American College of Cardiology -- Anaheim, California

Clinical Trials and Their Implications in the Management of Acute Myocardial Infarction


According to Dr. Christopher Granger, speaking at the American College of Cardiology 46th Scientific Session, clinical trials in the arena of myocardial infarction (MI) have been profuse and, in many cases, very helpful in determining optimum management of the condition. They have sensitised physicians to the importance of the following:
- the prophylactic use of aspirin (although, despite its known effectiveness in reducing 35-day mortality, 20% or more of acute-MI patients are still not being adequately treated with antiplatelet therapy),
- early treatment with thrombolytic agents,
- using lower dose i.v. heparin following thrombolysis, and
- giving preferential use to primary agents as opposed to ancillary therapy, unless otherwise indicated.

Early Treatment
Numerous studies have determined that the patients most likely to benefit from thrombolytic therapy are those with ST segment elevation and bundle branch block. Consistent findings have led to the general recommendation that thrombolytic therapy is warranted up to 12 hours after symptom onset, or perhaps slightly longer in patients with ongoing ischemia, ongoing ST segment elevation, and higher risk. The earlier the treatment, the better: for each hour earlier of treatment, two to five per 1,000 additional patient lives may be saved. In addition, patients treated within 70 minutes of symptom onset have been shown to have dramatically lower infarct size and dramatically lower mortality than patients treated later. The problem is that, since few patients present immediately following symptom onset, this wisdom has resulted in only modest gains.

In order to shorten the time to treatment even further, two trials [Myocardial Infarction Triage Intervention (MITI) and the European MI Project Trial] assessed the advantages of prehospital initiation of thrombolytic therapy. It was determined that despite a small trend towards better outcome, there is no statistically significant reduction in mortality owing to prehospital treatment. Although in Europe thrombolysis is routinely administered to eligible patients in the ambulance, in North America early identification of eligible patients in the ambulance, followed by immediate initiation of treatment upon arrival at the emergency department is favoured.

Treatment Comparisons
Various trials have shown that accelerated tissueplasminogen activators (tPA) are associated with a higher early patency, especially at the 60- to 90-minute period.

Surprisingly, a large study assessing intravenous heparin has demonstrated that although angiographic patency has been shown to be better with higher partial thromboplastin times (PTT), improved survival was associated with PTTs in the moderate elevation range (50- to 75-seconds). Patients with higher PTTs had a substantially higher risk of both systemic bleeding and intracranial hemorrhage, and no reduction at all in recurrent infarction.

A disturbing trend has appeared with respect to trials assessing the importance of reperfusion. Standard entry criteria has generally meant the exclusion of patients with lack of ST segment elevation or bundle branch block, late presentation, and contraindications. Yet, among acute MI-patients, those are precisely the ones who are at the highest risk of mortality (20% vs 7% risk of mortality in ineligible and eligible patients, respectively).

The GUSTO-IIB trial compared direct angioplasty to accelerated tPA– the composite primary endpoint being death, reinfarction, and disabling stroke – and demonstrated a slight trend in favour of direct angioplasty.

Ancillary therapies, including nitrates, angiotensin converting enzyme (ACE) inhibitors, and magnesium have been studied to determine whether or not they are capable of reducing mortality in acute MI. The first two have demonstrated a very marginal benefit (particularly captopril), while magnesium has been shown to have a deleterious effect.

An overview of various treatments has demonstrated the following overall reductions in mortality:
- thrombolytic therapy: 23%
- aspirin: 18%
- Beta-blockers (used during the acute, hospital phase of MI): 12%
- ACE inhibitors: 5% or 6%.
Additional trials are necessary to determine the proper role of intervention as well as the most cost-effective treatment regimens.