Beta blockers rediscovered, gain primary role in cardiology
Beta blockers rediscovered, gain primary role in cardiology
Cohorts, consortia calling for increased use in CHF, post-MI therapy
Hospital pharmacists and pharmacy and therapeutics teams need to reassess their institutions’ protocols for the use of beta blockers in the treatment of congestive heart failure (CHF) and post-myocardial infarction (MI) therapy, research shows.
The traditional beta is being roundly touted for its ability to curb morbidity and hospitalization in these patients, with current research decrying the underuse of beta blockers as much as it champions the drug’s benefits.
The case for beta blockers has been growing in recent years, with large-scale trials and cohorts given consistent high-profile space in major medical journals since 1997. Last November, the American Heart Association called on physicians to increase the use of beta blockers in post-MI therapy during the organization’s 69th scientific sessions in New Orleans. The American Medical Association also has noted its support for greater use of beta blockers.
This year, a consensus group of 150 heart failure researchers and cardiologists, working as the Advisory Council to Improve Outcomes Nationwide in Heart Failure (ACTION HF), strongly stressed the need for the inclusion of beta blockers in the treatment of CHF. The consortium recommends a four-drug regimen of traditional diuretics and digitalis, along with the combination of ACE inhibitors and beta blockers.
"We know that treatment with a four-drug combination is the optimal treatment for most patients with heart failure, and utilization of this strategy can dramatically affect the outlook for patients," says Milton Packer, MD, co-chair of ACTION HF and director of the Center for Heart Failure Research at New York Presbyterian Hospital. "If we could get every eligible heart failure patient to receive an ACE inhibitor and a beta blocker, we could prevent hundreds of thousands of hospitalizations and save tens of thousands of lives," he said in a written statement.
The recommendations follow 18 months of research by the group, which charged itself with reviewing every available study and cohort on CHF treatment. The group also stresses that only about 40% of eligible patients receive ACE inhibitors, while just 5% receive beta blockers.
Researchers and pharmacists say the reason for that is twofold, based on early concerns that beta blockers, by lowering the heart rate, would produce exactly the opposite effect desired. They also say other drugs, primarily calcium channel-blockers (CCBs), simply became more popular.
"I think the science just caught up with the reality," says Barry Browne, PharmD, coordinator of Drug Information Services at Scott & White Hospital in Temple, TX. "It had been the conventional wisdom in the mid to late 80s not to use beta blockers for CHF because of the resting effect. For post-MI, the idea is to give the heart a chance to rest with a beta blocker, and again the thought was betas should not be used for CHF simply because resting is bad," he says.
Benefits outweigh risks
The science Browne refers to centers on new information about the mechanism of heart failure; betas are thought to block the adverse action of certain hormones released when the heart is damaged. In other words, blocking of adrenaline receptors and the effects of those chemicals outweighs any slowing of the heart rate that beta blockers are known to cause as traditional hypertensive drugs. ACE inhibitors also work by blocking the release of "stress" hormones.
The assertion that beta blockers were squeezed out of the market by calcium channel-blockers is backed by a 1998 study at Massachusetts General Hospital. That study noted that despite existing guidelines calling for beta blocker use, prescriptions declined in the 80s as the use of CCBs rose. The study even followed drug advertisements in 210 issues of the New England Journal of Medicine, which found that in 1985, 12% of ad space dealt with beta blockers, and 5% advertised CCBs. By 1996, 27% of the ads were for CCBs, while no ads appeared for beta blockers the entire year.
If the case is being made for an increased use of, and a return to, beta blockers, then formulary considerations can’t be far behind for both CHF and post-MI therapy.
For CHF therapy, the biggest formulary consideration facing pharmacy and therapeutics committees is SmithKline Beecham’s Coreg (carvedilol), the first beta blocker approved for CHF. The drug offers beta-blocking and vasodilating effects, and like all beta blockers, it offers improved left-ventricular function by blocking excessive adrenergic stimulation. Carvedilol also shows no effect on cholesterol levels in trials.
The drug is specifically indicated for mild or moderate CHF, used in conjunction with digitalis, diuretics, and ACE inhibitors in heart failure of ischemic or cardiomyopathic origin due to left-ventricular systolic dysfunction. SmithKline Beecham recommends starting patients on the lowest possible dose, if the patient can tolerate it. Specifically, the company recommends a starting dose of 3.125 mg twice daily for two weeks, followed by an increase to 6.25 mg, then doubled every two weeks until tolerance is capped.
