Revista Española de Cardiología (English Edition) Revista Española de Cardiología (English Edition)
Rev Esp Cardiol. 2016;69:732-45 - Vol. 69 Num.08 DOI: 10.1016/j.rec.2016.03.007

Bivalirudin Versus Unfractionated Heparin in Acute Coronary Syndromes: An Updated Meta-analysis of Randomized Trials

Monica Verdoia a, Alon Schaffer a, Lucia Barbieri a, Harry Suryapranata b, Giuseppe De Luca a,

a Division of Cardiology, Azienda Ospedaliera-Universitaria “Maggiore della Carità”, Eastern Piedmont University, Novara, Italy
b Department of Cardiology, UMC St Radboud, Nijmegen, The Netherlands

Refers to

Keywords

Bivalirudin. Heparin. Percutaneous coronary intervention. Meta-analysis.

Abstract

Introduction and objectives

Contrasting data have been reported on bivalirudin as an anticoagulation strategy during percutaneous coronary interventions, offering theoretical benefits on bleeding complications but raising concerns on a potential increase in the risk of stent thrombosis. We performed an updated meta-analysis to evaluate the efficacy and safety of bivalirudin compared with unfractionated heparin in patients undergoing percutaneous interventions for acute coronary syndromes.

Methods

Literature archives and main scientific sessions were scanned. The primary efficacy endpoint was 30-day overall mortality. Secondary endpoints were stent thrombosis and major bleeding. A prespecified analysis was conducted according to clinical presentation.

Results

Twelve randomized trials were included, involving 32 746 patients (52.5% randomized to bivalirudin). Death occurred in 1.8% of the patients, with no differences between bivalirudin and heparin (odds ratio = 0.91; 95% confidence interval, 0.77-1.08; P = .28; P for heterogeneity = .41). Similar results were obtained for patients with non—ST-segment elevation and in ST-segment elevation myocardial infarction. A significantly higher rate of stent thrombosis was observed with bivalirudin (odds ratio = 1.42; 95% confidence interval, 1.09-1.83; P = .008; P for heterogeneity = .09). Bivalirudin was associated with a significant reduction in the rate of major bleeding (odds ratio = 0.60; 95% confidence interval, 0.54-0.75; P < .00001; P for heterogeneity < .0001), which, however, was related to the differential use of glycoprotein IIb/IIIa inhibitors (r = −0.02 [−0.033 to –0.0032]; P = .02) and did not translate into survival benefits.

Conclusions

In patients undergoing percutaneous coronary interventions, bivalirudin is not associated with a reduction in mortality compared with heparin but does increase stent thrombosis. The reduction in bleeding complications observed with bivalirudin does not translate into survival benefits but is rather influenced by a differential use of glycoprotein IIb/IIIa inhibitors.

Article

INTRODUCTION

Increasing complexity in patients admitted for acute coronary syndrome (ACS) is rendering more and more challenging the management of antithrombotic therapies, requiring continuous balancing between the risks of bleeding and thrombotic complications.1, 2, 3

Bivalirudin has been proposed as an alternative strategy to unfractionated heparin (UFH) for anticoagulation during percutaneous coronary interventions (PCI), offering several theoretical advantages including activity against clot-bound thrombin, inhibition of thrombin-induced platelet activation, short plasma half-life, and a lower dependence on renal clearance.4

Moreover, the first studies suggested that bivalirudin could provide similar effectiveness to UFH, but with a significant reduction in bleeding complications.5, 6 However, these trials did not consider patients with ACS, in whom the balance between bleeding and ischemic events is more complex.

In these settings, more recent clinical trials and pooled analyses7, 8, 9 have suggested that bivalirudin could be associated with an even higher risk of stent thrombosis and myocardial infarction, while offering no advantage in the reduction of hemorrhagic complications, besides raising the hypothesis that the differences in bleedings observed with bivalirudin could be affected by access-site bleedings or by greater use of glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, in association with UFH.

Therefore, the MATRIX trial10 has been conducted, comparing bivalirudin with UFH in ACS patients, randomly assigned to undergo PCI by either the radial or femoral route, showing no advantage from the use of bivalirudin in terms of ischemic, bleeding or combined endpoints. Therefore, the aim of the current study was to perform the most comprehensive meta-analysis to evaluate the safety and efficacy of bivalirudin compared with UFH during PCI, including the data from most recent randomized trials in the setting of ACS.

METHODS Eligibility and Search Strategy

The literature was scanned by formal searches of electronic databases (MEDLINE, Cochrane and EMBASE) for clinical studies and scientific session abstracts, searched on the TCT,11 EuroPCR,12 ACC,13 AHA,14 and ESC,15 websites for oral presentations and/or expert slide presentations from January 1990 to September 2015. The following keywords were used: “bivalirudin and acute coronary syndrome” or “bivalirudin versus heparin” or “bivalirudin and trial”. No language restrictions were enforced.

Data Extraction and Validity Assessment

Data were independently abstracted by 2 investigators. If the data were incomplete or unclear, authors were contacted, when possible. Disagreements were resolved by consensus. Data were managed according to the intention-to-treat principle.

Outcome Measures

The primary efficacy endpoint was overall mortality at 30 days of follow-up. The secondary endpoint was the occurrence of stent thrombosis at 30 days. The primary safety endpoint was the occurrence of major bleedings (according to per protocol definition) within the first 30 days from randomization. A prespecified meta-analysis was conducted according to patients’ presentation (non—ST-segment elevation ACS or ST-segment elevation myocardial infarction [STEMI]).

