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Blood pressure targets for hypertension in people with diabetes mellitus

  1. Jose Agustin Arguedas1,*,
  2. Viriam Leiva2,
  3. James M Wright3

Editorial Group: Cochrane Hypertension Group

Published Online: 30 OCT 2013

Assessed as up-to-date: 28 OCT 2013

DOI: 10.1002/14651858.CD008277.pub2


How to Cite

Arguedas JA, Leiva V, Wright JM. Blood pressure targets for hypertension in people with diabetes mellitus. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD008277. DOI: 10.1002/14651858.CD008277.pub2.

Author Information

  1. 1

    Universidad de Costa Rica, Depto de Farmacologia Clinica, Facultad de Medicina, San Pedro de Montes de Oca, Costa Rica

  2. 2

    University of Costa Rica, Escuela de Enfermeria, Facultad de Medicina, San Jose, Costa Rica

  3. 3

    University of British Columbia, Department of Anesthesiology, Pharmacology and Therapeutics, Vancouver, BC, Canada

*Jose Agustin Arguedas, Depto de Farmacologia Clinica, Facultad de Medicina, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica. drarguedas@ampmd.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 30 OCT 2013

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Characteristics of included studies [ordered by study ID]
ABCD-2V 2006

MethodsSingle-center, open-label, randomized trial. An independent Endpoint Committee, which was blinded to the study intervention arms, reviewed all cardiovascular events.

The mean follow-up period was 1.9 years.


Participants129 type-2 diabetic participants, 40 to 81 years of age, with a systolic BP < 140 mmHg, a diastolic BP between 80 and 90 mmHg, and without evidence of overt albuminuria (< 200µg/min). Exclusion criteria included pregnant or lactating women, need for any antihypertensive medications, documented myocardial infarction or cerebrovascular accident within the past 6 months, severe peripheral vascular disease, history of bilateral renal artery stenosis or stenosis in a solitary kidney, evidence of severe liver disease, hyperkalemia, or history of active cancer.


InterventionsParticipants were randomized to either intensive BP control aiming for a diastolic BP goal of 75 mmHg or to moderate BP control aiming to maintain DBP between 80 and 90 mmHg. Participants randomized to intensive BP control were started on valsartan 80 mg per day with a target diastolic BP of 75 mmHg. Antihypertensive medications were increased in a step-wise manner in order to achieve the BP target: valsartan 80 mg, then valsartan 160 mg/day, hydrochlorothiazide 12.5 - 25 mg per day, metoprolol 50 - 100 mg twice a day, additional medications at the discretion of the medical director.

Participants randomized to moderate BP control were placed on placebo to maintain their diastolic BP between 80 and 90 mmHg. During the study period, if the systolic BP reached > 140 mmHg and/or the diastolic BP reached > 90 mmHg, antihypertensive medications were initiated in the moderate BP control group following the same procedure mentioned for the intensive BP control group.


OutcomesThe primary outcome was a combination of surrogate markers of renal function. Deaths and cardiovascular events were also recorded.


NotesThe trial was stopped early because of funding constraints. The trial was sponsored by the industry.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not reported

Allocation concealment (selection bias)Unclear riskMethod not reported

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of participant and investigator not possible

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskTrial terminated early

Selective reporting (reporting bias)Unclear riskIndividual outcomes not reported

Other biasHigh riskTrial was terminated early; Industry funded

ABCD-H 1998

MethodsRandomized, open-label clinical trial.

An independent end point committee, which was blinded to the study intervention arms, reviewed all cardiovascular events.

The follow-up period was 5 years.


Participants472 participants, between the ages of 40 and 74 years, with type 2 diabetes mellitus and a diastolic blood pressure equal to or higher than 90 mm Hg were included.

Exclusion criteria included myocardial infarction or a cerebrovascular accident within the previous 6 months, coronary artery bypass surgery within the previous 3 months, unstable angina pectoris within the previous 6 months, congestive heart failure NYHA class III or IV, a demonstrated absolute need for ACE inhibitors or CCB, and a serum creatinine level > 3 mg/dL.


InterventionsPatients were randomized into two treatment arms consisting of "intensive" treatment with a diastolic blood pressure goal of 75 mmHg, and "moderate" treatment with a diastolic blood pressure goal of 80-89 mmHg.

They were also allocated to either nisoldipine or enalapril as the initial antihypertensive medication. If the target blood pressure was not achieved with increasing doses, then open-label antihypertensive medications were added in a step-wise fashion, initially with metoprolol, then hydrochlorothiazide or additional drugs, but neither a calcium channel blocker nor an ACE inhibitor.
Blood pressure recordings were obtained at the time when peak drug levels were expected and were an average of three seated readings obtained at each visit.


