The Journal of International Medical Research 2005; 33:

Transcription

1 The Journal of International Medical Research 2005; 33: Ambulatory Blood Pressure Comparison of the Anti-hypertensive Efficacy of Fixed Combinations of Irbesartan/hydrochlorothiazide and Losartan/hydrochlorothiazide in Patients with Mild-to-moderate Hypertension JM NEUTEL AND D SMITH Orange County Research Center, Tustin, CA, USA This study examined whether the greater anti-hypertensive efficacy of irbesartan monotherapy over losartan monotherapy extends to the respective fixed-dose combinations with hydrochlorothiazide (HCTZ) in patients with mild-to-moderate hypertension. Patients were treated with either irbesartan 150 mg/hctz 12.5 mg or losartan 50 mg/hctz 12.5 mg over a 4-week period. Twenty-four hour daytime and night-time mean blood pressure (BP), BP load and duration of action were assessed using ambulatory BP monitoring. Both treatment regimens significantly reduced BP from baseline for all efficacy variables assessed. A significant difference was noted in adjusted mean changes from baseline in 24-h ambulatory diastolic BP with irbesartan/hctz versus losartan/ HCTZ. Reduction in diastolic load was significantly greater with irbesartan/ HCTZ than with losartan/hctz as was mean ambulatory systolic BP during the last 4 h of the dosing interval. Both regimens were well tolerated, with no significant differences in terms of adverse event profile observed. Irbesartan 150 mg/ HCTZ 12.5 mg resulted in greater reductions in ambulatory BP than losartan 50 mg/hctz 12.5 mg. KEY WORDS: IRBESARTAN; HYDROCHLOROTHIAZIDE (HCTZ); LOSARTAN; ANGIOTENSIN II RECEPTOR BLOCKER; HYPERTENSION Introduction Several large clinical trials have demonstrated that the majority of patients need two or more anti-hypertensive agents to lower blood pressure (BP) to target levels. 1 4 In line with this clinical evidence, the latest report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines acknowledges that most patients require two or more anti-hypertensive drugs to achieve this goal. 5,6 The JNC 7 guidelines 620

2 also recommend a two-drug regimen (one of which should usually be a thiazide diuretic) from the outset if the BP is more than 20 mmhg above the systolic BP (SBP) goal, or more than 10 mmhg above the diastolic BP (DBP) goal. 5,6 The consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks (ISHIB) 7 recommends combination therapy as first-line treatment for patients with SBP of 15 mmhg or DBP of 10 mmhg above goal BP. Thiazide diuretics have been used successfully in combination with several different classes of anti-hypertensive agents, including calcium channel blockers, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs). Data show that when thiazide diuretics are used in combination with other anti-hypertensive agents they often have an additive or synergistic effect on BP reduction. 8,9 Furthermore, combination treatment involving a renin angiotensin aldosterone system (RAAS) inhibitor and hydrochlorothiazide (HCTZ) may provide a greater degree of enhanced anti-hypertensive efficacy than doubling the dose of a single agent, particularly in African Americans. 10 Thus, patients whose BP is uncontrolled on monotherapy may achieve BP control with a simple regimen of fixed-dose combination therapy. 11 Fixed-dose combinations of antihypertensive agents offer clinicians an alternative therapeutic option to improve compliance and clinical outcomes. When low doses of anti-hypertensive agents are used in fixed-dose combinations, complex regimens are avoided and dose-dependent adverse effects minimized, while marked gains in efficacy may be realized. 12,13 The role of ARBs may be particularly important in the field of combination therapy. As a class, ARBs used as monotherapy have been shown to provide BP reductions equivalent to those attained with agents of other anti-hypertensive classes Superior tolerability of the ARBs (comparable with placebo) to other antihypertensive classes is also well documented, and a meta-analysis extends these findings to superior tolerability with respect to cough when compared with ACE inhibitors. 22 In the choice of a specific ARB (either for monotherapy or as a component of fixeddose combination therapy), several intraclass differences should be considered. Clinical evidence from seven comparative trials of newer ARBs versus losartan indicates that irbesartan, candesartan cilexetil, and telmisartan provide superior BP reductions. Ambulatory blood pressure monitoring (ABPM) has provided evidence that ARBs with longer plasma elimination half-lives, such as irbesartan and telmisartan, may provide greater overall 24-h BP-lowering efficacy than ARBs with shorter plasmaelimination half-lives, such as valsartan and losartan. 28,30,31 As monotherapy, irbesartan has been shown to be superior to losartan in terms of anti-hypertensive efficacy, 23,24 although only about half of hypertensive patients have adequate BP control with single-agent therapy. 32 The current study, using ABPM, was designed to determine whether the greater anti-hypertensive efficacy of irbesartan monotherapy over losartan monotherapy extends to the respective fixeddose combinations with HCTZ, in patients with mild-to-moderate hypertension. Patients and methods STUDY DESIGN This was a randomized, parallel-group, open-label study. 621

