Felodipine (Once Daily) Versus Nifedipine (Four limes Daily) for Prinzmetal’s Angina Pectoris Diego Ardissino, MD, Stefano Savonitto, MD, Antonio Mussini, MD, Paola Zanini, MD, Albert0 Rolla, MD, Paolo Barberis, MD, Marco Sardina, MD, and Giuseppe Specchia, MD
In 30 consecutive patients with Prinzmetal’s angina pectoris, the antiischemic effect of felodipine, a new long-acting vasoselective calcium antagonist, administered at doses of 10 and 20 mg once daily was compared with that of the wellestablished therapeutic regimen with nifedipine administered at a dose of 20 mg 4 times daily. Twenty-four-hour Hoper monitoring was performed during a 2-day placebo run-in and at the end of each of 3 consecutive B-day periods during which the 3 active treatments were administered in randomized sequence. Three patients withdrew, whereas 27 completed the study. The therapeutic regimens tested proved to be similarly effective; primary end points (ischemic episodes recorded by Holter monitoring, and anginal attacks reported on diary cards) occurred in 5 patients (19%) during nifedipine treatment, and in 7 (26%) and 3 (11%) during felodipine treatment with 10 and 20 mg, respectively (p = not significant). The distribution of residual ischemic episodes demonstrated that treatment with felodipine once daily provides 24-hour antiischemic protection. Twenty-six patients were followed up with 20 mg of felodipine once daily for a mean of 6 f 5 months, and 21 of them (81%) remained free of symptoms and Holter-recorded ischemic attacks. It is concluded that for Prinsmetal’s angina pectoris, 24-hour antiischemit protection may be achieved with administration of felodipine once daily. The availability of a simplified therapeutic approach may constitute a real advantage in terms of patient compliance and improving the quality of life. (Am J Cardiol 1991;68:1587-1592)
alcium antagonists have proved to be effective in the treatment of Prinzmetal’s angina pectoris. Nifedipine,1-4 verapami15-7and diltiazem*-l1 have been shown to have comparable efficacy in reducing the occurrenceof angina, nitroglycerin consumption and ST-segmentchangesby Holter monitoring, both acutely and during chronic treatment. A recent study demonstrated that calcium antagonists improve prognosis in this syndrome by reducing the occurrence of myocardial infarction and mortality.12 Some recently developed calcium antagonists have promising pharmacological characteristicsfor the treatment of Prinzmetal’s angina, such as higher vascular selectivity and longer duration of action, which would allow once-daily administration. Although spontaneous remissionmay occur with Prinzmetal’s angina, continuous treatment is generally required13J4;therefore, the availability of a once-daily treatment may constitute a real advantagein terms of patient compliance and improving the quality of life. This study was performed to compare the short-term therapeutic efficacy of the dihydropyridine calcium antagonist felodipine, administered once daily, with that of its parent compound nifedipine administered at the well-establisheddoseof 20 mg 4 times daily. l5 The long-term efficacy and safety of felodipine was also evaluated.
C
METHODS
Patient selection: From August 1988 to October 1990, 30 consecutive patients were identified during hospitalization as having Prinzmetal’s variant angina pectoris and were enrolled in this study. AU patients had a typical history of chest pain at rest promptly relieved by nitroglycerin, an objective demonstration of transient ST-segmentelevation 20.1 mV on a standard 12-lead electrocardiogram during spontaneousattacks, and a positive responseto ergonovine or hyperventilation test performed according to methods that have been extensively described elsewhere.14J6None of the patients had any evidenceof myocardial necrosisafter From the Divisione di Cardiologia, Istituto di Riccvero e Cura a Carateither spontaneousor induced ischemic episodes.Exclutere Scientifico, Policlinicc San Matteo, Universita’degli Studi di Pavia, Pavia, and Servizio di Cardiologia, Policlinicc San Marco, Zingonia, sion criteria included: previous coronary artery bypass Italy. Manuscript received May 2, 1991;revised manuscript received or angioplasty; myocardial infarction within the precedand acceptedAugust 7,199 1. ing 6 months; congestive heart failure; systolic blood Addressfor reprints: Diego Ardissino, MD, Divisione di Cardiolopressure < 110 mmHg; electrocardiographicabnormaligia, IRCCS, Policlinico San Mattec, Universita’ di Pavia, 27100Pavia, Italy. ties that would interfere with the interpretation of STFELODIPINE AND NIFEDIPINE FOR ANGINA PECTORIS 1587
segment changes; known allergy to dihydropyridines; and serious concomitant illnesses. Written informed consent was obtained, and the study protocol and consent form were approved by the institutional review board. Study design: The study was a double-blind comparison (with the exception of the first 6 patients) of the short-term efficacy of felodipine extended-release tablets (10 and 20 mg once daily) with n&&pine capsules (20 mg 4 times daily) administered for 6 days each in randomized sequence,according to a 3 X 3 Latin square design. During run-in and the short-term study, blinding was maintained according to the double-dummy technique; patients were administered 2 felodipine tablets (10 mg) or placebo and 4 nifedipine capsules(20 mg) or placebo. Nifedipine was administered at 6.00 A.M. and 12.00 A.M., and at 6.00 P.M. and 12.00 P.M., whereasfelodipine was administered at 8.00 A.M. After completing this short-term protocol, patients began an open-label phase during which they received felodipine extended release tablets (20 mg) once daily. No concomitant prophylactic antianginal treatment was allowed during the entire study. Short-term study: After a 48-hour gradual withdrawal of previous antianginal medication patients began a 2-day placebo run-in period during which only sublingual nitroglycerin was administered to relieve anginal attacks. To prevent any possiblerisk while on placebo medication, patients were hospitalized in the coronary