below the target range for blood glucose (4-6 mmol/L): not included, time (min) above the target range for blood glucose (4-6 mmol/L): not included)

Time to achieve therapeutic control: Mean sampling interval (min)

Clinical events: Proportion of participants with hypoglycaemic episodes (blood glucose level < 2.9 mmol/L)

Healthcare costs: None

Improvement: None


Notes"Target glycemia was defined as BG [blood glucose] between 4.0 to 6.0 mmol/L. Hyperglycemia was defined as BG 7.0 mmol/L. Hypoglycemia was defined as a BG 2.9 mmol/L. Time within, above and below target range was calculated by assuming the linearity of BG level over time"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Consenting patients were allocated according to a computer-generated randomization schedule into the computer-assisted or manual group (Plan procedure, SAS software, SAS Institute, Cary, NC)"

Allocation concealment (selection bias)Low risk"Consenting patients were allocated according to a computer-generated randomization schedule into the computer-assisted or manual group (Plan procedure, SAS software, SAS Institute, Cary, NC)"

Baseline outcome measurements similarLow riskNo significant differences on preoperative blood glucose (table 1)

Baseline characteristics similarLow riskNo significant differences on participants demographic (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe blood glucose was measured in short intervals as requested by each algorithm before, during and after cardiopulmonary bypass (over maximum 320 min)

Blinding of outcome assessment (detection bias)
All outcomes
Low riskMain outcomes were objective. Hypoglycaemic episodes were clearly defined

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Terrell 2010

MethodsDesign: RCT
Unit of allocation: Provider
Unit of analysis: Medication, participant visit (cluster was taken into account in statistical analysis)
Power calculation: Not reported


ParticipantsProfession: Physicians
Level of training: Mixed
Clinical specialty: Emergency
Country: USA
Centre: 1 urban public hospital
Location of care: Inpatient care
Participants: 42 emergency medicine faculty and resident physicians randomized (intern physicians excluded). Subjects were adults with renal insufficiency who were being discharged home from the emergency department. 6015 participant visits with prescription initially written for a targeted medication. Among the 2783 visits in which creatinine level was estimated, 113 (4%) participant visits (corresponded to 119 prescriptions) resulted in prescription of at least 1 medication that required dosage adjustment (3232 participant visits excluded because of insufficient information in the electronic medical record to estimate the creatinine clearance)


InterventionsClinical problem: 10 high-use medications that require adjustments for renal impairment (amoxicillin, amoxicillin/clavulanate, cephalexin, ciprofloxacin, colchicine, hydrochlorothiazide, levofloxacin, lisinopril, ranitinide, trimethoprim/sulfamethoxazole)
Intervention: Computerized decision support (21 physicians) vs. control group (21 physicians). Decision support was provided when an intervention physician prescribed a targeted medication to a person whose creatinine level was below the threshold for dosage adjustment for that particular medication. The physician could either accept or reject the decision support's recommendation.
Computer advice: Given in real time
CDSS integration in CPOE: Yes
Starter: System-initiated
Type of intervention: Direct intervention
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: None (% excessively dosed prescriptions: reported, % visits with excessively dosed prescriptions: not included)

Physiological parameters: None

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: None

Improvement: None


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"A biostatistician randomly assigned physicians in blocks of 2, stratified by stage of training (i.e., faculty status and by year of residency training) into the intervention or control group"

Allocation concealment (selection bias)Low risk"A biostatistician randomly assigned physicians in blocks of 2, stratified by stage of training (i.e., faculty status and by year of residency training) into the intervention or control group"

Baseline outcome measurements similarLow riskNot stated

Baseline characteristics similarLow risk"There were no important differences in the characteristics of intervention and control physicians or the 2 groups of patients who received their care" (table 1)

Incomplete outcome data (attrition bias)
All outcomes
High risk46% of participant visits excluded because of insufficient data to estimate creatinine clearance

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPhysicians were randomized but the study was carried out in a single site and included a small sample of residents and academic emergency physicians

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasUnclear risk46% participant visits were excluded, only prescription that required dosage adjustment were analyzed and there was no adjustment for within-patient correlation

"Providers in the intervention group initially prescribed targeted medications more often than control physicians did and consequently had substantially more opportunities to adjust dosing"

Theil 1993 fentanyl

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Physicians
Level of training: Not reported
Clinical specialty: Other (anaesthesia)
Country: USA (Durham, North Carolina)

Centre: 1 University Medical Center (Duke University Medical Center)

Location of care: Inpatient care
Participants: 24 participants undergoing cardiac surgery with continuous infusion of IV anaesthetics


InterventionsClinical problem: Fentanyl
Intervention: Computer-controlled pump using pharmacokinetic model to achieve target serum level (n = 12) vs. infusion controlled by doctor (n = 12)

Computer advice: Given in real time
CDSS integration in CPOE: Yes
Starter: System-initiated
Type of intervention: Direct intervention

Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: None (fentanyl loading dose (μg/kg): reported, fentanyl maintenance infusion dose during cardiopulmonary bypass (μg/kg): reported, fentanyl total dose (μg/kg): reported, mean number of infusion changes during cardiopulmonary bypass (potential unit of error analysis): reported)

Serum concentrations and therapeutic range: None (mean plasma fentanyl concentration during cardiopulmonary bypass (ng/mL): reported)

Physiological parameters: None (haemodynamic values: not included)

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: None

Improvement: None


Notes"The primary objective for all patients was to maintain heart rate (HR) and mean arterial pressure (MAP) within 20% of baseline values. If possible, hemodynamic control was achieved by altering only the anesthetic infusions. Hypertension (MAP>20% baseline) and tachycardia (HR>20%) were initially treated by incremental increases in fentanyl or midazolam.[...] Hypotension (MAP>20%) prior to and during cardiopulmonary bypass (CPB) was treated by intravenous volume expansion, and a decrease in anesthetic delivery"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details

Allocation concealment (selection bias)Unclear riskNo details

Baseline outcome measurements similarLow riskNot applicable (people undergoing cardiac surgery)

Baseline characteristics similarLow riskNo significant differences on participants demographic (table 3)

Incomplete outcome data (attrition bias)
All outcomes
Low riskData were reported for all participants included

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants were randomized but blinded ("Both systems were attached to each patient by an independent operator")

