- Email: [email protected]
Overview of the Safety of Felodipine Based on Clinical Trials in Patients With Hypertension
Overview of the Safety of Felodipine Based on Clinical Trials in Patients With Hypertension Lennart Welin,
MD, PhD ,
Lars Elvelin, DDS, Anne Niklasson, and Dag Elmfeldt, MD, PhD
he safety of calcium antagonists has recently been questioned. A case-control study indicated T greater risk of myocardial infarction in hypertensive patients treated with short-acting calcium antagonists than in those treated with diuretics or b blockers.1 A metaanalysis of studies with short-acting nifedipine in patients with unstable angina pectoris and myocardial infarction found that high doses of nifedipine capsules were associated with increased mortality.2 A likely explanation of adverse clinical effects of nifedipine capsules is the sharp peak in plasma concentrations after each dose, which may cause excessive hypotension and baroreflex-mediated tachycardia.3 Felodipine is a newer generation dihydropyridine calcium antagonist, which dilates resistance vessels and reduces blood pressure without effects on cardiac contractility or conduction at therapeutic doses.4 It provides smooth drug plasma concentrations and stable blood pressure reduction with little or no effects on heart rate when given as extended-release tablets.5,6 The purpose of this report is to review the complete data on mortality and important cardiovascular events from clinical studies reported as of October 1995 using felodipine in hypertension. jjj All randomized, double-blind, controlled clinical studies of at least 1-week duration with felodipine in hypertension performed by Astra or its licensees and reported by October 1995 were pooled. The end points analyzed in the felodipine and reference groups were total mortality, myocardial infarction, stroke, angina pectoris, heart failure, malignant arrhythmias, serious bleeding, and hypotension/syncope. In addition, the combined end point of ‘‘major cardiovascular events’’ (cardiovascular death plus nonfatal myocardial infarction and stroke) was calculated. The records kept by Astra are complete, as all the events of interest fulfill the criteria for a serious adverse event, and must be reported and filed. An adverse event was defined as any unintended, unfavorable clinical sign, symptom, medical complaint, or clinically relevant change in laboratory tests, whether or not it is considered drug related. A serious adverse event was defined as an adverse event that suggests a significant hazard or disability to the patient.
From Clinical R&D, Astra Ha¨ssle AB, Mo¨lndal, Sweden. Dr. Welin’s address is: Clinical Drug Safety, Clinical R&D, Astra Ha¨ssle AB, S431 83 Mo¨lndal, Sweden. Manuscript received August 26 1996; revised manuscript received and accepted November 25, 1996.
996
RN,
Gunnar Olsson,
Data on total mortality, myocardial infarction, and stroke from 6 large, open postmarketing studies with felodipine in hypertensive patients are also included in the present report. Because these studies lack a control group, published data on mortality and morbidity from other large populations of treated hypertensive patients were used to put the findings in some perspective.7 – 11 Only descriptive data are presented, normalized to events per 1,000 patient-years. Formal statistical analyses were not performed because of rather few end points. jjj The comparisons between felodipine and reference drug (placebo or active) regarding mortality and cardiovascular events gave similar results in studies using extended-release tablets of felodipine once daily (73% of patients) or the plain tablet formulation twice daily (27% of patients). Furthermore, comparisons between groups yielded similar results if the drugs were given as monotherapy or added to existing background therapy, for example, with a b blocker. Therefore, the data presented are based on the pooled material of all felodipine studies, irrespective of formulation used or whether the drugs were given as monotherapy. There were 72 randomized, double-blind, placebo-controlled studies with felodipine in hypertensive patients. A total of 3,594 patients were given felodipine, and 1,926 patients received placebo for an average treatment duration of 65 and 67 days, respectively. More patients were given felodipine than placebo because of randomization to several felodipine doses in some of the studies. The drugs were given as monotherapy in approximately 60% of the patients and in the remainder as a combination, usually with a b blocker. Table I details the incidence of death and cardiovascular events in the 2 groups. Generally, the incidences were low and numerically lower in the felodipine than in the placebo group, indicating a favorable effect of felodipine. The only exception was syncope, which was seen more often among actively treated than placebo-treated patients. Felodipine was compared with an active reference drug in 89 randomized, double-blind studies (Table II). Felodipine was given to 3,860 patients and the active reference to 3,440 patients for an average treatment duration of 70 and 69 days, respectively. The reference compounds were other calcium antagonists (33% of the patients), diuretics (27%), angiotensin-converting enzyme inhibitors (16%), b blockers (15%), and other agents (9%). Generally, the mortality and the incidence of events were low
Q1997 by Excerpta Medica, Inc. All rights reserved.
