10 Life Expectancy Tetralogy of Fallot

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PEDIATRIC CARDIOLOGY

Life Expectancy Without Surgery in Tetralogy of Fallot

ENRIQUE G. BERTRANOU, MDEUGENE H. BLACKSTONE, MDJANE B. HAZELRIG, PhDMALCOLM E. TURNER, Jr., PhDJOHN W. KIRKLIN, MD, FACCBirmingham Alabama

From the Departments of Surgery andBiomathematics, University of Alabama Schoolof Medicine and Medical Center, Birmingham,Alabama. This study was supported in part byProgram Project Grant Ml 1310 from the NationalHeart, lung, and Blood Institute, Bethesda, Na-tional Institutes of Health, Maryland. Manuscriptreceived April 3, 1978, accepted May 2, 1978.Address for reprints: John W. Kirklin. MD, De-partment of Surgery, University Station, Bir-mingham, Alabama 35294.

All publlshed autopsy cases of patients with tetralogy of Fallot who diedwlthout surgical treatment were studled to determine the llfe expectancyof such persons. In addltkxi, the data from a study of persons wlth tetralogyallve In Denmark In 1949 were reanalyzed. The survival data from thesetwo sources were remarkably slmllar, lndkatlng that 86 percent of personswith tetralogy of Fallot not treated surgically llve to age 1 year, 49 percentto age 3 years and 24 percent to age 10 years; thereafter, the hazardfunction (or Instantaneous risk of death) remains constant. The chanceof survival Is slgnlflcantly less when pulmonary atresla, rather than ste-nosis, Is present.

Surgical treatment is indicated for most patients with tetralogy of Fallotand is usually effective. However, several questions remain unanswered,including how many infants with tetralogy should be treated surgicallyand whether patients with tetralogy who survive into the third and fourthdecades of life require an operation. Data on life expectancy and otheraspects of the natural history of persons with tetralogy of Fallot are re-quired to answer these questions.Randomized studies of the length of life with and without surgicaltreatment in patients with tetralogy of Fallot are not now possible.Therefore, we analyzed published clinical and autopsy data to estimatethe life expectancy of persons with tetralogy who were not treated sur-gically.

Material and MethodsThe 949Danish study:The material for our study came from two sources.The first was from Rygg et al.,* who determined the ages of all persons with te-tralogy of Fallot alive in Denmark in 1949. That year was chosen because until1949 no person in Denmark had had corrective surgery for tetralogy of Fallot.Fifty-four of the 216 persons with tetralogy had had palliative operations in 1948and 1949, and 5 had died at operation. Most of these 54 patients were older thanage 6 years and all were older than age 2 years at operation. For the purposes ofthe study, all 54 patients were considered to be alive at the end of 1949. Thenumber of births in Denmark in each of the 58 previous years was known. It wasassumed in the study that each year tetralogy of Fallot was present in 0.4 of every1,000 live births. From these data the number of persons born with tetralogy of

Fallot who were alive in 1949 at ages 1 to 59 years was calculated and their lengthof life estimated.Published autopsy cases:Our second source of data was reported autopsycases of tetralogy of Fallot. Most cases included were reviewed individually intheir original publication to determine whether the diagnosis was in fact tetralogyof Fallot, whether the age at death was known and, as far as possible, whetherthe death was related to the presence of the malformation. However, some datafrom reliable sources were presented as grouped information for example,10 cases dying between ages 1 to 10 years), and thus the individual cases couldnot be examined. In 54 cases sufficient data were presented to indicate that the

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FIGURE 1.Life expectancy of persons with tetralogy ofFallot, based on data from the Danish population study.Creases represent data points calculated in that study.The solld Ilno (with its 70 percent confidence limits en-closed by the dashed Ilnes) represents parametricanalysis of the data, which resulted in the equation (singlehit modeiig): Probability of dying = [ 1 - exp@tlm)]m,where exp is e, the base of the natural logarithms; p =exp(8) where fl = -6.2 f 0.25; t is age on January 1,1950 in months and m = 0.36 f 0.056. Significancelevels of coefficients, PO


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TETRALOGY OF FALLOT-BERTRANOU ET AL.

