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Antihypertensive drug therapy and blood pressure control in men and women: an international perspective

Abstract

Cardiovascular death represents the single largest cause of mortality in women with 70% of deaths attributable to modifiable risk factors, such as hypertension. This analysis aims at evaluating, whether there are gender disparities in antihypertensive drug usage and blood pressure (BP) control. We included 18 017 patients with arterial hypertension from the International Survey Evaluating Microalbuminuria Routinely by Cardiologists in patients with Hypertension (I-SEARCH). The study was conducted between September 2005 and March 2006 in 26 countries, and data on patient demographics, cardiovascular disease and risk factors, BP, and cardiovascular drug treatment were collected. Mean systolic blood pressure (SBP) was 2.1 mm Hg higher in women (150.6±0.35 mm Hg, n=8357/18 017) than in men (148.5±0.35 mm Hg; P<0.0001, n=9526/18 017), whereas no difference in diastolic BP was seen (88.2±0.20 vs 88±0.20 mm Hg; P=0.198). Gender differences in SBP were more pronounced in diabetic as compared with non-diabetic patients (3.5 vs 1.7 mm Hg, n=4272 vs n=13 611; P<0.0001) and became evident at an age 55 years old. Overall BP-control rate was 33.6% in men and 30.6% in women (P<0.0001) and was lower in diabetic as compared with non-diabetic patients. In all, 30% of patients used one, 40% used two and 30% used 3 drugs without gender differences. Response rates to different drug regimens appeared to be similar. However, women received more frequently thiazides and β-blockers, and less frequently ACE-inhibitors as monotherapy. Major efforts are required to improve BP-management, especially in women.

Introduction

Arterial hypertension represents a major therapeutic challenge to health-care systems, affects almost one billion people worldwide and its prevalence is expected to increase from 26.4% in 2000 to 29.2% in 2025.1 Although various pharmacological treatment options exist, BP control is suboptimal and major efforts are necessary to improve patients’ awareness and compliance as well as physicians’ adherence to treatment guidelines.2, 3Whereas recent evidence suggests that the association of blood pressure (BP) and the risk of ischaemic heart disease and stroke is similar in men and women and that BP lowering provides broadly similar mortality benefits, irrespective of the drug regimen used, other data suggest potential gender differences with regard to treatment efficacy.4, 5, 6, 7 Furthermore, women with known cardiovascular disease or cardiovascular risk factors are less likely to receive guideline-recommended drug therapy as compared with men, and BP-control rates appear to be lower in women at a higher age.8, 9, 10, 11 As cardiovascular disease is considered to be the single largest cause of mortality in women with 70% of cardiovascular deaths attributable to modifiable risk factors, such as hypertension, it is important to better understand gender disparities in hypertension management on a worldwide basis to ensure equal standards in treatment for both, men and women.12 This analysis from a large international survey in hypertensive patients aims at analysing, whether there are gender disparities with regard to BP levels, BP control and antihypertensive drugs usage.

Patients and methods

A large international survey was conducted in 26 countries in Europe, North America, Latin America, Middle East and Asia as well as in Turkey, Australia and Morocco between 14 September 2005 and 24 March 2006. In total, 22 282 consecutive patients, aged >18 years with currently treated or newly diagnosed arterial hypertension (seated systolic/diastolic blood pressure (SBP/DBP) >140/90 mm Hg at the office visit) were screened, out of which 21 794 patients gave written informed consent. Patients were enroled by hospital-based cardiologists or in the outpatient cardiology setting. Furthermore, data on patient demographics, cardiovascular risk profile- and co-morbidities, BP, antihypertensive- and cardiovascular drug therapy were collected on a case report form as described elsewhere.13 Institutional review board approval was obtained in each participating centre and the study was conducted in accordance with the ethical principles of the Declaration of Helsinki and the International Conference on Harmonization of Good Clinical Practice (ICH-GCP).

