J. Schmidt †
and
W. Rück ‡
*Ärztlicher Leiter Klinikum Buch, Wiltbergstr. 50, 13122 Berlin; †Straußstr. 4, 01324 Dresden; ‡Elsaßstr. 35, 44793 Bochum, Germany
Accepted: 19th December 1995
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Current Medical Research and Opinion (1996), 13, No. 7, 397-408
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The value of nifedipine in the treatment of hypertension,
coronary heart disease and myocardial infarction (post-infarction
therapy)
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J. Schulz,*
J. Schmidt † and W. Rück ‡ *Ärztlicher Leiter Klinikum Buch, Wiltbergstr. 50, 13122 Berlin; †Straußstr. 4, 01324 Dresden; ‡Elsaßstr. 35, 44793 Bochum, Germany Accepted: 19th December 1995 |
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The main problem linked with hypertension is its risk potential. Since in most cases no symptoms are noticeable over long periods, the disease is often well established before treatment can be initiated. Currently some 25% of all causes of death must be reckoned to be associated with hypertension which was either not treated at all or inadequately treated, and this points to the importance of possible cardiovascular sequelae. A correlation between the degree of hypertension and mortality, as well as the emergence of severe cardiovascular complications, has been established.9, 11, 15 The organs most often affected are the heart, the brain and the kidneys, which, when affected by sequelae, predominantly cause the increased mortality. For instance, mortality in hypertensive patients with systolic blood pressure values of up to 170 mm Hg is already twice as high as that of normotensive subjects, while it is up to eight times higher if pressure values exceed 200 mm Hg. Likewise, increased diastolic blood pressure is associated with a rise in mortality (Figure 1). Thus, the 2-year survival rate in untreated malign hypertension amounts to some 10% only, and even in lower-degree hypertension with diastolic pressure values of 95-105 mm Hg, the yearly mortality rate of 45-year-old men is almost three times as high as that of normotensive subjects. The risk potential of hypertension is also demonstrated very clearly by the fact that a 35-year-old man presenting a blood pressure of 150/100 mm Hg, if untreated, is likely to die before the age of 60, which curtails his statistical life expectancy by 14 years.
The risk potential of hypertension is determined to a substantial degree by the presence of other cardiovascular risk factors.9 The more other risk factors there are, the higher the number of probable cardiovascular complications, and the higher the death rate. This has been proved convincingly by numerous studies. Beside hypertension, smoking and disturbed fat metabolism are two of the most important risk factors. Figure 2 shows the 5-year mortality rates caused by CHD in men aged 35-37 years, as found in the MRFIT study.10
For a long time, it remained doubtful whether hypertensive patients over 60 would also benefit from an efficient antihypertensive therapy. To investigate this, corresponding studies using beta blockers and diuretics were performed with elderly hypertensive patients (> 60 years). The SHEP study showed that in patients over 60 with isolated systolic hypertension, i.e. the most frequent type of hypertension in elderly patients, treatment with diuretics and beta blockers significantly reduced cardiovascular morbidity and mortality with respect to the frequency of lethal and non-lethal strokes as well as the number of severe cardiovascular events.18 The STOP study investigated the treatment of diastolic hypertension in patients aged 70-84 years with a thiazide diuretic, a beta blocker (metoprolol or pindolol) as compared with a placebo group.3 In the verum groups, the effective decrease in blood pressure lowered the stroke risk by 47% and the risk of cardiovascular diseases by 40%. The frequency of myocardial infarction was altered only slightly (by 13%), while the number of cases of sudden cardiac death was reduced by 50% and the overall mortality by 43%.3 In the MRC study13 involving 4396 patients aged 65-74 years and suffering from diastolic hypertension, the treatment with beta blockers (atenolol) and/or thiazide diuretics (25 or 50 mg hydrochlorothiazide combined with 2.5 and 5 mg amilorid, respectively) reduced the cardiovascular risks. In the group treated with a beta blocker and a diuretic, the frequency of strokes could be reduced by 25% and that of coronary disorders by 19%. The incidence of all cardiovascular diseases was lowered by 17%. In the groups receiving one drug type only, the group treated with diuretics was superior to that given beta blockers, especially with respect to lowering cardiovascular risks.13
Summarizing these findings, a highly significant reduction in the overall mortality as well as cardiovascular morbidity and mortality is induced by beta blockers and diuretics in young as well as elderly hypertensive patients, and by nifedipine in elderly patients. This underlines the importance of an effective antihypertensive treatment to prevent cardiovascular complications associated with hypertension.