Y 0.9 N= 782wQ 0.8$I 0.7 06w *z5 0.523) 0.4g 0.3z 0.28g 0.1

A AGE (YEARS)N=782

N= 782- 0.8T r?8 0.7sg 0.6F0 0.53k 0.4P5 0.34 0.2

FIGURE 3. Life expectancy of persons with tetraiogy ofFallot, based on combined analysis of the Danish data andautopsy data. A, results to age 60 years; 8, results to age10 years on an expanded time scale; C, proportion ofpersons at risk of dying each year (hazard function), ac-cording to the age of the person. The greatest risk is inthe first year, of life. The actual data points (crosses)calculated in the Danish study are shown, as is the non-parametric actuarial analysis (ja9ged Ilne) from the au-topsy data. The smooth line (with its 70 percent confi-dence limits enclosed by the dashed liner) results from

0.0 . . . . . . . ..............~~~~~~.~~~~~~~.~~..~~~~~~..~~- a combined parametric analysis that yielded the same9 9co =

:9 equation as in Figure 1 with the coeffictents, B = -6.008 f 0.072 and m = 0.410 f 0.0172. Significance level of

AGE (YEARS) the coefficients, fs


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congenital pulmonary atresia among 566 autopsy cases oftetralogy of Fallot and knowing the survival data for the totalgroup, we derived survival curves for those presumed to havepulmonary stenosis PS) rather than atresia PA) as fol-lows:

A(t) = SPA(t) + (1 - dSPS(t) (1)where SCA t) = survival curve for 566 composite autopsy CA)cases; SPA t) = survival curve for 54 cases of tetralogy of Fallotwith pulmonary atresia; Spa t) = generated survival curve fortetralogy of Fallot with pulmonary stenosis rather than pul-monary atresia; and Y= 0.33, the assumed incidence rate ofpulmonary atresia at birth among patients with tetralogy ofFallot. Thus, the survival curve for the composite group isassumed to consist of the sum of the two separate survivalcurves proportionate to their respective incidence rates atbirth. Spa t) is derived by rearranging equation 1 algebrai-cally.

Statistical methods: Nonparametric descriptions of theautopsy series were made using the product-limit method ofKaplan and Meier.rs We modified their method to take intoaccount the data from individual case reports as well asgrouped data from which individual ages at death could notbe determined Hazelrig JB, Turner ME Jr, Blackstone EH,in preparation). Parametric estimates of survival applicableto both the autopsy data and the Danish data) were calculatedusing the family of survival equations described by Turnerand Pruitt.lg The data were fitted to the survival equationusing the method of maximal likelihood suggested by Grossand Clark20 and a nonlinear optimization program developedby Hazelrig et a1.21 The specific survival equation selectedfrom the family of equations was the one that did not fit thedata significantly worse than the generic equation.

he parametri c analy sis yielded formulas that could bedirectly manipulated to generate the hazard function X t),which is the instantaneous death rate:X t) = -s t)/s t) 2)

where S t) is the slope first derivative) of the survival func-tion S t). The formulas were also manipulated to generate thesurvival function for tetralogy of Fallot with pulmonary ste-nosis rather than pulmonary atresia, as described. The con-fidence limits for this calculated curve were computed fromthe variance Var) estimated by the equation:Var[SCA(t)] = a2Var[SPA(t)] + (1 - a)2Var[SPs(t)] (3)

because SPA(t) and S t) are independent. By algebraicmanipulation, Var[Sps(t)] could be computed.* The hazardfunction can be converted to a percent r isk per year for aconstant hazard rate by the formula 100 X 1 - exp[-Xl),where exp is the base of the natural logarithms.Results

The Danish study: According to the parametricanalysis of the Danish study, 64 percent of patients bornwith tetralogy of Fallot, including those with pulmonaryatresia, are alive at age 1 year, 54 percent at 2 years, 47percent at 3 years and 24 percent at age 10 years (Fig.1). The hazard function (or the instantaneous risk ofdeath at any given age) is highest in the first year of life,gradually declines until age 10 years and remains es-sentially constant at about a 6.4 percent risk per yearthereafter. Related to this is continual decrease in the

We are ndebted to Dr. Edwin Bradley of the Department of Bio-statistics for the development of these relations.


number of survivors, so that only 11 percent of personsborn with tetralogy of Fallot are alive at age 20 years, 6percent at 30 years and 3 percent at 40 years.Composite autopsy series: Parametric analysis ofthe composite autopsy data (566 cases) indicates that66 percent of patients born with tetralogy of Fallot,including those with pulmonary atresia, are alive at age1 year, 56 percent at 2 years, 48 percent at 3 years and22 percent at age 10 years (Fig. 2). The hazard functionis similar to that derived from the Danish study.

Combined series: Combined parametric analysis ofthe data from the Danish study and from autopsy re-ports (782 cases) is permissible because the survivalfunction for the two series was not significantly different(P = 0.2). The combined analysis indicates that 66percent of patientsborn with tetralogy of Fallot are aliveat age 1 year, 56 percent at 2 years, 49 percent at 3 yearsand 24 percent at age 10 years (Fig. 3, A and B). Thecombined hazard function remains constant after age10 years (F ig. 3C).

