Twice-daily verapamil for hypertension: A comparison with propranolol

Twice-DailyVerapamilfor Hypertension: A Comparisonwith Propranolo ROBERT S. HORNIJNG, MB, RODERICK I. JONES, MB, BRIAN A. GOULD, MD, TANSUKH SONECHA, MB, and EDWARD B. RAFTERY, MD

Recent reports have confirmed that some slow calcium channel inhibitors have useful antihypertensive properties because they produce dilatation of the peripheral arterioles without reflex tachycardia. Verapamil is such a drug, but its clinical role in the management of hypertension is not clear. An open crossover trial was performed to compare the 24hour profiles of blood pressure reduction after longterm therapy with a standard @-adrenoceptor blocker, propranolol, and verapamil. Nineteen patients were studied by continuous ambulatory intraarterial recording and the order of drug administration was determined by random allocation. The drugs were administered 2 ,times a day and titrated according to casual clinic pressures (propranolol, 40 to 240 mg 2 times a day; verapamil, 120 to 240

mg 2 times a day). Mean hourly blood pressure and heart rate values were obtained over a 24-hour cycle and the responses to isometric and dynamic exercise were also examined. The drugs produced a uniform and comparable reduction in blood pressure throughout the day, together with a reduction in heart rate, which was greater with propranolol. Comparable effects were also seen on the pressor responses to exercise. Both drugs were equally well tolerated and caused no patient withdrawals. Thus, oral verapamil given 2 times a day shows a degree of efficacy similar to that of propranolol and provides 24-hour blood pressure control. This slow calcium channel inhibitor was well tolerated and ma be used as initial therapy for hypertension. (Am J Cardiol 1986;57:93D-980)

T

he antihypertensive action of slow calcium-channel inhibitors such as verapamil and nifedipine has attracted increasing interest.1-4 They lower blood pressure primarily by reducing tone in vascular smooth muscle, which depends on the entry of calcium ions into the cell for normal contractiom5 Pressor responses to circulating smooth muscle agonists such as angiotensin II and norepinephrine may also be reducede6 These drugs can cause substantial reductions in blood pressure that can be maintained over 24 hours,7 with higher blood pressures decreasing to a proportionately greater degree than lower pressures.8 There is no reflex tachycardia with long-term treatment with nifedipine, whereas verapamil produces a modest reduction in heart rate. The slow calcium-channel inhibitors may be particularly useful when fi-adrenoceptor blocking drugs are From the Department of Cardiology and the Division of Clinical Sciences, Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex, United Kingdom, Address for reprints: Edward B. Raftery, MD, Department of Cardiology, Northwick Park Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, United Kingdom. 93D

contraindicated, as in patients with both hypertension and chronic obstructive airways disease or peripheral vascular diseases. We therefore undertook a clinical trial to compare the effects of verapamil and propran0101taken 2 times a day for essential hypertension. Our patients were studied by continuous intraarterial monitoring and were allowed to be ambulatory and sleep at home, thus providing blood pressure and heart rate “profiles” over a full 24 hours mostly away from the hospital environment. Further, we examined and compared the hemodynamic responses to both isometric and dynamic exercise before and during treatment with both drugs using a standard program of physiologic tests in the laboratory.

Methods Study design: This was an open, randomized, crossover study. A double-blind, placebo-controlled design was not believed necessary because it has been shown9 that there are no placebo effects on intraarterial blood pressure values when expressed as mean hourly values from fully ambulatory subjects. Patients were considered for inclusion in the trial if they had newly diagnosed untreated essential hyper-N

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TABLE I Supine Casual Clinic Pressure Trial of Propranolol Versus Verapamil

Pt

Untreated (Mean of 3 Readings) DBP SBP

Treated Propranolol SBP DBP

1

180

90

2 3 4 5 6 7

199 194 la7 161 156 160 190 197 177 172 161 177 170 165 175 187 la0 177.3 13.0 2.9 19

