Clinical Characteristics and Outcomes in Hypertensive Patients of Hispanic Descent
Juan M. Aranda, Jr, MD, University of Florida College of Medicine, Division of Cardiovascular Medicine, 1600 SW Archer Road, Room M421, PO Box 100277, Gainesville, FL 32610
In the United States, patients of Hispanic descent have higher rates of hypertension-related morbidity and mortality than patients from other ethnic groups even though the prevalence of hypertension among Hispanics is lower. This discrepancy likely reflects lower rates of hypertension awareness and control among Hispanics as well as a higher prevalence of diabetes mellitus and other cardiovascular risk factors in this population. Although available data suggest that patients of Hispanic descent who receive antihypertensive therapy experience responses and treatment benefits similar to those achieved by other ethnic groups, clinical trials of antihypertensive therapy have typically enrolled only small numbers of Hispanic patients. Agents targeting the renin-angiotensin system, namely angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, may be particularly useful in the Hispanic population given the ability of these drugs to protect against hypertension-related and diabetes-related end-organ damage independent of their blood pressure-lowering effects.
Patients of Hispanic descent are a rapidly growing minority group in the United States.1 According to the 2004 Current Population Survey from the US Census Bureau, approximately 40.4 million Hispanics are living in the United States, representing 14% of the total population.2 By the year 2025, the proportion of US citizens self-identified as Hispanic is expected to increase to 18.2%.3 The Hispanic population is a heterogeneous group composed of ethnically diverse individuals from several Latin American countries, making it difficult to generalize about the population as a whole. Mexican Americans represent the largest Hispanic subgroup (58.5%), followed by Puerto Ricans (9.6%) and Cuban Americans (3.5%).1
In the United States, the prevalence of hypertension among Hispanic groups (19% overall) and Mexican Americans (28.7% in males, 31.4% in females) is lower than the prevalence of hypertension in the general American population (33.6%),4 but recent data show that it is on the rise. Comparisons between National Health and Nutrition Examination Surveys (NHANES)5 conducted in 1988–1992 and 1999–2000 revealed that, among Hispanics, age-adjusted rates of prehypertension increased from 33.2% to 35.1% and stage 1 hypertension from 12.4% to 14.8%. Similarly, the age-adjusted prevalence of hypertension among Mexican Americans increased from 17.2% in 1988–1991 to 20.7% in 1999–2000 and to 27.8% in 2003–2004.6,7 Importantly, hypertension-related mortality rates increased substantially over this period in the United States, particularly among Hispanics, although differences in Hispanic subpopulations were evident.8
Contributing to the high rates of morbidity and mortality associated with hypertension in Hispanic populations is the high prevalence of other cardiovascular risk factors and comorbid conditions. For example, Hispanics are 1.5 times more likely to have diabetes mellitus and 1.5 times more likely to die of diabetes than non-Hispanic whites.9 Patients of Hispanic descent currently lead the diabetic epidemic in the United States, particularly in areas of South Florida, Texas, and California.10 This presents difficult challenges since the combination of hypertension and diabetes increases cardiovascular morbidity and mortality.11,12 Due largely to the higher prevalence of diabetes, Hispanics are twice as likely as whites to develop kidney disease.13 Hispanics, particularly women, have higher age-adjusted rates of overweight (39.6% vs 34.8%) and obesity (27.5% vs 23.5%) than non-Hispanic whites.9 The epidemic of obesity in the Hispanic population is not limited to adults; Hispanic children are more likely to be overweight than African American, Asian, or white children in the same age group.14 The metabolic syndrome—a constellation of metabolic abnormalities associated with elevated cardiovascular risk—is also much more common among Hispanics, particularly women, than among whites or African Americans.15 Of the risk determinants associated with this condition, abdominal obesity, impaired fasting glucose, and hypertriglyceridemia are all much more common among Hispanics than other ethnic groups. Hispanics are less likely to have adequate control of hypercholesterolemia and hypertension than other patient populations.16
