|
1-Pahor M; Guralnik JM; Salive ME; Corti MC; Carbonin P; Havlik RJ
Do calcium channel blockers increase the risk of cancer?
Comment In:Am J Hypertens. 1996 Oct;9(10 Pt 1):1045-6, author reply 1051-3
Am J Hypertens; 9(7):695-9, 1996 Jul.
Calcium channel blockers can block calcium signals that trigger cell differentiation and apoptosis, which are important mechanisms of cancer growth regulation. To ascertain whether calcium channel blocker use was associated with an increased risk of cancer, 750 hypertensive persons age > or = 71 years, with no history of cancer at baseline, were followed from 1988 through 1992. The patients were using either beta-blockers, angiotensin converting enzyme inhibitors or calcium channel blockers (verapamil, nifedipine, and diltiazem; mainly of the short-acting variety). Compared to beta-blockers (n = 424, 28 events), after adjusting for age, gender, race, smoking, body mass index, and number of hospital admissions not related with cancer, the relative risks of cancer (95% confidence interval) for angiotensin converting enzyme inhibitors (n = 124, 6 events) and calcium channel blockers (n = 202, 27 events) were 0.73 (0.30 to 1.78) and 2.02 (1.16 to 3.54), respectively. These findings indicate that calcium channel blocker therapy might increase the risk of cancer. New data are needed in patients using modern calcium channel blocker agents with more gradual absorption. This report should encourage further study of cancer outcomes in elderly patients who are vulnerable to cancer and who are receiving calcium channel blockers.
2-Pahor M; Guralnik JM; Ferrucci L; Corti MC; Salive ME; Cerhan JR; Wallace RB; Havlik RJ
Calcium-channel blockade and incidence of cancer in aged populations.
Comment In:Lancet. 1996 Aug 24;348(9026):487
Lancet; 348(9026):493-7, 1996 Aug 24.
BACKGROUND: Calcium-channel blockers can alter apoptosis, a mechanism for destruction of cancer cells. We examined whether the long-term use of calcium-channel blockers is associated with an increased risk of cancer. METHODS: Between 1988 and 1992 we carried out a prospective cohort study of 5052 people aged 71 years or more and who lived in three regions of Massachusetts, Iowa, and Connecticut USA. Those taking calcium-channel blockers (n = 451) were compared with all other participants (n = 4601). The incidence of cancer was assessed by survey of hospital discharge diagnoses and causes of death. These outcomes were validated by the cancer registry in the one region where it was available. Demographic variables, disability, cigarette smoking, alcohol consumption, blood pressure, body-mass index, use of other drugs, hospital admissions for other causes, and comorbidity were all assessed as possible confounding factors. FINDINGS: The hazard ratio for cancer associated with calcium-channel blockers (1549 person-years, 47 events) compared with those not taking calcium-channel blockers (17225 person-years, 373 events) was 1.72 (95% CI 1.27-2.34, p = 0.0005), after adjustment for confounding factors. A significant dose-response gradient was found. Hazard ratios associated with verapamil, diltiazem, and nifedipine did not differ significantly from each other. The results remained unchanged in community-specific analyses. The association between calcium-channel blockers and cancer was found with most of the common cancers. INTERPRETATION: Calcium-channel blockers were associated with a general increased risk of cancer in the study populations, which suggested a common mechanism. These observational findings should be confirmed by other studies.
3-Kaplan NM
Do calcium antagonists cause cancer?
Comment On:Lancet. 1996 Apr 20;347(9008):1061-5
Lancet; 348(9026):541-2, 1996 Aug 24.
4-Jackson G
Calcium antagonists: a scandal in need of an inquiry.
Int J Clin Pract; 57(6):455, 2003 Jul-Aug.
5-Beiderbeck-Noll AB; Sturkenboom MC; van der Linden PD; Herings RM; Hofman A; Coebergh JW; Leufkens HG; Stricker BH
Verapamil is associated with an increased risk of cancer in the elderly: the Rotterdam study.
Comment In: Eur J Cancer 39(1):98-105, 2003 Jan.
Eur J Cancer; 39(1):98-105,2003
The association between the use of calcium channel blockers (CCB) and cancer has received ample attention, but is still controversial. In this study, we have tested the hypothesis that the observed association between CCB and cancer in earlier studies could be explained by residual confounding or by misclassification of exposure because of the use of cross-sectional data on drug use. Data from the Rotterdam Study, a prospective population-based cohort study in the municipal area Ommoord, were used. The study population consisted of a cohort of 3204 participants aged 71 years or older who were followed from a baseline interview in the period 1991-1993 for the occurrence of incident cancer. Data on drug use were gathered at baseline and through the seven community pharmacies which served the Ommoord region during the study period between 1 January 1991 and 1 January 1999. Incident cancer events were gathered from a nationwide registry of hospitalisation data and from a specialised cancer centre in the Rotterdam region. We performed three analyses. First, we followed the method, and adjusted for the same risk factors, as in the earlier studies. In the second analysis, we included all risk factors that were univariately associated with cancer in the Rotterdam Study. In the third analysis, we included exposure to CCBs as time-varying co-variates, while adjusting for potential confounders. The relative risk (RR) of cancer associated with CCB was 1.4 (95% Confidence Interval (CI): 0.9-2.0) in the first analysis and lowered to 1.2 (95% CI: 0.8-1.8) upon adjustment for the different co-variates in the second. In both analyses, however, verapamil was significantly associated with cancer with RRs of 2.1 (95% CI: 1.1-4.0) and 2.0 (1.01-3.9), respectively, whereas no associations were found with the other CCB in this study, i.e. diltiazem and nifedipine. A significantly increased risk of cancer was found for intermediate daily doses of verapamil and diltiazem. Intake of other antihypertensives such as beta-blocking agents, diuretics and ACE-inhibitors was not associated with cancer. In the third analysis with exposure to CCB as time-varying co-variates, the risk increase was non-significant for use of 2 years or less, 1.0 (95% CI: 0.7-1.5), and for use for a cumulative period of more than 2 years, 1.3 (95% CI: 0.8-2.0). However, in all models the hazard ratio was statistically significantly increased for verapamil, but not for diltiazem and nifedipine. On the basis of these analyses, we found no increase in cancer in users of diltiazem and nifedipine, nor in users of other antihypertensives. In line with earlier studies, however, we found an increased risk of cancer in users of verapamil. At variance with the conclusions from several other studies, we think that it is too early to conclude that CCB are not associated with cancer.
