The hypertensive effects of the renin-angiotensin

Comparison of Telmisartan vs. Valsartan in the Treatment of Mild to Moderate Hypertension Using Ambulatory Blood Pressure Monitoring George Bakris, MD A prospective, randomized, open-label, blinded end-point trial compared telmisartan and valsartan for treating mild to moderate hypertension. Efficacy for 24-hour control of blood pressure was assessed using ambulatory blood pressure monitoring. Mean changes in diastolic blood pressure for the last 6 hours before dosing and the nighttime period were significantly greater with telmisartan than with valsartan (p<0.01 for the last 6 hours before dosing; p<0.05 for the nighttime period). Mean changes in systolic and diastolic blood pressures for the 24-hour interval, the morning, and the daytime periods were significantly greater with telmisartan than with valsartan (p<0.01). The incidence of all adverse events and the most common adverse events were comparable for patients receiving telmisartan and patients receiving valsartan. Neither treatment was associated with cough. These data suggest greater efficacy for telmisartan than valsartan in controlling blood pressure throughout the 24-hour dosing interval, including the last 6 hours before dosing, and the two agents were similarly well tolerated. (J Clin Hypertens. 2002;4:26 31) 2002 Le Jacq Communications, Inc. From the Department of Preventive Medicine and Internal Medicine, Rush Hypertension/Clinical Research Center, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL Address for correspondence: George Bakris, MD, 1700 W. Van Buren Street, Suite 470, Chicago, IL 60612 Manuscript received January 23, 2002; accepted February 26, 2002 The hypertensive effects of the renin-angiotensin system (RAS) are mediated by the binding of angiotensin II to the angiotensin type 1 (AT 1 ) receptor. Several antagonists of the AT 1 receptor have been developed for clinical use, including telmisartan, valsartan, losartan, eprosartan, irbesartan, and candesartan; these compounds are highly effective and generally well tolerated antihypertensive agents. 1 3 However, the AT 1 receptor antagonists differ in their pharmacokinetic properties. The angiotensin II receptor blocker (ARB) telmisartan has pharmacokinetic properties that suggest it has a duration of action sufficient for once-daily dosing, with a T max 1 hour and a T 1/2 of 24 hours. In contrast, losartan, which was the first ARB to be developed, has a T max of 3 4 hours and a T 1/2 of 6 9 hours, and valsartan, another ARB, has a T max of 2 4 hours and a T 1/2 of 6 hours. 4 However, receptor binding of these compounds may go beyond their measured half-lives. The most accurate way to measure the duration of action of an antihypertensive agent is to use ambulatory blood pressure monitoring (ABPM). 5 7 ABPM has other advantages compared with traditional cuff blood pressure measurements performed in a single clinic visit, such as greater reproducibility of data and the ability to rule out white coat hypertension. Furthermore, 24-hour ABPM data have greater clinical relevance compared with cuff measurements because this technique has been shown to more accurately predict the risk for target organ damage and cardiovascular events. 8 11 ABPM was used in a recent study published by Littlejohn et al. 12 that compared the efficacy of telmisartan and valsartan in the treatment of mild to 26 THE JOURNAL OF CLINICAL HYPERTENSION SUPPLEMENT 1 VOL. IV NO. IV JULY/AUGUST 2002

moderate hypertension. This study tested the hypothesis that telmisartan and valsartan, which have different pharmacokinetic properties, also differ in their efficacy for controlling blood pressure throughout the 24-hour dosing interval. The results of this study will be reviewed here. METHODS Adult patients with mild to moderate hypertension, defined as sitting diastolic blood pressure (DBP) of 95 114 mm Hg, sitting systolic blood pressure (SBP) of 140 200 mm Hg, and 24-hour mean SBP/DBP >130/85 mm Hg (determined using ABPM), and without significant metabolic or cardiovascular disease were enrolled in a prospective, randomized, open-label, blinded-end point (PROBE) study that compared the efficacy and tolerability of telmisartan 80 mg q.d. vs. valsartan 80 mg q.d. The study consisted of a 4-week placebo run-in period and an 8- week treatment period. Baseline measurements