Evidence-based Cardiology – part 9 pptx

stenosis; these patients should be considered as having severe stenosis. Since gradients are frequently measured ini- tially by Doppler ultrasound, a suggested conservative guideline for relating Doppler ultrasound gradient to severity of aortic stenosis (AS) in adults with normal cardiac output and normal average heart rate is shown in Table 53.3. A suggested grading of the degree of aortic stenosis is given in Table 53.4. Natural history The duration of the asymptomatic period after the development of severe aortic stenosis is uncertain. In a study of asymptomatic patients with varying degrees of severity of aortic stenosis, 21% of 143 patients 18 with a mean age of 72 years required valve replacement within 3 months of evalu- ation at a referral center. At 2 years the mortality was 10% and the event rate (death/valve replacement) in the remaining patients was 26%. Moreover, it is important to recognize that most patients in this study had only moderate aortic stenosis. In another study of 123 asymptomatic adults, 7 also with varying grades of severity of aortic stenosis aged 63Ϯ16 years, only the actuarial probability of death or aortic valve surgery is provided. It was 7Ϯ5% at 1 year, 38Ϯ8% at 3 years and 74Ϯ10% at 5 years. The event rate at 2 years for aortic jet velocity by Doppler ultrasound of Ͼ4·0 m/s (peak gradient by Doppler ultrasound Ͼ64 mmHg) was 79Ϯ18%, for a velocity of 3·0–4·0m/s (peak gradient 36–64mmHg) was 66Ϯ13%, and for a velocity of Ͻ3·0m/s (peak gradient of Ͻ36mmHg) was 16Ϯ16%. 7 Aortic jet velocity is influenced by the same parameters as aortic valve gradient (see above). Thus, the duration of the asymptomatic period, particularly in those aged Ն60 years, is probably very short. 19,20 Paul Dudley White in 1951 21 credited the first recorded occurrence of sudden death to T Bonet in 1679. 22 In the past 70 years the reported incidence of sudden death in eight series has ranged from 1 to 21%. Ross and Braunwald, 13 after reviewing seven autopsy series published before 1955, concluded the incidence was 3–5%. The incidence in asymptomatic adult patients has been 33% (one in three) 23 and 30% (three of ten). 14 This information is difficult to use in clinical decision making because important data are not available – that is, the incidence by actuarial analysis of sudden death in a significant number of asymptomatic patients with severe stenosis. It is reasonable to con- clude that the true incidence of sudden death in adults with severe aortic valve stenosis is unknown and that sudden death usually occurs after the onset of symptoms, however minor or minimal the symptoms may be. The incidence of sudden death is believed to be higher in children. The development of symptoms of angina, syncope, or heart failure, changes the prognosis of the patient with aortic valve stenosis. Average survival after the onset of symptoms is Ͻ2–3 years. Nearly 80% of asymptomatic patients with peak aortic valve velocity measured by Doppler echocardiography Ն4m/s develop symptoms within 3 years, and therefore careful clinical monitoring for the development of symptoms and progressive disease is indicated. Management Patients with valvular heart disease need antibiotic prophylaxis against infective endocarditis; those with rheumatic valves need additional antibiotic prophylaxis against recur- rences of rheumatic fever. 24 Surgery is recommended in those with severe valve stenosis and is the only specific and direct therapy for most adults with severe aortic stenosis. Rarely, in young patients, the aortic valve is suitable for balloon or surgical valvotomy. In most adults, surgery for aortic stenosis means valve replacement. 24,25 The operative mortality of valve replacement is Յ5%. 25–27 In those without associated coronary artery disease, heart failure or other comorbid conditions, it is Յ2% in experienced and skilled centers. 28 Aortic valve replacement in conjunction with coronary artery bypass carries a surgical mortality of about 7%. 27 The operative mortality in those Ն70 years and in octogenarians is much higher, aver- aging 8% for valve replacement and 13% for those undergo- ing valve replacement and associated coronary bypass surgery; 25 however, operative mortality in these patients is also dependent on the associated factors listed above. 29 Grade B Grade A Indications for surgery in aortic valve disease 769 Table 53.3 Doppler ultrasound gradient as an indica- tor of severe aortic stenosis (AS) Peak gradient Mean gradient AS severe Ն80 mmHg Ն70 mmHg High likely 60–79 mmHg 50–69 mmHg Probable Ͻ60 mmHg Ͻ50 mmHg Uncertain From Rahimtoola, 15 with permission Table 53.4 Grading of stenosis by aortic valve area (AVA) Aortic stenosis AVA (cm 2 ) AVA index (cm 2 /m 2 ) Mild Ͼ1·5 Ͼ0·9 Moderate 1·1–1·5 Ͼ0·6–0·9 Severe a Յ1·0 Յ0·6 a Patients with AVAs that are at borderline values between the moderate and severe grades (0·9–1·1 cm 2 ; 0·55– 0·65 cm 2 /m 2 ) should be individually considered. From Rahimtoola 15 with permission Patients with associated coronary artery disease (CAD) should have coronary bypass surgery at the same time as valve replacement, because it results in a lower operative mortality (4·0% v 9·4%) and better 10 year survival (49% v 36%). 28 This was in spite of the fact that those who underwent coronary bypass surgery had more CAD (34% had three vessel disease, 11% had left main artery disease, and 38% had single vessel disease) than those who did not undergo coronary bypass surgery (13% had three vessel disease, 1% had left main disease, and 65% had single vessel disease). 