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Relation between drug treatment and cancer In hypertenslves in the Swedish Trial in Old Patients with Hypertension 2: a 5-year, prospective, randomised, controlled trial
ARTICLES
Relation between drug treatment and cancer in hypertensives in the Swedish Trial in Old Patients with Hypertension 2: a 5-year, prospective, randomised, controlled trial Lars H Lindholm, Harald Anderson, Tord Ekbom, Lennart Hansson, Jan Lanke, Björn Dahlöf, Ulf de Faire, Kent Forsén, Thomas Hedner, Erland Linjer, Bengt Scherstén, P-O Wester, Torgil R Möller
Summary Background Is cancer related to hypertension and blood pressure? Do antihypertensive drugs promote cancer? Do antihypertensive drugs protect against cancer? We previously analysed the frequency of cardiovascular mortality and morbidity in elderly people who participated in the Swedish Trial in Old Patients with Hypertension 2 (STOPHypertension-2). We have also looked at the frequency of cancer in these patients. Methods We randomly assigned 6614 elderly patients with hypertension (mean age 76 years, median time of follow-up 5·3 years) to one of three treatment strategies: conventional drugs (diuretics or -blockers), calcium antagonists, or ACE inhibitors. We matched the patients to the Swedish Cancer Registry and compared our findings with expected values based on age, sex, and calendar-year-specific reference frequencies for the general Swedish population. We also compared the number of cancers between the three treatment groups. Findings At baseline, 607 (9%) patients had previous malignant disease. Diagnoses were closely similar to the distribution of cancer types that might be seen in elderly patients. During follow-up, there were 625 new cases of cancer in 590 patients. The frequency of cancer did not differ significantly between the treatment strategies, including all cancers and those at individual sites. The standardised incidence ratios (SIRs) for all cancers were also close to unity: 0·92 (95% CI 0·80–1·06) for conventional drugs, 0·96 (0·83–1·10) for calcium antagonists, and 0·99 (0·86–1·13) for ACE inhibitors. Interpretations No difference in cancer risk was seen between patients randomly assigned to conventional drugs, calcium antagonists, or ACE inhibitors. Thus, the general message to the practising physician is that more attention should be given to getting the blood pressure down than to the risk of cancer. Lancet 2001; 358: 539–44 Department of Public Health and Clinical Medicine, Umeå University, SE 901 85 Umeå, Sweden (Prof L H Lindholm MD, Prof P-O Wester MD, K Forsén); Department of Cancer Epidemiology, Lund University, Lund (H Anderson PhD, T Möller MD); Department of Community Medicine, Malmö University Hospital, Malmö (T Ekbom MD); Department of Public Health and Social Sciences, Uppsala University, Uppsala (Prof L Hansson MD, E Linjer BSc); Department of Statistics, Lund University (Prof J Lanke PhD); Department of Medicine (B Dahlöf MD) and Department of Clinical Pharmacology (Prof T Hedner MD) Sahlgrenska University Hospital, Göteborg; Department of Medicine, Karolinska University Hospital, Stockholm (Prof U de Faire MD); and Department of Community Health Sciences in Dalby/Lund, Lund University (Prof B Scherstén MD), Correspondence to: Prof Lars H Lindholm (e-mail: [email protected])
THE LANCET • Vol 358 • August 18, 2001
Introduction For more than 25 years, the risk of cancer in relation to use of antihypertensive drugs has been much discussed. Retrospective case-control studies and subgroup analyses from prospective intervention trials have suggested that several antihypertensive regimens (eg, reserpine, diuretics, -blockers, angiotensin-converting enzyme [ACE] inhibitors, and calcium antagonists) are associated with an increased cancer risk in the breast, kidney, and gastrointestinal tract, as well as with multiple cancer forms. However, these studies do not give plausible explanations for the development of multiple cancer forms from the various classes of antihypertensive drugs described. Additionally, increased risk is sometimes, but not always, related to long-term use of the drugs, and there might be a competing death risk (ie, cardiovascular vs cancer). The most important argument is that the increased risk of cancer death is seen in treated as well as untreated hypertensive patients, raising the possibility that hypertension is itself a risk factor for cancer. Dyer and colleagues1 reported that both systolic and diastolic blood pressures were related to 14-year mortality from cancer after adjustment for several factors such as age, cholesterol, and smoking. Investigators from several studies,2–5 but not all,6 have pointed out that hypertension seems a moderately large risk factor for cancer in various sites. Cardiovascular risk factors such as obesity, diabetes, and smoking seem to interact with increased blood pressure in a complex way and act as risk factors for cancer.2,7 Potential mechanisms that might contribute to an increased risk of cancer in hypertensive patients are unknown. In human beings and animals, the response to carcinogens can differ between those with hypertension and those with normal blood pressure.8,9 There has been much debate about the possible increase in risk of cancer after treatment with calcium antagonists, and researchers have also postulated that there is an association between renal cell carcinoma and use of diuretics.10 Therefore, we decided to analyse the frequency of cancer in elderly patients who participated in the Swedish Trial in Old Patients with Hypertension 2 (STOPHypertension-2). This 5-year prospective study was originally designed to compare cardiovascular mortality in elderly hypertensive men and women randomly assigned to three different treatment strategies: conventional drugs (diuretics or -blockers), calcium antagonists, or ACE inhibitors.11–13
Methods We have previously reported the study population, design, and main results of STOP-Hypertension-2.11–13 Briefly, between Sept 1, 1992, and Dec 30, 1994, we enrolled 6614 elderly patients (mean age 76 years, range 70–84 at baseline) from 312 health centres in Sweden (of about 850). The mean and median follow-up time was 5·0 years and 5·3 years, respectively. Follow-up with respect to occurrence of cancer and vital status ended on Dec 31,
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For personal use only. Reproduce with permission from The Lancet Publishing Group.
ARTICLES
Characteristic
All patients
Conventional Calcium ACE inhibitors drugs group antagonists group group
Demography Number of patients 6614 2213 2196 2205 Mean age (years) 76·0 76·0 75·9 76·1 Men 2196 (33·2%) 708 (32·0%) 747 (34·0%) 743 (33·7%) Mean body-mass 26·7 26·7 26·7 26·7 index (kg/m2) Smokers 595 (9·0%) 195 (8·8%) 193 (8·8%) 207 (9·4%) Mean supine blood 194/98 194/98 194/98 194/98 pressure (mm Hg) History of cancer Patients 607 All cancers 650 (100%) Breast 151 (23%) Colorectal 98 (15%) Prostate 77 (12%) Corpus uteri 50 (8%) Non-melanoma skin 38 (6%) Melanoma of skin 36 (6%) Urinary bladder 36 (6%) Parathyroid 31 (5%) adenoma
207 224 (100%) 56 (25%) 35 (16%) 24 (11%) 18 (8%) 13 (6%) 11 (5%) 13 (6%) 7 (3%)
192 208 202 (100%) 224 (100%) 48 (24%) 47 (21%) 23 (11%) 40 (18%) 32 (16%) 21 (9%) 18 (9%) 14 (6%) 10 (5%) 15 (7%) 9 (5%) 16 (7%) 10 (5%) 13 (6%) 8 (4%) 16 (7%)
*Values are numbers (%) unless otherwise indicated.
Table 1: Baseline characteristics of patients
1998; no patient was lost.13 Table 1 shows some baseline values, including history of cancer (further details given in original trial).13 Patients who had hypertension (blood pressure ⭓180 mm Hg systolic, ⭓105 mm Hg diastolic, or both) were randomly assigned to one of three groups. The first group received conventional antihypertensive therapy with -blockers (atenolol 50 mg, metoprolol 100 mg, or pindolol 5 mg daily) or a diuretic (a fixed-ratio combination of hydrochlorothiazide 25 mg plus amiloride 2·5 mg). In the second group, one of two ACE inhibitors were given— enalapril 10–20 mg, or lisinopril 10–20 mg daily. The third group received one of two calcium antagonists—felodipine 2·5–5·0 mg or isradipine 2·5–5·0 mg daily. The choices of drugs within the groups were not randomised. Patients on -blockers were given hydrochlorothiazide 25 mg plus amiloride 2·5 mg as additional treatment if the target blood pressure (⭐160/95 mm Hg) had not been reached at the 2month follow-up or later. Patients who had started on diuretic treatment were given any of the -blockers; those on ACE inhibitors were given hydrochlorothiazide 12·5–25·0 mg; and those on calcium antagonists were given any of the -blockers. After the initial dose-titrating period, patients were seen twice a year until the end of the study. Exclusion criteria were: contraindications for any of the study drugs; a requirement for any of the study drugs; orthostatic hypotension; participation in another study; severe or incapacitating illness; and unwillingness to participate.11 We obtained the cancer incidence in the study cohort from the Swedish Cancer Registry. This registry was established in 1958 as a population-based incidence register for the whole of Sweden. The registry is based on compulsory reporting from two independent sources: clinicians and pathologists or cytologists. Cases documented only from death certificates are reported separately and are not included in the statistics. The proportion of reported tumours has been estimated to be greater than 95% of all reportable tumours,14 and about 98% of all cases are confirmed microscopically. Even for individuals aged 80 years or more, the rate of microscopic confirmation is high (93–97%). Tumours that should be reported are: all malignant tumours, including lymphomas and leukaemias; premalignant disorders such as carcinomain-situ; all tumours within the central nervous system; and
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those with endocrine activity (except thyroid adenoma). All these, apart from the carcinoma-in-situ group, are included in the yearly statistics. However, basal-cell carcinoma is not a reportable tumour. Malignant disease is coded according to ICD-0-2, but this code is also translated into ICD-7 for site and WHO/CANC-24 for morphology. Since 1985, reports of tumours have been sent to the six regional cancer registries, who code and validate the reports, and once a year send their data to the Centre for Epidemiology at the National Board of Health and Welfare, for the production of national statistics. At the time of our analyses, national data were available up to 1997. We obtained data directly from the regional registries for 1998. The files of the STOP-Hypertension-2 study cohort were matched to the cancer registry files, and we linked records by means of the personal identification number (a civic registration number, which is unique for every permanent resident of Sweden) and thus unambiguously identified data in the registry. We calculated the standardised incidence ratios (SIRs) using person-years, with 5-year age groups, sex, and calendar-year-specific incidence data for the whole of Sweden as reference. Patients were followed up from randomisation until diagnosis of a third cancer, death, or end of follow-up, whichever occurred first. We calculated standardised mortality ratios (SMRs) in a similar way but with 1-year age groups, sex, and national Swedish mortality data for 5-year calendar-year groups as reference. CIs for SIRs were based on the Poisson distribution. Cancer frequency in the three treatment groups was compared for all sites and for some diagnoses by means of a 2 test for homogeneity. Many elderly people died during follow-up, and, hence in this population, the cumulative frequency function was used to show the occurrence of a new cancer. This function estimates the observable probability that a new cancer occurs before death within a specified time after randomisation. We analysed, using the log-rank test, the hazard of a first cancer after randomisation in the three treatment groups, with adjustment for death and end of follow-up. The Ethics Committee of Göteborg University approved the study and our analyses.
