Expert Review of Pharmacoeconomics & Outcomes Research
ISSN: 1473-7167 (Print) 1744-8379 (Online) Journal homepage: http://www.tandfonline.com/loi/ierp20
The clinical and economic impact of bivalirudin for percutaneous coronary intervention Nikesh Malik & Anthony H Gershlick To cite this article: Nikesh Malik & Anthony H Gershlick (2013) The clinical and economic impact of bivalirudin for percutaneous coronary intervention, Expert Review of Pharmacoeconomics & Outcomes Research, 13:6, 699-706 To link to this article: http://dx.doi.org/10.1586/14737167.2013.844650
Published online: 09 Jan 2014.
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Date: 13 September 2015, At: 08:31
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The clinical and economic impact of bivalirudin for percutaneous coronary intervention Expert Rev. Pharmacoecon. Outcomes Res. 13(6), 699–706 (2013)
Nikesh Malik* and Anthony H Gershlick Department of Cardiovascular Sciences, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK *Author for correspondence: Tel.: +44 116 256 3040 Fax: +44 116 287 5792 [email protected]
Bivalirudin (BVR) is a direct thrombin inhibitor used as an adjunctive antithrombotic agent in combination with aspirin and an ADP-receptor blocker in patients with acute coronary syndrome undergoing percutaneous coronary intervention. When compared to a strategy of heparin plus a glycoprotein IIb/IIIa inhibitor, BVR has been shown in a number of randomized clinical trials to be at least as effective at reducing ischemic endpoints and to have a consistently lower rate of bleeding complications. In addition, various economic analyses have shown it to be cost-effective compared to heparin plus a glycoprotein IIb/IIIa inhibitor and this, coupled with its proven clinical efficacy, has led to the incorporation of BVR into both EU and US clinical guidelines. Previous studies with BVR have mostly assessed its use in patients treated with aspirin and clopidogrel and further studies are ongoing to determine its role in combination with newer, more potent oral antiplatelet agents. KEYWORDS: bivalirudin • bleeding • clinical efficacy • economic impact • percutaneous coronary intervention
Coronary artery disease remains the leading cause of death worldwide. Patients presenting with acute coronary syndrome (ACS) in its various forms mostly share the same underlying pathophysiology, suffering varying degrees of intracoronary thrombosis precipitated by atherosclerotic plaque rupture or erosion [1]. Immediate management is aimed at alleviating symptoms, reducing clot burden, restoring coronary blood flow and so limiting myocardial damage. Both European and American clinical guidelines recommend an early invasive approach for most patients, along with appropriate adjuvant antithrombotic therapy [2,3]. This includes the use of dual antiplatelet therapy (DAPT) – aspirin and an ADP-receptor blocker – and an injectable anticoagulant at the time of percutaneous coronary intervention (PCI). The recommended anticoagulants are unfractionated heparin (UFH) with or without a routine glycoprotein IIb/IIIa inhibitor (GPI), or bivalirudin (BVR) – a direct thrombin inhibitor – with a GPI restricted to bailout use. Alternative agents include enoxaparin (a low molecular weight heparin) and fondaparinux (a factor Xa
www.expert-reviews.com
10.1586/14737167.2013.844650
inhibitor) [4,5]. In this review, we discuss the clinical and economic impact of BVR for PCI in the acute setting. Overview
An early invasive strategy of coronary angiography plus appropriate revascularization with adjunctive therapy is recommended for high risk patients presenting with ACS, including ST elevation myocardial infarction (STEMI), non-STEMI and unstable angina [1,2]. Intracoronary thrombosis is the triggering factor in the majority of cases [6] and identifying the most effective adjuvant antithrombotic therapy to use at the time of PCI, while minimizing bleeding risk, has been the topic of much research in this area. The addition of a GPI to heparin-based treatment in high-risk patients undergoing PCI has significantly reduced the rate of ischemic events [7]. However, this has been at the expense of a higher rate of bleeding complications, which is increasingly recognized as a major independent predictor of subsequent mortality in patients undergoing PCI [8–10]. By