28 Although this approach to CAD is generally approved, there are no randomized trials to support these recommendations. The presence of CAD, its site and severity can be estimated only by selective coronary angiography, which should be performed in all patients 35 years of age or older who are being considered for aortic valve surgery, and in those aged Ͻ35 years if they have left ventricular dysfunction, symptoms or signs suggesting CAD, or they have two or more risk factors for premature CAD (excluding gender). 25 The incidence of associated CAD will vary considerably depending on the prevalence of CAD in the population; 15,24 in general, in per- sons 50 years of age or older it is about 50%. 25 In severe aortic stenosis, valve replacement results in an improvement of survival (Figure 53.1) even if they have normal left ventricular function preoperatively. 14,30 Normal preoperative left ventricular function remains normal postoperatively if perioperative myocardial damage has not occurred. 31 Left ventricular hypertrophy regresses toward normal; 31,32 after 2 years, the regression continues at a slower rate up to 10 years after valve replacement. 32 In patients with excessive preoperative left ventricular hypertrophy, 33 the hypertrophy may regress slowly or not Evidence-based Cardiology 770 (A) (B) 100 % Survival 80 60 40 20 <0·05 125 87 51 35 Years Aortic stenosis 90 19 8 12345 2105 <0·001 P<0·001 χ 2 =23·5 0 P<0·000001 NH 2 20 40 60 Cumulative survival (%) 80 46 810 Time (years) BSA Figure 53.1 There are no prospective randomized trials of aortic valve replacement in severe aortic stenosis (AS), and there are unlikely to be any in the near future. Two studies have compared the results of aortic valve replacement with medical treatment in their own center during the same time period in symptomatic patients with normal left ventricular systolic pump function. (A) Patients who had valve replacement (closed circles) had a much better survival than those treated medically (open circles). (From Schwarz et al 30 with permission.) (B) Patients who were treated with valve replacement (BSA) had a better survival than those treated medically (NH). (From Horstkotte and Loogen 14 with permission.) These differences in survival between those treated medically and surgically are so large that there is a great deal of confidence that aortic valve replacement significantly improves the survival of those with severe aortic stenosis. Grade A at all. Preoperatively, these patients have a small left ventricular cavity, severe increase in wall thickness, and “super- normal” ejection fraction; this occurs in 42% of women and 14% of men in those aged Ն60 years. 33 After valve replacement their clinical picture often resembles that of hyper- trophic cardiomyopathy without outflow obstruction, which is a difficult clinical condition to treat, both in the early postoperative period and after hospital discharge; 33 therefore, surgery should be performed prior to development of excessive hypertrophy. Surviving patients are functionally improved. 25 After valve replacement, the 10 year survival is Ն60% and 15 year survival is about 45%. 25,34 One half or more of the late deaths are not related to the prosthesis but to associated cardiac abnormalities and other comorbid conditions. 34 Thus, the late survival will vary in different subgroups of patients. The older patients (Ն60 years) have a 12 year actuarial survival of Ն60%. 35 Relative survival refers to survival of patients compared to age- and gender-matched people in the population. The relative 10 year survival after surgery is significantly better in those aged Ն65 than in those aged Յ65 years (94% v 81% respectively, Figure 53.2); 36 the 94% relative survival is not significantly different from the 100% relative survival. Thus, surgery should not be denied to those Ն60–65 years old and should be performed early. 25,35–37 Patients who present with heart failure related to aortic valve stenosis should undergo surgery as soon as possible. Medical treatment in hospital prior to surgery is reasonable but ACE inhibitors should be used with great caution in such patients, and in such a dosage that hypotension and significant fall of blood pressure is avoided. They should not be used if the patient is hypotensive. If heart failure does not respond satisfactorily and rapidly to medical therapy, surgery becomes a matter of considerable urgency. 25 Catheter balloon valvuloplasty has a very limited role in adults with calcific aortic stenosis and carries a risk of Ͼ10%. In addition, restenosis and clinical deterioration occur within 6 to 12 months. In adults with aortic stenosis, balloon valvuloplasty is not a substitute for valve replacement but can be a bridge procedure in selected patients. 38 It usually improves patients’ hemodynamics and may make them better candidates for valve replacement. The operative mortality for patients with heart failure has declined: 25 years ago the operative mortality was Ͻ20%, 39 but in the current era it is Յ10%. 40 Although this is higher than in patients without heart failure, the risk is justified, because late survival in those who survive the operation is excellent and is far superior to that which can be expected with medical therapy. The 7 year survival of patients who survive operation is 84%. 41 The 5 year survival in those without associated CAD is greater than in those with CAD (69% v 39%, Pϭ 0·02). 40 Left ventricular function improves in most patients provided there has been no perioperative myocardial damage and becomes normal in two thirds of the patients, unless there was irreversible preoperative myocardial damage (Figure 53.3). 39,40 In addition, the operative survivors are functionally much improved. 39,40 Left ventricular hypertrophy and left ventricular dilation, if present preoperatively, regress toward normal. 39 Despite the excellent results of valve replacement in patients with severe aortic stenosis who are in heart failure, these results are not as good as for those who are not in heart failure; therefore, it is important to recognize that surgery should not be delayed until heart failure develops. Six per cent of older patients with aortic stenosis present in cardiogenic shock. 