Prazosin therapy for refractory variant angina

Prazosin

therapy

for refractory

variant

angina

The selective alpha, blocker prazosin was used to abolish Prinrmetal’s variant angina in six patients. All had had an acute transmural myocardial infarction, after which the angina1 attacks with transient ST segment elevation developed, and three of them had already suffered from variant angina prior to the infarction. Therapeutic trials with high doses of nifedipine, verapamil, nitrates, beta blockers, and (in one case) phenoxybenzamine were ineffective in all six patients. Prazosin, 8 to 30 mg/day, combined with low-dose nitrates or nifedipine completely abolished the attacks in four patients, markedly reduced their frequency and intensity in one patient, and had to be stopped in the sixth one because of hypotension and dizziness. Except for this last patient, the drug was well tolerated by all the others, and no changes in blood pressure were observed. In four patients discontinuation or reduction of prazosin resulted in exacerbation of symptoms, but its renewal was followed by disappearance of the attacks. Since the mean follow-up period in this study was 4 to 6 months, further evaluation appears necessary concerning the long-term effects of this drug in Prinrmetal’s variant angina. (AM HEART J 105262, 1983.)

Dan Tzivoni, M.D., Andre Keren, M.D., Jesaia Benhorin, M.D., Shmuel Gottlieb, M.D., Daphna Atlas, Ph.D.,* and Shlomo Stern, M.D. Jerusalem, Israel

In Prinzmetal’s variant angina pectoris,’ coronary arterial spasm plays a dominant role, and most reports on therapy for this condition describe the use of nitrates and/or calcium antagonists.2-5 Coronary vasoconstriction is mediated via the sympathetic alpha receptors,6-X and therefore some authors have used nonspecific alpha blockers, such as phentolamineg or phenoxybenzamine,“’ to relieve this phenomenon. Our report describes the use of the selective alpha,-blocking drug prazosin”-12 in patients with variant angina refractory to other drugs. METHODS

AND RESULTS

Case 1. A 52-year-old man had suffered from frequent angina1episodesfor 7 months prior to admission.He was treated with nifedipine, 30 mglday, and isosorbide dinitrate, 30 mg/day, during two periodsof hospitalization for anterior subendocardialmyocardial infarction. During the days before admissionthe frequency and intensity of his resting chest pain increased;therapy with verapamil, up to 360 mg/day, and propranolol, 160 mglday, wasineffective, and the patient required up to 40 tablets of sublingual nitroglycerin daily. On admission,the patient’s heart

From the Heiden Department of Cardiology. Hebrew 1Iniversity~Hadassah Medical School. Received

for publication

Reprint requests: ogy, Bikur Cholim *Dept.

262

of Biological

Nov.

25, 1981;

Bikur

accepted

Cholim Jan.

Hebrew

University.

and

5. 1982.

Dan Tzivoni, M.D., The H&den Department Hospital, P.O. Box 492, Jerusalem, Israel. Chemistry.

Hospital

of Cardiol-

rate wasregular at 70 bpm and blood pressurewas 110/70 mm Hg. ECG was compatible with recent transmural anteroseptal infarction (Fig. 1). Creatine kinase (CK) and aspartate aminotransferase@GOT) levels were elevated. During the first 10 days the patient had two to six episodesof chest pain per day, usually during the night and early morning, associatedwith ST segmentelevation in precordial leads V, , (Fig. 1). The attacks recurred during the 2 next weeksin spite of the administration of isosorbidedinitrate, up to 240 mglday, and nifedipine, up to 120mg/day. They respondedwell to sublingual isosorbide dinitrate but not to chewablenifedipine, and therefore the nifedipine was stopped. Therapy with phenoxybenzamine, 30 mglday for 2 days, was without effect. Prazosin, 3 mg/day, was started and the dose gradually increased. On the second day, while the patient was receiving 6 mg/day, improvement started, and when a doseof 30 mg/day wasreached,the episodesof chest pain became rare (one or two per week), milder, were not associatedwith any ST-T changes,and respondedimmediately to sublingual isosorbidedinitrate. Blood pressure did not changewith the prazosin therapy. A modified treadmill test prior to discharge was negative at a heart rate of 145 bpm. Coronary arteriography (Fig. 2) 40 days after the infarct showedan isolated lesion of 80% luminal narrowing of the left anterior descending artery. During catheterization, chest pain developed and complete obstruction of the narrowed segment was observed.After sublingual isosorbidedinitrate wasgiven, reopening of the artery with 80% narrowing was seen.At present, 8 months after the infarct and with the patient on a regimen of isosorbidedinitrate, 240 mg/day, and prazosin, 30 mg/day, only rare episodesof chest pain occur. 000’7-8703/83/02OSfie

+ 05$0050/O

1983

The

C. V. Mosby

Co.

Volume Number

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Fig. 1. Case1. Resting 12-lead ECG 7 days after transmural anteroseptal myocardial infarction (upper panel). Typical pattern of ST segment elevation in leads V,, during an episode of chest pain; note transient left anterior hemiblock (lower panel).

Fig. 2. Case 1. Selective arteriogram in right hem&&l

view of left coronary artery, demonstrating complete proximal obstruction of the left anterior descending artery during chest pain (panel A). Following sublingual isosorbide dinitrate, the artery partially reopened, demonstrating 80‘%,luminal narrowing (panel BJ.

Trial to reduce the prazosin dosageto 16 mg/day was followed by recurrence of anginal attacks; reestablishment of a dosageof 30 mg/day again abolished the attacks. Case 2. A 79-year-old woman known to suffer from mild angina wastreated with propranolol, 60 mg/day, and isosorbidedinitrate, 30 mg/day. Becauseof an increasein the frequency of her attacks, shewasreferred for hospitalization. Laboratory tests were normal, including CK and SGOT determinations and ECG examination. During the first 3 days the patient had repeatedepisodesof chest pain associatedwith ST segmentelevation in the inferior leads (Fig. 3); after the attacks the ST segmentreturned to the isoelectric line. The episodesrespondedonly partially to isosorbidedinitrate or chewable nifedipine. On the third day Q waves developed in the inferior leads, CK and SGOT levels increased, and an acute inferior infarction was diagnosed. Following the acute infarction, one or two episodesa day of chest pain continued and were associatedwith transient ST segmentelevation in the inferior leads(Fig. 3). Sublingual isosorbidedinitrate and chewable nifedipine adequately terminated the attacks, but intravenous

verapamil was ineffective. During a 2-week period, isosorbide dinitrate, 320 mgfday, nifedipine, 80 mglday, and heparin, 15,000units, did not prevent the episodes.Prazosin, 3 mgfday, wasstarted thereafter, and the dosagewas gradually increased to 8 mglday. Because of a drop in blood pressure,isosorbidedinitrate and nifedipine doses were reduced to 160 mg/day and 60 mglday, respectively, and blood pressureleveled around 115/70mm Hg. Consequent to this therapy the chest pain completely disappeared, and the patient was discharged 8 days later. During the g-month follow-up period with the samedrug therapy, the patient remained asymptomatic. Trial by the referring physician to stop prazosin therapy was followed by recurrence of chest pain; reinstitution of prazosin was again effective. Case 3. A 51-year-old man had acute anteroseptal infarction, and 6 months later the precordial pains recurred during effort, cold weather, and sometimeseven at rest. During a treadmill test, transient 1 to 2 mm ST segment elevation in the inferior wall leads (Fig. 4), associatedwith a short run of ventricular tachycardia and typical angina1pain, wasobserved.Nifedipine, 40 mg/day,

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PAM Fig. 3. Case 2. Normal resting l&lead ECG (upper panel, first rou~i 3 days prior to myocardial infarction. Typical pattern of ST segmentelevation in leadsL2~:< and aV, during an attack of chest pain (upper panel, second row). One week after the acute inferior wall infarction, without pain: Q waves in leads L,,, and aV, (lower panel, first row). Transient elevation of the ST segmentin leads L:! and aV,. during an episodeof chest pain (lower panel, second row).

and isosorbidedinitrate, 80 mglday, were started. Three weekslater the patient was admitted with acute inferior infarction. The first week of hospitalization was uneventful, but then attacks of chest pain started, mainly during the night, and were associatedwith 2 to 3 mm ST segment elevation in the inferior leads(Fig. 4). Isosorbidedinitrate, 120mglday, and nifedipine, 50 mglday, were ineffective in preventing the spontaneousanginal episodes.During the attacks, sublingual isosorbidedinitrate proved to be more effective than chewablenifedipine. Becauseof the increasing frequency of these episodes,prazosin wasstarted and the dosewasgradually increasedto 8 mglday. The number of the attacks decreasedgradually. Becauseof a decrease in blood pressure,nifedipine was stopped and isosorbide dinitrate was reduced to 60 mg/day. After these changes, blood pressurestabilized around 120/80 mm Hg and the patient becamesymptom free. Before discharge a modified treadmill test was normal. The patient left the hospital and, with a regimen of prazosin, 8 mg/day, and isosorbidedinitrate, had no recurrence of angina during a 5-month follow-up period. Case 4. A 63-year-old man without previous cardiac history was hospitalized becauseof episodesof severe nocturnal chest pain and acute inferior wall infarction. The early course was uneventful, but on the sixth day attacks of severechest pain recurred and were associated

with transient 1 to 2 mm ST segment elevation in the inferior leads. The pain wasresponsiveonly to narcotics. Nifedipine, 60 mgfday, isosorbidedinitrate, 80 mg/day, and intravenous heparin drip, 30,000 units/day, were unsuccessfulin preventing the attacks. The angina1episodesincreasedin frequency during the next days without signsof infarct extension, asjudged by ECG and repeated CK and CK-MB examinations. At this stageheparin was stopped because of microscopic hematuria, the other drugs were continued, and prazosin, 2 mglday, was started. The blood pressure dropped from 140/80 to 120/70 mm Hg, and the attacks continued at the rate of two or three times daily. Becauseof a further drop in blood pressure during the next 3 days, the doses of nifedipine and isosorbidedinitrate were gradually reduced to 40 mg/day for each drug, and the prazosin was increased to 10 mg/day. Because there was no further change in blood pressureand the episodesof chest pain disappeared, the usual postinfarction mobilization was started. After 7 asymptomatic days, prazosin was decreasedto 6 mg/day, but this wasfollowed by spontaneous recurrence of angina1episodesassociated with ST segmentelevations. Prazosin, 10mg/day, wasreinstituted, no changein blood pressurewasobserved,the complaints again disappeared,and after 10pain-free days the patient wasdischarged.Therapy with prazosin, 10 mglday, isosor-

Volume Number

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variant

angina

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Fig. 4. Case3. Normal leads L, and aVr at rest (left column). Immediately after stresstest, chest pain and ST segment elevation occurred (column 2). After the inferior wall myocardial infarction, Q wave inversion developed (column 3). During chestpain, reelevation of ST segmentsoccurred in the sameleads (column 4).

bide dinitrate, 40 mglday, and nifedipine, 40 mgfday, was maintained, and 4 months later the patient wassymptom free. Case 5. A 76-year-old man had subendocardialinfarction in 1980. Six months later anginal episodesstarted at rest and were unresponsiveto propranolol, 160 mg/day, and isosorbidedinitrate, 120mg/day. On admissionblood pressure was 140/80 mm Hg and heart rate 74 bpm. During the angina1episodes,transient ST segmentelevation in leads aV, and V,., and reciprocal ST-segment depressionin the inferior leadswere seen.During the next 4 days similar episodesrecurred three or four times a day

episodesof severe rest chest pain started, and ECG examination showed transient ST segment elevations in precordial leads.The attacks were unresponsiveto sublingual isosorbidedinitrate or chewable nifedipine, and an addition to therapy of oral nifedipine, 40 mglday, caused severeheadache.Prazosin, up to 3 mglday, was given and the number of angina1attacks decreased,but becauseof a drop in blood pressureto 80/60 mm Hg, severedizziness, fatigue, and palpitations, prazosin had to be stopped on the third day.

without enzyme elevation. Bed rest, propranolol,

Alpha-receptor blockade. Most reports on therapy for variant angina describe the efficacy of nitrates, calcium blockers, or proprano101.2-5*gr13 Levene and Freeman0 described a patient with angina refractory to nitrates, in whom alpha-adrenorecptor blockade by intravenous phentolamine abolished a 90% stenosis in the coronary artery during coronary angiography; subsequently, prolonged treatment with phenoxybenzamine markedly improved the clinical condition. In angina1 attacks in patients with variant angina, Yasueg reported 79 % suppression by intravenous phentolamine and 60% by oral phenoxybenzamine. l4 However, these agents may have deleterious cardiac effects because of their ability to block the presynaptic alpha receptors and thereby increase the release of norepinephrine, resulting in positive inotropic and chronotropic effects.15 In addition, norepinephrine, which is a potent alpha

160

mg/day, isosorbidedinitrate, 160mglday, and nifedipine, 40 mglday, did not achieve clinical improvement. Prazosin, 4 mg/day, wasstarted, propranolol wasreduced to 60 mglday, and isosorbide dinitrate and nifedipine were continued; within 3 days the patient became symptom free. No changes in heart rate or blood pressure were observed. A trial to stop prazosin while continuing all other drugs wasfollowed by three episodesof severechest pain associatedwith ST segmentelevation in leads aVr. and V,., within 12 hours. Prazosin was therefore reinstituted, followed again by disappearanceof chest pain. At this stagethe propranolol was stopped without any effect on the patient’s symptoms.During 2 months of follow-up the patient remained symptom free. Case 6. A 78-year-old man had unstable anginaand was hospitalized with acute anterior infarction. He wasknown to suffer from. chronic renal failure and mild diabetes. Blood pressure was 140/80 mm Hg, and heart rate was regular at 80 bpm. The early course was complicated by signs of left- and right-sided heart failure, and blood pressuredecreasedto lOO/SOmm Hg. On the twelfth day,

DISCUSSION

agonist, may increase coronary

reducing

coronary

tonus,s thereby

blood flow. Yasue and cowork-

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et al.

ersy. ‘” expressed their view that because of side effects such as weakness, palpitations, orthostatic hypotension, and nausea, the nonspecific alphablocking agents do not have an important role in the treatment of variant angina. In one of our patients phenoxybenzamine was tried without side effects, but it failed to improve the angina1 attacks. Prazosin. In our study, prazosin was used as a coronary vasodilator agent in patients with Prinzmetal’s angina. The patients were recovering from acute myocardial infarction, and three of them had had the same form of angina prior to the infarction. Prior therapy with large doses of isosorbide dinitrate and nifedipine failed to prevent the attacks. The addition of prazosin, 8 to 30 mg/day, abolished all attacks in four patients, markedly reduced the frequency and duration of attacks in one, and had to be discontinued because of hypotension in the sixth. The lack of effect on blood pressure of prazosin in all other patients who were normotensive at the beginning of therapy is of clinical significance. Prazosin is a potent postsynaptic alpha, blocking agent with almost no alpha, effects,*“.‘fi and no elevation of norepinephrine is associated with its use. Since the coronary arteries are richly supplied with alpha receptors,6-8 alpha-blocking agents are expected to cause coronary vasodilation; this effect is more prominent with the use of the selective alpha, blocker prazosin. Several investigators’7,‘” have demonstrated that calcium antagonists also exert substantial affinity for the alpha, receptors; thus their vasodilatory properties may be due to their combined effects as calcium antagonists and alpha, blockers. Prazosin, however, demonstrates a lO,OOO-fold affinity for the alpha, receptors, thus making it possibly a more potent vasodilator than the calcium antagonists. This may explain the better response of our patients to this drug after both calcium antagonists and nitrates had failed. Conclusions. Although in most patients treatment with nitrates and calcium blockers is sufficient to terminate or prevent episodes of variant angina, prazosin should be considered for patients whose condition is refractory to these drugs. Further studies are required before the exact role of prazosin

in the therapy of Prinzmetal’s lished.

angina can be estab-

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S, Muller JS, Mudge GH. et al: Therapy of cfxonar? vasoconstriction in patients with coronary artery disease. Am .I Cardiol 47:167, 1981. Pitt B, Elliot EC, Gregg DE: Adrenergic receptor activity in the coronary arteries of the unanesthetized dog rirc Res 21:7.5, 1967. McRaven DK, Mark AL. Abboud FM, et al: Kesponses oi coronary vessels to adrenergic stimuli. J Clin Invest 50:77Z 1971. Kelley KO. Feigel EO: Segmental alpha receptor mediated vasoconstrictilm in the canine coronary circulation. Clin Rcs 43:908, 197% Yasue H: l’athophysiology and treatment of coronary arterial spasm. Chest 78:216, 1980. Levene DL. Freeman MR: Alpha adrenoreceptor mediat.ed coronary art,erial spasm. .JAMA 236:1016. 1976. Cambridge D, Davey MJ, Massingham R: Pharmacology (I< antihypertensive drugs with special reference to vasodilators, alpha-adrenergic blocking agents and prazosin. Med .I Ausl 2(suppl):2. 1977. Cavero .I, Fenard S, Gomeni K. et al: Studies on Lhe mecha nism of the vasodilator effects of prazosin in dogs and rabhitx Eur .J Pharmacol 49:259, 1978. Guazzi M, Magrini F, Fiorentini C, et, al: Clinical, electrocardiographic, and hemodynamic effects of long-term use 01 propranolol in Prinzmetal’s variant angina pectoris. Br Heart .J 333889, 1971. Yasue H. ¬e S. ‘I’akizawa A. et al: Pathogenesls and treatment of angina at rest as seen from its response to various drugs. .Jpn Circ J 42: I, 1978. Hoffman BB. Lefkowitz RJ: Alpha-adrenergic receptor suhtypes. N Engl .J Med 302:1:~90, 1980. Prichard DC. Charness ME, Robertson D, et al: Prazoain: Differential affinities for two populations of alpha-adrenergic receptor binding sites. Eur J Pharmacol 50:87, 197X. Fairhurst AS. Wittacker MI,. Ehlert EJ: Interactions ot D-600 (methylverapamil) and local anesthetics with rat brain alpha adrenergic and mascarinic receptors. Biochem Pharmaco1 29:155C’, 1980. Atlas D. Adler M: Alpha adrenergic antagonists as possible calcium channel inhibitors. Proc Nat1 Acad Sci IJSA 78:1237. 1981.