chronic stable angina monotherapy: nifedipine versus propranolol

Chronic Stable Angina Monotherapy Nifedipine versus Propranolol MICHAEL B. HIGGINBOTHAM, M.B., KENNETH G. MORRIS, M.D., R. EDWARD COLEMAN, M.D., FREDERICK R. COBB, M.D. Durham. North Carolma

A placebo-controlled, double-blind, crossover study was conducted to determine the effects of nifedipine (60 to 90 mg per day) monotherapy and propranolol (240 mg per day) monotherapy on symptoms, angina threshold, and cardiac function in patients with chronic stable angina. Fol- lowing a two-week placebo period, patients were randomly assigned to receive either nifedipine or propranolol for a five-week treatment period, after which they crossed over to the alternative regimen. All 21 patients were men with chronic stable angina pectoris, 13 of whom had symptoms both at rest and on exertion. New York Heart Association functional class improved in patients taking either nifedipine or propranolol, and nitroglycerin consumption decreased with both treatments compared with placebo. Nifedipine significantly delayed the onset of chest pain and 1 mm of ST-segment depression during bicycle exercise; increases with propranolol were smaller and not statistically significant. Nine patients had a preferential clinical response to nifedipine compared with six patients to propranolol; this was unrelated to the presence or absence of pain at rest or to any baseline hemodynamic finding. Nifedipine and propranolol were equally effective in relieving exertional ischemia as shown by improvement in radionuclide ejection fraction at identical work loads. Exercise wall motion, as- sessed by a semiquantitati\;e wall motion score, also improved with both drugs. Propranolol treatment decreased exercise cardiac output by 14 percent (p = 0.01) through its effect on heart rate. In contrast, nifedipine treatment had no effect on cardiac output. Thus, nifedipine is more effective on several measurements than propranolol when administered as single drug therapy in stable angina and has the advantage of preserving cardiac output during exercise.

ogy, Duke University Medical Center and the Durham Veterans Administration Medl- cal Center, Durham, North Carolina. This study was supported by Research grant HL17670 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland; by

lina; and by General Medlcal Research Funds from the Veterans Adrninlstrabon Medl- cal Center, Durham, North Carolina. Requests for reprints should be addressed to Dr. Michael B. Hlgglnbotham, Cardiology Division, Box 31219, Duke University MedIcal

B eta-adrenergic receptor blocking agents are effective antianginal agents that relieve ischemia ‘by

reducing heart rate and myocardial contractility, thereby decreasing myocardial oxygen requirement [l-5]. Until recently, the place of beta-blockers as first-line maintenance therapy in chronic stable angina was not challenged, except for patients in \iihom these drugs appeared relatively contraindicated (those with obstructive airway disease, peripheral vascular disease, or left ventricular dysfunction) [5,6].

The calcium channel blocker nifedipine is also an effective antianginal agent [7-91 but, unlike beta-blockers, it is a potent systemic and coronary vasodilator [lo]. Recent reports of increased coronary vasomotor tone in patients with exertional angina [ll-131 have led to the suggestion that such agents should be con- sidered as alternative therapy to propranolol even in the absence of contraindications to beta-blockers. Ni- fedipine is currently indicated for the management of chronic stable angina without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta-blockers and/or organic nitrates or who cannot tolerate those agents. The role of nifedipine as first-line maintenance therapy in chronic stable angina is not established.

Accordingly, the present study was designed to compare the efficacy of nifedipine with that of propranolol in the treatment of chronic stable angina pectoris. In addition to comparing clinical end points, this study examined the effect of these agents on angina threshold, left ventricular volume and function, and central and peripheral hemodynamics at rest and during exercise [ 141.