100 74 90 80 90 a0 80 a0 a0 86 a0 80 90 70 80 80 82.6 6.8 1.6 19

a 9 10 11 12 13 14 15 16 17

ia

Mean SD SE

110 160 129 130 110 150 136 154 105 148 96 130 103 130 113 130 97 140 113 150 107 130 103 124 90 132 95 40 110 140 99 128 97 130 110 120 106.8 136.6 11.3 11.1 2.6 2.5 19 19 t = 7.881 p
a0

Treated Verapamil SBP DBP 140 130 120 150 160 150 160 160 160 124 130 138 128 140 130 140 134 140 140.7 12.8 2.9 19

90

a0 70 110 100 90 90 100 70 80 90 a0 70 80 90 a0 a0 90 85.8 10.7 2.5 19

t = a.059 p
blood pressure;

SD =

tension or if they were considered to be poorly controlled on existing medication. The blood pressure criteria for acceptance were mean casual clinic readings, taken from 3 consecutive visits at least 2 weeks apart, greater than 160 mm Hg systolic or 95 mm Hg diastolic (Korotkoff phase V), using a standard mercury-in-glass sphygmomanometer. Each patient had a full clinical examination and routine laboratory tests to exclude secondary hypertension. No patient had more than grade 2 hypertensive retinopathy or a blood urea level >8 mmol/liter. Patients were excluded if they had a clinical history of heart failure, myocardial infarction within the last 6 months or any other severe concomitant illness. Before entry into the trial [marked by the date of the first intraarterial recording], any previous antihypertensive medication was withdrawn and all patients were untreated for at least 4 weeks. Each patient gave informed consent, and the trial was approved by the hospital ethical committee. The technique of ambulatory blood pressure recording used has been carried out in this hospital for over a decade.lO Serious complications have been rare. The most common problem has been minor local hematoma formation at the site of cannulation in approximately 5% of a total of 2,000 studies performed in this department. Equipment and techniques: All patients participating in the trial came to the hospital in the morning for percutaneous insertion of a l-mm external diameter Teflon@ cannula (Plastimed, Seldicath size 3Frj into

ON VERAPAMIL

the brachial artery of the nondominant arm under local anesthesia. The blood pressure signal together with the electrocardiogram from chest electrodes were recorded using a specially designed transducer/perfusion unit, and a portable analog tape recorder (Medilog Mark I, Oxford Instruments Ltd). The recorder also incorporated a time channel and event marker. The equipment was small and light and patients could perform their usual activities with only minor inconvenience. Ambulatory recording protocol: After cannulation and equipment calibration, a short program of exercise testing in the laboratory was carried out, consisting of isometric exercise using a handgrip dynamometer at 50% of the maximal voluntary contraction for 2 minutes, and dynamic exercise using a bicycle ergometer at workloads increasing from 250 to 400,700 and 1,000 kpm at 3-minute intervals. This exercise was stopped whenever requested by the patients. After 5 minutes of recovery in the supine position, the equipment was recalibrated. The patients then left the hospital, returning only for equipment checks and repeat calibrations to allow for signal drift (not >5 mm Hg), at intervals of about 12 hours. Ambulatory recordings were continued for 24 to 36 hours and the cannula was then withdrawn, hemostasis ensured and the equipment removed. Treatment schedule: Each patient was then randomly allocated to treatment with either verapamil or propranolol taken 2 times a day. Every 2 weeks casual clinic blood pressures were checked and the dosage titrated accordingly, that is, propranolol, 40 to 80 to 160 to 240 mg 2 times a day, and verapamil, 120 to 160 to 200 to 240 mg 2 times a day. When each patient’s blood pressure appeared to be optimally controlled and stable (target less than 140/90 mm Hg, usually after 2 to 3 months’ therapy), a second intraarterial recording was performed exactly as before. They were then asked to stop all medication for the next 4 weeks, and then crossed over to the alternative regimen. This was followed by clinic visits and dose titration every 2 weeks as previously described. Finally, a third intraarterial recording was performed with exercise testing to complete the study. Each patient underwent the same level and duration of exercise during their physiologic tests, when intraarterial recordings were repeated. Data analysis: The tape recordings were replayed and written out using a linear direct-writing recorder (Watanabe]. This allowed assessment of the analog signal quality and editing of any artifact. Consecutive hourly mean values of blood pressure were measured using a purpose-built hybrid analog/digital computer.ll The data from all patients were pooled for each consecutive hour of the day, and pre- and post-therapy differences were assessed for statistical significance using a Student t test (%tailed) on the paired results. The recordings during isometric and dynamic exercise were computed using a digitizing program. For isometric exercise, the mean systolic and diastolic pressures over 20 beats every 30 seconds were computed and the peak response taken from these results. For dynamic exercise mean pressures over 30 beats at the end of each minute of exercise were digitized to con-

