Release Date: October 29, 2007
The patient, ZT, is a 61-year-old African American man who is a successful architect. He is currently taking metformin to control his type 2 diabetes mellitus, which was diagnosed 2 years ago, and hydrochlorothiazide (HCTZ) 25 mg once daily for hypertension, which was diagnosed approximately 1 year earlier. He has not been seen by a healthcare professional for the past year because of missed appointments that resulted from his busy schedule, but he does continue to take his medications as prescribed. With the exception of elevated blood glucose levels, ZT's laboratory values have been essentially normal in the past.
Recent changes at the patient's architecture firm require him to undergo a physical examination. ZT weighs 218 lb and stands 5'10" tall, with a body mass index (BMI) of 31 kg/m2. His blood pressure, which was confirmed on 2 other occasions, is 156/92 mm Hg and his electrocardiogram (ECG) is normal. Laboratory findings are as follows:
|Fasting glucose, 146 mg/dL|
Glycosylated hemoglobin, 6.9%
Total cholesterol, 211 mg/dL
Triglycerides, 184 mg/dL
High-density lipoprotein (HDL) cholesterol, 33 mg/dL
Low-density lipoprotein (LDL) cholesterol, 141 mg/dL
Creatinine, 1.4 mg/dL
Albumin, 75 mg/g
In 2003, the JNC 7 introduced a change in the classification of blood pressure to include a category called "prehypertension" for individuals with blood pressure values ranging from 120 to139 mm Hg systolic and/or 80 to 89 mm Hg diastolic. Individuals who fall into this category are at high risk for developing hypertension. They may benefit from early intervention with lifestyle modifications, which may reduce blood pressure, decrease the rate of progression of blood pressure to hypertensive levels with age, or even prevent the progression to hypertension. Table 1 shows the JNC 7 classification of BP for adults 18 years and older.
|Blood Pressure Classification||SBP (mm Hg)||DBP (mm Hg)|
|Normal||< 120||and < 80|
|Stage 1 hypertension||140-159||or 90-99|
|Stage 2 hypertension||≥ 160||or ≥ 100|
Based on the average of 2 or more properly measured, seated, BP readings on each of 2 or more office visits.
SBP: systolic blood pressure; DBP: diastolic blood pressure.
From Chobanian, JAMA., 2003.
According to NHANES (1976 to 2000), prehypertension and hypertension affect more than 100 million individuals in the United States. About 42 million men and 28 million women age 20 and over have prehypertension, 13 million men and 12 million women have stage 1 hypertension, and 4 million men and 7 million women have stage 2 hypertension.
Between 1988-1992 and 1999-2000, age- and sex-adjusted rates of prehypertension increased among non-Hispanic whites, African Americans, and Hispanics. African Americans had the highest age-adjusted prevalence of stage 1 (15.5%) and stage 2 hypertension (8.1%), and Hispanics had the second highest rate of stage 1 and stage 2 hypertension. During the same time period, age- and sex-adjusted rates of stage 2 hypertension decreased among non-Hispanic whites.
Analysis of data from the third NHANES survey found that of the estimated 41.9 million people with hypertension, 31% (about 13.1 million) were unaware of their hypertension, 17% (7 million) were aware of their condition but were not being treated, 29% (12 million) were being treated but their hypertension remained uncontrolled, and only 23% (9.7 million) had blood pressure adequately controlled with medication (Figure 1). Therefore, among the 21.7 million patients treated with medication, 45% (9 million) had adequately controlled blood pressure. Although individuals aged 65 and older make up only 19% of the population, they constituted 45% of the persons who were unaware of their condition, 32% of those who were aware of their condition but not being treated, and 57% of those who had treated but uncontrolled hypertension. Among individuals not being treated, hypertension was controlled in 65% of those who were 25 to 44 years old, 52% of those who were 45 to 54 years old, and 34% of those aged 65 and older.
Figure 1. Number of adults in the various categories of hypertension by age. From Hyman, N Engl J Med., 2001.
Although lack of access to healthcare is commonly associated with poor control of hypertension, 92% of subjects included in this analysis had health insurance. In addition, 86% reported having a usual source of care, and the average number of visits to physicians among individuals was 4.82 per year. The use of healthcare services did not differ between subjects who were unaware of their hypertension and those with acknowledged, untreated hypertension. Both groups had an average of 3 visits to physicians per year, and more than 40% of the subjects in each group were taking a prescription drug, but not for hypertension. Subjects with treated controlled hypertension and subjects with treated uncontrolled hypertension averaged about 6 visits to a physician in the previous year.
