- Top of page
- PATIENTS AND METHODS
- Acknowledgments and disclosure:
This study examined the effects of increasing the thiazide diuretic dose in a fixed-dose ARB/diuretic combination in patients with uncontrolled hypertension despite 6 weeks' open-label treatment with the ARB/diuretic combination, telmisartan 80 mg/hydrochlorothiazide 12.5 mg (T80/H12.5). 713 patients with trough seated DBP =90 mmHg were then randomized to 8 weeks' double-blind treatment with telmisartan 80 mg and an increased dose of 25 mg of hydrochlorothiazide (T80/H25) or T80/H12.5. Adjusted mean seated DBP changes from baselines of 95.3 (T80/H25) and 95.0 mmHg (T80/H12.5) were −7.1 and -−5.5 mmHg (difference: 1.6 mm Hg), respectively (P=.0012). Changes in systolic blood pressure from 147.9 mmHg (T80/H25) and 147.4 mmHg (T80/H12.5) were −9.8 and −7.1 mmHg (difference: 2.7 mm Hg) (P=.0003). Adverse events occurred in 31.5% (T80/H25) and 29.6% (T80/H12.5), with serious events in 1.4% and 0.8%, respectively. Hypokalemia was rare. These results show that higher-dose thiazide diuretic in combination with T80 in patients with hypertension uncontrolled by T80/H12.5 provides additional blood pressure reductions and is well tolerated.
Because of the detrimental long-term effects of hypertension on cardiovascular morbidity and mortality, recent guidelines advocate tight control of blood pressure.1–3 Certain patients, such as those with concomitant diabetes and/or chronic kidney disease, are at increased cardiovascular risk and require more rigorous control of blood pressure to improve prognosis.4,5 Programs to educate patients have increased their awareness of the seriousness of hypertension, and in recent years, the proportion of adults receiving treatment for hypertension has increased in both the United States and Europe.6–9 However, in many patients (most notably in Europe), elevated blood pressure is still inadequately controlled.10–12 In patients in whom target blood pressure is not reached with monotherapy, the use of ≥2 antihypertensive agents is recommended.1,2 Use of agents with complementary modes of action potentiates efficacy; adverse effects of the different agents may be counterbalanced when used in combination. One such recommended combination is an angiotensin receptor blocker (ARB) and a thiazide diuretic.1,2 Administration of the 2 drugs as a fixed-dose combination (FDC) in a single tablet also may have the advantage of encouraging patient compliance because of a simplified treatment regimen.13
Telmisartan is an ARB with a long elimination half-life.14 In clinical trials, telmisartan, as well as several other ARBs, has been shown to provide 24-hour control of blood pressure.15 The FDC of telmisartan 80 mg plus a low dose of the thiazide diuretic hydrochlorothiazide 12.5 mg (T80/H12.5) administered once daily is effective in many hypertensive patients16–18 and is approved as second-step treatment for patients whose blood pressure is not adequately controlled on other antihypertensive therapies. However, blood pressure targets still may not be achieved in some patients with this medication. In these patients, the use of telmisartan 80 mg plus a higher 25-mg dose of hydrochlorothiazide may provide additional reduction of blood pressure.
The present study (www. ClinicalTrials.gov, Identifier: NCT00239369) was conducted to determine whether a higher dose of a thiazide with the ARB resulted in further reduction in blood pressure in patients whose blood pressure was insufficiently controlled after 6 weeks' treatment with T80/H12.5. The study was also designed to compare the safety and tolerability of the 2 medications.
