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Closing the Gap: Treating Hypertension in Women

Samad, Zainab MD; Wang, Tracy Y. MD, MS; Frazier, Camille G. MD; Shah, Svati H. MD, MHS; Dolor, Rowena J. MD, MHS; Newby, L Kristin MD, MHS

doi: 10.1097/CRD.0b013e31817f9350
Review Article
Free

Hypertension is a common and readily modifiable risk factor for cardiovascular and cerebrovascular disease. Despite extensive clinical trial results and efforts to increase public awareness, it remains inadequately controlled in the general population. Women are particularly vulnerable. Recent data indicate both a growing prevalence of hypertension, particularly in the postmenopausal and African American populations, and significantly lower rates of adequate blood pressure control relative to men. Patient sex has an important influence on the nature of the disease, its management, and outcomes. This review will focus on sex-specific factors that contribute to hypertension in women, and current patterns and efficacy of treatment. In addition, we will highlight evidence-based options for antihypertensive treatment in women.

From the Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.

Correspondence: L. Kristin Newby, Duke Clinical Research Institute, Duke University Medical Center, P.O. Box 17969, Durham, NC 27715. E-mail: newby001@mc.duke.edu.

Fifty million Americans and approximately 1 billion individuals worldwide are affected by hypertension.1 The prevalence of hypertension in the general population continues to increase. In 2003–2004, 29.6% of participants in the National Health and Nutrition Examination Survey had hypertension, a slight increase from 1999 to 2000. Overall, women and men had a similar prevalence of hypertension (28.2% for women vs. 29.8% for men),2 but after menopause, women with hypertension significantly outnumber hypertensive men.2 The prevalence of hypertension increases steadily with age and is higher among blacks than whites across both sexes and all ages. Data from the Framingham Heart Study suggest that the residual lifetime risk of developing hypertension in 55-year-old normotensive individuals is 90%. This risk estimate is similar for women and men.3

Blood pressure is continuously, consistently, and independently related to the risk of cardiovascular disease events. In addition, the higher the blood pressure, the greater the risk of end organ damage; that is, myocardial infarction (MI), heart failure, stroke, and kidney disease.4 According to a recent analysis by the Women's Health Initiative (WHI) investigators, even prehypertension in women is associated with an increased risk of cardiovascular death [hazard ratio (HR), 1.58; 95% confidence interval (CI), 1.12–2.21], MI (HR, 1.76; 95% CI, 1.40–2.22), stroke (HR, 1.93; 95% CI, 1.49–2.50), and hospitalized heart failure (HR, 1.36; 95% CI, 1.05–1.77).5

Fortunately, antihypertensive therapy has been associated with statistically significant reductions in the incidence of stroke, MI, and heart failure.6 Accomplishing a sustained 12-mm Hg reduction in systolic blood pressure (SBP) over 10 years among patients with stage 1 hypertension will prevent 1 death for every 11 patients treated. The number needed to treat (NNT) is further reduced with increasing levels of baseline blood pressure and the presence of cardiovascular disease or target organ damage.1,7

Despite overwhelming evidence for the benefits of lowering blood pressure, the awareness, treatment, and control of hypertension remains dismal. In the 1999–2004 National Health and Nutrition Examination Survey, about 25% of hypertensive individuals were unaware of their diagnosis, 35% were untreated, and, at the time of blood pressure measurement, 63% did not have adequately controlled blood pressures. Women, the elderly, and Mexican Americans had the lowest rates of control.2 Elderly women also represent a growing subset of the population with a higher risk of hypertension-related cardiovascular disease who are receiving inadequate treatment.8

Although elevated blood pressure is a major public health problem in both sexes, most of our knowledge and rationale for treatment comes from studies conducted predominantly in men.9–11 This article will focus on what is known about the influences of sex on the natural history and pathophysiology of hypertension, selection of antihypertensive agents, and response to treatment.

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HYPERTENSION IN WOMEN

Although hypertension is less prevalent in premenopausal women than in age-matched men, a shift occurs after menopause such that by the sixth decade of life the condition is more common in women than in men.2 Blood pressure does not increase abruptly at menopause, however, and it may take 5–20 years for hypertension to develop.2 Compared with hypertensive men, women with high blood pressure are more likely to develop left ventricular hypertrophy (LVH), diastolic dysfunction, and a steep age-related increase in arterial stiffness.12 In addition, hypertension plays a greater role in the development of heart failure in women than in men.13

The pathophysiology of essential hypertension in men and women remains under investigation and the mechanisms responsible for the sexual dimorphism in blood pressure control are unclear. Sex-specific hemodynamic characteristics and the influence of sex hormones may account for some of the differences.

