Efficacy of Single-Pill Combination of Telmisartan 80 mg and Hydrochlorothiazide 25 mg in Patients with Cardiovascular Disease Risk Factors: A Prospective Subgroup Analysis of a Randomized, Double-Blind, and Controlled Trial

Objective. Report of prespecified and post hoc subgroup analyses of a randomized, controlled trial comparing telmisartan 80 mg/hydrochlorothiazide 25 mg (T80/H25) combination therapy with T80 monotherapy, according to the presence of cardiovascular disease (CVD) risk factors. Methods. Hypertensive patients were randomized (2 : 1) to receive T80/H25 or T80 for 6 weeks, following a 1-week, low-dose, and run-in period. Systolic blood pressure (SBP) and diastolic BP reductions and BP goal achievement were evaluated in patients with CVD risk factors: presence of diabetes mellitus (DM), renal impairment, increased body mass index (BMI), and 10-year estimated risk for coronary heart disease (CHD). Results. In total, 888 patients received treatment. Overall, T80/H25 therapy significantly reduced SBP more than T80 monotherapy, irrespective of patient subgroup. In patients with DM, renal impairment, high BMI, and high CHD risk, BP goal achievement rates (<140/90 mm Hg) at Week 7, among those treated with T80/H25, were 52.8%, 52.8%, 50.6%, and 38.5%, respectively. More patients with DM reached a guideline-based BP goal (<130/80 mm Hg) at 7 weeks with T80/H25 than with T80 monotherapy (16.7% versus 8.8%). Rates of treatment-related adverse events were low and comparable across patient subgroups. Conclusions. Antihypertensive treatment with T80/H25 single-pill combination is effective and generally well tolerated, irrespective of the presence of CVD risk factors.


Introduction
Hypertension commonly accompanies other cardiovascular disease (CVD) risk factors and comorbidities such as obesity, chronic kidney disease, diabetes mellitus (DM), and heart disease [1]. In these high CVD risk patients, early treatment of hypertension to attain blood pressure (BP) goals may be particularly important in order to help reduce CVD risk.
Around three quarters of patients with hypertension will require combination therapy in order to reach guidelinerecommended BP goals [2,3]. In high-risk hypertensive patients, the initial use of combination therapy may facilitate the achievement of BP goals [4] and help to lower the risk of target organ damage [2,[5][6][7][8]. This supports a strategy aimed at combining antihypertensive agents with complementary mechanisms of action [3,9].
The combination of an angiotensin II receptor blocker (ARB) plus a thiazide diuretic is endorsed by international hypertension guidelines [4,5]. As a result of evidence from the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) [10,11], telmisartan is the only ARB currently approved for the reduction of CVD morbidity in patients with manifest atherothrombotic CVD (history of coronary heart disease (CHD), International Journal of Hypertension stroke, or peripheral arterial disease) or type 2 DM with documented target organ damage.
A prior multinational, double-blind, and double-dummy study demonstrated that initial treatment with the single-pill combination (SPC) of telmisartan 80 mg (T80) plus hydrochlorothiazide (HCTZ) 25 mg (H25) therapy in patients with grade 2 or 3 hypertension significantly reduced BP and produced higher BP goal attainment compared with T80 alone [12]. The large patient population in that study provided an opportunity for analysis of the response to telmisartan/HCTZ SPC compared with T80 monotherapy treatment within different subpopulations of patients with grade 2 or 3 hypertension.
This current analysis evaluated the efficacy and tolerability of SPC T80/H25 compared with T80 monotherapy in patients with CVD risk factors: presence of DM, renal impairment, increased body mass index (BMI), and 10-year risk score for CHD (based on tertiles), with additional post hoc analyses according to alternative guideline-recommended 10-year CHD risk groups [13].