Data Analysis

The statistical analysis was performed using the Review Manager 5.23 freeware package, SPSS 17.0 statistical package. Odds ratios (OR) and 95% confidence intervals (95%CI) were used as summary statistics. The pooled OR was calculated by using a fixed effect model. The Breslow-Day test was used to examine the statistical evidence of heterogeneity across the studies (P < .1). A random-effect model was also applied to confirm our results (DerSimonian and Laird random-effects model). The study quality was evaluated by the same 2 investigators according to a score, which, as previously described,16 was expressed on an ordinal scale, allocating 1 point for the presence of each of the following: a) statement of objectives; b) explicit inclusion and exclusion criteria; c) description of the intervention; d) objective means of follow-up; e) availability of data on endpoint events; f) power analysis; g) description of statistical methods; h) multicenter design; i) discussion of withdrawals, and j) details on medical therapy. A meta-regression analysis was carried out to evaluate the following: the relationship between the benefits in mortality from bivalirudin vs UFH and patients’ risk profile (as log of the OR for mortality in the control group); the impact on mortality of the reduction in bleeding complications with bivalirudin (as log of the OR for bleeding events in the bivalirudin vs control groups); the bleeding reduction with bivalirudin and patients’ risk profile (as log of the OR for bleeding events in the control group). The study was performed in compliance with the Quality of Reporting of Meta-Analyses (PRISMA) guidelines.17

RESULTS Eligible Studies

A total of 12 randomized clinical trials5, 7, 8, 10, 18, 19, 20, 21, 22, 23, 24, 25 were finally included, for a total population of 32 746 patients (Figure 1). One study was excluded as it included only 24% of non—ST-segment elevation myocardial infarction (NSTEMI) patients.26 Detailed characteristics of included trials are shown in Table 1. Among them, 17 189 patients (52.5%) were randomized to bivalirudin and 15 557 patients (47.5%) to UFH with or without planned GPIIb/IIIa inhibitors. Preprocedural fondaparinux was administered in 100% of patients in 1 trial.22 As shown in Table 2, the mean age was 61.9 ± 2.1 years, with 19.5% of diabetics and 13.9% with renal failure. Use of GPIIb/IIIa inhibitors was 15.1% in the bivalirudin group (excluded in 3 trials5, 19, 25 and 49.7% in the UFH group (planned 100% in 5 trials).7, 18, 19, 23, 25 Six trials were conducted in STEMI patients,8, 10, 13, 15, 16, 18 while 8 trials focused on patients with ACS (unstable angina [UA]/NSTEMI).5, 7, 10, 19, 22, 23, 24, 25. Follow-up data were collected at 30 days in 10 trials,7, 8, 10, 18, 19, 20, 21, 23, 24, 25 in-hospital in 2 trials,5, 22 and in 1 follow-up was performed 48 hours after discharge.25

Flow diagram of the systematic overview process. PCI, percutaneous coronary intervention.

Figure 1. Flow diagram of the systematic overview process. PCI, percutaneous coronary intervention.