Ó 2013 Informa UK Ltd
ISSN 1473-7167
699
Downloaded by [University of California, San Diego] at 08:31 13 September 2015
Drug Profile
Malik & Gershlick
comparison, BVR has been shown in a number of clinical settings to have a lower rate of bleeding while maintaining clinical efficacy in terms of ischemic endpoints [11–14]. BVR is a 20-amino acid synthetic polypeptide that directly and specifically inhibits both fibrin-bound and soluble thrombin in a reversible manner. Thrombin is central in the process of thrombosis, catalyzing the conversion of fibrinogen to fibrin and activating the procoagulant factors V, VIII, XI and XIII. It also activates platelets, stimulating aggregation and granule release. BVR has an inhibitory effect on all of these actions, as well as some effect on ADP-induced platelet aggregation [15] and is licensed for use as an intravenous anticoagulant in adult patients undergoing PCI, including primary PCI in STEMI and in patients with unstable angina or non-STEMI for whom urgent or early intervention is planned [16]. Key clinical trials
A number of large clinical trials have compared the use of BVR with heparin plus a GPI in patients undergoing PCI for stable angina, unstable angina, NSTEMI and STEMI. Results from the most relevant studies are summarized in TABLE 1. BVR has consistently been associated with a reduced rate of major bleeding and similar rates of ischemia when compared to heparin plus a GPI. The REPLACE-2 trial (randomized evaluation in PCI linking angiomax to reduced clinical events), published in 2003, was a prospective, double-blind, international multi-center randomized clinical trial (RCT) assessing the efficacy of BVR, with a provisional GPI, as compared to heparin plus a routine GPI, in 6010 patients undergoing urgent or elective PCI. BVR met the pre-specified statistical criteria for non-inferiority to heparin plus a GPI for the primary combined end point of 30-day mortality, MI, urgent repeat revascularization, or inhospital major bleeding (odds ratio [OR]: 0.92; 95% confidence interval [CI]: 0.77–1.09; p = 0.32) and the secondary combined endpoint of 30-day mortality, MI or urgent repeat revascularization (OR: 1.09; 95% CI: 0.90–1.32; p = 0.40). In addition, BVR was associated with a significantly reduced rate of in-hospital major bleeding (2.4 vs 4.1%, p < 0.001) [11]. The ACUITY trial (Acute Catheterization and Urgent Intervention Triage Strategy), published in 2006, was a prospective, open-label, 3-arm, multicenter RCT comparing UFH or enoxaparin plus a GPI (arm A), with BVR plus a GPI (arm B) or BVR monotherapy (arm C) in 13,819 patients with ACS (unstable angina or NSTEMI) in whom urgent or early coronary intervention was planned. At 30 days, BVR plus a GPI (arm B) was non-inferior to heparin plus a GPI (arm A) with respect to the three primary endpoints of net clinical outcome (death/MI/unplanned revascularization/major bleeding), composite ischemia (death/MI/unplanned revascularization) and non-CABG major bleeding at 30 days. BVR alone (arm C) was non-inferior to heparin plus a GPI (arm A) with regards to the composite ischemia endpoint (relative risk [RR]: 1.08; 95% CI: 0.93–1.24; p = 0.32) and had significantly lower rates of major bleeding (RR: 0.53; 95% CI: 0.43–0.65; p < 0.001), 700