This analysis was conducted in 11 782 patients from Europe (Belgium, Germany, Greece, Italy, Spain, Sweden and Switzerland), 1559 patients from North America (Canada), 2868 patients from Asia (Hong Kong, Indonesia, Korea, Singapore, Taiwan, Thailand and Vietnam) and 1637 patients from Latin America (Colombia, Mexico and Peru) as well as 171 patients from Australia (total=18 017 patients). Patients with Caucasian, Asian or Hispanic ethnicity have been included in this analysis. For 17 883 patients, gender-specific data on demographics, cardiovascular risk factors/co-morbidities as well as SBP and DBP, and drug usage by drug class were available and analysed. SBP and DBP control was defined as BP140 and 90 mm Hg for non-diabetic patients, and 130 and 80 mm Hg for diabetic patients. Left ventricular hypertrophy was determined using 12-lead electrocardiogram and was defined as a Sokolow index of 3.5 mV. Statistical analyses were conducted using SAS version 9.1.3 (SAS Institute, Cary, NC, USA) and STATA version 9.0 (Stata Corporation, College Station, TX, USA). Statistical hypotheses were tested using t-test or χ2 test with a level of significance of 0.05 (two-sided). A linear model was used to estimate the least square means of BP according to gender, adjusted for age, the presence of antihypertensive treatment and ethnicity (Caucasian, Asian and Hispanic) as well as according to nine different age groups (adjusted for presence of antihypertensive treatment, diabetes and ethnicity). A logistic regression analysis was conducted to estimate the prevalence of antihypertensive drug usage according to gender (adjusted for age, treatment, ethnicity and diabetes), and BP-control rate according to gender (adjusted for age, diabetes, ethnicity and antihypertensive treatment) using predictive marginal probabilities. Adjusted continuous variables are depicted as adjusted means (LS mean)±s.e., unadjusted continuous variables as means±s.d. Categorical variables are depicted as percentages with 95% confidence intervals (95% CI).

Results

A total of 9526 (53.3%) men and 8357 (46.7%) women were included in this analysis. Women were about 2 years older than men (64.5 and 62.2 years, respectively; P<0.0001), had a longer duration of hypertension (9.5 vs 8.8 years; P<0.0001) and higher total, low-density lipoprotein and high-density lipoprotein cholesterol levels than men (5.4 vs 5.1 mg per 100ml, P<0.0001; 3.3 vs 3.1 mg per 100ml, P<0.0001; and 1.4 vs 1.3 mg per 100ml, P<0.0001, respectively). Prevalence of diabetes and a family history of myocardial infarction and coronary artery disease were similar in both populations, whereas cardiovascular co-morbidities, such as coronary artery disease, atrial fibrillation, left ventricular hypertrophy, ischaemic stroke, congestive heart failure and peripheral artery disease were seen more frequently in men. For details, see Table 1. Overall, 93.5% of hypertensive patients received pharmacological treatment (93.5% (95%CI 92.93–93.96%) of men (n=8723/9526) and 93.4% (92.86–93.95%) of women (n=7739/8357); P=0.925).

Table 1 Patient characteristics (means (s.e.) or percentages (95% CI))

Systolic and diastolic blood pressure in men and women with or without diabetes

Mean SBP was 148.5±0. 35 mm Hg in men and 150.6±0.35 mm Hg in women in the overall population (Δ 2.1 mm Hg; P<0.0001). In patients without diabetes mellitus, mean SBP was 148.6±0.40 mm Hg in men and 150.3±0.40 mm Hg in women (Δ 1.7 mm Hg; P<0.0001). Men with diabetes mellitus had a mean SBP of 147.7±0.88 mm Hg, whereas SBP in women was 151.2±0.88 mm Hg (Δ 3.5 mm Hg, P<0.0001).

In the overall population, mean DBP was 88±0.20 mm Hg in men and 88.2±0.20 mm Hg in women (Δ 0.2 mm Hg, P=0.198). In patients without diabetes, DBP was 88.6±0.23 mm Hg in men and 88.8±0.23 in women (Δ 0.2 mm Hg, P=0.336), whereas in patients with diabetes mellitus, DBP was 85.1±0.51 mm Hg in men and 85.4±0.51 in women (Δ 0.3 mm Hg, P=0.477). For details see Table 2. Similar results were obtained after additionally adjusting for waist circumference (data not shown).

