key: cord-351163-lyj94xn8
authors: Rocha-Singh, Krishna J.
title: Retrospective Real-World Studies of Paclitaxel and Mortality: Defining the Many Faces of Bias
date: 2020-05-14
journal: JACC Cardiovasc Interv
DOI: 10.1016/j.jcin.2020.05.006
sha: 
doc_id: 351163
cord_uid: lyj94xn8

[Figure: see text]

Meeting, did little to provide clarity. The FDA's internal meta-analyses of industry-sponsored, pivotal randomized controlled trials (RCTs) concluded that there was a 1.57 (95% CI, 1.16-2.13) increase in relative risk over 5-yrs. (2) Ultimately, the Advisory Panel concluded that, indeed, there was a late mortality signal present, but given the small sample size, missing data, lack of apparent dose-related effect, lack of potential physiologic mechanism, the finding should be interpreted with caution, given the remaining uncertainty of the risk magnitude and its impact on benefit/risk consideration of device use. (8) Ultimately, the Agency recommended that PTX devices be reserved for patients judged to be at "high-risk" for restenosis, in which the benefits of device use may outweigh their risk of use and updated device labeling to communicate the mortality risk (3). However, despite these pronouncements, the PTX mortality concern persists as an unresolved controversy, slowing patient enrollment clinical trials of PTX-coated devices in other vascular beds, consuming innumerable regulatory agency and societal financial and human resources, and prompted realignment of strategic investments and device development toward non-PTX coated devices. In the face of this unresolved issue, rooted in limitations of the underlying data, the medical care of these patients remains impacted.

Recently, Vascular InterVentional (VIVA) Physicians (4) reported their independent mortality assessment of manufacturer-supplied, independent patient-level data (IPD) from randomized controlled trials (RCTs) that evaluated FDA approved paclitaxel-coated balloons and stents used to treat peripheral arterial disease. Their primary analysis reported a 38% relative risk in mortality hazard (hazard ratio (HR)=1.38 with 95% CI 1.06, 1.8) through 5 years for paclitaxel-coated devices compared to uncoated devices. Notably, when the loss-to-follow-up rates of 25% and 27% in the control and treatment arms, respectively, were reduced to 9% and 10% through additional efforts to obtain complete follow-up-status, the increased mortality risk dropped to 27% (HR= 1.27 with a 95% CI 1.03, 1.58). No mechanism of action or association between doses and mortality was identified. The VIVA meta-analysis, based on the most complete available data set of mortality events from PTX-coated devices in RCTs to date, appeared to corroborate a PTX mortality signal identified by Katsanos et. al., and the FDA, although using patient-level data with more complete patient follow-up.

In subsequent public discussions, the FDA Center for Device and Radiologic Health Into this statistical cauldron, Bohme and colleagues (7) present their single-center, retrospective real-world analysis of DCB and POBA associated mortality in 1,579 patients followed for a mean follow-up of 52 months. After propensity score matching, they concluded that DCB use conferred a survival benefit. The investigators hypothesized this survival benefit may be from increased patient mobility, although they presented no data to support this theory.

The inclusion of this large, retrospective observational dataset must come with full acknowledgment of the potential inherent bias. Observational studies and randomized trials can contribute complementary evidence about the effects of treatments on mortality and non-fatal outcomes. However, due to the inherent potential for moderate and large biases, the role of observational studies is generally limited, as potential biases can obscure, over-estimate, and even reverse the real effect of the treatment under question. As such, their role in the direct assessment of the impact of a particular treatment on a major outcome (i.e., mortality) must be carefully scrutinized (9, 10) . First, it is essential to acknowledge the possible multiple confounding variables, extraneous influences, which may impact a conclusion. In this regard, Bohme et al., note that their analysis is a single-center study, casting doubt on generalizing their conclusions. More importantly, they fail to advise the reader of the risk of a substantial selection bias introduced by selecting only 800 patients from a database of over 7,000 patients. The study initiation period began in 2011, a timeframe in which both treatments were available. The nonrandom assignment interjects another selection bias: Over the six-year observation period, the ratio of patients who received DCB vs. POBA reversed, with DCB use increasing >200%. It may be unlikely that those not selected for analysis and received POBA in 2011 were different than those in 2017. Moreover, the rigor of the propensity score modeling is unstated; reliance on statistical significance for model selection rather than principles of causality and assessment of balance after matching are critical issues. (11) Furthermore, the potential for informational bias is a concern when such observational studies use electronic medical records to identify patients with preexisting conditions or who have undergone previous procedures that can be reported or that have been incorrectly/incompletely reported. As a result, such misclassification may distort the association between treatment exposure and outcome and alter conclusions. Importantly, the extent of potential attrition bias, those patients loss-to-follow-up was not fully defined. While the investigators acknowledge that when mortality could not be discerned in their database, either the patient or patient's physician was called. However, the exact loss-to-follow-up rates in the two treatment arms were not disclosed. Attrition bias is particularly concerning when it is unequal between treatment arms, as patients with missing vital status data may have poorer outcomes. Moreover, the inability of the investigators to define the cause of death in nearly half of the cases detracts from any inference of a potential mortality benefit of DCB use.

Close attention to study methodologies and inherent, undisclosed bias is essential to weighing the veracity of a study's conclusions. Bohme et. al., leave many questions unanswered, including the mechanism of observed increase in late term POBA-related mortality and how the risk/benefit profile of these devices may shift across patient populations. Regardless, critical analysis of any conclusion is part of a larger story that builds a body of knowledge and allows for the further consideration of the effect of DCBs vs. POBA on mortality, if any. However, as our medical community turns to address the challenges of the COVID-19 pandemic, this PTX mortality issue will take its rightful 'back burner' place to our more pressing concerns.

Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: A systematic review and meta-analysis of randomized controlled trials

Circulatory System Devices Panel of the Medical Device Advisory Committee

US Food and Drug Administration Update: Treatment of peripheral arterial disease with paclitaxel-coated balloons and paclitaxel-eluting stents potentially associated with increased mortality-letter to health care providers

Mortality and paclitaxel-coated devices: An individual patient data meta-analysis

Association of survival with femoropopliteal artery revascularization with drug-coated devices

Drug-eluting stent implantation and long-term survival following peripheral artery revascularization

Evaluation of mortality following paclitaxel drug-coated balloon angioplasty of femoropopliteal lesions in real world

Confounding, and Interaction: Lions and Tigers, and Bears

Reliable assessment of the effects of treatment on mortality and major morbidity, II: observational studies

An introduction to propensity score methods for reducing the effects of confounding in observational studies