Hypertension commonly accompanies other cardiovascular disease (CVD) risk factors and comorbidities such as obesity, chronic kidney disease, diabetes mellitus (DM), and heart disease [
Around three quarters of patients with hypertension will require combination therapy in order to reach guideline-recommended BP goals [
The combination of an angiotensin II receptor blocker (ARB) plus a thiazide diuretic is endorsed by international hypertension guidelines [
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 [
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
The trial was performed as 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. The trial was conducted between June 2009 and April 2010 (ClinicalTrials.gov identifier: NCT00926289). The study design was described in detail elsewhere [
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) [
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 m2 or eGFR ≥60 mL/min/1.73 m2. BMI categories were defined as <25 kg/m2, ≥25–<30 kg/m2, or ≥30 kg/m2.
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) [
The prespecified analysis according to the trial statistical analysis plan divided CHD risk by tertiles across the patient population, which provided 10-year CHD risk cutoffs of <3.62%, ≥3.62–<8.66%, and ≥8.66%. An additional
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) [
Efficacy endpoints assessed at Weeks 3, 5, and 7 were described previously [
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.
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 cut-off 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 double-blind 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
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, treatment-by-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.
The baseline characteristics of the entire cohort of 888 patients randomized and treated in the study were previously described [
The baseline BP characteristics of different patient subpopulations according to treatment group are shown in Table
Baseline characteristics in the different patient subpopulations, based on treated patients.
T40/T80 | T40/H12.5/T80/H25 | |
---|---|---|
DM*, yes | ( |
( |
Gender | 22 male/13 female | 38 male/36 female |
Age, mean ± SD | 61.8 ± 8.6 | 61.1 ± 9.2 |
BMI, mean ± SD | 30.7 ± 5.6 | 31.1 ± 5.3 |
SBP/DBP (mm Hg), mean ± SDa | 174.0 ± 9.7/103.6 ± 4.6 | 171.1 ± 8.4/103.3 ± 3.7 |
Range SBP/DBP (mm Hg)a | 163–193/97–118 | 156–195/94–112 |
DM*, no | ( |
( |
Gender | 147 male/112 female | 271 male/249 female |
Age, mean ± SD | 57.0 ± 12.1 | 56.2 ± 11.4 |
BMI, mean ± SD | 28.9 ± 5.6 | 29.4 ± 5.4 |
