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Low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease

  1. Esther J van Zuuren1,*,
  2. Zbys Fedorowicz2

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 12 JUN 2013

Assessed as up-to-date: 5 JUN 2013

DOI: 10.1002/14651858.CD010155.pub2


How to Cite

van Zuuren EJ, Fedorowicz Z. Low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD010155. DOI: 10.1002/14651858.CD010155.pub2.

Author Information

  1. 1

    Leiden University Medical Center, Department of Dermatology, Leiden, Netherlands

  2. 2

    The Cochrane Collaboration, UKCC (Bahrain Branch), Awali, Bahrain

*Esther J van Zuuren, Department of Dermatology, Leiden University Medical Center, PO Box 9600, B1-Q, Leiden, 2300 RC, Netherlands. E.J.van_Zuuren@lumc.nl.

Publication History

  1. Publication Status: New
  2. Published Online: 12 JUN 2013

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This is not the most recent version of the article. View current version (18 DEC 2015)

 
Characteristics of included studies [ordered by study ID]
Qari 2007

Methods
  • Randomised, double-blind, placebo-controlled trial.


Setting

  • King Abdulaziz University Hospital, King Fahd General Hospital and King Abdulaziz Oncology Center; Jeddah, Saudi Arabia.


Date of study

  • Not reported. Duration of intervention: 7 days.


Participants
  • N = 253 (121 male/132 female).
  • Mean age = 22.8 ± 4.5 years for tinzaparin group, 21.6 ± 3.8 years for control group.


Inclusion criteria of the trial

  • Participants > 12 years with SCA with homozygous sickle cell (SS) disease.
  • Admitted through the emergency room with painful vaso-occlusive crisis severe enough to require narcotic analgesia.


Exclusion criteria of the trial

  • Presence of medical or surgical contraindication to LMWH.
  • Pregnancy.
  • Low platelet counts (< 100,000/dl) or impaired haemostasis on admission in the form of INR > 1.4 or prolonged APTT > 5 seconds of the hospital normal range.
  • Complicated SCA.
  • History of CVA.
  • Current aplasia.
  • Acute chest syndrome.
  • Exchange transfusion.
  • Sequestration.
  • Anticoagulant therapy for other etiology.
  • Painful crises within the month before this admission.
  • Women on hormonal contraception.
  • History of painful crisis within the preceding month.
  • Other vascular complications of SCA (e.g. prior stroke, current aplasia, acute chest pain).


Randomised

  • N = 253.


Withdrawals/losses to follow-up

  • No reported losses.


Baseline data

  • Not reported.


InterventionsIntervention

  • Tinzaparin once daily 175 IU/kg s.c. for 7 days (127).


Comparator

  • Placebo once daily s.c. for 7 days (126).


Standard analgesia therapy: morphine 1 mg/h intravenous infusion and rehydration with normal saline.


OutcomesOutcomes of the trial  (as reported)

  • Clinical improvement and pain reported by the patient as zero degree on the NMS✴.
  • Therapy discontinuation after seven days regardless of the outcome,
  • Appearance of any complications including bleeding, heparin-induced thrombocytopenia or other complications✴.
  • Total period of hospitalisation in days✴.
  • Number of days on which the patient experienced the highest intensity on the NMS (Jaywant 2003)✴,
  • Duration of painful crisis in days✴.
  • Adverse events✴,


✴Denotes outcomes pre-specified for this review.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote (page 393): "..Patients were randomized consecutively into either the study group.."

Comment: Insufficient detail was reported about the method used to generate the allocation sequence to allow a clear assessment of whether it would produce comparable groups.

Allocation concealment (selection bias)Unclear riskThe method used to conceal the allocation sequence, that is, to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment was not reported.
Comment: Information was insufficient to permit a clear judgement.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote (page 393): "..double-blind.." and "All drug supplies were appropriately packaged, labeled, and kept in a locked, safe area under appropriate storage conditions with access limited to persons authorized by the investigator and those who [were] directly involved in the study."

Comment: The report did not provide sufficient detail about the specific measures used to blind study participants and personnel from knowledge of which intervention a participant received, to permit a clear judgement.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote (page 393): "..double-blind.."

Comment: The report did not provide sufficient detail about the specific measures used to blind study participants and personnel. It was unclear, therefore, whether the outcome measurement was likely to be influenced by the lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses reported.

Comment: We judged this as at low risk of bias.

Selective reporting (reporting bias)Low riskThe protocol for the study was not available, but the pre-specified outcomes and those mentioned in the methods section appear to have been reported.

Comment: We judged this as at a low risk of bias.

Other biasHigh riskOne of the investigators is employed by Leo Pharmaceutical Products, Athens, Greece, the manufacturer of tinzaparin.

The NMS scale for assessing pain severity is not a validated tool for pain assessment.

Comment: A potential risk of bias cannot be excluded.

