Effects of diltiazem, metoprolol, enalapril and hydrochlorothiazide on frequency of ventricular premature complexes

Effects of Diltiazem, Metoprolol, Enalapril and Hydrochlorothiazide on Frequency of Ventricular Premature Complexes Vasilios Papademetriou,

MD, Puneet Narayan, MD, and Peter Kokkinos, PhD

everal studies have demonstratedthat left ventricular (LV) hypertrophy on the electrocardiogram*~2 or the echocardiogram3,4is an ominous harbinger of increasedcardiovascularcomplications including sudden death. Increased prevalence of frequent and complex ventricular arrhythmias has been demonstratedin hypertensive patients with LV hypertrophy,5-7but their prognostic significance has not been clarified. In other subgroups, however, such as those with hypertrophic cardiomyopathy8,g ischemic heart diseaselo and LV hypertrophy associatedwith aortic valve disease,” arrhythmias have been shown to predict subsequent mortality. Becausethe prognostic significance of nonsustained ventricular arrhythmias in hypertensive patients has not yet been defined, treatment with currently available antiarrhythmic agents is not indicated. It is desirable, however, particularly in symptomatic patients with arrhythmias, to administer antihypertensive agents that may suppressor reduce ventricular ectopy and improve symptoms.In patients with hypertensiveLV hypertrophy and arrhythmias there are only limited data assessingthe effect of frequently used antihypertensive agents on cardiac arrhythmias. However, no study exists comparing the efficacy of several antihypertensive agentsin a welldefined hypertensive population with LV hypertrophy. This study was designedto assessthe effect of 4 frequently used antihypertensive agents on ventricular arrhythmias in patients with moderate to severe LV hypertrophy demonstratedby echocardiography.

S

Ventricular Mythmias occur frequently in pa tients with hypertensive left ventricular (LV) hypertmphy and have been associated with in creased iece of sudden death. In this study, the efFect of various antihypertensive mediw tions on ventricular anhythmias was evaluated in 31 hypertensive patients with moderate to severe LV hypertrophy. Patients were assessed at base line (after 3 weeks of placebo treatment) and after treatment with each of 4 monotherapies: diC tiazem 120 or 240 mg/day, metoprolol 100 or 200 mg,/day, enalaprill0 or 20 mg/day and hydm chlorothiazide 50 or 100 mg/day. Each drug ther apy was administered for 4 weeks. The sequence of each treatment was determined at random. Echocardiographic measurements and electrocalc diograms were obtained only at baseline. Bie chemical measurements and 48-hour Halter monk toring were obtained at baseline and at the end of each treatment. All treatments resulted in a significant but similar decrease in blood pressure. In the group as a whole diltiazem B V~R tricular premature complexes (VPCs) by 65% (p <0.05) and metoprolol by 52% (p = 0.07). Enalapril and hydrochlorothiazkle had no effect. In 12 pa tients with 25 WCs/hour at baseline, diRiazem and metoprolol decreased WCs by 55% (p eO.05). It is concluded that in hypertensive patients with moderate to severe LV hypeWophy, both diltiazem and metoprolol significantly reduce VPCs. (Am J Cardiol l-73242-245)

METHODS

From the Department of Veterans Affairs Medical Center and Georgetown University, Washington, D.C. This work was supported in part by a grant from CIBA-GEIGY, Summit, New Jersey. Manuscript received June 4, 1993; revised manuscript received August 2, 1993, and accepted August 3. Address for reprints: Vasilios Papademehiou, MD, Department of Veterans Affairs Medical Center, Hypertension Research (151E). 50 Irving Street, N.W., Washington, D.C. 20422.

242

THE AMERICANJOURNALOF CARDIOLOGY VOLUME73

Patients with mild to moderate hypertension (diastolic blood pressure 90 to 114mm Hg) and moderate to severe echocardiographic LV hypertrophy (posterior wall thickness 214 mm Hg) were eligible for the study. Patients with a history of myocardial infarction, angina pectoris, congestive heart failure, atria1 fibrillation, bundle branch block on the electrocardiogram,renal insufficiency (creatinine level 22.0 mg/dl), other clinically important chronic diseaseor inability to give informed consent were excluded from the study. Of 55 patients screened36 qualified for the study. Of these, 5 patients were excluded becauseof various reasons, such as poor compliance, failure to attend clinic visits, or becausethey refused participation in the study. Consenting patients underwent the following evaluations: complete history and physical examination, chest roentgenography,2-dimensional and M-mode echocardiography, electrocardiography, complete blood count and blood chemistry.