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Hemodynamic Characteristics in Hypertensive Women

Women have lower brachial SBP, diastolic blood pressure (DBP), and mean blood pressure than men. Under age 40, women have lower brachial pulse pressure than men, but this trend reverses in those aged 55 years and older.14 Various anatomic and physiologic differences may contribute to these differences between men and women. The comparatively smaller stature in women imposes a shorter total length of the arterial tree; this causes pressure wave reflections to reach the central aorta in early to mid systole, amplifying the peak systolic pressure. A higher heart rate in women leads to shorter diastolic periods, a more rapid fall-off in diastolic pressure, and significantly lower aortic DBP compared with men. Further, although no abrupt increase in blood pressure occurs at menopause, the loss of estrogen is associated with a significant increase in the intrinsic rigidity of the arterial wall due to elastin fragmentation and collagen accumulation. This, in turn, leads to an increase in the pulse wave velocity, resulting in more rapid increases in brachial systolic and central SBP in aging women than in men. The greater rise in SBP after menopause results in a higher pulse pressure in older women.15

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Role of Sex Hormones

The effects of sex hormones on renal sodium handling or vascular resistance may also explain differences in blood pressure control between men and women. Estrogen maintains normal endothelial function through stimulation of nitric oxide production,16 induces structural and functional alterations in the arterial wall that reduce vascular stiffness,16 and reduces sympathetic nervous system activity.17 Female sex hormones may also protect against salt-induced increases in blood pressure; indeed, Schulman et al18 found that the prevalence of salt sensitivity increased from 22.5% to 52.5% after ovariectomy (P = 0.01). Sex hormones may also influence blood pressure regulation through their effects on the renin angiotensin system (RAS). Evidence suggests that androgens increase blood pressure through stimulation of the RAS,19 whereas ovarian hormones have the opposite effect by reducing plasma renin and angiotensin-converting enzyme (ACE) activity.16

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RISK FACTORS FOR HYPERTENSION IN WOMEN

Oral Contraceptive Use

Oral contraceptive use is associated with an increase in blood pressure of about 2–8 mm Hg from baseline.20,21 Among the women in the prospective Nurses' Health Study II, current users of oral contraceptives had a significantly increased risk [relative risk (RR), 1.8; 95% CI, 1.5–2.3] of hypertension compared with never-users after adjustment for age, physical activity, family history of hypertension, body mass index, alcohol intake, cigarette smoking, and ethnicity.22 However, even among current oral contraceptive users, the incidence of hypertension attributed to oral contraceptive use is only 41.5 per 10,000 person-years. This risk decreased quickly with the cessation of oral contraceptive use. In terms of duration of use, compared with nonusers, women with 6 or more years of oral contraceptive use seemed to be at the highest risk of developing hypertension (RR, 2.1; 95% CI, 1.6–2.7). In addition, when compared with nonusers, women who used monophasic combination pills had a higher increase in risk of hypertension (RR, 2.3; 95% CI, 1.7–3.0) than those who used biphasic (RR, 1.7; 95% CI, 1.2–2.4) or triphasic (RR, 1.9; 95% CI, 0.9–4.1) combination pills.22

According to recommendations of the World Health Organization, oral contraceptive use is only absolutely contraindicated if the blood pressure is >160/100 mm Hg.23 However, physicians should be cautious in prescribing oral contraceptives for patients with even mild elevations of blood pressure because of the increased risk of stroke and MI among oral contraceptive users with hypertension.23,24

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Hormone-Replacement Therapy

Studies of the effects on blood pressure of menopausal hormone therapy have yielded conflicting results. In the WHI, women using hormone replacement therapy had a lower prevalence of hypertension (35%) than never users (41%), but users tended to be younger and thinner. After adjustment for these and other potentially confounding variables, the current use of hormone replacement therapy was associated with a 25% increase in the risk of hypertension compared with never use or past use.25 In a randomized substudy of the WHI, use of conjugated equine estrogen and medroxyprogesterone acetate was associated with a 1 mm Hg increase from baseline in SBP.25 Other studies, however, have found smaller26 or no increases27 in blood pressure associated with menopausal hormone therapy.

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Nutritional Factors

Data from 2 large prospective studies, the Nurses' Health Study I and II, have been used to examine the role of nutrition in the etiology of hypertension in women.28–30 In these studies, dietary calcium (RR, 0.78; 95% CI, 0.69–0.88) and magnesium (RR, 0.77; 95% CI, 0.67–0.88) were independently and significantly inversely associated with hypertension. Body mass index and daily intake of alcohol were positively and strongly associated with increased risk of hypertension. No independent associations with hypertension were observed for intake of potassium, fiber, or saturated and polyunsaturated fatty acids.28 In younger women (aged 27–44 years), a higher total folate intake was associated with decreased risk of incident hypertension (RR, 0.54; 95% CI, 0.45–0.66).29 Although habitual coffee consumption is not associated with increased risk of hypertension, consumption of sugared or diet cola is associated with it.31

