the importance of prompt blood pressure control

suppl. 1 VOl. 10 NO. 1 JaNuary 2008 THE JOurNal Of CliNiCal HypErTENsiON 13

Hypertension affects almost one-third of adults in the United States, but blood pressure is adequately controlled in only about 50% to 60% of persons with treated hypertension. Abundant clinical trial evidence has shown that antihypertensive therapy significantly reduces the risk of vascular events, and meta-analyses of observational and clinical trials have shown that greater reductions in blood pressure are associated with greater reductions in risk. Recent trials have also suggested that prompt control of blood pressure is beneficial in high-risk patients with hypertension. A post hoc analysis of a trial comparing an angiotensin II receptor block-er–based program with a calcium channel blocker–based treatment regimen found that the blood pressure response after 1 month (regardless of the drug used) predicted the risk of vascular events and survival. Therapy with ≥2 medications given separately or as a fixed combination is more likely than monotherapy to lower blood pressure to goal in part because drugs from different classes target different mechanisms that regulate blood pressure. Moreover, the likelihood of achieving blood pres-sure goals is greater if the time to achieve control is shortened, and prompt control of blood pres-sure is more likely with multiple-drug therapy than with monotherapy. (J Clin Hypertens (Greenwich). 2008;10(1 suppl 1):13–19) ©2008 Le Jacq

Hypertension affects about 26% of the adult population worldwide. The estimated disease

burden in 2000 was 972 million persons and is predicted to increase to 1.56 billion persons by 2025.1 in the united states, hypertension affects almost 30% of persons aged 40 years and older and 66% of those aged 60 years and older.2–4 The prevalence is similar in men and women and is highest in non-Hispanic black men and women. although data from the National Health and Nutrition Examination survey in the united states show improvements in the awareness, treatment, and control of hypertension over the past few years, blood pressure (Bp) is adequately controlled (<140/90 mm Hg) in only about 1 of 3 persons with hypertension (Table i).4 More recent data from a national Harris interactive poll and the Behavioral risk factor surveillance system in 2007 indicate that hypertension is being treated in high percentages of patients, but they confirm that the percentage of persons with treated hyperten-sion that is controlled to Bp goal is still only about 50% to 60%.5,6 Control of Bp is also suboptimal in European countries and in Canada.7 Clearly, greater efforts must be made to achieve goal Bp levels in more patients.

Importance of achIevIng Bp goalsinadequate control of Bp exacerbates an ongo-ing public health problem because hypertension markedly increases the risk of vascular morbidity and mortality.8 in addition, hypertension tends to cluster with other risk factors, such as obesity, diabetes mellitus or glucose abnormalities, and dyslipidemia, and the heightened risk of cardio-vascular disease seen in patients with hyperten-sion is compounded in the presence of these other risk factors.9,10 Hypertension also exacts a heavy

R e v i e w P a p e r

the Importance of prompt Blood pressure control

Jan Basile, MD

From the Primary Care Service Line, Ralph H. Johnson VA Medical Center, and the Division of General Internal Medicine/Geriatrics, Medical University of South Carolina, Charleston, SCAddress for correspondence: Jan Basile, MD, Ralph H. Johnson VA Medical Center, 109 Bee Street, Charleston, SC 29403E-mail: [email protected]

www.lejacq.com ID: 8027

The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright ©2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at [email protected] or 781-388-8511.

®

THE JOurNal Of CliNiCal HypErTENsiON suppl. 1 VOl. 10 NO. 1 JaNuary 200814

economic toll. The estimated direct health care cost for treatment of hypertension in the united states in 2007, which includes the cost of physicians, hos-pital and nursing home services, medications, and home health care, amounts to $49.3 billion. When indirect costs (loss of productivity) are added in, the total rises to $66.4 billion.11

