Patients with ischemic heart disease and hypertension are frequently treated with a "combination therapy" of a calcium antagonist and a β-blocker. Each drug in this combination can lower blood pressure and impair cardiac contractility, impulse formation, and conduction. Hypotension, worsening of myocardial function, impulse formation, and conduction defects might be expected to occur more often with combination therapy rather than therapy with either drug alone (1).
Numerous publications documenting the occurrence of cardiovascular adverse drug reactions (CVADRs) and case reports describing hypotension/shock, worsening heart failure, and bradyarrhythmias associated with combined therapy have been published (2-25); however, only a few specific studies have directly examined and analyzed the incidence of hospitalization due to CVADRs. We report our clinical experience with 26 patients who had cardiovascular side effects while receiving combination therapy with oral β-adrenergic and calcium entry-blocking agents.
PATIENTS AND METHODS
From January 1995 through December 1996, we prospectively studied CVADRs in 2,574 consecutive admissions to the Department of Internal Medicine C in Rambam Medical Center; 1,970 patients were admitted from the Emergency Room, 386 were transferred from other hospital departments, and 218 patients were admitted electively.
Data collection and evaluation
Adverse drug reactions were defined as any unintended and undesirable effect of a drug that occurred at doses used in humans for prophylaxis, diagnosis, or therapy. We determined the incidence of CVADRs in the hospital by extracting the total number of patients experiencing at least one CVADR and dividing this value by the total number of hospital admissions to the department of medicine. The CVADR incidence was expressed as the percentage of patients with a CVADR. A data-collection form was developed before the study for this purpose. In each patient, a detailed history of recent drug use was taken. Cardiovascular hemodynamic events were regarded as presyncope or syncope (defined as sudden, quick, and reversible brief collapse without or with loss of consciousness, respectively), hypotension (defined as systolic blood pressure ≤85 mm Hg), and pulmonary venous congestion (PVC) documented by chest radiograph; cardiac bradyarrhythmias were regarded as sinus bradycardia (SB), sinus arrest (SR), junctional escape rhythm (JER), and complete atrioventricular block (CAVB). The medications investigated included calcium channel blockers (diltiazem, verapamil, nifedipine) and β-blockers (propranolol, metoprolol, atenolol, oxprenolol). Cases with a suspected drug event contributing to cardiovascular complications were evaluated in joint meetings with the investigator, the senior physician of the department, and the patient's personal physician. Patients were excluded from the study when the cardiovascular events could have occurred without the contribution of combination therapy or if they had diaphragmatic wall acute myocardial ischemia or infarction, hyperkalemia, or concomitant use of other drugs that could have contributed to the cardiovascular events.
The overall incidence of CVADR in hospitalized patients was 1.0%. The 26 patients in the study consisted of 14 (54%) men and 12 (46%) women. The median age was 73 years (range, 44-92 years). CVADRs were the cause for hospitalization in 10 patients, an associated cause in nine patients, and developed during hospitalization in seven patients. Coronary heart disease and hypertension were present in 22 and 17 patients, respectively. The duration of hospitalization ranged between 2 and 18 days (median, 6 days). Table 1 shows the number of patients taking each of the different combination therapies (in bold) and the number of patients affected by drug-induced cardiovascular events. Diltiazem was the most common calcium antagonist (81%), whereas propranolol was the most common β-blocker (61%).
All patients with PVC also had cardiomegaly and depressed left ventricular systolic function documented by echocardiography. Presyncope and syncope occurred in four and six patients, respectively. The actual etiology for syncope could not be determined, but could have been primarily arrhythmic or hemodynamic events.
Electrophysiologic abnormalities were localized to the sinoatrial (SA) node in 17 patients and to the atrioventricular (AV) node in five patients. Figure 1 details the prevalence of specific bradyarrhythmias. Patients with SB had a heart rate (HR) of 30-58 beats/min (median, 48 beats/min); JER, an HR of 45-48 beats/min; and CAVB, a ventricular rate of 36-45 beats/min. One patient had SB interrupted by periods of SR of 1.9 s.