6-La Vecchia C; Bosetti C
Calcium channel blockers, verapamil and cancer risk.
Comment On:Eur J Cancer. 2003 Jan;39(1):98-105
Eur J Cancer; 39(1):7-8, 2003 Jan.
7-Preobrazhenskii DV; Sidorenko BA; Stetsenko TM; Kiktev VG
[Antihypertensive drugs and malignant neoplasia]
Antigipertenzivnye preparaty i zlokachestvennye novoobrazovaniia..
Kardiologiia; 42(5):62-7, 2002.
Analysis of epidemiological, cohort and randomized studies of antihypertensive drugs containing reports of development of malignant neoplasms shows that long term use of some antihypertensive drugs while preventing cardiovascular complications has been associated with increased risk of malignancies. Most convincing evidence exists for association between the use of diuretics and renal cancer. Association between the use of reserpine and breast cancer in women, between atenolol and some types of cancer in elderly men also can not be ruled out. There is no proof of existence of either negative or positive correlation between malignant neoplasia and long-term use of calcium antagonists, angiotensin converting enzyme inhibitors or angiotensin receptor blockers.
8-Lindberg G; Lindblad U; Löw-Larsen B; Merlo J; Melander A; Råstam L
Use of calcium channel blockers as antihypertensives in relation to mortality and cancer incidence: a population-based observational study.
Pharmacoepidemiol Drug Saf; 11(6):493-7, 2002 Sep.
PURPOSE: Treatment with blood pressure lowering drugs may reduce morbidity and mortality. However, the efficacy and effectiveness may differ between antihypertensive agents. The current investigation aimed to compare mortality and cancer incidence in hypertensive patients treated with calcium channel blockers (CCB) or with other antihypertensive drugs (AHD). METHODS: All patients in two outpatient clinics treated with AHD who underwent an annual check-up during 1989 or 1990 were selected. Fatal events were identified through 1997 and incident cancers through 1998. RESULTS: Two hundred and fourteen patients on CCB and 1029 on other AHD were identified. Overall mortality and the combined mortality from myocardial infarction and stroke were higher in CCB users; hazard ratios adjusted for sex, age, comorbidity and other and risk factors were 1.84 (95% CI 1.25-2.72) and 2.37 (95% CI 1.27-4.44), respectively. The risk estimates for cancer mortality and for cancer incidence did not differ significantly. CONCLUSIONS: Results from clinical trials as well as observational studies, including the present one, indicate a higher mortality risk and a higher cardiovascular morbidity risk associated with use of CCB. Accordingly, CCB should not be regarded as first line drugs in hypertension.
9-Zhu K; Daling JR; Pahor M
African-American ethnicity in epidemiological studies of calcium antagonists in relation to cancer.
Ethn Dis; 12(1):144-8, 2002 Winter.
10-Felmeden DC; Lip GY
Antihypertensive therapy and cancer risk.
Drug Saf; 24(10):727-39, 2001.
The aim of this article is to provide an overview of the available data linking antihypertensive drug therapy to cancer risk. In recent years, a number of mainly retrospective studies have reached different conclusions on the risk of cancer in patients with hypertension being treated with different antihypertensive drugs. At some point or another nearly all antihypertensive drugs have been suggested to increase the risk of cancer. Some studies have even found an association between hypertension itself and increased carcinogenesis. For calcium channel antagonists, beta-blockers and alpha-blockers, the available evidence seems to favour a neutral effect on cancer development and death rate. For ACE inhibitors, the overall data suggest a similar neutral effect on cancer or, possibly, a small protective effect. Perhaps the strongest evidence in favour of a link, although probably weak, between cancer and antihypertensive drugs is with the diuretics. Until further solid data are available from prospective clinical trials, we suggest that the management of hypertension should continue according to current treatment guidelines with little fear of any substantial cancer risk.
11-Grossman E; Messerli FH; Goldbourt U
Antihypertensive therapy and the risk of malignancies.
Eur Heart J; 22(15):1343-52, 2001 Aug.
AIMS: To assess the relationship between antihypertensive therapy and malignancy. METHODS AND RESULTS: A MEDLINE search for English-language articles published between January 1966 and August 1999 identified 29 prospective studies that reported cancer incidence or mortality and 28 case-control studies that reported specific drug use in cancer patients and controls. The association between rauwolfia derivatives and breast cancer was analysed in 5852 cases and 9776 controls, yielding an odds ratio (OR) of 1.25 (95% CI, 1.09-1.44). The association between diuretics and renal cell carcinoma was analysed in 4389 cases and 6566 controls, yielding a pooled OR of 1.54 (95% CI, 1.41-1.68). The association between atenolol and cancer death was analysed pooling three randomized controlled studies, including 1879 treated patients and 3078 non-treated patients, yielding a pooled OR of 1.36 (95% CI, 1.02-1.82); however, data from non-randomized studies did not confirm the latter. The association between calcium antagonists and malignancy was analysed pooling five randomized controlled studies, including 5451 treated patients and 5207 untreated ones, yielding a pooled OR of 0.78 (CI, 0.60-1.00). A meta-analysis of an additional five longitudinal studies, including 9087 treated patients and 15 559 non-treated patients, yielded a pooled OR of 1.04 (CI, 0.91-1.19). The association between ACE inhibitors and malignancy was analysed pooling two randomized controlled trials involving 1585 treated patients and 1567 non-treated patients, yielding a pooled OR of 1.57 (95% CI, 0.97-2.57); however, non-randomized studies showed no association or a decreased risk for malignancy with ACE inhibitors. CONCLUSIONS: With the exception of diuretics and renal cell carcinoma, the association between antihypertensive drugs and malignancy was either low grade (rauwolfia), uncertain (atenolol), absent (ACE inhibitors), or absent with a yet to be investigated inverse association (calcium antagonists). Ongoing long-term prospective studies with cardiovascular drugs should carefully monitor the risk of malignancy.
