Publications

Published: January 2000

The Safety of Calcium Antagonists: An Update

Prescriber Update 19: 4–13
January 2000

Professor Mark Richards, MD, PhD, FRACP National Heart Foundation Professor of Cardiovascular Studies & Director, The Christchurch Cardioendocrine Research Group, Christchurch School of Medicine, Christchurch.

Over the last few years there has been much debate about the safety of calcium channel blockers (CCBs). Recent studies have assessed whether CCBs increase the risk of coronary events in patients with hypertension (including diabetics) and those with prior coronary disease. Other studies have investigated whether there's a link between CCBs, cancer and gastrointestinal haemorrhage.
Longer-acting CCBs, irrespective of subclass, do not appear to increase the risk of coronary events in patients with hypertension. Results of a large, rigorous trial suggest intermediate-acting dihydropyridines may be a potential alternative to diuretics as first-line treatment for patients with isolated systolic hypertension. In diabetes with hypertension, some studies have shown a higher rate of major cardiovascular events with CCBs compared to ACE inhibitors, but this is yet to be finally confirmed. Further randomised trials are underway.
In coronary disease, longer-acting CCBs (including dihydropyridines) are safe, particularly when added to established treatment such as beta blockade, although they are not generally appropriate as first-line or monotherapy. In atherosclerotic coronary disease, short-acting dihydropyridine monotherapy should be avoided.
Observational and randomised trials do not support suggestions that CCBs may increase risks of cancer or bleeding.

Since 1995, in addition to the long established suggestion that monotherapy with short-acting calcium channel blockers (CCB) worsens outcomes in coronary disease1-6, reports have suggested haemorrhage7-9, increased incidence of cancer10,11 and poor cardiovascular outcomes in diabetes12,13 are potential adverse effects of this drug class. However, two important reviews and two landmark randomised controlled trials have subsequently provided considerable reassurance suggesting major changes to current practice are not warranted.14-17

CCBs & coronary risk in hypertension

A comprehensive overview of potential risks associated with calcium antagonist use has been conducted by an ad hoc sub-committee of the World Health Organisation and International Society of Hypertension (WHO/ISH).14 This addressed the issues of coronary heart disease risk, cancer and bleeding. The review was conducted with particular attention to minimising systematic and random errors.

With respect to coronary heart disease risk, data from randomised controlled trials and observational studies in hypertension and known coronary artery disease were considered. Because of inability to rule out selection bias, observational (case control and cohort) studies constitute far weaker evidence than data from randomised controlled trials. Generally (but not always) case control reports have suggested an increased risk of coronary events amongst patients receiving calcium antagonists and in particular short-acting dihydropyridine drugs.4,5,6,18 There is little evidence of increased risk among patients treated with long-acting calcium antagonists. A consistent finding was higher prevalence of prior cardiovascular disease among patients receiving treatment with short-acting calcium antagonists than amongst those receiving a long-acting CCB or a non-CCB antihypertensive agent. Hence, there is considerable potential for systematic error due to prescription indication bias.

The data from randomized trials available at the time of the WHO/ISH review were derived from a total of about 6,000 patients involved in several small studies. Coronary heart disease events were similarly distributed amongst CCB, placebo and other active treatment groups. However, only 50 cases of non-fatal myocardial infarction or death from coronary heart disease were observed. Consequently, no reliable determination of any plausible inter-group differences in risks could be made.

In an independent review, Stason et al15 analysed results from 98 controlled trials specifically of nifedipine used in hypertension published between 1966 and 1995. Numbers of coronary events were low. Fourteen adverse (coronary) events occurred in 5,198 exposures (0.27%) to nifedipine and 24 events in 5,402 exposures (0.44%) to other active drugs. The unadjusted odds ratios for all nifedipine-containing regimens versus controls were 0.49 (95% CI 0.22-1.09) for definitive events (including death, non-fatal myocardial infarction or stroke, revascularisation procedures) and 0.61 (95% CI 0.31-1.17) for all events (definitive plus increased angina). The odds ratios for nifedipine monotherapy (sustained or extended release in 91% of exposures) though tending towards harm, were not significant for definitive or all events (risk ratio 1.4; 95% CI 0.49-4.03 and risk ratio 1.39; CI 0.59-3.32 respectively). The odds ratios for nifedipine in combination with another drug (compared with placebo or other active drug) were significantly lower for definitive and all events (odds ratio 0.09; 95% CI 0.01-0.66 and odds ratio 0.15; 95%, CI 0.03-0.65 respectively). Differences in odds ratios between nifedipine as monotherapy and as part of combination therapy were statistically significant. The Stason overview is limited by low event rates but, if anything, suggests safety of sustained and extended release nifedipine in the treatment of mild or moderate hypertension when used in combination with other drugs.