FEBRUARY1,1994

Baseline evaluation: After eligibility for the study was determined, all drugs were tapered gradually and discontinued. Patients were then given placebo for 3 weeks. Blood pressurewas followed up weekly and patients developing diastolic blood pressure 2115mm Hg were treated and excluded from the study. At the end of the placebo period the following data were collected: serum electrolytes, blood urea nitrogen, creatinine, plasma lipids, electrocardiogram, 2-dimensional and M-mode echocardiogramsand 48-hour Holter monitoring. Sitting blood pressure and heart rate were determined 3 times and the average calculated. Treatment phase: All patients underwent sequential treatment with the following 4 regimens: metoprolol 100 mg./day for 2 weeks, increased to 200 mg/day if diastolic blood pressure remained 290 mm Hg; diltiazem 120 mg/day, increasedto 240 mg if diastolic blood pressure was 290 mm Hg; enalapril 10 mg, increasedto 20 mg/day; and hydrochlorothiazide 50 mg, increased to 100 mg/day if diastolic blood pressure remained 290 mm Hg. Each treatment was given for 4 weeks. Goal blood pressure of 190 mm Hg and 2.5 mm lower than the patient’s baseline with the high dose was acceptable. No patient was replaced for not achieving goal blood pressure.At the end of each treatmentthe following data were collected: 48-hour Holter monitoring, sitting blood pressure and heart rate, and serum electrolytes and chemistries. The sequenceof drug therapies was determined using the Latin square randomization method. Treatments were coded and codes kept by the research pharmacist.The treating physician and the patients were unaware of the type of treatment. Echocardiography: Two-dimensional and M-mode echocardiogramswere recorded from standard parasternal and apical windows using a commercially available echocardiograph (Hewlett Packard-500).M-mode echocardiograms were recorded on strip-chart paper at a speed of 50 mm/s and measurementswere determined according to the recommendationsof the American Society of Echocardiography.l2 AI1 echocardiogramswere recorded and measurementsobtained by an observer unaware of subjects’ clinical data. M-mode echocardiograms were accepted only if 2-dimensional evaluation had revealed normal LV function. LV mass (LVM) was calculated using the Devereux formula13: LVM (g) =

TABLE I Changes in Ventricular Arrhythmias with Antihypertensive Therapy (n = 31) VPCS Placebo Diltiazem Metoprolol

580 f 1,215 204 f 488*

Enalapril

281 549

f ”

579t 1,521

HCTZ

614

k

1,423

Couplets

6 t 20 329 4 2 13 12 + 62 125

VT Episodes

0.4 0.2 0.2 0.8 0.4

k + + 2 r

1 0.3 0.4 4 1.2

lp

<0.05; tp = 0.07 (drugvsplacebo). Results represent mean t SD/24 hours. Recordings were obtained for 2 consecubve 24.hour periods in each phase. HCTZ = hydrochlorothiazide; VPCs = ventricular premature complexes; VT = ventricular tachycardia (2 3 consecutive ventricular complexes).

1.04([LVDD + IVS + PWT13- [LVDD13- 13.6),where LVDD = LV diastolic dimension, IVS = intraventricular septum, and PWT = posterior wall thickness. mVW0W-w Ambulatory electrocardiographicmonitoring was performed for 48 hours during each phase.Each patient underwent 48-hour monitoring 5 times (1 taking placebo and the others at the end of each drug therapy). Monitoring was performed using a double-channel recorder (SpaceLabs model 90205, Haddonfield, New Jersey) and analysis was performed on a 2-channel cardioscanner (model MK3 Cardiodata Corp., Marlboro, Massachusetts). Analysis of all tapes was performed by an experienced technician. For quality control, 10%of all tapeswere analyzed by a secondtechnician without knowledge of patients’ clinical status. Interobserver variability of ~10% was found in premature beats, and a difference of ~3% was seen in couplets and ventricular tachycardia episodes. Statistical analysis of the results was performed using stepwise regression analysis of variance and Student’s paired t test. The study was approved by the Research and Development Committee at the Department of Veterans Affairs Medical Center, Washington, D.C. RESULTS

At baseline, all patients in the study had mild to moderate hypertension, normal serum potassium and magnesium levels, and normal renal function. By study design all patients had moderate to severe echocardiographic LV hypertrophy with an averageseptal thickness

Diastolic BP 110 FBBIJBE l. Blood pressure (BP) mqmnse to asive tmatmmt. The p values -W--~~WithplacelDo (P). There were no statmeAly signtRcant difbmm%betwwnd~Datapresented aremeanzkBD.D=diItiazem;E=enalqnil;