Most of the patients were treated conservatively. Twenty-two patients recovered and were discharged. Temporary transvenous pacemaker insertion was necessary in only one patient, who had CAVB. Two patients died of pump failure due to acute anteroseptal myocardial infarction, and two elderly patients died of cardiogenic shock with profound SB attributed to combination therapy.
The ability of calcium antagonists to block calcium-mediated electromechanical coupling in contractile tissue produces a direct negative inotropic effect and a decrease in systemic vascular resistance; in addition, the inhibition of transmembrane cellular flow of calcium during the slow inward current can produce depression of SA and AV nodal function (27,28). By decreasing cytosolic cyclic adenosine monophosphate (AMP) and interfering with intracellular calcium transport across the sarcoplasmic reticulum, adrenergic antagonists produce similar pharmacologic actions (29,30). Therefore additive depressant effects on vascular tone, cardiac contractility, impulse formation, and conduction might cause hypotension, worsening of myocardial function, impulse formation, and conduction defects more often with combination therapy. Several trials have found no important adverse effects with such combination treatment (20,31), whereas other reports have documented the occurrence of bradyarrhythmias, hypotension, and worsening heart failure with combination therapy (2-26).
This study demonstrated that bradyarrhythmias unexpectedly occurred with clinical doses of calcium antagonists plus β-blockers in 22 patients, none of whom had a history of SA or AV node dysfunction.
Verapamil in conjunction with a β-blocker warrants the greatest concern, because this combination has significant potential for profound bradycardia and heart block. Prolongation of PR interval is frequently seen, and a higher degree of heart block has been reported (16). One series noted that this complication occurred only in those patients with a resting heart rate <55 beats/min during therapy with propranolol alone (19). SB, JER, and CAVB occurred in three of our patients treated with combined verapamil (240 mg daily) and β-blocker. When these agents are used concurrently, reduced dosages, especially of the β-blocker, will likely result in a lower incidence of adverse effects with maintained efficacy.
Although the negative chronotropic effects of diltiazem may affect any level of the conduction system, most of the adverse reactions occurred at the SA node, and clinically manifested as SB, SR, or JER. This finding is in accordance with other reports (5,8,26,32). However, the combination of diltiazem and propranolol or metoprolol also affected the AV node and manifested as CAVB in three patients and one patient, respectively. Hossack (5) reported an 80-year-old woman with severe angina who experienced CAVB 48 h after diltiazem (240 mg daily) was added to propranolol (40 mg daily). Lamaison (33) reported on two patients with cardiogenic shock and SB when diltiazem was added to their treatment with β-blocker.
Although Morse (34) did not observe SB with the nifedipine-propranolol combination, we observed this arrhythmia and hypotension in one patient (nifedipine, 40 mg daily, propranolol, 60 mg daily). Nifedipine depresses SA and AV nodal conduction in isolated tissue preparations; however, conventional doses do not produce atrial or atrioventricular conduction abnormalities in humans (17).
In five patients, CAVB was associated with a combination of propranolol and either diltiazem or verapamil. The bradyarrhythmias recovered within 24 h after discontinuation of the offending drugs, and temporary pacemaker insertion was necessary in only one patient with CAVB. Sagie et al. (26) reported pacemaker insertion in four (40%) patients with symptomatic bradycardia induced by the combination of oral diltiazem and β-blockers. We conclude from our data that when sinus or AV node dysfunction occurs after administration of combination therapy, pacing should not be performed routinely, as recommended by Ishikawa et al. (8), because the resulting rhythm usually does not deteriorate into a malignant ventricular arrhythmia.
Hypotension may have been induced by the peripheral vasodilative effects of the calcium antagonists and/or by a low cardiac output secondary to the negative inotropic effects and bradyarrhythmias of both calcium antagonists and β-blockers. The treatment of hypotension included discontinuation of the offending drugs, fluid replacement, and inotropic drugs. Two cases in which combination therapy was associated with cardiogenic shock and bradycardia, with an immediate and dramatic response to intravenous calcium chloride, have been reported (12).
