Effect of Pravastatin on Outcomes after Cardiac Transplantation
Jon A. Kobashigawa, M.D., Steven Katznelson, M.D., Hillel Laks, M.D., Jay A. Johnson, M.D., Lawrence Yeatman, M.D., Xiu Ming Wang, M.D., David Chia, Ph.D., Paul I. Terasaki, Ph.D., Alejandro Sabad, B.A., Gregory A. Cogert, Kevin Trosian, B.A., Michele A. Hamilton, M.D., Jaime D. Moriguchi, M.D., Nobuyuki Kawata, M.D., Antoine Hage, M.D., Davis C. Drinkwater, M.D., and Lynne W. Stevenson, M.D.
Background Hypercholesterolemia is common after cardiac transplantationand may contribute to the development of coronary vasculopathy.Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitor, has been shown to be effective and safein lowering cholesterol levels after cardiac transplantation.Cell-culture studies using inhibitors of HMG-CoA reductase havesuggested an immunosuppressive effect.
Methods Early after transplantation, we randomly assigned consecutivepatients to receive either pravastatin (47 patients) or no HMG-CoAreductase inhibitor (50 patients).
Results Twelve months after transplantation, the pravastatingroup had lower mean (±SD) cholesterol levels than thecontrol group (193±36 vs. 248±49 mg per deciliter,P<0.001), less frequent cardiac rejection accompanied byhemodynamic compromise (3 vs. 14 patients, P = 0.005), bettersurvival (94 percent vs. 78 percent, P = 0.025), and a lowerincidence of coronary vasculopathy in the transplant as determinedby angiography and at autopsy (3 vs. 10 patients, P = 0.049).There was no difference between the two groups in the incidenceof mild or moderate episodes of cardiac rejection. In a subgroupof study patients, intracoronary ultrasound measurements atbase line and one year after transplantation showed less progressionin the pravastatin group in maximal intimal thickness (0.11±0.09mm, vs. 0.23±0.16 mm in the control group; P = 0.002)and in the intimal index (0.05±0.03 vs. 0.10±0.10,P = 0.031). In a subgroup of patients, the cytotoxicity of naturalkiller cells was lower in the pravastatin group than in thecontrol group (9.8 percent vs. 22.2 percent specific lysis,P = 0.014).
Conclusions After cardiac transplantation, pravastatin had beneficialeffects on cholesterol levels, the incidence of rejection causinghemodynamic compromise, one-year survival, and the incidenceof coronary vasculopathy.
Hypercholesterolemia is common after cardiac transplantation,affecting 60 to 80 percent of transplant recipients.1 In addition,hypercholesterolemia has been associated with the developmentof coronary vasculopathy in transplants,2,3,4 which is the majorfactor limiting long-term survival. Inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase lower blood cholesterol levels5and have been associated with the regression of atheroscleroticlesions in patients with atherosclerosis who are not transplantrecipients.6,7,8 In addition, studies in animals suggest thatthese drugs may affect coronary vasculopathy by a mechanismindependent of cholesterol lowering.9 In vitro studies withHMG-CoA reductase inhibitors have demonstrated the suppressionof natural killer cells,10,11 which could influence the developmentof acute rejection and subsequent coronary vasculopathy.
HMG-CoA reductase inhibitors have been used cautiously to treathypercholesterolemia in patients with cardiac transplants becauseof concern about the development of myositis and rhabdomyolysis.12,13Unlike lipophilic HMG-CoA reductase inhibitors, pravastatin(Pravachol, Bristol-Myers Squibb, Princeton, N.J.) is hydrophilic.Therefore, it may have fewer toxic effects on skeletal muscleand has been reported to be safe and effective in patients withtransplants.14 Therefore, we performed a prospective, randomized,open-label trial in patients with cardiac transplants to assessthe effect of pravastatin on cholesterol lowering, rejection,survival, and the development of coronary vasculopathy.