3 An investigational review board approved the study and all participating patients gave written consent. Following an initial 2-week placebo washout period (baseline), adult men and women 18 years of age with a mean seated DBP of mmhg were randomized to 4 weeks of active treatment with either irbesartan 150 mg/hctz 12.5 mg or losartan 50 mg/hctz 12.5 mg. The doses selected represent the recommended starting doses of each formulation. Patients were excluded from this study if they had severe, uncontrolled, or any secondary form of hypertension; a history of hypertensive encephalopathy, stroke/ transient ischaemic attack, myocardial infarction, or unstable angina pectoris in the past 6 months; a history of heart block greater than first-degree, Wolff-Parkinson- White syndrome, sick sinus syndrome, atrial fibrillation/flutter, congestive heart failure, or other clinically significant cardiac insufficiency manifestations, or haemodynamically significant valvular disease; gastrointestinal disease (e.g. liver disease based on serum glutamic-oxaloacetic transaminase or serum glutamic-pyruvic transaminase > 2 times the upper limit of normal, total bilirubin > 1.5 times the upper limit of normal), or past surgery that may interfere with drug absorption; type 2 diabetes mellitus or fasting blood sugar levels of > 175 mg/dl; were pregnant or lactating; used illicit drugs or significantly abused alcohol in the past 12 months; took concomitant medications that could interfere with the study objectives; or took an investigational drug within 1 month of study start. EFFICACY PARAMETERS Ambulatory BP monitoring was performed at the end of the placebo washout period (baseline) and at the end of the 4-week active treatment period to assess the efficacy and duration of action of each treatment regimen. To assess efficacy, 24-h mean BP, daytime mean BP, night-time mean BP, and SBP and DBP loads were analysed from ABPM data. The 24-h mean ambulatory BP was derived by calculating a mean value from each of the corrected individual 24-hourly means. Daytime mean ambulatory BP was obtained by calculating the mean of each of the individual hourly mean values between 06:00 and 21:59. Night-time mean ambulatory BP was obtained by calculating the mean of each of the individual hourly mean values between 22:00 and 05:59. Duration of action for each of the agents was assessed by analysing the mean reductions in ambulatory BP during the last 4 h of the dosing interval, as well as during the period from 06:00 to 12:00 (morning period). Morning mean ambulatory BP was obtained by calculating the mean of each of the individual hourly mean values between 06:00 and 12:00. Systolic load was derived by calculating the percentage of SBP readings > 140 mmhg between 06:00 and 21:59, and the percentage of SBP readings > 130 mmhg between 22:00 and 05:59. Diastolic load was calculated in a similar fashion by analysing the percentage of DBP readings > 90 mmhg between 06:00 and 21:59, and the percentage of DBP readings > 85 mmhg between 22:00 and 05:59. Thus, the systolic load is the total percentage of SBP readings above the defined values, and the diastolic load is the total percentage of DBP readings above the corresponding defined values, over the 24-h period. Office BP was measured at baseline and at the end of the active treatment period. Measurements were made with the patient in a seated position after a 5-min rest using the correct cuff size, as specified by the 622

