Inclusion Criteria

Literature Search

To identify articles relevant to each key question, we searched Medline (1994 to May 2006), Embase (1994 to May 2006), the Cochrane Central Register of Controlled Trials (Fall 2004 to May 2006), and reference lists of included review articles. In electronic searches, we combined terms for drug names, indications, and included study designs, all limited to human and English language (see Appendix C for complete search strategies). Pharmaceutical manufacturers were invited to submit dossiers. Aggrenox⁹ and Clopidogrel¹⁰ dossiers were received for the first version of this document. No dossier material was reviewed for the update. However, Boehringer Ingelheim Pharmaceuticals and Sanofi-aventis (on behalf of Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership) submitted comments on the draft of the updated report. All citations were imported into an electronic database (ProCite for Windows, Version 5.0.3.).

For Update 2, we searched Ovid MEDLINE^® (1996 to December Week 4 2010), the Cochrane Database of Systematic Reviews^® (2005 to December 2010), the Cochrane Central Register of Controlled Trials^®(4 ^th Quarter 2010), and Database of Abstracts of Reviews of Effects^®(4 ^th Quarter 2010) using included drugs, indications, and study designs as search terms (see Appendix C for complete search strategies). We attempted to identify additional studies through hand searches of reference lists of included studies and reviews. Finally, we requested dossiers of published and unpublished information from the relevant pharmaceutical companies for this review.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^® X2, 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.

We included English-language reports of randomized controlled trials that evaluated and included the newer antiplatelet agents (extended-release dipyridamole/aspirin, clopidogrel, ticlopidine, and prasugrel) in patients with acute coronary syndrome, stroke, transient ischemic attack, and symptomatic peripheral vascular disease, and that reported an included outcome. Included trials evaluated a newer antiplatelet agent compared with either another study antiplatelet agent or newer antiplatelet agent that met the inclusion criteria above.

To evaluate efficacy, we assessed controlled clinical trials. The validity of controlled trials depends on how they are designed. Properly randomized controlled trials are considered the highest level of evidence for assessing efficacy. Clinical trials that are not randomized or blinded and those that have other methodological flaws are less reliable but are also discussed in the report.

Likewise, we excluded trials that compared an antiplatelet agent only to placebo because the acceptable standard of care today would more than likely (if clinically warranted and possible) include at least aspirin therapy. Lastly, only trials that specifically utilized Aggrenox^® or their components together were included because the components of Aggrenox^® are not interchangeable with the individual components of aspirin and immediate -release dipyridamole (Persantine^®).

For many of the treatment outcomes, the newer antiplatelet agents were evaluated against some other standard of care, typically aspirin, rather than against another study antiplatelet agent. Although these trials provided indirect evidence regarding the comparative efficacy of these agents, they are not as useful as direct, head-to-head comparisons.

Clinical trials as well as observational cohort studies were included to evaluate rates of adverse events. Clinical trials typically either excluded patients who had experienced an adverse event on the therapy being evaluated or included a patient population where the risk of an adverse event was minimized in order to avoid a high dropout rate. Observational studies are a useful supplement to clinical trial data for adverse events because they may include a broader patient population with a large number of patients evaluated over a longer period of time. Many of the clinical trials of the newer antiplatelet agents included large patient populations with a long follow-up period, but not all were large or designed to rigorously evaluate adverse events. Only observational studies including more than 1000 patients with duration of at least 1 year or that focused on serious and rare adverse events were included in the assessment of adverse events. In order to evaluate the safety of the newer antiplatelet agents, we abstracted overall adverse effect reports, withdrawals due to adverse effects (a marker of more serious adverse events), serious adverse events reported (including mortality), and specific adverse effects or withdrawals due to specific adverse events (e.g., bleeding, neutropenia, diarrhea, rash).

Data Abstraction

The following data were abstracted from included trials: population characteristics (including sex, age, and ethnicity); eligibility; interventions (dose and duration); comparisons; numbers enrolled, withdrawn; lost to follow-up and analyzed; results for each relevant efficacy/effectiveness and harms outcomes; total withdrawals; withdrawals due to adverse events; and funding. We recorded intent-to-treat results when reported. If true intent-to-treat results were not reported, but loss to follow-up was very small, we considered these results to be intent-to-treat results. In cases where only per protocol results were reported, we calculated intent-to-treat results if the data for these calculations were available. Data abstraction was performed by 1 reviewer and independently checked by a second reviewer and differences were resolved by consensus.

Validity Assessment

We assessed the internal validity (quality) of trials based on the predefined criteria (see www.ohsu.edu/drugeffectiveness). These criteria are based on the US Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (United Kingdom) criteria.^{11, 12} 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 intent-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. A particular randomized trial might receive 2 different ratings, one for effectiveness and another for adverse events.

