INTRODUCTION — Asymptomatic patients with chronic aortic regurgitation (AR, also called aortic insufficiency) are generally managed in a conservative fashion and surgery is postponed until the patient develops symptoms, left ventricular (LV) systolic dysfunction, and/or severe LV dilatation. (See "Natural history and management of chronic aortic regurgitation in adults".)

Vasodilator therapy in patients with severe chronic AR is aimed at reducing the hemodynamic burden by reducing regurgitant volume. However, the efficacy of vasodilator therapy has not been established in asymptomatic AR as a means of mitigating changes in LV size and function and delaying the onset of symptoms and thus the need for corrective surgery.

The role of vasodilator therapy in chronic severe AR in adults will be reviewed here. Issues related to the pathophysiology, clinical features, and course and management of chronic AR and to acute AR are discussed separately. (See "Clinical manifestations and diagnosis of chronic aortic regurgitation in adults" and "Natural history and management of chronic aortic regurgitation in adults" and "Acute aortic regurgitation in adults".)

DETERMINANTS OF PROGNOSIS — Among asymptomatic patients with chronic AR and normal LV systolic function (ie, normal left ventricular ejection fraction [LVEF]), the likelihood of progressing to symptoms and/or LV dysfunction ranges from 0 to 19 percent per year according to the absence or presence of LV dysfunction and/or enlargement as determined in part from the LV end-systolic dimension (table 1) [1,2]. Values above 55-60 mm are considered to reflect a decompensated state (table 2) [1].

As will be described below, vasodilator therapy should be considered only in patients with severe chronic AR and LV dilation [1]. There is no evidence of benefit in patients with mild to moderate AR.

On physical examination, severe AR is characterized by a longer diastolic murmur, a displaced LV impulse, a wide pulse pressure, and the peripheral findings of a wide pulse pressure such as a water hammer (Corrigan's) pulse and other signs such as a head bob occurring with each heart beat (de Musset's sign). (See "Clinical manifestations and diagnosis of chronic aortic regurgitation in adults", section on 'Physical examination' and "Examination of the arterial pulse", section on 'Water hammer pulse'.)

However, the accuracy of physical examination is not reliable and a hemodynamic definition, usually by echocardiography, is the recommended method for determining the severity of AR. (See "Echocardiographic evaluation of the aortic valve", section on 'Aortic regurgitation'.)

For clinical purposes, the importance of defining severe chronic AR in asymptomatic patients is to identify those who might be candidates for more frequent monitoring. Almost all patients with chronic severe AR have or will develop LV dilation. Only severe AR is likely to produce LV dilation. Thus, one should look for other causes, such as a cardiomyopathy, when LV dilation is present in patients with mild to moderate AR.

DETERMINANTS OF REGURGITANT VOLUME — The regurgitant volume in aortic regurgitation is determined by two factors [3]:

●The magnitude and duration of the diastolic pressure gradient across the valve.

●The effective regurgitant orifice area. It has been assumed that the regurgitant orifice area is constant, but this notion may not be valid in patients with disease of the aortic root.

In contrast, the LV ejection fraction, systemic vascular resistance, systolic blood pressure, and ventricular afterload are not direct determinants of the regurgitant volume.

The duration of diastole is primarily a function of heart rate; as a result, bradycardia will increase AR flow [4,5]. Although pacing-induced tachycardia offers little benefit to patients with chronic AR, clinicians should be aware of the potential danger of bradycardia.

The other major determinant of regurgitant volume is the transvalvular pressure gradient throughout diastole. This provides a rationale for treating hypertension and reducing the aortic diastolic pressure in patients with AR.

CLINICAL TRIALS AND STUDIES — Small clinical trials have provided some evidence of benefit from vasodilators in asymptomatic patients with chronic severe aortic regurgitation and LV dilation, since these are the patients at risk for progression (table 1) [1]. However, some studies have found no benefit.

