HERO-2 claims success but future still uncertain for bivalirudin

November 29, 2001

Thu, 29 Nov 2001 23:30:00

Auckland, New Zealand - Bivalirudin (Angiomax? - The Medicines Company) should be considered as a new anticoagulant treatment option in patients with acute MI (AMI) treated with streptokinase, according to the investigators of the HERO-2 trial, which has just been published in the Lancet . However, because the trial did not reach its primary endpoint, it remains to be seen whether the company developing bivalirudin will file for approval of the drug in this indication.

As reported in heart wire , the results of HERO-2 were first presented at the XXIII Congress of the European Society of Cardiology in Stockholm in September 2001 - bivalirudin did not reduce the primary endpoint, 30-day mortality, compared with unfractionated heparin, but it did reduce the rate of adjudicated reinfarction within 96 hours by 30%, "validating the role of direct thrombin inhibition in this setting," say the researchers, led by Dr Harvey White (Green Lane Hospital, Auckland, NZ).

HERO-2 was a mega-trial in acute MI that randomized 17073 patients to unfractionated heparin or bivalirudin, given 3 minutes before streptokinase administration. All patients were also receiving aspirin. The trial's primary endpoint was 30-day mortality, and its major secondary endpoints were investigator-adjudicated reinfarction and bleeding. Patients from all over the world were enrolled in the trial, including a sizeable contingent from Russia (36% of the study population), Asia, Eastern Europe, and South America. There was also a very high percentage of female patients.

Although streptokinase is still the number-one fibrinolytic in use worldwide, it is not commonly used in the US; for this reason many US cardiologists felt that HERO-2 was almost obsolete before it began. Thus, the results of HERO-2 cannot easily be compared to other trials of fibrinolytics in acute MI such as GUSTO V and ASSENT-3. On the other hand, the study population in HERO-2 is representative of many countries in the world, and as such was viewed as an important study to conduct. "The reduction in reinfarction is a key finding of the HERO-2 trial, with potentially important implications for clinical practice. Early reinfarction after fibrinolysis is associated with an increased risk of further reinfarction, heart failure and death," White and colleagues say in their paper.

Bivalirudin, formerly known as hirulog, is a direct thrombin inhibitor that The Medicines Company is trying to position as a replacement for heparin. It was approved by the FDA in 2000 for use in unstable angina patients undergoing angioplasty, but it is not widely used for this indication because the trials used to gain approval were outdated and not representative of current clinical practice in the west. The future for bivalirudin is now unclear, with much hinging on a new ongoing trial in angioplasty (see sidebar).

Overall mortality rate high

In HERO-2, the overall 30-day mortality rate of 10.8% was higher than that seen in other similar trials (ASSENT-3 and GUSTO V), White and colleagues admit in their paper. This may be because "the patients in HERO-2 were older, and greater proportions were women and had anterior myocardial infarction or Killip class III or IV heart failure," they suggest. Moreover, the mortality rate in the western countries in HERO-2 was 6.7%, "which is similar to the rates seen in the other trials," they note.

A number of cardiologists commenting at the time the HERO-2 results were first presented made the point that bivalirudin's effects on reducing reinfarction might eventually translate into a mortality benefit in the longer-term, for example after 1-year follow-up. And White et al note that although HERO-2 was designed as a superiority trial, bivalirudin was not found to be inferior to unfractionated heparin, according to the criteria used in the GUSTO V study.

Key efficacy and net benefit endpoints in HERO-2*

Endpoint

Bivalirudin

Heparin

p value

10.5%
10.9%
0.46
10.6%
11.1%
0.36
12.9%
14.2%
0.023
12.6%
13.6%
0.07
1.6%
2.3%
0.001
12.7%
13.8%
0.049
*The endpoint of death is adjusted for sex and all factors in the GUSTO mortality risk model. The composite endpoints of death or investigator reported reinfarction and death, reinfarction, or nonfatal disabling stroke were not prespecified.

Bleeding concerns

There was some concern about the rates of bleeding with bivalirudin, which were higher in HERO-2 than in previous trials with the drug, with some observers suggesting that, in retrospect, the dose of bivalirudin used in the trial may have been too high. During his presentation at the ESC, White said that the increase in mild bleeding seen in HERO-2 was "approximately half the bleeding we have seen with the two trials [GUSTO V and ASSENT-3]." Although these differences could be related to variations in the way patients were managed, his team say in the Lancet paper, it must be noted that risk factors for bleeding, such as older age, more women, and higher Killip class, were more prevalent in the HERO-2 population. The most likely reason for part or all of the differences in the bleeding seen in HERO-2 between bivalirudin and heparin was probably the higher activated partial thromboplastin time (APTT) achieved with bivalirudin, they note.