Table 1. Characteristics of Included Studies

Study name Enrolment year Type Study population Inclusion criteria Exclusion criteria Quality score
ACUITY 7 2003-2005 Multicenter RCT ACS • Age > 18 y
• Symptoms of UA for > 10 min within the preceding 24 hours and at least 1 among: a) new ST-segment depression or transient elevation of ≥ 1 mm; b) raised troponin I, T, or CK-MB isozyme, or c) known coronary artery disease
• STEMI
• Shock
• Bleeding diathesis or major bleeding episode < 2 wk
• Thrombocytopenia
• Creatinine clearance < 30 mL/min
• Recent administration of abciximab, warfarin, fondaparinux, fibrinolytic agents, bivalirudin, or 2 or more doses of LMWH
• Allergy to study drugs or iodinated contrast that could not be adequately premedicated
10
HAS 5 1993-1994 Multicenter RCT UA, angina after myocardial infarction • Chest pain
• Age > 21 y
• Urgent angioplasty for UA
• Written informed consent
• Serum creatinine > 3.0 mg/dL
• Thrombolytic therapy within the previous 24 hours
• Scheduled for coronary atherectomy, stenting or laser angioplasty
• Scheduled for a staged angioplasty procedure
• Pregnancy
• Could not tolerate aspirin or heparin
9
EUROMAX 8 NA Multicenter RCT STEMI • Men and nonpregnant women
• Age ≥ 18 y
• Symptoms with a presumed diagnosis of STEMI < 12 h
• Any of the following conditions: ST-segment elevation ≥ 1 mm in 2 contiguous leads on ECG, presumed new LBBB, or ST-segment depression of ≥ 1 mm in at least 2 leads in V1-V3 with a positive terminal T wave.; intention of performing primary PCI < 2 h after first medical contact.
• Bleeding diathesis or hematological disease or history of intracerebral mass, aneurysm, arteriovenous malformation, hemorrhagic stroke, intracranial hemorrhage, or bleeding < 2 wk
• Surgery < 2 wk
• Warfarin (not if international normalized ratio known to be < 1.5)
• UFH, LMWH or bivalirudin before randomization
• Thrombolytic therapy < 48 h
• Absolute contraindications, or allergy that cannot be premedicated, to iodinated contrast or to any of the study medications
• Contraindications to angiography
• Pregnant or nursing mothers
• Creatinine clearance < 30 mL/min or dialysis
• Previous enrollment in this or other studies
• Not available primary PCI-capable hospital
• Estimated body weight of > 120 kg
10
HORIZONS-AMI 18 2005-2008 Multicenter RCT STEMI • Age ≥ 18 years
• Symptom duration of 20 min to 720 min
• ST-segment elevation ≥ 1mm in 2 or more contiguous leads, new LBBB, or true posterior myocardial infarction
• Contraindications to study drugs
• Previous administration of thrombolytic therapy, bivalirudin, GP inhibitors, LMWH, or fondaparinux for the present admission
• Warfarin use
• History of bleeding diathesis, coagulopathy, heparin-induced thrombocytopenia, intracerebral mass, aneurysm, arteriovenous malformation, or previous hemorrhagic stroke
• Stroke or TIA < 6 mo or any permanent neurological deficit
• Refusal to receive blood transfusions
• Gastrointestinal or genitourinary bleeding < 2 mo
• Major surgery < 6 wk
• Known platelet count < 100 000/μL or hemoglobin < 100 g/L
• Planned elective surgical procedure
• Coronary stent implantation < 30 d
• Life expectancy < 1 y
11
ISAR-REACT 4 19 NA Multicenter RCT Angina or UA with positive cardiac markers • Angina > 20 min or recurrent episodes within 48 h
• Increase of cardiac biomarkers
• Coronary stenosis requiring PCI
• Acute myocardial infarction < 48 hours
• Cardiogenic shock
• Pericarditis
• Malignancy or other comorbid conditions with life expectancy < 1 year
• Active bleeding or a bleeding diathesis or history
• Any history of intracranial bleeding or structural intracranial abnormalities
• Refusal to receive a transfusion
• Blood pressure > 180/110 mmHg despite therapy
• Planned staged PCI procedure within 30 d or PCI within the prior 30 d
• Hemoglobin < 100 g/L, platelet count < 100 × 109 cells/L or > 600 × 109 cells/L
• GFR < 30 mL/min or serum creatinine > 30 mg/L
• Allergy or intolerance to any study drug or to stainless steel or to contrast media
• Pregnancy
• Coumarin within 7 d
• GPIIb/IIIa inhibitors < 14 d, UFH within 4 h, LMWH < 8 h, and bivalirudin < 24 h
10
BRAVE-4 20 2009-2013 Multicenter RCT STEMI • Patients presenting within 24 h from symptom onset, with chest pain lasting ≥ 20 min and with ≥ 0.1 mV of ST-segment elevation in ≥ 2 adjacent limb leads or ≥ 0.2 mV in ≥ 2 contiguous precordial leads or new LBBB
• Informed written consent
• Age < 18 y
• Cardiogenic shock or prolonged CPR
• Active bleeding, bleeding diathesis, coagulopathy
• History of GI or genitourinary bleeding within the previous 2 mos
• Refusal to receive blood transfusion
• Major surgery in the last 6 wk
• History of intracranial bleeding or structural abnormalities
• Suspected aortic dissection
• Prior TIA, prior stroke
• Heparin-induced thrombocytopenia
• Prior administration of thrombolytics, bivalirudin, LMWH, or fondaparinux for the index myocardial infarction
• Known relevant hematological deviations: hemoglobin < 100 g/L, platelet count < 100 × 109/L
• Use of coumadin derivatives within the last 7 d
• Chronic therapy with NSAIDs (except aspirin), COX-2 inhibitors, prasugrel, ticagrelor
• Life expectancy < 1 y
• Severe liver disease
• Renal failure with GFR < 30 mL/min and/or dialysis
• Known allergy to the study medications
• Previous enrollment in this trial
• Women who are pregnant, who are of childbearing potential and test positive for pregnancy or are breastfeeding
• Inability to fully cooperate with the study protocol
10
HEAT-PPCI 21 2012 - 2013 Single center, RCT STEMI • STEMI patients activating primary PCI pathway • Active bleeding at presentation
• Factors precluding administration of oral antiplatelet therapy
• Intolerance/contraindication to trial medication
• Previous enrolment in this trial
8
SWITCH III 22 NA Multicenter
RCT
NSTEMI patients initially treated with fondaparinux and undergoing early invasive strategy • Age >18 y
• ACS without persistent ST-segment elevation meeting ≥ 1 of the following criteria: elevated CK-MB or troponin I or T (above upper limit of normal), or ECG indicative of ischemia (not persistent ST-segment elevation)
• PCI scheduled
• Willing to conform to the requirements of the study and voluntarily signs an informed consent
• Angioplasty of ≥1 coronary artery with target lesion stenosis < 100%
• Therapies including aspirin (dose per standard of care in each facility), clopidogrel loading dose of 600 mg if not already on clopidogrel chronic 75 mg treatment)
• ST-segment elevation within the preceding 48 h
• Patient weight > 400 pounds (181.2 kg) or < 110 pounds (50 kg)
• Patients receiving doses other than the 2.5 mg subcutaneous fondaparinux LMWH, GPIIb/IIIa inhibitors or bivalirudin within the preceding 24 h
• Treatment with UFH ≤90 min prior to fondaprinux administration
• Known bleeding diathesis, on warfarin therapy, or active bleeding within the previous 6 mo
• Diagnosis of acute bacterial endocarditis
• Cardiogenic shock or a need for intra-aortic balloon pump insertion
• Major/minor stroke or TIA within the past 6 mo
• Renal dysfunction (creatinine ≥ 3.0 mg/dL), status postrenal transplant, patients with angioplasty within the previous 30 d
• Contraindication to LMWH, UFH or bivalirudin
• Pregnant or lactating women
• Unprotected left main disease with ≥ 50% stenosis
• Patients requiring staged PCI
• Visual thrombus on angiography
9
BRIGHT 23 2012- 2013 Multicenter RCT STEMI/NSTEMI patients with planned emergency PCI • Age 18 to 80 y
• STEMI within 12 h of symptom onset, or within 12-24 h if ongoing chest pain, continuous ST elevation or new LBBB
• NSTEMI within 72 h of symptom onset
• Planned emergency PCI
• Written informed consent before catheterization
• Thrombolysis within 72 h
• Cardiogenic shock
• Any anticoagulant agents used within 48 hours before randomization
• Active bleeding or bleeding diathesis
• Hemoglobin < 100 g/L or platelet count < 100 × 109/L
• Creatinine clearance < 30 mL/min
• Known allergy to the study drugs or devices (including heparin induced thrombocytopenia)
9
TENACITY 24 2011 Single center, RCT ACS • Moderate-to-high-risk PCI: patients undergoing elective or urgent PCI with current or recent (< 1 mo) ACS (including primary but not rescue PCI), current or history of heart failure, depressed ventricular function, peripheral vascular disease, or insulin-dependent diabetes mellitus. Patients could also be included if their PCI included treatment for complex coronary anatomy • Abciximab within 14 d, thrombolytic therapy within 12 h, or tirofiban, eptifibatide, or LMWH within 10 h 8
PROTECT-TIMI 30 25 2003-2004 Multicenter
RCT
ACS • Age 18 to 80 y
• Hospitalized with UA/NSTEMI with chest discomfort or an anginal equivalent at rest > 10 min; consistent with ACS, with at least 1 high-risk feature (ie, diabetes mellitus, a positive cardiac troponin T or I or CK-MB, ST-segment deviation > 0.5 mm, or TIMI risk score
• PCI of a native coronary artery
• Unresponsive hypertension
• STEMI within 24 h
• PCI within the previous 2 wk
• Intraventricular conduction defect, pacing
• Left ventricular hypertrophy or any other electrocardiographic finding that could make continuous ECG monitoring uninterpretable
• Cardiogenic shock
• History of a bleeding diathesis or evidence of active bleeding within 30 d
• History of a hemorrhagic stroke at any time, stroke or TIA of any etiology within 30 days
• Platelet count of < 100 000/μL
• Major surgery within the previous 6 wk
• Any LMWH within the previous 12 h
• Treatment with any GPIIb/IIIa inhibitors in the previous 30 d or concurrent or anticipated treatment
• Concurrent treatment with warfarin
• Estimated creatinine clearance < 30 mL/min
• Treatment of in-stent restenosis; or anticipated or staged PCI within 48 h
9
MATRIX 10 October 2011-November 2014 Multicenter
RCT
ACS or STEMI For ACS all of the following 3 factors:
• History consistent with new, or worsening ischemia, occurring at rest or with minimal activity
• Enrolment within 7 d of the most recent symptoms
• Planned coronary angiography with indication to PCI; at least 2 of the following: age ≥ 60 years; troponin T or I or CK-MB above the upper limit of normal; ECG changes compatible with ischemia, ie, ST depression of ≥1 mm in 2 contiguous leads, T-wave inversion > 3 mm, or any dynamic ST shifts
For STEMI both:
• Chest pain for > 20 min with an ST-segment elevation ≥ 1 mm or greater in 2 or more contiguous leads, or with a new left bundle-branch block or with ST-segment depression of ≥ 1 mm in 2 or more of leads V1-V3 with a positive terminal T wave
• Admission either within 12 h of symptom onset or between 12 and 24 h after onset with continuing ischemia or previous fibrinolytic treatment
• Patients who cannot give informed consent or have a life expectancy < 30 d
• Allergy or intolerance to bivalirudin or UFH
• Treatment with LMWH within the past 6 h
• Treatment with any GP inhibitor in the previous 3 d
• Absolute contraindications or allergy, that cannot be premedicated, to iodinated contrast or to any of the study medications, including both aspirin and clopidogrel
• Contraindications to angiography, including but not limited to severe peripheral vascular disease
• If known, a creatinine clearance < 30 mL/min or dialysis dependent
• Previous enrolment in this study PCI in the previous 30 d
10

