Comparison of Telmisartan vs. Valsartan in the Treatment of Mild to Moderate Hypertension Using Ambulatory Blood Pressure Monitoring

Abstract

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.

The hypertensive effects of the renin‐angiotensin system (RAS) are mediated by the binding of angiotensin II to the angiotensin type 1 (AT₁) receptor. Several antagonists of the AT₁ 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 , ² , ³ However, the AT₁ 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 , ⁶ , 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 , ⁹ , ¹⁰ , 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 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).

Table I.

Patient Demographics

	Telmisartan (n=214)	Valsartan (n=212)	All (n=426)
Mean age, years (SD)	53.6 (10.4)	53.1 (9.6)	53.3 (10.0)
Age group, n (%)
<65 Years	183 (85.5)	182(85.8)	365 (85.7)
≥65 Years	31 (14.5)	30 (14.2)	61 (14.2)
Sex, n (%)
Men	146 (68.2)	144 (67.9)	290 (68.1)
Women	68 (31.8)	68 (32.1)	136(31.9)
Race, n(%)
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

Table II.

Mean Blood Pressure and Pulse Rate at Baseline

	Telmisartan	Valsartan	All
24‐Hour ABPM
N	199	197	396
SBP, mm Hg	150.9 (12.4)	152.0 (12.3)	152.0 (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)
Seated trough cuff
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

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 (Figure 1 and Figure 2), and the differences 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; Figure 1 and Figure 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 (Figure 3 and Figure 4).

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.; day‐time=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

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.

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).

Table III.

Mean Change From Baseline in Trough Cuff Blood Pressure

	Telmisartan (n=212)	Valsartan (n=212)	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

	Telmisartan (n=199)	Valsartan (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

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 adverse events was similar for the two treatment groups, and neither treatment was associated with cough (Table V).

Table V.

Treatment‐Emergent Adverse Events With Incidence ≥2%

Adverse Event, n (%)	Telmisartan (n=214)	Valsartan (n=212)
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

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 Investigator 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 , ¹⁶ , ¹⁷ , 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 angiotensin‐converting enzyme (ACE) inhibitors enalapril and lisinopril and similar to that of enalapril for the treatment of severe hypertension. ¹⁹ , ²⁰ , 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 AT₁ receptor, and a lack of interaction with the kallikrein‐kinin pathway, which has been linked to ACE inhibitor‐induced cough. ²³ , ²⁴ , 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 , ⁶ , 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.