Indeed, when the bleeding rates were adjusted for the 24-hour APTT - at which stage the anticoagulant effect of streptokinase would be expected to have almost completely subsided - "adjustment...did not reduce the reinfarction benefit, suggesting that bleeding might be attenuated without loss of efficacy by reducing the bivalirudin dose or by early dose adjustment based on the APTT," White and colleagues say.

Noncerebral bleeding


Endpoint

Bivalirudin (n=8516)

Heparin (n=8557)

Odds ratio

(95% CI)

p value

58 (0.7%)
40 (0.5%)
1.46 (0.98-2.19)
0.07
118 (1.4%)
90 (1.1%)
1.32 (1.00-1.74)
0.05
1087 (12.8%)
773 (9.0%)
1.47 (1.34-1.62)
<0.0001
118 (1.4%)
95 (1.1%)
1.25 (0.95-1.64)
0.11
To download tables as slides, click on slide logo below

Practical messages from HERO-2

Following the ESC meeting in Stockholm, experts discussed the HERO-2 findings in various forums on theheart.org and drew a number of conclusions. In a "Thumbs up, thumbs down" presentation, Dr Robert Califf (Duke Clinical Research Institute, Durham, NC) said that although he feels bivalirudin is better than unfractionated heparin, "this is not at the level of life and death." He added that countries currently using streptokinase as a matter of cost will find it difficult to switch to bivalirudin, because it did not show a mortality benefit in HERO-2. However in some nations, which may be using streptokinase by preference and could afford to use a more expensive lytic, "there is a strong case for bivalirudin," he said.

Meanwhile, in a panel discussion, Dr Valentin Fuster (Mount Sinai Medical Center, New York) commented that "it's going to be hard for antithrombins to take off" because there are lots of other things that reduce reinfarction, such as low-molecular weight heparins and clopidogrel.



What does the future hold for bivalirudin?

One of the problems for bivalirudin is that the trials that were conducted to gain US approval for use in angioplasty are quite old, and not representative of current clinical practice in western nations. For example they did not involve the use of stents and GP IIb/IIIa inhibitors. Key to the future success of bivalirudin will be how the drug fares in a number of ongoing trials, including the REPLACE study of bivalirudin in patients undergoing percutaneous coronary intervention.

The Medicines Company does have encouraging pilot data on bivalirudin in combination with GP IIb/IIIa blockers from the CACHET trial. This 200-patient trial also suggests that use of bivalirudin instead of heparin may permit physicians to reduce their use of GP IIb/IIIa blockers, without losing any benefit. This is where the new drug could really come into its own.

Results from part I of REPLACE, as reported by heart wire , show that bivalirudin exceeded expectations in those undergoing angioplasty with or without stent implantation. The 523 bivalirudin patients experienced a 22% reduction in the combined endpoint of death, MI, revascularization, or clinically significant bleeding compared with those receiving heparin. Part II of REPLACE is now underway, with plans to enroll 6000 patients. The trial will compare a heparin plus GP IIb/IIIa inhibitor group to a group receiving bivalirudin only, with a GP IIb/IIIa inhibitor administered only if needed. A third arm is also planned, but not confirmed, involving bivalirudin plus a GP IIb/IIIa inhibitor in all cases. The primary endpoint will be death, MI, revascularization, and clinically significant bleeding at 30-days, with follow-up out to 1 year. The trial is expected to end sometime in 2002.

If the REPLACE results show that bivalirudin alone can produce good results and allow lower use of GP IIb/IIIa blockers, this could really spell success for the product. But one factor that may discourage cardiologists from switching from heparin to bivalirudin is cost. Heparin costs very little (just $5 or $10), whereas bivalirudin costs $335 per vial.

The Medicines Company is also investigating the use of bivalirudin in CABG without use of the bypass pump, and in patients with heparin-induced thrombocytopenia (HIT) or HIT with thrombosis undergoing angioplasty.

- LN




Related links

1. [ HeartWire > News ; Sep 3, 2001]

2. [ Education > Thumbs up, thumbs down ; Oct 2, 2001]

3. [ Education > HeartBeat ; Sep 19, 2001]

4. [ HeartWire > News ; Dec 21, 2001]

5. [ HeartWire > News ; Jun 8, 2001]


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