Efficacy and Safety of Bivalirudin in Patients with Diabetes Mellitus (Full title below)

Efficacy and Safety of Bivalirudin in Patients with Diabetes Mellitus Undergoing Percutaneous Coronary Intervention in Current Clinical Practice

ABSTRACT: Objectives. This study sought to evaluate the short- and long-term efficacy and safety of bivalirudin in diabetic patients undergoing percutaneous coronary intervention (PCI) in contemporary clinical practice. Background. Early trials of platelet glycoprotein (GP) IIb/IIIa inhibitors have suggested a survival benefit in diabetic patients undergoing PCI. More recently, randomized trials have demonstrated that diabetic patients have similar protection from acute ischemic events, while lowering the risk of bleeding complications, when treated with bivalirudin monotherapy versus heparin plus GP IIb/IIIa blockade. However, the impact of bivalirudin use on long-term outcomes in diabetic patients undergoing PCI remains unclear. Methods. Using the Cornell Angioplasty Registry, we studied 786 consecutive diabetic patients undergoing urgent or elective PCI with a mean clinical follow up of 24.6 ± 7.8 months. Of these, 428 patients (54.5%) received bivalirudin monotherapy and 358 patients (45.5%) received unfractionated heparin (UFH) plus GP IIb/IIIa inhibition. The incidence of in-hospital death (0% vs. 0.3%; p = 0.46), post-procedural myocardial infarction (MI) (4.7% vs. 7.0%; p = 0.169), and major adverse cardiovascular events (MACE) (death, MI, stroke or urgent revascularization) (4.9% vs. 7.3%; p = 0.176) was similar in the two groups, with less minor bleeding (9.6% vs. 14.5%; p = 0.035) in the bivalirudin vs. UFH plus GP IIb/IIIa inhibitor group, respectively. By the end of follow up, there were 38 (8.9%) deaths in the bivalirudin vs. 19 (5.3%) deaths in the GP IIb/IIIa inhibitor arm (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.0–3.1; p = 0.04). However, after a propensity score-adjusted multivariate Cox regression analysis, there was no longer a significant difference in long-term mortality between the two groups (HR 1.63; χ2 = 2.61; 95% CI 0.90–2.94; p = 0.106). Conclusions. These findings indicate that in diabetic patients, bivalirudin monotherapy results in similar protection from acute ischemic events and long-term mortality, while lowering the risk of minor bleeding in comparison to UFH plus GP IIb/IIIa inhibition. J INVASIVE CARDIOL 2010;22:94–100 With the global prevalence of diabetes mellitus reaching over 170 million, diabetes remains a significant risk factor for cardiovascular events and deaths.1,2 Even in the era of revascularization, diabetic patients have worse outcomes after coronary artery bypass surgery or percutaneous interventions.3,4 Advances in antiplatelet and antithrombotic therapies have significantly reduced ischemic complications in patients undergoing percutaneous coronary intervention (PCI).5,6 Although diabetic patients appear to derive a greater benefit from the addition of glycoprotein (GP) IIb/IIIa inhibitors to unfractionated heparin (UFH) during PCI, GP IIb/IIIa inhibitor use has been associated with an increased risk of bleeding and thrombocytopenia.7,8 Initial studies have demonstrated similar anti-ischemic efficacy of bivalirudin monotherapy versus heparin plus GP IIb/IIIa inhibition in elective or urgent PCI.9,10 The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial further confirmed this finding in moderate- and high-risk acute coronary syndrome (ACS) patients undergoing PCI.11 The diabetic subset of patients in the ACUITY trial experienced a similar protection from ischemic events and less major bleeding complications by 30 days.11–13 However, the impact of bivalirudin therapy on long-term outcomes in diabetic patients undergoing PCI still remains unknown. The goal of this retrospective analysis was to investigate the short- and long-term efficacy and safety of bivalirudin in diabetic patients undergoing PCI in contemporary clinical practice. Methods Data collection. All patients undergoing PCI at the New York Presbyterian Hospital, Weill Cornell Medical College are enrolled in the Cornell Angioplasty Registry, details of which have been previously reported.9 A standard case report form delineating comprehensive patient demographics, pre-intervention clinical status, procedural findings and in-hospital complications is completed for each PCI performed. Immediate and