ACS, acute coronary syndrome; CK-MB, creatine kinase-myocardial band; COX-2, cyclooxygenase 2; CRP, cardiopulmonary resuscitation; ECG, electrocardiogram; GFR, glomerular filtration rate; GP, glycoprotein; GPIIb/IIIa, glycoprotein IIb/IIIa; INR, international normalized ratio; LBBB, left bundle branch block; LMWH, low-molecular weight heparin; NA, not available; NSAID, nonsteroidal anti-inflammatory drugs; NSTEMI, non—ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomized clinical trial; STEMI, ST-segment elevation myocardial infarction; TIA, transient ischemic accident; TIMI, Thrombolysis In Myocardial Infarction; UA, unstable angina; UFH, unfractionated heparin.

Table 2. Clinical Features of Patients in Included Studies

Study Study drug design Bivalirudin
dose
UFH
dose
Bivalirudin,
No.
UFH,
No.
Maximum
follow-up, days
Bivalirudin,
mean
age
UFH, mean age Bivalirudin,
male sex, %
UFH,
male sex, %
Bivalirudin,
DM, %
UFH,
DM, %
Bivalirudin,
GP inhibitors, %
UFH,
GP inhibitors, %
ACUITY 7 Periprocedural bivalirudin or periprocedural bivalirudin + planned GPIIb/IIIa inhibitors for 12-h to 18-h 0.75 mg/kg bolus infusion of 1.75 mg/kg per h for the procedure duration Bolus of 60 IU/kg plus infusion of 12 IU/kg per h 5228 2561 365 63 63 74 73 28 28 53 97
HAS 5 Periprocedural bivalirudin vs UFH 1.0 mg/kg of body weight, followed by a 4-h infusion of 2.5 mg/kg/h and a 14-h to 20-h infusion of 0.2 mg/kg/h Bolus dose of 175 U/kg followed by an 18-h to 24-h infusion at a rate of 15 U/kg/h 2161 2151 180 63 62 77 78 21 21 0 0
EUROMAX 8 Periprocedural bivalirudin vs heparin (provisional GPIIb/IIIa inhibitors) 0.75 mg/kg and infusion of 1.75 mg/kg/h continued for at least 4 hours after PCI 100 IU/kg or 60 IU with a GPIIb/IIIa inhibitor or enoxaparin 1089 1109 30 61 62 73.7 77.6 11.7 15.3 11.5 69.1
HORIZONS-AMI 18 Periprocedural bivalirudin vs UFH + planned GPIIb/IIIa inhibitors 0.75 mg/kg and infusion of 1.75 mg/kg/h Bolus of 60 IU/kg to an ACT of 200 s to 250 s 1800 1802 1095 59.8 60.7 77.1 76.1 16.5 17.3 7.2 94.5
ISAR -REACT 4 19 Bivalirudin vs UFH + planned abciximab 0.75 mg/kg of bivalirudin, followed by an infusion of 1.75 mg/kg/h for the duration of the procedure Bolus of 70 U/kg of UFH 860 861 365 67.5 67.5 76.9 76.8 28.3 29.8 0 100
BRAVE- 4 20 Periprocedural bivalirudin + prasugrel vs UFH + clopidogrel (provisional use of GPIIb/IIIa inhibitors) 0.75 mg/kg, followed by infusion of 1.75 mg/kg/h for the duration of the procedure (adjustment for CKD) Bolus of 70-100 U/kg of UFH 271 277 30 61.4 61.4 76 79 17 15 3 6.1
HEAT-PPCI 21 Periprocedural bivalirudin vs UFH (bailout GPIIb/IIIa inhibitors) Bolus of 0.75 mg/kg + infusion of 1.75 mg/kg/h for procedure duration 70 U/kg body weight preprocedure 915 914 28 62.9 63.6 71.5 73.1 12.6 15.1 13.5 15.5
SWITCH III 22 Periprocedural bivalirudin vs UFH (provisional use of GpIIb/IIIa inhibitors) Bolus of 0.75 mg/kg + infusion of 1.75 mg/kg/h for procedure duration Bolus of 60 U/kg, adjusted to achieve and maintain an ACT of above 200 s 51 49 In-hospital 63.3 62.2 72.5 63.3 13.7 20.4 3.9 12.2
BRIGHT 23 Periprocedural bivalirudin vs UFH (bailout GPIIb/IIIa inhibitors) 0.75 mg/kg bolus + 1.75 mg/kg/h infusion Heparin 100 U/kg bolus + additional dose if ACT < 200 s 735 1459 365 57.3 58.2 82.7 81.9 22.9 21.4 4.4 52.8
TENACITY 24 Periprocedural bivalirudin + planned GPIIb/IIIa inhibitors vs UFH + planned GpIIb/IIIa inhibitors 0.75 mg/kg bolus + 1.75 mg/kg/h infusion 50 U/kg 185 198 30 100 100
PROTECT-TIMI 30 25 Periprocedural bivalirudin vs eptifibatide plus UFH/enoxaparin 0.75 mg/kg bolus + 1.75 mg/kg/h infusion Double bolus of eptifibatide (180 μg/kg IV infusion for 18-h to 24-h plus reduced dose bolus of UFH (50 U/kg) or 0.5 mg/kg 284 573 48 h after discharge 59.7 60 68.3 66 44.4 36.5 0 99
MATRIX 10 Periprocedural bivalirudin vs UFH (provisional use of GpIIb/IIIa inhibitors, bailout only in bivalirudin group) 0.75 mg/kg bolus of bivalirudin, followed by infusion of 1.75 mg/kg/h until completion of the PCI, then either stopped or prolonged (full dose for up to 4 hours of a reduced dose of 0.25 mg/kg/h for > 6 h) according to assignment 70-100 U/kg (or 50-70 U/kg in patients receiving GPIIb/IIIa inhibitors) 3610 3603 30 65.4 65.4 75.7 75.7 22.6 21.8 4.6 25.9

