- Email: [email protected]
Usefulness of Magnetic Resonance Imaging to Guide Referral for Pulmonary Valve Replacement in Repaired Tetralogy of Fallot
Usefulness of Magnetic Resonance Imaging to Guide Referral for Pulmonary Valve Replacement in Repaired Tetralogy of Fallot Matthew J. Lewis, MD, MPHa,*, Daniel S. O’Connor, MDa, Anna Rozenshtien, MDb, Siqin Ye, MDa, Andrew J. Einstein, MD, PhDa, Jonathon M. Ginns, MDa, and Marlon S. Rosenbaum, MDa The aim of this study was to determine if adult patients with repaired tetralogy of Fallot are being referred for pulmonary valve replacement (PVR) earlier on the basis of cardiac magnetic resonance imaging (CMR) parameters despite the absence of CMR-based recommendations in the American College of Cardiology and American Heart Association joint guidelines. Variables defined by the guidelines were analyzed in conjunction with CMRbased parameters across 3 groups defined by the release of the guidelines: (1) patients referred before the guidelines, (2) patients referred 0 to 3 years after the guidelines, and (3) patients referred ‡3 years after the guidelines. Seventy-nine patients were identified. No significant trend was observed in guideline-defined variables. Significant trends in indexed right ventricular end-diastolic volume (p [ 0.034), indexed right ventricular end-systolic volume (p [ 0.001), and the right ventricular ejection fraction (p [ 0.005) were observed across groups. By multivariate regression, patients who underwent PVR ‡3 years after the release of the guidelines had a 29 ml/m2 smaller indexed right ventricular end-diastolic volume (p [ 0.01) and a 33 ml/m2 smaller indexed right ventricular end-systolic volume (p <0.001) compared with patients who underwent PVR before the release of the guidelines. PVR 0 to 3 years after the guidelines was not a significant predictor of either indexed right ventricular end-diastolic volume (p [ 0.93) or indexed right ventricular end-systolic volume (p [ 0.18). Patients referred for PVR ‡3 years after the guidelines had significantly smaller CMR-based right ventricular volumes without significant trends in guideline-defined variables. Given the increased use of CMR to guide PVR referral, revisiting the guidelines to address appropriate use of CMR derived thresholds is indicated. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;114:1406e1411)
Severe pulmonary regurgitation (PR) in adults with repaired tetralogy of Fallot (rTOF) plays an important role in patient outcomes1,2 and can lead to adverse sequelae, such as right ventricular dilation and biventricular dysfunction.3e6 Although pulmonary valve replacement (PVR) can be effective in reversing aberrant remodeling,7e12 uncertainty exists regarding the optimal timing of PVR.13 The American College of Cardiology (ACC) and American Heart Association (AHA) released joint guidelines in 2008 to aid decision making for PVR referral. These guidelines provided qualitative recommendations for PVR without specifying quantitatively what these constitute.14 In contrast, cardiac magnetic resonance imaging (CMR)ebased volumetric thresholds for referral for PVR have been suggested in a series of studies published from 2000 to 2012.15e18 Increasing variability in referral patterns for PVR have been observed,19 and asymmetric adoption of CMR-based thresholds may be partially responsible. The aim of this study was to determine if adult a
Division of Cardiology, Department of Medicine and bDivision of Thoracic Imaging, Department of Radiology, Columbia University Medical Center, New York, New York. Manuscript received May 8, 2014; revised manuscript received and accepted July 18, 2014. See page 1410 for disclosure information. *Corresponding author: Tel: (212) 305-6936; fax: (212) 305-0490. E-mail address: [email protected] (M.J. Lewis). 0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.07.082
patients with rTOF are being referred for PVR earlier on the basis of CMR parameters despite the absence of CMR-based recommendations in the ACC/AHA guidelines. Methods We conducted a retrospective, cohort study evaluating all patients aged 18 years with rTOF at the Schneeweiss Adult Congenital Heart Center at Columbia University who underwent PVR from January 1, 1999, to February 2, 2014. Patients followed long term at our center and those referred for a single visit before PVR were included. We divided patients into 3 groups to evaluate for temporal changes in clinical practice after the release of the guidelines on December 2, 2008. Group 1 included patients who underwent PVR before the release of the guidelines. Group 2 included patients who underwent PVR patients within 3 years of the release of the guidelines (December 2, 2008, to December 2, 2011). Group 3 included all patients who underwent PVR 3 years after the release of the guidelines (December 3, 2011, to February 2, 2014). A predetermined set of clinical variables and imaging characteristics based on previous studies and the ACC/AHA guidelines14,16,17 were defined before data acquisition, as described below. Clinical and demographic variables were determined via review of written and electronic medical records. Details and www.ajconline.org
Congenital Heart Disease/CMR and PVR in Tetralogy of Fallot Table 1 Patient characteristics Variable Male Age at PVR, mean, (years) Pulmonary artery stenosis Right sided arch Atrial septal defect Absent pulmonary valve Coarctation of the aorta Cor triatriatum Anomalous coronary Patent ductus arteriosus Prior Procedures Blalock-Taussig shunt Pulmonary artery stent PFO/ASD closure Tricuspid valve repair Maze Additional VSD closure Coarctation of the aorta repair Ligation of patent ductus arteriosus NYHA Class 2 Moderate Tricuspid Regurgitation RV-PA Gradient >50 mm HG Symptoms Peak VO2, median, (cc*kg/min) Time from PVR to CMR, median, (months)
All Patients (n ¼ 79)
CMR (n ¼ 71)
No CMR (n ¼ 8)
44 (56%) 36 1.2 11 (14%) 6 (8%) 2 (3%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%)
39 (55%) 35 1.2 10 (14%) 6 (8%) 2 (3%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%)
5 (63%) 41 5.1 1 (13%) 0 0 0 0 0 0 0
26 11 3 3 2 2 1 1
26 10 2 3 2 2 1 1
(37%) (14%) (3%) (4%) (3%) (3%) (1%) (1%)
0 1 (13%) 1 (13%) 0 0 0 0 0
21 (30%) 9 (13%) 0 (0) 31 (44%) 26.7 (8) 8.6 (15)
2 (25%) 2 (25%) 1 (13%) 5 (63%) 23.7 (11) —
(33%) (14%) (4%) (4%) (3%) (3%) (1%) (1%)
23 (29%) 11 (14%) 1 (1%) 36 (46%) 26.7 (9) 8.6 (15)
Values are mean SD, n (%), or median (interquartile range). ASD ¼ atrial septal defect; CMR ¼ cardiac MRI; NYHA ¼ New York Heart Association; PFO ¼ patent foramen ovale; PVR ¼ pulmonary valve replacement; RV-PA ¼ Right ventricle-pulmonary artery; VSD ¼ ventricular septal defect.