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Theil 1993 midazolam

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Physicians
Level of training: Not reported
Clinical specialty: Other (anaesthesia)
Country: USA (Durham, North Carolina)

Centre: 1 University Medical Center (Duke University Medical Center)

Location of care: Inpatient care
Participants: 24 participants undergoing cardiac surgery with continuous infusion of IV anaesthetics


InterventionsClinical problem: Midazolam
Intervention: Computer-controlled pump using pharmacokinetic model to achieve target serum level (n = 12) vs. infusion controlled by doctor (n = 12)

Computer advice: Given in real time
CDSS integration in CPOE: Yes
Starter: System-initiated
Type of intervention: Direct intervention

Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: None (midazolam loading dose (μg/kg): reported, midazolam maintenance infusion dose during cardiopulmonary bypass (μg/kg): reported, midazolam total dose (μg/kg): reported, mean number of infusion changes during cardiopulmonary bypass (potential unit of error analysis): reported)

Serum concentrations and therapeutic range: None (mean plasma midazolam concentration during cardiopulmonary bypass (ng/mL): reported)

Physiological parameters: None (haemodynamic values: not included)

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: None

Improvement: None


Notes"The primary objective for all patients was to maintain heart rate (HR) and mean arterial pressure (MAP) within 20% of baseline values. If possible, hemodynamic control was achieved by altering only the anesthetic infusions. Hypertension (MAP>20% baseline) and tachycardia (HR>20%) were initially treated by incremental increases in fentanyl or midazolam.[...] Hypotension (MAP>20%) prior to and during cardiopulmonary bypass (CPB) was treated by intravenous volume expansion, and a decrease in anesthetic delivery"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo details

Allocation concealment (selection bias)Unclear riskNo details

Baseline outcome measurements similarLow riskNot applicable (people undergoing cardiac surgery)

Baseline characteristics similarLow riskNo significant differences on participants demographic (table 3)

Incomplete outcome data (attrition bias)
All outcomes
Low riskData were reported for all participants included

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants were randomized but blinded ("both systems were attached to each patient by an independent operator")

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Vadher 1997

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Mixed (physicians + nurses)
Level of training: In training
Clinical specialty: Not reported
Country: UK (London)

Centre: 1 district general hospital (Whittington Hospital)

Location of care: Mixed
Participants: 148 inpatients requiring start of warfarin therapy


InterventionsClinical problem: Warfarin therapy initiation
Intervention: CDSS group (n = 72 ) vs. control group (n = 76)

Computer advice: Not reported
CDSS integration in CPOE: No
Starter: Not reported
Type of intervention: Not reported

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: None

Physiological parameters: None (time spent in days per 100 patient-days of treatment: reported)

Time to achieve therapeutic control: Median time to reach therapeutic prothrombin ratio (days), median to reach stable dose (days)

Clinical events: Thromboembolism, haemorrhage, death

Healthcare costs: None

Improvement: None


Notes"We developed an initiation regimen aiming for a therapeutic range of international normalised ratio of 2 to 3"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"We used simple randomization with a table of random numbers to assign the patients to management by doctors aided by the decision support system (intervention group) or to management by doctors alone (control group)"

Allocation concealment (selection bias)Unclear risk"We used simple randomization with a table of random numbers to assign the patients to management by doctors aided by the decision support system (intervention group) or to management by doctors alone (control group)." No further information provided

Baseline outcome measurements similarLow riskNot appropriate (warfarin therapy initiation)

Baseline characteristics similarLow riskNo apparent differences on baseline characteristics (table 1)

Incomplete outcome data (attrition bias)
All outcomes
High risk64/76 participants in the control group were followed up as outpatients and 53/72 in the intervention group. There was no description of missing data

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Vadher 1997 pop1

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant, participant time
Power calculation: Not reported


ParticipantsProfession: Mixed (physicians + nurses)
Level of training: Mixed
Clinical specialty: Other (cardiology)
Country: UK (London)

Centre: 1 district general hospital (Whittington Hospital)

Location of care: Outpatient care
Participants: Participants who had been initiated on warfarin therapy as inpatients and followed in the outpatient clinic. Most of these participants required anticoagulation for deep vein thrombosis, pulmonary embolus or atrial fibrillation


InterventionsClinical problem: Warfarin long-term therapy (therapeutic range 2-3)
Intervention: CDSS group (n = 37) vs. control group (n = 44)

Computer advice: Given in real time
CDSS integration in CPOE: Not reported
Starter: User-initiated
Type of intervention: Direct intervention

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Maintenance dose (mg/day)

Serum concentrations and therapeutic range: None

Physiological parameters: None (time spent in days per 100 patient-days of treatment: reported)

Time to achieve therapeutic control: None

Clinical events: Thromboembolism, haemorrhage

Healthcare costs: None

Improvement: None


NotesThe therapeutic range of INR was 2-3


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Simple randomization using random number tables was used"

Allocation concealment (selection bias)Unclear risk"Simple randomization using random number tables was used." No further information provided

Baseline outcome measurements similarLow riskNot applicable

Baseline characteristics similarLow riskNo apparent differences on baseline characteristics (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasHigh risk- The nurse-practitioners used the computer-decision support system and were compared to the clinician group of 3 junior doctors undergoing general professional training in general medicine

- The was a risk of contamination due to logistical problems ("it was difficult to shield the clinicians from the CDSS suggestions")

Vadher 1997 pop2

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant, participant time
Power calculation: Not reported
Concealment of allocation: Not reported


ParticipantsProfession: Mixed (physicians + nurses)
Level of training: Mixed
Clinical specialty: Other (cardiology)

Location of care: Outpatient care
Country: UK (London)

Centre: 1 district general hospital (Whittington Hospital)

Participants: Participants who had been on warfarin for more than 1 year. Most of the participants required anticoagulation for heart valve disease, valve replacement or recurrent thromboembolism


InterventionsClinical problem: Warfarin long term (therapeutic range 3-4.5)
Intervention: CDSS group (n = 50) vs. control group (n = 46)

Computer advice: Given in real time
CDSS integration in CPOE: Not reported
Starter: User-initiated
Type of intervention: Direct intervention

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Maintenance dose (mg/day)

Serum concentrations and therapeutic range: None

Physiological parameters: None (time spent in days per 100 patient-days of treatment: reported)

