bivalirudin in acute coronary syndromes and percutaneous coronary

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BIVALIRUDIN IN ACUTE C ORONARY SYNDROMES AND PERCUTANEOUS C ORONARY INTERVENTION: SHOULD WE USE IT? Yuli Ten, FRACP,and Gerard Devlin, FRACP Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ) Heart, Lung and Circulation 2013;22:793–800

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BIVALIRUDIN IN ACUTE CORONARY

SYNDROMES AND PERCUTANEOUS

CORONARY INTERVENTION: SHOULD WE

USE IT? Yuli Ten, FRACP,∗ and Gerard Devlin, FRACP

Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of

Australia and New Zealand (CSANZ)

Heart, Lung and Circulation 2013;22:793–800

BACKGROUND

Anti-thrombotic therapy remains a cornerstone in per-cutaneous coronary intervention (PCI) and acute coronary syndrome (ACS) management.

The search for newer anti-thrombotic drugs is ongoing with the goal to achieve an agent which leads to less bleeding complications without a reduction or indeed improvement in clinical efficacy, resulting in net clinical benefit.

This is because major bleeding remains a significant risk factor for mortality following PCI with higher 30 days and one year mortality reported in numerous studies .

Bleeding is associated with a five-fold increase in mor-tality and higher risk of myocardial infarction, stroke and stent thrombosis in ACS .

The postulated mechanisms for the increase in mortality with major bleeding include :

Anaemia and hypovolaemia which may contribute to myocardial ischaemia and death;

Bleeding may lead to discontinuation of aspirin, clopidogrel and heparin which may predispose patients to ischaemia, myocardial infarction, stroke and stent thrombosis .

In addition transfusion may increase relative tissue hypoxia and adversely affect outcomes through stored red blood cells acting as nitric oxide sink, which may promote vasoconstriction, platelet aggregation and ineffective oxygen delivery .

With the increasing recognition that bleeding is an important factor in patient outcomes, there has been a shifttowards reducing bleeding risks .

Indeed the prevention of bleeding has become as important a goal as the prevention of ischaemia

Bivalirudin is a direct and specific thrombin inhibitor and synthetic analogue of hirudin, which has been shown to reduce bleeding-related complications .

It has a class 1b indication for use as an anticoagulant during an invasive strategy .

Bivalirudin is currently recommended as an alternative anticoagulant in PCI.

In the 2011 Addendum to the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand(CSANZ) Guidelines for the Management of Acute Coronary Syndromes 2006, bivalirudin is recommended in preference to enoxaparin in the context of an invasive strategy in patients at high risk of bleeding .

In this article, we review the current evidence base, which supports its use.

PHARMACOLOGY OF BIVALIRUDIN V. HEPARIN

Unfractionated heparin has been the standard adjunctive antithrombin therapy during PCI for more than 30years.

Heparin works indirectly by binding to antithrombin III and converts antithrombin III from a slow to a rapid inactivator of thrombin, factors Xa, XIIa and IXa.

The heparin–antithombin III complex inactivates free thrombin but is unable to inactivate thrombin bound within the clot . A possible mechanism for this includes the inability of the bulky heparin–

antithrombin III complex to penetrate the clot. In addition the binding site for the heparin–antithrombin complex on

thrombin may be masked following attachment of the thrombin to fibrin.

Heparin is inactivated by inhibitors released by platelets including heparinase and platelet factor 4 .

Heparin binds to tissue and plasma proteins, which makes the bioavailability, clearance and thus dosing variable from patient to patient . In addition it has nonlinear anticoagulant response at therapeutic dose and a dose dependent half-life. The anticoagulant effects thus may vary from patient to patient. Heparin also has platelet activating effects

Bivalirudin specifically binds to both the active catalytic site and anion binding exosite of free and clot bound thrombin .

The binding of bivalirudin to thrombin is reversible as thrombin slowly cleaves the bivalirudin–thrombin bond resulting in recovery of thrombin active site functions.

Bivalirudin is able to inhibit both free and clot bound thrombin and is not inhibited by circulating inhibitors.

