Role of combination therapy in the treatment of hypertension: Focus on valsartan plus amlodipine

Abstract

Hypertension control is rare in clinical practice, particularly in high-risk patients. A large factor is therapeutic inertia deriving from poorly prescribed lifestyle changes, excess monotherapy use, and scarce on-treatment modifications. The use of drug combinations significantly improves blood pressure (BP) control; in particular, fixed combinations improve therapy without increasing daily pill intake, thereby favouring patient compliance and therapy continuation. The most widely used fixed combination is based on thiazide diuretics added to either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). Several large-scale clinical trials have been conducted showing that these combinations are effective in lowering BP. However, thiazide diuretics can reduce the metabolic benefits derived from renin-angiotensin-aldosterone system (RAAS) inhibitors in high metabolic risk patients. In contrast, ACE inhibitors or ARBs combined with dihydropyridine calcium channel antagonists (DHPCAs) exert a marked antihypertensive effect without decreasing metabolic protection by RAAS blockade. In the recent JIKEI heart study, approximately 60% of patients affected by hypertension, heart failure, coronary heart disease or their combination in the valsartan arm were simultaneously treated with DHPCAs. Of note, a 39% reduction in the primary endpoint of combined morbidity and mortality was reported in the valsartan compared with the non-valsartan arm. Furthermore, in a recent multinational study, 83% of 3161 hypertensive patients treated with valsartan and the DHCPA amlodipine reported a concontrolled BP after 8 weeks of treatment. As expected, amlodipine did not negatively influence the metabolic profile of patients, thereby supporting the role of ARB+DHPCA combinations as effective and promising tools in hypertension treatment. In summary, the combination of ARBs with DHPCAs is an effective strategy in hypertension treatment through synergy between their antihypertensive and vascular protective actions, persistent metabolic benefits deriving from RAAS inhibition, and reduced incidence of side effects.

Comparison of Fixed-dose Combinations of Amlodipine/Losartan Potassium/Chlorthalidone and Amlodipine/Losartan Potassium in Patients With Stage 2 Hypertension Inadequately Controlled With Amlodipine/Losartan Potassium: A Randomized, Double-blind, Multicenter, Phase III Study

“…A combination of ARB and CCB is particularly effective for decreasing BP and is recommended particularly in Asians because ARBs have fewer AEs than ACEis do in this population. [23][24][25] The incidence of cough has been reported to be 42-fold higher in East Asian patients than in white patients; thus, ACEis are rarely prescribed to control BP in Korea or other East Asian countries. 26 Among various ARBs, losartan-based combination therapies could effectively reduce BP and improve cardiovascular events.…”

Efficacy and Safety of Valsartan/Amlodipine Single-Pill Combination in 11,422 Chinese Patients with Hypertension: an Observational Study

“…However, in about 70% of patients, it is ineffective in achieving BP goals [25]. The use of combination therapy having complementary mechanisms of action is more effective than single agents in achieving optimal BP control [8, 26]. A SPC of Val and Aml has been well tolerated regardless of age, sex, race, or ethnicity [27, 28].…”

Improving vascular function in hypertension: potential benefits of combination therapy with amlodipine and renin–angiotensin–aldosterone system blockers

“…Studies conducted in animal models [46,[52][53][54] and tissues from failing human hearts [55] have produced promising results for the combination of amlodipine-RAAS inhibitor. Not only does this combination appear to improve nitric oxide availability but it also reduces the formation of inflammatory mediators, myocardial oxygen consumption, vascular resistance and neurohormonal system activity, and preserves cardiac structure.…”

“…Activation of the angiotensin type 1 receptor has been shown to increase calcium influx into the cell via L-type calcium channels and amlodipine administration reduced the vasoconstrictive response to angiotensin II [54,55]. Thus, combined RAAS and CCBs therapy can further reduce cytosol calcium concentrations, which can result in an enhanced peripheral vasodilator response [56][57][58].…”