Time to achieve therapeutic control: None

Clinical events: Thromboembolism, haemorrhage

Healthcare costs: None

Improvement: None


NotesThe therapeutic range of INR was 3-4.5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Simple randomization using random number tables was used"

Allocation concealment (selection bias)Unclear risk"Simple randomization using random number tables was used." No further information provided

Baseline outcome measurements similarLow riskNot applicable

Baseline characteristics similarLow riskNo apparent differences on baseline characteristics (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasHigh risk- The nurse-practitioners used the computer-decision support system and were compared to the clinician group of 3 junior doctors undergoing general professional training in general medicine

- The was a risk of contamination due to logistical problems ("it was difficult to shield the clinicians from the CDSS suggestions")

Verner 1992

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not done


ParticipantsProfession: Physicians
Level of training: Accredited/licensed
Clinical specialty: Internal medicine
Country: Israel (Tel Hashomer)

Centre: A 1400 bed regional teaching hospital (Sheba Medical Center)

Location of care: Inpatient care
Participants: 25 participants needing aminophylline therapy for acute asthma


InterventionsClinical problem: Theophylline
Intervention: Computer suggested dose based on individualized pharmacokinetic model to doctor (n = 10) vs. usual care (n = 15)

Computer advice: Not reported
CDSS integration in CPOE: No
Starter: User-initiated
Type of intervention: Not reported

Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: Loading dose of theophylline (mg)

Serum concentrations and therapeutic range: Serum theophylline concentration 20 minutes after completion of loading dose infusion (μg/mL) (% of time spent in therapeutic range (serum theophylline concentrations in 10-20 µg/mL): reported)

Physiological parameters: None

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: Mean hospitalization time (days)

Improvement: None


Notes"The computer program was used to estimate the predicted admission serum theophylline concentration, and the partial loading dose needed to achieve the target concentration which was set at 16 g/ml"


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High risk"Randomization was based on the final digit in the patient's identification card number (odds versus even)"

Allocation concealment (selection bias)High riskOdd versus even identification card number

Baseline outcome measurements similarLow riskNot applicable

Baseline characteristics similarHigh riskThere were significant differences between the groups (age, asthma/chronic obstructive lung disease and associated medical conditions)

Incomplete outcome data (attrition bias)
All outcomes
Low riskData were reported for all participants included

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

Wexler 2010

MethodsDesign: RCT
Unit of allocation: Provider (physicians team)
Unit of analysis: Participant (cluster was not taken into account in statistical analysis)
Power calculation: Done


ParticipantsProfession: Physicians
Level of training: In training
Clinical specialty: Internal medicine
Country: USA (Boston)
Centre: 1 tertiary care medical centre (Massachusetts General Hospital Diabetes Center)
Location of care: Inpatient care
Participants: 144 insulin-treated people with type 2 diabetes enrolled. 128 participants analyzed


InterventionsClinical problem: Insulin in general medical inpatients with type 2 diabetes
Intervention: Electronic basal-bolus insulin order template (n = 65 participants) vs. usual insulin ordering (n = 63 participants). The total daily dose of insulin required for the participant (basal (long-acting) and prandial (short-acting)) was calculated by multiplying the weight of the participant by 0.5 units/kg. A button to use insulin-dose calculator was available
Computer advice: Given in real time
CDSS integration in CPOE: Yes
Starter: System-initiated
Type of intervention: Direct intervention
Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: Basal insulin dose (units)

Serum concentrations and therapeutic range: None

Physiological parameters: Mean blood glucose (mg/dL)

Time to achieve therapeutic control: None

Clinical events: Proportion of participants with hypoglycaemia (< 60 mg/dL at any time) (severe hypoglycaemia (< 40 mg/dL at any time): not included, prolonged hyperglycaemia (3 consecutive glucose values > 240 mg/dL): not included)

Healthcare costs: Length of stay (days)

Improvement: None


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Using a computerized coin toss, we randomly assigned seven teams of providers (42 internal medicine residents) working in general medical acute care units to have the option to use the order template (intervention group) or to use usual insulin ordering (control group)"

Allocation concealment (selection bias)Low risk"Using a computerized coin toss, we randomly assigned seven teams of providers (42 internal medicine residents) working in general medical acute care units to have the option to use the order template (intervention group) or to use usual insulin ordering (control group)"

Baseline outcome measurements similarUnclear riskIt is unclear if the mean blood glucose values given at the beginning of the results were baseline data or results with all randomized participants (186 ± 56 mg/dL in intervention participants versus 206 ± 61 mg/dL in control participants (P value = 0.004))

Baseline characteristics similarLow riskThere was no significant differences on participants demographic or primary diagnosis (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Low risk144 insulin-treated people with type 2 diabetes were admitted, 16 participants whose point-of-care glucose values were between 60 and 180 mg/dL were excluded (non-target population)

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskTeam of providers were randomized but the study was carried out in a single site

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

White 1987

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not done


ParticipantsProfession: Mixed (physicians + pharmacists)
Level of training: Accredited/licensed
Clinical specialty: Other (anticoagulant clinic)
Country: USA (California)

Centre: 2 university hospitals (Veterans Administration Medical Center, Davis Medical Center)

Location of care: Inpatient care
Participants: 75 participants requiring anticoagulation with warfarin


InterventionsClinical problem: Warfarin initiation
Intervention: Initial dose suggested by Bayesian computer pharmacokinetic and pharmacodynamic model (n = 39) vs. usual care (n = 36)

Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: User-initiated
Type of intervention: Not reported

Calculated dose given as a recommendation: Yes


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: None (participant with supratherapeutic prothrombin ratio (PR) at any time: not included)

Physiological parameters: Days on warfarin PR therapeutic

Time to achieve therapeutic control: Time to reach a therapeutic PR, time to reach a therapeutic dose

Clinical events: Proportion of participants with a bleeding complication, death

Healthcare costs: Length of stay

Improvement: None


NotesThe therapeutic range was defined as PR = 1.8 ± 0.4, or, using a generalized formula, PR±(0.22)*(PR)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandom sequence generation not specified

Allocation concealment (selection bias)Unclear riskNo information provided

Baseline outcome measurements similarLow riskNot applicable

Baseline characteristics similarLow riskThere was no significant differences on demographic and clinical characteristics of participants (table 1)