Table 2 Systolic and diastolic blood pressure by gender in subgroups (mean (s.e.), adjusted for age, treatment and ethnicity)

SBP and DBP in men and women by age group

Systolic blood pressure was 148.3±2. 79 mm Hg at the age of 35–39 years in men and was not significantly higher at higher age (149.1±1.15 mm Hg at the age of 75 years). In contrast, in women, BP was 148.2±2.92 mm Hg at the age of 35–39 years and 153.7±1.14 mm Hg at the age of 75 years. A significant gender difference in SBP was observed at the age of 55 years, in which SBP in women was about 2 mm Hg higher as compared with men (P<0.05 for all age groups 55 years). DBP was lower at higher age (93.3±1.88 mm Hg in men and 93.1±1.97 mm Hg in women at the age of 35–39 years and 82.9±0.68 mm Hg in men and 83.8±0.67 mm Hg in women at the age of 75 years, P=0.031). At the age of 45–49 and 50–54 years DBP was significantly higher in men as compared with women (P=0.021 and P=0.017, respectively). For details, see Figure 1.

Figure 1
figure1

(a) Systolic blood pressure (SBP) levels in men and women by age group (mm Hg; LS means, adjusted for treatment, diabetes, ethnicity; #P<0.05). (b) Diastolic blood pressure (DBP) in men and women by age group (mm Hg; LS means, adjusted for treatment, diabetes and ethnicity; #P<0.05).

Pulse pressure in men and women by age group

The pulse pressure was 55±2.00 mm Hg in men and 55.1±2.10 mm Hg in women at the age of 35–39 years (P=0.9854), compared with 66.3±0.97 mm Hg in men and 69.9±0.96 mm Hg in women (P<0.0001) at the age of 75 years. The gender difference became statistically significant at an age higher than 45–49 years. For details, see Figure 2.

Figure 2
figure2

Pulse pressure in men and women by age group (mm Hg, LS means, adjusted for treatment, diabetes and ethnicity; #P<0.05).

Blood pressure-control rates in men and women with or without diabetes mellitus

Systolic blood pressure-control rates

In the overall population, SBP control was achieved in 37.7%. (36.69–38.75%) of men and 34% (32.92–35.06%) of women (P<0.0001). In patients without diabetes, 42.3% (41.12–43.51%) of men and 39.2% (37.91–40.42%) of women achieved SBP control (P=0.0004), whereas SBP control was achieved in only 22.8% (21.08–24.65%) of diabetic men and 18.8% (17.03–20.64%) of diabetic women (P=0.0018). For details, see Figure 3.

Figure 3
figure3

Blood pressure (BP)-control rates in men and women in subgroups (percentage, adjusted for age, treatment and ethnicity; Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure; #P<0.05 for gender differences).

Diastolic blood pressure-control rates

Diastolic blood pressure control was 63.6% (62.61–64. 66%) in the overall population in men as compared with 64.1% (63.01–65.19%) in women (P=0.545). In patients without diabetes, DBP was controlled in 70.3% (CI 69.31–71.38%) of men and 70% (CI 68.84–71.23%) of women (P=0.800), whereas in only 44.3% (42.19–46.47%) of diabetic men and 44.5% (42.17–46.86%) of diabetic women, DBP was controlled (P=0.908). For details, see Figure 3.

Overall blood pressure-control rates

Systolic and diastolic blood pressure-control rate in the overall population was achieved in 33.6% (32.56–34. 57%) of men and 30.6% (29.55–31.64%) of women (P<0.0001). In patients without diabetes, SBP/DBP-control rate was 38.4% (37.22–39.62%) in men and 34.9% (33.67–36.15%) in women (P<0.0001), whereas in patients with diabetes, only 19% (17.37–20.70%) of men and 16.1% (95% CI 14.45;17.84) of women achieved BP control (P=0.016). For details, see Figure 3.

