Key Articles and Guidelines in the Management of Hypertension

PRACTICE INSIGHTS Key Articles and Guidelines in the Management of Hypertension Simon de Denus, M.Sc.(Pharm.), Angela M. Hardy, Pharm.D., Kari L. Olson, Pharm.D., and Bryan Robinette, Pharm.D. Hypertension is a key risk factor for cardiovascular disease. Current management of hypertension, both pharmacologic and nonpharmacologic, is based on an extensive amount of published literature. We present a list of publications, clinical trials, meta-analyses, and clinical practice guidelines that we believe are essential in defining the current practice standards in the management of hypertension. Key Words: hypertension, clinical trials, meta-analysis, cardiovascular disease, key articles, treatment guidelines. (Pharmacotherapy 2004;24(10):1385–1399) OUTLINE Prevalence, Awareness, Treatment, and Control Clinical Practice Guidelines Meta-analyses of Clinical Trials Major Clinical Trials Diabetes Mellitus Diet Our understanding of the capital role played by hypertension as a risk factor for cardiovascular events and the importance of its treatment has greatly evolved in the past 75 years. 1 The literature supporting the management of hypertension is based on an extensive amount of evidence. In this article, publications that we believe are the most important in defining the current practice standards are reviewed. This list is the third list created (out of five) by members of the Cardiology Practice and Research Network of the American College of Clinical Pharmacy to provide clinicians with key publications in the various fields of cardiology: acute coronary From the Montreal Heart Institute and the Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada (Mr. de Denus); Kaiser Permanente Colorado, and the University of Colorado Health Sciences Center, Denver, Colorado (Drs. Hardy and Olson); and NorthEast Medical Center, Concord, North Carolina (Dr. Robinette). Address reprint requests to Simon de Denus, M.Sc.(Pharm.), Department of Pharmacy, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8; e-mail: [email protected]. syndromes,2 arrhythmias,3 hypertension, hyperlipidemia, and heart failure. Prevalence, Awareness, Treatment, and Control Wolf-Maier K, Cooper RS, Banegas JR, et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA 2003;289:2363–9. This retrospective review of eight international surveys assessed the geographic differences regarding the prevalence and treatment of hypertension. The authors demonstrated that hypertension was less prevalent in Canada (27.4%) and the United States (27.8%) than in Europe (44.2%) and that the proportion of patients receiving hypertensive agents was lowest in Europe (26.8%) compared with Canada (36.3%) and the United States (52.5%). Increased prevalence of hypertension was associated with increases in the risk of death from stroke and death from cardiovascular disease (CVD) in each country. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA 2003;290:199–206. This was the most recent analysis of National Health and Nutrition Examination Survey data to determine the prevalence, awareness, treatment, 1386 PHARMACOTHERAPY Volume 24, Number 10, 2004 and control of hypertension in the United States. The authors surveyed 5448 patients aged 18 years or older to determine hypertensive status, treatment, and control. Data from 1999-2000 indicated that hypertension was present in 28.7% of the population, an increase of 3.7% from a previous 1988–1991 cohort. A total of 68.9% were aware of their hypertension diagnosis. Treatment was started in 58.4% of patients with hypertension. Among those patients with hypertension and those actually treated, 31% and 53.1%, respectively, were controlled. These data indicate that better management of patients with hypertension is necessary. Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001; 345:1291–7. Although it was well established that persons with hypertension (blood pressure > 140/90 mm Hg) were at higher risk for CVD, there was limited information regarding the risk for CVD in persons with high-normal blood pressure. This study investigated the association between blood pressure category (optimal < 120/80 mm Hg vs normal 120–129/80–84 mm Hg vs high normal 130–139/85–89 mm Hg) at baseline and the occurrence of future CVD in 6859 participants in the Framingham Heart Study who were initially free of hypertension and CVD. Analysis showed that cardiovascular event rates increased in a stepwise manner across the three blood pressure categories. The risk was higher in men and in the elderly (age > 65 yrs). Clinical Practice Guidelines Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–72. These guidelines are the most recent recommendations for the management of hypertension and provide an update to the previous Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) 6 guidelines. The JNC 7 report classifies hypertension into prehypertension (systolic blood pressure 120–139 mm Hg or diastolic blood pressure 80–89 mm Hg), stage 1 hypertension (systolic 140–159 mm Hg or diastolic 90–99 mm Hg), and stage 2 hypertension (systolic ≥ 180 mm Hg or diastolic ≥ 100 mm Hg). The guidelines provide an algorithm for the treatment of hypertension. Treatment for patients with prehypertension consists of healthpromoting lifestyle modifications. The thiazide diuretics are considered first-line therapy for most patients with hypertension and no compelling indications. Patients with compelling indications (e.g., diabetes mellitus, heart failure) may require beginning other types of antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors or b-blockers. Most patients will require treatment with at least two agents. Blood pressure goals are less than 140/90 mm Hg for all patients except those with diabetes and chronic kidney disease, in whom the goal is less than 130/80 mm Hg. Canadian Hypertension Education Program, Evidence-Based Recommendations Task Force. The 2004 Canadian hypertension education program recommendations for the management of hypertension. Can J Cardiol 2004;20:31–59. Since 1999, the Canadian Hypertension Education Program (CHEP) meets yearly to update evidence-based recommendations for the management of hypertension. The guidelines highlight diagnostic modalities, blood pressure measurement, lifestyle changes, and pharmacologic treatment. The preferred first-line agents in patients with isolated systolic hypertension (ISH) and in patients with diastolic, with or without systolic, hypertension are addressed. Preferred agents for patients with compelling indications are also discussed. The target blood pressures established by these guidelines are less than 140/90 mm Hg in most patients, less than 130/80 mm Hg for patients with diabetes mellitus and those with renal disease, and less than 125/75 mm Hg in patients with proteinuria greater than 1 g/day. Guidelines Committee. 