Bivalirudin does not activate platelets and in contrast inhibits thrombin mediated platelet activation.

Because bivalirudin binds only to thrombin and has minimal tissue and plasma protein binding, it has predictable, dose dependent and reliable anticoagulant effects .

Bivalirudin exhibits linear pharmacokinetics with linear dose and concentration proportional anticoagulant activity.

The ACT, aPTT, TT and PT are prolonged by bivalirudin in a dose dependent manner.

Bivalirudin has a short half-life of 25 min and is cleared both renally and via proteolytic degradation. Dose adjustment is thus required in the presence of renal impairment.

THE EVIDENCE : ACUTE CORONARY SYNDROMES

AND PERCUTANEOUS CORONARY INTERVENTION

In the Hirudin Angioplasty study which was performed during the balloon angioplasty era, prior to the routine use of thienopyridines, GP IIbIIIainhibitors and stenting, bivalirudin was reported to be as effective as high dose heparin in reducing ischaemic complications (11.8%v. 12.9%; p = 0.26) and was associated with reduced bleeding (3.8% v. 9.8%; p < 0.001) .

Furthermore in a subgroup analysis of patients with post infarction angina, bivalirudin resulted in a lower incidence of ischaemic complications(9.1% v. 14.2%; p = 0.04) and bleeding (3.0% v. 11.0%;p < 0.001).

A meta-analysis of direct thrombin inhibitors including bivalirudin in acute coronary syndromes by theDirectThrombin Inhibitors Trialists’ Collaborative Group reviewed the use of direct thrombin inhibitors v.unfractionated heparin for up to seven days in 35,970 patients in 11 randomised trials performed in the era prior to the routine use of thienopyridines and GP IIbIIIainhibitors .

Compared with unfractionated heparin,direct thrombin inhibitors were associated with a lower risk of death or myocardial infarction at 30 days [7.4% v.8.2%; odds ratio (OR): 0.91; 95% CI: 0.84–0.99; p = 0.02] principally due to a lower risk of myocardial infarction [2.8%v. 3.5%; OR: 0.80 (0.71–0.9); p < 0.001].

The greatest benefit was seen in the use of direct thrombin inhibitors in PCI with 20 events prevented per 1000 patients treated.

Both bivalirudin and hirudin prevented death or MI. Compared to heparin, bivalirudin was associated with a reduction in bleeding.

The role of bivalirudin in contemporary PCI was examined in the Randomised Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE 2)trial .

In this trial, 6010 patients undergoing elective or urgent PCI were randomised to either bivalirudin with provisional GP IIbIIIa inhibition (n = 2999) or heparin (65 U/kg bolus with planned GP IIbIIIa inhibition)(n = 3011).

Bivalirudin with provisional GP IIbIIIa inhibition was noninferior to heparin and planned GP IIbIIIainhibition in the primary composite endpoint of death, myocardial infarction, urgent repeat revascularisation or in hospital major bleeding [bivalirudin (9.2%) v. heparin and planned GP IIbIIIa inhibitor (10.0%); OR: 0.92;95% CI: 0.77–1.09; p = 0.32].

There was significantly less major bleeding (41% relative reduction) with bivalirudin[bivalirudin (2.4%) v. heparin plus GP IIbIIIa inhibition(4.1%); p < 0.001].

At one year, there was a trend towards improved survival with bivalirudin, a survival advantage that was more marked in the highest risk subgroup .

Thus in elective or low risk PCI, bivalirudin with provisional GP IIbIIIa inhibition may be similar to heparin and planned GP IIbIIIa inhibitor in suppressing acute ischaemic endpoints and significantly reduces bleeding.

The issue of whether bivalirudin monotherapy was non-inferior to heparin plus planned GP IIbIIIa inhibitor in moderate to high-risk acute coronary syndromes wasexamined in the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial .

In this trial,13,819 patients with moder ate to high risk acute coronary syndromes undergoing an early invasive strategy were randomised in an open label multicentre trial to heparin plus a GP IIbIIIa inhibitor, bivalirudin plus a GP IIbIIIa inhibitor or bivalirudin alone.