Number of antihypertensive drugs used in men and women

In the overall population, 30.1% (29.12–31.04%) of men and 30.9% (29.84–31.90%) of women used one drug, 40% (38.95–41.00%) of men and 39.4% (38.32–40.50%) of women used two drugs, and 29.9% (28.98–30.90%) of men and 29.7% (28.70–30.74%) of women used three or more drugs (P=0.403 for comparison of three groups). With regard to the mean number of drugs used, no major gender disparities were observed in patients with either controlled or uncontrolled BP (2.05 drugs in men and 2.01 women in controlled patients (P=0.063); 2.11 drugs in men and 2.09 in women in uncontrolled patients (P=0.248)). In patients without diabetes, the average number of drugs used was 2.02 in men and 1.99 in women (P=0.155), whereas 2.31 drugs were used in diabetic men and 2.29 drugs in diabetic women (P=0.402). Significantly more drugs were used in diabetic vs non-diabetic men and women (P<0.0001 for both). For details, see Figure 4.

Figure 4
figure4

(a) Proportion of men and women using one or more antihypertensive drugs (percentage with 95% CI, adjusted for age, treatment, diabetes and ethnicity; P=0.403 for all groups men vs women). (b) Number of drugs used by gender in subgroups (LS means with P-values, adjusted for age, treatment and ethnicity; BP, blood pressure).

Classes of antihypertensive treatments used in men and women

Drug classes used in men and women with antihypertensive monotherapy

No disparities between men and women were seen for the usage of loop diuretics (0.7% (0.43–1.10%) vs 0.8% (0.54–1.33%), P=0.482), angiotensin receptor blockers (ARBs; 24.2% (22.51–25.90%) vs 21.9% (20.21–23.65%), P=0.064), calcium channel blockers (CCB) (15.1% (13.77–16.65%) vs 15.6% (14.11–17.18%), P=0.689), and α receptor blockers (0.7% (0.46–1.16%) vs 0.4% (0.21–0.75%), P=0.100). However, more women were treated with thiazide diuretics (2.4% (1.84–3.05%) vs 4.4% (3.57–5.31%), P<0.0001) and β-blockers (27.6% (25.75–29.49%) vs 24.2% (22.53–25.95%), but were less likely to receive angiotensin converting enzyme inhibitors (ACE-I; 29.8% (27.99–31.64%) vs 26.3% (24.47–28.14%), P=0.007). For details, see Figure 5a.

Figure 5
figure5

(a) Drug classes used in patients with monotherapy (percentage with 95% CI, adjusted for age, diabetes and ethnicity; Abbreviations: ACEs, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers, CCBs, calcium channel blockers; #P<0.05 for gender differences). (b) Dual-combination therapies used according to guideline recommendations in patients with dual therapy (percentage with 95%CI, adjusted for age, diabetes and ethnicity; P<0.05 for gender differences).

Drug classes used in men and women with antihypertensive dual therapy

Significantly more women received thiazide-containing dual therapies. Thiazides+CCBs were administered to 2.1%. (1.69–2.68%) of men and 3.2% (2.64–3.96%) of women (P=0.003), thiazides+ACE-Is to 9.3% (8.39–10.40%) of men and 11.1% (9.97–12.28%) of women (P=0.025) and thiazides+ARBs to 10.3% (9.29–11.41%) of men and 12.6% (11.38–13.85%) of women (P=0.004). No significant gender differences were seen for the combination of CCBs+β-blockers (8.6% (7.70–9.64%) in men and 8.7% (7.75–9.83%) in women, P=0.870), and CCBs+ACE-Is (10.8% (9.78–11.91%) in men and 9.7% (8.71–10.89%) in women, P=0.175). However, CCBs+ARBs were prescribed less frequently in women (9.8% (8.80–10.85%) in men and 8.2% (7.29–9.31%) in women, P=0.035). Other non-guideline-recommended dual therapy was used in 46.3% (44.54–47.99%) of men and 43.3% (41.51–45.16%) of women (P=0.022): β-blockers+ACE-Is were used in 22% (20.61–23.49%) of men and 15.2% (13.97–16.62%) of women (P<0.0001), followed by β-blockers+ARBs (11.2% (10.13–12.31%) for men and 10.9% (9.78–12.08%) for women). Other non-guideline-recommended therapies were thiazides+β-blockers and loop diuretics+ACE-Is or ARBs, in which no gender differences were observed. Drug combinations used in <1% are not depicted. For details, see Figure 5b.

