Author + information
- Published online June 5, 2017.
- Harold L. Dauerman, MD∗ ()
- ↵∗Address for correspondence:
Dr. Harold L. Dauerman, University of Vermont Medical Center, Division of Cardiology, McClure 1, 111 Colchester Avenue, Burlington, Vermont 05401.
In this issue of JACC: Cardiovascular Interventions, Jovin et al. (1) present a large U.S. registry comparing the efficacy of anticoagulation strategies in primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction. Bivalirudin versus heparin has been the subject of multiple studies (2). The rationale for this National Cardiovascular Data Registry (NCDR) CathPCI study is twofold: first, this study focuses only on patients undergoing primary PCI via the radial artery approach, and second, the results of aforementioned comparison studies remain controversial. The investigators push the boundaries of the bleeding hypothesis: if the radial approach is dramatically reducing access site–related bleeding, is there any need for additional bleeding avoidance strategies (3)?
One trial, HEAT-PPCI (Unfractionated Heparin Versus Bivalirudin in Primary Percutaneous Coronary Intervention), has answered this question clearly (4). There was no benefit to bivalirudin compared with heparin for bleeding complications or ischemic events in a trial in which more than 80% of primary PCI procedures were performed via the radial approach. This trial is controversial and discordant, possibly for multiple reasons: single-center design, use of potent oral antiplatelet therapy, low use of glycoprotein inhibitors (GPIs), lack of post-PCI bivalirudin infusions, and high use of radial versus femoral access (5).
A registry study can bring clarity to controversy by describing current practice and how it varies over time and by comparing treatment strategies. Given controversies surrounding the HEAT trial, the observations of the NCDR CathPCI registry regarding bivalirudin versus heparin among patients undergoing radial access for primary PCI might provide confirmation that a heparin-only strategy is sufficient. Two other nationwide registries have similarly weighed in on this controversial area: the British Cardiovascular Intervention Society (BCIS) and SCAAR (Swedish Coronary Angiography and Angioplasty Registry) (6–8). If we sum up the primary PCI patients represented in these 3 national registries, can we prove that HEAT is right about radial artery primary PCI?
Bivalirudin and nationalism
The first objective of a large registry is the easiest one to achieve: describe and compare clinical, procedural, and treatment characteristics. The NCDR CathPCI registry has been able to analyze millions of U.S. patients and documents the increased adoption of radial artery PCI over the past 5 years (9). The scientific value of these observations is limited by the ability to represent all U.S. practitioners (which NCDR does not do as a site-based but not a population-based registry) and to capture adjudicated, accurate data.
The practical value of national databases is the observation of real differences in our national approaches to primary PCI (Table 1): from 2009 to 2015, only 11% of U.S. patients undergoing primary PCI received a radial artery approach (1), compared with the approximately 50% rate of radial artery–based primary PCI in Sweden and the United Kingdom (6,7). The MATRIX (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial (10) demonstrated a mortality benefit for radial artery versus femoral artery PCI for acute coronary syndromes; thus, U.S. quality improvement might focus primarily on the adoption of radial artery–based primary PCI as opposed to unresolved pharmacological controversies.
Given this disparity between national primary PCI access strategies, variations are expected in pharmacological practices across the Atlantic. Bivalirudin is used in only 6.8% of U.K. patients undergoing primary PCI, compared with approximately one-half of U.S. and Swedish patients (6–8). Two explanations are plausible: 1) increased use of radial artery PCI makes pharmacological avoidance of bleeding with bivalirudin less important to practitioners in the United Kingdom; and 2) economic disincentives exist in the United Kingdom that would make the more expensive pharmacological approach less appealing. Although the radial argument has some merit, at least 50% of major bleeding occurs at nonaccess sites in patients with acute coronary syndromes (3). Thus, even a country with enthusiasm for the radial approach might be interested in pharmacological approaches to bleeding avoidance if they could be proved effective.
Is bivalirudin better than heparin for primary PCI?
Sweden and the United States, unlike the United Kingdom, demonstrate pharmacological equipoise: approximately 50% of patients undergoing primary PCI receive a bivalirudin strategy. Using the NCDR registry to answer the question of who is right is attractive, as there will be no question of power. Large sample sizes and many events make for ample statistical power in outcome comparisons. Furthermore, the NCDR analysis is confined to radial-only primary PCI and thus removes a potential variable among the prior trials.
