Abstract
Patients who have undergone the Fontan procedure are at risk for thrombosis, ventricular dysfunction, and valve regurgitation, but data to guide the medical treatment and prevention of these adverse outcomes in this population are lacking. This analysis examined medication usage among Fontan patients by putative indication and by study center. The medical history and current medications of 546 Fontan subjects, ages 6–18 years, were assessed in a Pediatric Heart Network multicenter cross-sectional study. Cardiac imaging was performed within 3 months of enrollment. The majority of the subjects (64%) were taking two or more medications. Antithrombotics were taken by 86% of those with a history of stroke, thrombosis, or both and 67% of those without such a history (P = 0.01). Conversely, 14% of those with a history of stroke, thrombosis, or both were taking no antithrombotic. Angiotensin-converting enzyme inhibitor (ACEi) therapy was independently associated with moderate or severe atrioventricular valve regurgitation (P = 0.004), right ventricular morphology (P < 0.001), and shorter time since Fontan (P = 0.004) but not with ventricular systolic dysfunction. Glycoside therapy and diuretic therapy each was associated with older age at Fontan (P = 0.001 and P = 0.023, respectively) and a history of post-Fontan arrhythmia (P < 0.001 and P = 0.003, respectively) but not with ventricular systolic dysfunction. Medication use rates varied widely among the centers, even with controls for center differences in patient characteristics. Prospective therapeutic trials are needed to guide the medical treatment of Fontan patients.
Keywords: Congenital, Drugs, Fontan procedure, Heart defects, Morbidity, Pediatrics
The Fontan procedure has provided excellent palliation for many patients with single ventricle cardiac malformations [10]. However, these individuals are at risk for important complications including thromboembolism, ventricular dysfunction, and valve regurgitation [2, 4, 7, 8, 11, 13, 17, 19]. Definitive approaches to treat and prevent these conditions, to maintain exercise capacity, and to improve functional status remain to be established.
The Pediatric Heart Network (Appendix) carried out a prospective cross-sectional study of 546 Fontan subjects, the largest such study to date [20]. The overarching aim of this study was to collect information to facilitate the development of future clinical trials in this population [1]. The goals of the current analysis were to describe current medication therapy, to examine center variation in medication usage, to identify surgical, demographic, and medical condition correlates of medication therapy, and to consider medication therapy in the context of putative clinical indications.
Materials and Methods
Patient Sample
The design of the Pediatric Heart Network Fontan Cross-Sectional Study has been reported previously [20]. The records of 1,078 children at the seven Network centers who had undergone a Fontan procedure were screened. This screening found 644 children fully eligible for the study, and 546 subjects ages 6 through 18 years were enrolled beginning in March 2003 and ending in April 2004. Local institutional review board or ethics committee approval was obtained at each center, and all subjects and/or their parents gave informed consent.
Medical History
The age of the study subjects at enrollment, their age at Fontan surgery, and the type of Fontan procedure were recorded. At study entry, a detailed medical record review was performed to identify history of thrombosis and history of stroke. For purposes of analysis, “history of stroke and/or thrombosis” was defined as a history of stroke, thrombosis, or both. Peripheral vein and artery thromboses were excluded.
Imaging Studies
The subjects underwent transthoracic echocardiography within 3 months of enrollment. Of the 546 subjects, 161 also underwent cardiac magnetic resonance imaging (cMRI). All imaging data were acquired according to uniform study protocols then analyzed in respective echocardiography and cMRI core laboratories. Ventricular anatomy was characterized by echocardiography as left (LV), right (RV), or mixed (e.g., unbalanced atrioventricular canal). The echocardiographic methods and criteria for severity of semilunar and atrioventricular (AV) valve regurgitation have been published previously [1].
For purposes of the current analysis, AV valve regurgitation was defined as moderate or severe AV valve regurgitation, semilunar valve regurgitation as moderate or severe semilunar valve regurgitation, and valve regurgitation as moderate or severe AV valve and/or semilunar valve regurgitation. Ventricular systolic dysfunction, whether LV or RV, was considered present if the ejection fraction was less than 55% by echocardiogram or cMRI, and was definitively determined for 486 subjects. Ventricular diastolic function was assessed by echocardiography using two grading systems: restrictive pattern present versus absent and grades of 0 (no impairment) to 3 (greatest impairment) in diastolic filling [15].