SBP/DBP (mm Hg), mean ± SDa | 173.1 ± 9.3/104.6 ± 5.0 | 172.4 ± 9.8/104.4 ± 5.0 |
Range SBP/DBP (mm Hg)a | 155–197/92–119 | 131–211/87–119 |
| ||
eGFR < 60 mL/min/1.73 m2 | ( |
( |
Gender | 10 male/11 female | 18 male/19 female |
Age, mean ± SD | 70.1 ± 9.1 | 65.4 ± 9.4 |
BMI, mean ± SD | 28.3 ± 5.0 | 30.7 ± 5.4 |
SBP/DBP (mm Hg), mean ± SDb | 177.7 ± 10.8/103.4 ± 5.9 | 173.1 ± 9.6/104.2 ± 5.0 |
Range SBP/DBP (mm Hg)b | 161–195/96–119 | 160–193/97–118 |
eGFR ≥ 60 mL/min/1.73 m2 | ( |
( |
Gender | 159 male/112 female | 288 male/265 female |
Age, mean ± SD | 56.6 ± 11.5 | 56.2 ± 11.1 |
BMI, mean ± SD | 29.1 ± 5.4 | 29.5 ± 5.4 |
SBP/DBP (mm Hg), mean ± SDb | 172.8 ± 9.2/104.6 ± 4.9 | 172.2 ± 9.7/104.2 ± 4.9 |
Range SBP/DBP (mm Hg)b | 155–197/92–118 | 131–211/87–119 |
| ||
BMI < 25 kg/m2 | ( |
( |
Gender | 38 male/22 female | 69 male/59 female |
Age, mean ± SD | 57.6 ± 11.9 | 57.3 ± 13.4 |
BMI, mean ± SD | 22.6 ± 2.0 | 23.2 ± 1.5 |
SBP/DBP (mm Hg), mean ± SDc | 172.5 ± 10.0/103.9 ± 4.9 | 170.3 ± 9.6/103.7 ± 4.5 |
Range SBP/DBP (mm Hg)c | 160–195/96–117 | 160–198/95–119 |
BMI 25–<30 kg/m2 | ( |
( |
Gender | 68 male/52 female | 125 male/96 female |
Age, mean ± SD | 59.6 ± 10.7 | 57.5 ± 10.1 |
BMI, mean ± SD | 27.2 ± 1.5 | 27.5 ± 1.4 |
SBP/DBP (mm Hg), mean ± SDc | 173.3 ± 8.7/103.9 ± 4.7 | 171.9 ± 9.6/104.1 ± 4.7 |
Range SBP/DBP (mm Hg)c | 160–197/92–118 | 131–195/87–119 |
BMI ≥ 30 kg/m2 | ( |
( |
Gender | 63 male/51 female | 115 male/130 female |
Age, mean ± SD | 55.4 ± 12.7 | 55.9 ± 11.0 |
BMI, mean ± SD | 34.6 ± 4.5 | 34.8 ± 4.1 |
SBP/DBP (mm Hg), mean ± SDc | 173.4 ± 9.7/105.3 ± 5.1 | 173.6 ± 9.6/104.6 ± 5.1 |
Range SBP/DBP (mm Hg)c | 155–194/95–119 | 143–211/91–119 |
| ||
CHD1 10-year risk <10% | ( |
( |
Gender | 63 male/124 female | 164 male/282 female |
Age, mean ± SD | 55.3 ± 12.5 | 55.4 ± 11.7 |
BMI, mean ± SD | 29.7 ± 6.2 | 29.8 ± 5.7 |
SBP/DBP (mm Hg), mean ± SDd | 172.9 ± 9.6/104.7 ± 5.3 | 172.0 ± 9.7/104.4 ± 5.0 |
Rangea SBP/DBP (mm Hg)d | 155–197/95–119 | 131–211/87–119 |
CHD2 10-year risk ≥10–<20% | ( |
( |
Gender | 76 male/1 female | 106 male/3 female |
Age, mean ± SD | 59.6 ± 9.5 | 59.3 ± 8.0 |
BMI, mean ± SD | 27.8 ± 4.1 | 28.4 ± 4.1 |
SBP/DBP (mm Hg), mean ± SDd | 172.3 ± 9.3/104.0 ± 4.3 | 172.4 ± 9.5/104.0 ± 4.2 |
Range SBP/DBP (mm Hg)d | 160–190/92–113 | 160–198/95–115 |
CHD3 10-year risk ≥20% | ( |
( |
Gender | 30 male/0 female | 39 male/0 female |
Age, mean ± SD | 66.5 ± 7.1 | 64.8 ± 9.0 |
BMI, mean ± SD | 29.3 ± 4.5 | 30.0 ± 4.5 |
SBP/DBP (mm Hg), mean ± SDd | 176.9 ± 7.3/104.2 ± 4.8 | 174.7 ± 10.2/102.7 ± 3.9 |
Range SBP/DBP (mm Hg)d | 164–191/97–118 | 156–195/94–115 |
| ||
CHD risk tertile 1 (<3.62%) | ( |
( |