MATERIALS AND METHODS Following gradual withdrawal of maintenance anti-

angina1 therapy, 24 men aged 41 to 69 years were se- lected for study on the basis of a history of stable exertional angina pectoris and objective evidence of ischemia during exercise multigated radionuclide angiography (development of chest pain and failure of the ejection fraction to increase by more than four points) [14]. Twenty-one of these subjects completed all phases of a double-blind, placebo-controlled protocol (Figure 1). Following cessation of previous maintenance therapy (which included long-acting nitrates in 13 patients, beta-adrenergic blocking drugs in 13 patients, and nifedipine in six patients) and a two-week placebo washout, nifedipine was given in single-blind fashion in a dose of 30 mg daily and titrated up to 90 mg daily to determine the maximal tolerated dose level. Then, patients underwent two double-blind treatment periods during which they received either nifedipine in the maximal tolerated dose or proprano- 101 in a dose of 240 mg per day.

Following the control period (single-blind placebo)

January 16, 1989 The American Journal of Medicine Volume 86 (suppl 1A) 1

1

1-2 wk 2wk 2wk 5wk 5wk Taper and ceaaa SE Nifedlplne DE DB

previous placebo tltratlon phaae 1 phase 2 therapy

t t t I Control Phase 1 Phase 2

evaluation* evaluation* evaluation*

*Evaluations Clinical: NYHAFC !

Number of angina1 attacks Number of nitroglycerin tablets } Diary

Exercise. Graded bicycle exercise Equilibrium RNA Expired gas snslysis

Figure 1. Study protocol. After wrthdrawal of previous antiangrnal therapy over a one- to two-week period, patients were grven a single-blind (SE) placebo for two weeks; baselme clinical and exercise evaluations were performed. After a SB dose titration of nifedrprne, patients were given, in random order, five weeks of nrfedipine in optimal dosage and five weeks of propranolol, 240 mg per day; clinical and exercise evaluations were repeated at the end of each double-blind (DE) phase. NYHAFC = New York Heart Association function classification; RNA = radionuclide angiography. Adapted with permission from [14].

NYHA Functional Class No. of Angina1 No. of Nitroglycerin Attacks/ Wk Tablets/ Wk

4 -.0011 ‘2 3 6

2 4

1 0

0 = c0ntrol, m = propranolol; = = mlediplne I

Figure 2. New York Heart Assocrabon (NYHA) functional class, frequency of angina1 attacks, and nitroglycerin consumption during administration of placebo, proprano- 101, and nifedrpine in 21 patients, Propranolol and nifediprne were equally effective in improving these three clinical variables. NS = not significant. Adapted with permrs- sion from (141.

Time to Time to Chest Pain 1 mm ST Depression

16 16 7.0131 7.002 7

12 12

Min 8 Min 8

4 4

0 0

0 = control; m = propranolol: m = nifedipine

gure 3. Exercise bme to the onset of chest parn and 1 mm electrocardiographic Fi ST-segment depression during administration of placebo (control), propranolol, and nifedipine in 21 patients. Nifedipine, but not propranolol, significantly increased these two exercise variables, NS = not significant. Adapted with permission from (141.

and each of the double-blind treatment phases, patients were evaluated by clinical symptoms and by bicycle exercise testing, which included radionuclide angiography for estimation of ejection fraction; wall motion abnormalities by a semi-quantitative scoring system; end-diastolic counts, stroke counts, and count output; and expired gas analysis to calculate oxygen

consumption at rest and at each stage of exercise. Ar- teriovenous oxygen (0,) difference was estimated from count output and O2 consumption by the Fick principle. Previous placebo-controlled studies from our laboratory have confirmed the reproducibility of these measurements during serial follow-up [ 151. Data from each treatment arm were compared by repeated- measures analysis of variance at rest and at the maximal work load achieved with placebo [141.

RESULTS

SYMPOSIUM ON ISCHEMIA / HIGGINBOTHAM ET AL

2 January 16, 1989 The American Journal of Medicine Volume 86 (suppl 1A)

Of the 21 patients completing the study, 17 tolerated 90 mg of nifedipine daily, three tolerated 60 mg daily, and one tolerated 30 mg daily. Propranolol, 240 mg daily, was tolerated by all subjects. Compliance was over 95 percent for each treatment phase.

Side Effects Adverse effects were noted in seven patients re-

ceiving placebo (three experienced dizziness), eight patients taking propranolol (four experienced dizziness), and 15 patients taking nifedipine (10 experienced dizziness). For all of these patients, side effects were mild and did not require discontinuation of medi- cation. However, two patients did withdraw from the study because of suspected drug-related adverse effects: dizziness for nifedipine and pulmonary edema for propranolol.

