Abstract
This post hoc analysis from the Sevikar Compared to the Combination of Perindopril Plus Amlodipine on Central Arterial Blood Pressure in Patients With Moderate‐to‐Severe Hypertension (SEVITENSION) study assessed the efficacy and tolerability of olmesartan (OLM) and amlodipine (AML) in reducing central systolic blood pressure (CSBP) compared with perindopril (PER) plus AML in hypertensive patients with type 2 diabetes. Patients were randomized to OLM/AML 40/10 mg or PER/AML 8/10 mg for 24 weeks. The primary efficacy endpoint was the absolute change in CSBP from baseline to week 24, which was greater with OLM/AML (−13.72±1.14 mm Hg) compared with PER/AML (−10.21±1.11 mm Hg). The between‐group difference was −3.51±1.60 mm Hg (95% confidence interval, −6.66 to −0.36 mm Hg) and was within the noninferiority margin (2 mm Hg) as well as the superiority margin (0 mm Hg). In addition, OLM/AML was associated with a higher proportion of patients achieving blood pressure normalization. In hypertensive patients with diabetes, the fixed‐dose combination of OLM/AML was superior to PER/AML in reducing CSBP, as well as other secondary endpoints.
Recently, a number of studies have demonstrated that central systolic blood pressure (CSBP) measurements could provide a better estimate of cardiovascular (CV) risk compared with the traditional method of measuring brachial blood pressure (BP). Indeed, CSBP provides valuable insights into arterial stiffness and organ damage.1, 2, 3, 4 Studies comparing different treatment regimens have found that patients in parallel treatment groups may display comparable levels of brachial BP measurements while at the same time showing major differences in CSBP, which may relate to differences seen in organ damage and CV outcomes.2
This phenomenon was highlighted by the Conduit Artery Function Evaluation (CAFE) study, a substudy of the Anglo‐Scandinavian Cardiac Outcomes Trial‐Blood Pressure Lowering Arm (ASCOT‐BPLA).5 ASCOT‐BPLA was an outcomes study which found that patients treated with a combination of the calcium channel blocker (CCB) amlodipine (AML) plus the angiotensin‐converting enzyme (ACE) inhibitor perindopril (PER) showed lower rates of CV outcomes, such as stroke and death, compared with patients treated with the β‐blocker atenolol plus the diuretic bendroflumethiazide. The substudy CAFE found that patients treated with AML/PER showed significantly greater reductions in CSBP compared with patients treated with atenolol plus bendroflumethiazide, despite similar reductions in brachial BP. These findings raise the possibility that the lower rates of CV outcomes seen in patients treated with AML/PER in ASCOT‐BPLA may be the result of larger reductions in CSBP.
The ONgoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)6 showed that compared with ACE inhibitors, angiotensin II receptor blockers (ARBs) are as effective at lowering BP and reducing CV risk and show improved tolerability. The results from ONTARGET suggested that it would be possible to use an ARB to provide the renin‐angiotensin system (RAS) blockade component and to combine this with AML to deliver effective lowering of CSBP free from the tolerability issues associated with the use of ACE inhibitors.
The results from the SEVIkar Compared to the Combination of Perindopril Plus Amlodipine on Central Arterial Blood Pressure in Patients With Moderate‐to‐Severe HyperTENSION (SEVITENSION) study7 confirmed that a combination of the ARB olmesartan (OLM) plus AML was not only noninferior to PER/AML in reducing CSBP, but was also superior for this endpoint, as well as a range of other hemodynamic variables that included measurements of office and ambulatory BP. The SEVITENSION study included patients with a range of factors that put them at increased risk of CV disease, including a substantial proportion of patients with diabetes.
Hypertension and diabetes commonly occur together. It is estimated that between 40% and 80% of diabetic patients may also be hypertensive.8, 9, 10 Patients who have both diabetes and hypertension are at a higher risk for CV events than patients with hypertension or diabetes alone.11, 12, 13 Indeed, diabetic patients with hypertension are at approximately a two‐fold risk for CV‐related events compared with those with normal BP.9 Furthermore, between 60% and 80% of patients with type 2 diabetes mellitus (T2DM) die as a result of CV complications, and high BP is associated with approximately 75% of these deaths.14, 15
RAS inhibitors have been found to be effective in preventing CV complications in diabetic patients.16, 17, 18 Because of the increased risk of CV events in hypertensive patients with diabetes, it is important to assess the effects of dual RAS‐calcium channel blockade on arterial stiffness in these patients. The aim of the present post hoc analysis was to assess the effects of OLM/AML compared with PER/AML in reducing CSBP and other hemodynamic variables in patients with diabetes who took part in the SEVITENSION study.
