Meta-Analysis: Secondary Prevention Programs for Patients with Coronary Artery Disease

Cardiovascular disease remains the most common cause of office visits, hospitalizations, and death in the United States: More than 13 million Americans have documented coronary artery disease (CAD), and costs for CAD are expected to exceed $393 billion in 2005 (1). Control of the CAD epidemic requires a multifaceted strategy targeting the currently recognized modifiable risk factors for CAD that account for more than 90% of risk, regardless of sex, age, or region (2). This strategy should include primary prevention maneuvers (for the general population and high-risk individuals) and secondary prevention programs (for patients with established CAD). Despite the abundant evidence base for CAD prevention (3), health outcomes studies consistently demonstrate gaps in applying this evidence to clinical practice; these gaps contribute to suboptimal patient outcomes (4). Secondary prevention programs are often proposed as a way to improve management and outcomes. Although several reviews have shown that cardiac rehabilitation reduces mortality in survivors of myocardial infarction (MI) (5-8), these conclusions are informed largely by trials that tested supervised exercise programs versus no exercise postinfarction. Since exercise training confers substantial physiologic and clinical benefits and activity levels are inversely proportional to cardiovascular mortality (9), it is not surprising that trials of exercise programs found positive effects on survival. However, few trials included in these reviews evaluated secondary prevention programs that were not primarily exercise-based. In an earlier review (10), we identified 12 randomized trials (9803 patients) of nonexercise-based secondary prevention programs in patients with established CAD. We demonstrated improvements in risk factor profiles and processes of care (particularly the prescription of proven efficacious therapies) but indeterminate effect on rates of death or recurrent MIs (10). Because current guidelines recommend that secondary prevention programs should not be restricted to supervised exercise programs but should address the full range of modifiable risk factors (11), we conducted a systematic review to update earlier work and to determine the effects of different types of secondary prevention programs (particularly those with a structured exercise component versus those without). Methods Data Sources We searched MEDLINE (19662004); the Cochrane Central Register of Controlled Trials, Issue 4, 2004; EMBASE (19802004); CINAHL (19822004); SIGLE (19802004); and PubMed (January 2004December 2004). We also conducted a cited reference search for our previous review (10) in Web of Science (19992004). We based the searches on the following terms: case management, comprehensive health care, disease management, health services research, home care services, clinical protocols, patient care planning, quality of health care, rehabilitation, nurse led clinics, special clinics, and myocardial ischemia. We hand-searched reference lists of all identified studies, review articles, and references provided by the Centers for Medicare & Medicaid Services and content experts (search strategy available upon request). We limited our search to English-language publications (no abstracts), and the search extends from 1966 to 2004 (we completed the search on 16 December 2004). Study Selection Two investigators independently reviewed the titles and abstracts of all citations to identify studies reporting the effect of secondary prevention programs on mortality, MI, or hospitalization rates in patients with CAD. Both investigators obtained the full text of potentially relevant articles and reviewed them by using prestandardized data abstraction forms and eligibility criteria defined a priori. Any discrepancies were resolved by consensus. We excluded studies if they were not randomized, if they did not include a usual care group, if the outcomes for CAD patients were not reported or were not obtainable from the study investigators, if they evaluated single-modality interventions except exercise (such as telephone follow-up), if they tested interventions delivered to inpatients, or if the interventions were not provided by health professionals (for example, mailed reminders, self-help groups, or self-directed interventions). Data Extraction and Quality Assessment Two investigators extracted all outcome data independently, and a third investigator checked the data. We assigned outcomes according to the intention-to-treat principle and by using the definitions from the primary studies. When necessary, we contacted original investigators to clarify the data for any trial published in the past decade. Authors for 10 of these 21 studies provided further data. Two investigators independently assigned each intervention to 1 of 3 groups: 1) programs that incorporated education and counseling