American Heart Journal
Volume 143, Issue 2 , Pages 189-192, February 2002

Improved efficacy and less bleeding: Further evidence of a unique uncoupling of benefit and risk with bivalirudin☆

Cardiology Department, Green Lane Hospital, Auckland, New Zealand

Article Outline

 

See related article on page 229 .

In this issue of the Journal Antman et el1 describe the results of the Thrombolysis in Myocardial Infarction (TIMI)-8 trial, which was stopped early 7 years ago. The purpose of the trial was to test an intravenous thrombin-specific anticoagulant, bivalirudin, that first underwent clinical trial in 1990. Why would readers be interested in the results of such a study that enrolled only 2.5% of its planned number of patients? Premature termination of clinical trials is typically associated with decreased safety or lack of efficacy and, as such, any analysis carries a risk of bias. The TIMI-8 trial, however, was not stopped early because of poor results from analyses of the data but because the sponsoring pharmaceutical company (Biogen Inc, Cambridge, Mass) made an economic decision to cease development of the product. This therefore reduces the likelihood of bias in the trial.

In TIMI-8, bivalirudin was found to reduce the combined incidence of death/myocardial infarction by 70% at 14 days (9.2% vs 2.9%) and major hemorrhage from 4.6% to 0%. Both these findings were nonsignificant. With use of a post hoc-defined end point combining death, myocardial infarction, and major hemorrhage, there was an 80% reduction from 13.8% with unfractionated heparin to 2.9% with bivalirudin (P = .03). Although limited, these results are important because they add to growing evidence that bivalirudin may consistently reduce the risk of both ischemic and bleeding complications in patients undergoing percutaneous coronary intervention and in those with non-ST-elevation acute coronary syndromes, and they again highlight the limitations of heparin.

Unfractionated heparin has been used since the 1980s and is the standard foundation anticoagulant, along with aspirin, for the management of acute coronary syndromes.2, 3 A meta-analysis by Eikelboom et al4 showed that the addition of heparin to aspirin in patients with unstable angina insignificantly reduced the relative risk of death/myocardial infarction (P = .06). The limitations of heparin are well known, including its inability to inhibit fibrin-bound thrombin (a powerful stimulus for thrombus generation), neutralization by platelet factor 4, ability to activate platelets, and associated bleeding complications. These limitations are particularly evident in high-risk patient populations such as the elderly, postinfarction patients with angina, and those with renal insufficiency.

In the past decade there has been considerable evolution in the management of acute coronary syndromes, including the development of low-molecular-weight heparins.5, 6, 7 Although low-molecular-weight heparin may be more efficacious than heparin in unstable angina, bleeding remains a concern, particularly in patients with renal insufficiency where clearance levels of low-molecular-weight fragments are reduced.8

Why is there a need for another anticoagulant regimen? First, as noted in TIMI-8,1 the event rates in patients with acute coronary syndromes remain far too high.7, 9, 10, 11 For example, in the recent Do Tirofiban and ReoPro Give Similar Efficacy Trial (TARGET),12 the composite end point of death/myocardial infarction/urgent target vessel revascularization occurred in 6.3% of patients who had an acute coronary syndrome and who received abciximab. Second, there is a clear need for safer anticoagulants. Most antithrombotic treatments, including the glycoprotein IIb/IIIa inhibitors, provide benefits at the cost of an increased bleeding risk. Direct thrombin inhibitors hold the promise to overcome some of the limitations of heparin. However, the direct thrombin inhibitor, hirudin, has a number of limitations related to its narrow therapeutic window and potential for bleeding,13, 14 probably related to its nonreversible binding, renal excretion, and half-life of 40 minutes.15 Major hemorrhages and transfusions are not innocuous and are costly. The increased use of clopidogrel9 and invasive management16, 17 calls for agents that allow for a seamless transition to the catheterization laboratory with a low risk of bleeding.

