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Cochrane Database of Systematic Reviews Protocol - Intervention

First‐line drugs inhibiting the renin angiotensin system versus other first‐line antihypertensive drug classes for hypertension

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the benefits and harms of drugs inhibiting the RAS in patients with elevated blood pressure (>130/85mmHg).

Background

Description of the condition

Hypertension is a worldwide health problem and has become a heavy burden on the health care system. Hypertension is associated with cardiovascular mortality and morbidity such as coronary artery disease, cerebrovascular disease, and peripheral vascular disease. Blood pressure (BP) is elevated in many people with type 2 diabetes, which is a major health problem worldwide, and the increased prevalence of diabetes mellitus (DM) is primarily due to the increase in type 2 diabetes mellitus (T2DM) (Inzucchi 2005). Among U.S. adults with diabetes, 71.0% had elevated BP (i.e., BP ≥130/85 mm Hg or current use of prescription medication for hypertension) (Geiss 2002). Elevated BP is associated with a spectrum of later health problems in people with diabetes, notably cardiovascular disease and kidney damage. Elevated BP has been identified as a major risk factor in progression of diabetic nephropathy (Aurell 1992). The risk of cardiovascular morbidity and mortality is also doubled in hypertensive patients when diabetes is present (DeStefano 1993). Review of the evidence‐base on this topic is distributed among guidelines primarily addressing diabetes (CPG 2008) or hypertension (JNC‐VII 2003). Antihypertensive agents used include angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), beta‐blockers and diuretics.

Description of the intervention

In the past 10 years, antagonism of the renin‐angiotensin system (RAS) has become a focus of therapeutic interventions for hypertension. The guidelines (ADA 2005, JNC‐VII 2003) that recommend the use of ACE inhibitors or ARBs in diabetics with renal disease base their recommendations on the results of placebo‐controlled trials, which have been interpreted to show that ACE inhibitors and ARBs have specific renoprotective effects beyond those resulting from lowering blood pressure alone. Blood‐pressure‐independent beneficial effects of ACE inhibitors and ARBs on cardiovascular outcomes have also been proposed, based on the results of several large multicentre placebo‐controlled trials, especially HOPE 2000, PROGRESS 2001 and RENAAL 2001 studies. A recent meta‐analysis (Saha 2008) indicated that in patients with DM treatment with tissue ACE inhibitors (ramipril 1.25 or 10 mg/day; perindopril 4 or 8 mg/day) when compared to placebo significantly reduced the risk of cardiovascular mortality by 14.9% (p=0.022), myocardial infarction (MI) by 20.8% (p=0.002) and the need for invasive coronary revascularization by 14% (p= 0.015) ; the risk of all‐cause mortality also tended to be lower (RR 0.913, 95% confidence intervals (CI) 0.825‐1.011) among patients randomized to tissue ACE inhibitors. A Cochrane systematic review (Strippoli 2006) from 13 randomised controlled trials (RCTs) in 10070 patients showed a significant reduction in the risk of end‐stage renal disease (ESRD) with ACE inhibitors or ARBs compared to placebo/no treatment (RR 0.60, 95% CI 0.39 to 0.93; RR 0.78, 95% CI 0.67 to 0.91, respectively), and ACE inhibitors at the maximum tolerable dose were found from 10 studies in 2034 patients to significantly reduce the risk of all‐cause mortality in placebo controlled studies (RR 0.78, 95% CI 0.61 to 0.98, ARR 0.04, NNT 24.56).

The evidence of benefit in terms of mortality and morbidity using ACE inhibitors or ARBs versus other antihypertensive agents is not clear. Some studies suggested that RAS inhibitors might prevent or delay cardiovascular events in some subgroups, but their role in the broader group of people with hypertension remains unknown (CAPPP 2001, LIFE 2002). Some trials provide evidence of benefit of RAS inhibitors on renal function over other antihypertensive drugs (ABCD‐HT 2000, LIFE 2002, MARVAL 2002). However, clinically relevant outcomes or hard endpoints such as combined renal dysfunction or renal failure were not examined.