4 American Heart Association recommendations, 33 on the non-dominant arm. Three BP measurements were taken at 1-min intervals and recorded, with the average of these readings used as the patient response for the visit. Korotkoff phase 1 and phase 5 were used for measuring SBP and DBP, respectively. RESPONDER AND CONTROL RATES Responders were identified based on two different criteria: attainment of either (i) a mean 24-h ambulatory DBP of < 90 mmhg or a reduction in mean 24-h ambulatory DBP of 10 mmhg from baseline; or (ii) a mean 24-h ambulatory DBP of < 85 mmhg or a reduction in mean 24-h ambulatory DBP of 10 mmhg from baseline. Controlled patients were defined as patients who had a mean 24-h ambulatory DBP of < 90 mmhg, irrespective of baseline BP. SAFETY AND TOLERABILITY The effect of each study treatment regimen on heart rate (based on pulse rate measurements) was evaluated as a safety parameter. Pulse rate was measured during each visit with the patient seated. The occurrence of any adverse experiences or serious adverse events was also monitored. A serious adverse event was defined as any untoward medical occurrence that, at any dose of the regimens used, resulted in or was associated with the development of any of the following: death; life-threatening event; in-patient hospitalization or prolonged hospital stay; cancer; congenital anomaly/ birth defect; overdose (i.e. accidental or intentional ingestion of any dose of a product considered both excessive and medically important); drug dependency or drug abuse; or an important medical event (i.e. one that may not be life-threatening or require hospitalization, but in which medical or surgical intervention may be indicated to prevent one of the other mentioned serious outcomes). STATISTICAL ANALYSIS All ABPM data and case report data were entered into a Microsoft Access database designed for this protocol. Data integrity was assured by double entry and resolution of any discrepancies. Relevant data needed to determine efficacy and safety endpoints as specified in the protocol were exported and transferred to SAS (Windows version 6.12, Cary, NC, USA) for analysis. Numerical data were assessed by analysis of covariance under the general linear model procedure, where the baseline values were used as the covariant. Categorical data were evaluated with the Mantel Haenzel test. Significance was set at P All analyses were performed on an intent-to-treat basis. Results BASELINE CHARACTERISTICS A total of 16 patients were randomized to treatment with irbesartan 150 mg/hctz 12.5 mg and 15 patients to losartan 50 mg/ HCTZ 12.5 mg. Baseline data showed no important differences between groups in terms of age, height, weight and body mass index (Table 1), although the proportions of men and white patients were higher in the irbesartan/hctz treatment group (81% men, 88% whites) than the losartan/ HCTZ group (44% men, 53% whites). The mean office BP was 146.8/97.9 mmhg in the irbesartan/hctz group and 145.9/ 98.9 mmhg in the losartan/hctz group. Thirty patients completed the study (15 patients in each treatment group). 623

5 TABLE 1: Patient demographics and clinical characteristics at baseline for this study comparing fixed combination treatments for mild-to-moderate hypertension Irbesartan 150 mg/ Losartan 50 mg/ HCTZ 12.5 mg HCTZ 12.5 mg n Age (years) 54.3 ± ± 9.3 Gender, n (%) Men 13 (81) 7 (47) Women 3 (19) 8 (53) Race, n (%) White 14 (88) 8 (53) African American 1 (6) 1 (7) Asian 1 (6) 2 (13) Latino 0 2 (13) Other 0 2 (13) Height, m 1.73 ± ± 0.1 Weight, kg 90.9 ± ± 18.2 BMI, kg/m ± ± 6.1 Office BP, mmhg DBP 97.9 ± ± 3.4 SBP ± ± h ABPM, mmhg DBP 92.6 ± ± 7.7 SBP ± ± 8.5 Unless otherwise indicated, values are mean ± SEM. ABPM, ambulatory blood pressure monitoring; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; HCTZ, hydrochlorothiazide; SBP, systolic blood pressure. EFFICACY The irbesartan/hctz and the losartan/hctz treatment regimens both resulted in significant reductions from baseline in ambulatory SBP (P < 0.01; Figs 1A and 1B) and DBP (P < 0.01; Figs 2A and 2B) for all efficacy variables assessed, with reductions maintained throughout the dosing interval and during the morning period. 24-h mean BP At the end of the active treatment period, mean 24-h ambulatory BP for patients in the irbesartan/hctz group was 132.8/81.8 mmhg compared with 132.0/83.1 mmhg for those in the losartan/hctz group. The adjusted mean change from baseline in 24-h ambulatory DBP was 10.5 ± 1.1 mmhg with the irbesartan/hctz regimen versus 6.1 ± 1.1 mmhg with the losartan/ HCTZ regimen, representing a reduction of 4.4 mmhg with irbesartan/hctz versus losartan/hctz (P = 0.01; Table 2 and Fig. 3). There was a non-significant trend towards a greater reduction in mean 24-h ambulatory SBP with irbesartan/hctz compared with losartan/hctz ( 16.0 ± 2.0 mmhg versus 624