 
Characteristics of ongoing studies [ordered by study ID]
NCT01419977

Trial name or titleTreatment of Sickle Cell Patients Hospitalized in Pain Crisis With Prophylactic Dose Low-molecular-weight Heparin (LMWH) Versus Placebo

Methods
  • Randomised, double-blind, placebo-controlled trial.


Setting:

  • Duke University, Durham, North Carolina, US.


Date of study:

  • Started May 2011, currently recruiting. Duration of intervention 7 days with follow-up at 2 weeks.

Participants
  • N = 100.


Inclusion criteria of the trial

  • Documented HgbSS or HgbS-β0-thalassaemia by previous haemoglobin electrophoresis.
  • Age greater than 18 years.
  • Admit diagnosis of vaso-occlusive crisis.


Exclusion criteria of the trial

  • End-stage renal disease (creatinine > 3.0 mg/dl).
  • Use of antiplatelet or anticoagulation medication for an alternative indication.
  • Use of steroids or immunosuppressive medications.
  • Platelet count less than 100 × 109/L.
  • History or development of heparin-induced thrombocytopenia.
  • Packed red blood cell transfusion in the past month.
  • Recent hospitalisation with discharge within the past 1 week.

InterventionsIntervention

  • Dalteparin 5000 units s.c.


Comparator

  • Placebo s.c.

OutcomesOutcomes of the trial  (as reported):

  • Reduction in hypercoagulable markers.
  • Reduction in clinical pain scores✴.


✴Denotes outcomes pre-specified for this review.

Starting dateMay 2011.

Contact informationNirmish Shah nirmish.shah@duke.edu

Notes

 
Comparison 1. Tinzaparin versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of the pain1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 2 Number of hospitalisations days1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 3 Number of adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Summary of findings for the main comparison. Tinzaparin compared to placebo for people with sickle cell disease

Tinzaparin compared to placebo for people with sickle cell disease

Patient or population: people with sickle cell disease
Settings: hospitals
Intervention: tinzaparin
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboTinzaparin

pain intensity
Numerical pain scale
Follow-up: mean 7 days
See comment1See comment1253
(1 study)
⊕⊕⊝⊝
low2

pain duration
Scale from 1 to 7
Follow-up: mean 7 days
The mean pain duration in the control groups was
4.35 days
The mean pain duration in the intervention groups was
1.78 lower
(1.94 to 1.62 lower)
253
(1 study)
⊕⊕⊕⊝
moderate2

the requirement for opiate treatment
Follow-up: mean 7 days
See comment3See comment3253
(1 study)
⊕⊕⊝⊝
low2

number of serious complications of SCD4 - not reportedSee comment4See comment4Not estimable4-See comment4

number of other sickle-related events4 - not reportedSee comment4See comment4Not estimable4-See comment4

quality of life (e.g. absence from school, lost time at work, mobility) as assessed by any validated questionnaire, either generic or SCD specific4 - not reportedSee comment4See comment4Not estimable4-See comment4

hospitalisation (number and duration)
Scale from 0 to 12.
Follow-up: mean 7 days
The mean hospitalisation (number and duration) in the control groups was
12.06 days
The mean hospitalisation (number and duration) in the intervention groups was
4.98 lower
(5.48 to 4.48 lower)
253
(1 study)
⊕⊕⊝⊝
low2

participant satisfaction with the medication assessed by any appropriate and validated questionnaire (either generic or SCD specific)4 - not reportedSee comment4See comment4Not estimable4-See comment4

adverse events associated with the use of anticoagulants (e.g. bleeding)
Follow-up: mean 7 days
RR 4.96
(0.24 to 102.31)
253
(1 study)
⊕⊕⊕⊕
high

*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 (CI)) 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 precise data were reported. The authors indicated that at day 2 and at day 3, the pain severity score was lower in the tinzaparin group than in the placebo group (P < 0.01 (ANOVA)), in addition to day 4 (P < 0.05 (ANOVA)).
2 Sequence generation is unclear, as are allocation concealment and measurements to blind investigators and participants. A potential conflict of interest cannot be excluded, as one of the investigators is an employee of the manufacturer of tinzaparin. The NMS scale is not a validated tool for pain assessment.
3 All participants received standard analgesia therapy consisting of morphine 1 mg/h intravenous infusion and rehydration with normal saline.
4 This outcome measure was not assessed.
 
Table 1. Glossary of Terms

TermDefinition

AnticoagulantA substance that prevents coagulation (clotting) of blood.

GenotypeThe genotype of an individual is the set of inherited instructions carried within its genetic code. Not all organisms with the same genotype look or act the same way because appearance and behaviour are modified by environmental and developmental conditions.

HaemoglobinThe iron-containing oxygen-transport metalloprotein in the red blood cells. Haemoglobin in the blood carries oxygen from the respiratory organs (lungs) to the rest of the body.

HeterozygousA cell is said to be heterozygous when it contains two different alleles of a gene.

HomozygosityA cell is said to be homozygous for a particular gene when identical alleles of the gene are present on both homologous chromosomes. The individual is called a homozygote.

LyseTo destroy or dissolve cells.

NecrosisThe premature death of cells in living tissue.

