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Abstract

  1. Top of page
  2. Abstract
  3. TREATMENT GUIDELINES RECOMMEND AGGRESSIVE BP THERAPY
  4. LOWER BP IMPROVES CV OUTCOMES
  5. CHOOSING APPROPRIATE TREATMENT
  6. CONCLUSIONS
  7. References

Hypertension management is both routine and a challenge. Updated guidelines emphasize the need to achieve increasingly stringent blood pressure goals to reduce cardiovascular morbidity and mortality; however, the blood pressure of many patients who have been diagnosed with hypertension is not well controlled. Treating prehypertension nonpharmacologically may preempt the progression to hypertension, whereas early and aggressive management of hypertension with antihypertensive agents reduces short- and long-term cardiovascular risk. Treatment decisions should follow current guidelines while evaluating recently published clinical studies. When choosing between agents from different therapeutic classes or combining agents, physicians should consider current and targeted blood pressure levels, the patient's demographic profile, the presence or absence of compelling cardiovascular and metabolic indications, other comorbidities, and concurrent medication(s).

Despite effective antihypertensive agents and aggressive treatment guidelines, the incidence of hypertension continues to increase; it climbed 30% between 1994 and 2000, according to National Health and Nutrition Examination Surveys (NHANES).1 Between 1999 and 2002, the prevalence of hypertension was estimated at 28.6% of the US population, amounting to more than 66 million people.1 At least part of this increase may be attributed to better methods of detection, especially among the elderly, for whom the definition of isolated hypertension had been changed from >160/<90 mm Hg to >140/<90 mm Hg.

NHANES data from 1999 to 2002 indicate that 63.4% of hypertensive individuals were aware of their condition but only 45.3% received treatment and 34% were controlled (blood pressure [BP] <140/90 mm Hg).2 The consequences of uncontrolled hypertension are considerable. Coronary heart disease (CHD), the leading cause of death in the United States, was responsible for 502,189 deaths in 2001.3,4 With approximately 49% of CHD cases related to hypertension, hypertension-related CHD mortality can be estimated at 246,000 cases per year.3,4 Data on cardiovascular (CV) mortality/morbidity, however, indicate a decrease of >60% in strokes and >50% in CHD deaths over the past 30 years; a large part of this has been attributed to the better management of hypertension.5 More has to be done, however.

These data emphasize the additional need to educate the public about the serious effects of hypertension and to continue to educate physicians about the benefits of aggressive hypertension therapy.

TREATMENT GUIDELINES RECOMMEND AGGRESSIVE BP THERAPY

  1. Top of page
  2. Abstract
  3. TREATMENT GUIDELINES RECOMMEND AGGRESSIVE BP THERAPY
  4. LOWER BP IMPROVES CV OUTCOMES
  5. CHOOSING APPROPRIATE TREATMENT
  6. CONCLUSIONS
  7. References

Based on data from clinical trials of hypertensive agents in various patient populations, national and international organizations concerned with hypertension and other CV risk factors have established similar BP goals. Each of the organizations recommend a BP <140/90 mm Hg for patients with no other CV risk factors. For those with other risk factors such as diabetes or kidney disease, guidelines recommend a BP <130/80 mm Hg. Some organizations recommend BP goals that are even lower for hypertensive or prehypertensive individuals who have comorbidities.6–10

International Society on Hypertension in Blacks

Because of compelling evidence that shows a higher prevalence of hypertension and poorer CV and renal outcomes in African Americans compared with white Americans, the International Society on Hypertension in Blacks (ISHIB) recommends combination therapy in patients who have systolic BP (SBP) ≥15 mm Hg or diastolic BP (DBP) ≥10 mm Hg above BP goal compared with BP ≥20 mm Hg/10 mm Hg above goal for recommendations from the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). The ISHIB also recommends a BP goal <130/80 mm Hg for hypertensive patients with nondiabetic renal disease accompanied with proteinuria >1 g/d.6

The National Kidney Foundation

To prevent the progression of kidney disease, the National Kidney Foundation states that BP of 125/75 mm Hg is preferable in patients with proteinuria (macroalbuminuria, ie, >300 mg albumin/g creatinine).7,8

The American Diabetes Association

Hypertension affects 20%–60% of individuals with diabetes. For this reason, the American Diabetes Association advises that all patients with diabetes have routine BP measurements at each doctor visit. The American Diabetes Association's guidelines for individuals with diabetes recommend BP <130/80 mm Hg.9

