This post is not about desirable personal characteristics but about 2 studies that have attempted to determine if PCI combined with optimal medical therapy (OMT) is better than OMT alone in patients with stable angina. This is an important question because a lot of costly PCIs are done on patients with stable angina. I am not a cardiologist so I will not comment on the technical aspects of these studies but will instead focus on design issues that I think temper the results of these important studies, especially FAME2.
FAME2 was released online this week by the New England Journal of Medicine (http://www.nejm.org/doi/full/10.1056/NEJMoa1205361?query=featured_home) while COURAGE was published in 2007 (http://www.nejm.org/doi/full/10.1056/NEJMoa070829). COURAGE was the first trial to combine state of the art (at the time) PCI with state of the art medical therapy (which still holds true today) for CAD. COURAGE has been criticized because many of the patients were VA patients and for the use of mostly bare metal stents. Critics have ignored the fact that bare metal stents are similar to drug eluting stents (DES) in most outcomes except for restenosis.
FAME2 enrolled patients with stable angina, who had one coronary vessel with at least 50% stenosis that was suitable for PCI. Inherent in these inclusion criteria is the angiographic knowledge of the patient’s coronary anatomy. Often in clinical practice we make decisions on treatment without this knowledge; but based on symptoms and noninvasive assessments alone. Study design quality was generally good: randomization was used, randomization scheme was concealed, intention to treat analysis was used, the 2 study groups were similar at the start of the study, and the groups were treated equally other than the treatment under study. Patients and clinicians were not blinded but this is less important in this study as the outcomes were fairly objective.
So what problems do I have with FAME2? Whenever you read a study and identify a limitation you should always ask yourself what impact that limitation could have on the results of the study. I am especially trying to identify design issues that bias the results towards one group over the other.
- The endpoint of the trial is a composite of death from any cause, nonfatal MI or unplanned hospitalization leading to urgent revascularization. Patients would consider each component equally important in a good composite and clearly death would be much less preferred than urgent revascularization. Each of the components of the composite should have a similar biological mechanism and clearly they don’t. Finally the components of a good composite should be affected fairly equally by the intervention and here they aren’t (death is insignificantly reduced by 67%, MI is increased insignificantly by 5%, and revascularization is reduced by 87%). This doesn’t mean we reject the trial it just means you should look at each individual component instead of using the composite.
- All stenoses with a fractional flow reserve (FFR) <0.8 were treated with the current state of the art DES. Sounds great…..fix everything you see. The problem is that this biases the study positively toward the PCI group because if you fix everything and not just lesions that cause ischemia by functional testing you will leave fewer lesions to cause any problems in the future and thus need less revascularization.
- The trial was stopped early. Too early considering there were no formal stopping rules. Furthermore the trial was stopped because the PCI group needed less urgent revascularizations than the OMT group….a finding that was predictable as I mention in #1 above. By stopping a trial early you never know what the longer term effects of your study will be (both good and bad) .
- The landmark analysis using day 7 as the landmark point seems arbitrary and its rationale isn’t explained in the manuscript. This will also bias findings positively towards PCI because PCI has immediate effects whereas medications take more time to work.
- The study wasnt blinded and knowledge of the treatment arm could definitely influence treatment decisions. Knowing a patient was in the OMT arm and still having angina might lead to the recommendation of PCI more often than intensifying OMT.
So what should readers of FAME2 take away from the study? In patients with stable angina PCI only reduces angina and the need for future “urgent” revascularizations and this reduction is likely overestimated. PCI doesn’t prevent death and it doesn’t prevent MIs. COURAGE showed us the same thing. Optimal medical therapy works and we should strive to get patients on OMT as outlined by COURAGE and FAME2. Finally, all studies have limitations; there is no perfect study but understanding what effect the limitations would be expected to have on the outcomes can help us better temper the results.