Gender | 11 male/81 female | 26 male/176 female |
Age, mean ± SD | 55.8 ± 14.5 | 55.6 ± 14.2 |
BMI, mean ± SD | 30.0 ± 6.5 | 29.6 ± 6.2 |
SBP/DBP (mm Hg), mean ± SDe | 172.2 ± 9.8/104.8 ± 5.0 | 172.1 ± 10.3/103.9 ± 4.8 |
Rangea SBP/DBP (mm Hg)e | 155–194/95–118 | 131–211/87–119 |
CHD risk tertile 2 (≥3.62–<8.66%) | ( |
( |
Gender | 43 male/40 female | 108 male/104 female |
Age, mean ± SD | 54.4 ± 10.1 | 55.2 ± 9.4 |
BMI, mean ± SD | 29.1 ± 5.9 | 30.2 ± 5.3 |
SBP/DBP (mm Hg), mean ± SDe | 174.2 ± 9.4/105.1 ± 5.6 | 171.7 ± 9.2/105.0 ± 5.2 |
Range SBP/DBP (mm Hg)e | 160–197/95–119 | 143–194/91–119 |
CHD risk tertile 3 (≥8.66%) | ( |
( |
Gender | 115 male/4 female | 175 male/5 female |
Age, mean ± SD | 61.1 ± 9.6 | 59.9 ± 8.8 |
BMI, mean ± SD | 28.5 ± 4.5 | 28.9 ± 4.5 |
SBP/DBP (mm Hg), mean ± SDe | 173.2 ± 9.0/103.8 ± 4.3 | 173.1 ± 9.5/103.7 ± 4.3 |
Range SBP/DBP (mm Hg)e | 160–191/92–118 | 156–198/94–117 |
SBP/DBP data from FAS (
aDM (yes) FAS: T40/T80,
beGFR < 60 FAS: T40/T80,
cBMI < 25 FAS: T40/T80,
dCHD1 FAS: T40/T80,
eCHD tertile 1 FAS: T40/T80,
BMI: body mass index; CHD: coronary heart disease; DBP: diastolic blood pressure; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; FAS: full analysis set; H12.5: hydrochlorothiazide 12.5 mg; H25: hydrochlorothiazide 25 mg; MedDRA: Medical Dictionary for Regulatory Activities; SBP: systolic blood pressure; SD: standard deviation; T40: telmisartan 40 mg; T80: telmisartan 80 mg.
Probability of developing CHD over 10 years: descriptive statistics and distribution of patients within estimated 10-year CHD risk categories, based on treated patients.
T40/T80 | T40/H12.5/T80/H25 | Total | |
---|---|---|---|
Total patients ( |
294 | 594 | 888 |
Overall probability of developing CHD over 10 years | |||
Mean (SD) | 9.06 (7.89) | 7.66 (7.12) | 8.12 (7.41) |
Range (min–max) | 0.35–51.06 | 0.04–49.39 | 0.04–51.06 |
Patients in CHD risk category, |
|||
CHD 1 (<10%) | 187 (63.6) | 446 (75.1) | 633 (71.3) |
CHD 2 (10–<20% ) | 77 (26.2) | 109 (18.4) | 186 (20.9) |
CHD 3 (≥20%) | 30 (10.2) | 39 (6.6) | 69 (7.8) |
Percentages may not sum to 100% due to rounding.
CHD: coronary heart disease; H12.5: hydrochlorothiazide 12.5 mg; H25: hydrochlorothiazide 25 mg; SD: standard deviation; T40: telmisartan 40 mg; T80: telmisartan 80 mg.
Efficacy results for the entire study population at Week 7 were previously reported in detail [
The observed adjusted mean reductions in SBP/DBP from baseline according to treatment group and patient subpopulations are shown in Table
SBP and DBP reductions (mm Hg) from baseline to Week 7 in overall patient population and different patient subgroups, based on the FAS.