Results The overall mortality rate of the STOP-Hypertension-2 cohort was lower than that of the general Swedish population (table 2), but this difference diminished over time. At baseline, according to National Cancer Registry data, 607 patients had a history of previous malignant disease, 43 of whom had two cancers (table 1). The prevalence was thus 9%. The diagnoses listed in table 1 represents about 80% of all cancers in the cohort and are closely related to the distribution of cancer types that might be seen in patients at this age, except for the high prevalence of parathyroid adenoma (0·5%). During follow-up there were 625 new cases of cancer in 590 patients. For the entire cohort, and for both men and Follow-up (years)
Deaths Observed
Expected
Standardised mortality ratio
0–1 >1–2 >2–3 >3–4 >4–5 >5
136 162 188 241 227 157
277·31 293·38 309·05 323·31 296·19 209·27
0·49 0·55 0·61 0·75 0·77 0·75
Total
1111
1708·51
0·63
Table 2: Observed and expected number of deaths during follow-up
THE LANCET • Vol 358 • August 18, 2001
For personal use only. Reproduce with permission from The Lancet Publishing Group.
ARTICLES
Tumour site
All
All sites Gastrointestinal tract Respiratory tract Breast Female genital organs Prostate Lymphoma and leukaemia
Men
Women
Observed/Expected
SIR (95% CI)
Observed/Expected
SIR (95% CI)
Observed/Expected
SIR (95% CI)
625/652·85 150/157·56 35/41·13 67/68·69 33/39·51 101/100·20 41/47·52
0·96 (0·88–1·04) 0·95 (0·81–1·12) 0·85 (0·59–1·18) 0·98 (0·76–1·24) 0·84 (0·58–1·17) 1·01 (0·82–1·22) 0·86 (0·62–1·17)
281/303·17 60/65·54 20/24·13 0/0·50 .. 101/100·20 16/20·19
0·93 (0·82–1·04) 0·92 (0·70–1·18) 0·83 (0·51–1·28) 0·00 (0·00–7·31) .. 1·01 (0·82–1·22) 0·79 (0·45–1·29)
344/349·68 90/92·04 15/16·99 67/68·18 33/39·51 .. 25/27·33
0·98 (0·88–1·09) 0·98 (0·79–1·20) 0·88 (0·49–1·46) 0·98 (0·76–1·25) 0·84 (0·58–1·17) .. 0·92 (0·59–1·35)
SIR=standardised incidence ratio.
Table 3: Frequency of cancer ICD-7 code
140–209 140 141, 143, 144 142 145–148 150 151 153 154 1550 1551–1559 157 160 161 1620–1621 1622 170 171 172–174 175 176 177 178 180 181 190 191 193 194 196, 197 200, 202 201 203 2040, 2050, 2060, 2070 2041 2051 208
Tumour site
All
Men
Observed/ expected
SIR (95% CI)
Observed/ expected
All sites Lip Oral cavity Salivary glands Pharynx Oesophagus Stomach Colon Rectum Liver, primary Biliary passages Pancreas Nasal cavity and sinuses Larynx Trachea, bronchus, and lung Pleura Breast Cervix uteri Corpus uteri Ovary Vulva and vagina Prostate Testis Kidney Urinary tract Malignant melanoma of skin Skin (melanoma excluded) Nervous system Thyroid gland Bone and soft tissue Non-Hodgkin lymphoma Hodgkin’s disease Multiple myeloma Acute leukaemia
625/652·85 4/2·95 2/4·19 0/1·08 1/1·42 5/5·35 16/22·98 70/63·36 31/31·28 8/7·37 3/9·70 17/17·52 1/0·84 2/2·19 31/36·61 1/1·49 67/68·69 4/4·13 17/19·56 10/11·60 2/4·22 101/100·20 0/0·17 22/16·20 39/35·79 22/15·87 39/49·90 9/9·66 2/3·04 5/3·91 20/21·76 0/1·11 10/10·32 3/5·07
0·96 (0·88–1·04) 1·36 (0·37–3·48) 0·48 (0·06–1·72) 0·00 (0·00–3·41) 0·70 (0·02–3·92) 0·93 (0·30–2·18) 0·70 (0·40–1·13) 1·10 (0·86–1·40) 0·99 (0·67–1·41) 1·09 (0·47–2·14) 0·31 (0·06–0·90) 0·97 (0·56–1·55) 1·19 (0·03–6·66) 0·91 (0·11–3·30) 0·85 (0·58–1·20) 0·67 (0·02–3·75) 0·98 (0·76–1·24) 0·97 (0·26–2·48) 0·87 (0·51–1·39) 0·86 (0·41–1·59) 0·47 (0·06–1·71) 1·01 (0·82–1·22) 0·00 (0·00–22·12) 1·36 (0·85–2·06) 1·09 (0·77–1·49) 1·39 (0·87–2·10) 0·78 (0·56–1·07) 0·93 (0·43–1·77) 0·66 (0·08–2·37) 1·28 (0·42–2·99) 0·92 (0·56–1·42) 0·00 (0·00–3·34) 0·97 (0·46–1·78) 0·59 (0·12–1·73)
281/303·17 3/1·93 1/1·64 0/0·45 0/0·83 2/3·01 9/11·61 26/24·27 14/14·21 2/3·62 1/2·59 6/6·23 1/0·43 2/1·79 17/20·80 0/1·11 0/0·50 0/0·00 0/0·00 0/0·00 0/0·00 101/100·20 0/0·17 9/7·18 23/22·86 10/6·68 20/26·17 4/3·38 0/0·76 1/1·78 8/9·25 0/0·41 6/4·30 1/2·05
Chronic lymphatic leukaemia Chronic myeloid leukaemia Polycythaemia vera
8/6·67 0/0·70 0/1·89
1·20 (0·52–2·36) 0·00 (0·00–5·25) 0·00 (0·00–1·95)
1/3·24 0/0·36 0/0·58
Women SIR (95% CI)
Observed/ expected
SIR (95% CI)
0·93 (0·82–1·04) 1·55 (0·32–4·53) 0·61 (0·02–3·40) 0·00 (0·00–8·23) 0·00 (0·00–4·46) 0·66 (0·08–2·40) 0·78 (0·35–1·47) 1·07 (0·70–1·57) 0·98 (0·54–1·65) 0·55 (0·07–1·99) 0·39 (0·01–2·15) 0·96 (0·35–2·09) 2·34 (0·06–13·06) 1·11 (0·13–4·03) 0·82 (0·48–1·31) 0·00 (0·00–3·32) 0·00 (0·00–7·31) ·· ·· ·· ·· 1·01 (0·82–1·22) 0·00 (0·00–22·12) 1·25 (0·57–2·38) 1·01 (0·64–1·51) 1·50 (0·72–2·75) 0·76 (0·47–1·18) 1·18 (0·32–3·03) 0·00 (0·00–4·85) 0·56 (0·01–3·13) 0·86 (0·37–1·70) 0·00 (0·00–8·97) 1·40 (0·51–3·04) 0·49 (0·01–2·72)
344/349·68 1/1·0 1/2·55 0/0·63 1/0·60 3/2·34 7/11·38 44/39·09 17/17·07 6/3·75 2/7·12 11/11·29 0/0·41 0/0·40 14/15·81 1/0·37 67/68·18 4/4·13 17/19·56 10/11·60 2/4·22 0/0·00 0/0·00 13/9·02 16/12·93 12/9·19 19/23·73 5/6·29 2/2·28 4/2·13 12/12·51 0/0·69 4/6·03 2/3·02
0·98 (0·88–1·09) 0·99 (0·02–5·50) 0·39 (0·01–2·18) 0·00 (0·00–5·83) 1·68 (0·04–9·35) 1·28 (0·26–3·75) 0·62 (0·25–1·27) 1·13 (0·82–1·51) 1·00 (0·58–1·59) 1·60 (0·59–3·49) 0·28 (0·03–1·02) 0·97 (0·49–1·74) 0·00 (0·00–8·98) 0·00 (0·00–9·32) 0·89 (0·48–1·49) 2·67 (0·07–14·87) 0·98 (0·76–1·25) 0·97 (0·26–2·48) 0·87 (0·51–1·39) 0·86 (0·41–1·59) 0·47 (0·06–1·71) ·· ·· 1·44 (0·77–2·47) 1·24 (0·71–2·01) 1·31 (0·67–2·28) 0·80 (0·48–1·25) 0·80 (0·26–1·86) 0·88 (0·11–3·17) 1·88 (0·51–4·81) 0·96 (0·50–1·68) 0·00 (0·00–5·31) 0·66 (0·18–1·70) 0·66 (0·08–2·39)
0·31 (0·01–1·72) 0·00 (0·00–10·21) 0·00 (0·00–6·32)
7/3·43 0/0·34 0/1·31
2·04 (0·82–4·21) 0·00 (0·00–10·81) 0·00 (0·00–2·82)
SIR=standardised incidence ratio.