February 26, 1986

struct a time-response curve. For each test, heart rate values were extracted in the same way as blood pressure. The pre- and post-therapy differences were again assessed using a Student paired t test. Where paired data were missing because of different exercise times in the same patient, these data were omitted from the analysis and only data from patients who completed the trial, including “crossover,” i.e., had 3 intraarterial recordings, were included for analysis.

Results Nineteen patients (14 men, 5 women] entered the study. Their mean age was 49.3 years [range 25 to 64) and mean supine clinic blood pressure at the time of entry to the trial was 177 f 13/107 f 11 mm Hg (Table

MEAN DAYTIME ( 1200-i 800HRS) INTRAARTERIAL Untreated

l

. Propranolol

BP

n= 18

220 -

180-

* 9

160. *

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I). Mean duration of treatment with propranolol was 9.2 weeks (range 4 to 20) and with verapamil was 7.5 weeks (range 4 to 13). The mean dosage of propranolol was 126 mg 2 times a day and that of verapamil was 185 mg 2 times a day. Complete data were obtained from 18 patients; 1 patient’s third (verapamilj study was rejected because of a faulty cannulation. Ambulatory blood pressures: Individual intraarterial blood pressure reductions on both drugs were calculated as “mean daytime” values by averaging the mean hourly values between 1200 and 1800 hours in each study (Fig. 1). The mean daytime blood pressure values for all patients were 174 f 4.7/101 f 3.6 untreated and 139 f 5.5/80 f 3.0 during propranolol and 148 f 4.5/85 f 3.4 mm Hg during verapamil treatment. These reductions were highly significant (p
120. .

&oo.El n 80.

140.

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*

120. 139 174 L- p
60-

101 L-p
80 _J 200

MEAN DAYTIME (1200-1800HRS) Untreated

l

INTRAARTERIAL

180-

BP -s I

n= 18

4 Verapamil

L c? z $ h

140-

200.

-0

180.

s al

F 120.

+

1 Systolic

160140120-

Diastolic

loo-

80 60 -

5 loo-*

160-

40 -J

* 80-

1401201

*

174 148 L- p
601

a-i 101 L-- p
FIGURE 1. Individual mean daytime (1200 to 1800 hours) systolic and diastolic blood pressures (BP) untreated and during propranolol treatment (fop) and untreated and during verapamil treatment (bOffOn7).

~~III~IIIIIIII~IIIIIIIII~ 12 14 16 18 20 22 24 2

4

6

8 10 12

Time of day (hours) 4 Untreated 0 Propranolol A Verapamil FIGURE 2. Circadian variation of heart rate and systolic and diastolic blood pressures according to Ureatment regimen.