ACT, activated clotting time; CKD: chronic kidney disease; DM, diabetes mellitus; GP, glycoprotein; GPIIb/IIIa, glycoprotein IIb/IIIa; IV, intravenous; UFH: unfractionated heparin.

Clinical Outcome Overall mortality

Data on overall mortality were available in 32 472 patients (99.1%). Death occurred in 563 (1.7%) of patients. As shown in Figure 2, no difference in mortality was observed between bivalirudin and UFH (1.6%, [276 of 17 070] vs 1.8% [287 of 15 402], OR = 0.91; 95%CI, 0.77-1.08; P = .28; P for heterogeneity = .41).

Bivalirudin vs unfractionated heparin on overall mortality (within 30 days) with odds ratios and 95% confidence intervals. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial. 95%CI, 95% of confidence interval.

Figure 2. Bivalirudin vs unfractionated heparin on overall mortality (within 30 days) with odds ratios and 95% confidence intervals. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial. 95%CI, 95% of confidence interval.

Similar results were obtained for patients with UA/NSTEMI (0.96%, [99 of 10 248] vs 0.8% [62 of 7843], OR = 1.13; 95%CI, 0.82-1.55; P = .47; P for heterogeneity = .56) and in STEMI (2.6% [177 of 6822] vs 3% [225 of 7559], OR = 0.84; 95%CI, 0.69-1.02; P = .08; P for heterogeneity = .37; P for interaction = .12).

No difference in mortality with bivalirudin was confirmed by applying a random-effect model to the analysis (OR = 0.91; 95%CI, 0.76-1.09; P = .31; P for heterogeneity = .41), with no difference in non—ST-segment elevation ACS and STEMI patients.

By meta-regression analysis no significant relationship was observed between benefits in mortality with bivalirudin compared with UFH, and patient risk profiles or the reduction in bleeding complications (r = −0.50 [−1.12 to 0.14]; P = .12) and (r = −0.29 [−0.75 to 0.17]; P = .22) (Figure 3 respectively). Lack of impact on survival for the reduction in bleeding complications was similarly observed among patients with UA/NSTEMI (r = −1.05[−2.5 to 0.40]; P = .16) and STEMI (r = −0.94[−1.19 to 3.08]; P = .39).

Fixed-effect meta-regression analyses for the risk (odds ratio) of mortality between bivalirudin and unfractionated heparin according to patients’ risk profile (A) or the reduction in major bleedings with bivalirudin (B). The size of the circle corresponds to the statistical weight of each study.

Figure 3. Fixed-effect meta-regression analyses for the risk (odds ratio) of mortality between bivalirudin and unfractionated heparin according to patients’ risk profile (A) or the reduction in major bleedings with bivalirudin (B). The size of the circle corresponds to the statistical weight of each study.

Stent thrombosis

Data on stent thrombosis were available in 19977 patients (60.8%), out of 8 studies.7, 8, 13, 14, 15, 16, 17, 18 Stent thrombosis occurred in 264 (1.3%) of patients. Bivalirudin significantly increased the risk of stent thrombosis (1.5% [168 of 10 947] vs 1% [96 of 9030], OR = 1.42; 95%CI, 1.09-1.83; P = .008; P for heterogeneity = .09), as shown in Figure 4.

Bivalirudin vs unfractionated heparin on stent thrombosis (within 30 days), with odds ratios and 95% confidence intervals. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial. 95%CI, 95% of confidence interval. *Data of the MATRIX trial<cross-ref><sup>10</sup></cross-ref> not available according to clinical presentation.

Figure 4. Bivalirudin vs unfractionated heparin on stent thrombosis (within 30 days), with odds ratios and 95% confidence intervals. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial. 95%CI, 95% of confidence interval. *Data of the MATRIX trial 10 not available according to clinical presentation.

A similar trend for bivalirudin was confirmed when a random-effect model was applied to the analysis (OR = 1.46; 95%CI, 0.97-2.19; P = .07; P for heterogeneity = .09).

Major Bleeding Complications (per Protocol Definition)

Bleedings, as per protocol definition, were reported within the first 30 days from randomization in 32 731 patients (99.9%). A major bleeding occurred in 1537 patients (4.7%), with a significant reduction of events in patients treated with bivalirudin compared with UFH (3.9%, [667 of 17 183] vs 5.6% [870 of 15 548]; OR = 0.60; 95%CI, 0.54-0.75; P < .00001; P for heterogeneity < .0001) (Figure 5). Similar results were obtained in patients with non—ST-segment elevation ACS (3.9% [410 of 10 361] vs 5.8% [467 of 7089], OR = 0.58; 95%CI, 0.50-0.67; P < .00001; P for heterogeneity = .0004). or STEMI (3.7% [257 of 6822] vs 5.3% [403 of 7559], OR = 0.64; 95%CI, 0.54-0.75; P < .00001; P for heterogeneity = .004; P for interaction = .37).

