Types of studies

The studies must be double‐blind randomized controlled trials (DBRCTs), with a parallel design, randomizing participants to the renin inhibitor group or to the ARB group, and must have a minimum follow‐up of four weeks.

Types of participants

We will include people with primary hypertension, and will exclude people with proven secondary hypertension.

Hypertension is defined as an office systolic blood pressure (BP) ≥ 140 mmHg or an office diastolic BP ≥ 90 mmHg, or both. If ambulatory BP is measured, diagnostic criteria are as follows: daytime systolic BP ≥ 135 mmHg or diastolic BP ≥ 85 mmHg, or both; night‐time systolic BP ≥ 120 mmHg or diastolic BP ≥ 70 mmHg, or both; 24‐hour systolic BP ≥ 130 mmHg or diastolic BP ≥ 80 mmHg, or both.

Types of interventions

Intervention: renin inhibitors.

Control: angiotensin receptor blockers.

Renin inhibitors include: aliskiren, ciprokiren, ditekiren, enalkiren, remikiren, rasilez, tekturna, terlakiren and zankiren.

Angiotensin receptor blockers include: abitesartan, azilsartan, candesartan, elisartan, embusartan, eprosartan, forasartan, irbesartan, KT3‐671, losartan, milfasartan, olmesartan, saprisartan, tasosartan, telmisartan, valsartan and zolasartan.

Types of outcome measures

Electronic searches

The Cochrane Hypertension Information Specialist will search the following databases from date of inception for published, unpublished, and ongoing studies:

• the Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (CRS‐Web);

• the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS‐Web);

• MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations;

• Embase Ovid (from 1974 onwards);

• ClinicalTrials.gov (www.clinicaltrials.gov)

• World Health Organization International Clinical Trials Registry Platform (www.who.it.trialsearch).

The subject strategies for databases will be modelled on the search strategy designed for MEDLINE in Appendix 1. Where appropriate, these will be combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Lefebvre 2011)). Searches for this review have been combined with the related review Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors for primary hypertension.

Searching other resources

• The Hypertension Information Specialist will search the Hypertension Specialised Register segment (which includes searches of MEDLINE and Epistemonikos for systematic reviews) to retrieve published systematic reviews related to this review title, so that we can scan their reference lists to identify additional relevant trials.

• We will check the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials.

• We will contact experts/organisations in the field to obtain additional information on relevant trials.

• We may contact original authors for clarification and further data if trial reports are unclear.

• We will not perform a separate search for adverse effects of interventions used for the treatment of hypertension. We will consider adverse effects described in included studies only.

Selection of studies

We will import references and abstracts of search results into Reference Manager software.

Two review authors will independently perform the initial screening of the results of the searches, to exclude obviously irrelevant citations. We will acquire the full texts of the remaining citations (translated into English if necessary), and will independently screen them for the prespecified inclusion criteria, and record reasons for exclusion. We will check the reference lists of pertinent articles and reviews for additional relevant citations. A third review author will resolve any disagreements or discrepancies.

Data extraction and management

Two review authors will independently extract data from the included studies using a standard data extraction form. The data will include study design, randomization, blinding, drugs, duration of the study, baseline characteristics and outcomes.

A third review author will cross‐check the data, resolve discrepancies, and confirm all numeric calculations and graphic interpolations.

Assessment of risk of bias in included studies

We will assess risks of bias in each included trial, using the 'Risk of bias' methods given in the Cochrane Handbook (Higgins 2011). Two review authors will independently rate the risks of bias in each study as 'low risk', 'high risk ' or 'unclear risk', with a third review author resolving any discrepancy.

We will present the assessment of risk of bias in the following domains:

1. Sequence generation;

2. Allocation concealment;

3. Blinding of participants and personnel;

4. Blinding of outcome assessment;

5. Incomplete outcome data;

6. Selective reporting;

7. Other potential bias.

Measures of treatment effect

We will base data synthesis and quantitative analysis of outcomes upon intention‐to‐treat principles as much as possible, using Review Manager 5 software (RevMan).

For dichotomous variables (all‐cause mortality, total cardiovascular events, renal events, withdrawal due to adverse events and serious adverse events), we will use a risk ratio (RR) with a 95% confidence interval (CI).

For continuous variables (change in systolic and diastolic blood pressure and change in heart rate), weighted mean difference (WMD) with 95% CI are the effect variables. In case of different methods of measurement across the included studies, we will calculate a standardized mean difference (SMD) with a 95% CI.

Unit of analysis issues

The unit of analysis will be the individual trial. For trials having more than two arms, we will only include arms relevant to this review. Where studies include more than one intervention group with a single comparator arm, we will include both intervention groups.

Dealing with missing data

We will contact the investigators to request any missing data.

If the studies did not report a standard deviation (SD) for a continuous outcome, we will impute the SD in the following hierarchy:

1. Pooled SD calculated either from the t‐statistic corresponding to an exact P value reported or from the 95% CI of the mean difference between the intervention and control group;

2. SD at the end of treatment;

3. SD at baseline;

4. Weighted mean SD of change calculated from at least three other trials using the same class of drug (at any dose).

Assessment of heterogeneity

We will consider a P value of 0.10 or less from the Chi² test as statistically significant for heterogeneity (Deeks 2011). Furthermore, we will use the I² statistic for quantifying inconsistency across studies, following the rough guide to interpretation as described in Deeks 2011:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%: considerable heterogeneity.

Assessment of reporting biases

We will assess suspected reporting biases using funnel plots. As a rule of thumb, tests for funnel plot asymmetry should be used only when there are at least 10 studies included in the meta‐analysis, because when there are fewer studies the power of the tests is too low to distinguish chance from real asymmetry.

Data synthesis

We will use RevMan to perform data synthesis and analysis. One review author will input the data and a second will check them. We will pool the data using the Mantel‐Haenszel fixed‐effect model if there is no or low heterogeneity, and a random‐effects model when significant heterogeneity is present.

If there is only one trial on an outcome, or where meta‐analysis is not applicable, we will provide a narrative description of the results.

Subgroup analysis and investigation of heterogeneity

We will perform the following subgroup analyses if possible:

1. Participants:

   1. Gender;

   2. Age;

   3. Race;

   4. Baseline blood pressure level;

   5. Co‐morbid conditions: e.g. diabetes, heart diseases, renal diseases, cardiovascular diseases.

2. Treatments:

   1. Doses of drugs;

   2. Duration of treatment.

Sensitivity analysis

We will perform sensitivity analyses to test the robustness of the results in the following domains:

1. Sponsorship: trials that were industry‐sponsored versus non‐industry sponsored;

2. SD: trials with reported SDs versus those with imputed SDs;

3. Risk of bias: trials that have a high risk of bias versus those having a low risk of bias.