While some clinical trials have shown that lowering BP reduces CV risk, others have sought to determine whether a particular agent or combination of agents is more effective in lowering BP than other agents (Figure 2). In addition, some trials have focused on the impact that lifestyle changes have on BP.
Figure 2. Combination therapy achieves blood pressure (BP) goals. The figure shows the number of antihypertensive medications required by patients in different clinical trials to achieve target systolic (SBP) goals. The clinical trials are those that randomly assigned patients to different levels of BP reduction. Most of the patients in these trials had hypertension plus diabetes or renal disease or cardiovascular disease. UKPDS indicates United Kingdom Prospective Diabetes Study; RENAAL, Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; IDNT, Irbesartan in Diabetic Nephropathy Trial; HOT, Hypertension Optimal Treatment study; INVEST, International Verapamil SR and Trandolapril Study; ABCD, Appropriate Blood Pressure Control in Diabetes; MDRD, Modification of Diet in Renal Disease study; and AASK, African-American Study of Kidney Disease and Hypertension. Updated and adapted from Bakris et al.25
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Dietary Approaches to Stop Hypertension
Studies of the Dietary Approaches to Stop Hypertension (DASH) eating plan,14 in which all food was prepared and given to the patients, indicate that lifestyle modifications, including reducing sodium intake, are crucial to lowering BP. Reducing sodium intake is particularly important in the United States, where men consume about 4200 mg/d of sodium and women consume about 3300 mg/d.
The DASH diet is high in fruits, vegetables, and low-fat dairy products.14,15 Studies have found that DASH menus containing 1500 mg of sodium reduce SBP by 11.5 mm Hg in patients with hypertension and by 7.1 mm Hg in those without hypertension.14,15
Sacks and colleagues14 randomized patients to 3 different levels of dietary sodium intake (150 mmol/d, 100 mmol/d, and 50 mmol/d; measured by urinary sodium excretion) and 2 different diets (the DASH diet and a diet typical of the average American diet). The DASH diet resulted in significantly lower SBP than the control diet at every sodium intake level (P<.001).
The American Medical Association is again requesting the Food and Drug Administration (FDA) to reduce the maximum allowable level of sodium in processed and restaurant foods by 50%. In addition, the FDA is asked to consider removing salt from the “generally recognized as safe” classification list, which contains foods and food additives that can be used without restrictions.16
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was designed as a randomized, multicenter, double-blind study comparing 4 different antihypertensive agents, a diuretic (chlorthalidone), a dihydropyridine calcium channel blocker (CCB) (amlodipine), an angiotensin-converting enzyme inhibitor (ACEI) (lisinopril), and an α-blocker (doxazosin), as initial therapy in 44,000 hypertensive patients 55 years and older with at least one other CHD risk factor.17
After an interim analysis, the doxazosin arm was discontinued. A significantly higher risk of stroke, congestive heart failure, angina with hospitalization, and coronary revascularization procedures was observed in the doxazosin group compared with the chlorthalidone group, although the primary outcome of fatal CHD and nonfatal myocardial infarction (MI) was not significantly different.18
The study was continued with the other 3 agents. The dose of each drug was titrated monthly to the maximum tolerated dose to achieve the BP goal of <140/90 mm Hg.
If the BP goal was not achieved with the maximum tolerated dose of blinded study medication, open-label step-2 or step-3 medication was added at the physician's discretion. If goal BP was not achieved with step-2 drugs (reserpine, clonidine, atenolol), the protocol allowed hydralazine as a step-3 drug. When clinically indicated, other drugs, including low doses of open-label drugs from step-1 drug classes, were allowed. The mean follow-up period was 4.9 years.17
After 5 years, the mean number of drugs used was 2.0±1.0. The number of patients who required multiple drugs to reach or remain at goal increased every year during the study; although all patients had begun treatment with monotherapy, 29% and 63% were taking 2 or more antihypertensive drugs at 6 months and 5 years, respectively. At baseline, only 27.4% of the patients were at goal, whereas 65.6% of patients were at goal at 5 years,17 highlighting the need for combination therapy to bring many hypertensive patients to BP goal.
