Original Papers The Effects of Amlodipine Compared to Losartan in Patients With Mild to Moderately Severe Hypertension Robert A. Philips, MD, PhD;" Robert A. Kloner, MD, PhD? Richard H. Grimm, Jr, MD, PhD;? Myron Weinberger, MDé ‘The calcium channel blocker amlodipine and angio- tonsin Il receptor blocker losartan, with of without hydrochlorothiazide (HCTZ), were compared for the treatment of mild to moderate hypertension in a multicenter, double-blind, parallel-group clinical trial. Following a 2wveek placebo run-in, 440 adults (45-80 years old) were randomized to receive either amlodipine 5 mg once daily or losartan 50 mg once daily. Patients who failed to meet the sitting dias- tolic blood pressure (BP) reduction goal of <90 mm Hg after 6 weeks had their dose increased to 10 mg amlodipine or had 12.5 mg of HCTZ added to the losartan 50 mg. A total of 42.3% of losartan: and 43.6% of amlodipine subjects achieved a diastolic BP. of £90 mm Hig at initial dose (low dose). Of those swho completed treatment at the low dose, 71% of the amlodipine- and 81% of the losartan-treated patients niet BP goal. This difference was not statisti- cally significart, Of those who received a dosage adjustment, a significantly greater percentage of anslodipine-treated patients (59%) than losar- tan/HCTZ-treated patients (42%) reached BP goal at the lat visit (p=0.009), Including both high- and rom the Lenox Fil Hospital and Nao York University School of Medicine, New York, NYS Los Angels Cardiology Associates Tear Isic Good Samaritan FHrspital and University of Souther California, Les Angeles, CA The Berman Coter for Outcomts and Circa! Research, Mirmeapols, MINE Indiana University School of Nene, Indianapolis, IN! Address for correspondence Rober A. Phils, MD, PhD, Chairman and Professor (NYU), Deparment of Medicine, Lenox Hill Hospital, 100 Ease 77th Seret, New York, NY 10021 E-mail: 8Pilips@lenoxhilinet Manuscript received November 9, 20013 accepted January 7, 2002 VOL V NO. JANUARYIFEBRUARY 2003, low-dose subjects, 63.8% of amlodipine and 55.1% of losartan patients achicved a diastolic BP of $90 mom: Hg at the last maintenance visit; this difference sas not significant (p=0.07). Overall, reductions in ‘mean sitting BP from baseline to the end of treat- ont seer sigwificanily greater i the amlodipine group than in the losartan group for both diastolic BP 12.6 vs. 10.3 mm Hg; p=0.002) and systolic BP (-16.1 us, 13.7 mm Hg; p=0.018). Additionally, the response rate was significantly greater after treat ‘ment with amlodipine than with losartan in African Americans (62.5% vs, 41.4%; p=0.033) and the cther mostly Hispanic patients (67.7% vs. 53.5% =0.039), Both treatment groups showed significant reductions from baseline in 24-hour ambulatory BP at the end of treatment, with no difference between them. Adverse events were consistent with the safety profile of each drug. It is concluded that, while both amlodipine and losartan demonstrated a significant benefit for the treatment of mild to moderate Fyper- tension, there were greater reductions in most BP reasurements following treatment with amlodipine in comparison to losartan with or without HICTZ. (J Clin Hypertens. 2003;5:17-23,30) 02003 Le fag Communications, Ine ypertension is among the most common modi- fable risk factors for myocardial infarction (ML, congestive heart failure (CHF), stroke, periph- eral vascular disease, and end-stage renal disease.~$ Although there are many classes of antihyperten- sives, their specific roles in therapy are still being defined, Morsover, there are distiner variations in clinical response by different patient groups based on. race and age. Studies have shown that elderly Afvican Americans may be more responsive 0 diuretics or "THE JOURNAL OF CLINICAL HYPERTENSION — Material may be protected by copyright law (Title 17, U.S. Code)calcium channel blockers (CBs), Caucasians to angiorensin-converting enzyme (ACE) inhibitors and B blockers, and elderly patients may be less respon- sive 0 B blockers than younger patients.6? The selection of @ first-line antihypertensive agent must be based not only on efficacy and out- come, but also tolerability and compliance, which includes both quality-of life considerations and cost.8 Other considerations include concomitant disorders, dosing frequency as it relates to adher- ence with therapy, frequency and severity of adverse effects including drug interactions, and the effect of therapy on the circadian pattern of blood. pressure. A prolonged duration of action is useful both to compensaze for missed doses and to mini- mize the circadian effects of blood pressure."