Other systematic reviews related to this review are summarized below in chronological order by date of publication.

A systematic review and meta‐analysis by Casas et al assessed the effect of RAS inhibitors and other antihypertensive drugs on renal outcomes (Casas 2005). In this review, the effects of ACE inhibitors or ARBs in placebo‐controlled trials were indirectly compared to the effects of other antihypertensive drug in patients with type 1 or 2 diabetes or without diabetes. In patients with diabetic nephropathy, no benefit was seen in comparative trials of ACE inhibitors or ARBs on the doubling of creatinine, ESRD, glomerular filtration rate (GFR), or creatinine levels. Placebo‐controlled trials of ACE inhibitors or ARBs decreased all renal outcomes, but also reduced blood pressure.

A Cochrane systematic review (Strippoli 2005) of RCTs comparing any antihypertensive agent with placebo or another agent in hypertensive or normotensive patients with diabetes and no kidney disease was published. This review assessed the renal outcomes and all‐cause and cardiovascular mortality. It showed that compared to placebo, ACE inhibitors significantly reduced the development of microalbuminuria (six trials, 3840 patients: RR 0.60, 95% CI 0.43 to 0.84, ARR 0.03 and NNT 33.81) but not doubling of creatinine or ESRD or all‐cause mortality. Compared to CCBs, ACE inhibitors significantly reduced progression to microalbuminuria (four trials,1210 patients: RR 0.58, 95% CI 0.40 to 0.84, ARR 0.05 and NNT 20).

A meta‐analysis of double‐blinded RCTs by Siebenhofer et al compared ARBs to placebo or standard anti‐hypertensive treatment in T2DM (3 trials, 4423 patients included) and examined clinical endpoints (all‐cause mortality, cardiovascular morbidity and mortality, and ESRD) (Siebenhofer 2004). The only statistical significant benefit of ARBs was the reduction of ESRD compared with placebo (OR 0.73, 95% CI 0.60 to 0.89, ARR 0.05 and NNT 20). ARBs failed to show superiority to standard anti‐hypertensive treatment (CCB, beta‐blockers) in total mortality and cardiovascular morbidity and mortality. However, ACEI were not included in this meta‐analysis.

A systematic review and meta‐analysis by Pahor et al assessed therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with T2DM and hypertension (Pahor 2000). This meta‐analysis showed a significant benefit of ACE inhibitors compared with alternative treatments (CCB, beta‐blockers, diuretics) on acute MI (63% reduction, P<0.001, ARR 0.06 and NNT 17), cardiovascular events (51% reduction, P<0.001, ARR 0.08 and NNT 13), and all‐cause mortality (62% reduction, P = 0.010, ARR 0.02 and NNT 40) but not stroke. However, ARBs were not included in this review. Renal outcomes (ESRD, GFR, serum creatinine or albuminuria) were not reported.

A meta‐analysis of 100 controlled and uncontrolled trials in 2494 subjects with diabetes assessed the effect on proteinuria of different classes of antihypertensive agents (ACEI inhibitors, CCBs, beta‐blockers and control) (Kasiske 1993). This review showed that ACE inhibitors produced the greatest reductions in urine albumin and protein excretion compared with other antihypertensive agents (P<0.05 vs calcium channel blockers; P<0.05 vs control). ACE inhibitors achieved these beneficial effects on renal function independent of changes in blood pressure. This meta‐analysis examined surrogate markers rather than clinically relevant endpoints (such as end‐stage renal failure, all‐cause mortality).

How the intervention might work

The RAS is a potential pathophysiologic mechanism causing diabetic heart disease. Angiotensin II (Ang II) is thought to play an important role in the pathogenesis of cardiovascular complications (Dzau 2001). The role of the RAS on diabetic nephropathy has also been extensively studied (Kocks 2002).

