Results from recent cardiovascular drug trials
Jury still out on reducing intracranial bleeds
ASSENT 3: Enoxaparin plus tenecteplase significant in treatment of AMI
Heart attack patients who received a new therapy regimen consisting of the single-bolus thrombolytic agent tenecteplase (TNKase/Metalyse) and the low-molecular-weight heparin enoxaparin sodium (Lovenox) injection experienced the most significant clinical efficacy and safety benefits in the ASSENT 3 (ASsessment of the Safety and Efficacy of New Thrombolytic regimens) trial. The treatment regimen also yielded the lowest 30-day mortality rate (5.35%) ever reported in a large-scale clinical trial of acute myocardial infarction (AMI). Results of the study are published in the Aug. 25 issue of The Lancet.
ASSENT 3 enrolled 6,095 heart attack patients at more than 500 sites worldwide. Patients were randomized to receive one of three treatments within six hours of the onset of symptoms. Treatment arms included:
• full-dose tenecteplase plus enoxaparin (Group A);
• half-dose tenecteplase plus weight-adjusted, reduced-dose unfractionated heparin (UFH) in combination with a 12-hour infusion of the glycoprotein IIb/IIIa inhibitor abciximab (ReoPro) (Group B);
• full-dose tenecteplase plus weight-adjusted UFH (Group C).
The primary endpoints were the composites of 30-day mortality, in-hospital reinfarction or in-hospital refractory ischemia (efficacy endpoint), and the above efficacy endpoint plus in-hospital intracranial hemorrhage or in-hospital major bleeding complications (efficacy plus safety endpoint).
Results showed that compared with unfractionated heparin, adjunctive therapy with abciximab or enoxaparin reduces ischemic complications of AMI treated with tenecteplase. The enoxaparin regimen, however, had fewer bleeding complications and is easier to administer. One of the investigators of the study also has said that the enoxaparin arm worked out to be less expensive than the abciximab arm.
Gusto V: No significant mortality reduction for half-dose reteplase and abciximab
A large clinical trial has shown that the combination of the glycoprotein IIb/IIIa inhibitor abciximab (ReoPro) and a half-dose of the fibrinolytic agent reteplase (Retavase) failed to show a significant reduction in mortality compared to full-dose reteplase alone. The combination therapy did reduce the numbers of percutaneous coronary interventions and coronary bypass surgeries needed compared to the reteplase group, however, and did not significantly increase intracranial hemorrhage or nonfatal disabling stroke.
The results of GUSTO V (Global Use of Strategies To open Occluded coronary arteries), the first phase III combination trial with heart attack patients, were published in the June 16 issue of The Lancet. The largest trial of its kind, GUSTO V involved 16,588 patients suffering acute myocardial infarction; 1,240 of these patients came from Canada.
At 30 days, the mortality in the combination therapy group was 5.6% (compared to 5.9% in the reteplase patients); this was the lowest mortality rate ever observed in a large clinical trial involving a fibrinolytic agent. Patients treated with the combination therapy also were 34% less likely to experience reinfarction than the patients receiving only reteplase.
One note of caution: Based on the current data, the study did not recommend the combination therapy for the elderly, as patients older than 75 years of age showed an increase in intracranial hemorrhage with the combination.
HERO-2: Bivalirudin reduces reinfarction for AMI patients getting streptokinase
Thrombospecific inhibition by the anticoagulant bivalirudin (Angiomax) may provide advantages over unfractionated heparin for acute MI (AMI) patients getting streptokinase, according to new data presented at the XXIII Congress of the European Society of Cardiology (ESC) in Stockholm, Sweden.
Harvey White, MD, of Green Lane Hospital in Auckland, New Zealand, and principal investigator of the Hirulog Early Reperfusion (HERO-2) trial, reported the results to ESC Congress delegates.
HERO-2 randomized 17,073 AMI patients to unfractionated heparin or bivalirudin, given three minutes before streptokinase administration. All patients also were receiving aspirin. In the trial, bivalirudin reduced the combined incidence of death or investigator-reported second myocardial infarction compared to heparin at 30 days by 1.3% (14.2% in patients treated with heparin vs. 12.9% in patients treated with bivalirudin).
Patients treated with bivalirudin, however, had a 30% reduction in second myocardial infarction at 96 hours compared to heparin. The reduction in second myocardial infarction also was statistically significant at 30 days, both when the second myocardial infarctions were determined by the treating clinician and when adjudicated by an independent panel of experts.
The overall incidence rate of intracranial hemorrhage was 0.5%; there was not a significant increase in the incidence in patients treated with bivalirudin compared to patients treated with heparin. Furthermore, White said, there was a not a significant increase in other severe bleeding or other blood transfusions in bivalirudin patients compared to heparin patients.
What about the bleeding?
These drug trials are moving toward finding a cardiovascular drug therapy that would have a lower overall incidence of intracranial bleeds, says David Roffman, PharmD, BCPS, associate professor at the University of Maryland School of Pharmacy in Baltimore. However, the jury is still out on the results.
"We are talking about huge populations of patients in multiple studies before we can really come to that conclusion," he says. "The incidence of intracranial bleeds is still less than 1%. If it turns out that this [therapy] looks to be the safest, I think this is the way people will tend to go."
The evidence, however, tends to show that primary angioplasty is less risky because it doesn’t involve the intracranial hemorrhage issue. That makes the discussion about full-dose vs. half-dose thrombolytic mute, he says.
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