Methods
Selection of Patients
From July 1, 1992, through February 1, 1994, 107 adult patientsunderwent cardiac transplantation in our program. Eight patientsdied during the initial hospitalization after transplantationand were therefore not enrolled in the study, and two patientsdeclined to participate in the study. The remaining 97 patientswere randomly assigned to pravastatin (47 patients) or no pravastatin(50 patients) in addition to their immunosuppressive treatmentwith cyclosporine, prednisone, and azathioprine. The study designwas approved by the institutional review board.
Study Design
The patients randomly assigned to receive pravastatin beganreceiving a dose of 20 mg per day one to two weeks after transplantation.If they tolerated this dose after receiving it for one month,the dose was increased to 40 mg per day. Before discharge fromthe hospital, all the patients received dietary counseling froma staff nutritionist about following a low-fat, low-cholesteroldiet. After six months, patients in the control group who hadcholesterol levels of 300 mg per deciliter (7.76 mmol per liter)or higher were treated with cholestyramine (taken four hoursafter the dose of cyclosporine). During the first year aftertransplantation, endomyocardial biopsies, right heart catheterization,and echocardiography were performed, and blood was obtainedfor the determination of cholesterol, alkaline phosphatase,serum aspartate aminotransferase, serum alanine aminotransferase,and creatine kinase concentrations, a complete blood count,and trough cyclosporine levels (whole-blood fluorescence polarizationimmunoassay, Abbott, Abbott Park, Ill.). These tests were performedweekly for the first month after transplantation, then everytwo weeks for one month, every three weeks for two months, everymonth for two months, and every two months for six months. Allendomyocardial-biopsy specimens were examined by pathologistsunaware of the treatment assignments.
All patients with cardiac transplants who presented with signsand symptoms of heart failure underwent endomyocardial biopsy.These patients were presumed to have cardiac rejection regardlessof the results of the biopsy. Hemodynamic compromise was consideredto be present when any of the following criteria were met: acardiac index <2.0 liters per minute per square meter ofbody-surface area; a pulmonary-artery wedge pressure >20mm Hg; a short-term decrease in the left ventricular ejectionfraction (detected echocardiographically) by an absolute valueof 0.20 as compared with the value on the previous echocardiogram;or sudden death due to cardiac rejection confirmed at autopsy.
The primary end points for the study included the effects ofpravastatin on cholesterol levels, cardiac rejection, survival,and the development of coronary vasculopathy in the transplant.Survival was defined as remaining alive without requiring asecond transplantation.
Angiography and Intracoronary Ultrasonography
Coronary angiography and intracoronary ultrasonography wereperformed at base line (four to six weeks after transplantation)and one year after transplantation to determine whether coronaryvasculopathy was present in each patient. A diagnosis of coronaryvasculopathy was made if there was stenosis (luminal narrowing)of 50 percent or more or substantial distal pruning of the coronaryarteries on the one-year angiogram as compared with the base-lineangiogram. The base-line and one-year angiograms were reviewedside by side by two independent reviewers who were unaware ofthe patient's name, the date of the angiogram, and the treatmentassignment. Intracoronary ultrasonography was performed immediatelyafter coronary angiography in the left anterior descending coronaryartery with a 30-MHz, 4.3-French intracoronary ultrasound catheter(CVIS, Sunnyvale, Calif.). The recordings included a 30-secondslow pulling back of the catheter from its most distal position(in the mid-distal left anterior descending artery) to the leftmain portion of the left coronary artery. The ultrasound recordingswere analyzed by quantitative morphometry, which included 10randomly selected sites taken from the left anterior descendingartery during the slow pulling back of the catheter. The measurementswere recorded during diastole on super VHS and analyzed off-lineby computerized planimetry. These measurements included themaximal intimal thickness, the plaque area, the total vesselarea, and the intimal index, defined as the ratio of the plaquearea to the overall vessel area. The intracoronary ultrasoundimages were analyzed by one reviewer (to minimize variability)who was unaware of the treatment assignments.
Immunosuppression
All patients received the immunosuppressant agents cyclosporine,prednisone, and azathioprine. Episodes of focal moderate ormoderate cardiac rejection (grades 2 and 3, respectively, ofthe classification system of the International Society for Heartand Lung Transplantation) were diagnosed on the basis of ananalysis of the endomyocardial-biopsy specimens by pathologistswho were unaware of the treatment assignments.
