Effect of Antihypertensive Drug Treatment on Cardiovascular Outcomes in Women and Men

The effectiveness of antihypertensive drug treatment is well established and has been quantified in terms of overall reduction in the relative risk for stroke and other cardiovascular disease events [1, 2]. Risk for cardiovascular events (especially myocardial infarction) differs greatly between men and women, and these differences are not explained by other risk factors [3]. It remains unclear, however, whether the effect of antihypertensive treatment in reducing cardiovascular risk is dependent on sex. In a 1986 review, MacMahon and colleagues [4] stated that event rates, particularly those for fatal events and nonfatal myocardial infarction, were substantially lower in women than in men. The striking benefits of study treatments for the risk of fatal and non-fatal stroke were evident for both men and women. A reduction in total mortality could not be demonstrated for women, but the treatment effect for women was not significantly different from that in men, among whom there was an important and statistically significant reduction in mortality. This comment was based on the results of two trials: the Hypertension Detection and Follow-up Program (HDFP) [5] and the Medical Research Council trial of treatment of mild hypertension (MRC35-64) [6]. In their 1991 analysis of data from these trials plus data from the European Working Party on High Blood Pressure in the Elderly (EWPHE) trial [7] and the Australian therapeutic trial in mild hypertension [8], Anastos and colleagues [9] concluded that the few data that do exist suggest that gender, like race and age, significantly influences the natural course of hypertension and the response to treatment . The data regarding aggressive treatment of white women are equivocal; there is concern that such treatment may actually be harmful. Since these reviews were published, reports of three additional trials of antihypertensive treatment in older hypertensive men and women have appeared in print: the Medical Research Council trial of treatment of hypertension in older adults (MRC 65-74) [10], the Systolic Hypertension in the Elderly Program (SHEP) [11], and the Swedish Trial in Old Patients with Hypertension (STOP) [12]. More recently, other reviewers have stated that antihypertensive medications do not appear to be as effective in women as in men [13] and that when treated, women often achieve less benefit than do men [14]. The INDANA (INdividual Data ANalysis of Antihypertensive intervention trials) project [15] offers the opportunity to provide more evidence on the effects of antihypertensive treatment in women; results are based on individual patient data from all of the randomized, controlled trials mentioned in the preceding paragraphs. The two main objectives of the current study are to quantify the average treatment effect in each sex separately and to determine whether treatment effect differs significantly between women and men. Methods The INDANA project (whose rationale, objectives, and methods are described in detail elsewhere [15]) is a collaboration of representatives from most of the large randomized, controlled trials of antihypertensive drug treatment. Its results are derived from centralized files of the baseline and follow-up data available for all patients enrolled in the trials. The Trials Our report is based on seven trials [5-710-12, 16] (Table 1) in which both men and women were enrolled. The inclusion criteria for the trials in the INDANA project are discussed elsewhere [15]. In summary, the steering group of the project made the following decisions: The data from the Australian trial [8] were not included in the analysis because separate outcomes are not available without censoring bias; the EWPHE trial [7] data were included only for the analysis of mortality end points (separate nonfatal outcomes are not available without censoring bias); and the data from HDFP [5] were considered in a sensitivity analysis (analysis was done with and without these data because of the originality of the trial design, which compared specific antihypertensive care systems with usual care). The data from the Veterans Administration and National Heart, Lung, and Blood Institute feasibility trial [17] are available in the INDANA database but have not yet been submitted to control and extraction procedures. Thus, these data were not used in our analysis. Because this trial has only a small weight in terms of patient-years and observed events, its exclusion is unlikely to change the results presented here. Table 1. Main Characteristics of the Seven Antihypertensive Drug Trials That Enrolled Men and Women* Outcomes According to the INDANA protocol, seven outcomes were analyzed: 1) fatal strokes; 2) fatal and nonfatal strokes, excluding transient ischemic attacks; 3) fatal coronary events [including sudden death, which was defined as unexpected and unexplained death occurring within a maximal interval of 24 hours after symptom