Side effects to watch for include dizziness, bradycardia, hypotension, or signs of worsening heart failure. Contraindications include patients with bronchial asthma. The drug is available in 3.125 mg, 6.25 mg, 12.5 mg, and 25 mg strengths in 100-tablet bottles at $154 a bottle.
For hospital pharmacists such as Browne at Scott & White, there are several formulary considerations to weigh. "Coreg needs to be monitored on the dose change, and there is the problem of finding the time to monitor patients in a primary care setting. You need someone who will watch patients very closely," says Browne.
"The drug is not a cure, so the question is, do you add it to your formulary knowing there is a limit and that there is monitoring? You don’t want to put all of your patients on Coreg. In mild cases it may not be needed, and in severe cases it may not help, so the best benefits would be for select patients," he says.
More clinical information is expected from a large post-market study begun by SmithKline Beecham aimed at enrolling 6,000 CHF patients in a yearlong tracking surveillance program. The company hopes to publish the results in 2000.
The evidence that’s been mounting the case for beta blockers in CHF and post-MI treatment has peaked during the last three years, with early 1999 reports coinciding with coordinated announcements like that from the Advisory Council to Improve Outcomes Nationwide in Heart Failure.
In January, for example, the American Heart Association detailed the results of a study in which death rates were nearly halved among 2,647 patients with mild or moderate heart failure who were given beta blockers. Patients received either diuretics and ACE inhibitors or the two drugs and the beta blocker bisoprolol. All of the patients in the study had been diagnosed with left-ventricular systolic dysfunction leading to stable, symptomatic heart failure.
Doses started at 1.25 mg per day, increasing to 10 mg per day over six months. Patients in the beta blocker group had 34% fewer deaths from all causes and 44% fewer sudden deaths.
"The trial is an important turning point," says the hospital association’s Harlan Krumholz, MD. "Small studies have been accumulating, suggesting the value of beta blockers for patients with heart failure, but this trial provides the first real convincing evidence that patients with mild or moderate heart failure live longer and have less need for hospitalization when treated with beta blockers." Krumholz, an associate professor of medicine at Yale University, points out, however, that the study was inconclusive concerning patients with severe heart failure. "We need more information about these [patient] groups."
Some of the earlier studies Krumholz refers to also pertain to beta blockers in post-MI therapy. One such study followed the use and outcomes of beta blocker therapy in 1,165 patients following cases of acute MI treated within a Kaiser HMO plan in northern California.
The study basically found that beta blockers were being underprescribed, despite being "beneficial in patients after an acute myocardial infarction," in part due to concern over the relatively large dosages physicians thought were needed. That led to fewer and lower doses being prescribed than have been found to be effective in clinical trials. But the study found that smaller doses worked just as well in terms of patient mortality. (For details, see Arch Intern Med 1998; 158:449-53.)
As to the results of the study, researchers wrote, "Of the 37.7% of patients prescribed beta blocker therapy, 48.1% were treated with dosages less than 50% of the dosage found to be effective in preventing cardiac death in large randomized clinical trials. Compared with patients not receiving beta blockers, those treated with lower-dosage therapy appeared to have a greater reduction in cardiovascular mortality than patients treated with a higher dosage."
Some patients get CCB instead
A similar study pointed out that among patients 65 or older with no contraindications to beta blockers, only 50% were getting prescriptions, and those patients receiving CCBs were even less likely to be given a beta blocker. The national cohort study examined more than 100,000 patients, finding that of the 45,308 clearly eligible for beta blockers, only half were receiving them. (For details, see JAMA 1998; 280:623-629.) The study also found that the patients who did receive beta blockers had a 14% lower risk of mortality at one year after discharge.
A year earlier, Harvard researchers made the same point in a cohort of post-acute MI Medicare patients in New Jersey. (See JAMA 1997; 277:115-121.) In that study, of the 3,737 patients over age 65 deemed eligible for beta blockers, 785 received them; the majority received CCBs instead.
The Harvard researchers concluded that "those patients who did receive beta blocker therapy following acute MI were 43% less likely to die within two years than patients who received calcium channel blockers and about 22% less likely to be rehospitalized. Yet, as a whole, elderly patients were three times more likely to receive a new prescription for costlier calcium channel blockers than for beta blockers."
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