Olmesartan in Hypertensive Patients With Chronic HF
Olmesartan in Hypertensive Patients With Chronic HF
Baseline characteristics were comparable between the olmesartan and the control groups (Table 2). The mean age was 66 and 75% of the patients were male. Functional class of HF was in NYHA Class II in 93% and Class III in 7%, and underlying heart disease included ischaemic heart disease in 48% and dilated cardiomyopathy in 21%. Mean systolic/diastolic blood pressure was 128/74 mmHg, and mean left ventricular ejection fraction (LVEF) was 54%. At the time of randomization, ACE inhibitors and β-blockers were prescribed in 81 and 72% of the patients, respectively.
At the time of randomization, systolic/diastolic blood pressure was 128.7/74.8 ± 18.2/12.2 and 127.1/73.8 ± 18.1/11.7 mmHg in the olmesartan and the control group, respectively (P = 0.081/0.311). Changes in systolic/diastolic blood pressure in both groups are shown in Figure 2. There was no significant difference in systolic/diastolic blood pressure at any point between the two groups.
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Figure 2.
Time course in blood pressure. Blood pressure values are presented as mean ± standard deviations. There were no statistical differences in systolic or diastolic blood pressure at each point between the olmesartan and the control groups.
In the olmesartan group, olmesartan was not prescribed in 18 (3.1%), 56 (9.4%), 70 (12.1%), 65 (11.2%), 48 (10.7%), 19 (9.7%), and 1 (4.5%) patients at 0, 1, 2, 3, 4, 5, and 6 years after randomization, respectively. In the control group, the cumulative incidence of any ARB use was none (0%), 2 (0.3%), 4 (0.7%), 8 (1.4%), 8 (1.4%), 8 (1.4%), and 8 (1.4%) at 0, 1, 2, 3, 4, 5, and 6 years after randomization, respectively. In the olmesartan group, mean dose of olmesartan (mg/day) at 0, 1, 2, 3, 4, 5, and 6 years after randomization was 9.5, 13.3, 15.4, 16.1, 17.4, 17.9, and 16.5, respectively.
When the primary endpoint occurred or the SUPPORT trial ended, 58 patients (10.0%) were not taking olmesartan in the olmesartan group, whereas four patients (0.7%) were taking ARB in the control group. Subgroup analysis revealed that in the olmesartan group treated with ACE inhibitors alone, β-blockers alone, and both of them at the time of randomization, discontinuation of the ARB was noted in 13 (8.0%), 15 (14.2%), and 30 patients (10.0%), respectively, due to the occurrence of the primary endpoint or the end of the study.
During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96–1.46, P = 0.112] (Figure 3 and Table 3). Subgroup analysis according to the baseline medication revealed that the incidence of the primary endpoint was more frequent in the olmesartan group than that in the control group, when combined with both ACE inhibitors and β-blockers [38.1% (114/299) vs. 28.2% (88/312), HR 1.47; 95% CI 1.12–1.95, P = 0.006], whereas there was no difference in the primary endpoint when combined with β-blockers alone or ACE inhibitors alone (Figure 4). Similarly, when combined with both ACE inhibitors and β-blockers, olmesartan was associated with increased incidence of all-cause death [19.4% (58/299) vs. 13.5% (42/312), HR 1.50; 95% CI 1.01–2.23, P = 0.046], a component of the primary endpoint, whereas olmesartan was associated with decreased mortality when combined with β-blockers alone [9.4% (10/106) vs. 22.1% (23/104), HR 0.41; 95% CI 0.19–0.85, P = 0.017], but not with ACE inhibitors alone (see Supplementary material online, Figure S1 and Table S2http://eurheartj.oxfordjournals.org/content/suppl/2015/01/26/ehu504.DC1). Subgroup analysis revealed that additive use of olmesartan was associated with an increase in the primary endpoint in the subgroups of systolic blood pressure (SBP) of <130 mmHg, estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m, BNP level of >100 pg/mL, and high-sensitive C-reactive protein level of >1 mg/L (see Supplementary material online, Table S3http://eurheartj.oxfordjournals.org/content/suppl/2015/01/26/ehu504.DC1), which was primarily due to the triple combination therapy (see Supplementary material online, Figure S2http://eurheartj.oxfordjournals.org/content/suppl/2015/01/26/ehu504.DC1). There were no interactions of the impacts of olmesartan with age, gender, body mass index, diabetes, diastolic blood pressure, left ventricular hypertrophy, LVEF, or use of spironolactone (see Supplementary material online, Table S3http://eurheartj.oxfordjournals.org/content/suppl/2015/01/26/ehu504.DC1).
