drugs, a middle-aged population of Renfrew and Paisley, towns close to Glasgow [5], and the general population of the West of Scotland [6].

Transcription

1 Original article Cancer risk of hypertensive patients taking calcium antagonists David J. Hole a, Charles R. Gillis a, Iain R. McCallum b, Gordon T. McInnes c, Pauline L. MacKinnon a, Peter A. Meredith c, Lilian S. Murray c, James W.K. Robertson b and Anthony F. Lever c 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 patients were prescribed calcium antagonist and 0 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 incident cancers in the calcium antagonist group, representing relative risks of.0 [% confidence interval (CI) 0..] compared with Introduction Pahor and colleagues [,] reported an increased incidence of cancer among elderly patients taking calcium antagonists: incident cancers among patients, representing a significantly higher relative risk of. compared with controls. However, with incident cancers in a large group of patients taking calcium antagonists Jick et al. [] found a relative risk of. only [% confidence interval (CI) 0..]. They considered a causal relation of calcium antagonists and cancer unlikely. Another negative finding has been published recently []. Our study is of incident cancers amongst patients of the Glasgow Blood Pressure Clinic, all taking calcium antagonists. Comparison was with incident cancers in three control groups, namely clinic patients taking other the non-calcium antagonist group,.0 (% CI 0..) compared with Renfrew Paisley controls and.0 (% CI 0..) 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. J Hypertens : Rapid Science Ltd. Journal of Hypertension, : Keywords: cancer incidence, cancer mortality, calcium antagonists, calcium channel blockers c Department of Medicine and Therapeutics, University of Glasgow, Western Infirmary and a West of Scotland Cancer Surveillance Unit, Ruchill Hospital, Glasgow, and b CSC Computer Sciences Ltd, Paisley, UK. Sponsorship: A.F.L. was supported in this work by grants from the British Heart Foundation and Tenovus-Scotland. Correspondence to Professor Anthony F. Lever, Department of Medicine & Therapeutics, Western Infirmary, Glasgow G NT, UK. Tel: + /0; fax: + / 00 Received July Revised 0 October Accepted October drugs, a middle-aged population of Renfrew and Paisley, towns close to Glasgow [], and the general population of the West of Scotland []. Methods Most of our methods were those used to assess cancer in Glasgow Clinic patients taking atenolol []. Record linkage was established then between the West of Scotland Cancer Registry [] and the clinic []. The latter has 0 patients currently on its database: for each it has a record of clinical findings, drug treatment and investigations and each is flagged with the Registrar General, Scotland, providing information on dates and causes of death []. The Registry also holds information on all incident cancers in the West of Scotland, population []. Its sources are hospital clinicians, pathologists and 0- Rapid Science Ltd

2 0 Journal of Hypertension, Vol No general practitioners for information on incident cancers and the Registrar General, for information on fatal cancers. Completeness and accuracy of these data is such that the Registry qualifies for inclusion in Cancer Incidence in Five Continents, the only internationally accepted publication on the incidence of cancer []. Computerized record linkage between clinic and cancer registry provided a list of potential matches for incident cancer (International Code of Disease 0 0). The correctness of each match was checked by P.L.MacK. She has experience of diagnostic coding but had no access to information on patients treatment. Drug treatment was classified by P.A.M. and G.T.McI. without knowledge of patients cancer status. Treatment data were then transferred to the registry for addition of incident cancers and analysis. To avoid ascertainment bias no other special searches for cancer cases amongst clinic patients were conducted. Three sets of risk ratios for observed : expected cancers were calculated using data from patients taking calcium antagonists ( observed ) and from three control groups ( expected cancers). The latter were derived, first, from data for the