6 A B Systolic blood pressure (mmhg) Baseline Irbesartan/HCTZ 150 mg/12.5 mg Hours Systolic blood pressure (mmhg) Baseline Losartan/HCTZ 50 mg/12.5 mg Hours FIGURE 1: The 24-h ambulatory systolic blood pressure profiles at baseline (end of placebo treatment) and after 4 weeks treatment with (A) irbesartan/ hydrochlorothiazide (HCTZ) and (B) losartan/hctz for mild-to-moderate hypertension (15 subjects per group) 11.1 ± 2.0 mmhg, Table 3). At study end, both regimens had resulted in significant reductions in ambulatory SBP and DBP variability (P < 0.01), possibly indicating a smoothing effect of both agents on 24-h SBP and DBP. Daytime/night-time mean BP The reduction in daytime mean ambulatory DBP was significantly greater with the irbesartan/hctz regimen than with the losartan/hctz regimen ( 11.1 ± 1.5 mmhg versus 6.1 ± 1.5 mmhg, P < 0.03; Table 2). There was a non-significant trend towards a greater reduction in mean daytime ambulatory SBP with irbesartan/hctz compared with losartan/hctz ( 16.3 ± 2.5 mmhg versus 11.9 ± 2.5 mmhg; Table 3). Similarly, there was a non-significant trend in favour of the irbesartan/hctz regimen versus the losartan/hctz regimen with respect to night-time ambulatory SBP/DBP ( 14.8/ 9.1 mmhg versus 10.4/ 6.5 mmhg; Tables 2 and 3). Systolic/diastolic load Both treatment regimens reduced systolic and diastolic load significantly from baseline (P < 0.01). Reduction in diastolic load was significantly greater with the irbesartan/ HCTZ regimen than with the losartan/hctz regimen ( 0.33 ± 0.05% versus 0.17 ± 0.05%, 625

7 A Diastolic blood pressure (mmhg) B Baseline Irbesartan/HCTZ 150 mg/12.5 mg Hours Diastolic blood pressure (mmhg) Baseline Losartan/HCTZ 50 mg/12.5 mg Hours FIGURE 2: The 24-h ambulatory diastolic blood pressure profiles at baseline (end of placebo treatment) and after 4 weeks treatment with (A) irbesartan/ hydrochlorothiazide (HCTZ) and (B) losartan/hctz for mild-to-moderate hypertension (15 subjects per group) TABLE 2: Reduction in ambulatory diastolic blood pressure for all efficacy parameters in a comparative study of combination therapy for the treatment of mild-to-moderate hypertension Irbesartan 150 mg/ Losartan 50 mg/ P-value (between- HCTZ 12.5 mg (n = 15) HCTZ 12.5 mg (n = 15) group comparison) 24-h, mmhg 10.5 ± ± Daytime, mmhg 11.1 ± ± 1.5 < 0.03 Night-time, mmhg 9.1 ± ± 1.6 NS Last 4 hours, mmhg 9.9 ± ± 1.5 NS Morning, mmhg 11.9 ± ± 1.8 NS Diastolic load (%) 0.33 ± ± 0.05 < 0.05 All values are adjusted mean changes ± SEM. HCTZ, hydrochlorothiazide; NS, not significant. 626

8 Diastolic blood pressure (mmhg) Irbesartan/HCTZ 150 mg/12.5 mg Losartan/HCTZ 50 mg/12.5 mg Hours FIGURE 3: The 24-h ambulatory diastolic blood pressure profiles after 4 weeks treatment with irbesartan/hydrochlorothiazide (HCTZ) or losartan/hctz in patients with mild-to-moderate hypertension (15 subjects per group) TABLE 3: Reduction in ambulatory systolic blood pressure for all efficacy parameters in a comparative study of combination therapy for the treatment of mild-to-moderate hypertension Irbesartan 150 mg/ Losartan 50 mg/ P-value (between- HCTZ 12.5 mg (n = 15) HCTZ 12.5 mg (n = 15) group comparison) 24-h, mmhg 16.0 ± ± 2.0 NS Daytime, mmhg 16.3 ± ± 2.5 NS Night-time, mmhg 14.8 ± ± 2.1 NS Last 4 h, mmhg 16.7 ± ± 1.7 < 0.02 Morning, mmhg 17.2 ± ± 2.4 NS Systolic load (%) 0.29 ± ± 0.06 NS All values are adjusted mean changes ± SEM. HCTZ, hydrochlorothiazide; NS, not significant. P = 0.04). Reduction in systolic load in irbesartan/hctz-treated patients was numerically greater than that in losartan/ HCTZ treated patients, although the difference did not reach statistical significance ( 0.29 ± 0.06% versus 0.25 ± 0.06%). Last 4 h of dosing interval The reduction in mean ambulatory SBP during the last 4 h of the dosing interval was significantly greater with irbesartan/hctz than with losartan/hctz ( 16.7 ± 1.8 mmhg versus 10.1 ± 1.7 mmhg, P < 0.02; Table 3). For the same period there was a nonsignificant trend towards greater reduction in ambulatory DBP with irbesartan/hctz treatment than with losartan/hctz treatment ( 9.9 mmhg versus 5.8 mmhg; Table 2). Morning mean BP Although the irbesartan/hctz regimen demonstrated a numerically larger reduction 627