Table 4: Frequency of cancers in the STOP-Hypertension-2 cohort
women, the SIR for all cancers was very close to unity, with narrow CIs (tables 3 and 4). When the data were analysed for 0–9 months, over 9–36 months, and over 36 months after randomisation, the SIRs were similar: 0·92 (95% CI 0·73–1·13), 0·97 (0·86–1·10), and 0·96 (0·84–1·08), respectively. Thus, there was no peak in the frequency of cancers at the start of follow-up. For the various tumour sites, the recorded number of cases for both men and women were closely similar to what is expected from Swedish national reference data and random variation (table 3). The SIRs for all cancers were similar for the three treatment groups (tables 5 and 6, figure 1). Also, for different tumour sites, SIRs were fairly similar in the three treatment arms. Analysis by sex did not yield any significant differences (data not shown). Moreover, when the analyses were done after exclusion of 607 patients with a history of cancer at baseline, the outcome was essentially the same (data not shown). Figure 2 shows a comparison between
THE LANCET • Vol 358 • August 18, 2001
the treatment groups of the cumulative frequency of cancer. The 5-year-risk was about 9% in all treatment groups, and no difference in cancer hazard was found (p=0·67, log-rank test). In the conventional drug group, 1642 (74%) of 2211 patients received a diuretic as an allocated drug. Treatment with diuretic drugs might cause kidney cancer,10 and hence the observed and expected numbers for kidney cancer were assessed in this subgroup. Four cases were recorded, compared with 4·03 expected. Table 7 shows the proportion of patients who received randomly assigned treatment (with and without supplementary treatment). After 4 years, nearly all patients (93%) in the conventional drugs group and most in the calcium antagonist and ACE inhibitor groups (77% and 71%, respectively) received medication from their assigned class of drug. The high compliance in the conventional drugs group is accounted for by the allowed change from a -blocker to a diuretic or vice versa, with adherence to the protocol.
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For personal use only. Reproduce with permission from The Lancet Publishing Group.
ARTICLES
Tumour site
Conventional drugs Observed/Expected
All sites 200/217·01 Gastrointestinal tract 42/52·55 Respiratory tract 9/13·62 Breast 23/23·42 Female genital organs 10/13·44 Prostate 34/32·32 Lymphoma and leukaemia 17/15·84
Calcium antagonists
ACE inhibitors
p*
SIR (95% CI)
Observed/Expected
SIR (95% CI)
Observed/Expected 95% CI)
0·92 (0·80–1·06) 0·80 (0·58–1·08) 0·66 (0·30–1·25) 0·98 (0·62–1·47) 0·74 (0·36–1·37) 1·05 (0·73–1·47) 1·07 (0·63–1·72)
209/217·56 57/52·34 13/13·83 19/22·54 10/13·03 32/33·96 10/15·82
0·96 (0·83–1·10) 1·09 (0·82–1·41) 0·94 (0·50–1·61) 0·84 (0·51–1·32) 0·77 (0·37–1·41) 0·94 (0·64–1·33) 0·63 (0·30–1·16)
216/218·28 51/52·70 13/13·69 25/22·73 13/13·04 35/33·91 14/15·86
0·99 (0·86–1·13) 0·97 (0·72–1·27) 0·95 (0·51–1·62) 1·10 (0·71–1·62) 1·00 (0·53–1·70) 1·03 (0·72–1·44) 0·88 (0·48–1·48)
0·77 0·31 0·65 0·68 0·74 0·89 0·41
SIR=standardised incidence ratio. *p value for homogeneity between groups by 2 test.
Table 5: Frequency of cancers for every treatment group ICD-7 code
140–209 140 141, 143, 144 142 145–148 150 151 153 154 1550 1551–1559 157 160 161 1620–1621 1622 170 171 172–174 175 176 177 178 180 181 190 191 193 194 196, 197 200, 202 201 203 2040, 2050, 2060, 2070 2041 2051 208
Tumour site
Conventional drugs
Calcium antagonists
ACE inhibitors
Observed/ expected
SIR (95% CI)
Observed/ expected
SIR (95% CI)
Observed/ expected
SIR (95% CI)
All sites 200/217·01 Lip 1/0·97 Oral cavity 2/1·40 Salivary glands 0/0·36 Pharynx 0/0·47 Oesophagus 0/1·77 Stomach 2/7·62 Colon 22/21·17 Rectum 9/10·41 Liver, primary 2/2·45 Biliary passages 1/3·26 Pancreas 6/5·87 Nasal cavity and sinuses 0/0·28 Larynx 0/0·72 Trachea, bronchus, and lung 9/12·13 Pleura 0/0·49 Breast 23/23·42 Cervix uteri 1/1·41 Corpus uteri 6/6·65 Ovary 2/3·94 Vulva and vagina 1/1·44 Prostate 34/32·32 Testis 0/0·05 Kidney 6/5·40 Urinary tract 17/11·78 Malignant melanoma of skin 4/5·29 Skin (melanoma excluded) 15/16·46 Nervous system 4/3·24 Thyroid gland 0/1·03 Bone and soft tissue 1/1·30 Non-Hodgkin lymphoma 9/7·25 Hodgkin’s disease 0/0·37 Multiple myeloma 3/3·44 Acute leukaemia 1/1·69
0·92 (0·80–1·06) 1·03 (0·03–5·76) 1·43 (0·17–5·17) 0·00 (0·00–10·24) 0·00 (0·00–7·84) 0·00 (0·00–2·08) 0·26 (0·03–0·95) 1·04 (0·65–1·57) 0·86 (0·40–1·64) 0·82 (0·10–2·95) 0·31 (0·01–1·71) 1·02 (0·38–2·22) 0·00 (0·00–13·22) 0·00 (0·00–5·15) 0·74 (0·34–1·41) 0·00 (0·00–7·59) 0·98 (0·62–1·47) 0·71 (0·02–3·96) 0·90 (0·33–1·96) 0·51 (0·06–1·83) 0·70 (0·02–3·88) 1·05 (0·73–1·47) 0·00 (0·00–68·91) 1·11 (0·41–2·42) 1·44 (0·84–2·31) 0·76 (0·21–1·93) 0·91 (0·51–1·50) 1·24 (0·34–3·16) 0·00 (0·00–3·60) 0·77 (0·02–4·30) 1·24 (0·57–2·36) 0·00 (0·00–9·96) 0·87 (0·18–2·55) 0·59 (0·01–3·29)
209/217·56 0/0·99 0/1·39 0/0·36 0/0·48 2/1·79 6/7·64 27/21·00 11/10·42 5/2·46 0/3·21 6/5·82 1/0·28 1/0·74 11/12·31 0/0·50 19/22·54 1/1·36 5/6·45 3/3·83 1/1·39 32/33·96 0/0·06 8/5·42 12/12·00 9/5·29 14/16·58 2/3·23 2/1·01 2/1·30 4/7·24 0/0·37 3/3·43 1/1·69
0·96 (0·83–1·10) 0·00 (0·00–3·74) 0·00 (0·00–2·65) 0·00 (0·00–10·28) 0·00 (0·00–7·70) 1·12 (0·14–4·04) 0·79 (0·29–1·71) 1·29 (0·85–1·87) 1·06 (0·53–1·89) 2·04 (0·66–4·75) 0·00 (0·00–1·15) 1·03 (0·38–2·25) 3·58 (0·09–19·94) 1·35 (0·03–7·52) 0·89 (0·45–1·60) 0·00 (0·00–7·41) 0·84 (0·51–1·32) 0·74 (0·02–4·10) 0·77 (0·25–1·81) 0·78 (0·16–2·29) 0·72 (0·02–4·01) 0·94 (0·64–1·33) 0·00 (0·00–65·47) 1·48 (0·64–2·91) 1·00 (0·52–1·75) 1·70 (0·78–3·23) 0·84 (0·46–1·42) 0·62 (0·08–2·24) 1·99 (0·24–7·18) 1·54 (0·19–5·55) 0·55 (0·15–1·41) 0·00 (0·00–10·04) 0·87 (0·18–2·55) 0·59 (0·01–3·30)
216/218·28 3/0·99 0/1·40 0/0·36 1/0·47 3/1·79 8/7·73 21/21·19 11/10·45 1/2·47 2/3·24 5/5·83 0/0·28 1/0·73 11/12·18 1/0·50 25/22·73 2/1·37 6/6·45 5/3·83 0/1·39 35/33·91 0/0·06 8/5·38 10/12·02 9/5·28 10/16·85 3/3·20 0/1·01 2/1·31 7/7·27 0/0·37 4/3·44 1/1·69
0·99 (0·86–1·13) 3·02 (0·62–8·82) 0·00 (0·00–2·64) 0·00 (0·00–10·20) 2·11 (0·05–11·78) 1·68 (0·35–4·90) 1·04 (0·45–2·04) 0·99 (0·61–1·52) 1·05 (0·53–1·88) 0·41 (0·01–2·26) 0·62 (0·07–2·23) 0·86 (0·28–2·00) 0·00 (0·00–13·24) 1·36 (0·03–7·60) 0·90 (0·45–1·62) 2·00 (0·05–11·12) 1·10 (0·71–1·62) 1·46 (0·18–5·29) 0·93 (0·34–2·02) 1·31 (0·42–3·05) 0·00 (0·00–2·65) 1·03 (0·72–1·44) 0·00 (0·00–64·81) 1·49 (0·64–2·93) 0·83 (0·40–1·53) 1·70 (0·78–3·23) 0·59 (0·28–1·09) 0·94 (0·19–2·74) 0·00 (0·00–3·65) 1·53 (0·18–5·51) 0·96 (0·39–1·98) 0·00 (0·00–10·01) 1·16 (0·32–2·97) 0·59 (0·01–3·30)
Chronic lymphatic leukaemia Chronic myeloid leukaemia Polycythaemia vera
1·81 (0·49–4·62) 0·00 (0·00–15·76) 0·00 (0·00–5·79)
2/2·23 0/0·23 0/0·63
0·90 (0·11–3·24) 0·00 (0·00–15·70) 0·00 (0·00–5·90)
2/2·23 0/0·23 0/0·63
0·90 (0·11–3·25) 0·00 (0·00–15·80) 0·00 (0·00–5·86)
4/2·22 0/0·23 0/0·64
SIR=standardised incidence ratio.
