Amlodipine, Telmisartan Combination better than Monotherapy: TEAMSTA 5 Study
The hypertensive pressure continues to mount!
Hypertension or high blood pressure (BP) affects 1.39 billion people worldwide. Nearly 25% men and 20% women suffer from this condition which is also one of the leading causes of death. Globally, hypertension is responsible for 10.4 million deaths per year. Lack of BP control is associated with development of several complications such as stroke, ischaemic heart disease, stroke, heart failure (HF) and chronic kidney disease (CKD). In fact, nearly 57% of stroke mortality and 24% of coronary artery disease (CAD)-related deaths are correlated with hypertension.
Data from the great India BP survey shows that 1 out of every 3 adults in India suffers from hypertension. Moreover, only 51% of the affected individuals were aware of their condition. This is compounded by dismal BP control rates which range from 11 to 20%. Greater prevalence of hypertension in younger Indians (20-44 yrs) is also a worrying trend with cardiovascular (CV) deaths occurring a decade earlier as compared to developed countries. All these aspects make it imperative that better screening and treatment strategies are employed to ensure optimal management of hypertension.
Switch to combination when monotherapy proves inadequate
Hypertensive therapy aims to not only reduce BP levels but also takes into account the underlying CV disease (CVD) risk. In this regard, the latest guidelines acknowledge that first-line antihypertensive agents which prevent CVD include diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs) and beta-blockers. However, beta-blocker use is recommended only in special situations such as HF, angina, post-MI, atrial fibrillation, or younger women with, or planning, pregnancy.
Since monotherapy often proves insufficient to achieve adequate BP control, hypertension guidelines have evolved from stepped-care therapy to using a combination of two drugsto enhance antihypertensive efficacy. Majority of patients with hypertension need treatment with 2 or more drugs to achieve their BP goals and to decrease the associated risk CV morbidity and mortality. Hence in the case of patients with Stage 2 hypertension [systolic BP (SBP) ≥140 or diastolic BP (DBP) ≥90 mmHg] or Grade 2 hypertension (SBP≥160 and/or DBP≥90 mmHg) and in those whose BP is uncontrolled and >20/10 mmHg above target, use of two agents in combination is recommended.
Since nearly 1 out of every 4 patients on antihypertensive therapy do not adhere to their prescribed medication, the International Society of Hypertension (ISH), the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) and the American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend the use of a two-drug combination, preferably as a single- pill combination (SPC) to achieve BP control, enhance adherence and attenuate overall CVD risk. The safety and efficacy aspects of one such SPC vs monotherapy are discussed below.
The TEAMSTA-5 study – Improved efficacy & greater tolerability with SPC
Amlodipine is considered the gold standard in antihypertensive efficacy whereas Telmisartan is the only ARB indicated for the reduction of CV morbidity in patients with atherothrombotic CVD. Their compatible pharmacokinetic profiles can provide 24-hr BP control when given as a SPC. Moreover, addition of Telmisartan to Amlodipine can aid in attenuation of the oedema associated with the former, improving tolerability. The TEAMSTA – 5 study evaluated the efficacy and safety of the SPCs of Telmisartan 40/80mg and Amlodipine 5 mg (T40⁄A5 or T80⁄A5) vs monotherapy with Amlodipine 5/10 mg (A10) in hypertensive patients who were inadequately controlled on Amlodipine alone.
Design of the study
The TEAMSTA-5 study was a multicenter, multinational, randomized, double-blind, parallel-group study which was conducted over an eight-week period. Patients (n=1097) were recruited from 129 centers across several countries between October 2007 and October 2008. After being screened, the patients underwent a 6-week open-label, treatment run-in period with Amlodipine 5 mg (A5). Post-randomization, patients were segregated for 8 weeks into 4 treatment groups as follows:
• SPC of T40 ⁄ A5 (n=277),
• SPC of T80 ⁄ A5 (n=277),
• A5 monotherapy (n=267) or
• A10 monotherapy (n=276)
The medication was consumed orally in the morning between 8 to 10 am.