in-hospital events are recorded. Patient follow up is obtained by means of publicly available mortality data through the Social Security Death Index,14 as well as through regularly scheduled phone contacts. The current study included all consecutive patients with a diagnosis of diabetes mellitus and undergoing PCI for the period of January 1, 2004 through December 31, 2005. For patients who had multiple PCIs during the defined study period, only the initial PCI was included in this analysis. Patients presenting with an ST-elevation myocardial infarction (STEMI) ≤ 7 days, hemodynamic instability/shock, receiving thrombolytic therapy ≤ 7 days, or those with severe renal insufficiency (serum creatinine ≥ 4 mg/dL) were excluded. We also excluded patients who received neither bivalirudin nor a GP IIb/IIIa inhibitor during PCI. The study was approved by the institutional review board of the Weill Medical College of Cornell University. Blood samples for cardiac markers (CK, CK-MB and cTnI) were obtained routinely prior to PCI and 8, 16 and 24 hours after PCI. Procedural data. Bivalirudin was administered as a 0.75 mg/kg intravenous (IV) bolus followed by an infusion of 1.75 mg/kg per hour for the duration of the PCI procedure. Upstream administration of bivalirudin prior to PCI was not practiced during the reported study period. Provisional or “bailout” GP IIb/IIIa inhibition in addition to bivalirudin was provided during the PCI at any time for angiographic or procedural complications. Patients receiving UFH alone or UFH plus GP IIb/IIIa inhibition upstream would have an activated clotting time (ACT) monitored prior to PCI, and the institutional practice would be to continue receiving UFH ± GP IIb/IIIa inhibition during PCI if the ACT was ≥ 175 seconds. Patients receiving upstream enoxaparin 1 mg/kg subcutaneously every 12 hours would receive no anticoagulation during PCI if enoxaparin was administered 70% lesions in ≥ 2 major coronary arteries/ branches or a left main coronary artery lesion of > 50%. Multivessel PCI was defined as a coronary intervention in ≥ 2 major coronary arteries/branches or in the left main coronary artery. Multilesion PCI was defined as a coronary intervention in ≥ 2 lesions of a single coronary artery or multiple coronary arteries. Congestive heart failure referred to patients with New York Heart Association Class III or IV heart failure during admission. MACE was defined as post-PCI death, emergency cardiac surgery/PCI, cerebral vascular accident (CVA) or MI. Vascular injury referred to an access site complication requiring mechanical intervention. Peripheral vascular disease included patients with carotid, aortofemoral or lower extremity vascular disease documented by a radiologic study, history of a vascular intervention or of a CVA. Major bleeding was defined as a drop in hemoglobin level ≥ 4 g/dL. Minor bleeding was defined as a drop in hemoglobin level ≥ 2 g/dL and Results Patient population. There were 3,611 PCIs performed on 3,105 consecutive patients undergoing urgent or elective PCI during the defined period. Of these, 601 patients presented with a STEMI ≤ 7 days, hemodynamic instability/shock, received thrombolytic therapy within ≤ 7 days, or had severe renal insufficiency (serum creatinine ≥ 4 mg/dL) and were excluded. This analysis included 786 diabetic patients undergoing urgent or elective PCI with periprocedural use of bivalirudin or UFH plus GP IIb/IIIa platelet inhibitors. Of these, 428 patients (54.5%) received bivalirudin monotherapy and 358 patients (45.5%) received UFH plus GP IIb/IIIa inhibition. Baseline characteristics of two groups are listed in Table 1. The majority of the PCIs (65%) were performed for unstable coronary syndromes. Patients presenting with unstable angina or NSTEMI were more likely to receive UFH plus GP IIb/IIIa platelet inhibitors (69.6%) rather than bivalirudin monotherapy (60.7%). A large number of patients (60%) had either angina at rest or angina causing marked limitations of ordinary physical activity (Canadian Cardiovascular Society [CCS] Class III–IV). Patients were more likely to be treated with UFH plus GP IIb/IIIa agents if they had the following clinical characteristics: younger age, presentation with NSTEMI/unstable angina, prior MI, lower ejection fraction, higher baseline hemoglobin and creatinine clearance. Femoral vascular access was used in > 99% of the procedures. Angiographic and