timing of each patient’s initial surgical repair and any subsequent procedure, including PVR, were recorded. Patients were considered symptomatic if they reported dyspnea, decreased exercise tolerance, or exertional chest pain before PVR. The presence of clinically significant arrhythmias was defined as sustained, nonsinus supraventricular tachycardia or sustained ventricular tachycardia documented on 12-lead electrocardiography, Holter monitoring, or electrophysiology. Right ventricular outflow tract obstruction was defined as a gradient 50 mm Hg by preoperative cardiac catheterization. We reviewed reports from preoperative 2-dimensional color Doppler transthoracic echocardiograms for each patient. All studies were performed and interpreted at the Schneeweiss Adult Congenital Heart Center by cardiologists with years of expertise in congenital cardiac echocardiography. The severity of PR and tricuspid regurgitation was graded visually. Patients were classified as having mild or less tricuspid regurgitation or moderate or greater tricuspid regurgitation by transthoracic echocardiography. Right ventricular function was assessed and defined as normal or abnormal (including mild, moderate, and severe dysfunction) on the basis of echocardiographic appearance. CMR studies were performed with breath holding and electrocardiographic gating using a Signa 1.5-T magnetic
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Table 2 Demographic and clinical characteristics of participants, by timing of pulmonary valve replacement
Age at PVR, mean, (years) Echocardiographic data Moderate TR Elevated RVOT gradient Decreased RV function Symptoms Dyspnea Chest Pain Any Arrhythmia Any Symptom NYHA Class 2 Peak VO2†, median (cc*kg/min)
Group 1*
Group 2*
Group 3*
p-value for trend
37 1.7
35 2.2
36 2.6
0.73
6 (17%) 4 (11%) 22 (61%)
2 (8%) 1 (4%) 6 (25%)
3 (17%) 1 (5%) 7 (39%)
0.29 0.36 0.17
10 (28%) 2 (6%) 9 (25%) 12 (33%) 14 (39%) 24.4 (10)
12 (50%) 2 (8%) 8 (33%) 12 (50%) 8 (33%) 26.3 (8)
5 (28%) 3 (17%) 2 (11%) 12 (67%) 1 (5%) 28.5 (6)
0.18 0.29 0.20 0.16 0.17 0.09
Values are mean SD, n (%), or median (interquartile range). NYHA ¼ New York Heart Association; PVR ¼ pulmonary valve replacement; RV ¼ right ventricular; RVOT ¼ right ventricular outflow tract; TR ¼ tricuspid valve regurgitation. * Group 1 represents patients referred before the guidelines, Group 2 represents patients referred 0e3 years after the release of the guidelines, and Group 3 represents patients released 3 years after the release of the guidelines. † Peak VO2 was assessed in 50 patients.
resonance imaging scanner (GE Healthcare, Milwaukee, Wisconsin) and an 8-channel phased array. Before June 2003, short axis cine gradient echocardiographic images were obtained with the following parameters: repetition time 8.8 ms, echo time 15.2 ms, flip angle 15 , 8 views per segment, field of view 30 cm, acquisition matrix 256 128, slice thickness 8 mm with no gap, and receiver bandwidth 31.25 kHz. From June 2003 onward, short-axis cine images were acquired using a steady-state free precession pulse sequence with the following parameters: repetition time 3.6 ms, echo time 11.5 ms, flip angle 45 , 24 views per segment, field of view 35 cm, acquisition matrix 192 160, slice thickness 8 mm with no gap, receiver bandwidth 125 kHz. Images were reviewed and analyzed using ReportCARD software (GE Healthcare). A single reader with training and years of expertise in CMR imaging who was blinded to clinical status and the results of echocardiography performed CMR image analysis. Cine loops were used to select images at enddiastole and end-systole. End-diastole and end-systole were defined independently for the right and left ventricles as the phases with the largest and smallest volumes, respectively. Endocardial segmentation was performed by manual tracing of each end-diastolic and end-systolic short-axis view; areas were multiplied by slice thickness and summed to calculate right and left ventricular volumes. By convention, trabeculations and papillary muscles were considered part of the ventricular cavity in systole and diastole. Ejection fractions were calculated using the end-diastolic and end-systolic values. Testing for a significant trend across groups was conducted using Goodman and Kruskal’s gamma statistic for categorical variables. For continuous variables, we used an extension of Wilcoxon’s rank-sum test developed by Cuzick20 to test for trend across groups. To assess between-group differences in
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Figure 1. Box plot of RVEDVi by time from guidelines. Median is indicated by the line in the middle of each box, first and third quartiles by the ends of the box, and minimum and maximum values by the ends of the whiskers. There was a significant trend (p ¼ 0.034) in RVEDVi across groups. The median RVEDVi for group 1 was 191 ml/m2, compared with 189 ml/m2 for group 2 and 154 ml/m2 for group 3.