9 versus the losartan/hctz regimen in morning ambulatory SBP, this difference was not statistically significant ( 17.2 ± 2.4 mmhg versus 11.7 ± 2.4 mmhg). There was a nonsignificant trend towards greater reduction in mean morning ambulatory DBP for the irbesartan/hctz group than for the losartan/ HCTZ group ( 11.9 ± 1.8 mmhg versus 6.9 ± 1.8 mmhg; Table 2). Responder and control rates A total of 86.7% of patients treated with irbesartan/hctz and 80.0% of those treated with losartan/hctz achieved a mean 24-h ambulatory DBP of < 90 mmhg or a reduction in mean 24-h ambulatory DBP of 10 mmhg from baseline (responder definition i). In addition, 60.0% of patients receiving irbesartan/hctz and 53.3% of those receiving losartan/hctz achieved a mean 24-h ambulatory DBP of < 85 mmhg or a reduction in mean 24-h ambulatory DBP of 10 mmhg from baseline (responder definition ii). There were no statistically significant differences between the two treatment regimens in response rates. The control rate for irbesartan/hctz was 33.3%, whereas that for losartan/hctz was 36.7%. There was no significant difference between the two groups. SAFETY AND TOLERABILITY Both treatment regimens resulted in very small increases in mean heart rate (based on 24-h, daytime, and night-time pulse rate data) during each of the measured periods. For the irbesartan/hctz regimen, heart rate was not significantly different from baseline during each of the measured periods. For the losartan/hctz regimen, heart rate was considerably greater than baseline for the 24-h mean and daytime mean values. No differences were observed between the two treatment arms with respect to adverse events or tolerability. The most commonly reported adverse events in the irbesartan/ HCTZ group were cold symptoms (n = 2) and sore throat (n = 2). The most commonly reported adverse event in the losartan/hctz group was headache (n = 3). Discussion In the current study, irbesartan 150 mg/ HCTZ 12.5 mg resulted in greater reductions from baseline in ambulatory BP than losartan 50 mg/hctz 12.5 mg in patients with mild-to-moderate hypertension after 4 weeks treatment. A significantly greater reduction in ambulatory SBP was observed over the last 4 h of the dosing interval with irbesartan/hctz treatment versus losartan/hctz treatment; reductions in all other SBP ABPM parameters were numerically greater with irbesartan/hctz than with losartan/hctz. Significantly greater reductions in ambulatory DBP were observed in irbesartan/hctz-treated patients than in losartan/hctz-treated patients in 24-h mean, daytime mean and diastolic load. One limitation in this study is the small patient populations in each group. The small number of patients included in each treatment group may mean that the study was underpowered to detect statistically significant differences between the two groups. These BP efficacy benefits were in the context of well-tolerated treatment regimens. This extends existing information, showing that irbesartan monotherapy is superior to losartan monotherapy in terms of antihypertensive efficacy, to the two respective fixed-dose combinations. These results support earlier efficacy studies with combination irbesartan/hctz therapy. This combination considerably reduced BP compared with placebo in three previous trials In one placebo-controlled, 628