OutcomesThe primary end point was the change in 24-hour creatinine clearance. Secondary end points included cardiovascular events, retinopathy, clinical neuropathy, and urinary albumin excretion.


NotesPatients were also randomized to either nisoldipine or enalapril as the initial antihypertensive medication. A test for interaction between study-drug assignment and blood-pressure-control strategy showed that no interaction was present.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskParticipants assigned to "moderate" treatment had a greater prevalence of established vascular disease, which became significant when combined with ABCD-N.

Allocation concealment (selection bias)Unclear riskMethod not reported

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of participant and investigator not possible

Incomplete outcome data (attrition bias)
All outcomes
High riskData on losses to follow-up was not reported

Selective reporting (reporting bias)Unclear riskNot all outcomes reported

Other biasUnclear riskFunding not reported

ABCD-N 2002

MethodsRandomized, open label controlled clinical trial. An independent end point committee, which was blinded to the study intervention arms, reviewed all cardiovascular events. The follow-up period was 5 years.


Participants480 participants, aged 40 - 74 years, with type 2 diabetes mellitus were included. All of them had a baseline diastolic blood pressure between 80 and 89 mmHg and were not receiving antihypertensive medications at the randomization visit.

The main exclusion criteria were: myocardial infarction or cerebrovascular accident within the previous 6 months, coronary artery bypass surgery within the previous 3 months, unstable angina pectoris within the previous 6 months, congestive heart failure NYHA class III or IV, a demonstrated absolute need for ACE inhibitors or CCB, and a serum creatinine level > 3 mg/dl.


InterventionsParticipants were randomized into 2 treatment arms consisting of 'intensive' or 'moderate' treatment. The goal in the 'intensive' treatment group was to achieve a decrease of 10 mmHg below baseline in diastolic blood pressure (i.e. 70 - 79 mmHg), whereas the goal in the 'moderate' treatment group was to maintain a diastolic blood pressure between 80 and 89 mmHg.

Participants in the 'moderate' therapy group were given placebo, whereas those randomized to 'intensive' therapy received either nisoldipine or enalapril in a blinded manner as the initial antihypertensive medication. If the target blood pressure was not achieved with increasing doses, then open-label antihypertensive medications were added in a step-wise fashion, initially with metoprolol, then hydrochlorothiazide or additional drugs, but not a calcium channel blocker nor ACE inhibitor.

Blood pressure recordings were obtained at the time when peak drug levels were expected and were an average of 3 seated readings obtained at each visit.


OutcomesThe primary end point was the change in 24-hour creatinine clearance. Secondary end points included cardiovascular events, retinopathy, clinical neuropathy, and urinary albumin excretion.


NotesParticipants randomized to intensive therapy received either nisoldipine or enalapril in a blinded manner as the initial antihypertensive medication. Participants in the moderate group were given placebo. However, by the end of the study 117 participants (48%) initially randomized to moderate therapy required treatment (systolic blood pressure > 159 and/or diastolic blood pressure > 89 mmHg on 2 consecutive visits). These individuals were started on either nisoldipine or enalapril according to randomization at entry into the study with the goal of maintaining the systolic blood pressure < 160 mmHg and diastolic blood pressure < 90 mmHg.

A test for interaction between study drug assignment and blood-pressure control strategy showed that no interaction was present


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskParticipants assigned to 'moderate' treatment had a greater prevalence of established vascular disease, which became significant when combined with ABCD-N.

Allocation concealment (selection bias)Unclear riskMethod not reported

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of participant and investigator not possible

Incomplete outcome data (attrition bias)
All outcomes
High riskData on losses to follow-up was not reported

Selective reporting (reporting bias)Unclear riskNot all outcomes reported

Other biasUnclear riskFunding not reported

ACCORD BP 2010

MethodsRandomized multicenter trial performed in the United States and Canada. An independent end point committee, which was blinded to the study intervention arms, reviewed all cardiovascular events.

The mean follow-up was 4.7 years


Participants4733 participants were included in the ACCORD BP trial. Participants were eligible if they had type 2 diabetes mellitus and a glycated hemoglobin level of 7.5% or more, and were 40 years of age or older with cardiovascular disease or 55 years of age or older with anatomical evidence of a substantial amount of atherosclerosis, albuminuria, left ventricular hypertrophy, or at least 2 additional risk factors for cardiovascular disease (dyslipidemia, hypertension, smoking, or obesity). Participants with a systolic blood pressure between 130 and 180 mmHg who were taking 3 or fewer antihypertensive medications and who had the equivalent of a 24-hour protein excretion rate of less than 1.0 g were also eligible for the blood pressure trial.

