Abstract
Aims
Given controversy over anticoagulation regimens for percutaneous coronary intervention (PCI), we performed an updated meta-analysis of randomized controlled trials (RCTs) to compare bivalirudin versus heparin.
Methods and results
Medline/Pubmed and Cochrane CENTRAL were searched for all RCTs comparing bivalirudin with provisional glycoprotein IIb/IIIa inhibitor (GPI) use versus heparin with provisional or routine GPI use for PCI. Pooled estimates of 30 day outcomes, presented as risk ratios (RR) [95% confidence intervals], were generated with random-effect models. Our analysis included 14 studies with 30,446 patients that were randomized to bivalirudin with provisional GPI use (n = 14,869) versus heparin with provisional (n = 6451) or routine GPI use (n = 9126). There was no significant difference between anticoagulation with bivalirudin compared with heparin for death (RR 0.95 [0.78–1.14]) or myocardial infarction (RR 1.10 [0.97–1.25]). Early stent thrombosis was significantly greater with bivalirudin compared with heparin (RR 1.61 [1.18–2.20], p = 0.003), especially in patients undergoing primary PCI (2.15 [1.15–4.03], p = 0.02). However, bivalirudin reduced the risk of major bleeding (RR 0.59 [0.51–0.70], p < 0.0001) and TIMI major bleeding (RR 0.59 [0.48–0.72], p < 0.0001) compared with heparin. Meta-regression analysis demonstrated that bleeding risk with use of heparin significantly increases with increasing GPI use (p = 0.02).
Conclusion
Meta-analysis of 14 RCTs with 30,446 patients demonstrated that bivalirudin is associated with higher risk of stent thrombosis but lower risk of major bleeding compared with heparin.
1
Introduction
Optimal anticoagulation during percutaneous coronary intervention (PCI) remains an area of controversy. Randomized controlled trials comparing bivalirudin versus heparin demonstrated less major bleeding with bivalirudin . However, meta-analysis of observational studies and randomized controlled trials (RCT) comparing bivalirudin versus heparin with provisional glycoprotein IIb/IIIa inhibitors (GPI) demonstrated an increased risk of stent thrombosis with bivalirudin . These data raised the question of whether use of heparin with only provisional or bailout GPI use would result in adequate anticoagulation while significantly reducing bleeding risk compared with heparin plus routine GPI use. Additionally, changes in PCI such as increasing use of radial access may further reduce the risk of access site bleeding . More rapid platelet inhibition with increasing utilization of novel P2Y12 inhibitors, including prasugrel and ticagrelor, may also help reduce the risk of stent thrombosis . Recently, three late breaking clinical trials were presented at the American College of Cardiology Annual Meeting and one at China Interventional Therapeutics Annual Meeting comparing bivalirudin versus heparin with provisional or routine GPI use for primary PCI in patients with ST elevation myocardial infarction (STEMI) and in patients undergoing elective PCI for stable or unstable angina . Thus, we performed a meta-analysis of RCTs comparing anticoagulation for PCI with bivalirudin versus heparin with provisional and routine GPI use to determine whether recent changes in PCI have led to changes in 30 day outcomes for stent thrombosis and major bleeding.
2
Methods
2.1
Study search, selection, and abstraction
Two independent reviewers (MJL and TL) systematically searched (April 2014) MEDLINE/PubMed, Cochrane CENTRAL, and available abstract data, applying the search terms “percutaneous coronary intervention” AND “bivalirudin” AND “heparin”. We also obtained presentation slides of the late breaking clinical trials previously mentioned in theintroduction. We included only patients randomized to: a) anticoagulation with bivalirudin with provisional GPI use versus heparin with either provisional or routine GPI use, b) for PCI, c) during the modern era of coronary stenting, and d) had 30 day outcomes data. We excluded any study or group of patients that: a) limited comparison to bivalirudin with routine GPI use; b) incorporated other methods of anticoagulation such as direct thrombin inhibitors; and c) all studies that were not RCTs. Data were abstracted by the same two investigators (MJL and TL) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . We collected 30 day outcomes data for all-cause mortality, myocardial infarction, definite stent thrombosis , major bleeding defined by the studies, and Thrombolysis in Myocardial Infarction (TIMI) major bleeding .
2.2
Data synthesis and analysis
Dichotomous variables are reported as proportions (percentages) while continuous variables are reported as mean (standard deviation) or median. Binary outcomes from individual studies were combined with random-effect models, leading to computations of risk ratios with 95% confidence intervals (RR [95% CIs]). I 2 was calculated as a measure of statistical heterogeneity; I 2 values of 25%, 50%, and 75% represented mild, moderate, and severe inconsistency, respectively. Small study or publication bias was explored with funnel plots and Peters’ test . Meta-regression analysis was performed to assess the correlation of certain variables with certain outcomes. Statistical analysis was performed using Review Manager (RevMan) 5 version 5.2.11 freeware package (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008) and Comprehensive Meta-Analysis version 2 (trial version) with statistical significance for hypothesis testing set at the 0.05 two-tailed level and for heterogeneity testing at the 0.10 two-tailed level.