Study Design.
The trial was performed as a 7-week, multinational, phase IV, randomized, double-blind, activecontrolled, parallel-group, and forced-titration study in patients with grade 2 or 3 hypertension. The trial was conducted between June 2009 and April 2010 (ClinicalTrials.gov identifier: NCT00926289). The study design was described in detail elsewhere [12]. In brief, after an open-label, placebo run-in treatment period of 1-14 days, patients were randomized 2 : 1 to double-blind treatment with SPC telmisartan 40 mg (T40)/HCTZ 12.5 mg or T40 monotherapy for 1 week before uptitration to the target dose of SPC T80/H25 or T80 monotherapy, respectively, for the remaining 6 weeks. The trial was conducted under the guidelines specified by the Declaration of Helsinki and International Conference on Harmonisation Tripartite Harmonised Guidelines for Good Clinical Practice. The study protocol was approved by the health authority in each country and by the institutional review board or ethics committee of each center. Study participants provided written informed consent.

Patients and Subgroups for Analysis.
Patients were recruited at 102 participating centers in eight countries (Bulgaria, China, France, Georgia, Romania, Russia, South Korea, and the United States). Eligible patients were men or women age ≥18 years with grade 2 or 3 hypertension (mean seated in-clinic trough cuff systolic BP (SBP) ≥160 mm Hg and diastolic BP (DBP) ≥100 mm Hg) who met the inclusion criteria (described in detail elsewhere) [12]. Study exclusion criteria included mean SBP ≥200 mm Hg and/or DBP ≥120 mm Hg; severe renal impairment (serum creatinine >3.0 mg/dL and/or creatinine clearance <30 mL/min and/or clinical markers of severe renal impairment); congestive heart failure (New York Heart Association Functional Class III or IV); severe obstructive coronary artery disease; aortic stenosis; contraindications to a placebo run-in period (e.g., stroke within the past 6 months, myocardial infarction, cardiac surgery, percutaneous transluminal coronary angioplasty, unstable angina, or coronary artery bypass graft within 3 months prior to the start of the placebo run-in period); and uncontrolled DM (glycated hemoglobin ≥10%).
In this analysis, patients were evaluated for inclusion into baseline CVD risk factor subgroups: DM, renal function, BMI, and 10-year CHD risk score. The DM subgroup included those with a diagnosis of type 1 DM, type 2 DM, diabetic retinopathy/nephropathy, or the presence of recognized Medical Dictionary for Regulatory Activities codes for DM. Renal function categories were defined by estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 or eGFR ≥60 mL/min/1.73 m 2 . BMI categories were defined as <25 kg/m 2 , ≥25-<30 kg/m 2 , or ≥30 kg/m 2 .
For 10-year CHD risk score, the probability of developing CHD over 10 years was estimated (based on a risk score developed from the Framingham Heart Study) for all treated patients for whom a baseline laboratory value for total cholesterol and high-density lipoprotein (HDL) was available. This risk score estimated the probability of developing CHD over 10 years based on baseline values for age, gender, total cholesterol and HDL, BP category, presence of DM (yes/no), and smoking status (yes/no) [14]. The method used in this analysis to assess the 10-year risk for CHD was based upon a version of the Framingham Risk Score described by Wilson et al., which included DM as a measured parameter [14].

Efficacy and Safety Evaluations.
At each study visit, seated trough cuff BP was measured approximately 24 hours (20-30 hours) after the last study drug intake, with the mean taken from three consecutive measurements performed approximately 2 minutes apart using a standard manual cuff sphygmomanometer or other validated device (with cuff size conforming with American Heart Association Guidelines) [15]. BP measurements were performed at screening, at the start of the open-label placebo run-in treatment period, at the end of the run-in treatment period prior to randomization (i.e., at baseline), and then after 1, 3, 5, and 7 weeks of doubleblind treatment.
Efficacy endpoints assessed at Weeks 3, 5, and 7 were described previously [12] and included the primary endpoint measure of change from baseline to final visit (Week 7) in mean seated trough cuff SBP. Secondary and other endpoints included change from baseline to final visit (Week 7) in mean seated trough cuff DBP, the proportion of patients achieving overall BP goal (defined as a mean seated trough cuff SBP/DBP <140/90 mm Hg), the proportion of patients with DM achieving overall BP goal (defined as a mean seated trough cuff SBP/DBP <130/80 mm Hg), the proportion of patients achieving SBP goal (mean SBP <140 mm Hg), the proportion of patients achieving DBP goal (mean DBP <90 mm Hg), the proportion of patients with a mean seated trough cuff SBP reduction of >30 mm Hg, and the proportion of patients with mean seated trough cuff SBP reduction of >40 mm Hg. Other secondary endpoints were described in the primary study publication [12].
The assessment of adverse events (AEs) by risk group was not prespecified but is included here and included serious AEs and those leading to treatment discontinuation, with intensity and causal relationship to the study treatment determined by the investigator.