38 The hospital mortality in such patients is near 50%. The subsequent mortality is also very high if the patients have not had their aortic stenosis relieved. 38 Thus, these patients need to be managed aggressively by emergency surgery with or without catheter balloon valvuloplasty as a “bridge” procedure. 38 Grade B Indications for surgery in aortic valve disease 771 100 90 80 70 60 50 40 0510 Years Post-op Relative survival (%) ASу 65 94% AS<65 81% Figure 53.2 Data from the Karolinska Institute in Sweden has provided an interesting perspective on the long-term survival after valve replacement in patients with aortic stenosis (AS) aged Ն65 years. They have examined the relative survival – compared the survival of the patient who has undergone aortic valve replacement with another age and sex matched person in the same population. Actuarial survival Ϯ95% confidence interval is shown. Patients under the age of 65 had a relative survival of 81% which is significantly lower than 100%, and is also lower than that of those aged Ն65 years. On the other hand, patients who underwent valve replacement at age Ն65 had a relative survival of 94% at the end of 10 years and this was not significantly different from 100%. These data indicate that survival following valve replacement for aortic stenosis in patients aged Ն65 is not significantly different from age- and sex-matched individuals in the population without aortic stenosis; and the late relative survival of patients aged Ն65 years is much better than that of patients aged Ͻ65. (From Lindblom et al 36 with permission.) Boxes 53.1 and 53.2 summarize the results of valve replacement in those with severe aortic stenosis and the factors predictive of a worse postoperative survival, less recov- ery of left ventricular function, and less improvement of symptoms in those with severe aortic stenosis and preoperative left ventricular systolic dysfunction. 15,25,29–32,34–36,39–41 Patients with severe left ventricular dysfunction, low aortic valve gradient, and small calculated aortic valve area repre- sent a difficult patient population. There is controversy regard- ing the best management of these patients, in part related to the difficulty differentiating patients with true severe aortic valve stenosis from patients with moderate aortic valve stenosis and severe left ventricular dysfunction. Differentiating these two patient groups may have an important impact on the management decision and the operative outcome. Thus, patients with low gradient aortic valve stenosis should not be denied aortic valve replacement. A recent series confirms that Evidence-based Cardiology 772 1·0 0·9 0·8 0·7 0·6 0·5 0·4 0·3 0·2 Peri-op MI and late CHB Pre-op Post-op Post-op: Perivalvular aortic incompetence 0·1 Ejection fraction Mean ± SE P<0·001 ejection fraction normalized in two thirds of the patients and, in the two patients with the lowest ejection fraction (0·18 and 0·19), ejection fraction normalized in both. These data indicate that there is probably no lower limit of ejection fraction at which time these patients become inoperable. This also indicates that the lower the ejection fraction, the more urgent the need for valve replacement. (From Smith et al 39 with permission.) Box 53.1 Results of valve replacement in patients with severe aortic valve stenosis ● Improved symptoms and survival in symptomatic patients, especially in those with left ventricular systolic dysfunction, clinical heart failure, and in those aged Յ65 years ● Improvement in left ventricular systolic dysfunction, which normalizes in two thirds of patients ● Regression of left ventricular hypertrophy ● Improvement in functional class, more marked in those with severe symptoms preoperatively Box 53.2 Factors predictive of a less favorable outcome ● Extent and severity of associated comorbid conditions ● Presence and severity of clinical heart failure preoperatively ● Severe associated coronary artery disease ● Severity of depression of preoperative left ventricular ejection fraction ● Duration of preoperative left ventricular systolic dysfunction ● Extent of preoperative irreversible myocardial damage ● Skill and experience of operating and other associated professional teams ● Extent of perioperative myocardial damage ● Complications of a prosthetic heart valve Figure 53.3 Examination of changes in LVEF in each individ- ual patient among those who had left ventricular systolic dysfunction and clinical heart failure. After valve replacement the LVEF improved from 0·34 to 0·63. All but one patient showed an improvement in LVEF; the only patient who showed deterioration in ejection fraction suffered a perioperative myocardial infarction and had a complete heart block; and the only patient who showed only a small increase in ejection fraction had had a myocardial infarct prior to valve replacement. Note that the surgical mortality is high and late survival lower than expected. Importantly however, most survivors experienced improvement in functional class and ejection fraction. 