Methods
Patients
The CAFE substudy has provided important insights into the effects of dual‐combination therapy with RAS and calcium channel blockade on central BP; therefore, the SEVITENSION study set out to recruit patients with similar characteristics to aid the comparison of results. As such, SEVITENSION enrolled male and female Caucasian patients aged 40 to 80 years from 16 centers across Spain, who were hypertensive and had three or more additional risk factors. Additional risk factors included age older than 55 years in men and older than 65 years in women, smoking, dyslipidemia, abnormal glucose tolerance test, abdominal obesity, family history of premature cardiovascular disease, left ventricular hypertrophy, cerebrovascular disease, heart disease, advanced retinopathy, atherosclerosis, and renal disease. The diabetic subgroup consisted of all patients from SEVITENSION who had T2DM.
For the diabetic subgroup, inadequate BP control was defined as having an systolic BP (SBP) >130 mm Hg or diastolic BP (DBP) >80 mm Hg according to 2007 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for the management of arterial hypertension, as these were the active guidelines at the start of the study.19
Design
The full trial design and rationale of the SEVITENSION study have previously been described (clinicaltrials.gov identifier NCT01101009).20 A subgroup analysis of the SEVITENSION study is presented here.
SEVITENSION involved a 2‐ to 4‐week open‐label, run‐in period that depended on patients' existing treatment at study entry. At weeks −4 to −2, patients not currently receiving AML as part of their antihypertensive treatment received AML 5 mg in addition to their current therapy, except for patients receiving other CCBs, which were discontinued. During weeks −2 to 0, all patients received AML 10 mg monotherapy as their only hypertensive medications and had all other antihypertensive medications discontinued. Patients receiving AML 10 mg monotherapy prior to the study entered the randomization period directly. Except for patients who were receiving AML 10 mg monotherapy prior to the study, this resulted in all other patients being treated with AML 5 mg for at least 2 weeks (together with any former medication except for CCBs) and then receiving AML 10 mg without other antihypertensive medication for another 2 weeks prior to randomization. After randomization to double‐blind treatment, patients were followed for 24 weeks.
Interventions
Patients were randomized into one of two treatment groups: active treatment or matching placebo. In the OLM arm, patients received a single‐pill fixed‐dose combination of OLM 40 mg and AML 10 mg plus PER/AML placebo. In the PER arm, patients received a combination of PER 8 mg plus AML 10 mg and OLM/AML placebo. For patients whose BP was not at target at weeks 4, 8, 12, and 18, hydrochlorothiazide (HCTZ) 12.5 mg was added to their regimen; patients already receiving 12.5 mg HCTZ were uptitrated to HCTZ 25 mg. If BP remained >180/110 mm Hg after the addition of HCTZ 25 mg, they were removed from the study.
Endpoints
The primary efficacy endpoint was the absolute change in CSBP from baseline (week 0) to final examination (week 24) with OLM/AML vs PER/AML using the last‐observation‐carried‐forward (LOCF) approach in the per‐protocol set (PPS). CSBP was measured by tonometry with the SphygmoCor® Vx Pulse Wave Velocity System.
The secondary endpoints included absolute change in seated SBP; mean 24‐hour, daytime, and nighttime ambulatory SBP; and the proportion of patients achieving normalized BP according to 2007 ESH/ESC guidelines for the management of arterial hypertension19 and 2009 ESH guidelines reappraisal.21 All secondary endpoints were measured in the full analysis set (FAS). Brachial BP was measured using calibrated tensiometers (OMRON). 24‐hour ambulatory BP was measured using standard measurement devices (Spacelabs) to record 24‐hour BP profiles. Daytime measurements were taken at 15‐minute intervals between 6 am and 9:59 pm and nighttime measurements were taken at 30‐minute intervals between 10 pm and 5:59 am.