Table 6: Frequency of cancers for all treatment groups in the STOP-Hypertension-2 cohort
Discussion We saw no significant deviation from the expected number for any cancer type. There was no increase in the frequency of cancer during the first part of the study, which might have been expected because patients had more frequent visits to the health centre than usually take place. When comparing with the general population, we only matched for age, sex, and calendar-year, and thus did not adjust for risk factors such as obesity, smoking, previous smoking, alcohol, &c, or for possible protective factors such as participating in STOP-Hypertension-2, residence in rural areas, &c. However, county data in the Swedish Cancer Registry,15 indicate that people living in rural areas have only a slightly lower (<10%) frequency of cancer than average. The presence of cancer was not an obvious factor in patients’ enrolment—eg, an elderly gentleman with prostate cancer or an elderly woman who had had breast cancer were likely to be enrolled if they met the inclusion criteria. When the analyses were done after patients who had a history of
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Conventional drugs
Calcium antagonists
ACE inhibitors
Total
0·7
0·8 0·9 1·0 1·1 1·2 Standardised incidence ratio
1·3
Figure 1: Standardised incidence ratio for all cancers and 95% CIs
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Cumulative frequency of cancer
0·12
ACE inhibitor Calcium antagonist Conventional drugs
0·10 0·08 0·06 0·04 0·02 0 0
2 4 6 Time from randomisation (years) Figure 2: Cumulative frequency of cancer by treatment group
cancer at baseline were excluded, the outcome was essentially the same. The overall mortality of the STOP-Hypertension-2 cohort was lower than expected from the general Swedish population. The SMRs were lower during years 1 and 2 than during year 4 and beyond, which could be explained by the exclusion criteria of the trial,11 especially by that of excluding elderly patients with severe or incapacitating illness. However, the overall mortality of STOPHypertension-2 was higher than that of the actively treated patients in our previous STOP-Hypertension study,16 in which the mean follow-up was 2·1 years. STOPHypertension was a placebo-controlled trial, which might have led to the selection of healthier patients than in STOPHypertension-2.11 0·5% of patients in the present study had had parathyroid adenoma before enrolment, which is associated with hypertension.17 The availability of a comprehensive cancer registration in Sweden made it possible to identify nearly all cases of cancer and to compare observed frequency with expected frequency from the general Swedish population, matched for age and sex. However, the cohort was somewhat selected, even though the investigators tried to enroll all elderly people with hypertension cared for in almost 40% of all Swedish health centres. We also did not have information about which antihypertensive drugs these elderly patients had taken before enrolment, but in line with the Swedish guidelines on hypertension,18 they were likely to have had a diuretic, -blocker, or both, which might account for the high compliance in the conventional drugs group. Moreover, median time of follow-up was only 5·3 years, which is important because many cancers take a longer time than this follow-up to develop. However, a randomised trial of longer duration than ours is not easily done, and additionally, after 5 years, there is a large risk that many patients will stop taking their assigned treatment. Follow-up (year)
1 2 3 4 5
Conventional drugs
Calcium antagonists
ACE inhibitors
Without
With
Without With
Without With
90% 85% 84% 83% 80%
5% 8% 10% 10% 13%
63% 53% 48% 43% 39%
54% 43% 38% 35% 32%
23% 30% 33% 34% 38%
26% 33% 35% 36% 39%
Numbers of patients are in parentheses.
Table 7: Patients who received randomly assigned drug class with or without additional antihypertensive drugs among those who attended annual visit
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Many patients in STOP-Hypertension-2 received more than one antihypertensive drug; we do not have information on how these drugs interact with respect to development of cancer. Moreover, many patients took one or more drugs from the other treatment groups as a replacement or a supplement for their assigned drug, which affected the intention-to-treat comparison, and made the interpretation somewhat difficult. Hence we intend later to try to analyse according to actual medication. Findings from several studies1,3–5 show no relation, in populations, between blood pressure and cancer. A report from Scotland19–21 was based on a cohort of 15 411 participants who had their blood pressure measured about 20 years before the study. There were 1392 fatal cancers and investigators noted no relation between cancer risk and diastolic blood pressure. The cancer numbers recorded in the untreated hypertensives of the Glasgow blood pressure clinic did not differ from those expected in a control population matched for age, sex, and smoking habits.20 Likewise, in a cohort of 8006 middle-aged JapaneseAmerican men living in Hawaii, who were examined from 1965 to 1968 and followed up for 20 years,6 there was no association between blood pressure and total frequency of cancer (1155 cases of cancer). In that study, the relative risk of cancer incidence was 1·03 for people with a systolic blood pressure of 160 mm Hg or greater, after adjustment for age, smoking, alcohol, and measures related to obesity. Also, Peeters and colleagues,4,22 in a prospective study, assessed 11 011 women aged 50–65 years at enrolment, in a breast-cancer screening project, who were followed up for 19 years. Hypertension was a significant risk factor for cancer.4 However, when adjustment for confounders was made, there was no significant increased cancer risk; the decline in risk was mainly attributable to the effect of bodymass index.22 The risk was similar in treated and nontreated hypersensitive women. Our findings are thus in line with those from Hawaii,6 Glasgow,19,20 and Utrecht.22 The SIRs for cancer at all sites were very close to unity for all three treatment groups. The cumulative frequency curves were also quite similar, and, moreover, no difference between the treatments could be detected for any specific site. Therefore, our study does not lend support to the hypothesis that any of the three treatment strategies promote cancer, nor to the hypothesis that any of these strategies protect against cancer. Thus, a drug regimen that effectively lowers blood pressure is more important than the risk of cancer. Several groups of antihypertensive drugs have been suspected of being linked to an increased cancer risk: reserpine, diuretics, -blockers, ACE inhibitors, and calcium antagonists. ACE inhibitors have also been shown to protect against cancer.19 The most intense debate on calcium antagonist treatment and cancer started after Pahor and colleagues23,24 reported their findings. 5052 elderly people, aged 71 years or greater, were followed up for a mean of 3·7 years; 451 were treated with calcium antagonists.24 The hazard ratio for cancer associated with calcium antagonists compared with those not on calcium antagonists was 1·72 (95% CI 1·27–2·34). To account for the increased risk, Pahor and colleagues,24 suggested that calcium antagonists could alter apoptosis. A major drawback of that study was that patients were not randomly assigned to the different types of treatment; those treated with calcium antagonists were more ill than the others. Other previous studies (for example refs 19,20,25,26), have not linked calcium antagonist treatment to cancer. However, these studies are susceptible to bias because none was based on a prospective, randomised, controlled design. We followed up over 4000 hypertensive patients for 5 years or more, and more than 1000 for 6 years or more.13
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Our findings on cancer are in accordance with those of other studies19,20,27–29 that showed no increased risk in patients randomly assigned to treatment with calcium antagonists. However, we could not confirm the protective effect of treatment with ACE inhibitors against some cancers suggested in one study.19 Contributors The subcommittee on cancer included H Anderson, T Ekbom, J Lanke, K Forsén, and T R Möller. L H Lindholm chaired the committee. All other authors were members of the STOP-Hypertension-2 steering committee, which oversaw the study on behalf of The Swedish Hypertension Society, and have commented on the manuscript. A full list of the STOPHypertension-2 Investigators is given in the original study.13
Acknowledgments The study was endorsed by the Swedish Society of Hypertension and supported by grants from Astra (AstraZeneca), Merck Sharp and Dohme, Sandoz (Novartis) and Zeneca (AstraZeneca). We thank B Midberg and G Andersson for computer program development.
References 1
Dyer AR, Stamler J, Berkson DM, Lindberg HA, Stevens E. High blood-pressure: a risk for cancer mortality? Lancet 1975; 1: 1051–56. 2 Filipovsky J, Ducimetiere P, Darne B, Richard JL. Abdominal body mass distribution and elevated blood pressure are associated with increased risk of death from cardiovascular cancer in middle-aged men: the results of a 15-to 20-year follow-up in the Paris prospective study I. Int J Obes 1993; 17: 197–203. 3 Rosengren A, Himmelmann A, Wilhelmsen L, Branehög I, Wedel H. Hypertension and long-term cancer incidence and mortality among Swedish men. J Hypertens 1998; 16: 933–40. 4 Peeters PH, van Noord PA, Hoes AW, Grobbee DE. Hypertension, antihypertensive drugs, and mortality from cancer among women. J Hypertens 1998; 16: 941–47. 5 Soler M, Chatenoud L, Negri E, Parazzini F, Franceschi S, La Vecchia C. Hypertension and hormone-related neoplasms in women. Hypertension 1999; 34: 320–25. 6 Grove JS, Nomura A, Severson RK, Stemmermann GN. The association of blood pressure with cancer incidence in a prospective study. Am J Epidemiol 1991; 134: 942–47. 7 Wannamethee G, Shaper AG. Blood pressure and cancer in middle-aged British men. Int J Epidemiol 1996; 25: 22–31. 8 Hamet P. Cancer and hypertension: an unresolved issue. Hypertension 1996; 28: 321–24. 9 Lindholm L, Bryngelsson T, Pero R. Hypertension, age, and smoking related to genotoxic sensitivity in human lymphocytes: a population study. Environ Res 1986; 40: 202–09. 10 Shapiro JA, Williams MA, Weiss NS, Stergachis A, LaCroix AZ, Barlow WE. Hypertension, antihypertensive medication use, and risk of renal cell carcinoma. Am J Epidemiol 1999; 149: 521–30.