There is abundant evidence that antihyperten-sive treatment can reduce the risk of cardiovas-cular events: stroke by 35% to 40%, myocardial infarction by 20% to 25%, and heart failure by >50%.12–14 in a meta-analysis of prospective obser-vational studies, lower systolic and diastolic Bp values (down to 115/75 mm Hg) were associated with lower risks of vascular mortality.13 a meta-analysis of clinical trials reported that the major determinant of clinical outcomes is the achieved systolic Bp level and not necessarily specific medi-cations.15 These data suggest that there may not be a threshold systolic Bp value below which no further reduction in risk is seen.8

adequate Bp control is key to reducing the risk of cardiovascular events, and the benefits of this therapeutic approach are especially pronounced in high-risk groups such as patients with dia-betes mellitus.15–17 in the diabetic cohort of the Hypertension Optimal Treatment (HOT) study,17 the lower the achieved diastolic Bp level (81 mm Hg vs 85 mm Hg), the greater the reduction in the risk of cardiovascular morbidity and mortality. in the united Kingdom prospective Diabetes study (uKpDs 38),18 significant reductions in the risk of any diabetes-related end points, stroke, and micro-vascular disease were observed in diabetic patients in whom lower Bp levels were achieved (mean Bp level over 9 years of 144/82 mm Hg) compared with those in whom they were not achieved (mean Bp level of 154/87 mm Hg).

evIdence for the BenefIt of prompt Bp controlin addition to adequate Bp control, prompt Bp control is an important goal of therapy in high-risk patients.16 results from several clinical trials, including the Valsartan antihypertensive long-Term use Evaluation (ValuE),19 the systolic Hypertension in Europe (syst-Eur) trial,20 the study on Cognition and prognosis in the Elderly (sCOpE),21 the anglo-scandinavian Cardiac Outcomes Trial–Blood pressure lowering arm (asCOT-Bpla),22 and the antihypertensive and lipid-lowering Treatment to prevent Heart attack Trial (allHaT),23 suggest that the risk of vascu-lar events is significantly influenced by the time it takes to achieve Bp control.

results of ValuE indicated that there was no significant difference in the primary end point (composite of cardiac mortality and morbidity) between patients who received valsartan-based therapy (angiotensin ii receptor blocker) and those who received amlodipine-based therapy (calcium channel blocker) (hazard ratio, 1.04; 95% confi-dence interval [Ci], 0.94–1.15; P=.49), but there was a difference in overall cardiovascular events: the calcium channel blocker group had fewer events (789 [10.4%]) than the angiotensin ii recep-tor blocker group (810 [10.6%]).19 Throughout the study, Bp was significantly lower in amlodipine-treated patients than in valsartan-treated patients (P<.0001). The between-group difference in Bp was 4.0/2.1 mm Hg at 1 month and about 2.0/1.6 mm Hg from 6 months on.19 The differences in outcome have been attributed by some investiga-tors to this early Bp response. according to a post hoc analysis of ValuE results, the Bp response after 1 month predicted the risk of vascular events and survival. regardless of drug treatment,

Table I. Awareness, Treatment, and Control of Hypertension, NHANES 1999–2004a and Recent SurveysPatients, % (SE)

NHANES 1999–2000

NHANES 2001–2002

NHANES 2003–2004

Harris Interactive 2007 BRFSS 2007

Awareness 63.0 (3.2) 62.5 (3.0) 66.5 (3.2) — —Treatment 47.3 (2.4) 50.1 (2.6) 53.7 (2.8) >90 >70Control (all patients

with hypertension)25.0 (1.8) 30.3 (2.2) 33.1 (2.3)b >50 —

Control (patients with treated hypertension)

51.3 (5.8) 63.9 (6.0) 63.9 (5.9) — —

Abbreviation: BRFSS, Behavioral Risk Factor Surveillance System. aNational Health and Nutrition Examination Survey (NHANES) data are weighted to the US population, and rates shown are age-adjusted. bP<.01 for the difference between 1999 and 2000 and 2003 and 2004. Adapted from Ong et al,4 Moser and Franklin,5 and the Centers for Disease Control and Prevention (CDC).6


®


patients whose hypertension responded immediate-ly and those in whom target Bp was achieved by 6 months demonstrated significant reductions in risk of cardiovascular events.24 (immediate response was defined as no increase in Bp in previously treated patients who switched to the study drug or a 10-mm Hg decrease in Bp in patients with previ-ously untreated hypertension at 1 month.)