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Thursday Mar 06 12:33 AM
MD, PhD ,
0002-9149/97/$17.00 PII S0002-9149(97)00034-9
EL–AJC (v. 79, no. 7 ’97)
0906
TABLE I Mortality and Incidence of Cardiovascular Events in 72 Double-Blind Hypertension Studies Comparing Felodipine* With Placebo† Felodipine
Mortality (total) Cardiovascular Noncardiovascular Myocardial infarction Stroke Major cardiovascular events‡ Malignant arrhythmias Angina pectoris Congestive heart failure Syncope Bleeding (serious)
Placebo
No. of Patients
Events/1,000 Patient-Years
No. of Patients
Events/1,000 Patient-Years
3 3 0 2 4 7 0 4 2 8 2
4.7 4.7 0 3.1 6.2 10.9 0 6.2 3.1 12.4 3.1
4 4 0 5 4 11 0 5 2 2 4
11.3 11.3 0 14.2 11.3 31.2 0 14.2 5.7 5.7 11.3
*Felodipine—n Å 3,594; patient-years Å 643, i.e., average treatment duration 65 days. † Placebo—n Å 1,926; patient-years Å 353, i.e., average treatment duration 67 days. ‡ Cardiovascular mortality / nonfatal myocardial infarction / nonfatal stroke.
TABLE II Mortality and Incidence of Cardiovascular Events in 89 Double-Blind Hypertension Studies Comparing Felodipine* With Other Antihypertensive Drugs† Felodipine
Mortality (total) Cardiovascular Noncardiovascular Myocardial infarction Stroke Major cardiovascular events‡ Malignant arrhythmias Angina pectoris Congestive heart failure Syncope Bleeding (serious)
Other Drugs
No. of Patients
Events/1,000 Patient-Years
No. of Patients
Events/1,000 Patient-Years
7 7 0 2 7 13 0 12 4 7 3
9.5 9.5 0 2.7 9.5 17.6 0 16.2 5.4 9.5 4.1
8 4 4 4 4 10 0 11 6 8 3
12.3 6.1 6.1 6.1 6.1 15.4 0 16.9 9.2 12.3 4.6
*Felodipine—n Å 3,860; patient-years Å 740, i.e., average treatment duration 70 days. † Other antihypertensive drugs—n Å 3,440; patient-years Å 651, i.e., average treatment duration 69 days. ‡ Cardiovascular mortality / nonfatal myocardial infarction / nonfatal stroke.
and similar in the felodipine and reference groups. Table III differs from Table II because studies comparing felodipine with other calcium antagonists have been omitted. Although the figures were generally small, they indicated a more favorable effect of felodipine on most events. A total of 60,827 patients with hypertension (mean age 59 years), representing 8,681 patient-years of felodipine exposure, were included in 6 large, open, postmarketing studies of 6 to 12 week’s duration. Table IV gives the number of deaths and the incidence of fatal and nonfatal myocardial infarction and stroke in these studies. Felodipine was administered as extended-release tablets once daily in all studies except the Australian study, in which plain tablets were given twice daily. The pooled data showed that total deaths were 3.3 (95% confidence interval [CI] 2.2 to 4.8), the incidence of myocardial infarction was 2.3 (CI 1.4 to 3.6), and the incidence of stroke 1.8 (CI 1.0 to 3.0) per 1,000 patient-years. Figure 1 also presents event rates in the active intervention groups in 5 large and well-known clinical antihypertensive treatment trials of 2 to 6 years’ duration using diuretics and b blockers.7 – 11 The data do not indicate a higher event rate during treatment with felodipine compared with other antihypertensive treatment.