In this study, all patients with pulmonary venous congestion also had cardiomegaly and depressed left ventricular systolic function documented by echocardiography. The combination of β-adrenergic blocker therapy and diltiazem (17,18), verapamil (35,36), and nifedipine (3,7) has been associated with congestive heart failure. In the intact circulation, the direct negative inotropic and chronotropic effects of the calcium antagonist are counterbalanced by stimulation of α- and β-adrenergic reflexes (1,37). When β-adrenergic reflexes are attenuated by the presence of a β-blocker or by left ventricular dysfunction, these drugs depress cardiac contractility; the magnitude of this effect is dependent on the dose of the β-blocker and the severity of cardiac dysfunction (1,38). Combination therapy may adversely affect left ventricular performance. Strauss et al. (17) documented the occurrence of clinical congestive heart failure in a patient with baseline left ventricular dysfunction and severe angina pectoris. Although the patient had tolerated propranolol therapy for years without difficulty, and high-dose diltiazem monotherapy with an excellent clinical response, the combination of them resulted in the development of congestive heart failure.
It is difficult to assess why some patients develop CVADRs while receiving combination therapy. Whether it reflects differences between patients and their underlying cardiac dysfunction, rather than a pharmacologic effect of the combination therapy, is unknown.
In conclusion, CVADRs are not uncommon in elderly patients with ischemic heart disease or hypertension being treated with combination therapy. This study illustrates that this therapy may unpredictably cause serious hemodynamic events and marked suppression of SA node activity and prolongation of AV conduction in some patients. Enhanced therapeutic monitoring may be warranted when a calcium antagonist, especially diltiazem or verapamil, is combined with β-blockers.
1. Packer M, Leon MB, Bonow RO, et al. Hemodynamic and clinical effects of combined verapamil and propranolol therapy in angina pectoris. Am J Cardiol
2. Anastassiades CJ. Nifedipine and β-blocker drugs. Br Med J
3. Opie LH, White DA. Adverse interaction between nifedipine and beta-blockade. Br Med J
4. Staffurth JS, Emery P. Adverse interaction between nifedipine and beta-blockade [Letter]. Br Med J
5. Hossack KF. Conduction abnormalities due to diltiazem [Letter]. N Engl J Med
6. Hung J, Lamb I, Connolly SJ, et al. The effect of diltiazem and propranolol alone and in combination on exercise performance on left ventricular function in patients with stable effort angina: a double-blind randomized placebo-controlled study. Circulation
7. Robson RH, Vishwanath MC. Nifedipine and beta-blockade as a cause of cardiac failure. Br Med J
8. Ishikawa T, Imamura T, Koiwaya Y, Tanaka K. Atrioventricular dissociation and sinus arrest induced by oral diltiazem [Letter]. N Engl J Med
9. Boden WE, Korr KS, Bough EW. Nifedipine-induced hypotension and myocardial ischemia in refractory angina pectoris. JAMA
10. Hutchison SJ, Lorimer AR, Lakhdar A, McAlpine SG. Beta-blocker and verapamil: a cautionary tale. Br Med J
11. McGourty JC, Silas JH. Beta-blocker and verapamil: a cautionary tale [Letter]. Br Med J
12. Henry M, Kay MM, Viccellio P. Cardiogenic shock associated with calcium-channel and beta-blockers: reversal with intravenous calcium chloride. Am J Emerg Med
13. Johnson DL, Lesoway R, Humen DP, Kustok WJ. Clinical and hemodynamic evaluation of propranolol in combination with verapamil, nifedipine, and diltiazem in exertional angina pectoris: a placebo-controlled double-blind, randomized cross-over study. Am J Cardiol
