Author + information
- †Zena and Michael A. Wiener Cardiovascular Institute of the Icahn School of Medicine at Mount Sinai, New York, New York
- ‡Cardiovascular Research Foundation, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Roxana Mehran, The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1030, New York, New York 10029.
Bleeding complications after transcatheter aortic valve replacement (TAVR) are common. Reported rates of major bleeding at 30 days include 9.3% and 16.8% in the high- and extreme-risk cohorts of the PARTNER (Placement of Aortic Transcatheter Valve) trial (1,2), 24.1% in the extreme-risk cohort of the CoreValve U.S. Pivotal Trial (3), and 7.2% to 9.7% in large international registries (4). Major or life-threatening bleeding events, as classified by the Valve Academic Research Consortium (5), are potent predictors of mortality (6–9). To the extent that anticoagulation used during TAVR may influence periprocedural bleeding risk, there is a need to identify best anticoagulation strategies to minimize clinically important bleeding while maintaining antithrombotic efficacy.
A joint expert consensus document published in March 2012 favors use of anticoagulation during TAVR to maintain an activated clotting time (ACT) of >300 s (10), but the basis for this target and means to achieve it are ill-defined. In this issue of JACC: Cardiovascular Interventions, Bernelli et al. (11) contribute important new observations from a comparison of 2 strategies for initial unfractionated heparin dosing during TAVR on the basis of weight or baseline ACT.
The investigators conceived an ACT-based dosing strategy after noticing that ACT was often elevated in TAVR patients at baseline. Their protocol specified initial administration of 5,000, 4,000 or 3,000 U of unfractionated heparin for ACT <140 s, 140 to 175 s, or ≥175 s, respectively. Over a span of 5 years, this ACT-based dosing strategy was used with roughly equal frequency (n = 174) in comparison with a conventional dosing strategy of 80 units of unfractionated heparin per kilogram of actual body weight (n = 188). In all patients, after initial dosing, unfractionated heparin was titrated in an unspecified manner to achieve an ACT of 200 to 300 s. For the present analysis, the investigators retrospectively compared patients at a single center selected for each strategy with respect to a primary outcome measure of 30-day major bleeding.
Consistent with reported outcomes, major bleeding was common at 30 days (21.0%), mostly procedure-related (82.4%), and associated with increased mortality. Differences in bleeding between the 2 treatment groups were striking, with a nearly 4.5-fold higher incidence of major bleeding among patients treated with a weight-based dosing strategy (33.5% vs. 7.5%, p < 0.001), as well as a significantly higher rate of life-threatening bleeding (20.2% vs. 12.1%, p = 0.04). Upon multivariable adjustment, use of an ACT-based dosing strategy was associated with better than 6:1 odds of freedom from 30-day major bleeding.
Although these differences in bleeding are dramatic, these findings must be interpreted with caution. Retrospective analysis is flawed for the purpose of comparing strategies, even with propensity adjustment as the investigators did. Despite a nonparsimonious model incorporating 42 separate variables, likelihood of residual confounding remains. In particular, it is notable that of the 4 operators at this single center, 2 preferred 1 dosing strategy and 2 preferred the other. Although choice of strategy was “fairly balanced,” as the investigators note, it is difficult to separate the choice of strategy here from the choice of operator. Given the importance of technical skill and experience in optimizing vascular access and closure in TAVR, operator differences in this relatively small sample may have exerted significant impact on bleeding outcomes. Indeed, in a separate analysis of the data excluding the earliest 59 patients to account for a learning curve, differences in life-threatening bleeding were attenuated.
Second, this study calls into question the appropriate use of ACT for anticoagulation monitoring in the particular setting of TAVR. With current practice derived largely empirically from the PARTNER trial and extrapolation from percutaneous coronary intervention (4), we may inadequately account for hemostatic differences between patients with coronary disease and patients with severe aortic stenosis.