2003 European Society of Hypertension–European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011–53. In the past, the European Society of Hypertension together with the European Society of Cardiology did not create hypertension guidelines but rather endorsed the guidelines prepared by the World Health Organization–International Society of Hypertension. These guidelines are the first recommendations specifically directed toward management of the European population. The concept of “prehypertension” was not adopted from JNC 7. The European guidelines define KEY ARTICLES IN THE MANAGEMENT OF HYPERTENSION de Denus et al blood pressure as follows: optimal less than 120/80 mm Hg, normal 120–129/80–84 mm Hg, high normal 130–139/85–89 mm Hg, grade 1 hypertension 140–159/90–99 mm Hg, grade 2 hypertension 160–179/100–109 mm Hg, grade 3 hypertension 180 mm Hg or greater/110 mm Hg or greater, and ISH 140 mm Hg or greater/less than 90 mm Hg. Stratification of cardiovascular risk was updated to include diabetes, abdominal obesity, microalbuminuria, and C-reactive protein. The guidelines provide an algorithm for when to start antihypertensive treatment; however, specific recommendations for which drug to begin are not included. The European guidelines take the position that all classes of antihypertensive drugs can be considered as initial therapy. However, they do highlight conditions favoring the use of particular drug classes. The blood pressure goals are set forth as less than 140/90 mm Hg for most patients and, similar to JNC 7, less than 130/80 mm Hg for patients with diabetes. Arauz-Pacheco C, Parrott MA, Raskin P, for the American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care 2003;26(suppl 1):S80–2. The recommendations in this article are based on the American Diabetes Association Technical Review “Treatment of Hypertension in Patients with Diabetes” that was published in 2002 by the same authors (Diabetes Care 2002;25:134–47). That article is a concise review of relevant literature focusing on both nondrug and drug therapy in patients with type 1 and type 2 diabetes. The recommendations presented are for screening and diagnosis based on expert opinion. Treatment recommendations based on levels of evidence (A, B, C) are summarized. Douglas JG, Bakris GL, Epstein M, et al. Management of high blood pressure in AfricanAmericans: consensus statement of the Hypertension in African-Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med 2003;163:525–41. The prevalence of hypertension in AfricanAmericans is extremely high. This group of patients is at particular risk for hypertensionrelated complications. These guidelines refute the common belief that hypertension is more difficult to control in African-Americans. The guidelines highlight the importance of cardiovascular risk assessment, lifestyle changes, and pharmacologic treatment. Particularly, the 1387 authors recommend combination therapy as initial therapy in patients with a systolic blood pressure of 15 mm Hg or more above the target blood pressure or a diastolic blood pressure of 10 mm Hg or more above. In patients requiring a more modest reduction in blood pressure, the authors suggest diuretics, calcium channel blockers (CCBs), b-blockers, ACE inhibitors, or angiotensin II receptor blockers (ARBs) as monotherapy but acknowledge that the last three classes of agents may not be as effective to lower blood pressure in African-Americans as in Caucasians. Choices of agents in patients with compelling indications are also discussed. Meta-analyses of Clinical Trials Messerli FH, Grossman E, Goldbourt U. Are bblockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA 1998;279:1903–7. Diuretics have been shown to be efficacious and safe for elderly patients; however, the role of b-blockers in the elderly is less clear. This metaanalysis was done to determine the efficacy of bblockers compared with thiazides on cardiovascular morbidity and mortality and all-cause morbidity. The authors identified all randomized studies of at least 1 year’s duration that evaluated bblockers or thiazides in elderly patients (age > 60 yrs) with hypertension. There were 10 studies involving 16,164 patients included in the analysis. Cerebrovascular events were reduced by 39% and 26% for thiazides and b-blockers, respectively. Stroke mortality was reduced by 33% and 24% for thiazides and b-blockers, respectively. The odds for coronary heart disease (CHD) were reduced by 26% with diuretics, however, not with b-blockers. Both cardiovascular mortality and all-cause mortality were reduced with thiazides, however, not with b-blockers. The results from this analysis suggest that diuretics should be first-line therapy over bblockers in elderly patients with hypertension. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet 2000;355:865–72. The authors reviewed studies of patients aged 60 years or older with systolic blood pressure greater than 160 mm Hg and diastolic blood pressure less than 95 mm Hg. The studies evaluated the outcomes of total and cardiovascular mortality, all cardiovascular complications, fatal 1388 PHARMACOTHERAPY Volume 24, Number 10, 2004 and nonfatal stroke, fatal and nonfatal coronary events, and sudden death. A total of 15,693 patients from eight studies were included. Various antihypertensive strategies were used; however, in most cases a stepped-care approach was taken. Total mortality was positively correlated with systolic blood pressure but was inversely correlated with diastolic blood pressure. Active treatment reduced total mortality by 13% (p=0.02) and cardiovascular deaths by 18% (p=0.01). The meta-analysis also found that treatment was more beneficial in men, patients aged 70 years or older, and patients with previous cardiovascular complications. Pahor M, Psaty BM, Alderman MH, et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials. Lancet 2000;356:1949–54. Observational and some randomized trials had shown that CCBs may increase the risk of coronary events. The purpose of this metaanalysis was to determine whether intermediateor long-acting CCBs were superior, equal, or inferior to other antihypertensive therapies in reducing coronary vascular events. Eligible studies were those that used a randomized controlled design, enrolled patients with hypertension, compared a CCB with another agent, assessed cardiovascular end points, had at least 2 years of follow-up, and enrolled at least 100 patients. Nine studies were included. The control of both systolic and diastolic blood pressure was similar among those treated with or without CCBs. The odds ratios (ORs) for acute myocardial infarction (OR 1.26, 95% confidence interval [CI] 1.11–1.43), heart failure (OR 1.25, 95% CI 1.07–1.46), and major cardiovascular events (OR 1.10, 95% CI 1.02–1.18) favored other antihypertensive therapy over CCBs. No differences were noted in the outcomes of stroke or all-cause mortality. Neal B, MacMahon S, Chapman N, for the Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood pressure–lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000;356:1955–64. Calcium channel blockers and other blood pressure–lowering agents have been shown to reduce mortality and other cardiovascular morbidities among a variety of different patient populations. Various studies were included in this analysis to evaluate the benefit of ACE inhibitors and CCBs and of different intensities of blood pressure control. The primary outcome measures were stroke, CHD, heart failure, cardiovascular death, any cardiovascular event, or total mortality. In studies comparing ACE inhibitors with placebo, most patients included had a history of CVD or diabetes mellitus. Significant decreases of 20–30% were noted in the rate of stroke, CHD, major cardiovascular events, cardiovascular death, and total mortality. When comparing CCBs with placebo (most patients had hypertension), significant decreases of 30–40% were noted in the rate of stroke, major cardiovascular events, and cardiovascular death. In studies comparing more intensive versus less intensive interventions, significant decreases were noted in the rate of stroke, CHD, and major cardiovascular events in the more intensive groups; however, no differences were noted in the rate of heart failure, CHD, cardiovascular death, or total mortality. No differences were noted in any end point in studies that compared ACE inhibitors with b-blockers or thiazides; however, marginal differences were noted in some end points in studies that compared CCBs with b-blockers or thiazides, or CCBs with ACE inhibitors. Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a metaanalysis. Lancet 2001;358:1305–15. Several trials previously conducted suggested that certain antihypertensive agents offered cardiovascular protection independent of blood pressure lowering. This meta-analysis aimed to determine whether pharmacologic properties of specific antihypertensive drugs (b-blockers, diuretics, ACE inhibitors, CCBs, a-blockers) or reduction of systolic blood pressure accounted for these differences in cardiovascular outcomes. Twenty-seven trials including 136,124 patients were analyzed. Analyses suggested that all antihypertensive agents had similar long-term efficacy and safety. In general, the greater the blood pressure reduction, the greater the cardiovascular benefit. In those studies that suggested a difference in outcomes with a specific agent, blood pressure differences between groups were sufficient to account for differences in the outcome. There were a few noted exceptions. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the rate of heart failure with doxazosin therapy was double that with KEY ARTICLES IN THE MANAGEMENT OF HYPERTENSION de Denus et al chlorthalidone treatment. Blood pressure differences between the groups could account for only a 10–20% increase in the occurrence of heart failure. Also, compared with b-blockers and diuretics, CCBs demonstrated a greater reduction in the risk of stroke (in some cases this was true despite a higher systolic blood pressure) and less reduction in risk of acute myocardial infarction (despite similar or greater blood pressure reduction). Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 2003;289:2534–44. The primary goal of this network meta-analysis was to compare low-dose diuretics with placebo or other first-line antihypertensive therapies (bblockers, CCBs, ACE inhibitors, ARBs, and ablockers) on major health outcomes (risk of CHD, heart failure, stroke, cardiovascular events, cardiovascular mortality, and all-cause mortality). A total of 192,478 patients from 42 randomized controlled trials were included. Low-dose diuretics were shown to be superior to placebo on all cardiovascular end points and on all-cause mortality. Furthermore, low-dose diuretics were shown to be as effective as or superior to all other first-line agents on all end points studied. The authors therefore highlighted that low-dose diuretics should be considered the most effective first-line antihypertensive agents to prevent cardiovascular morbidity and mortality in patients with uncomplicated hypertension. Gueyffier F, Boutitie F, Boissel JP, et al. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men: a meta-analysis of individual patient data from randomized, controlled trials. The INDANA Investigators. Ann Intern Med 1997;126:761–7. This meta-analysis included seven randomized, controlled clinical trials from the Individual Data Analysis of Antihypertensive Intervention Trials database. The primary goal was to determine if there is a difference in hypertension treatment effect between men and women. Equal numbers of men (19,957) and women (20,802) were included in the analysis, with most patients treated with either b-blockers or thiazide diuretics. No difference was noted in relative risk reduction between men and women. The benefit for women was primarily in prevention of strokes, whereas men benefited to an equal degree in prevention of both coronary events and 1389 strokes. The absolute risk reduction attributable to antihypertensive treatment for both men and women is dependent on untreated risk, underlying the need to predict the untreated cardiovascular risk accurately for individual patients in order to rationalize and individualize antihypertensive treatment. Major Clinical Trials The IPPPSH Collaborative Group. Cardiovascular risk and risk factors in a randomized trial of treatment based on the b-blocker oxprenolol: the international prospective primary prevention study in hypertension (IPPPSH). J Hypertens 1985;3:379–92. Before the publication of IPPPSH, studies had shown that b-blockers could reduce total mortality, sudden death, and nonfatal reinfarction in patients after an acute myocardial infarction. However, only observational studies existed that suggested b-blockers were cardioprotective in patients with essential hypertension. The primary objective of IPPPSH was to evaluate antihypertensive regimens that contained oxprenolol compared with regimens without this agent. There were 6357 patients with essential hypertension (diastolic blood pressure 100-125 mm Hg) randomly assigned to slow-release oxprenolol (3185 patients) or placebo (3172 patients) in a double-blind fashion. Other agents could be added as necessary to achieve a goal diastolic blood pressure of less than (or equal to) 95 mm Hg. After 3–5 years of follow-up, no significant difference was noted in sudden death, fatal acute myocardial infarction, and fatal cerebrovascular accidents between groups. Wilhelmsen L, Berglund G, Elmfeldt D, et al. bBlockers versus diuretics in hypertensive men: main results from the HAPPHY trial. J Hypertens 1987;5:561–72. Previous studies had shown that diuretic-based regimens lowered mortality and morbidity from stroke and heart failure in patients with hypertension; however, the effect on CHD was unknown. Studies were emerging on the efficacy of b-blockers in patients with CHD, but little information was known on the efficacy of these agents in patients without CHD. The Heart Attack Primary Prevention in Hypertension trial enrolled 6569 men aged 40–64 years with no history of heart disease and with a diastolic blood pressure of 100–130 mm Hg. Patients were randomly assigned in an open-label fashion to 1390 PHARMACOTHERAPY Volume 24, Number 10, 2004 receive either atenolol or metoprolol (3297 patients) and bendrofluazide or hydrochlorothiazide ([HCTZ] 3272 patients) and followed for a mean of 45.1 months. The proportion of patients achieving the goal diastolic blood pressure of less than 95 mm Hg did not differ between groups. No difference was noted in the rate of CHD. No differences were noted in the number of stroke events or deaths between groups. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the systolic hypertension in the elderly program (SHEP). JAMA 1991;265:3255–64. Isolated systolic hypertension is an independent risk factor for strokes and CVD, and its prevalence increases with age. At the time the SHEP trial was conducted, the benefit of treating ISH, particularly in elderly patients, was uncertain. Anecdotal reports had suggested an increase in the risk of strokes after starting antihypertensive treatment. The SHEP trial was a multicenter, double-blind trial in which 4736 elderly patients (age ≥ 60 yrs, mean age 72 yrs) with ISH (blood pressure 160–219/< 90 mm Hg) were randomly assigned to antihypertensive therapy (step 1 chlorthalidone, step 2 atenolol) or placebo, to evaluate the risk of stroke. The results established that the treatment of ISH with a chlorthalidone-based regimen not only significantly reduced the risk of stroke in elderly patients, but also reduced the combined end point of major cardiovascular events. Dahlof B, Lindholm LH, Hansson L, et al. Morbidity and mortality in the Swedish trial in old patients with hypertension (STOP-Hypertension). Lancet 1991;338:1281–5. At the time of this study, the benefits of antihypertensive therapy in patients younger than 70 years were well established. The benefits of antihypertensive therapy in the elderly (age > 70 yrs) were less clear. The STOP-Hypertension trial was designed to evaluate the benefits of conventional antihypertensive therapy (bblockers and/or diuretics) in patients aged 70–84 years. Active treatment resulted in a significant reduction in blood pressure associated with significant reductions in cardiovascular morbidity and mortality, as well as total mortality. These results were seen early in the study and became more pronounced with time. This was the first study to demonstrate that the benefits of treating hypertension in the elderly are similar to those seen with antihypertensive therapy in younger patients. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992;304:405–12. At the time of this trial, the benefits of treating hypertension in patients aged 35–64 years were well established. However, the data on the effect of treating hypertension in the elderly were limited. This trial compared atenolol, HCTZ, and combined therapy with HCTZ and amiloride in terms of reducing cardiovascular and all-cause mortality in patients aged 65–74 years. Overall, the results of this trial showed that active treatment led to a significant reduction in cardiovascular events. These results were attributed primarily to significant reductions in all outcomes in patients treated with diuretic therapy. Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs cooperative study group on antihypertensive agents. N Engl J Med 1993;328:914–21. This was one of the first studies that compared the blood pressure–lowering effects of different classes of antihypertensive agents. In this study, 1292 men with diastolic blood pressure of 95–109 mm Hg were randomly assigned to receive placebo, HCTZ, atenolol, captopril, clonidine, diltiazem, or prazosin, with the dosage titrated to a goal diastolic blood pressure of less than 90 mm Hg and maintenance of diastolic blood pressure at less than 95 mm Hg 1 year after treatment. All agents performed significantly better than placebo. The diltiazem group had the highest proportion of patients (59%) achieving the outcome measure, which was not significantly better than atenolol (51%), clonidine (50%), or HCTZ (46%). In addition, there were differences in response rates based on age and race. The study results suggest that both race and age have a role in response to antihypertensive agents; however, more studies are needed to evaluate differences in clinical outcomes among drug classes. The authors concluded that antihypertensive treatment should likely be tailored to the individual patient because, overall, only small differences in efficacy were noted among agents. Neaton JD, Grimm RH Jr, Prineas RJ, et al. Treatment of mild hypertension study: final KEY ARTICLES IN THE MANAGEMENT OF HYPERTENSION de Denus et al results. Treatment of mild hypertension study research group. JAMA 1993;270:713–24. This study compared the safety and efficacy of lifestyle modification alone and lifestyle modification in addition to monotherapy with one of five antihypertensive agents (acebutolol, amlodipine, enalapril, chlorthalidone, and doxazosin) in patients with stage 1 hypertension. The results demonstrated that drug treatment in addition to lifestyle modification is more effective than lifestyle modification alone not only in lowering blood pressure, but also in preventing clinical events. Earlier studies suggested an increased rate of CHD events below a threshold diastolic blood pressure. This study disproved this J-curve relationship. The peak effect of lifestyle modification was seen at 6 months or less, which confirmed the JNC 5 recommendation that drug therapy should be added if blood pressure remains uncontrolled after 6 months of lifestyle modification. The study was inadequately powered to compare the different drug treatments in terms of their ability to affect cardiovascular morbidity and mortality; however, some significant differences were detected in surrogate parameters; most notably, chlorthalidone demonstrated the greatest reduction in left ventricular hypertrophy. Siscovick DS, Raghunathan TE, Psaty BM, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med 1994;330: 1852–7. The Multiple Risk Factor Intervention Trial suggested that treatment with high-dose thiazide diuretics might increase the risk of sudden cardiac death. This study evaluated the risk of primary cardiac arrest with respect to thiazide therapy at varying dosages, in combination with potassium-sparing diuretics or in combination with potassium supplementation. Overall, thiazide therapy was not associated with a higher risk of cardiac arrest when compared with bblockade. A dose-response relationship was identified and demonstrated that moderate-dose (50 mg/day) and high-dose (100 mg/day) thiazide therapy conferred a higher risk than did low-dose (25 mg/day) thiazide therapy. Addition of a potassium-sparing diuretic further reduced the risk of sudden cardiac death. Addition of potassium supplementation had no impact on risk. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active 1391 treatment for older patients with isolated systolic hypertension. The systolic hypertension in Europe (Syst-Eur) trial investigators. Lancet 1997;350:757–64. Prior studies demonstrated the benefit of diuretics on reducing clinical outcomes in elderly patients. The Syst-Eur trial was a double-blind study designed to evaluate the role of CCBs in reducing cardiovascular complications in the elderly. Patients aged 60 years or older with systolic blood pressure of 160–219 mm Hg and diastolic blood pressure less than 95 mm Hg were randomly assigned to receive nitrendipine (2398 patients) or placebo (2297 patients) and followed for an average of 24 months. Procedures were in place for additional therapy with enalapril or HCTZ, if necessary. A significant decrease was noted in the primary end point of fatal and nonfatal stroke in the CCB group. Also, significant decreases were noted in fatal and nonfatal cardiac events, but no difference was noted in cardiovascular or all-cause mortality. Although the Syst-Eur trial did not find mortality benefit, it was one of the first studies to demonstrate a clinical benefit of CCBs in elderly patients. Philipp T, Anlauf M, Distler A, Holzgreve H, Michaelis J, Wellek S. Randomised, double blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment: results of the HANE study. HANE trial research group. BMJ 1997; 315:154–9. The Hydrochlorothiazide, Atenolol, Nitrendipine, Enalapril (HANE) study compared the antihypertensive efficacy of b-blockers, thiazides, ACE inhibitors, and CCBs in a more general hypertensive population than had been previously evaluated. The HANE study was a double-blind, randomized, multicenter trial comparing HCTZ 12.5 mg/day (215 patients), atenolol 25 mg/day (215 patients), nitrendipine 10 mg/day (218 patients), and enalapril 5 mg/day (220 patients) in patients aged 21–70 years with diastolic blood pressure of 95–120 mm Hg. Dosages were titrated to achieve a target diastolic blood pressure of less than 90 mm Hg. Significantly more patients receiving atenolol achieved the target blood pressure compared with those receiving the other agents. At week 48, atenolol remained significantly better than HCTZ and nitrendipine, but was similar to enalapril. The HANE study demonstrated that the newer antihypertensive agents such as CCBs and ACE 1392 PHARMACOTHERAPY Volume 24, Number 10, 2004 inhibitors were not superior to b-blockers in lowering blood pressure. Furthermore, studies evaluating clinical outcomes with CCBs and ACE inhibitors were still needed. Liu L, Wang G, Gong L, et al. Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. J Hypertens 1998;16:1823–9. This study was conducted to evaluate the efficacy of antihypertensive therapy in reducing fatal and nonfatal strokes among an elderly Chinese population with ISH. A total of 2394 patients were randomly assigned in a single-blind fashion to receive nitrendipine (1253 patients) or placebo (1141 patients). Captopril, HCTZ, or both were added to both groups as necessary for blood pressure reduction. After a mean followup of 3 years, the nitrendipine group had significantly fewer strokes compared with the placebo group (20.8 vs 13.0 strokes/1000 patientyrs, p=0.01). In addition, significant decreases were noted in total mortality, cardiovascular mortality, and stroke mortality in the active treatment group. This study had limitations in that approximately 20% of the population studied did not meet inclusion criteria. Furthermore, the method of blinding treatments may have been flawed. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the hypertension optimal treatment (HOT) randomised trial. The HOT study group. Lancet 1998;351:1755–62. The HOT trial had two aims: first, to test whether the relationship between blood pressure and the risk of CVD is shaped as a J-curve, and second, to evaluate the benefit of low-dose aspirin (75 mg/day) in patients with hypertension. In this study, 18,790 patients were randomly assigned to three different diastolic blood pressure targets (≤ 90, ≤ 85, or ≤ 80 mm Hg) with a felodipine-based regimen of antihypertensive agents. They were then randomly assigned in a double-blind fashion to receive aspirin or placebo. Major cardiovascular events were similar among groups, mainly because a similar diastolic blood pressure was reached in all groups (85.2, 83.2, and 81.1 mm Hg, respectively). Therefore, it was not possible to prove or refute the J-curve hypothesis. Nonetheless, the benefit of a more aggressive blood pressure lowering was observed in diabetic patients as the risk for cardiovascular events decreased across the groups (p=0.005 for trend). The use of aspirin reduced the risk of cardiovascular events by 15% (p=0.03), mainly through a reduction of acute myocardial infarctions. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the captopril prevention project (CAPPP) randomised trial. Lancet 1999;353: 611–16. The CAPPP trial was the first large randomized trial to compare an ACE inhibitor (captopril) with conventional antihypertensives (diuretics, b-blockers, or both at the discretion of the investigator). In this prospective, randomized open trial with blinded end points, captopril was given at a dosage of 50–100 mg/day or twice/day. A total of 10,985 patients (diastolic blood pressure ≥ 100 mm Hg on two occasions) were included. No significant difference was observed on the primary end point of myocardial infarction, stroke, or cardiovascular death between the captopril group (11.1 events/1000 patient-yrs) and the conventional group (10.2 events/1000 patient-yrs, p=0.52), although the rate of fatal and nonfatal strokes was higher in the captopril group (p=0.044). Therefore, although the results of the CAPPP trial suggest that there is no major difference on the efficacy of captopril to prevent major cardiovascular events compared with conventional antihypertensives, the trial was not able to demonstrate that captopril was superior to such agents as initially hypothesized or to exclude moderate differences between treatments. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity. The Swedish trial in old patients with hypertension-2 study. Lancet 1999;354:1751–6. At the time of this study, it was well established that treatment of hypertension with conventional therapy (b-blockers and diuretics) resulted in significant decreases in cardiovascular morbidity and mortality. Questions remained, however, regarding the safety and efficacy of newer antihypertensive agents (ACE inhibitors and CCBs). The CAPPP trial raised concerns that an ACE inhibitor–based regimen may be less protective than a conventional regimen, and the CCBs had never been compared with conven- KEY ARTICLES IN THE MANAGEMENT OF HYPERTENSION de Denus et al 1393 tional treatment. The STOP-Hypertension-2 trial was designed to compare conventional therapy with newer antihyptensive agents in terms of cardiovascular morbidity and mortality. The results demonstrated that old and new antihypertensive drugs were similar in blood pressure reduction and prevention of cardiovascular morbidity and mortality. Compared with CCBs, there were significantly fewer fatal and nonfatal acute myocardial infarctions and less frequency of heart failure in the ACE inhibitor group. This was the first study to establish the safety and efficacy of CCBs in this population, and it confirmed the protective benefits of ACE inhibitors. was superior to an antihypertensive regimen of diuretics or b-blockers in reducing the risk of stroke, acute myocardial infarction, or cardiovascular death in 10,881 patients with hypertension (diastolic blood pressure ≥ 100 mm Hg). No significant differences between treatment was observed between treatment groups (diltiazem 16.6 events/1000 patient-yrs vs diuretics or bblockers 16.2 events/1000 patient-yrs, p=0.97). Therefore, although the initial hypothesis of the superiority of diltiazem was not achieved, the results of this study suggest that treatment with diltiazem could provide similar benefit to that of diuretics and b-blockers, although moderate differences could not be excluded. Lakshman MR, Reda DJ, Materson BJ, Cushman WC, Freis ED. Diuretics and b-blockers do not have adverse effects at 1 year on plasma lipid and lipoprotein profiles in men with hypertension. Department of Veterans Affairs cooperative study group on antihypertensive agents. Arch Intern Med 1999;159:551–8. Previous studies suggested a detrimental effect on plasma lipid and lipoprotein profiles with various antihypertensive agents, mainly thiazide diuretics and b-blockers. Most of these studies were short in duration, and long-term data with these drugs were lacking. This study was designed to evaluate the potential adverse lipid effects of six different classes of antihypertensive drugs in 1292 men with diastolic hypertension. Patients were randomly assigned to receive HCTZ, atenolol, captopril, clonidine, diltiazem, or prazosin and were followed for 1 year. After 8 weeks of treatment, those who did not respond to HCTZ showed small increases in apolipoprotein B and total cholesterol levels compared with those who did respond. No other agents showed significant lipid changes at 8 weeks. After 1 year, none of the agents were associated with significant lipid changes except for minor decreases in high-density lipoprotein cholesterol levels in patients treated with HCTZ, clonidine, and atenolol. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting CCB or diuretic in the international nifedipine GITS study: intervention as a goal in hypertension treatment (INSIGHT). Lancet 2000; 356:366–72. The INSIGHT study was a randomized, double-blind, multicenter study to compare the efficacy of long-acting nifedipine 30 mg (3157 patients) with co-amilozide (HCTZ 25 mg plus amiloride 2.5 mg, 3164 patients). Patients had a blood pressure of at least 150/95 mm Hg or a systolic blood pressure greater than 160 mm Hg plus at least one cardiovascular risk factor. Mean blood pressure decreased by 33/17 mm Hg and remained at approximately 138/82 mm Hg for the remainder of the study. No differences were seen in the primary end point of death from any cardiovascular or cerebrovascular cause, nonfatal stroke, acute myocardial infarction, and heart failure. The authors concluded that the choice of treatment should be based on a regimen with the best tolerability and blood pressure response for an individual patient rather than on efficacy alone. Hansson L, Hedner T, Lund-Johansen P, et al. Randomised trial of effects of calcium antagonists compared with diuretics and b-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic diltiazem (NORDIL) study. Lancet 2000;356:359–65. The NORDIL study was a prospective, randomized, open-label study with blinded end points that tested the hypothesis that diltiazem PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood pressure– lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033–41. In this prospective, randomized, placebocontrolled trial, the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) investigators evaluated the effect of blood pressure–lowering treatment (perindopril with or without indapamide) on the risk of experiencing a stroke (fatal or nonfatal) in 6105 patients with 1394 PHARMACOTHERAPY Volume 24, Number 10, 2004 or without hypertension who had a history of stroke or transient ischemic attack. Randomization took into account the intention of the treating physician to give perindopril alone or in combination with indapamide. Overall, the risk of experiencing a stroke was significantly reduced in the active treatment group, as was the risk of experiencing a major cardiovascular event (stroke, acute myocardial infarction, or cardiovascular death). Further analysis revealed significant heterogeneity of treatment effect, mainly that monotherapy with perindopril had no significant effect on the risk of experiencing these end points and that the clinical benefit was observed only in patients receiving the combination therapy. Benefit was apparent among patients with and those without hyper-tension. Overall, this study provided evidence that a blood pressure–lowering treatment consisting of a combination of perindopril and indapamide reduces the risk of stroke in patients with a history of stroke or transient ischemic attack, irrespective of their initial blood pressure, but that perindopril monotherapy does not. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002;288:2421–31. Agodoa LY, Appel L, Bakris GL, et al, for the African-American Study of Kidney Disease and Hypertension (AASK) Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001;285:2719–28. The AASK trial was designed to compare the effects of two levels of blood pressure control (achieved mean blood pressure 122/78 vs 141/85 mm Hg) and three antihypertensive drug classes (b-blocker metoprolol 50–200 mg/day, ACE inhibitor ramipril 2.5–10 mg/day, and dihydropyridine-CCB amlodipine 5–10 mg/day) on glomerular filtration rate, end-stage renal disease, and death. Although slight trends favored the lower blood pressure goal in participants with baseline proteinuria greater than 300 mg/dl, overall no additional benefit was noted with more aggressive blood pressure control. The study may not have been adequately powered to detect a difference in this parameter. In terms of absolute glomerular filtration rate at the end of study, no difference among treatment groups was detected. This result was due to an acute increase in glomerular filtration rate in the amlodipine group. In terms of the chronic glomerular filtration rate decline, ramipril was superior to metoprolol, which was superior to amlodipine. A significant increase in proteinuria was seen in the amlodipine group, whereas a significant decrease was seen in the ramipril and metoprolol groups. In terms of end-stage renal disease and death, both ramipril and metoprolol were found to be superior to amlodipine. This study was the first to demonstrate a renoprotective effect of ACE inhibitors in the AfricanAmerican population and supports the use of ACE inhibitors as first-line therapy over bblockers and dihydro-pyridine-CCBs for prevention of renal outcomes. The results of the AASK trial do not support additional blood pressure reduction as a strategy to prevent the progression of hypertensive nephrosclerosis. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995–1003. The LIFE trial compared losartan with atenolol in terms of reducing cardiovascular morbidity and mortality in patients aged 55–80 years with essential hypertension and left ventricular hypertrophy. Patients were randomly assigned to receive losartan or atenolol 50 mg/day. Dosage titration to 100 mg/day as well as the addition of other antihypertensive agents were performed to reach a target blood pressure of less than 140/90 mm Hg. The primary end point was cardiovascular morbidity and mortality. Other outcome measures included total mortality, angina or heart failure requiring hospitalization, revascularization procedures, resuscitated cardiac arrest, and newonset diabetes mellitus. The results showed that both treatments resulted in similar blood pressure reduction. Losartan was better tolerated, resulting in a lower rate of discontinuation due to adverse effects. Treatment with a losartan-based regimen resulted in a significant reduction in the primary outcome, as well as stroke and new-onset diabetes. This was the first trial to demonstrate cardioprotective benefits of ARBs in any population. The lower rate of new-onset diabetes confirmed the results of previous studies with ACE inhibitors. 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;283:1967–75. KEY ARTICLES IN THE MANAGEMENT OF HYPERTENSION de Denus et al The ALLHAT trial was the largest ever trial comparing different antihypertensive agents. It was a randomized, double-blinded trial designed to compare newer antihypertensive agents like aadrenergic blockers (doxazosin), ACE inhibitors (lisinopril), and CCBs (amlodipine) with a thiazide diuretic (chlortalidone) in hypertensive patients aged 55 years or older and with at least one coronary artery disease risk factor. The doxazosin arm was discontinued prematurely, and results were reported in this article because of a higher number of cardiovascular events in the doxazosin group (9067 patients) compared with that in the chlorthalidone group (15,268 patients). Although no significant difference was seen on the primary end point of CHD (fatal CHD and nonfatal acute myocardial infarction), doxazosin use was associated with a significant increase of combined cardiovascular events (fatal CHD, nonfatal acute myocardial infarction, stroke, coronary revascularization, angina, heart failure, and peripheral artery disease) compared with chlorthalidone (25.5% vs 21.8%, p<0.001). These results demonstrated that a-adrenergic blockers are not as protective as thiazide diuretics and therefore should not be considered as firstline agents in high-risk hypertensive patients. ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to ACE inhibitor or CCB vs diuretic: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2002;288:2981–97. This article presents the results of the chlortalidone (15,255 patients), amlodipine (9048), and lisinopril (9054 patients) groups from ALLHAT. After a mean follow-up of 4.9 years, no significant difference was observed on the primary end point of CHD among the groups. Similarly, all-cause mortality was similar among the groups. Nonetheless, compared with chlortalidone, the use of amlodipine was associated with an increased risk of heart failure (relative risk [RR] 1.38, 95% CI 1.25–1.52), whereas the use of lisinopril was associated with an increased risk of the combined CVD (RR 1.10, 95% CI 1.05–1.16), stroke (RR 1.15, 95% CI 1.02–1.30), and heart failure (RR 1.19, 95% CI 1.07–1.31). Results were consistent in all prespecified subgroups (elderly patients, women, AfricanAmericans, patients with diabetes mellitus). Therefore, the results of ALLHAT demonstrated that the efficacy of thiazide diuretics is unsurpassed in the treatment of hypertension, 1395 and, because of their lower cost, these agents should be considered the preferred agents in most patients with uncomplicated hypertension. Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583–92. In the Second Australian National Blood Pressure Study, a prospective, randomized, openlabel study with blinded end points, the investigators compared an ACE inhibitor–based regimen (enalapril recommended) with a diuretic-based regimen (HCTZ recommended) in 6083 elderly patients aged 65–84 years. An ACE inhibitor regimen significantly reduced the risk of all-cause mortality or cardiovascular events compared with the diuretic regimen (56.1 events/1000 patient-yrs vs 59.8 events/1000 patient-yrs, p=0.05), despite similar blood pressure reduction in both groups during the trial. These results conflicted with the results of ALLHAT, which had been published only months earlier. Black HR, Elliott WJ, Grandits G, et al. Principal results of the controlled onset verapamil investigation of cardiovascular end points (CONVINCE) trial. JAMA 2003;289:2073–82. Psaty BM, Drummond DR. Stopping medical research to save money: a broken pact with researchers and patients [editorial]. JAMA 2003;289:2128–31. The CONVINCE trial was a randomized, double-blind, controlled trial that compared verapamil controlled-onset extended-release with either atenolol or low-dose HCTZ. This trial included 16,602 patients aged 55 years or older with hypertension plus an additional risk factor for CVD. The trial was stopped 2 years early by the sponsor for commercial reasons when only 729 of the planned 2246 primary events (acute myocardial infarction, stroke, or cardiovascular death) had occurred. The study was therefore not powered to demonstrate the superiority or equivalency of verapamil compared with atenolol or HCTZ. The authors of the accompanying editorial discuss the ethical implications of stopping a clinical trial for commercial reasons. Diabetes Mellitus Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. The 1396 PHARMACOTHERAPY Volume 24, Number 10, 2004 collaborative study group. N Engl J Med 1993; 329:1456–62. This was the first study designed to show that ACE inhibitors have renal protective effects independent of their blood pressure–lowering effects in patients with insulin-dependent diabetes mellitus and diabetic nephropathy (serum creatinine level ≤ 2.5 mg/dl and urinary protein excretion ≥ 500 mg/day). A total of 409 patients were randomly assigned in a 1:1 fashion to receive either captopril or placebo. Significantly fewer captopril-treated patients had a doubling in serum creatinine level and a slower annual decline in creatinine clearance compared with patients in the placebo group. Captopril was also associated with a 50% reduction in the risk of combined end points of death, dialysis, and transplantation. These benefits were independent of the small difference observed in blood pressure between the two groups. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with ISH. Systolic hypertension in the elderly program cooperative research group. JAMA 1996;276:1886–92. In this subgroup analysis of the SHEP study, the authors evaluated patients with non–insulindependent diabetes and nondiabetic patients with ISH who were treated with chlorthalidone or placebo. A total of 4736 patients (583 patients with non–insulin-dependent diabetes) with ISH (systolic blood pressure ≥ 160 mm Hg) were included in the study. After 5 years of follow-up, the major CVD rates (fatal plus nonfatal stroke, nonfatal acute myocardial infarction, fatal CHD, major CHD events, and all-cause mortality) for patients with and without diabetes were significantly lower for active treatment compared with placebo. The absolute risk reduction with active treatment compared with placebo was twice as great in patients with diabetes compared with that in patients without diabetes, suggesting increased baseline risk in the diabetic patient population. Tatti P, Pahor M, Byington RP, et al. Outcome results of the fosinopril versus amlodipine cardiovascular events randomized trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998;21:597–603. This was an open-label, randomized, prospective trial comparing an ACE inhibitor (fosinopril) with a CCB (amlodipine) in 380 patients with type 2 diabetes and hypertension. The 380 patients were randomly assigned in a 1:1 fashion, with average follow-up of 3.5 years. Both therapies were effective in lowering blood pressure. Both agents produced similar biochemical effects on total cholesterol, highdensity lipoprotein cholesterol, hemoglobin A1c, fasting serum glucose, or plasma insulin. Fosinopril-treated patients had a significantly lower risk of the combined outcomes of acute myocardial infarction, stroke, or hospitalization for angina compared with that in the amlodipinetreated patients (hazards ratio 0.49, 95% CI 0.26–0.95). Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non–insulin-dependent diabetes and hypertension. N Engl J Med 1998;338:645–52. This study was designed to help answer the question of safety and effectiveness of CCBs in hypertensive patients with non–insulindependent diabetes and to evaluate the effect of moderate versus intensive blood pressure control on the occurrence and complications of diabetes. The Appropriate Blood Pressure Control in Diabetes study was designed to evaluate moderate (target diastolic blood pressure 80–89 mm Hg) and intensive (target diastolic blood pressure ≤ 75 mm Hg) blood pressure control on the frequency and progression of complications of type 2 diabetes. Nisoldipine and enalapril were compared as first-line antihypertensive agents on the secondary end point of acute myocardial infarction. Nisoldipine was associated with a significantly higher rate of fatal and nonfatal acute myocardial infarctions despite similar control of blood pressure, lipids, glucose, and smoking behavior. These results suggested that CCBs may not be as protective as other agents to reduce cardiovascular events. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998;317: 713–20. In this study, which was a continuation of the United Kingdom Prospective Diabetes Study 38, the investigators evaluated the effects of tight blood pressure control (target blood pressure < 150/< 85 mm Hg) with either an ACE inhibitor (captopril) or a b-blocker (atenolol) on preventing macrovascular and microvascular complications KEY ARTICLES IN THE MANAGEMENT OF HYPERTENSION de Denus et al of type 2 diabetes. A total of 758 patients were allocated to the tight blood pressure control arm (captopril 400 patients, atenolol 358 patients), with 390 patients included in the less tight blood pressure control arm. Both agents were equally effective at reducing blood pressure in the tight control arm with a similar number of patients in each group requiring three or more antihypertensive agents. Both agents were also equally effective at reducing macrovascular and microvascular complications. Neither agent was superior at preventing diabetic complications, suggesting that the absolute blood pressure reduction may be more important than the specific antihypertensive agent used. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703–13. The macrovascular and microvascular complications of type 2 diabetes may be decreased by tight blood pressure control compared with less tight control, but data are lacking. This study compared tight blood pressure control (< 150/85 mm Hg) with less tight control (< 180/105 mm Hg) on diabetes-related end points in 1148 hypertensive patients with type 2 diabetes. The median follow-up was 8.4 years. An ACE inhibitor or b-blocker was used as the main treatment in the tight blood pressure control arm. The mean blood pressure was significantly lower in the tight control arm than in the less tight control arm. Tight blood pressure control also produced significant reductions in diabeticrelated end points, death related to diabetes, strokes, and microvascular end points compared with less tight blood pressure control. Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic hypertension in Europe trial investigators. N Engl J Med 1999;340:677–84. Some epidemiologic evidence suggests that dihydropyridine CCBs may be harmful in patients with diabetes. In this post hoc analysis of the SHEP study, the authors used the dihydropyridine CCB nitrendipine to address the treatment outcomes in a cohort of both patients with and without diabetes who had ISH. A total of 4695 patients (10.5% with diabetes) were randomized and followed for a median of 2 years. Blood pressure control was similar in both patients with and without diabetes. Active 1397 treatment with nitrendipine reduced overall mortality, cardiovascular mortality, fatal and nonfatal strokes, and all cardiac events in both diabetic and nondiabetic patients, with the diabetic cohort receiving significantly more benefit in all treatment outcomes. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000;321:1440–4. Both ACE inhibitors and ARBs have been shown to reduce urinary albumin excretion in hypertensive type 2 diabetic patients, but no head-to-head comparisons or combination studies had been performed. This prospective, double-blind study evaluated the effects of candesartan, lisinopril, or a combination of both in 199 hypertensive type 2 diabetic patients. Both treatments produced similar reductions in diastolic blood pressure and urinary albumin: creatinine ratio at 24 weeks, but the combination therapy group was superior to either treatment alone. Combination therapy with an ACE inhibitor and an ARB was well tolerated and more effective in reducing blood pressure and urinary albumin:creatinine ratio in hypertensive type 2 diabetic patients. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–60. The Irbesartan Diabetic Nephropathy Trial was conducted to determine whether the use of an ARB would protect against the progression of nephropathy in hypertensive patients with type 2 diabetes. In this study, 1715 patients were randomly assigned in a double-blind fashion to receive irbesartan, amlodipine, or placebo with a target blood pressure of less than 135/85 mm Hg. The primary end point was a doubling of serum creatinine level, development of end-stage renal disease, or death. The risk of reaching the primary end point was significantly lower in the irbesartan group compared with the amlodipine group (p=0.006) and placebo group (p=0.02), mainly through a reduction of the progression of renal dysfunction. No difference in the risk of mortality was observed among the groups. No significant difference was observed between the 1398 PHARMACOTHERAPY Volume 24, Number 10, 2004 placebo group and the amlodipine group. Therefore, this study established the efficacy of irbesartan to prevent the progression of nephropathy in patients with type 2 diabetes, although the value of ARBs compared with ACE inhibitors remains to be established. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–9. Agents that block the renin-angiotensin system have been shown to slow the progression of nephropathy in patients with type 1 diabetes, but less data exist for patients with type 2 diabetes, the most common type. This study evaluated the benefits of ARB therapy on the composite end point of progression of renal disease (doubling of serum creatinine level, end-stage renal disease) or death in patients with type 2 diabetes. A total of 1513 patients were randomly assigned to receive placebo or losartan 50-100 mg/day and followed for a mean of 3.4 years. Losartan treatment significantly reduced the rate of doubling of serum creatinine level and end-stage renal disease compared with placebo but had no effect on mortality. There was a significant difference in favor of losartan on lowering the rate of first hospitalization for heart failure. The results of this study suggest that ARBs are effective for reducing the progression of nephropathy in patients with type 2 diabetes. Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359: 1004–10. Hypertensive diabetic patients with evidence of left ventricular hypertrophy are at very high risk for cardiovascular complications. The best antihypertensive agent in this population is unclear. This double-blind, randomized, parallelgroup study evaluated the effects of atenolol and losartan in 1195 hypertensive type 2 diabetic patients with electrocardiographic evidence of left ventricular hypertrophy. The primary end point of cardiovascular death, stroke, or acute myocardial infarction was reached in significantly more atenolol-treated patients after a mean follow-up of 4.7 years. Mean blood pressure was similar between groups, but the composite end point of cardiovascular morbidity and mortality occurred significantly more often in the atenololtreated patients. The beneficial effects of losartan appear to be independent of its blood pressure– lowering effects. Snow V, Weiss KB, Mottur-Pilson C. The evidence base for tight blood pressure control in the management of type 2 diabetes mellitus. Ann Intern Med 2003;138:587–92. Type 2 diabetes is a major cause of morbidity and mortality in the United States and worldwide. Most patients with type 2 diabetes also have concomitant hypertension. Recent studies evaluating the effects of tight blood pressure control over less tight control have shown dramatic benefits on reducing diabetic complications. These clinical guidelines provide a concise review of the relevant literature related to tight blood pressure control in patients with type 2 diabetes. The article also reviews the literature related to the benefits of tight blood pressure control, target blood pressure levels, and the effectiveness of different classes of antihypertensive drugs. Four recommendations are drawn from this literature review to aid the clinician in the treatment of patients with type 2 diabetes and concomitant hypertension. Vijan S, Hayward RA. Treatment of hypertension in type 2 diabetes mellitus: blood pressure goals, choice of agents, and setting priorities in diabetes care. Ann Intern Med 2003;138:593–602. This article is a review of randomized trials that reported either microvascular or macrovascular outcomes and evaluated the pharmacologic treatment of hypertension in patients with diabetes mellitus. It is a concise review of the major pharmacologic hypertension studies performed in diabetic patients and is separated into two categories: studies evaluating the effects of hypertension control if the comparison examined an antihypertensive drug versus placebo, and those evaluating the effects of different target blood pressure levels. Treating type 2 diabetic patients with hypertension to goals of less than 135/80 mm Hg provides significant benefits. Most patients require multiple agents to achieve these blood pressure goals, with thiazide diuretics, ACE inhibitors, and ARBs as the best first-line treatments. Aggressive blood pressure control may be the most important factor in preventing adverse outcomes in type 2 diabetic patients with hypertension. Diet Midgley JP, Matthew AG, Greenwood CM, Logan AG. Effect of reduced dietary sodium on KEY ARTICLES IN THE MANAGEMENT OF HYPERTENSION de Denus et al blood pressure: a meta-analysis of randomized controlled trials. JAMA 1996;275:1590–7. This meta-analysis was performed to evaluate the evidence on the effect of sodium restriction on lowering blood pressure in normotensive and hypertensive individuals. Decreases in systolic blood pressure in response to sodium restriction of 100 mEq/day were 2.4–6.3 mm Hg in hypertensive patients. African-American patients and patients older than 45 years demonstrated a greater change in blood pressure for an equivalent change in dietary intake of sodium. In normotensive patients, no significant change was noted in blood pressure in response to the 100mEq/day sodium restriction. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997;336:1117–24. The Dietary Approaches to Stop Hypertension (DASH) diet emphasizes fruits, vegetables, and low-fat dairy products and is reduced in total and saturated fat and cholesterol. This study evaluated the impact of the DASH diet on blood pressure and demonstrated that this diet lowers blood pressure substantially in both people with and those without hypertension as compared with a typical American diet. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (DASH) diet. DASH-sodium collaborative 1399 research group. N Engl J Med 2001;344:3–10. This trial evaluated the effect of different levels of dietary sodium (high 3.5 g/day, intermediate 2.4 g/day, low 1.4 g/day) in conjunction with the DASH diet or a control diet (typical American diet) on blood pressure in hypertensive and normotensive patients (blood pressure ranges 120–159/80–95 mm Hg). The results demonstrated a stepwise decrease in blood pressure control across the three levels of dietary sodium intake regardless of the diet. The reduction of blood pressure in response to dietary sodium restriction was less in combination with the DASH diet than that seen in combination with the control diet. The low-sodium DASH diet produced the most significant reductions in blood pressure. Compared with the high-sodium control diet, the low-sodium DASH diet lowered systolic blood pressure by 11.5 mm Hg in hypertensive patients and 7.1 mm Hg in normotensive patients. In hypertensive patients, the effects of the lowsodium DASH diet were equal to or greater than that of single-drug therapy. References 1. Hay JH. The significance of a raised blood pressure. BMJ 1931;2:43–7. 2. Dobesh PP, Brouse SD, Johnson DC, et al. Key articles and guidelines relative to treatment of patients with acute coronary syndromes. Pharmacotherapy 2004;24:105–44. 3. Cheng JW, Frank L, Garrett SD, et al. Key articles and guidelines in pharmacotherapeutic management of arrhythmias. Pharmacotherapy 2004;24:248–79.