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere were 4/36 participants in the physician-dosed group and 3/39 in the computer-dosed group which data could not be analyzed. Incomplete data were unlikely to overturn the study results

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Low riskAll relevant outcomes were reported in the results section

Other biasLow riskNo evidence of other risk of biases

White 1991

MethodsDesign: RCT
Unit of allocation: Participant
Unit of analysis: Participant
Power calculation: Not reported


ParticipantsProfession: Nurses
Level of training: Mixed
Clinical specialty: Not reported
Country: USA (California)

Centre: 1 university hospital (Davis Medical Center)

Location of care: Outpatient care

Participants: 50 participants needing anticoagulation with warfarin (long-term oral therapy)


InterventionsClinical problem: Long-term warfarin adjustment
Intervention: Maintenance dose suggested by Bayesian computer pharmacokinetic model (n = 24) vs. usual care (n = 26)

Computer advice: Given in real time
CDSS integration in CPOE: No
Starter: User-initiated
Type of intervention: Direct intervention

Calculated dose given as a recommendation: Not reported


OutcomesDose of drug administered to the participant: None

Serum concentrations and therapeutic range: None

Physiological parameters: None (proportion of participants within target (final prothrombin time): reported)

Time to achieve therapeutic control: None

Clinical events: None

Healthcare costs: None

Improvement: None


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskRandom sequence generation not specified

Allocation concealment (selection bias)Unclear riskNo information provided

Baseline outcome measurements similarLow risk"There were no significant differences between the groups with respect to age, gender, target prothrombin times, percentage of patients initially below the target, percentage of patients initially above the target, or the mean of the absolute value of the differences between initial prothrombin times and the corresponding target prothrombin times (Table 1)"

Baseline characteristics similarLow risk"There were no significant differences between the groups with respect to age, gender, target prothrombin times, percentage of patients initially below the target, percentage of patients initially above the target, or the mean of the absolute value of the differences between initial prothrombin times and the corresponding target prothrombin times (Table 1)"

Incomplete outcome data (attrition bias)
All outcomes
Low risk2/26 participants in the nurse-specialist group and 1/24 participant in the computer group did not return for follow-up. Incomplete data were unlikely to overturn the study results

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes were objective

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants were randomized

Selective reporting (reporting bias)Unclear riskOutcomes were not described in the methods section

Other biasLow riskNo evidence of other risk of biases

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Abbrecht 1982- Not computerized drug dosage (computer controlled pump not under physician control)

Absalom 2003- Not computerized drug dosage (automatic control of the propofol infusion using closed-loop system)

Albisser 2007- Not computerized drug dosage (prediction of future glycaemia and future risks of hypoglycaemia and hyperglycaemia)

Alvis 1985- Design

Barletta 2009- Design (before and after study without control group)

Barras 2008- Not computerized drug dosage (trial comparing individualized dosing of enoxaparin based on participa nt weight and renal function to conventional dosing)

Barras 2010- Not computerized drug dosage (dose calculated from an equation including the weight of the participa nt)

Bartal 2003- Not computerized drug dosage (utility of pharmacokinetic monitoring of aminoglycoside levels in the context of once-daily treatment (primary endpoint: renal toxicity))

Berg 2009- Not computerized drug dosage (individually tailored treatment duration)

Burger 2003- Not computerized drug dosage (t able with therapeutic drug monitoring rules depending on the concentration ratio method (standardized pharmacokinetic curve))

Bury 2005- Not computerized drug dosage

Caraballo 2008- Not computerized drug dosage (alerts)

Carter 1987a- Not computerized drug dosage

Cavalcanti 2009- Design ( the target range for blood glucose was different according to the interventions or the conventional treatment)

Chan 2006- Design (before and after study without control group)

Chiarelli 1990- Participa nt aid not under physician control

Cohen 2007- Not computerized drug dosage (trial comparing growth hormone dosing using a prespecified algorithm to conventional growth hormone dose)

Collins 2004- Not computerized drug dosage (alerts)

Cupissol 1996- Not computerized drug dosage (control of the cisplatin infusion using automatic pump)

Demakis 2000- Not computerized drug dosage (reminder to standard of care)

Dillon 1989- Design (some participa nts in the standardized dosing arm crossed-over to pharmacokinetic dosing arm)

Donovan 2010- Not computerized drug dosage (alerts)

Doran 2004- Design (cohort with 4 participa nts)

Dortch 2008- Design (retrospective study)

Evans 1998- Design (before and after study without control group)

Evans 1998a- Not computerized drug dosage (no recommendation to the healthcare professional: chemotherapy protocol)

Evans 1999- Design (before and after study without control group)

Faber 2006- Not computerized drug dosage (individualize d dosing concerned the day of administration)

Feldstein 2006- Not computerized drug dosage (alert for prescribing laboratory monitoring test)

Fety 1998- Not computerized drug dosage (no recommendation to the healthcare professional: chemotherapy protocol)

Field 2009- The dose advice was not individualized (maximal suggested dose)

Field 2009a- The dose advice was not individualized (maximal suggested dose)

Fihn 1994- Absence of relevant data for primary outcome

Fitzmaurice 1996- Absence of relevant data for primary outcome

Fitzmaurice 1998- Design

Flanders 2009- Design (before and after study without control group)

Fritsch 2009- Not computerized drug dosage (target-controlled inhalation induction)

Fukudo 2009- Design (control group without random or quasi-random allocation)

Gamelin 2008- Not computerized drug dosage (table with dose-adjustment algorithm according to plasma concentration)

Ghazal-Aswad 1997- Conference publication (contact author failed due to erroneous email)

Gopakumaran 2004- Discussion

Griffey 2012- The dose advice was not individualized (most commonly used dose)

Guarracino 2001- Not computerized drug dosage (evaluation of automated protamine dose assay)

Guarracino 2003- Design (n ot a comparative study)

Hermayer 2007- Design (before and after study without control group)

Hobbs 1996- Absence of relevant data for primary outcome

Hoffman 2004- Not computerized drug dosage (dose adjustment based on the occurrence of adverse events)

Horn 2002- Design

Hwang 2004- Design

Jankovic 1999- The 15 participa nts from the Jankovic study were included in the Mihajlovic study (60 participa nts)