Statistical Analysis
The primary efficacy endpoint was analyzed using a parametric analysis of covariance (ANCOVA) using treatment as a main effect and baseline CSBP as a covariate. The primary objective was one‐sided noninferiority (α=0.025) of OLM/AML compared with PER/AML in the change in CSBP from week 0 to week 24. The primary endpoint was analyzed in the PPS, which included all members of the FAS who had no major protocol violations. The FAS was used to analyze all secondary endpoints and included all patients who were randomized to treatment, received one or more dose of medication, and had CSBP measured at baseline with at least one follow‐up measurement.
The secondary endpoints were analyzed from baseline to final examination using the same ANCOVA analysis as the primary endpoint with the corresponding baseline values as covariates.
The noninferiority of OLM/AML compared with PER/AML was shown if the upper limit of the 95% confidence interval (CI) was below 2 mm Hg. In addition, if the 95% CI lies above 0 mm Hg, then there is evidence of superiority at the 5% level and superiority can be tested. This is in accordance with the Committee for Proprietary Medicinal Products, which states that it is acceptable to calculate the P value associated with a test of superiority in such situations.22
The proportion of patients with normalized BP at week 24 was analyzed by a chi‐square test using the LOCF approach.
Results
Patients
A total of 600 patients were enrolled into the SEVITENSION study and 486 patients were randomized to treatment.7 Of these, 233 patients had diabetes mellitus (Figure 1) and were randomized into the safety analysis set (SAF II), with a total of 111 patients randomized to OLM/AML and 122 to PER/AML. From the SAF II, 22 patients did not provide efficacy measurements and were excluded from the FAS, which contained 211 patients (OLM/AML, n=101; PER/AML, n=110). A further 24 patients had major protocol violations and were not included in the PPS (OLM/AML, n=91; PER/AML, n=96). Major protocol violations were defined as non‐Caucasian patients, patients with no baseline or postbaseline CSBP measurement, compliance not within range (80%–120%), participation in another clinical trial at the time of the study or ≤1 month prior to study start, premature discontinuation, and the use of prohibited concomitant medication.
Figure 1.
Patient flow. AML indicates amlodipine; FAS, full analysis set; OLM, olmesartan; PER, perindopril; PPS, per‐protocol set; SAF II, safety analysis set. Major protocol deviations were defined as non‐Caucasian patients, patients with no baseline or postbaseline central systolic blood pressure measurement, compliance not within range (80%–120%), participation in any other clinical trial currently or ≤1 month prior to study start, premature discontinuation, and the use of prohibited concomitant medication.
The baseline patient characteristics and demographics for the 233 patients in the SAF II are shown in Table 1. Mean age was 61.7±9.0 years, 72.5% were men, and mean BMI was 31.8±4.31 kg/m2. There were no significant differences in patient characteristics or demographics between the two treatment groups. In addition, compared with the total study population, the diabetic subgroup had no significant differences in patient characteristics.
Table 1.
Baseline Demographics and Patient Characteristics of the Diabetic Subgroup
| Characteristic | OLM/AML 40/10 mg | PER/AM 8/10 mg | Total |
|---|---|---|---|
| Safety Analysis Set | (n=111) | (n=122) | (N=233) |
| Mean age, y | 60.9 (9.2) | 62.4 (8.8) | 61.7 (9.0) |
| Males | 80 (72.1) | 89 (73.0) | 169 (72.5) |
| Caucasian | 111 (100) | 122 (100) | 233 (100) |
| Bodyweight, kg | 86.2 (13.90) | 87.4 (14.93) | 86.8 (14.43) |
