Cardiovascular disease (CVD) is the leading cause of death among women worldwide, causing 1 in every 4 female deaths.¹ Although 1 of 4 women in the United States has some form of CVD, only 54% of women recognize that heart disease is their number 1 killer.² Multiple studies have noted that women tend to have a higher mortality and morbidity from cardiovascular events compared to men. Women are less likely than men to receive aggressive or invasive treatment for heart disease compared to men.³ There is also often a failure for both health care providers and women themselves to recognize either the underlying risks or the associated symptoms of CVD.⁴ It is therefore imperative for health care providers to understand its risk factors and recommendations regarding the management of this disease.

Calculation of a woman’s 10-year risk of cardiovascular events is an important step in assisting women to know which modifiable risk factors could influence the risk of future disease. A 10-year risk score of CVD has become standard as an assessment tool for risk stratification. A 10-year risk of coronary heart disease (CHD) can be determined based on age, gender, and conventional risk factors, including high blood pressure (BP), dyslipidemia, glucose intolerance, and smoking.⁵

The first major model was the Framingham risk calculator. The original Framingham risk prediction algorithm to predict CHD (known as FRS-CHD) incorporated age; sex; diabetes; systolic and diastolic BPs; levels of total, low-density lipoprotein, and high-density lipoprotein cholesterol; and smoking to estimate a 10-year risk for angina, myocardial infarction (MI), or death due to CHD.⁶

Despite their prominent use, the applicability of Framingham-based algorithms to modern populations has been questioned.^7,8,9 Framingham-based scores are based on a homogeneous, geographically limited, Caucasian, male-dominated cohort from a prior generation when cardiovascular risk profiles and preventive pharmacotherapy were both less well developed and less used than in modern cohorts. Multiple studies in diverse populations suggest that Framingham-based risk-scoring systems may misclassify risk, particularly in women, and overestimate CHD risk.⁹ In response, the Reynolds Risk Score (RRS) was developed in 2007 and included parental history of premature CHD and measurement of high-sensitivity C-reactive protein.⁸ Most recently, the American Heart Association (AHA) and the American College of Cardiology (ACC) developed a new atherosclerosis cardiovascular disease (ASCVD) risk score to guide ASCVD risk-reducing therapy.¹⁰ This new risk score uses the same traditional risk factors as the original FRSs and offers separate equations for white and African American men and women. As noted, each risk model has its limitations and therefore should be used with caution. In women, using the Reynolds score as adjunct to other risk scores may yield value for reclassification, especially for those patients who fall into the intermediate-risk category.¹¹

Taking into account the tools and current guidelines as discussed, it is recommended that clinicians include a global risk assessment for all patients 20 to 79 years of age who are free from clinical ASCVD.^12,13 This risk assessment should be repeated every 4 to 6 years in persons who are found to be at low 10-year risk (<7.5%). Beginning at age 40 years, formal estimation of the absolute 10-year risk of ASCVD is recommended. Long-term or lifetime risk estimation is recommended for all persons who are between 20 and 39 years of age and for those between 40 and 59 years of age who are determined to be at low 10-year risk (<7.5%).

Directly screening for coronary artery disease with an electrocardiogram (ECG) in asymptomatic people has not been shown to be an effective tool. The US Preventive Services Task Force (USPSTF) recommends against routine screening with resting or exercise ECG for asymptomatic adults at low risk (10-year CHD risk <10%) for CHD events (evidence grade D). In addition, the task force could not find conclusive evidence that screening high- or intermediate-risk patients provided benefit. They acknowledged that a screening ECG can find minor and clinically insignificant abnormalities that could result in further unnecessary invasive testing.

Many risk factors for CVD are modifiable by specific preventive measures. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries, 9 potential modifiable risk factors accounted for 94% population-attributable risk of first MI in women worldwide. These risk factors include smoking, dyslipidemia, hypertension, diabetes, abdominal obesity, psychosocial factors, daily consumption of fruit and vegetables, regular alcohol consumption, and regular physical activity.¹⁴ There are varying recommendations on screening for each of these risk factors. In addition, there is also a variable amount of evidence on the impact of treatment for some of these risk factors. In addition to these factors, there are some female-specific and nontraditional risk factors that are emerging, but with limited evidence (Table 6-1).