care unit under continuous electrocardiographic monitoring; the run-in period could be shortened, and the active double-blind treatment begun, if ischemia were severe enough to warrant the administration of active medication. Twenty-four-hour Holter monitoring was performed on the last day of the run-in period, and patients were then randomized to 1 of the 3 treatment sequences.On the last day of each phase of the active crossoverstudy, 24-hour Holter monitoring was repeated. During the study, patients kept a record by means of diary cards of the number, duration and severity of angina1 attacks, and the number of sublingual nitroglycerin tablets consumed. Blood samplesfor determination of plasma concentrations of nifedipine and felodipine were obtained by standardizedvenipuncture 2 to 3 hours after drug intake on the 5th day of each period and were immediately centrifuged. Plasma was immediately stored at -2OOC in opaque tubes and was kept frozen until analysis. Long-term follow-up: During long-term follow-up, felodipine (20 mg) was administered once daily at 8 A.M. Patients were examined every 2 months, and 24hour Holter monitoring was repeatedat each examination. Diary cards to record anginal symptoms, nitro-
1588
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68
glycerin consumption and side effects were kept by the patients as describedpreviously. A reduction in dosage to 10 mg of felodipine was allowed if the patient had no symptoms and signs of myocardial ischemia for the previous 6 months. In the case of persisting angina1 attacks or ischemic episodes,the investigators could administer nitrates or another calcium antagonist to patients. Patients undergoing coronary revascularization were withdrawn from the study; however, their maximal follow-up time was computed, and they were considered to have concluded the study. Study end points: The primary end points of the study were ischemic episodesrecorded on Holter monitoring and anginal attacks reported in the diary cards during active treatment. A secondary end point of the study was the circadian distribution of residual ST-segment changeson Holter monitoring as a measureof the 24-hour antiischemic activity of the drug regimens. Halter monitoring: Ambulatory electrocardiographic monitoring was performed using a Dehnar Avionics Electrocardiocorder model 445 with a frequency responseof 0.05 to 100 Hz, thereby meeting the American Heart Association specificationsfor heart rate and ST-segmentchanges.The leads showing the most evident electrocardiographic changes during spontaneous attacks were monitored. Leads with abnormal wavesor significant ST-segment shifts at rest were avoided, and control recordingswere obtained for each patient in the supine, prone, standing and sitting positions to ensure that the ST-segmentwas not affected by body position. The systemwas calibrated before and after each placement. Patients were instructed to pressthe “event button” on the recorder if they experiencedchest pain, and to report episodesof chest pain and consumption of nitroglycerin on the diary card. Tapes were analyzed at 60 times the real time under continuous visual inspection, and an episodeof transient &hernia was defined as I1 mm ST-segment elevation or depressionoccurring 80 ms after the J point, lasting for 2 1 minute and separatedfrom other episodesby > 1 minute. When a significant ST-segmentchange was noted on the monitor, the episode was recorded on electrocardiographic paper at 25 mm/s. Coronary arteriography: Selective coronary arteriography was performed in multiple views using the Sones or Judkins techniques after premeditation with 10 mg of diazepam. Narrowings of 170% were considered to be significant coronary stenoses.When a lesion was noted, the vesselwas filmed again after intracoronary administration of nitroglycerin. Patients were classified as having l-, 2- or 3-vessel disease according to the number of vesselswith significant coronary stenoses.
DECEMBER 15, 1991
Statistical analysis: The proportion of patients with either Holter-recorded ischemic episodesor angina1attacks during the randomized treatments were compared by meansof the McNemar test, with a 2-tailed p value 70%) 2-vessel disease (> 70%) *Two
2812 54 k 7 5 (17%) 9 (30%) 25 (83%)
16 (53%) 3 (10%) 6t 11 5+-7 4.1 * 4.5
10 (33%) 28* 7 (25%) 5 (17%) 13 (47%) 3 (11%)
patients refused coronary angiagraphy.
Short-term study: A dramatic reduction in ST-segment changes,angina1symptomsand nitroglycerin consumption was observedafter the initiation of the active medications irrespective of the drug administered (Table II). A complete absenceof signs and symptomswas observedin 22 patients during period 1, in 23 during period 2, and in 21 during period 3. The “per treatment” analysis irrespectiveof the sequenceof administration showed an equal number of patients with residual ischemic events and symptoms with all 3 randor+zed drugs (Table III). During the run-in period, ischemic ST-segmentchangesrecordedby Holter monitoring were distributed throughout the 24 hours with a preferential clustering between 1:00 and 6:00 A.M. (Figure 1). There was no correlation between the occurrence of residual ischemic episodesobservedduring all 3 active treatments and the time from last drug administration (Figure 1). Side effects were mild and infrequent. During the placebo run-in period, no patient reported any side effect; 1 reported flushing during all 3
TABLE II Time Course of lschemic Episodes, Angina1 Attacks and Nitroglycerin Consumption During the Short-Term Study Irrespective of the Randomized Treatments
No. of pts. with ischemic episodes or angina1 attacks 24-hour Holter No. of pts. with ischemic episodes Total no. of ischemic episodes Asymptomatic Symptomatic Diary cards No. of pts. with angina1 attacks Total no. of angina1 attacks Nitroglycerin consumption No. of days df observation No significant
Rlln-I? (27 pts.)
Period 1 (27 pts.)
Period 2 (27 pts.)
Period 3 (27 pts.)
22
5
4
6
19
3 8 7
2 3
3 2
1
1
1
2
1
4 13 3 152
4 14
5 9
122 80 42 20 56 25 46
10
157
1 163
differences were observed among the 3 pemds.