42 A small gradient across the valve may be associated with a small calculated aortic valve area that would be in a range indicating severe aortic stenosis. There are at least two possible causes for this clinical circumstance. First, there is a small or reduced stroke volume and a normal or near normal systolic ejection time; thus, the gradient is small and the calculated aortic valve area correctly indicates severe aortic stenosis. The second consideration is that the stroke volume is reduced, and thus the valve needs to open only to a small extent to allow the left ventricle to eject the small stroke volume. The calculated aortic valve area accurately reflects the extent to which the valve has opened but overestimates the severity of aortic stenosis. Use of a provocative test using an inotropic agent, such as dobutamine, 43,44,45 may allow one to make the correct differentiation between the two. Dobutamine increases systolic flow per second owing to increases in stroke volume or shortening of ejection time or both. In the first circumstance described above, dobutamine will result in an increase in gradient but the calculated valve area remains more or less unchanged. On the other hand, in the second circumstance described above, the gradient may or may not increase with dobutamine but the calculated valve area increases significantly, indicating that the stenosis is not severe. When the dobutamine test is used, it is important to measure cardiac output and simultaneous left ventricular and aortic pressures both before and during dobutamine infusion. Alternatively, the gradient and valve area may be assessed by echocardiography/Doppler during dobutamine infusion; however, one needs to be certain that cardiac output has increased significantly with dobutamine. Surgery should be advised for the symptomatic patient who has severe aortic stenosis. In young patients, if the valve is pliable and mobile, simple balloon valvuloplasty or surgical commissurotomy may be feasible. Older patients and even young patients with calcified, rigid valves will require valve replacement. In view of the dismal natural history of symptomatic patients with severe aortic stenosis, the excellent outcome after surgery, and the uncertain natural history of the asymptomatic patient, it is reasonable to recommend aortic valve replacement in select asymptomatic patients in centers with the appropriate skill and experience. The combined risk of surgery and late complications of a valve prosthesis must be weighed against the risk of sudden death. There is no con- sensus about valve replacement in the truly asymptomatic patient. Clearly, if the patient has left ventricular dysfunction, obstructive CAD or other valve disease that needs surgery, and has severe aortic stenosis, then aortic valve replacement should be performed. Some would recommend valve replacement in all asymptomatic patients with severe aortic stenosis, while others would recommend it in all those with Grade B aortic valve area of Յ0·70cm 2 and in selected patients only with aortic valve area of 0·71–1·0cm 2 . Exercise testing should be avoided in symptomatic patients with aortic stenosis but has been used by some cardiologists to help determine which patients with asymptomatic aortic stenosis should be referred for aortic valve replacement. 19 In a small series, Amato and colleagues reported no serious exercise-related complications. During follow up, 6% of the asymptomatic patients (4/66) experienced sudden death; all had a positive exercise test and an aortic valve area of Յ0·6cm 2 . The exercise test was considered positive if there was a horizontal or down sloping ST segment depression of Ն1mm in men or Ն2mm in women, or an up sloping ST segment depression of Ն3mm in men, measured 0·08 seconds after the J point. The exercise test was also considered positive if precordial chest pain or near syncope occurred, if the ECG showed a complex ventricular arrhythmia, or if systolic blood pressure failed to rise by Ն20mmHg during exercise compared with baseline. It must be emphasized that this is a controversial issue. Some cardiologists advise against exercise testing in any patient with severe aortic valve stenosis, especially when the extent of coronary artery disease is not known. Recommendations: aortic valve replacement/repair in severe aortic stenosis 1 Indication Class ● Symptomatic patients I ● Asymptomatic patients with: ● associated significantly obstructed I CAD needing surgery ● other valve or aortic disease needing I surgery ● left ventricular systolic dysfunction IIa ● aged Ն60–65 years IIa ● abnormal response to exercise IIa ● severe left ventricular hypertrophy IIb (Ն15 mm) ● significant arrhythmias IIb ● left ventricular dysfunction on exercise IIb ● Prevention of sudden death III in asymptomatic patients CAD, coronary artery disease Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective. Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefullness/efficacy of a procedure or treatment. IIa: Weight of evidence or opinion is in favor of usefullness/efficacy. IIb: Usefullness/efficacy is less well established by evidence/opinion. Class III: Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful, and in some cases, may be harmful. Grade B Indications for surgery in aortic valve disease 773 Chronic aortic valve regurgitation Etiology The causes of chronic aortic regurgitation are: 46 ● aortic root/annular dilation ● congenital bicuspid valve ● previous infective endocarditis ● rheumatic ● in association with other diseases. In developed countries, aortic root/annular dilation and congenital bicuspid valve are the commonest causes of severe chronic aortic regurgitation. Natural history During the first world war, Sir Thomas Lewis and his colleagues 47 at Hampstead and Colchester Military Hospitals reported to the Medical Research Council highlighting the inadequacy of the knowledge of heart disease, especially from the standpoint of prognosis. Sir Thomas Lewis pro- posed a system, 48 subsequently called “after histories”, 48 which was a prospective follow up of patients. All patients in RT Grant’s “after histories” 48 had valvular heart disease – most had aortic regurgitation – in which the patient charac- teristics were defined and described in detail, particularly by the degree of cardiac enlargement and the grade of cardiac failure. This probably was the start of databases or registries in cardiovascular medicine. Chronic aortic valve regurgitation is a condition of combined volume and pressure overload. With progression of the disease, compensatory hypertrophy and recruitment of preload reserve permit the left ventricle to maintain a normal ejection performance despite the elevated afterload. The majority of patients remain asymptomatic throughout the compensated phase, which may last decades. The natural history of chronic aortic valve regurgitation can be considered by three different eras: the era of syphilis, the era of rheumatic fever/carditis, and the current era of non- invasive quantification of left ventricular function. Era of syphilis The data are from the 1930s and 1940s, and thus largely prior to availability of antibiotics. 