Some significant differences were observed among the 3 arms of the study: chlorthalidone was more effective than lisinopril in lowering BP and decreasing strokes and heart failure and was superior to amlodipine in preventing heart failure; however, no significant differences in the primary outcome, fatal and nonfatal CHD events, were noted between amlodipine (relative risk, 0.98; 95% confidence interval, 0.90–1.07; P=.65) or lisinopril (relative risk, 0.99; 95% confidence interval, 0.91–1.08; P=.81) vs chlorthalidone.19
Valsartan Antihypertensive Long-Term Use Evaluation
The objective of the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE)20,21 was to compare the long-term effects of a valsartan-based compared with an amlodipine-based treatment on the incidence of cardiac morbidity and mortality in patients who achieved the same level of BP control. The most important knowledge gained from this trial, however, was the beneficial effect of early reduction in BP on cardiac outcomes, especially in high-risk patients.
VALUE was a prospective, multinational, double-blind, randomized, active-controlled, parallel-group trial of 15,245 hypertensive patients with high CV risk according to an algorithm based on CV risk profiles developed in the Framingham Heart Study. CV risk factors included cigarette smoking, diabetes, hypercholesterolemia, left ventricular hypertrophy, proteinuria, and increased serum creatinine. Disease factors included previous MI, peripheral vascular disease, and previous stroke or transient ischemic attack.20
The trial lasted 66 months, with a mean follow-up of 4.2 years. During the early phases of treatment, amlodipine-based therapy was significantly more effective in reducing SBP than valsartan. The overall difference in SBP was 2.23 mm Hg and in DBP was 1.5 mm Hg. The difference between the 2 drugs in lowering SBP was significant (P<.001) at every time point. The rapid and greater lowering of SBP persisted as a long-term benefit for the amlodipine patients. After 6 months of treatment, however, both drugs were relatively equal in efficacy for lowering BP. The amlodipine groups showed significantly better CV outcomes in the first 6 months of the study, when BP differences between treatment groups were greatest; however, no significant differences were found overall between the 2 agents in the primary composite end point of cardiac morbidity and mortality or all-cause mortality.21
Anglo-Scandinavian Cardiac Outcome Trial
The Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) was a prospective, randomized, open, blinded end point evaluation study of 19,257 hypertensive patients without previous MI or coronary artery disease (CAD) who had ≥3 risk factors for a CV event. Mean patient age was 63 years; median follow-up was 5.5 years.22
The study showed a slight differential in BP reduction: SBP was 2.7 mm Hg lower in patients given a CCB with an ACEI added, if necessary, than in patients on a β-blocker regimen with a diuretic added, if necessary. Although the primary outcome of nonfatal MI and fatal CHD was not significantly different between the 2 treatment arms, the CCB-based treatment strategy resulted in significantly fewer fatal and nonfatal strokes, total CV events and procedures, and all-cause mortality compared with the β-blocker-based strategy. The benefits of the CCB-based strategy were seen early and continued for at least 6 years. The data safety monitoring board recommended stopping the BP control arm of the study in October 2004 because of the difference in events.22
The International Verapamil SR and Trandolapril Study
The International Verapamil SR and Trandolapril Study (INVEST) was an international, open, blinded, end point evaluation study comparing β-blocker- and CCB-based treatment strategies in 22,576 hypertensive CAD patients aged 50 years and older. An ACEI was recommended in both arms for patients who developed heart failure, diabetes, or renal impairment during the trial. Mean follow-up was 2.7 years.23
The trial showed that BP control can be achieved in most hypertensive patients with CAD using a multidrug strategy.23
Furthermore, the 2 regimens provided equal BP reduction and were clinically equivalent in preventing death, MI, and stroke. Either strategy could be used in a clinically stable patient with CAD who requires BP control. The major difference between the 2 strategies was that there were fewer cases of new-onset diabetes among the patients on the CCB-based regimen.23
Trial of Preventing Hypertension
In the Trial of Preventing Hypertension (TROPHY), 809 participants who had prehypertension defined by JNC 7 guidelines as 120/80 mm Hg to 139/89 mm Hg were randomized to candesartan (n=409) or placebo (n=400) for 2 years. Both groups were instructed to make lifestyle changes to reduce their BP. Data were available for analysis from 772 participants (candesartan, 391; placebo, 381).24
During the first 2 years of the study, hypertension developed in 53 subjects in the candesartan group and 154 in the placebo group, which represented a relative risk reduction of 66.3% for the candesartan group (P<.001).24
At the end of 2 years, candesartan was discontinued, and all study participants received placebo for 2 years. The group originally randomized to the antihypertensive agent benefited by a relative risk reduction of new-onset hypertension 4 years after study initiation regardless of age, sex, weight, or ethnicity: 208 of 391 patients in the candesartan group and 240 of 381 in the placebo group developed hypertension, a relative risk reduction of 15.6% (P<.007).24