12-Goldstein MR
Does amlodipine increase cancer incidence?
Comment On:Circulation. 2000 Sep 26;102(13):1503-10
Circulation; 104(2):E5, 2001 Jul 10.
13-Kizer JR; Kimmel SE
Epidemiologic review of the calcium channel blocker drugs. An up-to-date perspective on the proposed hazards.
Comment In:Arch Intern Med. 2001 Nov 26;161(21):2627-8
Arch Intern Med; 161(9):1145-58, 2001 May 14.
In the setting of soaring popularity, postmarketing studies of calcium channel blockers came to suggest an increase in a variety of major adverse end points. The evidence, however, was largely observational, and large-scale trials capable of addressing the concerns were wanting. Clinical trials now support the safety and efficacy of the long-acting dihydropyridines for patients with both uncomplicated and diabetic hypertension, although conventional therapies and, in the latter case, angiotensin-converting enzyme inhibitors have superior proof of benefit. By contrast, short-acting dihydropyridines should be avoided. In the acute coronary syndromes, beta-blockers remain the treatment of choice; the evidence for nondihydropyridines remains inconclusive. Stable angina calls for beta-blockers as first-line therapy and nondihydropyridines as second-line therapy, whereas in ventricular dysfunction, safety data for nondihydropyridines are lacking. Initial reports of cancer, bleeding, and suicide have been contradicted by subsequent data, making the associations uncertain or unlikely. Remaining questions await completion of ongoing trials to better define the indications for these agents.
14-Nakagawa Y; Shimada K
[Anti-hypertensive agents and cancer]
Nippon Rinsho; 58 Suppl 2:180-2, 2000 Feb.
15-Sorensen HT; Olsen JH; Mellemkjaer L; Marie A; Steffensen FH; McLaughlin JK; Baron JA
Cancer risk and mortality in users of calcium channel blockers. A cohort study.
Cancer; 89(1):165-70, 2000 Jul 1.
BACKGROUND: Data regarding the association between the use of calcium channel blockers and cancer risk have been conflicting. In the current study, the authors examined the cancer risk and mortality in users of calcium channel blockers in North Jutland County, Denmark. METHODS: The authors conducted a cohort study using record linkage between a population-based prescription database, the Danish Cancer Registry, and the Danish Death Registry including 23, 167 users of calcium channel blockers who received >/=2 prescriptions between January 1, 1989 and December 31, 1995. The authors calculated the standardized incidence ratios and standard mortality ratios for cancer, along with corresponding 95% confidence intervals (95% CI). RESULTS: Overall, 967 incident cases of cancer occurred, resulting in a standardized incidence ratio of 1.04 (95% CI, 0.98-1.11). There was a slightly elevated nonsignificant risk of tobacco-related cancer. No increased risk of breast or colon carcinoma was observed. The cancer mortality was close to that expected in the background population (standardized mortality ratio of 0.97; 95% CI, 0.89-1.04). CONCLUSIONS: This large-scale, population-based cohort study adds to the increasing evidence indicating no substantial association between the use of calcium channel blockers and the incidence rate of cancer or cancer mortality.
16-Stahl M; Bulpitt CJ; Palmer AJ; Beevers DG; Coles EC; Webster J
Calcium channel blockers, ACE inhibitors, and the risk of cancer in hypertensive patients: a report from the Department of Health Hypertension Care Computing Project (DHCCP)
Comment In:J Hum Hypertens. 2000 May;14(5):285-6
J Hum Hypertens; 14(5):299-304, 2000 May.
OBJECTIVE: Recent studies have shown inconsistent results on the risk of cancer in hypertensive patients using calcium channel blockers (CCBs) and angiotensin-converting enzyme (ACE) inhibitors. We investigated a large number of patients from the Department of Health Hypertension Care Computing Project (DHCCP) observational database treated with these drugs for hypertension to see whether the use of CCBs for hypertension is associated with an increased risk of cancer mortality and the use of ACE inhibitors with a reduction. DESIGN: Matched case-control study and a longitudinal study of survival from 1 year after presentation. PATIENTS: A total of 11663 patients treated for hypertension from 1971 through 1987. They were recruited on presentation to one of the hospital hypertension clinics or general practices involved. MAIN OUTCOME MEASURES: Death with any mention of cancer on the death certificate in patients treated with an Index drug group; CCBs, ACE inhibitors, beta adrenergic blocking drugs (BBs), or receiving a diuretic. The treatment groups were mutually exclusive. RESULTS: A total of 391 cases of cancer were matched with 1050 controls. In this case-control study the adjusted relative risk estimate in comparison to diuretic treatment for CCBs was 0.79 (95% CI 0.37 to 1.69), and for CCBs plus a diuretic, 1.05 (0.65 to 1.69). Non-significant results were also observed for ACE inhibitors (1.48 (0.43 to 5.1), and 1.40 (0.56 to 3.50) with a diuretic), and also for the BB and methyldopa groups. In the longitudinal survival study, the adjusted relative risk estimate for CCBs was 1.1 (0.60 to 1.94) and 1.0 (0.53 to 1.86) for CCBs plus a diuretic, and for ACE inhibitors 1.33 (0.37 to 4.76) and 1.47 (0.67 to 3.23), respectively. CONCLUSIONS: In this population there was no increased cancer mortality with the use of CCBs and a relative risk greater than 1.7 to 2.0 was excluded with 95% confidence. The suggestion that ACE inhibitors reduce cancer mortality was not supported with best estimates of relative risk of 1.3 to 1.5 and exclusion of values less than 0.4 to 0.7.
17-Grossman E; Messerli FH
Calcium antagonists, ACE inhibitors, and the risk of cancer in hypertensive patients.
Comment On:J Hum Hypertens. 2000 May;14(5):299-304
J Hum Hypertens; 14(5):285-6, 2000 May.