Hypertension

Hypertension is a well-established risk factor for adverse cardiovascular outcomes, including mortality from CHD and stroke.^15,16,17 The lifetime risk of developing CHD is significantly higher among patients with hypertension.¹² The benefits of treating hypertension to prevent important health outcomes are well documented. For this reason, there are a number of suggestions on screening for hypertension as a means to early identification and risk factor modification. The American Congress of Obstetricians and Gynecologists (ACOG) recommends BP screening as part of women’s annual health care visit.¹⁸ The USPSTF also recommends BP screening in adults (grade A).¹⁹ The Joint National Committee (JNC) recommends a screening interval of every 2 years for patients with BP less than 120/80 mm Hg and every year for patients with a BP of 120/80 mm Hg. Once an elevation of BP greater than 120/80 mm Hg is present, follow-up for further elevations and, ultimately, decisions on treatment will need to be discussed with the patient.

A diagnosis of hypertension requires 3 separate measures of an elevated BP done at different times. A single elevated BP would be considered “elevated BP without the diagnosis of hypertension.” White-coat hypertension is the elevation of BP in a physician’s office or a clinical setting but not in other settings (e.g., at home). An ambulatory BP monitor can be ordered to confirm BP trends over a 24-hour period.²⁰ This helps in the diagnostic process if there is any concern about persistent hypertension or inconsistent office BP numbers.

Essential hypertension is far and away the most common cause of persistent elevation of BP. Although a full review of the workup of secondary hypertension is beyond the scope of this chapter, it is important to recognize the features found on history and physical that can point in that direction. This is particularly important in the young patient without a family history of hypertension.²¹ In the patient presenting with elevated BP, particular attention should be given to potential pharmaceutical causes of elevated BP, including nonsteroidal anti-inflammatory drugs (NSAIDs), hormonal contraception, licorice ingestion, sympathomimetic medications, and over-the-counter cold medications.²¹

Management for hypertension begins with therapeutic lifestyle modification. However, even under the most optimal conditions, many patients diagnosed with hypertension will need pharmacological management to optimize BP control. There have been a number of landmark trials that looked at the effect of BP management and medication choices.

Evidence for Treatment of Hypertension

The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial (2002) was a randomized, double-blind, multicenter trial with 33, 357 patients; 47% were women, and 35% were black. The mean age was 67, and 29 was the average body mass index (BMI).²² It compared amlodipine to lisinopril to chlorthalidone with the primary outcome of fatal CHD and nonfatal MI. Secondary outcomes included a combination of all-cause mortality, CHD, stroke, combined coronary vascular disease, angina, coronary revascularization, peripheral arterial disease, cancer, and end-stage renal disease. Findings suggested no significant difference between the amlodipine group and the chlorthalidone group for either the primary or secondary outcomes. Subgroup analysis of women only showed no difference in the primary outcome of time to first cardiovascular event and only showed a mild protective effect of chlorthalidone against stroke. Chlorthalidone is a stronger thiazide diuretic then hydrochlorothiazide and is much less commonly used in the United States. Overall, this study was similar to the other major studies, showing that either angiotensin-converting enzyme inhibitors (ACE-Is), calcium channel blockers (CCBs), or thiazide diuretics are appropriate first-line antihypertensive agents with no difference between the primary outcome of fatal CHD and nonfatal MI.

The Anglo–Scandanvian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) study (2003) was a double-blind, randomized, multicenter trial of 19,257 patients; only 23% were female, 95% were Caucasian, and 37% were under age 60 with this entire group having 28.7 median BMI.²³ In the study, there was no difference between the calcium channel blocker/ACE-I arm and the β-blocker/diuretic arm when nonfatal MI plus fatal MI was the primary end point (hazard ratio [HR] 0.90, confidence internal [CI] 0.79–1.02, p = 0.12). The lack of significant difference was likely due to the similar change in BP in the group from 164/94 to 136/78 mm Hg after treatment. The subgroup analysis of all participants found that there was a significant protective effect for the amlodipine/ACE-I arm for all-cause mortality (HR 0.89, CI 0.81–0.99, p = .025); risk of development of diabetes (HR 0.70, CI 0.63–0.78, p = < .0001); cardiovascular mortality (HR 0.76, CI 0.65–0.89, p = .001); and total/nonfatal stroke (HR 0.77, CI 0.66–0.89, p = .003).²³ The ASCOT-BPLA study suggested that CCBs and ACE-I were superior to β-blockers/diuretics in overweight and heavier individuals in subgroup analysis. The subgroup analysis of women suggested that women had a similar reduction in overall BP with similar end point outcomes as the general study population.

