The Acute Myocardial Infarction STudy of ADenosine (AMISTAD) used myocardial perfusion imaging using Tc-99 sestamibi to evaluate infarct size. This was the primary endpoint of this trial, which evaluated the use of adenosine, a purine nucleoside, as an adjunct to thrombolytic therapy.

Sestamibi imaging of infarct size often involves 2 measurements. The measurement of the acute perfusion defect reflects myocardium at risk. The final perfusion defect measurement, which occurs at least 5 days later, reflects the infarct size. The difference between these two measurements indicates the amount of myocardial salvage.

Validation of sestamibi imaging is extensive, according to Dr. Gibbons. There are multiple lines of evidence for validation, including an association between smaller infarct size on sestamibi and better patient outcomes.

Acute imaging with sestamibi can measure the area at risk and estimate collateral flow. The final sestamibi measurement provides time to therapy, infarct size and differential benefit (small versus large infarct). By contrast, mortality trials only provide time to therapy. As a result, sestamibi trials require far fewer patients to show a benefit, and the direct cost of sestamibi trials is much less.

Endpoints in MI Trials   Sestamibi Mortality Area at risk (Yes) No Collateral flow (Yes) No Time to therapy Yes Yes Infarct size Yes No Differential benefit Yes No Patients required/arm 140 10,000 Cost ($ millions) 2 ≧ 35

Dr. Gibbons said his laboratory at Mayo Clinic has served as the core laboratory for 14 completed sestamibi trials in acute myocardial infarction. This included the ALIVE trial of adenosine/angioplasty, and the AMISTAD I and II trials, which evaluated adenosine with thrombolysis as the reperfusion modality.

Before the randomized adenosine trials, Mayo Clinic performed a single-center pilot study of adenosine with angioplasty. Myocardial salvage in this study appeared to be far higher than historical controls.

Myocardium at risk was virtually identical. Infarct size was lower in the adenosine group, though the sponsor stopped this pilot trial early. However, even with this small sample, there is a strong trend favoring adenosine. These results led to the subsequent randomized ALIVE trial.

The AMISTAD trial of adenosine with thrombolysis included 236 patients with ST-elevation myocardial infarction. They were randomized to receive intravenous adenosine 70 mcg/kg/min or placebo beginning at the time of thrombolytic therapy and continuing for 3 hours. The thrombolytic was tPA in 62% and streptokinase in 38%. The primary endpoint was infarct size by sestamibi.

In anterior myocardial infarction patients, the adenosine group had a smaller infarct size (67% reduction, p < 0.01). In contrast, there was no significant difference in infarct size in the non-anterior myocardial infarction patients. Excess bradycardia and hypotension in the inferior infarct group represented possible adverse effects.

Dr. Gibbons said that with existing therapy, inferior infarcts are very small. Therefore, it is far more difficult to detect incremental benefit with adjunctive therapy.

The subsequent AMISTAD II trial enrolled only patients with anterior infarcts. This was because of the lack of benefit and possible adverse effects in the inferior infarct group in AMISTAD I.

The AMISTAD II trial included 2,018 patients randomized to the same 70 mcg/kg/min dose, a lower dose, or placebo over 3 hours, started within 15 minutes of reperfusion. Investigators followed patients for 6 months for the clinical endpoint of combined death and new heart failure. A substudy examined infarct size using sestamibi in 243 patients assessed after 5 days.

Unfortunately, there was no significant difference in the clinical endpoint at 6 months. This may have resulted because investigators decided to pool the low and high adenosine doses for analysis, according to Dr. Gibbons. Use of streptokinase also probably influenced the results.

Investigators found that 82% of placebo-treated patients survived free of congestive heart failure at 6 months. In the pooled adenosine group, survival free of heart failure was 84%. The relative risk reduction of 11% was not significant. When investigators re-analyzed the adenosine doses separately, they found more of an effect in the high-dose group. However, this analysis did not have enough power to detect a treatment benefit.

Infarct size data were not different between placebo and pooled adenosine doses. However, with doses re-analyzed separately, there was a 57% reduction in the high-dose group. This was similar to the reduction in infarct size in AMISTAD I, which was statistically significant.

Despite some important trial design issues, the results of AMISTAD II do seem to corroborate the substantial reduction in infarct size investigators found in AMISTAD I. Therefore, adenosine merits further evaluation in properly designed clinical trials. However, because commercial interest has waned, such a trial would probably require support from a public entity, such as the National Heart, Lung and Blood Institute (NHLBI).