Efficacy and Safety of the Combination of Telmisartan and Amlodipine with Hydrochlorothiazide in the Treatment of Hypertension

Current Recommendations

The European Society of Cardiology recommends starting hypertension therapy with a combination treatment using low doses of an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB, sartan) together with a calcium channel blocker (CCB) or a thiazide diuretic. If the dual combination is not sufficient, the guidelines recommend continuing with a triple combination of ACEi/ARB with CCB and a thiazide diuretic.

Study Methodology and Course

An 8-week multicenter randomized double-blind phase IIIb study was conducted in South Korea from June 2015 to November 2016. Individuals included were patients with essential hypertension defined as an average sitting systolic blood pressure (MSSBP) ≥ 140 and < 200 mmHg or ≥ 130 and < 200 mmHg in patients with diabetes or chronic kidney disease who were on antihypertensive medication, or ≥ 160 and < 200 mmHg in untreated patients, all for a duration of at least 4 weeks. The average age of the participants was 62.8 years, and 79% were men.

During the 4-week run-in period (period 1), each patient was administered 1 tablet of TA (40/5 mg) daily. Patients with an insufficient response to TA after 4 weeks were randomized into 2 groups: 155 individuals to TAH treatment and 155 individuals continued on TA. The TAH group took 1 tablet of TA (40/5 mg) + hydrochlorothiazide (12.5 mg) daily, while the control group took 1 tablet of TA (40/5 mg) + placebo. The treatment lasted 2 weeks (period 2). Patients who completed period 2 continued with a 6-week treatment (period 3) with double the dosage of TAH and TA.

The primary efficacy endpoint was the change in MSSBP after 8 weeks of treatment. Secondary endpoints included the change in MSSBP at week 2, the change in MSDBP (mean sitting diastolic blood pressure), the proportion of patients who achieved target blood pressure, and the proportion of patients whose antihypertensive effect reached a predefined intensity (systolic BP reduction of > 20 mmHg or diastolic BP reduction of > 10 mmHg) after 2 and 8 weeks of treatment. Tolerability of the combination therapy and the occurrence of treatment-emergent adverse events (TEAEs) were also assessed.

Results

After 8 weeks of therapy, the mean reduction in MSSBP and MSDBP was significantly greater in the TAH group than in the TA group (MSSBP: −18.7 vs. −12.2 mmHg; p < 0.001; MSDBP: −9.3 vs. −7.0 mmHg; p = 0.013). Similar results were observed for the comparison after 2 weeks of treatment.

After 2 weeks, 31.8% of patients in the TAH group and 13.8% in the TA group reached target BP, and after 8 weeks, 52.3% of patients in the TAH group and 24.8% in the TA group achieved this (p < 0.001 for both comparisons). The required intensity of effect was achieved by 33.8% of patients in the TAH group and 21.1% in the TA group at week 2 (p = 0.013) and by 56.3% of patients in the TAH group and 34.6% in the TA group at week 8 (p < 0.001).

Both groups had a similar prevalence of TEAEs during period 2; however, during period 3, when the dose was doubled, prevalence significantly increased in the TAH group compared to the TA group. Overall, TEAEs occurred in 29.0% of patients in the TAH group compared to 16.3% in the TA group (p = 0.008). The adverse events were mild (n = 58) or moderate (n = 13) in intensity, most commonly dizziness and headache.

Conclusion

The TAH triple combination was more effective than the TA dual combination in patients with essential hypertension who were insufficiently responsive to TA. It was also shown to be a well-tolerated treatment modality with a favorable risk-to-benefit ratio. However, it is important to consider that the study population consisted only of Korean patients, and extending the results to the (Central) European population may encounter potential pathophysiological differences.

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Source: Sung K. C., Oh Y. S., Cha D. H. et al. Efficacy and tolerability of telmisartan/amlodipine + hydrochlorothiazide versus telmisartan/amlodipine combination therapy for essential hypertension uncontrolled with telmisartan/amlodipine: the phase III, multicenter, randomized, double-blind TAHYTI Study. Clin Ther 2018; 40 (1): 50−63.e3, doi: 10.1016/j.clinthera.2017.11.006.