| Height, cm | 165.3 (9.29) | 165.1 (9.18) | 165.2 (9.22) |
| BMI, kg/m2 | 31.5 (4.05) | 32.0 (4.54) | 31.8 (4.31) |
| Men aged >55 y/women aged >65 y | 69 (62.2) | 88 (72.1) | 157 (67.4) |
| Smoker | 15 (13.5) | 32 (26.2) | (47 (20.2) |
| Dyslipidemia | 102 (91.9) | 109 (89.3) | 211 (90.6) |
| Abnormal glucose tolerance test | 6 (5.4) | 11 (9.0) | 17 (7.3) |
| Abdominal obesity | 94 (84.7) | 106 (86.9) | 200 (85.8) |
| Family history of premature CV disease | 9 (8.1) | 10 (8.2) | 19 (8.2) |
| Left ventricular hypertrophy | 18 (16.2) | 27 (22.1) | 45 (19.3) |
| Cerebrovascular disease | 8 (7.2) | 7 (5.7) | 15 (6.4) |
| Heart disease | 5 (4.5) | 7 (5.7) | 12 (5.2) |
| Advanced retinopathy | 2 (1.8) | 6 (4.9) | 8 (3.4) |
| Atherosclerosis | 4 (3.6) | 3 (2.5) | 7 (3.0) |
| Renal disease | 33 (29.7) | 31 (25.4) | 64 (27.5) |
| Per Protocol Set | n=91 | n=96 | N=187 |
|---|---|---|---|
| Central SBP, mm Hg | 133.5 (11.90) | 134.7 (11.16) | 134.1 (11.51) |
| Full Analysis Set | n=101 | n=110 | N=211 |
|---|---|---|---|
| Blood pressure, mm Hg | |||
| Seated SBP | 147.5 (11.93) | 148.6 (12.96) | 148.1 (12.46) |
| 24‐h ambulatory SBP | 135.4 (12.47) | 134.1 (10.79) | 134.7 (11.63) |
| Daytime ambulatory SBP | 138.9 (12.91) | 137.9 (11.53) | 138.4 (12.20) |
| Nighttime ambulatory SBP | 127.3 (13.71) | 125.7 (11.72) | 126.5 (12.71) |
| Central DBP | 84.8 (8.81) | 85.2 (9.03) | 85.0 (8.91) |
| Seated DBP | 84.1 (8.50) | 83.7 (8.72) | 83.9 (8.60) |
| 24‐h ambulatory DBP | 78.5 (8.22) | 77.7 (7.60) | 78.0 (7.90) |
| Daytime ambulatory DBP | 81.0 (8.94) | 80.5 (7.71) | 80.7 (8.31) |
| Nighttime ambulatory DBP | 72.7 (7.88) | 71.6 (8.56) | 72.1 (8.23) |
Abbreviations: AML, amlodipine; BMI, body mass index; CV, cardiovascular; DBP, diastolic blood pressure; DP4, dipeptidyl peptidase‐4 inhibitor; HbA1c, glycated hemoglobin; OLM, olmesartan; PER, perindopril; SBP, systolic blood pressure; SGLT‐2, sodium‐glucose linked transporter‐2. Continuous variables are mean (standard deviation) and categorical values are patient number (percentage).
At final examination, in the SAF II, 15.9% of patients were receiving add‐on HCTZ 12.5 mg (OLM/AML, 15.3%; PER/AML, 16.4%) and 54.9% were receiving HCTZ 25 mg (OLM/AML, 49.5%; PER/AML, 59.8%).
The most common risk factors were dyslipidemia (90.6%), abdominal obesity (85.5%), and age (67.4%). The majority of patients had four risk factors (43.3%), followed by five (26.6%) and three (15.5%) risk factors,
Primary Efficacy Variable
A greater absolute change in CSBP from baseline was seen in the OLM/AML group compared with the PER/AML group (−13.72±1.14 vs −10.21±1.11 mm Hg; P<.0001; Figure 2). The point estimate for the difference between the two treatment groups was −3.51 (standard error, 1.60) mm Hg (95% CI, −6.66 to −0.36 mm Hg) in the PPS. Because the upper limit of the 95% CI was below the noninferiority margin (2 mm Hg), the noninferiority of OLM/AML over PER/AML was observed. In addition, the superiority of OLM/AML was demonstrated, with the upper 95% CI below 0 mm Hg. This was seen in the FAS (P=.0041) and supported in the PPS (P=.0291) (Figure 3).
Figure 2.
Absolute change in central systolic blood pressure (CSBP) from baseline (week 0) to final examination (week 24) by randomized treatment group (last observation carried forward in the per‐protocol set). AML indicates amlodipine; OLM, olmesartan; PER, perindopril.
Figure 3.
Forest plot of the differences in absolute change of central systolic blood pressure (CSBP) between diabetic patients treated with OLM/AML 40/10 mg and PER/AML 8/10 mg from baseline (week 0) to final examination (week 24) for the primary efficacy endpoint (per protocol set) and in the full analysis set. AML indicates amlodipine; OLM, olmesartan; PER, perindopril.