? ‘The primary end point of this study was to com- pare the antihypertensive efficacy of once daily amlodipine, 5 mg or 10 mg, with losartan, 50 mg or losartan SOmg/hydrochlorothiazide (HCTZ) 12.5 mg ‘on seated diastolic blood pressure (DBP). High-dose amlodipine was compared with 2 losartawHCTZ, ‘combination because the addition of HCTZ to losar- tau is inure efficacious tau ineseased doses of losat~ tan alone and reflects current clinical practice." PATIENTS AND METHODS “This double blind, multicenter, randomized, parallel group study included male and female’ patients between the ages of 4 and 80 years with mild ro mod- rately severe essential bypectension, A diagnosis of mild to moderate hypertension was defined as the average of nvo sitting DBPs (sDBP) in the range of 95-116 mm Hg while a patient was off all antihyper tensive treatment during the placebo run-in weeks. Patients were excluded if they had any form of sec- ondary hypertension, had significant hematologic, hepatic or renal disease, had a history of MI, cere- brovascular accident, or coronary artery surgery with- in the 6 months prior to the trial, or had 2 history of gout or insulin-dependent diabetes. Additional exclue sion criteria included pregnancy ot failure to practice effective methods of contraception, concomitant use of any investigational drug, or known hypersensitivity to amlodipine, losartan, HCTZ, or other sulfonamide derived drugs. Written informed consent was required prior to stady entry, ‘After a 2-week placebo run-in period, during which time parients were monivored for adherence 10 scudly drug regimens, patients had baseline 24-hour ambula- tory blood pressure monitored and clinic blood pres- sure recorded. They were then randomized to receive cube aulnlipive 5 ng daily or fosastan 50 mg daily. Seudy medications were scheduled to be taken in the ‘morning and all office evaluations were performed before the morning dose. Ar the end of 6 woeks of this fixed-dose phase, those patients who hed reached the goal of 2 DBP $90 mm Hg were maintained on their ‘Table I, Patient Baseline Characteristics AMLODIPINE LOSARTAN P VALE N=218 N=222 ee (year) ‘Mean (8D) 57.6 (28.50) $7.6 (48.11) on7 ‘Minimur-Maximam 3807 3879 Gender N(%) Male 130(59.6) 141 (63.5) 0.436 Female ss (404) 81.(36.5) Race N (%) ‘Caucasian 132 (69.7) 146 (69.8) ‘African American BUs.1) 31 (14.0) Asians 34) ity Other 30(13.8) 36 (162) Body mass index ‘Nica j28D) 29.1 (43.85) 7 (88.34) oa Duration of hypertension (years) ‘Mean (38D) 12.2 (48.63) 11.8 (29.08) 0.496 Sitting DBP (mm He) ‘Mean (SD) 100.3 (24.04) 99.7 (83.7) 0.108 Sitting SBP (mm Hg) ‘Mean (88D 153.4 (412.33) 154.5 (212.69) os? Siting pulse pressure (mm Hg) Mean (38D) 53.2 (411.53) 54.8 11.71) 0.190) [DBPSRP=diawolicnystolic blood peoaurs "for continuous variables, ¢ value from analysis of variance with terms for site and creatment. For discrete variables, p Value from Cochran Mantel-Haenszel ca-square test, adjusted for sites "82% were Hispanic THE JOURNAL OF CLINICAL HYPERTENSION, ‘VOL. V NO. JANUARYFESRUARY 2005 ‘Material may be protected by copyright law (Title 17, U.S, Codey-—————— —lesartan 50 mg/nydrochlorothiazide 12.5 mg; ‘some patients did not maintain blood pressure goal at che low dose; cee ree outing soe ‘Table IL Responders 10 Treatment (Sitting DBP Reduced to 90 mm Hg) AMLODIENE LOSARTAN VALUE ‘Overall Last maintenance 125/196 (63.8%) 113/208 (55.1%) 0.070 Low dose” | End of fixed dose 951218 (43.6%) 93/220 (42.3 9%) 0.764 | |, Lase maintenance S476" (71.1%) 561659" (81.3%) 0.479 High dose® Lo Tas maintenance 