Orlando, FL - Results of two trials confirm the benefit of carvedilol (CoregR, GlaxoSmithKline), a beta blocker with alpha blocking properties, in a broad range of patients, from those with left ventricular dysfunction post-MI, to those with severe heart failure (HF). First results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) and secondary endpoints from the Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS) were presented here today at the American College of Cardiology 50th Annual Scientific Session.

Positive results with beta blockers in HF such as those reported in the US Carvedilol study, CIBIS II with bisoprolol, and MERIT-HF with metoprolol, have focused on patients with mild-to-moderate HF.

"We now have evidence across the entire spectrum of disease, from the time of initial injury, when patients start dilating and develop mild to moderate symptoms, now all the way through to a point when the symptoms become progressive, are present at rest, or on minimal exertion," COPERNICUS principal investigator Dr Milton Packer (Columbia University College of Physicians and Surgeons, New York) told heartwire in an interview.

	I'm personally confident that physicians will rapidly respond and do the right thing.

Packer estimated that about 15-20% of patients with HF are getting beta blockers, but feels that number should be closer to 80%. "I'd like to think that physicians will be persuaded by data, and now that we have given them two additional trials that should be persuasive, I'm personally confident that physicians will rapidly respond and do the right thing."

Dr Barry M Massie (UCSF), who moderated the late breaking clinical trials session, pointed out that while uptake of beta blocker therapy for those with mild-to-moderate HF has been "tremendous" in the cardiology community, these are two groups of patients in which beta blockers have been used reluctantly or not at all.

	It's pretty clear from these studies that both of those groups can be treated safely, the drugs are well tolerated, and with added benefit, sometimes very strong added benefit.

"I think we're fortunate to have these two trials put together because they encompass those two groups - those with very severe degrees of heart failure, and those with acute MI with significant LV dysfunction already on ACE inhibitors," he told doctors here. "It's pretty clear from these studies that both of those groups can be treated safely, the drugs are well tolerated, and with added benefit, sometimes very strong added benefit.

"The message I'd hope we could get out to the public, the primary care physicians and cardiologists, is that there aren't any more exclusions among stable patients, either in the post-MI setting or the chronic heart failure setting," Massie added.

COPERNICUS: secondary endpoints

The COPERNICUS trial enrolled 2289 patients with severe HF (LVEF <25%), who were randomized to carvedilol in a target dose of 25 mg bid for up to 29 months. The primary endpoint of this trial, presented in August 2000 at the European Society of Cardiology meeting in Amsterdam, showed a 35% reduction in mortality, a significant reduction with a nominal p value of 0.00013, and an adjusted value of 0.0014. The trial was actually stopped early for efficacy.

In this presentation, data were reported on a variety of secondary endpoints, all uniformly positive in favor of carvedilol therapy.


COPERNICUS: Effect of carvedilol on the combined risk of morbidity and mortality

Endpoint Relative risk reduction Odds ratio p value Death or hospitalization for any reason 24% 0.76 0.00004 Death or hospitalization for a CV reason 27% 0.73 0.00002 Death and hospitalization for HF 31% 0.69 0.000004

When hospitalizations were considered alone, patients treated with carvedilol were significantly less likely to be hospitalized either once or on multiple occasions. When all hospitalizations were considered, including repeat hospitalizations, the carvedilol group had 20% fewer hospitalizations for any reason, 28% fewer hospitalizations for a cardiovascular reason, and 33% fewer hospitalizations for HF, all highly significant findings.

Patients in the treatment group spent 27% fewer days in hospital for any reason compared to those in the placebo group, reflecting both fewer total hospitalizations and a shorter duration of each hospitalization.

Endpoint Reduction with carvedilol p value Total days in hospital 27% 0.0005 Number of hospitalizations 20% 0.0017 Days per hospitalization 9% 9%

While in hospital, those on carvedilol required significantly fewer intravenous treatments for HF, including IV diuretics or positive inotropic agents, and had fewer echocardiographic evaluations of ventricular function.

"These observations suggest that carvedilol not only reduced the frequency of hospitalizations, but also decreased the severity of hospitalizations that occurred on treatment," Packer said.

Carvedilol treatment was also associated with improvements in patients' overall sense of well-being by their own assessment.

Patients on carvedilol reported increased side effects including bradycardia, dizziness, headache, hypotension, and presyncope, but treatment was associated with a lower risk of serious adverse events, particularly those associated with the progression of HF. Fewer patients in the treatment group required withdrawal of treatment for an adverse event or for another reason, Packer added.