Tetralogy of Fallot with pulmonary atresia: Theli fe expectancy of patients with tetralogy of Fallot andpulmonary atresia (54 cases) is shorter, according to theautopsy data (Fig. 4, A and B). By parametric analysisonly 66 percent of patients are alive at age 6 months, 50percent at 1 year, 33 percent at 2 years, 25 percent at 3years and 8 percent at age 10 years. The 70 percentconfidence limits are wider than in the previous analysesbecause of the smaller number of cases. The hazardfunction is very high in the first few years of life (Fig.4C).Tetralogy of Fallot without pulmonary atresia:The data from the autopsy study for all persons withtetralogy of Fallot known to be without pulmonaryatresia (195 cases) are shown in Figure 5. The deriveddata (see Material and Methods) for persons with te-tralogy of Fallot without pulmonary atresia are shownin Figure 6. The differences between the curves from the195 cases and those from the derived data are largely inthe first few years of life. The derived parametricanalyses indicate that 75 percent of patients are aliveat age 1 year, 60 percent at 3 years and 30 percent at age10 years.For completeness and ease of reference, the curves forpersons with tetralogy of Fallot and those known to havepulmonary atresia and the derived curves for thosewithout pulmonary atresia are shown in Figure 7. Ingeneral, persons with pulmonary atresia have theshortest life, and those with pulmonary stenosis havea better prognosis. The confidence limits of all survivalcurves overlap in the older age group, suggesting thatthere may be no significant differences among olderpatients in the three groups. In addition, the confidencelimits of all curves overlap in the first 3 months oflife.

DiscussionEvaluation of methods and their possible limitations: The Danish study assumed that 0.4 instancesof the tetralogy of Fallot occurred in each 1,000 livebirths, and other studies22-25 indicate that this as-sumption is reasonable. The similarity of the results in

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TETRALOGY OF FALLOT-B ERTRANOU ET AL.

N=54

A AGE (YEARS)

AGE YEARS)

N=54

1 .o0.9 c N=54

+-- 0.8Eg 0.75

0.6Fu 0.5

FIGURE 4. Life expectancy of persons with tetralogy ofFallot and known pulmonary atresia, based on autopsydata. The portrayal in A, B and C is as in Figure 3. Thesmooth line represents the equation (positive genericmocWe): Probabilfty of dying = [ 1 - (1 + pt/mu)- ]m.

0.1 where (as in Fig. 2) fi = -3.3 f 0.85, t is age in months,m = 0.7 f 0.22 and v = 1.4 f 0.80. Signtficance level0.0 . . . . . . . ............................................... of coefficients: Ps = 0.0003. Pm = 0.0001 and P = 0.090 0 9 0; 0; 9

(chl square test for single hit model being different fromthis generic model, P = 0.006 ; correlation between

AGE (YEARS) coefficients, f~,~ = -0.938, ~6.~= - 0.097 and r,,, =0.558. N = number of patients.

462 Beptember 1979 The American Journal of CARDIOLOGY Vdum~ 42


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FIGURE 5. Life expectancy of persons with tetralogy ofFallot and known pulmonary stenosis (not atresia), basedon autopsy data from 195 patients. The smooth linerepresents the equation: Probability of dying = 1 -exp(-Kt), where exp is e. the base of the natural loga-rithms; p = exp((3), where p = -4.94 f 0.082, and t isage in months. Significance level of coefficient, ffl


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AGE (YEARS)

PULMONARY ATRESIA

ISMsrfved serlos)

FIGURE 7. Combination of parametric equations fromAGE (YEARS) Figures 3.4 and 6. The presentations in A, B and C areas in Figure 3.

464 September 1078 The Amorlcan Journal of CARDIOLOGY Volume 42


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value. Serial correlation of the actuarial estimates mayproduce errors throughout the calculated life table; thegrouped data were especially troublesome in this regard,generating estimates that were at times outside thetheoretical binomial limits.he paramet ri c technique overcomes these disad-vantages by generating continuous estimates at all ages