The 4-year open-label extension20 of the double-blind placebo-controlled syst-Eur trial in hyper-tensive patients aged 60 years and older offered an opportunity to compare immediate therapy (persons in the active-treatment arm of the double-blind study) with delayed therapy (persons in the placebo arm of the double-blind trial who started active therapy in the extension trial). immediate antihypertensive therapy was associated with a 28% reduction (95% Ci, 7%–44%) in the relative risk of stroke (P=.01) and a 15% reduction (95% Ci, 2%–26%) in cardiovascular complications (P=.03) compared with delayed therapy. These risk reductions were entirely due to the significant benefits associated with initiation of active treat-ment immediately after randomization during the double-blind phase of the study; there were no between-group differences in any end points dur-ing the extension trial.20 Table ii shows systolic Bp findings in both groups at enrollment in the open-label phase and at study end.

in sCOpE, there was only a modest difference in Bp (3.2/1.6 mm Hg) between candesartan (angio-tensin ii receptor blocker) treatment and placebo treatment (patients who received therapy other than candesartan). This small effect was associated with modest, nonsignificant reductions in major cardiovascular events25; however, the design of sCOpE allowed the use of open-label antihyper-tensive agents as needed beginning 3 months after randomization. This complicates interpretation of the results. By study end, 84% of patients in the control group were receiving open-label antihyper-tensive therapy.25 a post hoc analysis comparing candesartan-treated patients with patients in the placebo arm who did not receive add-on therapy found that a greater reduction in systolic Bp in

the candesartan arm (4.6/2.6 mm Hg) was associ-ated with significant reductions in the relative risk of major cardiovascular events (32%; P=.013), cardiovascular-related mortality (29%; P=.049), and total mortality (27%; P=.018).21 in the overall population, candesartan-based therapy significant-ly reduced the incidence of nonfatal stroke (27.8%; P=.04).25 although this effect could reflect delayed therapy in the placebo group, it has been specu-lated that candesartan has an independent stroke-protective effect.16

More than 19,000 high-risk hypertensive patients were randomized in asCOT-Bpla to amlodipine-based therapy (5–10 mg, with perindopril 4–8 mg added, as necessary, to achieve a Bp goal of <140/90 mm Hg) or to atenolol-based therapy (50–100 mg, with bendroflumethiazide 1.25–2.5 mg added as necessary to achieve goal Bp).22 The trial was stopped early, after a median 5.5 years of follow-up, because of an increase in total mortality in the atenolol-based arm. The amlodipine-based therapy group had fewer (but not statistically significant) primary events (nonfatal myocardial infarction and fatal coronary heart disease) than the atenolol group (429 vs 474; unadjusted haz-ard ratio, 0.90; 95% Ci, 0.79–1.02; P=.10). The investigators noted that the effective Bp lowering achieved by the amlodipine-based regimen, partic-ularly in the first year of follow-up, likely contrib-uted to the differential in the overall cardiovascular benefits that was noted.22 similarly, after 1 year of treatment in allHaT, chlorthalidone had lowered systolic Bp significantly more than did amlodipine or lisinopril (P<.001), although diastolic Bp reduc-tions were greater with amlodipine. This may have contributed to the final results of the trial.23

The assessment of treatment benefit has tradi-tionally involved a number of approaches, includ-ing consideration of Bp reduction, clinical out-comes, differences between drug classes, and the generalizability of clinical trial findings to real-world practice.26 long-term therapeutic benefits have also been investigated by prolonging the observation of patients after the initially planned conclusions of trials, as was the case with the

Table II. Between-Group Differences in SBP in the Syst-Eur Open-Label Extension StudyEnrollment in Open-Label Extension Study End

SBP in placebo group, mm Hg 160.4±16.2 143.5±13.9SBP in active-treatment group, mm Hg 151.0±14.6 142.9±14.2SBP difference, mm Hg (average) 9.4a 0.7b

Patients with SBP <150 mm Hg, % (placebo/active treatment) 25.7/50.5c 74/76d

Abbreviations: SBP, systolic blood pressure; Syst-Eur, Systolic Hypertension in Europe. a95% confidence interval, 8.3–10.4. b95% confidence interval, –0.3 to 1.6. cP<.001; dP=.17. Adapted from data in Staessen et al.20