were taken at the end of the placebo run-in. Investigators were blinded to the end points. The main efficacy end points were the changes from baseline in SBP and DBP during the last 6 hours of the 24-hour dosing interval (midnight to 6 a.m.), as measured with ABPM. Other efficacy outcomes assessed with ABPM included the changes in SBP and DBP during the morning period (6 a.m. to noon), the daytime period (6 a.m. to 10 p.m.), the nighttime period (10 p.m. to 6 a.m.), and the entire 24-hour period. Changes in sitting trough SBP and DBP (from cuff measurements), and the proportion of SBP responders (patients achieving a 10 mm Hg reduction in mean 24-hour SBP) and DBP responders (patients achieving both a 10 mm Hg reduction in mean 24-hour DBP and a mean 24-hour DBP of <80 mm Hg) were also assessed by ABPM. Safety outcomes included adverse events and changes in the results of physical examinations, laboratory tests, and 12-lead electrocardiograms. Data analysis was performed by individuals blinded to patients treatment. This study was approved by institutional review boards at participating centers, and all patients provided written informed consent. RESULTS A total of 214 patients were randomized to receive telmisartan 80 mg, and 212 patients were randomized to receive valsartan 80 mg. The treatment groups were similar with respect to age, sex, race, and history and severity of hypertension (Table I). The mean age of patients in the study was 53.3 years, and most of the patients (85.7%) were aged <65 years. More than one half were male (68.1%), and most were white (83.3%). The mean duration of hypertension was 10.2 years (median, 7.5 years). Mean 24-hour SBP/DBP at baseline was 151.4/93.8 mm Hg, and the trough cuff SBP/DBP at baseline was 157.1/100.8 mm Hg (Table II). Mean changes in DBP and SBP for the last 6 hours before dosing and the nighttime period were greater for the telmisartan group than for the valsartan group (Figures 1 and 2), and the differences Table I. Patient Demographics (N=214) ALL (N=426) Mean age, years (SD) 53.6 (10.4) 53.1 (9.6) 53.3 (10.0) Age group, n (%) Sex, n (%) Race, n (%) <65 Years 183 (85.5) 182 (85.8) 365 (85.7) 65 Years 31 (14.5) 30 (14.2) 61 (14.3) Men 146 (68.2) 144 (67.9) 290 (68.1) Women 68 (31.8) 68 (32.1) 136 (31.9) White 179 (83.6) 176 (83.0) 355 (83.3) Black 31 (14.5) 33 (15.6) 64 (15.0) Asian 4 (1.9) 3 (1.4) 7 (1.6) Duration of hypertension, years Mean 10.2 10.3 10.2 Median 7.0 8.0 7.5 Adapted with permission from Can J Cardiol. 2000;16:1123 1132. 12 SUPPLEMENT 1 VOL. IV NO. IV JULY/AUGUST 2002 THE JOURNAL OF CLINICAL HYPERTENSION 27

Table II. Mean Blood Pressure and Pulse Rate at Baseline 24-Hour ABPM Seated trough cuff ALL N 199 197 396 SBP, mm Hg 150.9 (12.4) 152.0 (12.3) 151.4 (12.3) DBP, mm Hg 93.3 (6.1) 94.3 (6.4) 93.8 (6.3) Pulse rate, bpm 78.8 (9.4) 78.8 (9.4) 78.8 (9.4) N 212 212 424 SBP, mm Hg 157.0 (12.9) 157.1 (12.4) 157.1 (12.6) DBP, mm Hg 100.3 (4.9) 101.2 (5.1) 100.8 (5.0) Pulse rate, bpm 74.9 (8.2) 74.4 (9.0) 74.7 (8.6) Values are means±sd. ABPM=ambulatory blood pressure monitoring; bpm=beats per minute; DBP=diastolic blood pressure; SBP=systolic blood pressure; Reproduced with permission from Can J Cardiol. 2000;16:1123 1132 12 between the groups in mean changes in DBP were significant (p<0.01 for the last 6 hours before dosing; p<0.05 for the nighttime period; Figure 1). Mean changes in SBP and DBP for the 24-hour interval, the morning, and the daytime periods were significantly greater for the telmisartan group than for the valsartan group (p<0.01; Figures 1 and 2). The 24-hour blood pressure profiles showed that treatment with telmisartan was associated with greater mean changes in hourly SBP and DBP over the 24-hour dosing interval for almost all time points, compared with valsartan (Figures 3 and 4). Mean decreases in sitting trough SBP and DBP were significantly greater for patients receiving telmisartan than for patients receiving valsartan (p<0.01 for SBP; p=0.01 for DBP; Table III). The proportion of SBP treatment responders was significantly greater in the telmisartan group than in the valsartan group (p<0.01), and the proportion of DBP treatment responders was numerically greater for the telmisartan group relative to the valsartan group (Table IV). The safety outcomes for the telmisartan and valsartan groups were similar. Most adverse events were mild to moderate in nature. The incidence of all adverse events for patients receiving telmisartan (44.4%) and patients receiving valsartan (44.3%) was comparable, the incidence of the most common Figure 1. Adjusted* mean changes from baseline (±SEM) in systolic blood pressure, determined by ambulatory blood pressure monitoring. Morning=6 a.m. 11:59 a.m.; daytime=6 a.m. 9:59 p.m.; nighttime=10 p.m. 5:59 a.m.; last 6 hours refers to time before dosing. *Adjusted for the main effect of center and using baseline as a covariate; p <0.01 vs. valsartan. 