11 Dahlöf B, Hansson L, Lindholm LH, et al. STOP-Hypertension-2: a prospective intervention trial of “newer” versus “older” treatment alternatives in old patients with hypertension. Blood Pressure 1993; 2: 136–41. 12 Lindholm LH, Hansson L, Dahlöf B, et al. The Swedish Trial in Old Patients with Hypertension (STOP-Hypertension-2): a progress report. Blood Pressure 1996; 5: 300–04. 13 Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2. Lancet 1999; 354: 1751–56. 14 Mattsson B. Cancer registration in Sweden (thesis). Stockholm: Karolinska Institutet, 1984. 15 The Oncological Centres in Sweden. Atlas of cancer incidence in Sweden. Uppsala: Oncological Centre, 1995: 1–92. 16 Dahlöf B, Lindholm LH, Hansson L, Scherstén B, Ekbom T, Wester P-O. Morbidity and mortality in the Swedish trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338: 1281–85. 17 Hellström J, Birke G, Edvall CA. Hypertension in hyperparathyroidism. Br J Urol 1958; 30: 13–34. 18 The Norwegian-Swedish Expert Group. The Medical Product Agency. Treatment of hypertension in the elderly. Blood Pressure 1994; 3: 219–22. 19 Lever AF, Hole DJ, Gillis CR, et al. Do inhibitors of angiotensin-I-converting enzymes protect against risk of cancer? Lancet 1998; 352: 179–84. 20 Levere AF, Hole DJ, Gillis CR, et al. Is cancer related to hypertension or to its treatment? Clin Exper Hypertens 1999; 21: 937–46. 21 Hole DJ, Jawthorne VM, Isles CG, et al. Incidence of and mortality from cancer in hypertensive patients. BMJ 1993; 306: 609–11. 22 Peeters PH, van Noord PA, Hoes AW, Fracheboud J, Gimbrère CH, Grobbe DE. Hypertension and breast cancer risk in a 19-year follow-up study (the DOM cohort). J Hypertens 2000; 18: 249–55. 23 Pahor M, Guralnik JM, Salive ME, Corti M-C, Carboni P, Havlik RJ. Do calcium channel blockers increase the risk of cancer? Am J Hypertens 1996; 9: 695–99. 24 Pahor M, Guralnik JM, Ferrucci L, et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet 1996; 348: 493–97. 25 Jick H, Jick S, Derby LE, Vasilakis C, Myers MW, Meier CR. Calcium channel blockers and risk of cancer. Lancet 1997; 349: 525–28. 26 Hole DJ, Gillis CR, McCallum IR, et al. Cancer risk of hypertensive patients taking calcium antagonists. J Hypertens 1998; 16: 119–24. 27 Gong L, Zhang W, Zhu J, et al. Shanghai trial of nifedipine in the elderly (STONE). J Hypertens 1996; 14: 1237–45. 28 Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: 757–64. 29 Liu L, Wang JG, Gong L, et al. Comparison of active treatment and placebo for older Chinese patients with isolated systolic hypertension. J Hypertens 1998; 16: 1823–29.
A more comprehensive list of references is available from the corresponding author
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Relation between drug treatment and cancer in hypertensives in the Swedish Trial in Old Patients with Hypertension 2: a 5-year, prospective, randomised, controlled trial Lars H Lindholm, Harald Anderson, Tord Ekbom, Lennart Hansson, Jan Lanke, Björn Dahlöf, Ulf de Faire, Kent Forsén, Thomas Hedner, Erland Linjer, Bengt Scherstén, P-O Wester, Torgil R Möller
Summary Background Is cancer related to hypertension and blood pressure? Do antihypertensive drugs promote cancer? Do antihypertensive drugs protect against cancer? We previously analysed the frequency of cardiovascular mortality and morbidity in elderly people who participated in the Swedish Trial in Old Patients with Hypertension 2 (STOPHypertension-2). We have also looked at the frequency of cancer in these patients. Methods We randomly assigned 6614 elderly patients with hypertension (mean age 76 years, median time of follow-up 5·3 years) to one of three treatment strategies: conventional drugs (diuretics or -blockers), calcium antagonists, or ACE inhibitors. We matched the patients to the Swedish Cancer Registry and compared our findings with expected values based on age, sex, and calendar-year-specific reference frequencies for the general Swedish population. We also compared the number of cancers between the three treatment groups. Findings At baseline, 607 (9%) patients had previous malignant disease. Diagnoses were closely similar to the distribution of cancer types that might be seen in elderly patients. During follow-up, there were 625 new cases of cancer in 590 patients. The frequency of cancer did not differ significantly between the treatment strategies, including all cancers and those at individual sites. The standardised incidence ratios (SIRs) for all cancers were also close to unity: 0·92 (95% CI 0·80–1·06) for conventional drugs, 0·96 (0·83–1·10) for calcium antagonists, and 0·99 (0·86–1·13) for ACE inhibitors. Interpretations No difference in cancer risk was seen between patients randomly assigned to conventional drugs, calcium antagonists, or ACE inhibitors. Thus, the general message to the practising physician is that more attention should be given to getting the blood pressure down than to the risk of cancer. Lancet 2001; 358: 539–44 Department of Public Health and Clinical Medicine, Umeå University, SE 901 85 Umeå, Sweden (Prof L H Lindholm MD, Prof P-O Wester MD, K Forsén); Department of Cancer Epidemiology, Lund University, Lund (H Anderson PhD, T Möller MD); Department of Community Medicine, Malmö University Hospital, Malmö (T Ekbom MD); Department of Public Health and Social Sciences, Uppsala University, Uppsala (Prof L Hansson MD, E Linjer BSc); Department of Statistics, Lund University (Prof J Lanke PhD); Department of Medicine (B Dahlöf MD) and Department of Clinical Pharmacology (Prof T Hedner MD) Sahlgrenska University Hospital, Göteborg; Department of Medicine, Karolinska University Hospital, Stockholm (Prof U de Faire MD); and Department of Community Health Sciences in Dalby/Lund, Lund University (Prof B Scherstén MD), Correspondence to: Prof Lars H Lindholm (e-mail: [email protected])
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Introduction For more than 25 years, the risk of cancer in relation to use of antihypertensive drugs has been much discussed. Retrospective case-control studies and subgroup analyses from prospective intervention trials have suggested that several antihypertensive regimens (eg, reserpine, diuretics, -blockers, angiotensin-converting enzyme [ACE] inhibitors, and calcium antagonists) are associated with an increased cancer risk in the breast, kidney, and gastrointestinal tract, as well as with multiple cancer forms. However, these studies do not give plausible explanations for the development of multiple cancer forms from the various classes of antihypertensive drugs described. Additionally, increased risk is sometimes, but not always, related to long-term use of the drugs, and there might be a competing death risk (ie, cardiovascular vs cancer). The most important argument is that the increased risk of cancer death is seen in treated as well as untreated hypertensive patients, raising the possibility that hypertension is itself a risk factor for cancer. Dyer and colleagues1 reported that both systolic and diastolic blood pressures were related to 14-year mortality from cancer after adjustment for several factors such as age, cholesterol, and smoking. Investigators from several studies,2–5 but not all,6 have pointed out that hypertension seems a moderately large risk factor for cancer in various sites. Cardiovascular risk factors such as obesity, diabetes, and smoking seem to interact with increased blood pressure in a complex way and act as risk factors for cancer.2,7 Potential mechanisms that might contribute to an increased risk of cancer in hypertensive patients are unknown. In human beings and animals, the response to carcinogens can differ between those with hypertension and those with normal blood pressure.8,9 There has been much debate about the possible increase in risk of cancer after treatment with calcium antagonists, and researchers have also postulated that there is an association between renal cell carcinoma and use of diuretics.10 Therefore, we decided to analyse the frequency of cancer in elderly patients who participated in the Swedish Trial in Old Patients with Hypertension 2 (STOPHypertension-2). This 5-year prospective study was originally designed to compare cardiovascular mortality in elderly hypertensive men and women randomly assigned to three different treatment strategies: conventional drugs (diuretics or -blockers), calcium antagonists, or ACE inhibitors.11–13
Methods We have previously reported the study population, design, and main results of STOP-Hypertension-2.11–13 Briefly, between Sept 1, 1992, and Dec 30, 1994, we enrolled 6614 elderly patients (mean age 76 years, range 70–84 at baseline) from 312 health centres in Sweden (of about 850). The mean and median follow-up time was 5·0 years and 5·3 years, respectively. Follow-up with respect to occurrence of cancer and vital status ended on Dec 31,
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Characteristic
All patients
Conventional Calcium ACE inhibitors drugs group antagonists group group
Demography Number of patients 6614 2213 2196 2205 Mean age (years) 76·0 76·0 75·9 76·1 Men 2196 (33·2%) 708 (32·0%) 747 (34·0%) 743 (33·7%) Mean body-mass 26·7 26·7 26·7 26·7 index (kg/m2) Smokers 595 (9·0%) 195 (8·8%) 193 (8·8%) 207 (9·4%) Mean supine blood 194/98 194/98 194/98 194/98 pressure (mm Hg) History of cancer Patients 607 All cancers 650 (100%) Breast 151 (23%) Colorectal 98 (15%) Prostate 77 (12%) Corpus uteri 50 (8%) Non-melanoma skin 38 (6%) Melanoma of skin 36 (6%) Urinary bladder 36 (6%) Parathyroid 31 (5%) adenoma
207 224 (100%) 56 (25%) 35 (16%) 24 (11%) 18 (8%) 13 (6%) 11 (5%) 13 (6%) 7 (3%)
192 208 202 (100%) 224 (100%) 48 (24%) 47 (21%) 23 (11%) 40 (18%) 32 (16%) 21 (9%) 18 (9%) 14 (6%) 10 (5%) 15 (7%) 9 (5%) 16 (7%) 10 (5%) 13 (6%) 8 (4%) 16 (7%)
*Values are numbers (%) unless otherwise indicated.
