Other AreasFen-Phen
AHP SettlementEndnotes (1-21)
In defining the "Levels of Severity " which qualify class members for matrix compensation benefits, the Settlement requires the application of a standardized methodology or protocol.
Endnotes have been used in the description of levels of valvular heart disease to indicate reference to a standardized methodology or protocol. The referenced methodologies or protocols, together with the corresponding endnote, are as follows: (Also see endnotes 22-30)
1. See Harrison's Principles of Internal Medicine, 1878, 1885 (14th ed. 1998).
2. See C. Otto, The Practice of Clinical Echocardiography, 589-91, 592-93 (1997):
Mitral regurgitation can be associated with rheumatoid arthritis. The mitral valve may have the following echocardiographic features: rheumatoid nodules present-usually <0.5 cm in diameter; may occur at any location on leaflet, homogeneous soft tissue reflectance and irregular body border; usually rounded shape.
The following echocardiographic features of valvular abnormalities associated with Systemic Lupus Erythematosus include: diffuse valvular thickening-aortic and mitral valves, decreased leaflet mobility, and presence of Libman-Sacks vegetations, usually <1 cm in diameter.
3. See J.P. Singh, et al., "Prevalence and Clinical Determinants of Mitral, Tricuspid and Aortic Regurgitation (The Framingham Heart Study)," American J. Cardiology, 83:897-902 (1999):
| Table I Definitions of Grades of Regurgitation | ||
|---|---|---|
| GRADES | MR | AR |
| Absent | -- | -- |
| Trace | w/in 1 cm of valve | JH/LVOH <10% |
| Mild | RJA/LAA <19% | 10%-24% |
| Moderate | 20%-40% | 25%-49% |
| Severe | >41% | >50% |
| Valvular regurgitation was assessed qualitatively using these semiquantitative categories as guidelines.JH= jet height; LAA= left atrial area; LVOH= left ventricular outflow height; RAA= right atrial area; RJA= regurgi-tant jet area; w/in= within. | ||
Conventional pulsed Doppler echocardiography was performed routinely in apical 4- and 5-chamber views by selective placement of the sample volume on the color Doppler echocardiographic regurgitation signals when present. Valvular regurgitation was diagnosed using color-coded Doppler imaging proximal to the valve plane during its closure and extended into the chamber proximal to the valve. For color Doppler studies, gain settings were adjusted to eliminate background speckling and to maximize the extent of intracavity velocity coding. MR was sought from the parasternal long-axis, apical 4- and 2-chamber, apical long-axis, and subcostal views. AR was sought using the parasternal long-axis, parasternal shortaxis, apical 5-chamber, and apical long-axis views.
MR was considered to be present if blue, green, or mosaic signals were seen originating from the mitral valve and spreading into the left atrium during systole. AR was considered to be present if red, yellow, or mosaic signals (blue in the parasternal long axis) were seen originating from the aortic valve and spreading into the left ventricle during diastole. Valvular regurgitation was assessed qualitatively using semiquantitative guidelines and graded none, trace, mild, moderate, or severe (Table I).
4. Id.
5. Helmcke, F., Nanda, N.C., Hsiung, M.C., Soto, B., Adey C.K., Goyal, R.G., Gatewood, R.P., Jr., "Color Doppler Assessment of Mitral Regurgitation with Orthogonal Planes," Circulation, 75(1):175-83 (1987):
Three two-dimensional echocardiographic planes (parasternal long and short axis, apical four-chamber view) were used to analyze variables of the mitral regurgitant jet signals in the left atrium. The best correlation with angiography was obtained when the regurgitant jet area (RJA) (maximum or average from three planes) expressed as a percentage of the left atrial area (LAA) obtained in the same plane as the maximum regurgitant area was considered. The maximum RJA/LAA was under 20% in 34 of 36 patients with angiographic grade I mitral regurgitation, between 20% and 40% in 17 of 18 patients with grade II mitral regurgitation, and over 40% in 26 of 28 patients with severe mitral regurgitation.