Blood pressure-control rates in patients receiving guideline-recommended dual therapies

The control rate was 44.1% (33.04–55.88%) in men and 39% (30.07–48.68%) in women using thiazides+CCBs (P=0.50), and 41.7% (36.21–47.39%) in men and 31.4% (26.51–36.81%) in women using thiazides+ACE-Is (P=0.008). BP was controlled in 39% (33.86–44.33) of men and 40.9% (35.78–46.21%) of women, treated with thiazides+ARBs (P=0.607), and 39.2% (33.68–44.98%) in men and 34.5% (29.08–40.42%) in women treated with CCBs+β-blockers (P=0.260). CCBs+ACE-Is were associated with a BP-control rate of 31.2% (26.38–36.54%) in men and 28% (22.92–33.77%) women (P=0.389), whereas CCBs+ARBs with a control rate of 33.2% (28.20–38.69%) in men and 34.1% (28.35–40.38%) in women (P=0.833). For details, see Figure 6.

Figure 6
figure6

Blood pressure (BP) control rates for guideline-recommended dual therapies (percentage with 95% CI, adjusted for age, diabetes and ethnicity; for abbreviations see Figure 5a; #P<0.05 for gender differences).

Discussion

This analysis provides insights from a recent, large international study in men and woman with currently treated or newly diagnosed arterial hypertension. Earlier data from NHANES (1999–2004) has shown significant gender disparities in BP levels, in which SBP was about 4 mm Hg higher in women, but DBP was 3.5 mm Hg lower than in men, resulting in a trend towards a lower BP-control rate in women (50.8% men vs 55.9% women uncontrolled).14 These findings are supported by data from the Framingham cohort, in which control rates in women >60 years old were markedly lower than in men.11 However, another analysis from a large sample of patients, including five European countries, suggested higher BP-control rates in women as compared with men, which differed from country to country.15

Our data from an international sample of pharmacologically treated patients shows a significantly higher mean SBP ( 2.1 mm Hg), but no difference in mean DBP ( 0.2 mm Hg) in women as compared with men, resulting in a SBP-control rate of 37.7% in men, but only 34% in women. The overall BP-control rate was generally low, and significantly lower in women (30.6%) as compared with men (33.6%), driven by the observed disparity in SBP. When looking at patients with concomitant diabetes mellitus, overall BP-control rate was not only expectedly lower, but gender disparity in SBP levels was more pronounced ( 3.5 mm Hg); data that have been described earlier by Kjeldsen et al.12 in a large survey conducted in Europe. Although the absolute difference in BP-control rate seems somewhat small, the detected difference in mean SBP of 2.1 mm Hg (3.5 mm Hg in the diabetic population) appears to be clinically meaningful, because it has been shown that a decrease in mean SBP of 2 mm Hg is associated with a 7% reduction in ischaemic heart disease-mortality and a 10% reduction in stroke-mortality.16 Furthermore, the potential health burden of the observed gender disparity in SBP levels at an age 55 years is even more concerning in light of the fact that the prevalence of hypertension appears to be higher in elderly women than men.17 Our data also shows significant gender disparities with regard to pulse pressure, occurring already at the age of 45 years, about 10 years earlier than the observed differences in SBP. This finding highlights the importance of using pulse pressure at an early stage of hypertension as a risk stratification tool, because pulse pressure—as opposed to SBP and DBP alone—has been shown to be a better predictor for adverse outcomes, especially in women.18

Data from previous large hypertension trials have shown that most patients need combination therapy to achieve sufficient BP control. However, in only 50% of trials, patients actually reached this goal.19 Recent data from NHANES (1999–2004) shows that approximately 30% of patients were treated with two drugs and 15% of patients with three or more antihypertensive drugs, and no gender differences could be detected;20 findings that were also confirmed by a recent cross-sectional US-survey in about 12 000 patients treated in the primary care setting.21 Our data do not show gender disparities in the usage of antihypertensive drug combination therapy and indicates, that physicians obviously apply international treatment guidelines equally well to men and women, irrespective of the presence or absence of controlled BP. Nevertheless, gender disparities with regard to SBP levels and BP control are more pronounced in diabetics. Our data further shows that more antihypertensive drugs are prescribed to both, diabetic men and women.