14. Kenny J, Bergman DG, Kerkez S, Jewitt DE. Beneficial effects of diltiazem combined with beta-blockade in angina pectoris. Eur Heart J
15. Kenny J, Kiff P, Holmes J, Jewitt DE. Beneficial effects of diltiazem and propranolol, alone and in combination, in patients with stable angina pectoris. Br Heart J
16. Leon MB, Rosing DR, Bonow, Epstein SE. Combination therapy with calcium-channel blockers and beta-blockers for chronic stable angina pectoris. Am J Cardiol
17. Strauss WE, Parisi AF. Superiority of combined diltiazem and propranolol therapy for angina pectoris. Circulation
18. Strauss WE, Egan T, McIntyre KM, Parisi AF. Combination therapy with diltiazem and propranolol: precipitation of congestive heart failure. Clin Cardiol
19. Winniford MD, Fulton KL, Hillis LD. Symptomatic sinus bradycardia during concomitant propranolol-verapamil administration. Am Heart J
20. Humen DP, O'Brien P, Purves P, et al. Effort angina with adequate beta-receptor blockade: comparison with diltiazem alone and in combination. J Am Coll Cardiol
21. Oesterle SN, Alderman EL, Beier-Scott L, et al. Diltiazem and propranolol in combination: hemodynamic effects following acute intravenous administration. Am Heart J
22. Misra M, Thakur R, Bhandari K. Sinus arrest caused by atenolol-verapamil combination. Clin Cardiol
23. O'Hara MJ, Khurmi NS, Bowles MJ, Raftery EB. Diltiazem and propranolol combination as the treatment of choice in stable angina pectoris. Clin Cardiol
24. Strauss WE, Parisi AF. Combined use of calcium-channel and beta-adrenergic blockers for the treatment of chronic stable angina: rationale, efficacy, and adverse effects. Ann Intern Med
25. Packer M. Combined beta-adrenergic and calcium-entry blockade in angina pectoris. N Engl J Med
26. Sagie A, Strasberg B, Kusnieck J, Sclarovsky S. Symptomatic bradycardia induced by the combination of oral diltiazem and beta-blockers. Clin Cardiol
27. Fleckenstein A. Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Annu Rev Pharmacol Toxicol
28. Kohlhardt M, Fleckenstein A. Inhibition of the slow inward current by nifedipine in mammalian ventricular myocardium. Naunyn Schmiedebergs Arch Pharmacol
29. Nayler WG, Chipperfield D, Lowe TE. The negative inotropic effects of adrenergic beta-receptor-blocking drugs on human heart muscle. Cardiovasc Res
30. White R, Shinebourne E. The interaction of sympathetic stimulation and blockade on calcium uptake of the sarcoplasmic reticulum. Cardiovasc Res
31. Kostuk WJ, Pflugfelder PW. Comparative effects of calcium entry blocking drugs, beta-blocking drugs, and their combination in patients with chronic stable angina. Circulation
32. Hassell AB, Creamer JE. Profound bradycardia after addition of diltiazem to a beta-blocker. Br Med J
33. Lamaison D, Vacher D, Berenfeld A, et al. Combination of slow release diltiazem and beta-blocker in arterial hypertension: 2 cases of cardiogenic shock with severe bradycardia. Therapie
34. Morse JR. Comparison of combination nifedipine-propranolol and diltiazem-propranolol with high-dose diltiazem monotherapy for stable angina pectoris. Am J Cardiol
35. Subramanian B, Bowles MJ, Davies AB, Raftery EB. Combined therapy with verapamil and propranolol in chronic stable angina. Am J Cardiol
36. Seabra-Gomes R, Rickards A, Sutton R. Hemodynamic effects of verapamil and practolol in man. Eur J Cardiol
37. Angus JA, Richmond DR, Dhumma-Upakorn P, et al. Cardiovascular action of verapamil in the dog with particular reference to myocardial contractility and atrioventricular conduction. Cardiovasc Res
38. Chew CY, Hecht HS, Collett JT, et al. Influence of severity of ventricular dysfunction on hemodynamic responses to intravenously administered verapamil in ischemic heart disease. Am J Cardiol