The JNC

JNC guidelines have emerged as the standard in managing hypertension and are used by most primary care physicians in the United States (Figure I).6 The Seventh Report of the JNC (JNC 7)10 recommends BP <140/90 mm Hg for lower-risk individuals with hypertension who have no other compelling conditions. JNC 7 also recommends BP <130/80 mm Hg for patients with diabetes or chronic kidney disease. The guidelines suggest that most hypertensive patients will require 2 or more antihypertensive agents from different drug classes to reach BP goal. As a result, the guidelines advise clinicians to consider initiating therapy with 2 medications in patients whose initial BPs are >20 mm Hg above systolic goal or >10 mm Hg above diastolic goal.10

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Figure 1. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) treatment algorithm. JNC 7 recommends the addition of a second drug from a different class when adequate doses of a single agent fail to achieve the patient's blood pressure (BP) goal. Initiation of therapy with 2 drugs (either separate or as a fixed-dose combination) when systolic BP (SBP) is >20 mm Hg and diastolic BP (DBP) >10 mm Hg above goal (ie, ≥160/100 mm Hg). It also states that patients whose BP is elevated and who have comorbid conditions may require more than 2 antihypertensive agents as initial therapy. HTN indicates hypertension; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β-blocker; and CCB, calcium channel blocker. Reproduced with permission from the Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.10

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LOWER BP IMPROVES CV OUTCOMES

  1. Top of page
  2. Abstract
  3. TREATMENT GUIDELINES RECOMMEND AGGRESSIVE BP THERAPY
  4. LOWER BP IMPROVES CV OUTCOMES
  5. CHOOSING APPROPRIATE TREATMENT
  6. CONCLUSIONS
  7. References

In general, CHD death rates increase as SBP and DBP rise. Until the mid-1970s and early 1980s, DBP was considered the best predictor of coronary events and stroke; however, it has long been established that SBP is a better predictor of CV outcomes. SBP is strongly associated with age-specific mortality rates from stroke and almost as strongly associated with age-specific mortality rates from ischemic heart disease and other vascular diseases.11,12 Because the prevalence of isolated systolic hypertension increases with advancing age, elderly people should be screened routinely and treated for hypertension if SBPs are consistently >140 mm Hg.13

A meta-analysis of 61 prospective observational studies in nearly 1 million patients in Europe, North America, Australia, Japan, and China who had no previous vascular disease showed that the risk of CV events is reduced by 35%–60% for every 20-mm Hg reduction in SBP in nearly all age groups.11 Investigators determined the number of deaths attributable to stroke, ischemic heart disease, other vascular causes, and nonvascular causes during 5 decades of age at risk (in subjects aged 40–89 years). In correlating mortality during each decade at death to the estimated usual BP at the start of that decade, it was found that a 20-mm Hg difference in usual SBP included a hazard approximately equivalent to a 10-mm Hg difference in usual DBP. While the relative risk reduction associated with BP lowering in older patients was lower than other age groups, the absolute risk remained clinically important. The relationships continued, without evidence of a threshold, down to at least 115/75 mm Hg. As a result, the risk of ischemic heart disease at 140/90 mm Hg is about 30% higher than at 120/80 mm Hg, suggesting that the lower the BP, the better the outcome for the patient.11

CHOOSING APPROPRIATE TREATMENT

  1. Top of page
  2. Abstract
  3. TREATMENT GUIDELINES RECOMMEND AGGRESSIVE BP THERAPY
  4. LOWER BP IMPROVES CV OUTCOMES
  5. CHOOSING APPROPRIATE TREATMENT
  6. CONCLUSIONS
  7. References

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.

image

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

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. TREATMENT GUIDELINES RECOMMEND AGGRESSIVE BP THERAPY
  4. LOWER BP IMPROVES CV OUTCOMES
  5. CHOOSING APPROPRIATE TREATMENT
  6. CONCLUSIONS
  7. References

All treatment guidelines for hypertension recommend early and aggressive therapy to reduce the risk of CV mortality and morbidity. In addition to therapeutic lifestyle changes, most hypertension patients may require multiple antihypertensive agents to achieve therapeutic goals. Clinical trials have determined that an average of 3.2 antihypertensive medications are required daily in patients with hypertension and other risk factors to achieve at least suboptimal BP levels, according to the National Kidney Foundation.24 Suboptimal levels are above the recommended BP of <140/90 mm Hg, <130/80 mm Hg in patients with type 2 diabetes, and <125/75 mm Hg in patients with chronic kidney disease and >1 g proteinuria.25