non-calcium antagonist group after adjustment for risk as below. Risk ratio was then cancer risk for calcium antagonist group compared with cancer risk for non-calcium antagonist group. Second, data were derived from a longitudinal cohort study of men and women of Renfrew and Paisley surveyed between and, followed up to the present time and with adjustment for age, sex, year of observation and smoking habit []. Third, data were obtained for the West of Scotland population adjusted for age, sex and year of observation []. Observed values were treated as data from a Poisson distribution with mean equal to the number expected. Probability values were derived from the Poisson distribution and were two-tailed. Adjustment for multiple tests of significance was made by using Bonferroni s correction [] when appropriate. Table Characteristics of patients by treatment group Calcium Non-calcium All antagonists antagonists patients Men Number Mean age at first prescription (years)... Aged > 0 years (%)... Smokers (%)...0 Women Number 0 Mean age at first prescription (years)...0 Aged > 0 years (%)... Smokers (%)... Total numbers 0 0 Average follow-up years.0.. All patients prescribed first treatment between January 0 and December. The study population comprised 0 patients seen in the clinic between January 0, the year calcium antagonists were first prescribed, and December, the end of follow-up for cancer (Table ). The calcium antagonist group was of patients with a first prescription for one or more of eight types of calcium antagonist (verapamil, diltiazem, nifedipine, amlodipine, nicardipine, felodipine, lacidipine and perhexilene). Of the patients eligible for a -year follow-up of calcium antagonist administration (still living and with first prescriptions for calcium antagonist before January ), (%) were still being seen in the clinic and of these (%) were still taking a calcium antagonist. In total 0 calcium antagonist patients have been discharged from the clinic to a shared-care programme []; 0 are still being followed up and 0 of these (%) are taking a calcium antagonist currently. The noncalcium antagonist group was of 0 patients with a first prescription for antihypertensive drugs other than a calcium antagonist. At no time during follow-up did any of these receive a calcium antagonist. For a -month period during the midpoint of follow-up,, other drugs being prescribed to patients in calcium antagonist and non-calcium antagonist groups, respectively, were diuretics (to and % of patients), -blockers (to and % of patients) and angiotensin converting enzyme inhibitors (to and % of patients). For individual patients the follow-up for cancer was from the date on which the calcium antagonist had first been prescribed (calcium antagonist group) or from the date on which an antihypertensive drug, other than calcium antagonist, had first been prescribed (non-calcium antagonist group). Depending on which came first, follow-up ended for all patients at the date of diagnosis of cancer, the date of death or December. Patients known to have cancer before first prescription of drugs were excluded, as were patients receiving no treatment. Results Incident cancer Between 0 and first prescriptions of a calcium antagonist increased from to % of all first prescriptions in the clinic. During the same period, there was no increase in incidence of cancer among patients receiving calcium antagonists: compared with non-calcium antagonist controls relative risk was.0 (CI 0..; Fig. ). Compared with West of Scotland and Renfrew and Paisley controls it was.0 and.0, respectively, with narrower confidence intervals (Table, Fig. ). A similarly negative pattern was seen in the non-calcium antagonist group and for men and women of both groups (Table ). Cancer mortality Cancer mortality among patients prescribed a calcium antagonist was not increased (Table ): risk ratio was.0