It may be difficult to reduce the prevalence of hypertension and its impact on morbidity and mortality in Hispanic populations because of low levels of blood pressure (BP) awareness, treatment, and control. According to 2003–2004 NHANES data, 63.5% of Mexican Americans were aware that they had hypertension, 48.3% were treated for the condition, and 26.5% had controlled hypertension.7 Among non-Mexican Hispanics, 73% were aware that they had hypertension, 67% were receiving treatment, and 35% had controlled hypertension.17 A large population-based study in Los Angeles County found that 52% of Hispanics with hypertension were not receiving any antihypertensive medication.18 Even among those who received antihypertensive therapy, Mexican Americans were 29% less likely than whites to achieve BP control at a level <140/90 mm Hg. In a retrospective review of medical records obtained from 12 clinics, intensifying antihypertensive therapy was associated with achieving BP control, but Hispanics were significantly (P=.02) less likely than white or black patients to receive this step-up in therapy when the current regimen was not sufficient.19
Hispanics face a number of barriers to adequate BP awareness and control, including, in many cases, poor comprehension of the English language, poor patient-physician communication, cultural differences, low socioeconomic status, and low rates of health insurance coverage.20–23 Factors important for improving compliance with antihypertensive therapy among Hispanic patients are language proficiency and clinician understanding of cultural and health beliefs and attitudes.24,25 Moreover, Hispanics have generally been inadequately represented in large clinical trials of antihypertensive therapy; accordingly, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)26 does not provide specific guidance on hypertension treatment in the Hispanic population. This paper therefore reviews available data on treatment in Hispanic men and women with hypertension and discusses the potential rationale for using renin-angiotensin system (RAS)-based antihypertensive therapy in this patient population.
STUDIES OF ANTIHYPERTENSIVE THERAPY IN HISPANICS
Lifestyle modification is an important component of hypertension management regardless of ethnicity.26 Weir and colleagues27 showed that dietary salt restriction enhanced the antihypertensive efficacy of an angiotensin-converting enzyme (ACE) inhibitor and calcium channel blocker (CCB) in Hispanic patients with salt-sensitive hypertension. The beneficial impact of dietary salt restriction in Hispanics was comparable to that seen in both white and black cohorts. When lifestyle modifications alone are not sufficient, drug therapy should be initiated and titrated to achieve BP control (<140/90 mm Hg in most patients, but <130/80 mm Hg for those with comorbid conditions such as diabetes or chronic kidney disease).26 To achieve these goals, many patients require ≥2 antihypertensive medications.
As previously mentioned, Hispanic patients have generally been inadequately represented in large clinical hypertension trials. The efficacy of antihypertensive therapy in Hispanic populations, whether administered as monotherapy or combination therapy, can be gleaned from small, randomized controlled trials or subgroup analyses of larger studies. For example, in the Irbesartan/HCTZ Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial,28 a fixed-dose combination of an angiotensin II receptor blocker (ARB) and diuretic was evaluated in patients whose systolic BP (SBP) remained uncontrolled after treatment with the diuretic alone. In the subgroup of 119 Hispanic patients (14.4% of the study cohort), treatment with hydrochlorothiazide (HCTZ) 12.5 mg/d for 2 weeks followed by a combination of irbesartan 150 mg and HCTZ 12.5 mg/d for 8 weeks followed by an additional 8 weeks of irbesartan 300 mg and HCTZ 25 mg/d resulted in mean reductions of 22.9±13.2 mm Hg in SBP (P<.001) and 10.6±8.1 mm Hg in diastolic BP (P<.001) from baseline. These reductions were comparable to the BP reductions achieved in the white and African American subgroups in this study. Similarly, in the Valsartan-Managing Blood Pressure Aggressively and Evaluating Reductions in hsCRP (Val-MARC) study,29 valsartan/HCTZ was more effective than valsartan alone in lowering BP in Hispanic patients as in those of other ethnicities.
