What are the risks of ACE?

Angiotensin-converting enzyme (ACE) inhibitors are often underadministered because of fear of hypotension. Although first-dose hypotension is more likely in patients with high plasma angiotensin II levels (renal artery stenosis, malignant hypertension with low sodium and potassium, severe heart failure treated with high-dose diuretics), it is often unpredictable. In unstable patients, the risk can be minimized by using a drug with a short half-life such as captopril, or one with a smoother first-dose effect, such as perindopril, trandolapril, or quinapril. If hypotension does occur, it can be managed by increasing the intravascular volume.

Since angiotensin II helps to maintain glomerular filtration pressure, ACE inhibitors may impair renal function, causing elevation of the serum creatinine (reflecting the decrease in glomerular filtration rate). However, this is reversible. A serum creatinine >3.5 mg/dL contraindicates the initiation or continuation of ACE inhibition. In such cases, it is important to adjust the doses of other drugs interfering with renal function or depending on renal metabolism, notably aspirin and other nonsteroidal anti-inflammatory drugs, and digoxin.

Inhibitors in heart failure?

Hyperkalemia is a potential side effect of ACE inhibitor therapy. Concomitant potassium-sparing diuretics should be used with caution, at decreased doses or temporarily withdrawn, as appropriate.

Cough is an unpleasant and common side effect with effects on quality of life that can justify ACE-inhibitor withdrawal. However, it is first mandatory to exclude cough as a symptom of incipient cardiac decompensation or pulmonary disease.

Cough may occur in the first weeks or months of ACE-inhibitor therapy. Although unclear, the mechanism is presumed due to decreased bradykinin breakdown. Risk is not increased by underlying structural lung disease or asthma, neither of which contraindicate ACE-inhibitor therapy. A cardiac origin, reflecting worsening heart failure, must be excluded in any complaint of cough, and therapy withdrawn if the cough is persistent and impairs quality of life. Switching to a different ACE inhibitor is rarely effective. Downtitration or treatment withdrawal usually suffices, but the most effective option is to switch to an angiotensin II receptor blocker.

Should angiotensin II type 1 receptor blockers be combined with ACE inhibitors and/or p-blockers?

In recent years, P-blockers and angiotensin-converting enzyme (ACE) inhibitors have become the drugs of choice for treating heart failure. After adequate dose titration, inhibition of the P-adrenergic system improves morbidity and mortality. Similarly, ACE inhibition improves prognosis, in particular in heart failure due to postischemic cardiomyopathy. To what extent can these drugs be combined with angiotensin II type 1 receptor (ATj) blockers (ARBs)?

Combining ARBs with ACE inhibitors

The benefits of ACE inhibitors are due to the inhibition not only of ACE, but also of kininase- mediated bradykinin degradation. This results in the persistent bradykinin-mediated release of nitric oxide. But because there are non-ACE enzyme pathways for converting angiotensin I to angiotensin II, the negative effects of angiotensin II mediated by ATj (cellular hypertrophy, peripheral vasoconstriction) may persist over time, despite ACE inhibition. These mechanisms form the rationale for combining ARBs with ACE inhibitors with the aim of securing major survival and morbidity benefits in heart failure.

The large, multicenter, randomized, controlled Valsartan Heart Failure Trial (Val-HeFT) evaluated the prognostic benefit of valsartan, an ARB, in heart failure. The patients, who had been stabilized on optimized medical therapy, including ACE inhibitors in 93% of cases, were randomized to valsartan $160 mg twice daily or placebo and followed for over 2 years, until the 906th death occurred. Data analysis showed that the combination of the two classes conferred:

‚ No advantage in overall mortality over ACE inhibition alone.

‚ Decreased mortality and morbidity (combined end point).

‚ Decreased incidence of signs and symptoms of heart failure and, by extension, a significant reduction in hospitalizations for exacerbated heart failure.

Combining ARBs with p-blockers

P-Blockers are effective in heart failure because of the associated increase in adrenergic tone, which hastens disease progression via mechanisms such as tachycardia and increased systemic vascular resistance (increased cardiac workload), resulting in eventual multiorgan failure. Blocking these detrimental effects, particularly in the heart, has major benefits. The 2001 Task Force Report proposes the use of ARBs when ACE inhibitors are contraindicated or not tolerated, hence introducing the possibility of combining ARBs with P-blockers. Does this combination offer the same degree of protection, tolerability and safety profile as that between an ACE inhibitor and P-blocker?

The multicenter, randomized, controlled Losartan Heart Failure Survival Study (ELITE II), comparing survival and tolerability between losartan and captopril in elderly heart failure patients, found that survival in the subgroup taking P-blockers at randomization was better in those started on captopril than in those started on losartan. However, Val-HeFT did not confirm these results, finding no difference in the combined end point of mortality and morbidity between the two subgroups: both had a combined risk of undergoing an event within 2 years of around 20%, the lowest combined risk for any therapeutic combination.

These results suggest that ARBs can be combined with (3-blockers when ACE inhibitors are contraindicated or not tolerated. Patients should be closely supervised during the initial months to determine whether the combination is appropriate in their case.

Combining ARBs with both ACE inhibitors and P-blockers

Few data are available on the effect of triple therapy in heart failure, leaving aside the feasibility and demands on patient compliance of such a schedule in daily practice. The Val-HeFT data indicate that triple therapy has no additional benefit in terms of combined mortality and morbidity over other combinations, despite theoretical considerations in its favor. Until this result is reversed or elucidated by other studies (such as the Candesartan in Heart failure-Assessment of Reduction in Morbidity and mortality [CHARM] trial), triple therapy in heart failure is not recommended (Table, Figure).

Combination with ACE inhibitors improves heart failure and decreases hospitalization for exacerbated heart failure

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