Antibiotics for Restenosis?
May 1, 2000
Antibiotics for Restenosis?
A German trial from Munich, Roxithromycin for Prevention of Restenosis after Stenting (IRAS-3), randomized more than 1000 subjects to antibiotic or placebo to determine whether there is a role for bacterial infection in restenosis. All individuals had successful stent implantation. No laboratory tests documenting Chlamydia pneumoniae exposure were obtained. Treatment consisted of one month of roxithromycin, 300 mg daily, or placebo. Clinical follow-up was obtained at 30 days and one year, and angiographic follow-up was obtained at six months. The primary end point was restenosis rate at six months. Secondary end points included typical clinical events. Many of these patients had prior acute coronary syndromes; more than 80% of the lesions were complex and at least 3 mm in size. The results showed no reduction in the restenosis rates, which were approximately 30% in both groups. In addition, major coronary end points, including heart attack and death, were comparable at 30 days, at approximately 3% in each group. At eight months, the Q-wave MI rates were equivalent. Angiographic data indicated no difference between restenosis, late loss of luminal diameter, or other parameter.
Comment by Jonathan Abrams, MD
An infectious etiology of atherosclerosis is a fascinating and exciting concept. It is more than likely that chronic low-grade infections may contribute to an inflammatory milieu in patients who are otherwise predisposed to develop vascular disease. It makes sense that this is more of a long-term issue than related to acute infection rapidly initiating adverse coronary events, but this is speculative. A presentation from representatives of William Beaumont Hospital in Michigan reported at the American College of Cardiology (ACC) meeting indicated that seropositivity to C. pneumoniae was not associated with restenosis, although inflammatory markers were strongly associated with this complication. It appears unlikely that antibiotic therapy will improve outcomes in angioplasty with or without stenting.
Safety of Antihypertensive Agents
ALLHAT, a major comparative antihypertensive study under way for a number of years and funded by the National Heart Lung and Blood Institute, reported immediately prior to the ACC meeting that there was a problem with the arm of the protocol that involved doxazosin. Four active drugs are being evaluated in ALLHAT: clorthalidone, doxazosin, amlodopine, and lisinopril. The doxazosin arm was discontinued because of an increased incidence of heart failure and "other cardiovascular events," compared to chlorthalidone. The investigators suggest that all patients on the alpha-antagonist talk to their physicians about continuing this antihypertension medication.
Comment by Jonathan Abrams, MD
The mechanism of action of an adverse outcome with doxazosin, if any, is unclear. Because there are only active treatment arms and no placebo control in ALLHAT, it may be that clorthalidone was more effective in decreasing events than the alpha blocker; both decreased blood pressure to a comparable degree, similar to the other two agents in the trial. Nevertheless, it appears that the use of doxazosin, and possibly other alpha adranergic antagonists, should be limited for the majority of patients undergoing hypertensive treatment. There are an ample number of other highly effective drugs available. For the individuals with benign prostatic hypertrophy (BPH), particularly when symptomatic, it remains unclear as to whether these drugs should be discontinued. There are no data to support this action and, until further analysis of the ALLHAT experience has been made public, it would appear that individuals with BPH and hypertension should continue on the drug, particularly if they have had a favorable urologic response.
Oral IIB/IIIa Platelet Inhibitors: More Bad News
The SYMPHONY trial, discussed in the last issue of Clinical Cardiology Alert, used the oral glycoprotein platelet inhibitor sirafiban, and indicated that there is no benefit with this drug. SYMPHONY II used aspirin in three patient groups and also used a low- and a high-dose sirafiban. The results of this trial were negative and, in fact, the high-dose group appeared to have more adverse outcomes than placebo-treated patients. Thus, in spite of millions of dollars and multiple randomized clinical trials, the oral IIb-IIIa inhibitor story does not look promising. Other oral agents with different pharmacologic antiplatelet properties are being evaluated, and it is certainly possible that this approach will pay off in the future. As of now, none of these drugs is available for clinical use.
Intravenous IIb-IIIa Inhibition
Another study of IIb-IIIa platelet inhibition, PARAGON-B, used lamifiban plus unfractionated heparin and aspirin and compared outcomes with heparin and aspirin alone in 5225 subjects with an acute coronary syndrome (chest pain duration < 12 hours and no ST elevation). The primary end point of 30-day composite of death, MI, or recurrent ischemia was no different between the two groups, and there also was no difference in the event rate at six months. There was somewhat more bleeding in the lamifiban patients. However, in a subanalysis, those individuals who were troponin positive did have a significant decrease in primary and secondary end points.
HART-2
The HART-2 trial examined whether low molecular weight heparin (LMWH) was superior to unfractionated heparin (UH) when tissue plasminogen activator (tPA) is given for acute MI. It was an angiographic study, with coronary arteriograms being performed at 90 minutes. The results indicated that enoxaparin was associated with less reocclusion and comparable bleeding rates. Early patency (90 minutes) was slightly higher (80% vs 75% TIMI 2-3 flow) with MWH. Death and the need for emergency prothrombin consumption index (PCI) were similar. Reocclusion rates at one week were lower with LMWH (3.1% vs 9.1%).
Comment by Jonathan Abrams, MD
The HART-2 trial is one of a number of investigations currently determining whether combination therapy with antiplatelet or antithrombin agents in addition to thrombolytics can produce higher patency rates with acceptable bleeding complications. This study does not support a change in our current use of unfractionated heparin but is encouraging. It may be that this approach will be clinically useful in the future. The PARAGON B study confirms that there is variability among the various IIb-IIIa clinical trials. However, tirafiban and eptifabatide have been positive in similar patient groups. The relationship between an elevated troponin and major efficacy of a IIb-IIIa inhibitor has been documented in several IIb-IIIa trials and is an important finding. Thus, it appears that patients with unstable angina or non-ST segment elevation MI, who have an elevated troponin, should be strongly considered to receive intravenous IIb-IIIa therapy, starting even before a planned angiography for possible PCI. A meta-analysis by Heidenreich and Hlatky, presented at the ACC meeting, confirmed that there is a substantial increased risk of death in individuals with positive troponin I or T in acute coronary syndromes, compared to normal troponin.
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