Elsevier

The Lancet

Volume 358, Issue 9281, 18 August 2001, Pages 539-544
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(01)05704-XGet rights and content

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 (STOP-Hypertension-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 β-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% Cl 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.

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, β-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, 3, 4, 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 (STOP-Hypertension-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 β-blockers), calcium antagonists, or ACE inhibitors.11, 12, 13

Section snippets

Methods

We have previously reported the study population, design, and main results of STOP-Hypertension-2.11, 12, 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, 1998; no patient was lost.13 Table 1 shows some

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

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

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