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RISK REDUCTION

There is a relative paucity of data regarding many important aspects of hypertension treatment in women. The existing data point toward important influences of sex on the natural history of hypertension, selection of antihypertensive agents, and the response to treatment. The Individual Data Analysis of Antihypertensive Interventions Trials Group examined the benefit of hypertension treatment among women by pooling data for female participants in 7 randomized controlled trials. Results showed a significant 29% risk reduction in fatal cerebrovascular events (95% CI, 4–47%; P = 0.03), a 38% risk reduction in nonfatal and fatal cerebrovascular events (95% CI, 27–48%; P < 0.001), and a 26% risk reduction in overall cardiovascular events (95% CI, 17–34%; P < 0.001) among women.32 Another systematic review of 11 randomized controlled trials pooling data from a total of 23,000 women sought to address the question of whether the benefit of hypertension treatment varied with age or race.33 The results demonstrated a significant reduction in the relative risk of cardiovascular events with antihypertensive treatment in women across all subgroups of age and race examined. Among treated African American women, there was a 53% reduction in fatal and nonfatal cerebrovascular events (95% CI, 29–69%; 5-year NNT = 39) and 45% reduction in fatal and nonfatal cardiovascular events (95% CI, 18–63%; 5-year NNT = 21).33 In women aged 55 years and older (90% white), there was a 38% reduction in fatal and nonfatal cerebrovascular events (95% CI, 27–47%; 5-year NNT = 78) and a 25% reduction in fatal and nonfatal cardiovascular events (95% CI, 17–33%; 5-year NNT = 58).33 Despite similar risk reduction in cerebrovascular and cardiovascular outcomes among women aged 30–54 years compared with women older than 55 years, the 5-year NNTs were 3–4 times higher among the younger women, demonstrating their lower cardiovascular risk.33–36 It is plausible that the significant relative risk reduction seen in cerebrovascular and cardiovascular events among women aged 30–54 years may have been due in part to results among African American women, who are at higher risk compared with age-matched white women and who comprised 21% of the younger subgroup of women.33,37

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PATTERNS OF TREATMENT AND CONTROL

Findings from several studies highlight the imperative for improving treatment of hypertension among women. For example, patterns of hypertension prevalence, treatment, and control were studied in the original Framingham Heart Study cohort, which included 2979 women among the 5296 participants. As anticipated, the prevalence of hypertension increased with age: 27.3% among participants younger than 60 years of age, 63% in those aged 60–79 years, and 74% in those aged 80 years or older. In this cohort, 68.9% of hypertensive women were receiving treatment, of whom 60% were on 1 antihypertensive agent, 30% were on 2, and 10% were on 3 or more agents. Use of thiazide diuretics increased with age, with women being the predominant users. The most remarkable finding of this analysis was that only 32.4% of treated men and women had controlled blood pressures (<140/90 mm Hg), a figure which declined with advancing age, mainly due to the significantly lower rates of control among older women than older men (Fig. 1). 38

FIGURE 1.

FIGURE 1.

Similar findings were observed in the WHI.39 In this study, although older hypertensive women (aged 70–79 years) were as likely to be on treatment (63.2%) as younger women (64.2%), a substantially smaller percentage of older women had controlled blood pressures (29.3% vs. 41.3% for younger women). The most commonly used monotherapy drug class was calcium channel blockers (CCBs), used in 16.4% of treated hypertensive subjects, and the least common drug class was β-blockers, used in 9.2%. Diuretics and ACE inhibitors as monotherapy were used in approximately 14.5% of treated hypertensive subjects, while 38.1% were using combination therapy (≥2 drug classes).39

The prevalence and treatment of hypertension were also examined in 15,904 patients presenting with acute coronary syndrome who were randomized in the 2 Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Postacute Coronary Syndromes (SYMPHONY) trials.40 In the US cohort, of which 29% were women, hypertension was more prevalent among women than men within every age decile. Hypertensive women were treated with a greater number of antihypertensive agents than were men, but the median SBP at presentation was 3 mm Hg higher among women than among men. Hypertensive women more often received CCBs (35% vs. 30% for men) and diuretics (33% vs. 19%) and less often received β-blockers (51% vs. 57%). Of note, 15% of women noted to be hypertensive upon presentation were not taking antihypertensive medications.40

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OPTIONS FOR TREATMENT OF HYPERTENSION

Lifestyle Modification

Major lifestyle modifications shown to lower blood pressure include weight reduction,41,42 dietary sodium reduction,43 increased physical activity,44,45 and reduction of alcohol consumption among heavy drinkers.46 In addition to supplementing antihypertensive drug efficacy, these changes decrease cardiovascular risk.

The updated (2007) American Heart Association (AHA) guidelines for prevention of heart disease in women47 and the updated (2006) AHA/American College of Cardiology guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease48 both recommend physical activity of moderate intensity for a minimum of 30 minutes on most, and preferably all, days of the week. Both guidelines also recommend a diet rich in fruits, vegetables, and whole-grain high-fiber foods; consumption of fish rich in fish oil at least twice a week; limitation of daily intake of saturated fat to <10% of total consumption, and if possible to <7%; and limitation of cholesterol to <300 mg per day, alcohol intake to no more than 1 drink per day, and sodium intake to <2.3 g per day (approximately 1 tsp of salt).47,48

