Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease | 2019
Is There a Real Association Between Paclitaxel Devices and Mortality? Time to Pause and Re‐Evaluate What We Know About This Statistical Finding
Abstract
D rug-eluting stents (DES) and drug-coated balloons (DCB) were approved in the United States on November 2012 and February 2015, respectively. Before this, the majority of patients with lower extremity femoropopliteal peripheral artery disease were treated with PTA (percutaneous transluminal angioplasty) or nitinol, self-expanding stents. However, these devices had significant rates of restenosis, which frequently led to repeat revascularization and were associated with increased healthcare costs. Therefore, the approval of DES and DCB had a profound impact on the management of lower extremity peripheral artery disease and led to the transitional passthrough code approval by Center for Medicare and Medicaid Services, which has rarely been designated for vascular devices. Since then, numerous analyses have consistently shown the clinical superiority of DCB over balloon angioplasty with long-term (5-year) data. Moreover, both DES and DCB have been shown to be cost-effective therapies, with improved quality of life. Indeed, given the strength of evidence, many experts have encouraged better reimbursement for DES and DCB to encourage wider utilization of these proven technologies. In addition, professional societies have graded this therapy as a class I recommendation with highest evidence. However, on December 6, 2018, the Journal of the American Heart Association (JAHA) published a meta-analysis by Katsanos et al that revealed an increase in long-term mortality with DES and DCB. Briefly, the study evaluated 28 randomized control trials across 12 devices for the treatment of femoropopliteal disease. At 1 year, the analysis included 4432 patients and showed no difference between the paclitaxel-eluting arm and the control arm for all-cause mortality (2.3% versus 2.3%, relative risk 1.06, 95% CI 0.72– 1.61). However, at 2 years with 2316 patients (n=12 studies), there was an increase in all-cause mortality with paclitaxel devices compared with control (7.2% versus 3.8%, relative risk 1.68, 95% CI 1.15–2.47). Similarly, at 4–5 years with 863 patients (n=3 studies), there was a persistently higher risk of all-cause mortality for paclitaxel devices compared with control (14.7% versus 8.1%, relative risk 1.93, 95% CI 1.27– 2.93). That increased risk was demonstrated as stable in various sensitivity analyses, including DES versus DCB. Moreover, the authors used a dose calculation formula to demonstrate that trials with a higher dose of paclitaxel had a higher risk ratio (highest with a 3.5-mg dose). This dose response was confirmed on meta-regression with 0.4% increased risk for every paclitaxel mg-year. Overall, the Katsanos et al meta-analysis was well conducted, given the available data; however, it also had many limitations. Most importantly, it did not provide an explanation for or proof of a causal relationship, but rather a hypothesisgenerating statistical association. It was a summary level meta-analysis which did not include patient-level data to adjust for clinical and angiographic differences between those who died and those who did not. Less than 50% of the included trials reported data beyond 1 year, 1 had 4-year results, and only 2 reached the 5-year time point. There were a significant number of patients lost to follow-up who were not accounted for in this meta-analysis. Furthermore, the study was conducted as an intention-to-treat analysis; while this is the most valid approach to assess efficacy in randomized clinical trials, it does not represent the “true paclitaxel exposure” when assessing a safety signal, particularly because many of these trials had substantial crossover to the experimental treatment arm. Additionally, the dosedependent relationship is likely to be flawed, because the equation used to assess the paclitaxel dose/time relationship From the Case Western Reserve University School of Medicine and Harrington Heart and Vascular Institute, University Hospitals, Cleveland, OH (M.H.S.); The Smith Center for Outcomes Research in Cardiology (E.A.S.) and Division of Cardiology, Department of Medicine (E.A.S.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Department of Surgery, Prince of Wales Hospital, Sydney, Australia (R.L.V.); University of New South Wales, Sydney, Australia (R.L.V.). Correspondence to: Mehdi H. Shishehbor, DO, MPH, PhD, Case Western Reserve University School of Medicine, University Hospitals, 11100 Euclid Ave, Lakeside 3rd Floor, Cleveland, OH 44106. E-mail: [email protected] J Am Heart Assoc. 2019;8:e012524. DOI: 10.1161/JAHA.119.012524. a 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.