TABLE III Mortality and Incidence of Cardiovascular Events in 58 Double-Blind Hypertension Studies Comparing Felodipine* With Other Antihypertensive Drugs, Excluding Calcium Antagonists† Other Drugs Excluding Calcium Channel Blockers
Felodipine
Mortality (total) Cardiovascular Noncardiovascular Myocardial infarction Stroke Major cardiovascular events‡ Malignant arrhythmias Angina pectoris Congestive heart failure Syncope Bleeding (serious)
No. of Patients
Events/1,000 Patient-Years
No. of Patients
Events/1,000 Patient-Years
4 4 0 2 6 10 0 8 4 7 3
7.1 7.1 0 3.6 10.7 17.8 0 14.2 7.1 12.5 5.3
7 3 4 4 3 8 0 10 5 7 3
14.8 6.3 8.4 8.4 6.3 16.9 0 21.1 10.5 14.8 6.3
*Felodipine, n Å 2,699; patient-years Å 562, i.e., average treatment duration 76 days. † Other antihypertensive drugs excluding calcium antagonists, n Å 2,290; patient-years Å 474, i.e., average treatment duration 76 days. ‡ Cardiovascular mortality / nonfatal infarction / nonfatal stroke.
BRIEF REPORTS
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TABLE IV Overview of Large, Postmarketing Studies With Felodipine in Hypertension Study (country)
No. of Patients
Treatment Duration (d)
Patient-Years
Mean Age (yr)
Men (%)
1 (Germany) 2 (France) 3 (France) 4 (Australia) 5 (Germany) 6 (Belgium) Total
19,177 18,164 13,787 5,071 3,470 1,158 60,827
42 60 60 56 84 63 42–84
2,109 2,660 2,233 716 775 188 8,681
58 61 61 58 57 58 59
53 48 52 46 54 47 50
Deaths* 8 10 4 7
(3.8) (3.8) (1.8) (9.8) 0 0 29 (3.3)
Myocardial Infarction* 5 5 1 6 1 2 20
(2.4) (1.9) (0.4) (8.4) (1.3) (10.6) (2.3)
Stroke* 4 5 2 5
(1.9) (1.9) (0.9) (7.0) 0 0 16 (1.8)
*Numbers in parentheses represent event rate/1,000 patient-years of exposure.
FIGURE 1. Total mortality and incidence of myocardial infarction and stroke in 6 postmarketing studies (PMS) with felodipine (n Å 60,827, patient-years Å 8,681) and in the active intervention groups in 5 major hypertension studies (Australian Study, 7 Medical Research Council [MRC] 1985 8 and 1992, 9 Systolic Hypertension in the Elderly Program [SHEP], 10 and Swedish Trial in Old Patients [STOP] with Hypertension. 11 The 95% confidence intervals for the felodipine data are indicated by bars.
jjj This report summarizes the worldwide safety experience from clinical studies with felodipine in hypertension. All studies performed by Astra or its licensees, whether published or unpublished, were included in this analysis, avoiding any publication bias in favor of positive studies. There was no indication that antihypertensive treatment with felodipine increases the risk of death or major cardiovascular events on short-term exposure. Results from prospective, randomized, controlled, long-term studies with felodipine or other calcium antagonists focusing on the incidence of major cardiovascular events are thus far not available. However, several such trials are ongoing and results will be available in a few years.12,13 In the Hypertension Optimal Treatment Study, which investigates the relationship between 3 target diastolic blood pressures and major cardiovascular events, felodipine is being used as the baseline antihypertensive drug.14,15 At present, all patients have been followed for ¢2 years and the total exposure amounts to approximately 60,000 patient998
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years. To date, the observed incidence of events is lower than expected based on the risk calculated from baseline characteristics of the study population. Potentially harmful effects of calcium antagonists that recently have been proposed are hypotensive, proischemic, proarrhythmic, prohemorrhagic, and negative inotropic effects.2 In the current analysis of felodipine studies, we found no support for such effects. For example, serious bleeding appeared to be less common with felodipine than with placebo, and occurred with a similar incidence as other active drugs. With regard to hypotension / syncope, more episodes were reported with felodipine than with placebo, but there was no difference between felodipine and other active antihypertensive drugs. In conclusion, in a safety analysis including all double-blind, randomized studies and postmarketing studies with felodipine in hypertension, there was no indication that felodipine treatment increases total mortality or the incidence of cardioAPRIL 1, 1997
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0906
vascular events. On the contrary, there was a trend for fewer cardiovascular events with felodipine than with placebo.