Figure 3. Box plot of RVEF by time from guidelines. Median is indicated by the line in the middle of each box, first and third quartiles by the ends of the box, minimum and maximum nonoutlier values by the ends of the whiskers, and outlier points are plotted individually. There was a significant trend (p ¼ 0.005) in RVEF across groups. The median RVEF for group 1 is 37%, compared with 45% for group 2 and 43% for group 3.
performed using Stata version 13.1 (StataCorp LP, College Station, Texas). Results
Figure 2. Box plot of RVESVi by time from guidelines. Median is indicated by the line in the middle of each box, first and third quartiles by the ends of the box, and minimum and maximum values by the ends of the whiskers. There was a significant trend (p ¼ 0.001) in RVESVi across groups. The median RVESVi for Group 1 was 112 ml/m2, compared with 102 ml/m2 for group 2 and 86 ml/m2 for group 3.
CMR parameters of interest, including indexed right ventricular end-diastolic volume (RVEDVi), indexed right ventricular end-systolic volume (RVESVi), and the right ventricular ejection fraction (RVEF), we first constructed univariate linear regression models with individual predictors. On the basis of the univariate analysis, we constructed multivariate linear regression models. Age at PVR and moderate or greater tricuspid regurgitation were prespecified for inclusion in the model, and any additional covariates reaching p <0.20 in univariate analysis were included.21 For linear regression models, the time from release of guidelines variable was modeled as a categorical variable, with group 1 defined as the reference group. All statistical analyses were
Seventy-nine patients with rTOF underwent surgical PVR at our institution from February 18, 1999, to February 2, 2014. Every patient had moderate or greater PR. Thirty-six patients (46%) were in group 1, 24 patients (30%) were in group 2, and 19 patients (24%) were in group 3. Table 1 summarizes the demographic and preoperative characteristics of our patients. Table 2 summarizes the demographic and clinical characteristics of patients by timing of PVR. There was no significant trend in any demographic or clinical characteristic across groups (Table 2). Of the 79 patients with rTOF who underwent PVR, preoperative CMR data were available for 71 patients (90%). The remaining 8 patients who did not undergo preoperative CMR had pacemakers or implantable cardioverter-defibrillators. Ten outside hospital CMR studies were reviewed for accuracy but not overread, because of software incompatibility. The number of CMR studies reviewed but not overread did not differ significantly across groups (p ¼ 0.30). Median time from CMR to PVR was 8.6 months and did not differ significantly between groups (p ¼ 0.84). Box plots of RVEDVi, RVESVi, and RVEF by group are illustrated in Figures 1, 2, and 3. There were significant decreasing trends in RVEDVi (p ¼ 0.034) and RVESVi (p ¼ 0.001) and an increasing trend in RVEF (p ¼ 0.005) across groups. Univariate and multivariate predictors of RVEDVi, RVESVi, and RVEF are listed in Table 3. Notably, patients in group 3 had significantly decreased RVEDVi and RVESVi compared with patients who underwent PVR before the release of the guidelines, whereas patients in group 2 did not. After controlling for age at PVR and the degree of tricuspid regurgitation at the time of PVR in a multivariate model, referral for PVR 3 years after the release of the guidelines (group 3) remained significantly associated with decreased RVEDVi and RVESVi compared with group 1.
Congenital Heart Disease/CMR and PVR in Tetralogy of Fallot
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Table 3 Univariate and Multivariate Predictors of Select CMR Parameters Variable/Increment
Univariate Predictors Coefficient (95% CI)
RVEDVI/(ml/m2) Time of PVR Pre-Guidelines 0e3 years After 3 years After Moderate TR Age at PVR/year Male RV-PA gradient>50 Any clinical symptom RVESVI/(ml/m2) Time of PVR Pre-Guidelines 0e3 years After 3 years After Moderate TR Age at PVR/year Male RV-PA gradient>50 Any clinical symptom RVEF/(%) Time of PVR Pre-Guidelines 0e3 years After 3 years After Moderate TR Age at PVR/year Male RV-PA gradient>50 Any clinical symptom
Multivariate Predictors p
0.8 28 30 0.7 4 22 9
Ref (21, 19) (51, 6.3) (4, 56) (2, 0.2) (21, 15) (62, 18) (27, 9)
Ref 0.93 0.01 0.03 0.14 0.70 0.27 0.32
12 33 29 0.2 8 8 7
Ref (28, 4) (50, 16) (8, 50) (1, 0.5) (23, 7) (41, 25) (22, 8)
Ref 0.13 <0.001 0.01 0.50 0.28 0.64 0.38
5.9 5.5 3.9 0.02 2.3 5.3 2.6
Ref (2, 10) (1, 10) (9.1, 1.3) (0.2,0.16) (1, 6) (13, 2) (0.9, 6)
Ref 0.002 0.01 0.14 0.82 0.20 0.17 0.14
Coefficient (95% CI)
p
0.9 29 30 0.7
Ref (18, 20) (50, 8) (5, 54) (2, 0.1)
Ref 0.93 0.01 0.02 0.08
10 33 27 0.3
Ref (26, 4.7) (49, 16) (7.4, 47) (1.0, 0.3)
Ref 0.18 <0.001 0.01 0.30
5.7 5.4 3.3 0.01
Ref (2, 10) (1, 10) (8, 2) (0.2, 0.2)
Ref 0.004 0.01 0.19 0.91
RVEDVI ¼ indexed right ventricular end diastolic volume; RVEF ¼ right ventricular ejection fraction; RVESVI ¼ indexed right ventricular end systolic volume; RV-PA ¼ right ventricular-pulmonary artery; PVR ¼ pulmonary valve replacement; TR ¼ tricuspid valve regurgitation.