Medication Therapy
For each subject, a complete list of active cardiac and noncardiac medications was ascertained at enrollment by interview and review of the medical record. Cardiac medications were grouped as antithrombotics, angiotensin-converting enzyme inhibitors (ACEi), glycosides, diuretics, calcium channel blockers, β-adrenoreceptor blockers, and antiarrhythmic agents. For analysis purposes, antithrombotic therapy was defined as none, aspirin or clopidogrel alone, or intensive (warfarin, low molecular weight heparin, or unfractionated heparin with or without other antithrombotics).
Statistical Analysis
Chi-square and Fisher’s exact tests were used to compare medication use rates by absence or presence of medical complications, specifically, history of stroke, history of thrombosis, history of stroke and/or thrombosis, AV valve regurgitation, semilunar valve regurgitation, valve regurgitation, ventricular systolic dysfunction, and valve regurgitation and/or ventricular systolic dysfunction. For antithrombotic therapy (none vs. aspirin or clopidogrel vs. warfarin with or without other antithrombotics), a multinomial regression model was used due to the presence of nonproportional odds. Medication use rates by center were compared univariately using the chi-square and Fisher’s exact tests. Multivariable logistic regression was used to compare medication use by center adjusted for covariates including medical complications, age at Fontan, years since Fontan, age at enrollment, gender, race/ethnicity, ventricular morphologic type, type of Fontan, history of arrhythmia after Fontan, and median number of interventional cardiac catheterizations and surgical interventions since completion of Fontan. These covariates were included in the multivariable model if they differed by center or between those receiving and those not receiving medication.
Results
Demographics
Table 1 provides the demographics and characteristics of the subjects. The centers varied significantly in distribution of race/ethnicity (P < 0.001), age at Fontan (P < 0.001), and years since Fontan at time of enrollment (P < 0.001), as well as in the median number of interventional cardiac catheterizations (P < 0.001) and surgical interventions (P = 0.003) since Fontan. Ventricular type also varied among centers (P = 0.004), with ranges of 35–60% for LV, 25–43% for RV, and 12–27% for mixed type.
Table 1.
Fontan cross-sectional study subject characteristics and therapies (P values reflect differences among study centers)
| Characteristic at enrollment | n (%) | P value |
|---|---|---|
| n | 546 | |
| Age (years) | 11.9 ± 3.4 | 0.24 |
| Males | 329 (60.3) | 0.56 |
| Race/ethnicity | < 0.001 | |
| Hispanic | 35 (6.4) | |
| Non-Hispanic, white | 397 (72.7) | |
| Non-Hispanic, black | 50 (9.2) | |
| Non-Hispanic, other | 35 (6.4) | |
| Unknown | 29 (5.3) | |
| Ventricular type | 0.004 | |
| Left | 265 (48.5) | |
| Mixed | 184 (33.7) | |
| Right | 97 (17.8) | |
| Age at Fontan (years) | 3.4 ± 2.1 | < 0.001 |
| Years since Fontan | 8.6 ± 3.4 | < 0.001 |
| Catheterization interventions: median (range)a | 0 (0–8) | < 0.001 |
| Surgical interventions: median (range)a | 0 (0–9) | 0.003 |
| Current medications | < 0.001 | |
| No medication | 60 (11.0) | |
| One medication | 136 (24.9) | |
| Two or more medications | 350 (64.1) | |
| Current cardiac medications | < 0.001 | |
| No medication | 73 (13.4) | |
| One medication | 177 (32.4) | |
| Two or more medications | 296 (54.2) | |
| Any antithrombotic | 372 (68.1) | < 0.001 |
| Aspirin or clopidogrel only | 295 (54.0) | |
| Intensiveb | 77 (14.1) | |
| ACEi | 313 (57.3) | < 0.001 |
| Glycoside | 144 (26.4) | 0.01 |
| Diuretics | 85 (15.6) | < 0.001 |
ACEi angiotensin-converting enzyme inhibitor
No. of procedures since Fontan completion
Warfarin, heparin, low molecular weight heparin, dipyridamole, tirofiban
Medical Complications
After the Fontan, a history of stroke, thrombosis, or both was present in 8% of the subjects, ventricular systolic dysfunction in 37%, AV valve regurgitation in 19%, semilunar valve regurgitation in 9%, and valve regurgitation in 33% (Fig. 1). No significant differences in the prevalence of these medical complications were found among the centers, although there was a trend toward a difference in the prevalence of AV valve regurgitation (9–31%; P = 0.056).
