This Changes Nothing: Treatment of Stable Ischemic Heart Disease in 2018
A point-counterpoint piece by Dr. North Noelck, M.D., M.P.H.
Controversy surrounds recent publications determining the optimal approach to management of patients with stable ischemic heart disease.
The Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA, Lancet 11/2017) trial and Fractional Flow Reserve (FFR)-Guided PCI versus Medical Therapy in Stable Coronary Disease (FAME 2, NEJM 7/2018) trial offer differing conclusions on the approach to angina therapy. Here, we discuss the role of medical therapy versus percutaneous coronary intervention (PCI) in stable ischemic heart disease (SIHD). First- a brief description of the trials and results.
The FAME 2 Trial used an invasive pressure-wire based fractional flow reserve (FFR) index to confirm functional significance of anatomically visible stenosis (i.e. the likelihood that a coronary plaque was stenotic and able to induce myocardial ischemia). Patients with at least one stenosis that was functionally significant (defined as an FFR ≥ 0.80) were randomly assigned to FFR-guided PCI versus the best available medical therapy (the trial was non-blinded). The primary end-point was a composite of death, myocardial infarction, or urgent revascularization. Over the course of 5 years at least one primary end-point event occurred in 62 patients (13.9%) in the PCI group, as compared with 119 (27.0%) in the medical-therapy group (hazard ratio, 0.46; 95% confidence interval, 0.34 to 0.63; p-value: < 0.001). The conclusion: FFR-guided PCI reduced the need for urgent revascularization when compared with medical therapy alone for functionally significant stenoses.
The (ORBITA) Trial was performed to assess the efficacy of PCI compared with a sham placebo procedure for angina relief among patients with stable angina. The ORBITA trial demonstrated that among carefully selected patients with stable angina, PCI does not result in significantly greater improvements in exercise times or anginal frequency compared with sham procedure despite the presence of anatomically and functionally (FFR positive) significant stenoses.
In Favor of Medical Management
PCI in the treatment of acute coronary syndromes (ACS) was painstakingly proven to provide benefit over medical management by the end of the 20th century. We have continued to innovate and later permutations of PCI have improved on the safety of the procedure (less bleeding) and durability of the outcomes (less stent thrombosis and in-stent restenosis). As stenting became more prevalent its use was expanded to patients with SIHD, and cardiologists began to question whether medications alone or medications with stenting provided improved outcomes. Trials published in 2007 (COURAGE, NEJM) and 2009 (BARI 2D, NEJM) failed to show a durable benefit of PCI over medical therapy alone when angiography alone was the tool to assess stenoses.
FFR promised a functional assessment of ischemia which could improve upon the use of angiography alone in selecting which stenoses would benefit from PCI (see the original FAME trial). FAME 2 was designed to compare this new and fancy tool to optimal medical therapy in SIHD. The trial was positive (FFR-guided PCI was deemed more effective), but there are some points to be made – specifically regarding the efficacy of medical therapy. At randomization 67% of patients had class II to IV angina. This decrease to 29% at 30 days, 19% at 6 months, and 16% at 12 months. Over the course of 5 years, approximately half of the patients in the medical group did end-up receiving revascularization at some point. Thus, from many perspectives, it seems sounder to defer PCI: 1) less up-front peri-procedural risk; 2) avoidance of dual antiplatelet therapy; and 3) reduced cost. Why intervene on all patients to avoid the need to intervene on a few?
Popular teaching would have you believe that stents can reduce angina symptoms in patients with SIHD, and our clinical experience confirms this. The authors of the ORBITA trial were not so sure. They randomized a small number of patients to PCI or a blinded sham procedure (neither patients nor assessing physicians knew which group was which) and then performed cardiopulmonary exercise testing, dobutamine stress echocardiography, and administered a symptom questionnaire. Exercise time was increased, but was not significantly greater in PCI patients compared to patients who had the sham procedure (28.4 seconds vs. 11.8 seconds, respectively, p-value= 0.2). There was also no significant difference in reported angina between the groups. And so, it appears we re-learn the power of the placebo effect.
In Defense of Percutaneous Coronary Intervention
The heart of this question lies in our ability to discern which patients are more likely to benefit from revascularization compared to those that will respond appropriately to medical therapy. Over the years we have identified patients that benefit from revascularization: those with 3 vessel disease or significant left main coronary artery stenoses. We have proven the benefits of PCI in patients suffering from STEMI and NSTEMI markedly improving survival rates compared to medical therapy and reducing intermediate and long-term sequelae.
FAME 2 has received significant criticism primarily because the demonstrated benefit of PCI was limited to the “soft” endpoint of urgent revascularization. Allowing for the significant reduction achieved in symptomatic relief by medications the FAME 2 data is remarkable for more rapid relief and a durable result in the PCI group. At randomization, 70% of patients had class II or greater angina. By 30 days after enrollment only 10% of PCI patients had angina compared to 29% in the medical therapy arm (RR 0.36; 95% CI 0.26-0.49, P<0.001). data-preserve-html-node="true" This significant reduction in angina is carried through 3 years where only 5.2% of subjects in the PCI group complained of angina compared to 9.6% in the medical therapy arm (RR 0.54; 95% CI 0.33-0.89; P=0.014). It is clear PCI affords patients with SIHD rapid and durable relief from anginal symptoms. ORBITA appears to call into question the theory that that relieving the functionally ischemic stenoses is the true source of angina relief. This small study of carefully selected individual with a short duration of follow-up found that exercise was improved somewhat in both the sham and PCI groups. However, functional testing with dobutamine stress echocardiography noted an improvement in wall motion from baseline in subjects who underwent PCI and no improvement in those who underwent the sham procedure. With this data we can safely conclude that PCI is physiologically effective and significantly reduced a patient’s ischemic burden.
Take-Home Points: At the present, I believe the following can be concluded from these differing studies: Optimal medical therapy should be the first line therapy for cardiac angina. However, PCI remains a viable option for relief from cardiac angina in stable ischemic heart disease. Stay tuned for results of the ISCHEMIA trial (it’s sure to be definitive).