Bivalirudin alone compared to heparin plus a GP IIbIIIainhibitor was associated with similar rates of ischaemia (7.8% v. 7.3% respectively; p = 0.32; relative risk (RR): 1.03; 95% CI: 0.93–1.24)and significantly reduced major bleeding (3.0% v. 5.7%;p < 0.001; RR: 0.53; 95% CI: 0.43–0.65) which translated to reduced net clinical outcome of ischaemic end points and major bleeding (10.1% v. 11.7%; p = 0.02; RR: 0.86;95% CI: 0.77–0.97).

Bivalirudin plus a GP IIbIIIa inhibitor was similar to heparin plus a GP IIbIIIa inhibitor in reducing ischaemic endpoints (7.7% v. 7.3%; p = 0.39; RR:1.07; 95% CI: 0.92–1.23) with similar bleeding endpoints(5.3% v. 5.7%; p = 0.38; RR: 0.93; 95% CI: 0.78–1.10) and net clinical outcomes (11.8% v. 11.7%; p = 0.93; RR: 1.01; 95% CI: 0.90–1.12) respectively.

At one year, there was no significant difference in composite ischaemia [heparin plus GP IIb/IIIa inhibitor (17.8%) v. bivalirudin plusGP IIb/IIIa inhibitor (19.4%) v. bivalirudin monotherapy(19.2%); p = NS] and mortality between all three groups(3.2% v. 3.3% v. 3.1%; p = ns).

This study suggests that in moderate to high risk acute coronary syndromes, bivalirudin monotherapy may be equivalent to heparin plus a GP IIbIIIa inhibitor in reducing ischaemia and leads to a reduction in major bleeding.

Similarly in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment4 (ISAR-REACT 4), abciximab and unfractionated heparin as compared with bivalirudinfailed to reduce the primary endpoint of death, large recurrent myocardial infarction, urgent target vessel revascularisation or major bleeding within 30 days and increased the risk of bleeding among patients with NSTEMI who underwent an invasive strateg

The role of bivalirudin in primary PCI for acute myocardial infarction was investigated in the Harmonizing Outcomes with Revascularization and Stents in AcuteMyocardial Infarction (HORIZONS-AMI) .

In thistrial, 3602 patients with ST-segment elevation myocardial infarction who were undergoing primary PCI within 12 h were randomised in an open label manner in a 1:1 ratio to heparin plus a GP IIbIIIa inhibitor or bivalirudin alone

The two primary endpoints of this trial were major bleeding and net adverse clinical events defined as the combination of major bleeding or major adverse clinical events defined as death, reinfarction and target vessel revascularisation for ischaemiaand stroke within 30 days.

Primary PCI with bivalirudin compared to heparin plusGPIIbIIIa inhibition was associated with reduced net adverse clinical events (9.2% v. 12.1%; RR: 0.76; 95% CI:0.63–0.92; p = 0.005) due to reduced major bleeding (4.9%v. 8.3%; RR: 0.60; 95% CI: 0.46–0.77; p < 0.001).

Thirty day death from cardiac causes (1.8% v. 2.9%; RR: 0.62;95% CI: 0.40–0.95; p = 0.03) was significantly reduced in the bivalirudin group.

Thirty day death from all causes(2.1% v. 3.1%; RR: 0.66; 95% CI: 0.44–1.00; p = 0.047) was not significantly different.

Death from cardiac causes(including deaths from stent thrombosis) at 30 days was reduced by an absolute 1% and a relative reduction of37.9% in favour of bivalirudin.

Heparin bolus was given in the emergency room to two-thirds of the patients in the bivalirudin group with bivalirudincommenced in the cardiac catheterisation laboratory.

Bivalirudin significantly reduced bleeding independent of whether heparin was given preprocedurally .