More than two thirds of hypertensive individuals cannot achieve BP control on monotherapy.17 Clinical data support the notion that multidrug therapy is superior to monotherapy in reducing BP but, in most studies, the BP achieved with multidrug regimens may be suboptimal (Figure 2).25 JNC 7 guidelines recommend that antihypertensive therapy with more than 1 agent be considered as initial treatment when a patient's BP is >20 mm Hg above SBP goal or >10 mm Hg above DBP goal (ie, ≥160/100 mm Hg).10 In ALLHAT, 60% of patients who reached the goal of <140/90 mm Hg required at least 2 agents.17

Initiating therapy with 2 or more drugs decreases BP to goal faster and at lower doses of the individual drugs than starting with monotherapy. Lowering BP quickly may also achieve a better CV outcome, as shown in the VALUE and ASCOT trials. Fixed-dose combination agents can also be considered and may be particularly useful if the patient has difficulty in complying with a multidrug regimen.

Deciding which drug classes to use in specific patients should be in accordance with guidelines and demographic considerations as well as level of BP, with other comorbidities and medications taken concurrently. In the quest to further reduce CV morbidity and mortality, the importance of aggressive antihypertensive treatment and good BP control cannot be overemphasized.

References

  1. Top of page
  2. Abstract
  3. TREATMENT GUIDELINES RECOMMEND AGGRESSIVE BP THERAPY
  4. LOWER BP IMPROVES CV OUTCOMES
  5. CHOOSING APPROPRIATE TREATMENT
  6. CONCLUSIONS
  7. References
  • 1
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  • 2
    Centers for Disease Control and Prevention. Racial/ethnic disparities in prevalence, treatment, and control of hypertension—United States, 1999–2002. MMWR Morb Mortal Wkly Rep. 2005;54:79.
  • 3
    American Heart Association. Cardiovascular disease statistics. Available at: http:www.americanheart.orgpresenter.jhtml?identifier=4478. Accessed October 28, 2004.
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    Anderson RN, Smith BL. Deaths: leading causes for 2001. Natl Vital Stat Rep. 2003;52:185.
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    Moser M. Hypertension treatment: a success study. J Clin Hypertens (Greenwich). 2006;8:313314.
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    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 International Society on Hypertension in Blacks. Arch Intern Med. 2003;163:525541.
  • 7
    Keane WF, Eknoyan G. Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): a position paper of the National Kidney Foundation. Am J Kidney Dis. 1999;33:10041010.
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    Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the National Kidney Foundation (NKF) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Am J Kidney Dis. 2003;42:617622.
  • 9
    Arauz-Pacheco C, Parrott MA, Raskin P. Hypertension management in adults with diabetes. Diabetes Care. 2004;27(suppl 1):S65S67.
  • 10
    Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:12061252.
  • 11
    Lewington S, Clarke R, Qizilbash N, et al., for the Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:19031913.
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    National Institutes of Health. National Heart, Lung, and Blood Institute. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). Available at: http:www.nhlbi.nih.govguidelinescholesterolatp3full.pdf. Accessed June 21, 2006.
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    Neaton JD, Wentworth DN, Cutler J, et al. Risk factors for death from different types of stroke. Multiple Risk Factor Intervention Trial Research Group. Ann Epidemiol. 1993;3:493499.
  • 14
    Sacks FM, Svetkey LP, Vollmer WM, et al, for the DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med. 2001;344:310.
  • 15
    US Dept of Health and Human Services. National Heart, Lung, and Blood Institute. Your guide to lowering your blood pressure with DASH. Available at: http:www.nhlbi.nih.govhealthpublichearthbpdash. Accessed June 26, 2006.
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    Japsen B, Schmeltzer J. Doctors hoping to dash salt's “safe” label. Chicago Tribune. June 13, 2006:1.
  • 17
    Cushman WC, Ford CE, Cutler JA, et al, for the ALLHAT Collaborative Research Group. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich). 2002;4:393404.
  • 18
    The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2000;283:19671975.
  • 19
    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;288:29812997.
  • 20
    Mann J, Julius S. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial of cardiovascular events in hypertension. Rationale and design. Blood Press. 1998;7:176183.
  • 21
    Julius S, Kjeldsen SE, Weber M, etal, for the VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:20222031.
  • 22
    Dahlof B, Sever PS, Poulter NR, et al, for the ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895906.
  • 23
    Pepine CJ, Handberg EM, Cooper-DeHoff RM, etal, for the INVEST Investigators. A calcium antagonist vs a noncalcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003;290:28052816.
  • 24
    Julius S, Nesbitt SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354:16851697.
  • 25
    Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36:646661.