2
Methods
2.1
Study search, selection, and abstraction
Two independent reviewers (MJL and TL) systematically searched (April 2014) MEDLINE/PubMed, Cochrane CENTRAL, and available abstract data, applying the search terms “percutaneous coronary intervention” AND “bivalirudin” AND “heparin”. We also obtained presentation slides of the late breaking clinical trials previously mentioned in theintroduction. We included only patients randomized to: a) anticoagulation with bivalirudin with provisional GPI use versus heparin with either provisional or routine GPI use, b) for PCI, c) during the modern era of coronary stenting, and d) had 30 day outcomes data. We excluded any study or group of patients that: a) limited comparison to bivalirudin with routine GPI use; b) incorporated other methods of anticoagulation such as direct thrombin inhibitors; and c) all studies that were not RCTs. Data were abstracted by the same two investigators (MJL and TL) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . We collected 30 day outcomes data for all-cause mortality, myocardial infarction, definite stent thrombosis , major bleeding defined by the studies, and Thrombolysis in Myocardial Infarction (TIMI) major bleeding .
2.2
Data synthesis and analysis
Dichotomous variables are reported as proportions (percentages) while continuous variables are reported as mean (standard deviation) or median. Binary outcomes from individual studies were combined with random-effect models, leading to computations of risk ratios with 95% confidence intervals (RR [95% CIs]). I 2 was calculated as a measure of statistical heterogeneity; I 2 values of 25%, 50%, and 75% represented mild, moderate, and severe inconsistency, respectively. Small study or publication bias was explored with funnel plots and Peters’ test . Meta-regression analysis was performed to assess the correlation of certain variables with certain outcomes. Statistical analysis was performed using Review Manager (RevMan) 5 version 5.2.11 freeware package (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008) and Comprehensive Meta-Analysis version 2 (trial version) with statistical significance for hypothesis testing set at the 0.05 two-tailed level and for heterogeneity testing at the 0.10 two-tailed level.
3
Results
Using PubMed, Cochrane CENTRAL, and available abstract data, we applied the following search term “percutaneous coronary intervention” AND “bivalirudin” AND “heparin” and identified 419 citations. Implementing our inclusion/exclusion criteria defined in the methods, we evaluated 55 abstracts, of which we assessed 29 as full-text publications or as abstract slides presented at National Meetings. We excluded studies due to duplication of data , non-RCT design , RCT prior to the modern stenting era , lack of 30 day event data , routine GPI use with bivalirudin , or use of another anticoagulant . Our search flow diagram can be found in Fig. 1 . For our meta-analysis, we included 14 RCTs with 30,446 patients that were randomized to either bivalirudin with provisional GPI use (n = 14,869) or heparin with provisional GPI use (n = 6451) or heparin with routine GPI use (n = 9126) . Baseline study characteristics can be found in Table 1 . Baseline patient characteristics can be found in Table 2 . The included patients in our study had a pooled mean age of 64 ± 4, 74% were male, 25% had prior MI, 67% had hypertension, 25% had diabetes mellitus, 32% were current smokers, 22% underwent PCI for stable angina, 17% for unstable angina, 33% for STEMI, 20% NSTEMI, and 8% for other causes such as silent ischemia or positive stress test. Among patients randomized to bivalirudin, provisional GPI use was 6.5%. Among patients randomized to heparin, GPI use amongst the provisional group was 17.5% and 99% amongst the routine group. Drug-eluting stents were utilized in 57% of patients, 88% of patients were treated with clopidogrel, 10% were treated with ticagrelor or prasugrel, and all studies predominantly employed femoral access except Xiang (25%) , European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) trial (48%) , Bivalirudin vs. Heparin Monotherapy and Glycoprotein IIb/IIIa plus Heparin for Patients with Acute Myocardial Infarction Undergoing Coronary Stenting (BRIGHT) trial (79%) , and How Effective are Antithrombotic Therapies in PPCI (HEAT-PPCI) trial (81%) , with data regarding radial access not available from the Bavarian Reperfusion AlternatiVes Evalation (BRAVE) 4 trial .
