Why are acei contraindicated in aortic stenosis

Despite that animal models suggested cardioprotective effects of RASi more than 20 years ago, RCT have been historically sparse. The recent study by Dalsgaard et al. The hypothesis was further tested by Bull et al. Among symptomatic patients, Chockalingam et al. Patients with preserved left ventricular ejection fraction who received enalapril reported improved symptoms i. In addition to the putative protective effects of RASi on left ventricular remodelling and function, research has suggested that the angiotensin-converting enzyme is present in sclerotic and stenotic lesions of the aortic valve possibly delivered by low-density lipoprotein particles , but not in normal valves, 27 and that use of RASi may attenuate the progression of aortic valve calcification.

Our analyses were based on published studies only. A search at clinicaltrials. The echocardiographic measures of the various studies were collected based on local institutional protocols and were not harmonized for this study, which may have affected our results. Within this context, most of the studies also only included patients without systolic dysfunction or very few patients with systolic dysfunction and extrapolation of the findings to patients with impairments in systolic function can therefore not be done.

Also, some patients with aortic stenosis may have had concomitant aortic insufficiency, which may or may not have contributed to the improvements observed with RASi treatment. Moreover, the randomized clinical trials were too small and of too short follow-up to separately perform meaningful meta-analyses of hard endpoints.

Finally, we did not investigate whether RASi may or may not also have influenced the risk of atherosclerotic events. Based on published literature, RASi appear to be safe to use and perhaps effective in reducing need of AVR surgery in patients with AVS and a preserved left ventricular ejection fraction. Thus, current evidence does not support that AVS should be regarded a contraindication for continuation of RASi in patients already in treatment for other important indications such as hypertension or heart failure.

These questions are of clinical importance, given the burden of AVS in the Western world, and should hence be a research priority. Otto CM Prendergast B. Aortic-valve stenosis—from patients at risk to severe valve obstruction. N Engl J Med ; : — Google Scholar. Carotid plaque, intima-media thickness, and incident aortic stenosis: a prospective cohort study. Arterioscler Thromb Vasc Biol ; 34 : — Temporal trends in the incidence and prognosis of aortic stenosis: a nationwide study of the Swedish population.

Circulation ; : — Left ventricular hypertrophy in aortic valve stenosis: preventive or promotive of systolic dysfunction and heart failure? Eur Heart J ; 26 : — Guidelines on the management of valvular heart disease version Eur Heart J ; 33 : — Aortic stenosis. Lancet ; : — Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies.

O'Brien KD. Pathogenesis of calcific aortic valve disease: a disease process comes of age and a good deal more. Arterioscler Thromb Vasc Biol ; 26 : — Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. Syst Rev ; 4. Impact of hypertension and renin-angiotensin system inhibitors in aortic stenosis. Eur J Clin Invest ; 43 : — Eur Heart J Cardiovasc Imaging ; 16 : — Safety and efficacy of angiotensin-converting enzyme inhibitors in symptomatic severe aortic stenosis: symptomatic cardiac obstruction-pilot study of enalapril in aortic stenosis SCOPE-AS.

Accordingly, recent clinical practice guidelines recommend that hypertension be treated in patients with AS. Systemic hypertension aggravates the total LV pressure overload that is already at a tipping point in patients with severe aortic stenosis.

As such, antihypertensive treatment is needed to reduce the LV pressure overload. Antihypertensive treatment with severe AS patients should be started at low doses with careful titration. It should also be emphasized that hypertension can interfere with the accurate assessment of AS severity and that valve and LV hemodynamics should be re-evaluated after optimal blood pressure control in hypertensive patients with severe AS.

The main objectives of this review are to briefly review how hypertension adversely affect the progression of AS and review the current evidence regarding the potential benefits of antihypertensive treatment both before and after aortic valve replacement AVR. Despite the knowledge that hypertension is an important medical problem that requires effective treatment to reduce cardiovascular morbidity and mortality, there has been reluctance to treat hypertension in patients with severe AS.

Also, there was a concern that the possibility of diastolic hypotension and the subsequent reduction in coronary blood flow will have deleterious effects, especially when considering that many of these patients are predisposed to increased risk of myocardial ischemia under conditions of increased myocardial oxygen demand. Hypertension, by increasing the afterload, accelerates the progression of AS and LV hypertrophy and has been shown to be an independent predictor for adverse cardiovascular outcomes.

Future clinical trials to establish the ideal target BP in AS is needed. Recent clinical studies are indeed showing that use of RAS inhibition may have clinical benefit in patients with severe AS. In a retrospective analysis of patients who underwent 2 serial electron beam computed tomographic scans, the use of angiotensin converting enzyme ACE inhibitors, compared to non ACE inhibitor group, was associated with significant lower rate of aortic valve calcium accumulation.

In fact, RAS inhibition was associated with a potentially beneficial effect in blood pressure and reduction in LV mass progression.

This study demonstrated that enalapril was associated with improvement of the functional class and 6-minute walking distance after 4 and 12 weeks of follow-up. They revealed that the ACE inhibitor group showed significant decreased SBP and increased systemic arterial compliance. Ramipril also had trend to slow the progression of AVA decrease 0.

Theoretically, as non ACE pathway such as chymase activation are increased in the aortic valves and angiotensin II type 1 receptors are increased in the aortic valves, ARBs may have benefit comparable to ACE inhibitors in patients with AS with a retrospective study suggesting that ARBs are more effective than ACE inhibitors at reducing aortic valve calcium and LV remodeling.