Exclusion criteria included a body mass index of more than 45, a serum creatinine level of more than 1.5 mg per deciliter, and other serious illness.


InterventionsIntensive therapy was defined by a target systolic blood pressure < 120 mmHg, whereas standard therapy targeted a systolic blood pressure< 140 mmHg.

There was no specific drug regimen to achieve the target blood pressure. However, all the antihypertensive regimens were to include drug classes that had been shown to result in a reduction in cardiovascular events among participants with diabetes.


OutcomesThe primary outcome was the first occurrence of a major cardiovascular event, which was defined as the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Prespecified secondary outcomes included the combination of the primary outcome plus revascularization or hospitalization for congestive heart failure, the combination of a fatal coronary event, nonfatal myocardial infarction, or unstable angina; nonfatal myocardial infarction; fatal or nonfatal stroke, nonfatal stroke, death from any cause, death from cardiovascular causes, and hospitalization or death due to heart failure.


NotesThe entire ACCORD trial enrolled 10,251 participants with type 2 diabetes mellitus considered to be at high risk. All participants were randomly assigned to either intensive or standard glycemic control. In addition, 4733 participants were also randomly assigned (in a 2-by-2 factorial design) to either intensive or standard blood pressure control (the ACCORD blood pressure trial).

The trial was conducted between January 2001 and October 2005


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk

Allocation concealment (selection bias)Low risk

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of participant and investigator not possible

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Selective reporting (reporting bias)Low risk

Other biasLow riskThe trial was sponsored by the National Heart, Lung, and Blood Institute from the United States. No other funding reported.

HOT 1998

MethodsRandomized, open-label, 3-by-2 factorial design controlled trial, with blinded endpoint evaluation (PROBE) design. An Independent Clinical Event Committee, masked to the group allocation, evaluated all clinical events. The trial was conducted in 26 countries from Europe, Asia, North and South America. The average follow-up was 3.8 years.


ParticipantsThe entire study population was composed of 18,790 patients with elevated blood pressure, aged 50 - 80 years. Of these, 1501 participants had diabetes at baseline and constitute the population included in this analysis.

Baseline diastolic blood pressure between 100 mmHg and 115 mmHg on 2 occasions, at least 1 week apart, was an inclusion criterion.

The main exclusion criteria were malignant hypertension, secondary hypertension, diastolic blood pressure > 115 mmHg, stroke or myocardial infarction within 12 months prior to randomization, decompensated congestive heart failure, other serious concomitant diseases which could affect survival during the next 2 - 3 years, participants who required a beta-blocker, ACE inhibitor or diuretic for reasons other than hypertension, participants who required antiplatelet or anticoagulant therapy, and insulin-treated diabetics.


InterventionsParticipants were randomly assigned to one of 3 diastolic blood pressure target groups: ≤ to 90 mmHg, ≤ 85 mmHg, or ≤ 80 mmHg and to low dose acetylsalicylic acid 75 mg or placebo.

Blood pressure was measured 3 times, by an oscillometric semiautomatic device, with the participant in the sitting position after 5 minutes of rest. The time of day when blood pressure was measured was not specified.

Block randomization was performed taking into consideration the following baseline variables: age, sex, previous antihypertensive therapy, smoking, previous myocardial infarction, previous coronary heart disease, previous stroke and diabetes mellitus.

All participants were treated with the same drugs in the same order. The following were the required steps allowed to attempt to achieve the target blood pressure:
Step 1- felodipine 5 mg once a day;
Step 2- a starting dose of an angiotensin converting enzyme (ACE) inhibitor or beta-blocker was added;
Step 3- the dose of felodipine was increased to 10 mg once a day;
Step 4- the dose of the ACE inhibitor or the beta-blocker was doubled;
Step 5- a diuretic was added.


OutcomesThe outcomes measured were: total and cardiovascular mortality, all (fatal and non-fatal) myocardial infarctions including silent infarctions, all (fatal and non-fatal) strokes, and major cardiovascular events (all myocardial infarctions plus all strokes plus other cardiovascular deaths).


NotesIn the entire trial 24% of all investigators' reported events were rejected by the Clinical Event Committee. The corresponding number for the subgroup of participants with diabetes was not specified.