Fig. 1.
Distribution of post-Fontan complications by center and the percentage of Fontan subjects at each of the seven centers with a history of thrombosis and/or stroke, with ventricular dysfunction, and with moderate or severe valve regurgitation. Each center is represented by a color
Current Medications
Most of the subjects (89%) were taking at least one medication, and 64% were taking two or more medications. More than half (54%) were taking two or more cardiac medications (i.e., antithrombotics, ACEi, glycosides, and diuretics; Fig. 2). The noncardiac medications included anticonvulsants, gastrointestinal medications, bronchodilators, hormonal agents, and biologics.
Fig. 2.
Percentage of Fontan subjects taking no medication (hatched bar), one medication (open bar), or two or more medications (black bar) for all medications and for cardiac medications
Antithrombotics
Of the 546 subjects, 295 (54%) were taking aspirin or clopidogrel alone, 77 (14%) were taking intensive antithrombotics (69 of these were taking warfarin alone), and 174 (32%) were taking no antithrombotics (Table 2 and Fig. 3). The majority of the subjects with a history of stroke, thrombosis, or both (86%) were taking at least one antithrombotic compared with 67% of the subjects without such history (P = 0.01). Conversely, 14% of those with a history of stroke, thrombosis, or both were taking no antithrombotic. Multivariable analysis showed that intensive antithrombotic therapy was most strongly associated with a history of stroke, thrombosis, or both (odds ratio, 26 vs. no antithrombotic and 19 vs. aspirin or clopidogrel alone; P < 0.001). It was more weakly associated with the number of surgical interventions after Fontan (P = 0.008) and negatively associated with years since Fontan (P < 0.001). Notably, intensive antithrombotic use was more common among the subjects with a history of arrhythmia after Fontan (30/111, 27%) than among those without such history (48/434, 11%). However, a history of arrhythmia was not an independent predictor of antithrombotic use (P = 0.06) when added to the model in Table 2, due to its positive correlation with number of surgical interventions after Fontan (mean, 1.0 ± 1.5 vs. 0.2 ± 0.7 surgical interventions for subjects with vs. those without a history of arrhythmia, respectively).
Table 2.
Correlates of antithrombotic usage (P values are from multinomial logistic regression modeling)
| Predictor | Outcome |
P Value | ||
|---|---|---|---|---|
| Intensive antithrombotic | Aspirin/clopidogrel | No antithrombotic | ||
| n | 77 | 295 | 174 | |
| Center | < 0.001 | |||
| Male (%) | 49.4 | 62.7 | 60.9 | 0.25 |
| Ethnicity (%) | 0.56 | |||
| Hispanic | 9.5 | 6.4 | 6.3 | |
| Non-Hispanic, black | 5.4 | 12.0 | 7.5 | |
| Non-Hispanic, other | 6.8 | 5.3 | 9.4 | |
| Non-Hispanic, white | 78.4 | 76.3 | 76.9 | |
| Age at Fontan (years) | 4.0 ± 2.6 | 3.4 ± 2.1 | 3.2 ± 1.9 | 0.03 |
| Years since Fontan | 8.7 ± 4.2 | 8.1 ± 3.4 | 9.3 ± 3.1 | < 0.001 |
| Age at enrollment (years) | 12.6 ± 4.0 | 11.3 ± 3.3 | 12.4 ± 3.2 | < 0.001 |
| Ventricular type (%) | 0.34 | |||
| Left | 59.7 | 45.1 | 49.4 | |
| Mixed | 16.9 | 19.7 | 14.9 | |
| Right | 23.4 | 35.3 | 35.6 | |
| No. of surgical interventionsa | 1.0 ± 1.6 | 0.3 ± 0.7 | 0.3 ± 0.9 | < 0.001 |
| Number of catheterization interventionsa | 1.1 ± 1.4 | 0.8 ± 1.1 | 0.8 ± 0.2 | 0.31 |
| History of thrombosisa (%) | 32.5 | 2.7 | 2.9 | < 0.001 |
| History of strokea (%) | 9.1 | 1.0 | 0.6 | < 0.001 |
| History of stroke/thrombosisa (%) | 37.7 | 3.1 | 3.5 | < 0.001 |
| Multivariable model | OR (95% CI) |
|||
|---|---|---|---|---|
| Intensive antithrombotic vs. no antithrombotic | Intensive antithrombotic vs. aspirin/clopidogrel | Aspirin/clopidogrel vs. no antithrombotic | ||
| Center | < 0.001 | |||
| History of stroke/thrombosisa | 26.06b (8.62–78.79) | 18.95b (7.44–48.26) | 1.38 (0.41–4.60) | < 0.001 |
| Years since Fontan | 0.90b (0.82–1.00) | 1.05 (0.96–1.14) | 0.86b (0.80–0.93) | < 0.001 |
| No. of surgical interventionsa | 1.52b (1.13–2.05) | 1.43b (1.09–1.87) | 1.07 (0.80–1.43) | 0.008 |
Number of procedures and history of thrombosis and stroke since Fontan completion
Odds ratio differs from one (P < 0.05)
OR odds ratio, CI confidence interval, AV atrioventricular
Fig. 3.