At the time of the Stason and WHO/ISH reviews only one controlled trial in hypertension of a long-acting formulation of nifedipine was available for comment. However, the Shanghai Trial of Nifedipine in the Elderly (STONE) had design flaws including alternate assignment to active treatment or placebo instead of randomised allocation. Further, only 4 cases of myocardial infarction were reported amongst these 1,632 Chinese patients.19 A significant reduction in stroke was observed. The incidence of coronary disease in this population is so low as to prevent any conclusions concerning the effect of CCBs on coronary event rates.

Recently a substantial, rigorous, controlled trial of a dihydropyridine CCB in hypertension has provided encouraging results.16 The "Syst-Eur" trial was a randomised, double blind comparison of placebo and active treatment for older patients with isolated systolic hypertension in which 4,695 patients were randomly assigned to nitrendipine 10-40mg daily (with the possible addition of enalapril 5-20mg daily and hydrochlorothiazide 12.5-25mg daily), or matching placebos. Active treatment reduced total stroke from 13.7 to 7.9 per 1,000 patient-years (42% reduction; p=0.003). All fatal and non-fatal cardiovascular (including coronary) end points were reduced by 31% (p<0.001). This trial demonstrated that among elderly patients with isolated systolic hypertension, antihypertensive drug treatment based upon a dihydropyridine calcium antagonist (nitrendipine) reduced the rate of cardiovascular complications to a comparable degree as diuretic-based treatment in other positive trials. Nitrendipine has a terminal plasma half-life of 12 hours. Compared with the placebo group there were no differences observed in non-cardiovascular death, rates of cancer or of bleeding.

A recently published17 randomised controlled trial ("STOP-2") compared the efficacy of "old" (diuretics and beta-blockers) with "new" (ACE inhibitors and CCBs) drug therapy in elderly hypertensives. Overall, "old" and "new" (including felodipine and isradipine) treatments were associated with similar rates of cardiovascular mortality and morbidity. However, in a post hoc sub-analysis, those receiving ACE inhibitor-based treatment incurred significantly fewer myocardial infarctions and had a lower frequency of congestive heart failure than those receiving CCB-based treatment.

In summary, the best available evidence from randomised controlled trials indicates intermediate or long-acting dihydropyridine calcium antagonists in the elderly with hypertension reduce events compared with placebo but may not be as effective as ACE inhibitors in reducing myocardial infarctions or heart failure.

CCBs & coronary risk in coronary disease

The WHO/ISH review14 of randomised trials of CCBs in patients with coronary syndromes involved data from a total of over 20,000 patients. About 600 cases of myocardial infarction and 2,000 deaths were reported. The overview provided no conclusive evidence of any effects of CCBs on risk of myocardial infarction or on all cause mortality. A non-significant increased risk of MI was observed in patients receiving a dihydropyridine (odds ratio 1.19; 95% CI 0.92-1.53) with a marginally significant decreased risk in patients assigned the heart rate lowering drugs verapamil or diltiazem (odds ratio 0.79; 95% CI 0.67-0.94), but post hoc exploration of sub-groups did not find significant heterogeneity between the effects of different CCBs.

In patients with heart failure (frequently secondary to coronary disease), two substantial placebo controlled trials (PRAISE and V-Heft III) have studied the effect of dihydropyridine agents added to established anti-heart failure therapy (felodipine and amlodipine).20,21 Coronary events reported in these two studies were not significantly different between placebo and treatment groups, but again the small number of events limits the ability of these studies to detect plausible modest increases or decreases in risk with CCBs in this setting.