Clinical Response Nifedipine and propranolol were equally effective in

reducing New York Heart Association functional class, the number of angina1 attacks, and nitroglycerin consumption (Figure 2). Though most patients re- sponded to both nifedipine and propranolol, a preferential response (based on a 50 percent difference in angina attacks) was seen for nifedipine in nine patients and propranolol in six patients; this preferential response was unrelated to the presence (in 13 patients) or absence of rest angina.

Exercise Responses Both nifedipine and propranolol tended to prolong

exercise time to the onset of chest pain and ST- segment depression; however, this improvement was significant only for nifedipine (Figure 3). This response was independent of which agent was given first, excluding an order effect.

Heart Rate and Blood Pressure Propranolol significantly reduced heart rate and

blood pressure (Figure 4) at rest and during exercise. In contrast, nifedipine did not affect heart rate and reduced diastolic blood pressure by a small amount during exercise. Consequently, rate pressure product was reduced by propranolol but not by nifedipine.

Left Ventricular Function and Volumes Ejection fraction was not affected at rest by either

nifedipine or propranolol (Figure 5). During exercise at similar work loads, the ejection fraction was significantly improved with both drugs. Similarly, wall motion (Figure 5) was unaffected at rest but exercise- induced wall motion abnormalities were improved by both propranolol and nifedipine.

End-diastolic volume, measured as end-diastolic counts, tended to increase with propranolol and to decrease with nifedipine at rest. During exercise, end-

SYMPOSIUM ON ISCHEMIA I HIGGINBOTHAM ET AL

Figure 4. Heart rate and blood pressure at rest (upright) and during exercrse (at matched work loads) durrng long-term treatment with placebo (control), propranolol, and nrfedipine In 21 pabents. Propranolol reduced both heart rate and blood pressure, especially durrng exercrse. Ni- fedrprne did not affect heart rate, but srgnifr- cantly reduced exercrse diastolic blood pressure. Adapted wrth permrsslon from [14].

Figure 5. Ejection fractron and wall motion score at rest (upright) and during exercise (at matched work loads and rate-pressure products) during long-term treatment with placebo (control), propranolol, and nrfedrprne in 21 patients. Wall motion score Indicates increased seventy of wall motion abnormalities, Global and regional left ventricular function were unaffected at rest, and improved equally with propranolol and nifedrpine during exercise. NS = not signrficant. Adapted with permrssron from [14].

Heart rate (beats per

minute)

BlOOd pressure (mm W

220

190

160

130

100

Rest (upright)

Control - Propranolol - - - - -

Nlfedipine -

Equal workload (control MAX)

Rest (upright) Equal workload (control MAX)

~.0091 r.0161

A0 Ejection fraction

.40


Equal rate-pressure product

(propranolol MAX)

5 Wall

motion score

3

1 Rest (upright) Equal workload Equal rate-pressure

(control MAX) product (propranolol MAX)

0 = control; m = propranolol; m = nifedipine


+20

End-diastolic counts

(% change ’ from control)

-20

-40

+40

L.021 J

Rest (upright)

(.0*42) LNS-’

Equal workload (control MAX)

+20

Stroke counts

(% change ’ from control)

-20

‘-NSA LNSA

-40 Rest (upright) Equal workload

(control MAX) m = propranolol; m = nifedipine

*Significantly different from placebo. J Figure 6. Long-term effects of propranolol and nifedipine on end-diastolic counts and stroke counts at rest (upright) and during exercise (at matched work loads), expressed as a percent change from placebo (percent from control) In 21 patients. Nifedipine significantly reduced end-diastolic counts during exercise. Neither drug affected stroke counts. NS = not significant. Adapted with permission from [14].

diastolic counts decreased by 11 percent with nifedipine (Figure 6). Stroke counts (an estimate of stroke volume) were slightly increased on both drugs with placebo but neither change was significant.

