Why is amlodipine banned in Canada

ALARMING FINDINGS
FOR THE SAFETY OF CALCIUM ANTAGONISTS

The calcium antagonists verapamil (ISOPTIN and others) and nifedipine (ADALAT and others) have been used millions of times for three and two decades respectively. There is still a lack of prospective long-term studies that prove a beneficial effect on the course of disease and mortality in high blood pressure and myocardial ischemia. A meta-analysis and some as yet unpublished studies (see box) spark a controversy about established therapeutic habits. Instead of the expected benefit, certain calcium channel blockers appear dose dependent to increase the risk of dying from the consequences of coronary heart disease or of suffering a heart attack from hypertension.

NIFEDIPINE CONSUMPTION IN GERMANY

Every year, German doctors prescribe more than 30 million packs of calcium antagonists worth 1.5 billion DM - around 60% for ischemic heart disease and 30% for people with hypertension. Every second prescription is for nifedipine. About half a million people take a short-acting preparation of dihydropyridine. Since the fall of the Wall, CORINFAR (Arzneimittelwerk Dresden) has been favored by prescriptions over ADALAT. Successor drugs that weaken sales of the former bestseller No. 1 ADALAT (a-t 9 [1987], 79) in the old federal states are rarely prescribed in the new federal states.

The meta-analysis gives cause for criticism, for example because of the inadequate age-related statistical validation and the inhomogeneous selection of the studies.6,7 "Even a rotten fish makes a bouillabaisse stink",8 comments a clinician from New Orleans, who is cited by Bayer as a protagonist for calcium channel blockers, the increasing concerns about short-acting preparations of the nifedipine-type. Claims that long-acting calcium channel blockers are "safe and effective"8, cannot be substantiated due to the lack of prospective long-term studies.

The US National Heart, Lung and Blood Institute issued an official statement in early September warning against the use of short-acting nifedipine preparations. Such preparations should be used "if at all, only with great caution in the case of high blood pressure, angina pectoris or myocardial infarction, especially in high doses".1 The UK Hypertension Society has temporarily suspended its recommendations that include calcium channel blockers.4 The Swiss Association against High Blood Pressure considers the funds to be "still usable". Differentiated use should avoid possible risks.5 A statement from the German Hypertension League is pending.

ABOUT THE TOPIC

A number of new publications postulate an increase in cardiac risks and excess mortality in hypertensive patients and patients with coronary artery disease who take calcium channel blockers.

  • According to the recently published meta-analysis of 16 controlled studies with a total of 8,350 patients suffering from coronary artery disease, short-acting nifedipine endangers life expectancy in a dose-dependent manner:2 Compared with placebo, 80 mg daily almost triples the mortality risk (relative risk 2.83), while the influence of 60 mg daily (relative risk 1.18) or 30 to 60 mg (1.06) cannot be statistically confirmed.
  • In a case control study, short-acting calcium antagonists of the nifedipine, diltiazem (DILZEM and others) and verapamil types increase the risk of myocardial infarction in patients with high blood pressure compared to diuretics or beta blockers by 60% each (cf. a-t 4 [1995], 33). The risk of calcium channel blockers increases with higher doses, while fewer myocardial infarctions occur with increasing doses of beta blockers.3
  • According to data to be published in the Journal of the American Geriatrics Society in November, the risk of death in hypertensive patients who take a calcium channel blocker or beta blocker increases significantly with nifedipine, not significantly with diltiazem, and not at all with verapamil.1
  • The as yet unpublished multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) compares the dihydropyridine derivative isradipine (LOMIR, VASCAL) with diuretics. A "trend" towards more frequent cardiovascular events during high pressure therapy with isradipine can be seen.1

SAME EFFECTS AND BUT NOTABLE DIFFERENCES: More than 35 calcium channel blockers are in clinical use worldwide. All have the same antianginal and antihypertensive effects. They expand the smooth vascular muscles by inhibiting the influx of extracellular calcium via calcium channels ("calcium channel blockers"). The different types of action differ not only in their binding to the calcium channel (see table). Dihydropyridines increase the heart rate, while representatives of the verapamil and diltiazem types inhibit the AV conduction and, under certain circumstances, can also be used against ventricular extrasystoles and tachyarrhythmias.

