Role of Calcium Channel Blockers and Beta Blockers in CHF

By: Lunbao Huang Pharm D. Candidate c/o 2013

–

The seventh report of the Joint National Committee on high blood pressure (JNC-7) states that most classes of antihypertensive drugs such as angiotensin converting enzyme inhibitors (ACEIs), angiotensin-II receptor blockers (ARBs), beta-blockers (BBs), diuretics, and aldosterone-receptor antagonists can be used for hypertensive heart failure patients except calcium channel blockers (CCBs).¹ JNC-7 recommends using ACEIs and BBs to treat hypertension in patients with Stage B and Stage C left ventricular dysfunction. ARBs are used in patients who cannot tolerate the adverse effects from ACEIs.^{1, 2, 12} BBs are used based on clinical studies that demonstrate a decrease in morbidity and mortality.¹ The ALLHAT study suggests that CCBs (more specifically, amlodipine, a dihydropyridine,) are shown to be effective monotherapy antihypertensives. However, amlodipine was associated with a higher incidence of heart failure compare to thiazide-diuretics and ACEIs.³

The three groups of BBs are the selective beta-1 adrenergic receptor blockers, the nonselective beta-1 and beta-2 adrenergic receptor blockers, and the nonselective beta-blockers with alpha-receptor blocking activity. A study done on nonselective beta-blockers with alpha-blocking activity in 2001’s Packer et. al. reveals that the intervention group taking carvedilol experiences less death than the placebo group during treatment of heart failure patients.⁴ This same trial also demonstrates that sustaining a very low blood pressure (systolic <100 mmHg) may be desirable in some heart failure patients.^{1, 4} Some nonselective beta-blockers such as acebutolol and pindolol have intrinsic sympathomimetic activity (ISA). These beta-blockers with ISA have partial agonist activity at beta-receptors while still blocking both beta-receptors. This drug activity is therapeutic for bradycardic patients. However, there has been no benefit shown with using these agents in hypertensive patients with heart failure. MERIT-HF suggests that using metoprolol CR/XL in patients with symptomatic heart failure would improve survival and reduce the need for hospitalization due to worsening of heart failure.⁵ A more updated post-MERIT-HF study shows that BBs still reduce morbidity and mortality in patients with heart failure.⁶

The two sub-classes of CCBs are dihydropyridines and the non-dihydropyridines. Dihydropyridines’ mechanism of action mostly focuses on decreasing peripheral resistance by vasodilation. Non-dihydropyridines work mostly at the heart as negative inotrope and chronotropes. They decrease heart rate and contractility, thus decreasing oxygen demand by the heart. This is why they are beneficial for patients with angina, atrial fibrillation and atrial flutters (i.e. heart attacks). A research support article suggests that using a combination of digoxin with a BB or a non-dihydropyridine CCB is better than using digoxin alone in controlling both resting and exercising heart rate in patients with atrial fibrillation or systolic functional heart failure.

A recent study done by Braun et al. on patients with congestive heart failure (CHF) demonstrates that BBscan improve left ventricular function in CHF patients.⁷ A total of 63 patients were separated into 3 groups. The first group contains 20 patients who used metoprolol and felodipine. The second group contains 23 patients using metoprolol and placebo. The third group contains 20 patients using placebo only. Treatment includes a month of titrating, 2-6 months of treatment, and six more months of follow up. A way to measure outcome is with hemodynamic tools such as measuring left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDD). The metoprolol and placebo group shows an increase in LVEF (P<0.01) and increase in LVEDD (P<0.05). In contrast, the combined therapy with the long-acting calcium antagonist felodipine neutralizes these beneficial effects of metoprolol therapy to almost placebo level. Clinically, the study suggests the use of BBs only for treatment of hypertension in CHF patients. The study provides evidence based on hemodynamic measurements that the combination of dihydropyridines diminishes the effect of BBs so a combination method is not preferred in CHF patients without hypertension. While deciding between using CCBs and BBs, the current indication for treatment of heart failure patient with hypertension remains a low dose selective BBs.^{6, 9}

In conclusion, there have not been many studies done on CCBs used in heart failure patients since seeing a high mortality rate in pioneer trials. It is debatable whether more studies on the subject will trump the known danger of CCB use in heart failure patients. ACC/AHA guidelines suggest that it is safe to use BBs in Stage B Class I (regardless to ejection fraction, evidence A) and Stage Class I, IIa, IIb and III. CCBs are used for Stage C Class III heart failure patients even though it is not recommended as discussed previously.⁸ Many studies and guidelines continue to support ACEIs as first line agents for heart failure.^{1, 8, 10} CCBs are used as last line agents for patients with comorbid systolic heart failure.¹³ It is beneficial to use non-dihydropyridines for patients with angina and paroxysmal supraventricular tachycardia (PVST) because of their negative inotropice and chronotropic effects. ACC/AHA guidelines recommend a four drug combination of a diuretic, an ACEI (or alternative of an ARB), a BB and digoxin for routine management of left heart failure.^{1, 8, 10, 11, 12}
SOURCES:

1. National Institutes of Health: National Heart, Lung, and Blood Institute. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Washington DC; US Department of Health and Human Services, 2004; NIH publication No. 04-5230.
2. Cohn JN, Tognoni G.  A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.  The Valsartan Heart Failure Trial Investigators. N Engl J Med 2001; 345:1667-75.
3. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981-97.
4. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344:1651-
5. Tepper D.  Frontiers in congestive heart failure: Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).  MERIT-HF Study Group. Congest Heart Fail 1999; 5:184-5.
6. Beta-blocker treatment of chronic systolic heart failure improves prognosis even in patients meeting one or more exclusion criteria of the MERIT-HF study Eur Heart J. 2005; 26:2689-2697,
7. Braun M, Edelmann F, Knapp M, et. al. The Calcium channel blocker felodipine attenauates the positive hemodynamic effects of beta-blocker metoprolol in severe dilated cardiomyopathy- A prospective, randomized, double-blind and placebo-controlled study with invasive hemodynamic assessment. International Journal of Cardiology Feb 2009; 123:2: 248-256
8. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al.  ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: Executive summary.  A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the International Society for Heart and Lung Transplantation; endorsed by the Heart Failure Society of America. Circulation 2001; 104:2996-3007.
9. CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 1994; 90:1765-73.
10. The SOLVD Investigators.  Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325:293-302.
11. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al.  The effect of spironolactone on morbidity and mortality in patients with severe heart failure.  Randomized aldactone evaluation study investigators. N Engl J Med 1999; 341:709-17.
12. McMurray J, Ostergren J, Pfeffer M, Swedberg K, Granger C, Yusuf S, et al.  Clinical features and contemporary management of patients with low and preserved ejection fraction heart failure: Baseline characteristics of patients in the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) programme. Eur J Heart Fail 2003; 5:261-70.
13. Kazik A, Wilczek K, & Polonski, L. Management of diastolic heart failure. Cardiology Journal. 2010; 17:6:558-565.