Discussion The optimal timing of PVR in adult patients with rTOF and moderate or greater PR remains a complex issue. Because late mortality data are limited, most studies addressing postPVR outcomes have focused on imaging parameters derived from CMR as principal end points of interest. As a result, CMR-based volumetric thresholds have gained traction for identifying patients at highest risk for irreversible right ventricular remodeling and, consequently, which patients should undergo PVR. However, the current ACC/AHA guidelines do not provide recommendations regarding the use of CMR parameters to inform timing of PVR. The 2008 ACC/AHA guidelines for PVR in asymptomatic patients with rTOF with severe PR are limited to class II indications and include patients with moderate or greater right ventricular dilatation or dysfunction, sustained arrhythmias, moderate or greater tricuspid regurgitation, or right ventricular outflow tract obstruction. These recommendations are problematic for several reasons. First, they are nonquantitative with regard to how “moderate” and “severe” are defined and thus subject to considerable interobserver variation. Second, most adult patients with rTOF and hemodynamically significant PR have right ventricular dilatation that could be characterized as moderate.
Recommending PVR for all of these patients may be overly aggressive. Third, the presence of an akinetic right ventricular outflow tract patch or scar frequently results in variability in the echocardiographic interpretation of right ventricular size and function. Finally, despite the overwhelming use of CMR as the diagnostic modality of choice for right ventricular assessment in adult patients with congenital heart disease,22 specific CMR parameters are not addressed in the guidelines. We found significant trends in CMR parameters after the release of the guidelines, implying that patients are being referred with smaller right ventricular volumes for PVR. This was confirmed in our multivariate analysis, in which time of referral 3 years after the release of the guidelines was significantly associated with smaller preoperative RVEDVi and RVESVi, whereas time of referral 0 to 3 years after release was not. In contrast, there were no significant trends observed in variables defined by the guidelines as indications for PVR in asymptomatic patients. These results suggest that patients are being referred earlier for PVR without a corresponding change in the number of patients meeting guideline defined criteria. On the basis of our results, increased use of CMR may be contributing to earlier referral for PVR. Although
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unrecognized factors may have also affected referral times, the decision to proceed to PVR is heavily dependent on clinical and imaging characteristics. For example, although the expectation of future valve-in-valve option may prompt earlier referral for surgical PVR, clinical and imaging values still form the basis for referral. In our study, patient symptoms and echocardiographic findings were consistent across groups and did not show a significant trend. In contrast, CMR-based volumes at the time of PVR showed a significant trend across groups. In fact, the median RVEDVi at time of PVR in our latest cohort was 154 ml/m2, a value in line with the recommendations made in current publications. In aggregate, these findings suggest that the use of CMR and CMR-based indexes may be driving referral. As such, a consensus statement by the ACC and AHA regarding their proper use should be considered. Clinical practice guidelines are “systematically developed statements” designed to limit variability in care and foster the implementation of medical advances.23 Because of the plurality of provider educational and experiential backgrounds, guidelines are of particular importance in adult congenital heart disease, for which practice patterns can vary greatly. Modifying existing guidelines to integrate clinical data with CMR would ensure that eligible patients undergo testing in a timely fashion while discouraging PVR referrals based solely on volumetric thresholds. Because research suggesting the potential benefit of CMR-derived thresholds continues to accumulate in the absence of long-term data, a framework defining the appropriate use of CMR is necessary to minimize variability and ensure proper use. The absence of these data has likely contributed to significant variability in physician referral patterns and may be responsible for providers at tertiary care centers recommending PVR at smaller right ventricular volumes.19 As a retrospective study, there were limitations inherent in our study design. We are unable to show a definitive relation between publications advocating CMR-based thresholds and referral patterns and can only suggest this by showing a lack of significance in other potential drivers of PVR referral. By grouping time periods in 3-year increments on the basis of the release of the ACC/AHA guidelines, we may have limited our ability to draw conclusions regarding the effect of time on referral patterns. Finally, regional differences in care may account for some of the changes observed in our study; however, as a referral center with a large catchment area, we believe our findings are indicative of current practice nationally.
