Late Breaking Clinical Trials from the American College of Cardiology Meeting, March 30-31, 1998

CONFERENCE COVERAGE

Synopsis: Again, recently completed clinical trials have been presented at a structured session without accompanying written material. Thus, this report on the results of these trials is gathered by several of us furiously scribbling in a darkened room. Please donhold us to the accuracy of every number, but I believe we have the major conclusions of these reports correct.

Source: The American College of Cardiology Meeting. Atlanta, GA. March 30-31, 1998.

ARCH: Amiodarone Reduces CABG Hospitalization

This study evaluated 300 patients undergoing common open heart operations (CABG or valve surgery) at one center and randomized them to intravenous amiodarone for two days vs. placebo. Patients with prior atrial fibrillation or antiarrhythmia therapy, digoxin or calcium blocker use, or hemodynamic compromise (shock, balloon pump) were excluded, but beta-blocker therapy was continued (half the patients). The incidence of postoperative atrial fibrillation was reduced in the amiodarone group (35% vs 42%). Hospital stays were not different in the two groups (7.5 vs 8.2 days) but were shorter in those developing atrial fibrillation who were on amiodarone (7.1 vs 9.1 days). The investigators conclude that two days of intravenous amiodarone prophylaxis post common cardiac surgery procedures in stable patients reduces the incidence of atrial fibrillation and shortens hospital stays in those who develop atrial fibrillation.

COMMENT BY MICHAEL H. CRAWFORD, MD

Although significant, the reduction in atrial fibrillation and hospital stays for those in fibrillation is not impressive enough to recommend this approach routinely. It may be worth considering in those at high risk of developing atrial fibrillation, such as those with a prior history or large left atrium or those in whom atrial fibrillation would be dangerous, such as patients with left ventricular hypertrophy.

CASH: Cardiac Arrest Study Hamburg

This study started in 1985 and was designed to compare implantable cardioverter defibrillators (ICD) vs. propafenone, amiodarone, or metoprolol. An interim analysis in 1992 showed increased mortality in the propafenone group, so this arm was stopped. The final report involves 349 patients who were survivors of cardiac arrest and had documented ventricular tachy-arrhythmias. Patients with myocardial ischemia, who made up more than 80% of the patients, had revascularization first, then an electrophysiologic study. The primary end point was total mortality on an intention-to-treat basis. The overall crossover rate between ICD and drugs was 6%, and less than 10% of the patients stopped drug therapy. After a minimum two-year follow-up, total mortality was 12% on ICD vs. 20% on amiodarone and 20% on metoprolol. Sudden cardiac death was reduced to 2% on ICD vs. 11% on each drug.

COMMENT BY MICHAEL H. CRAWFORD, MD

The superiority of ICD as compared to drugs for cardiac arrest survivors is not surprising, but the equal benefit of amiodarone and beta blockers is interesting. One potential explanation for this finding is that more than 80% of the patients in the trial had ischemic heart disease.

CIDS: Canadian Implantable Defibrillator Study

This trial evaluated 659 patients with cardiac arrest or syncope due to ventricular tachyarrhythmias and randomized them to amiodarone vs. ICD. Crossovers were 22% from amiodarone to ICD and 30% from ICD to amiodarone. Also, more of the patients in the ICD group were on beta blockers or sotolol (60%) vs. the amiodarone group (25%). At the end of three years, all-cause mortality was 30% in the amiodarone group vs. 25% in the ICD group-this difference was not statistically significant. Subgroup analysis by clinical events, ejection fraction, and the presence or absence of ischemic cardiomyopathy did not reveal any significant differences.

COMMENT BY MICHAEL H. CRAWFORD, MD

This patient group represents a less severe arrhythmia disturbance population compared to the CASH study, since patients with syncope/pre-syncope with documented ventricular arrhythmias were included. Like the CASH study, more than 80% of the patients had ischemic heart disease, and many were on beta blockers or other anti-arrhythmic drugs. These factors may have contributed to the less impressive performance of the ICD in this study.