Adjusted mean SBP/DBP reduction from baseline | Adjusted mean treatment difference of T80/H25 versus T80 (95% CI) | |||
---|---|---|---|---|
T80 | T80/H25 | SBP | DBP | |
Overall population | −28.5/−15.4 | −37.0/−18.6 | −8.5 (−10.6, −6.4) | −3.2 (−4.5, −1.9) |
DM | ||||
Yes | −26.7/−17.2 | −34.2/−18.6 | −7.6 (−13.0, −2.2) | −1.5 (−4.8, 1.9) |
No | −28.7/−15.1 | −37.4/−18.6 | −8.6 (−10.8, −6.4) | −3.4 (−4.8, −2.1) |
eGFR category | ||||
<60 mL/min/1.73 m2 | −20.3/−13.3 | −33.8/−17.0 | −13.5 (−20.5, −6.5) | −3.7 ( −8.1, 0.6) |
≥60 mL/min/1.73 m2 | −28.9/−15.5 | −37.2/−18.7 | −8.2 (−10.4, −6.1) | −3.2 (−4.5, −1.8) |
BMI category | ||||
<25 kg/m2 | −30.1/−16.6 | −36.0/−19.5 | −5.9 (−10.0, −1.7) | −2.9 (−5.5, −0.3) |
25–<30 kg/m2 | −28.9/−14.9 | −37.5/−18.9 | −8.6 (−11.7, −5.5) | −4.0 (−5.9, −2.1) |
≥30 kg/m2 | −27.1/−15.2 | −37.0/−17.8 | −9.9 (−12.9, −6.8) | −2.6 (−4.6, −0.7) |
10-year CHD risk category | ||||
CHD1 (risk < 10%) | −29.5/−15.7 | −38.3/−19.1 | −8.8 (−11.2, −6.3) | −3.4 (−4.9, −1.9) |
CHD2 (risk ≥ 10–<20%) | −27.2/−14.9 | −33.1/−17.3 | −5.9 (−9.8, −2.0) | −2.4 (−4.8, 0.1) |
CHD3 (risk ≥ 20%) | −25.3/−14.7 | −32.9/−16.3 | −7.7 (−14.0, −1.4) | −1.6 (−5.5, 2.3) |
10-year CHD risk by tertiles | ||||
CHD risk tertile 1 (<3.62%) | −31.1/−17.9 | −38.9/−19.6 | −7.8 (−11.2, −4.5) | −1.7 (−3.8, 0.4) |
CHD risk tertile 2 (≥3.62–<8.66%) | −27.4/−13.4 | −37.7/−18.9 | −10.3 (−13.8, −6.9) | −5.5 (−7.6, −3.3) |
CHD risk tertile 3 (≥8.66%) | −27.2/−14.9 | −33.9/−17.2 | −6.7 (−9.9, −3.6) | −2.4 (−4.3, −0.4) |
BMI: body mass index; CHD: coronary heart disease; CI: confidence interval; DBP: diastolic blood pressure; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; FAS: full analysis set; H25: hydrochlorothiazide 25 mg; SBP: systolic blood pressure; T80: telmisartan 80 mg.
Treatment difference (95% CI) of SPC T80/H25 versus T80 for changes in mean seated trough cuff (a) SBP and (b) DBP from baseline to Week 7 by patient subgroup (FAS). BMI: body mass index; CHD: coronary heart disease; CI: confidence interval; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; FAS: full analysis set; H25: hydrochlorothiazide 25 mg; SBP: systolic blood pressure; SPC: single-pill combination; T80: telmisartan 80 mg.
ORs (95% CI) of SPC T80/H25 versus T80 for BP goal rates. (a) SBP (<140 mm Hg), (b) DBP (<90 mm Hg), and (c) SBP/DBP goal (<140/90 mm Hg) at Week 7 by patient subgroup (FAS). BP: blood pressure; BMI: body mass index; CHD: coronary heart disease; CI: confidence interval; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; FAS: full analysis set; H25: hydrochlorothiazide 25 mg; OR: odds ratio; SBP: systolic blood pressure; SPC: single-pill combination; T80: telmisartan 80 mg.
ORs (95% CI) of SPC T80/H25 versus T80 for proportion of patients with seated trough cuff SBP reduction (a) >30 mm Hg and (b) >40 mm Hg at Week 7 by patient subgroup (FAS). BMI: body mass index; CHD, coronary heart disease; CI: confidence interval; eGFR, estimated glomerular filtration rate; FAS: full analysis set; H25: hydrochlorothiazide 25 mg; OR: odds ratio; SBP: systolic blood pressure; SPC, single-pill combination; T80: telmisartan 80 mg.