At one year, the rate of net adverse clinical events was lower in the bivalirudin group compared to the heparin plus GP IIbIIIainhibitorgroup [15.6% v. 18.3%; hazard ratio (HR): 0.83; 95% CI:0.71–0.97; p = 0.022] due to a reduction in major bleeding in the bivalirudin group (5.8% v. 9.2%; HR: 0.61,0.48–0.78; p < 0.0001).

The one year MACE was similar between both groups (11.9% v. 11.9%; HR: 1.0, 0.82–1.21;p = 0.98), however, the one year rate of cardiac mortality (2.1% v. 3.8%; HR: 0.57; 95% CI: 0.38–0.84; p = 0.005)and all cause mortality (3.5% v. 4.8%; HR: 0.71; 95% CI:0.51–0.98; p = 0.037) were lower in the bivalirudin group.

In this trial, more deaths occurred following major bleeding (26 deaths) than either reinfarction (10 deaths) or definite stent thrombosis (five deaths).

In conclusion the HORIZONS-AMI trial suggests that the prevention of haemorrhagic complications following primary PCI for STEMI is factorial in improved short and longterm survival.

Bivalirudin monotherapy compared to heparin plusGP IIbaIIIa inhibitor results in reduced major bleeding and therefore a net clinical benefit .

In light of these findings, the CSANZ has recommended that amongst patients undergoing primary PCI for STEMI, bivalirudin should be considered as an alternative to heparin and GPIIbIIIainhibitor

THE ROLE OF CLOPIDOGREL LOADING

In the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment(ISAR-REACT 3) trial, bivalirudin was compared with unfractionated heparin alone in a double blind trial in 4570 troponin negative, stable and unstable angina patients undergoing PCI following pretreatment with 600 mg loading dose of clopidogrel at least 2 h prior to the procedure.

There was no significant difference in the primary endpoint of composite death, myocardial infarction, urgent target vessel revascularisation within 30 days after revascularisation or major bleeding during hospitalisation [bivalirudin (8.3%) v. unfractionatedheparin (8.7%)(RR: 0.94; 95% CI: 0.77– 1.15; p = 0.57)].

Major bleeding was reduced in the bivalirudin group [bivalirudin(3.1%) v. unfractionated heparin (4.6%) (RR: 0.66; 95% CI: 0.49–0.90;p = 0.008)].

The results of the primary endpoint remained consistent at one year [bivalirudin (17.1%) v. heparin(17.5%); HR: 0.98; 95% CI: 0.86–1.13; p = 0.816] (19).

This study suggests that in low risk, troponin negative patients who are preloaded with 600 mg of clopidogrel at least 2 h prior to PCI, bivalirudin may not confer any additional net clinical benefit. A reduction in major bleeding, an independent secondary endpoint, was however observed with bivalirudin, consistent with other trials

In the ACUITY trial, patients who were not pretreated with clopidogrel were noted to have more ischaemicendpoints with bivalirudin monotherapy than with unfractionated heparin/enoxaparin plus GP IIbIIIainhibitor (9.1% v. 7.1%; RR: 1.29; 95% CI: 1.03–1.63;p = 0.054) [12].

In patients pretreated with clopidogrel however, bivalirudin monotherapy resulted in similar ischaemicendpoints to heparin plus GP IIbIIIa inhibitor(7.0% v. 7.3% respectively; RR: 0.97; 95% CI: 0.80–1.17).

The suboptimal results in patients not pretreated with clopidogrel implies that platelet inhibition remains important even with potent antithrombin activity and emphasises the importance of clopidogrel pretreatment in all high risk acute coronary syndrome patients undergoing an invasive strategy .

The updated ACC/AHA guidelines recommend that bivalirudin is a reasonable anticoagulant for PCI in patients preloaded with clopidogrel.

A 600 mg loading dose of clopidogrel has been associated with greater and more rapid inhibition of platelet aggregation and therefore less ischaemiacompared to a 300 mg dose .

In a substudy from the HORIZONS-AMI trial, a 600 mg loading dose in comparison to 300 mg dose of clopidogrel in the setting of primary PCI was asso-ciated with lower 30 day mortality (1.9% v. 3.1%; p = 0.03),reinfarction (1.3% v. 2.3%; p = 0.02) and stent thrombosis(1.7% v. 2.8%; p = 0.04) without an increase in bleeding .

