Late Breaking Trials From the AHA Meetings
Conference Coverage
Synopsis: The holy grail of interventional cardiology is the prevention of restenosis following percutaneous coronary interventions. Two approaches were presented as late breaking trials at the American Heart Association meeting in November. The first, represented by CART 1, is systemic therapy administered orally. The second, represented by ELUTES, is local therapy from a drug eluting stent.
CART 1 Canadian Antioxidant Restenosis Trial
Probucol is a lipophilic vascular protectant agent (anti-oxidant) withdrawn from the market because of prolonged QTc and ventricular arrhythmias. AGI 1067 is a similar, but better, agent. Patients undergoing one vessel PCI received AGI for 2 weeks before and 4 weeks after PCI with or without stent. IVUS with 3-D reconstruction was used after PCI in 100%; most also got it before PCI and 6 months later. In this study presented by Jean-Claude Tardif, 5 groups were studied: placebo, probucol, and AGI 70, 140, and 280 mg/d. Three hundred five patients were randomized, of which 81% received stents. There were no baseline differences in clinical or angiographic characteristics between the 5 groups.
Results: QTc was increased by probucol but not AGI. Maximum lumen area (MLA) was not different after PCI at the intervention site between groups. Follow-up data are contained in Table 1.
The change in luminal volume of the reference segment by 3D IVUS at 4 weeks was significantly decreased on placebo, NS with Probucol, but increased by the highest 2 doses of AGI. In conclusion, AGI: 1) decreases restenosis; 2) increases reference segment volume; 3) does not increase QTc; and 4) may prevent restenosis and atherosclerotic progression in general.
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Table 1 |
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CART 1 Data Results |
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| Placebo | Probucol | AGI dose: 1 | 2 | 3 | Statistical Significance | |
| MLA (mm2) | 2.7 | 3.7 | 2.8 | 3.2 | 3.7 | Plac vs Prob, AGI dose signif. |
| Stent area (mm2) | 6.7 | 7.9 | 6.3 | 7.3 | 7.3 | Same as above |
| Restenosis (%) | 38 | 26 | *AGI combo 26 % | Prob, AGI vs. placebo signif. | ||
| PCI failure (pts) | 9 | 0 | *AGI combo 3 | Plac vs. Prob sig. | ||
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* All patients in all 3 dose ranges were combined. |
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Comment by Michael H. Crawford, MD
Two earlier small trials of probucol were positive, but it was withdrawn from the US market because of safety concerns and because it decreased HDL cholesterol. No data were given in this presentation on cholesterol levels, but probucol increased QTc as expected. Thus, it was gutsy to include probucol, but it made the study more interesting and tied it to previous data on this type of agent. Another strength of this study was the dose ranging of AGI. The differences seen at different doses adds credibility to the study. In addition, IVUS is objective and was a positive part of the study. It is interesting that on the IVUS measures, probucol was better than the new agent.
Clinical outcomes are hard to discern from this small study, but the trends are encouraging. We will need a larger, longer study to assess clinical restenosis. The major difficulty with this approach is the need to give AGI before PCI. Also, the magnitude of effect is less than reported with drug-coated stents. If they pan out, what is the role of AGI? Perhaps as combination therapy when elective procedures are planned.
ELUTES: European Evaluation of Paclitaxel Eluting Stents
Background: Restenosis occurs in 10-15% of patients and up to 40% in diabetics. Paclitaxel is an antineoplastic chemotherapeutic agent that prevents mitosis, is lipophillic, and enters cells in high concentration. Therefore, one can give a brief low dose and get a good effect. Patients undergoing PCI of a single coronary lesion with the Cook V-flex stent, 3 or 3.5 mm in diameter and 16 mm long were studied. In this study, presented by Anthony H. Gershlick, patients were randomized between bare stent and a drug-coated stent (no polymer) and followed for 6 months for percent-diameter stenosis (%DS), late lumen loss (LL), target lesion revascularization (TLR), and major adverse cardiac events (MACE). Four doses of coated stent were tested (10-fold difference in dose from lowest to highest). Patients also got ASA and clopridogel for 3 months. There were no differences in baseline clinical or catheterization characterization between groups. Six-month angiography was performed in 91% of the patients who were not different between groups.
Results: Six-month safety data showed event free rate equal in placebo and high dose at 89%. There was no late stent thrombosis (see Table 2).
Conclusions: Instent restenosis decreased from 21-3% by high-dose paclitaxel stent. Also, %DS and LL were significantly reduced.