Drugs inhibiting the RAS include: renin inhibitors, ACE inhibitors and ARBs. These drugs inhibit the enzymatic action of renin, the conversion of Ang I to Ang II or blocking the Ang II receptors, respectively.

ACE inhibitors and ARBs block the RAS further downstream, whereas renin inhibitors prevent the formation of renin, which is responsible for all "downstream" events leading to production of Ang II and subsequently stimulation of its receptors. It has been proposed that renin inhibitors might provide more effective means of blockade of the RAS than ACE inhibitors or ARBs (Duprez 2006).

Why it is important to do this review

RAS inhibitors are widely prescribed for treatment of hypertension. Furthermore for people with diabetes, the JNC‐VII treatment guidelines recommended that anti‐hypertensive drug therapy be initiated for blood pressure >130/85 mm Hg, ACE inhibitors and ARBs are specifically promoted for diabetic patients on the basis of postulated advantages with regard to the reduction of diabetic nephropathy and cardiovascular morbidity and mortality. Despite widespread use of ACE inhibitors and ARBs for diabetes, the efficacy compared to other antihypertensive drugs is still unclear. A systematic review is needed in order to establish the benefits and harms in terms of clinically relevant outcomes (especially all‐cause mortality and morbidity, renal and cardiovascular outcomes) of RAS inhibitors compared to other antihypertensive drugs in patients with elevated blood pressure.

Objectives

To evaluate the benefits and harms of drugs inhibiting the RAS in patients with elevated blood pressure (>130/85mmHg).

Methods

Criteria for considering studies for this review

Types of studies

Study design must meet the following criteria:

  • randomized controlled trials (RCTs) with parallel design

  • double‐blind

  • minimum follow‐up of 6 months

Types of participants

Patients with primary elevated blood pressure (>130/85mmHg). Patients with proven secondary hypertension are excluded.

Types of interventions

  • RAS inhibitors include ACE inhibitors, ARBs or renin inhibitors

  • ACE inhibitors include: alacepril, altiopril, benazepril, captopril, ceronapril, cilazapril, delapril, derapril, enalapril, enalaprilat, fosinopril, idapril, imidapril, lisinopril, moexipril, moveltipril, pentopril, perindopril, quinapril, ramipril, spirapril, temocapril, trandolapril, zofenopril;

  • ARBs include: candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan, KT3‐671;

  • Renin inhibitors include: aliskiren, remikiren

Comparators

  • Any other antihypertensive drug class including: thiazides, beta blockers, calcium channel blockers, alpha blockers, or CNS active drugs.

Types of outcome measures

Primary outcomes

  • All‐cause mortality

  • All‐cause serious morbidity (Non‐fatal serious adverse events)

  • Cardiovascular outcomes:

    • Cardiovascular death

    • Fatal and non‐fatal myocardial infarction

    • Fatal and non‐fatal stroke

  • Renal outcomes:

    • End stage renal failure (ESRF, defined as a requirement for maintenance dialysis)

Secondary outcomes

  • Change in or end‐point systolic and diastolic BP

  • Change in or end‐point heart rate

Search methods for identification of studies

Electronic searches

The Database of Abstracts of Reviews of Effectiveness (DARE) and the Cochrane Database of Systematic Reviews will be searched for related reviews.

The following electronic databases will be searched for primary studies:

  1. The Cochrane Central Register of Controlled Trials (CENTRAL)

  2. English language databases, including MEDLINE (1966‐) and EMBASE (1982‐)

Electronic databases will be searched using a strategy combining a variation of the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐maximizing version (2008 revision) with selected MeSH terms and free text terms relating to antihypertensives and hypertension.  No language restrictions will be used.  The MEDLINE search strategy (Appendix 1) will be translated into the other databases using the appropriate controlled vocabulary as applicable. 

Full strategies for all English language databases will be included in the Appendices of the review.

Searching other resources

Other sources:

  1. International Clinical Trials Registry Platform (WHO ICTRP)

  2. OpenSIGLE (System for Information on Grey Literature in Europe)

  3. Hand searching of those high‐yield journals and conference proceedings which have not already been hand searched on behalf of the Cochrane Collaboration.