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Disclosures The authors have no conflicts of interest to disclose. 1. Luijnenburg SE, Helbing WA, Moelker A, Kroft LJ, Groenink M, Roos-Hesselink JW, de Rijke YB, Hazekamp MG, Bogers AJ, Vliegen HW, Mulder BJ. 5-Year serial follow-up of clinical condition and ventricular function in patients after repair of tetralogy of fallot. Int J Cardiol 2013;169:439e444. 2. Frigiola A, Redington AN, Cullen S, Vogel M. Pulmonary regurgitation is an important determinant of right ventricular contractile dysfunction in patients with surgically repaired tetralogy of Fallot. Circulation 2004;110:153e157. 3. Gatzoulis MA, Balaji S, Webber SA, Siu SC, Hokanson JS, Poile C, Rosenthal M, Nakazawa M, Moller JH, Gillette PC, Webb GD,
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Redington AN. Risk factors for arrhythmia and sudden cardiac death late after repair of tetralogy of Fallot: a multicentre study. Lancet 2000;356:975e981. Geva T, Sandweiss BM, Gauvreau K, Lock JE, Powell AJ. Factors associated with impaired clinical status in long-term survivors of tetralogy of fallot repair evaluated by magnetic resonance imaging. J Am Coll Cardiol 2004;43:1068e1074. Nollert G, Fischlein T, Bouterwek S, Bohmer C, Klinner W, Reichart B. Long-term survival in patients with repair of tetralogy of fallot: 36-year follow-up of 490 survivors of the first year after surgical repair. J Am Coll Cardiol 1997;30:1374e1383. Warnes CA. The adult with congenital heart disease: born to be bad? J Am Coll Cardiol 2005;46:1e8. Dave HH, Buechel ER, Dodge-Khatami A, Kadner A, Rousson V, Bauersfeld U, Pretre R. Early insertion of a pulmonary valve for chronic regurgitation helps restoration of ventricular dimensions. Ann Thorac Surg 2005;80:1615e1620. Buechel ER, Dave HH, Kellenberger CJ, Dodge-Khatami A, Pretre R, Berger F, Bauersfeld U. Remodelling of the right ventricle after early pulmonary valve replacement in children with repaired tetralogy of Fallot: assessment by cardiovascular magnetic resonance. Eur Heart J 2005;26:2721e2727. Frigiola A, Tsang V, Nordmeyer J, Lurz P, van Doorn C, Taylor AM, Bonhoeffer P, de Leval M. Current approaches to pulmonary regurgitation. Eur J Cardiothorac Surg 2008;34:576e580. Quail MA, Frigiola A, Giardini A, Muthurangu V, Hughes M, Lurz P, Khambadkone S, Deanfield JE, Tsang V, Taylor AM. Impact of pulmonary valve replacement in tetralogy of fallot with pulmonary regurgitation: a comparison of intervention and nonintervention. Ann Thorac Surg 2012;94:1619e1626. Lurz P, Coats L, Khambadkone S, Nordmeyer J, Boudjemline Y, Schievano S, Muthurangu V, Lee TY, Parenzan G, Derrick G, Cullen S, Walker F, Tsang V, Deanfield J, Taylor AM, Bonhoeffer P. Percutaneous pulmonary valve implantation: impact of evolving technology and learning curve on clinical outcome. Circulation 2008;117:1964e1972. Therrien J, Siu SC, McLaughlin PR, Liu PP, Williams WG, Webb GD. Pulmonary valve replacement in adults late after repair of tetralogy of Fallot: are we operating too late? J Am Coll Cardiol 2000;36: 1670e1675. Lee C, Park CS, Lee CH, Kwak JG, Kim SJ, Shim WS, Song JY, Choi EY, Lee SY. Durability of bioprosthetic valves in the pulmonary position: long-term follow-up of 181 implants in patients with congenital heart disease. J Thorac Cardiovasc Surg 2011;142: 351e358. Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, del Nido P, Fasules JW, Graham TP Jr, Hijazi ZM, Hunt SA, King ME, Landzberg MJ, Miner PD, Radford MJ, Walsh EP, Webb GD, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Buller CE, Creager MA, Ettinger SM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Page RL, Riegel B, Tarkington LG, Yancy CW; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American Society of Echocardiography; Heart Rhythm Society; International Society for Adult Congenital Heart Disease; Society for Cardiovascular Angiography, Interventions; Society of Thoracic Surgeons. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Management of Adults With Congenital Heart Disease). Developed in collaboration with the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;52:e143ee263. Oosterhof T, Meijboom FJ, Vliegen HW, Hazekamp MG, Zwinderman AH, Bouma BJ, van Dijk AP, Mulder BJ. Long-term follow-up of homograft function after pulmonary valve replacement in patients with tetralogy of fallot. Eur Heart J 2006;27:1478e1484. Therrien J, Provost Y, Merchant N, Williams W, Colman J, Webb G. Optimal timing for pulmonary valve replacement in adults after tetralogy of Fallot repair. Am J Cardiol 2005;95: 779e782.
Congenital Heart Disease/CMR and PVR in Tetralogy of Fallot 17. Geva T, Gauvreau K, Powell AJ, Cecchin F, Rhodes J, Geva J, del Nido P. Randomized trial of pulmonary valve replacement with and without right ventricular remodeling surgery. Circulation 2010;122: 201e208. 18. Lee C, Kim YM, Lee CH, Kwak JG, Park CS, Song JY, Shim WS, Choi EY, Lee SY, Baek JS. Outcomes of pulmonary valve replacement in 170 patients with chronic pulmonary regurgitation after relief of right ventricular outflow tract obstruction: implications for optimal timing of pulmonary valve replacement. J Am Coll Cardiol 2012;60:1005e1014. 19. Wald RM, Lyseggen E, Oechslin EN, Webb GD, Silversides CK. Variability in surgical referral patterns for pulmonary valve
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replacement in adults with repaired tetralogy of Fallot. Congenit Heart Dis 2009;4:231e238. Cuzick J. A Wilcoxon-type test for trend. Stat Med 1985;4:87e90. Maldonado G, Greenland S. Simulation study of confounder-selection strategies. Am J Epidemiol 1993;138:923e936. Orwat S, Diller GP, Baumgartner H. Imaging of congenital heart disease in adults: choice of modalities. Eur Heart J Cardiovasc Imaging 2014;15:6e17. Cabana MD, Rand CS, Powe NR, Wu AW, Wilson MH, Abboud PA, Rubin HR. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA 1999;282:1458e1465.