procedural characteristics are summarized in Table 2. The use of stents (94%) or DES (88%) was high in this population. Multilesion (50%) and multivessel PCI (17%) were performed with similar frequency in the two groups. The use of rescue GP IIb/IIIa inhibition in bivalirudin-treated patients was 12.6%. In the UFH plus GP IIb/IIIa inhibitor group, eptifibatide was the most commonly used GP IIb/IIIa inhibitor (85%), whereas abciximab was used in a minority of cases. In-hospital outcomes. Angiographic success was similarly high in both groups (Table 3). The overall mortality for the entire study sample was low, 0.1%. The unadjusted incidence of post-procedural MI (4.7% vs. 7.0%; OR 0.65, 95% CI 0.36–1.20; p = 0.169) and MACE (4.9% vs. 7.3%; OR 0.66, 95% CI 0.36–1.19; p = 0.176) was similar in the bivalirudin versus UFH plus GP IIb/IIIa platelet inhibitors groups, respectively. There was a lower incidence of all (major and minor) bleeding (10.7% vs. 15.6%; OR 0.65, 95% CI 0.43–0.99; p= 0.044), driven by a reduction in minor bleeding (9.6% vs. 14.5%; OR 0.62, 95% CI 0.40-0.96; p = 0.035) in the bivalirudin group. There was no significant difference in major or minor bleeding rates when defined with thrombolysis in myocardial infarction (TIMI) criteria. The length of hospitalization since the admission or since the PCI date was similar in the two groups. A propensity score-adjusted multivariate analysis was performed to account for baseline differences among the two groups and for potential operator-driven bias towards selection of a specific antithrombotic strategy. After correcting for baseline differences, the adjusted rates of in-hospital MI (OR 0.93, 95% CI 0.47–1.84; p = 0.840) and MACE (OR 0.93, 95% CI 0.48–1.81; p = 0.831) remained similar in the two groups. After propensity score-adjusted analysis, there was a trend toward less bleeding events (major and minor) with bivalirudin therapy (OR 0.65, 95% CI 0.40–1.07; p = 0.090), caused by a significant reduction in minor bleeding events (OR 0.59, 95% CI 0.35-0.98; p = 0.043). Patients presenting with ACS had a greater incidence of both ischemic and bleeding events post PCI. The incidence of in-hospital MACE was 7.3% vs. 3.6% (OR 2.09; 95% CI 1.02–4.28; p = 0.041), and any bleeding events was 16.3% vs. 6.9% (OR 2.65; 95% CI 1.57–4.46; p Discussion This study investigated short- and long-term efficacy and safety of bivalirudin monotherapy in diabetic patients undergoing elective or urgent PCI. The analysis of 786 consecutive diabetic patients demonstrated that bivalirudin monotherapy results in similar protection from acute ischemic events, while lowering the risk of minor bleeding, in comparison to UFH plus GP IIb/IIIa platelet inhibition. These findings were also observed in high-risk subsets of patients with ACS or positive troponin markers. In addition, the use of bivalirudin was associated with similar long-term all-cause mortality after 2 years when compared with UFH plus GP IIb/IIIa platelet inhibitors. Patients with diabetes mellitus develop coronary atherosclerosis at an accelerated rate, therefore predisposing them to higher rates of MI and cardiovascular death.16-18 Several mechanisms have been proposed to explain this finding including endothelial dysfunction in the microvasculature, increased platelet aggregation and reactivity and heightened inflammatory state.19,20 Therefore, providing potent antithrombotic and antiplatelet pharmacotherapy has been paramount in preventing periprocedural ischemia in ACS and during PCI in diabetic patients. Administration of GP IIb/IIIa inhibitors along with UFH in patients undergoing PCI has become a widespread practice with a goal of preventing periprocedural ischemic events.5,6 Several trials have demonstrated a particular benefit of GP IIb/IIIa inhibitors in diabetic patients undergoing PCI.7 In fact, a recent meta-analysis revealed a significant mortality benefit in diabetic patients presenting with ACS and receiving GP IIb/IIIa inhibitors.21 On the other hand, the addition of GP IIb/IIIa inhibitors to the traditional antithrombotic therapy has been associated with an increased risk of bleeding events, particularly in diabetics.13 Several studies have shown bivalirudin monotherapy to be an effective choice of antithrombotic therapy in patients undergoing PCI, with less risk of bleeding in comparison to heparin plus GP IIb/IIIa inhibitors.9–11,16 A subgroup analysis