ATLAS: Assessment of Treatment with Lisinopril and Survival

This study randomized 3164 patients with heart failure and an ejection fraction less than 30% to low-dose lisinopril (2.5-5 mg/d) or high doses (32.5-35 mg/d). The primary end point was all-cause mortality, and the patients were followed for a mean of 46 months. Approximately one-third of patients in each group stopped the study medication, but the analysis was intention to treat. The primary end point of all-cause mortality was not different between the low- and high-dose groups (45% low vs 43% high). The secondary end points of cardiac death and death plus hospitalization for cardiac reasons were also not statistically different. However, death and hospitalization for any cause were significantly less in the high-dose group (80%) vs. the low-dose group (84%; P < 0.002).

COMMENT BY MICHAEL H. CRAWFORD

Interestingly, this was one of the studies that was reported in USA Today because of the admonition to practicing physicians that if we just used higher doses of angiotensin converting enzyme inhibitors, we would keep more people out of the hospital and improve survival. You can see that this conclusion is a stretch from the data presented. Also, this study does not answer the question of the effectiveness of a 10-20 mg/d lisinopril dose. This dosage range was used in some of the large post myocardial infarction trials and is one that is frequently seen in clinical practice.

ARGAMI-II: Argatroban in Acute Myocardial Infarction

Argatroban is a synthetic, competitive inhibitor of thrombin derived from arginine. It inhibits free and bound thrombin in a reversible action that does not cause thrombocytopenia. Given intravenously, it may accelerate reperfusion for up to three hours. This study randomized 1200 patients receiving thrombolytic therapy to low-dose argatroban, high-dose argatroban, or heparin alone. After the first 600 patients, an interim analysis showed that the low-dose argatroban arm had a higher cardiac event rate than the other two arms, and it was eliminated. Thus, 494 patients who received high-dose argatroban and 507 who received heparin alone were compared in the final analysis. Mortality (6% vs 5%) was no different between the argatroban and heparin groups, respectively, nor was recurrent myocardial infarction (2.6% vs 3.4%). Complications such as bleeding, heart failure, and stroke were also similar between the two groups. The investigators conclude that argatroban in patients receiving thrombolytic therapy for acute myocardial infarction was equally safe and as efficacious as heparin.

COMMENT BY MICHAEL H. CRAWFORD, MD

This drug was just released on the market and costs the same per patient as tissue plasminogen activator. The advantages of this agent are the one-dose ease of administration and the lack of thrombocytopenia, a side effect of heparin. It has been proposed that argatroban may replace thrombolysis, but this study did not address that issue.

Epilog Stent: Trial of Abciximab in Stenting and Comparison with Abciximab Plus Balloon

This randomized, multicenter study evaluated 900 patients with greater than 60% coronary artery stenosis who were undergoing percutaneous revascularization. The patients were randomized to three arms: balloon angioplasty and abciximab; stent plus abciximab, and stent with placebos. The complications of death and Q-wave myocardial infarction were significantly reduced in both abciximab arms, with the greatest benefit observed in the stent plus abciximab patients. Also, there was no instance of abrupt closure in the stent plus abciximab arms. Bleeding complications were low. The investigators conclude that abciximab enhances the safety of coronary artery stenting and that stenting plus abciximab is a suitable choice for most patients undergoing percutaneous revascularization.

COMMENT BY MICHAEL H. CRAWFORD, MD

In a news conference, the principal investigator, Eric Topol, MD, quoted basketball great Michael Jordan: "There is nothing left to prove," and stated that the only issue regarding abciximab is cost.