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
At Week 7, T80/H25 produced greater SBP and DBP reductions compared with T80 monotherapy in patients with or without DM (Table
In patients without DM, greater proportions of patients achieved SBP goal (<140 mm Hg) and DBP goal (<90 mm Hg) with SPC T80/H25 therapy compared to T80 monotherapy (SBP: 64.1% versus 43.0%; DBP: 68.1% versus 51.8%). In patients with DM, SBP and DBP goal rates were also higher in the SPC T80/H25 group compared with the T80 group (SBP: 58.3% versus 41.2%; DBP: 66.7% versus 58.8%) (Figure
In patients without DM, a greater proportion achieved SBP reductions of >30 or >40 mm Hg from baseline to Week 7 with SPC T80/H25 therapy compared with T80 monotherapy (>30 mm Hg: 68.7% versus 46.6%; >40 mm Hg: 41.3% versus 23.1%). In patients with DM, these SBP reductions were also achieved in a higher proportion of patients receiving combination therapy versus T80 monotherapy (>30 mm Hg: 62.5% versus 47.1%; >40 mm Hg: 34.7% versus 29.4%) (Figure
No significant treatment-by-subgroup interactions were found between patients within different eGFR categories with respect to treatment differences in BP reductions and control rates (Table
At Week 7, T80/H25 produced larger SBP and DBP reductions compared with T80 monotherapy in patients within both eGFR categories (Table
SPC T80/H25 therapy also allowed higher rates of BP goal attainment (<140/90 mm Hg) in patients with eGFR ≥60 (55.7% compared with 35.5% for T80) and in patients with eGFR <60 (52.8% compared with 19.0% for T80).
SBP goal attainment (<140 mm Hg) was also higher in patients receiving SPC T80/H25 compared with T80 monotherapy, regardless of baseline eGFR (eGFR ≥60: 63.8% versus 43.9%; eGFR <60: 55.6% versus 23.8%). The DBP goal of <90 mm Hg for patients with eGFR ≥60 was more commonly achieved in the SPC T80/H25 group (68.5%) compared with the T80 group (53.1%). In patients with eGFR <60, the rates of DBP goal attainment were 58.3% and 42.9%, respectively (Figure
SBP reductions >30 and >40 mm Hg were attained in more of the patients who received SPC T80/H25 compared with T80 monotherapy, regardless of baseline eGFR (>30 mm Hg: 68.7% versus 47.3% in patients with eGFR ≥60; 55.6% versus 33.3% in patients with eGFR <60; >40 mm Hg: 40.9% versus 24.4% in patients with eGFR ≥60; 33.3% versus 9.5% in patients with eGFR <60) (Figure
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
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
At Week 7, SPC T80/H25 produced higher rates of BP goal attainment (<140/90 mm Hg) versus T80 monotherapy across the three BMI categories (BMI < 25: 58.2% versus 45.8%; BMI 25–<30: 59.3% versus 33.0%; BMI ≥ 30: 50.6% versus 30.6%). The SBP goal (<140 mm Hg) was more commonly achieved in the SPC T80/H25 group compared with the T80 group (BMI < 25: 64.8% versus 55.9%; BMI 25–<30: 65.0% versus 38.3%; BMI ≥ 30: 61.2% versus 40.5%). The DBP goal (<90 mm Hg) was also more commonly achieved in the SPC T80/H25 group compared with the T80 group (BMI < 25: 71.3% versus 57.6%; BMI 25–<30: 73.4% versus 54.8%; BMI ≥ 30: 61.2% versus 47.7%) (Figure
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
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
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
A summary of AEs reported during the study according to patient subpopulations is provided in Table
Summary of AE frequencies in the different patient subpopulations, based on treated patients.
