Effects of Diltiazem, Metoprolol, Enalapril and Hydrochlorothiazide on Frequency of

Ventricular Premature Complexes Vasilios Papademetriou, MD, Puneet Narayan, MD, and Peter Kokkinos, PhD

Ventricular Mythmias occur frequently in pa tients with hypertensive left ventricular (LV) hy- pertmphy 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 dilti- azem and metoprolol significantly reduce VPCs.

(Am J Cardiol l-73242-245)

From the Department of Veterans Affairs Medical Center and George- town 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 accept- ed 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.

S everal studies have demonstrated that left ventricu- lar (LV) hypertrophy on the electrocardiogram*~2 or the echocardiogram3,4 is an ominous harbinger

of increased cardiovascular complications including sud- den death. Increased prevalence of frequent and com- plex ventricular arrhythmias has been demonstrated in hypertensive patients with LV hypertrophy,5-7 but their prognostic significance has not been clarified. In other subgroups, however, such as those with hypertrophic cardiomyopathy8,g ischemic heart diseaselo and LV hypertrophy associated with aortic valve disease,” ar- rhythmias have been shown to predict subsequent mortality. Because the prognostic significance of nonsus- tained ventricular arrhythmias in hypertensive patients has not yet been defined, treatment with currently avail- able antiarrhythmic agents is not indicated. It is desir- able, however, particularly in symptomatic patients with arrhythmias, to administer antihypertensive agents that may suppress or reduce ventricular ectopy and improve symptoms. In patients with hypertensive LV hypertrophy and arrhythmias there are only limited data assessing the effect of frequently used antihypertensive agents on car- diac arrhythmias. However, no study exists comparing the efficacy of several antihypertensive agents in a well- defined hypertensive population with LV hypertrophy.

This study was designed to assess the effect of 4 fre- quently used antihypertensive agents on ventricular ar- rhythmias in patients with moderate to severe LV hy- pertrophy demonstrated by echocardiography.

METHODS Patients with mild to moderate hypertension (dia-

stolic blood pressure 90 to 114 mm 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, an- gina pectoris, congestive heart failure, atria1 fibrillation, bundle branch block on the electrocardiogram, renal in- sufficiency (creatinine level 22.0 mg/dl), other clinically important chronic disease or inability to give informed consent were excluded from the study.

Of 55 patients screened 36 qualified for the study. Of these, 5 patients were excluded because of various rea- sons, such as poor compliance, failure to attend clinic visits, or because they refused participation in the study.

Consenting patients underwent the following evalua- tions: complete history and physical examination, chest roentgenography, 2-dimensional and M-mode echocar- diography, electrocardiography, complete blood count and blood chemistry.

242 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 FEBRUARY 1,1994

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 pressure was followed up weekly and pa- tients developing diastolic blood pressure 2115 mm Hg were treated and excluded from the study. At the end of the placebo period the following data were collected: se- rum electrolytes, blood urea nitrogen, creatinine, plasma lipids, electrocardiogram, 2-dimensional and M-mode echocardiograms and 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 dia- stolic blood pressure remained 290 mm Hg; diltiazem 120 mg/day, increased to 240 mg if diastolic blood pres- sure was 290 mm Hg; enalapril 10 mg, increased to 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 treatment the following data were collected: 48-hour Holter monitoring, sitting blood pressure and heart rate, and serum electrolytes and chemistries. The sequence of drug therapies was deter- mined 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 echocardiograms were recorded from standard paraster- nal and apical windows using a commercially available echocardiograph (Hewlett Packard-500). M-mode echo- cardiograms were recorded on strip-chart paper at a speed of 50 mm/s and measurements were determined according to the recommendations of the American So- ciety of Echocardiography. l2 AI1 echocardiograms were recorded and measurements obtained by an observer un- aware of subjects’ clinical data. M-mode echocardio- grams 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 Couplets VT Episodes

Placebo 580 f 1,215 6 t 20 0.4 k 1 Diltiazem 204 f 488* 329 0.2 + 0.3 Metoprolol 281 f 579t 4 2 13 0.2 + 0.4 Enalapril 549 ” 1,521 12 + 62 0.8 2 4 HCTZ 614 k 1,423 125 0.4 r 1.2

l p <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 Am- bulatory electrocardiographic monitoring 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 (Space Labs 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 tapes were an- alyzed by a second technician without knowledge of pa- tients’ clinical status. Interobserver variability of ~10% was found in premature beats, and a difference of ~3% was seen in couplets and ventricular tachycardia epi- sodes.