The analysis of the treatment administered to 291 cases who suffered a myocardial infarction during the observation period, and to 1240 controls (without myocardial infarction), compared with hypertensive patients treated with diuretics (relative risk, rr = 1), showed a relative risk of 1.08 for beta blockers, 1.07 for ACE inhibitors and 1.25 for calcium antagonists (Table I). These differences were non-significant, i.e. none of the treatment groups differed significantly from the group treated with diuretics with respect to the infarction rate. There was only one sub-group of hypertensive patients treated with high doses of calcium antagonists or a combination of high-dosage calcium antagonists and diuretics who presented a significantly increased relative risk. Unfortunately, the information available so far on this issue does not include details on the dosage used. Furthermore, the various calcium antagonists used were pooled. This study and the conclusions deducted from it were rightly criticised by renowned cardiologists. From the available data, it may not be concluded that hypertensive patients under mono-therapy with calcium antagonists are more at risk of suffering myocardial infarction than those treated with diuretics, beta blockers or ACE inhibitors. When considering the numerous study results showing the benefits of an antihypertensive treatment using diuretics and beta blockers in reducing the risk of acquiring and dying of severe cardiovascular complications, seeing that the treatment with calcium antagonists or ACE inhibitors does not significantly differ from that with diuretics, it may be reckoned that calcium antagonists may also have a positive effect. The findings indicating that the risk might possibly be higher with nifedipine preparations characterized by a quick onset, but short action (dosage > 80 mg/day), as they are predominantly used in the USA, are not applicable as they are to the situation in Germany. Here, the majority of preparations used are slow-release formulations administered in dosages of 2 × 20 mg or 1 × 30-50 mg per day. Moreover, the retrospective American statements should be verified in controlled prospective studies.
| Antihypertensive drugs | Risk ratio |
|---|---|
| Diuretics | 1.00 |
| Beta-Blockers | 1.08 (0.70-1.66) |
| ACE-inhibitors | 1.07 (0.65-1.80) |
| Calcium antagonists | 1.25 (0.78-1.98) |
Adapted from Psaty et al.16
The recently much cited report published by Furberg et al.5 which contained a meta-analysis of 16 randomized clinical studies including three trials involving patients with unstable angina pectoris, claims that nifedipine preparations with quick onset and short action given in a daily dosage of > 60 mg increased the mortality risk. While a daily dosage of 30-60 mg did not enhance mortality as compared with the control group, patients given a daily dosage of 80 or > 100 mg nifedipine had an increased mortality risk (Table II). In Germany, however, slow-release preparations displaying a gradual onset of action are usually used. This underlines that the preparations and dosages usually administered in Germany to patients with unstable angina pectoris involve no increased mortality risk. The claims that high-dosage, fast-acting nifedipine preparations are associated with an increased mortality risk should be verified in further targeted, prospective studies; they emphasize that calcium antagonists of the dihydropyridine type should be used with caution in unstable angina pectoris. When judging the results of Furberg et al.,5 it must be taken into account that the type of meta-analysis performed has been strongly criticized by leading cardiologists. Numerous mistakes in grouping the patients covered by retrospective analysis as well as the fact that patients in the control group received varying treatment, also with beta blockers, qualify the claim of an increased relative risk.