resulting in a significantly lower incidence of the net clinical outcome endpoint (RR: 0.86; CI: 0.77–0.97; p = 0.02). At 1 year, there was no significant difference between any of the three groups with regards to composite ischemia or mortality [12,17]. The HORIZONS-AMI trial (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction), published in 2008, was a prospective, open-label, parallel group, international multicenter RCT comparing the safety and efficacy of BVR versus UFH plus a GPI in 3602 STEMI patients undergoing primary PCI. The two primary endpoints of the study were major bleeding and net adverse clinical events (NACE), defined as a combination of non-CABG major bleeding and major adverse cardiovascular events, MACE (death/ reinfarction/target-vessel revascularization/stroke) within 30 days. BVR monotherapy was associated with a significantly lower 30-day incidence of NACE (RR: 0.76; 95% CI: 0.63–0.92; p = 0.005), which was driven by a significantly lower rate of major bleeding with BVR (RR: 0.60; 95% CI: 0.46–0.77; p < 0.001). There was an increased rate of acute stent thrombosis (within 24 h of PCI) in the BVR arm, but the overall rate of stent thrombosis at 30 days was not significantly different between the two groups. Although the trial was underpowered for lowfrequency endpoints, including death, BVR was associated with significantly lower 30-day rates of cardiac mortality and overall mortality [13]. These results were maintained at 1 year and 3 years follow-up [18,19]. The ISAR-REACT 4 trial (intracoronary stenting and antithrombotic regimen: rapid early action for coronary treatment 4), published in 2011, was a prospective, double-blind RCT comparing the use of BVR versus UFH plus a GPI in 1721 acute NSTEMI patients undergoing PCI. No significant difference was found between the two groups with respect to the primary combined endpoint of death, recurrent MI, urgent target-vessel revascularization and major bleeding within 30 days (RR: 0.99; 95% CI: 0.74–1.32; p = 0.94). However, bivalirudin was associated with a significantly reduced rate of the secondary safety endpoint of major bleeding (RR: 1.84; 95% CI: 1.10–3.07; p = 0.02) [14]. Safety & tolerability
BVR is contraindicated in patients with active bleeding or with an increased risk of bleeding due to a hemostatic disorder. It should also be avoided in severe uncontrolled hypertension, sub-acute bacterial endocarditis, severe renal impairment (eGFR
ISSN: 1473-7167 (Print) 1744-8379 (Online) Journal homepage: http://www.tandfonline.com/loi/ierp20
The clinical and economic impact of bivalirudin for percutaneous coronary intervention Nikesh Malik & Anthony H Gershlick To cite this article: Nikesh Malik & Anthony H Gershlick (2013) The clinical and economic impact of bivalirudin for percutaneous coronary intervention, Expert Review of Pharmacoeconomics & Outcomes Research, 13:6, 699-706 To link to this article: http://dx.doi.org/10.1586/14737167.2013.844650
Published online: 09 Jan 2014.
Submit your article to this journal
Article views: 36
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierp20 Download by: [University of California, San Diego]
Date: 13 September 2015, At: 08:31
Drug Profile
Downloaded by [University of California, San Diego] at 08:31 13 September 2015
The clinical and economic impact of bivalirudin for percutaneous coronary intervention Expert Rev. Pharmacoecon. Outcomes Res. 13(6), 699–706 (2013)
Nikesh Malik* and Anthony H Gershlick Department of Cardiovascular Sciences, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK *Author for correspondence: Tel.: +44 116 256 3040 Fax: +44 116 287 5792 [email protected]
Bivalirudin (BVR) is a direct thrombin inhibitor used as an adjunctive antithrombotic agent in combination with aspirin and an ADP-receptor blocker in patients with acute coronary syndrome undergoing percutaneous coronary intervention. When compared to a strategy of heparin plus a glycoprotein IIb/IIIa inhibitor, BVR has been shown in a number of randomized clinical trials to be at least as effective at reducing ischemic endpoints and to have a consistently lower rate of bleeding complications. In addition, various economic analyses have shown it to be cost-effective compared to heparin plus a glycoprotein IIb/IIIa inhibitor and this, coupled with its proven clinical efficacy, has led to the incorporation of BVR into both EU and US clinical guidelines. Previous studies with BVR have mostly assessed its use in patients treated with aspirin and clopidogrel and further studies are ongoing to determine its role in combination with newer, more potent oral antiplatelet agents. KEYWORDS: bivalirudin • bleeding • clinical efficacy • economic impact • percutaneous coronary intervention