FELODIPINE AND NIFEDIPINE FOR ANGINA PECTORIS
1589
1~Bl.E III lschemic Episodes, Angina1 Attacks and Nitroglycerin Consumption During the Short-Term Study Irrespective of the Sequence of Administration Felodipine Nifedipine (27 pts.)
No. of pts. with ischemic episodes or angina1 attacks 24-hour Holter No. of patients with ischemic episodes Total no. of ischemic episodes Asymptomatic Symptomatic Diary cards No. of pts. with angina1 attacks Total no. of angina1 attacks Nitroglycerin consumption No. of days of observation No significant
differences were observed among the 3 treatment
treatments, and another reported flushing and gastralgia while receiving felodipine (20 mg). Long-term fellow-up: Twenty-six of the 27 patients completing the short-term study were followed up with felodipine for a period of 4 days to 16 months (mean 6
24 h
24 h
Felodipine 10 mu once daily
1590
20 mg (27 pts.)
5
7
3
3 7 6 1
3 4 1 3
2 2 2 0
4 13 2 162
6 16 12 148
3 7 0 162
groups.
f 5 months). The remaining patient was excluded becausehe was resident in an area too far away from our institution for follow-up to be possible.In all, 73 examinations were performed, and 1,440 hours of Holter monitoring were obtained. During this period, 21 pa-
24 h 12
Run-in
10 mg (27 pts.)
pm
Nifedipine 20 mg q.i.d.
24 h
Felodipine 20 mg once daily
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68
DECEMBER 15, 1991
FIGURE1. Twenty-four-hour distributii of symptomatic [b/ack &c/es) and asymptomatic (white circles) isdwmii opisodos on Wtor monitoring during run-in, 20 mg of nifodipino 4 times daily (q.i.d.), and 10 and 20 mg of folodipiti e daily. Each panel represents a W-hour clock; times of drug administration tire roprosontod by radii.
tients were free of symptoms and ischemic ST-changes on Holter monitoring. Two of these patients were withdrawn becauseof the developmentof ankle edema.The dosageof felodipine was reducedto 10 mg once daily in 12 patients who achieved a complete responsefor >6 months; no patient had anginal symptoms or electrocardiographic ischemia after dose reduction. Among 5 patients who did not achieveremission,4 reported anginal attacks, and &hernia was detected during Holter monitoring in 4 (2 had both painful and painless episodes, 1 had only painless, and 1 had only painful). Nitrates or another calcium antagonist were administered to 3 patients; the other 2 who had significant coronary artery diseaseunderwent coronary angioplasty. DISCUSSION Coronary artery spasm has been demonstrated as the pathogenetic mechanism of Primmetal’s angina.17J8Therefore, the therapeutic approach to this syndrome has been directed at preventing the occurrence of coronary spasm.Calcium antagoniststhat reduce the vascular smooth muscle cell contractility proved extremely effective in controlling symptoms and electrocardiographic signs of ischemia in these patients.‘-” In a previous study, we demonstrated the effectivenessof felodipine in preventing hyperventilation-induced coronary spasmin patients with Prinzmetal’s angina.lg Because felodipine is a long-acting calcium antagonist that has been shown to have 24-hour effectivenessas an antihypertensive agent20v21 we decided to test its clinical efficacy as a once-daily antiischemic treatment for Prinzmetal’s angina. Before inclusion in this study, all patients reported frequent angina1attacks, had a positive responseto provocative tests and had ST-segment elevation on electrocardiogram during spontaneo-usattacks. Nineteen patients also showed ischemic ST-segment changes on Holter monitoring, and 20 reported anginal attacks during the ran-in period preceding the study. The initiation of treatment with the calcium antagOnkt PrOdUCd a prompt, dramatic RdUCtiOIl iIT the frequency of angina1attacks, nitroglycerin consumption and ischemic changeson Holter monitoring. The therapeutic regimens tested in this study proved to be similarly effective and tolerated, no difference was detected betweeneither nifedipine and felodipine or felodipine at 2 different dosages.Analysis of the 24-hour distribution of residual ischemic episodesdemonstrated that treatment with felodipine once daily ensures 24-hour antiischemic protection. Spontaneousremission appears to be a frequent event in Prinzmetal’s angina,13J4and thus the absenceof a placebo control may be considered as a limitation of the present study. However, the promptness and completeness of remission observed
during all 3 periods of active treatment makesit unlikely that there was a spontaneousremission of the disease.Moreover, in view of the fact that calcium antagonists have been shown to improve prognosisin Prinzmetal’s angina12and that cardiac deaths and nonfatal myocardial infarctions occur mostly before hospital diicharge or within the first few months after hospitalization22-25we consideredit unethical to conduct a placebo-controlled study. An active-controlled study is more appropriate to test the efficacy of the new dihydropyridine calcium antagonist felodipine for Prinzrnetal’s angina, and consequentlyit was comparedwith its parent compound nifedipine administered at a well-established dosagein accordancewith previous reports on this syndrome.15Owing to the high antiischemic efficacy of calcium antagonists in Prinzmetal’s angina and to the relative rarity of this disease,the sample size required to reach a reasonably high power to exclude a statistically significant difference in efficacy between 2 active calcium antagonistswould require an exceedingly long period of time for patient enrollment, evenfor a specialized institution like ours. As a matter of fact, the 30 consecutivepatients reported in this study constitute the entire number of patients with Prinzmetal’s angina seen in our department during >2 years. However, our study allowed us to exclude, with a power of 0.8 and a type 1 error of 0.05, a difference betweenthe least and the most effective treatment >21% based on the measurement of efficacy as a binary outcome. The longterm effectivenessof administration of felodipine once daily was confirmed by the results of the follow-up study during which 81% of the patients remained completely free of symptoms and signs of myocardial ischemia.