®


extension of the syst-Eur trial.20 findings from this trial, along with evidence from the other tri-als discussed above, underscore the importance of considering prompt Bp control as well. The 2007 guidelines of the Task force for the Management of arterial Hypertension of the European society of Hypertension (EsH) and the European society of Cardiology (EsC) emphasize the importance of prompt Bp control by stating that antihypertensive treatment should be initiated in high-risk patients before evidence of significant cardiovascular dam-age develops.27

although prompt Bp control appears to be an important approach to maximizing cardiovascular protection, current guidelines acknowledge the dif-ficulty of achieving this goal. The seventh report of the Joint National Committee on prevention, Detection, Evaluation, and Treatment of High Blood pressure (JNC 7)14 recognizes that many patients require more than 1 drug and recommends initial multiple-drug therapy in high-risk patients (eg, those with diabetes or kidney disease) as well as in patients with stage 2 hypertension in whom monotherapy is unlikely to be adequate. The 2007 EsH/EsC guidelines27 emphasize that even with the use of multiple drugs, it may be difficult to lower systolic Bp to <140 mm Hg and even more difficult to achieve a target of <130 mm Hg in diabetic patients and patients with existing car-diovascular or kidney disease. recently published guidelines28 from the american Heart association have expanded the definition of high-risk patients who have a systolic Bp target of <130 mm Hg to include those with known coronary artery disease or coronary artery disease equivalents, such as carotid artery disease, peripheral arterial disease, and abdominal aortic aneurysm, as well as to those with a 10-year framingham risk score of ≥10%. in addition, the american Heart association guide-lines state that for patients with Bp levels ≥20/10 mm Hg above goal, treatment should start with 2 antihypertensive drugs.28

The need to achieve more prompt Bp con-trol in high-risk hypertensive patients favors multiple-drug therapy and quicker adjustment of doses.27 according to JNC 7, patients with uncontrolled Bp should be followed up and med-ication adjusted at least monthly until the goal Bp is attained; those with stage 2 hypertension or complicating comorbid conditions should be followed up more frequently.14 after the Bp goal is attained, patient follow-up at 3- to 6-month intervals is recommended to ensure that desir-able Bp levels are maintained.

in terms of multiple drug therapy, fixed-dose combinations of 2 medications may have advan-tages in many cases over the use of 2 agents sepa-rately. Therapeutic inertia—the tendency of some physicians to accept higher-than-recommended Bp levels in their patients, as well as the reluctance to increase doses, add other antihypertensive agents, or use fixed-dose combinations—has been identified as an important barrier to achieving Bp control.29 (Note: Therapeutic inertia is discussed more fully in the article by Dr William J. Elliott on pages 20–26 in this supplement.) it has been suggested that the longer it takes to control Bp, the more likely it is that the physician will accept inadequate Bp control; thus, the likelihood is that Bp control will be greater if the time to achieve control is shortened.30 another situation in which combination therapy may be use-ful is in patients with diastolic Bp minimally above goal and systolic Bp substantially above goal, as is frequently noted in elderly hypertensive persons. physician inertia may result in control of diastolic Bp with monotherapy, while elevated systolic hyper-tension persists. in contrast, combination or multi-ple-drug therapy may well control both systolic and diastolic Bp simultaneously and promptly.

comBInatIon therapy may facIlItate prompt Bp controlusing medications from different drug classes results in additive Bp-lowering effects because the drugs target different mechanisms that regulate Bp.31,32 The lower doses that are usually involved in multiple-drug therapy compared with mono-therapy help to reduce adverse events and increase adherence to medication regimens.14,33 several studies and a meta-analysis of >20,000 patients have reported that fixed-dose combinations, in particular, can simplify the treatment regimen; this also favors adherence.34 for example, a retrospec-tive study that examined adherence patterns of patients treated with a fixed-dose combination of amlodipine and benazepril compared with an angiotensin-converting enzyme inhibitor plus a cal-cium channel blocker prescribed as separate drugs found that the fixed-dose combination was associ-ated with higher adherence rates (88% vs 69%; P<.0001).35 Higher adherence rates mean that prompt Bp control is more likely to be achieved.

an analysis of several randomized treatment trials with >3 years’ follow-up found a significant correla-tion between the reduction from baseline in diastolic Bp and the number of drugs used.36 similarly, a Veterans affairs study reported a significant correla-tion between the number of antihypertensive drugs