6. See Centers for Disease Control and Prevention, "Cardiac Valvulopathy Associated with Exposure to Fenfluramine or Dexfenfluramine: US Department of Health and Human Services Interim Public Health Recommendations," MMWR Morb. And Mortal. Wkly Rep., 46:1061-66 (1997):
Minimal degrees of regurgitation (i.e., trace or mild mitral regurgitation [MR] or trace aortic regurgitation [AR]) are relatively common in the general population and are not generally considered abnormal. Therefore, in this analysis, a case of fenfluramine- or dexfenfluramine-associated cardiac valvulopathy was defined as documented AR of mild or greater severity and/or MR of moderate or greater severity after exposure to these drugs.
7. See Singh, supra, note 3.
8. Id.
9. E. Braunwald, Heart Disease. A Textbook of Cardiovascular Medicine 796-98 (1997):
Although pulmonary hypertension is widely recognized as developing in patients with left atrial hypertension due to mitral stenosis, it can also occur in patients with pure mitral regurgitation. In one series, nearly half of a cohort of 41 patients with severe mitral regurgitation had pulmonary artery systolic pressures in excess of 50 mm Hg (citation omitted).
Left ventricular diastolic failure may result from hypertension; aortic stenosis; ischemic heart disease; hypertrophic restrictive and congestive cardiomyopathies; and constrictive pericarditis. Because chronic increases in mean left ventricular filling pressure exceeding 25mm Hg are uncommon, the resulting pulmonary arterial hypertension is only moderate unless reactive pulmonary hypertension also occurs. In the absence of the latter, a normal pulmonary artery mean pressure of 15 mm Hg may arise to approximately 30 mm Hg as a result of left ventricular diastolic dysfunction. Because cardiac output is usually reduced in such patients, the mean pulmonary artery pressure would be considerably less than 30 mm Hg if pulmonary vascular resistance remains unchanged. However, many patients with left ventricular diastolic dysfunction exhibit increased pulmonary vascular resistance and moderately severe pulmonary hypertension.
10. H. Feigenbaum, Echocardiography 201-03 (5th ed. 1994):
The principle technique for determining pulmonary artery pressure involves the use of the tricuspid regurgitant jet and the Bernoulli equation. By determining the right ventricular systolic pressure and ruling out the existence of any obstruction in the right ventricular outflow tract, one can determine the pulmonary artery systolic pressure. This technique is probably the most accurate for quantitating pulmonary artery pressure (citation omitted).
11. K.L. Chan, et al., "Comparison of Three Doppler Ultrasound Methods in the Prediction of Pulmonary Artery Pressure," I 9:549-54 (1987):
Pulmonary artery pressure was noninvasively estimated by three Doppler echocardiographic methods in 50 consecutive patients undergoing cardiac catheterization. First, a systolic transtricuspid gradient was calculated from Doppler-detected triscuspid regurgitation; clinical jugular venous pressure or a fixed value of 14 mm Hg was added to yield systolic pulmonary artery pressure. Second, acceleration time from pulmonary flow analysis was used in a regression equation to derive mean pulmonary artery pressure. Third, right ventricular isovolumic relaxation time was calculated from Doppler-determined pulmonary valve closure and tricuspid valve opening; systolic pulmonary artery pressure was then derived from a nomogram.
In 48 patients (96%) at least one of the methods could be employed. A tricuspid pressure gradient, obtained in 36 patients (72%), provided reliable prediction of systolic pulmonary artery pressure. The prediction was superior when 14 mm Hg rather than estimated jugular venous pressure was used to account for right atrial pressure. In 44 patients (88%), pulmonary artery flow was analyzed. Prediction of mean pulmonary artery pressure was unsatisfactory (r= 0.65) but improved (r= 0.85) when only patients with a heart rate between 60 and 100 beats/min were considered. The effect of correcting pulmonary flow indexes for heart rate was examined by correlating different flow indexes before and after correction for heart rate. There was a good correlation between corrected acceleration time and either systolic (r= -0.85) or mean (r= -0.83) pulmonary artery pressure. Because of a high incidence of arrhythmia, right ventricular relaxation time could be determined in only 11 patients (22%).
Noninvasive prediction of pulmonary artery pressure is feasible in most patients. Among the three methods, tricuspid gradient measurement seems to be the most useful and practical. Heart rate correction may improve the accuracy of using acceleration time in predicting pulmonary artery pressure; Doppler-determined right ventricular relaxation time seems to be of limited usefulness.