Bivalirudin monotherapy however compared to heparin plus GP IIbIIIa inhibitor was associated with less bleeding and net adverse clinical event independent of the higher loading dose of clopidogrel.

THE EFFECT OF SWITCHING FROM HEPARIN

TO BIVALIRUDIN

Bivalirudin In the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIaInhibitors (SYNERGY trial), crossover from enoxaparin to unfractionated heparin or vice versa was associated with increased risks of bleeding, myocardial infarction and death .

Postulated mechanisms for this include under anticoagulation from switching from one therapy to another and therefore creating a gap in anticoagulation or over-anticoagulation from stacking of two antithombintherapies with prolonged factor antiXa activity without a sufficient washout period .

Based on this result, the American College of Cardiology (ACC), American HeartAssociation (AHA) and the European Society of Cardiology (ESC) have recommended consistent antithrombotic therapy from the pre-PCI phase throughout the PCI itself.

The benefits of reduced bleeding and equivalent ischaemic protection with bivalirudin however were pre-served when switching from heparin or enoxaparin plusGPIIb/IIIa inhibitors to bivalirudin .

In a substudy from the ACUITY trial, switching from unfractionated heparin or enoxaparin plus a GP IIb/IIIainhibitor to bivalirudin monotherapy resulted in similar composite ischaemic outcomes [6.9% (bivalirudin) v. 7.4% (consistent therapy); risk ratio: 0.93; 95% CI: 0.75–1.16; p = 0.52] and a 51% relative reduction in major bleeding [2.8%(bivalirudin) v. 5.8% (consistent therapy), risk ratio: 0.49,95% CI: 0.36–0.66; p < 0.01] compared with consistent unfractionated heparin/enoxaparin plus a GP IIbIIIa inhibitor .

The crossover from heparin or enoxaparin to bivalirudin at PCI does not result in an excess of bleeding but has a protective effect by reducing bleeding by 51%.

This finding has important implications given that many Non-STEMI-ACS patients are pretreated with heparin or enoxaparinprior to PCI and given the recommendations from ACC, AHA and ESC for consistent antithombin therapy from pre PCI to PCI.

Heparin is commonly given in the emergency department in the setting of primary PCI. The HORIZONS-SWITCH Analysis, which examined the effects of switching from early heparin given in the emergency department to bivalirudin in patients undergoing primary PCI for STEMI found lower rates of major bleeding which translated to lower early and late cardiac mortality .

At 30 days, the rate of major bleeding was 7.6% in the bivalirudin group compared with 12.3% in the continued heparin plus GP IIb/IIIa inhibitor group (p = 0.0001).

Cardiac mortality was reduced at 30 days (1.6% v. 2.9%;p = 0.04) and at two years (2.3% v. 3.8%; p = 0.04).

The reduced bleeding and cardiac mortality with bivalirudinwere independent of the preprocedure ACT.

This study suggests that switching from heparin to bivalirudin is safe and preserves the benefits of bivalirudin in the setting of primary PCI.

THE EFFECT OF BIVALIRUDIN ON SUBGROUPS

Subgroups Major studies have identified the elderly, females, renal impairment and anaemia as independent risk factors for bleeding .

Independent periprocedural risk factors for major bleeding include the use of GP IIb/IIIa inhibitors, prolonged time to sheath removal, prolonged procedure time, access site selection, right heart catheterisation and use of intra-aortic balloon pump.

The elderly are at increased risk of both ischaemic and bleeding events .

In a substudy from the ACUITY trial, increasing age was associated with increased ischaemic events and bleeding .

In patients ≥75years, bivalirudin monotherapy was associated with comparable ischaemic outcomes (12.2% v. 11%; p = 0.57) but with less TIMI major bleeding (1.7% v. 3.6%; p < 0.05) compared to heparin plus GP IIb/IIIa inhibitors.