®


used and reduction in systolic Bp. in that study, the percentage of patients with Bp control was highest in nondiabetic patients taking ≥2 agents and in dia-betic patients taking ≥3 medications.37 an analysis of 119 randomized placebo-controlled trials of antihypertensive treatment confirmed the additive Bp-lowering effects of multiple-drug therapy (Table iii).32 The addition of a second drug to the regimen more than doubled the Bp-lowering effects.

a recent study evaluated combination therapy with amlodipine/valsartan (calcium channel block-er/angiotensin ii receptor blocker) compared with amlodipine or valsartan monotherapy. as expected, Bp control (<140/90 mm Hg) was achieved in more patients taking combination therapy at weeks 2 and 4 compared to those receiving monotherapy with either agent.38 another study evaluated patients who were randomized to either fixed-dose combi-nation therapy with ramipril and felodipine or to monotherapy with either drug.39 after 4 weeks of treatment, an additive and significant reduction in both systolic and diastolic Bp values was seen in patients treated with the fixed-dose combination compared with the monotherapy groups (P<.004 for fixed-dose combination vs either monotherapy).39 significant differences were also observed in the responder rates between the fixed-dose combina-tion therapy and the monotherapies. Combination therapy was well tolerated, with fewer patients reporting adverse events compared with patients on monotherapy.39 another study involving patients with stage 2 hypertension that did not respond to monotherapy reported that a fixed-dose combina-tion of trandolapril and verapamil was effective for Bp control; the recommended therapeutic goal of <140/90 mm Hg was reached in 75% of patients at 8 weeks.40 according to the investigators, this early high rate of response may be important for the reduction of cardiovascular events.

We await the results of randomized controlled trials designed to assess the superiority of one

particular combination strategy over others in achieving prompt control and reducing cardiovas-cular event end points. an ongoing trial, avoiding Cardiovascular Events Through Combination Therapy in patients living with systolic Hypertension (aCCOMplisH),41 may provide answers to some of these questions. The aCCOMplisH trial involves more than 12,000 high-risk patients who were randomized to 1 of 2 fixed-dose combinations as initial therapy: amlodipine/benazepril or benazepril/hydrochlorothiazide. The primary composite end point is cardiovascular disease death, nonfatal myo-cardial infarction, nonfatal stroke, hospitalization for unstable angina pectoris, or revascularization procedures.41 preliminary results indicate impressive early Bp control rates, with combination therapy resulting in a 73% control rate in the overall trial population at 6 months, compared with only 37% controlled at baseline.42

conclusIonsThe suboptimal rate of Bp control worldwide sug-gests that the implications of trial results have not been well integrated into clinical practice. The most advantageous antihypertensive treatment strategy requires a global approach to risk factor manage-ment. identifying high-risk patients with elevated Bp and implementing the treatment strategy most likely to achieve an early and effective Bp response before significant cardiovascular damage develops is an important part of global risk management. One strategy that may be effective in achieving prompt Bp control and reducing cardiovascular events is the use of multiple-drug therapy, particu-larly fixed-dose combination therapy.

Disclosure: Dr Basile receives grant/research support from the National Heart, Lung, and Blood Institute, Boehringer Ingelheim (ONTARGET), and Novartis. He has served as a consultant for AstraZeneca, Merck, Novartis, and Daiichi Sankyo and has served on the Speakers’ Bureau of Abbott, AstraZeneca, Boehringer Ingelheim, Forest, Merck, Novartis, Pfizer, and Daiichi Sankyo. The author acknowledges the

Table III. Effects of 2 Antihypertensive Agents on Blood PressureAverage Decrease in Blood Pressurea

Systolic, mm Hg (SD) Diastolic, mm Hg (SD)Observed

First drug monotherapy 7.0 (0.4) 4.1 (0.3)Second drug monotherapy 8.1 (0.3) 4.6 (0.3)2 Drugs 14.6 (0.5) 8.6 (0.4)

Expectedb 15.1 8.7Difference between observed and expectedc –0.5 (–1.4 to 0.4)d –0.1 (–1.0 to 0.8)d

Based on results of 119 randomized placebo-controlled trials. aTreated minus placebo. bSum of first and second drugs used alone. cThe small difference between observed and expected likely occurred because at initiation of second drug, blood pressure (BP) had already been lowered by first drug. d95% confidence interval. Adapted from Law et al.32


®


assistance of Landmark Programs, Inc. in preparing this review article and styling the paper for journal submission. Editorial support was funded by Novartis Pharmaceuticals Corporation and the author received an honorarium for time and effort spent preparing this article.

