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Norris S, Weinstein J, Peterson K, et al. Drug Class Review: Direct Renin Inhibitors, Angiotensin Converting Enzyme Inhibitors, and Angiotensin II Receptor Blockers: Final Report [Internet]. Portland (OR): Oregon Health & Science University; 2010 Jan.

Methods

Inclusion Criteria

Populations

Adults with any of the following indications:

Excluded:

We defined microalbuminuria as an albuminuria level by timed collections of 20 to 200 micrograms per minute,18 30–300 milligrams/24 hours,19, 20 or a proteinuria level via spot protein to creatinine ratio of 30–300 milligrams protein/gram creatinine.19, 20 We defined overt proteinuria (or macroalbuminuria) as proteinuria greater than 300 mg/24 hours on timed collection, or greater than 0.15 milligram protein per milligram creatinine on spot value.20 We defined abnormal renal function as an elevated creatinine or an estimated glomerular filtration rate below 60 ml/min/1.73 m2 or an abnormal creatinine clearance.20

Drugs

Table 2 lists the drugs included in this report.

Table 2. DRI, ACE-I, and AIIRA drugs available in the United States or in Canada.

Table 2

DRI, ACE-I, and AIIRA drugs available in the United States or in Canada.

Effectiveness and efficacy outcomes

Harms

  • Numbers of adults who experienced the following:
    • One or more adverse event
    • One or more serious adverse event (life threatening or requiring medical intervention, including hospitalization)
  • Total withdrawals due to any adverse event
  • Specific harms (including, but not limited to hypotension, hyperkalemia, acute kidney injury, cough, angioedema, gastrointestinal effects) or withdrawals due to specific harms
  • Harms considered to be major are defined as those that required unanticipated and/or urgent medical treatment (including, but not limited to hypotension, hyperkalemia, acute kidney injury, angioedema)

Study designs

Effectiveness/efficacy outcomes

    1. Compared aliskiren to placebo
    2. Made direct inter-class comparisons between individual DRI, ACE-I and AIIRA drugs. Trials that assume a class effect and only provide a comparison to a treatment group consisting of multiple AIIRAs or multiple ACE-Is (trials that don’t stratify by individual AIIRAs or ACE-Is) will be excluded.

Harms

  1. Randomized controlled trials, controlled clinical trials, and good-quality systematic reviews included for effectiveness/efficacy outcomes that:
    1. Compared aliskiren to placebo
    2. Made direct inter-class comparisons between DRI, ACE-I and AIIRA drugs.
  2. Large single-group or multi-group population-based cohort (N 1000) or case-control (N≥500 cases) studies that evaluated major harms. If studies with these sample sizes were not identified studies of N≥200 were considered.

Literature Search

We searched Ovid MEDLINE® (1950-June week 2, 2009), the Cochrane Database of Systematic Reviews® (2nd Quarter 2009), and the Cochrane Central Register of Controlled Trials® (2nd Quarter, 2009) using included drugs, indications, and study designs as search terms. (See Appendix B for complete search strategies). We attempted to identify additional studies through hand searches of reference lists of included studies and reviews. In addition, we searched the US Food and Drug Administration’s Center for Drug Evaluation and Research website for medical and statistical reviews of individual drug products. Finally, we requested dossiers of published and unpublished information from the relevant pharmaceutical companies for this review. All received dossiers were screened for studies or data not found through other searches. All citations were imported into an electronic database (Endnote® XI, Thomson Reuters).

Study Selection

Selection of included studies was based on the inclusion criteria created by the Drug Effectiveness Review Project participants, as described above. Two reviewers independently assessed titles and abstracts of citations identified through literature searches for inclusion using the criteria below. Full-text articles of potentially relevant citations were retrieved and again were assessed for inclusion by both reviewers. Disagreements were resolved by consensus. Results published only in abstract form were not included because inadequate details were available for quality assessment.

Data Abstraction

The following data were abstracted from included trials: study design; setting; population characteristics, including sex, age, ethnicity, and diagnosis; eligibility and exclusion criteria; interventions (dose and duration); comparisons; numbers screened, eligible, enrolled, and lost to follow-up; method of outcome ascertainment; and results for each outcome. We recorded intention-to-treat results when reported. If true intention-to-treat results were not reported, but loss to follow-up was very small, we considered these results to be intention-to-treat results. In cases where only per protocol results were reported, we calculated intention-to-treat results if the data for these calculations were available. Data abstraction was performed by one reviewer and independently checked by a second reviewer.