71/120 (59.2%) 57/136 (41.9%) 0.009 DBP=diastolic Blood pressure; *p value for difference between ewo teatment groups using Cochran Mantel-Haenszel chi-square rest, adjusted for sites high dose and low dose; “amlodipine 5 mg, losartan $0 mg: ‘amlodipine 10 mg, assigned medication for the duration of the study, unless limited by side effects. Those whose average sDBP was greater than 90 mm Hg had their dose of amlodipine adjusted 10 10 mg or HCTZ 125 mg adided tothe losartan 50-mg dose, unless limited by side effects. The titration phase, during which dose adjust ‘ment could occur, lasted 6 weeks, Potassium supple- ments were provided as required t0 maintain K> levels. 23.4 mEqJL. For the lat 4 weeks of the study, the main- tenance phase, patients remained on their optimum, dose of amlodipine or losartan or losarta/HCTZ. as determined in the titcation phase. At the end of treat- ‘ment, all patients had 24-hour ambulatory blood pres- sre monitored and clinic blood pressure recorded. STATISTICAL METHODS The intention-to-treat population, which included all randomized patients who took at least one dose of study medication, was used for all efficacy and safety analyses. For the “responder” analyses, the (Shiodipne SLosatan ‘DBP SSP Dep SBP PP Figure 1. Mean change in diastole (DBP) and stole bloodpressure (SBP od sting pe pressure oe He) rom sein tthe inal act fomodipne vx. loaatan "The mean reduction from baseline in the amlodipine group as staristcallysanficantly greater than that in te losartan group. VOL. NO. JANUARYIFERRUARY 2005, data sets analyzed included patients at the end of the fixed-dose period and end of maintenance (last ‘maintenance visit). For the analyses of mean change from baseline to the end of treatment, the last-observation-carry-forward method was used. For continuous data, baseline comparability of the treatment groups was assessed using analysis of vari ance (ANOVA) techniques with terms for site and treatment, The baseline differences in categoric vari ables were assessed with Cochran-Mantel-Hlaenszel chi-square tests, adjusted for site. ANOVA methods ‘were used to assess change from baseline within treat ‘ment groups and to compare differences between, ‘mearment groups. Baseline was defined as che mean of the last two placebo washout visits. The ANOVA ‘model included baseline as a covariate, and site and treatment as effecs. Treatment effects were compared using least squareadjusted means. Proportions of patients reaching blood pressure goal were assessed with Cochran-Mantel-Haenszel chi-square tests, strat ified by site. For ambulatory blood pressure, hourly ‘means, calculated by averaging all valid readings taken from “on the hour” to $9 minutes into the hous, were analyzed using a similar ANOVA model as described above. Additionally, a subset analysis was performed based on patient race, classified as Caveasian, African American, Asian, oF other (82% were Hispanic). For all analyses, patients must have had both a baseline and a visit value to be included. All efficaey parame- ters were ascesced at the 0.08 «level RESULTS Investigators from 23 centers in the United States enrolled 559 patients between May, 1997 and September, 1998. OF the patients enrolled, 440 completed the placebo run-in phase and were ran- domized to receive treatment with either amlodip- 18) or losartan (n=222). One hundred nineteen patients discontinued during the placebo run-in phase. ‘The majority of these patients either "THE JOURNAL OF CLINICAL HYPERTENSION Material may be protected by copyright law (Title 17, U.S. Code)drank Leeeran | BI Arioipe A -hk Losatan Figure 2A, Mean chara from baseline in sitting dias- toll blood pressure (non gh “ did not meet enteance criteria (n=84) or withdrew consent (n=22). There were no differences between the two treatment groups in baseline demographic characteristics including age, race, gender, severity or Aication of hypertensian, and mean blood peessire (Table 1), Twenty-four patients from the amlodipine group and 18 from the losartan group were diseon- tinued prior to the conclusion of the study. In the