Secondary Efficacy Variables
Similar to the primary efficacy endpoint, all secondary endpoints demonstrated the noninferiority of OLM/AML compared with PER/AML. In addition, a number of secondary variables demonstrated the superiority of OLM/AML over PER/AML.
Hemodynamic Variables
OLM/AML was associated with a greater decrease in mean 24‐hour SBP/DBP compared with PER/AML (−11.29/−6.01 mm Hg and −8.64/−4.69 mm Hg, respectively). In addition, the 95% CI was below the noninferiority margin for both 24‐hour SBP (Figure 4A) and DBP (Figure 4B) indicating the noninferiority of OLM/AML. Similar results were found for daytime SBP/DBP, nighttime SBP/DBP, seated SBP/DBP, and central DBP (CDBP) (Figure 4A and 4B). In addition, the 95% CI for nighttime SBP and seated SBP (Figure 4A) and CDBP (Figure 4B) were below 0 mm Hg, indicating the superiority of OLM/AML compared with PER/AML for these endpoints.
Figure 4.
Forest plot of the differences in 24‐hour systolic blood pressure (SBP), daytime SBP, nighttime SBP, and seated SBP (A) and central diastolic blood pressure (DBP), 24‐hour DBP, daytime DBP, nighttime DBP, and seated DBP (B) between diabetic patients treated with OLM/AML 40/10 mg and PER/AML 8/10 mg from baseline (week 0) to final examination (week 24) in the full analysis set. AML indicates amlodipine; CDBP, central diastolic blood pressure; CSBP, central systolic blood pressure; FAS, full analysis set; OLM, olmesartan; PER, perindopril.
BP Normalization
At week 24, a significantly higher proportion of patients treated with OLM/AML had normalized BP (<130/80 mm Hg according to the study protocol) compared with PER/AML (37.6% vs 21.8%; P=.0118). In addition, OLM/AML was associated with a significantly higher proportion of patients with normalized BP according to the 2009 ESH guidelines reappraisal21 (<140/90 mm Hg) compared with PER/AML (73.3% vs 59.1%; P=.0300; Figure 5).
Figure 5.
Proportion of diabetic patients with normalized blood pressure at week 24 across the treatment groups according to the 2007 European Society of Hypertension (ESH)/European Society of Cardiology guidelines (systolic blood pressure/diastolic blood pressure 130/80 mm Hg) and the 2009 ESH guidelines reappraisal (systolic blood pressure/diastolic blood pressure 140/90 mm Hg) in the full analysis set. AML indicates amlodipine; OLM, olmesartan; PER, perindopril.
Tolerability
Both OLM/AML and PER/AML were well tolerated with a similar proportion of patients with more than one drug‐related treatment‐emergent adverse event (TEAE) (OLM/AML, 21.6%; PER/AML, 27.0%) (Table 2). The most common TEAE in both groups was peripheral edema, which affected 18.9% of OLM/AML patients and 19.7% of PER/AML patients. Cough was experienced by 2.7% of OLM/AML and 5.7% of PER/AML patients (Table 2).
Table 2.
Safety Observations During the Double‐Blind Treatment Period in the Safety Analysis Set
| Characteristic | OLM/AML 40/10 mg (n=111) | PER/AML 8/10 mg (n=122) | Total (N=233) |
|---|---|---|---|
| ≥1 TEAE | 50 (45.0) | 60 (49.2) | 110 (47.2) |
| ≥1 drug‐related TEAE | 24 (21.6) | 33 (27.0) | 57 (24.5) |
| ≥1 serious TEAE | 2 (1.8) | 3 (2.5) | 5 (2.1) |
| ≥1 serious drug‐related TEAE | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Deaths | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Discontinued because of TEAE | 7 (6.3) | 13 (10.7) | 20 (8.6) |
| Discontinued because of drug‐related TEAE | 6 (5.4) | 12 (9.8) | 18 (7.7) |
| Patients with ≥1 TEAE | |||
| Peripheral edema | 21 (18.9) | 29 (20.5) | 46 (19.7) |
| Nasopharyngitis | 6 (5.4) | 7 (5.7) | 13 (5.6) |
| Cough | 3 (2.7) | 8 (6.6) | 11 (4.7) |
| Erectile dysfunction | 1 (0.9) | 2 (1.6) | 3 (1.3) |
| Malaise | 2 (1.8) | 1 (0.8) | 3 (1.3) |
| Erythema | 0 (0.0) | 2 (1.6) | 2 (0.9) |
| Flushing | 2 (1.8) | 0 (0.0) | 2 (0.9) |
Abbreviations: AML, amlodipine; OLM, olmesartan; PER, perindopril; TEAE, treatment‐emergent adverse event.