(as expected of any regression equation of low order);by treating unknown data as if they followed the ex-pected survivorship curve for the known data, therebyallowing us to combine longitudinal information (au-topsy series) with cross-sectional information (Danishseries),which, as far as we know, has not previously beenpossible; and by treating individual events indepen-dently. In addition, the advantages of expressing asurvivorship function as a simple formula have beenrecognized for many years, particularly in reports onindustrial reliability.20J sWith this method, the hazardfunction is easily calculated and provides insight intothe changing risk among survivors. In addition, re-gression coefficients of different series can be comparedso that statisticaldifferences are easily determined, andthe formulas can be manipulated to generate such usefulfunctions as surgical salvage, given the data on naturalhistory and surgical risk. The scheme used in para-metric analysis s unique in that a particular ormula forthe survivorship function is not assumed at the outset,but instead a flexible, high-order generic model is firstfitted and then simplified, f possible, to one of the manyformulas in the family of equations derived from thegeneric model.Definition and material: We intended to include allpersons with a morphologic diagnosis of tetralogy ofFallot-that is, all those with atrioventricular (A-V)concordant connection and a large ventricular septaldefect in the left ventricular outflow tract immediatelybeneath the aortic valve, biventricular origin of theaorta, origin of the pulmonary artery from right ven-tricle and pulmonary stenosis that was at least partlyinfundibular and severe enough to produce markedright ventricular hypertrophy. Pulmonary atresia,whenpresent, was pulmonary truncal, valvular, infundibularor valvular and infundibular, and the remnant of thepulmonary artery was above the right ventricle. Theventricular septal defect was subpulmonary in somecases. No case with complete A-V canal was included.We attempted to exclude cases with absent left andright pulmonary arteries, so-called truncus arteriosustype IV.2gWe presume that the survival curves we derived forpersons who have pulmonary atresia are applicableprognostically to persons who have atresia in the firstfew months of life, and that those derived for personswith pulmonary stenosis rather than atresia are appli-cable to persons who have tetralogy of Fallot with pul-monary stenosis n the first few months of li fe, whetheror not they are cyanotic at that time or manifest pul-monary atresia ater n life. The clinician must refine theprognostic prediction for an individual patient fromthese curves on the basis of severity of the patientscyanosis and thus of the pulmonary stenosis.We included in. he autopsy group only patients be-


lieved to have died of causes related to their malfor-mation. I f the patient was known to have died of anunrelated cause such as tuberculosis or typhoid fever,the cause was excluded so that the survival data wouldbe applicable at the present time.Evaluation of role of severity of pulmonary ste-nosis in survival: The life expectancy of the group ofpatients with tetralogy of Fallot from the autopsy studyis strikingly similar to that derived from the Danishstudy, in which a completely different study techniquewas used. This finding strongly suggests that bothstudies correctly predict the life expectancy of personswith tetralogy.The data support the generally accepted concept thatthe natural history of persons born with tetralogy ofFaIlot is determined primarily by the severity of thepulmonary stenosis, as demonstrated by the tendencyof persons with pulmonary atresia to die at a youngerage than those without pulmonary atresia or the groupas a whole. The infants with pulmonary atresia who diein the early months of life probably lack large discretebronchial collateral arteries and die as a result ofgradual spontaneous closure of the patent ductus ar-teriosus, which Bharati et a130 ound in 81 percent ofcases. Large bronchial arteries or, less commonly,large discrete paramediastinal vessels or coronary-pulmonary artery fistulas,31are present in many of thepatients with tetralogy of Fallot and congenital pul-monary atresia (38 of 80 surgicalcases n the experienceof Alfieri et a1.32)and do not close spontaneously. Al-though these vesselsoften allow the infant to survive theearly months of li fe, the collateral pulmonary flow theyprovide is frequently insufficient to prevent arterialdesaturation and cyanosis. Thus, many such patientsdie in childhood. Those who reach the third decade oflife have a large collateral pulmonary blood flow andprobably as a result are at that age at less risk of dyingat any given time than persons with classic tetralogy ofFallot without pulmonary atresia.In the subset of persons with tetralogy of Fallot andpulmonary stenosis, the pulmonary stenosis usuallybecomes more severe with time and results n increasingarterial desaturation, cyanosis, polycythemia and,ultimately death, usually from hypoxia, pulmonarythromboses or cerebral thromboses or abscesses. Inpatients surviving into the fourth and fifth decades oflife, congestive heart failure may cause death.Therapeutic implications: Because about one halfof surgically untreated patients with tetralogy of Fallotdie in the first 2 years of li fe, surgical programs forpersons with this malformation must include techniquesfor surgical intervention in the early months and yearsof li fe. Also, because the hazard function does not de-crease in the third to fifth decades of life, the personwith tetralogy in this age group is still subject to therisks of the malformation.Institutions reporting that less than half of their pa-tients treated surgically for tetralogy of Fallot areyounger than 2 years of age may be delaying surgicalintervention unwisely or may have a patient populationthat represents less than the ful l spectrum of cases oftetralogy of F allot.

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10 Life Expectancy Tetralogy of Fallot

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