Jannuzzi 2000- Not computerized drug dosage (dosage based on serum drug level monitoring)

Jellinek 2005- Not computerized drug dosage (decision support algorithm)

Judge 2006- Not computerized drug dosage (alerts)

Jung 2009- Not computerized drug dosage (no individualized dose recomme nded to the healthcare professional: protocol for adjustment of growth hormone dosage)

Kazemi 2011- Design (before and after study without control group)

Kirk 2005- Design (cohort study)

Koide 2000- Design (before after study)

Kristrom 2009- The dose advice was not individualized (dose selection within an interval using a predicted response)

Kroese 2005- Design (n ot a comparative study)

la Cour Freiesleben 2009- Not computerized drug dosage (paper nomogram)

Lester 2006- Not computerized drug dosage (email with low-density lipopr o tein therapeutic goal)

Ligtenberg 2006- Not a study but a comment on Plank 2006

Lillis 2003- Design (case history)

Liu 2006- Not computerized drug dosage (closed-loop system)

Manotti 2001 maintenance- Absence of relevant data for primary outcome

Mar Fernandez 1996- Not computerized drug dosage (no recommendation to the healthcare professional: pharmacokinetic model used for drug monitoring)

Mar Fernandez 2009- Not computerized drug dosage (predictive performance of population models)

Matheny 2008- Not computerized drug dosage (reminders for annual intervals for laboratory monitoring)

Maurizi 2011- Participa nt aid not under physician control (advice delivered directly to the participa nt: self monitor glucose)

McCluggage 2010- Design (historical control group)

McCowan 2001- Not computerized drug dosage (software that implements guidelines during consultations)

McCoy 2008- Not computerized drug dosage (alerts)

McCoy 2010- Not computerized drug dosage (alerts)

McDonald 1976- Not computerized drug dosage (reminders)

McDonald 1980- Not computerized drug dosage (dose prescribing rather than drug dosage)

McMichael 1993- Absence of relevant data for primary outcome (n o professional behaviour change or participa nt outcomes)

McMullin 1997- Design (n ot a comparative study)

McMullin 2004- Not computerized drug dosage (list of prescriptions most appreciate)

McMullin 2005- Not computerized drug dosage (list of prescriptions most appreciate)

Motykie 1999- Design (historical control group)

Mullett 2001- Design (before and after study without control group)

Murchie 1989- Absence of relevant data for primary outcome

Nash 2005- Not computerized drug dosage (thresholds)

Newby 2002- Not computerized drug dosage (automated adjustment)

Nieuwenhuyze 1995- Participa nt aid not under physician control

Nightingale 2000- Not computerized drug dosage (dose prescribing rather than drug dosage)

Oppenheim 2002- Design ( not a comparative study)

Overhage 1997- The dose advice was not individualized (' response orders' )

Palen 2006- Not computerized drug dosage (alert for prescribing laboratory monitoring test)

Pea 2002- Absence of relevant data for primary outcome

Peck 1973- Absence of relevant data for primary outcome

Peters 1996- Participa nt aid not under physician control

Peterson 1986- Participa nt aid not under physician control

Peterson 2005- Not computerized drug dosage (screen showing the most commo nly used dose)

Peterson 2007- Not computerized drug dosage (screen showing a default dose and minimum/maximum dose)

Phillips 2008- Design (n ot a comparative study)

Piazza 2009- Not computerized drug dosage (alerts)

Poller 1993- Absence of relevant data for primary outcome

Popovic-Todorovic 2003- Not computerized drug dosage (rules without calculation)

Proost 2003- Discussion (p resentation of the project PharmDIS-e+)

Roberts 2010- Design (before and after study without control group)

Rochon 2006- Discussion

Rood 2005- Absence of relevant data for primary outcome

Rothschild 2002- Absence of relevant data for primary outcome (survey)

Rothschild 2003- Not computerized drug dosage (feedback)

Rothschild 2005- Not computerized drug dosage (smart infusion pumps providing decision support feedback)

Rotman 1996- Not computerized drug dosage

Roumie 2005- Not computerized drug dosage (alert with guidelines or goal blood pressure)

Ruiz 1993- Not computerized drug dosage (closed-loop system)

Ryff-de Leche 1992- Not computerized drug dosage (infusion not under physician control)

Santana 2003- Not computerized drug dosage (treatment plan in 2 cohorts)

Santana 2005- Design (n ot a comparative study)

Schneider 2005- Not computerized drug dosage (organizational computer program)

Schrezenmeir 2002- Participa nt aid not under physician control (advice delivered directly to the participa nt)

Shiach 2002- Not computerized drug dosage (comparison of 2 systems of prothrombin time measurement)

Shieh 2006- Not computerized drug dosage (comparison of 2 protocols for drug controller)

Soper 2006- Design (historical control group)

Sparano 2006- Not computerized drug dosage (trial comparing 2 therapies)

Strack 1985- Design

Tamblyn 2003- Not computer drug dosage

Tamblyn 2008- Not computerized drug dosage (adherence calculation)

Tamblyn 2010- Not computerized drug dosage (adherence calculation)

Terrell 2009- Not computerized drug dosage (recommendation on substitute therapies)

Thomson 2011- Design (before and after study without control group)

Tierney 2005- Not computerized drug dosage (reminders)

Tomek 2011- Conference publication (the author was contacted by January 201 2 but the message could not be delivered because the recipient ad d ress was rejected ) )

Traugott 2011- Design (before and after study without control group)

Trivedi 2007- Design (discussion)

Trivedi 2007a- Not computerized drug dosage (decision support tool without calculation)

van der Bol 2010- Not computerized drug dosage (dose calculated from an equation)

van Leeuwen 2005- Abstract corresponding to the study published in 2007 (excluded study: van Leeuwen 2007)

van Leeuwen 2007- Design (n o control group: comparison of 2 computer algorithms)

van Lent-Evers 1999- Design (historical control group)

Van Wyk 2008- Not computerized drug dosage (screening and treatment of dyslipidaemia)

Verstappen 2007- Not computerized drug dosage (CAMERA study: comparison of 2 strategies of management in early rheumatoid arthritis)

Verstappen 2010- Not computerized drug dosage (CAMERA study: comparison of 2 strategies of management in early rheumatoid arthritis)