T80 | T80/H25 | |
---|---|---|
Overall | ( |
( |
Patients with any AE, |
49 (17.0) | 94 (16.0) |
Patients with treatment-related AEs, |
8 (2.8) | 27 (4.6) |
Patients with AEs leading to discontinuation, |
8 (2.8) | 6 (1.0) |
Patients with serious AEs, |
0 (0) | 0 (0) |
| ||
DM, yes | ( |
( |
Patients with any AE, |
6 (17.6) | 5 (6.9) |
Patients with treatment-related AEs, |
1 (2.9) | 2 (2.8) |
Patients with AEs leading to discontinuation, |
0 (0) | 0 (0) |
Patients with serious AEs, |
0 (0) | 0 (0) |
DM, no | ( |
( |
Patients with any AE, |
43 (16.9) | 89 (17.3) |
Patients with treatment-related AEs, |
7 (2.7) | 25 (4.9) |
Patients with AEs leading to discontinuation, |
8 (3.1) | 6 (1.2) |
Patients with serious AEs, |
0 (0) | 0 (0) |
| ||
eGFR category <60 mL/min/1.73 m2 | ( |
( |
Patients with any AE, |
4 (19.0) | 12 (33.3) |
Patients with treatment-related AEs, |
0 (0) | 6 (16.7) |
Patients with AEs leading to discontinuation, |
0 (0) | 1 (2.8) |
Patients with serious AEs, |
0 (0) | 0 (0) |
eGFR category ≥60 mL/min/1.73 m2 | ( |
( |
Patients with any AE, |
45 (16.9) | 81 (14.8) |
Patients with treatment-related AEs, |
8 (3.0) | 21 (3.8) |
Patients with AEs leading to discontinuation, |
8 (3.0) | 5 (0.9) |
Patients with serious AEs, |
0 (0) | 0 (0) |
| ||
BMI < 25 kg/m2 | ( |
( |
Patients with any AE, |
8 (13.6) | 29 (22.7) |
Patients with treatment-related AEs, |
2 (3.4) | 10 (7.8) |
Patients with AEs leading to discontinuation, |
2 (3.4) | 3 (2.3) |
Patients with serious AEs, |
0 (0) | 0 (0) |
BMI 25–<30 kg/m2 | ( |
( |
Patients with any AE, |
22 (18.6) | 25 (11.5) |
Patients with treatment-related AEs, |
4 (3.4) | 7 (3.2) |
Patients with AEs leading to discontinuation, |
3 (2.5) | 2 (0.9) |
Patients with serious AEs, |
0 (0) | 0 (0) |
BMI ≥ 30 kg/m2 | ( |
( |
Patients with any AE, |
19 (17.0) | 40 (16.6) |
Patients with treatment-related AEs, |
2 (1.8) | 10 (4.1) |
Patients with AEs leading to discontinuation, |
3 (2.7) | 1 (0.4) |
Patients with serious AEs, |
0 (0) | 0 (0) |
| ||
CHD1 (10-year risk <10%) | ( |
( |
Patients with any AE, |
35 (19.1) | 72 (16.4) |
Patients with treatment-related AEs, |
4 (2.2) | 18 (4.1) |
Patients with AEs leading to discontinuation, |
4 (2.2) | 5 (1.1) |
Patients with serious AEs, |
0 (0) | 0 (0) |
CHD2 (10-year risk ≥10–<20%) | ( |
( |
Patients with any AE, |
10 (13.2) | 17 (15.7) |
Patients with treatment-related AEs, |
2 (2.6) | 7 (6.5) |
Patients with AEs leading to discontinuation, |
2 (2.6) | 1 (0.9) |
Patients with serious AEs, |
0 (0) | 0 (0) |
CHD3 (10-year risk ≥20%) | ( |
( |
Patients with any AE, |
4 (13.3) | 5 (12.8) |
Patients with treatment-related AEs, |
2 (6.7) | 2 (5.1) |
Patients with AEs leading to discontinuation, |
2 (6.7) | 0 (0) |
Patients with serious AEs, |
0 (0) | 0 (0) |
AE: adverse event; BMI: body mass index; CHD: coronary heart disease; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; H25: hydrochlorothiazide 25 mg; T80: telmisartan 80 mg.
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/m2, the rate was 22.7%, and in patients with a low eGFR <60 mL/min/1.73 m2, the rate was 33.3%.