"In contrast to earlier reports with the use of beta blockers in heart failure, we did not observe an increase in the risk of worsening heart failure during the initiation and up-titration of the drug, despite the advanced severity of the disease in the patients in this study," he concluded. BR> CAPRICORN: LV dysfunction after MI

The CAPRICORN trial set out to examine the effect of carvedilol in patients at the other end of the heart failure spectrum - those with left ventricular dysfunction (LVEF < 40%) after an MI, with or without HF.

Previous trials showing benefit from beta blockers in the post-MI setting were done in the 70s and 80s, said principal investigator Dr Henry J Dargie (University of Glasgow, Glasgow, Scotland). Since that time, post-MI treatment has changed significantly with the wider use of aspirin, and the introduction of thrombolytic and PCI interventions.

"Patients with heart failure were generally excluded from these trials, and there are no reports of measurement of left ventricular function, so it can be stated that those trials were, essentially, trials in low-risk patients," he said. "Our objective therefore was to evaluate the effect of carvedilol on clinical outcomes in patients with left ventricular dysfunction following acute myocardial infarction, but treated according to evidence based medicine in the modern era."

ACC/AHA guidelines already advise doctors to start beta blockers in high risk post-MI patients, including those with LV dysfunction, at 5 to 28 days. However, Dr Sidney Smith (University of North Carolina, Chapel Hill, NC), chief science officer of the AHA, pointed out that carvedilol, "is a newer beta blocker with additional properties. These are patients that were sicker and there has been a reluctance to use beta blockers acutely. So I would think it reasonable to study this medication, and certainly these findings, released at a major meeting, will help forward the use of beta blockers."

Shifting gears - and endpoints

CAPRICORN randomized 1959 patients from 163 centers in 17 countries to treatment with carvedilol or placebo. The original primary endpoint of the CAPRICORN trial was all-cause mortality with a conventional level of significance (0.05). Secondary endpoints included all-cause mortality or cardiovascular hospitalization, sudden death, and hospitalization for HF.

However, Dargie explained, "during the trial, the steering committee was informed by the DSMB during a blinded analysis that the overall mortality rate was less than we had predicted, and that the trial could not be completed using all-cause mortality as the primary endpoint."

The steering committee elected to change the primary endpoint to a co-primary endpoint that included the original endpoint, all-cause mortality, and the first-prespecified secondary endpoint of all-cause mortality or cardiovascular hospitalizations. Accordingly the level of significance, the alpha, became 0.005 for all-cause mortality, and 0.045 for the combined endpoint. The other secondary endpoints were unchanged. After 1.3 years of follow-up, the target number of events (633) was reached.

For the original primary endpoint, all-cause mortality, they saw an absolute risk reduction of 3%, and a 23% relative risk reduction, but because of the re-specified statistical criteria, it did not reach statistical significance. "Nevertheless, death clearly is, next to myocardial infarction, the most important endpoint," Dargie said. "It was our original prespecified primary endpoint, and clearly represents a highly significant clinical outcome." The second primary combined endpoint showed a trend favoring carvedilol but this did not reach statistical significance.


CAPRICORN: Primary endpoints

Endpoint Placebo Carvedilol Hazard ratio (CI) p value All-cause mortality 151 (15%) 116 (12%) 0.77 (0.60-0.98) 0.031 All-cause mortality or CV hospitalization 367 (37%) 340 (35%) 0.92 (0.80-1.07) 0.296

Reductions were also seen in secondary endpoints, most notably in all-cause mortality and nonfatal MI, where they saw a, "highly and clinically significant result," Dargie said.

Endpoint Hazard ratio p value Sudden death 0.74 0.098 Heart failure hospitalization 0.86 0.215 Nonfatal MI 0.59 0.014 All-cause mortality and nonfatal MI 0.71 0.002

To download tables as slides, click on the slide icon below

Tolerability was good in these patients, he added, with 75% reaching the top or second-top dose, and a similar number of withdrawals seen in both groups.

From this data, they calculate that the number needed to treat for 1 year to prevent one death is 43, identical, but in addition to, the benefit seen with ACE inhibitors in this same population.

"CAPRICORN bridges the gap between heart failure - so eloquently presented by Dr Packer earlier - and those patients with left ventricular dysfunction in the CCU, in whom the most dramatic effects are on major coronary events," Dargie concluded. "It is clear that the benefit of beta blockade should now be extended to those high risk patients with MI who have LV dysfunction, who have not had the benefit of this treatment in the past."

Susan Jeffrey sjeffrey@conceptis.com

For a full listing of HeartWire articles please go to theheart.org. HeartWire is the news service of theheart.org. Copyright HeartWire 2001. All rights reserved. Republication or redistribution of HeartWire content is prohibited without prior written consent.

				2001 theheart.org info@theheart.org