3 Cancer risk with calcium antagonists Hole et al (CI 0..) compared with non-calcium antagonist controls and 0. compared with West of Scotland and with Renfrew and Paisley controls. Risk for women tended to be higher than that for men (Table ). Fig. Previous Studies Table Incident cancer by treatment group Incident cancers Patient- % Confidence Patients years Observed Expected Ratio interval All patients 0.* Calcium antagonist group All patients 0.* Men 0.* Women 0.* Non-calcium antagonist group All patients 0.* Men 0.* Women 0.* *For West of Scotland controls. For Renfrew and Paisley controls. Using data above for observed cancer and patientyears of follow-up, the crude relative risk for incident cancer is. for patients in the calcium antagonist group compared with that for the non-calcium antagonist group. However, patients in the calcium antagonist group were years older (Table ). Adjustment for age and other variables (see Methods) gave a relative risk of.0. Pahor I Pahor II Glsagow BP clinic vs Jick non-ccb Renfrew-Paisley West of Scotland odds ratio + % ci Relative risk (odds ratio) with % confidence intervals for incident cancer in the calcium antagonist (CCB) group of three previous studies (Pahor et al. [,] and Jick et al. []) and in three analyses from the Glasgow Blood Pressure (BP) Clinic: with non-calcium antagonist group as controls and with Renfrew Paisley and West of Scotland controls. Class of calcium antagonist No class stood out as having a high risk (Table ): for dihydropyridines, the largest group, relative risk was 0.. For the smaller numbers taking verapamil and diltiazem it was. and 0., respectively, with wider confidence intervals (Table ). Anatomical site of cancer The ten commonest cancer sites were analysed separately. Numbers of cancers per site were small, variation of relative risk values large. Four types of cancer were present in significant excess: two each in calcium antagonist and non-calcium antagonist groups (Table ). With correction for multiple testing [] three of the four tests were no longer significant. Excess of kidney cancer in the calcium antagonist group remained significant. Age Patients aged years or more were examined separately. Compared with West of Scotland controls relative risk for incident cancer in the calcium antagonist group was.0 (CI 0..; patients, mean age. years at midpoint of follow-up). It was also.0 for the non-calcium antagonist group (CI 0..; patients aged. years at mid-point of follow-up). Is there a change of cancer risk during treatment? A drug can increase cancer by stimulating existing cancers or by causing new cancers. Because the former would produce only a transient increase of cancer, we assessed first and second -year periods of follow-up. Compared with West of Scotland controls relative risk for the calcium antagonist group was.0 for the first period ( patients; CI 0..0) and.0 for the second ( patients; CI 0..).

4 Journal of Hypertension, Vol No Table Table Cancer deaths by treatment group Cancer deaths % Confidence Patients Observed Expected Ratio interval All patients 0.* 0.* Calcium antagonist group All patients.0* Men.* Women.* Non-calcium antagonist group All patients * Men.* Women.* *For West of Scotland controls; For Renfrew and Paisley controls. Patient-years of follow-up for cancer are as in Table. Incident cancers by class of calcium antagonist Number of cancers Class/name of calcium Duration of follow-up Expected % Confidence antagonist Patients for cancer (years) Observed follow-up Ratio interval All Classes Verapamil Diltiazem All dihydropyridines Nifedipine Amlodipine Nicardipine Felodipine Lacidipine Patients taking perhexiline are included in All classes, but not in separate subgroups here. For patients receiving more than one class of calcium antagonist, follow-up for cancer is from the date of first prescription for all classes until December. It follows that total years of follow-up and numbers of cancers for the three subgroups are greater than those for all classes, for which analysis was based on first calcium antagonist prescribed only. Table Sites of cancers in patients treated with calcium antagonist and non-calcium antagonist drugs Calcium antagonist Non-calcium antagonist Calcium antagonist : non-calcium antagonist Site of cancer Observed Expected Observed Expected ratio of relative risks Lung Skin *... Colorectal Breast... Stomach.. 0. Bladder... Kidney **... Pancreas. **. 0. Ovary.. 0. Melanoma. *. 0. Others All sites Expected values are those for West of Scotland data. Results of significance tests are those without the Bonferroni correction. *P < 0.0, **P < 0.0, versus expected.