Nifedipine — The effect of long-term nifedipine therapy was studied in an initial randomized, double blind, placebo-controlled trial of 72 asymptomatic patients in Italy with chronic severe AR [6]. After 12 months, nifedipine (20 mg twice daily), reduced the systolic pressure and LV volume, and increased the ejection fraction. The only change in the placebo group was a small decrease in the ejection fraction. All study patients remained asymptomatic and none required surgery during the follow-up period.

In a subsequent report, the same investigators followed the course of 143 asymptomatic patients with isolated severe AR (mean blood pressure 152/59 mmHg) and normal LV function (mean LVEF 63 percent) who were randomly assigned to receive either nifedipine (20 mg twice daily) or digoxin (0.25 mg/day); the trial was not blinded [7]. The following benefits were noted in the nifedipine group:

●In the first year, valve replacement was not required in any patient treated with nifedipine compared with approximately 6 percent of those treated with digoxin.

●After six years, as determined by actuarial analysis, valve replacement was required significantly less often in the patients treated with nifedipine (15 versus 34 percent) (figure 1). The patients who underwent valve replacement, independent of which drug was used, had a fall in LVEF from 62 percent at baseline to 46 percent before surgery.

Because of the design of this study, one cannot distinguish between a beneficial effect of nifedipine and a deleterious effect of digoxin. In addition, it is possible that the nonblinded nature affected the results.

Outcome after AVR — Further evidence supporting benefit from nifedipine therapy comes from a third study from the same group showing evidence of improved outcomes after surgery in those patients who progress and require aortic valve replacement (AVR) [8]. 266 patients in randomized trials of nifedipine versus placebo in asymptomatic patients with a normal LVEF progressed to left ventricular dysfunction and underwent AVR. The following were main findings:

●The mean duration of therapy before surgery was much longer with nifedipine (16 versus 3 years with placebo), again showing slowed progression.

●Although the two surgical groups were hemodynamically similar at baseline, the LVEF normalized in all patients who had received nifedipine, but remained low in 28 percent of those who had not.

●At 10 year follow-up, the LVEF (62 versus 48 percent) and patient survival (85 versus 78 percent) were significantly higher in the nifedipine group.

The mechanism(s) by which nifedipine therapy before surgery might improve long-term outcomes after surgery are not known.

ACE inhibitors — Small randomized trials and studies of angiotensin converting enzyme (ACE) inhibitors in patients with chronic AR have shown inconsistent evidence of benefit as illustrated by the following studies [9-12]:

●In one trial, 76 patients with asymptomatic AR were randomly assigned to treatment with enalapril or hydralazine [9]. After one year, a decrease in arterial pressure was seen in both groups. The patients receiving enalapril (31 mg/day) showed a decrease in ventricular chamber size, whereas there was no significant change in those treated with hydralazine (177 mg/day).

●These positive findings were not confirmed in a randomized trial comparing captopril (25 mg three times daily for six months) with placebo in 23 patients with isolated severe AR [11]. There was no change in either arterial pressure or ventricular chamber size in the patients treated with captopril.

●As described below, no benefit was seen from enalapril therapy in a long-term randomized trial [13].

However, an observational study of 2,266 patients with at least moderate AR found an association between treatment with ACE inhibitors or angiotensin II receptor blocker (ARB) therapy and reduced all-cause mortality, fewer cardiovascular events, and fewer AR events (heart failure hospitalization, heart failure death, or AVR) at mean 4.4 year follow-up [12]. While this result suggests a potential role for ACE inhibitor or ARB therapy in patients with AR, the mechanism of benefit was not addressed. Randomized, prospective, controlled clinical trials are needed to determine if ACE inhibitor treatment might be beneficial in adults with chronic aortic regurgitation.

Hydralazine — Two trials evaluated the efficacy of hydralazine in chronic AR. In one, 45 largely asymptomatic patients were randomly assigned to hydralazine or placebo [14]. Hydralazine, at an average dose of 215 mg/day, did not affect blood pressure or heart rate. At 24 months, hydralazine therapy was associated with a significant decrease in ventricular volume and increase in LVEF.