88 66 44 22 0

ARRHYTHMIAS IN LEFTVENTRICULARHYPERTROPHY 243

of 15.8 f 2 mm, a posterior wall thickness of 14.7f 1.4 mm and LV mass index of 207 f 48 g/m2. Of these patients 23 met electrocardiographic criteria for LV hypert@v. mBctdmabnBntonbkmd m At baseline, systolic and diastolic blood pressureswere 166 Z!Z18 and 102 + 6 mm Hg, respectively. To achieve goal blood pressure 11 patients required the high dose of diltiazem, 3 needed the high dose of metoprolol and enalapril and 6 required the high dose of hydrochlorothiazide. Results of treatment on blood pressure are shown in Figure 1. Blood pressure changesfrom baseline were statistically significant for all 4 regimens. There was no significant difference between regimens.

TABLE II Ventricular Arrhythmias in Patients with > 5 VPCs/Hour at Baseline (n = 12) . VPCS Placebo Diltiazem Metoprolol Enalapril HCTZ

1,468 501 500 1,118 1,378

f t k 2 2

Couplets

1,619 623* 797* 2,251 2,093

14 r 6 + 9 + 29 + 3k8

32 15 20 99

VT Episodes 0.8 k 2 0.3 k 0.5 0.3 + 0.6 227 122

*p <0.05. Data represent mean 2 SD/24-hour recordings. Abbreviabons as I” Table I.

PVCY24hr.

EfiWtitreabnentonmwAt baseline (at the end of the placebo phase), ventricular ectopy was not infrequent in this patient population. The averagenumber of VPCs per 24 hours was 580 + 1,215 (mean + SD) and the average number of couplets and ventricular tachycardia episodes per 24 hours was 6 f 20 and 0.4 f 1, respectively (Table I). Diltiazem and metoprolol therapy resulted in a 65 and 52% decrease in ventricular premature complexes (VPCs) (p <0.05), (p = 0.07), respectively (Figure 2). Enalapril and hydrochlorothiazide therapies resulted in no significant change. Couplets and ventricular tachycardia episodes decreasedwith diltiazem and metoprolol but differences did not reach statistical significance. Of the 31 patients who completed this study, 12 had 25 VPCs/hour on the baseline recording. The effect of treatmenton arrhythmias in thesepatients is summarized in Table II. In these patients both diltiazem and metopro101resulted in a 66% (p co.05 for both drugs) reduction in VPCs, whereas enalapril and hydrochlorothiazide had no effect (Figure 3). DISCUSSION

This is the lirst report that comparesthe effect of 4 classesof antihypertensive regimens on ventricular arrhythmias in hypertensive patients with moderate to severe LV hypertrophy. Results indicate that the calcium

All patients (n=$l)

620 465

PVCl24hr

FIGURE 2. Changes in premature ventdo ular complexes (PVC). *p 40.05; **p q 0.07; other abbreviations as in Figure 1.

Patients with r5 PVC/hr (n=12)

1,600 1,200

FIBURE 3. Changes in premature ve4Rrio ular conlplexes (PVC). *p <0.05; other &bmviations as in Figure 1.