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Figure 3.
Kaplan–Meier curves for the primary endpoint for overall patients.
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Figure 4.
Kaplan–Meier curves for the primary endpoint for subgroups according to the baseline medication. (A) Patients treated with angiotensin-converting enzyme inhibitors but not with β-blockers. (B) Patients treated with β-blockers but not with angiotensin-converting enzyme inhibitors. (C) Patients treated with both angiotensin-converting enzyme inhibitors and β-blockers. ACEI, angiotensin-converting enzyme inhibitors; BB, β-blockers.
There were no differences in secondary or other endpoints between the olmesartan and the control groups except for development of renal dysfunction [16.8% (97/578) vs. 10.7% (61/568), HR 1.64; 95% CI 1.19–2.26, P = 0.003] (Table 3). Subgroup analysis revealed that additive use of olmesartan, when combined with both ACE inhibitors and β-blockers, was significantly associated with increased incidence of renal dysfunction [21.1% (63/299) vs. 12.5% (39/312), HR 1.85; 95% CI 1.24–2.76, P = 0.003] (see Supplementary material online, Table S2http://eurheartj.oxfordjournals.org/content/suppl/2015/01/26/ehu504.DC1). In contrast, when combined with ACE inhibitors alone, use of olmesartan was not associated with renal dysfunction and was rather associated with decreased incidence of atrial fibrillation [2.4% (4/170) vs. 8.8% (13/148), HR 0.26; 95% CI 0.09–0.80, P = 0.019] (see Supplementary material online, Table S2http://eurheartj.oxfordjournals.org/content/suppl/2015/01/26/ehu504.DC1).
Results
Patient Characteristics
Baseline characteristics were comparable between the olmesartan and the control groups (Table 2). The mean age was 66 and 75% of the patients were male. Functional class of HF was in NYHA Class II in 93% and Class III in 7%, and underlying heart disease included ischaemic heart disease in 48% and dilated cardiomyopathy in 21%. Mean systolic/diastolic blood pressure was 128/74 mmHg, and mean left ventricular ejection fraction (LVEF) was 54%. At the time of randomization, ACE inhibitors and β-blockers were prescribed in 81 and 72% of the patients, respectively.
Drug Adherence and Blood Pressure
At the time of randomization, systolic/diastolic blood pressure was 128.7/74.8 ± 18.2/12.2 and 127.1/73.8 ± 18.1/11.7 mmHg in the olmesartan and the control group, respectively (P = 0.081/0.311). Changes in systolic/diastolic blood pressure in both groups are shown in Figure 2. There was no significant difference in systolic/diastolic blood pressure at any point between the two groups.
(Enlarge Image)
Figure 2.
Time course in blood pressure. Blood pressure values are presented as mean ± standard deviations. There were no statistical differences in systolic or diastolic blood pressure at each point between the olmesartan and the control groups.
In the olmesartan group, olmesartan was not prescribed in 18 (3.1%), 56 (9.4%), 70 (12.1%), 65 (11.2%), 48 (10.7%), 19 (9.7%), and 1 (4.5%) patients at 0, 1, 2, 3, 4, 5, and 6 years after randomization, respectively. In the control group, the cumulative incidence of any ARB use was none (0%), 2 (0.3%), 4 (0.7%), 8 (1.4%), 8 (1.4%), 8 (1.4%), and 8 (1.4%) at 0, 1, 2, 3, 4, 5, and 6 years after randomization, respectively. In the olmesartan group, mean dose of olmesartan (mg/day) at 0, 1, 2, 3, 4, 5, and 6 years after randomization was 9.5, 13.3, 15.4, 16.1, 17.4, 17.9, and 16.5, respectively.