Although an increase in bleeding would seem to be an expected consequence of more effective anticoagulation, trials of bivalirudin have uncoupled this relationship. A meta-analysis of TIMI-8, the Hirulog and Early Reperfusion/Occlusion (HERO)-I trial, and the Bivalirudin Angioplasty Trial demonstrated a highly significant reduction in hemorrhagic events in patients receiving bivalirudin compared with heparin, with a combined odds ratio of 0.41 (95% CI 0.32-0.52, P < .001).18

The clinical efficacy of bivalirudin has been consistent across all the trials examined to date,18 including a recent pilot trial.19 In 144 patients undergoing treatment with bivalirudin, abciximab was administered at the discretion of the operator, and 64 patients received unfractionated heparin (70 μg/kg) plus abciximab. The composite end point of death/myocardial infarction/revascularization was significantly reduced in the patients randomized to receive bivalirudin (14.0% vs 5.9%, P < .05), and there was no difference in the rates of major bleeding (6.3% with unfractionated heparin vs 2.4% with bivalirudin). In the recent Comparison of Abciximab Complications with Hirulog (and Abciximab Backup) for Ischemic Events Trial (CACHET),20 208 patients undergoing percutaneous coronary intervention were randomized to receive unfractionated heparin and either abciximab or bivalirudin (of whom 24% also received abciximab). Stenting was performed in 88% of patients. There were no deaths, and the composite end point of myocardial infarction/revascularization/major hemorrhage within 7 days was reduced from 14.1% in patients given unfractionated heparin plus abciximab to 3.5% in those given bivalirudin (P < .05).21

Perhaps of equal significance is the fact that in high-risk patient populations heparin is less effective and causes more bleeding than bivalirudin does. In the Bivalirudin Angioplasty Study, postinfarction patients randomized to bivalirudin had significantly better outcomes than patients randomized to heparin.22 Subanalysis of other high-risk patient subgroups, such as women, the elderly, patients with low body weight, and patients with renal insufficiency, showed that they all fared better on bivalirudin than on heparin.23, 24

In the recent HERO-2 Trial,25 17,073 patients with evolving ST-elevation myocardial infarction were randomized to receive either unfractionated heparin or bivalirudin before streptokinase. There was no significant reduction in mortality (adjusted mortality rates 10.4% with bivalirudin vs 10.9% with heparin, odds ratio 0.96, 95% CI 0.86-1.07), but there was a 30% reduction in the incidence of reinfarction within 96 hours (1.5% with bivalirudin vs 2.2% with heparin, odds ratio 0.70, 95% CI 0.56-0.88). The overall bleeding rates were low. The rates of severe bleeding and intracranial hemorrhage were not significantly increased with bivalirudin, but moderate and mild bleeding were more common with bivalirudin (P = .05 and P < .01, respectively). At first glance these findings may appear to be inconsistent with those of other bivalirudin studies, which have reported increased efficacy and decreased bleeding. However, from the patient's point of view (ie, transfusion rates), the bleeding rates were low (25%-40% of the rates seen with tenecteplase and enoxaparin in the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen [ASSENT]-3 Trial26 and with reteplase and abciximab in the Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO]-V Trial),27 although the HERO-2 population had greater risk factors for bleeding such as a higher proportion of women and lower body weights. Although these low bleeding rates could be partly explained by the low rates of in-hospital percutaneous coronary intervention in HERO-2 (5.5% overall and 18.3% in the Western countries), the increase in transfusions was nonsignificant (1.4% with bivalirudin vs 1.1% with unfractionated heparin, P = .11), unlike the increases seen with enoxaparin and abciximab in ASSENT-3 and GUSTO-V. Furthermore, in HERO-2 the activated partial thromboplastin times (aPTT) were 40% higher in patients given bivalirudin than in those given heparin, and 50% to 100% of the increased bleeding seen with bivalirudin could be accounted for by adjustment of the aPTT without attenuating the 30% reduction in reinfarction.