Bivalirudin vs unfractionated heparin on major bleeding complications according to protocol definition (within 30 days), with odds ratios and 95% confidence intervals. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial. 95%CI, 95% of confidence interval.

Figure 5. Bivalirudin vs unfractionated heparin on major bleeding complications according to protocol definition (within 30 days), with odds ratios and 95% confidence intervals. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial. 95%CI, 95% of confidence interval.

The result was confirmed when a random-effect model was applied to the meta-analysis (OR = 0.60; 95%CI, 0.46-0.77; P < .0001; P for heterogeneity < .0001).

By meta-regression analysis, no significant relationship was observed between benefits in bleeding complications with bivalirudin compared with UFH, and patient risk profiles (r = −0.09 [−0.58 to 0.39]; P = .71), whereas a positive association was found between the reduction in bleeding events with bivalirudin and the differential rate of GPIIb/IIIa use (r = −0.02[−0.033 to −0.0032]; P = .02) (Figure 6).

Fixed-effect meta-regression analyses for the risk (odds ratio) of major bleedings between bivalirudin and unfractionated heparin according to patients’ risk profile (A) or the differential rate of glycoprotein IIb/IIIa inhibitors use in the 2 groups (B). The size of the circle corresponds to the statistical weight of each study.

Figure 6. Fixed-effect meta-regression analyses for the risk (odds ratio) of major bleedings between bivalirudin and unfractionated heparin according to patients’ risk profile (A) or the differential rate of glycoprotein IIb/IIIa inhibitors use in the 2 groups (B). The size of the circle corresponds to the statistical weight of each study.

Discussion

This is the most comprehensive meta-analysis evaluating the effectiveness and safety of bivalirudin, compared with UFH in patients undergoing coronary angioplasty in the settings of ACS or STEMI. Our main finding is that bivalirudin does not reduce mortality compared with UFH but does increase stent thrombosis. However, bivalirudin is associated with a significant reduction in major bleeding complications, mainly driven by those trials administering more aggressive antithrombotic therapy with GPIIb/IIIa inhibitors in association with UFH, although this reduction did not translate into survival benefits.

The PCI is nowadays the most widely preferred strategy for the treatment of coronary artery disease,27 even in most complex coronary anatomies and especially in the setting of STEMI, where early revascularization has dramatically improved the outcome of these patients.28, 29, 30 Antithrombotic therapies have made important contributions to improving myocardial perfusion and to preventing thrombotic complications after PCI.31, 32, 33 However, progressive population aging and the increasing rate of comorbidities in patients admitted for ACS render the management of antiplatelet drugs and anticoagulation more complex, requiring a mediation between the risk of thrombosis and bleeding complications.34

Bivalirudin has emerged in the last years as an alternative anticoagulation strategy to UFH during PCI. In the first randomized trial (HAS [Hirulog Angioplasty Study])5 comparing bivalirudin with heparin in over 4000 patients undergoing PCI for a recent ACS, bivalirudin was at least as effective as UFH in preventing ischemic events and also provided a lower risk of bleeding.

Similar findings were achieved by the ACUITY trial,7 in which bivalirudin provided a significant reduction in major bleeding complications in the PCI-treated population, although it slightly increased the rate of recurrent myocardial infarction.

Analogous benefits in bleeding were reported in the HORIZONS-AMI trial,18 in which, despite a higher occurrence of stent thrombosis, bivalirudin reduced mortality in patients undergoing primary PCI, suggesting that higher-risk STEMI patients could be those that could derive the greatest benefit from bivalirudin.

Therefore, expectations of bivalirudin have been high, presenting it as the safest treatment, especially in those settings with a higher hemorrhagic risk.

However, the NAPLES-III trial,35 including elective patients undergoing PCI with a high bleeding risk score, has shown no clear benefits from the use of bivalirudin instead of UFH. Similar results have been achieved in the larger ISAR-REACT-3 trial,6 including elective patients or unstable patients with negative troponin, in which despite the higher dose of UFH (140 IU/kg), only a weak reduction in terms of TIMI (Thrombolysis In Myocardial Infarction) major bleeding events was observed with bivalirudin.

Indeed, patients with ACS commonly have a higher risk of bleeding complications than those with stable coronary artery disease, leading to worse outcomes.36 However, the beneficial effects of bivalirudin on hemorrhagic complications have also been questioned in most recent trials including unstable patients, such as the SWITCH-III, BRAVE-4 and HEAT-PPCI studies,20, 21, 22 and in real-life registries. In particular, MacHaalany et al37 have reported no difference in net clinical adverse events or ischemic or bleeding complications with bivalirudin vs UFH, as bivalirudin reduced both ischemic and bleeding complications in patients undergoing PCI through the femoral route, but not in radial-treated patients, suggesting a potential interaction of access-site bleedings influencing the results with bivalirudin.

In addition, in a recent meta-analysis, Cavender et al38 have clearly shown that the positive effects of bivalirudin on major bleeding could be observed only when GPIIb/IIIa inhibitors were used predominantly in the UFH arm only, otherwise displaying no significant impact on bleeding. Moreover, in this meta-analysis, when compared with traditional UFH, a bivalirudin-based regimen increased the risk of myocardial infarction and stent thrombosis, confirming the safety warning that had already emerged from previous trials.

Aiming to define the safety and effectiveness of bivalirudin in PCI, and to shed light on the role of access-site and concomitant therapies, the MATRIX trial10 has recently included more than 7000 patients with ACS or STEMI undergoing a double randomization to bivalirudin or UFH and to transradial or transfemoral PCI. The study was negative for both endpoints of major adverse cardiovascular events and net adverse clinical events, with bivalirudin not emerging as statistically superior to UFH at 30 days but displaying a higher-than-expected rate of myocardial infarction and stent thrombosis. Moreover, no significant interaction of access-site was noted.