REFERENCES 1. Heupler FA Jr, Proudtit WL. Nifedipine therapy for refractory coronary arterial spasm.Am J Cardiol 1979;44:798-803. 2. Goldberg S, Reichek N, Wilson J, Hirshfeld JW Jr, Mutler J, Kastor JA. Nifedipine in the treatment of Prinzmetal’s (variant) angina. Am J Cardiol 1g7g;44804-810,
’ M, SalernoJA, Tavazzi L, Ray M, Medici A, Chimienti M, Specchia 3. Previtali G, BobbaP.Treatment with anginaat rest with nifedipine:a short-termcontrolled study. Am J Cardiol 1980;45:825-830. 4. Antman E, Muller J, Goldberg S, McAlpin R, Rubentire M, Tabatznik B, Ltang C, Heupler F, Achuff S, Reichnek N, Geltman E, Kerin NZ, Neff R, Braunwald E. Nifedipine therapy for coronary-artery spasm.N Engl J Med 1g8~30~126g-1273, ’ ’ 0, Maseri A, Simonetti I. Managementof unstableangina at rest by 5. Parodi verapamil. A double-blindcross-overstudy in the coronary care unit. Br Heart J 1979;41:167-174. 6. JohnsonSM, Mauritson DR, Willerson JT, Hillis LD. A controlled trial of verapamil for Primmetal’s variant angina. N Engl J Med 1981;304:862-866. 7. Parodi 0, Simonetti I, L’Abbate A, Maseri A. Verapamil versuspropranolol for angina at rest. Am J Cardiol 1982;50:923-928. 6. Rosenthal SJ, Ginsburg R, Lamb IH, Bairn DS, SchroederJS. Efficacy of diltiazem for control of symptomsof coronary arterial spasm.Am J Cardiol
FELODIPINE AND NIFEDIPINE FOR ANGINA PECTORIS 1591
1980;46:1027-1032. 9. PepineCJ, FeldmanRL, Whittle J, Curry RC, Conti CR. Effect of diltiazem in patients with variant angina: a randomized double-blind trial. Am Heart J 1981;101:719-725. 10. SchroederJS, FeldmanRL, GileaTD, FriedmanMJ, De Maria AN, Kinney EL, Mallon SM, Pitt B, Meyer R, BastaLL, Curry RC, GrovesBM, Mac Alpin RN. Multiclinic controlled trial of diltiazem for Prinzmetal’sangina.Am J Med 1982;72:227-232. 11. FeldmanRL, PepineCJ, Whittle J, Curry RC, Conti CR. Short- and longterm responsesto diltiazem in patients with variant angina. Am J Cardiol 1982;49:554-559. 12. Yasue H, Takizawa A, Nagao M, Nishida S, Harie M, Kubota J, Omote S, Takaoka K, Okumura K. Long-term prognosisfor patients with variant angina and influential factors. Circularion 1988;78:1-9. 13. Waters DD, Bouchard A, Theroux P. Spontaneousremissionis a frequent outcome of variant angina. J Am Co11 Cardiol 1983;2:195-199. 14. Prcvitali M, Panciroli C, Ardissino D, Chimienti M, Angoli L, Salerno JA. Spontaneousremissionof variant angina documentedby Holter monitoring and ergonovine testing in patients treated with calcium antagonists.Am J Cardiol 1987;59:235-240. 15. Belier GA. Calcium antagonistsin the treatment of Prinzmetal’sangina and unstable angina pectoris. Circulation 1989;80:78-87. 16. Ardissino D, De Servi S, Barberis P, Demicheli G, Falcone C, Ochan M, SpecchiaG, Montemartini C. Significance of hyperventilation-inducedST segment depressionin patients with coronary artery disease.J Am CON Cardiol 1989;13:804-810.
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68
17. Oliva PB, Potts DE, Pluss RG. Coronary arterial spasmin Prinzmetal’s angina: documentation by coronary arteriography. N Engl J Med 1973;288: 745-751. 16. Maseri A, Mimmo R, Chierchia S, Marcheai C, Pesola A, L’Abbate A. Coronary spasm as a cause of myccardial &hernia in man. Chest 1975;68: 625-633. 19. Ardissino D, Savonitto S, Zanini P, De Servi S, Barberis P, Cavallotti G, SpecchiaG, Montemartini C. Effect of felodipine on hyperventilation-induced ischemicattacks in variant angina pectoris. Am J Cardiol 1989;63:104-107. 20. Campbell LM, Ross JRM, Goves JR, Lees TV, McCullagh A, Barnes P, Timerick SJB, RichardsonPDI. A dose-finding,placebo-controlledstudy of extendedreleasefelodipine once daily in treatment of hypertension.J Cardiowsc Pharmcol 1989;14:869-873. 21. Liedholm H, Melander A. A placebo-controlleddose-response study of felodipine extendedreleasein hypertensivepatients.J Cmdiooasc Pharmncol1989;14: 109-113. 22. SeveriS, DaviesG, Maseri A, Mar&o P, L’Abbate A. Long-term prognosis of “variant” angina with medical treatment. Am J Cardiol 1980;46:226-232. 23. Waters DD, Miller DD, Szlachic J, BouchardA, Methe M, Kreeft J, Theroux P. Factorsinfluencing the long-termprognosisof treated patientswith variant angina. Circulation 1983;68:258-265. 24. Mark DB, Califf RM, Morris KG, Arrell F, Pryor DP, Hlatky MA, Lee KL, Rosati RA. Clinical characteristicsand long-termsurvival of patientswith variant angina. Circulation 1984;69:880-888. 25. Walling A, Waters DD, Miller DD, Roy D, Pelletier GB, Theroux P. Longterm prognosisof patients with variant angina. Circulation 1987;76:990-997.
