“Evidence based medicine is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of the individual patient. It means integrating individual clinical expertise with the best available external clinical evidence from systematic research.” Dr.David Sackett, 1996
Randomized controlled clinical trials (RCTs) have been long considered as highest level evidence and have formed the basis of most current treatments in cardiovascular medicine. Despite their strengths, the limitations of RCTs are increasingly recognized in applying evidence in the clinical practice; this is especially true when various RCTs report conflicting findings. We have encountered this frequently in interventional cardiology where new technologies and treatments have to face intense scrutiny before becoming part of routine practice.
Last year two large much awaited RCTs–COAPT and MITRA-FR report their findings1, 2. To a cursory eye the results look conflicting and few of my colleagues in general internal medicine even describe them as ‘confusing’.
Larger of the two–the COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) is a RCT conducted across 78 centers in the United States and Canada1. COAPT investigators randomized 614 patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy1. Patient in device group had significantly lower rate of hospitalization for heart failure [35.8% per patient-year in the device group as compared with 67.9% per patient-year in the control group (hazard ratio, 0.53; 95% confidence interval [CI], 0.40 to 0.70; P<0.001) and all-cause mortality [29.1% of the patients in the device group as compared with 46.1% in the control group (hazard ratio, 0.62; 95% CI, 0.46 to 0.82; P<0.001)] within 24 months of follow-up1. Further, rate of freedom from device-related complications exceeded a prespecified safety threshold1. Whereas investigators in MITRA-FR trial (Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) randomized 152 patients with heart failure and severe secondary mitral regurgitation in a 1:1 ratio, to undergo percutaneous mitral-valve repair in addition to receiving medical therapy (intervention group) or to receive medical therapy alone (control group)2. At 12 month follow authors reported no significant difference in the rate of death [24.3% in the intervention group and 22.4% in the control group (hazard ratio, 1.11; 95% CI, 0.69 to 1.77)] or unplanned hospitalization for heart failure [48.7% in the intervention group and 47.4% in the control group (hazard ratio, 1.13; 95% CI, 0.81 to 1.56)] between patients who underwent percutaneous mitral-valve repair in addition to receiving medical therapy and those who received medical therapy alone2.
A closer look and detailed analysis of both RCTs can explain the differences in outcomes.
First, patient populations enrolled in these RCTs were different in terms of baseline valvular and ventricular characteristics1,2. Compared to MITRA-FR, COAPT enrolled patients with more severe mitral regurgitation [effective regurgitant orifice area-41 mm2 vs. 31 mm2]. Further, in COAPT the left ventricular end-diastolic volume (reflecting the status of the left ventricle) was smaller. Second, patient selection in COAPT was more stringent and only patients who are truly refractory to medical therapy [at the maximum tolerated dose before randomization] were included. This is reflected in higher baseline N-terminal pro–B-type natriuretic peptide levels among patients in COAPT trial. Also, percentage of patients who received more than a single clip was higher in COAPT. Whether this contributes to higher proportion of patients with moderate to severe MR at end of follow up in MITRA-FR remains unclear. Furthermore, the follow up period in MITRA-FR was 12 months, which could also contribute to difference in its finding with COAPT, where the Kaplan–Meier survival curves start diverging after 12 months. Long term follow up data from MITRA-FR can further clarify this.
In this era of evidence based medicine, results of COAPT and MITRA-FR once again exemplified how critical it is for clinicians to understand the methodology and patient characteristics enrolled in RCTs before extrapolating the finding to their patients. Not every secondary mitral regurgitation patient is a candidate for Clip. Patient selection is the key. The answer to ‘clip or not to clip’ is in knowing our patient well, including and not limited to their baseline clinical and echocardiographic parameters and optimal medical management of their heart failure before offering them this novel therapy. Sir William Osler has summarized it well more than a century ago, “He who studies medicine without books sails an uncharted sea, but he who studies medicine without patients does not go to sea at all3.
- Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter Mitral-Valve Repair in Patients with Heart Failure. N Engl J Med. 2018 Dec 13;379(24):2307-2318.
- Obadia JF, Messika-Zeitoun D, Leurent G et al. Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation. N Engl J Med. 2018 Dec 13;379(24):2297-2306.
- Osler W. (1904) Aequanimitas, With Other Addresses to Medical Students, Nurses and Practitioners of Medicine, Books and men (P Blakiston, Philadelphia, PA)]