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Pharmacologic Therapy

Women generally respond to antihypertensive agents similarly to men. When choosing the appropriate agent, however, certain sex-specific factors are important to consider; for example, certain agents are inappropriate for use in pregnancy and some drug-related adverse effects are more common in women than in men. Clinical guidelines1,47 for antihypertensive agent choice are summarized in Table 1 and the use of the most common antihypertensive drug classes in women is discussed in more detail below. Note, however, that the majority of hypertensive patients (more than two-thirds) will require 2 or more antihypertensive agents selected from different classes to control blood pressure.1

TABLE 1

TABLE 1

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Diuretics

Thiazide diuretics, which lower blood pressure by reducing extracellular volume and peripheral vascular resistance, have formed the cornerstone of antihypertensive therapy in many cardiovascular outcome trials. A meta-analysis of these trials that included a total of 192,478 patients found that low-dose diuretics were the most effective first-line antihypertensive treatment for prevention of cardiovascular morbidity and mortality.49 This finding was confirmed by the results of the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT),50 which included 47% women, and showed that chlorthalidone-based treatment was similar to or superior to lisinopril-based treatment or amlodipine-based treatment in preventing the primary end point of combined cardiovascular events as well as individual components. At study end, however, 63% of participants were on an antihypertensive regimen that included 2 or more drugs, potentially complicating comparisons between individual drugs. Based on the available data from a meta-analysis of placebo-controlled trials evaluating low-dose diuretics, major health outcomes for chlorthalidone, and other thiazide-like drugs seem to be similar.51

According to the Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the 2007 AHA guidelines for cardiovascular disease prevention in women, thiazide-type diuretics should be part of the treatment regimen for most patients unless contraindicated or if there are compelling indications for other agents.1,47 The 2007 AHA guidelines further note that initial drug treatment for high-risk women (eg, those with coronary disease, chronic kidney disease, or the presence of 1 or more cardiovascular disease risk factors in addition to hypertension) should be with a β blocker and/or ACE inhibitor or angiotensin receptor blockers (ARB), with the addition of a diuretic as needed to achieve blood pressure control.47 In postmenopausal women, thiazide diuretics seem to be associated with reduced risk of bone loss and hip fracture.52,53

Despite evidence from clinical trials and recommendations by consensus groups, diuretics remain underused, most likely due to concerns about electrolyte and metabolic derangement. In a recent analysis of the ALLHAT data, the risk of developing fasting glucose levels >125 mg/dL was modestly higher among patients treated with chlorthalidone compared with amlodipine or lisinopril users.54 However, there is no conclusive evidence that this diuretic-associated increase in blood glucose levels increases the rate of clinical events.55 In hypertensive patients with hyperlipidemia or diabetes, cardiovascular morbidity and mortality are still reduced with diuretic use. Furthermore, concerns about hypokalemia-induced arrhythmias, although not ill-founded, are, in the most part, overstated.56

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β-Blockers

β-blockers exert their blood pressure-lowering effect by blocking the actions of catecholamines on β-adrenergic sites, thus decreasing vascular tone and cardiac output. They also inhibit the release of renin. In a meta-analysis of 13 randomized controlled trials, Lindholm et al57 questioned the use of β-blockers as first-line agents in the management of hypertension. Their argument was based primarily on the increased risk of stroke, which was 16% higher for users of β-blockers than for users of any other drug class (95% CI, 4–30%). This finding was confirmed in a systematic review by Khan and McAlister,58 who also showed that this excess risk associated with β-blocker use was driven largely by data from trials that enrolled older patients. Notably, younger patients randomly assigned to β-blockers exhibited similar rates of cardiovascular death, MI, or stroke as those assigned to other antihypertensive agents, and β-blockers were more efficacious than placebo in these patients. Among patients with stable angina pectoris, acute coronary syndrome, or heart failure, JNC 7 recommended that β-blockers be one of the first-line agents to control blood pressure.1 This recommendation is based on data from several trials that demonstrated a mortality benefit with β-blockers.59–63 Moreover, the AHA guidelines for cardiovascular disease prevention in women state that initial drug treatment for high-risk women should be with a β blocker and/or ACE inhibitor or ARB, with the addition of a diuretic as needed to achieve blood pressure control.47 Importantly, β-blockers can be used safely in pregnancy.1

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Angiotensin-Converting Enzyme Inhibitors

ACE inhibitors decrease the production of angiotensin II, a potent vasoconstrictor, thereby lowering SBP, DBP, and mean arterial blood pressure in hypertensive subjects and in salt-depleted normotensive subjects.1 They seem to be less potent in hypertensive blacks than whites,64 necessitating the addition of a thiazide diuretic.65 ACE inhibitors also decrease the risk of end-organ damage. Thus, JNC 7 recommends ACE inhibitors for “compelling indications,” which include congestive heart failure, ischemic heart disease, chronic kidney disease, and diabetic nephropathy.66–70 These high-risk patients are generally treated with an ACE inhibitor as part of combination therapy to a lower blood pressure goal (<130/80 mm Hg).