12 Figure 2. Adjusted* mean changes from baseline (±SEM) in diastolic blood pressure determined by ambulatory blood pressure monitoring. Morning=6 a.m. 11:59 a.m.; daytime=6 a.m. 9:59 p.m.; nighttime=10 p.m. 5:59 a.m.; last 6 hours refers to time before dosing. *Adjusted for the main effect of center and using baseline as a covariate; p<0.01 vs. valsartan; p<0.05 vs. valsartan. 12 28 THE JOURNAL OF CLINICAL HYPERTENSION SUPPLEMENT 1 VOL. IV NO. IV JULY/AUGUST 2002

Figure 3. Mean change from baseline in mean hourly systolic blood pressure, determined by ambulatory blood pressure monitoring. Dosing occurred during the morning; hours 1 6 relative to dosing correspond to approximately 6:00 a.m. to noon. Figure 4. Mean change from baseline in mean hourly diastolic blood pressure, determined by ambulatory blood pressure monitoring. Dosing occurred during the morning; hours 1 6 relative to dosing correspond to approximately 6:00 a.m. to noon. adverse events was similar for the two treatment groups, and neither treatment was associated with cough (Table V). DISCUSSION In a study reported by Littlejohn et al., 12 the efficacy and tolerability of telmisartan 80 mg and valsartan 80 mg for controlling blood pressure throughout the 24-hour dosing interval were directly compared. One limitation in interpreting these data is that since the usual starting doses are 80 mg/d for valsartan and 40 mg/d for telmisartan, the doses compared here are not necessarily equivalent. However, other studies have used the 80-mg dose, so for the purposes of comparison to other studies this dose is appropriate. Mean changes in DBP for the last 6 hours before dosing and the nighttime period were significantly greater for the telmisartan group than for the valsartan group, and the mean changes in SBP for those time periods were numerically greater for the telmisartan group. Mean changes in 24-hour, morning, and daytime SBP and DBP were significantly greater in the telmisartan group relative to the valsartan group. The 24-hour blood pressure profiles showed that telmisartan treatment was associated with greater mean decreases in hourly blood pressure at almost every time point, compared with valsartan treatment; differences in outcomes between the two treatment groups were greatest during the daytime hours. The PROBE design for clinical trials, used in this study, has some advantages over the randomized, double-blind, placebo-controlled trial design. These advantages include lower cost; less time required for completion, treatment, and follow-up; administration in an open manner, similar to that of treatment in the community setting; and the ability to recruit patients who would not be eligible for enrollment in a placebo-controlled study. 13 Investiga- Table III. Mean Change From Baseline in Trough Cuff Blood Pressure P VALUE SBP, mm Hg 13.5 (0.9) 9.7 (0.9) <0.01 DBP, mm Hg 8.9 (0.5) 7.1 (0.5) 0.01 Values are means±sem. DBP=diastolic blood pressure; SBP=systolic blood pressure Table IV. Blood Pressure Response Rates (N=199) (N=197) P VALUE SBP response,* % of patients 45.7 30.0 <0.01 DBP response, % of patients 57.3 48.7 0.09 DBP=diastolic blood pressure; SBP=systolic blood pressure; *defined as a reduction from baseline in the mean 24-hour SBP of 10 mm Hg; defined as a mean 24-hour DBP of <80 mm Hg or a reduction from baseline of 10 mm Hg SUPPLEMENT 1 VOL. IV NO. IV JULY/AUGUST 2002 THE JOURNAL OF CLINICAL HYPERTENSION 29

