Month: April 2013

Whether closure of a patent foramen ovale is effective in the prevention of recurrent ischemic stroke in patients who have had a cryptogenic stroke is unknown. Two recently published multicenter studies have demonstrated no significant benefit of closure of a patent foramen ovale over medical therapy alone. Both studies were published in March 2013 issue of the New England Journal of Medicine.

The first study was reported by Dr. Bernhard Meier and colleagues (for the PC investigators) and conducted in 29 centers in Europe, Canada, Brazil, and Australia. Patients with a patent foramen ovale and ischemic stroke, transient ischemic attack (TIA), or a peripheral thromboembolic event were randomly assigned to undergo closure of the patent foramen ovale with the Amplatzer PFO Occluder or to receive medical therapy.

The primary end point was a composite of death, nonfatal stroke, TIA, or peripheral embolism. Analysis was performed on data for the intention-to-treat population.  The mean duration of follow-up was 4.1 years in the closure group and 4.0 years in the medical-therapy group. The primary end point occurred in 7 of the 204 patients (3.4%) in the closure group and in 11 of the 210 patients (5.2%) in the medical-therapy. Nonfatal stroke occurred in 1 patient (0.5%) in the closure group and 5 patients (2.4%) in the medical-therapy group, and TIA occurred in 5 patients (2.5%) and 7 patients (3.3%), respectively.

The second was reported by Dr. John D Carroll and colleagues (for the RESPECT investigators). In this prospective, multicenter, randomized, event-driven trial, they randomly assigned patients, in a 1:1 ratio, to medical therapy alone or closure of the patent foramen ovale. They enrolled 980 patients (18 to 60 years of age; mean age, 45.9 years) at 69 sites. 499 were randomly assigned to the closure group and 481 to the medical-therapy group. The medical-therapy group received one or more antiplatelet medications (74.8%) or warfarin (25.2%).

The authors of both studies concluded that closure of a patent foramen ovale for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy.

Source:

1) – Meier B, et al (for the PC Trial Investigators). N Engl J Med 2013; 368:1083-1091 March 21, 2013 DOI: 10.1056/NEJMoa1211716

2) – Carroll JD, et al (for the RESPECT Investigators).  N Engl J Med 2013; 368:1092-1100 March 21, 2013 DOI: 10.1056/NEJMoa1301440

In a study published on April 1, 2013 issue of the Journal of the American College of Cardiology, by Dr. Martin Ruwald (University of Rochester Medical Center, New York) and colleagues, comparing carvedilol to metoprolol in treatment of patients with heart failure reported that treatment with carvedilol was associated with a significant reduction in the risk of hospitalization for heart failure or death when compared with patients treated with metoprolol.  Treatment with carvedilol is associated with a significant 30% reduction in the risk of hospitalization for heart failure (HF) or death when compared with patients treated metoprolol, according to a new analysis of the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy  (MADIT-CRT).

In this analysis of MADIT-CRT, which included 1515 patients with left ventricular ejection fraction (LVEF) <30%, QRS duration >130 ms, and NYHA functional class 1 or 2, the primary end point of hospitalization for HF or death from any cause occurred in 132 patients (30%) taking carvedilol and 243 patients (23%) taking metoprolol. During the 3.4-year follow-up, 48 patients (10%) taking carvedilol and 104 patients (11%) taking metoprolol died.

The benefit of carvedilol over metoprolol was more pronounced in the subgroup of patients with a cardiac resynchronization therapy defibrillator (CRT-D), where carvedilol was associated with a significant 39% reduction in the risk of hospitalization for HF or death, and in those with left bundle branch block (LBBB). In the LBBB patients with a CRT-D, treatment with carvedilol was associated with a 49% reduction in risk compared with metoprolol.

There was also a pronounced dosage-dependent relationship between outcome and dose in carvedilol, which was not found in metoprolol-treated patients. The researchers note that mean Carvedilol and metoprolol doses in MADIT-CRT were 18 mg and 64 mg, respectively. These dosages are comparable to real-life dosages administered to patients in the clinical setting, although somewhat lower than in previous randomized controlled trials, according to the researchers.

In multivariate analysis, the reduction in the primary end point with carvedilol translated into a 30% reduction in risk compared with metoprolol, a benefit that was driven primarily by a reduction in HF hospitalizations. There was only a trend toward a reduction in the risk of ventricular tachycardia/ventricular fibrillation (VT/VF). The reduction in the risk of hospitalization for HF/death from any cause was more pronounced in patients receiving CRT-Ds.

Both metoprolol and carvedilol have a class IA indication in the management of patients with HF, with choice of the drug left to the discretion of the physician. In the Carvedilol or Metoprolol European Trial  (COMET), there was an absolute 5.7% survival benefit with carvedilol over metoprolol.

A number of small studies have shown differences between carvedilol and metoprolol in terms of the effect on ejection fraction and hemodynamics. A previous publication reported on 150 patients with heart failure who were randomly assigned to carvedilol or metoprolol. Carvedilol caused greater anti-adrenergic effects than metoprolol, larger increases in left ventricular ejection fraction, and greater decreases in mean pulmonary artery and pulmonary wedge pressure. Both drugs improved symptoms, submaximal exercise tolerance, and quality of life to a similar degree. Left ventricular ejection fraction may be a surrogate parameter for outcome in chronic heart failure patients, but the question ultimately remains whether these hemodynamic differences in favor of carvedilol will result in an advantageous effect on mortality or hospitalization in these patients.

Source:

1. Ruwald MH, Ruwald AC, Jons C, et al. Effect of metoprolol versus carvedilol on outcomes in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). J Am Coll Cardiol 2013; 61:1518-1526.
2. Poole-Wilson PA et al. Comparison of Carvedilol and Metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003 Jul 5; 362(9377):7-13.
3. Merta M. et al. Differential effects of beta-blockers in patients with heart failure: A prospective, randomized, double-blind comparison of the long-term effects of metoprolol vs. carvedilol. Circulation 2000;102:546-551.