49 The duration from syphilis infec- tion to death was 20 years. The duration of the asymptomatic period after aortic regurgitation was 5 years in 60% of patients; and the 5 year survival was 95%. Once symptoms had developed, the 10 year survival ranged from 40 to 60%. Heart failure was associated with a 1 year survival of 30–50%, and 10 year survival of 6%. In a study of 161 patients reported in 1935, the 10 year survival after heart failure had developed was 34% but was 66% in those treated with arsenic. 49 Syphilis still occurs, but current therapy of syphilis is cheap and efficacious if diagnosed early. Syphilitic aortic regurgitation is not common, and the outcome in syphilitic aortic regurgitation may be more benign in the current era. Era of rheumatic fever/carditis Although the incidence of rheumatic valve disease is low in developed countries, rheumatic heart disease remains the most common form of valve disease in many parts of the world. Moreover, some people now domiciled in the developed world have had their initial attack(s) of acute rheumatic fever whilst living in less developed countries. The detection of a murmur after the episode of acute rheumatic fever averages 10 years. 49 The average interval from detection of murmur to development of symptoms is 10 years and the percentage of patients remaining symptom- free 10 years after detection of the murmur is 50%. 49 In 1971, Spagnuolo and coworkers 50 reported the 15 year actuarial follow up of 174 young people who had a median follow up of 10 years. Patients were considered to be in a cumulative high-risk group if they had systolic blood pressure Ͻ140mmHg and/or diastolic blood pressure Ͼ40mmHg, moderate or marked left ventricular enlargement on chest radiography, and two of three ECG abnormalities (S in V2ϩR in V5Ն 51mm, ST segment depression or T wave inversion in left ventricular leads). The group’s findings are summa- rized in Table 53.5. Evidence-based Cardiology 774 Table 53.5 Reported outcome in 174 young people followed for a mean of 10 years after an episode of rheumatic fever Symptoms/outcome Outcome % (years) ● Cumulative high-risk group ● mortality 6 30 ● angina 7 60 ● heart failure 6 60 ● mortality or angina 6 87 or heart failure ● Cumulative low-risk group ● Mortality 6 0 15 5 a ● Angina 5 2 ● Heart failure 6 2 15 5 ● Mortality or angina 15 8 or heart failure a The one patient (of the 72 patients) in this subgroup who died had developed two of the three risk factors. In 1973, Goldschlager and coworkers 51 reported on the duration of the asymptomatic period in 126 patients with varied etiology (Table 53.6). Current era In the current era, patients have been followed after non- invasive tests (echocardiography/Doppler ultrasound, radionuclide LVEF) or after invasive studies (cardiac catheterization or angiography). Reported outcomes are shown in Table 53.7. As outlined in Table 53.7, 52–58,64 the natural history of patients with chronic aortic valve regurgitation depends on the presence or absence of symptoms and on the status of the left ventricle. In asymptomatic patients with normal left ventricular function, data would suggest the progression to symptoms and or left ventricular systolic dysfunction in approximately 4% per year. Sudden death occurs very rarely, 0·1% per year, and asymptomatic left ventricular dysfunction occurs at a rate of 1–3% per year, depending on the fre- quency of follow up. There are limited data on asymptomatic patients with reduced left ventricular systolic function. However, available data would suggest that most of these patients will develop symptoms warranting surgery within two to three years, at an average rate of Ͼ25% per year. Limited data are available on the natural history of symptomatic patients with severe aortic valve regurgitation. These patients have a poor prognosis despite medical therapy, with reported mortality rates of 10 and 20% per year in patients with angina and heart failure, respectively. Important limitations of some of the studies in the litera- ture must be kept in mind. For example, the “natural history” group in one study was composed of several subsets of patients 53 and 36% of this group were on medications for symptoms. Another concern is the true rate of the development of asymptomatic left ventricular dysfunction. 54 At least 25% of patients who develop left ventricular systolic dysfunction do so before they have symptoms, thus emphasizing the need for quantitative assessment of left ventricular systolic function at follow up in asymptomatic patients with severe aortic regurgitation and normal left ventricular systolic function. More recent studies indicate a poor outcome of symptomatic patients with medical therapy, even among those with preserved systolic function (Table 53.8). 