Table 2ELUTES Data Results
Placebo Dose 1 2 3 4 P value %DS 34 33 26 23 14 P < 0.01 LL(mm) .73 .72 .47 .47 .10 P < .005 Instent restensis (%) 21 — — — 3 P = .055Comment by Michael H. Crawford, MD
This is one of several trials in which early data have been published in the last year. Several antineoplastic agents are being tested: rapamycin, paclitaxel, and actinomycin-D are the major players. One issue has been the effect of the polymers used to bind the drugs to the stents. Earlier studies showed they could increase restenosis. This trial is interesting because it is the first to report results with a polymer-free drug-eluting stent. Also important is the dose of drug delivered locally, because too much drug can cause injury, endothelial retraction, and late instent thrombosis. Of interest in this study was the fact that only the highest dose of paclitaxel tested was significantly better than placebo. In addition, there is the issue of whether these agents merely delay the onset of restenosis. Only long-term trials will answer this question. Finally, cost is an issue since these stents will be more expensive.
Earlier this year, an interim analysis of the SCORE trial of paclitaxel-coated stents was presented. In this trial, 266 patients were randomized to bare vs. coated stents. Restenosis was reduced from 37% in the bare stent group vs. 6% in the coated. Edge effect was reduced by two thirds, and neointimal hyperplasia was decreased from 4.5% to 1.3%. However, stent thrombosis was 5.5% in the coated stent group vs. zero in the bare group; myocardial infarction was 7.1% vs. zero; and MACE was 10.2 vs. zero. Thus, restenosis looked good in this study but the increase in serious adverse events was worrisome. The ELUTES data look considerably better than this.
Also, TAXUS no. 1 was presented earlier in the year. It evaluated the safety and performance of a paclitaxel-coated NIR stent. This study showed an increase in lumen size and a reduction in %DS and LL at 6 months. Also, restenosis was zero compared to the bare-stent rate of l1%. There was no edge effect and no thrombosis observed.
The RAVEL trial, also presented earlier this year, evaluated a rapamycin-coated stent and showed zero restenosis at 6 months vs. 26% with the bare-stent control. Also, MACE was only 3% vs. 27% with the bare stent. In addition, there was no late loss or edge effect. Except for the MACE results in SCORE, these early results are encouraging and prompted one interventional cardiologist who heard this data to exclaim, "wake me, I must be dreaming."
Besides oral systemic agents such as AGI, the other competition for drug-eluting stents is brachytherapy. Drug-coated stents appear attractive when compared to radiation therapy because of ease of delivery, lack of need for a radiation specialist to assist, and no geographic miss or edge effect issues. If the early effectiveness of coated stents is maintained with longer-term studies and cost is not prohibitive, this technology will revolutionize interventional cardiology. It will be wonderful for patients and interventional cardiologists. Those heavily invested in brachytherapy and cardiac surgeons will be the losers.
Clinical Outcomes For The Prevention of Post Operative Arrhythmias (COPPA)
Peter Kowey, MD, and colleagues performed a study to assess the efficacy of oral propafenone therapy begun immediately preceding coronary artery bypass surgery and continuing to hospital discharge on the incidence of postoperative atrial fibrillation. One hundred ninety-three patients with a mean age of 63 years were entered into the study. Patients received propafenone at either 150 mg every 8 hours, or 225 mg every 8 hours, or placebo. The drug was started within the 24 hours before operation and continued until either hospital discharge or 15 days postoperation. Patients were monitored throughout the period and the primary end point was detection by telemetry of greater than 5 minutes of atrial fibrillation or atrial flutter. In the placebo group, 23% of patients developed atrial fibrillation or atrial flutter with a mean time to arrhythmia of 3.7 days. There was no difference in arrhythmia incidence in the low-dose propafenone group in which 22% of the patients developed atrial fibrillation or atrial flutter at a mean time of 3.4 days. However, only 12% of the patients in the high dose of propafenone group developed atrial fibrillation or atrial flutter with a mean time of arrhythmia of 4.8 days. There was only 1 death in the study in a patient in the high-dose propafenone group. There was no significant difference in lengths of stay between the 3 groups. Kowey et al concluded that moderate dose propafenone in hospital protects against the development of atrial arrhythmias above beta blockers, but does not change length of stay.