  4. Reference lists of all papers and relevant reviews identified

  5. Authors of relevant papers will be contacted regarding any further published or unpublished work

  6. Authors of trials reporting incomplete information will be contacted to provide the missing information

  7. ISI Web of Science will be searched for papers which cite studies included in the review

Data collection and analysis

The initial search of all the databases will be performed to identify citations with potential relevance. The initial screen of these abstracts will exclude articles whose titles and/or abstracts are clearly irrelevant. The full text of remaining articles will then be retrieved (and translated into English where required) to assess whether the trials meet the pre‐specified inclusion criteria. The bibliographies of pertinent articles, reviews and texts will be searched for additional citations. Two independent reviewers will assess the eligibility of the trials using a trial selection form. A third reviewer will resolve discrepancies.

Selection of studies

References and abstracts of search results will be imported to Reference Manager software. Selection of studies will be based on the criteria listed above.

Data extraction and management

Data will be extracted independently by two reviewers using a standard form, and then cross‐checked. All numeric calculations and graphic interpolations will be confirmed by a second person.

Assessment of risk of bias in included studies

We will assess the risk of bias for each trial according to Cochrane risk of bias guidelines using the following six domains:

  1. Sequence generation

  2. Allocation concealment

  3. Blinding or objective assessment of primary outcomes

  4. Incomplete outcome data

  5. Selective outcome reporting

  6. Other biases

Measures of treatment effect

Quantitative analysis of outcomes will be based on intention‐to‐treat principles as much as possible. For dichotomous outcomes, results will be expressed as relative risk (RR) with 95% confidence intervals (CI). For combining continuous variables (systolic and diastolic BP and heart rate), we will use weighted mean difference (with 95% CI), whereby the trials are weighted according to the number of subjects in the trial and the within‐study variance.

Dealing with missing data

In case of missing information in the included studies, investigators will be contacted (using email, letter and/or fax) to obtain the missing information.

When trials do not report a within‐study variance for the effect change of continuous data, the standard deviation (SD) will be imputed using the following hierarchy:

  1. Pooled standard deviation calculated either from the t‐statistic corresponding to an exact p‐value reported or from the 95% CI of the mean difference between treatment group and comparative group.

  2. Standard deviation at the end of treatment.

  3. Standard deviation at baseline.

  4. Weighted mean standard deviation of change calculated from at least 3 other trials using the same dose regimen.

  5. Weighted mean standard deviation of change calculated from other trials using any dose.

Assessment of heterogeneity

Heterogeneity between trials will be tested using chi‐squared test, where p<0.05 will be taken to indicate significant heterogeneity. The fixed effect model will be used when there is homogeneity and the random effect model will be used to test for statistical significance where there is heterogeneity.

Assessment of reporting biases

We will be using funnel plots to investigate publication reporting bias when suspected.

Data synthesis

Data synthesis and analyses will be done using the Cochrane Review Manager software, RevMan 5.
We will describe data results in tables and forest plots according to Cochrane guidelines. In addition we will give full details for all trials included and excluded. A standard QUORUM flow diagram will also be included.

Subgroup analysis and investigation of heterogeneity

If appropriate, subgroup analyses will be performed.

  • Heterogeneity among participants could be related to:

    • Gender

    • Age

    • Presence of diabetes at initiation of antihypertensive treatment (time of trial entry)

    • Baseline blood pressure

    • Previous renal disease

    • Previous cardiovascular disease

  • Heterogeneity in treatments could be related to:

    • Dose of drugs

    • Duration of therapy

Sensitivity analysis

Robustness of the results will be tested using several sensitivity analyses, including:

  • Trials that are industry‐sponsored versus non‐industry sponsored

  • Trials with reported standard deviations of effect change vs. imputed standard deviations

  • Trials that have a high risk of bias versus those with a low risk of bias