Although we will need evidence from larger, randomized outcome studies, recent data suggests the benefit of RAS inhibitors, especially ACE inhibitors in patients with AS. Therefore, ACE inhibitors are likely the preferred agents for treating hypertension with careful titration and dosage to avoid hypotension Figure 1. In a study by Hansson et al. In AS that are associated with significant aortic regurgitation AR , the use of beta blockers, by increasing the diastolic filling period, potentially increase the severity of the valve regurgitation.

On the contrary, in a double blind, randomized study in 75 asymptomatic patients with moderate to severe AR, treatment with controlled release metoprolol for 6 months had no significant effect on LV volumes. The above mentioned results suggest that beta blockers may have beneficial hemodynamic effects in AS and may be improve the clinical outcome in patients with severe AS. However, the results should be confirmed in future prospective, randomized trials.

Vasodilator therapy is a cornerstone in the management of patients with LV dysfunction. However, vasodilators were traditionally contraindicated in patients with severe AS due to concerns that they may precipitate life-threatening hypotension. However, recent studies have demonstrated the beneficial effects of vasodilatation and afterload reduction in patients with severe AS with heart failure.

At baseline, the mean SD ejection fraction was 0. After 24 hours of nitroprusside infusion, the cardiac index increased to 2. This study demonstrated that nitroprusside rapidly and markedly improves cardiac function in patients with decompensated heart failure due to severe LV systolic dysfunction and AS and indicates that afterload reduction with arterial vasodilation may improve the hemodynamics of severe AS with reduced ejection fraction with minimal side effects.

However, the beneficial effect of after load reduction with RAS inhibitors for a longer duration in severe AS with reduced ejection fraction needs to be confirmed in future clinical trials. More recently, Eleid et al. Nitroprusside infusion was associated with improvement in mean pulmonary artery pressure and LV end diastolic pressure while increasing the aortic valve area and mean pressure gradient.

Hypertension is frequently associated with low gradient severe AS and may be a factor to overestimate the severity of the degree of AS. Therefore, in asymptomatic low pressure gradient severe AS patients with associated hypertension, initial treatment of hypertension may result in down classification of the severity of the aortic stenosis and allow for medical treatment in some of these patients.

This dataset from Nadir and colleagues is intriguing because they did not study the severity of the valve disease, but instead chose to study clinical events in AS patients. The mechanism of the benefit is not immediately clear. It may relate to protection against myocardial fibrosis and hypertrophy, which are arrhythmogenic substrates.

Alternatively, it may reduce vascular events, such as myocardial infarction. It is important to recognize that there were significant differences in baseline characteristics between groups. The authors performed several different statistical analyses that all demonstrated similar findings, which increases the confidence in their results. Despite this rigorous statistical methodology, there are likely to be confounding factors for which their analyses could not account.

Therefore, it is important to interpret the data cautiously. I think it is too soon to make such recommendations. However, if another indication for such a therapy exists, such as concomitant hypertension, then ACEIs or ARBs would be a reasonable choice for an antihypertensive. The guidelines only mention and justify the use of ACE-Inhibitors in patients with significant aortic stenosis who have depressed left ventricular function and who are not candidates for aortic valve surgery 4 — with no mention being made of patients with normal left ventricular function and those who are potential candidates for surgery.

Although not designed to assess the safety of ACE-Inhibitor use in patients with aortic stenosis, the findings of a retrospective study indicate that a significant number of patients with aortic stenosis seen in daily clinical practice receive treatment with ACE-Inhibitors because of concomitant arterial hypertension of patients 5. There are also data suggesting that their use may be safe in aortic stenosis.

In the SCOPE-AS trial, symptomatic patients with severe aortic stenosis and normal left ventricular function who were no candidates for surgery, were randomized to treatment with enalapril or placebo7. ACE-inhibitors were well tolerated in these patients, however patients, having reduced left ventricular functions, were prone to develop hypotension. Finally, Jimenez-Candil and colleagues designed an elegant drug withdrawal study. Both the withdrawal and the careful reintroduction of the drug were well tolerated.

While taking the ACE-Inhibitor, patients had a lower blood pressure, higher transvalvular gradients but kept an unchanged exercise capacity and symptomatic status. These data suggest that there might be a role for ACE-Inhibitors therapy in patients with aortic stenosis in the future. Nevertheless, prospective, randomized trials are required before initiating ACE-Inhibitor therapy can generally be recommended in these patients. In the frequent cases of clinically stable patient with aortic stenosis already receiving an ACE-Inhibitor, it might be preferable not to discontinue the treatment.

However it has to be considered that with an increasing severity of AS, reducing the dosage of ACE-Inhibitors might be necessary, since hypertension may become less accentuated and even hypotension may develop as a result of further narrowing of the aortic valve. In contrast to aortic stenosis, the use of an ACE-Inhibitor in aortic regurgitation is definitely not harmful.

The rationale for prescribing vasodilator therapy in patients with chronic aortic regurgitation is that vasodilation leads to a reduction in the peripheral resistance, in the regurgitant volume, thus increasing the effective stroke volume. But are these hemodynamic effects translated into an improved outcome? Sconamiglio and colleagues have reported that patients with chronic aortic regurgitation who were randomized to a vasodilator treatment with nifedipine were less likely to require valve replacement within the following years than patients who were randomized to digitalis therapy 9.

However, recently, Evangelista and colleagues have observed no significant differences in outcomes between patients with severe aortic regurgitation randomized to placebo, nifedipine or ACE-inhibitors 9, While the two studies are limited by their relatively small size, it is very unlikely that larger studies giving a definite answer will be performed in the near future.

In the meantime, it is certainly neither an obligation nor a mistake to initiate vasodilator therapy in patients with significant aortic regurgitation.