The criteria used to rate observational studies of adverse events reflect aspects of the study design that are particularly important for assessing adverse event rates. We rated observational studies as good quality for adverse event assessment if they adequately met 6 or more of the 7 predefined criteria, fair quality if they met 3 to 5 criteria, and poor quality if they met 2 or fewer criteria.

Included systematic reviews were also rated for quality. We rated the internal validity based 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.

Two reviewers independently assessed each study and differences were resolved by consensus.

Grading the Strength of Evidence

We graded strength of evidence based on the guidance established for the Evidence-based Practice Center Program of the Agency for Healthcare Research and Quality.¹³ Developed to grade the overall strength of a body of evidence, this approach incorporates 4 key domains: risk of bias (includes study design and aggregate quality), consistency, directness, and precision of the evidence. It also considers other optional domains that may be relevant for some scenarios, such as a dose-response association, plausible confounding that would decrease the observed effect, strength of association (magnitude of effect), and publication bias. For the purposes of this review, a rating of “indirect” was given to all aspirin-controlled trials. For rating of precision, we adopted the GRADE system’s suggestion of downgrading evidence with a 95% confidence interval around the estimate of effect that includes both 1) no effect and (2) appreciable benefit or appreciable harm, using a threshold of 25% for both appreciable benefit and harm.

Table 2 describes the grades of evidence that can be assigned. Grades reflect the strength of the body of evidence to answer key questions on the comparative effectiveness, efficacy, and harms of newer antiplatelet agents. Grades do not refer to the general efficacy or effectiveness of pharmaceuticals. Two reviewers independently assessed each domain for each outcome and differences were resolved by consensus.

Table 2

Definitions of the grades of overall strength of evidence.

Among the many outcomes assessed in trials of newer antiplatelet agents, we focused on rating the strength of evidence for only a subset of 4 that the Drug Effectiveness Review Project participants judged to represent the most clinically important and reliable: all-cause mortality, cardiovascular mortality, major bleeding, and withdrawals due to adverse events. We also rated the strength of the evidence for the following treatment- or population-specific outcomes: (1) neutropenia in trials including ticlopidine; (2) myocardial infarction in patients with acute coronary syndromes; (3) revascularization in patients undergoing stenting or bypass grafting; and (4) stroke recurrence in patients with a recent stroke or transient ischemic attack. Composite cardiovascular outcomes are very common in trials of antiplatelet agents. However, composite endpoints have been found to carry an inherent risk of misleading interpretation when they are comprised of component endpoints that have wide variance in both importance to patients and in contribution to the composite endpoint event rate.¹⁴ For this reason, we considered composite endpoints to be of lower priority in this review and did not formally rate the strength of their results.

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. Studies that evaluated one antiplatelet against another provided direct evidence of comparative effectiveness and adverse event rates. Where possible, these data are the primary focus. Direct comparisons were preferred over indirect comparisons; similarly, effectiveness and long-term safety outcomes were preferred to efficacy and short-term tolerability outcomes. In theory, trials that compare antiplatelet agents with other drug classes or with placebo can also provide evidence about effectiveness. This is known as an indirect comparison and can be difficult to interpret for a number of reasons, primarily heterogeneity of trial populations, interventions, and outcomes assessment. Data from indirect comparisons are used to support direct comparisons, where they exist, and are used as the primary comparison where no direct comparisons exist. Indirect comparisons should be interpreted with caution.

Quantitative analyses were conducted using meta-analyses of outcomes reported by a sufficient number of studies that were homogeneous enough that combining their results could be justified. In order to determine whether meta-analysis could be meaningfully performed, we considered the quality of the studies and the heterogeneity among studies in design, patient population, interventions, and outcomes. When meta-analysis could not be performed, the data were summarized qualitatively. When the number of studies was sufficiently large to reliably estimate the tau-squared statistic, random effects models were used to estimate pooled effects.¹⁶ We generally set this number at 4 or more studies. When estimating pooled effects from a smaller number of studies, fixed-effects models were used.

The Q statistic and the I² statistic (the proportion of variation in study estimates due to heterogeneity) were calculated to assess heterogeneity in effects between studies.^{17, 18} Potential sources of heterogeneity were examined by analysis of subgroups of study design, study quality, patient population, and variation in interventions. All supplemental analyses were performed using Stats Direct statistical software (version 2.7.8, 3/15/2010).

Peer Review

We requested and received peer review of the report from 2 content 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: Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, and Eli Lilly and Company.