amlodipine treatment group. the discontinuations were due to adverse events (15), withdrawal of con- sent (4), and other reasons (5). In the losartan treat ment group, the discontinuations were due to adverse events (7), lack of efficacy (3), withdrawal of consent (7), and other reasons (1). Primary End Point ‘The mean change in sDBP from baseline to the end. of teeatment was statistically significantly greater in the amlodipine group (-12.6 mam Hg; N=218) than in the losartan-losarta/HCTZ group (-10.3 mm Hg; N=222) (p=0,002; Figure 1). As seen in Figure 2A, which presents the change from base- line in blood pressures throughout the study peri- cod, the magnitude of reduction from baseline sDBP ‘was greater in the amlodipine group. Aer 6 weeks on the starting low dose, 95 (43.6%) of the amlodipine-treated patients and 93 (42.3%) of the losartan-treated patients reached the sDBP goal of 590 mm Hg. Of these patients, 71.1% of amlodipine and 81.2% losartan-treated patients continued to meet goal at the last maintenance visit {9=0.479; Table Il). Of the patients who required the higher dose (amlodipine 10 mg, N=1205 losartan 50 myHCTZ 12.5 mg, N=136), the percentage of patients reaching sDBP goal was significantly greater in patients receiving amlodipine (59.2%) than in patients receiving losartan (41.9%) {9=0.009; Table If}. Overall, including both high and low-dose patients, at the last maintenance visit "THE JOURNAL OF CLINICAL HYPERTENSION Figure 2B, Mean change from baseline tn sti ‘petal Blood pressure tm Hg) ® 63.2% of patients achieved goal blood pressure on amlodipine vs, 55.1% on losartan (p=0.070). Thus, this difference was not statistically significant. Secondary Fad Points AA statistically significant (p=0.018) greater reduction from baseline in favor of amlodipine was observed for sitting systolic blood pressure (sSBP) (amlodipine, =16.1 mm He; losartan, ~13.7 mm Hig) at the end of treatment (Figure 1). Additionally, significantly greater reductions were also observed in the amlodipine treat- ‘ment group as compared tothe losartan group in mean standing DBP and SBP (p=0.017 and p=0.033, respec- tively), though the nwo treatments were comparable in sitting pulse pressure changes (Figure 1). The reduction from baseline in sSBP was greater in the amlodipine {group throughout the study period (Figure 2B). Ambulatory Blood Pressure Monitoring Both amlodipine and losartan treatment groups showed statistically significant reductions from baseline in all hourly ambulatory DBP measure- ‘ments ranging from ~9.9 mm Hg to ~6.6 mim Hg, and from ~10.5 mm Hg to ~7.1 mm Hg, respec- tively, throughout a 24-hour period at the end of treatment. There were no statistically signiticant differences between the treatment groups, although losartan-teeated patients tended to show greater decreases than amlodipine-treated patients in the evening hours (Figure 3), Similarly, both treatment groups showed statistical- ly significant reductions from baseline in all hourly ambulatory SBP measurements, although there were ro statistically significant becween-group differences, Ambulatory SBP decreases from hascline tended to be ‘greater in the amlodipine group chan in the losartan ‘Broup in the early morning hours, whereas losartan ‘generally tended to be more effective in the ate after ‘noon to evening hours (Figure 3B) VOL. V NO.1 JANUARY/FEBRUARY 2003 a Vaterial may be protected by copyright law (Title 17, U.S, Code ass {Figure 3A. 24-hour ambulatory diastolic blood pres: sure (mins High change from baseline to final vist Race Subgroups ‘When treatment response was analyzed by race, there ‘was no significant difference between treatments in the ‘number of Caucasian patients who reached DBP goal. However there was « significantly greater tccatment response in amlodipine-treated vs. losartan-treated patients inthe African American subgroup (62.5% vs. 41.4%) and the other mostly Hispanic subgroup (67.7% vs, $3.5%) at the last maintenance visit (p=0.083 and =0.039, respectively) Adverse Events, “The overall frequency of adverse events berween che two treatment groups was