18-Cohen HJ; Pieper CF; Hanlon JT; Wall WE; Burchett BM; Havlik RJ
Calcium channel blockers and cancer.
Am J Med; 108(3):210-5, 2000 Feb 15.
PURPOSE: We sought to explore the relation that has been previously reported between calcium channel blockers and an increased risk of cancer. SUBJECTS AND METHODS: We followed 3,511 participants, age 65 years or older, in the Duke Established Populations for Epidemiologic Studies of the Elderly for up to 10 years. Information about use of medications was obtained at baseline and 3 and 6 years later. Information about hospitalization for cancer, or death from cancer, was obtained from Health Care Financing Administration data and death certificates. RESULTS: Of the 133 users of calcium channel blockers, 16 (12%) developed cancer, compared with 548 (16%) of 3,378 nonusers (hazard ratio = 0.9; 95% confidence interval, 0.5 to 1.5). Adjusting for baseline and time-dependent covariates, such as race, diabetes, or blood pressure, for dose or class of calcium channel blockers, or for length of follow-up, had no effect. CONCLUSIONS: Use of calcium channel blockers does not appear to be related to cancer risk. Earlier reports showing such a relation may have been the result of chance.
19-Lever AF; Hole DJ; Gillis CR; McInnes GT; Meredith PA; Murray LS; Reid JL
Is cancer related to hypertension or to its treatment?
Clin Exp Hypertens; 21(5-6):937-46, 1999 Jul-Aug.
Three questions related to cancer and blood pressure are discussed. (i) Is cancer related in some way to hypertension, or to blood pressure? Several studies show a relation of blood pressure and cancer in populations. However, our own experience, based on a cohort of 15,411 subjects with BP measured in the 1970s and with 1,392 fatal cancers since, shows no relation of cancer risk and diastolic pressure. Nor were cancer numbers (n=72) observed in the 1,078 untreated hypertensives of the Glasgow Blood Pressure Clinic different from those expected (n=71.2) in a control population matched for age, sex and smoking habit. (ii) Do antihypertensive drugs promote cancer? Atenolol and calcium channel blockers have been suspected of this, but evidence of larger studies, including two of our own, is negative: relative risk for cancer in our patients taking CCB was 1.02 (CI 0.82-1.27). (iii) Do antihypertensive drugs protect against cancer? A study of ours based on the Glasgow Clinic raises this possibility: relative risk for incident cancer amongst 1,559 patients taking ACE inhibitor was 0.72 (CI 0.55-0.92).
20-Mason RP
Effects of calcium channel blockers on cellular apoptosis: implications for carcinogenic potential.
Cancer; 85(10):2093-102, 1999 May 15.
BACKGROUND: A small number of well-publicized, retrospective epidemiologic reports have suggested a causal relation between the use of calcium channel blockers (CCBs) for the treatment of hypertension and an increased risk for cancer. The biologic mechanism proposed to explain this possible relation is that CCBs interfere with apoptosis, an active cell death process required for the regulation of normal cell populations in the body. Because an elevation in cellular calcium (Ca2+) is thought to be involved in apoptosis, it has been argued that CCBs could inhibit apoptosis, leading directly to tumor promotion. METHODS: A comprehensive and critical review of the scientific literature was conducted specifically to evaluate the effects of pharmacologic CCBs on apoptosis and tumor development in various experimental models. RESULTS: A review of the scientific literature revealed that CCBs have complex and often contradictory effects on cellular apoptosis. In various experimental models of cancer, CCBs did not promote neoplastic growth. By contrast, CCB treatment was associated with an inhibition of tumor growth in certain models of neoplasia and was also an effective adjuvant therapy in the treatment of certain drug-resistant tumors. Additional large epidemiologic studies have failed to support the hypothesis that CCB use is associated with an increased susceptibility for cancer. CONCLUSIONS: A biologic link between the use of CCBs and increased human risk for cancer development as a result of modulating cellular apoptosis is not supported by the scientific literature.
21-Sajadieh A; Storm HH; Hansen JF
Verapamil and risk of cancer in patients with coronary artery disease. DAVIT Study Group. Danish Verapamil Infarction Trial.
Am J Cardiol; 83(9):1419-22, A9, 1999 May 1.
The risk of cancer in users of verapamil was assessed in a long-term follow-up of 1,775 patients who were randomized to verapamil or matching placebo in the Danish Verapamil Infarction Trial-II in the years 1985 to 1987. During 10,474 patient-years, no increased risk of cancer was observed for the verapamil-treated men or women compared with the age- and sex-matched background population.
22-Kanamasa K; Kimura A; Miyataka M; Takenaka T; Ishikawa K
Incidence of cancer in postmyocardial infarction patients treated with short-acting nifedipine and diltiazem. Secondary Prevention Group.
Cancer; 85(6):1369-74, 1999 Mar 15.
BACKGROUND: Recent reports suggest a possible link between nifedipine (but not diltiazem) and an increased risk of cancer in patients being treated with calcium antagonists. METHODS: A total of 1054 postmyocardial infarction patients were divided randomly into those being treated with calcium antagonists (n = 566 [nifedipine, 425 patients and diltiazem, 141 patients]) and controls (no calcium antagonist; n = 488). The patients were followed for 26.3 months, and the incidences of cardiac events as well as cancer were compared among the 3 groups. RESULTS: Thirteen patients (2.7%) in the control group developed cancer, whereas 15 patients in the nifedipine group (3.5%; odds ratio, 1.34; 95% confidence interval [95% CI], 0.63-2.85) and 3 patients in the diltiazem group (2.1%; odds ratio, 0.89; 95% CI, 0.27-2.93) developed cancer. CONCLUSIONS: Diltiazem appears to present no increased risk of cancer. The incidence of cancer was slightly higher in the patients receiving nifedipine than in those not being treated with a calcium antagonist, which is consistent with earlier reports; however, this increase was not statistically significant.
23-Mason RP
Calcium channel blockers, apoptosis and cancer: is there a biologic relationship?
J Am Coll Cardiol; 34(7):1857-66, 1999 Dec.
