Prompt BP Control with an Early Combination Therapy: Role of a Fixed-Dose Combination of an ARB and a CCB

Now it is well established that a combination therapy leads to a significant reduction in Blood Pressure. The rationale behind the combination therapy is targeting multiple pathways leading to a blood pressure decrease, and the current understanding that these pathways are diverse in various individuals. Anti-hypertensive mono-therapy usually reduces the BP by its action on one or at the best two mechanisms whereas, in contrast, a combination therapy allows us to target several different hypertensive mechanisms to achieve a faster BP control.

Among the different combinations, the RASIs (ARBs/ACEIs), in combination with CCBs, were found to reduce cardiovascular mortality, nonfatal myocardial infarction, and nonfatal cerebral vascular disease as compared to the other combinations, despite achieving a similar reduction in blood pressure. (2) Meta-analyses also showed that this combination in hypertensive patients with Type II Diabetes achieved a greater reduction in mortality than mono-therapy or other combinations. (3) One of the essential benefits provided by the ARB plus CCB combination was the excellent end-organ protection. This combination provided better control in the central hemodynamic(s) as compared to the combination of an ARB with a diuretic. (4) Azilsartan plus cilnidipine is a recent addition to the ARB plus CCB combinations available today.

Azilsartan is a newer addition to ARB class. All major head-to-head randomized controlled trials indicate that azilsartan exhibits more potent antihypertensive action than any other drugs in its class. This potent antihypertensive action includes better clinical systolic blood pressure (SBP), diastolic blood pressure (DBP), and 24-hour ambulatory blood pressure. It is the only ARB recommended in salt-sensitive hypertensive patients. Azilsartan treatment for 24 weeks significantly reduced the day-to-day BPV in the morning. Azilsartan also decreased the arterial stiffness as determined by the CAVI, suggesting the mechanism underlying the reduction in home BPV. (5) Because of its inverse agonistic effects, azilsartan has potential effects beyond BP control which include amelioration of deleterious effects of angiotensin II such as cardiac hypertrophy, fibrosis, insulin resistance, and stabilization of coronary plaques. Azilsartan has almost similar side effect profile as other ARB, but better and prolonged BP control. (6) Azilsartan exhibited renal protective effects based on significant reductions in u-AGT and UACR. (7) Azilsartan improves diastolic function in HF patients with hypertension, and it may be the preferred option over other angiotensin II receptor blockers in patients with HFpEF.(8)

Cilnidipine is a 4 th generation CCB which blocks L and N-type calcium channel. Cilnidipine is highly vaso-selective. Along with BP reduction, it provides end-organ protection. Cilnidipine lowered BP variability significantly compared to other CCBs. Cilnidipine has cardioprotective, reno-protective as well as neuroprotective action. Cilnidipine is superior than amlodipine in improving central aortic blood pressure & arterial stiffness. Cilnidipine can improve LV function after short-term treatment. Being L- & N-type CCBs, cilnidipine improve LV diastolic function in hypertensive patients, partially through a decrease in uric acid levels. Cilnidipine effectively suppresses cardiac hypertrophy compared with other CCBs. It has a better safety profile with less tachycardia and a lower incidence of pedal edema compared to amlodipine. A probable explanation for the significant reduction of heart rate with cilnidipine and lesser pedel edema is due to the inhibition of cardiac sympathetic overactivity by blocking L- and N-type calcium channels.

A study, evaluating the FDC of Azilsartan with Cilnidipine (40/5 or 40/10) resulted in a significant reduction in SBP & DBP when compared to an individual mono-therapy with azilsartan 40 mg or cilnidipine 10 mg (P = 0.0001). The FDC also resulted in a significant reduction in ABPM parameters. (9)

Along with the BP reduction, the Azilsartan plus Cilnidipine combination is associated with multiple benefits such as Cilnidipine, when combined with an ARB, provides a superior anti- proteinuric effect compared to Amlodipine. (10)

With changing dynamics of the anti-hypertensive treatment, newer drugs and newer combination therapies are being added to our armamentarium. ARB plus CCB is ideally one of the most effective and preferred combinations. Azilsartan plus Cilnidipine appears to be one of the most promising combinations in providing prompt BP control with effective end-organ protection.

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2. Chi C, Tai C, Bai B, et al. Angiotensin system blockade combined with calcium channel blockers is superior to other combinations in cardiovascular protection with similar blood pressure reduction: a meta-analysis in 20,451 hypertensive patients. J Clin Hypertens (Greenwich). 2016;18:801-8.

3. Remonti LR, Dias S, Leitão CB, Kramer CK, Klassman LP, Welton NJ, Ades AE, Gross JL. Classes of antihypertensive agents and mortality in hypertensive patients with type 2 diabetes-Network meta-analysis of randomized trials. J Diabetes Complications. 2016;30:1192-200.

4. Matsui Y, Eguchi K, O'Rourke MF, Ishikawa J, Miyashita H, Shimada K, Kario K. Differential effects between a calcium channel blocker and a diuretic when used in combination with angiotensin II receptor blocker on central aortic pressure in hypertensive patients. Hypertension. 2009;54:716-23.

5. Miyoshi T, Suetsuna R, Tokunaga N, Kusaka M, Tsuzaki R, Koten K, Kunihisa K, Ito H. Effect of azilsartan on day-to-day variability in-home blood pressure: a prospective multicenter clinical trial. Journal of clinical medicine research. 2017 Jul;9(7):618.

6. Pradhan A, Tiwari A, Sethi R. Azilsartan: Current Evidence and Perspectives in Management of Hypertension. International Journal of Hypertension. 2019 Nov 3;2019.

7. Takami T, Okada S, Saito Y, Nishijima Y, Kobori H, Nishiyama A. Effects of olmesartan and azilsartan on albuminuria and the intrarenal renin-angiotensin system. World journal of research and review. 2018 Jan;6(1):7.

8. Sakamoto M, Asakura M, Nakano A, Kanzaki H, Sugano Y, Amaki M, Ohara T, Hasegawa T, Anzai T, Kitakaze M. Azilsartan, but not candesartan improves left ventricular diastolic function in patients with hypertension and heart failure. International Journal of Gerontology. 2015 Dec 1;9(4):201-5.

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10. Fujita T, Ando K, Nishimura H, Ideura T, Yasuda G, Isshiki M, Takahashi K. Antiproteinuric effect of the calcium channel blocker cilnidipine added to renin-angiotensin inhibition in hypertensive patients with chronic renal disease. Kidney international. 2007 Dec 2;72(12):1543-9.