Wasmuth 2007- Design (cohort study)

Wasmuth 2007a- Not computerized drug dosage (trial comparing 2 doses of treatment)

Whipple 1991- Not computerized drug dosage (the clinical pharmacist calculated the dose and interval of aminoglycoside concentration)

White 1984- Absence of relevant data for primary outcome

Willcourt 1994- Participa nt aid not under physician control

Wilson 2002- Design (cohort study)

Yamamoto 2005- Not computerized drug dosage (dose calculated from an equation)

 
Characteristics of studies awaiting assessment [ordered by study ID]
Anderson 2011

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Anderson 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Caduff 2013

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Dumont 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Horibe 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Jeanne 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Joerger 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Kelly 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Kim 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Magee 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Nieuwlaat 2011

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Nieuwlaat 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Overgaard 2010

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Pielmeier 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Radhakrishnan 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Rasmussen 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Spaniel 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Tamblyn 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Whitehead 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

Wiltshire 2012

Methods

Participants

Interventions

Outcomes

NotesNot yet assessed

 
Comparison 1. Serum concentrations and therapeutic range

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Serum concentrations (mg/L) - part A (SMD > 0 in favour of the intervention)9Std. Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 Aminoglycoside antibiotics: peak concentration
4372Std. Mean Difference (IV, Random, 95% CI)0.79 [0.46, 1.13]

    1.2 Theophylline
4201Std. Mean Difference (IV, Random, 95% CI)0.41 [-0.20, 1.02]

    1.3 Lidocaine
120Std. Mean Difference (IV, Random, 95% CI)1.32 [0.33, 2.32]

 2 Serum concentrations (ng/L) - part B (SMD < 0 in favour of the intervention)3Std. Mean Difference (IV, Random, 95% CI)Subtotals only

    2.1 Midazolam
124Std. Mean Difference (IV, Random, 95% CI)-1.43 [-2.34, -0.51]

    2.2 Fentanyl
124Std. Mean Difference (IV, Random, 95% CI)0.27 [-0.53, 1.08]

    2.3 Antidepressants: steady-state plasma concentration
160Std. Mean Difference (IV, Random, 95% CI)-0.68 [-1.20, -0.16]

 3 Proportion of participants within therapeutic range3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Aminoglycoside antibiotics: % of participants with peak concentrations adequate after 2 days
272Risk Ratio (M-H, Random, 95% CI)4.44 [1.94, 10.13]

    3.2 Anti-rejection drugs
1125Risk Ratio (M-H, Random, 95% CI)0.71 [0.38, 1.32]

 4 Proportion of participants with toxic drug levels2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Theophylline
2109Risk Ratio (M-H, Random, 95% CI)0.53 [0.25, 1.13]

 
Comparison 2. Physiological parameters

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Oral anticoagulants: % time in target INR range613581Mean Difference (IV, Random, 95% CI)3.68 [0.90, 6.45]

 2 Insulin: % time in target glucose range4234Mean Difference (IV, Random, 95% CI)22.18 [9.94, 34.43]

 3 Insulin: mean blood glucose (mg/dL)9520Std. Mean Difference (IV, Random, 95% CI)-0.72 [-1.03, -0.42]

 
Comparison 3. Time to achieve therapeutic control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Time to achieve therapeutic range5Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 Oral anticoagulants: time to achieve therapeutic prothrombin ratio (days)
2223Mean Difference (IV, Random, 95% CI)-0.58 [-1.84, 0.69]

    1.2 Insulin: time to achieve therapeutic control (h)
3134Mean Difference (IV, Random, 95% CI)0.53 [-1.22, 2.27]

 2 Time to stabilization3Std. Mean Difference (IV, Random, 95% CI)Subtotals only

    2.1 Oral anticoagulants: time to stabilization (days)
3255Std. Mean Difference (IV, Random, 95% CI)-0.56 [-1.07, -0.04]

 
Comparison 4. Clinical improvement

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Aminoglycoside antibiotics2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Number of participants cured
2271Risk Ratio (M-H, Random, 95% CI)1.12 [1.02, 1.22]

 2 Anti-rejection drugs2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 No biopsy-confirmed rejections
2170Risk Ratio (M-H, Fixed, 95% CI)1.15 [1.00, 1.32]

 
Comparison 5. Clinical adverse events

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death1014046Risk Ratio (M-H, Random, 95% CI)1.08 [0.80, 1.45]

    1.1 Oral anticoagulants
513499Risk Ratio (M-H, Random, 95% CI)1.09 [0.78, 1.51]

    1.2 Aminoglycoside antibiotics
3326Risk Ratio (M-H, Random, 95% CI)0.66 [0.14, 3.10]

    1.3 Theophylline
191Risk Ratio (M-H, Random, 95% CI)0.18 [0.01, 3.64]

    1.4 Cyclosporine
1130Risk Ratio (M-H, Random, 95% CI)1.0 [0.06, 15.65]

 2 Anticoagulants: events7Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Bleeding
6552Risk Ratio (M-H, Random, 95% CI)0.65 [0.30, 1.41]

    2.2 Thromboembolism
4355Risk Ratio (M-H, Random, 95% CI)3.25 [0.66, 16.03]

 3 Anticoagulants: event rates4Rate Ratio (Random, 95% CI)Subtotals only

    3.1 Bleeding
418902Rate Ratio (Random, 95% CI)0.81 [0.60, 1.08]

    3.2 Thromboembolism
418902Rate Ratio (Random, 95% CI)0.68 [0.49, 0.94]

 4 Insulin9Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Hypoglycaemia (< 60 mg/dL)
7378Risk Ratio (M-H, Random, 95% CI)0.71 [0.35, 1.48]

    4.2 Severe hypoglycaemia (< 40 mg/dL)
4292Risk Ratio (M-H, Random, 95% CI)0.69 [0.11, 4.31]

 5 Aminoglycoside antibiotics4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Nephrotoxicity
4493Risk Ratio (M-H, Random, 95% CI)0.67 [0.42, 1.06]

 6 Anti-rejection drugs2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 Cytomegalovirus infections
2170Risk Ratio (M-H, Random, 95% CI)0.90 [0.58, 1.40]

 
Comparison 6. Healthcare resources

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Length of stay (days)918507Std. Mean Difference (IV, Random, 95% CI)-0.15 [-0.33, 0.02]