However, as the MATRIX trial included both STEMI and NSTEMI ACS patients, it remains to be determined whether any subset of patients, according to the type of ACS presentation, could most benefit from bivalirudin

In view of the relevant results of this recent large trial, the present study represents the most up-to-date meta-analysis comparing bivalirudin to UFH in patients undergoing PCI for ACS, including a prespecified subanalysis according to presentation.

Our main findings are consistent with those of previous studies showing no difference in mortality with the 2 antithrombotic regimes. As expected, bivalirudin significantly reduced the rate of major bleeding complications, but this reduction did not translate into mortality benefits. Moreover, the observed reduction in hemorrhagic complications was significantly related to the rate of GPIIb/IIIa inhibitors administered in association with UFH.

Thus, according to the present findings, and considering the potential safety concerns about the higher risk of urgent target-vessel revascularization or stent thrombosis associated with the use of bivalirudin,10, 38 which have not been overcome by a longer post-PCI bivalirudin infusion, the use of the most validated and less economically-demanding strategies, such as traditional UFH-based strategies, should be advocated for patients with ACS undergoing PCI.

Limitations

The first limitation of our study is the lack of an extended follow-up. However, bivalirudin is an intravenous drug with very fast onset of action and short half-life, thus displaying its effects only in the periprocedural period. In fact, even in the trials with longer follow-up, the differences in cardiovascular endpoints were achieved within the first month after randomization.18 One trial included mostly STEMI patients (87.7% vs 12.3% NSTEMI patients).23 As we were not able to obtain data according to the presentation, we therefore pooled this study with trials on STEMI.

Moreover, for the endpoint of stent thrombosis, the MATRIX trial10 had to be excluded due to the lack of separate data according to clinical presentation. However, the results on the overall population in this trial were in line with our present findings of an enhanced risk of ST in the bivalirudin arm, even when administered in a prolonged infusion.

Another limitation is the variable protocol of bivalirudin administration, with an extended post-PCI infusion performed in 2 trials8, 10 and variations in the dosage of UFH in the control group, with 2 trials even allowing enoxaparin.8, 25 However, in most of the included studies, UFH was administered at similar dosages, ranging from 60 U/kg to 75 U/kg.

CONCLUSIONS

In patients with ACS undergoing PCI, bivalirudin is not associated with a reduction in mortality compared with UFH and increases the risk of stent thrombosis. Moreover, the reduction in bleeding complications observed with bivalirudin is strictly dependent from the rate of GPIIb/IIIa inhibitor administration and does not translate into survival benefits.

CONFLICTS OF INTEREST

None declared.

WHAT IS KNOWN ABOUT THE TOPIC?

  • Bleeding complications represent the Achilles’ heel of antithrombotic therapies during PCI.

  • The previously reported advantages in hemorrhagic risk reduction with bivalirudin during PCI have recently been questioned by potential interactions with access-site and concomitant antiplatelet strategies.

  • In the recent MATRIX trial, bivalirudin did not provide safety benefits compared with UFH and was associated with a higher-than-expected rate of myocardial infarction and stent thrombosis.

WHAT DOES THIS STUDY ADD?

  • We provide the most comprehensive meta-analysis to evaluate the safety and efficacy of bivalirudin compared with UFH, including data from the most recent randomized trials in the setting of ACS.

  • Our main finding is that bivalirudin does not provide any benefit in mortality reduction compared with UFH and increases stent thrombosis.

  • However, bivalirudin is associated with a significant reduction in major bleeding complications, mainly driven by those trials where more aggressive antithrombotic therapy with GPIIb/IIIa inhibitors was administered only in association with UFH, and not translating into survival benefits.

Received 16 November 2015
Accepted 25 January 2016

Corresponding author: Division of Cardiology, Ospedale Maggiore della Carità, Eastern Piedmont University, C.so Mazzini 18, 28100 Novara, Italy. giuseppe.deluca@med.unipmn.it