of diabetic patients in the REPLACE-2 trial demonstrated a similar reduction of the combined endpoint of death, MI or urgent revascularization in the bivalirudin-treated patients versus heparin plus GP IIb/IIIa inhibitors group (5.7% vs. 5.9%; p = 0.39) at 30 days.16 Similar ischemic outcomes were observed in a diabetic subset of the ACUITY trial, with a comparable reduction in composite ischemic outcomes (7.9% vs. 8.9%; p = 0.39) at 30 days in the bivalirudin- and GP IIb/IIIa-treated patients, respectively.13 Interestingly, the rate of combined ischemic events in our analysis of diabetics (4.9% in bivalirudin-treated patients) is similar to the frequency of ischemic events seen in the REPLACE-2 trial.16 This suggests a similarity in the population that was studied, which included patients undergoing either elective PCI or PCI for low- to intermediate-risk ACS. Despite previously reported findings of a decreased bleeding risk with bivalirudin in the REPLACE-2 trial, the use of bivalirudin monotherapy in diabetics was not associated with a statistically significant reduction in major bleeding events in that trial, although there was a reduction in minor REPLACE-2 bleeding events in comparison to the heparin plus GP IIb/IIIa inhibitors group.16 Our study confirms these data, demonstrating a reduction only in minor bleeding events associated with bivalirudin monotherapy group without a significant reduction in major bleeding events. However, when the TIMI bleeding rates were calculated, our study did not demonstrate a significant reduction in TIMI major or minor bleeding, probably due to a smaller diabetic patient cohort studied and a lower incidence of TIMI bleeds. These findings are in contrast to the results of the ACUITY trial, which demonstrated a significant reduction in both major (3.7% vs. 7.1%; p 75 years, lower creatinine clearance, and a higher incidence of anemia in bivalirudin-treated patients. After correcting for baseline differences among the two groups and for potential operator-driven bias towards selection of a specific antithrombotic strategy, our analysis confirms findings of the REPLACE-2 and ACUITY trials, demonstrating similar long-term mortality between the two study groups. Therefore, this study provides further reassurance regarding long-term safety (> 1 year) with bivalirudin use in diabetic population. Study limitations. We acknowledge several limitations in this study. First, our analysis was derived from a single high-volume tertiary care center population. Second, although data in the current study were collected prospectively, this is a retrospective analysis and is subject to the limitations of such analyses. It is possible that different operators may have treated patients differently with respect to selection of an antithrombotic therapy as well as the timing of clopidogrel administration. Furthermore, propensity score-adjusted multivariate regression modeling, although effective at adjusting for variables included in the model, cannot adjust for variables not recorded in the database. Even though a statistical difference in the ischemic endpoints between the two strategies was no longer found after a propensity score-adjusted analysis, this study was underpowered for equivalency and an adequately powered study would be needed to demonstrate equivalency of the two strategies. Conclusions In diabetic patients undergoing PCI, bivalirudin monotherapy appears to be as effective as heparin plus GP IIb/IIIa inhibitors in preventing short-term ischemic events, while lowering the risk of minor bleeding complications. Furthermore, bivalirudin and heparin plus GP IIb/IIIa inhibition have similar efficacy with respect to long-term all-cause mortality.

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From the Greenberg Division of Cardiology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, New York. The authors report no conflicts of interest in connection with this manuscript. Manuscript submitted September 15, 2009, provisional acceptance given October 12, 2009, final version accepted November 17, 2009. Address for correspondence: Dmitriy N. Feldman, MD, Assistant Professor of Medicine, New York Presbyterian Hospital, Weill Cornell Medical College, Greenberg Division of Cardiology, 520 East 70th Street, Starr-434 Pavilion, New York, NY 10021. E mail: dnf9001@med.cornell.edu

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