Statistical analysis of the results was performed us- ing stepwise regression analysis of variance and Stu- dent’s paired t test. The study was approved by the Re- search 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 echocardio- graphic LV hypertrophy with an average septal thickness

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;

Diastolic BP

110

88

66

44

22

0

ARRHYTHMIAS IN LEFT VENTRICULAR HYPERTROPHY 243

of 15.8 f 2 mm, a posterior wall thickness of 14.7 f 1.4 EfiWtitreabnentonmwAt mm and LV mass index of 207 f 48 g/m2. Of these pa- baseline (at the end of the placebo phase), ventricular tients 23 met electrocardiographic criteria for LV hy- ectopy was not infrequent in this patient population. The pert@v. average number of VPCs per 24 hours was 580 + 1,215

mBctdmabnBntonbkmd m At baseline, (mean + SD) and the average number of couplets and systolic and diastolic blood pressures were 166 Z!Z 18 and ventricular tachycardia episodes per 24 hours was 6 f 102 + 6 mm Hg, respectively. To achieve goal blood 20 and 0.4 f 1, respectively (Table I). Diltiazem and pressure 11 patients required the high dose of diltiazem, metoprolol therapy resulted in a 65 and 52% decrease 3 needed the high dose of metoprolol and enalapril and in ventricular premature complexes (VPCs) (p <0.05), 6 required the high dose of hydrochlorothiazide. Results (p = 0.07), respectively (Figure 2). Enalapril and hy- of treatment on blood pressure are shown in Figure 1. drochlorothiazide therapies resulted in no significant Blood pressure changes from baseline were statistically change. Couplets and ventricular tachycardia episodes significant for all 4 regimens. There was no significant decreased with diltiazem and metoprolol but differences difference between regimens. did not reach statistical significance.

TABLE II Ventricular Arrhythmias in Patients with > 5 VPCs/Hour at Baseline (n = 12) .

VPCS Couplets VT Episodes

Placebo 1,468 f 1,619 14 r 32 0.8 k 2 Diltiazem 501 t 623* 6 + 15 0.3 k 0.5 Metoprolol 500 k 797* 9 + 20 0.3 + 0.6 Enalapril 1,118 2 2,251 29 + 99 227 HCTZ 1,378 2 2,093 3k8 122

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

Of the 31 patients who completed this study, 12 had 25 VPCs/hour on the baseline recording. The effect of treatment on arrhythmias in these patients is summarized in Table II. In these patients both diltiazem and meto- pro101 resulted in a 66% (p co.05 for both drugs) re- duction in VPCs, whereas enalapril and hydrochloro- thiazide had no effect (Figure 3).

DISCUSSION This is the lirst report that compares the effect of 4

classes of antihypertensive regimens on ventricular ar- rhythmias in hypertensive patients with moderate to se- vere LV hypertrophy. Results indicate that the calcium

PVCY24hr. All patients (n=$l)

620

465 FIGURE 2. Changes in premature ventdo ular complexes (PVC). *p 40.05; **p q

0.07; other abbreviations as in Figure 1.

PVCl24hr Patients with r5 PVC/hr (n=12)

1,600

1,200

600

400

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

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 enala- pril and hydrochlorothiazide had no significant effect.

In experimental animals calcium antagonists, espe- cially verapamil and diltiazem, have been shown to pos- sess important antiarrhythmic properties, and to protect against lethal ventricular arrhythmias.14J5 Clinical ex- perience, however, with these agents has been rather dis- appointing. Wellens et all6 reported that verapamil failed to prevent reentry ventricular tachycardia and was inef- fective in preventing arrhythmias induced by pro- grammed 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 arrhyth- mias.‘s In hypertensive patients with mild LV hypertro- phy, Messerli et al l9 found that 6-month therapy with calcium antagonists resulted in significant decrease in ar- rhythmias. This effect was attributed to the concomitant decrease in LV mass. In our study, a decrease in ar- rhythmias 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 cardiovascu- lar morbidity and mortality and to protect against sud- den deam20 In patients who have had myocardial infarc- tion, B blockers reduce ventricular ectopy,21 but 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 com- plex arrhythmias benefited from propranolol to the same extent as those without arrhythmias.22 In our study metoprolol decreased VPCs by >50% in hypertensive patients with moderate to severe LV 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 extensive- ly studied both in experimental animals and humans. In animal studies, angiotensin-converting enzyme inhibitors greatly reduced reperfusion arrhythmias, suppressed in- ducibility by programmed electrical stimulation and im- proved several electrophysiologic variables.

Relevant studies in humans using angiotensin-con- vetting enzyme inhibitors have been mostly performed in patients with stable congestive heart failure. In 1 study23 enalapril was evaluated in 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 suggested that angiotensin-converting enzyme inhibitor therapy can re- duce VPCs by 50 to 90%. 24,25 Two other studies, how- ever, in similar patient populations using captopril failed to demonstrate any improvement in ventricular arrhyth- mias.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. Al- though some studies indicated worsening of arrhythmias with diuretic therapy and hypokalemia,28 the majority of the published trials revealed no change or a trend toward improvement.29,30 Although there are limited data as- sessing the effect of diuretic drugs in patients with LV hypertrophy, data in patients with advanced LV hyper- trophy are lacking. The present study demonstrated that diuretic therapy did not increase cardiac arrhythmias in patients with moderate to severe LV hypertrophy, thus extending previous observations to this subgroup of pa- tients.

Clinical implicatii Nonsustained ventricular ar- rhythmias have been identified as grave prognostic indi- cators in post-myocardial infarction patients, patients with hypertrophic cardiomyopathies, dilated cardiomy- opathy and other patient subgroups with 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 severe LV hypertrophy, the prognostic significance of nonsustained ventricular arrhythmias has not been clarified. Results of this study suggest that metoprolol and diltiazem can be used in these patients to achieve blood pressure control and suppression of ventricular ectopy.

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