Percentage of Fontan subjects taking no antithrombotic (hatched bar), aspirin or clopidogrel only (open bar), or intensive antithrombotics (solid bar), by history of thrombosis and/or stroke
ACEi
A majority of the subjects (57%) were taking an ACEi, namely, enalapril, lisinopril, captopril, fosinopril, enalaprilat, benazepril, or ramipril. In multivariable modeling, three independent correlates of ACEi therapy emerged (Table 3): RV morphology (P < 0.001), AV valve regurgitation (P = 0.004), and shorter time since Fontan (P = 0.004). Neither ventricular systolic nor diastolic dysfunction correlated with ACEi therapy (comprehensive analysis of ventricular function by echocardiography and MRI for this cohort has been reported previously) [1, 16].
Table 3.
Correlates of angiotensin-converting enzyme inhibitor (ACEi) usage (P values are from logistic regression modeling)
| Predictor | ACEi use | No ACEi use | OR (95% CI) | P value |
|---|---|---|---|---|
| na | 313 | 233 | ||
| Center (%) | < 0.001 | |||
| Male | 62.6 | 57.1 | 1.26 (0.89–1.78) | 0.19 |
| Ethnicity (%) | 0.11 | |||
| Hispanic | 7.8 | 5.4 | 1.35 (0.65–2.79) | NS |
| Non-Hispanic, black | 8.1 | 11.7 | 0.65 (0.36–1.17) | NS |
| Non-Hispanic, other | 5.1 | 9.0 | 0.53 (0.26–1.06) | NS |
| Non-Hispanic, white | 79.0 | 73.9 | 1.00 | – |
| Age at Fontan (years) | 3.5 ± 2.3 | 3.3 ± 1.9 | 1.05 (0.96–1.14) | 0.30 |
| Years since Fontan | 8.3 ± 3.5 | 8.9 ± 3.4 | 0.95 (0.90–0.99) | 0.03 |
| Age at enrollment (years) | 11.7 ± 3.4 | 12.1 ± 3.4 | 0.96 (0.92–1.01) | 0.13 |
| Ventricular type (%) | < 0.001 | |||
| Left | 42.5 | 56.7 | 0.40 (0.27–0.59) | < 0.001 |
| Mixed | 15.3 | 21.0 | 0.39 (0.23–0.64) | < 0.001 |
| Right | 42.2 | 22.3 | 1.00 | – |
| No. of surgical interventionsb | 0.4 ± 1.0 | 0.4 ± 1.0 | 1.09 (0.91–1.31) | 0.37 |
| No. of catheter interventionsb | 0.9 ± 1.2 | 0.8 ± 1.1 | 1.12 (0.96–1.30) | 0.14 |
| History of arrhythmiab (%) | 24.4 | 15.0 | 1.73 (1.12–2.69) | 0.015 |
| AV valve regurgitationc (%) | 22.8 | 13.8 | 1.85 (1.16–2.94) | 0.01 |
| Semilunar valve regurgitationc (%) | 9.3 | 8.3 | 1.13 (0.51–2.51) | 0.78 |
| Valve regurgitationc (%) | 38.4 | 25.7 | 1.80 (1.12–2.88) | 0.02 |
| Vent. systolic dysfunctionc (%) | 39.4 | 34.1 | 1.26 (0.87–1.82) | 0.23 |
| Valve regurgitation and/or vent. dysfunctionc (%) | 67.0 | 58.9 | 1.41 (0.93–2.14) | 0.10 |
| Vent diastolic dysfunctionc (%) | 65.9 | 60.6 | 1.25 (0.80–1.97) | 0.33 |
| Valve regurgitation and/or vent. systolic and/or diastolic dysfunctionc (%) | 93.2 | 89.2 | 1.66 (0.82–3.37) | 0.16 |
| Multivariable model (n = 528; R2 = 0.16) | OR (95% CI) |
P value | |
|---|---|---|---|
| ACEi use vs. no ACEi | |||
| Center | < 0.001 | ||
| Ventricular type | < 0.001 | ||
| Left | 0.40 | (0.25–0.62) | |
| Mixed | 0.25 | (0.14–0.45) | |
| Right | 1.00 | – | |
| Years since Fontan | 0.92 | (0.87–0.97) | 0.004 |
| AV valve regurgitation | 2.12 | (1.26–3.55) | 0.004 |
Sample size may be smaller for some predictors
