Heart Failure: Treat with Beta-Blockers or ACE Inhibitors?
Heart failure, a common condition encountered in primary care, is generally associated with significant morbidity and mortality. National guidelines outline pharmacotherapy options, such as beta-blockers and angiotensin converting enzyme (ACE) inhibitors, and recommend both starting and target doses for these agents (Table).1 As both classes can lower blood pressure, physicians are often forced to decide which agent will be increased to a higher dose as titration of both can lead to dose-limiting hypotension. Available clinical trial evidence, however, provides the guidance to make the choice between titration of a beta-blocker or an ACE inhibitor relatively easy.
A Case Study
CK is a 63-year-old black male complaining of worsening shortness of breath and weight gain over the past 4 weeks. At the hospital, he was diagnosed with heart failure. His records indicate that, in addition to amlodipine 10 mg daily for high blood pressure, CK was initiated on metoprolol succinate 25 mg daily, lisinopril 5 mg daily, and furosemide 20 mg as needed for weight gain over 3 lb in 24 hours. Laboratory results show potassium of 4 mEq/L, serum creatinine of 0.9 mg/dL, and an ejection fraction of 35%.
Two weeks later, CK has returned to your office for a follow-up visit. He has a blood pressure of 138/84 mm Hg and a heart rate of 82 beats per minute.
Clinical Question
As beta-blockers and ACE inhibitors possess antihypertensive effects (and beta-blockers also reduce heart rate), caution must be used when titrating these medications towards their target doses so as to limit the risk for hypotension and bradycardia
Let’s make an analogy. If blood pressure in the heart failure patient is equivalent to money for the consumer, keep in mind that there is only a finite amount of money and each medication used for heart failure is associated with a cost. Since we want to make the most of our withdrawals and ensure funds are used wisely, the question is: Are beta-blockers or ACE inhibitors a better use of a patient’s money?
Evidence
Three beta-blockers—carvedilol, metoprolol succinate, and bisoprolol—are recommended by 2013 American College of Cardiology Foundation/American Heart Association guidelines for the treatment of heart failure associated with a reduced ejection fraction (HFrEF) based on favorable clinical trial results that demonstrated improvements in both morbidity and mortality.1 Note: Only metoprolol succinate, not metoprolol tartrate, is associated with positive outcome data; metoprolol tartrate has been shown to be inferior to carvedilol in a head-to-head study and likely should not be used for any patient with heart failure.2,3
ACE inhibitors are also recommended for heart failure, but unlike beta-blockers, the benefits afforded by ACE inhibitors appear to be a class effect—ie, all agents provide equivalent benefits.
Starting a patient on both a beta-blocker and an ACE inhibitor instantly provides benefit to the HFrEF patient in terms of morbidity (eg, heart failure-related hospitalizations) and mortality, and is universally recommended by heart failure guidelines, but the titration of these agents leads to differential effects for the patient.
RESEARCH
The ATLAS (Assessment of Treatment with Lisinopril and Survival) study compared 5 mg vs. 40 mg daily dosages of lisinopril. The results showed that the 40 mg dosage lowered the number of heart failure-related hospitalizations compared to the 5 mg dosage, but did not have a differential effect on mortality.4
The SOLVD (Studies of Left Ventricular Dysfunction) study also found similar results with enalapril—a 20 mg daily dose of enalapril did reduce hospitalizations for heart failure, but did not improve mortality rates. Higher doses of the ACE inhibitors were also associated with more hyperkalemia, hypotension, and increases in serum creatinine levels as compared to lower doses.4,5
Studies with the beta-blockers carvedilol and metoprolol succinate found that titrating the dose upwards toward the target dose was associated with morbidity and mortality reductions as compared to simply continuing the starting dose; this method is now recommended by the national guidelines. However, in some cases, titration may not be possible; common reasons for intolerability included fatigue, hypotension, and bradycardia.
Recent retrospective evaluations of these studies have shown that a larger reduction in baseline heart rate was a more important determinant of benefit than the actual beta-blocker dose achieved. Therefore, there is some suggestion that titrating the beta-blocker to a target heart rate of 58 to 64 beats per minute may be more important than achieving a specific target dose, but this strategy has not been evaluated prospectively in clinical trials.6 It reasons, however, that higher doses of beta-blockers (moving towards the target dose) would be expected to lower heart rate better than the starting doses, so the 2 strategies would have significant overlap when employed and likely lead to similar reductions in morbidity and mortality.
Clinical Application
The initiation of a beta-blocker and an ACE inhibitor translates to significant reductions in morbidity and mortality in patients with HFrEF. Evidence shows that titration of beta-blockers to higher doses is associated with improved morbidity and mortality compared to starting doses. While this benefit appears to have a stronger relationship to the degree of heart rate reduction compared to the target dose achieved, higher doses of beta-blockers would invariably be expected to lower the heart rate. On the contrary, further titration of the ACE inhibitor does not confer additional benefit in mortality, although hospital admissions related to heart failure are reduced at the higher doses.
Referring back to our money analogy, it seems that our patient’s capital would be better spent titrating the beta-blocker upward as both morbidity and mortality are improved; if funds were spent on the ACE inhibitor titration, only morbidity would be improved.
Finally, in the case of CK (or any other patient on hypertensives other than a beta-blocker or an ACE inhibitor) if hypotension were limiting the titration of either the beta-blocker or ACE inhibitor, we would consider discontinuation of amlodipine. Although it’s antihypertensive effects may help to lower overall cardiovascular risk, it has no specific benefits for heart failure and preference should be given to the up-titration of medications shown to have benefit in reducing heart failure outcomes.
Outcome of the Case
CK is not showing signs or symptoms of heart failure today and his blood pressure and heart rate allow for his heart failure medications to be titrated upwards. Due to the benefits afforded by titration of the beta-blocker, we would recommend titration of metoprolol succinate to 50 mg daily, with the dose being doubled every 2 weeks until reaching a target dose of 200 mg daily or a target heart rate of 60 beats per minute.
If CK does not tolerate higher doses, the highest tolerated dose would be used. If CK reaches the target dose or heart rate for the beta-blocker, and his blood pressure is amenable, dose titration of the ACE inhibitor could be considered next.
Eric A. Dietrich, PharmD, BCPS, graduated from UF College of Pharmacy in 2011 and completed a 2-year fellowship in family medicine where he was in charge of a coumadin clinic. He now works for the UF Colleges of Pharmacy and Medicine.
Kyle Davis, PharmD, BCPS, graduated from the University of Florida College of Pharmacy in 2011 and completed a PGY-1 at Jackson Memorial Hospital and a PGY-2 in internal medicine at Indiana University Health and Butler College of Pharmacy. He currently works at Jackson Memorial Hospital in Miami, FL.
References:
1. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-327.
2. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;
353(9169):2001-2007.
3. Poole-Wilson PA, Swedberg K, Cleland JG, et al; Carvedilol Or Metoprolol European Trial Investigators. 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;362(9377):
7-13.
4. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. 1999;100(23):2312-2318.
5. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med. 1991;325(5):293-302.
6. Cullington D, Goode KM, Clark AL, Cleland JG. Heart rate achieved or beta-blocker dose in patients with chronic heart failure: which is the better target? Eur J Heart Fail. 2012;14(7):737-747.