In contrast, no evidence of improvement in left ventricular size or function was noted at 12 months in the second trial (cited above) in which hydralazine (average dose 177 mg/day) was compared with enalapril [9]. There is no obvious reason for these disparate results, except perhaps that the dose of hydralazine and the duration of treatment differed in the two studies.

Comparative trial — In an attempt to more clearly define the role of vasodilators, 95 consecutive patients with asymptomatic severe chronic AR (mean blood pressure 144/76 mmHg) and an LVEF ≥50 percent were randomly assigned to open-label therapy with nifedipine (20 mg twice daily), enalapril (20 mg/day), or no therapy [13]. Patients with other valve disease, hypertension, atrial fibrillation, coronary disease, Marfan syndrome, or an ascending aortic aneurysm were excluded. Predefined criteria for AVR were the onset of symptoms and/or an LVEF <50 percent or an end-systolic dimension ≥50 mm that were confirmed by a second examination.

At a mean follow-up of seven years, there was no significant difference in the three groups in the rate of AVR (41 percent with nifedipine, 50 percent with enalapril, and 39 percent in the control group), or in LVEF, left ventricular size or mass, or the regurgitant volume. At one year after AVR, all patients had a normal LVEF and the left ventricular end-systolic and end-diastolic diameters had fallen to a similar degree in the three treatment groups.

Possible explanations for conflicting data — Why the comparative trial did not replicate the beneficial effects of nifedipine in the Italian studies cited above, including the persistence of benefit from preoperative therapy after AVR [6-8], is not clear (see 'Nifedipine' above). The following explanations have been proposed [15]:

●The mechanism of benefit in the randomized Italian trial is uncertain, since nifedipine did not reduce the left ventricular end-systolic volume or increase the ejection fraction [7]. Furthermore, the control group in this trial was treated with digoxin, not placebo.

●The doses used may have been too low in the comparative trial, since there was no effect on blood pressure or regurgitant severity in either of the treatment groups [13]. However, the nifedipine dose was the same as used in the Italian trials (20 mg twice daily).

●The patients in the comparative trial may have had less severe disease as suggested by a much lower pulse pressure (68 versus 93 mmHg).

●The comparative trial may have been underpowered to detect a benefit.

Clinical trial and study summary — Vasodilators have the potential to reduce the hemodynamic burden on the volume-loaded left ventricle in severe AR. However, randomized trials of nifedipine and ACE inhibitors have produced conflicting findings as to whether there is [6,7,9] or is not [13] a benefit from vasodilator therapy. Although less well studied, data are also conflicting about the efficacy of hydralazine therapy [9,14].

THERAPEUTIC DECISIONS

Major society guidelines — The 2006 ACC/AHA valvular guidelines (with 2008 focused update) include the following recommendations for vasodilator therapy for AR [1]:

●Vasodilator therapy is indicated for patients with severe AR with symptoms or LV dysfunction when surgery is not recommended because of additional cardiac or noncardiac factors.

●Vasodilator therapy is reasonable for short-term therapy to improve the hemodynamic profile of patients with AR with severe heart failure symptoms and severe LV dysfunction before proceeding with AVR.

●Effectiveness is not well established for long-term vasodilator therapy in asymptomatic patients with severe AR and LV dilatation with normal systolic function.

●Vasodilator therapy is not indicated for long-term therapy in asymptomatic patients with mild to moderate AR and normal LV systolic function.

●Vasodilator therapy is not indicated for long-term therapy in potential candidates for AVR including asymptomatic patients with LV systolic dysfunction and symptomatic patients with either normal LV function or mildly to moderately depressed LV systolic function; instead, these patients should be referred for valve replacement.

The 2007 by the European Society of Cardiology (ESC) valvular guidelines include the following conclusions regarding vasodilator therapy for chronic AR [2]:

●In patients with chronic severe AR and heart failure, angiotensin converting enzyme (ACE) inhibitors are the treatment of choice when surgery is contraindicated or in cases with persistent postoperative LV dysfunction.

●In asymptomatic patients with AR with high blood pressure, treatment of hypertension with ACE inhibitors or dihydropyridine calcium channel blockers is warranted.