DECEMBER 15. 1991
In 30 consecutive patients with Prinzmetal’s angina pectoris, the antiischemic effect of felodipine, a new long-acting vasoselective calcium antagonist, administered at doses of 10 and 20 mg once daily was compared with that of the wellestablished therapeutic regimen with nifedipine administered at a dose of 20 mg 4 times daily. Twenty-four-hour Hoper monitoring was performed during a 2-day placebo run-in and at the end of each of 3 consecutive B-day periods during which the 3 active treatments were administered in randomized sequence. Three patients withdrew, whereas 27 completed the study. The therapeutic regimens tested proved to be similarly effective; primary end points (ischemic episodes recorded by Holter monitoring, and anginal attacks reported on diary cards) occurred in 5 patients (19%) during nifedipine treatment, and in 7 (26%) and 3 (11%) during felodipine treatment with 10 and 20 mg, respectively (p = not significant). The distribution of residual ischemic episodes demonstrated that treatment with felodipine once daily provides 24-hour antiischemic protection. Twenty-six patients were followed up with 20 mg of felodipine once daily for a mean of 6 f 5 months, and 21 of them (81%) remained free of symptoms and Holter-recorded ischemic attacks. It is concluded that for Prinsmetal’s angina pectoris, 24-hour antiischemit protection may be achieved with administration of felodipine once daily. The availability of a simplified therapeutic approach may constitute a real advantage in terms of patient compliance and improving the quality of life. (Am J Cardiol 1991;68:1587-1592)
alcium antagonists have proved to be effective in the treatment of Prinzmetal’s angina pectoris. Nifedipine,1-4 verapami15-7and diltiazem*-l1 have been shown to have comparable efficacy in reducing the occurrenceof angina, nitroglycerin consumption and ST-segmentchangesby Holter monitoring, both acutely and during chronic treatment. A recent study demonstrated that calcium antagonists improve prognosis in this syndrome by reducing the occurrence of myocardial infarction and mortality.12 Some recently developed calcium antagonists have promising pharmacological characteristicsfor the treatment of Prinzmetal’s angina, such as higher vascular selectivity and longer duration of action, which would allow once-daily administration. Although spontaneous remissionmay occur with Prinzmetal’s angina, continuous treatment is generally required13J4;therefore, the availability of a once-daily treatment may constitute a real advantagein terms of patient compliance and improving the quality of life. This study was performed to compare the short-term therapeutic efficacy of the dihydropyridine calcium antagonist felodipine, administered once daily, with that of its parent compound nifedipine administered at the well-establisheddoseof 20 mg 4 times daily. l5 The long-term efficacy and safety of felodipine was also evaluated.
C
METHODS
Patient selection: From August 1988 to October 1990, 30 consecutive patients were identified during hospitalization as having Prinzmetal’s variant angina pectoris and were enrolled in this study. AU patients had a typical history of chest pain at rest promptly relieved by nitroglycerin, an objective demonstration of transient ST-segmentelevation 20.1 mV on a standard 12-lead electrocardiogram during spontaneousattacks, and a positive responseto ergonovine or hyperventilation test performed according to methods that have been extensively described elsewhere.14J6None of the patients had any evidenceof myocardial necrosisafter From the Divisione di Cardiologia, Istituto di Riccvero e Cura a Carateither spontaneousor induced ischemic episodes.Exclutere Scientifico, Policlinicc San Matteo, Universita’degli Studi di Pavia, Pavia, and Servizio di Cardiologia, Policlinicc San Marco, Zingonia, sion criteria included: previous coronary artery bypass Italy. Manuscript received May 2, 1991;revised manuscript received or angioplasty; myocardial infarction within the precedand acceptedAugust 7,199 1. ing 6 months; congestive heart failure; systolic blood Addressfor reprints: Diego Ardissino, MD, Divisione di Cardiolopressure < 110 mmHg; electrocardiographicabnormaligia, IRCCS, Policlinico San Mattec, Universita’ di Pavia, 27100Pavia, Italy. ties that would interfere with the interpretation of STFELODIPINE AND NIFEDIPINE FOR ANGINA PECTORIS 1587
segment changes; known allergy to dihydropyridines; and serious concomitant illnesses. Written informed consent was obtained, and the study protocol and consent form were approved by the institutional review board. Study design: The study was a double-blind comparison (with the exception of the first 6 patients) of the short-term efficacy of felodipine extended-release tablets (10 and 20 mg once daily) with n&&pine capsules (20 mg 4 times daily) administered for 6 days each in randomized sequence,according to a 3 X 3 Latin square design. During run-in and the short-term study, blinding was maintained according to the double-dummy technique; patients were administered 2 felodipine tablets (10 mg) or placebo and 4 nifedipine capsules(20 mg) or placebo. Nifedipine was administered at 6.00 A.M. and 12.00 A.M., and at 6.00 P.M. and 12.00 P.M., whereasfelodipine was administered at 8.00 A.M. After completing this short-term protocol, patients began an open-label phase during which they received felodipine extended release tablets (20 mg) once daily. No concomitant prophylactic antianginal treatment was allowed during the entire study. Short-term study: After a 48-hour gradual withdrawal of previous antianginal medication patients began a 2-day placebo run-in period during which only sublingual nitroglycerin was administered to relieve anginal attacks. To prevent any possiblerisk while on placebo medication, patients were hospitalized in the coronary care unit under continuous electrocardiographic monitoring; the run-in period could be shortened, and the active double-blind