Combination of Candesartan with ACE Inhibitors in the Treatment of Hypertension and Heart Failure

Sartan + ACEi = Complete Blockade of the RAAS System?

ACE inhibitors reduce the production of angiotensin II by their effect, causing vasodilation and a decrease in blood pressure. However, it has been proven that angiotensin II can also be produced through alternative pathways independent of ACE inhibitors. For this reason, AT₁ receptor blockers for angiotensin II, known as sartans, were developed. Therefore, the combination of ACEi with sartans should theoretically ensure a more complete blockade of the RAAS system, thus guaranteeing higher treatment efficiency. In practice, however, this combination is not commonly recommended due to the presumed higher rate of side effects and the lack of impact on the number of cardiovascular events.

Combination Therapy More Effective than Monotherapy

The combination of an ACE inhibitor and a sartan led to a more significant decrease in blood pressure compared to monotherapy in several clinical studies and meta-analyses. According to the conclusion of one study, this dual blockade of the RAAS system led to a reduction in average blood pressure during 24-hour monitoring by 7.1/3.4 mmHg after 12 weeks of treatment, with office blood pressure values dropping by 12.9/2.2 mmHg.

Studies Confirm the Effect of Combining ACEi with Candesartan in the Treatment of Hypertension

The AMAZE study examined the effect of adding candesartan compared to doubling the existing dose of lisinopril. In a group of hypertensive patients, the addition of 16 or 32 mg of candesartan to lisinopril monotherapy resulted in a statistically more significant reduction in blood pressure compared to patients who had their lisinopril dose increased from 20 to 40 mg.

Additive Treatment with Candesartan Has a Positive Impact on Congestive Heart Failure

In a study published in 2013, the effect of adding 8 or 16 mg of candesartan as adjunctive therapy to the existing treatment of patients with NYHA class III–IV congestive heart failure was examined. The efficacy of treatment, in connection with the addition of candesartan, slightly improved over the 24-week observation period, with statistically significant differences compared to the control group taking placebo. Changes were observed in resting right atrial pressure, wedge pressure, and systemic vascular resistance during maximum physical exertion.

Another study demonstrated that adding candesartan to treatment reduced the number of recurrent hospitalizations due to heart failure by up to 17% and significantly reduced cardiovascular mortality.

Results from another study showed that concomitant treatment with candesartan and enalapril in patients with chronic heart failure more effectively prevented left ventricular remodeling and enlargement, led to a greater reduction in blood pressure, and resulted in a more significant increase in ejection fraction compared to individual monotherapies.

Side Effects are a Limitation of Combination Therapy with ACEi and Sartans

Despite the aforementioned positives, a meta-analysis showed that the combination of ACE inhibitors and sartans is associated with an increased incidence of side effects, particularly hyperkalemia, symptomatic hypotension, and worsening renal function with a significant rise in creatinine in patients with heart failure.

Concurrent Administration of ACEi and Sartans Reserved for Cases of Intolerance to Primarily Recommended Combinations

According to current recommendations, it is advised to add a mineralocorticoid receptor antagonist (spironolactone, eplerenone) to the combination of ACEi and beta-blocker for symptomatic patients with heart failure (NYHA II−IV). Sartans are reserved for cases of ACEi intolerance in patients with heart failure with a left ventricular ejection fraction of ≤ 40%, where they are administered in combination with a beta-blocker and a mineralocorticoid receptor antagonist, or they are used in combination with ACEi and a beta­-blocker in case of intolerance to the mineralocorticoid receptor antagonist.

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Sources:
1. Václavík J. Combination of ACE inhibitors and sartans –  when is it recommended? Cardiological Review − Internal Medicine 2014; 16 (6): 481−484.
2. Gasanin E., Dragutović I., Banković D., Mitrović V. Effects of combination of AT1-antagonist candesartan cilexetil and ACE-inhibitors in patients with congestive heart failure. Srp Arh Celok Lek 2013; 141 (1−2): 29−34.
3. Cífková R. Innovations in the treatment of resistant hypertension. Chapters from Cardiology for General Practitioners 2019; 11 (1): 17−20.