No. of procedures or positive history since Fontan completion
Measured at study enrollment
OR odds ratio, CI confidence interval, AV atrioventricular
Cardiac Glycosides
A minority of the subjects (26%) were taking a cardiac glycoside, either digoxin (n = 142) or digitoxin (n = 2). In multivariable modeling, glycoside therapy was independently associated with older age at the time of Fontan (P = 0.001), greater numbers of surgical interventions since the Fontan (P = 0.004), and history of post-Fontan arrhythmia (P < 0.001), but not with valve regurgitation or ventricular function (Table 4).
Table 4.
Correlates of glycoside usage (P values are from logistic regression)
| Predictor | Glycoside use | No glycoside use | OR (95% CI) | P value |
|---|---|---|---|---|
| na | 144 | 402 | ||
| Center (%) | 0.01 | |||
| Male | 54.9 | 62.2 | 0.74 (0.50–1.09) | 0.12 |
| Ethnicity (%) | 0.38 | |||
| Hispanic | 9.4 | 5.8 | 1.62 (0.79–3.34) | NS |
| Non-Hispanic, black | 7.2 | 10.6 | 0.69 (0.33–1.42) | NS |
| Non-Hispanic, other | 7.2 | 6.6 | 1.10 (0.51–2.36) | NS |
| Non-Hispanic, white | 76.3 | 77.0 | 1.00 | – |
| Age at Fontan (years) | 3.9 ± 2.4 | 3.3 ± 2.0 | 1.14 (1.04–1.24) | 0.003 |
| Years since Fontan | 9.0 ± 3.9 | 8.4 ± 3.2 | 1.05 (1.00–1.11) | 0.07 |
| Age at enrollment (years) | 12.8 ± 3.8 | 11.5 ± 3.2 | 1.11 (1.05–1.17) | < 0.001 |
| Ventricular type (%) | 0.88 | |||
| Left | 47.2 | 49.0 | 0.90 (0.59–1.38) | NS |
| Mixed | 17.4 | 17.9 | 0.91 (0.52–1.58) | NS |
| Right | 35.4 | 33.1 | 1.00 | – |
| No. of surgical interventionsb | 0.8 ± 1.4 | 0.3 ± 0.7 | 1.65 (1.33–2.03) | < 0.001 |
| No. of catheter interventionsb | 0.9 ± 1.4 | 0.8 ± 1.1 | 1.11 (0.95–1.30) | 0.20 |
| History of arrhythmiab | 41.7 | 12.7 | 4.90 (3.15, 7.63) | < 0.001 |
| AV valve regurgitationc | 21.6 | 18.0 | 1.25 (0.78–2.03) | 0.36 |
| Semilunar valve regurgitationc | 10.8 | 8.2 | 1.36 (0.59–3.13) | 0.47 |
| Valve regurgitationc | 38.7 | 31.2 | 1.39 (0.85–2.28) | 0.19 |
| Ventricular systolic dysfunctionc | 41.1 | 35.6 | 1.26 (0.83–1.92) | 0.27 |
| Valve regurgitation and/or ventricular dysfunctione | 68.3 | 61.8 | 1.33 (0.83–2.15) | 0.24 |
| Multivariable model (n = 545; R2 = 0.12) | OR (95% CI) |
P value | |
|---|---|---|---|
| Glycoside use vs. no glycoside use | |||
| No. of surgical interventions | 1.38 | (1.11–1.71) | 0.004 |
| Age at Fontan (years) | 1.16 | (1.06–1.26) | 0.001 |
| History of arrhythmiab | 3.99 | (2.48–6.40) | < 0.001 |
Sample size may be smaller for some predictors
No. of procedures or positive history since Fontan completion
Measured at study enrollment
Diuretics
A minority of the subjects (16%) were taking diuretics including ethacrynic acid, furosemide, aldactone, and hydrochlorothiazide. In multivariable analysis, diuretic therapy was associated with greater numbers of surgical interventions (P = 0.001) and interventional cardiac catheterizations (p = 0.001) since Fontan, history of post-Fontan arrhythmia (P = 0.003), and older age at the time of Fontan (P = 0.023; Table 5).