10 parallel-group study, the addition of 12.5 mg HCTZ daily for 2 weeks to the treatment regimen of patients uncontrolled on irbesartan monotherapy (at dosages of mg) or placebo led to additional dose-related reductions in seated DBP (ranging from 1.6 mmhg with placebo to 7.7 mmhg with irbesartan 300 mg) and in seated SBP (ranging from 0.3 mmhg with placebo to 12.0 mmhg with irbesartan 300 mg). 34 In a multicentre, double-blind, randomized trial, 178 patients with mean 24-hour ambulatory DBP 85 mmhg and seated DBP mmhg received either once-daily irbesartan 75 mg/hctz 12.5 mg, irbesartan 150 mg/hctz 12.5 mg or placebo for 8 weeks. 35 The reductions in mean 24-h ambulatory BP and office seated BP for irbesartan/hctz combinations were significantly greater than for placebo (P < 0.01). 35 Long-term extension studies document that the reductions in BP attained with irbesartan/hctz combination therapy are maintained up to at least 1 year of continuous therapy. 36 Guideline recommendations are converging to support the need for combination therapy to achieve BP control, and highlight the benefits of coadministration of thiazide diuretics and ARBs. 5 7 Interestingly, the finding that only about one-third of all patients in the current study achieved adequate BP control (defined as mean 24-h ambulatory DBP of < 90 mmhg, irrespective of baseline BP) with the starting doses of the fixed-dose combination regimen emphasizes the need for dose titration, multiple agents and combination therapies in the management of hypertension. In addition, the importance of aggressively managing BP to goal underscores the positive outcomes of incremental BP lowering with one regimen compared with another, as demonstrated in this study. In summary, our data support the role of ARB/HCTZ fixed-dose combination therapy as an early step in the management of patients with hypertension who require more than one anti-hypertensive agent to achieve BP goal. This rationale is based on the comparable efficacy and superior tolerability of the members of the ARB class when compared with agents belonging to other antihypertensive drug classes. Furthermore, these data corroborate other similar data indicating that fixed-dose ARB/HCTZ combinations safely and effectively control BP. In this study, irbesartan/hctz resulted in BP reductions greater than those attained with losartan/hctz. We conclude that superior BP reductions observed with irbesartan versus losartan monotherapy extend to fixed-dose combination therapy with HCTZ. Conflicts of interest The authors have an indirect financial interest in and provide consulting services to Integrium, the clinical research organization that provided clinical management for this trial. Received for publication 17 May 2005 Accepted subject to revision 17 June 2005 Revised accepted 27 July 2005 Copyright 2005 Cambridge Medical Publications References 1 ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: Major cardiovascular events in hypertensive 629

11 patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipidlowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA 2000; 283: UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 1998; 317: Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, 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. HOT Study Group. Lancet 1998; 351: Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr, et al: National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. 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: Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr, et al: Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: Douglas JG, Bakris GL, Epstein M, Ferdinand KC, Ferrario C, Flack JM, et al: Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Management of high blood pressure in African Americans: consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med 2003; 163: Neutel JM, Black HR, Weber MA: Combination therapy with diuretics: an evolution of understanding. Am J Med 1996; 101: 61S 70S. 9 Prisant LM, Neutel JM, Papademetriou V, DeQuattro V, Hall WD, Weir MR: Low-dose combination treatment for hypertension versus single-drug treatment-bisoprolol/hydrochlorothiazide versus amlodipine, enalapril, and placebo: combined analysis of comparative studies. Am J Ther 1998; 5: Weir MR, Smith DH, Neutel JM, Bedigian MP: Valsartan alone or with a diuretic or ACE inhibitor as treatment for African American hypertensives: relation to salt intake. Am J Hypertens 2001; 14: Neutel JM, Smith DH, Weber MA: Low-dose combination therapy: an important first-line treatment in the management of hypertension. Am J Hypertens 2001; 14: Waeber B, Brunner HR: Rationale for the use of very-low-dose combinations as first-line treatment of hypertension. J Hypertens Suppl 2001; 19: S3 S8. 13 Prisant LM: Fixed low-dose combination in first-line treatment of hypertension. J Hypertens Suppl 2002; 20: S11 S Mimran A, Ruilope L, Kerwin L, Nys M, Owens D, Kassler-Taub K, et al: A randomised, doubleblind comparison of the angiotensin II receptor antagonist, irbesartan, with the full dose range of enalapril for the treatment of mild-tomoderate hypertension. J Hum Hypertens 1998; 12: Larochelle P, Flack JM, Marbury TC, Sareli P, Krieger EM, Reeves RA: Effects and tolerability of irbesartan versus enalapril in patients with severe hypertension. Irbesartan Multicenter Investigators. Am J Cardiol 1997; 80: Neutel J, Germino W, Smith D, Park J-S, Reilly K, Triscari J: The antihypertensive efficacy and safety of irbesartan compared with amlodipine for the treatment of mild-to-moderate hypertension (abstract D068). Am J Hypertens 1999; 12 (pt 2): 128A. 17 Stumpe KO, Haworth D, Hoglund C, Kerwin L, Martin A, Simon T, et al: Comparison of the angiotensin II receptor antagonist irbesartan with atenolol for treatment of hypertension. Blood Press 1998; 7: Townsend R, Haggert B, Liss C, Edelman JM: Efficacy and tolerability of losartan versus enalapril alone or in combination with hydrochlorothiazide in patients with essential hypertension. Clin Ther 1995; 17: Kloner RA, Weinberger M, Pool JL, Chrysant SG, Prasad R, Harris SM, et al: Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study Investigators. Comparative effects of candesartan cilexetil and amlodipine in patients with mild systemic hypertension. Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study Investigators. Am J Cardiol 2001; 87: Corea L, Cardoni O, Fogari R, Innocenti P, Porcellati C, Provvidenza M, et al: Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: a comparative study of the efficacy and safety against amlodipine. Clin Pharmacol Ther 1996; 60: Holwerda NJ, Fogari R, Angeli P, Porcellati C, Hereng C, Oddou-Stock P, et al: Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy and safety compared with placebo and enalapril. 630