Severe pulmonary regurgitation (PR) in adults with repaired tetralogy of Fallot (rTOF) plays an important role in patient outcomes1,2 and can lead to adverse sequelae, such as right ventricular dilation and biventricular dysfunction.3e6 Although pulmonary valve replacement (PVR) can be effective in reversing aberrant remodeling,7e12 uncertainty exists regarding the optimal timing of PVR.13 The American College of Cardiology (ACC) and American Heart Association (AHA) released joint guidelines in 2008 to aid decision making for PVR referral. These guidelines provided qualitative recommendations for PVR without specifying quantitatively what these constitute.14 In contrast, cardiac magnetic resonance imaging (CMR)ebased volumetric thresholds for referral for PVR have been suggested in a series of studies published from 2000 to 2012.15e18 Increasing variability in referral patterns for PVR have been observed,19 and asymmetric adoption of CMR-based thresholds may be partially responsible. The aim of this study was to determine if adult a
Division of Cardiology, Department of Medicine and bDivision of Thoracic Imaging, Department of Radiology, Columbia University Medical Center, New York, New York. Manuscript received May 8, 2014; revised manuscript received and accepted July 18, 2014. See page 1410 for disclosure information. *Corresponding author: Tel: (212) 305-6936; fax: (212) 305-0490. E-mail address: [email protected] (M.J. Lewis). 0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.07.082
patients with rTOF are being referred for PVR earlier on the basis of CMR parameters despite the absence of CMR-based recommendations in the ACC/AHA guidelines. Methods We conducted a retrospective, cohort study evaluating all patients aged 18 years with rTOF at the Schneeweiss Adult Congenital Heart Center at Columbia University who underwent PVR from January 1, 1999, to February 2, 2014. Patients followed long term at our center and those referred for a single visit before PVR were included. We divided patients into 3 groups to evaluate for temporal changes in clinical practice after the release of the guidelines on December 2, 2008. Group 1 included patients who underwent PVR before the release of the guidelines. Group 2 included patients who underwent PVR patients within 3 years of the release of the guidelines (December 2, 2008, to December 2, 2011). Group 3 included all patients who underwent PVR 3 years after the release of the guidelines (December 3, 2011, to February 2, 2014). A predetermined set of clinical variables and imaging characteristics based on previous studies and the ACC/AHA guidelines14,16,17 were defined before data acquisition, as described below. Clinical and demographic variables were determined via review of written and electronic medical records. Details and www.ajconline.org
Congenital Heart Disease/CMR and PVR in Tetralogy of Fallot Table 1 Patient characteristics Variable Male Age at PVR, mean, (years) Pulmonary artery stenosis Right sided arch Atrial septal defect Absent pulmonary valve Coarctation of the aorta Cor triatriatum Anomalous coronary Patent ductus arteriosus Prior Procedures Blalock-Taussig shunt Pulmonary artery stent PFO/ASD closure Tricuspid valve repair Maze Additional VSD closure Coarctation of the aorta repair Ligation of patent ductus arteriosus NYHA Class 2 Moderate Tricuspid Regurgitation RV-PA Gradient >50 mm HG Symptoms Peak VO2, median, (cc*kg/min) Time from PVR to CMR, median, (months)
All Patients (n ¼ 79)
CMR (n ¼ 71)
No CMR (n ¼ 8)
44 (56%) 36 1.2 11 (14%) 6 (8%) 2 (3%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%)
39 (55%) 35 1.2 10 (14%) 6 (8%) 2 (3%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%)
5 (63%) 41 5.1 1 (13%) 0 0 0 0 0 0 0
26 11 3 3 2 2 1 1
26 10 2 3 2 2 1 1
(37%) (14%) (3%) (4%) (3%) (3%) (1%) (1%)
0 1 (13%) 1 (13%) 0 0 0 0 0
21 (30%) 9 (13%) 0 (0) 31 (44%) 26.7 (8) 8.6 (15)
2 (25%) 2 (25%) 1 (13%) 5 (63%) 23.7 (11) —
(33%) (14%) (4%) (4%) (3%) (3%) (1%) (1%)
23 (29%) 11 (14%) 1 (1%) 36 (46%) 26.7 (9) 8.6 (15)
Values are mean SD, n (%), or median (interquartile range). ASD ¼ atrial septal defect; CMR ¼ cardiac MRI; NYHA ¼ New York Heart Association; PFO ¼ patent foramen ovale; PVR ¼ pulmonary valve replacement; RV-PA ¼ Right ventricle-pulmonary artery; VSD ¼ ventricular septal defect.
timing of each patient’s initial surgical repair and any subsequent procedure, including PVR, were recorded. Patients were considered symptomatic if they reported dyspnea, decreased exercise tolerance, or exertional chest pain before PVR. The presence of clinically significant arrhythmias was defined as sustained, nonsinus supraventricular tachycardia or sustained ventricular tachycardia documented on 12-lead electrocardiography, Holter monitoring, or electrophysiology. Right ventricular outflow tract obstruction was defined as a gradient 50 mm Hg by preoperative cardiac catheterization. We reviewed reports from preoperative 2-dimensional color Doppler transthoracic echocardiograms for each patient. All studies were performed and interpreted at the Schneeweiss Adult Congenital Heart Center by cardiologists with years of expertise in congenital cardiac echocardiography. The severity of PR and tricuspid regurgitation was graded visually. Patients were classified as having mild or less tricuspid regurgitation or moderate or greater tricuspid regurgitation by transthoracic echocardiography. Right ventricular function was assessed and defined as normal or abnormal (including mild, moderate, and severe dysfunction) on the basis of echocardiographic appearance. CMR studies were performed with breath holding and electrocardiographic gating using a Signa 1.5-T magnetic
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Table 2 Demographic and clinical characteristics of participants, by timing of pulmonary valve replacement
Age at PVR, mean, (years) Echocardiographic data Moderate TR Elevated RVOT gradient Decreased RV function Symptoms Dyspnea Chest Pain Any Arrhythmia Any Symptom NYHA Class 2 Peak VO2†, median (cc*kg/min)
Group 1*
Group 2*
Group 3*
p-value for trend
37 1.7
35 2.2
36 2.6
0.73
6 (17%) 4 (11%) 22 (61%)
2 (8%) 1 (4%) 6 (25%)
3 (17%) 1 (5%) 7 (39%)
0.29 0.36 0.17
10 (28%) 2 (6%) 9 (25%) 12 (33%) 14 (39%) 24.4 (10)
12 (50%) 2 (8%) 8 (33%) 12 (50%) 8 (33%) 26.3 (8)
5 (28%) 3 (17%) 2 (11%) 12 (67%) 1 (5%) 28.5 (6)
0.18 0.29 0.20 0.16 0.17 0.09
Values are mean SD, n (%), or median (interquartile range). NYHA ¼ New York Heart Association; PVR ¼ pulmonary valve replacement; RV ¼ right ventricular; RVOT ¼ right ventricular outflow tract; TR ¼ tricuspid valve regurgitation. * Group 1 represents patients referred before the guidelines, Group 2 represents patients referred 0e3 years after the release of the guidelines, and Group 3 represents patients released 3 years after the release of the guidelines. † Peak VO2 was assessed in 50 patients.