Perhaps the most interesting observation of this study is the one that inspired it: the elevated baseline ACT in patients with severe aortic stenosis (159.1 s, compared with 136.1 in contemporary control subjects with coronary artery disease). ACT is a point-of-care test that measures the time necessary for whole blood to clot upon introduction of an activator of the intrinsic coagulation cascade, such as celite, kaolin, or glass beads (12). Although useful for measuring the effects of high-dose heparin or the direct thrombin inhibitor bivalirudin, ACT may also be influenced by abnormalities of platelet count or function. This is highly pertinent in severe aortic stenosis, in which high molecular weight multimers of von Willebrand factor may fragment across the calcific aortic valve. When combined with submucosal angiodysplasias and tendency to gastrointestinal bleeding, this acquired deficiency of von Willebrand factor forms the basis for what is known as Heyde syndrome (13). Variable accompanying deficiency of factor VIII, which binds von Willebrand factor in plasma, impairs the intrinsic coagulation cascade, with potential impact on both the effects of heparin and the ACT (14).
Whatever the means of determining dosing, it is likely that lower total doses of heparin contributed to observed differences in bleeding events. Patients in the ACT-guided dosing group received 33% less heparin overall (4,000 vs. 6,000 U, p < 0.001). It has been hypothesized, and the investigators discuss, that the advanced age, frailty, and comorbidities common to patients undergoing TAVR may alter the pharmacokinetics and pharmacodynamics of heparin such that lower doses are needed to achieve the desired antithrombotic effect.
Whereas it is plausible that reduced heparin dosing may reduce periprocedural bleeding events, the determination of whether this constitutes a best strategy for anticoagulation awaits the results of a large, prospective randomized trial designed to evaluate not only bleeding endpoints but also carefully adjudicated thrombotic endpoints including stroke. In this study, there were 5 strokes (1.4%) and 4 transient ischemic attacks (1.1%), figures that are low in comparison with results of the PARTNER (4.7%) (2) and CoreValve trials (3.9%) (3) and reported registries outside of Italy (1.9% to 5.0%) (4).
Above all, this study underscores the opportunity to improve bleeding avoidance during TAVR. Beyond heparin, additional options for anticoagulation are on the horizon with potential to reduce periprocedural bleeding, including bivalirudin, now well established as a bleeding-avoidance strategy during percutaneous coronary intervention (15). We look forward to the results of the ongoing BRAVO 2/3 (Effect of Bivalirudin on Aortic Valve Intervention Outcomes 2/3) randomized trial of bivalirudin versus unfractionated heparin in patients undergoing transfemoral TAVR (16).
↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
Dr. Tomey has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Mehran has received institutional research grant support from The Medicines Company, Bristol-Myers Squibb, sanofi-aventis and Eli Lilly, and Daiichi Sankyo; has received consulting fees from Abbott Vascular, AstraZeneca, Boston Scientific, Covidien, CSL Behring, Janssen Pharmaceuticals, Maya Medical, Merck & Co., Inc., Regado Biosciences, and sanofi-aventis; and has served on advisory boards for Covidien, Janssen Pharmaceuticals, and sanofi-aventis.
- American College of Cardiology Foundation
- Popma J.J.
- Rodés-Cabau J.,
- Dauerman H.L.,
- Cohen M.G.,
- et al.
- Kappetein A.P.,
- Head S.J.,
- Généreux P.,
- et al.
- Ussia G.P.,
- Barbanti M.,
- Petronio A.S.,
- et al.
- Borz B.,
- Durand E.,
- Godin M.,
- et al.
- Holmes D.R. Jr..,
- Mack M.J.,
- Kaul S.,
- et al.
- Bernelli C.,
- Chieffo A.,
- Montorfano M.,
- et al.
- Bates S.M.,
- Weitz J.I.
- National Heart, Lung, and Blood Institute
- Dauerman H.L.,
- Rao S.V.,
- Resnic F.S.,
- Applegate R.J.