| Dosage | Risk ratio |
|---|---|
| 30 mg/day | 1.01 |
| 40 mg/day | 1.09 |
| 50 mg/day | 1.03 |
| 60 mg/day | 1.18 |
| 80 mg/day | 2.83 |
| > 100 mg/day | 2.20 |
For dihydropyridines, and thus for calcium antagonists of the nifedipine type, no evidence of an effective secondary preventive action has been generated so far. The studies available in this respect show no reduction in cardiovascular mortality or in the rate of recurrent infarction, indicating on the contrary even a slightly, though non-significantly, increased risk of recurrent infarction and mortality. Dihydropyridines therefore should be recommended for the treatment of post-infarction angina, but not for secondary prevention of myocardial infarction. The possibly increased risk of recurrent infarction and mortality must be further investigated in more detailed trials. In this context, the meta-analysis published by Furberg et al.,5 should be taken into account. They analysed the results of 16 randomized clinical studies, including 12 trials in patients having suffered myocardial infarction, using short-acting nifedipine preparations in a dosage of 30-120 mg/day. When considering all patient data, the nifedipine group presented a slightly increased relative risk (rr = 1.16). When breaking down the data according to dose-effect relations, patients given nifedipine in a dosage of 30-50 mg/day had no increased mortality risk. The dosage of 60 mg/day involved a relative risk of 1.18 and thus a trend towards an increased mortality. Patients given doses of 80 and > 100 mg/day had a relative risk of 2.83 and 2.20, respectively, and thus a clearly increased mortality risk as compared with the control group or with patients receiving 30-50 mg/day (Table II). Even if, owing to the limited meaningfulness of this meta-analysis, no rash conclusions as to the use of nifedipine preparations should be drawn, these results confirm that nifedipine in this presentation form (fast onset, short duration of action) is not suitable for the prevention of myocardial infarction, and they call for caution in using these preparations in high doses when treating post-infarction patients. It must be taken into account that beta blockers, and now some ACE inhibitors, have been proven efficiently to prevent secondary myocardial infarction, so these preparations should certainly be given preference when treating post-infarction patients.
The situation is slightly different with respect to verapamil and diltiazem. Verapamil was investigated in two rather extensive studies (DAVIT-I and DAVIT-II). The DAVIT-I study involved 3500 patients with established or suspected myocardial infarction who were treated with verapamil for 6 months. When compared with a control group, no decrease in mortality was found,4 while retrospective analysis revealed a tendency towards a reduced mortality after 4 weeks. In the DAVIT-II study, the verapamil treatment was initiated only 1-3 weeks after the onset of the infarction and carried on for a period of 16 months.19 In this study, the number of deaths could be reduced from 116 of 897 patients in the placebo group to 95 of 878 patients in the verapamil group. When considering all data available on verapamil, a slight decrease in mortality of 9% was proven without being backed up by statistics. Moreover, there was a clear-cut reduction in the number of recurrent infarctions which amounted to 171 of 2624 patients in the placebo group, yet to only 138 of 2606 patients treated with verapamil.
In the studies available for diltiazem, no reduction in cardiovascular mortality in post-infarction patients was found.14 A sub-group analysis, however, revealed a much more complex picture depending on the overall clinical situation connected with the infarction. For instance, patients without pulmonal congestion who received diltiazem showed a lower cumulative rate of cardiac events (8%) than those under placebo, while patients with pulmonal congestion developed more cardiac disorders when treated with diltiazem (26%) than those given placebo (18%). Patients with an ejection fraction of > 40% as well as patients with non-Q-wave infarction benefitted from diltiazem medication. These patients of the diltiazem group showed a clearly reduced number of cardiac events as compared with those from the placebo group.
| Effect | Benefit by |
|---|---|
| Antianginal | CHD |
| Vasospasmolytic | CHD, pAOD, TIA |
| Improvement of peripheral blood flow | pAOD |
| Bronchodilatative | Obstructive respiratory diseases |
| Nephroprotective | Diabetic nephropathia |
| Regression of left ventricular hypertrophia | Left ventricular hypertrophia |
| Inhibition of progression of atherosclerosis | Atherosclerosis |
| Rheological effects (inhibition of aggregation) | CHD, pAOD, TIA |
Indisputably, calcium antagonists are important in treating chronic stable angina pectoris (exertion angina) and vasospastic angina (Prinzmetal's angina or variant angina). In unstable angina pectoris, calcium antagonists should be used only in strictly limited indications and not as first choice. In these cases, high-dosage nifedipine preparations with fast onset of action should be administered only after carefully weighing-up the risks and benefits and, whenever possible, in combination with a beta blocker.
Calcium antagonists are not recommended for treating acute myocardial infarction (cf. also expert information on the preparations).
In the post-infarction phase, calcium antagonists may be administered starting in the first or second week after the onset of the infarction to treat stable post-infarction or vasospastic angina pectoris. In the treatment of unstable angina following myocardial infarction, the above restrictions must be observed. Secondary prevention of myocardial infarction is, according to the current state of knowledge, not achievable with calcium antagonists of the nifedipine type. In these cases, beta blockers and ACE inhibitors (e.g. lisinopril) should be used in preference. In contrast to nifedipine preparations, verapamil and diltiazem may possibly reduce the frequency of recurrent infarction.
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