Calcium channel blockers (CCBs) represent a chemically and pharmacologically diverse group of agents that are widely used for the treatment of hypertension and angina. A small number of retrospective, observational analyses have raised concern about a potential causal link between CCB use and an increased risk for cancer development. Despite the absence of cancer findings in extensive preclinical studies, it has been proposed that CCBs may work differently in humans by interfering with apoptosis, leading to an increased potential for abnormal cell proliferation and tumor growth. This biologic hypothesis has attracted considerable attention in the medical community but has not been critically evaluated. An analysis of the basic and clinical literature was conducted to examine biologic relationships among cell Ca2+ modulation, apoptosis, and cancer. In addition to a comprehensive review of the cellular and animal data, the results of large observational studies were included in this analysis. Results of this review demonstrated that the effects of CCBs on apoptosis are complex as both increases and decreases in intracellular Ca2+ have been linked to this form of programmed cell death. Most studies show that an effect (either positive or negative) of CCBs on apoptosis requires doses in the supra-pharmacologic range, and are therefore not clinically relevant. Results of large and methodologically robust observational studies fail to provide support for the hypothesis that CCB use is associated with an increased susceptibility for cancer incidence. A comprehensive analysis of the basic and clinical evidence does not support a causal relationship between the therapeutic use of CCBs and an increased incidence of cancer development as a result of interfering with apoptosis.
24-Messerli FH; Grossman E
The calcium antagonist controversy: a posthumous commentary.
Am J Cardiol; 82(9B):35R-39R, 1998 Nov 12.
In 1995, some retrospective reports showed that certain patients treated with short-acting calcium antagonists were at increased risk for myocardial infarction and had a higher mortality rate compared with patients treated with other cardiovascular drugs. Subsequent reports attempted to establish a connection between calcium antagonists and disorders as diverse as malignancy, Parkinsonism, cognitive dysfunction, and suicide. However, other retrospective studies and, more compelling, several prospective studies have reported that calcium antagonists exert a beneficial effect on morbidity and mortality in a variety of cardiovascular disorders such as hypertension, ischemic heart disease after myocardial infarction, and congestive heart failure due to dilated cardiomyopathy. Calcium antagonists are a heterogeneous drug class, and distinct differences have been documented between short- and long-acting, as well as between dihydropyridine and nondihydropyridine, agents. Sympathetic activation, which is a risk factor for coronary events, occurs with short-acting agents only and is absent with long-acting calcium antagonists. Recent data make it extremely unlikely that calcium antagonists increase the risk of malignancy by affecting apoptosis or immunosuppression or both. Long-acting calcium antagonists have distinct benefits in patients with hypertension and diabetes and may be more beneficial than other drugs in patients with diabetes and left ventricular hypertrophy.
25-Degaute JP
[Which calcium antagonists for hypertension?]
Quels antagonistes calciques dans l'hypertension artérielle?.
Rev Med Brux; 19(4):A389-92, 1998 Sep.
Calcium antagonists have been used for treatment of cardiovascular diseases for more than 25 years. Several recent retrospective studies have suggested that chronic treatment with short-acting dihydropyridines increased the incidence of cardiac events, cancer and gastrointestinal bleedings. Randomized prospective studies have, however, never been able to confirm these observations. In addition, well-conducted studies using verapamil and diltiazem have suggested that these calcium antagonists may even improve cardiovascular mortality and morbidity of the hypertensive patient. There is therefore no reason to believe that the questionable results derived from retrospective studies of the effects of short-acting calcium antagonists on cardiac and noncardiac events may apply to the newer generation of long-acting calcium antagonists.
26-Michels KB; Rosner BA; Walker AM; Stampfer MJ; Manson JE; Colditz GA; Hennekens CH; Willett WC
Calcium channel blockers, cancer incidence, and cancer mortality in a cohort of U.S. women: the nurses' health study.
Cancer; 83(9):2003-7, 1998 Nov 1.
BACKGROUND: Some studies have suggested that the use of calcium channel blockers may increase the risk of cancer. A possible association of the use of calcium channel blockers with cancer incidence and cancer mortality was addressed using data from the Nurses' Health Study. METHODS: In this study, a total of 18,635 female nurses reported regularly taking at least 1 of 4 cardiovascular medications in 1988: diuretics, beta-blockers, calcium channel blockers, and/or angiotensin-converting enzyme (ACE) inhibitors. Cancer incidence and cancer deaths were ascertained until 1994. RESULTS: During 6 years of follow-up, 852 women were newly diagnosed with cancer and 335 women died of cancer. Women who reported the use of calcium channel blockers had no increased risk of newly diagnosed cancer compared with those taking other cardiovascular drugs (relative risk=1.02; 95% CI 0.83-1.26). The relative risk of dying from cancer associated with the self-reported use of calcium channel blockers was 1.25 (95% CI 0.91-1.72). Relative risks were adjusted for the following self-reported factors: age; weight; height; cholesterol level; systolic and diastolic blood pressure; smoking; alcohol intake; physical activity; menopausal status; postmenopausal hormone use; aspirin use; and history of diabetes, cancer, stroke, myocardial infarction, coronary artery bypass graft or percutaneous transluminal coronary angioplasty, angina, and hypertension. Regarding site specific cancer incidence and mortality, only lung cancer incidence was somewhat increased (RR=1.61; 95% CI 0.88-2.96). CONCLUSIONS: These data suggest no important increase in overall cancer incidence or cancer mortality related to the self-reported use of calcium channel blockers.
27-Pahor M; Furberg CD
Is the use of some calcium antagonists linked to cancer? Evidence from recent observational studies.
Drugs Aging; 13(2):99-108, 1998 Aug.