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)30 compared the efficacy of a diuretic, CCB, or ACE inhibitor in preventing fatal coronary heart disease (CHD) or nonfatal myocardial infarction in 33,357 patients with hypertension and one other CHD risk factor. Additional agents to achieve BP control were added at the discretion of the physician. Risk of primary outcome events or all-cause mortality did not differ across treatment arms during the mean 4.9-year follow-up, although stroke risk (a secondary outcome) was 15% higher with lisinopril than with chlorthalidone (95% confidence interval [CI], 2%–30%; P=.02). Findings in the cohort of 5246 Hispanic patients (15.7% of total) with regard to all end points were comparable to those observed in non-Hispanic patients.
The International Verapamil SR/Trandolapril Study (INVEST)31 compared a CCB-based strategy starting with verapamil SR with a β-blocker-based strategy starting with atenolol in 22,576 hypertensive patients with CHD. This trial included 8405 Hispanic patients (35.6% of the total enrollment), mostly from Puerto Rico, and represents one of the largest databases of Hispanic patients in a clinical trial of hypertension. Trandolapril was the primary add-on therapy in the verapamil group and HCTZ was the primary add-on therapy in the atenolol group when additional treatment was needed to achieve BP goals and provide end-organ protection. The 2 study arms did not differ with respect to BP lowering or the primary outcomes of nonfatal myocardial infarction, nonfatal stroke, or death. In the Hispanic cohort, 22% had evidence of left ventricular hypertrophy, 30% had diabetes, and 48% had hypercholesterolemia, with only 30% receiving lipid-lowering agents. The average body mass index in the Hispanic cohort was 29 kg/m2, demonstrating that these patients were significantly overweight. Seventy-eight percent of Hispanic patients in INVEST required >1 antihypertensive medication. Regardless of treatment assignment or comorbid condition, however, the Hispanic cohort achieved significantly greater reductions in SBP than the non-Hispanic cohort (−21.3 vs −17.4 mm Hg; P<.001) and, correspondingly, had a 13% reduction in risk of cardiovascular events compared with the non-Hispanics.
Findings from INVEST involving the Hispanic cohort present some interesting implications. Improvement in compliance, with appropriate communication (medication prescriptions in Spanish), adherence, and aggressive hypertension management can result in adequate BP reduction in this patient population. This superior BP control results in lower associated mortality in Hispanic patients with hypertension and coronary artery disease.
RATIONALE FOR RAS-BASED THERAPY IN HISPANIC POPULATIONS
Prevention of New-Onset Diabetes
Several studies have shown that RAS-based therapy, specifically ACE inhibitors and ARBs, significantly reduces the risk of new-onset diabetes,30,32–35 which is an important benefit given the high prevalence of diabetes in the Hispanic population. The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE)35 randomly assigned 15,245 high-risk hypertensive patients to the ARB valsartan or the CCB amlodipine, including 9995 patients (65.6%) without diabetes at enrollment. In this latter subgroup, valsartan significantly reduced the risk of new-onset diabetes by 23% relative to amlodipine (odds ratio [OR], 0.77; 95% CI, 0.69–0.87). Compared with amlodipine, valsartan significantly reduced each criterion used to define diabetes, including an adverse event report of diabetes (OR, 0.72; 95% CI, 0.62–0.84), new use of blood glucose-lowering drugs (OR, 0.83; 95% CI, 0.70–0.99), and fasting blood glucose ≥7.0 mmol/L at the end of the study (OR, 0.78; 95% CI, 0.67–0.92).
The Heart Outcomes Prevention Evaluation (HOPE)32 evaluated the benefit of the ACE inhibitor ramipril. HOPE included 5887 patients with vascular disease, mostly CHD, who did not have diabetes at baseline. In this cohort, ramipril significantly reduced the risk of new-onset diabetes by 34% compared with placebo during the 4-year treatment period (relative risk [RR], 0.66; 95% CI, 0.51–0.85). Ramipril reduced the proportion of patients with a diagnosis of diabetes and hemoglobin A1c values ≥110% of the normal range (RR, 0.60;95% CI, 0.43–0.85) as well as use of blood glucose-lowering drugs (RR, 0.56; 95% CI, 0.41–0.77).