Statistical
Analysis. The objective of these analyses was to investigate whether SPC T80/H25 provided greater BP reductions compared with T80 monotherapy among patient subgroups of DM, renal impairment, and at specific cutoff values for BMI and 10-year risk score for CHD. Efficacy analyses were performed on data from the full analysis set (FAS), defined as randomized patients who received at least one dose of double-blind trial medication, and for whom a baseline measurement and at least one postdose trough efficacy measurement during the high-dose doubleblind treatment period were available. Safety analyses were performed on all randomized patients who received at least one dose of the allocated treatment.
The sample size of the trial was calculated to ensure sufficient statistical power to show superiority of SPC T80/H25 over T80 monotherapy with respect to the primary and key secondary endpoints within the overall study population. The subgroup analyses were not powered per se to determine the efficacy of SBP H25/T80 versus T80 according to the different patient subpopulations reported here or to test for treatmentby-subgroup interactions. Because this was an exploratory, "proof of concept" analysis and because no adjustments were made to correct for multiplicity, the statistical models were not applied for the purpose of providing statistical significance.
values were calculated for the interaction of subgroup and treatment and are considered statistically significant with a value of <0.05. These values provide an indication of whether the differences between treatments differ across subgroup categories (e.g., BMI).
A restricted maximum-likelihood-based, mixed-effect model, and repeated measures approach (using baseline and all available longitudinal observations at each postbaseline visit during the high-dose treatment phase) was utilized for the primary endpoint analysis, as well as for changes from baseline in DBP. This model included the fixed, categorical effects of treatment, country, week, and treatment-by-week interaction, subgroup, and treatment-by-subgroup interaction, with the continuous covariates of baseline mean seated trough cuff SBP or DBP, and baseline-by-week interaction. An unstructured covariance structure was used to model within-patient errors. The difference in least squares means of treatments (SPC T80/H25 versus T80 monotherapy) with a 95% confidence interval (CI) was calculated for each subgroup.
The outcomes of proportion of patients achieving BP, SBP, and DBP goals, and substantial SBP reductions (>30 or >40 mm Hg), were evaluated using logistic regression with fixed effects for treatment, country, subgroup, treatmentby-subgroup interaction, and the respective baseline value (DBP or SBP) as a covariate. Last trough observation carried forward was employed to account for missing data in the analysis of binary endpoints of BP goal achievement and BP reductions. Odds ratios (ORs) with 95% CIs were calculated and reported for the effect of SPC T80/H25 versus T80 monotherapy in different patient subpopulations.

Patient Characteristics.
The baseline characteristics of the entire cohort of 888 patients randomized and treated in the study were previously described [12]. The efficacy analyses were performed on data from 285 patients in the T80 group and 573 patients in the SPC T80/H25 group (FAS total, 858). The safety analyses were performed on data from all 888 treated patients. Compliance with trial medication was high in both treatment groups (at least 96.6% of patients in either treatment group took ≥80% to ≤120% of their trial medication at each visit) [13].
The baseline BP characteristics of different patient subpopulations according to treatment group are shown in Table 1. More patients did not have a diagnosis of DM than those who had a diagnosis with DM (treated set, = 779 and = 109, resp.). More patients had eGFR ≥60 mL/min/1.73 m 2 ( = 824) compared with those with eGFR <60 mL/min/1.73 m 2 ( = 58). Regarding BMI, 188 treated patients had baseline BMI <25 kg/m 2 , 341 treated patients had BMI ≥25-<30 kg/m 2 , and 359 treated patients had BMI ≥30 kg/m 2 . The distribution of patients in low, medium, and high estimated 10-year CHD risk categories is displayed in Table 2. CHD risk was, overall, well matched between the SPC T80/H25 and T80 treatment arms. The majority of patients within this study, 71.3%, were within the lower-risk CHD1 category (<10% risk), 20.9% were in the medium-risk category (≥10%−<20% risk), and 7.8% of patients were within the CHD3 category (≥20% risk).
The observed adjusted mean reductions in SBP/DBP from baseline according to treatment group and patient subpopulations are shown in Table 3. Treatment differences for SPC T80/H25 compared with T80 are depicted in Figure 1. The ORs and 95% CIs for the proportions of     International Journal of Hypertension  patients achieving BP goal and for the proportions of patients achieving SBP reductions >30 or >40 mm Hg, for treatment with SPC T80/H25 versus T80, in the different patient subpopulations, are displayed in Figures 2 and 3, respectively [12]. Descriptions of results according to subpopulations follow.

