Author + information
- Doralisa Morrone, MD∗ (, )
- Mario Marzilli, MD,
- Paul Kolm, PhD and
- William S. Weintraub, MD
- ↵∗Cardiothoracic Department, Division of Cardiology, University Hospital of Pisa, via Paradisa 2, Pisa 56124, Italy
Since 1990, multiple randomized clinical trials (RCTs) and subsequent meta-analyses have compared the outcome of percutaneous coronary intervention (PCI) medical therapy for stable ischemic heart disease with no difference in primary outcome (death and/or myocardial infarction [MI]) between the 2 approaches. The reasons for this are not clear. It is certainly possible that there is no difference between the 2 strategies; alternatively, the patient populations may not have been appropriate, or the study hypothesis may not have been sufficiently focused on the right question.
From 1980 until now, approximately 195,213 patients have been screened for enrollment in trials, of whom only 3.2% were randomized and about 26% did not have a positive noninvasive test for ischemia or symptoms of angina. Moreover, the percentage of patients with coronary atherosclerosis included in the trials, without proven ischemia or angina, is quite variable among the studies (Figure 1).
It can be difficult to interpret the results of the clinical trials because of missing data in the published papers and because the differing knowledge about ischemia at the time of each trial. At the time of the earlier RCTs, the common thought was that the simple presence of stable stenosis, even in the absence of a positive provocative test, was associated with an adverse cardiovascular event, and for this reason, PCI should be able to improve the natural history. It was consistent with the original hypothesis to include patients with angiographic coronary artery disease (CAD), even in the absence of inducible ischemia. Only recently—in the era of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial (1) and the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) trial (2)—that the fundamental prognostic significance of inducible ischemia has been more appreciated, and even then not entirely consistently. Thus, the COURAGE trial conclusively demonstrated that PCI as an initial therapeutic strategy does not reduce the risk of death, MI, or other major cardiovascular events when added to optimal medical therapy (OMT) in patients with stable ischemic heart disease. However, even the COURAGE trial cannot be generalized to patients with a large ischemic burden (1).
In 2009, the FAME investigators reported that PCI guided by fractional flow reserve (FFR) could reduce the incidence of cardiovascular events when compared with angiographically guided PCI. The primary endpoint (composite of major cardiac events) at 1 year occurred in significantly fewer patients in the FFR-guided group than in the angiographic-guidance group (13.2% vs. 18.3%; p = 0.02) (2,3). Recently, on the basis of the FAME I trial, De Bruyne et al. (4) hypothesized that in patients with stable CAD and stenosis, PCI performed on the basis of the FFR would be superior to OMT. The 2-year follow-up of the FAME 2 trial reported that the benefit of FFR-guided PCI was a decrease in urgent revascularization at the expense of 351 more revascularizations in the PCI group when compared with the OMT group, without an effect on death or MI. Still, 10% of patients in the PCI group had angina at 6-month follow-up despite optimal revascularization, with 80% in the OMT group free from angina. Patients included in the registry group of the FAME 2 trial had the same clinical presentation despite absence of the significant stenosis (4).
RCTs remain the most accepted design for estimating the effects of interventions, but they have not consistently answered the question of primary interest: are these results generalizable to patients with ischemic heart disease? The answer is equivocal because clinical trials have not consistently represented patients with ischemia that could potentially benefit from PCI. RCTs comparing OMT to PCI are associated with 2 main problems: low generalizability (trials with strict selection criteria) or suboptimal internal validity (e.g., proven CAD without proven ischemia). Trials comparing OMT to PCI do not uniformly and consistently reflect the ischemic population. Moreover, the complexity of the mechanisms contributing to myocardial ischemia is largely underestimated, and thousands of revascularization procedures are performed every year (5). Clinical trials are the most powerful method to avoid bias, and selection of the right population that could benefit from revascularization is mandatory.
Please note: Dr. Kolm is a statistical editor for the Journal of the American College of Cardiology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation