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Angina pectoris and sudden death in the absence of atherosclerosis following ergotamine therapy for migraine
Angina Pectoris and Sudden Death in the Absence of Atherosclerosis Following Ergotamine Therapy for Migraine
In a woman with migraine headaches, angina-like symptoms devcloped and sudden death occurred following the administration of therapeutic doses of ergotamine. The lack of atherosclerosis at autopsy suggested coronary vasospasm as a possible mechanism for her death. The ergot alkaloids, which are widely used in the treatment of migraine, are potent vasoconstrictors. We report here the development of angina-like symptoms and sudden death in a woman given therapeutic doses of ergotamine for migraine. At autopsy, no coronary atherosclerosis was found. CASE REPORT
From the Johns Hopkins Hospital. Baltimore. hlarylanc!, and the Department of Phxmacolo~. Vandcrl)ilt hletlical Center. Nashville. TonnesSW Requests for reprints should lx: atltlrcsscd to Dr. D;l\rid Robertson, Dcplrtmcnt of Pharnxccology. Vantleri~ilt Medical (kntcr, Nashville, ‘ranncssee 37232. Manuscript acccptcd Dccemt1trr 14, 1978.
A 47 year old white wnman was admitted to The Johns Hopkins IHospital for recurrent severe headaches. These had been present since the aga of 14 and had never been evaluated. She had been managed on combinations of aspirin. acetaminophen, propoxyphene and meperidine but not with ergot alkaloids. Her past medical history was significant for thyrotoxicosis for which she WJS treated four years previously with radioactive iodine. There was no history of Raynaud’s phenomenon. At the time of admission, the patient was noted to ha\re normal \Gtal signs oxccpt for an irregularly irregular heart rate of 98/min and fine skin. She complained of mild heat intolerance, and an electrocardiogram showed atrial fibrillation. Her ncurologic evaluation including computcrizell axial tomographic scan and bilateral carotid angiography was within normal limits. The thyroid was diffusely enlarged. and blood thyroxine by ratlioimmltnoassa~ was 18.9 pg/lOO ml [normal 5 to 12 /.qg/lOO ml]. The T-index was 5.0 (normal I.2 to 4.21. The patient was given methimazole for her hyperthyroidism and ergotamine for her headaches. No cardiac glycoside \~vasgi\-en. but after four tla>~ the heart rate returned to the normal range. During the follobving nine days she received a total of 8.75 mg of ergotamine tartrate. Twel~c hours after her last dose of ergotamine, the patient became anxious anal complained of numbness in the left arm, retrosternal chest tightness and ~
July 1979
The American
Journal
of Medicine
Volume
67
177
ANGINA PECTORIS, SUDDEN DEATH AND ERGOTAMINE-BENEDICT,
veins were found. The heart was of normal size, and there was
no coronary atherosclerosis. No evidence of myocardial infarction was found. Since this patient had had an episode of typical angina pectoris associated with premature ventricular beats, it seemed likely that her ventricular fibrillation was brought on by a second episode of ischemia. An association between her sudden death and the ergotamine therapy is suggested but not proved. COMMENTS
Although there have been occasional reports of provocation of myocardial ischemia by ergot alkaloids, it was formerly assumed that such attacks occurred in people with clinical or subclinical atherosclerotic coronary artery disease [l]. However, in the past four years, keen interest in ergonovine maleate has followed the observation that a large percentage of subjects with vasospastic or Prinzmetal angina experience a reproduction of their chest pain and electrocardiographic changes when given this drug [z]. There are now considerably more than 1,000 patients described in the literature with symptoms suggestive of vasospastic angina [3,4]. Furthermore, recent studies suggest that vasospasm may be important in the pathogenesis of as many as 40 per cent of myocardial infarctions [5]. In the face of these observations, it is perhaps surprising that ergotamine tartrate, which shares many characteristics with ergonovine maleate, has been recognized so infrequently as a cause of myocardial ischemia. Indeed, some investigators have considered such symptoms as fleeting paresthesias, chest pain and muscle cramps as being insufficiently serious to warrant cessation of therapy [6].
ROBERTSON
The clinical course of the patient in this report seems consistent with vasospastic cardiac ischemia predisposing to abnormalities of rhythm. Abnormalities of rhythm have been frequently reported in cases of vasospastic angina, and the absence of coronary atherosclerosis in this patient supports this interpretation. Our patient did not exhibit Raynaud’s phenomenon (71 or evidence of spasm in other locations, however. Other cases of myocardial ischemia [10-E!] and sudden death [l&15,19] with ergot alkaloids have been reported, but this has not previously been shown to occur in the absence of atherosclerosis. It is noteworthy that in three of the 15 reported cases the patients had associated hyperthyroidism, as did our patient. It is not clear why hyperthyroidism should predispose to ergot toxicity in these patients. There are several possible reasons why myocardial ischemia may occur more frequently after the administration of ergonovine maleate than after ergotamine tartrate administration. First, there may be a dosage effect since ergotamine is frequently given orally and is only 62 per cent absorbed by this route [8]. Second, although ergotamine possesses some potency as an alpha-blocker, ergonovine maleate has little or none [9]. Thus, with ergotamine, the alpha-blocking properties may antagonize somewhat the intrinsic vasoconstrictive properties. We believe caution is indicated when a patient receiving ergot alkaloids experiences symptoms suggestive of angina pectoris. We believe discontinuation of ergot in such cases should be coupled with careful monitoring and the institution of nitrate therapy.
REFERENCES 1. 2.
3. 4. 5. G. 7. 8.
9.
10. 11.
178
Stein I: The ergonovine test for coronary insufficiency. Angiology 14: 23.1963. Curry RC, Pepine CJ, Sabom MB, et al.: Effects of ergonovine in patients with and without coronary artery disease. Circulation 56: 803. 1977. Robertson RM: Variant angina. Johns Hopkins Postgraduate Course ~014, 1978. Hillis LD, Braunwald E: Coronary-artery spasm. N Engl J Med 299: 695,1978. Oliva P. Breckinridge J: Arteriographic evidence of coronary arterial spasm in acute myocardial infarction. Circulation 56: 336, 1977. Bradfield JM: A new look at the use of ergotamine. Drugs 11: 449.1976. Robertson D, Oates JA: Variant angina and Raynaud’s phenomenon. Lancet 1: 452,1978. Aellig WH, Neusch E: Comparative pharmacokinetic investigations with tritium-labelled ergot alkaloids after oral and intravenous administration in man. Int J Clin Pharmacol Biopharm 15: 106,1977. Nickerson M, Collier B: Drugs inhibiting adrenergic nerves and structures innervated by them. The Pharmacological Basis of Therapeutics, [Goodman LS, Gilman A, eds), New York, Macmillan. 1976. Fuchs M, Blumenthal L: Use of ergot preparations in migraine. JAMA 143: 1462.,1950. Lab% M, Justin-BesanFon L, Gouyen J: Accidents con&cutifs au traitement de la maladie de basedow par le tartrate
July 1979
The American Journal of Medicine
12. 13. 14. 15. IG. 17. 18. 19. 20.
21. 22.
Volume 67
d’ergotamine. Bull MBm Sot Mcd HBp Paris 53: 429, 1929. Labb& M. lustin-Besancon L. Boulin R. et al: L’annine de poitrine &gotaminiq&. Presse Mbd 37: 1069, 1929u. Carter JB: Cardiac manifestations following ergotamine tartrate therapy for migraine. JAMA 114: 2298, 1940. McNerney J, Leedham C: Acute coronary insufficiency pattern following intravenous ergotamine studies. Am Heart J 39: 629,195O. Zimmerman 0: StBrung der goron&durchblutund durch ergotamin. Klin Wochenschr 14: 500.1935. LichTman S: Clinical experience with ergotamine tartrate. JAMA 160: 148,1936. Bcrnreiter M: Severe angina pectoris and electrocardiographic changes after Cafergot medication. J Kansas Mcd Sot 66: 464,1965. Baillie TW: Ventricular ectopic activity following intravenous errometrine. Anaesthesia 24: 253, 1969. Browning DJ: Seriousside effectsof ergometrinc and its use in routine obstetric practice. Med J Austral 1: 956. 1974. Goldfischer JD: Acute myocardial infarction secondary to ergot therapy. N Engl J Med 262: 860.1948. Scherf D, Schlachman M: Electrocardiorrauhic and clinical stuiiies on action of crgotamine tartr~~tc’and dihydroergotamine. Am J Med Sci 216: 673, 1948. Snell NJC. Russell-Smith C, Coysh HL: Myocardial ischaemia in migraine sufferers taking ergotamine. Postgrad Mcd J 54: 37, 1978.
In a woman with migraine headaches, angina-like symptoms devcloped and sudden death occurred following the administration of therapeutic doses of ergotamine. The lack of atherosclerosis at autopsy suggested coronary vasospasm as a possible mechanism for her death. The ergot alkaloids, which are widely used in the treatment of migraine, are potent vasoconstrictors. We report here the development of angina-like symptoms and sudden death in a woman given therapeutic doses of ergotamine for migraine. At autopsy, no coronary atherosclerosis was found. CASE REPORT
From the Johns Hopkins Hospital. Baltimore. hlarylanc!, and the Department of Phxmacolo~. Vandcrl)ilt hletlical Center. Nashville. TonnesSW Requests for reprints should lx: atltlrcsscd to Dr. D;l\rid Robertson, Dcplrtmcnt of Pharnxccology. Vantleri~ilt Medical (kntcr, Nashville, ‘ranncssee 37232. Manuscript acccptcd Dccemt1trr 14, 1978.
A 47 year old white wnman was admitted to The Johns Hopkins IHospital for recurrent severe headaches. These had been present since the aga of 14 and had never been evaluated. She had been managed on combinations of aspirin. acetaminophen, propoxyphene and meperidine but not with ergot alkaloids. Her past medical history was significant for thyrotoxicosis for which she WJS treated four years previously with radioactive iodine. There was no history of Raynaud’s phenomenon. At the time of admission, the patient was noted to ha\re normal \Gtal signs oxccpt for an irregularly irregular heart rate of 98/min and fine skin. She complained of mild heat intolerance, and an electrocardiogram showed atrial fibrillation. Her ncurologic evaluation including computcrizell axial tomographic scan and bilateral carotid angiography was within normal limits. The thyroid was diffusely enlarged. and blood thyroxine by ratlioimmltnoassa~ was 18.9 pg/lOO ml [normal 5 to 12 /.qg/lOO ml]. The T-index was 5.0 (normal I.2 to 4.21. The patient was given methimazole for her hyperthyroidism and ergotamine for her headaches. No cardiac glycoside \~vasgi\-en. but after four tla>~ the heart rate returned to the normal range. During the follobving nine days she received a total of 8.75 mg of ergotamine tartrate. Twel~c hours after her last dose of ergotamine, the patient became anxious anal complained of numbness in the left arm, retrosternal chest tightness and ~
July 1979
The American
Journal
of Medicine
Volume
67
177
ANGINA PECTORIS, SUDDEN DEATH AND ERGOTAMINE-BENEDICT,
veins were found. The heart was of normal size, and there was
no coronary atherosclerosis. No evidence of myocardial infarction was found. Since this patient had had an episode of typical angina pectoris associated with premature ventricular beats, it seemed likely that her ventricular fibrillation was brought on by a second episode of ischemia. An association between her sudden death and the ergotamine therapy is suggested but not proved. COMMENTS
Although there have been occasional reports of provocation of myocardial ischemia by ergot alkaloids, it was formerly assumed that such attacks occurred in people with clinical or subclinical atherosclerotic coronary artery disease [l]. However, in the past four years, keen interest in ergonovine maleate has followed the observation that a large percentage of subjects with vasospastic or Prinzmetal angina experience a reproduction of their chest pain and electrocardiographic changes when given this drug [z]. There are now considerably more than 1,000 patients described in the literature with symptoms suggestive of vasospastic angina [3,4]. Furthermore, recent studies suggest that vasospasm may be important in the pathogenesis of as many as 40 per cent of myocardial infarctions [5]. In the face of these observations, it is perhaps surprising that ergotamine tartrate, which shares many characteristics with ergonovine maleate, has been recognized so infrequently as a cause of myocardial ischemia. Indeed, some investigators have considered such symptoms as fleeting paresthesias, chest pain and muscle cramps as being insufficiently serious to warrant cessation of therapy [6].
ROBERTSON
The clinical course of the patient in this report seems consistent with vasospastic cardiac ischemia predisposing to abnormalities of rhythm. Abnormalities of rhythm have been frequently reported in cases of vasospastic angina, and the absence of coronary atherosclerosis in this patient supports this interpretation. Our patient did not exhibit Raynaud’s phenomenon (71 or evidence of spasm in other locations, however. Other cases of myocardial ischemia [10-E!] and sudden death [l&15,19] with ergot alkaloids have been reported, but this has not previously been shown to occur in the absence of atherosclerosis. It is noteworthy that in three of the 15 reported cases the patients had associated hyperthyroidism, as did our patient. It is not clear why hyperthyroidism should predispose to ergot toxicity in these patients. There are several possible reasons why myocardial ischemia may occur more frequently after the administration of ergonovine maleate than after ergotamine tartrate administration. First, there may be a dosage effect since ergotamine is frequently given orally and is only 62 per cent absorbed by this route [8]. Second, although ergotamine possesses some potency as an alpha-blocker, ergonovine maleate has little or none [9]. Thus, with ergotamine, the alpha-blocking properties may antagonize somewhat the intrinsic vasoconstrictive properties. We believe caution is indicated when a patient receiving ergot alkaloids experiences symptoms suggestive of angina pectoris. We believe discontinuation of ergot in such cases should be coupled with careful monitoring and the institution of nitrate therapy.
REFERENCES 1. 2.
3. 4. 5. G. 7. 8.
9.
10. 11.
178
Stein I: The ergonovine test for coronary insufficiency. Angiology 14: 23.1963. Curry RC, Pepine CJ, Sabom MB, et al.: Effects of ergonovine in patients with and without coronary artery disease. Circulation 56: 803. 1977. Robertson RM: Variant angina. Johns Hopkins Postgraduate Course ~014, 1978. Hillis LD, Braunwald E: Coronary-artery spasm. N Engl J Med 299: 695,1978. Oliva P. Breckinridge J: Arteriographic evidence of coronary arterial spasm in acute myocardial infarction. Circulation 56: 336, 1977. Bradfield JM: A new look at the use of ergotamine. Drugs 11: 449.1976. Robertson D, Oates JA: Variant angina and Raynaud’s phenomenon. Lancet 1: 452,1978. Aellig WH, Neusch E: Comparative pharmacokinetic investigations with tritium-labelled ergot alkaloids after oral and intravenous administration in man. Int J Clin Pharmacol Biopharm 15: 106,1977. Nickerson M, Collier B: Drugs inhibiting adrenergic nerves and structures innervated by them. The Pharmacological Basis of Therapeutics, [Goodman LS, Gilman A, eds), New York, Macmillan. 1976. Fuchs M, Blumenthal L: Use of ergot preparations in migraine. JAMA 143: 1462.,1950. Lab% M, Justin-BesanFon L, Gouyen J: Accidents con&cutifs au traitement de la maladie de basedow par le tartrate
July 1979
The American Journal of Medicine
12. 13. 14. 15. IG. 17. 18. 19. 20.
21. 22.
Volume 67
d’ergotamine. Bull MBm Sot Mcd HBp Paris 53: 429, 1929. Labb& M. lustin-Besancon L. Boulin R. et al: L’annine de poitrine &gotaminiq&. Presse Mbd 37: 1069, 1929u. Carter JB: Cardiac manifestations following ergotamine tartrate therapy for migraine. JAMA 114: 2298, 1940. McNerney J, Leedham C: Acute coronary insufficiency pattern following intravenous ergotamine studies. Am Heart J 39: 629,195O. Zimmerman 0: StBrung der goron&durchblutund durch ergotamin. Klin Wochenschr 14: 500.1935. LichTman S: Clinical experience with ergotamine tartrate. JAMA 160: 148,1936. Bcrnreiter M: Severe angina pectoris and electrocardiographic changes after Cafergot medication. J Kansas Mcd Sot 66: 464,1965. Baillie TW: Ventricular ectopic activity following intravenous errometrine. Anaesthesia 24: 253, 1969. Browning DJ: Seriousside effectsof ergometrinc and its use in routine obstetric practice. Med J Austral 1: 956. 1974. Goldfischer JD: Acute myocardial infarction secondary to ergot therapy. N Engl J Med 262: 860.1948. Scherf D, Schlachman M: Electrocardiorrauhic and clinical stuiiies on action of crgotamine tartr~~tc’and dihydroergotamine. Am J Med Sci 216: 673, 1948. Snell NJC. Russell-Smith C, Coysh HL: Myocardial ischaemia in migraine sufferers taking ergotamine. Postgrad Mcd J 54: 37, 1978.