Table 5.
Correlates of diuretics usage (P values are from logistic regression)
| Predictor | Diuretics use | No diuretics use | OR (95% CI) | P value |
|---|---|---|---|---|
| na | 85 | 461 | ||
| Center (%) | < 0.001 | |||
| Male | 57.7 | 60.7 | 0.88 (0.55–1.41) | 0.59 |
| Ethnicity (%) | 0.34 | |||
| Hispanic | 9.9 | 6.2 | 1.77 (0.77–4.08) | NS |
| Non-Hispanic, black | 13.6 | 8.9 | 1.68 (0.81–3.48) | NS |
| Non-Hispanic, other | 6.2 | 6.9 | 0.99 (0.37–2.67) | NS |
| Non-Hispanic, white | 70.4 | 78.0 | 1.00 | – |
| Age at Fontan (years) | 4.0 ± 2.3 | 3.3 ± 2.1 | 1.14 (1.03–1.25) | 0.008 |
| Years since Fontan | 8.1 ± 4.3 | 8.6 ± 3.3 | 0.96 (0.90–1.03) | 0.21 |
| Age at enrollment (years) | 12.0 ± 3.8 | 11.8 ± 3.3 | 1.02 (0.95–1.09) | 0.67 |
| Ventricular type (%) | 0.23 | |||
| Left | 40.0 | 50.1 | 0.65 (0.39–1.09) | NS |
| Mixed | 20.0 | 17.4 | 0.64 (0.49–1.78) | NS |
| Right | 40.0 | 32.5 | 1.00 | – |
| No. of surgical interventionsb | 0.9 ± 1.5 | 0.3 ± 0.8 | 1.60 (1.31–1.97) | < 0.001 |
| No. of catheter interventionsb | 1.2 ± 1.5 | 0.8 ± 1.1 | 1.31 (1.10–1.55) | 0.003 |
| History of arrhythmiab (%) | 40.0 | 16.7 | 3.32 (2.02–5.46) | < 0.001 |
| AV valve regurgitationc (%) | 28.1 | 17.3 | 1.87 (1.09–3.21) | 0.024 |
| Semilunar valve regurgitationc (%) | 11.4 | 8.5 | 1.38 (0.49–3.84) | 0.54 |
| Valve regurgitationc (%) | 47.3 | 30.6 | 2.04 (1,13–3.65) | 0.017 |
| Ventricular systolic dysfunctionc (%) | 42.3 | 36.1 | 1.29 (0.78–2.16) | 0.33 |
| Valve regurgitation and/or ventricular dysfunctionc (%) | 72.9 | 61.8 | 1.66 (1.90–3.07) | 0.11 |
| Multivariable model (n = 545; R2 = 0.13) | OR (95% CI) |
P value | |
|---|---|---|---|
| Diuretics use vs. no diuretics | |||
| Center | < 0.001 | ||
| No. of surgical interventionsb | 1.46 | (1.17–1.82) | 0.001 |
| No. of catheter interventionsb | 1.44 | (1.16–1.78) | 0.001 |
| Age at Fontan (years) | 1.13 | (1.02–1.26) | 0.023 |
| History of arrhythmiab | 2.42 | (1.35–4.33) | 0.003 |
Sample size may be smaller for some predictors
No. of procedures or positive history since Fontan completion
Measured at study enrollment
OR odds ratio, CI confidence interval, AV atrioventricular
Other Cardiac Medications
The numbers of subjects taking a beta blocker (n = 19), a calcium channel blocker (n = 1), or other antiarrhythmic agents (n = 19) were too small to analyze meaningfully.