1. Psaty BM, Heckberg SR, Koepsell TD, Siscovick DS, Raghunathan TE,
Weiss NS, Rosendaal FR, Lemaitre RN, Smith NL, Wahl PW, Wagner EH, Furberg CD. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995;274:620–625. 2. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326–1331. 3. Epstein M. Calcium antagonists: still appropriate as first line antihypertensive agents. Am J Hypertens 1996;9:110–121. 4. Little WC, Cheng C-P, Elvelin L, Nordlander M. Vascular selective calcium entry blockers in the treatment of cardiovascular disorders. Focus on felodipine. Cardiovasc Drug Ther 1995;9:657–663. 5. Pannarale G, Puddu PE, Monti F, Irace L, Bentivoglio M, Collauto F, Barsotti A, Corea L, Trevi G, Campa PP, Jacono A. Twenty-four-hour antihypertensive efficacy of felodipine 10 mg extended-release: the Italian inter-university study. J Cardiovasc Pharmacol 1996;27:255–261. 6. Elvelin L, Jo¨nsson L. The effect of dihydropyridine calcium antagonists on heart rate: studies of felodipine. Curr Ther Res 1994;55:736–746.
7. Report by the Management Committee. The Australian therapeutic trial in mild hypertension. Lancet 1980;i:1261–1267. 8. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985;291:97–104. 9. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. Br Med J 1992;304:405–412. 10. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1991;265:3255–3264. 11. Dahlo¨f B, Lindholm LH, Hansson L, Scherste´n B, Ekbom T, Wester P-O. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991;338:1281–1285. 12. Grimm RH Jr, Whelton DP, Pressel S, for the ALLHAT Research Group. The antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT): update on recruitment and baseline characteristics. Am J Hypertens 1996;9:26A. 13. Dahlo¨f B, Hansson L, Lindholm LH, Scherste´n B, Wester P-O, Ekbom T, Hedner T, De Faire U. STOP-Hypertension 2: a prospective intervention trial of ‘‘newer’’ versus ‘‘older’’ treatment alternatives in old patients with hypertension. Blood Press 1993;2:136–141. 14. Hansson L, for the HOT Study Group. The Hypertension Optimal Treatment Study (The HOT study). Blood Press 1993;2:62–68. 15. Hansson L, Zanchetti A, for the HOT Study Group. The Hypertension Optimal Treatment (HOT) Study: 12-month data on blood pressure and tolerability. With special reference to age and gender. Blood Press 1995;4:313–319.
BRIEF REPORTS
/ 2w1e 0906 Mp
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MD, PhD ,
Lars Elvelin, DDS, Anne Niklasson, and Dag Elmfeldt, MD, PhD
he safety of calcium antagonists has recently been questioned. A case-control study indicated T greater risk of myocardial infarction in hypertensive patients treated with short-acting calcium antagonists than in those treated with diuretics or b blockers.1 A metaanalysis of studies with short-acting nifedipine in patients with unstable angina pectoris and myocardial infarction found that high doses of nifedipine capsules were associated with increased mortality.2 A likely explanation of adverse clinical effects of nifedipine capsules is the sharp peak in plasma concentrations after each dose, which may cause excessive hypotension and baroreflex-mediated tachycardia.3 Felodipine is a newer generation dihydropyridine calcium antagonist, which dilates resistance vessels and reduces blood pressure without effects on cardiac contractility or conduction at therapeutic doses.4 It provides smooth drug plasma concentrations and stable blood pressure reduction with little or no effects on heart rate when given as extended-release tablets.5,6 The purpose of this report is to review the complete data on mortality and important cardiovascular events from clinical studies reported as of October 1995 using felodipine in hypertension. jjj All randomized, double-blind, controlled clinical studies of at least 1-week duration with felodipine in hypertension performed by Astra or its licensees and reported by October 1995 were pooled. The end points analyzed in the felodipine and reference groups were total mortality, myocardial infarction, stroke, angina pectoris, heart failure, malignant arrhythmias, serious bleeding, and hypotension/syncope. In addition, the combined end point of ‘‘major cardiovascular events’’ (cardiovascular death plus nonfatal myocardial infarction and stroke) was calculated. The records kept by Astra are complete, as all the events of interest fulfill the criteria for a serious adverse event, and must be reported and filed. An adverse event was defined as any unintended, unfavorable clinical sign, symptom, medical complaint, or clinically relevant change in laboratory tests, whether or not it is considered drug related. A serious adverse event was defined as an adverse event that suggests a significant hazard or disability to the patient.