In animal and in vitro studies, several calcium antagonists have been shown to block apoptosis (programmed cell death), a natural cellular defence against cancer. On the basis of these studies, it has been hypothesised that calcium antagonists may function as cancer promoters and that they might cause cancer in humans. The association between the use of calcium antagonists and cancer has been addressed recently in 6 independent epidemiological studies. Four of these studies--2 cohort and 2 case-control--found a significantly higher risk of cancer among users of certain calcium antagonists as compared with either non-users or with users of other antihypertensive agents. The other 2 studies failed to find support for this association. All studies had limitations of varying types and significance. The emerging pattern from these investigations includes the following features: (i) the strength of the association appears to be dependent on daily dosage, ranging from no association in users of low dosages to a 2-fold (or possibly higher) increased risk in users of higher dosages; (ii) the time lag to the appearance of this association appears to be at least 2 to 3 years; (iii) an association with a higher risk of cancer has been found primarily for verapamil, while no such relationship has been reported for diltiazem; and (iv) no highly consistent associations have been shown with specific cancer sites or histological types. More data, preferably from long-term randomised clinical trials, are required before firm conclusions can be drawn.
28-McCarty MF
Selenium, calcium channel blockers, and cancer risk--the Yin and Yang of apoptosis?
Med Hypotheses; 50(5):423-33, 1998 May.
It is increasingly clear that apoptosis plays a crucial role in the promotional phase of cancer development. Initiated pre-neoplastic clones in rat liver experience a high rate of apoptosis, and this rate has an important impact on the survival and growth of these clones. Suppression of apoptosis appears to be a universal property of cancer promoters, suggesting conversely that agents which inhibit cancer induction during the promotional phase increase the rate of apoptosis in initiated cells. Modulation of apoptosis is a likely explanation for recent striking evidence that use of calcium channel blockers substantially increases, whereas supplemental selenium substantially decreases, human cancer incidence. Non-genotoxic measures which are likely to upregulate apoptosis in pre-neoplastic/neoplastic cells--and thus may be useful in prevention and/or therapy--include selenium, retinoids/carotenoids, green tea polyphenols, caloric restriction, downregulation of IGF-I activity, high-dose tamoxifen and other protein kinase C antagonists, withdrawal or blockade of trophic hormones, isoflavones, limonene, vitamin D and cholecalciferol analogs, dietary fiber/sodium butyrate, hyperthermia, benzaldehyde derivatives, and creatine.
29-Jonas M; Goldbourt U; Boyko V; Mandelzweig L; Behar S; Reicher-Reiss H
Nifedipine and cancer mortality: ten-year follow-up of 2607 patients after acute myocardial infarction.
Cardiovasc Drugs Ther; 12(2):177-81, 1998 May.
Recent publications contended that the use of short-acting calcium antagonists may double the risk of cancer incidence and possibly increase mortality in hypertensive patients. The purpose of this study was to assess the risk ratio for cancer mortality associated with nifedipine in a large population of patients post-myocardial infarction. Cancer mortality data, over a 10-year period, were obtained on 2607 hospital survivors of acute myocardial infarction who were screened, but not included, in the Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT I) study. In this group of patients, 526 (20%) were on nifedipine, according to their treating physicians' decision. In the cohort of screened patients not included in SPRINT I, there were 22 (4.2%) cancer-related deaths in the patients on nifedipine compared with 114 (5.5%) in the group not treated with nifedipine (P = 0.23). In multivariate analysis, the 10-year cancer mortality risk ratio associated with nifedipine therapy was 1.06 (95% CI 0.52-2.18). The current analysis shows no evidence of an increased risk of cancer mortality in a large number of patients treated at baseline with nifedipine.
30-Duprez DA; De Buyzere ML; Clement DL
Calcium antagonists, is there a real concern about safety?
Acta Clin Belg; 53(2):61-5, 1998 Apr.
Calcium antagonists are widely used in the treatment of arterial hypertension and, or in ischemic heart disease. During the last 3 years, controversial articles and editorials have been published concerning the potential risk of calcium antagonists in regard to mortality, cancer and haemorrhage. The information has been mainly derived from case-control studies. The major concern about such observational studies of treatment outcome is the large potential for systematic error to affect the results. However, overviews of controlled trials with calcium antagonists do not provide clear evidence of an effect of calcium antagonists on mortality, risk of cancer and risk of bleeding.
31-Straka RJ; Swanson AL; Parra D
Calcium channel antagonists: morbidity and mortality--what's the evidence?
Comment In:Am Fam Physician. 1998 Apr 1;57(7):1484, 1492
Am Fam Physician; 57(7):1551-60, 1998 Apr 1.
Recent studies have shown an association between the use of calcium channel antagonists for the treatment of hypertension and an increased risk of myocardial infarction, gastrointestinal hemorrhage and cancer. The interpretation of the results of these studies and their application to clinical practice requires an understanding of study design constraints, conflicting results and limitations in extrapolating study findings to other dosage strengths, formulations or agents within the calcium channel antagonist class. A review and critique of these studies provides background information on the controversial subject of using calcium channel antagonists for the treatment of hypertension. Despite the limitations of these studies, clinicians may want to select other classes of agents, including diuretics and beta blockers, as first-line therapy until the morbidity and mortality effects related to the use of calcium channel antagonists are clearly known.
32-Rosenberg L; Rao RS; Palmer JR; Strom BL; Stolley PD; Zauber AG; Warshauer ME; Shapiro S
Calcium channel blockers and the risk of cancer.
Comment In:JAMA. 1998 Aug 19;280(7):600
JAMA; 279(13):1000-4, 1998 Apr 1.
CONTEXT: Recent epidemiologic studies have raised the concern that calcium channel blocker use may increase the risk of cancer overall and of several specific cancers. OBJECTIVE: To assess whether calcium channel blocker use increases the risk of cancer overall and of specific cancers. DESIGN: Case-control drug surveillance study based on data collected from 1983 to 1996. SETTING: Hospitals in Baltimore, Md, New York, NY, and Philadelphia, Pa. PATIENTS: A total of 9513 patients aged 40 to 69 years with incident cancer of various sites and 6492 controls aged 40 to 69 years admitted for nonmalignant conditions. MAIN OUTCOME MEASURES: Incident cancer overall and 23 specific cancers. RESULTS: Calcium channel blocker use was unrelated to the risk of cancer overall (relative risk [RR], 1.1; 95% confidence interval [CI], 0.9-1.3). Use was not significantly associated with increased risks of individual cancers, including those previously implicated, except cancer of the kidney (RR, 1.8; 95% CI, 1.1 -2.7). Recent use, use for 5 or more years, and use of individual calcium channel blocker drugs were also not associated with cancer incidence. Use of beta-blockers and angiotensin-converting enzyme inhibitors was generally unrelated to cancer overall or individual cancers, but both were associated with kidney cancer (RR, 1.8; 95% CI, 1.3-2.5; and RR, 1.9; 95% CI, 1.2-3.0, respectively). CONCLUSIONS: The present study suggests that the use of calcium channel blockers is unrelated to an increase in the overall risk of cancer or of individual cancers, except kidney cancer, which has been associated with hypertension or drugs to treat hypertension in previous studies.