Although the diagnosis and treatment of hypertension in asymptomatic patients is critical, it is also important to treat hypertension aggressively to ensure achievement of recommended blood pressure goals. An early onset of antihypertensive effect has been shown to provide additional advantages in terms of lowering clinical event rates. The VALUE trial was a randomized, double-blind, parallel-group comparison of valsartan vs amlodipine in hypertensive patients. More than 15,000 patients with untreated hypertension who were at high risk for cardiac events were randomized to receive 1 of the study therapies for the duration of the study. Mean follow-up time was 4.2 years. The main outcome, the composite of cardiac mortality and morbidity, did not differ between groups (10.6% valsartan group vs 10.4% amlodipine group; hazard ratio, 1.04 [0.94-1.15]). Analysis of the VALUE study by Weber and associates, which examined blood pressure-lowering and clinical event rates between patients who achieved immediate vs delayed blood pressure control, found that patients who responded immediately were less likely to be at risk for a cardiac event, stroke, or death (Table 2).
|Fatal and nonfatal cardiac events||0.88 (0.79-0.97)†||0.88 (0.77-1.02)||0.87 (0.75-1.01)|
|Fatal and nonfatal stroke||0.83 (0.71-0.98)‡||0.85 (0.68-1.06)||0.84 (0.65-1.07)|
|All-case death||0.90 (0.81-0.99)‡||0.89 (0.77-1.02)||0.91 (0.78-1.05)|
|Myocardial infarction||0.89 (0.76-1.04)||1.08 (0.87-1.33)||0.73 (0.58-0.92)†|
|Heart failure hospitalizations||0.87 (0.75-1.01)||0.81 (0.66-1.01)||0.90 (0.73-1.11)|
†P < .01; ‡P < .05; *for valsartan, n = 4353 and 3159; for amlodipine, n = 4983 and 2504; for combined, n = 9336 and 5663, respectively. From Weber, Lancet., 2004.
Other trials suggest that delays of 3 months to 2 years in initiating antihypertensive therapy can increase the risk of certain cardiovascular endpoints, particularly stroke. Although older treatment guidelines recommended starting with low doses of antihypertensive agents and titrating upward and adding other agents slowly, current data support more aggressive treatment to get patients to blood pressure goal faster.
According to the World Health Organization (WHO), suboptimal blood pressure control (> 115 mm Hg systolic blood pressure) accounts for more than 62% of cerebrovascular disease. In addition, death from both ischemic heart disease and stroke has been shown to increase progressively and linearly from levels as low as 115 mm Hg systolic BP and 75 mm Hg diastolic BP and upward in individuals ranging in age from 40 to 89 years of age. Mortality from both ischemic heart disease and stroke doubles with every 20 mm Hg systolic or 10 mm Hg diastolic increase in blood pressure. In addition, data from the Framingham Heart Study indicate that blood pressure between 130-139/85-89 mm Hg is associated with a more than twofold increase in relative risk from cardiovascular disease compared with blood pressure below 120/80 mm Hg.
Type 2 diabetes mellitus is associated with a 70% to 80% chance of premature death from cardiovascular disease and stroke. The coexistence of diabetes and hypertension is particularly troublesome because of the strong association of the 2 conditions with all cardiovascular disease, stroke, progression of renal disease, and diabetic nephropathy. The United Kingdom Prospective Diabetes Study (UKPDS) was a prospective observational study conducted in 23 hospital-based clinics in England, Scotland, and Northern Ireland. Patients were randomized to a policy of tight control of blood pressure with either a beta-blocker or angiotensin-converting enzyme (ACE) inhibitor or to a policy of less tight control. The study found that for each 10 mm Hg decrease in systolic blood pressure, there was an associated reduction in rates of diabetes-related mortality (15%, P < .0001), myocardial infarction (11%, P < .0001), and microvascular complications (13%, P < .0001). A number of other studies, including the Hypertension Optimal Treatment (HOT) Trial, the Systolic Hypertension in the Elderly Program (SHEP), the European Trial on Systolic Hypertension in the Elderly (Syst-EUR), the Heart Outcomes Prevention Evaluation (HOPE) Study, the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study, and the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), have demonstrated that adequate blood pressure control improves cardiovascular disease outcomes, especially stroke, when aggressive blood pressure targets are achieved.