RefeRences 1 Kearney pM, Whelton M, reynolds K, et al. Global bur-

den of hypertension: analysis of worldwide data. Lancet. 2005;365:217–223.

2 Centers for Disease Control and prevention. Quickstats: percentage of persons aged ≥20 years with hypertension, by race/ethnicity—united states, 1999–2002. MMWR. 2005;54:826.

3 Cheung BMy, Ong Kl, Man yB, et al. prevalence, aware-ness, treatment, and control of hypertension: united states National Health and Nutrition Examination survey 2001–2002. J Clin Hypertens (Greenwich). 2006;8:93–98.

4 Ong Kl, Cheung BMy, Man yB, et al. prevalence, aware-ness, treatment, and control of hypertension among united states adults 1999–2004. Hypertension. 2007;49:69–75.

5 Moser M, franklin sf. Hypertension management: results of a new national survey for the Hypertension Education foundation: Harris interactive. J Clin Hypertens (Greenwich). 2007;9:316–323.

6 Centers for Disease Control and prevention (CDC). prevalence of actions to control high blood pressure—20 states, 2005. MMWR. 2007;56(17):420–423.

7 Wolf-Maier K, Cooper rs, Kramer H, et al. Hypertension treatment and control in five European countries, Canada, and the united states. Hypertension. 2004;43:10–17.

8 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;360:1903–1913.

9 Basile J, Houston M, ferrario C. incremental risk-factor reduction improves overall cardiovascular benefit: is it time to abandon the silos? J Clin Hypertens (Greenwich). 2006;8:686–688.

10 Düsing r. Overcoming barriers to effective blood pressure control in patients with hypertension. Curr Med Res Opin. 2006;22:1545–1553.

11 rosamond W, flegal K, friday G, et al, for the american Heart association statistics Committee and stroke statistics subcommittee. Heart disease and stroke sta-tistics–2007 update: a report from the american Heart association statistics Committee and the stroke statistics subcommittee. Circulation. 2007;115:e69–e171.

12 Blood pressure lowering Treatment Trialists’ Collaboration. Effects of aCE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospec-tively designed overviews of randomised trials. Lancet. 2000;356:1955–1964.

13 Blood pressure lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospective-ly-designed overviews of randomised trials. Lancet. 2003;362:1527–1535.

14 seventh report of the Joint National Committee on prevention, Detection, Evaluation, and Treatment of High Blood pressure. Hypertension. 2003;42:1206–1252.

15 staessen Ja, li y, Thijs l, et al. Blood pressure reduction and cardiovascular prevention: an update including the 2003–2004 secondary prevention trials. Hypertens Res. 2005;28:385–407.

16 Basile JN, Chrysant s. The importance of early antihyper-tensive efficacy: the role of angiotensin ii receptor blocker therapy. J Hum Hypertens. 2006;20:169–175.

17 Hansson l, Zanchetti a, Carruthers sG, et al, for the HOT study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: princi-pal results of the Hypertension Optimal Treatment (HOT)

randomised trial. Lancet. 1998;351:1755–1762. 18 uK prospective Diabetes study Group. Tight blood pres-

sure control and risk of macrovascular and microvascu-lar complications in type 2 diabetes: uKpDs 38. BMJ. 1998;317:703–713.

19 Julius s, Kjeldsen sE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the ValuE randomised trial. Lancet. 2004;363:2022–2031.

20 staessen Ja, Thijs l, fagard r, et al. Effects of immedi-ate versus delayed antihypertensive therapy on outcome in the systolic Hypertension in Europe trial. J Hypertens. 2004;22:847–857.

21 lithell H, Hansson l, skoog i, et al, for the sCOpE study Group. The study on Cognition and prognosis in the Elderly (sCOpE): outcomes in patients not receiv-ing add-on therapy after randomization. J Hypertens. 2004;22:1605–1612.