Table 1: Baseline characteristics of patients
1998; no patient was lost.13 Table 1 shows some baseline values, including history of cancer (further details given in original trial).13 Patients who had hypertension (blood pressure ⭓180 mm Hg systolic, ⭓105 mm Hg diastolic, or both) were randomly assigned to one of three groups. The first group received conventional antihypertensive therapy with -blockers (atenolol 50 mg, metoprolol 100 mg, or pindolol 5 mg daily) or a diuretic (a fixed-ratio combination of hydrochlorothiazide 25 mg plus amiloride 2·5 mg). In the second group, one of two ACE inhibitors were given— enalapril 10–20 mg, or lisinopril 10–20 mg daily. The third group received one of two calcium antagonists—felodipine 2·5–5·0 mg or isradipine 2·5–5·0 mg daily. The choices of drugs within the groups were not randomised. Patients on -blockers were given hydrochlorothiazide 25 mg plus amiloride 2·5 mg as additional treatment if the target blood pressure (⭐160/95 mm Hg) had not been reached at the 2month follow-up or later. Patients who had started on diuretic treatment were given any of the -blockers; those on ACE inhibitors were given hydrochlorothiazide 12·5–25·0 mg; and those on calcium antagonists were given any of the -blockers. After the initial dose-titrating period, patients were seen twice a year until the end of the study. Exclusion criteria were: contraindications for any of the study drugs; a requirement for any of the study drugs; orthostatic hypotension; participation in another study; severe or incapacitating illness; and unwillingness to participate.11 We obtained the cancer incidence in the study cohort from the Swedish Cancer Registry. This registry was established in 1958 as a population-based incidence register for the whole of Sweden. The registry is based on compulsory reporting from two independent sources: clinicians and pathologists or cytologists. Cases documented only from death certificates are reported separately and are not included in the statistics. The proportion of reported tumours has been estimated to be greater than 95% of all reportable tumours,14 and about 98% of all cases are confirmed microscopically. Even for individuals aged 80 years or more, the rate of microscopic confirmation is high (93–97%). Tumours that should be reported are: all malignant tumours, including lymphomas and leukaemias; premalignant disorders such as carcinomain-situ; all tumours within the central nervous system; and
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those with endocrine activity (except thyroid adenoma). All these, apart from the carcinoma-in-situ group, are included in the yearly statistics. However, basal-cell carcinoma is not a reportable tumour. Malignant disease is coded according to ICD-0-2, but this code is also translated into ICD-7 for site and WHO/CANC-24 for morphology. Since 1985, reports of tumours have been sent to the six regional cancer registries, who code and validate the reports, and once a year send their data to the Centre for Epidemiology at the National Board of Health and Welfare, for the production of national statistics. At the time of our analyses, national data were available up to 1997. We obtained data directly from the regional registries for 1998. The files of the STOP-Hypertension-2 study cohort were matched to the cancer registry files, and we linked records by means of the personal identification number (a civic registration number, which is unique for every permanent resident of Sweden) and thus unambiguously identified data in the registry. We calculated the standardised incidence ratios (SIRs) using person-years, with 5-year age groups, sex, and calendar-year-specific incidence data for the whole of Sweden as reference. Patients were followed up from randomisation until diagnosis of a third cancer, death, or end of follow-up, whichever occurred first. We calculated standardised mortality ratios (SMRs) in a similar way but with 1-year age groups, sex, and national Swedish mortality data for 5-year calendar-year groups as reference. CIs for SIRs were based on the Poisson distribution. Cancer frequency in the three treatment groups was compared for all sites and for some diagnoses by means of a 2 test for homogeneity. Many elderly people died during follow-up, and, hence in this population, the cumulative frequency function was used to show the occurrence of a new cancer. This function estimates the observable probability that a new cancer occurs before death within a specified time after randomisation. We analysed, using the log-rank test, the hazard of a first cancer after randomisation in the three treatment groups, with adjustment for death and end of follow-up. The Ethics Committee of Göteborg University approved the study and our analyses.
Results The overall mortality rate of the STOP-Hypertension-2 cohort was lower than that of the general Swedish population (table 2), but this difference diminished over time. At baseline, according to National Cancer Registry data, 607 patients had a history of previous malignant disease, 43 of whom had two cancers (table 1). The prevalence was thus 9%. The diagnoses listed in table 1 represents about 80% of all cancers in the cohort and are closely related to the distribution of cancer types that might be seen in patients at this age, except for the high prevalence of parathyroid adenoma (0·5%). During follow-up there were 625 new cases of cancer in 590 patients. For the entire cohort, and for both men and Follow-up (years)
Deaths Observed
Expected
Standardised mortality ratio
0–1 >1–2 >2–3 >3–4 >4–5 >5
136 162 188 241 227 157
277·31 293·38 309·05 323·31 296·19 209·27
0·49 0·55 0·61 0·75 0·77 0·75
Total
1111
1708·51
0·63
Table 2: Observed and expected number of deaths during follow-up
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Tumour site
All
All sites Gastrointestinal tract Respiratory tract Breast Female genital organs Prostate Lymphoma and leukaemia
Men
Women
Observed/Expected
SIR (95% CI)
Observed/Expected
SIR (95% CI)
Observed/Expected
SIR (95% CI)
625/652·85 150/157·56 35/41·13 67/68·69 33/39·51 101/100·20 41/47·52
0·96 (0·88–1·04) 0·95 (0·81–1·12) 0·85 (0·59–1·18) 0·98 (0·76–1·24) 0·84 (0·58–1·17) 1·01 (0·82–1·22) 0·86 (0·62–1·17)
281/303·17 60/65·54 20/24·13 0/0·50 .. 101/100·20 16/20·19
0·93 (0·82–1·04) 0·92 (0·70–1·18) 0·83 (0·51–1·28) 0·00 (0·00–7·31) .. 1·01 (0·82–1·22) 0·79 (0·45–1·29)
344/349·68 90/92·04 15/16·99 67/68·18 33/39·51 .. 25/27·33
0·98 (0·88–1·09) 0·98 (0·79–1·20) 0·88 (0·49–1·46) 0·98 (0·76–1·25) 0·84 (0·58–1·17) .. 0·92 (0·59–1·35)
SIR=standardised incidence ratio.
Table 3: Frequency of cancer ICD-7 code
140–209 140 141, 143, 144 142 145–148 150 151 153 154 1550 1551–1559 157 160 161 1620–1621 1622 170 171 172–174 175 176 177 178 180 181 190 191 193 194 196, 197 200, 202 201 203 2040, 2050, 2060, 2070 2041 2051 208
Tumour site
All
Men
Observed/ expected
SIR (95% CI)
Observed/ expected
All sites Lip Oral cavity Salivary glands Pharynx Oesophagus Stomach Colon Rectum Liver, primary Biliary passages Pancreas Nasal cavity and sinuses Larynx Trachea, bronchus, and lung Pleura Breast Cervix uteri Corpus uteri Ovary Vulva and vagina Prostate Testis Kidney Urinary tract Malignant melanoma of skin Skin (melanoma excluded) Nervous system Thyroid gland Bone and soft tissue Non-Hodgkin lymphoma Hodgkin’s disease Multiple myeloma Acute leukaemia
625/652·85 4/2·95 2/4·19 0/1·08 1/1·42 5/5·35 16/22·98 70/63·36 31/31·28 8/7·37 3/9·70 17/17·52 1/0·84 2/2·19 31/36·61 1/1·49 67/68·69 4/4·13 17/19·56 10/11·60 2/4·22 101/100·20 0/0·17 22/16·20 39/35·79 22/15·87 39/49·90 9/9·66 2/3·04 5/3·91 20/21·76 0/1·11 10/10·32 3/5·07
0·96 (0·88–1·04) 1·36 (0·37–3·48) 0·48 (0·06–1·72) 0·00 (0·00–3·41) 0·70 (0·02–3·92) 0·93 (0·30–2·18) 0·70 (0·40–1·13) 1·10 (0·86–1·40) 0·99 (0·67–1·41) 1·09 (0·47–2·14) 0·31 (0·06–0·90) 0·97 (0·56–1·55) 1·19 (0·03–6·66) 0·91 (0·11–3·30) 0·85 (0·58–1·20) 0·67 (0·02–3·75) 0·98 (0·76–1·24) 0·97 (0·26–2·48) 0·87 (0·51–1·39) 0·86 (0·41–1·59) 0·47 (0·06–1·71) 1·01 (0·82–1·22) 0·00 (0·00–22·12) 1·36 (0·85–2·06) 1·09 (0·77–1·49) 1·39 (0·87–2·10) 0·78 (0·56–1·07) 0·93 (0·43–1·77) 0·66 (0·08–2·37) 1·28 (0·42–2·99) 0·92 (0·56–1·42) 0·00 (0·00–3·34) 0·97 (0·46–1·78) 0·59 (0·12–1·73)
281/303·17 3/1·93 1/1·64 0/0·45 0/0·83 2/3·01 9/11·61 26/24·27 14/14·21 2/3·62 1/2·59 6/6·23 1/0·43 2/1·79 17/20·80 0/1·11 0/0·50 0/0·00 0/0·00 0/0·00 0/0·00 101/100·20 0/0·17 9/7·18 23/22·86 10/6·68 20/26·17 4/3·38 0/0·76 1/1·78 8/9·25 0/0·41 6/4·30 1/2·05
Chronic lymphatic leukaemia Chronic myeloid leukaemia Polycythaemia vera
8/6·67 0/0·70 0/1·89
1·20 (0·52–2·36) 0·00 (0·00–5·25) 0·00 (0·00–1·95)
1/3·24 0/0·36 0/0·58
Women SIR (95% CI)
Observed/ expected
SIR (95% CI)
0·93 (0·82–1·04) 1·55 (0·32–4·53) 0·61 (0·02–3·40) 0·00 (0·00–8·23) 0·00 (0·00–4·46) 0·66 (0·08–2·40) 0·78 (0·35–1·47) 1·07 (0·70–1·57) 0·98 (0·54–1·65) 0·55 (0·07–1·99) 0·39 (0·01–2·15) 0·96 (0·35–2·09) 2·34 (0·06–13·06) 1·11 (0·13–4·03) 0·82 (0·48–1·31) 0·00 (0·00–3·32) 0·00 (0·00–7·31) ·· ·· ·· ·· 1·01 (0·82–1·22) 0·00 (0·00–22·12) 1·25 (0·57–2·38) 1·01 (0·64–1·51) 1·50 (0·72–2·75) 0·76 (0·47–1·18) 1·18 (0·32–3·03) 0·00 (0·00–4·85) 0·56 (0·01–3·13) 0·86 (0·37–1·70) 0·00 (0·00–8·97) 1·40 (0·51–3·04) 0·49 (0·01–2·72)
344/349·68 1/1·0 1/2·55 0/0·63 1/0·60 3/2·34 7/11·38 44/39·09 17/17·07 6/3·75 2/7·12 11/11·29 0/0·41 0/0·40 14/15·81 1/0·37 67/68·18 4/4·13 17/19·56 10/11·60 2/4·22 0/0·00 0/0·00 13/9·02 16/12·93 12/9·19 19/23·73 5/6·29 2/2·28 4/2·13 12/12·51 0/0·69 4/6·03 2/3·02
0·98 (0·88–1·09) 0·99 (0·02–5·50) 0·39 (0·01–2·18) 0·00 (0·00–5·83) 1·68 (0·04–9·35) 1·28 (0·26–3·75) 0·62 (0·25–1·27) 1·13 (0·82–1·51) 1·00 (0·58–1·59) 1·60 (0·59–3·49) 0·28 (0·03–1·02) 0·97 (0·49–1·74) 0·00 (0·00–8·98) 0·00 (0·00–9·32) 0·89 (0·48–1·49) 2·67 (0·07–14·87) 0·98 (0·76–1·25) 0·97 (0·26–2·48) 0·87 (0·51–1·39) 0·86 (0·41–1·59) 0·47 (0·06–1·71) ·· ·· 1·44 (0·77–2·47) 1·24 (0·71–2·01) 1·31 (0·67–2·28) 0·80 (0·48–1·25) 0·80 (0·26–1·86) 0·88 (0·11–3·17) 1·88 (0·51–4·81) 0·96 (0·50–1·68) 0·00 (0·00–5·31) 0·66 (0·18–1·70) 0·66 (0·08–2·39)
0·31 (0·01–1·72) 0·00 (0·00–10·21) 0·00 (0·00–6·32)
7/3·43 0/0·34 0/1·31
2·04 (0·82–4·21) 0·00 (0·00–10·81) 0·00 (0·00–2·82)
SIR=standardised incidence ratio.