57,65 Sir William Broadbent 66 stated 100 years ago that “The age of the patient at the time when the lesion is acquired is Indications for surgery in aortic valve disease 775 Table 53.6 Asymptomatic period observed in 126 patients following an episode of rheumatic fever Age group (years) Patients symptomatic at 10 years a (%) 11–20 0 21–30 24 31–40 35 41–50 71 51–60 77 61–70 89 a Symptoms were those of dyspnea, fatigue and, less frequently, chest pain and palpitations. Patients deteriorated from NYHA functional Class I to Classes II, III, or IV. From Goldschlager et al. 50 Table 53.7 Outcomes of patients with severe aortic regurgitation Outcome Incidence Asymptomatic patients with normal left venticular systolic function 52–59 progression to symptoms 2·4–5·7% per year and/or left ventricular (average 3·8% systolic dysfunction per year) progression to asymptomatic left ventricular dysfunction: follow up at 12 month intervals a54 0·9% per year follow up at 6 month intervals a58 3·4% per year Sudden death 0·1% per year Asymptomatic patients with left ventricular systolic dysfunction 60–61 progression to cardiac symptoms Ͼ25% per year Symptomatic patients 50,62–64 mortality rate average Ͼ10% per year angina Ͼ10% per year heart failure Ͼ20% per year a See text for details. Table 53.8 Likelihood of symptoms or left ventricular dysfunction or death ● Left ventricular end-diastolic dimension Ն70 mm 10% per year Ͻ70 mm 2% per year ● Left ventricular end-systolic dimension Ն50 mm 19% per year End-systolic dimension Ͼ25 mm/m 2 8% per year 40–49 mm 6% per year Ͻ40 mm 0% per year the most important consideration in prognosis…”. In asymptomatic patients with normal left ventricular systolic function, the independent predictors of symptoms, left ventricular systolic dysfunction, and death by multivariate analysis were: older age, decreasing resting LVEF, and left ventricular dimension on M-mode echocardiography. 54 However, in many of these patients, M-mode images were not obtained from two dimensionally directed echocardio- grams. Very importantly, most of these dimensions were obtained in the United States, and US women have smaller left ventricular dimensions than men, even when they become symptomatic. 67 Thus, it is unlikely that the above criteria apply to women and almost certainly will not be applicable to populations of smaller body size, for example, Asians, Latin Americans, sub-Saharan Africans, and Orientals. The left ventricular dimension should be corrected to body surface area. 68 Patients also develop symptoms and/or left ventricular systolic dysfunction at a faster rate if their initial left ventricular end-diastolic volume is Ն150ml/m 2 when compared to those with volumes Ͻ150ml/m 2 . 53 Older age also appears to increase the annual mortality. 68 Patients with severe ventricular dilation when exercised have shown mean pulmonary artery wedge pressure Ն20mmHg and/or exercise ejection fraction Ͻ0·50, and such patients have demonstrated reduced exercise capacity, with reduced maximum V O 2 . 69,70 Patients who present with ventricular tachycardia, ventricular fibrillation or syncope and have inducible ventricular tachycardia on electrophysiologic studies have an 80% probability of a serious arrhythmic event up to 4 years of follow up, versus 47% in those in whom ventricular tachycardia could not be induced (P Ͻ 0·005). 71 Acute severe aortic valve regurgitation usually causes sudden severe symptoms of heart failure or cardiogenic shock. The sudden large regurgitant volume load is imposed on a normal size left ventricle causing marked elevation in left ventricular end-diastolic pressure and left atrial pressure. Echocardiography is invaluable in determining the severity and etiology of aortic valve regurgitation. 10 The etiology of acute aortic valve regurgitation may have an important impact on the treatment, which is usually emergency surgery. Management options Angina is a result of a relative reduction of myocardial blood flow because of an increased need or associated obstructive CAD or both. 25 It does not respond to nitrates as well as in aortic stenosis. The options are to reduce the amount of aortic regurgitation and/or to revascularize the myocardium by coronary bypass surgery or by percutaneous catheter tech- niques. Clinical heart failure is treated with the traditional first-line triple therapy, that is, digitalis, diuretics, and ACE inhibitors. Parenteral inotropic and vasodilator therapy may be needed for those in severe heart failure. 72 The only direct method(s) to reduce the amount of regurgitation is by arterial dilators 73 and valve surgery – that is, valve replacement or valve repair. Arterial dilators In chronic aortic valve regurgitation, therapy with vasodilat- ing agents is designed to improve forward stroke volume and reduce regurgitant volume. These effects should trans- late into reductions in left ventricular end-diastolic volume, wall stress, and afterload, resulting in preservation of left ventricular systolic function and reduction in left ventricular mass. These effects have been observed in small numbers of patients receiving hydralazine. 73 In a trial of 80 patients over 2 years 74 in which 36% of patients were symptomatic (NYHA class II) and were being treated with digitalis and diuretics, hydralazine produced very minor improvements of left ventricular size and function. 74 Side effects associated with long-term use of hydralazine seriously impaired com- pliance and only 46% of the patients completed the trial. Hydralazine is rarely used currently. Occasionally it is used for a short period of time, to tide the patient over an acute reversible complication or in preparation for elective surgery in selected patients with left ventricular dysfunction. Less consistent results have been reported with ACE inhibitors, depending on the degree of reduction in arterial pressure and end-diastolic volume. In an acute study in the catheterization laboratory, 20 patients were randomized to either oral nifedipine or oral captopril. 