Getting the right therapeutic dose of any drug is not always easy. Using antibiotics to treat infection or antihypertensive drugs to lower blood pressure can be measured easily by simple physiologic measurements.
The treatment of heart failure with beta-blockers or ACE inhibitors, however, has been largely defined by clinical trials, which by their nature use one dosage and usually provide the clinician with limited information about the range of the best and most effective dosages. The rigor of choosing the correct dosage in clinical trials is often limited to small, underpowered phase II studies carried out well before the major phase III trials, which are designed to support efficacy and safety, usually at that one dosage. And still, physicians usually pick the lowest dose, following Hippocrates’ dictum to "do no harm." This dilemma has particular importance in picking the best dose of a beta-blocker in heart failure.
A recent presentation at the annual congress of the European Society of Cardiology by Dr. L. Brent Mitchell ("Full-dose beta-blockers still show benefit," October 2013, p. 26) sheds some important light on the benefit of maximum dosing with beta-blockers in heart failure patients treated with cardiac resynchronization therapy (CRT) or implantable cardiac defibrillators (ICDs) in whom bradycardia escape pacing was present.
Although all patients received standard drug therapy, patients receiving less than 50% of the full recommended dose of beta-blocker had a worse outcome in regard to mortality and rehospitalization when compared with patients receiving the full recommended dose, regardless of the beta-blocker used. Roughly one-half of these heart failure ICD/CRT patients were receiving less than half of the recommended dose for heart failure therapy. Older patients and those with more advance heart failure tended to receive the lower dose. In this patient population with pacemaker-controlled low heart rate, the issue of beta-blocker–induced bradycardia is no longer an issue: the higher the better.
In patients with atrial-controlled heart rates with sinus rhythm or atrial fibrillation, however, the induction of bradycardia has been an issue as physicians up-titrate dosages. The effect on morbidity and mortality of varying doses of metoprolol succinate (Toprol) was examined in the MERIT-HF trial (J. Am. Coll. Cardiol. 2002;40:491-8), in which physicians were encouraged to up-titrate to the highest dose. The limitation of up-titration was bradycardia. The high-dose (greater than 100 mg/day) and low-dose (100 mg/day or less) patients received 192 mg and 76 mg/day, respectively. Despite the different maximal doses, the final heart rate achieved with the up-titration was 68 beats/min. Patients receiving the high dose and low dose achieved the same relative benefit of therapy. The low-dose patient group was older and had a higher New York Heart Association functional class.
These observations suggest that there was a significant variability in the patient’s sensitivity to beta-blocker therapy, but the achievement of a low heart rate, regardless of dose, was effective in achieving the best therapeutic benefit. In a small dose-ranging study, patients were randomized to receive 50 or 200 mg/day of Toprol. The patients receiving 200 mg demonstrated an increase in ejection fraction and a decrease in end systolic volume, compared with the 50 mg–dose patients, who failed to evidence any hemodynamic improvement (Circulation 2007;116:49-56).
These observations emphasize the uncertainties of drug dosing in heart failure with our standard therapy. The benefit of high doses of beta-blockers in the ICD/CRT trial in patients whose heart rate was controlled with bradycardia pacing provides important support for the use of high doses in these individuals. In patients whose heart rate was controlled by atrial rhythms in the MERIT-HF trial, heart rate became the major limitation of drug therapy. In these patients, up-titration to maximal heart rate expressed the presence of a variable sensitivity to beta-blockade. The achievement of a slow heart rate, regardless of dose, appeared to achieve a similar benefit on heart failure outcomes.
Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies, and was the co-principal investigator of the MERIT-HF trial.