The ACCOMPLISH (Avoiding cardiovascular events through combination therapy in patients living with systolic hypertension) trial (2008) was a randomized, controlled, double-blind, multicenter trial with 11,506 patients; 39.5% were women, and 31 kg/m² was the average BMI.²⁴ This trial compared benazepril/amlodipine to benazepril/hydrochlrorothiazide. The primary outcome singular measure was time to first cardiovascular event and included sudden death from cardiac causes, MI, stroke, coronary intervention, congestive heart failure, or resuscitation after sudden cardiac arrest. In the study, there was no significant difference between the ACE-I/CCB arm and the ACE-I/diuretic group (8.1% vs. 9.7%, respectively, with p = .06).²⁴ Similar to the subgroup results of the ASCOT-BPLA study, subgroup analysis in ACCOMPLISH showed that, in obese women, either the combination of ACE-I/CCB or ACE-I/diuretic was equally effective at reducing primary outcomes.

The effect of Antihypertensive Agents on cardiovascular events in patients with coronary disease and normal blood pressure; the CAMELOT (Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis) trial (2004), was a double-blind, randomized, multicenter trial done in the United States and Europe.²⁵ There were about 2000 patients in the trial; it compared amlodipine to enalapril and placebo. The primary outcome was incidence of adverse cardiovascular events. This included a composite of death, nonfatal MI, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina/congestive heart failure, stroke/transient ischemic attack or new diagnosis of peripheral arterial disease. Amlodipine was found to have a significantly better result than placebo, reducing cardiovascular adverse events from 23.1% to 16.6% (HR 0.69, CI 0.54–0.88, p = .003) with a number needed to treat of 16 patients to prevent 1 adverse event.²⁵ CAMELOT also found that amlodipine was better than placebo but similar to enalapril. Critics of this study are skeptical of the results because of the high dropout rate. Women and obese participants were not separately reported in this study.

Hypertension Treatment Recommendations

The current Eighth JNC (JNC8) guidelines give clear suggestions on the use of medication for the treatment of hypertension¹² (Table 6-2).

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  Age 18–29: Initiate treatment with antihypertensives for systolic BP 140 mm Hg or greater or diastolic BP 90 mm Hg or greater. Treatment goal is BP less than 140/90 mm Hg (level of evidence E: expert opinion).

  
  
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  Age 30–59: Initiate treatment with antihypertensives for systolic BP 140 mm Hg or greater or diastolic BP 90 mm Hg or greater. Treatment goal BP less than 140/90 mm Hg (level of evidence A for diastolic goals: multiple randomized trials).

  
  
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  Age 60 or greater: Initiate treatment for systolic BP 150 mm Hg or greater or diastolic BP 90 mm Hg or greater. Treatment goal is BP less than 150/90 mm Hg (level of evidence A: multiple randomized trials).

  
  
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  Age 60 or greater with chronic kidney disease (CKD) or diabetes: BP goal is less than 140/90 mm Hg (level of evidence E: expert opinion).

  
  
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  In the general non-black population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic, CCB, ACE-I, or angiotensin receptor blocker (ARB) (moderate recommendation: grade B).

  
  
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  In the general black population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic or CCB. (For the general black population, moderate recommendation: grade B; for black patients with diabetes, weak recommendation: grade C).

If the goal BPs (<150/90 mm Hg) are not reached for patients’ older than 65 or are less than 140/90 mm Hg for patients aged less than 65, then the goals of treatment include the following (Table 6-3):

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  If goal BP is not reached within a month of treatment, increase the dose of the initial drug or add a second drug from one of the classes in the recommendation (thiazide-type diuretic, CCB, ACE-I, or ARB). The clinician should continue to assess BP and adjust the treatment regimen until the goal BP is reached.

  
  
  
  
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    If goal BP cannot be reached with 2 drugs, add and titrate a third drug from the list provided. Do not use an ACE-I and an ARB together in the same patient.

  
  
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  If the goal BP cannot be reached using only the drugs in the recommendation because of a contraindication or the need to use more than 3 drugs to reach the goal BP, antihypertensive drugs from other classes can be used.

  
  
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  Referral to a hypertension specialist may be indicated for patients in whom the goal BP cannot be attained using the previous strategy or for the management of complicated patients for whom additional clinical consultation is needed.

Certain patient populations and comorbidities could benefit from different antihypertensive choices (Table 6-4):

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  The ACE-Is are generally thought to be the antihypertensives of choice for patients with mild CKD, diabetes and nephropathy, previous MI, or heart failure with ejection fraction (EF) less than 40%.^20,26,27,28

  
  
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  In patients with minor intolerance to ACE-Is, ARBs are generally used. However, ARBs should be avoided in patients who have anaphylaxis with an ACE-I.

  
  
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  The β-blockers are indicated after MI and in heart failure with EF less than 40%.²⁸

  
  
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  Thiazide diuretics are preferred in African Americans, the elderly, and patients with heart failure and for secondary stroke prevention.^20,22,28

Antihypertensive Side Effects