Medication Therapy by Center
The number of cardiac medications that subjects were taking at study entry varied widely among the seven centers. The percentage of subjects at each center taking no cardiac medication ranged from 0 to 26%. Those taking one cardiac medication ranged from 5 to 40%, and those taking two or more cardiac medications ranged from 34 to 95%. Similarly, the use of specific medicine classes varied significantly across the different centers (Fig. 4). Univariate analysis showed the subjects’ medication usage ranged from 33 to 97% for antithrombotics (P < 0.01), 32 to 76% for ACEi (P < 0.001), 22 to 55% for glycosides (P < 0.005), and 7 to 45% for diuretics (P < 0.001).
Fig. 4.
Medication usage by study center and percentages of Fontan subjects taking each class of medication at each center. The color designation for each center is identical to that in Fig. 1
We reexamined center usage with attention to demographic and medical history factors that differed by center and between those receiving and those not receiving medication. After adjustment for these factors, center usage of antithrombotics, ACEi, and diuretics still differed significantly (P < 0.001), whereas center use of glycosides did not (P = 0.17).
Discussion
Patients with Fontan palliation of single ventricle heart disease may experience a range of important complications including thromboembolism, ventricular dysfunction, and valve regurgitation [2, 4, 7, 8, 11, 13, 17, 19]. Currently, there is a paucity of data to guide the use of medications to treat and prevent these adverse outcomes in this population [5]. The empiric use of anticoagulant and antiplatelet agents has been based on the well-documented risk of thrombotic complications for Fontan patients, but these complications still occur for patients receiving such preventive therapy, and neither retrospective nor prospective studies have proven efficacy [8, 14]. In Fontan patients, ACEi may improve vascular endothelial function but not cardiac output or exercise capacity [9, 12]. Published guidelines for ACEi and digoxin treatment of single ventricle dysfunction are based on limited evidence [6, 18]. The merits of ACEi therapy for valve regurgitation for single ventricle patients have not been studied [3, 6].
In the current study, we sought to characterize current medication usage as part of a multicenter cross-sectional analysis of 546 Fontan subjects, the largest such study to date. The findings show that a majority of the subjects were taking two or more cardiac medications including antithrombotics, ACEi, cardiac glycosides, and diuretics. As noted, no definitive evidence-based indications currently exist for the use of any of these classes of medicines by Fontan patients. However, to the extent that putative indications can be inferred, prescribed therapy has correlated with a putative indication for some of these medicines but not for others. In this study, antithrombotic use was associated with a history of stroke, thrombosis, or both, and ACEi use was associated with AV valve regurgitation. However, digoxin use was not associated with either valve regurgitation or ventricular systolic dysfunction, although it was associated with a history of post-Fontan arrhythmia.
Furthermore, where correlation between medication use and putative indication could be demonstrated, the aforementioned correlation was imperfect. For example, substantial numbers of subjects with no history of stroke or thrombosis were taking antithrombotics, whereas others with such a history were not. The use of antithrombotics with patients who had no history of stroke or thrombosis, and similarly the use of ACEi and digoxin with patients who had no valve regurgitation or ventricular dysfunction may well have been aimed at primary prevention of these conditions, however unproven.
The findings also show striking differences in the use of these medicines across the different centers. For example, the proportion of patients taking antithrombotics ranged from a low of 33% at one center to a high of 97% at another center. Similar disparities were found for ACEi, glycosides, and diuretics. For the most part, these disparities could not be accounted for by center differences in patient demographics or medical history.
Both the imperfect correlation between medication use and putative indication and the center variation in medication use undoubtedly reflect the fact that clinical scientific evidence on which to base prescription decisions for the Fontan population is lacking. Indeed, few published guidelines of any kind exist to inform these decisions [18]. Thus, it is perhaps not surprising that practitioners at any one center might evolve parochial prescribing practices based on local anecdotes and individual biases. The findings reported in this article highlight the need for rigorous, prospective therapeutic trials with the growing population of Fontan patients.