In summary, in stable angina, acute coronary syndromes or in heart failure secondary to ischaemia, evidence from placebo-controlled trials does not provide clear evidence of adverse effects on risk of coronary events. There are trends towards benefit from non-dihydropyridine CCBs, and towards harm from dihydropyridine monotherapy (mostly short-acting nifedipine) whereas dihydropyridines added to other antianginals (e.g. β-blockers) or antihypertensive drugs may offer benefit.

Cancer risk

Pahor and colleagues reported that CCBs were associated with an increased risk of cancer in a prospective cohort study of over 5,000 people aged 71 years or more.11 Patients taking CCBs (n=451) had an increased risk of newly diagnosed cancer (risk ratio 1.72; CI 1.27-2.34, p=0.0005) after attempted adjustment for confounding factors. The authors also claimed a significant dose response gradient was found. All classes of CCBs appeared to be implicated.

In contrast to this provocative report, analyses based on the totality of evidence from a large number of cohort studies have not corroborated this association according to the Prospective Studies Collaboration as reported by the ad hoc sub-committee of WHO/ISH.14 The Syst-Eur study found no increased incidence of cancer in the actively treated group. Further, in contradistinction to findings by Pahor and colleagues, a more recent report from Scotland found no evidence of CCB-related increases in cancer risk in over 5,000 hypertensive patients followed since 1981.22 From this date both ACE inhibitors and CCBs became widely used in the treatment of high blood pressure in this area. The group included over 2,000 who had been treated at some time with a calcium antagonist. Intriguingly, although no increased cancer risk appeared to be associated with CCB usage a reduced risk was seen in patients treated with an ACE inhibitor. Again (as for calcium antagonists and risk of coronary events) confounding by indication is a possible explanation for the finding by some investigators of an association between CCBs and cancer. At entry to the study reported by Pahor and colleagues11, there was a more frequent history of ill health amongst patients taking a calcium antagonist. Despite efforts to control for potentially confounding factors in such studies, perfect control can never be assumed and confounding by indication always remains as a potential alternative explanation for positive findings.

In summary, data from observational studies does not provide good evidence of an adverse effect of calcium antagonists on cancer risk.

Bleeding risk

Pahor and colleagues have also suggested an increased risk of gastrointestinal haemorrhage with CCB use in hypertensive patients over 67 years of age.7 The underlying rationale is that CCBs might inhibit platelet aggregation whilst also preventing the normal vasoconstrictor response to bleeding. One randomised controlled trial of nimodipine (a dihydropyridine) was stopped in a series of patients undergoing cardiac valve surgery due to more deaths observed in those allocated to active treatment. There appeared to be an excess of major bleeding with nimodipine.8 Four observational studies have provided conflicting data with the balance of evidence against a pro-haemorrhagic effect from CCBs. Two cohort studies suggested increased haemorrhage with CCBs compared with other antihypertensive agents.7,9 In contrast, a large comparison of outcomes between over 2,000 CCB-treated patients coming to cardiac surgery and nearly 3,000 surgery patients not receiving CCBs, did not indicate any increase in transfusions or re-operations for bleeding in association with CCB use.23 A smaller series of 120 patients undergoing coronary graft surgery also found no association with increased post-operative bleeding in patients receiving a CCB.24 In coronary heart disease, a review of several randomised controlled trials of calcium antagonist use involving over 15,000 patients and approximately 14,000 patient-years of treatment, indicated no bleeding excess in association with CCBs.14

In cerebrovascular disease and in particular subarachnoid haemorrhage, an overview of 6 randomised controlled trials of nimodipine including over 1,200 patients, indicated a reduction in poor outcomes after subarachnoid haemorrhage. There was no excess of any adverse effect such as increased re-bleeding.25 In 9 randomised controlled trials, 3,700 patients suffering acute ischaemic stroke were allocated to nimodipine or control. Again there was no evidence of any adverse effect of CCB use on death or clinical deterioration.26

In summary, the overview of observational studies and randomised trials does not support the suggestion that CCBs increase bleeding risk.