HIGHLIGHTS
Inclusion criteria
• Adult men and women (≥18 years) with essential hypertension
• With seated DBP ≥95 mmHg in those undergoing treatment or DBP ≥100 mmHg in treatment-naȉve patients
• Who failed to respond adequately to a 6-week therapy with A5 at baseline (defined as DBP≥90mmHg)
Exclusion criteria
• Patients with suspected or known secondary hypertension
• Those with mean seated SBP≥200 mmHg and/or mean seated DBP≥120 mmHg at screening or at start of the run-in period, or mean seated SBP≥180 mmHg and⁄or mean seated DBP≥120 mmHg at the end of the run-in period
• Those with symptomatic congestive heart failure (CHF), significant hepatic impairment, severe renal impairment or any other condition that inhibits safe completion of the protocol
• Women who are pregnant, nursing, or premenopausal, or those of childbearing potential not using adequate birth control
• Patients with previous symptoms characteristic of angioedema when on ACEI/ARB 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
Change from baseline in seated trough DBP and the incidence of oedema (defined as peripheral oedema, oedema or generalized oedema)
Secondary efficacy endpoints after 8 weeks of therapy
• Change from baseline in seated trough SBP
• Proportion of patients achieving DBP response (mean seated DBP <90 or reduction ≥10 mmHg) and SBP response (mean seated SBP <140 or reduction ≥15 mmHg), and
• Proportion of patients achieving DBP goal (mean seated DBP <90 mmHg), SBP goal (mean seated SBP <140 mmHg), and BP goal (defined as mean seated BP <140/90 mmHg)
Results
Switching patients from monotherapy to a combination of Amlodipine + Telmisartan resulted in:
• 65% greater reduction in BP
Both the SPCs T80⁄A5 and T40/A5 caused significantly greater reductions in seated trough SBP and DBP vs baseline compared to A5 or A10 alone. This reduction vs baseline remained significant even after adjusting for reduction with monotherapy (Figure 1).
• Up to 50% higher BP response rates
BP response rates (SBP <140 or reduction ≥15mmHg and DBP<90 or reduction ≥10 mmHg) were significantly greater with T80/A5 and T40/A5 than with A5 alone (Figure 2). The odds of achieving BP response with T80/A5 and T40/A5 were 2.80 times and 3.44 times greater than that with A5 monotherapy. These odds were 1.32 and 1.62 times higher, respectively, than for A10 therapy alone.
• 2 times more patients achieve BP goal
BP goals (SBP<140 mmHg and DBP<90 mmHg) were also achieved by a significantly greater proportion of patients treated with T80/A5 and T40/A5 vs A5 alone (Figure 3).
Patients on the combination were 2 times more likely than the patients on A5 to achieve their BP goals. The overall BP target achievement rates remained significantly higher with the combination vs. A5/A10 monotherapy.(figure 3)
Oedema was the most common side-effect observed with maximum incidence seen in the A10 monotherapy group (27.9%). Both the SPCs showed significantly lower incidence of oedema compared to A10 monotherapy. In fact, even the pooled SPC groups showed a 2-fold lower oedema incidence (4.3%) than that seen with A5 monotherapy (8.6%).
The overall incidence of adverse events with the T⁄A SPCs was similar to that observed with A5 monotherapy and lower than that seen with A10 treatment. Rates of discontinuations due to adverse events were similar amongst the study groups. The only exception was the oedema-related discontinuation which was higher in the A10 monotherapy group.
Conclusion
Nearly 1 out of every 2 patients with hypertension on monotherapy are unable to achieve their BP targets. Drug up-titration may result in improved efficacy but with concomitant increase in adverse effects. Hence, switching to a combination of agents, in the form of a SPC, offers enhanced efficacy and tolerability. The TEAMSTA-5 study compared the safety and efficacy of the T/A SPCs with both low- and up-titrated dose of Amlodipine monotherapy. SPC therapy resulted in significantly greater reductions in BP, BP response and BP goal achievement rates compared to monotherapy. Moreover, these benefits were coupled with a better safety profile. Thus patients who are unable to achieve adequate BP control on Amlodipine monotherapy can consider switching to a T/A SPC to achieve their BP targets without compromising on safety.
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