similar and consistent with the known safety profile of the drugs. Of the 218 patients who received amlodipine, 126 (S7.8%) patients experienced at least one adverse event (of any causality), Ten patients had an adverse event rated as severe: seven were on the low dose and three were on the high dose. OF the 222 patients who received losar- tan, 123 (55.4%) patients experienced at least one adverse event (of any causality) no difference between ‘groups). Eleven patients had an adverse event rated as. severe: eight were on che low dose and three were on the high dose, "The most frequent treatment-related. adverse event (23%) in the amlodipine group was peripheral edema, with most cases rated as mild. There ‘was no individual trearment-related adverse event that ‘occurred with an incidence >3% in the losartan group. DISCUSSION This study was conducted in a nondiabetic population that was froe of preexisting cardiovascular and renal disease. In patients with uncomplicated hypertension (risk group A of the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and ‘Treatment of High Blood Pressure [JNC VI] guide- lines?) the most important goat to prevent cardiovas- cular outcomes is 0 lower blood pressure £0 <140/90 OL. NO.I JANUARYIEEERUARY 2005, Figure 38. 24-hoar ambulatory systolic blood pressure {nt high ange fom basebne fo final vit ‘mam Hyg: the choiee of agent may be irrelevant, ane lifestyle modification is an important first step in thera py. This i supported by recently reported trials in uncomplicated hypertensives (Hypertension Optimal Treatment [HOT], Systolic Hypertension in Carope [Syst-Eucl,'* Swedish Trial in Old Patients with Hypertension-2 [STOP-2},' International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment [INSIGHT] end Nordic Diltiazem [NORDIL}”). HOT demonstrated that in patients with uncomplicated hypertension, lowering blood pres- sure co <140/90 mm Hg was associated with signifieant reduction in risk, and this “standard” remains a goal. The STOP-2 study, which compared efficacy of “old” (diuretics and 8 blockers) vs, “new” (CCBs and ACE inhibitors), found that all agents were equally effica- cious in their ability to prevent overall cardiovascular morbidity or mortality in elderly patients with hyper- tension, However, in STOP-2, ACE inhibitors prevent- ed more Mls and episodes of CHF than CCBs. ‘The authors imply that this might have been due co an c error (ie, an effect was detected when none existed), because “48 statistical comparisons were done.” The INSIGHT study compared a long-acting preparation of nifedipine, Nifedipine-GITS, ro diurevic-based therapy. Both treatments were equally effective in reducing stroke and total cardiovascular events, but there was greater incidence of MI and CHF in the CCB group. Similarly, the NORDIL stady reported that diltiazem. ‘was equally effective as a diuretic and B blocker thera- py in preventing the combined primary end point of all stroke, MI, and other cardiovascular death, but the CCB was more effecive in reducing stroke. There was a mend toward fewer Mls and CHE in the other treat meat group. Taken a3 a whole these studies suggest that in the patient with uncomplicated hypertension, it is the degree of blood pressure lowering which is mest Important, and probably not the specific drug used, except for the differences noted above, ‘THE JOURNAL OF CLINICAL. HYPERTENSION Material may be protected by copyright law (Title 17, U.S. Code)‘Thus, for uncomplicated hypertension patients, outcome differences may be of some importance but comparative effectiveness of agents becomes a relevant consideration, No single drug, or even class of drugs, ean be considered the appropriate starting agent forall patients. Studies have demonstrated that there are dis- ‘tinct variations in clinical response by different patient groups based on race and age.1¥ Another considera- tion in drug selection is duration of action, to benefit patient's compliance and to achiove the goal of consis- tent blood pressure reduction, since blood pressure follows a circadian pattern with the greatest elevation