treatment begun, if ischemia were severe enough to warrant the administration of active medication. Twenty-four-hour Holter monitoring was performed on the last day of the run-in period, and patients were then randomized to 1 of the 3 treatment sequences.On the last day of each phase of the active crossoverstudy, 24-hour Holter monitoring was repeated. During the study, patients kept a record by means of diary cards of the number, duration and severity of angina1 attacks, and the number of sublingual nitroglycerin tablets consumed. Blood samplesfor determination of plasma concentrations of nifedipine and felodipine were obtained by standardizedvenipuncture 2 to 3 hours after drug intake on the 5th day of each period and were immediately centrifuged. Plasma was immediately stored at -2OOC in opaque tubes and was kept frozen until analysis. Long-term follow-up: During long-term follow-up, felodipine (20 mg) was administered once daily at 8 A.M. Patients were examined every 2 months, and 24hour Holter monitoring was repeatedat each examination. Diary cards to record anginal symptoms, nitro-
1588
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68
glycerin consumption and side effects were kept by the patients as describedpreviously. A reduction in dosage to 10 mg of felodipine was allowed if the patient had no symptoms and signs of myocardial ischemia for the previous 6 months. In the case of persisting angina1 attacks or ischemic episodes,the investigators could administer nitrates or another calcium antagonist to patients. Patients undergoing coronary revascularization were withdrawn from the study; however, their maximal follow-up time was computed, and they were considered to have concluded the study. Study end points: The primary end points of the study were ischemic episodesrecorded on Holter monitoring and anginal attacks reported in the diary cards during active treatment. A secondary end point of the study was the circadian distribution of residual ST-segment changeson Holter monitoring as a measureof the 24-hour antiischemic activity of the drug regimens. Halter monitoring: Ambulatory electrocardiographic monitoring was performed using a Dehnar Avionics Electrocardiocorder model 445 with a frequency responseof 0.05 to 100 Hz, thereby meeting the American Heart Association specificationsfor heart rate and ST-segmentchanges.The leads showing the most evident electrocardiographic changes during spontaneous attacks were monitored. Leads with abnormal wavesor significant ST-segment shifts at rest were avoided, and control recordingswere obtained for each patient in the supine, prone, standing and sitting positions to ensure that the ST-segmentwas not affected by body position. The systemwas calibrated before and after each placement. Patients were instructed to pressthe “event button” on the recorder if they experiencedchest pain, and to report episodesof chest pain and consumption of nitroglycerin on the diary card. Tapes were analyzed at 60 times the real time under continuous visual inspection, and an episodeof transient &hernia was defined as I1 mm ST-segment elevation or depressionoccurring 80 ms after the J point, lasting for 2 1 minute and separatedfrom other episodesby > 1 minute. When a significant ST-segmentchange was noted on the monitor, the episode was recorded on electrocardiographic paper at 25 mm/s. Coronary arteriography: Selective coronary arteriography was performed in multiple views using the Sones or Judkins techniques after premeditation with 10 mg of diazepam. Narrowings of 170% were considered to be significant coronary stenoses.When a lesion was noted, the vesselwas filmed again after intracoronary administration of nitroglycerin. Patients were classified as having l-, 2- or 3-vessel disease according to the number of vesselswith significant coronary stenoses.
DECEMBER 15, 1991
Statistical analysis: The proportion of patients with either Holter-recorded ischemic episodesor angina1attacks during the randomized treatments were compared by meansof the McNemar test, with a 2-tailed p value 70%) 2-vessel disease (> 70%) *Two
2812 54 k 7 5 (17%) 9 (30%) 25 (83%)
16 (53%) 3 (10%) 6t 11 5+-7 4.1 * 4.5
10 (33%) 28* 7 (25%) 5 (17%) 13 (47%) 3 (11%)
patients refused coronary angiagraphy.
Short-term study: A dramatic reduction in ST-segment changes,angina1symptomsand nitroglycerin consumption was observedafter the initiation of the active medications irrespective of the drug administered (Table II). A complete absenceof signs and symptomswas observedin 22 patients during period 1, in 23 during period 2, and in 21 during period 3. The “per treatment” analysis irrespectiveof the sequenceof administration showed an equal number of patients with residual ischemic events and symptoms with all 3 randor+zed drugs (Table III). During the run-in period, ischemic ST-segmentchangesrecordedby Holter monitoring were distributed throughout the 24 hours with a preferential clustering between 1:00 and 6:00 A.M. (Figure 1). There was no correlation between the occurrence of residual ischemic episodesobservedduring all 3 active treatments and the time from last drug administration (Figure 1). Side effects were mild and infrequent. During the placebo run-in period, no patient reported any side effect; 1 reported flushing during all 3
TABLE II Time Course of lschemic Episodes, Angina1 Attacks and Nitroglycerin Consumption During the Short-Term Study Irrespective of the Randomized Treatments
No. of pts. with ischemic episodes or angina1 attacks 24-hour Holter No. of pts. with ischemic episodes Total no. of ischemic episodes Asymptomatic Symptomatic Diary cards No. of pts. with angina1 attacks Total no. of angina1 attacks Nitroglycerin consumption No. of days df observation No significant
Rlln-I? (27 pts.)
Period 1 (27 pts.)
Period 2 (27 pts.)
Period 3 (27 pts.)
22
5
4
6
19
3 8 7
2 3
3 2
1
1
1
2
1
4 13 3 152
4 14
5 9
122 80 42 20 56 25 46
10
157
1 163
differences were observed among the 3 pemds.