ACE inhibitors are contraindicated in women who are contemplating pregnancy and in pregnant women because of the risk of fetal developmental abnormalities.71 They are also contraindicated in patients with a history of angioedema. Women have a 3-fold higher risk than men of developing ACE inhibitor-related cough, although the reason for this elevated risk is unclear.72,73

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Angiotensin Receptor Blockers

ARBs selectively bind to the angiotensin II AT1 receptor, blocking the vasoconstrictor effects of angiotensin II. These agents lower SBP, DBP, and mean arterial pressure in hypertensive patients and decrease the risk of target organ damage, and they are known to be well tolerated.1

The Losartan Intervention For End point reduction in hypertension (LIFE) study, which randomized 9193 high-risk hypertensive patients (4963 women) with LVH by electrocardiographic criteria to treatment with losartan or atenolol, showed greater benefit with losartan (25% reduction in composite outcome; 95% CI, 0.56–1.01; P = 0.06), and greater left ventricular mass reduction among women than men treated with losartan.74 The valsartan antihypertensive long-term use evaluation, which included 8777 men and 6468 women, compared CCB-based therapy [amlodipine plus hydrochlorothiazide (HCTZ) or other drugs] with ARB-based therapy (valsartan plus HCTZ or other drugs) and found no significant difference in cardiac morbidity or mortality, or all-cause mortality between treatment groups.75 CCB-based therapy was associated with greater reductions in blood pressure, especially in the early phases of treatment, compared with ARB-based treatment, although a later analysis showed that blood pressure reduction and control rates were similar in patients on either monotherapy.76 Similarly in the VALsartan In Diastolic Dysfunction (VALIDD) study, 384 patients with hypertension and echocardiographic evidence of diastolic dysfunction were randomized to treatment with valsartan or placebo for 38 weeks; other agents, but not an inhibitor of the renin-angiotensin-aldosterone system, could be added to either regimen to achieve a blood pressure goal of <135/80 mm Hg. Diastolic dysfunction was improved similarly in both treatment groups, although valsartan was associated with greater improvement in isovolumic relaxation time and systolic longitudinal velocity.77 The apparent lack of effect of diastolic dysfunction of RAS inhibition may be explained by the fact that the patient population was young, with mild hypertension, and without heart failure; RAS inhibition may have a greater effect on diastolic dysfunction in patients with more myocardial fibrosis and LVH.77

Similarly, in the International Verapamil-Trandolapril Study (INVEST), which included 22,575 (>50% women) hypertensive coronary artery disease patients aged 50 years or older, of whom more than 50% were women, there was no significant difference in the primary outcome measure between men and women.78 However, a subsequent subgroup analysis indicated that Hispanic women had better blood pressure control and fewer cardiovascular events than non-Hispanic white women (5.17% for Hispanic women vs. 12.3% for non-Hispanic white women; adjusted HR, 0.84; 95% CI, 0.71–0.98; P = 0.03).79

ARBs are of proven benefit among patients with heart failure.1 They favorably affect the progression of diabetic nephropathy and nondiabetic renal disease by reducing progression to macroalbuminuria.80,81 For these reasons, JNC 7 recommends ARB use in these patients as a component of combination therapy with blood pressure goals of <130/80 mm Hg.1 Moreover, according to the AHA guidelines, women at high risk of a cardiovascular disease event should be treated initially with a β blocker and/or ACE inhibitor or ARB, with the addition of a diuretic as needed to achieve blood pressure control.47

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Direct Renin Inhibitors

Renin represents the rate limiting step in Angiotensin II production; hence it serves as an important target for inhibiting the renin-angiotensin aldosterone system. The FDA approved the use of aliskiren, the first of a new class of oral direct renin inhibitors in 2007. Phase II and III clinical trials have proven the efficacy of aliskiren in treating mild-to-moderate hypertension as monotherapy or in combination with CCBs, ACE inhibitors, or ARBs.82 In a study of obese patients with stage I to II hypertension, aliskiren in combination with HCTZ was better than HCTZ alone and achieved blood pressure control comparable to the combinations of irbesartan/HCTZ and amlodipine/HCTZ.83 As suspected, preliminary results of the aliskiren in the evaluation of proteinuria in diabetes (AVOID) trial demonstrated a 20% reduction in proteinuria when aliskiren was added to losartan in patients with type II diabetes and proteinuria.84 Further investigations are underway to study the end organ protective effects of aliskiren.

Aliskiren is generally well tolerated with a side effect profile similar to other drug classes. Patients taking aliskiren reported less cough as compared with those on ramipril, in 1 study.85 This drug is contraindicated in pregnant women.