PhenotypeThe composite of an individual's observable characteristics or traits, such as its morphology, development, biochemical or physiological properties and behaviour.

P-selectinA cell adhesion molecule (CAM) on the surfaces of activated endothelial cells (thin layer of cells that lines the interior surface of blood vessels), which line the inner surface of blood vessels, and activated platelets (thin layer of cells that lines the interior surface of blood vessels).

PolarizeAggregate.

Tumour necrosis factor-αA cytokine; cell-signalling (transmitting information between cells) protein involved in systemic inflammation; a member of a group of cytokines that stimulate the acute phase reaction.

 
Table 2. Classes of anticoagulants

Coumarins (Vitamin K antagonists)
  1. Warfarin.
  2. Acenocoumarol and phenprocoumon.
  3. Atromentin.
  4. Phenindione.

Heparins and derivative substances
  1. Unfractionated heparin.
  2. Fractionated heparin or LMWHs such as dalteparin, enoxaparin, tinzaparin, nadroparin, bemiparin, certoparin, parnaparin and reviparin.

Factor Xa inhibitors
  1. Synthetic pentasaccharide inhibitors of factor Xa such as fondaparinux and idraparinux.
  2. Direct factor Xa inhibitors such as rivaroxaban and apixaban.

Direct thrombin inhibitorsLepirudin, hirudin, bivalirudin, desirudin, argatroban, dabigatran

 LMWH: low-molecular-weight heparin
 
Table 3. Contact with investigators

Study IDResponseAdditionalComment

Qari 2007e-mail sent 6-1-2013

mousas@acp.edu, shaker.mosua@acphs.edu

follow-up e-mail sent 15-1-2013
mousas@acp.edu; shaker.mosua@acphs.edu; drqari@hotmail.com

Both Mousa mail-addressed seem to be incorrect. Could not find more recent ones.

 
Table 4. Research recommendations based on a gap in the evidence of the effects of low-molecular-weight heparins for managing vaso-occlusive crises in people with sickle cell disease

Core elementsIssues to considerStatus of research for this review

Evidence (E)What is the current state of the evidence?This systematic review identified one RCT, which provided insufficient high-level evidence of the efficacy and safety of LMWH for managing vaso-occlusive crises in people with SCD.

Population (P)Diagnosis, disease stage, co-morbidity, risk factors, gender, age, ethnic group, specific inclusion or exclusion criteria, clinical settingInclusion criteria

  • Participants with sickle cell disease (all different genotypes).
  • Painful vaso-occlusive crisis severe enough to require narcotic analgesia.


Exclusion criteria

  • Contraindication to LMWH.
  • Pregnancy.
  • Low platelet counts (< 100,000/dl) or impaired haemostasis on admission in the form of INR > 1.4 or prolonged APTT > 5 seconds of the hospital normal range.
  • History of CVA.
  • Current aplasia.
  • Acute chest syndrome.
  • Exchange transfusion.
  • Sequestration.
  • Anticoagulant therapy for other etiology.
  • Patients with painful crises within the month before this admission.
  • Women on hormonal contraception.
  • History of painful crisis within the preceding month.
  • Other vascular complications of sickle cell disease (such as prior stroke, current aplasia, acute chest pain).

Intervention (I)Type, frequency, dose, duration, prognostic factorThe study duration should be 1-2 weeks to assess a low-molecular-weight heparin. Concomitant pain medications allowed for ethical reasons but should be similarly available in both treatment arms.

Comparison (C)Type, frequency, dose, duration, prognostic factorNo treatment or placebo treatment. Concomitant pain medications allowed for ethical reasons but should be similarly available in both treatment arms.

Outcome (O)Which clinical or patient-related outcomes will the researcher need to measure, improve, influence, or accomplish? Which methods of

measurement should be used?
  • Pain: duration and intensity (assessed with a validated patient-reported outcomes instrument either generic or SCD specific).


  • Requirement for opiate treatment (dose, type and frequency).
  • Number of serious complications of SCD (e.g. stroke, acute chest syndrome, infection, acute splenic sequestration).
  • Number of other sickle-related events (e.g. priapism, leg ulceration).
  • Quality of life (e.g. absence from school, lost time at work, mobility) as assessed by any validated questionnaire, either generic or SCD specific.
  • Hospitalisation (number and duration).
  • Participant satisfaction with the medication assessed by any appropriate and validated questionnaire (either generic or SCD specific).
  • Adverse events associated with the use of anticoagulants (e.g. bleeding).

Time Stamp (T)Date of literature search or recommendation1 January 2013.

Study TypeWhat is the most appropriate study design to address the proposed question?
  • Randomised controlled trial (adequately powered/multi-centred).
  • Method: concealment of allocation sequence.
  • Blinding: blinding of participants, trialists and outcome assessors.
  • Setting: hospital/university.

 APTT: activated partial thromboplastin time
CVA: cerebral vascular accident
INR: international normalized ratio
LMWH: low-molecular-weight heparins
RCT: randomised controlled trial
SCD: sickle cell disease