| Enrollment Period | Multicenter | STEMI | Anticoagulation | Patients | GPI | DES | Radial access | Clopidogrel or Ticlopidine | Prasugrel or Ticagrelor | |
|---|---|---|---|---|---|---|---|---|---|---|
| Heparin with Provisional GPI Use | ||||||||||
| ARMYDA-7 BIVALVE | June 2009–June 2011 | Yes | No | Standard Bivalirudin | 198 | 12% | 27% | 2% | 100% | 0% |
| UFH 75 IU/kg bolus | 203 | 14% | 28% | 2% | 100% | 0% | ||||
| ARNO | Oct 2006–July 2008 | No | No | Standard Bivalirudin | 425 | 15% | 76% | 2% | 100% | 0% |
| UFH 100 IU/kg bolus | 425 | 28% | 77% | 2% | 100% | 0% | ||||
| BRAVE 4 | Sept 2009–Dec 2013 | Yes | Yes | Standard Bivalirudin | 271 | 3.0% | 82% | NR | 3.7% | 94.6% |
| UFH 70–100 IU/kg bolus | 277 | 6.1% | 82% | NR | 90.2% | 7.1% | ||||
| BRIGHT | May 2012–June 2013 | Yes | Yes | Standard Bivalirudin | 728 | 4.4% | NR | 78.5% | 100% | 0% |
| UFH 100 IU/kg bolus | 724 | 5.7% | NR | 78.9% | 99.9% | 0% | ||||
| EUROMAX | Mar 2010–June 2013 | Yes | Yes | Bivalirudin 0.75 mg/kg bolus and 1.75 mg/kg/h infusion during procedure and 0.25 mg/kg/h infusion > 4 h after PCI | 1089 | 11.5% | 49% | 48% | 48% | 48% |
| UFH 100 IU/kg bolus (60 IU/kg if GP IIb/IIIa inhibitor given) or enoxaparin 0.5 mg/kg bolus | 460 | 25.4% | 64% | 41% | 38% | 62% | ||||
| HEAT PPCI | Feb 2012–Nov 2013 | No | Yes | Standard Bivalirudin | 905 | 13.5% | 80% | 80% | 12% | 88% |
| UFH 70 IU/kg bolus | 907 | 15.5% | 80% | 82% | 10% | 90% | ||||
| ISAR-REACT 3 | Sept 2005–Jan 2008 | Yes | No | Standard Bivalirudin | 2289 | 0.2% | 88% | NR | 100% | 0% |
| UFH 140 IU/kg bolus | 2281 | 0.2% | 87% | NR | 100% | 0% | ||||
| NAPLES III | NR | No | No | Standard Bivalirudin | 418 | 0.5% | 81% | 0.5% | NR | NR |
| UFH 70 IU/kg bolus | 419 | 1.3% | 84% | 0.5 | NR | NR | ||||
| Xiang 2013 | NR | Yes | No | Bivalirudin 0.75 mg/kg bolus and 1.75 mg/kg/h infusion and continued after PCI | 109 | 0.9% | NR | 22.9% | 100% | 0% |
| UFH 130 IU/kg bolus | 108 | 3.7% | NR | 26.9% | 100% | 0% | ||||
| Heparin with Routine GPI Use | ||||||||||
| ACUITY | Aug 2003–Jan 2007 | Yes | No | Bivalirudin 0.1 mg/kg bolus 0.25 mg/kg/h infusion and at PCI 0.5 mg/kg bolus and 1.75 mg/kg/h infusion discontinued after procedure | 2619 | 9% | 60% | NR | 100% | 0% |
| UFH 60 IU/kg bolus and 12 IU/kg/h infusion. Enoxaparin 1 mg/kg Q12H SQ with additional 0.3 mg/kg or 0.75 mg/kg bolus IV before PCI if SQ dose more than 8 or 16 hours respectively. | 2561 | 97% | 61% | NR | 100% | 0% | ||||
| BRIGHT | UFH 60 IU/kg bolus | 726 | 100% | NR | 78.7% | 99.9% | 0% | |||
| EUROMAX | UFH 100 IU/kg bolus (60 IU/kg if GP IIb/IIIa inhibitor given) or enoxaparin 0.5 mg/kg bolus | 649 | 100% | 44% | 54% | 49% | 51% | |||
| HORIZONS-AMI | Mar 2005–May 2007 | Yes | Yes | Standard Bivalirudin but option to continue if clinically indicated | 1800 | 7.5% | 72% | NR | 98.7% | 0% |
| UFH 60 IU/kg bolus | 1802 | 97.7% | 72% | NR | 98.2% | 0% | ||||
| ISAR-REACT 4 | July 2006–May 2011 | Yes | No | Standard Bivalirudin | 860 | 0% | 88% | 0.47% | 100% | 0% |
| UFH 70 IU/kg bolus | 861 | 100% | 89% | 0.23% | 100% | 0% | ||||
| NAPLES | Oct 2005–Feb 2008 | No | 0% | Standard Bivalirudin | 167 | 0.5% | 81% | 2.4% | 100% | 0% |
| UFH 70 IU/kg bolus | 168 | 100% | 84% | 4.3% | 100% | 0% | ||||
| REPLACE-2 | Oct 2001–Aug 2002 | Yes | 0% | Standard Bivalirudin | 2993 | 7.2% | 0% | NR | 91.9% | 0% |
| UFH 65 IU/kg bolus | 3008 | 100% | 0% | NR | 91.5% | 0% | ||||
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