occurring at the time of awakening,'® In this study amlodipine proved to be more effective than losartan in achieving the primary end point of reducing mean sitting and standing dias- tolic and systolic blood pressures, although there was no difference in the percentages of each dro in who reached goal pressure at the initial dosages. In the group of patients requiring higher doses of amlodipine or losactanHCTZ, there were signifi cantly more patients who reached blood pressure goal at the last maintenance visit in the amlodipine treatment group (59%) as compared to the losar- tanfHICTZ treatment group (42% /=0.009).. In the subgroup analysis by race, among African American patients at the last maintenance visit, 63% had met the blood pressure geal on amlodip- ine compared with 41% on losartan or losar- tanfHCTZ (p=0.033). Comparable results were seen with the other, mostly Hispanic, subgroup: 68% treated with amlodipine hed reached blood pressure goal compared with 54% treated with losartan or losartan/HCTZ (p=0.039), The 24-hour DBP and SBP results showed statis- tically positive hourly changes from baseline for both treatments, There appeared to be a trend toward a greater reduction with amlodipine com- pared co losarcan in the early morning in the ambu- latory SBP measurements, and conversely, a relative advantage for losartan in the evening. Though not statistically significant, the trend toward greater improvement with amlodipine in reducing SBP in the morning hours may be of some importance, given that this period represents the greatest risk of cardiovascular adverse events 20 In patients with complicated hypertension (risk group C of the JNC VI guidelinest2), ie, those with multiple cisk factors, clinical cardiovascular disease, diabetes, oF renal disease, the evidence points to ben- fits of blocking the renin-angiotensin aldosterone axis as part of the initial treatment regimen. Irbesactan in patients with nephropathy due to type 2 diabetes (IDNT),21 African American Study of ‘THE JOURNAL OF CLINICAL YPERTENSION Kidney Disease and Hypertension (AASh Reduetion of End Points in Nor-Insuli Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL}!5 have recently demonstrated better renal outcomes among patients with diabetic and nondiabetic renal disease and overt proteinuria ‘when treated with angiotensin-converting enzyme {ACE) inhibitors or angiotensin II receptor blockers as part oftheir antihypertensive regimen. However, in AASK, chis advantage did not extend to those patients with <300 me!24 hour of proteinuria, In this group, there was no difference in clinical outcome between those treated with ramipril or amlodipine. And, in IDNT, thece is inconsistency in renal and cardiovas- cular outcomes. Although irbesartan had an advan- tage over amlodipine for renal outcomes and inci- dence of CHE, there was a nonsignificant lower risk of coronary events with amlodipine when compared with irbesartan, ‘Most recentiy, the Losartan Intervention for End Point Reduction in Hypertension (LIFE)? a study of losartan compared with a 8 blocker in hypertensives svith left ventricular hypertrophy, has demonstrated lower rates of combined cardiovascular deal, stoke, and Ml in the group treated with a losarcan-based reg: men, The results of this study are consistent with the hypothesized benefit of blocking the renin-angiovensin- aldosterone system, but also ecve to confirm that high- risk patients often need multiple drays to achieve theie blood pressure goals. In the LIFE tral, where subjects could be treated with HCTZ and other drugs when necessary to achieve blood pressure goals of 140/90, at least 66% of losartan assigned subjects required atleast ‘ovo drugs, and yer only 48% achieved the study blood pressure goal. This is consistent with all other outcome trial including chose with amlodipine os other CCBs, where the majority of subjects required more than one rug for blood pressure control. ‘The question remains: Does it matter which agents are used to lawer blood presenter? The Antihypertensive and Lipid -Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), atrial