Bivalirudin is theoretically a promising alternative to unfractionated heparin (UFH). It is a direct thrombin inhibitor and has the ability to block circulating and clot-bound thrombin and prevent thrombin-mediated platelet activation.1 Glycoprotein IIb/IIIa inhibitors (GPI), such as the selective antibody abciximab or the small molecules tirofiban and eptifibatide on the other hand, are not alternatives to heparin but can, in addition to UFH, inhibit platelet aggregation by directly blocking their GPIIb/IIIa receptor. Either of these two strategies is used during most percutaneous coronary procedures for anti-aggregation/anti-coagulation and they contribute significantly to the procedural costs.2 The choice between the two drug strategies is influenced by the patient’s ischemic and bleeding risk and somewhat (we suspect largely) by operator’s preference. Often, bivalirudin is preferred because of its simple protocol and the reduced risk for bleeding. But are we sacrificing something in our need for simplicity and the desire to minimize bleeding?
Results based on “real-world” data such as presented by Kim et al3 are especially important in this field. This study compares outcomes of diabetic patients treated with bivalirudin versus GPI. Diabetics are more likely to develop stable or unstable coronary artery disease, need PCI, and remain at higher risk for complications from any revascularization procedure.4 On one hand, the effect of GPI antagonists has been demonstrated to be especially effective in this group5 while they are at higher risk for bleeding on the other hand.6,7 Platelet aggregation is significantly influenced by diabetes highlighting the need for effective antiplatelet therapy in this population.7 The analysis by Kim et al is based on a registry of a single high-volume center; between 60 and 70% of the patients had NSTEMI or unstable angina while 30 to 40% were elective interventions. Of these, 428 patients (54.5%) received bivalirudin, and 358 patients (45.5%) received unfractionated heparin (UFH) plus GP IIb/IIIa inhibition. The incidence of in-hospital death, post-procedural myocardial infarction, and MACE (defined as death, MI, stroke, or urgent revascularization) was similar in both groups, with less minor bleeding (9.6% vs. 14.5%; p = 0.035) in the bivalirudin group. Although, unadjusted mortality was higher in the bivalirudin group (HR 1.80, 95%CI 1.0–3.1; p = 0.040), after a multivariate propensity-score based adjusted multivariate Cox regression analysis, this difference was no longer statistically significant (HR 1.63, 95%CI 0.90–2.94; p = 0.106). The authors used appropriate statistical methods to adjust for confounding factors. The authors readily acknowledge the limitations of their study, such as the inability to control for variables that were not measured and possibility of residual confounding. Of note, another drawback is the limited study size, especially in the context of the multivariate analysis. The reason why randomized trials in this field enrolled several thousand patients is the rarity of the endpoint occurrence. The main conclusion of the study is that minor bleeding risk is decreased with bivalirudin in this real-world population while major bleeding or risk for ischemic events may be comparable between both treatments.
The truth is rarely pure and never simple.
Oscar Wilde, The Importance of Being Earnest, 1895, Act I
These data are in line with findings of recent randomized trials and other observational studies.6,8 The substudy of the REPLACE 2 trial in diabetic patients consistently found similar outcomes for ischemic events and major bleeding but reduced risk for minor bleeding.9 Taken together, these data suggest that the decision to use bivalirudin versus GPI should not be influenced by a patient’s diabetic status. Of note, neither the present study by Kim et al nor the REPLACE 2 diabetic substudy were prospectively planned non-inferiority studies and absence of statistical significance between two treatments does not necessarily prove their equivalence. Several recent trials met their prespecified endpoint demonstrating non-inferiority of bivalirudin versus GPI and in addition found reduced bleeding risk.10,11 Yet, most interventionalists have not switched to using bivalirudin exclusively and the use of GPI remains common in clinical practise. Firstly, while bleeding is a major predictor of death, no trial has demonstrated a reduction in mortality with bivalirudin despite convincing reduction in bleeding events. It is plausible that the non-significant trends towards increased ischemic events in the bivalirudin arm is countering the survival benefit one might expect with reduced bleeding. Secondly, some of these trials used composite endpoints that included opposite outcomes such as bleeding and ischemic events which can be problematic to balance especially as the definition of what is a major hard endpoint has been extended beyond death and near fatal bleeding or a Q-wave MI to include other endpoints with less morbid implications.10,11 Taking a careful look at the data, some doubt may arise about a truly non-inferior efficacy of bivalirudin compared to GPI, especially in patients who are not pre-loaded with clopidogrel (which represents a large proportion of “real-world” patients). In the ACUITY trial, patients assigned to bivalirudin monotherapy who were not pretreated with clopidogrel had a significantly increased risk for ischemic events as compared with those treated with GPI.12 Unlike in many randomized prospective trials where clopidogrel is frequently given prior to PCI, clopidogrel is often given during or shortly after the procedure in everyday practice. Over the mid and longer term, clopidogrel is (so far) the most important “anti-ischemic” agent after stent implantation. However, when administered to a clopidogrel naïve patient it takes several hours until sufficient platelet inhibition is achieved; clopidogrel is a pro-drug and has first to be metabolized to its active form, 2-oxoclopidogrel. The key challenge for every day practice had been for a long time to define the optimal antithrombotic strategy in patients who presented to the catheterization laboratory without prior clopidogrel therapy. This question may be less important now with the availability of prasugrel which with its rapid onset of action and better bio-availability can overcome the drawbacks associated with clopidogrel loading in the catheterization laboratory.
While clinical trials provide answers for what is best in a large well selected population, extrapolation of these results to an individual patient defines the synergy of the art and science of medicine. Whether to minimize an ischemic event at all cost by using GPI and placing him/her at a higher risk for bleeding or making the opposite trade by using bivalirudin to minimize bleeding risk should not be a polarized debate. An anticoagulation strategy guided by a careful evaluation of the individual patient’s risk for bleeding and ischemic events can help the operator tailor the right drug for the right patient.
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From the Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, and VA Ann Arbor Health Care System, Ann Arbor, Michigan.
Disclosure: P. Meier is supported by a research fellowship grant by the Swiss National Research Foundation SNF and SSMBS.
Address for correspondence: Hitinder Gurm, University of Michigan Cardiovascular Center, 2A394, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-5853. E-mail: hgurm@med.umich.edu
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