There were low rates of discontinuations caused by drug‐related TEAEs across both treatment groups (OLM/AML, 5.4%; PER/AML, 9.85%) and no incidence of mortality in either treatment group.
Discussion
This study shows that for hypertensive patients with diabetes, who have inadequately controlled BP on AML monotherapy, the dual combination of OLM/AML was noninferior and indeed superior to PER/AML in reducing CSBP. In addition, the noninferiority of OLM/AML to PER/AML was observed in a number of hemodynamic variables and in the proportion of patients with normalized BP.
Available evidence suggests that CSBP measurements provide a more accurate assessment of CV risk compared with brachial BP measurements.3, 23 The ASCOT study, and the CAFE substudy, have provided some important insights into the effects of antihypertensive treatment on CSBP, notably with regard to the benefits of dual RAS‐calcium channel blockade. Thus, the study design and inclusion criteria used in SEVITENSION were based on ASCOT to facilitate comparison and allow assessment of whether dual RAS‐calcium channel blockade using an ARB would have similar effects on central BP. The maximum RAS blocker dose used in ASCOT was PER 8 mg, which is also the highest dose recommended for the treatment of hypertension.24 Since the maximum recommended dose of OLM is 40 mg, this was selected as the most suitable for providing the RAS blocker component in SEVITENSION.
The significance of the present findings is the demonstration that dual RAS‐calcium channel blockade is highly effective in reducing CSBP in hypertensive patients with diabetes. Studies have shown that both type 1 and 2 diabetes are associated with increased arterial stiffness, and this may help to explain the increase in CV risk in these patients since the heart needs to work harder to generate higher pressures to pump blood through stiffer central arteries.25, 26 Increased arterial stiffness also leads to raised SBP through elevations in pulse wave velocity (PWV) and pressure wave reflection. Hypertensive patients with diabetes have been shown to have significantly higher PWV compared with those without diabetes,27 and the proportion of individuals with an increased PWV has been reported to be greater among hypertensive patients with diabetes compared with nondiabetic hypertensive patients.26 The mechanisms by which abnormal glucose metabolism affect vascular structure and function are uncertain, but deteriorating glucose tolerance is associated with increased central and peripheral arterial stiffness, and this may contribute to the increased CV risk seen in patients with both impaired glucose metabolism and diabetes.28 The increase in arterial stiffness caused by deteriorating glucose tolerance may result in a negative feedback loop of arterial stiffness and damage to microcirculation.29
Current treatment guidelines point out that the beneficial effects of RAS blockers on renal function make it reasonable to use an ACE inhibitor or an ARB in the management of hypertensive patients with diabetes. The guidelines also point out that CCBs have been shown to be useful in these patients, especially when combined with a RAS blocker.23 The implications of the present findings are that dual RAS‐calcium channel blockade with an ARB/CCB combination has an important role to play in lowering BP and reducing CV risk in patients with diabetes. If supported by further research, treatment guidelines may need to be modified to specify that an ARB/CCB combination is the recommended treatment option for hypertensive patients with diabetes whose BP cannot be adequately controlled with a single agent.
The results presented here are in accordance with those of previous studies involving OLM/AML. A long‐term (52 weeks) subgroup analysis of the Combination of Olmesartan medoxomil and Amlodipine besylate in Controlling High blood pressure (COACH) study30 assessed the efficacy of OLM/AML in a number of subgroups including diabetic patients. In the diabetic subgroup, OLM/AML was effective in reducing seated BP, with similar reductions noted in patients with and without diabetes. Similar to the results presented here, in COACH, 26.9% of diabetic patients achieved BP normalization (<130/80 mm Hg). Furthermore, results from the APEX study, which also involved diabetic patients, found that a titration regimen involving OLM/AML was effective in reducing BP throughout a 24‐hour period in patients with hypertension and T2DM.31
In the SEVITENSION study, OLM/AML was superior to PER/AML for the absolute change in CSBP from baseline to final examination in both the total population and the diabetic subgroup. In addition, OLM/AML was superior in reducing seated SBP and DBP, 24‐hour ambulatory SBP and DBP, and nighttime SBP in the total population. In the diabetic subgroup, only nighttime SBP and seated SBP were superior. The frequency of adverse events was similar in the two treatment groups in the diabetic subanalysis, and these frequencies were also similar to those seen in the total population. In the primary analysis of the SEVITENSION study, a higher proportion of PER/AML recipients (7.5%) discontinued the study compared with patients treated with OLM/AML (5.7%). In this post hoc analysis, this effect was even more pronounced. The proportion of diabetic patients who discontinued in the SEVITENSION study was almost twice as large with PER/AML (9.9%) compared with OLM/AML (5.4%).