FELODIPINE AND NIFEDIPINE FOR ANGINA PECTORIS
1589
1~Bl.E III lschemic Episodes, Angina1 Attacks and Nitroglycerin Consumption During the Short-Term Study Irrespective of the Sequence of Administration Felodipine Nifedipine (27 pts.)
No. of pts. with ischemic episodes or angina1 attacks 24-hour Holter No. of patients with ischemic episodes Total no. of ischemic episodes Asymptomatic Symptomatic Diary cards No. of pts. with angina1 attacks Total no. of angina1 attacks Nitroglycerin consumption No. of days of observation No significant
differences were observed among the 3 treatment
treatments, and another reported flushing and gastralgia while receiving felodipine (20 mg). Long-term fellow-up: Twenty-six of the 27 patients completing the short-term study were followed up with felodipine for a period of 4 days to 16 months (mean 6
24 h
24 h
Felodipine 10 mu once daily
1590
20 mg (27 pts.)
5
7
3
3 7 6 1
3 4 1 3
2 2 2 0
4 13 2 162
6 16 12 148
3 7 0 162
groups.
f 5 months). The remaining patient was excluded becausehe was resident in an area too far away from our institution for follow-up to be possible.In all, 73 examinations were performed, and 1,440 hours of Holter monitoring were obtained. During this period, 21 pa-
24 h 12
Run-in
10 mg (27 pts.)
pm
Nifedipine 20 mg q.i.d.
24 h
Felodipine 20 mg once daily
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68
DECEMBER 15, 1991
FIGURE1. Twenty-four-hour distributii of symptomatic [b/ack &c/es) and asymptomatic (white circles) isdwmii opisodos on Wtor monitoring during run-in, 20 mg of nifodipino 4 times daily (q.i.d.), and 10 and 20 mg of folodipiti e daily. Each panel represents a W-hour clock; times of drug administration tire roprosontod by radii.
tients were free of symptoms and ischemic ST-changes on Holter monitoring. Two of these patients were withdrawn becauseof the developmentof ankle edema.The dosageof felodipine was reducedto 10 mg once daily in 12 patients who achieved a complete responsefor >6 months; no patient had anginal symptoms or electrocardiographic ischemia after dose reduction. Among 5 patients who did not achieveremission,4 reported anginal attacks, and &hernia was detected during Holter monitoring in 4 (2 had both painful and painless episodes, 1 had only painless, and 1 had only painful). Nitrates or another calcium antagonist were administered to 3 patients; the other 2 who had significant coronary artery diseaseunderwent coronary angioplasty. DISCUSSION Coronary artery spasm has been demonstrated as the pathogenetic mechanism of Primmetal’s angina.17J8Therefore, the therapeutic approach to this syndrome has been directed at preventing the occurrence of coronary spasm.Calcium antagoniststhat reduce the vascular smooth muscle cell contractility proved extremely effective in controlling symptoms and electrocardiographic signs of ischemia in these patients.‘-” In a previous study, we demonstrated the effectivenessof felodipine in preventing hyperventilation-induced coronary spasmin patients with Prinzmetal’s angina.lg Because felodipine is a long-acting calcium antagonist that has been shown to have 24-hour effectivenessas an antihypertensive agent20v21 we decided to test its clinical efficacy as a once-daily antiischemic treatment for Prinzmetal’s angina. Before inclusion in this study, all patients reported frequent angina1attacks, had a positive responseto provocative tests and had ST-segment elevation on electrocardiogram during spontaneo-usattacks. Nineteen patients also showed ischemic ST-segment changes on Holter monitoring, and 20 reported anginal attacks during the ran-in period preceding the study. The initiation of treatment with the calcium antagOnkt PrOdUCd a prompt, dramatic RdUCtiOIl iIT the frequency of angina1attacks, nitroglycerin consumption and ischemic changeson Holter monitoring. The therapeutic regimens tested in this study proved to be similarly effective and tolerated, no difference was detected betweeneither nifedipine and felodipine or felodipine at 2 different dosages.Analysis of the 24-hour distribution of residual ischemic episodesdemonstrated that treatment with felodipine once daily ensures 24-hour antiischemic protection. Spontaneousremission appears to be a frequent event in Prinzmetal’s angina,13J4and thus the absenceof a placebo control may be considered as a limitation of the present study. However, the promptness and completeness of remission observed
during all 3 periods of active treatment makesit unlikely that there was a spontaneousremission of the disease.Moreover, in view of the fact that calcium antagonists have been shown to improve prognosisin Prinzmetal’s angina12and that cardiac deaths and nonfatal myocardial infarctions occur mostly before hospital diicharge or within the first few months after hospitalization22-25we consideredit unethical to conduct a placebo-controlled study. An active-controlled study is more appropriate to test the efficacy of the new dihydropyridine calcium antagonist felodipine for Prinzrnetal’s angina, and consequentlyit was comparedwith its parent compound nifedipine administered at a well-established dosagein accordancewith previous reports on this syndrome.15Owing to the high antiischemic efficacy of calcium antagonists in Prinzmetal’s angina and to the relative rarity of this disease,the sample size required to reach a reasonably high power to exclude a statistically significant difference in efficacy between 2 active calcium antagonistswould require an exceedingly long period of time for patient enrollment, evenfor a specialized institution like ours. As a matter of fact, the 30 consecutivepatients reported in this study constitute the entire number of patients with Prinzmetal’s angina seen in our department during >2 years. However, our study allowed us to exclude, with a power of 0.8 and a type 1 error of 0.05, a difference betweenthe least and the most effective treatment >21% based on the measurement of efficacy as a binary outcome. The longterm effectivenessof administration of felodipine once daily was confirmed by the results of the follow-up study during which 81% of the patients remained completely free of symptoms and signs of myocardial ischemia.