Doppler recordings were obtained from apical, parasternal and subcostal positions. The tricuspid regurgitation signal moved away from the transducer and consisted of a relatively dense high velocity spectral representation. Systematic search for the Doppler signal of tricuspid regurgitation was performed to achieve optimal recording, which consisted of highest maximal velocity with a distinct envelope on the spectral display. No correction was used to compensate for any presumed angle between the ultrasound beam and the direction of maximal velocity flow. The modified Bernoulli equation was employed to derive a systolic transtricuspid gradient that equals 4 v2, in which v is the maximal regurgitant velocity in meters per second.
There is no systematic difference in systolic pulmonary artery pressure between the Doppler-derived and manometric measurements. In individual patients, considerable difference may occur. This may be related to the variability of the angle between the ultrasound beam and the blood flow. The SEE was similar to that reported in other series (citations omitted). With an estimated pressure of 50 mm Hg, the 95% limits were 34 and 66 mm Hg. Such an estimate is probably within the bounds of clinical usefulness, because pulmonary artery pressure is a dynamic measurement and can vary by more than 30% within a 24 hour period (citation omitted).
12. See R.O. Bonow, et al., "Guidelines for the Management of Patients with Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines" (Committee on Management of Patients with Valvular Heart Disease), JACC 32:1510-14 (1998):
Chronic Severe Aortic Regurgitation
Description of Figure: Management strategy for patients with chronic severe aortic regurgitation. Preoperative coronary angiography should be performed routinely as determined by age, symptoms, and coronary risk factors. Cardiac catheterization and angiography may also be helpful when there is discordance between clinical findings and echocardiography. In some centers, serial follow-up may be performed with RVG or MRI rather than echocardiography to assess LV volume and systolic function.
Abbreviations:
DD= end-diastolic dimension,
RVG= radionuclide ventriculography,
SD= end-systolic dimension.
Asymptomatic patients with normal systolic function but severe AR and significant LV dilatation (enddiastolic dimension >60mm) require more frequent and careful reevaluation, with a history and physical examination every 6 months and echocardiography every 6 to 12 months, depending on the severity of dilatation and stability of measurements. If stable, echocardiographic measurements are not required more frequently than every 12 months. In patients with more advanced LV dilatation (end-diastolic dimension >70 mm or end-systolic dimension >50 mm), for whom the risk of developing symptoms or LV dysfunction ranges between 10% and 20% per year (citations omitted), it is reasonable to perform serial echocardiograms as frequently as every 4 to 6 months. Serial chest x-rays and ECGs have less value but are helpful in selected patients.
Repeat echocardiograms are also recommended when the patient has onset of symptoms, there is an equivocal history of changing symptoms or exercise tolerance, or there are clinical findings suggesting worsening regurgitation or progressive LV dilatation. Patients with echocardiographic evidence of progressive ventricular dilatation or declining systolic function have a greater likelihood of developing symptoms or LV dysfunction (citation omitted) and should have more frequent follow-up examinations (every 6 months) than those with stable LV function.
Indications for Aortic Valve Replacement. In patients with pure, chronic AR, AVR should be considered only if AR is severe. Patients with only mild AR are not candidates for valve replacement, and if such patients have symptoms or LV dysfunction, other etiologies should be considered, such as CAD, hypertension, or cardiomyopathic processes. If the severity of AR is uncertain after a review of clinical and echocardiographic data, additional information may be needed, such as invasive hemodynamic and angiographic data. The following discussion applies only to those patients with pure, severe AR.
(1) SYMPTOMATIC PATIENTS WITH NORMAL LV SYSTOLIC FUNCTION. AVR is indicated in patients with normal systolic function (defined as ejection fraction >0.50 at rest) who have NYHA functional Class III or IV symptoms.
New onset of mild dyspnea has different implications in severe AR, especially in patients with increasing LV chamber size or evidence of declining LV systolic function into the low normal range.