The number needed to treat to prevent one major bleed was lowest in the age group ≥75 (23 to prevent one bleed) and even lower in the PCI subgroup ≥75 (16 to prevent one bleed).

In a subgroup analysis from the ACUITY trial, females had comparable 30 day ischaemic outcomes to males (7%v. 8%; p = 0.07) but had significantly increased 30 day rates of non-CABG major bleeding (8% v. 3%; p < 0.0001) .

The use of bivalirudin in females resulted in similar 30 day ischaemic outcomes (7% v. 6%; p = 0.15) with significantly reduced 30 day major bleeding (5% v. 10%; p < 0.0001) in comparison to heparin plus GP IIbIIIa inhibitors.

Renal impairment is associated with an increase in periprocedural bleeding, ischaemic complications and target vessel revascularisation .

Renal impairment in the Global Registry of Acute Coronary Events (GRACE) registry was associated with a 1.48 fold increase in the risk of bleeding (p = 0.0004) among 24,045 patients with acute coronary syndromes .

In a subgroup analysis from the REPLACE 2 trial, renal impairment (defined as a creatinine clearance ≤60 mL/min) was associated witha 1.72 fold increase in risk of bleeding (p = 0.028), 1.45 fold increase in ischaemic events (p = 0.028) and 3.85-fold increase in 12 month mortality (p < 0.001) .

In a meta-analysis of three randomised trials comparing bivalirudin with heparin during PCI, bivalirudin was associated withgreater absolute benefit in reducing combined bleeding and ischaemic complications with worsening degrees of renal impairment

Anaemia is both a predictor of ischaemia and majorbleeding .

In a meta-analysis of 39,922 patients in 16 TIMI clinical trials of acute coronary syndromes, anaemia was noted to be a major predictor of major cardiovascular events in both STEMI and Non-STEMI .

In a subanalysis of the REPLACE 2 trial, major bleeding was more common in anaemic compared to non-anaemicpatients.(4.9% v. 2.8%; p = 0.0001) . The use of bivalirudinhowever in anaemic patients was associated with a lower risk of major bleeding in comparison to heparin and GP IIb/IIIainhibitors (3.5% v. 6.2%; p = 0.0221)

WHAT THE GUIDELINES SAY

In its updated 2011 guidelines on the management of NSTEMI-ACS, the ESC has recommended that the prevention of bleeding should be as important as the prevention of ischaemia .

Some of the measures recommended include the choice of safer drugs, titration of optimal dose of antithrombotic agent (taking into account the patient’s age, sex and CrCl), reduced duration of antithrombotic agent, avoiding upstream GP IIbIIIa unless recurrent ischaemia and radial access over femoral access site

In the updated guidelines of the ESC and CSANZ on the management of Non-STEMI ACS and recommendations from the Working Group on Thrombosis of the European Society of Cardiology, antithombotic agents such as bivalirudinwhich produce similar anti-ischaemic efficacy while reducing bleeding complications should be used in preference .

The CSANZ has further recommended that among patients at high risk of bleeding during an invasive strategy, bivalirudin should be considered in preference to heparin or enoxaparin plus GP IIbIIIa inhibitor .

Amongst patients undergoing primary PCI for STEMI, bivalirudin can be considered as an alternative to heparin plus GP IIbIIIa inhibitor .

In the updated2011 ACC/AHA guidelines for Non-STEMI-ACS patients undergoing PCI who are at high risk of bleeding, the use of bivalirudin is reasonable

CONCLUSION

Major bleeding carries a mortality hazard comparable to myocardial infarction and is associated with significant morbidity, mortality and hospital costs in patients undergoing PCI for STEMI and Non-STEMI-ACS.

Bivalirudin significantly reduces bleeding in low to high risk Non-STEMI-ACS and primary PCI in STEMI and provides similar protection to combination heparin plus GP IIbIIIa inhibitor in reducing ischaemic events.

Bivalirudin with its ability to reduce bleeding in PCI should be considered in patients at high bleeding risk for PCI, which include STEMI presentations, the elderly, females, renal impairment and the anaemic.