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Calcium Channel Blockers

CCBs lower blood pressure by blocking L-type voltage gated calcium channels in the heart and blood vessels, thus decreasing peripheral resistance and cardiac output. Clinical data have demonstrated that nondihydropyridine CCBs, alone or in combination with an ACE inhibitor or an ARB, lower blood pressure in hypertensive patients with nephropathy associated with proteinuria.86

In a cohort of 30,219 postmenopausal women with no prior history of cardiovascular disease, CCB monotherapy was associated with a slightly elevated risk of cardiovascular death (HR, 1.57; 95% CI, 1.04–2.35), an association that became nonsignificant after adjustment for other risk factors and exclusion of women with diabetes.87 A 2-drug-class regimen of CCBs plus diuretics was associated with higher risk of cardiovascular mortality compared with the combination of β-blockers and diuretics (HR, 1.85; 95% CI, 1.02–3.36).87

Pahor et al88 analyzed 9 clinical trials and found that blood pressure reduction was similar between CCBs and other drug classes; however, intermediate- and long-acting CCBs were associated with a higher risk of MI, congestive heart failure, and combined cardiovascular events. There were no significant differences for stroke or all-cause mortality. The authors concluded that the longer-acting CCBs cannot be recommended as first-line agents.88 However, a case-control report comparing long-acting and short-acting CCBs on cardiovascular outcomes in hypertensive patients indicated that the use of short-acting, but not long-acting CCBs was associated with increased risk of a cardiovascular event.89

CCBs are generally prescribed as adjunctive therapy in patients with difficult-to-control hypertension.

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CONCLUSIONS

Hypertension is a readily modifiable risk factor for cardiovascular disease; however, hypertension prevalence among women continues to increase, while awareness of hypertension and both treatment and treatment to target remain far from ideal. Data point toward equal benefits of blood pressure lowering among men and women, and suggest that African American women and elderly women may accrue the greatest benefit from treatment. Guidelines recommendations and data for compelling indications in the selection of antihypertensive therapy, indicate that most patients, including women, will require combination therapy (ie, ARB or ACE inhibitor combined with a thiazide diuretic) to reach blood pressure goals. Increased awareness and a more systematic, evidence-based approach to diagnosis and treatment of hypertension are critical to improve the clinical outcomes of women with hypertension.