com- paring chlorthalidone with lisinopril, doxazosin, or amlodipine has recenily complered and is sched- uled to report its results early in 2003. The study has already demonstrated that in high-risk patients, chlorthalidone was more effective in pre- venting combined cardiovascular events than dox- azosin.26 With large numbers of diabeties, African Americans and other ethnic minorities, and the eld- erly, this large trial is uniquely poised to answer questions regarding the relative effectiveness of these deugs in ceducing the rates of the cardiovas- cular complications of hypertension. VOL V NO. JANUARY/FEBRUARY 2003, ~—Material may be protected by copyright law (Title 17, U.S, Codey-—————— CONCLUSION “The results of this study support the antihypertensive efficacy and safety of amlodipine, losartan, and losar- taWHCTZ combination for the treatment of mild 0 moderately severe essential hypertension in adults Significant improvements from baseline in primary and secondary efficacy measures were generally observed for both treatment arms throughout the study period, and both regimens were equally well tolerated. Howeves, monotherapy with amlodipine had signifi cantly better efficacy than losartan monotherapy or in combination with HCTZ, in the reduction of sDBP and. SBP in this low-risk hypertensive population, Whether or not these differences can be extrapolated to differ- ‘ences in cardiovascular outcome cannot be answered by the results of this eral, Acknowledrnts: This study cas supported by Pfizer Ine. and ccnduce bythe following investigators: Stephen Auerbach, MD, Calforsia Professions! Research Cente, Newport Bosch, CAs Mand Camcss-iems, Nu, suas Heat Kesesrc Use, Hs Steven Chrysant, MD, Oklzboma Cardiovascular and Hypertension Cnien, Ollshowns Cty, ON; Micha! Denker, MD, Advanced Biomedical Kessorch, Ine, Hackensack, NJ Thomas Garland, MD, Gorlnd & Associotes, Lavronceile, Nj; Brace Ganett, MD, The Medica! Rewsreh' Cantey Inc, Wasington, D.C: Francisco Gonzales, MD, Reval Dynamics, Ine, New (Orie, LA: Richart! Grin, MD, Berman Caer for Clinica! Research, Minnesiolis, MN; Jefery Herbst, MD, Hill Tap esearch, Portland, OR; Jordan Holteman, MD, Veteons Affrs Medical Center Mivmeapoi, BIN: Robert A. Kloner, MD, PED, Las Angels Cardiology Ascites, Hear lettate Goo! Samiritan “Hospital and Unierty of Southern Califor, Los gees, CA Andrew Lewin, MD, National Research Ising, Los Angles, Ct “Thomas Marbury, MD, Orlendo Clinical Resareh Conten Orlando, Fl; David O'Dell, MD, Unveriy of Nebraska Medal Center, Omaha, NE: Andre Patron, DO, South Florida Clinical esaireh Contr, Hollywood, FL; Robert A. Pile, MD, PhD, “Lena Hil Hospital and NYU School of Bsicne, New York, NY: James Pool, MD, The Methodist Hospital Baylor College of “Medicine; Houston, TX; Ronald Smith, MD, Bowman Gry Schoo! of Medicine, Wake Forest Univesity, Winston Salo, NC Malcolm Sperling, MD, Edinger Medical Group, Fewstain Valley C4: Michael Tuck MD, VA Medical Conte, Sepulveds, CA: Abrabamt Wake MD-LACRC Ine, Ve Nune Ch: Mamie Wrinhorgor MD. Inlun University Shoo! of Melicine, Indianaputs, IN: Daniel Wistran, MD, Carialogy Physics, ne, Salon, MAL REFERENCES 1 Whelton PK. Epidemiology of Hypertension. Lemcet 1994;34421 0110, 2 MeMahos 5, exo R, Cutler J rl. Blood pressure stroke, and coronary heat disease, part Is prolonged diferences in blood pressure: prospecrve observacional sadies corrected for the represtion dlttion bias: Laneet, 1990338765774, 3 Gallin &y Peto R, MacMaswn 8, etal Blood presare, sitoke, and coronary heart disease, part I shorecerm ‘edctons in blood pressure: overview of randomized li foal tale in their epidemiologienl cortext, Lancet 3990;335.827-838, 4 Whelion 9K, Perasger TY, Klag MI, e al. Epidemiology of blood pressure renal disease, J Hypertens 892;10\supp! ‘VoL. V_NO.1 JANUARYIFEBRUARY 2008 Material may be protected by copyright law (Title 17, U.S. Code) — 2 B 1“ 1s 16 2 Seamer J, Stamler R, Noston JD. Blood pressure, systlie and diastole and edrdiovascalar risk U. 8. populaton ‘Issa. 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