onset]; 4) fatal and nonfatal major coronary events (using criteria for major coronary heart disease obtained from patient histories in HDFP) [1]; 5) cardiovascular-related mortality, including death from pulmonary thromboembolism; 6) major cardiovascular events [combining the second, fourth, and fifth outcomes and excluding such minor cardiovascular events as angina pectoris, intermittent claudication, or nonfatal congestive heart failure]; and 7) total mortality. Statistical Analysis Summarized data (number of patients and number of events) were extracted from the INDANA database by sex and by trial according to the intention-to-treat principle. For the group assigned to receive active treatment, the odds ratio compared with controls was estimated by sex for each outcome according to the Peto method [18]. The odds ratio in women was compared with the odds ratio in men by determining whether the ratio was different from 1. This interaction between sex and treatment effect was checked after adjustment for the main baseline risk factors (age, baseline smoking habits, systolic blood pressure, serum cholesterol level, presence of diabetes, and history of stroke or myocardial infarction) in a multivariate logistic model [19] fitted by outcome. For HDFP [5], we censored data at the date of the end of the trial intervention. Two deaths in the trial by Coope and Warrender [16] that were caused by pulmonary embolism were included with cardiovascular-related mortality in our analysis; one early cancer-related death in this trial was included in the analyses of total mortality because of the intention-to-treat principle. To illustrate the difference in the treatment effect between men and women, we applied two graphical approaches to the second and fourth outcomes (all strokes and all coronary events). First, each trial was represented by sex in a treatment-effect graph [20] in which the x-axis is the risk observed in the control group (Rc) and the y-axis is the risk observed in the treated group (Rt) (Figure 1). The odds ratio line, with a slope equal to the odds ratio and a null intercept, indicates the treatment effect by sex. The principal diagonal of the plane Rt x Rc represents the absence of treatment effect (Rt = Rc; odds ratio, 1). The vertical distance between the odds ratio line and the principal diagonal indicates the absolute risk reduction for a given untreated risk. Second, the absolute risk reduction attributable to treatment and its CI were computed by tertiles of individually predicted risk for each sex and were plotted against the average predicted risk in each tertile (Figure 2). The predicted risk was derived from individual scoring built on the results of a multivariate logistic model, including the major risk factors mentioned above. Tertiles were computed to contain similar numbers of events. Figure 1. Effect of antihypertensive treatment on absolute risk for fatal and nonfatal stroke (left) and fatal and nonfatal coronary events (right). Figure 2. Absolute risk reduction of fatal and nonfatal stroke (left) and fatal and nonfatal coronary events (right) by untreated risk level and sex. Meta-analysis computations were done using Easy-MA software [21]; data management and logistic regression were done using SAS software [22]. Results The key features of the seven trials are presented in Table 1. Five of the trials addressed hypertension in older persons, and two studied mild to moderate hypertension in younger persons. The drugs used in the trials were primarily thiazide diuretics, -blockers, or both. The data for these seven trials contained in the INDANA database represent 97.5% of all existing data from all applicable trials in terms of patient-years of follow-up during the active phase of the trials. The combined trial data on risk factors by sex (Table 2) show that, on average, women were older; had a higher baseline cholesterol level, a higher systolic blood pressure, and a lower smoking rate; and less frequently had a history of myocardial infarction. Because these baseline characteristics were similar for the active treatment and control groups, these groups are combined in Table 2. Table 2. Main Cardiovascular Risk Factors by Sex* For each of the seven outcomes, Table 3 and Table 5 shows the number of events in the active treatment and control groups that occurred in men and women, both within each trial and in all trials combined. Table 3. Events by Trial and Sex* Table 5. Table 3. Continued The exclusion of the HDFP data from the analysis changes neither the direction nor the magnitude of the odds ratio for either sex and does not affect the differences between men and women. These data are therefore included in the results presented. In Table 4, the combined odds ratios for all trials are shown separately for men and women; these odds ratios were estimated using a fixed-effects method. In women, odds ratios favoring treatment were statistically significant for strokes (both fatal and either fatal or nonfatal) and major car