Comparison between two strategies for rejection detection after heart transplantation: Routine endomyocardial biopsy versus gallium-67 cardiac imaging

ELSEVIER

Comparison Between Two Strategies for Rejection Detection After Heart Transplantation: Routine Endomyocardial Biopsy Versus Gallium-67 Cardiac Imaging E.A. Bocchi, A.O. Mocelin, G. Bellotti, and F. Pileggi

A.V. de Moraes, C. Menegheti,

H

EART TRANSPLANTATION has evolved from a experimental procedure to the treatment of choice for selected patients with end-stage heart disease.’ Despite improvements in immunosuppressive regimens, acute cellular allograft rejection is still a major complication of heart transplantation, being the second most important cause of death after transplantation.2 Usually, the diagnosis of rejection is made by histologic changes observed on endomyocardial biopsy samples3 The endomyocardial biopsy (EMB) is an invasive procedure associated with morbidity, costs, and even fatal complications.4 Several noninvasive methods have been studied as alternatives to endomyocardial biopsy for rejection diagnosis, but none has achieved widespread acceptance because of inadequate predictive p0wer.j Increased cardiac uptake of gallium-67 is a marker of inflammatory activity and has been shown to be correlated with the diagnosis of moderate or severe rejection by endomyocardial biopsy in heart transplant recipients.6 The aim of this investigation was to evaluate a strategy of cardiac gallium-67 scintigraphy for rejection screening after heart transplantation. We compared the results and costs of this strategy with routine endomyocardial biopsy surveillance.

METHODS Study Design

We identified all patients who were discharged from the Heart Institute after undergoing heart transplantation from May 1990 to February 1995. From this group, we identified 24 patients who were managed exclusively with endomyocardial biopsies (EMB) for routine rejection surveillance (Group l), and 10 patients (Group 2) who were followed primarily with gallium-67 scintigraphy after the second week postoperation. Group 2 patients underwent EMB if the cardiac gallium-67 scintigraphy results were considered positive for inflammatory process. Survival, the number of treated rejection episodes, the number of EMBs performed, the incidence and severity of tricuspid regurgitation, and the costs with rejection surveillance during a l-year follow-up were evaluated for each group. Costs were estimated using the amounts charged by our institution for a typical procedure.

0041-1315/97/$17.00 PII SO041 -1345(96)00315-6

M. de Lourdes Higuchi,

F. Bacal, N. Stolf,

Studied Population

The studied patients were divided in two groups according to the strategy for routine rejection detection after heart transplantation. Group 1 included 24 patients, mean age 44 t 11 years, 21 male (88%), and the etiology of the heart failure was idiopathic dilated cardiomyopathy in 13 patients (54.2%), ischemic heart disease in 6 patients (25%), Chagas’ disease in 2 patients (8.3%), and valve heart disease in 3 patients (12.5%). Group 2 consisted of 10 patients, mean age 43 5 16 years, 7 male (70%), and the etiology was idiopathic dilated cardiomyopathy in 6 patients (60%) and Chagas’ heart disease in 4 patients (40%). Maintenance immunosuppression was similar in both groups and was based on cyclosporine (Sandoimune or cyclosporine-A BiosintCtica), azathioprine, and prednisone. Also, both groups were followed by the same transplantation team under similar orientation and protocol, except for rejection surveillance. The protocol also included serial doppler-echocardiographic studies during follow-up. Endomyocardial

Biopsy

The patients underwent percutaneous right ventricular EMB through the right internal jugular vein with the use of a modified Stanford-Caves bioptome.’ Group 1 patients underwent EMB according to a standard schedule for rejection surveillance. Our routine was to perform this procedure weekly during the first posttransplantation month, every other week during the second and third months, and monthly thereafter. Group 2 patients underwent EMB only when a cardiac gallium-67 scintigraphy suggested cardiac inflammation. Both groups had biopsies performed after completing treatment of a rejection episode. Specimens were stained with hematoxylin and eosin for microscopic examination, and results were graded according to the International Society for Heart and Lung Transplantation (ISHLT) criteria.’ The patients with diagnosis of acute cellular rejection ISHLT grade 3 or 4 received pulsotherapy with corticosteroids. Gallium-67

Cardiac Scintigraphy

Gallium-67 cardiac scintigraphy was performed 48 hours after the intravenous injection of 111 to 148 MBq “‘Ga citrate. Patients were

From the Heart Institute, Medical School of the Stio Paulo University, SBo Paulo, Brazil. Address reprint requests to Prof Dr Edimar Alcides Bocchi, Rua Oscar Freire 2077, apto 161, SBo Paulo, Brazil, CEP 05409-011.