Bibliography

1. Savonitto S, De Luca G, Goldstein P, van T’ Hof A, Zeymer U, Morici N, et al. Antithrombotic therapy before, during and after emergency angioplasty for ST elevation myocardial infarction. Eur Heart J Acute Cardiovasc Care. 2015. Available at: http://dx.doi.org/10.1177/2048872615590148
2. De Luca L, Tomai F, Verdoia M, De Luca G. Evaluation and management of special subgroups after primary percutaneous coronary intervention. Am Heart J. 2010;160:S22-7.
Medline
3. De Luca G, Bellandi F, Huber K, Noc M, Petronio AS, Arntz HR, et al. Early glycoprotein IIb-IIIa inhibitors in primary angioplasty-abciximab long-term results (EGYPT-ALT) cooperation: individual patient's data meta-analysis. J Thromb Haemost. 2011;9:2361-70.
Medline
4. Weitz JI, Buller HR. Direct thrombin inhibitors in acute coronary syndromes: present and future. Circulation. 2002;105:1004-11.
Medline
5. Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: Final report reanalysis of the Hirulog Angioplasty Study. Am Heart J. 2001;142:952-9.
Medline
6. Shulz S, Mehilli J, Ndrepepa G, Neumann FJ, Birkmeier KA, Kufner S, et al. Bivalirudin vs. unfractionated heparin during percutaneous coronary interventions in patients with stable and unstable angina pectoris: 1-year results of the ISAR-REACT 3 trial. Eur Hear J. 2010;31:582-7.
7. Stone GW, White HD, Ohman EM, Bertrand ME, Lincoff AM, McLaurin BT, et al, Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial investigators. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet. 2007;369:907-19.
Medline
8. Steg PG, van’t Hof A, Hamm CW, Clemmensen P, Lapostolle F, Coste P, et al, EUROMAX Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J Med. 2013;369:2207-17.
Medline
9. Verdoia M, Schaffer A, Barbieri L, Suryapranata H, De Luca G. Bivalirudin as compared to unfractionated heparin in patients undergoing percutaneous coronary revascularization: A meta-analysis of 22 randomized trials. Thromb Res. 2015;135:902-15.
Medline
10. Valgimigli M, Frigoli E, Leonardi S, Rothenbühler M, Gagnor A, Calabrò P, et al, MATRIX Investigators. Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes. N Engl J Med. 2015;373:997-1009.
Medline
11. The Source for Interventional Cardiovascular New and [cited 2015 Nov 6]. Available at: www.tctmd.com.
12. European Association of Percutaneous Cardiovascular Interventions [cited 2015 Nov 6]. Available at: www.europcr.com.
13. American College of Cardiology [cited 2015 Nov 6]. Available at: www.acc.org.
14. American Heart Association [cited 2015 Nov 6]. Available at: www.aha.org.
15. European Society of Cardiology [cited 2015 Nov 6]. Available at: www.escardio.org.
16. Biondi-Zoccai GG, Abbate A, Agostoni P, Parisi Q, Turri M, Anselmi M, et al. Stenting versus surgical bypass grafting for coronary artery disease: systematic overview and meta-analysis of randomized trials. Ital Heart J. 2003;4:271-80.
Medline
17. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151:W65-94.
Medline
18. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, et al, HORIZONS-AMI Trial Investigators. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet. 2011;377:2193-204.
Medline
19. Shulz S, Kastrati A, Ferenc M, Massberg S, Birkmeier KA, Laugwitz KL, et al. One-year outcomes with abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary interventions in patients with non-ST-segment elevation myocardial infarction: updated results from the ISAR-REACT 4 trial. EuroIntervention. 2013;9:430-6.
Medline
20. Schulz S, Richardt G, Laugwitz KL, Morath T, Neudecker J, Hoppmann P, et al, Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 Investigators. Prasugrel plus bivalirudin vs. clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2014;35:2285-94.
Medline
21. Shahzad A, Kemp I, Mars C, Wilson K, Roome C, Cooper R, et al, HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. 2014;384:1849-58.
Medline
22. Waksman R, Bertrand O, Driesman M, Gruberg L, Rossi J, Mehta S, et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndrome initially treated with fondaparinux: results from an international, multicenter, randomized pilot study (SWITCH III). J Interv Cardiol. 2013;26:107-13.
Medline
23. Han Y, Guo J, Zheng Y, Zang H, Su X, Wang Y, et al, BRIGHT Investigators. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA. 2015;313:1336-46.
Medline
24. Moliterno DJ, TENACITY Steering Committee and Investigators. A randomized two-by-two comparison of high-dose bolus tirofiban versus abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary revascularization and stent placement: the tirofiban evaluation of novel dosing versus abciximab with clopidogrel and inhibition of thrombin (TENACITY) study trial. Catheter Cardiovasc Interv. 2011;77:1001-9.
Medline
25. Gibson CM, Morrow DA, Murphy SA, Palabrica TM, Jennings LK, Stone PH, et al, TIMI Study Group. A randomized trial to evaluate the relative protection against post-percutaneous coronary intervention microvascular dysfunction, ischemia, and inflammation among antiplatelet and antithrombotic agents: the PROTECT-TIMI-30 trial. J Am Coll Cardiol. 2006;47:2364-7.
Medline
26. Feldman A, Suleiman K, Bushari L, Rozner E, Freedberg N, Nahum A, et al. Bivalirudin Vs Unfractionated Heparin during Percutaneous Coronary Intervention in High Risk Patients for Bleeding. AntiCoagulant Regimen In high risk PAtients for Bleeding -ACRIPAB Trial. Eur Heart J. 2012;33(Suppl 1):842.
27. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37:267-315.
Medline
28. De Luca G, Marino P. Advances in antithrombotic therapy as adjunct to reperfusion therapies for ST-segment elevation myocardial infarction. Thromb Haemost. 2008;100:184-95.
Medline
29. De Luca G, Van’t Hof AW, Gibson CM, Cutlip D, Zeymer U, Noc M, et al, EGYPT cooperation. Impact of time from symptom onset to drug administration on outcome in patients undergoing glycoprotein IIb-IIIa facilitated primary angioplasty (from the EGYPT cooperation). Am J Cardiol. 2015;115:711-5.
Medline
30. De Luca G, Parodi G, Sciagrà R, Venditti F, Bellandi B, Vergara R, et al. Time-to-treatment and infarct size in STEMI patients undergoing primary angioplasty. Int J Cardiol. 2013;167:1508-13.
Medline
31. De Luca G, Marino P. Adjunctive benefits from low-molecular-weight heparins as compared to unfractionated heparin among patients with ST-segment elevation myocardial infarction treated with thrombolysis. A meta-analysis of the randomized trials. Am Heart J. 2007;154:1085.e1-6.
32. De Luca G, Verdoia M, Suryapranata H. Benefits from intracoronary as compared to intravenous abciximab administration for STEMI patients undergoing primary angioplasty: a meta-analysis of 8 randomized trials. Atherosclerosis. 2012;222:426-33.
Medline
33. De Luca G, Navarese EP, Cassetti E, Verdoia M, Suryapranata H. Meta-analysis of randomized trials of glycoprotein IIb/IIIa inhibitors in high-risk acute coronary syndromes patients undergoing invasive strategy. Am J Cardiol. 2011;107:198-203.
Medline
34. Bortnick AE, Epps KC, Selzer F, Anwaruddin S, Marroquin OC, Srinivas V, et al. Five-year follow-up of patients treated for coronary artery disease in the face of an increasing burden of co-morbidity and disease complexity. Am J Cardiol. 2014;113:573-9.
Medline
35. Briguori C, Visconti G, Focaccio A, Donahue M, Golia B, Selvetella L, et al. Novel approaches for preventing or limiting events (Naples) III trial: randomized comparison of bivalirudin versus unfractionated heparin in patients at increased risk of bleeding undergoing transfemoral elective coronary stenting. JACC Cardiovasc Interv. 2015;8:414-23.
Medline
36. Budaj A, Eikelboom JW, Mehta SR, Afzal R, Chrolavicius S, Bassand JP, et al, OASIS 5 Investigators. Improving clinical outcomes by reducing bleeding in patients with non-ST-elevation acute coronary syndromes. Eur Heart J. 2009;30:655-61.
Medline
37. MacHaalany J, Abdelaal E, Bataille Y, Plourde G, Duranleau-Gagnon P, Larose É, et al. Benefit of bivalirudin versus heparin after transradial and transfemoral percutaneous coronary intervention. Am J Cardiol. 2012;110:1742-8.
Medline
38. Cavender MA, Sabatine MS. Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials. Lancet. 2014;384:599-606.
Medline

1885-5857/© 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved

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