    1.1 Oral anticoagulants
2105Std. Mean Difference (IV, Random, 95% CI)-0.12 [-1.10, 0.86]

    1.2 Insulin
1128Std. Mean Difference (IV, Random, 95% CI)0.18 [-0.17, 0.53]

    1.3 Theophylline
3151Std. Mean Difference (IV, Random, 95% CI)-0.20 [-0.56, 0.16]

    1.4 Aminoglycoside antibiotics
2295Std. Mean Difference (IV, Random, 95% CI)-0.35 [-0.58, -0.12]

    1.5 Anti-rejection drugs
117828Std. Mean Difference (IV, Random, 95% CI)-0.04 [-0.07, -0.01]

 
Summary of findings for the main comparison. Computerized advice on drug dosage for leading serum concentrations within therapeutic range

Computerized advice on drug dosage for leading serum concentrations within therapeutic range

Patient or population: patients with leading serum concentrations within therapeutic range
Settings: outpatient/inpatient
Intervention: computerized advice on drug dosage

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlComputerized advice on drug dosage

Serum concentrations - aminoglycoside antibiotics: peak concentration
Follow-up: 2 days
-The mean serum concentrations - aminoglycoside antibiotics: peak concentration in the intervention groups was
0.79 standard deviations higher
(0.46 to 1.13 higher)
-372
(4 studies)
⊕⊕⊝⊝
low1,2,3
SMD 0.79 (95% CI 0.46 to 1.13)

Serum concentrations - theophylline-The mean serum concentrations - theophylline in the intervention groups was
0.41 standard deviations higher
(0.2 lower to 1.02 higher)
-201
(4 studies)
⊕⊕⊝⊝
low3,4,5
SMD 0.41 (95% CI -0.2 to 1.02)

Proportion of participants within therapeutic range - aminoglycoside antibiotics: % of participants with peak concentrations adequate after 2 days
Follow-up: 2 days
Study populationRR 4.44
(1.94 to 10.13)
72
(2 studies)
⊕⊕⊕⊝
moderate3,6
-

135 per 1000600 per 1000
(262 to 1000)

Moderate

151 per 1000670 per 1000
(293 to 1000)

Proportion of participants with toxic drug levels - theophyllineStudy populationRR 0.53
(0.25 to 1.13)
109
(2 studies)
⊕⊕⊕⊝
moderate3,7
-

273 per 1000145 per 1000
(68 to 308)

Moderate

217 per 1000115 per 1000
(54 to 245)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; SMD: standardized mean difference.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Lack of blinding of participants and personnel in all studies. Incomplete outcome data in three studies. Random sequence generation and allocation concealment unclear in one study.
2 I2 = 51%.
3 No funnel plot was performed since the validity conditions were not met.
4 No blinding of participants and personnel in the two studies. Random sequence generation and allocation concealment unclear in one study.
5 I2 = 76%
6 Lack of blinding of participants and personnel, incomplete outcome data in all studies. Participants were not similar at baseline in one study.
7 No blinding of participants and personnel in the two studies. Random sequence generation and allocation concealment unclear in one study.
 
Summary of findings 2. Computerized advice on drug dosage for leading physiological parameters within therapeutic range

Computerized advice on drug dosage for leading physiological parameters within therapeutic range

Patient or population: patients with leading physiological parameters within therapeutic range
Settings: outpatient/inpatient
Intervention: computerized advice on drug dosage

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlComputerized advice on drug dosage

Oral anticoagulants: time in target INR range (%)-The mean oral anticoagulants: time in target INR range (%) in the intervention groups was
0.19 standard deviations higher
(0.06 to 0.33 higher)
-13,581
(6 studies)
⊕⊝⊝⊝
very low1,2,3
SMD 0.19 (95% CI 0.06 to 0.33)

Insulin: time in target glucose range (%)-The mean insulin: time in target glucose range (%) in the intervention groups was
1.27 standard deviations higher
(0.56 to 1.98 higher)
-234
(4 studies)
⊕⊕⊝⊝
low3,4,5
SMD 1.27 (95% CI 0.56 to 1.98)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; INR: international normalized ratio; SMD: standardized mean difference.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 No information given on random sequence generation and allocation concealment in half of the studies.
2 I2 = 79%.
3 No funnel plot was performed since the validity conditions were not met.
4 No blinding of participants and personnel in all studies.
5 I2 = 83%.
 
Summary of findings 3. Computerized advice on drug dosage for reducing time to achieve therapeutic control

Computerized advice on drug dosage for reducing time to achieve therapeutic control

Patient or population: patients with reducing time to achieve therapeutic control
Settings: outpatient/inpatient
Intervention: computerized advice on drug dosage

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlComputerized advice on drug dosage

Time to achieve therapeutic range - oral anticoagulants: time to achieve therapeutic prothrombin ratio (days)-The mean time to achieve therapeutic range - oral anticoagulants: time to achieve therapeutic prothrombin ratio (days) in the intervention groups was
0.22 standard deviations lower
(0.69 lower to 0.26 higher)
-223
(2 studies)
⊕⊕⊝⊝
low1,2,3
SMD -0.22 (95% CI -0.69 to 0.26)

Time to achieve therapeutic range - insulin: time to achieve therapeutic control (hours)-The mean time to achieve therapeutic range - insulin: time to achieve therapeutic control (hours) in the intervention groups was
0.14 standard deviations lower
(0.98 lower to 0.7 higher)
-194
(4 studies)
⊕⊝⊝⊝
very low3,4,5
SMD -0.14 (95% CI -0.98 to 0.7)

Time to stabilization - oral anticoagulants: time to stabilization (days)-The mean time to stabilization - oral anticoagulants: time to stabilization (days) in the intervention groups was
0.56 standard deviations lower
(1.07 to 0.04 lower)
-255
(3 studies)
⊕⊝⊝⊝
very low3,6,7
SMD -0.56 (95% CI -1.07 to -0.04)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; SMD: standardized mean difference.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Allocation concealment was unclear, and there was no blinding of participants and personnel in both studies.
2 I2 = 66%.
3 No funnel plot performed but very small studies in favour of the intervention.
4 In all studies: the random sequence generation and the allocation concealment were unclear, and there was no blinding of participants and personnel.
5 I2 = 86%. Meta-analysis should be interpreted with caution.
6 Sequence generation and/or allocation concealment were unclear in all studies. There was no blinding of participants and personnel in all studies. Data were incomplete in two studies.
7 I2 = 71%.
 