For the body of evidence in adults with hypertension, complete data abstraction for the majority of trials was publicly available in a good-quality systematic review completed by the Duke Evidence-based Practice Center in November, 2007.21, 22 (http://www.effectivehealthcare.ahrq.gov/healthInfo.cfm?infotype=rr&ProcessID=12%20&DocID=48). We therefore only completed de novo data abstraction for additional trials that we identified.

Validity Assessment

We assessed the internal validity (quality) of trials based on the predefined criteria listed in Appendix C. These criteria are based on the US Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (United Kingdom) criteria.23, 24 We rated the internal validity of each trial based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intention-to-treat analysis. Trials that had a fatal flaw were rated poor quality; trials that met all criteria were rated good quality; the remainder were rated fair quality. As the fair-quality category is broad, studies with this rating vary in their strengths and weaknesses: The results of some fair-quality studies are likely to be valid, while others are only possibly valid. A poor-quality trial is not valid; the results are at least as likely to reflect flaws in the study design as a true difference between the compared drugs. A fatal flaw is reflected by failure to meet combinations of items of the quality assessment checklist. Quality assessment of all trials was independently performed by 1 reviewer. Disagreements were resolved by consensus. We did not rate the quality of observational studies.

For the trials of adults with hypertension for which quality assessments were previously completed by the Duke Evidence-based Practice Center (http://www.effectivehealthcare.ahrq.gov/healthInfo.cfm?infotype=rr&ProcessID=12%20&DocID=48), de novo quality assessment was initially independently performed by one Oregon Evidence-based Practice Center reviewer (K.P.). Only in cases where there was a disagreement between the quality assessment of the initial Oregon Evidence-based Practice Center reviewer and the Duke Evidence-based Practice Center, was a second independent quality assessment completed (L.H.).

Included systematic reviews were also rated for quality (see Appendix C). We rated the internal validity based on a clear statement of the questions(s); reporting of inclusion criteria; methods used for identifying literature (the search strategy), validity assessment, and synthesis of evidence; and details provided about included studies. Again, these studies were categorized as good when all criteria were met.

The overall strength of evidence for a body of evidence for each key question and outcome reflects the risk of bias of the studies (based on quality and study designs), consistency of results, directness of the evidence, and the precision of pooled estimates.25 Strength of evidence was graded as very low, low, moderate, or high. In order to simplify our approach for this review, we did not grade bodies of evidence in which only a single study was available and “Strength of Evidence” grades are listed as “not applicable” in the Summary of Evidence (Table 7).

Data Synthesis

We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. We reviewed studies using a hierarchy of evidence approach, where the best evidence is the focus of our synthesis for each question, population, intervention, and outcome addressed. Both in the Evidence Tables and throughout the report, for all creatinine levels reported in units of micromole/L, we converted to units of mg/dL by dividing by 88.4.

As there were no occasions in which a particular outcome was reported by a sufficient number of studies that were homogeneous enough that combining their results could be justified, no quantitative analyses were conducted using meta-analyses in this review. Therefore, the data were summarized only qualitatively throughout the report.

We define statistical significance as alpha=0.05.

Peer Review

We requested and received peer review of the report from 3 experts. Their comments were reviewed and, where possible, incorporated into the final document. All comments and the authors’ proposed actions were reviewed by representatives of the participating organizations of the Drug Effectiveness Review Project before finalization of the report. Names of peer reviewers for the Drug Effectiveness Review Project are listed at www.ohsu.edu/drugeffectiveness.

Public Comment

This report was posted to the Drug Effectiveness Review Project website for public comment. We received comments from 3 pharmaceutical companies.

Copyright © 2009, Oregon Health & Science University, Portland, Oregon.
Cover of Drug Class Review: Direct Renin Inhibitors, Angiotensin Converting Enzyme Inhibitors, and Angiotensin II Receptor Blockers
Drug Class Review: Direct Renin Inhibitors, Angiotensin Converting Enzyme Inhibitors, and Angiotensin II Receptor Blockers: Final Report [Internet].
Norris S, Weinstein J, Peterson K, et al.
Portland (OR): Oregon Health & Science University; 2010 Jan.

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