BP control in Severe Hypertension: Combination of Amlodipine and Telmisartan more efficacious than monotherapy
India at the brink of a hypertension epidemic!
Globally >1 billion adults suffer from hypertension and this figure is expected to rise to 1.5 billion in the next decade.(1) Evidence from the Indian National Family Health Survey showed that nearly 40.6% of Indians in the age group of 15 to 49 years are affected by hypertension.(2)
The presence of comorbidities along with hypertension complicates the disease process. Coexistence of diabetes and hypertension was found in 4.5% with the simultaneous presence of diabetes, hypertension and dyslipidaemia in 1.8% of the population.(3) Comorbidities are correlated with worse health outcomes in patients with their management being more complex.(4) It is suggested that nearly 3 out of every 4 patients suffer from uncontrolled hypertension(5) and it is thus imperative that severe hypertension with or without comorbidities should be managed swiftly and effectively to reduce the cardiovascular (CV) burden associated with this condition.
Combination therapy more effective than monotherapy in those with elevated or severe hypertension
The latest guidelines approve the use of any of the first-line antihypertensive agents for the treatment of hypertension(6-8) and acknowledge that combination therapy is often needed, more so as an SPC, to achieve better control/adherence in patients with uncontrolled hypertension. A combination of agents from two distinct classes was also found to be five times more effective in lowering blood pressure (BP) than uptitrating dose of one agent.(9) In this regard, the combination of a renin-angiotensin system (RAS) blocker with a calcium channel blocker (CCB) has been suggested as one of the preferred combinations. Treatment with ARBs has resulted in lower discontinuation and adverse event rates amongst all other antihypertensive therapies.(8) Thus an SPC of an ARB and CCB, which have complementary mechanisms of actions constitute a rational combination(5) and can be highly effective in the treatment of hypertension uncontrolled on monotherapy. The efficacy of one such SPC is discussed here.
The TEAMSTA Severe study – Greater efficacy & comparable tolerability with SPC vs individual agents(5)
Amlodipine is a first-line antihypertensive agent with proven effects on outcomes in several studies.10 The antihypertensive efficacy of ARBs is well-known with Telmisartan having the longest half-life amongst them.(8,11) The complementary pharmacokinetic and side-effect profiles of both Amlodipine and Telmisartan
make their combination suitable for an SPC which provides 24-hr BP control.(9,10,11) The TEAMSTA severe study evaluated the efficacy and safety of the SPC of Telmisartan 80 mg and Amlodipine 10 mg (T80⁄A10) vs monotherapy with its individual components i.e. Amlodipine 10 mg (A10) and Telmisartan 80 mg (T80) in patients with severe hypertension [systolic⁄diastolic blood pressure (SBP ⁄ DBP) ≥180 ⁄ 95 mmHg)].(5)
Design of the study
The TEAMSTA severe study was a multinational, multicenter, randomized, double-blind, parallel-group, forced-titration study conducted over 8 weeks. Patients (n=858) were recruited from 114 centres across 11 countries. After screening, suitable patients underwent a 1 day to 2 week single-blind, placebo run-in period and were randomized to one of the 3 treatment groups – T80/A10 SPC, A10 monotherapy or T80 monotherapy. Those on Amlodipine were assigned to lower doses for 2 weeks (i.e. T80/A5 or A5) and then up-titrated to T80 ⁄A10 or A10 for the remaining 6 weeks of the study. Those on T80 monotherapy remained on the same treatment throughout the 8-week period.
The treatment groups were:
• SPC of T80 ⁄ A10 (n=421),
• T80 monotherapy (n=217) and
• A10 monotherapy (n=220)
The trial medication was taken in the morning once daily at around the same time. Other antihypertensive/ related medications which may impact BP were not allowed during the study.