REFERENCES 1. Heupler FA Jr, Proudtit WL. Nifedipine therapy for refractory coronary arterial spasm.Am J Cardiol 1979;44:798-803. 2. Goldberg S, Reichek N, Wilson J, Hirshfeld JW Jr, Mutler J, Kastor JA. Nifedipine in the treatment of Prinzmetal’s (variant) angina. Am J Cardiol 1g7g;44804-810,
’ M, SalernoJA, Tavazzi L, Ray M, Medici A, Chimienti M, Specchia 3. Previtali G, BobbaP.Treatment with anginaat rest with nifedipine:a short-termcontrolled study. Am J Cardiol 1980;45:825-830. 4. Antman E, Muller J, Goldberg S, McAlpin R, Rubentire M, Tabatznik B, Ltang C, Heupler F, Achuff S, Reichnek N, Geltman E, Kerin NZ, Neff R, Braunwald E. Nifedipine therapy for coronary-artery spasm.N Engl J Med 1g8~30~126g-1273, ’ ’ 0, Maseri A, Simonetti I. Managementof unstableangina at rest by 5. Parodi verapamil. A double-blindcross-overstudy in the coronary care unit. Br Heart J 1979;41:167-174. 6. JohnsonSM, Mauritson DR, Willerson JT, Hillis LD. A controlled trial of verapamil for Primmetal’s variant angina. N Engl J Med 1981;304:862-866. 7. Parodi 0, Simonetti I, L’Abbate A, Maseri A. Verapamil versuspropranolol for angina at rest. Am J Cardiol 1982;50:923-928. 6. Rosenthal SJ, Ginsburg R, Lamb IH, Bairn DS, SchroederJS. Efficacy of diltiazem for control of symptomsof coronary arterial spasm.Am J Cardiol
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1980;46:1027-1032. 9. PepineCJ, FeldmanRL, Whittle J, Curry RC, Conti CR. Effect of diltiazem in patients with variant angina: a randomized double-blind trial. Am Heart J 1981;101:719-725. 10. SchroederJS, FeldmanRL, GileaTD, FriedmanMJ, De Maria AN, Kinney EL, Mallon SM, Pitt B, Meyer R, BastaLL, Curry RC, GrovesBM, Mac Alpin RN. Multiclinic controlled trial of diltiazem for Prinzmetal’sangina.Am J Med 1982;72:227-232. 11. FeldmanRL, PepineCJ, Whittle J, Curry RC, Conti CR. Short- and longterm responsesto diltiazem in patients with variant angina. Am J Cardiol 1982;49:554-559. 12. Yasue H, Takizawa A, Nagao M, Nishida S, Harie M, Kubota J, Omote S, Takaoka K, Okumura K. Long-term prognosisfor patients with variant angina and influential factors. Circularion 1988;78:1-9. 13. Waters DD, Bouchard A, Theroux P. Spontaneousremissionis a frequent outcome of variant angina. J Am Co11 Cardiol 1983;2:195-199. 14. Prcvitali M, Panciroli C, Ardissino D, Chimienti M, Angoli L, Salerno JA. Spontaneousremissionof variant angina documentedby Holter monitoring and ergonovine testing in patients treated with calcium antagonists.Am J Cardiol 1987;59:235-240. 15. Belier GA. Calcium antagonistsin the treatment of Prinzmetal’sangina and unstable angina pectoris. Circulation 1989;80:78-87. 16. Ardissino D, De Servi S, Barberis P, Demicheli G, Falcone C, Ochan M, SpecchiaG, Montemartini C. Significance of hyperventilation-inducedST segment depressionin patients with coronary artery disease.J Am CON Cardiol 1989;13:804-810.
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17. Oliva PB, Potts DE, Pluss RG. Coronary arterial spasmin Prinzmetal’s angina: documentation by coronary arteriography. N Engl J Med 1973;288: 745-751. 16. Maseri A, Mimmo R, Chierchia S, Marcheai C, Pesola A, L’Abbate A. Coronary spasm as a cause of myccardial &hernia in man. Chest 1975;68: 625-633. 19. Ardissino D, Savonitto S, Zanini P, De Servi S, Barberis P, Cavallotti G, SpecchiaG, Montemartini C. Effect of felodipine on hyperventilation-induced ischemicattacks in variant angina pectoris. Am J Cardiol 1989;63:104-107. 20. Campbell LM, Ross JRM, Goves JR, Lees TV, McCullagh A, Barnes P, Timerick SJB, RichardsonPDI. A dose-finding,placebo-controlledstudy of extendedreleasefelodipine once daily in treatment of hypertension.J Cardiowsc Pharmcol 1989;14:869-873. 21. Liedholm H, Melander A. A placebo-controlleddose-response study of felodipine extendedreleasein hypertensivepatients.J Cmdiooasc Pharmncol1989;14: 109-113. 22. SeveriS, DaviesG, Maseri A, Mar&o P, L’Abbate A. Long-term prognosis of “variant” angina with medical treatment. Am J Cardiol 1980;46:226-232. 23. Waters DD, Miller DD, Szlachic J, BouchardA, Methe M, Kreeft J, Theroux P. Factorsinfluencing the long-termprognosisof treated patientswith variant angina. Circulation 1983;68:258-265. 24. Mark DB, Califf RM, Morris KG, Arrell F, Pryor DP, Hlatky MA, Lee KL, Rosati RA. Clinical characteristicsand long-termsurvival of patientswith variant angina. Circulation 1984;69:880-888. 25. Walling A, Waters DD, Miller DD, Roy D, Pelletier GB, Theroux P. Longterm prognosisof patients with variant angina. Circulation 1987;76:990-997.
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