resonance imaging scanner (GE Healthcare, Milwaukee, Wisconsin) and an 8-channel phased array. Before June 2003, short axis cine gradient echocardiographic images were obtained with the following parameters: repetition time 8.8 ms, echo time 15.2 ms, flip angle 15 , 8 views per segment, field of view 30 cm, acquisition matrix 256 128, slice thickness 8 mm with no gap, and receiver bandwidth 31.25 kHz. From June 2003 onward, short-axis cine images were acquired using a steady-state free precession pulse sequence with the following parameters: repetition time 3.6 ms, echo time 11.5 ms, flip angle 45 , 24 views per segment, field of view 35 cm, acquisition matrix 192 160, slice thickness 8 mm with no gap, receiver bandwidth 125 kHz. Images were reviewed and analyzed using ReportCARD software (GE Healthcare). A single reader with training and years of expertise in CMR imaging who was blinded to clinical status and the results of echocardiography performed CMR image analysis. Cine loops were used to select images at enddiastole and end-systole. End-diastole and end-systole were defined independently for the right and left ventricles as the phases with the largest and smallest volumes, respectively. Endocardial segmentation was performed by manual tracing of each end-diastolic and end-systolic short-axis view; areas were multiplied by slice thickness and summed to calculate right and left ventricular volumes. By convention, trabeculations and papillary muscles were considered part of the ventricular cavity in systole and diastole. Ejection fractions were calculated using the end-diastolic and end-systolic values. Testing for a significant trend across groups was conducted using Goodman and Kruskal’s gamma statistic for categorical variables. For continuous variables, we used an extension of Wilcoxon’s rank-sum test developed by Cuzick20 to test for trend across groups. To assess between-group differences in
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Figure 1. Box plot of RVEDVi by time from guidelines. Median is indicated by the line in the middle of each box, first and third quartiles by the ends of the box, and minimum and maximum values by the ends of the whiskers. There was a significant trend (p ¼ 0.034) in RVEDVi across groups. The median RVEDVi for group 1 was 191 ml/m2, compared with 189 ml/m2 for group 2 and 154 ml/m2 for group 3.
Figure 3. Box plot of RVEF by time from guidelines. Median is indicated by the line in the middle of each box, first and third quartiles by the ends of the box, minimum and maximum nonoutlier values by the ends of the whiskers, and outlier points are plotted individually. There was a significant trend (p ¼ 0.005) in RVEF across groups. The median RVEF for group 1 is 37%, compared with 45% for group 2 and 43% for group 3.
performed using Stata version 13.1 (StataCorp LP, College Station, Texas). Results
Figure 2. Box plot of RVESVi by time from guidelines. Median is indicated by the line in the middle of each box, first and third quartiles by the ends of the box, and minimum and maximum values by the ends of the whiskers. There was a significant trend (p ¼ 0.001) in RVESVi across groups. The median RVESVi for Group 1 was 112 ml/m2, compared with 102 ml/m2 for group 2 and 86 ml/m2 for group 3.
CMR parameters of interest, including indexed right ventricular end-diastolic volume (RVEDVi), indexed right ventricular end-systolic volume (RVESVi), and the right ventricular ejection fraction (RVEF), we first constructed univariate linear regression models with individual predictors. On the basis of the univariate analysis, we constructed multivariate linear regression models. Age at PVR and moderate or greater tricuspid regurgitation were prespecified for inclusion in the model, and any additional covariates reaching p <0.20 in univariate analysis were included.21 For linear regression models, the time from release of guidelines variable was modeled as a categorical variable, with group 1 defined as the reference group. All statistical analyses were
Seventy-nine patients with rTOF underwent surgical PVR at our institution from February 18, 1999, to February 2, 2014. Every patient had moderate or greater PR. Thirty-six patients (46%) were in group 1, 24 patients (30%) were in group 2, and 19 patients (24%) were in group 3. Table 1 summarizes the demographic and preoperative characteristics of our patients. Table 2 summarizes the demographic and clinical characteristics of patients by timing of PVR. There was no significant trend in any demographic or clinical characteristic across groups (Table 2). Of the 79 patients with rTOF who underwent PVR, preoperative CMR data were available for 71 patients (90%). The remaining 8 patients who did not undergo preoperative CMR had pacemakers or implantable cardioverter-defibrillators. Ten outside hospital CMR studies were reviewed for accuracy but not overread, because of software incompatibility. The number of CMR studies reviewed but not overread did not differ significantly across groups (p ¼ 0.30). Median time from CMR to PVR was 8.6 months and did not differ significantly between groups (p ¼ 0.84). Box plots of RVEDVi, RVESVi, and RVEF by group are illustrated in Figures 1, 2, and 3. There were significant decreasing trends in RVEDVi (p ¼ 0.034) and RVESVi (p ¼ 0.001) and an increasing trend in RVEF (p ¼ 0.005) across groups. Univariate and multivariate predictors of RVEDVi, RVESVi, and RVEF are listed in Table 3. Notably, patients in group 3 had significantly decreased RVEDVi and RVESVi compared with patients who underwent PVR before the release of the guidelines, whereas patients in group 2 did not. After controlling for age at PVR and the degree of tricuspid regurgitation at the time of PVR in a multivariate model, referral for PVR 3 years after the release of the guidelines (group 3) remained significantly associated with decreased RVEDVi and RVESVi compared with group 1.