• Adult patients (≥18 yrs) with mean seated cuff SBP ≥180 mmHg and DBP ≥95 mmHg able to stop their current antihypertensive therapy without substantial risks
• In patients with severe hypertension, effective and safe control of BP levels is very important
• The SPC of Amlodipine and Telmisartan achieved a swift reduction in BP levels along with higher BP goal achievement and response rates in nearly all patients with severe hypertension compared to monotherapy with the individual components
• Patients with suspected or known secondary hypertension
• Those with mean seated cuff SBP ≥200 mmHg and⁄or mean seated cuff DBP ≥120 mmHg
• Those with symptomatic congestive heart failure, clinically relevant cardiac arrhythmias or hepatic impairment, severe renal impairment, unstable/uncontrolled diabetes or any other condition that would not allow for the safe completion of the protocol
• Women who were pregnant, nursing or premenopausal or those of childbearing potential not using adequate birth control
• Patients with previous symptoms characteristic of angioedema when on RAS blocker therapy
• History of drug or alcohol dependency <6 months prior to the study, and
• Those who were not compliant with the study medication during the run-in treatment period
Primary endpoint after 8 weeks of therapy
The primary end point was change from baseline in mean seated in-clinic trough cuff SBP
Secondary endpoints after 1, 2, 4, and 6 weeks
• Change from baseline in mean seated in-clinic trough cuff SBP of treatment
• SBP control (SBP <140 mm Hg or <130 mm Hg) or DBP control (DBP <90 mm Hg or <80 mm Hg)
• Overall BP goal achievement (SBP <140 and DBP <90 mmHg)
Pre-specified subgroup analyses
• SBP categories in 10 mm Hg increments (≥180 to <190 mmHg and ≥190 to <200 mm Hg)
• Presence or absence of the metabolic syndrome (i.e. patients with type 2 diabetes and body mass index ≥30 kg ⁄m2)
• All adverse events, including reported or diagnosed oedema, that occurred throughout the entire study period were recorded
Treatment with the SPC of T80/A10 resulted in:
• Nearly 48 mmHg reduction in SBP with T80/A10 SPC
At the end of 8 weeks, treatment with T80/A10 resulted in greater reductions from baseline in seated trough cuff SBP vs T80 or A10 monotherapy (Figure 1). The adjusted mean reduction in seated trough cuff SBP was significantly greater with T80⁄A10 compared to T80 (10.6 mmHg; p<0.0001) and A10 (4.4 mmHg; p=0.0002) monotherapy (Figure 1). The reductions in seated trough cuff SBP were maintained irrespective of baseline SBP category (Figure 2).
• 80% of maximum SBP reduction with T80/A10 SPC achieved within the first 2 weeks of therapy
The reduction in the adjusted mean SBP in the T80 ⁄A10 SPC group were significantly greater than that seen with either monotherapy group at all time points of BP measurement (overall, P<0.0001 vs T80 and P≥0.0077 vs A10).
In fact, 80% of maximum effect on SBP was achieved with the SPC in the first 2 weeks itself (Figure 3).
The reduction at week 2 with T80/A10 was also significantly greater than that for individual monotherapies at that time point [7.8 mmHg and 4.6 mmHg more reduction in SBP when compared to T80 (P<0.0001) and A5 (P=0.0001), respectively].
Changes in seated trough cuff DBP vs baseline were similarly significantly greater with T80/A10 SPC (-18.7 mmHg) compared to individual T80 (-13.8 mmHg; p<0.0001) or A10 (-16.3 mmHg; p=0.0006) monotherapy at the end of 8 weeks.
Subgroup analyses showed that the mean reduction in SBP vs baseline remained greater with the SPC as compared to the monotherapy groups for all patient groups irrespective of age, race, body mass index, type 2 diabetes and presence of metabolic syndrome.
• 2 times greater patients achieved BP goal (<140/90 mmHg) with T80/A10 SPC
Greater proportion of patients reached the BP goals of <140/90 mmHg BP in the T80/A10 SPC groups than either of the monotherapy groups. In fact, BP goal was achieved by 2 times more number of patients with T80/A10 SPC than with A10 monotherapy (Figure 4).
Similarly, the 24-hour ambulatory BP goal of <130 ⁄ 80 mmHg was also achieved by >2 times the number of patients on T80⁄A10 SPC than those on A10 monotherapy (82.7% of vs 37.9%; P<0.0001).
• 99.7% of patients achieved SBP response with T80/A10 SPC
The SBP⁄DBP response rates i.e. SBP <140 or ≥10 mmHg reduction and DBP<90 or ≥10 mmHg reduction were higher with the T80 ⁄A10 SPC compared with either monotherapy.
Overall, 99.7% in the T80⁄A10 group had an SBP response compared to the T80 and A10 monotherapy groups (Figure 5). Even in the case of the more stringent SBP response (<140 or ≥15 mmHg reduction) the response rates were 99%, 88.7% and 98.5% for the T80 ⁄A10 SPC, T80 and A10 groups, respectively.
DBP response rates were also higher with T80/A10 (91.4%) than for the T80 (69.3%) and A10 (83.9%) groups.
The SPC of T80⁄A10 SPC was safe and well-tolerated with adverse event rates similar to the monotherapy groups. Most of them (98.5%) were of mild-to-moderate intensity.
The high prevalence of uncontrolled hypertension with or without the presence of comorbidities has necessitated the use of combination therapy to achieve BP targets. The TEAMSTA severe study showed that the T⁄A SPC was more efficacious than the individual components in decreasing BP levels and improving BP goal achievement/response rates in adults with severe hypertension. Moreover, this efficacy was swift (within 2 weeks), sustained over the study period and across patient groups irrespective of the presence of comorbidities. Thus, the T/A SPC is an effective treatment modality in this increasingly difficult-to-treat population and can help reduce the long-term burden of CV morbidity and mortality associated with hypertension.
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