From Clinical R&D, Astra Ha¨ssle AB, Mo¨lndal, Sweden. Dr. Welin’s address is: Clinical Drug Safety, Clinical R&D, Astra Ha¨ssle AB, S431 83 Mo¨lndal, Sweden. Manuscript received August 26 1996; revised manuscript received and accepted November 25, 1996.
996
RN,
Gunnar Olsson,
Data on total mortality, myocardial infarction, and stroke from 6 large, open postmarketing studies with felodipine in hypertensive patients are also included in the present report. Because these studies lack a control group, published data on mortality and morbidity from other large populations of treated hypertensive patients were used to put the findings in some perspective.7 – 11 Only descriptive data are presented, normalized to events per 1,000 patient-years. Formal statistical analyses were not performed because of rather few end points. jjj The comparisons between felodipine and reference drug (placebo or active) regarding mortality and cardiovascular events gave similar results in studies using extended-release tablets of felodipine once daily (73% of patients) or the plain tablet formulation twice daily (27% of patients). Furthermore, comparisons between groups yielded similar results if the drugs were given as monotherapy or added to existing background therapy, for example, with a b blocker. Therefore, the data presented are based on the pooled material of all felodipine studies, irrespective of formulation used or whether the drugs were given as monotherapy. There were 72 randomized, double-blind, placebo-controlled studies with felodipine in hypertensive patients. A total of 3,594 patients were given felodipine, and 1,926 patients received placebo for an average treatment duration of 65 and 67 days, respectively. More patients were given felodipine than placebo because of randomization to several felodipine doses in some of the studies. The drugs were given as monotherapy in approximately 60% of the patients and in the remainder as a combination, usually with a b blocker. Table I details the incidence of death and cardiovascular events in the 2 groups. Generally, the incidences were low and numerically lower in the felodipine than in the placebo group, indicating a favorable effect of felodipine. The only exception was syncope, which was seen more often among actively treated than placebo-treated patients. Felodipine was compared with an active reference drug in 89 randomized, double-blind studies (Table II). Felodipine was given to 3,860 patients and the active reference to 3,440 patients for an average treatment duration of 70 and 69 days, respectively. The reference compounds were other calcium antagonists (33% of the patients), diuretics (27%), angiotensin-converting enzyme inhibitors (16%), b blockers (15%), and other agents (9%). Generally, the mortality and the incidence of events were low
Q1997 by Excerpta Medica, Inc. All rights reserved.
/ 2w1e 0906 Mp
996
Thursday Mar 06 12:33 AM
MD, PhD ,
0002-9149/97/$17.00 PII S0002-9149(97)00034-9
EL–AJC (v. 79, no. 7 ’97)
0906
TABLE I Mortality and Incidence of Cardiovascular Events in 72 Double-Blind Hypertension Studies Comparing Felodipine* With Placebo† Felodipine
Mortality (total) Cardiovascular Noncardiovascular Myocardial infarction Stroke Major cardiovascular events‡ Malignant arrhythmias Angina pectoris Congestive heart failure Syncope Bleeding (serious)
Placebo
No. of Patients
Events/1,000 Patient-Years
No. of Patients
Events/1,000 Patient-Years
3 3 0 2 4 7 0 4 2 8 2
4.7 4.7 0 3.1 6.2 10.9 0 6.2 3.1 12.4 3.1
4 4 0 5 4 11 0 5 2 2 4
11.3 11.3 0 14.2 11.3 31.2 0 14.2 5.7 5.7 11.3
*Felodipine—n Å 3,594; patient-years Å 643, i.e., average treatment duration 65 days. † Placebo—n Å 1,926; patient-years Å 353, i.e., average treatment duration 67 days. ‡ Cardiovascular mortality / nonfatal myocardial infarction / nonfatal stroke.