Table 4: Frequency of cancers in the STOP-Hypertension-2 cohort
women, the SIR for all cancers was very close to unity, with narrow CIs (tables 3 and 4). When the data were analysed for 0–9 months, over 9–36 months, and over 36 months after randomisation, the SIRs were similar: 0·92 (95% CI 0·73–1·13), 0·97 (0·86–1·10), and 0·96 (0·84–1·08), respectively. Thus, there was no peak in the frequency of cancers at the start of follow-up. For the various tumour sites, the recorded number of cases for both men and women were closely similar to what is expected from Swedish national reference data and random variation (table 3). The SIRs for all cancers were similar for the three treatment groups (tables 5 and 6, figure 1). Also, for different tumour sites, SIRs were fairly similar in the three treatment arms. Analysis by sex did not yield any significant differences (data not shown). Moreover, when the analyses were done after exclusion of 607 patients with a history of cancer at baseline, the outcome was essentially the same (data not shown). Figure 2 shows a comparison between
THE LANCET • Vol 358 • August 18, 2001
the treatment groups of the cumulative frequency of cancer. The 5-year-risk was about 9% in all treatment groups, and no difference in cancer hazard was found (p=0·67, log-rank test). In the conventional drug group, 1642 (74%) of 2211 patients received a diuretic as an allocated drug. Treatment with diuretic drugs might cause kidney cancer,10 and hence the observed and expected numbers for kidney cancer were assessed in this subgroup. Four cases were recorded, compared with 4·03 expected. Table 7 shows the proportion of patients who received randomly assigned treatment (with and without supplementary treatment). After 4 years, nearly all patients (93%) in the conventional drugs group and most in the calcium antagonist and ACE inhibitor groups (77% and 71%, respectively) received medication from their assigned class of drug. The high compliance in the conventional drugs group is accounted for by the allowed change from a -blocker to a diuretic or vice versa, with adherence to the protocol.
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Tumour site
Conventional drugs Observed/Expected
All sites 200/217·01 Gastrointestinal tract 42/52·55 Respiratory tract 9/13·62 Breast 23/23·42 Female genital organs 10/13·44 Prostate 34/32·32 Lymphoma and leukaemia 17/15·84
Calcium antagonists
ACE inhibitors
p*
SIR (95% CI)
Observed/Expected
SIR (95% CI)
Observed/Expected 95% CI)
0·92 (0·80–1·06) 0·80 (0·58–1·08) 0·66 (0·30–1·25) 0·98 (0·62–1·47) 0·74 (0·36–1·37) 1·05 (0·73–1·47) 1·07 (0·63–1·72)
209/217·56 57/52·34 13/13·83 19/22·54 10/13·03 32/33·96 10/15·82
0·96 (0·83–1·10) 1·09 (0·82–1·41) 0·94 (0·50–1·61) 0·84 (0·51–1·32) 0·77 (0·37–1·41) 0·94 (0·64–1·33) 0·63 (0·30–1·16)
216/218·28 51/52·70 13/13·69 25/22·73 13/13·04 35/33·91 14/15·86
0·99 (0·86–1·13) 0·97 (0·72–1·27) 0·95 (0·51–1·62) 1·10 (0·71–1·62) 1·00 (0·53–1·70) 1·03 (0·72–1·44) 0·88 (0·48–1·48)
0·77 0·31 0·65 0·68 0·74 0·89 0·41
SIR=standardised incidence ratio. *p value for homogeneity between groups by 2 test.
Table 5: Frequency of cancers for every treatment group ICD-7 code
140–209 140 141, 143, 144 142 145–148 150 151 153 154 1550 1551–1559 157 160 161 1620–1621 1622 170 171 172–174 175 176 177 178 180 181 190 191 193 194 196, 197 200, 202 201 203 2040, 2050, 2060, 2070 2041 2051 208
Tumour site
Conventional drugs
Calcium antagonists
ACE inhibitors
Observed/ expected
SIR (95% CI)
Observed/ expected
SIR (95% CI)
Observed/ expected
SIR (95% CI)
All sites 200/217·01 Lip 1/0·97 Oral cavity 2/1·40 Salivary glands 0/0·36 Pharynx 0/0·47 Oesophagus 0/1·77 Stomach 2/7·62 Colon 22/21·17 Rectum 9/10·41 Liver, primary 2/2·45 Biliary passages 1/3·26 Pancreas 6/5·87 Nasal cavity and sinuses 0/0·28 Larynx 0/0·72 Trachea, bronchus, and lung 9/12·13 Pleura 0/0·49 Breast 23/23·42 Cervix uteri 1/1·41 Corpus uteri 6/6·65 Ovary 2/3·94 Vulva and vagina 1/1·44 Prostate 34/32·32 Testis 0/0·05 Kidney 6/5·40 Urinary tract 17/11·78 Malignant melanoma of skin 4/5·29 Skin (melanoma excluded) 15/16·46 Nervous system 4/3·24 Thyroid gland 0/1·03 Bone and soft tissue 1/1·30 Non-Hodgkin lymphoma 9/7·25 Hodgkin’s disease 0/0·37 Multiple myeloma 3/3·44 Acute leukaemia 1/1·69
0·92 (0·80–1·06) 1·03 (0·03–5·76) 1·43 (0·17–5·17) 0·00 (0·00–10·24) 0·00 (0·00–7·84) 0·00 (0·00–2·08) 0·26 (0·03–0·95) 1·04 (0·65–1·57) 0·86 (0·40–1·64) 0·82 (0·10–2·95) 0·31 (0·01–1·71) 1·02 (0·38–2·22) 0·00 (0·00–13·22) 0·00 (0·00–5·15) 0·74 (0·34–1·41) 0·00 (0·00–7·59) 0·98 (0·62–1·47) 0·71 (0·02–3·96) 0·90 (0·33–1·96) 0·51 (0·06–1·83) 0·70 (0·02–3·88) 1·05 (0·73–1·47) 0·00 (0·00–68·91) 1·11 (0·41–2·42) 1·44 (0·84–2·31) 0·76 (0·21–1·93) 0·91 (0·51–1·50) 1·24 (0·34–3·16) 0·00 (0·00–3·60) 0·77 (0·02–4·30) 1·24 (0·57–2·36) 0·00 (0·00–9·96) 0·87 (0·18–2·55) 0·59 (0·01–3·29)
209/217·56 0/0·99 0/1·39 0/0·36 0/0·48 2/1·79 6/7·64 27/21·00 11/10·42 5/2·46 0/3·21 6/5·82 1/0·28 1/0·74 11/12·31 0/0·50 19/22·54 1/1·36 5/6·45 3/3·83 1/1·39 32/33·96 0/0·06 8/5·42 12/12·00 9/5·29 14/16·58 2/3·23 2/1·01 2/1·30 4/7·24 0/0·37 3/3·43 1/1·69
0·96 (0·83–1·10) 0·00 (0·00–3·74) 0·00 (0·00–2·65) 0·00 (0·00–10·28) 0·00 (0·00–7·70) 1·12 (0·14–4·04) 0·79 (0·29–1·71) 1·29 (0·85–1·87) 1·06 (0·53–1·89) 2·04 (0·66–4·75) 0·00 (0·00–1·15) 1·03 (0·38–2·25) 3·58 (0·09–19·94) 1·35 (0·03–7·52) 0·89 (0·45–1·60) 0·00 (0·00–7·41) 0·84 (0·51–1·32) 0·74 (0·02–4·10) 0·77 (0·25–1·81) 0·78 (0·16–2·29) 0·72 (0·02–4·01) 0·94 (0·64–1·33) 0·00 (0·00–65·47) 1·48 (0·64–2·91) 1·00 (0·52–1·75) 1·70 (0·78–3·23) 0·84 (0·46–1·42) 0·62 (0·08–2·24) 1·99 (0·24–7·18) 1·54 (0·19–5·55) 0·55 (0·15–1·41) 0·00 (0·00–10·04) 0·87 (0·18–2·55) 0·59 (0·01–3·30)
216/218·28 3/0·99 0/1·40 0/0·36 1/0·47 3/1·79 8/7·73 21/21·19 11/10·45 1/2·47 2/3·24 5/5·83 0/0·28 1/0·73 11/12·18 1/0·50 25/22·73 2/1·37 6/6·45 5/3·83 0/1·39 35/33·91 0/0·06 8/5·38 10/12·02 9/5·28 10/16·85 3/3·20 0/1·01 2/1·31 7/7·27 0/0·37 4/3·44 1/1·69
0·99 (0·86–1·13) 3·02 (0·62–8·82) 0·00 (0·00–2·64) 0·00 (0·00–10·20) 2·11 (0·05–11·78) 1·68 (0·35–4·90) 1·04 (0·45–2·04) 0·99 (0·61–1·52) 1·05 (0·53–1·88) 0·41 (0·01–2·26) 0·62 (0·07–2·23) 0·86 (0·28–2·00) 0·00 (0·00–13·24) 1·36 (0·03–7·60) 0·90 (0·45–1·62) 2·00 (0·05–11·12) 1·10 (0·71–1·62) 1·46 (0·18–5·29) 0·93 (0·34–2·02) 1·31 (0·42–3·05) 0·00 (0·00–2·65) 1·03 (0·72–1·44) 0·00 (0·00–64·81) 1·49 (0·64–2·93) 0·83 (0·40–1·53) 1·70 (0·78–3·23) 0·59 (0·28–1·09) 0·94 (0·19–2·74) 0·00 (0·00–3·65) 1·53 (0·18–5·51) 0·96 (0·39–1·98) 0·00 (0·00–10·01) 1·16 (0·32–2·97) 0·59 (0·01–3·30)
Chronic lymphatic leukaemia Chronic myeloid leukaemia Polycythaemia vera
1·81 (0·49–4·62) 0·00 (0·00–15·76) 0·00 (0·00–5·79)
2/2·23 0/0·23 0/0·63
0·90 (0·11–3·24) 0·00 (0·00–15·70) 0·00 (0·00–5·90)
2/2·23 0/0·23 0/0·63
0·90 (0·11–3·25) 0·00 (0·00–15·80) 0·00 (0·00–5·86)
4/2·22 0/0·23 0/0·64
SIR=standardised incidence ratio.