about coronary risk factors with a supervised exercise program (either in a group setting, per traditional comprehensive cardiac rehabilitation programs, or individually delivered), 2) programs that included education and counseling about coronary risk factors but had no exercise component (either delivered in a group setting or individually), and 3) supervised exercise programs only. Data Synthesis and Analysis We performed analyses by using RevMan 4.2 (Update Software, Oxford, United Kingdom). Our outcomes of interest were all-cause mortality and recurrent MIs. Because the outcomes were relatively common, we calculated risk ratios and used the I2 statistic to assess for heterogeneity in each outcome of interest. We combined studies by using the DerSimonian and Laird random-effects model. For the primary analysis, we used data from the longest follow-up period reported in each trial. In a priori sensitivity analyses, we pooled data for 3 follow-up periods (12, 24, and 60 months). To evaluate whether different types of secondary prevention programs had different effects, we calculated the summary risk ratio for each program type and used adjusted indirect comparisons to compare different types of interventions, according to the method of Song and colleagues (12). Role of the Funding Source An earlier version of this evidence report was produced under contract to the Agency for Healthcare Research and Quality, Rockville, Maryland (contract no. 290-02-0023). The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Study Selection and Evaluation We identified 6345 citations from electronic databases (n= 6207), reference lists (n= 45), and the Centers for Medicare & Medicaid Services (n= 93). After the initial screening, we reviewed 254 full manuscripts and excluded 179 of these studies after detailed evaluation (Figure 1). Figure 1. Flow of trials through the selection process. Sixteen disagreements among the reviewers about eligibility of the studies occurred for a value of 0.81. All disagreements were resolved by consensus. Of the randomized trials that were eligible for inclusion (13-87), 9 were reported in more than 1 publication. The second publication reported different end points in 2 cases (13-16), results from different follow-up periods in 5 cases (13, 17-26), and results from the subgroup of patients with cardiac disease in 1 case (27, 28). The ninth trial (the World Health Organization [WHO] trial) (29) included 24 collaborating centers; however, the original investigators excluded 7 sites because of poor participant follow-up and 4 sites because of statistically significant differences between the intervention and control groups at baseline. We included the outcome data from the remaining 13 sites as 1 trial for our analysis, an approach validated by the nonsignificant test results for statistical heterogeneity for all-cause mortality and MI. While the 2 Finnish centers in the WHO trial published their results separately (and for several follow-up periods), we included only their 3-year outcome data with the other 11 WHO sites for consistency of data presentation (30-32). Studies Included in the Systematic Review Table 1 presents summary data from the 63 unique randomized trials that were eligible for our systematic review (13-87). Our search retrieved 51 trials that were not included in our previous systematic review (which was limited to literature published before 1999 and excluded any studies with exercise components) (10) and 26 trials that were not included in a more recent systematic review of cardiac rehabilitation (which was limited to literature published before 2003 and included few individual counseling programs) (8). Table 1. Description of Included Studies Qualitative Data Synthesis In all trials, patients who were randomly assigned to the control groups received usual care (this was generally undefined). Table 1 describes the types of secondary prevention programs; few trials described the intensity of the interventions. Almost all trials enrolled highly selected study samples: Forty-five trials recruited patients after acute MI or a coronary revascularization procedure. Thirty-five trials excluded elderly patients, and 19 trials excluded women (Table 1). Indeed, women constituted fewer than 50% of study participants in all but 2 trials. No trial was double-blind (which is not surprising, considering the nature of the intervention), and very few trials described randomization procedures or accounted for discrepancies between sample sizes at recruitment and follow-up. As a result, Jadad quality scores clustered around 2 (Table 2). Furthermore, only 15 (24%) trial reports described adequate allocation concealment. Table 2. Methodologic Quality of Included Studies No trial reported side effects with the secondary prevention programs beyond the adverse clinical outcomes described later. Quantitative Data Synthesis All-Cause Mortality Only 1 of the 40 trials reporting this outcome f