TABLE II Mortality and Incidence of Cardiovascular Events in 89 Double-Blind Hypertension Studies Comparing Felodipine* With Other Antihypertensive Drugs† Felodipine
Mortality (total) Cardiovascular Noncardiovascular Myocardial infarction Stroke Major cardiovascular events‡ Malignant arrhythmias Angina pectoris Congestive heart failure Syncope Bleeding (serious)
Other Drugs
No. of Patients
Events/1,000 Patient-Years
No. of Patients
Events/1,000 Patient-Years
7 7 0 2 7 13 0 12 4 7 3
9.5 9.5 0 2.7 9.5 17.6 0 16.2 5.4 9.5 4.1
8 4 4 4 4 10 0 11 6 8 3
12.3 6.1 6.1 6.1 6.1 15.4 0 16.9 9.2 12.3 4.6
*Felodipine—n Å 3,860; patient-years Å 740, i.e., average treatment duration 70 days. † Other antihypertensive drugs—n Å 3,440; patient-years Å 651, i.e., average treatment duration 69 days. ‡ Cardiovascular mortality / nonfatal myocardial infarction / nonfatal stroke.
and similar in the felodipine and reference groups. Table III differs from Table II because studies comparing felodipine with other calcium antagonists have been omitted. Although the figures were generally small, they indicated a more favorable effect of felodipine on most events. A total of 60,827 patients with hypertension (mean age 59 years), representing 8,681 patient-years of felodipine exposure, were included in 6 large, open, postmarketing studies of 6 to 12 week’s duration. Table IV gives the number of deaths and the incidence of fatal and nonfatal myocardial infarction and stroke in these studies. Felodipine was administered as extended-release tablets once daily in all studies except the Australian study, in which plain tablets were given twice daily. The pooled data showed that total deaths were 3.3 (95% confidence interval [CI] 2.2 to 4.8), the incidence of myocardial infarction was 2.3 (CI 1.4 to 3.6), and the incidence of stroke 1.8 (CI 1.0 to 3.0) per 1,000 patient-years. Figure 1 also presents event rates in the active intervention groups in 5 large and well-known clinical antihypertensive treatment trials of 2 to 6 years’ duration using diuretics and b blockers.7 – 11 The data do not indicate a higher event rate during treatment with felodipine compared with other antihypertensive treatment.
TABLE III Mortality and Incidence of Cardiovascular Events in 58 Double-Blind Hypertension Studies Comparing Felodipine* With Other Antihypertensive Drugs, Excluding Calcium Antagonists† Other Drugs Excluding Calcium Channel Blockers
Felodipine
Mortality (total) Cardiovascular Noncardiovascular Myocardial infarction Stroke Major cardiovascular events‡ Malignant arrhythmias Angina pectoris Congestive heart failure Syncope Bleeding (serious)
No. of Patients
Events/1,000 Patient-Years
No. of Patients
Events/1,000 Patient-Years
4 4 0 2 6 10 0 8 4 7 3
7.1 7.1 0 3.6 10.7 17.8 0 14.2 7.1 12.5 5.3
7 3 4 4 3 8 0 10 5 7 3
14.8 6.3 8.4 8.4 6.3 16.9 0 21.1 10.5 14.8 6.3
*Felodipine, n Å 2,699; patient-years Å 562, i.e., average treatment duration 76 days. † Other antihypertensive drugs excluding calcium antagonists, n Å 2,290; patient-years Å 474, i.e., average treatment duration 76 days. ‡ Cardiovascular mortality / nonfatal infarction / nonfatal stroke.