Congenital Heart Disease/CMR and PVR in Tetralogy of Fallot
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Table 3 Univariate and Multivariate Predictors of Select CMR Parameters Variable/Increment
Univariate Predictors Coefficient (95% CI)
RVEDVI/(ml/m2) Time of PVR Pre-Guidelines 0e3 years After 3 years After Moderate TR Age at PVR/year Male RV-PA gradient>50 Any clinical symptom RVESVI/(ml/m2) Time of PVR Pre-Guidelines 0e3 years After 3 years After Moderate TR Age at PVR/year Male RV-PA gradient>50 Any clinical symptom RVEF/(%) Time of PVR Pre-Guidelines 0e3 years After 3 years After Moderate TR Age at PVR/year Male RV-PA gradient>50 Any clinical symptom
Multivariate Predictors p
0.8 28 30 0.7 4 22 9
Ref (21, 19) (51, 6.3) (4, 56) (2, 0.2) (21, 15) (62, 18) (27, 9)
Ref 0.93 0.01 0.03 0.14 0.70 0.27 0.32
12 33 29 0.2 8 8 7
Ref (28, 4) (50, 16) (8, 50) (1, 0.5) (23, 7) (41, 25) (22, 8)
Ref 0.13 <0.001 0.01 0.50 0.28 0.64 0.38
5.9 5.5 3.9 0.02 2.3 5.3 2.6
Ref (2, 10) (1, 10) (9.1, 1.3) (0.2,0.16) (1, 6) (13, 2) (0.9, 6)
Ref 0.002 0.01 0.14 0.82 0.20 0.17 0.14
Coefficient (95% CI)
p
0.9 29 30 0.7
Ref (18, 20) (50, 8) (5, 54) (2, 0.1)
Ref 0.93 0.01 0.02 0.08
10 33 27 0.3
Ref (26, 4.7) (49, 16) (7.4, 47) (1.0, 0.3)
Ref 0.18 <0.001 0.01 0.30
5.7 5.4 3.3 0.01
Ref (2, 10) (1, 10) (8, 2) (0.2, 0.2)
Ref 0.004 0.01 0.19 0.91
RVEDVI ¼ indexed right ventricular end diastolic volume; RVEF ¼ right ventricular ejection fraction; RVESVI ¼ indexed right ventricular end systolic volume; RV-PA ¼ right ventricular-pulmonary artery; PVR ¼ pulmonary valve replacement; TR ¼ tricuspid valve regurgitation.
Discussion The optimal timing of PVR in adult patients with rTOF and moderate or greater PR remains a complex issue. Because late mortality data are limited, most studies addressing postPVR outcomes have focused on imaging parameters derived from CMR as principal end points of interest. As a result, CMR-based volumetric thresholds have gained traction for identifying patients at highest risk for irreversible right ventricular remodeling and, consequently, which patients should undergo PVR. However, the current ACC/AHA guidelines do not provide recommendations regarding the use of CMR parameters to inform timing of PVR. The 2008 ACC/AHA guidelines for PVR in asymptomatic patients with rTOF with severe PR are limited to class II indications and include patients with moderate or greater right ventricular dilatation or dysfunction, sustained arrhythmias, moderate or greater tricuspid regurgitation, or right ventricular outflow tract obstruction. These recommendations are problematic for several reasons. First, they are nonquantitative with regard to how “moderate” and “severe” are defined and thus subject to considerable interobserver variation. Second, most adult patients with rTOF and hemodynamically significant PR have right ventricular dilatation that could be characterized as moderate.
Recommending PVR for all of these patients may be overly aggressive. Third, the presence of an akinetic right ventricular outflow tract patch or scar frequently results in variability in the echocardiographic interpretation of right ventricular size and function. Finally, despite the overwhelming use of CMR as the diagnostic modality of choice for right ventricular assessment in adult patients with congenital heart disease,22 specific CMR parameters are not addressed in the guidelines. We found significant trends in CMR parameters after the release of the guidelines, implying that patients are being referred with smaller right ventricular volumes for PVR. This was confirmed in our multivariate analysis, in which time of referral 3 years after the release of the guidelines was significantly associated with smaller preoperative RVEDVi and RVESVi, whereas time of referral 0 to 3 years after release was not. In contrast, there were no significant trends observed in variables defined by the guidelines as indications for PVR in asymptomatic patients. These results suggest that patients are being referred earlier for PVR without a corresponding change in the number of patients meeting guideline defined criteria. On the basis of our results, increased use of CMR may be contributing to earlier referral for PVR. Although
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unrecognized factors may have also affected referral times, the decision to proceed to PVR is heavily dependent on clinical and imaging characteristics. For example, although the expectation of future valve-in-valve option may prompt earlier referral for surgical PVR, clinical and imaging values still form the basis for referral. In our study, patient symptoms and echocardiographic findings were consistent across groups and did not show a significant trend. In contrast, CMR-based volumes at the time of PVR showed a significant trend across groups. In fact, the median RVEDVi at time of PVR in our latest cohort was 154 ml/m2, a value in line with the recommendations made in current publications. In aggregate, these findings suggest that the use of CMR and CMR-based indexes may be driving referral. As such, a consensus statement by the ACC and AHA regarding their proper use should be considered. Clinical practice guidelines are “systematically developed statements” designed to limit variability in care and foster the implementation of medical advances.23 Because of the plurality of provider educational and experiential backgrounds, guidelines are of particular importance in adult congenital heart disease, for which practice patterns can vary greatly. Modifying existing guidelines to integrate clinical data with CMR would ensure that eligible patients undergo testing in a timely fashion while discouraging PVR referrals based solely on volumetric thresholds. Because research suggesting the potential benefit of CMR-derived thresholds continues to accumulate in the absence of long-term data, a framework defining the appropriate use of CMR is necessary to minimize variability and ensure proper use. The absence of these data has likely contributed to significant variability in physician referral patterns and may be responsible for providers at tertiary care centers recommending PVR at smaller right ventricular volumes.19 As a retrospective study, there were limitations inherent in our study design. We are unable to show a definitive relation between publications advocating CMR-based thresholds and referral patterns and can only suggest this by showing a lack of significance in other potential drivers of PVR referral. By grouping time periods in 3-year increments on the basis of the release of the ACC/AHA guidelines, we may have limited our ability to draw conclusions regarding the effect of time on referral patterns. Finally, regional differences in care may account for some of the changes observed in our study; however, as a referral center with a large catchment area, we believe our findings are indicative of current practice nationally.
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