5 Cancer risk with calcium antagonists Hole et al Discussion The first analysis by Pahor et al. [] was of cases of cancer among 0 subjects taking calcium antagonists, a significantly increased relative risk of.0 compared with controls taking -blockers. Confidence intervals were wide (Fig. ). Their second analysis [], an expansion of the first, concerned cancers among patients prescribed a calcium antagonist. Relative risk was now. and still significant (Fig. ). Jick et al. [] had cancers in their calcium antagonist group with a relative risk of.. Although this was not a significantly increased risk (Fig. ), their confidence intervals did not exclude the possibility of a 0% increase in risk. Thus, the issue was not resolved. The recent study of Olsen et al. [] was of cancer patients, each of whom had at least one prescription for a calcium antagonist. For these the risk ratio was.0 (CI 0..0) compared with general population controls. Follow-up was for years. This and an earlier study of ours [] had the advantage of longer follow-ups, years in the present study. Earlier analyses in [] and [] detected no excess of cancer among Glasgow Clinic patients compared with Renfrew Paisley controls [] and with West of Scotland controls []. Among the Glasgow Clinic patients we found no excess of cancer among patients taking atenolol []. In the present study, compared with three control groups, relative risk for incident cancer was.0,.0 and.0 (Fig. ). There is no trend here towards increased risk. Narrower confidence intervals make unlikely a risk greater than %. Our study and those of Jick et al. [] and Olsen et al. [] had greater power than did those of Pahor et al. [,] to test the null hypothesis that calcium antagonists do not cause cancer. Wide confidence intervals for the Pahor studies (Fig. ) indicate less precision. Patients in our study were younger than those of Pahor et al. [,] and Jick et al. []. Although older patients may be at greater risk from calcium antagonists, our subgroup analysis of older patients did not suggest this. Four of 0 tests in 0 types of site-specific cancer showed significant increases: two each for patients in calcium antagonist and control groups. These were probably artefacts of multiple testing in small subgroups because, with allowance for such testing, only the excess of kidney cancer remained significant. In an earlier study of atenolol [] we noted and discussed possible reasons for an excess of kidney cancer among patients attending a hypertension clinic. Studies of this sort are vulnerable to ascertainment bias, particularly when different methods are used to identify cancer in members of calcium antagonist and control groups. We avoided this by using the same system of cancer certification throughout [], by avoiding special new searches and by keeping blinded and separate the assessments of treatment and of cancer (see Methods). We can be less certain of having avoided selection bias. One form this might take is that calcium antagonists are more often, or less often, prescribed than are other drugs for a reason that relates to cancer. There has been much discussion recently of other potential confounders in studies of calcium antagonists and cancer [0]. The issue will be better resolved by randomized controlled trials of calcium antagonists currently under way. Are the risks of cancer more closely related to hypertension than to its treatment? Results of several studies have raised this possibility [ ]. In this event, since most hypertensive patients receive antihypertensive drugs, their cancer risk could be wrongly linked to one or more of these. Our own experience [,] is somewhat against this: cancer risk is no different for hypertensive patients than it is for the general population from which these patients derive. Finally, there is the question of whether specific treatments produce specific types of cancer. Diuretics have been incriminated as a cause of kidney cancer (discussed by Chow et al. []) but, here again, there is uncertainty about whether hypertension or its treatment is the primary event. As discussed earlier [], selection bias is our favoured explanation for the excess of kidney cancers in a hypertension clinic; it is not the only explanation. In conclusion, we found no evidence for an increase of cancer among patients taking calcium antagonists. A relative risk close to.0 in comparison with three control groups showed no trend towards increased risk. Despite relatively narrow confidence intervals, we cannot exclude an increase in risk of incident cancer less than %. Acknowledgements We thank Miss Ann Matheson for help in the preparation of the manuscript and literature surveys. References Pahor M, Guralnik JM, Salive ME, Corti M-C, Carbonin P, Havlik RJ. Do calcium channel blockers increase the risk of cancer? Am J Hypertens, :. Pahor M, Guralnik JM, Ferrucci L, Corti, M-C, Salive ME, Cerhan JR, et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet, :. Jick H, Jick S, Derby LE, Vasilakis C, Meyers MW, Meier CR. Calciumchannel blockers and risk of cancer. Lancet, :. Olsen JH, Sorensen HT, Friis S, McLaughlin JK, Steffensen FH, Nielsen GL. Cancer risk in users of calcium channel blockers. Hypertension, :0 0. Hole DJ, Hawthorne VM, Isles CG, McGhee SM, Robertson JWK, Gillis CR, et al. Incidence of and mortality from cancer in hypertensive patients. BMJ, 0:0. Gillis CR, Hole DJ, Lamont D, Boyle P, Graham A. Cancer incidence in the West of Scotland. In Cancer Incidence in Five Continents. Vol V. Edited by Muir C, Waterhouse J, Mack T, Powell J, Whelan S. Lyons: International Association for Research on Cancer; :0 0. Isles CG, Walker LM, Beevers DG, Brown I, Cameron HL, Clarke J, et al. 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