Table V. Treatment-Emergent Adverse Events With Incidence 2% ADVERSE EVENT, N (%) (N=214) Headache 22 (10.3) 22 (10.4) Upper respiratory tract infection 15 (7.0) 13 (6.1) Accident, household 4 (1.9) 8 (3.8) Dizziness 6 (2.8) 7 (3.3) Fatigue 4 (1.9) 6 (2.8) Pain 2 (0.9) 6 (2.8) Pharyngitis 5 (2.3) 5 (2.4) Sinusitis 5 (2.3) 5 (2.4) Back pain 5 (2.3) 1 (0.5) Reproduced with permission from Can J Cardiol. 2000;16:1123 1132. 12 tor bias is avoided by blinding the investigators to the end points and by having individuals who are blinded to patients treatment assignments analyze the data. In the telmisartan vs. valsartan PROBE study, ambulatory blood pressure findings constituted the blinded end point. A complete evaluation of the efficacy of an antihypertensive agent includes assessment of 24-hour blood pressure control. Most antihypertensive medications are taken once daily, which is preferable to more frequent dosing because of greater patient compliance with once-daily dosing. 14 Dosing is commonly performed during the morning to provide blood pressure control during the daytime hours, when blood pressure would reach its highest levels. However, morning administration may result in very low plasma drug concentrations throughout the last several hours before dosing and the first few hours after dosing, which are hours that coincide with a circadian increase in blood pressure that is believed to contribute to the heightened risk for cardiovascular and cerebrovascular events observed for this time period. 15 18 The efficacy of telmisartan for controlling blood pressure over the 24-hour dosing interval also has been shown to be significantly greater than that of another ARB, losartan, as well as that of amlodipine, a calcium channel blocker. Treatment with telmisartan resulted in significantly greater mean decreases in SBP and DBP during the last 6 hours before dosing, compared with losartan treatment. 7 Similarly, telmisartan was associated with significantly greater mean decreases in SBP and DBP during the last 6 hours before dosing, compared with amlodipine. 6 The significant efficacy findings of the studies comparing telmisartan with valsartan, losartan, and amlodipine indicate that telmisartan is highly effective during the early morning hours before dosing, which coincide with the greatest cardiovascular risk during the day. In addition, clinical studies have shown the efficacy of telmisartan for treatment of mild to moderate hypertension to be similar to that of the angiotensinconverting enzyme (ACE) inhibitors enalapril and lisinopril and similar to that of enalapril for the treatment of severe hypertension. 19 21 These findings are in contrast to a common misperception that the ACE inhibitors, which are older drugs and therefore have a larger body of clinical data, are more effective than the ARBs. Although the ARBs and the ACE inhibitors have shown similar efficacy for lowering blood pressure in clinical trials, there are more data on cardiovascular morbidity and mortality for ACE inhibitor treatment than for therapy with ARBs. However, key outcome data on telmisartan should be provided by the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), which will enroll more than 23,400 patients with cardiovascular disease, peripheral vascular disease, or diabetes mellitus along with target organ damage and follow them for up to 5.5 years. The ONTARGET study will compare the effects of telmisartan, ramipril, and telmisartan plus ramipril combination therapy on a combined end point consisting of cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure. 22 Treatment with such ARBs as telmisartan, unlike ACE inhibitor therapy, has not been associated with cough. 4 The excellent tolerability associated with ARBs is consistent with their specific mechanism of action via the AT 1 receptor, and a lack of interaction with the kallikrein-kinin pathway, which has been linked to ACE inhibitor-induced 30 THE JOURNAL OF CLINICAL HYPERTENSION SUPPLEMENT 1 VOL. IV NO. IV JULY/AUGUST 2002

cough. 23 25 In this study, treatment with telmisartan and valsartan was similarly well tolerated, and the adverse event profiles for these agents were comparable to those seen in other studies. 5 7 Therapy with ARBs has been recommended for patients who do not tolerate ACE inhibitor treatment because ARBs are better tolerated and limited data suggest that ARB treatment may confer similar survival benefits. The Telmisartan Randomized Assessment Study in ACE Inhibitor-Intolerant Patients With Cardiovascular Disease (TRANSCEND) will provide outcome data for telmisartan treatment in patients with cardiovascular disease who are intolerant of ACE inhibitor therapy. The TRANSCEND study will enroll 5000 patients and will have the same end points as ONTARGET. 