Antihypertensive drugs have been shown to provide cardiovascular protection beyond blood-pressure lowering. In a meta-analysis conducted by Staessen and colleagues, calcium channel blockers and ACE inhibitors were found to provide similar overall cardiovascular protection compared with older drug classes (diuretics and beta-blockers). Calcium channel blockers provided more reduction in the risk of stroke, but less reduction in the risk of myocardial infarction.
The most recently published meta-analysis of the BPLTCC found that that ACE inhibitors produced a blood pressure-independent reduction in the relative risk of coronary heart disease of about 9%; this effect was not detected for ARBs. However, both ACE inhibitors and ARBs showed comparable blood pressure-dependent reductions for the risk of stroke, coronary heart disease, and heart failure.
Lifestyle modifications, including weight loss and physical activity, remain the cornerstone of hypertension management, regardless of whether or not patients require pharmacologic therapy. According to the JNC 7 guidelines, treatment of hypertension should begin with lifestyle modifications. If blood pressure goal (< 140/90 mm Hg; < 130/80 mm Hg for patients with diabetes) is not reached, patients should be started on thiazide-type diuretics, ACE inhibitors, ARBs, or calcium channel blockers.[1,12] Recent data would suggest that beta-blockers are not good first-line drugs for the primary prevention of hypertension. More than two thirds of patients with hypertension require more than 1 drug to achieve blood pressure goal.[1,13] A second drug from a different class should be initiated when use of a single agent in adequate doses fails to achieve the blood pressure goal.
The JNC 7 guidelines also discuss specific compelling indications where a particular treatment may be preferred based upon clinical trial data (Table 3). Selection of initial therapy should take compelling indications into consideration.
If a drug fails to lower blood pressure at the usual dose, it is unlikely to produce antihypertensive effects at higher doses. The physician can begin a trial of sequential monotherapy until an effective agent is found, but this requires lengthy titration periods and patients may become frustrated and lose confidence in the treating physician.
More than two thirds of patients with hypertension require more than 1 drug, either as separate prescriptions or in fixed-dose combinations, to achieve blood pressure goal.[1,13] Fixed-dose combinations are preferred to improve compliance. The initiation of therapy with more than 1 agent brings patients to blood pressure goal in a more timely fashion, with fewer medications, additions, or changes needed than with initiation with monotherapy. The use of multidrug combinations often results in greater blood pressure reduction at lower doses of the component agents, thereby resulting in fewer side effects.[1,15]
Potential advantages of using fixed-dose combinations include greater convenience and simplification of the treatment regimen, as well as cost savings when compared with individual components prescribed separately. In some instances, however, the cost of two drugs separately may be less expensive than fixed-dose products; physicians should consider the cost of therapy and attempt to minimize cost while maximizing compliance. The starting dose of most fixed-dose combinations is usually below the doses used in clinical outcome trials. Therefore, the doses of these agents should be titrated upward to achieve the blood pressure goal before adding other drugs.
According to the JNC 7, starting therapy with 2 drugs, separately or as fixed-dose combinations, should be considered when systolic blood pressure is > 20 mm Hg above goal or diastolic blood pressure is > 10 mm Hg above the desired goal for the individual patient. In ALLHAT, which included patients with difficult-to-treat hypertension, 66% of patients reached blood pressure goal by 5 years, with 63% of patients taking 2 or more medications. JNC 7 recommends that patients undergo monthly follow-up after initiating antihypertensive therapy to have their medications adjusted until the blood pressure goal is reached.
In general, diuretics are recommended as one element of combination therapy to achieve blood pressure control. However, in high-risk patients, specific classes of antihypertensive agents have been shown to improve disease outcomes.[1,17] According to the JNC 7 guidelines and ADA recommendations, renin-angiotensin system (RAS) blockade is an important component of treatment for patients with diabetes and hypertension.[1,12] The ADA guidelines state that all patients with diabetes and hypertension should be treated with an ACE inhibitor or ARB. If greater reduction in blood pressure is needed, a diuretic should be added to the regimen. Clinical trials of antihypertensive therapy for preventing vascular complications have reported that many patients with diabetes required 3 or more drugs to achieve the more stringent blood pressure goals set forth by the JNC 7 and the ADA for patients with diabetes (< 130/80 mm Hg).