Coronary artery disease remains the leading cause of death worldwide. Patients presenting with acute coronary syndrome (ACS) in its various forms mostly share the same underlying pathophysiology, suffering varying degrees of intracoronary thrombosis precipitated by atherosclerotic plaque rupture or erosion [1]. Immediate management is aimed at alleviating symptoms, reducing clot burden, restoring coronary blood flow and so limiting myocardial damage. Both European and American clinical guidelines recommend an early invasive approach for most patients, along with appropriate adjuvant antithrombotic therapy [2,3]. This includes the use of dual antiplatelet therapy (DAPT) – aspirin and an ADP-receptor blocker – and an injectable anticoagulant at the time of percutaneous coronary intervention (PCI). The recommended anticoagulants are unfractionated heparin (UFH) with or without a routine glycoprotein IIb/IIIa inhibitor (GPI), or bivalirudin (BVR) – a direct thrombin inhibitor – with a GPI restricted to bailout use. Alternative agents include enoxaparin (a low molecular weight heparin) and fondaparinux (a factor Xa
www.expert-reviews.com
10.1586/14737167.2013.844650
inhibitor) [4,5]. In this review, we discuss the clinical and economic impact of BVR for PCI in the acute setting. Overview
An early invasive strategy of coronary angiography plus appropriate revascularization with adjunctive therapy is recommended for high risk patients presenting with ACS, including ST elevation myocardial infarction (STEMI), non-STEMI and unstable angina [1,2]. Intracoronary thrombosis is the triggering factor in the majority of cases [6] and identifying the most effective adjuvant antithrombotic therapy to use at the time of PCI, while minimizing bleeding risk, has been the topic of much research in this area. The addition of a GPI to heparin-based treatment in high-risk patients undergoing PCI has significantly reduced the rate of ischemic events [7]. However, this has been at the expense of a higher rate of bleeding complications, which is increasingly recognized as a major independent predictor of subsequent mortality in patients undergoing PCI [8–10]. By
Ó 2013 Informa UK Ltd
ISSN 1473-7167
699
Downloaded by [University of California, San Diego] at 08:31 13 September 2015
Drug Profile
Malik & Gershlick
comparison, BVR has been shown in a number of clinical settings to have a lower rate of bleeding while maintaining clinical efficacy in terms of ischemic endpoints [11–14]. BVR is a 20-amino acid synthetic polypeptide that directly and specifically inhibits both fibrin-bound and soluble thrombin in a reversible manner. Thrombin is central in the process of thrombosis, catalyzing the conversion of fibrinogen to fibrin and activating the procoagulant factors V, VIII, XI and XIII. It also activates platelets, stimulating aggregation and granule release. BVR has an inhibitory effect on all of these actions, as well as some effect on ADP-induced platelet aggregation [15] and is licensed for use as an intravenous anticoagulant in adult patients undergoing PCI, including primary PCI in STEMI and in patients with unstable angina or non-STEMI for whom urgent or early intervention is planned [16]. Key clinical trials
A number of large clinical trials have compared the use of BVR with heparin plus a GPI in patients undergoing PCI for stable angina, unstable angina, NSTEMI and STEMI. Results from the most relevant studies are summarized in TABLE 1. BVR has consistently been associated with a reduced rate of major bleeding and similar rates of ischemia when compared to heparin plus a GPI. The REPLACE-2 trial (randomized evaluation in PCI linking angiomax to reduced clinical events), published in 2003, was a prospective, double-blind, international multi-center randomized clinical trial (RCT) assessing the efficacy of BVR, with