Telmisartan/hydrochlorothiazide versus valsartan/hydrochlorothiazide in obese hypertensive patients with type 2 diabetes:  the SMOOTH study

Background:  The SMOOTH study compares telmisartan/hydrochlorothiazide (T/HCTZ) with valsartan/hydrochlorothiazide (V/HCTZ) therapy.

Objective:  SMOOTH was designed to compare the change in mean ambulatory blood pressure (ABP) from baseline to the last 6 hours of the 10 week trial.

Methods:  This multicenter (118 centers in 8 countries) study used a placebo run-in period followed by a prospective, randomized, open-label, blinded-endpoint design.  Inclusion criteria:  men and women aged 30 years or older; mild-to-moderate hypertension; 24-hour mean ambulatory SBP > 130 mm Hg and/or DBP > 85 mm Hg; type 2 diabetes that has remained stable; and a BMI < 27 kg/m2 in non-Asians and > 24 kg/m2 in Asians.  Exclusion criteria:  mean seated SBP > 180 mm Hg or mean seated DBP > 110 mm Hg during any visit of the placebo run-in period; fasting serum glucose > 17 mmol/l (300 mm/dl); pre-menopausal women who were nursing, pregnant, or not using adequate contraception; history of coronary disease, congestive heart failure, a recent acute cardiovascular event or stroke, or secondary hypertension; hepatic or renal impairment; and night-shift workers.  The use of corticosteroids, cholestyramine, colestipol resins, and medications known to affect BP was also prohibited.  A total of 840 patients were randomized (428 – T/HCTZ, 412 – V/HCTZ).  Patients were randomized to either telmisartan 80 mg or valsartan 160 mg monotherapy for 4 weeks, and then received add-on HCTZ 12.5 mg for the remaining 6 weeks.  The duration of the study was 10 weeks.  The primary outcome measure was the change from baseline in mean ambulatory SBP and DBP during the last 6 hours of the 24-hour dosing interval at the end of the 10 week study period.  The secondary outcome measures were changes from baseline in mean 24-hour, morning, daytime, and night-time ambulatory SBP and DBP; changes in trough seated clinic BP; and response rates based on both 24-hour mean ambulatory SBP and DBP.  The power was approximately 90%.

Results:  There were 743 patients that actually completed the trial (T/HCTZ, n=378; V/HCTZ, n=365).  In regards to primary outcomes, after 10 weeks’ treatment, T/HCTZ provided significantly greater mean BP lowering compared with V/HCTZ in the last 6 hours of the 24-hour dosing interval.  Mean SBP/DBP changes were –18.4/-9.7 mm Hg in T/HCTZ-treated patients and –14.5/-7.7 mm Hg in V/HCTZ-treated patients.  In other words, there was an adjusted mean difference in favor of T/HCTZ of 3.9 mm Hg SBP and 2.0 mm Hg DBP.  Overall, the mean BP was 139.1/82.4 mm Hg (V/HCTZ) and 135.6/81.2 mm Hg (T/HCTZ).  In regards to secondary outcomes, T/HCTZ produced significantly greater reductions in 24-hour mean BP than V/HCTZ during the 24-hour dosing interval (SBP 3.0 mm Hg, p = 0.002; DBP 1.6 mm Hg, p = 0.0006). In addition, during the morning, daytime and nighttime periods, patients receiving T/HCTZ had significantly greater reductions in mean ambulatory SBP and DBP compared with those taking V/HCTZ (p < 0.003). Reductions in trough seated clinic BP after 10 weeks' treatment were significantly greater with T/HCTZ compared with V/HCTZ (SBP 3.2 mm Hg, p = 0.0017; DBP 1.2 mm Hg; p = 0.0446). The advantage of telmisartan was already apparent after 4 weeks of treatment with monotherapy (SBP 2.5 mm Hg: p = 0.0106; DBP 0.8 mm Hg: p = 0.1370). The mean BP achieved with monotherapy was 146.6/86.3 mm Hg (valsartan) and 143.3/85.5 mm Hg (telmisartan). Safety was not sufficiently addressed in the study.  Other secondary measures were relatively similar between the two groups.

Strengths:  Large sample size, appropriate power, and level of significance.  Standard deviation (not SEM) was used to report variability.

Weaknesses:  Open-label, prospective design, no control.  The open-label design would allow bias to be introduced into the study.  The prospective design prevents investigators from being absolutely positive of the causative agent.  Furthermore, without a control there is no group to which compare the treatment group to.  Also, potential conflict of interest existed as one of the authors had direct ties to the manufacturer of telmisartan.  Moreover, the manufacturer funded the SMOOTH trial.  Finally, compliance was not addressed.

Conclusion:  There is not enough data to suggest changing an existing regimen.  The results of the study were not clinically significant with respect to changes from baseline.  Both T/HCTZ and V/HCTZ have a place in treating hypertension.  Adverse effects were similar between the two therapies therefore adverse effects would not have a real weight on choice of drug.  Future studies are needed to substantiate results.

Sharma AM, Davidson J, Koval S, and Lacourciere Y.  Telmisartan/hydrochlorothiazide versus valsartan/hydrochlorothiazide in obese hypertensive patients with type 2 diabetes:  the SMOOTH study.  Cardiovascular Diabetology 2007, 6:28.

Casey R. Watts, PharmD Candidate