DM.
Only one patient in the SPC T80/H25 treatment group had type 1 DM. No significant treatment by subgroup interactions were found between patients with DM and those without DM with respect to treatment differences in BP reductions and control rates (Table 3 and Figures 1, 2, and 3). At Week 7, T80/H25 produced greater SBP and DBP reductions compared with T80 monotherapy in patients with or without DM (Table 3 and Figure 1) (Figure 3).

BMI.
No significant treatment-by-subgroup interactions were found between groups of patients within different BMI categories with respect to treatment differences in BP reductions and control rates (Table 3 and Figures 1, 2, and 3). BMI is expressed in kg/m 2 .
Treatment with SPC T80/H25 consistently produced greater reductions in SBP and DBP at Week 7 compared with T80 monotherapy across all three baseline BMI categories (Table 3, Figure 1) (Figure 2). A similar pattern was observed for SBP reductions of >30 mm Hg, which were achieved in a greater proportion of patients receiving SPC T80/H25 across all three BMI categories (Figure 3).

10-
Estimated CHD Risk. The responses of patients within different 10-year CHD risk categories with regard to treatment differences in SBP and DBP reductions are shown in Table 3 for the post hoc guideline-driven CHD risk categories and also for the prespecified subgroups of CHD risk divided by tertiles. ORs for treatment differences in SBP/DBP reductions and control rates are displayed in Figures 1, 2, and  3 for the guideline-driven CHD risk categories. No significant treatment-by-subgroup interactions were found. At Week 7, reductions in mean SBP and DBP were greater in patients receiving SPC T80/H25 compared with T80 monotherapy across all three CHD risk categories (Table 3 and Figure 1). At Week 7, SPC T80/H25 produced higher rates of BP goal attainment (<140/90 mm Hg) versus T80 monotherapy across the three CHD categories (CHD1: 58.6% versus 36.3%; CHD2: 49.0% versus 37.3%; CHD3: 38.5% versus 17.9%). The SBP goal (<140 mm Hg) was more commonly achieved in the SPC T80/H25 group compared with the T80 group (CHD1: 67.0% versus 45.6%; CHD2: 54.8% versus 44.0%; CHD3: 46.2% versus 21.4%). The DBP goal (<90 mm Hg) was also more commonly achieved in the SPC T80/H25 group compared with the T80 group (CHD1: 69.8% versus 52.2%; CHD2: 62.5% versus 54.7%; CHD3: 61.5% versus 50.0%) (Figure 2). A similar pattern was observed for SBP reductions of >30 mm Hg, which were achieved in a greater proportion of patients receiving SPC T80/H25 across all three CHD categories (Figure 3).