Additive effects of antihypertensive agents should be considered in other populations at high risk. The prevalence of hypertension, diabetes, heart failure, and end-stage renal disease among African Americans is substantially higher than in other racial/ethnic groups.[18,19] Guidelines from the Hypertension in African Americans Working Group of the ISHIB state that most African American patients require at least 2 drugs to reach blood pressure goals. While the JNC 7 recommends initiating combination therapy when blood pressure is ≥ 20/10 mm Hg above goal, the ISHIB recommends combination therapy in patients with blood pressure that is ≥ 15/10 mm Hg above goal. The treatment regimens recommended by the ISHIB for African American patients with hypertension include a diuretic plus an ACE inhibitor, a diuretic plus an ARB, a diuretic plus a beta-blocker, or an ACE inhibitor plus a calcium channel blocker.
The INCLUSIVE trial evaluated the efficacy and safety of irbesartan/hydrochlorothiazide fixed combinations in 1005 patients (≥ 18 years) with uncontrolled systolic blood pressure (140-159 mm Hg; 130-159 mm Hg for patients with type 2 diabetes mellitus) after at least 4 weeks of treatment with antihypertensive monotherapy. Once qualifying patients discontinued previous antihypertensive monotherapy, they entered a sequential 4-phase treatment period: placebo for 4 to 5 weeks; HCTZ 12.5 mg once daily for 2 weeks; irbesartan/HCTZ 150/12.5 mg for 8 weeks (1 fixed-combination tablet once daily); and irbesartan/HCTZ 300/25 mg for 8 weeks (2 irbesartan/HCTZ 150/12.5 mg fixed-combination tablets once daily). The primary efficacy endpoint of the study was the mean change in systolic blood pressure from the end of the placebo run-in period (baseline) to the end of the irbesartan/HCTZ 300/25-mg treatment period.
Of the patients who completed the placebo phase and entered the HCTZ 12.5 mg treatment phase, 52% were women, 23% were African American, and 14% were Hispanic. In addition, 30% had type 2 diabetes mellitus and 46% had the metabolic syndrome. Baseline blood pressure was 154.0 ± 10.3/91.3 ± 8.9 mm Hg. A total of 614 patients completed the 18-week study.
The mean change in systolic blood pressure from baseline to week 18 was -21.5 ± 14.3 mm Hg (P < .001). Figure 2 shows the mean change from baseline in systolic and diastolic blood pressure at the end of each of the study's treatment phases. Diastolic blood pressure also decreased significantly during the study period (-10.4 ± 8.7 mm Hg; P < .001). The mean blood pressure at week 18 was 132.9 ± 13.8/81.1 ± 0.7 mm Hg.
Figure 2. Mean change from baseline in systolic and diastolic blood pressure at the end of each treatment phase in the INCLUSIVE trial. SBP: systolic blood pressure; DBP: diastolic blood pressure. From Neutel, J Clin Hypertens (Greenwich)., 2005.
Overall, 77% of patients previously not at goal reached their systolic blood pressure goal, 83% of patients reached their diastolic blood pressure goal, and 69% achieved both systolic and diastolic blood pressure goals. Irbesartan was generally well tolerated in the study, with dizziness reported as the most common drug-related adverse event (3% of patients). Similar trends were reported in a subgroup analysis of patients with the metabolic syndrome and/or type 2 diabetes mellitus.
Neutel and associates conducted a study examining the effect of irbesartan/HCTZ vs irbesartan monotherapy as initial therapy in patients with severe hypertension (seated diastolic blood pressure > 110 mm Hg). In this double-blind, active-controlled, multicenter trial, patients were randomized to receive either irbesartan 150 mg/HCTZ 12.5 mg once daily titrated to irbesartan 300 mg/HCTZ 25 mg once daily or irbesartan 150 mg once daily titrated to 300 mg once daily. Dose titration occurred during the first week of the study. As shown in Figure 3, 33.2% of patients receiving monotherapy and 47.2% of patients receiving combination therapy reached the primary endpoint by week 5 (trough seated diastolic blood pressure < 90 mm Hg). The overall frequency of adverse events was lower in the irbesartan/HCTZ group vs the monotherapy group (29.9% vs 36.1%).
Figure 3. Percentage of patients receiving irbesartan monotherapy or combined irbesartan/HCTZ achieving seated diastolic blood pressure goal of < 90 mm Hg. IRB: irbesartan; HCTZ: hydrochlorothiazide; SeDBP: seated diastolic blood pressure. From Neutel, J Clin Hypertens., 2006.