The first reports of a deterioration in the blood supply to the heart with nifedipine date back to 1978. The paradox pro-ischemic effects can be recognized by the increase in anginal complaints. Coronary patients in whom the collateral bed has not yet formed are less likely to have ischemic effects of nifedipine to fear.2 "Coronary robbery effects"are also described for nifedipine variants such as nicardipine (ANTAGONIL) and nisoldipine (BAYMYCARD) in patients with stable angina pectoris.

If the blood pressure falls due to systemic vasodilation, norepinephrine is released in a compensatory manner. The following Reflex tachycardia counteracts the antianginal effect. The mechanism is blamed for heart oxygen starvation.12 The stimulation of the sympathetic nervous system shortens the diastole, i.e. the phase of the cardiac cycle in which the coronary vessels are supplied with blood passively by pressure.5 The prognosis worsens with decreased cardiac output or acute coronary syndromes. This is especially true for short-acting dihydropyridines.

Excessive decreases in blood pressureischemic complications such as coronary attacks or strokes can trigger, especially during the night when the pressure is already physiologically reduced. Noticeable fluctuations in blood pressure, which are observed under the influence of rapidly absorbed active ingredients such as nifedipine, nicardipine, felodipine and isradipine, even with long-term use, cannot always be prevented with slow-release preparations. The neurohumoral countermeasures with activation of the sympathetic nervous system, as is to be expected after short-acting nifedipine preparations, could be insignificant when prescribing sustained-release preparations and could not be the cause of the increased mortality.2,9 However, if the increase in mortality were caused by vasodilation, longer-acting formulations with continuous release such as ADALAT OROS may even exacerbate the problem.9

Because they lower the contractility (negative inotropic effect), calcium channel blockers prohibit themselves in patients with congestive heart failure. Amlodipine may be an exception. At least in a small subset of patients with dilated cardiomyopathy, mortality could even decrease.2

Prohemorrhagic Effects of calcium antagonists are undisputed and have been reported by us earlier (a-t 5 [1995], 49): A study with nimodipine (NIMOTOP) during heart valve replacement had to be stopped prematurely because of bleeding complications.

NETWORK EXPERIENCE: A pensioner was treated for drowsiness, dizziness and syncope for two years. She falls several times and sustains head injuries. Only after stopping the nifedipine derivative nimodipine (NIMOTOP), which she receives against concentration disorders if there is a suspicion of the onset of organic brain psychosyndrome, does it improve (NETZWERK report 7533). On the first day of taking nimodipine for cerebral circulatory disorders, a 74-year-old woman collapsed (4395). A 69-year-old bites the ADALAT 10 mg capsule that he received from the emergency doctor. He collapses at a blood pressure of 75/55 and suffers a transitory ischemic attack (5187). In a 48-year-old woman, intake of ADALAT 10 mg capsules was followed by peripheral vasodilation and tachycardia with a reactive increase in blood pressure from 145/100 mm Hg to 180/110 mm Hg (2351). 20 drops of APRICAL (equivalent to 20 mg nifedipine) reduce the excessive blood pressure (220/115 mmHg) of a 65-year-old woman so much that she dies despite being admitted to the hospital (3805). Two people develop increasing heart failure taking PIDILAT 10 or NIFEDIPIN 10 STADA (1266, 1315). The heart of a 57-year-old decompensates while taking the nifedipine-atenolol combination NIF-TEN 50 RETARD (2907). A pensioner developed absolute tachyarrhythmia on NIFEDIPINE RATIOPHARM 10, later also after taking 5 mg of nifedipine (1802). A few days after switching from ADALAT RETARD to COROTREND RETARD, a 79-year-old and an 84-year-old woman suffer a heart attack (2376, 2377).