Summary of findings 4. Computerized advice on drug dosage for leading to fewer clinical adverse events

Computerized advice on drug dosage for leading to fewer clinical adverse events

Patient or population: patients with leading to fewer clinical adverse events
Settings: outpatient/inpatient
Intervention: computerized advice on drug dosage

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlComputerized advice on drug dosage

DeathStudy populationRR 1.08
(0.8 to 1.45)
14,046
(10 studies)
⊕⊕⊝⊝
low1,2
-

12 per 100013 per 1000
(10 to 18)

Moderate

28 per 100030 per 1000
(22 to 41)

Anticoagulants: events - bleedingStudy populationRR 0.65
(0.3 to 1.41)
552
(6 studies)
⊕⊕⊝⊝
low2,3
-

61 per 100040 per 1000
(18 to 86)

Moderate

65 per 100042 per 1000
(20 to 92)

Anticoagulants: events - thromboembolismStudy populationRR 3.25
(0.66 to 16.03)
355
(4 studies)
⊕⊝⊝⊝
very low2,4,5
-

11 per 100036 per 1000
(7 to 176)

Moderate

7 per 100023 per 1000
(5 to 112)

Insulin - hypoglycaemia (< 60 mg/dL)Study populationRR 0.71
(0.35 to 1.48)
378
(7 studies)
⊕⊕⊝⊝
low2,6
-

90 per 100064 per 1000
(31 to 133)

Moderate

67 per 100048 per 1000
(23 to 99)

Insulin - severe hypoglycaemia (< 40 mg/dL)Study populationRR 0.69
(0.11 to 4.31)
292
(4 studies)
⊕⊝⊝⊝
very low2,7,8
-

14 per 10009 per 1000
(2 to 59)

Moderate

8 per 10006 per 1000
(1 to 34)

Aminoglycoside antibiotics - nephrotoxicityStudy populationRR 0.67
(0.42 to 1.06)
493
(4 studies)
⊕⊕⊝⊝
low2,9
-

162 per 1000108 per 1000
(68 to 172)

Moderate

154 per 1000103 per 1000
(65 to 163)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 No (or unclear) blinding of participants and personnel in all studies. In half of the studies: sequence generation and/or allocation concealment were unclear, and the data were incomplete.
2 No funnel plot was performed since the validity criteria were not met.
3 In all studies: sequence generation or allocation concealment, or both were unclear, and there was no blinding of participants or personnel. Data were incomplete or unclear in four studies.
4 Allocation concealment was unclear in all studies. There was no blinding of participants and personnel in all studies and the blinding of outcome assessment was unclear in one study. Data were incomplete or unclear in all studies.
5 Large confidence intervaI due to very small studies (n = 335 for four studies) and a few events (n = 8).
6 No (or unclear) sequence generation or allocation concealment, or both in all studies. No (or unclear) blinding of participants or personnel in all studies. Selective reporting in one study.
7 Random sequence generation and allocation concealment were unclear in half of the studies. No (or unclear) blinding of participants or personnel in all studies.
8 Large confidence interval due to only three events for 292 participants.
9 No blinding of participants and personnel in all studies. Incomplete outcome data in three studies. Baseline characteristics not comparable in one study.
 
Summary of findings 5. Saving healthcare resources for saving healthcare resources

Saving healthcare resources for saving healthcare resources

Patient or population: saving healthcare resources
Settings:
Intervention: saving healthcare resources

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlSaving healthcare resources

Length of stay (days)-The mean length of stay (days) in the intervention groups was
0.15 standard deviations lower
(0.33 lower to 0.02 higher)
-18,507
(9 studies)
⊕⊝⊝⊝
very low1,2
SMD -0.15 (95% CI -0.33 to 0.02)

Length of stay (days) - oral anticoagulants-The mean length of stay (days) - oral anticoagulants in the intervention groups was
0.12 standard deviations lower
(1.1 lower to 0.86 higher)
-105
(2 studies)
⊕⊝⊝⊝
very low2,3,4,5
SMD -0.12 (95% CI -1.1 to 0.86)

Length of stay (days) - insulin-The mean length of stay (days) - insulin in the intervention groups was
0.18 standard deviations higher
(0.17 lower to 0.53 higher)
-128
(1 study)
⊕⊕⊕⊕
high6
SMD 0.18 (95% CI -0.17 to 0.53)

Length of stay (days) - theophylline-The mean length of stay (days) - theophylline in the intervention groups was
0.2 standard deviations lower
(0.56 lower to 0.16 higher)
-151
(3 studies)
⊕⊕⊝⊝
low2,7,8
SMD -0.2 (95% CI -0.56 to 0.16)

Length of stay (days) - aminoglycoside antibiotics-The mean length of stay (days) - aminoglycoside antibiotics in the intervention groups was
0.35 standard deviations lower
(0.58 to 0.12 lower)
-295
(2 studies)
⊕⊕⊕⊝
moderate2,9
SMD -0.35 (95% CI -0.58 to -0.12)

Length of stay (days) - anti-rejection drugs-The mean length of stay (days) - anti-rejection drugs in the intervention groups was
0.04 standard deviations lower
(0.07 to 0.01 lower)
-17,828
(1 study)
⊕⊕⊕⊝
moderate2,10
SMD -0.04 (95% CI -0.07 to -0.01)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; SMD: standardized mean difference.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 I2 = 57%.
2 No funnel plot was performed since the validity criteria were not met.
3 No blinding of participants and personnel in all studies, and blinding of outcome assessment unclear in half of the studies. Random sequence generation or allocation concealment, or both unclear in all studies.
4 I2 = 81%. Meta-analysis should be interpreted with caution.
5 Although small studies (n = 105 for all the studies).
6 To be interpreted with caution since based on only one monocentric study of 128 participants.
7 No blinding of participants and personnel in the three studies. No or unclear random sequence generation and allocation concealment in two studies.
8 Although small studies (n = 151 for all studies).
9 No blinding of participants and personnel in all studies.
10 Alternating time series design with four consecutive two-month period.