0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

586

Transplantation

Proceedings,

29, 586-588

(1997)

REJECTION

DETECTION AFTER HEART TX

587

Table 1. Comparison Between Endomyocardial Biopsy Strategy and Gallium-67 Cardiac Imaging Strategy After 1 Year Follow-Up EMS

1 Year Survival EMB Number/Patient Treated

Rejection

Tricuspid Cost/Patient

P

75%

80%

NS

3.4 -t 1.6

.OOOl

1.9 2 1.5

0.9 + 0.9

.06

82%

44%

.O!i

18%

11%

(TR)

TR

(US$)

Ga-67 Strategy

10.1 ? 3.5 Episodes

Regurgitation

Moderate/Severe

Strategy

8,220

2 2,713

EMB means endomyocardial biopsy: Ga-67,

5,257

gallium-67

NS

2 1,851

cardiac

,002

imaging;

NS,

not significant.

scanned in the anterior projection. Images with 625,000 counts were obtained using a wide-field-of-view scintillation camera with a high-energy collimator and 3 separate analyser windows capable of detecting the 93. 185, and 300 keV “Ga peaks. The images were then processed in a nuclear medicine computer with a 256 X 256 matrix and enhanced by less than 20% of the maximum pixels. Density of the myocardium gallium uptake was compared with the lungs and ribs or sternum uptake density. Scans were interpreted as positive if the density was equal to or greater than that of the ribs uptake, and equivocal if density was less than that of the ribs uptake but greater than that of the lungs.

Statistical Survival

Analysis curves

were

estimated

using

the Kaplan-Meier

product-

The unpaired Student’s I-test was used to compare continuous variables while categorical variables were compared using Fisher’s exact test. Results are expressed as mean ? 1 SD. A P value <.05 was considered to be statistically significant. limit

method

and were compared

using the log-rank

method.

RESULTS

The mean number of gallium-67 cardiac scintigraphies performed during follow-up was 7.0 t 2.7 per patient, and 27% of them were considered positive for inflammatory process. The EMB histologic analysis found ISHLT grade 3 or 4 rejection in 50% of the patients with a positive gallium-67 cardiac scintigraphy. The gallium-67 cardiac imaging strategy significantly reduced the mean number of EMBs and the costs associated with rejection detection during the first posttransplant year (Table 1). We found a smaller incidence of tricuspid regurgitation in Group 2 patients. There was also a trend toward a smaller incidence of moderate or severe TR in this group. The reductions in costs and number of performed EMBs were not associated with increased mortality. The l-year survival rate was 75% and 80% for patients managed with routine EMB and gallium-67 scintigraphy screening. respectively.

and consequently

the costs,

during

Our results demonstrated that a routine gallium-67 scintigraphy strategy reduced the number of EMBs performed.

l-year

follow-up.

The search for an accurate noninvasive method to diagnose rejection in cyclosporine-treated heart recipients has been intense. The presence of lymphocytic infiltrates in acutely rejecting allografts led to the evaluation of gallium-67 as a possible agent for the radionuclide diagnosis of allograft rejection.“.’ In addition to these previous reports, our study supports a possible role for screening with cardiac gallium-67 scintigraphy, despite its limited specificity, as a useful method after heart transplantation. This group of heart transplant recipients, though small, represents the first to be followed with serial cardiac gallium-67 imaging. The survival rate has been interpreted as indication that this method is safe. However, humoral re,jection may be a limitation for this method. Much attention continues to focus on the cost-effectiveness and costs of heart transplantation. However, few investigations have compared costs of methods for noninvasive diagnosis of rejection and its consequences. Our study showed that despite all the improvements in heart transplantation, costs may still be reduced. Our prevalence of moderate/severe tricuspid regurgitation was in the 12% to 32% range seen in previous reports.“’ This complication is associated with flail tricuspid leaflets and can be clinically significant, even to the point of needing surgical correction. It has been reported that the number of biopsies performed after heart transplantation appears to affect risk for development of tricuspid regurgitation due to a flail tricuspid leaflet.’ ’The smaller tricuspid regurgitation incidence observed in our scintigraphy group is compatible with serial EMBs playing a role as a cause of this complication. Noninvasive methods for rejection diagnosis could be a new approach to prevent tricuspid regurgitation. In summary, this initial experience indicates that the cardiac gallium-67 scintigraphy approach for screening of rejection is a strategy that can be effectively and safely performed after heart transplantation. This approach may reduce the morbidity and costs for selected patients after heart transplantation. Prospective randomized studies with larger patient samples are needed to further evaluate the potential of this method in the management of transplanted patients.

REFERENCES 1. Bocchi EA, Bellotti G, Moreira Transplant 15 (in press), 1996

DISCUSSION

the

Also, it was observed that the cardiac gallium-67 scintigraphy approach may be a safe and reliable strategy in selected patients after heart transplantation for noninvasive screening diagnosis of rejection.

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Surg 99:500.

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VA, et al: J Thorac

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BOCCHI, MOCELIN,

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