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REFERENCES

1. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on detection, evaluation, and treatment of high blood pressure. JAMA. 2003;289:2560–2572.
2. Ong KL, Cheung BMY, Man YB, et al. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999–2004. Hypertension. 2007;49:59–75.
3. Vasan SR, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study. JAMA. 2002;287:1003–1010.
4. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality. Lancet. 2002;360:1903–1913.
5. Hsia J, Margolis KL, Eaton CB, et al. Prehypertension and cardiovascular disease risk in the Women's Health Initiative. Circulation. 2007;115:855–860.
6. Neal B, MacMahon S, Chapman N; Blood Pressure Lowering Treatment Trialists' Collaboration. Effect of ACE inhibitors, calcium antagonists, and other blood pressure lowering drugs: results of prospectively designed overviews of randomised trials. Lancet. 2000;356:1955–1964.
7. Ogden LG, He J, Lydick E, et al. Longterm absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification. Hypertension. 2000;35:539–543.
8. Fu Q, Levine BJ. Hypertension and antihypertensive therapy in elderly women: how much do we really know? Hypertension. 2006;47:323–324.
9. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension: results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA. 1967;202:1028–1034.
10. Helgeland A. Treatment of mild hypertension: a five year controlled drug trial. The Oslo Study. Am J Med. 1980;69:725–732.
11. Multiple Risk Factor Intervention Trial Research Group. Multiple risk factor intervention trial: risk factor changes and mortality results. JAMA. 1982;248:1465–1477.
12. Os I, Oparil S, Gerdts E, et al. Essential hypertension in women. Blood Press. 2004;13:272–278.
13. Lloyd-Jones DM, Larson MG, Leip EP, et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106:3068–3072.
14. Smulyan H, Asmar RG, Rudnicki A, et al. Comparative effects of aging in men and women on the properties of the arterial tree. J Am Coll Cardiol. 2001;37:1374–1380.
15. Safar ME, Smulyan H. Hypertension in women. Am J Hypertens. 2004;17:82–87.
16. Oparil S, Miller AP. Gender and blood pressure. J Clin Hypertens. 2005;7:300–309.
17. Ashraf MS, Vongpatanasin W. Estrogen and hypertension. Curr Hypertens Rep. 2006;8:368–376.
18. Schulman IH, Aranda P, Raij L, et al. Surgical menopause increases salt sensitivity of blood pressure. Hypertension. 2006;47:1168–1174.
19. Reckelhoff JF. Gender differences in the regulation of blood pressure. Hypertension. 2001;37:1199–1208.
20. Cardoso F, Polonia J, Santos A, et al. Low dose oral contraceptives and 24-hour ambulatory blood pressure. Int J Gynaecol Obstet. 1997;59:237–243.
21. Dong W, Colhoun HM, Poulter NR. Blood pressure in women using oral contraceptives: results from the health survey for England 1994. J Hypertens. 1997;15:1063–1068.
22. Chasen-Taber L, Willett WC, Manson JE, et al. Prospective study of oral contraceptives and hypertension in the United States. Circulation. 1996;94:483–489.
23. Seibert C, Barbouche E, Fagan J, et al. Prescribing oral contraceptives for women older than 35 years of age. Ann Intern Med. 2003;138:54–64.
24. World Health Organization. Low dose combined oral contraceptives. In: Improving Access to Quality Care in Family Planning: Medical Eligibility Criteria for Contraceptive Use. 2nd ed. Geneva, Switzerland: World Health Organization; 2000.
25. Oparil S. Women and hypertension: what did we learn from the Women's Health Initiative? Cardiol Rev. 2006;14:267–275.
26. Scuteri A, Bos AJ, Brant LJ, et al. Hormone replacement therapy and longitudinal changes in blood pressure in postmenopausal women. Ann Intern Med. 2001;135:229–238.
27. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1995;273:199–208.
28. Witteman JC, Willett WC, Stampfer MJ, et al. A prospective study of nutritional factors and hypertension among US women. Circulation. 1989;80:1320–1327.
29. Forman JP, Rimm EB, Stampfer MJ, et al. Folate intake and the risk of incident hypertension among US women. JAMA. 2005;293:320–329.
30. Song Y, Sesso HD, Manson JAE, et al. Dietary magnesium intake and risk of incident hypertension among middle-aged and older US women in a 10-year follow-up study. Am J Cardiol. 2006;98:1616–1621.
31. Winkelmayer WC, Stampfer MJ, Willett WC, et al. Habitual caffeine intake and the risk of hypertension in women. JAMA. 2005;294:2330–2335.
32. Gueyffier R, Boutitie F, Boissel JP, et al. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men: a meta analysis of individual patient data from randomized, controlled trials. Ann Intern Med. 1997;126:761–767.
33. Quan A, Kerlikowske K, Gueyffier F, et al. Efficacy of treating hypertension in women. J Gen Intern Med. 1999;14:718–729.
34. Alderman MH. Blood pressure management: individualized treatment based on absolute risk and the potential for benefit. Ann Intern Med. 1993;119:329–335.
35. Cook RJ, Sackett DL. The number needed to treat: a clinical useful measure of treatment. BMJ. 1995;310:452–454.
36. Jackson R, Barham P, Bills J, et al. Management of raised blood pressure in New Zealand: a discussion document. BMJ. 1993;307:107–110.
37. Quan A, Kerlikowske K, Gueyffier F, et al; INDANA Investigators. Pharmacotherapy for hypertension in women of different races. Cochrane Database Syst Rev. 2000;CD002146.
38. Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the spectrum: current outcomes and control in the community. JAMA. 2005;294:466–472.
39. Wassertheil-Smoller S, Anderson G, Psaty BM, et al. Hypertension and its treatment in postmenopausal women: baseline data from the Women's Health Initiative. Hypertension. 2000;36:780–789.
40. Frazier CG, Shah SH, Armstrong PW, et al. Prevalence and management of hypertension in acute coronary syndrome patients varies by sex: observations from the Sibrafiban versus spirin to Yield Maximum Protection from ischemic Heart events post-acute cOroNary sYdromes (SYMPHONY) randomized clinical trials. Am Heart J. 2005;150:1260–1267.
41. The Trials of Hypertension Prevention Collaborative Research Group. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high normal blood pressure: the Trials of Hypertension Prevention, Phase II. Arch Intern Med. 1997;157:657–667.
42. He J, Whelton PK, Appel LJ, et al. Long term effects of weight loss and dietary sodium reduction on incidence of hypertension. Hypertension. 2000;35:544–549.
43. Chobanian AV, Hill M. National heart, lung and blood institute workshop on sodium and blood pressure: a critical review of current scientific evidence. Hypertension. 2000;35:858–863.
44. Whelton SP, Chin A, Xin X, et al. Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials. Ann Intern Med. 2002;136:493–503.