A study by Gleim and colleagues examined the effect of adding low-dose HCTZ 12.5 mg to high-dose losartan 100 mg in hypertensive patients whose blood pressure remained uncontrolled with losartan (100 mg) monotherapy. Losartan 100 mg was administered to 376 patients during a 4-week, single-blind, filter period, during which time sitting diastolic blood pressure was measured at weeks 2 and 4. Patients with a mean trough sitting diastolic blood pressure of 90 to 120 mm Hg with stable blood pressure were eligible to enter the double-blind treatment period of the study. A total of 292 patients were enrolled in the double-blind period, with 147 randomized to the losartan/HCTZ group and 145 randomized to the losartan 100-mg group. Most patients in the double-blind treatment period were white (65%) and male (58%), with a mean age of 53.8 years (range, 24-87 years). More than 75% of patients had received previous antihypertensive therapy.
At the time of randomization to the double-blind treatment period, trough sitting diastolic blood pressure values were similar for both groups (97.5 and 97.0 mm Hg for the combination and monotherapy groups, respectively). Figure 4 shows that at week 6, the mean change in sitting diastolic blood pressure from baseline was significantly greater in patients who received combination therapy (8.3 mm Hg) than in those who received monotherapy (5.2 mm Hg) (P < .0001). In addition, the proportion of responders was significantly greater in the combination therapy group than in the monotherapy group (63% vs 44%; P < .0001). The mean trough sitting systolic blood pressure at randomization to the double-blind treatment period was also similar for both groups (147.3 and 144.3 mm Hg for the combination and monotherapy groups, respectively). At week 6, the mean trough sitting systolic blood pressure decreased 9.4 mm Hg in the combination group and 4.9 mm Hg in the monotherapy group (P = .006) (Figure 4). The incidence of adverse events was similar for both groups; 26% of the patients who received combination therapy and 28% of patients who received monotherapy reported adverse events.
Figure 4. Mean change (95% confidence interval) in trough blood pressure from prerandomization baseline (end of filter period) to week 6 of the double-blind treatment period. L100/HCTZ12.5: losartan 100 mg/hydrochlorothiazide 12.5 mg/ SiDBP: sitting diastolic blood pressure; SiSBP: sitting systolic blood pressure. From Gleim, Clin Ther., 2006.
Although the combination of losartan and HCTZ is among the agents not approved as first-line antihypertensives, it may be used as initial therapy when the hypertension is severe enough that the value of achieving prompt blood pressure control exceeds the risk of initiating combination therapy. In addition, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee recently recommended extended use of the combination product irbesartan plus HCTZ for the first-line treatment of hypertension.
Despite the large body of evidence that hypertension is a major risk factor for cardiovascular disease, blood pressure control rates remain low in the United States. Only about one fourth of individuals with hypertension maintain adequate control of blood pressure using medications.
The continued problem of poor blood pressure control can be attributed to a number of factors, including a reluctance of physicians to titrate medications (due to concerns such as increasing side effects and cost), the resistance to use combination therapy in the management of hypertension, and the lower optimal blood pressure goals set forth by various organizations in recent years. Poor adherence with hypertension management strategies is also a major obstacle to achieving adequate control of high blood pressure.
Several factors affect compliance with pharmacologic therapy, including the choice of the initial antihypertensive agent, the tolerance of side effects and of the agent in general, as well as the number of changes in the drug regimen.
Strategies to improve adherence must involve the patient, the provider, and the healthcare system. They should include patient education about hypertension and the importance of treatment, description of the potential complications of uncontrolled treatment, and simplification of the drug regimen with once-a-day dosing and/or a fixed-dose combination product.
Early and aggressive lowering of blood pressure may help to slow the processes involved in the progression of cardiovascular disease. Other potential benefits include improved tolerability, stroke prevention, and the prevention of diabetes.
In addition to improvement in clinical outcomes, there may be psychological benefits from early blood-pressure lowering. One study found that poor blood pressure control was associated with feelings of hopelessness, frustration with treatment, and perceived tension with blood pressure measurement. Early and aggressive treatment using combination therapy may help patients achieve blood pressure goal sooner, which may reduce these negative feelings and encourage patients to continue therapy longer.
Supported by an independent educational grant from Bristol-Myers Squibb and Sanofi-Aventis
Joel M. Neutel, MD
Assistant Clinical Professor of Medicine, University of California, Irvine, California; Chief, Department of Clinical Pharmacology and Hypertension, VA Medical Center, Long Beach, California; Director of Research, Orange County Heart Institute and Research Center, Orange, California; Principal Investigator, Memorial Research Medical Clinic, Long Beach, California.
Disclosure: Dr. Neutel has disclosed that he has received honoraria as a speaker from Forest, Pfizer, Biovail, Novartis, Bristol-Myers Squibb, Sanofi-Aventis, and Boehringer Ingelheim