- Top of page
- PATIENTS AND METHODS
- Acknowledgments and disclosure:
In hypertensive patients, blood pressure is frequently poorly controlled despite pharmacologic intervention; target values are not achieved in many patients. In our study, patients had previously received up to 3 different antihypertensive agents without adequate reduction in blood pressure. This inadequacy of blood pressure control is consistent with the findings of recent large-scale surveys in different European countries.10–12 poor blood pressure control may be attributed to the use of low doses of medication or not using multiple agents.22 Poor blood pressure control, however, is not always the fault of the prescribing physician; part of the problem may be due to poor patient compliance or lack of appreciation of the clinical significance of hypertension.22
Prior to entering this study, patients had received a variety of antihypertensive agents. The most common class of antihypertensive medication given was diuretics, either alone or together with other classes of agents. Hydrochlorothiazide 12.5 mg administered once daily has been shown to reduce blood pressure in approximately one-half to two-thirds of patients who are responsive to this class of drugs.23 The use of higher doses may provide additional control of blood pressure but may be associated with increased incidence of adverse effects. These adverse effects may provide an explanation of why some patients are more likely to discontinue thiazide diuretics than other classes of antihypertensives, such as ARBs.24 ARBs were the next most commonly prescribed antihypertensive. The ineffective lowering of blood pressure among patients receiving such treatment may have been due to some ARBs not providing 24-hour control. A recent meta analysis reported that telmisartan was statistically more effective than valsartan or losartan in reducing 24-hour mean blood pressure.25
After the end of the run-in phase, which involved switching from previous antihypertensive therapy to an FDC of T80/H12.5, mean blood pressure was substantially reduced, even in patients in whom the guideline-defined blood pressure goal of seated DBP < 90 mm Hg at trough was not reached.1–3 Our study showed that in those patients in whom the target DBP was not attained with T80/H12.5, there was a further significant reduction in seated trough DBP (the primary efficacy end point) if patients were treated with the higher dose of a thiazide with the ARB. T80/H25 also proved superior to T80/H12.5 in reducing trough seated SBP, resulting in a further reduction in SBP of 2.7 mm Hg. This blood pressure reduction could be of long-term clinical significance, as a meta-analysis of data from more than 1 million patients participating in 61 outcome studies suggested that a reduction in SBP of 2 mm Hg could be associated with a 10% reduction in the risk of fatal stroke and a 7% reduction in the risk of death from other vascular causes.21
Although the start of run-in blood pressure values cannot be directly compared with the end point values (since not all were taken at trough), the changes from the start of the run-in to end point are of interest since they illustrate blood pressure reductions in patients whose blood pressure was uncontrolled despite receipt of as many as 3 antihypertensive agents and who were then switched to an ARB plus hydrochlorothiazide. The SBP/DBP reductions (14.0/9.2 and 12.3/7.9 mm Hg for T80/25 and T80/12.5, respectively) were statistically significant and likely to be of clinical significance.
The secondary efficacy end points also demonstrate the superiority of the higher-thiazide dose formulation in providing blood pressure control in a higher proportion of patients. The findings of our study are consistent with a large-scale, placebo-controlled study conducted in the United States in patients with stage 1 or 2 hypertension that demonstrated the antihypertensive efficacy of T80/H25 after 8 weeks' treatment and showed its superiority to another ARB combination of valsartan 160 mg plus hydrochlorothiazide 25 mg.26
The large proportion (68%) who did not respond adequately to T80/H12.5 may be due to the restrictive inclusion criteria, which only enrolled patients with documented uncontrolled hypertension. Patients enrolled in this study had elevated blood pressure (154.1/97.6 mm Hg) despite prior treatment with 1 to 3 antihypertensive agents. Analysis of previous trials (which did not deliberately include patients resistant to prior therapy) of T80/H12.5 indicated that 35% of patients did not respond adequately to this regimen (unpublished data). It should be noted that even in patients who failed to respond to 6 weeks of open-label T80/H12.5 therapy, further reductions in blood pressure were seen in patients who were randomized to further T80/H12.5 therapy during the 8-week double-blind stage of the study. There are a number of possible explanations for this observation. One is that the 6-week open-label treatment was not sufficiently long to achieve a stable reduction in blood pressure in patients with uncontrolled hypertension. Alternatively, it may be that patients were expecting to receive a more effective treatment after randomization, and hence there was a placebo-like effect. Regression to the mean may also have contributed to the additional reduction in blood pressure after 8 weeks' double-blind treatment with the lower-dose formulation.
The additional blood pressure lowering provided by T80/H25 did not appear to have any detrimental effect on adverse events, and both the low- and high-dose hydrochlorothiazide formulations were equally well tolerated. A previous dose-ranging study has shown that tolerability of various dose combinations of telmisartan and hydrochlorothiazide was comparable to that of telmisartan monotherapy.27 Most notably, the combination protected against potassium depletion, which is widely recognized as a relatively common side effect of higher-dose hydrochlorothiazide, especially dosages >50 mg/d. In our study, hypokalemia was a rare event and was detected in only 3 patients, only 1 of whom was treated with T80/H25; none of these patients required a potassium supplement.
In conclusion, treatment with T80/H25 provides a further reduction of blood pressure in patients with difficult-to-treat hypertension that does not respond adequately to treatment with T80/H12.5. The additional blood pressure lowering, which may have a positive benefit on long-term cardiovascular prognosis, was achieved without compromising tolerability and safety.