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TABLE II Reductions of Intraarterial Isometric Exercise (handgrip)

IN HYPERTENSION-FOCUS

Blood Pressure at Peak of

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TABLE Ill Reductions of Intraarterial Blood Pressure at the Eighth Minute of Dynamic Exercise (bicycle ergometer)

Pt

Untreated

Propranolol

Verapamil

Pt

Untreated

Propranolol

Verapamil

7 2 3 4 5 6 7 6 9 10 77 12 13 14 Mean so

2771756 2741123 2571765 173188 2291142 240/126 2231722 778/706 2781727 174/703 772193 189/707 208/173 227/775 212/720 33122

164197 201/717 184/112 765187 183/l 72 230/722 273/709 145184 798/708 750/99 174190 278l714 163188 790/709 184l103 26112
203/729 737/63 2281143 175196 274/121 157190 164197 131176 195/109 165195 754165 167/701 767169 198/104 776/707 26179
1 2 3 7 9 10 11 12 73 74 Mean SD

297/731 266/134 217167 247/l 16 275/l 18 217/718 797/715 273/704 234/720 257/126 2341117 f30/14

277/706 161/709 271/716 201/95 164/700 190/102 76319 7 784/98 193/96 790/102 797/704 f76/70
2411128 2371729 243/707 773186 169/66 206/703 168160 206/95 203/96 799/708 206/705 f29/76
P Difference between pre-exercise 34122 Mean (n = 14) f87/27 SD P NS = not significant;

and peak exercise 47/27 f20173 NS, NS

blood pressures: 34/22 f 1419 NS, NS

SD = standard deviation.

the circadian curve of blood pressure as derived from mean hourly values over a 24-hour cycle, but both drugs achieved significant reductions in blood pressure consistently throughout the day and night (p
P SD = standard devia$on.

the bicycle ergometer, when 10 patients were still exercising, was 234 f 30/117 f 14 mm Hg, which was reduced to 191 f 16/104 f 10 mm Hg during proprano101(p
Discussion The choice of treatment for hypertension has widened considerably since the introduction of slow calcium channel inhibitors. Their mode of action in reducing vascular smooth muscle tone and thus peripheral resistance makes these drugs potentially useful in the treatment of all grades of hypertension as well as for hypertensive emergencies.12J3 We compared the effects of long-term therapy with verapamil and propranolol, and by focusing on their 24-hour profiles of action, also provided information about the optimal frequency of oral dosage, which is not well defined for verapamil. Ambulatory blood pressure changes over 24 hours: Both drugs when administered twice daily cause substantial and uniform reductions in blood pressure, with no appreciable change in the circadian pattern

February 26, 1986

(Fig. 2). A slightly greater effect was seen with propranolol, but this only achieved statistical significance for 2 hours during the day; otherwise, the efficacy of the 2 drugs was comparable, The consistent reduction in blood pressure throughout the day and night observed with propranolol was an interesting finding. Previous studies of atenolol14 and pindolol,15J6 using the same methods, have shown that these P-adrenoceptor blocking drugs were effective in reducing ambulatory blood pressure during the day but not at night or during the early morning. Changing the time of drug administration of atenolol from morning to evening and the frequency of dosage of pindolol from once to 2 times a day did not alter the profiles of action. In contrast, metoprolo12 times a day provided a consistent reduction in blood pressure over 24 hours.17 Such differences in the behavior of P-adrenoceptor blockers with respect to 24-hour blood pressure control are not fully understood. The results are not related to pretreatment levels of blood pressure, daytime activity or sleep patterns. The different profiles of action may represent individual variation in response to these drugs within patient groups or may even be an indicator of different modes of action in hypertensive subjects. In this study we have shown that a 12-hourly dosage regimen with verapamil (120 to 240 mg 2 times a day] was sufficient to provide continuous control of blood pressure over 24 hours. These results are consistent with reports that repeated oral administration of the drug may prolong the elimination half-life up to 12 hours because of saturation of hepatic enzyme systems as plasma levels increase.18,1g Preexercise and peak blood pressures were reduced by both drugs to a similar extent without any change in the degree of the blood pressure increase. Because only absolute blood pressures were lowered, it can be deduced that the cardiovascular reflexes responsible for these circulatory responses were not altered by either drug, a finding that confirms the observations of other workers.20 Ambulatory heart rate changes over 24 hours: An interesting finding was the consistent reduction in heart rate induced by verapamil during both the exercise and ambulatory periods of recording. After shortterm administration, vasodilators induce a decrease in arterial pressure, which initiates several compensatory reflex mechanisms. 21,22These include a reflex tachycardia owing to increased sympathetic activity mediated by the baroreceptors and stimulation of renin release. However, it is likely that with long-term administration this reflex sympathetic activity diminishes as baroreceptor resetting takes place. Previous studies with long-term oral therapy have also shown a modest reduction in heart rate with verapami17J3 and no significant change with nifedipine.24 Verapamil has a direct depressant effect on sinus node activity, demonstrated by animal experiments;25 thus, the reduction in heart rate may be a combination of reflex and direct effects of the drug on the sinus node.