Cardiac Output Cardiac output was significantly reduced (by ap-

proximately 14 percent) with propranolol therapy both at rest and during exercise, and arteriovenous oxygen difference increased by a similar amount (Fig- ure 7). In contrast, nifedipine did not affect cardiac output.

COMMENTS This study confirms that when used alone as main-

tenance therapy for stable angina pectoris, nifedipine is at least equally as effective as propranolol in relieving chest pain and reduces the need for nitroglycerin. An advantage was seen for nifedipine in delaying the onset of chest pain and ST-segment depression during exercise testing.

Both drugs were used in high doses: nifedipine at the maximal tolerated dose level (usually 90 mg per day); and propranolol at a dose of 240 mg per day, which has been previously demonstrated to produce maximal or near-maximal beta-blockade and antianginal effect [5,16].

Although both nifedipine and propranolol were well tolerated in this study, nifedipine produced side effects more frequently at the dose levels used than did propranolol. These were generally mild, however, and

SYMPOSIUM ON ISCHEMIA / HIGGINBOTHAM ET AL

4 January 16, 1989 The American Journal of Medicine Volume 86 (suppl 1A)

related to the vasodilatory property of the drug. Stud- ies have shown [17,18] that the coadministration of food slows the increase in heart rate and decrease in blood pressure, thus providing a smoother hemodynamic profile. The adverse effect of pulmonary edema seen with propranolol may reflect the negative inotro- pie effects of this agent.

The hemodynamic findings in this study provide some insight into the comparative mechanisms of action of nifedipine and propranolol. As has been demonstrated previously 13-51, propranolol reduced ischemia (as demonstrated by improved ejection fraction and decreased exercise-induced wall motion abnormalities) by reducing heart rate and blood pressure and thereby reducing the myocardial oxygen requirement.

In contrast, in this study nifedipine had little effect on blood pressure and no effect on heart rate, so that the exercise rate-pressure product was unchanged. This suggests that the relief of ischemia with nifedipine may have resulted from an increase in coronary blood flow [19], although a decrease in myocardial oxygen requirement due to a diminished left ventricular volume cannot be excluded [20]. It is of interest to note that, in contrast to previous findings following short-term administration of nifedipine 121-261, long-

output m&t

from control)

+40 r

I L.022 J L.005’


A-V02 difference

(percent change ’ from control)

-20 -

L A LNSJ L.014’

-40 Rest (upright) Equal workload

(control MAX)

m = propranolol; m = nifedfpfne l Significantly different from placebo.

Figure 7. Long-term effects of propranolol and mfediptne on count output and arteriovenous oxygen difference at rest (upnght) and during exercise (at matched work loads), expressed as a percent change from placebo (percent from control) In 21 patients. A decrease in count output both at rest and during exercise with propranolol was accompanied by a reciprocal Increase in arteriovenous oxygen difference. Nifedipine did not affect central cardiovascular function. NS = not significant. Adapted with permission from [14].

SYMPOSIUM ON ISCHEMIA/ HIGGINBOTHAM ET AL

term nifedipine therapy did not result in a reflex increase in heart rate. This illustrates the point that the mechanism of action of drugs administered chronically cannot necessarily be inferred from the results ob- tained following short-term administration.

The different actions of nifedipine and propranolol also resulted in differential effects on stroke volume and cardiac output. The marked decrease in heart rate with propranolol resulted in a slightly enhanced stroke volume, possibly due to a combination of increased left ventricular size (Starling mechanism) and improved left ventricular function secondary to the relief of ischemia. However, as has been seen in nor- mal subjects 1271, compensatory increases in stroke volume were inadequate to compensate for the marked reduction in heart rate caused by propranolol, so that cardiac output decreased and arteriovenous oxygen increased. In contrast, nifedipine, which had no effect on heart rate, maintained (or slightly improved) stroke volume and cardiac output during exercise. These findings support the concept of improved oxygen delivery to exercising muscles with nifedipine as opposed to propranolol and suggest a potential functional benefit from nifedipine in subjects who engaged in long-term exercise rehabilitation.

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chronic stable angina monotherapy: nifedipine versus propranolol

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