22 Dahlöf B, sever ps, poulter Nr, et al, for the asCOT investigators. prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perin-dopril as required versus atenolol adding bendroflume-thiazide as required, in the anglo-scandinavian Cardiac Outcomes Trial-Blood pressure lowering arm (asCOT-Bpla): a multicentre randomized controlled trial. Lancet. 2005;366:895–906.

23 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 block-er vs diuretic: the antihypertensive and lipid-lowering Treatment to prevent Heart attack Trial (allHaT). JAMA. 2002;288:2981–2997.

24 Weber Ma, Julius s, Kjeldsen sE, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the ValuE trial. Lancet. 2004;363:2049–2051.

25 lithell H, Hansson l, skoog i, et al, for the sCOpE study Group. The study on Cognition and prognosis in the Elderly (sCOpE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21:875–886.

26 Weycker D, Edelsberg J, Vincze G, et al. risk of diabetes in a real-world setting among patients initiating antihy-pertensive therapy with valsartan or amlodipine. J Hum Hypertens. 2007;21:374–380.

27 The Task force for the Management of arterial Hypertension of the European society of Hypertension (EsH) and of the European society of Cardiology (EsC). 2007 Guidelines for the management of arterial hypertension. Eur Heart J. 2007;28:1462–1536.

28 rosendorff C, Black Hr, Cannon Cp, et al. Treatment of hypertension in the prevention and management of isch-emic heart disease: a scientific statement from the american Heart association Council for High Blood pressure research and the Councils on Clinical Cardiology and Epidemiology and prevention. Circulation. 2007;115:2761–2788.

29 Okonofua EC, simpson KN, Jesri a, et al. Therapeutic inertia is an impediment to achieving the Healthy people 2010 blood pressure control goals. Hypertension. 2006;47:345–351.

30 Neutel JM, smith DHG. improving patient compliance: a major goal in the management of hypertension. J Clin Hypertens (Greenwich). 2003;5:127–132.

31 sica Da. rationale for fixed-dose combinations in the treatment of hypertension: the cycle repeats. Drugs. 2002;62:443–462.

32 law M, Wald N, Morris J. lowering blood pressure to prevent myocardial infarction and strokes: a new preven-tive strategy. Health Technol Assess. 2003;7:1–94.

33 law Mr, Wald NJ, Morris JK, et al. Value of low dose combination treatment with blood pressure low-ering drugs: analysis of 354 randomised trials. BMJ. 2003;326:1427–1434.


®


34 Bangalore s, Kamalakkannan G, parkar s, et al. fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120:713–719.

35 Gerbino pp, shoheiber O. adherence patterns among patients treated with fixed-dose combination versus sepa-rate antihypertensive agents. Am J Health Syst Pharm. 2007;64:1279–1283.

36 Elliot WJ. is fixed combination therapy appropriate for initial hypertension treatment? Curr Hypertens Rep. 2002;4:278–285.

37 Bizien MD, Jue sG, panning C, et al. Blood pressure control and factors predicting control in a treatment-compliant male veteran population. Pharmacotherapy. 2004;24:179–187.

38 philipp T, Glazer r, Wernsing M, et al. Dual calcium channel and angiotensin ii receptor blockade is superior to amlodipine or valsartan alone for optimal hyperten-sion control. J Clin Hypertens (Greenwich). 2007;9(suppl a):a39. abstract p-83.

39 scholze J, Bida M, Hansen a, et al. initiation of hypertension

treatment with a fixed-dose combination or its mono-components—does it really matter? Int J Clin Pract. 2006;60:265–274.

40 rubio-Guerra af, arceo-Navarro a, lozano-Nuevo JJ, et al. Efficacy of a fixed-dose combination of trandolapril-verapamil in patients with stage 2 hypertension inad-equately controlled by monotherapy. Clin Drug Investig. 2005;25:445–451.

41 Jamerson Ka, Bakris Gl, Wun CC, et al. rationale and design of the avoiding cardiovascular events through com-bination therapy in patients living with systolic hyperten-sion (aCCOMplisH) trial: the first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension. Am J Hypertens. 2004;17:793–801.

42 Jamerson K, Bakris Gl, Dahlöf B, et al, for the aCCOMplisH investigators. Exceptional early blood pressure control rates: the aCCOMplisH trial. Blood Press. 2007;16:80–86.


®

the importance of prompt blood pressure control

Documents