12 J Hypertens 1996; 14: Pylypchuk GB: ACE inhibitor- versus angiotensin II blocker-induced cough and angioedema. Ann Pharmacother 1998; 32: Oparil S, Guthrie R, Lewin AJ, Marbury T, Reilly K, Triscari J, et al: An elective-titration study of the comparative effectiveness of two angiotensin II-receptor blockers, irbesartan and losartan. Irbesartan/Losartan Study Investigators. Clin Ther 1998; 20: Kassler-Taub K, Littlejohn T, Elliott W, Ruddy T, Adler E: Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators. Am J Hypertens 1998; 11: Andersson OK, Neldam S: The antihypertensive effect and tolerability of candesartan cilexetil, a new generation angiotensin II antagonist, in comparison with losartan. Blood Press 1998; 7: Gradman AH, Lewin A, Bowling BT, Tonkon M, Deedwania PC, Kezer AE, et al: Comparative effects of candesartan cilexetil and losartan in patients with systemic hypertension. Candesartan Versus Losartan Efficacy Comparison (CANDLE) Study Group. Heart Dis 1999; 1: Lacourciere Y, Asmar R: A comparison of the efficacy and duration of action of candesartan cilexetil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients: a placebocontrolled, forced titration study. Candesartan/ Losartan study investigators. Am J Hypertens 1999; 12: Mallion J, Siche J, Lacourciere Y: ABPM comparison of the antihypertensive profiles of the selective angiotensin II receptor antagonists telmisartan and losartan in patients with mildto-moderate hypertension. J Hum Hypertens 1999; 13: Hedner T, Oparil S, Rasmussen K, Rapelli A, Gatlin M, Kobi P, et al: A comparison of the angiotensin II antagonists valsartan and losartan in the treatment of essential hypertension. Am J Hypertens 1999; 12: Israili ZH: Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. J Hum Hypertens 2000; 14 Suppl 1: S73 S Mancia G, Korlipara K, van Rossum P, Villa G, Silvert B: An ambulatory blood pressure monitoring study of the comparative antihypertensive efficacy of two angiotensin II receptor antagonists, irbesartan and valsartan. Blood Press Monit 2002; 7: Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, 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: Kirkendall WM, Feinleib M, Freis ED, Mark AL: Recommendations for human blood pressure determination by sphygmomanometers. Subcommittee of the AHA Postgraduate Education Committee. Circulation 1980; 62: 1146A 1155A. 34 Pool JL, Guthrie RM, Littlejohn TW, 3rd, Raskin P, Shephard AM, Weber MA, et al: Dose-related antihypertensive effects of irbesartan in patients with mild-to-moderate hypertension. Am J Hypertens 1998; 11: Howe P, Phillips P, Saini R, Kassler-Taub K: The antihypertensive efficacy of the combination of irbesartan and hydrochlorothiazide assessed by 24-hour ambulatory blood pressure monitoring. Irbesartan Multicenter Study Group. Clin Exp Hypertens 1999; 21: Raskin P, Guthrie R, Flack J, Reeves R, Saini R: The long-term antihypertensive activity and tolerability of irbesartan with hydrochlorothiazide. J Hum Hypertens 1999; 13: Address for correspondence JM Neutel, MD Orange County Research Center, Myford Road, Tustin, CA 92780, USA. jmneutel@aol.com 631