The trial was conducted between October 1992 and August 1997


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSubgroup analysis

Allocation concealment (selection bias)Unclear riskSubgroup analysis

Blinding (performance bias and detection bias)
All outcomes
Unclear riskBlinding of participant and investigator not possible

Incomplete outcome data (attrition bias)
All outcomes
High riskData on losses to follow-up was not reported

Selective reporting (reporting bias)High riskData on participants with diabetes represent a subgroup analysis of the entire HOT trial. The baseline characteristics in the subgroup of participants with diabetes are unknown, and therefore an unbalance at baseline cannot be ruled out.

Other biasHigh riskIndustry funded

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

HDS 1996This study was excluded from the meta-analysis because the target for systolic blood pressure in the 'tight control' group was higher than that stated in our protocol. In addition and more importantly the targets for both systolic and diastolic blood pressure in the 'less tight control group' were much higher than specified in the protocol for this systematic review.

Lewis 1999It was excluded because it did not provide data on any of the outcomes defined for this systematic review.

SANDS 2008This trial was not included because the dual intervention would not allow to address the events specifically associated with a lower blood pressure target. Besides, both systolic blood pressure targets in this trial were within the values considered as 'lower targets' in our systematic review.

Steno-2 2003This trial was not included because the multifactorial intervention prevented any inference as to whether any difference in clinical outcomes could be attributed to a lower blood pressure target or to any of the other combined interventions.

UKPDS 38 1998This study was excluded from the meta-analysis because the target for systolic blood pressure in the 'tight control' group was higher than that stated in our protocol. In addition and more importantly the targets for both systolic and diastolic blood pressure in the 'less tight control group' were much higher than specified in the protocol for this systematic review.

 
Comparison 1. Systolic blood pressure

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

 1 Total mortality1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 2 Cardiovascular mortality1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 3 Non-CV mortality1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 4 Total serious adverse events1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 5 Myocardial infarction1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 6 Stroke1Risk Difference (M-H, Fixed, 95% CI)Subtotals only

 7 Congestive heart failure1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 8 End-stage renal failure1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 9 All other serious adverse events1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 10 Systolic blood pressure achieved1Mean Difference (IV, Fixed, 95% CI)Subtotals only

 11 Diastolic blood pressure achieved1Mean Difference (IV, Fixed, 95% CI)Subtotals only

12 Withdrawals due to adverse events00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 13 Number of antihypertensive drugs needed per patient1Mean Difference (IV, Fixed, 95% CI)Subtotals only

 
Comparison 2. Diastolic blood pressure

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

 1 Total mortality42580Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.53, 1.01]

 2 Cardiovascular mortality32451Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.52, 1.19]

 3 Non-CV mortality32451Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.36, 1.06]

4 Total serious adverse events00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Myocardial infarction32451Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.64, 1.40]

 6 Stroke32451Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.42, 1.05]

 7 Congestive heart failure2950Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.58, 1.92]

8 End-stage renal failure00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

9 All other serious adverse events00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 10 Systolic blood presure achieved31079Mean Difference (IV, Fixed, 95% CI)-7.31 [-8.69, -5.93]

 11 Diastolic blood pressure achieved31079Mean Difference (IV, Fixed, 95% CI)-6.85 [-7.41, -6.28]

12 Withdrawals due to adverse events00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

13 Number of antihypertensive drugs used per patients00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Summary of findings for the main comparison.

Lower blood pressure (BP) targets compared with standard BP targets for mortality and morbidity

Patient or population: Diabetes Mellitus with elevated blood pressure

Settings: outpatients

Intervention: BP < 130/85 mmHg

Comparison: BP < 140 - 160/90 - 100 mmHg

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

Assumed riskCorresponding risk

Standard BP targetsLower BP targets

Total mortality

Systolic targets
RR 1.05 (0.84 to 1.30)4734
(1)
⊕⊕⊝⊝
low4
Only one RCT


Medium risk population

60 per 10001 63 per 1000
(50 to 78)



Total mortality

Diastolic targets
Low risk populationRR 0.73 (0.53 to 1.01)2580
(4)
⊕⊝⊝⊝
very low5
High risk of bias

30 per 10002 22 per 1000
(16 to 30)

Medium risk population

60 per 10001 44 per 1000
(32 to 61)

High risk population

100 per 10003 73 per 1000
(53 to 101)

Total serious adverse events

Systolic targets
RR 1.01 (0.91 to 1.13)4734
(1)
⊕⊕⊝⊝
low6
Only one RCT


Medium risk population

214 per 10001 216 per 1000
(197 to 244)



*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.

 1Based on the event rate in the standard BP target group.
2One-half the medium event rate.
3Medium event rate times 1.7.
4Only one RCT and confidence intervals includes a 25% increase.
5Inadequate sequence generation, no blinding, subgroup analysis and early termination.
6Only one RCT and no blinding.