In the overall study population, and irrespective of cause, the five AEs most frequently occurring under treatment with SPC T80/H25, as determined by number of patients receiving SPC T80/H25 with this AE, were dizziness (1.9% of patients), nasopharyngitis (1.4%), pollakiuria (0.9%), vertigo (0.7%), and cough (0.7%). Among patients with DM receiving SPC T80/H25, the most frequently reported AEs, as determined by number of patients with this AE, each occurring in one patient (1.4%), were anal abscess, hypotension, elevated blood uric acid, cough, hypertriglyceridemia, and proctalgia. In patients with eGFR <60 mL/min/1.73 m2 who received treatment with SPC T80/H25, the most frequently reported AE was dizziness (
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 treatment-related AEs compared with the overall study population was observed in patients with DM (2.8%), patients with eGFR < 60 mL/min/1.73 m2 (16.7%), patients with BMI < 25 kg/m2 (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
Frequency of the most commonly observed treatment-related AEs occurring in patients receiving SPC T80/H25 treatment: by treatment group and patient subpopulation;
Total |
Dizziness | Syncope | Pollakiuria | Blood uric acid increased | ||||||
---|---|---|---|---|---|---|---|---|---|---|
T80 | T80/H25 | T80 | T80/H25 | T80 | T80/H25 | T80 | T80/H25 | T80 | T80/H25 | |
Overall |
|
|
3 (1.0) | 11 (1.9) | 0 (0) | 3 (0.5) | 0 (0) | 5 (0.9) | 0 (0) | 3 (0.5) |
| ||||||||||
DM, yes |
|
|
0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (1.4) |
DM, no |
|
|
3 (1.2) | 11 (2.1) | 0 (0) | 3 (0.6) | 0 (0) | 5 (1.0) | 0 (0) | 2 (0.4) |
| ||||||||||
BMI < 25 |
|
|
0 (0) | 5 (3.9) | 0 (0) | 0 (0) | 0 (0) | 2 (1.6) | 0 (0) | 1 (0.8) |
BMI 25–<30 |
|
|
1 (0.8) | 4 (1.8) | 0 (0) | 1 (0.5) | 0 (0) | 1 (0.5) | 0 (0) | 2 (0.9) |
BMI ≥ 30 |
|
|
2 (1.8) | 2 (0.8) | 0 (0) | 2 (0.8) | 0 (0) | 2 (0.8) | 0 (0) | 0 (0) |
| ||||||||||
eGFR < 60 |
|
|
0 (0) | 2 (5.6) | 0 (0) | 1 (2.8) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
eGFR ≥ 60 |
|
|
3 (1.1) | 9 (1.6) | 0 (0) | 2 (0.4) | 0 (0) | 5 (0.9) | 0 (0) | 3 (0.5) |
| ||||||||||
CHD1 |
|
|
3 (1.6) | 10 (2.3) | 0 (0) | 2 (0.5) | 0 (0) | 2 (0.5) | 0 (0) | 1 (0.2) |
CHD2 |
|
|
0 (0) | 1 (0.9) | 0 (0) | 1 (0.9) | 0 (0) | 2 (1.9) | 0 (0) | 2 (1.9) |
CHD3 |
|
|
0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (2.6) | 0 (0) | 0 (0) |
Data based on treated set. eGFR expressed in mL/min/1.73 m2; BMI expressed in kg/m2.
BMI: body mass index; CHD: coronary heart disease; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; H25: hydrochlorothiazide 25 mg; T80: telmisartan 80 mg.
The presented results reflect prespecified and
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 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 [
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 [
H. Bays has received research grants from Boehringer Ingelheim, as well as other pharmaceutical companies. L. Ruilope has previously served on advisory boards and received speaker honoraria from Boehringer Ingelheim. M. Mattheus and B. Völker are employees of Boehringer Ingelheim. P. Gao and D. Zhu declared no potential conflict of interests. The authors received no compensation in relation to the development of this paper.
The authors were fully responsible for all content and editorial decisions, were involved at all stages of paper development, and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Danielle Russell, PhD, of PAREXEL, during the preparation of this paper.