BRIEF REPORTS
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TABLE IV Overview of Large, Postmarketing Studies With Felodipine in Hypertension Study (country)
No. of Patients
Treatment Duration (d)
Patient-Years
Mean Age (yr)
Men (%)
1 (Germany) 2 (France) 3 (France) 4 (Australia) 5 (Germany) 6 (Belgium) Total
19,177 18,164 13,787 5,071 3,470 1,158 60,827
42 60 60 56 84 63 42–84
2,109 2,660 2,233 716 775 188 8,681
58 61 61 58 57 58 59
53 48 52 46 54 47 50
Deaths* 8 10 4 7
(3.8) (3.8) (1.8) (9.8) 0 0 29 (3.3)
Myocardial Infarction* 5 5 1 6 1 2 20
(2.4) (1.9) (0.4) (8.4) (1.3) (10.6) (2.3)
Stroke* 4 5 2 5
(1.9) (1.9) (0.9) (7.0) 0 0 16 (1.8)
*Numbers in parentheses represent event rate/1,000 patient-years of exposure.
FIGURE 1. Total mortality and incidence of myocardial infarction and stroke in 6 postmarketing studies (PMS) with felodipine (n Å 60,827, patient-years Å 8,681) and in the active intervention groups in 5 major hypertension studies (Australian Study, 7 Medical Research Council [MRC] 1985 8 and 1992, 9 Systolic Hypertension in the Elderly Program [SHEP], 10 and Swedish Trial in Old Patients [STOP] with Hypertension. 11 The 95% confidence intervals for the felodipine data are indicated by bars.
jjj This report summarizes the worldwide safety experience from clinical studies with felodipine in hypertension. All studies performed by Astra or its licensees, whether published or unpublished, were included in this analysis, avoiding any publication bias in favor of positive studies. There was no indication that antihypertensive treatment with felodipine increases the risk of death or major cardiovascular events on short-term exposure. Results from prospective, randomized, controlled, long-term studies with felodipine or other calcium antagonists focusing on the incidence of major cardiovascular events are thus far not available. However, several such trials are ongoing and results will be available in a few years.12,13 In the Hypertension Optimal Treatment Study, which investigates the relationship between 3 target diastolic blood pressures and major cardiovascular events, felodipine is being used as the baseline antihypertensive drug.14,15 At present, all patients have been followed for ¢2 years and the total exposure amounts to approximately 60,000 patient998
THE AMERICAN JOURNAL OF CARDIOLOGYT
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998
VOL. 79
Thursday Mar 06 12:33 AM
years. To date, the observed incidence of events is lower than expected based on the risk calculated from baseline characteristics of the study population. Potentially harmful effects of calcium antagonists that recently have been proposed are hypotensive, proischemic, proarrhythmic, prohemorrhagic, and negative inotropic effects.2 In the current analysis of felodipine studies, we found no support for such effects. For example, serious bleeding appeared to be less common with felodipine than with placebo, and occurred with a similar incidence as other active drugs. With regard to hypotension / syncope, more episodes were reported with felodipine than with placebo, but there was no difference between felodipine and other active antihypertensive drugs. In conclusion, in a safety analysis including all double-blind, randomized studies and postmarketing studies with felodipine in hypertension, there was no indication that felodipine treatment increases total mortality or the incidence of cardioAPRIL 1, 1997
EL–AJC (v. 79, no. 7 ’97)
0906
vascular events. On the contrary, there was a trend for fewer cardiovascular events with felodipine than with placebo.
1. Psaty BM, Heckberg SR, Koepsell TD, Siscovick DS, Raghunathan TE,
Weiss NS, Rosendaal FR, Lemaitre RN, Smith NL, Wahl PW, Wagner EH, Furberg CD. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995;274:620–625. 2. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326–1331. 3. Epstein M. Calcium antagonists: still appropriate as first line antihypertensive agents. Am J Hypertens 1996;9:110–121. 4. Little WC, Cheng C-P, Elvelin L, Nordlander M. Vascular selective calcium entry blockers in the treatment of cardiovascular disorders. Focus on felodipine. Cardiovasc Drug Ther 1995;9:657–663. 5. Pannarale G, Puddu PE, Monti F, Irace L, Bentivoglio M, Collauto F, Barsotti A, Corea L, Trevi G, Campa PP, Jacono A. Twenty-four-hour antihypertensive efficacy of felodipine 10 mg extended-release: the Italian inter-university study. J Cardiovasc Pharmacol 1996;27:255–261. 6. Elvelin L, Jo¨nsson L. The effect of dihydropyridine calcium antagonists on heart rate: studies of felodipine. Curr Ther Res 1994;55:736–746.
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BRIEF REPORTS
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