PACT: Plasminogen Activator and Angioplasty Compatibility Trial

In this study, 606 patients who were younger than 75 years with acute myocardial infarction, without stroke, or prior CABG were randomized to direct angiography and immediate angioplasty vs. a 50 mg bolus of t-PA followed by angiography and angioplasty, if feasible, or another bolus of t-PA. Follow-up angiography was done in one week. All patients received aspirin and heparin. Time from t-PA to coronary angiography was 51 minutes, and time from t-PA to angioplasty was 93 minutes. Initial TIMI flow (pre-angioplasty) was better in the t-PA group (TIMI 3 flow 33% vs 15%; TIMI 2 flow 28% vs 20%). Angioplasty efficacy was not affected by prior t-PA at this dose: TIMI 3 flow after angioplasty was observed in 58% vs. 62% with t-PA alone. The complications of angioplasty were not increased by prior t-PA. The investigators conclude that pretreatment with 50 mg of t-PA increased coronary artery patency prior to angioplasty, which could result in better left ventricular function (not reported) and which did not compromise the safety and efficacy of angioplasty.

COMMENT BY MICHAEL H. CRAWFORD, MD

This study can only be interpreted in light of this trial environment with careful patient selection and a conservative t-PA dose. It cannot be extrapolated to usual frontloaded t-PA dosing in a more diverse patient group. However, it does raise the issue of the proper use of angioplasty in patients who have received thrombolysis. Immediate angiography with less than TIMI 3 flow may indicate a need for angioplasty. However, since the one week TIMI flow was the same in both arms, perhaps the added expense of t-PA is unnecessary if primary angioplasty is available.

Stent TAMI: Primary Angioplasty in Myocardial Infarction Trial with Stents

This study randomized 900 patients within 12 hours of acute myocardial infarction to primary angioplasty vs. primary angioplasty with a heparin-coated Palmaz-Schatz stent. The primary end point was combined death, recurrent myocardial infarction, stroke, or ischemia-driven revascularization at six months. Of the 448 patients randomized to primary angioplasty alone, 67 crossed over to stent. Initial success with regard to TIMI grade flow was similar in both groups, and, at one month, there was no difference in death, recurrent myocardial infarction, or stroke between the two groups. However, later revascularization was only 1% in the stent group vs. 3.5% in the angioplasty group. At the six-month catheterization, minimal alluminal diameter was significantly greater in the stented lesions as compared to the angioplasty lesions, and the residual stenosis was considerably less in the stent group. The investigators conclude that heparin-coated stents resulted in a larger lumen and a decreased incidence of later ischemia-driven revascularization as compared to angioplasty alone in acute myocardial infarction patients.

COMMENT BY MICHAEL H. CRAWFORD, MD

Despite the decreased incidence of later revascularization in the stent group, it is interesting that there was no difference in death, recurrent myocardial infarction, or stroke between the two groups. Although patients certainly benefit from not having to have recurrent procedures, it would be interesting to know what the cost difference was between these strategies.

TOSCA: Total Occlusion Study of Canada

This study randomized 410 patients with complete coronary artery occlusions to balloon angioplasty vs. stent placement. The primary end point was failure of TIMI 3 flow maintenance at the six-month recatheterazation. Secondary end points included clinical outcomes at one year. Failed patency was more common in the angioplasty group (20%) vs. the stent group (11%). Despite greater late loss, minimum lumen diameter remained greater in the stent group than the angioplasty group, and fewer stent patients had restenosis (56%) vs. angioplasty patients (70%). Also, repeat revascularization within six months was more common in the angioplasty group (14%) vs. the stent group (7%). At one-year follow-up, coronary events were similar between the two groups. The investigators conclude that stenting for totally occluded coronary arteries improved six-month patency and decreased the need for repeat revascularization as compared to balloon angioplasty alone.

COMMENT BY MICHAEL H. CRAWFORD, MD

Again, a cost analysis would be of interest here. Despite improved patency at six months, overall clinical events at one year were no different between the two arms. Also, the incredibly high restenosis rate in both groups suggests that percutaneously attacking totally occluded lesions should only be done in patients with demonstrable ischemia in whom surgical revascularization is not indicated.