INVEST represents the largest experience describing the association between RAS blockade and reduction of new-onset diabetes in Hispanic patients. Hispanic ethnicity was associated with an overall increase in risk of new-onset diabetes (hazard ratio [HR], 1.19; 95% CI, 1.04–1.36). The use of trandolapril in the verapamil SR strategy was associated with reduced risk of new-onset diabetes (HR, 0.85; 95% CI, 0.76–0.95). Interestingly, the higher the dose of ACE inhibition, the greater the reduction in new-onset diabetes. Conversely, the higher the doses of atenolol and HCTZ in the atenolol arm, the greater the risk of diabetes.31
These studies indicate that RAS-based therapy reduces the risk of new-onset diabetes in patients with hypertension or other cardiovascular disorders and, as illustrated by the INVEST results, this benefit is evident in Hispanic patients. Several mechanisms have been proposed to explain why RAS-based therapy reduces diabetes risk including improved insulin and glucose delivery to skeletal muscle, regulation of glucose transport and insulin signaling to reduce insulin resistance, and blockade of the local RAS in the pancreas to prevent β-cell damage.36
RAS-based therapy is renoprotective in hypertensive patients with type 2 diabetes as illustrated by several trials with ARBs and ACE inhibitors. Therefore, this therapy is important to consider in Hispanic patients, who have a high prevalence of diabetes and kidney failure.13 Although we in the medical community continue to face the problem of underrepresentation of Hispanic patients in hypertensive renal protection studies involving RAS blockade, post hoc analyses of small numbers of Hispanic patients suggest that Hispanics derive benefit from RAS blockade with regard to preservation of renal function. The Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) trial37 compared losartan with placebo in 1513 type 2 diabetes patients with nephropathy. Patients in both groups continued to receive their standard antihypertensive therapy, although ACE inhibitors and ARBs were replaced with other agents during an open-label run-in phase. Losartan significantly reduced the risk of the primary end point—a composite of serum creatinine doubling, end-stage renal disease (ESRD), or death—by 16% (95% CI, 2%–28%; P=.02) compared with placebo. Furthermore, in a recent post hoc analysis from the RENAAL trial, losartan's renoprotective effects were seen in all ethnic groups studied. At month 6 of the study, treatment-induced change in albuminuria predicted longer-term renoprotective effect similarly for black, white, Asian, and Hispanic patients.38
Taken together, these studies show that RAS-based therapy is renoprotective in hypertensive patients with type 2 diabetes. Importantly, the renoprotective effects of these agents were independent of their BP-lowering effects. Although Hispanic patients are underrepresented in clinical trials, the high incidence of diabetes along with concomitant end-organ damage suggests that Hispanics require RAS blockade in their antihypertensive regimens.
Hispanics represent a rapidly growing segment of the US population. Although hypertension prevalence is not higher among Hispanics, Hispanics are more likely to have undiagnosed and uncontrolled hypertension than other ethnic groups. Moreover, they have high rates of hypertension-related morbidity and mortality, reflecting the high prevalence of diabetes and other cardiovascular risk factors in this population, including obesity and the metabolic syndrome. Although Hispanic patients have not been well represented in clinical trials of antihypertensive therapy, available evidence suggests that they respond similarly to other ethnic groups and achieve comparable benefits. RAS-based therapy may be particularly useful for treating hypertension in the Hispanic population inasmuch as these agents protect against end-organ damage and potentially reduce the risk of new-onset diabetes. The authors continue to emphasize the need to enroll and actively recruit patients of all ethnic groups in cardiovascular trials to provide evidence-based data on end-organ protective effects of RAS blockade.
Acknowledgment and disclosures:
We thank Lisa A. Hamilton, MA, for editorial assistance and manuscript preparation. Dr Aranda, Jr, has served as a consultant for Novartis Pharmaceuticals Corporation. This paper was funded by Novartis Pharmaceuticals Corporation.