(2) SYMPTOMATIC PATIENTS WITH LV DYSFUNCTION. Patients with NYHA-functional Class II, lII, or IV symptoms and with mild to moderate LV systolic dysfunction (ejection fraction 0.25 to 0.49) should undergo AVR. Patients with functional Class IV symptoms have worse postoperative survival rates and lower likelihood of recovery of systolic function compared with patients with less severe symptoms, but AVR will improve ventricular loading conditions and expedite subsequent management of LV dysfunction. Symptomatic patients with advanced LV dysfunction (ejection fraction <0.25 and/or end-systolic dimension >60mm) present difficult management issues. Some patients will manifest meaningful recovery of LV function after operation, but many will have developed irreversible myocardial changes. The mortality associated with valve replacement approaches 10%, and postoperative mortality over the subsequent few years is high. Valve replacement should be considered more strongly in patients with NYHA functional Class II and III symptoms, especially if (1) symptoms and evidence of LV dysfunction are of recent onset and (2) intensive short-term therapy with vasodilators, diuretics, and/or intravenous positive inotropic agents results in substantial improvement in hemodynamics or systolic function. However, even in patients with NYHA functional Class IV symptoms and ejection fraction <0.25, the high risks associated with AVR and subsequent medical management of IV dysfunction are usually a better alternative than the higher risks of long-term medical management alone (citations omitted).
(3) ASYMPTOMATIC PATIENTS. AVR in asymptomatic patients remains a controversial topic, but it is generally agreed that valve replacement is indicated in patients with LV systolic dysfunction LV systolic dysfunction is defined as an ejection fraction below normal at rest. The lower limit of normal will be assumed to be 0.50, realizing that this lower limit is technique dependent and may vary among institutions (citation omitted).
It is recommended that 2 consecutive measurements be obtained before proceeding with a decision to recommend surgery in the asymptomatic patient. These consecutive measurements could be obtained with the same test repeated in a short time period (for example, a second echocardiogram after an initial echocardiogram) or with a separate independent test (for example, a radionuclide ventriculogram or a contrast left ventriculogram after an initial echocardiogram). Valve replacement is also recommended in patients with severe LV dilatation (end-diastolic dimension >75mm or endsystolic dimension >55mm), even if ejection fraction is normal.v
Patients with severe AR in whom the degree of dilatation has not reached but is approaching these threshold values (for example, LV end-diastolic dimension of 70 to 75 mm or end-systolic dimension of 50 to 55 mm) should be followed carefully with frequent echocardiograms every 4 to 6 months. In addition, it is reasonable to recommend AVR in such patients if there is evidence of declining exercise tolerance or abnormal hemodynamic responses to exercise, for example, an increase in pulmonary artery wedge pressure > 25 mm Hg with exercise.
A decrease in ejection fraction during exercise should not be used as an indication for AVR in asymptomatic patients with normal systolic function at rest, because the exercise ejection fraction response is multifactorial and the strength of the evidence is limited. The ejection fraction response to exercise has not proved to have independent prognostic value in patients undergoing surgery (citation omitted).
Valve replacement should also not be recommended in asymptomatic patients with normal systolic function merely because of evidence of LV dilation as long as the dilation is not severe (end-diastolic dimension <75 mm or end-systolic dimension <55 mm). Patients who demonstrate progression of IV dilatation or progressive decline in ejection fraction on serial studies represent a higher-risk group who require careful monitoring (citation omitted), but such patients often reach a new steady state and may do well for extended periods of time. Hence, valve replacement is not recommended until the threshold values noted above are reached or symptoms or LV systolic dysfunction develop.
| Recommendations for Aortic Valve Replacement in Chronic Severe Aortic Regurgitation | |
|---|---|
| INDICATION | CLASS |
| 1. Patients with NYHA functional Class III or IV symptoms and preserved IV systolic function, defined as normal ejection fraction at rest (ejection fraction > 0.50). | I |
| 2. Patients with NYHA functional class II symptoms and preserved LV systolic function (ejection fraction > 0.50 at rest) but with progressive IV dilatation or declining ejection fraction at rest on serial studies or declining effort tolerance on exercise testing. | I |
| 3. Patients with Canadian Heart Association functional Class II or greater angina with or without CAD. | I |
| 4. Asymptomatic or symptomatic patients with mild to moderate LV dysfunction at rest (ejection fraction 0.25 to 0.49). | I |
| 5. Patients undergoing coronary artery bypass surgery or surgery on the aorta or other heart valves. | I |