Treatment with OLM/AML was associated with a greater number of patients achieving BP control compared with PER/AML. Based on the 2009 ESH guidelines update definition of normalized BP (<140/90 mm Hg),21 a significantly higher proportion of patients treated with OLM/AML had normalized BP compared with those treated with PER/AML (73.3% vs 59.1%; P=.03). A similar pattern was also seen with the study protocol definition of normalized BP (ie, <130/80 mm Hg), based on the 2007 ESH/ESC guidelines for the management of atrial hypertension, which were applicable at the time of study design,19 although it resulted in lower proportions of OLM/AML and PER/AML recipients achieving normalization (37.6% vs 21.8%; P=.0118). The lower BP goal for diabetic patients has since been modified in the 2013 ESH/ESC guidelines for the management of atrial hypertension, which recommend a BP goal of <140/85 mm Hg for diabetic patients.23 Based on this goal, it is likely that OLM/AML would still show improvements over PER/AML.
Study Limitations
This study has some limitations. First, it may be difficult to extrapolate these findings to the general hypertensive population since only Spanish Caucasian patients were enrolled and because the study design was based on that of the CAFE substudy, with all patients having diabetes and at least two additional risk factors. Second, only patients with T2DM were enrolled, and although there is no reason to suspect that the results would be any different in patients with type 1 diabetes mellitus, this cannot be confirmed without clinical evaluation. Finally, the duration of the SEVITENSION study was too short to assess change in the rate of CV events.
Conclusions
The results from this subgroup analysis found that OLM/AML was noninferior to PER/AML in reducing CSBP in a subgroup of hypertensive patients with diabetes. Moreover, OLM/AML was found to have superior BP‐lowering effects compared with PER/AML.
At the time of final examination, a higher proportion of patients treated with OLM/AML had normalized BP according to both the 2007 ESH/ESC guidelines for the management of arterial hypertension and the 2009 ESH guidelines reappraisal, compared with PER/AML.
Both treatments were well tolerated and diabetic patients showed no signs of having an additional risk for TEAE compared with the general population. Furthermore, OLM/AML was associated with a lower incidence of cough compared with PER/AML and a clinically relevant lower rate of discontinuations.
This analysis shows that a single‐pill fixed‐dose combination of OLM/AML 40/10 mg was associated with significant BP‐lowering effects and demonstrates the importance of this type of dual‐combination therapy in the treatment of higher‐risk hypertensive patients with diabetes.
Disclosures
Dr Ruilope has served as an advisor and speaker for Daiichi Sankyo.
Acknowledgments
This study was sponsored by Daiichi Sankyo Europe GmbH, Munich, Germany. Prof Dr Luis Ruilope was the coordinating investigator and acted as the medical expert for the study. Medical writing assistance during the preparation of this manuscript was funded by Daiichi Sankyo Europe GmbH and provided by Matthew Bexon of inScience Communications, Springer Healthcare, Chester, UK.
The author wishes to express gratitude to the investigators, study nurses, and coordinators who were involved in the SEVITENSION study. The SEVITENSION study investigators were: Jose Abellan, Pedro Aranda, Cesar Cerezo, Jose Antonio Divison, Luis Garcia Ortiz, Juan Garcia Puig, Pablo Gomez, Jorge Gomez Cerezo, Nieves Martell, Anna Oliveras, Enrique Rodilla, Jose Saban, Julian Segura, Carmen Suarez, and Luis Vigil.
J Clin Hypertens (Greenwich). 2016;18 528–535. DOI: 10.1111/jch.12673 © 2015 Wiley Periodicals, Inc.
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