Comment by John DiMarco, MD, PhD
Although this study shows some decrease in the proportion of patients developing atrial fibrillation on high- dose propafenone, the effect was relatively small with no difference in the length of stay. Although there was only 1 death in this entire study, one should be cautious about the use of propafenone in patients who are not completely revascularized. Since atrial fibrillation after uncomplicated bypass surgery is usually a self-limiting process with most patients returning to sinus rhythm 6 weeks after surgery even without therapy, the benefits of in-hospital routine propafenone seem limited. Further studies using propafenone in patients at high risk of atrial fibrillation, eg, in patients with mitral or aortic valve disease but without ischemic heart disease, would be interesting.
Azimilide Post Infarct Survival Evaluation Trial—ALIVE
The ALIVE trial, presented by A. John Camm, MD, was a double-blind placebo-controlled study that examined the effects of a new Class III antiarrhythmic drug, azimilide, on all-cause mortality in patients with recent myocardial infarction. Although the study initially was designed to assess the effects of both 75 mg/d and 100 mg/d dosages, the 75 mg/d arm was discontinued early and the results presented concern only patients treated with 100 mg/d. A preplanned substudy focused on the ability of heart rate variability to predict all-cause mortality in patients with recent myocardial infarction and systolic dysfunction.
The study was a multinational trial. It enrolled 3717 patients within 5-21 days of myocardial infarction. All patients randomized had to have an ejection fraction between 15-35%. Patients underwent a 24-hour Holter monitor upon enrollment and a heart rate variability (HRV) index was calculated. The HRV index was computed as the total number of analyzable sinus rhythm RR intervals divided by their modal frequency. The study group was then dichotomized into groups having an HRV index as either less than or equal to 20 units or greater than 20 units. In this study, patient dosing could be initiated either in-hospital (73%) or out-of-hospital (27%). Azimilide, at a dose of 100 mg/d, had neither a beneficial nor adverse effect on all-cause mortality. The all-cause mortality was 11.6% in both groups. Among those higher-risk patients with a heart rate variability index less than or equal to 20 units, the mortality was 15% in the placebo group and 14.1% in the azimilide group (P = NS).When controlled for rates in placebo-treated patients, all-cause mortality rates in azimilide- treated patients were similar whether treatment was initiated in the hospital or out of the hospital. More patients discontinued treatment due to excessive QTc prolongation on 100 mg of azimilide (3.7%) compared to placebo (0.2%). There was a slight decrease in the incidence of new onset atrial fibrillation or atrial flutter during azimilide therapy (0.5% vs 1.2%; P = 0.04). Overall patient withdrawals due to adverse effects were comparable between 100 mg of azimilide (7.1%) and placebo (6.6%).
Five cases of torsade de pointes were documented and confirmed by an events committee during therapy with azimilide (0.3%) vs. one on placebo (0.1%). Severe neutropenia (absolute neutrophil counts less than or equal to 500 cells per mL occurred more frequently on 100 mg of azimilide (0.9%) compared to placebo (0.2%). None of these patients experienced life-threatening infections, and neutrophil counts recovered within 1-18 days after discontinuation of the drug.
Camm and colleagues conclude that azimilide showed no beneficial or adverse effects on all-cause mortality in low ejection fraction patients after myocardial infarction. Adverse reactions to azimilide were uncommon. These results were used to provide further support for the development of azimilide as a treatment for atrial fibrillation and atrial flutter in patients with structural heart disease.
Comment by John P. DiMarco, MD, PhD
This study represents the new paradigm for antiarrhythmic drug development. During development of a new agent for therapy of ventricular arrhythmias, the manufacturer is now required to show that the drug decreases the frequency of defibrillator shocks and does not increase all overall mortality when used to treat symptomatic nonsustained ventricular arrhythmias or atrial arrhythmias. In order for an antiarrhythmic drug to receive an indication for treatment of atrial arrhythmias in patients with structural heart disease, the drug must demonstrate that it does not result in excess mortality used in patients with significant heart disease. This new drug development paradigm was first used during the clinical trials with dofetilide. The same paradigm is now being used in the development of azimilide. Azimilide has a different electrophysiologic profile in that it blocks both the rapid and slow components of the drug inward rectifying potassium channel. Azimilide also has a long elimination half-life meaning that steady state levels are slowly approached after initiation of maintenance therapy. The ALIVE trial confirmed that azimilide therapy at a dose of 100 mg/d has relatively few adverse reactions and does not increase overall mortality in patients with recent myocardial infarction and low ejection fractions. However, no benefit in terms of mortality was seen. It remains to be demonstrated that azimilide will favorably affect the incidence of defibrillator shocks or be highly effective in the treatment of patients with atrial fibrillation, but its pro-arrhythmic risk at this dose appears to be low.
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