Calcium antagonists in diabetes with hypertension

The interim results of the Appropriate Blood Pressure Control in Diabetes (ABCD) trial have led to the Data and Safety Monitoring Committee recommending stopping the study in patients with hypertension who had been assigned to nisoldipine because of a marked difference in the number of myocardial infarctions (25 in the nisoldipine group versus 5 in the enalapril group).12 This is a small number of events. Even if the difference between the rates of myocardial infarction is real, it is not possible to know whether the ACE inhibitor is particularly beneficial or the calcium channel blocker harmful.

The FACET study13 was a randomised trial comparing fosinopril with amlodipine in diabetes with hypertension. The rate of major cardiovascular events was lower in patients receiving fosinopril than amlodipine. Renal function, lipid profile and diabetic control appeared similar in the two groups providing no ready rationale as to why event rates should differ. The systolic blood pressure was actually significantly more reduced in the amlodipine group, ruling out insufficient antihypertensive effect as a plausible explanation. It remains possible that both CCBs and ACE inhibitors are effective in diabetics with hypertension, but that ACE inhibitors are more effective. Alternatively, CCBs may be actually detrimental but there are no appropriate controlled data to allow this conclusion. The total number of events in both the ABCD and FACET studies is small and it is not possible to exclude the possibility that the findings are simply due to chance. Although the evidence is clearly inconclusive, ACE inhibitors are clearly beneficial and should be used as primary therapy in diabetes with hypertension. Results from both FACET and ABCD studies are consistent with those from the STOP-2 study.17

Clearer conclusions may be provided from the diabetic sub-groups included in the current generation of randomised trials (of treatment in hypertension and assorted cardiovascular risk groups) due to report within the next few years.27 There are over 30 of these. More than 100,000 patients have undergone randomisation in trials comparing CCBs with other drug regimens. Notably, one large trial, the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) has separate safety monitoring for primary trial end points in the sub-group with diabetes.28 The monitoring committee recently recommended the trial continue according to protocol and not withdraw diabetic patients from exposure to CCBs. The implication is that no statistically significant harmful effect has been observed in this patient subgroup.

In conclusion, there is no compelling evidence that CCBs increase risk of adverse cardiovascular outcomes in diabetes with hypertension.

The Mibefradil experience

In mid-1998 the prototype T-channel calcium antagonist mibefradil was withdrawn from the market approximately one year after the granting of marketing approval in Europe and the United States.29 This reflected reports of serious interactions with other drugs. Interactions were predictable from the pharmacology of the drug which inhibits the action of cytochrome P450 3A4. When given concurrently with other drugs that are metabolised by this enzyme, concentrations of these drugs and their biological actions may be expected to increase. Consequently, a wide array of other drugs cannot be taken concurrently with mibefradil. These include amiodarone, cyclosporin, erythromycin, imipramine, simvastatin and tamoxifen among others. Hence this class of CCBs has made a false start, and realisation of the therapeutic potential of T-channel blockers must await agents with an alternative route of metabolism.

Summary and conclusions

Brands of calcium channel blockers marketed in New Zealand

Dihydropyridine Phenylalkylamine Benzothiazepine
Short-acting
isradipine
Dynacirc

nifedipine
Nyefax
verapamil hydrochloride
Civicor
Isoptin
Verpamil
diltiazem hydrochloride
Apo-Diltiazem
Cardizem
Dilcard
Dilzem
Longer-acting
amlodipine besylate
Norvasc

felodipine
Agon SR
Plendil ER

isradipine
Dynacirc SRO

nifedipine
Adalat Oros & Adalat Retard
Alpha-Nifedipine Retard
Nyefax Retard

nimodipine
Nimotop (limited indication)
verapamil hydrochloride
Civicor Retard
Isoptin SR
Verpamil SR
diltiazem hydrochloride
Cardizem CD
Dilacor XR
Dilzem SR & Dilzem LA
* No product containing nitrendipine is approved in New Zealand
** Nisoldipine is approved in New Zealand as Syscor but is not marketed

Correspondence to Professor Mark Richards, Department of Medicine, Christchurch School of Medicine, PO Box 4345, Christchurch, New Zealand. Phone 03 364 1116, fax 03 364 1115, e-mail barbara.griffin@chmeds.ac.nz

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