a provisional GPI, as compared to heparin plus a routine GPI, in 6010 patients undergoing urgent or elective PCI. BVR met the pre-specified statistical criteria for non-inferiority to heparin plus a GPI for the primary combined end point of 30-day mortality, MI, urgent repeat revascularization, or inhospital major bleeding (odds ratio [OR]: 0.92; 95% confidence interval [CI]: 0.77–1.09; p = 0.32) and the secondary combined endpoint of 30-day mortality, MI or urgent repeat revascularization (OR: 1.09; 95% CI: 0.90–1.32; p = 0.40). In addition, BVR was associated with a significantly reduced rate of in-hospital major bleeding (2.4 vs 4.1%, p < 0.001) [11]. The ACUITY trial (Acute Catheterization and Urgent Intervention Triage Strategy), published in 2006, was a prospective, open-label, 3-arm, multicenter RCT comparing UFH or enoxaparin plus a GPI (arm A), with BVR plus a GPI (arm B) or BVR monotherapy (arm C) in 13,819 patients with ACS (unstable angina or NSTEMI) in whom urgent or early coronary intervention was planned. At 30 days, BVR plus a GPI (arm B) was non-inferior to heparin plus a GPI (arm A) with respect to the three primary endpoints of net clinical outcome (death/MI/unplanned revascularization/major bleeding), composite ischemia (death/MI/unplanned revascularization) and non-CABG major bleeding at 30 days. BVR alone (arm C) was non-inferior to heparin plus a GPI (arm A) with regards to the composite ischemia endpoint (relative risk [RR]: 1.08; 95% CI: 0.93–1.24; p = 0.32) and had significantly lower rates of major bleeding (RR: 0.53; 95% CI: 0.43–0.65; p < 0.001), 700
resulting in a significantly lower incidence of the net clinical outcome endpoint (RR: 0.86; CI: 0.77–0.97; p = 0.02). At 1 year, there was no significant difference between any of the three groups with regards to composite ischemia or mortality [12,17]. The HORIZONS-AMI trial (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction), published in 2008, was a prospective, open-label, parallel group, international multicenter RCT comparing the safety and efficacy of BVR versus UFH plus a GPI in 3602 STEMI patients undergoing primary PCI. The two primary endpoints of the study were major bleeding and net adverse clinical events (NACE), defined as a combination of non-CABG major bleeding and major adverse cardiovascular events, MACE (death/ reinfarction/target-vessel revascularization/stroke) within 30 days. BVR monotherapy was associated with a significantly lower 30-day incidence of NACE (RR: 0.76; 95% CI: 0.63–0.92; p = 0.005), which was driven by a significantly lower rate of major bleeding with BVR (RR: 0.60; 95% CI: 0.46–0.77; p < 0.001). There was an increased rate of acute stent thrombosis (within 24 h of PCI) in the BVR arm, but the overall rate of stent thrombosis at 30 days was not significantly different between the two groups. Although the trial was underpowered for lowfrequency endpoints, including death, BVR was associated with significantly lower 30-day rates of cardiac mortality and overall mortality [13]. These results were maintained at 1 year and 3 years follow-up [18,19]. The ISAR-REACT 4 trial (intracoronary stenting and antithrombotic regimen: rapid early action for coronary treatment 4), published in 2011, was a prospective, double-blind RCT comparing the use of BVR versus UFH plus a GPI in 1721 acute NSTEMI patients undergoing PCI. No significant difference was found between the two groups with respect to the primary combined endpoint of death, recurrent MI, urgent target-vessel revascularization and major bleeding within 30 days (RR: 0.99; 95% CI: 0.74–1.32; p = 0.94). However, bivalirudin was associated with a significantly reduced rate of the secondary safety endpoint of major bleeding (RR: 1.84; 95% CI: 1.10–3.07; p = 0.02) [14]. Safety & tolerability
BVR is contraindicated in patients with active bleeding or with an increased risk of bleeding due to a hemostatic disorder. It should also be avoided in severe uncontrolled hypertension, sub-acute bacterial endocarditis, severe renal impairment (eGFR