Table 6: Frequency of cancers for all treatment groups in the STOP-Hypertension-2 cohort
Discussion We saw no significant deviation from the expected number for any cancer type. There was no increase in the frequency of cancer during the first part of the study, which might have been expected because patients had more frequent visits to the health centre than usually take place. When comparing with the general population, we only matched for age, sex, and calendar-year, and thus did not adjust for risk factors such as obesity, smoking, previous smoking, alcohol, &c, or for possible protective factors such as participating in STOP-Hypertension-2, residence in rural areas, &c. However, county data in the Swedish Cancer Registry,15 indicate that people living in rural areas have only a slightly lower (<10%) frequency of cancer than average. The presence of cancer was not an obvious factor in patients’ enrolment—eg, an elderly gentleman with prostate cancer or an elderly woman who had had breast cancer were likely to be enrolled if they met the inclusion criteria. When the analyses were done after patients who had a history of
542
Conventional drugs
Calcium antagonists
ACE inhibitors
Total
0·7
0·8 0·9 1·0 1·1 1·2 Standardised incidence ratio
1·3
Figure 1: Standardised incidence ratio for all cancers and 95% CIs
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ARTICLES
Cumulative frequency of cancer
0·12
ACE inhibitor Calcium antagonist Conventional drugs
0·10 0·08 0·06 0·04 0·02 0 0
2 4 6 Time from randomisation (years) Figure 2: Cumulative frequency of cancer by treatment group
cancer at baseline were excluded, the outcome was essentially the same. The overall mortality of the STOP-Hypertension-2 cohort was lower than expected from the general Swedish population. The SMRs were lower during years 1 and 2 than during year 4 and beyond, which could be explained by the exclusion criteria of the trial,11 especially by that of excluding elderly patients with severe or incapacitating illness. However, the overall mortality of STOPHypertension-2 was higher than that of the actively treated patients in our previous STOP-Hypertension study,16 in which the mean follow-up was 2·1 years. STOPHypertension was a placebo-controlled trial, which might have led to the selection of healthier patients than in STOPHypertension-2.11 0·5% of patients in the present study had had parathyroid adenoma before enrolment, which is associated with hypertension.17 The availability of a comprehensive cancer registration in Sweden made it possible to identify nearly all cases of cancer and to compare observed frequency with expected frequency from the general Swedish population, matched for age and sex. However, the cohort was somewhat selected, even though the investigators tried to enroll all elderly people with hypertension cared for in almost 40% of all Swedish health centres. We also did not have information about which antihypertensive drugs these elderly patients had taken before enrolment, but in line with the Swedish guidelines on hypertension,18 they were likely to have had a diuretic, -blocker, or both, which might account for the high compliance in the conventional drugs group. Moreover, median time of follow-up was only 5·3 years, which is important because many cancers take a longer time than this follow-up to develop. However, a randomised trial of longer duration than ours is not easily done, and additionally, after 5 years, there is a large risk that many patients will stop taking their assigned treatment. Follow-up (year)
1 2 3 4 5
Conventional drugs
Calcium antagonists
ACE inhibitors
Without
With
Without With
Without With
90% 85% 84% 83% 80%
5% 8% 10% 10% 13%
63% 53% 48% 43% 39%
54% 43% 38% 35% 32%
23% 30% 33% 34% 38%
26% 33% 35% 36% 39%
Numbers of patients are in parentheses.
Table 7: Patients who received randomly assigned drug class with or without additional antihypertensive drugs among those who attended annual visit
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Many patients in STOP-Hypertension-2 received more than one antihypertensive drug; we do not have information on how these drugs interact with respect to development of cancer. Moreover, many patients took one or more drugs from the other treatment groups as a replacement or a supplement for their assigned drug, which affected the intention-to-treat comparison, and made the interpretation somewhat difficult. Hence we intend later to try to analyse according to actual medication. Findings from several studies1,3–5 show no relation, in populations, between blood pressure and cancer. A report from Scotland19–21 was based on a cohort of 15 411 participants who had their blood pressure measured about 20 years before the study. There were 1392 fatal cancers and investigators noted no relation between cancer risk and diastolic blood pressure. The cancer numbers recorded in the untreated hypertensives of the Glasgow blood pressure clinic did not differ from those expected in a control population matched for age, sex, and smoking habits.20 Likewise, in a cohort of 8006 middle-aged JapaneseAmerican men living in Hawaii, who were examined from 1965 to 1968 and followed up for 20 years,6 there was no association between blood pressure and total frequency of cancer (1155 cases of cancer). In that study, the relative risk of cancer incidence was 1·03 for people with a systolic blood pressure of 160 mm Hg or greater, after adjustment for age, smoking, alcohol, and measures related to obesity. Also, Peeters and colleagues,4,22 in a prospective study, assessed 11 011 women aged 50–65 years at enrolment, in a breast-cancer screening project, who were followed up for 19 years. Hypertension was a significant risk factor for cancer.4 However, when adjustment for confounders was made, there was no significant increased cancer risk; the decline in risk was mainly attributable to the effect of bodymass index.22 The risk was similar in treated and nontreated hypersensitive women. Our findings are thus in line with those from Hawaii,6 Glasgow,19,20 and Utrecht.22 The SIRs for cancer at all sites were very close to unity for all three treatment groups. The cumulative frequency curves were also quite similar, and, moreover, no difference between the treatments could be detected for any specific site. Therefore, our study does not lend support to the hypothesis that any of the three treatment strategies promote cancer, nor to the hypothesis that any of these strategies protect against cancer. Thus, a drug regimen that effectively lowers blood pressure is more important than the risk of cancer. Several groups of antihypertensive drugs have been suspected of being linked to an increased cancer risk: reserpine, diuretics, -blockers, ACE inhibitors, and calcium antagonists. ACE inhibitors have also been shown to protect against cancer.19 The most intense debate on calcium antagonist treatment and cancer started after Pahor and colleagues23,24 reported their findings. 5052 elderly people, aged 71 years or greater, were followed up for a mean of 3·7 years; 451 were treated with calcium antagonists.24 The hazard ratio for cancer associated with calcium antagonists compared with those not on calcium antagonists was 1·72 (95% CI 1·27–2·34). To account for the increased risk, Pahor and colleagues,24 suggested that calcium antagonists could alter apoptosis. A major drawback of that study was that patients were not randomly assigned to the different types of treatment; those treated with calcium antagonists were more ill than the others. Other previous studies (for example refs 19,20,25,26), have not linked calcium antagonist treatment to cancer. However, these studies are susceptible to bias because none was based on a prospective, randomised, controlled design. We followed up over 4000 hypertensive patients for 5 years or more, and more than 1000 for 6 years or more.13
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ARTICLES
Our findings on cancer are in accordance with those of other studies19,20,27–29 that showed no increased risk in patients randomly assigned to treatment with calcium antagonists. However, we could not confirm the protective effect of treatment with ACE inhibitors against some cancers suggested in one study.19 Contributors The subcommittee on cancer included H Anderson, T Ekbom, J Lanke, K Forsén, and T R Möller. L H Lindholm chaired the committee. All other authors were members of the STOP-Hypertension-2 steering committee, which oversaw the study on behalf of The Swedish Hypertension Society, and have commented on the manuscript. A full list of the STOPHypertension-2 Investigators is given in the original study.13
Acknowledgments The study was endorsed by the Swedish Society of Hypertension and supported by grants from Astra (AstraZeneca), Merck Sharp and Dohme, Sandoz (Novartis) and Zeneca (AstraZeneca). We thank B Midberg and G Andersson for computer program development.
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A more comprehensive list of references is available from the corresponding author
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