FOLLOWS FOR CLINICAL USE: If nifedipine cannot be dispensed with, the dose must be carefully titrated so that the blood pressure does not suddenly drop.

Recommendations for High pressure therapy, in which all activity classes come first - such as the level scheme of the German League for the treatment of high blood pressure - are based on surrogate criteria such as lowering blood pressure and not on clinically proven success. Only thiazide diuretics and beta-blockers have been shown to prolong life in controlled long-term studies and are considered the first choice in the USA and Canada.10,11 There are clear net effects in terms of reducing strokes, myocardial infarction and fatal cardiovascular complications (a-t 12 [1993], 130). Low thiazide doses, corresponding to 12.5 to 25 mg hydrochlorothiazide (ESIDRIX et al.), Are more tolerable and obviously even better than the high doses that are still used today (e.g. in DIGNORETIK; a-t 7 [1990], 66).11

Calcium channel blockers or ACE inhibitors can be considered if first-line drugs are not tolerated - e.g. in asthma - or if further lowering of blood pressure is required.11 There are few areas of application for short-acting nifedipine, for example when blood pressure has to be lowered rapidly (a-t 6 [1988], 56; 5 [1995], 50) and there is no risk of myocardial ischemia or for people with RAYNAUD disease.7 Long-term studies are ongoing with retarded nifedipine and nifedipine derivatives such as amlodipine (NORVASC; a-t 4 [1994], 35), felodipine (MODIP, MUNOBAL) and nitrendipine (BAYOTENSIN). Preliminary results of a simple blind study with 20 mg nifedipine retard twice daily in comparison with placebo in Italy in the summer of this year in 70 to 80 year olds show a positive influence on comorbidities and death.7

If a change is considered, the equieffective daily doses for lowering blood pressure must be taken into account: 30 mg nifedipine, 180 mg diltiazem, 240 mg verapamil, 80 mg propranolol (DOCITON etc.), 100 mg metoprolol (BELOC etc.), 80 mg nadolol (SOLGOL) and 50 mg atenolol (TENORMIN et al.).3

As long as the suspicion of excess mortality after calcium channel blockers in coronary heart disease has not been refuted, the stable angina pectoris Long-term nitrates and beta-blockers take precedence. If beta blockers are out of place - after all, they too have contraindications - you should opt for a calcium channel blocker that tends to lower the heart rate, such as verapamil or diltiazem.7

At unstable angina calcium channel blockers should not be used or only used in combination with a beta blockade, 5 if nitrates and / or beta blockers do not have an adequate effect. Verapamil is not an option because of pronounced bradycardia and / or hypotension.

All calcium channel blockers are in the early stages of the acute heart attack contraindicated. In people with impaired cardiac output after an infarction, they increase the risk of congestive heart failure (a-t 10 [1992], 104). Thrombolysis, acetylsalicylic acid (ASPIRIN and others) and beta blockers without intrinsic activity such as atenolol or metoprolol (a-t 11 [1990], 17; 2 [1994], 21; 4 [1994], 34) remain the means of choice here. ACE inhibitors also seem to improve the chances of survival of heart attack patients with cardiac insufficiency if they are additionally taken after stabilization (a-t 3 [1994], 26).

CONCLUSION: After decades of mass prescription of calcium channel blockers, reservations about their widespread use are accumulating. "It cannot be denied that prospective studies with calcium channel blockers are lacking in hypertension, which document a reduction in mortality and morbidity in addition to lowering blood pressure. All morbidity and mortality studies in hypertension were carried out with diuretics, beta blockers and older antihypertensive drugs."5 This quote characterizes the dilemma of contemporary medicine. Strategies for treating cardiovascular disease require hard clinical data, not guesswork. Low-dose thiazide diuretics such as hydrochlorothiazide (ESIDRIX et al.) And "cardioselective" beta blockers such as atenolol (TENORMIN et al.) Have proven effective. They reduce the incidence of cardiovascular diseases and the mortality of hypertensive patients. After a heart attack, acetylsalicylic acid (ASPIRIN and others) and beta blockers reduce the re-infarction rate and mortality.