600 400

244

THE AMERICAN JOURNAL OF CARDIOLOGY

VOLUME 73

FEBRUARY 1,1994

antagonist diltiazem and the B blocker metoprolol caused a significant reduction in VPCs, whereas enalapril and hydrochlorothiazide had no significant effect. In experimental animals calcium antagonists, especially verapamil and diltiazem, have been shown to possessimportant antiarrhythmic properties, and to protect against lethal ventricular arrhythmias.14J5Clinical experience, however, with these agentshas been rather disappointing. Wellens et all6 reported that verapamil failed to prevent reentry ventricular tachycardia and was ineffective in preventing arrhythmias induced by programmed electrical stimulation. Sung et alI7 concluded that verapamil is effective only in arrhythmias resulting from triggered activity. There are only limited studies examining the an&rhythmic properties of diltiazem in humans. In the Multicenter Diltiazem Post-Infarction Trial, diltiazem failed to reduce ventricular arrhythmias.‘s In hypertensive patients with mild LV hypertrophy, Messerli et al l9 found that 6-month therapy with calcium antagonistsresulted in significant decreasein arrhythmias. This effect was attributed to the concomitant decrease in LV mass. In our study, a decreasein arrhythmias was noted after 4 weeks of therapy, and it is unlikely that LV hypertrophy regression had occurred in such a brief period of time. In patients after myocardial infarction, B blockers have conclusively been shown to improve cardiovascular morbidity and mortality and to protect against sudden deam20In patients who have had myocardial infarction, B blockers reduce ventricular ectopy,21but it is questionable whether this antiectopic effect is essential in prophylaxis against sudden death. For example in the Beta-Blocker Heart Attack Trial careful examination of the population enrolled revealed that patients with complex arrhythmias benefited from propranolol to the same extent as those without arrhythmias.22 In our study metoprolol decreasedVPCs by >50% in hypertensive patients with moderate to severeLV hypertrophy and 5 VPCs/hour on baseline Holter monitoring. Whether this effect is meaningful in protecting against sudden death in these patients cannot be determined from the present study. The role of angiotensin-converting enzyme inhibitors in reducing ventricular arrhythmias has been extensively studied both in experimental animals and humans. In animal studies, angiotensin-convertingenzyme inhibitors greatly reduced reperfusion arrhythmias, suppressedinducibility by programmed electrical stimulation and improved several electrophysiologic variables. Relevant studies in humans using angiotensin-convetting enzyme inhibitors have been mostly performed in patients with stable congestive heart failure. In 1 study23enalapril was evaluatedin 33 stable patients with ejection fraction ~35%. Enalapril therapy resulted in a significant reduction of VPCs, couplets and short runs of ventricular tachycardia. Other studies suggestedthat angiotensin-converting enzyme inhibitor therapy can reduce VPCs by 50 to 90%.24,25Two other studies, however, in similar patient populations using captopril failed to demonstrateany improvement in ventricular arrhythmias.26,27 In the present study enalapril had no effect on ventricular arrhythmias in the population tested.

The effects of diuretic drugs have been extensively studied in patients with uncomplicated hypertension. Although some studies indicated worsening of arrhythmias with diuretic therapy and hypokalemia,28the majority of the published trials revealedno changeor a trend toward improvement.29,30Although there are limited data assessing the effect of diuretic drugs in patients with LV hypertrophy, data in patients with advanced LV hypertrophy are lacking. The present study demonstratedthat diuretic therapy did not increase cardiac arrhythmias in patients with moderate to severe LV hypertrophy, thus extending previous observations to this subgroup of patients. Clinical implicatii Nonsustained ventricular arrhythmias have been identified as grave prognostic indicators in post-myocardial infarction patients, patients with hypertrophic cardiomyopathies, dilated cardiomyopathy and other patient subgroupswith cardiac disease. On the other hand, in patients with normal hearts,VPCs, couplets or short runs of ventricular tachycardia have been shown to have no effect on prognosis. In hypertensive patients with moderate to severeLV hypertrophy, the prognostic significance of nonsustained ventricular arrhythmias has not been clarified. Results of this study suggestthat metoprolol and diltiazem can be used in these patients to achieve blood pressurecontrol and suppressionof ventricular ectopy. 1. Kannel WB, Gordon T, Castelli WP, Mergolis JR. Electrocardiographic left ventricular hypetrophy and risk of coronary heart disease: the Framingham Study. Ann Intern Med 1970;72:813-822. 2. Kannel WB, Dannenberg AL, Levy D. Population implications of electrocardiographic left ventricular hypatmphy. Am J Cardiol 1987;60:851-931. 3. Castle PN, Devereux RB, Milner M, Zullo G, Harshfield GA, Pickering TG, Laragh JH. Value of echocardiographic meawrements of left venhicular mass in predicting cardiovascular morbid events in hypertensive men. Ann Intern Med 1986; 105:173-178. 4. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart SNdy. IV En~l J Med 1990;322:1561-1566. 5. Messerli FH, Ventura HO, Elizardi DJ, Dunn FG, Frohlich ED. Hypertension and sudden death: increased ventricular ectopic activity in left ventricular hertrophy. Am .I Med 1984;77:18-22. 6. McLenachan JM, Henderson E, Morris Kl, Dxgie HJ. Ventricular arrhythmias in patients with hypertensive left ventricular hypettrophy. N Engl J Med 1987;317: 787-792. 7. Papademeuiou V, Price M, Notargiacomo A, Gottdiener J, Fletcher RD, Freis ED. Effect of diuretic therapy on ventticular arrhythmias in hypertensive patients with or without left ventricular hypertrophy. Am Hearr J 1985; 110:59>599. 8. McKenna WJ, England D, Doi YL, Deanfield JE, Oakley C, Goodwin JF. Arrhythmia in hypatrophic cardiomyopathy. 1. Influence on prognosis. Br Heart J 1981:46:16&172. 9. Maron BJ, Savage DD, Wolfson JK, Epstein SE. Prognostic significance of 24 hour ambulatory electrocardiographic monitoring in patients with hypettrophic cardiomyopathy: a prospective study. Am J Cardiol 1981;48:252-257. 10. Rubaman W, Weinblatt E, Goldberg JD, Frank CW, Shapiro S. Ventricular premature beats and mortality after myocardial infarction. N En@ J Med 1977297: 75cL7-757. 11. Olshausen K, Schawrz F, Apfelbxk J, Rohrig N, Kramer B, Kubler W. Determinants of the incidence and severity of ventricular arrhythmias in aortic valve disease. Am J Cardiol 1983;51:1103-1109. 12. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic mea197&58x1072-1083. surements. Circulation 13. Devereux RB, Liebson PR, Horan HJ. Recommendations concerning use of echocardiography in hypertension and general population research. Hypertension 1987;9(suppl ll):97-104. 14. Billman GE, Hoskin RS. Cocaine-induced ventricular fibrillation: protection afforded by the calcium antagonist verapamil. FASEB J 1988;2:2m5. 16. Anastasiou-Nana M, Anderson JL, Nanas J. Experimental antifibrillatory cf. fats of calcium channel blockade with diltiazem. Comparison with B-blockade and nitroglycerin. J Cardiovasc Phormocol 1984;6:78l&787. 16. Wellens HJJ, Tan SL, Bar FWH, Duren DR. Lie KI, Dohmen HM. Effect of