Study Limitations
The cross-sectional design of this study had inherent limitations. The sample cohort was necessarily biased in that it included only survivors. Medication use for individual patients may have changed over time but was recorded only at study enrollment. The extent to which medicines may have prevented outcomes such as stroke or improved others such as ventricular function in this population is unknown. Possible indications for medication usage have been inferred, but no data on the prescribers’ actual rationales were collected.
Conclusions
A majority of the study subjects were taking two or more cardiac medications at enrollment in this cross-sectional study. There was imperfect correlation between medication use and possible therapeutic indications, although some medicines may have been prescribed for preventive reasons. There was striking variation in the use of these medicines across the seven centers.
Acknowledgments
This paper is dedicated to the memory of Page A. W. Anderson, MD, who originated it before his untimely death in November 2008. This study was supported by U01 grants HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, and HL068288 from the National Heart, Lung, and Blood Institute.
Appendix: Pediatric Heart Network Membership
National Heart, Lung, and Blood Institute: Gail Pearson, Mario Stylianou, Judith Massicot-Fishera, Marsha Mathis, Victoria Pemberton
Data Coordinating Center: New England Research Institutes, Lynn Sleeper, Steven Colan, Paul Mitchella, Dianne Gallagher, Patti Nash, Gloria Klein, Minmin Lu
Network Chair: Lynn Mahony, University of Texas Southwestern Medical Center
Clinical Site Investigators
Children’s Hospital Boston: Jane Newburger (PI), Stephen Rotha, Roger E. Breitbart, Jonathan Rhodes, Jodi Elder, Ellen McGrath
Children’s Hospital of New York: Welton M. Gersony (PI), Seema Mitala, Beth Printza, Ashwin Prakasha, Darlene Servedioa
Children’s Hospital of Philadelphia: Victoria Vetter (PI), Bernard J. Clarka, Mark Fogel, Steven Paridon, Jack Rychik, Margaret Harkinsa, Jamie Koh
Duke University: Page A. W. Anderson (PI, deceased), Rene Herlonga, Lynne Hurwitz, Jennifer S. Li, Ann Marie Nawrockia
Medical University of South Carolina: J. Philip Saul (PI), Andrew M. Atz, Andrew D. Blaufoxa, Girish Shirali, Jon Lucasa, Amy Blevinsa
Primary Children’s Medical Center, Salt Lake City: LuAnn Minich (PI), Richard Williams, Linda Lambert, Michael Puchalski
Hospital for Sick Children, Toronto: Brian McCrindle (PI), Timothy Bradley, Kevin Romana, Jennifer Russell, Shi-Joon Yoo, Elizabeth Radojewski, Nancy Slater
Core Laboratories
Cardiac MRI, Children’s Hospital Boston: Tal Geva (Director); Andrew J. Powell
Echocardiography, Children’s Hospital Boston: Steven Colan (Director), Marcy Schwartza, Renee Margossian
Protocol Review Committee: Michael Artman, Chair; Dana Connolly, Timothy Feltes, Julie Johnson, Jeffrey Krischer, G. Paul Matherne.
Data and Safety Monitoring Board: John Kugler, Chair; Kathryn Davis, David J. Driscoll, Mark Galantowicz, Sally A. Hunsberger, Thomas J. Knight, Catherine L. Webb, Lawrence Wissow.
aNo longer at the institution listed
Contributor Information
Page A. W. Anderson, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
Roger E. Breitbart, Email: roger.breitbart@cardio.chboston.org, Department of Cardiology, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA
Brian W. McCrindle, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
Lynn A. Sleeper, Center for Statistical Analysis and Research, New England Research Institutes, Watertown, MA, USA
Andrew M. Atz, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
Daphne T. Hsu, Department of Pediatrics, Children’s Hospital of New York, New York, NY, USA
Minmin Lu, Center for Statistical Analysis and Research, New England Research Institutes, Watertown, MA, USA.
Renee Margossian, Department of Cardiology, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
Richard V. Williams, Department of Pediatrics, Primary Children’s Medical Center, Salt Lake City, UT, USA
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