This uncoupling of ischemic and bleeding complications with bivalirudin is unique among the existing anticoagulants. Properties that may contribute to this uncoupling effect include bivalirudin's consistent anticoagulant effect, ability to reversibly bind to both fibrinbound and free circulating thrombin, and short half-life of about 25 minutes.15

As the population ages and the incidence of coronary artery disease continues to rise, renal impairment is becoming more prevalent in patients with acute coronary syndromes. The need for a suitable anticoagulant is vital, especially in the elderly and in patients undergoing percutaneous coronary intervention, where the effects of contrast media may further impair renal function. There is therefore a growing need for an anticoagulant whose pharmacokinetics and pharmacodynamics are not substantially altered in patients with renal impairment. Bivalirudin is a small (20 amino acid) peptide that is broken down predominantly by intracellular proteolysis. Unchanged bivalirudin and its amino acid constituents are cleared through the kidney. The clearance of bivalirudin is therefore only reduced by 20% in patients with severe renal impairment.23

In the Bivalirudin Angioplasty Study of 4312 patients undergoing percutaneous coronary intervention,22 75% of patients had renal impairment (46% mild [glomerular filtration rate (GFR) 60-89 mL/min], 28% moderate [GFR 30-59 mL/min], and 1% severe [GFR < 30 mL/min]). Even higher rates of renal impairment might be expected in unselected patients. Regardless of the degree of renal impairment, patients treated with bivalirudin had fewer bleeding complications than those treated with heparin.

Bivalirudin has been shown to be effective and safe in patients with renal impairment. Because the plasma clearance and half-life are prolonged in patients with moderate or severe renal impairment, adjustments of the infusion dose and monitoring of the activated clotting time are recommended.23

The management of the groin and sheath pulling after percutaneous coronary intervention has changed extensively in recent years. Because of lack of staff and economic considerations, suture devices are often used to close the femoral puncture site at the end of the procedure. With the likelihood of further moves toward shorter and even day-stay procedures, anticoagulation with a drug that has a short half-life (such as bivalirudin) and substantial evidence of decreased bleeding rates compared with contemporary heparin regimens21 may have an important practical advantage, with the potential to remove sheaths shortly after percutaneous coronary intervention.28

In 1997 bivalirudin was licensed to The Medicines Company (Cambridge, Mass), and it has since been tested in the HERO-2 trial25 and in a series of trials in patients undergoing percutaneous coronary intervention. New data with bivalirudin have been obtained in patients undergoing stenting in combination with thienopyridines and glycoprotein IIb/IIIa antagonists. Additional work is ongoing in patients undergoing coronary artery bypass grafting, patients with heparin-induced thrombocytopenia, and patients undergoing percutaneous coronary intervention. Further research is planned in patients undergoing vascular surgery neonates, and patients undergoing primary angioplasty.

Bivalirudin is the first anticoagulant approved by the US Food and Drug Administration for use in patients undergoing percutaneous coronary intervention, where it has been shown to be superior to heparin. Although there is clearly a need for more data regarding bivalirudin use in patients with other indications, the evidence is mounting that this agent provides an unprecedented net clinical benefit by uncoupling efficacy and bleeding. Bivalirudin may well become the foundation anticoagulant for use in patients with acute coronary syndromes.

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References 

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☆ Reprint requests: Harvey D. White, DSc, Cardiology Department, Green Lane Hospital, Private Bag 92 189, Auckland 1030, New Zealand. E-mail: harveyw@adhb.govt.nz Am Heart J 2002;143:189-92.

PII: S0002-8703(02)96449-5

doi:10.1067/mhj.2002.120407

Refers to article:

  • Bivalirudin as a replacement for unfractionated heparin in unstable angina/non-ST-elevation myocardial infarction: Observations from the TIMI 8 trial

    Elliott M. Antman, Carolyn H. McCabe, Eugene Braunwald, for the TIMI 8 Investigators
    American Heart Journal February 2002 (Vol. 143, Issue 2, Pages 229-234)

American Heart Journal
Volume 143, Issue 2 , Pages 189-192, February 2002

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