45. Church TS, Earnest CP, Skinner JS, et al. Effects of different doses of physical activity on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women with elevated blood pressure: a randomized controlled trial. JAMA. 2007;297:2081–2091.
46. Xin X, He J, Frontini MG, et al. Effects of alcohol reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2001;38:1112–1117.
47. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115:1481–1501.
48. Smith SC, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. Circulation. 2006;113:2363–2372.
49. Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003;289:2534–2544.
50. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981–2997.
51. Psaty BM, Lumley T, Furberg CD. Meta-analysis of health outcomes of chlorthalidone-based vs nonchlorthalidone-based low-dose diuretic therapies. JAMA. 2004;292:43–44.
52. Bolland MJ, Ames RW, Horne AM, et al. The effect of treatment with thiazide diuretic for 4 years on bone density in normal post menopausal women. Osteoporos Int. 2007;18:479–486.
53. Felson DT, Sloutskis D, Anderson JJ, et al. Thiazide diuretics and the risk of hip fracture: results from the Framingham Study. JAMA. 1991;265:370–373.
54. Barzilay JI, Davis BR, Cutler JA, et al; ALLHAT Collaborative Research Group: fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2006;166:2191–2201.
55. Zillich AJ, Garg J, Basu S, et al. Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension. 2006;48:219–224.
56. Moser M. Why are physicians not prescribing diuretics more frequently in the management of hypertension? JAMA. 1998;279:1813–1816.
57. Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005;366:1545–1553.
58. Khan N, McAlister FA. Re-examining the efficacy of beta blockers for the treatment of hypertension: a meta-analysis. CMAJ. 2006;174:1737–1742.
59. Braunwald E, Antman EM, Beasly JW, et al. ACC/AHA 2002 guidelines update for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol. 2002;40:1366–1374.
60. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left ventricular dysfunction: the CAPRICORN randomized trial. Lancet. 2001;357:1385–1390.
61. β-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction, I: mortality results. JAMA. 1982;247:1707–1714.
62. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–1658.
63. CIBIS Investigators and Committees. A randomized trial of beta blockade in heart failure: The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation. 1994;90:1765–1773.
64. Veterans Administration Co-operative Study Group of Antihypertensive Agents. Racial differences in response to low-dose captopril are abolished by the addition of hydrochlorothiazide. Br J Clin Pharmacol. 1982;14(Suppl 2):97S–101S
65. Douglas JG, Bakris GL, Epstein M, et al. Management of high blood pressure in African Americans: Consensus Statement of the Hypertension in African Americans Working Group of the International Society of Hypertension in Blacks. Arch Intern Med. 2003;163:525–541.
66. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429–1435.
67. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.
68. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993;329:1456–1462.
69. Yusuf S, Pepine CJ, Garces C, et al. Effect of enalapril on myocardial infarction and angina in patients with low ejection fractions. Lancet. 1992;340:1173–1178.
70. Pfeffer MA, Lamas GA, Vaughan DE, et al. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med. 1988;319:80–86.
71. Pryde PG, Sedman SB, Nugent CE, et al. Angiotensin-converting enzyme inhibitor fetopathy. J Am Soc Nephrol. 1993;3:1575–1582.
72. Visser LE, Stricker BH, van der Velden J, et al. Angiotensin converting enzyme inhibitor associated cough: a population-based case-control study. J Clin Epidemiol. 1995;48:851–857.
73. Brown NJ, Vaughan DE. Angiotensin converting enzyme inhibitors. Circulation. 1998;97:1411–1420.
74. Bella JN, Palmieri V, Wachtell K, et al. Sex-related difference in regression of left ventricular hypertrophy with antihypertensive treatment: the LIFE study. J Hum Hypertens. 2004;18:411–416.
75. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomized trial. Lancet. 2004;363:2022–2031.
76. Julius S, Weber MA, Kjeldsen SE, et al. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial: outcomes in patients receiving monotherapy. Hypertension. 2006;48:385–391.
77. Solomon SD, Janardhanan R, Verma A, et al; for the VALsartan In Diastolic Dysfunction (VALIDD) investigators: effect of angiotensin receptor blockade and antihypertensive drugs on diastolic dysfunction in patients with hypertension and diastolic dysfunction: a randomized trial. Lancet. 2007;369:2079–2087.
78. Pepine CJ, Handbdrg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: the International Verapamil-Trandolapril Study (INVEST): a randomized trial. JAMA. 2003;239:2805–2816.
79. Cooper-DeHoff RM, Zhou Q, Gaxiola E, et al. Influence of Hispanic ethnicity of blood pressure control and cardiovascular outcomes in women with CAD and hypertension: findings from INVEST. J Womens Health (Larchmt). 2007;16:632–640.
80. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–869.
81. Lewis EJ, Hunsicker LG, Clarker WR, et al. Renoprotective effect of the angiotensin receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–860.
82. Sepehrdad S, Frishman WH, Stier CT Jr, et al. Direct inhibition of renin as a cardiovascular pharmacotherapy: focus on aliskiren. Cardiol Rev. 2007;15:242–256.
83. Jordan J, Engeli S, Boye SW, et al. Direct renin inhibition with aliskiren in obese patients with arterial hypertension. Hypertension. 2007;49:1047–1055.
84. Parving H-H, Lewis JB, Lewis EJ, et al. Aliskiren in the evaluation of proteinuria in diabetes (AVOID). Presented at: American Society of Nephrology Renal Week, October 31–November 5, 2007, San Francisco, CA. Poster SA-P01051.
85. Andersen K, Weinberger MH, Egan B, et al. Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial. J Hypertens. 2008;26:589–599.
86. Bakris GL, Weir MR, Secic M, et al. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int. 2004;65:1991–2002.
87. Wassertheil-Smoller S, Psaty B, Greenland P, et al. Association between cardiovascular outcomes and antihypertensive drug treatment in older women. JAMA. 2004;292:2849–2859.
88. Pahor M, Psaty BM, Alderman MH, et al. Health outcomes associated with calcium antagonists compared with other fist line antihypertensive therapies. Lancet. 2000;356:1949–1954.
89. Alderman MH, Cohen H, Roque R, et al. Effect of long-acting and short-acting calcium antagonists on cardiovascular outcomes in hypertensive patients. Lancet. 1997;349:594–598.
Keywords:

antihypertensive agents; cardiovascular diseases; hypertension; women

© 2008 Lippincott Williams & Wilkins, Inc.