●The notion that vasodilators can delay surgery in asymptomatic nonhypertensive patients with AR is unproven.

Our approach — We agree with the above ACC/AHA valvular guideline recommendations. In addition, we suggest long-term vasodilator therapy in asymptomatic patients with hypertension and any degree of AR as recommended in the ESC guidelines. This includes the systolic hypertension associated with severe chronic AR, which can increase systolic wall stress and reduce forward stroke volume [16]. However, as noted in the comparative trial, it is often difficult to substantially lower the systolic pressure with vasodilators in patients with severe AR [13].

Choice of drug — If a vasodilator is indicated, the optimal drug remains uncertain. The ACC/AHA and European Society of Cardiology guidelines do not specify a vasodilator choice for asymptomatic AR [1,2]. However, the benefits of ACE inhibitors in patients with other causes of asymptomatic or symptomatic ventricular dilation suggest that these agents may also be of greater value in patients with AR.

As a result, many cardiologists use ACE inhibitors rather than nifedipine when vasodilator therapy is given. Treatment is started at a low dose and titrated to the typical dose used for heart failure, as tolerated by blood pressure.

Other antihypertensive drugs — The role of other antihypertensive drugs for blood pressure control in patients with chronic AR treated with an ACE inhibitor or nifedipine is not well studied. Once a patient is on maximal ACE inhibitor therapy, we would add other antihypertensive drugs only for a diastolic pressure over 90 mmHg, which would be rare in severe AR, and possibly for a systolic pressure over 160 mmHg. However, a high systolic pressure is common in severe AR and is often difficult to reduce.

If further antihypertensive drug therapy is given, we suggest avoiding beta blockers. By slowing the heart rate, beta blockers prolong diastole, thereby increasing the diastolic regurgitant time and the regurgitant volume per beat.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease".)

SUMMARY AND RECOMMENDATIONS — Asymptomatic patients with chronic aortic regurgitation (AR, also called aortic insufficiency) are generally managed in a conservative fashion unless they develop an indication for aortic valve replacement (AVR; usually symptoms or LV dysfunction). Conservative therapy includes periodic monitoring for progressive disease that would fulfill criteria for surgery. (See "Natural history and management of chronic aortic regurgitation in adults".)

Randomized trials have produced conflicting findings as to whether there is or is not a benefit from vasodilator therapy. (See 'Clinical trials and studies' above.)

Recognizing the limitations of the data, we treat as follows. (See 'Therapeutic decisions' above.)

●We suggest long-term vasodilator therapy in asymptomatic patients with hypertension and any degree of AR (Grade 2C). This includes the systolic hypertension associated with severe chronic AR, which can increase wall stress [16]. However, it is often difficult to lower the blood pressure with vasodilators in patients with severe AR [13].

●We recommend against long-term vasodilator therapy in patients who are not at risk for progression including those with mild to moderate AR and those with what appears to be severe AR without LV enlargement (table 1) (Grade 1B). (See 'Determinants of prognosis' above.)

●If a vasodilator is given, we suggest an angiotensin converting enzyme (ACE) inhibitor in preference to nifedipine (Grade 2B). Treatment is started at a low dose and titrated to the typical dose used for heart failure, as tolerated by blood pressure. Nifedipine is an acceptable alternative to an ACE inhibitor.

●Whether or not vasodilators are used, it is imperative to follow the patient closely in order to detect the earliest symptoms or exercise intolerance, and to perform serial studies of LV size and function. The development of symptoms and/or LV systolic dysfunction are indications for AVR or aortic valve repair (figure 2 and table 3). (See "Natural history and management of chronic aortic regurgitation in adults".)

●We recommend vasodilator therapy for patients with severe AR with symptoms and/or LV dysfunction when surgery is not recommended because of additional cardiac issues or noncardiac comorbidities (Grade 1B).

●We suggest vasodilator therapy as short-term therapy for patients with AR with severe heart failure and LV dysfunction before proceeding with AVR (Grade 2B).