When the primary endpoint occurred or the SUPPORT trial ended, 58 patients (10.0%) were not taking olmesartan in the olmesartan group, whereas four patients (0.7%) were taking ARB in the control group. Subgroup analysis revealed that in the olmesartan group treated with ACE inhibitors alone, β-blockers alone, and both of them at the time of randomization, discontinuation of the ARB was noted in 13 (8.0%), 15 (14.2%), and 30 patients (10.0%), respectively, due to the occurrence of the primary endpoint or the end of the study.
Primary Endpoint
During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96–1.46, P = 0.112] (Figure 3 and Table 3). Subgroup analysis according to the baseline medication revealed that the incidence of the primary endpoint was more frequent in the olmesartan group than that in the control group, when combined with both ACE inhibitors and β-blockers [38.1% (114/299) vs. 28.2% (88/312), HR 1.47; 95% CI 1.12–1.95, P = 0.006], whereas there was no difference in the primary endpoint when combined with β-blockers alone or ACE inhibitors alone (Figure 4). Similarly, when combined with both ACE inhibitors and β-blockers, olmesartan was associated with increased incidence of all-cause death [19.4% (58/299) vs. 13.5% (42/312), HR 1.50; 95% CI 1.01–2.23, P = 0.046], a component of the primary endpoint, whereas olmesartan was associated with decreased mortality when combined with β-blockers alone [9.4% (10/106) vs. 22.1% (23/104), HR 0.41; 95% CI 0.19–0.85, P = 0.017], but not with ACE inhibitors alone (see Supplementary material online, Figure S1 and Table S2http://eurheartj.oxfordjournals.org/content/suppl/2015/01/26/ehu504.DC1). Subgroup analysis revealed that additive use of olmesartan was associated with an increase in the primary endpoint in the subgroups of systolic blood pressure (SBP) of <130 mmHg, estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m, BNP level of >100 pg/mL, and high-sensitive C-reactive protein level of >1 mg/L (see Supplementary material online, Table S3http://eurheartj.oxfordjournals.org/content/suppl/2015/01/26/ehu504.DC1), which was primarily due to the triple combination therapy (see Supplementary material online, Figure S2http://eurheartj.oxfordjournals.org/content/suppl/2015/01/26/ehu504.DC1). There were no interactions of the impacts of olmesartan with age, gender, body mass index, diabetes, diastolic blood pressure, left ventricular hypertrophy, LVEF, or use of spironolactone (see Supplementary material online, Table S3http://eurheartj.oxfordjournals.org/content/suppl/2015/01/26/ehu504.DC1).
(Enlarge Image)
Figure 3.
Kaplan–Meier curves for the primary endpoint for overall patients.
(Enlarge Image)
Figure 4.
Kaplan–Meier curves for the primary endpoint for subgroups according to the baseline medication. (A) Patients treated with angiotensin-converting enzyme inhibitors but not with β-blockers. (B) Patients treated with β-blockers but not with angiotensin-converting enzyme inhibitors. (C) Patients treated with both angiotensin-converting enzyme inhibitors and β-blockers. ACEI, angiotensin-converting enzyme inhibitors; BB, β-blockers.
Secondary Endpoints
There were no differences in secondary or other endpoints between the olmesartan and the control groups except for development of renal dysfunction [16.8% (97/578) vs. 10.7% (61/568), HR 1.64; 95% CI 1.19–2.26, P = 0.003] (Table 3). Subgroup analysis revealed that additive use of olmesartan, when combined with both ACE inhibitors and β-blockers, was significantly associated with increased incidence of renal dysfunction [21.1% (63/299) vs. 12.5% (39/312), HR 1.85; 95% CI 1.24–2.76, P = 0.003] (see Supplementary material online, Table S2http://eurheartj.oxfordjournals.org/content/suppl/2015/01/26/ehu504.DC1). In contrast, when combined with ACE inhibitors alone, use of olmesartan was not associated with renal dysfunction and was rather associated with decreased incidence of atrial fibrillation [2.4% (4/170) vs. 8.8% (13/148), HR 0.26; 95% CI 0.09–0.80, P = 0.019] (see Supplementary material online, Table S2http://eurheartj.oxfordjournals.org/content/suppl/2015/01/26/ehu504.DC1).
Adverse Events
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