75 Nifedipine produced a reduction of regurgitant fraction but captopril did not. Nifedipine produced a greater increase of forward stroke volume and cardiac output and a greater fall of systemic vascular resistance. This study showed that, acutely, nifedipine was superior to an ACE inhibitor. A short- term 6 month randomized trial of a small number of patients showed that the results with captopril were similar to placebo – that is, there were no significant changes in M-mode echocardiographic left ventricular dimensions. 76 A randomized trial of 72 patients for 12 months of long- acting nifedipine showed statistically significant reductions of left ventricular end-diastolic volume index and left ventricular mass, and increase of LVEF. 58 The role of long-acting nifedipine on patient outcome has been evaluated in a prospective, randomized trial of 143 asymptomatic patients with chronic, severe aortic valve regurgitation, and normal left ventricular systolic function; 69 patients were randomized to long-acting nifedipine and 74 patients to digoxin. The patients were evaluated at 6 month intervals for med- ication complication and had a history, physical examination, ECG, chest radiograph, and echocardiographic/ Doppler study. Two independent blinded observers read each echocardiographic/Doppler study. Criteria for valve replacement were established prior to the start of the study. If left ventricular dysfunction developed, this had to be Evidence-based Cardiology 776 confirmed by a repeat echocardiographic/Doppler study at 1 month and by preoperative left ventricular angiographic study. At 6 years, the need for valve replacement was 34Ϯ6% in the digoxin-treated group and 15Ϯ3% in the nifedipine-group, P Ͻ 0·001 (Figure 53.4). 58 Thus, for every 100 patients treated with nifedipine, 19 fewer valve replacements were needed at the end of 6 years; note that even after 6 years, the curves are not parallel and do not converge (see Figure 53.4). Compared to the digoxin group, the nifedipine-treated group demonstrated a reduction in left ventricular volume and mass. Ejection fraction increased in the digoxin arm of the trial, and left ventricular volumes and mass increased. After aortic valve replacement, 12 of 16 patients (75%) in the digoxin group and all six patients in the nifedipine group who had an abnormal LVEF before surgery had a normal ejection fraction. Eighty-five per cent of patients in the digoxin arm of the trial, who underwent valve replacement, developed an abnormal ejection fraction and only three patients had valve replacement for symptoms. Moreover, patients in the digoxin arm of the trial had an outcome similar to that reported in the natural history studies. Long-acting nifedipine is the drug of choice for asymptomatic patients with severe chronic aortic valve regurgitation and normal left ventricular systolic function unless there is a contraindication to its use. 25 The goal of vasodilator therapy is to reduce systolic blood pressure. The dose should be increased until there is a measurable decrease in blood pressure or side effects. Vasodilator therapy is not indicated in patients with normal left ventricular dimension and/or normal blood pressure. ACE inhibitors are not of proven benefit in asymptomatic patients with severe chronic aortic valve regurgitation and normal left ventricular systolic function. Valve surgery (replacement/repair) Surgery for aortic valve regurgitation should only be considered when the degree of regurgitation is severe. However, the presence of severe aortic valve regurgitation does not mandate surgery. The critical issue is to choose the best time for surgical intervention. Aortic valve repair or replacement should be performed in most symptomatic patients irrespective of the degree of left ventricular dysfunction. Postoperative survival is better after valve replacement in symptomatic patients with normal or mildly impaired left ventricular systolic function (ejection fraction [EF]Ն 0·45) than in those with greater impairment of left ventricular systolic function (EF Ͻ 0·45). 77 In one study, patients with preoperative left ventricular EF of Ն0·60 had a better survival than those with left ventricular EF of Ͻ0·60. 78 Extreme left ventricular dilation (end-diastolic dimension Ͼ80) associated with aortic valve regurgitation occurs primarily in men and is often associated with left ventricular dysfunction. Extreme left ventricular dilation, however, is not a marker of irreversible left ventricular dysfunction. Operative risk and late postoperative survival are acceptable in these patients. 79 In the setting of severe left ventricular dysfunction (EF Ͻ0·25), the risk of aortic valve surgery increases and potential benefits decline, since left ventricular dysfunction may be on the basis of irreversible myocardial damage. However, even in the highest risk patients, the risk of surgery and postoperative medical therapy for heart failure are usually less than the risk of long- term medical management alone. Aortic valve surgery for asymptomatic patients is more controversial but is indicated in the setting of left ventricular dysfunction with an EFՅ0·50 and in the setting of severe left ventricular dilation (end-diastolic dimension Ͼ75mm or end systolic dimension Ͼ55mm), even if the ejection fraction is normal. The threshold values of end-diastolic and end- systolic dimension recommended for aortic valve replacement in asymptomatic patients may need to be adjusted to body surface area. In one series, it was noted that a left ventricular end-systolic dimension corrected for body surface area (LVS/BSA) of Ն25mm/m 2 was associated with increased mortality when followed conservatively. 1,68,79 After valve replacement, patients with normal preoperative left ventricular systolic function have reductions of left ventricular volumes and hypertrophy. 80 In the majority of patients with normal preoperative left ventricular function, there is an increase in EF after valve replacement, presum- ably because of a reduction of myocardial stress. 