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As might be predicted, propranolol had a more profound effect in slowing the heart rate, and significantly greater reductions were found during most of the ambulatory period, although not between 2200 and 0600 hours. Acceptability of verapamil in the treatment of hypertension: With regard to adverse effects, only a limited comparison can be made because of the relatively small number of patients in this study. Generally, both drugs were equally well tolerated and no serious adverse reactions were encountered in this trial. Un-

n=

1414

14 14 14 14 14 14 14 106

14 13 12 12 12

I-rrTl-Tnl 123456789

nil-l 12345

240 220

Systoli

200 180 160 140

B 9

120

Diastoli

100

u,

80

@

m

i 60A

n 12 preexercise

exercise

recovery

Time (minutes) + Untreated 0 Propranolol A Verapamil FIGURE exercise

3. Blood according

pressure and heart rate to treatment regimen.

responses

to dynamic

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doubtedly, as experience of long-term medication with slow calcium-channel inhibitors in hypertension increases, the relative incidence of adverse effects and general acceptability will be more evident. We conclude from this study that verapamil can produce substantial reduction in blood pressure over 24 hours when given 2 times a day. This profile of action and the effects on blood pressure during exercise were comparable to those of propranolol, and therefore this slow calcium-channel inhibitor may be suitable as first line treatment of hypertension, particularly when /3adrenoceptor blockers are contraindicated. However, further studies are still needed to elucidate the role of slow calcium-channel inhibitors in combination with other antihypertensive drugs, especially /3-adrenoceptor blockers. Acknowledgment: We are indebted to Heather Prince and Stewart Dashwood for technical assistance, and to Dr. Peter M. M. Cashman, who designed the computer analysis system.

References 1. Lewis GRJ, Morley KD, Maslowski AH, Bones PJ. VeropomiI in the management of hypertensive patients. Aust NZ J Med 1979;9:62-64. 2. Leonetti G, Sala C, Bianchini C, Terzoli L, Zanchetti A. Antihypertensive and renal effects of orally administered verapamil. Eur r Clin Phormacol 1984;18:375-382. 3. Olivari MT, Bartorelli C, Polese A, Fiorentini C, Moruzzi P, Guazzi MD. Treatment of hypertension with nifedipine, a calcium antagonistic agent. Circulation 1979;59:1056-1062. 4. Lederballe-Pedersen 0, Mikkelsen S. Acute and chronic effects of nifedipine in arterial hypertension. Eur J CIin Pharmacol 1978;14:375-381, 5. Fleckenstein A. Specific pharmacology of calcium in myocardium. cardiac pacemakers, and vascular smooth muscle. Annu Rev Pharmacol Toxic01 1977;17:149-160. 6. Millar JA, McLean K, Reid JL. Calcium antagonists decrease adrenal and vascular responsiveness to angiotensin II in normal man. CIin Sci 1981; 61:65s-68s. 7. Gould BA, Mann S, Kieso H, Bala Subramanian V, Raftery EB. The 24 hour ambulatory blood pressure profile with verapamif. Circulation 1982;65:22-27. 8. MacGregor GA, Markandu ND, Bayliss J, Brown M, Roulston JE. Circum-

ON VERAPAMIL

stantial evidence that an abnormality of calcium transport may be important in essential hypertension. CIin Sci 1981;60:6P.