Another potential explanation for the observed gender disparities in BP control could be a preferential prescription of certain antihypertensive drug classes in men or women. Our analysis shows no major differences in the prescription of certain drug classes. However, significantly less ACE-Is as monotherapy, but more thiazides (monotherapy and combination therapy) and β-blockers (monotherapy) were prescribed in women, data that have been described by other groups.11, 20, 21, 22 These findings might be partly explained by the threefold increased risk of women to develop ACE-inhibitor-related cough or potential beneficial effects of thiazides on bone density in postmenopausal women.23, 24 Furthermore, safety concerns in prescribing ACEs to women of childbearing age might have contributed to the lower number of ACE-inhibitor prescriptions. However, only a small proportion of women aging 18–40 years were included (2.5%), and about two-thirds of women were >60 years old. According to our data, a high proportion of patients (>40%) used non-guideline-recommended dual-combination therapy, the majority β-blockers together with RAS-blocking agents. It can only be speculated, why β-blockers and ACE-Is were the most frequently prescribed combination therapy overall, and why there was a significantly higher prescription rate of this combination in men as compared with women, whereas no such gender difference could be observed for β-blockers and ARBs. However, 28% of men but only 15.2% of women had coronary artery disease, in which β-blockers and ACE-Is are a recommended and inexpensive standard therapy. Furthermore, men had more frequently congestive heart failure, left ventricular hypertrophy and a history of atrial fibrillation, all of which can be effectively treated with β-blockers and ACE-Is.

Our study did not analyse, whether antihypertensive drugs were dosed differently in men and women. However, it has been shown, that women seem to be more prone to develop side effects and might metabolise antihypertensive agents differently, factors that could also have an effect on drug dosing.25 Thus, drug doses might have been lower in women. Furthermore, gender differences in drug response (ability to control BP) might contribute to the lower BP-control rates observed in women. Our data indicate broadly similar BP-control levels in all guideline-recommended dual therapies and supports findings from a recent large analysis in more than 100 000 patients from prospective clinical trials, in which BP reduction appeared to be comparable in men and women, irrespective of drug classes used.6, 26 However, our data have to be interpreted with caution because of the observational design of our study, which did not take into consideration gender differences in patient profiles and BP levels before initiation of antihypertensive treatment in the different patient groups.

In summary, our data from a recent worldwide study in pharmacologically treated hypertensive patients reveal a poorer BP control and a higher pulse pressure in women as compared with men. These differences were because of higher SBP levels in women at the age of 55 years. Gender disparities with regard to SBP levels appeared to be more pronounced in diabetics, and differences in pulse pressure were detected about 10 years earlier than disparities in SBP. Combination therapy was prescribed equally to both men and women and drug response to guideline-recommended dual therapy appeared to be similar, but gender disparities with regard to antihypertensive drug class prescription, drug dosage or drug response could represent potential explanations for our findings. Generally, BP-control rates were low, because only one-third of patients achieved the BP goal. Major efforts are required to improve BP control in both, men and women.

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Acknowledgements

This study was funded by a research grant of Sanofi Aventis. MT, MB, MV and BVK received support from Sanofi Aventis. We thank Sam Zhong for the statistical support provided. HRN and MB are supported by a grant of the Deutsche Forschungsgemeinschaft (KFO 196: NE 1460/1-1 and Zentralprojekt).

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Correspondence to H-R Neuberger.

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Thoenes, M., Neuberger, HR., Volpe, M. et al. Antihypertensive drug therapy and blood pressure control in men and women: an international perspective. J Hum Hypertens 24, 336–344 (2010). https://doi.org/10.1038/jhh.2009.76

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Keywords

  • blood pressure
  • gender
  • drug usage

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