13. See Id.
14. See Id.
15. See Singh, supra note 3.
16. See Id.
17. See Braunwald, supra note 9.
18. See A.E. Weyman, Principles and Practice of Echocardiography 1290-92 (1994).
| Normal Cross-Sectional Values* | ||||
|---|---|---|---|---|
 |
Parasternal Long Axis View | N | Mean + SD* | Range |
| Left Atrium(end-systole): | ||||
| Antero-posterior dimension | ||||
| 5.) Maxium | 62 | 3.0 + 0.3 | 2.3-3.8 | |
| 6.) Mid-cavity | 62 | 3.0 + 0.3 | 2.3-3.8 | |
* All linear dimensions are in cm, and areas are in cm2
Indicates the preferable view for obtaining a particular measurement.
| Normal Cross-Sectional Values* | ||||
|---|---|---|---|---|
|
Apical Four Chamber View | N | Mean + SD* | Range |
| Left Atrium(end-systole): | ||||
| Supero-inferior dimension | ||||
| 5.) Maxium | 68 | 4.1 + 0.6 | 2.9-5.3 | |
| 6.) Mid-cavity | 68 | 4.1 + 0.6 | 2.9-5.3 | |
* All linear dimensions are in cm, and areas are in cm2
Indicates the preferable view for obtaining a particular measurement.
19. See W.L. Henry et. al., "Report of the American Society of Echocardiography Committee on Nomenclature and Standards in Two-dimensional Echocardiography," Circulation, 62:212-17 (1980):
Nomenclature for Transducer Location
Discription of figure: Diagram indicating the nomenclature to describe the locations on the body from which echocardiographic studies can be obtained.
AO = aorta;
RA = right atrium;
PA = pulmonary artery;
RV = right ventricule;
LA = left atrium;
LV = left ventricle.
The Committee recommends that when the transducer is placed in the suprasternal notch that it be referred to as in the suprasternal location. When the transducer is located near the midline of the body and beneath the lowest ribs, the transducer should be referred to as in the subcostal location. When the transducer is located over the apex impulse, the Committee recommends that this be referred to as the apical location. If the term apical is used alone, it will be assumed that this refers to a left-sided apical position. The area bounded superiorly by the left clavicle, medially by the sternum and inferiorly by the apical region will be referred to as the parasternal location. If the term parasternal is used alone, it will be assumed to be the left parasternal location. In those unusual situations in which the apex impulse is palpated on the right chest, a transducer placed over the right-sided apex impulse will be referred to as in the right apical location. The region bounded superiorly by the right clavicle, medially by the sternum and inferiorly by the right apical region will be referred to as the right parasternal location.
Imaging Planes
Three orthogonal planes will be used to describe the imaging planes used to visualize the heart with twodimensional echocardiography. The imaging plane that transects the heart perpendicular to the dorsal and ventral surfaces or the body and parallel to the long axis of the heart will be referred to as the long-axis plane. The plane that transects the heart approximately parallel to the dorsal and ventral surfaces of the body will be referred to as the four-chamber plane.
Two Dimensional Echocardiographic Imaging Planes
Description of figure: Diagram indicat-ing the nomenclature to describe the locations on the body from which echocardiographic studies can be obtained.
AO = aorta;
RA = Right atrium;
PA = pulmonary artery;
RV = right ventricle;
LA = left atrium
LV = left ventricle.
Identification of Two-dimensional Images
The Committee recommends that two-dimensional images be identified by referring to the transducer location and the imaging plane. For example, if the transducer is placed in the parasternal location and oriented so that the imaging plane transects the heart parallel to the long-axis of the heart, the Committee recommends that the resulting image be referred to as a parasternal long-axis view. As another example, if the transducer is placed in the apical location and oriented so that the four-chamber imaging plane is used, the Committee recommends that the resultant image be referred to as an apical four-chamber view.