ARRHYTHMIASIN LEFTVENTRICULARHYPERTROPHY 245

verapamil studied by programmed electtical stimulation of the heart in patients with paroxysmal reentrant supraventricular tachycardia. Br Heart J 1977;39:1059-1066. 17. Sung RJ, Sharpiro WA, Shen EN, Morady F, Davis J. Effects of verapamil on ventricular tachycardia possibly caused by reentry, automaticity and triggered activity. J C/in Inwst 1983:72:3X&360. 19. The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfaction after myocardial infarction. N Engl Med 1988;319:38.%392. 19. Messerli FH, Nunez BD, Nunez MM, Garavaglia GE, Schmieder RE, Ventura HO. Disparate effects of calcium enhy blocker and diuretic therapy on cardiac arrhythmias. Arch Intern Med 1989;149:1263-1267. 20. Norwegian Multicenter Study Group. Timolol-induced reduction in mortality in patients surviving acute myccadial infarction. N Engl J Med 1981;3C!4:801-807. 21. Morganroth J. Antiarrhythmic effects of beta-adrenergic blocking agents in be nign or potentially lethal ventricular arrhythmia. Am J Cardiol 1987;60: IOc14D. 22. Friedmen L, Byington RP, Capone RJ, Furberg CD, Goldstein S, Lichstein E. Effect of propranolol in patients with myocardial infarction and ventricular arrhythmia. J Am Co/l Cardiol 1986;7:1-8. 23. Pomini G, Gribaldo R, Rugna A, Lupia M, Molfese G, Garenza P. Reduction of complex ventricular arrhythmias after enalapril treatment in patients with advanced stable heat failure. G Ital Cardiol 1991;21:59-65.

246

THE AMERICAhIJOURNALOF CARDIOLOGY VOLUME73

24. Webster MWI, Fitzpatrick A, Nicholls MG, lkram H, Wells JE. Effect of enalapril on ventricular arrhythmias in congestive heat failure. Am J Cardioi 1985; 56:566. 25. The Captopri-Digoxin Multicenter Research Group: Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heat failure. JAMA 1988;259:539. 29. Poquet F, Ferguson J, Ronlean J. The antiarrhythmic effect of the ACE inhibitor captopril in patients with congestive heart failure largely due to its potassium sparing effect. Can J Cardiol 1992;8:589-595. 27. Cocchieri G, Alunni GF, Del Favero A, Fortunati F, Bardelli G, Capponi EA. Regi L, Bosch& E. Comparative effects of ibobamine and captopril in mild congestive heart failure. Focus on the long-term effects of inodilation on ventricular anhythmias. Cardioiology 1990,77(supp1)5:3642. 28. Holland OB, Nixon JV, Kuhnen 1. Diuretic-induced ventricular ectopic activity. Am J Med 1981;70:762-168. 29. Papademetriou V, Bunis JF, Notargiacomo A, Fletcher RD. Freis ED. Thazide therapy is not a cause of arrhythmia in patients with systemic hypertension. Arch Intern Med 1988;148:1272-1276. 30. Siegel D, Hulley S, Black D, Cheitlin MD, Sebastian A, Se&y DG, Hearst N, Fine R. Diuretics, semm and intracellular electrolyte levels and ventricular arrhythmias in hypertensive men. JAMA 1992267: 1083-1089.

FEBRUARY1, 1994