Safety and Tolerability.
A summary of AEs reported during the study according to patient subpopulations is provided in Table 4. The proportion of patients experiencing treatment-related AEs in SPC T80/H25 and T80 monotherapy groups was low across most of the patient subpopulations. The proportion of patients with AEs leading to treatment discontinuation was low and comparable across almost all investigated patient subpopulations except the subpopulation of patients with CHD3 (two patients (6.7%) had an AE that resulted in discontinuation within this group). Only one patient experienced a serious AE during the treatment period and that was in the T40 group prior to uptitration. No deaths occurred during the course of the study.
The overall proportion of patients reporting any AE during treatment with SPC T80/H25 was 16.0%. An increase in the rate of AEs was not observed with the presence of DM, increasing BMI, or increasing CHD risk. The frequency of any AE was similar across many of the assessed subpopulations; however, in the subpopulation of patients with DM, the rate was 6.9%, in patients with a low BMI <25 kg/m 2 , the rate was 22.7%, and in patients with a low eGFR <60 mL/min/1.73 m 2 , the rate was 33.3%.
The overall rate of AEs deemed by the study investigator to be treatment related was 4.6% in the SPC T80/H25 group. A difference in the frequency of treatmentrelated AEs compared with the overall study population was observed in patients with DM (2.8%), patients with eGFR < 60 mL/min/1.73 m 2 (16.7%), patients with BMI < 25 kg/m 2 (7.8%), and patients in the middle CHD risk category CHD2 (6.5%). The most frequent drug-related AEs in the T80/H25 treatment arm were dizziness and pollakiuria (each 0.7%), syncope, and blood uric acid increase (each 0.5%). A breakdown of the frequencies of these four AEs within each subpopulation is provided in Table 5.

Discussion
The presented results reflect prespecified and post hoc subgroup analyses of efficacy and safety data obtained during a 7-week, multinational, phase IV, randomized, double-blind, active-controlled, parallel-group, and forced-titration study in patients with grade 2 or 3 hypertension. In this analysis, SPC T80/H25 similarly reduced SBP and DBP across specific subgroups of patients with CVD risk factors of DM, being overweight/obese, renal impairment, and CHD risk, and those without these CVD risk factors. Additionally, SPC T80/H25 consistently provided greater reductions in SBP and DBP over 7 weeks compared with T80 monotherapy, irrespective of the presence or absence of these CVD risk factors. SPC T80/H25 increased rates of BP goal attainment in all CVD risk groups, including patients with renal impairment, and in overweight to obese patients. Patients with DM were approximately twice as likely to reach a guideline-based BP goal (SBP/DBP < 130/80 mm Hg) over 7 weeks with SPC T80/H25 than with T80 monotherapy (16.7% versus 8.8%), although the sample size of patients with DM was small.
A limitation of this study is that it was designed with a relatively short duration of treatment (7 weeks). Due to the aforementioned reasons, the results obtained from these subgroup analyses should be interpreted under consideration of their exploratory character. However, this is the first report on the efficacy of SPC T80/H25 in specific patient    Blood uric acid increased  T80  T80/H25  T80  T80/H25  T80  T80/H25  T80  T80/H25  T80  T80/ subpopulations according to the presence or absence of CVD risk factors (DM, being overweight/obese, renal impairment, and high CHD risk). BP control is important in all hypertensive patients but is especially pertinent in those with additional CVD risk factors, since elevated BP is associated with significant increases in CV risk [16]. It is recognized that combination therapy can reduce BP to a greater extent and achieve BP goals more promptly [6], so high-risk individuals are likely to benefit from protective interventions without any delay. Initial combination therapy is increasingly recommended by guidelines, particularly for patients with CVD risk factors [6], and well-tolerated combinations can facilitate improved treatment adherence, a key factor in achieving successful BP control. Outcome studies have demonstrated that for every 20 mm Hg reduction in SBP, there is a 40-50% reduction in CVD [17]. The degree of BP reductions observed with SPC T80/H25 during this study would be expected to reduce CVD morbidity and mortality among patients at high risk for CVD [5,6]. These analyses indicate that SPC T80/H25 is an effective and generally well-tolerated antihypertensive combination that is suitable for treating a wide range of patients with grade 2 or 3 hypertension, in the presence or absence of additional CVD risk factors.

Conclusions
These analyses indicate that in patients with grade 2 or 3 hypertension, SPC T80/H25 consistently provided greater BP reductions and increased attainment of BP goals compared with T80 monotherapy among patient subgroups with CVD risk factors. No consistent pattern of differences in AEs was seen in this short trial. The majority of patients with hypertension will require combination therapy to reach BP goals [5,18]. The results of this trial indicate that treatment with SPC T80/H25 in patients with grade 2 or 3 hypertension provides greater BP reductions and higher rates of goal attainment compared with T80 monotherapy. Antihypertensive treatment with the T80/H25 single-pill combination is effective and generally well tolerated, irrespective of the presence of additional CVD risk factors.