The conclusion of the NCDR radial primary PCI registry analysis seems to confirm the HEAT trial: there is no benefit with bivalirudin compared with heparin for either ischemic events or bleeding reduction. And as in HEAT, there is a 2.11-fold (95% confidence interval: 1.73 to 2.75) increased risk for acute stent thrombosis with use of the shorter acting bivalirudin anticoagulation strategy compared with heparin (4). A final nail in the bivalirudin primary PCI coffin would be confirmation by other large national registries; unfortunately, the BCIS and SCAAR analyses do not clearly confirm HEAT, and on closer inspection, it is not clear that NCDR does either.
In the BCIS primary PCI registry, only 6.8% of the nation received bivalirudin, and thus the analysis needs to be approached cautiously (6). The bivalirudin group is a selected population: although propensity-adjusted analyses is scientifically appropriate, residual confounding is possible. The BCIS analysis importantly recognizes the clear confounding of adjunctive GPI use in the heparin group (2) and thus describes 3 distinct groups: heparin only, heparin plus GPI, and bivalirudin. Using a 3-way comparison, 1 group stands out as having a higher early and late mortality after primary PCI: heparin only. The mechanism of the heparin only–associated mortality is not obvious from this registry analysis: bleeding rates are low (<1.0%) in all 3 groups, and variation in acute stent thrombosis rates is not reported.
Similarly, the SCAAR registry divides primary PCI anticoagulation into 3 distinct groups: heparin only, heparin plus GPI, and bivalirudin (7). Unlike HEAT and NCDR, there is no observed increased risk for acute stent thrombosis with a bivalirudin strategy. Again, some caution is required in making any strong conclusions about the comparative outcomes of the heparin-only group, as it represents only 10% of the primary PCI population. The SCAAR group presents a focused comparison of heparin-only versus bivalirudin patients undergoing primary PCI. Again, there are no differences in early stent thrombosis rates and similar rates of major bleeding (8). But the BCIS-like association is seen: patients undergoing primary PCI with heparin only had higher rates of both crude and adjusted mortality compared with bivalirudin-based primary PCI.
Are BCIS and SCAAR providing results opposite to both NCDR and HEAT? Is bivalirudin a better primary PCI anticoagulant? The NCDR analysis did not use a 3-group structure; its overall conclusions on heparin lump both heparin-only and heparin-plus-GPI strategies together such that the majority of patients in the heparin group actually did get adjunctive GPI: multivariate analysis is used to control for the GPI confounding, but this is not necessarily adequate. Thus, an important NCDR sensitivity analysis excludes patients receiving adjunctive GPIs and demonstrates: 1) increased risk for acute stent thrombosis with bivalirudin compared with heparin only; 2) a reduction in bleeding with bivalirudin versus heparin only; and 3) a disturbing increased risk for death with heparin only (odds ratio: 0.76; 95% confidence interval: 0.65 to 0.88 for bivalirudin in hospital mortality compared with heparin only).
Thus, we are left struggling for answers yet again. Despite more than 150,000 analyzed patients in national registries and 5 randomized clinical trials comparing primary PCI among patients treated with bivalirudin versus heparin strategies, we remain with 2 opposite conclusions: 1) HEAT is right: stent thrombosis is worse with bivalirudin, without any bleeding or mortality benefit in primary PCI; or 2) HEAT is wrong: as per the NCDR, BCIS, and SCAAR national registries, there is a mortality disadvantage to using heparin only compared with bivalirudin, which may or may not be related to bleeding reduction. Unfortunately, population size, statistical power, and national pride are not enough; if we really want to know whether bivalirudin is needed in radial-based primary PCI, we need to repeat HEAT.
Given the growth of radial primary PCI in the United States, a trans-Atlantic trial of radial access primary PCI is possible: an international, multicenter, 1,000-patient trial comparing radial-access primary PCI patients treated with heparin only versus bivalirudin, a <20% GPI bailout rate in both arms, and routine use of a 2-h post-intervention infusion at the PCI dose. Does bivalirudin still increase stent thrombosis risk? Does bivalirudin reduce bleeding complications compared with heparin only in radial-access patients? Does a heparin-only strategy confer a mortality risk? Until this trial is run, the large national registries will show us how our nations compare but tell us little about who is actually right.
↵∗ 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. Dauerman is a consultant for Medtronic, Edwards Lifesciences, and Boston Scientific; and has received research grants from Boston Scientific, Edwards Lifesciences, and Medtronic.
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