33-Hole DJ; Gillis CR; McCallum IR; McInnes GT; MacKinnon PL; Meredith PA; Murray LS; Robertson JW; Lever AF
Cancer risk of hypertensive patients taking calcium antagonists.
J Hypertens; 16(1):119-24, 1998 Jan.
OBJECTIVE: To measure rates of incident and fatal cancer in hypertensive patients taking calcium antagonists and to compare these with rates in three control groups. DESIGN: A retrospective analysis of cancer in patients of the Glasgow Blood Pressure Clinic prescribed either a calcium antagonist or other antihypertensive drugs (non-calcium antagonist group). Record linkage of the clinic with the West of Scotland Cancer Registry and with the Registrar General, Scotland provided information on incidence of cancer and on deaths and their causes. PATIENTS: 2297 patients were prescribed calcium antagonist and 2910 were prescribed antihypertensive drugs other than calcium antagonist. MAIN OUTCOME MEASURES: Relative risk of cancer, the ratio of observed to expected cancers in the calcium antagonist group, was estimated using expected values based on three control groups; namely the non-calcium antagonist group, a middle-aged population of Renfrew and Paisley and the West of Scotland population. RESULTS: There were 134 incident cancers in the calcium antagonist group, representing relative risks of 1.02 [95% confidence interval (CI) 0.82-1.271 compared with the non-calcium antagonist group, 1.01 (95% CI 0.84-1.18) compared with Renfrew-Paisley controls and 1.02 (95% CI 0.85-1.19) compared with West of Scotland controls. Findings for cancer mortality were similarly negative. Risks were no higher for older patients. CONCLUSIONS: Our study lends no support to the suggestion that calcium antagonists cause cancer.
34-Braun S; Boyko V; Behar S; Reicher-Reiss H; Laniado S; Kaplinsky E; Goldbourt U
Calcium channel blocking agents and risk of cancer in patients with coronary heart disease. Benzafibrate Infarction Prevention (BIP) Study Research Group.
Comment In:J Am Coll Cardiol. 1998 Mar 15;31(4):809-10
J Am Coll Cardiol; 31(4):804-8, 1998 Mar 15.
OBJECTIVES: This analysis sought to estimate the risk ratio for cancer incidence and cancer-related mortality associated with the use of calcium channel blocking agents (CCBs) in a large group of patients with chronic coronary heart disease (CHD). BACKGROUND: Recent publications contend that the use of short-acting CCBs may double the risk of cancer incidence and possibly increase mortality in hypertensive patients. METHODS: Cancer incidence data were obtained for 11,575 patients screened for the Bezafibrate Infarction Prevention (BIP) study, one-half of whom were treated at the time of screening with CCBs, over a mean follow-up period of 2.8 years. Cause-specific mortality was available through September 1996 (mean follow-up 5.2 years). The statistical power of detecting an odds ratio > or = 1.5 (given the cancer incidence rate of 2.1 in the nonusers of CCBs) was 0.91. The power declined to 0.77, 0.54 and 0.41, with declining odds ratios of 1.4, 1.3 and 1.25, respectively. RESULTS: Of 246 incident cancer cases, 129 occurred among the users (2.3%) and 117 among nonusers of CCBs (2.1%). After adjustment for age, gender and smoking, the odds ratio estimates for all cancers combined was 1.07 (95% confidence interval [CI] 0.83 to 1.37) for CCB users relative to nonusers. The adjusted risk ratio for all-cause mortality for age, gender and smoking and pertinent prognostic clinical characteristics was estimated at 0.94 (95% CI 0.85 to 1.04). The adjusted risk ratio for cancer-related mortality was 1.03 (95% CI 0.75 to 1.41). CONCLUSIONS: Patients with CHD treated with CCBs exhibited a similar risk of cancer incidence and total and cancer-related mortality compared with nonusers of CCBs. This analysis provides a certain assurance that CCB use in middle-aged and elderly patients with CHD is not associated with a meaningful difference in cancer incidence and related mortality.
35-Howes LG; Edwards CT
Calcium antagonists and cancer. Is there really a link?
Drug Saf; 18(1):1-7, 1998 Jan.
Recent publications have raised concerns about a possible link between calcium antagonist therapy and the development of cancer. Comparisons of the methodology and results of these studies with other studies where an association between calcium antagonist therapy and cancer has not been apparent suggests that the association is most likely to be due to selection bias or chance. Clinical and biochemical studies have not produced a consistent plausible mechanism for a causative link between calcium antagonists and the development of cancer. Further prospective data that will be available from long-term morbidity and mortality trials of the use of calcium antagonists in cardiovascular diseases will be of value in establishing the safety of these drugs.
36-Cheng JW; Behar L
Calcium channel blockers: association with myocardial infarction, mortality, and cancer.
Clin Ther; 19(6):1255-68; discussion 1253-4, 1997 Nov-Dec.