22 The results of the study reported here demonstrate greater efficacy for telmisartan than for valsartan in controlling blood pressure throughout the 24-hour dosing interval, including the last 6 hours before dosing. Both agents were well tolerated and most adverse events were mild to moderate in severity. REFERENCES 1 Oliverio MI, Coffman TM. Angiotensin-II receptors: new targets for antihypertensive therapy. Clin Cardiol. 1997;20:3 6. 2 Weber MA. Comparison of type 1 angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors in the treatment of hypertension. J Hypertens. 1997;15(suppl): S31 S36. 3 Drincic V, Koshy S, Bakris G. Angiotensin receptor blocker use for hypertension treatment in the elderly. Ann Long-Term Care. 1999;7:305 308. 4 Bakris GL, Giles TD, Weber MA. Clinical efficacy and safety profiles of AT 1 receptor antagonists. Cardiovasc Rev Reports. 1999;20(2):77 120. 5 Neutel J, Weber M, Pool J, et al. Valsartan, a new angiotensin II antagonist: antihypertensive effects over 24 hours. Clin Ther. 1997;19:447 458. 6 Lacourcière Y, Lenis J, Orchard R, et al. A comparison of the efficacies and duration of action of the angiotensin II receptor blockers telmisartan and amlodipine. Blood Press Monit. 1998;3:295 302. 7 Mallion JM, Siché JP, Lacourcière Y, and the Telmisartan Blood Pressure Monitoring Group. 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; 13:657 664. 8 Neutel JM, Smith DH, Weber MA. What are the approaches for evaluating antihypertensive treatment by 24-h ambulatory blood pressure monitoring? Blood Press Monit. 1999;4(suppl 2):S23 S28. 9 Pickering TG, Coats A, Mallion JM, et al. Blood Pressure Monitoring. Task Force V: White-coat hypertension. Blood Press Monit. 1999;4:333 341. 10 Waeber B, Brunner HR. Clinical value of ambulatory blood pressure monitoring in the assessment of antihypertensive therapy. Blood Press Monit. 1999;4:263 266. 11 White WB. Ambulatory blood pressure as a predictor of target organ disease and outcome in the hypertensive patient. Blood Press Monit. 1999;4:181 184. 12 Littlejohn T, Mroczek W, Marbury T, et al. A prospective, randomized, open-label trial comparing telmisartan 80 mg and valsartan 80 mg in patients with mild to moderate hypertension using ambulatory blood pressure monitoring. Can J Cardiol. 2000;16:1123 1132. 13 Hansson L, Hedner T, Dahlöf B. Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Prospective Randomized Open Blinded End-Point. Blood Press. 1992;1:113 119. 14 National Heart, Lung, and Blood Institute. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Washington, DC: National Institutes of Health; 1997. Publication NIH 98 4080. 15 Muller JE, Stone PH, Turi ZG, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985;313(21):1315 1322. 16 Muller JE, Ludmer PL, Willich SN, et al. Circadian variation in the frequency of sudden cardiac death. Circulation. 1987;75:131 138. 17 Cooke HM, Lynch A. Biorhythms and chronotherapy in cardiovascular disease. Am J Hosp Pharm. 1994;51:2569 2580. 18 Cooke-Ariel H. Circadian variations in cardiovascular function and their relation to the occurrence and timing of cardiac events. Am J Health Syst Pharm. 1998;55(suppl 3):S5 S11. 19 Karlberg BE, Lins LE, Hermansson K. Efficacy and safety of telmisartan, a selective AT1 receptor antagonist, compared with enalapril in elderly patients with primary hypertension. TEES Study Group. J Hypertens. 1999;17:293 302. 20 Neutel JM, Frishman WH, Oparil S, et al. Comparison of telmisartan with lisinopril in patients with mild-to-moderate hypertension. Am J Ther. 1999;6:161 166. 21 Neutel JM, Smith DH, Reilly PA. The efficacy and safety of telmisartan compared to enalapril in patients with severe hypertension. Int J Clin Pract. 1999;53:175 178. 22 Yusuf S. From the HOPE to the ONTARGET and the TRANSCEND studies: challenges in improving prognosis. Am J Cardiol. 2002;89(2A):18A 26A. 23 Fuller RW, Dixon CM, Cuss FM, et al. Bradykinin-induced bronchoconstriction in humans. Mode of action. Am Rev Respir Dis. 1987;135:176 180. 24 Goodfriend TL, Elliot ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med. 1996;329:1649 1654. 25 Messerli FH, Weber MA, Brunner HR. Angiotensin II receptor inhibition. A new therapeutic principle. Arch Intern Med. 1996;156:1957 1965. SUPPLEMENT 1 VOL. IV NO. IV JULY/AUGUST 2002 THE JOURNAL OF CLINICAL HYPERTENSION 31