31,81 Left Grade B Grade A Indications for surgery in aortic valve disease 777 Incidence of aortic-valve replacement (%) Digoxin Nifedipine Years after randomization 0123456 40 P<0·001 30 20 10 0 Figure 53.4 The role of long term, long acting nifedipine therapy in asymptomatic patients with severe aortic regurgitation and normal left ventricular systolic pump function was evaluated in 143 asymptomatic patients in a prospective randomized trial. By actuarial analysis, at 6 years, 34 Ϯ 6% of patients in the digoxin group underwent valve replacement versus 15Ϯ 3% of those in the nifedipine group ( P Ͻ 0·001). This randomized trial demonstrates that long term arteriolar dilator therapy with long acting nifedipine reduces and/or delays the need for aortic valve replacement in asymptomatic patients with severe aortic regurgitation and normal left ventricular systolic pump function. (From Scognamiglio et al 52 with permission.) [...]... 199 7 ;95 :226 2–7 0 6.Carabello BA Timing of valve replacement in aortic stenosis Moving closer to perfection Circulation 199 7 ;95 :224 1–3 7.Hsieh K, Keane JF, Nadas AS, Bernhard WF, Castaneda AR Long-term follow-up of valvotomy before 196 8 for congenital aortic stenosis Am J Cardiol 198 6;58:33 8–4 1 8.McBride LR, Nannheim KS, Fiore AC et al Aortic valve decalcification J Thorac Cardiovasc Surg 199 0;100:3 6–4 2... Coll Cardiol 199 6;27:67 0–7 83.Izumoto H, Kawazoe K, Ishibashi K et al Aortic valve repair in dominant aortic regurgitation Japan J Thorac Cardiovasc Surg 2001; 49: 35 5 9 84.Rapaport E Natural history of aortic and mitral valve disease Am J Cardiol 197 5;35(Suppl 2):22 1–7 85.Chizner MA, Pearle DL, deLeon AC Jr The natural history of aortic stenosis in adults Am Heart J 198 0 ;99 (Suppl 4):41 9 2 4 86.O’Keefe... baseline hemodynamic variables Pre PCWP (mmHg) Pre AOSP (mmHg) Event-free survival (%) 6 mth Ͻ18 Ͻ18 Ͻ18 1 8–2 5 1 8–2 5 1 8–2 5 Ͼ25 Ͼ25 Ͼ25 12 mth 18 mth 24 mth Ն140 11 0–1 39 Ͻ110 79 73 64 65 58 46 51 42 30 41 31 19 Ն140 11 0–1 39 Ͻ110 74 68 58 59 50 38 43 34 22 32 23 13 Ն140 11 0–1 39 Ͻ110 63 55 43 44 35 23 28 19 10 18 10 4 Abbreviations: AOSP, aortic systolic pressure; PCWP, pulmonary capillary wedge pressure Reproduced... asymptomatic patients Circulation 198 0;61:48 4 9 2 60.McDonald I, Jelinek V Serial M-mode echocardiography in severe chronic aortic regurgitation Circulation 198 0;62: 1 29 1–6 61.Bonow R Radionuclide angiography in the management of asymptomatic aortic regurgitation Circulation 199 1;84: I. 296 –I.302 62.Hegglin R, Scheu H, Rothlin M Aortic insufficiency Circulation 196 8;38(Suppl 15):V77–V92 63.Rapaport E Natural history... Circulation 198 8; 77:134 5–5 5 33.Carroll J, Carroll EP, Feldman T et al Sex-associated differences in left ventricular function in aortic stenosis of the elderly Circulation 199 2;86:1 09 9 1 07 34.Hammermeister K, Sethi G, Henderson W, Oprian C, Kim T, Rahimtoola S A comparison of outcomes in men 11 years after heart-valve replacement with a mechanical valve or bioprosthesis N Engl J Med l 993 ;328:128 9 9 6 35.Murphy... patients Circulation 198 5;71:116 2 9 12.Rahimtoola S “Prophylactic” valve replacement for mild aortic valve disease at time of surgery for other cardiovascular disease? No J Am Coll Cardiol 199 9;33:200 9 1 5 13.Ross JJr, Braunwald E Aortic stenosis Circulation 196 8;36 (Suppl IV):6 1–7 14.Horstkotte D, Loogen F The natural history of aortic valve stenosis Eur Heart J 198 8;(Suppl E):5 7–6 4 15.Rahimtoola S Perspective... 1 897 67.Klodas E, Enriquez-Sarano M, Tajik A, Mullany C, Bailey K, Seward J Surgery for aortic regurgitation in women: contrasting indications and outcomes compared with men Circulation 199 6 ;94 :247 2–8 68.Dujardin K, Enriquez-Sarano M, Schaff H, Bailey K, Seward J, Tajik A Mortality and morbidity of aortic regurgitation in clinical practice A long-term follow-up study Circulation 199 9; 99 :185 1–7 69. Boucher... Ann Thorac Surg 199 0; 49: 74 0–5 54.Lieberman EB, Wilson JS, Harrison JK et al Aortic valve replacement in adults after balloon aortic valvuloplasty Circulation 199 4 ;90 (Suppl II):II20 5–8 55.Bernard Y, Etievent J, Mourand JL et al Long-term results of percutaneous aortic valvuloplasty compared with aortic valve replacement in patients more than 75 years old J Am Coll Cardiol 199 2;20: 79 6–8 01 56.Goldman L,... Am Coll Cardiol 199 4; 23:107 6–8 39. Smith N, McAnulty J, Rahimtoola S Severe aortic stenosis with impaired left ventricular function and clinical heart failure: results of valve replacement Circulation 197 8;58:25 5–6 4 40.Connolly H, Oh J, Orszulak T et al Aortic valve replacement for aortic stenosis with severe left ventricular dysfunction Prognostic indicators Circulation 199 7 ;95 :2 39 5–2 400 41.Rahimtoola... results from the UK Heart Valve Registry Circulation 199 7 ;96 :340 3–8 17.Edwards FH, Peterson ED, Coombs LP et al Prediction of operative mortality after valve replacement surgery J Am Coll Cardiol 2001;37:88 5 9 2 18.Fremes SE, Goldman BS, Ivanou J, Weisel RD, David TE, Salerno T Valvular surgery in the elderly Circulation 198 9; 80(Suppl I):17 7 9 0 19. Levinson JR, Akins CW, Buckley MJ et al Octogenarians . tolerance IIa ● LV systolic dysfunction –LVEF 0·2 5–0 · 49 I –LVEF 0·1 8–0 ·24 IIb ● Asymptomatic patients with: ● LV systolic dysfunction –LVEF 0·2 5–0 · 49 I –LVEF 0·1 8–0 ·24 IIb ● normal LV function and: ●. Post Cribier 26 92 75 30 0.5 0 .9 Safian 28 170 71 36 0.6 0 .9 Block 29 162 61 27 0.5 0 .9 Lewin 39 125 87 32 0.6 1.0 Evidence-based Cardiology 786 In general, balloon aortic valvuloplasty resulted in a 5 0–7 0% decrease. aortic regurgitation and normal left ventricular function. N Engl J Med 199 4;331:68 9 9 5. Evidence-based Cardiology 780 59. Henry W, Bonow R, Rosing D, Epstein S. Observations on the optimum time

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