The purpose of this study was to review the results of trials assessing the association between the use of calcium channel blockers (CCBs) and mortality, myocardial infarction (MI), and cancer. Possible mechanisms of such relationships are discussed and recommendations regarding the use of CCBs made. Since 1995, 10 controversial studies have been published that associate the use of CCBs with an increased risk of mortality, MI, and cancer; these findings have caused widespread anxiety and frustration among patients and physicians. For health care professionals to properly advise patients, the facts surrounding this controversy should be reviewed. To do this, we reviewed and assessed English-language clinical studies, abstracts, editorials, and review articles pertaining to the use of CCBs and mortality, MI, and cancer in humans. The designs of ongoing prospective, randomized studies are discussed. Based on current published studies, the US Food and Drug Administration has agreed to a label warning against off-label use of short-acting nifedipine in patients with hypertension, acute MI, or nonvasospastic unstable angina. Practitioners should exercise caution when prescribing CCBs, especially to high-risk patients (e.g., those with congestive heart failure or clinical or subclinical coronary artery disease). When possible, long-acting CCBs should be used.
37-Dong EW; Connelly JE; Borden SP; Yorzyk W; Passov DG; Kupelnick B; Luo D; Ross SD
A systematic review and meta-analysis of the incidence of cancer in randomized, controlled trials of verapamil.
Pharmacotherapy; 17(6):1210-9, 1997 Nov-Dec.
We conducted a systematic review of all published randomized, controlled trials to assess the risk of cancer or death in patients receiving verapamil for hypertension, angina pectoris, or cardiac arrhythmias. Meta-analysis comparing the risk of new cancers, cancer deaths, and all deaths was performed. Thirty-nine trials comprising 11,201 patients were eligible. Study durations ranged from 8 days-6 years (mean 29.5 wks). Nine trials (6507 patients) were 24 weeks in duration or longer. For cancer and cancer death, OR was 1.20 (95% CI = 0.60-2.42) for verapamil versus active controls and 0.73 (95% CI = 0.39-1.39) for verapamil versus placebo. For all deaths, OR was 1.13 (95% CI = 0.70-1.82) for verapamil versus active controls and 0.85 (95% CI = 0.71-1.00) for verapamil versus placebo. Sensitivity analysis for the 9 trials 24 weeks' duration or longer gave similar results. There is no statistically significant increased risk of cancer or deaths with verapamil compared with active controls or placebo.
38-Kritchevsky SB; Pahor M
Calcium-channel blockers and risk of cancer.
Comment In:Lancet. 1997 Jun 7;349(9066):1699-700
Lancet; 349(9062):1400, 1997 May 10.
39-Olsen JH; Sorensen HT; Friis S; McLaughlin JK; Steffensen FH; Nielsen GL; Andersen M; Fraumeni JF; Olsen J
Cancer risk in users of calcium channel blockers.
Comment In:Hypertension. 1997 Dec;30(6):1641-2
Hypertension; 29(5):1091-4, 1997 May.
Ca2+ channel blockers may cause cancer by inhibiting apoptosis or reducing intracellular Ca2+ in certain tissues. Recent findings suggest that drug users are at increased risk for cancer in general and for colon cancer in particular. We conducted a study in one Danish county of 17911 patients who received at least one prescription of Ca2+ channel blockers between 1 January 1991 and 31 December 1993. The patients were identified from records in the National Health Insurance Program, which refunds part of the price of such drugs. Cancer occurrence and rate were determined by use of the files of the Danish Cancer Registry and compared with county-specific incidence rates for various categories of cancer. During the follow-up period of up to 3 years, 412 cancers were observed among users of Ca2+ channel blockers, compared with 414 expected, to yield an age- and sex-standardized incidence ratio (SIR) of 1.00 (95% confidence interval, 0.90 to 1.10). There was no indication of an excess risk in the subgroup of likely long-term users or users of specific drugs. The SIR of colon cancer, a site of a priori interest, was 0.8 (95% confidence interval, 0.5 to 1.1) on the basis of 34 cases. Although the results are reassuring, the lack of association could reflect the relatively short follow-up after registration in the prescription database. Continued monitoring of cancer risk is planned.
40-Jick H; Jick S; Derby LE; Vasilakis C; Myers MW; Meier CR
Calcium-channel blockers and risk of cancer.
Lancet; 349(9051):525-8, 1997 Feb 22.
BACKGROUND: Previous studies have been interpreted as suggesting an increase in risk of cancer among users of calcium-channel blockers compared with users of beta-blockers. To explore this issue further, we studied a large group of hypertensive patients to investigate the relation of calcium-channel blockers and cancer. METHODS: In cohorts of users of calcium-channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, and beta-blockers, we identified all cases of cancer diagnosed in 1995. We used a nested case-control analysis to estimate the risk of cancer among users of calcium-channel blockers and ACE inhibitors, with users of beta-blockers as a reference group. The study was based on information taken from the General Practice Research Database, and the study population was restricted to patients with at least 4 years of medical history recorded on computer. FINDINGS: The study was based on 446 cases of cancer and 1750 controls. The relative risk estimates for all cancers combined were 1.27 (95% CI 0.98-1.63) and 0.79 (0.58-1.06) for users of calcium-channel blockers and ACE inhibitors, respectively, relative to users of beta-blockers. There was little difference in risk estimates with duration of use of calcium-channel blockers of less than 1.0 year (relative risk 1.46), 1.0-3.9 years (1.26), and 4.0 years or more (1.23). INTERPRETATION: The small positive association between calcium-channel blockers and risk of cancer is unlikely to be causal since there is no increase in risk with increasing duration of calcium-channel blocker use.
41-Zimlichman R
Questioning the study size in Pahor et al.
Comment On:Am J Hypertens. 1996 Jul;9(7):695-9
Am J Hypertens; 9(10 Pt 1):1046-7, author reply 1051-3, 1996 Oct.
42-Kaplan NM
Do calcium antagonists cause death, gastrointestinal bleeding, and cancer?
Am J Cardiol; 78(8):932-3, 1996 Oct 15.
Recent reports from an uncontrolled, retrospective cohort study in elderly hypertensives implicate short-acting calcium antagonists in causing increased mortality, gastrointestinal bleeding, and cancer. Multiple serious flaws in the study make the validity of these findings highly suspect and there remains absolutely no evidence that long-acting calcium antagonists are unsafe.
43-Daling JR
Calcium channel blockers and cancer: is an association biologically plausible?
Am J Hypertens; 9(7):713-4, 1996 Jul.
|