9. Gould BA, Mann S, Davies AB, Altman DG, Raftery EB. Does placebo lower blood pressure? Lancet 198X2:1377-1381. 10. Millar-Craig MW, Hawes D, Whittington J. New system for recording ambulatory blood pressure in man. Med Biol Eng Comput 1978; 16:727-731. 11. Cashman PMM, Stott FD, Millar Craig MW. Hybrid system for fast data reduction on fongterni blood pressure recordings. Med BioI Eng Comput 1979;17:629-636. 12. Guazzi M, Olivari MT, Polese A, Fiorentini C, Magrini F. Moruzzi P. Nifedipine: o new antihypertensive with rapid action. Clin Phormacol Ther 1977;22:528-532. 13. Kuwajima I, Ueda K, Kamata C, Matsushita S, Kuramoto K. A study of the effects of nifedipine in hypertensive crises and severe hypertension. /pn Heart J 1978;19:455-466. 14. Millar-Craig MW, Kenny D, Mann S, Bala Subramanian V, Raftery EB. Effect of once doily atenolol on ambulatory blood pressure. Br Med J 1979;1:237-239. 15. Mann S, Millar-Craig MW, Bala Subramanian V, Raftery EB. Once daily beta-blockade in hypertension; an ambulatory assessment.Br r CIin Pharmacof 1981;12:223-228. 16. Floras J’S, Jones JV, Hassan MO, Sleight P. Ambulatory double-blind administration of atenolol, metoprolol, pindolol and slow release propranolol. Br Med r 1982;285:1387-1392. 17. Mann S, Millar-Craig NW, Altman DG, Melville DI. Raftery EB. The effects of metoprolol on ambulatory blood pressure. Clin Sci 1979;57: 375s-377s. 18. Freedman SB, Richmond DR. Ashley JJ,Kelly DT. Verapamil kinetics in

normal subjects and patients with coronary artery spasm. Clin Pharmacol Ther 1981;30:644-652, 19. Shand DG, Haminlle SC, Aanonsen L, Pritchett ELC. Reduced verapamif clearance during long term oral administration. CIin Pharmacol Ther 1981:30:701-703. 20. Taylor SH, Silke B, Ahuja RC, Okoli R. Influence of nicardipine on the blood pressure at rest and on the pressor responses to cold isometric exertion and dynamic exercise in hypertensive patients. f Cardiovasc Pharmacol. unpublished observations. 21. Lederballe Pedersen 0, Mikkelsen E, Christensen NJ, Kornerup HJ, Pedersen EB. Effect of nifedipine on plasma renin, oldosterone and catecholamines in arterial hypertension. Eur 1 Cfin Pharmocol 1979; 15:235-240. 22. Atterhog JG, Ekelund LG. Haemodynamic effects of intravenous verapamil at rest and during exercise in subjectively healthy middle aged men. Ear f Clin Pharmacol 1975;8:317-322. 23. Ross G, Jorgensen CR. Cardiovoscufor actions of iproveratril. [ Pharmacol Exp Ther 1967;158:504-507. 24. Dargie HJ. Lynch P, Krikler S. Krikler D. A comparison of the hypotensive effect of calcium antagonism and beta blockade. Eur r CIin Invest 1980;10:9. 25. Wit AL, Cranefield PF. Effect of verapomif on the sine-otriaf and atrioventricular nodes of the rabbit and the mechanism by which it arrests reentrant otrio-ventricular tachycardia. Circ Res 1974;35:413-425.