Long-Axis View
Description of figure: Diagram of the transducer orientation used to obtain the long axis view of the heart. Note that the transducer index mark is always pointed either in the direction of the patient's head or the patient's left side.
Four-Chamber View
Description of figure: Diagram of the transducer orientation used to obtain the four-chamber view of the heart.
Parasternal Long-Axis
Description of figure: Illustration of the long-axis, two-dimensional images that result when the transducer is used to visualize the parasternal long-axis view.
20. See R.O. Bonow, supra note 12 at 1533-35.
Chronic Severe Mitral Regurgitation
Description of figure: Management strategy for patients with chronic severe mitral regurgitation.
Abbreviations: AF= atrial fibrillation, EF= ejection fraction, ESD= end-systolic diameter, FC= functional class, MV= mitral valve, NYHA= New York Heart Association, PHT= pulmonary hypertension.
Timing of Surgery for Symptomatic Patients With Normal Left Ventricular Function. Patients with symptoms of congestive heart failure despite normal LV function on echocardiography (ejection fraction>0.60 and endsystolic dimension <45 mm) require surgery. Surgery should be performed in patients with mild symptoms and severe MR (Figure 6), especially if it appears that mitral valve repair rather than replacement can be performed. The feasibility of repair is dependent on several factors, including valve anatomy and surgical expertise. Successful surgical repair improves symptoms, preserves LV function, and avoids the problems of a prosthetic valve. When repair is not feasible, MVR with chordal preservation should relieve symptoms and maintain LV function.
Timing of Surgery for Asymptomatic or Symptomatic Patients with Left Ventricular Dysfunction. Preoperative variables that are predictive of postoperative survival, symptomatic improvement, and postoperative IV function are summarized in Table 20.
The timing of surgery for asymptomatic patients was controversial, but most would now agree that mitral valve surgery is indicated with the appearance of echocardiographic indicators of LV dysfunction. These include LV ejection fraction <0.60 and/or LV end-systolic dimension >45mm (Figure 6). Surgery performed at this time will likely prevent further deterioration in LV function and improve longevity. This is true whether repair or replacement is performed, although repair is clearly preferred. Although some recommend a slightly lower threshold ejection fraction (0.55), it must be emphasized that, unlike timing of AVR for AR, LV ejection fraction should not be allowed to fall into the lower limit of the normal range in patients with chronic MR (citations omitted).
Mitral valve surgery should also be recommended for symptomatic patients with evidence of LV systolic dysfunction (ejection fraction <0.60, end-systolic dimension >45 mm). Determining the surgical candidacy of the symptomatic patient with MR and far-advanced LV dysfunction is a common clinical dilemma. The question that often arises is whether the patient with MR has such advanced IV dysfunction that he or she is no longer a candidate for surgery. Often such cases present difficulty in distinguishing primary cardiomyopathy with secondary MR from primary MR with secondary myocardial dysfunction. In the latter case, if mitral valve repair appears likely, surgery should still be contemplated, provided ejection fraction is >0.30 (Figure).
Asymptomatic Patients With Normal Left Ventricular Function. Repair of a severely regurgitant valve may be contemplated in an asymptomatic patient with normal LV function in order to preserve LV size and function and prevent the sequelae of chronic MR.
This approach is often recommended in hemodynamically stable patients with newly acquired severe MR, such as might occur with ruptured chordae. Surgery is also recommended in an asymptomatic patient with chronic MR with recent onset of episodic or chronic atrial fibrillation in whom there is a likelihood of successful valve repair.
| Recommendation for Mitral Valve Surgery in Nonischemic Severe Mitral Regurgitation | |
|---|---|
| Indication | Class |
| 1. Acute Symptomatic MR in which repair is likely. | I |
| 2. Patients with NYHA functional Class II, III, IV systoms with normal LV function defined as ejection fraction >60 and end-systolic dimension <45mm. | I |
| 3. Symptomatic or asymptomatic patients with mild LV dysfunction, ejection fraction 0.50 to 0.60, and end-systolic dimension 45 to 50mm. | I |
| 4. Symptomatic or asymptomatic patients with moderate LV dysfunction, ejection fraction 0.30 to 0.50, and/or end-systolic dimension 50 to 55 mm. | I |
21. See Id.