Assay of Natural-Killer-Cell Cytotoxicity
Before the completion of the study, a reduction in the rateof cardiac rejection accompanied by hemodynamic compromise wasapparent in the pravastatin group. An assay of peripheral-bloodnatural killer cells (based on previous in vitro studies) wasperformed in the final 20 patients randomized, to determinewhether pravastatin was causing further immunosuppression inthe study group as compared with the control group. Blood sampleswere collected for the analysis of cytotoxicity of natural killercells for six months during the follow-up period, at the timeof the routine endomyocardial biopsies. The assay of natural-killer-cellcytotoxicity was performed as described by Wang et al.15
Statistical Analysis
Appropriate two-tailed t-tests and chi-square tests were usedto assess the differences between study groups. The Wilcoxonlog-rank statistic was used to compare Kaplan–Meier survivalcurves. Pearson correlation coefficients were used to measurethe strength of the linear relation between two variables. Ananalysis of variance (assuming compound symmetry in an unbalancedrepeated measure) was used to assess differences between groupsin the weighted average (weighted for multiple samples overtime) of natural-killer-cell cytotoxicity. The mean percentageof specific lysis for each group was estimated as a measureof natural-killer-cell cytotoxicity with the BMDP statisticalsoftware package. In all tests, P values of 0.05 or less wereconsidered to indicate statistical significance.
Results
Characteristics of the Patients
There were no differences between the pravastatin group andthe control group at base line, except for a higher number ofsecond transplantations in the control group (in seven patients,as compared with three patients receiving pravastatin) (Table 1).Because patients with second transplants have higher ratesof morbidity and mortality, we conducted additional analysesfor the primary end points from which these patients were excluded.After transplantation, there were no significant differencesbetween the two study groups in maintenance doses of immunosuppressantagents or trough cyclosporine blood levels, although slightlymore patients in the pravastatin group were able to be weanedfrom prednisone (Table 2).
Table 2. Characteristics of Immunosuppression after Transplantation, According to Study Group.
There were no significant differences between groups in thenumber of infectious complications requiring antibiotic therapy(5 in the pravastatin group vs. 8 in the control group), thenumber of episodes of clinical cytomegalovirus infection (4vs. 5), the degree of renal impairment at one year (mean [±SD]serum creatinine level, 1.6±0.4 vs. 1.8±0.4 mgper deciliter [140±40 vs. 160±40 µmol perliter]), or the use of calcium-channel blockers (14 vs. 13 patients)or angiotensin-converting–enzyme inhibitors (9 vs. 14patients) to treat hypertension. There was no difference betweenthe groups in blood pressure (mean of measurements 3, 6, 9,and 12 months after transplantation, 125±13/77±10mm Hg in the pravastatin group and 122±14/79±10mm Hg in the control group).
Cholesterol Levels
Base-line cholesterol levels were similar in the two study groups(174±51 mg per deciliter [4.50±1.32 mmol per liter]in the pravastatin group vs. 184±51 mg per deciliter[4.76±1.32 mmol per liter] in the control group). Duringthe first year after transplantation, the mean cholesterol level(as averaged from the levels measured at 3, 6, 9, and 12 months)was significantly lower in the pravastatin group than in thecontrol group (193±36 vs. 248±49 mg per deciliter[4.99±0.93 vs. 6.41±1.27 mmol per liter], P<0.001)(Figure 1). All the patients in the pravastatin group were receiving40 mg of pravastatin per day by two months after transplantation.The pravastatin group, as compared with the control group, hadsignificantly lower mean low-density lipoprotein cholesterollevels (116±32 vs. 158±27 mg per deciliter [3.00±0.82vs. 4.08±0.70 mmol per liter], P<0.001), lower meantriglyceride levels (148±67 vs. 219±144 mg perdeciliter [1.67±0.76 vs. 2.47±1.62 mmol per liter],P = 0.006), and higher mean high-density lipoprotein cholesterollevels (52±19 vs. 43±13 mg per deciliter [1.34±0.49vs. 1.11±0.34 mmol per liter], P = 0.039). The resultsof the lipid analysis did not change significantly when the10 patients with second transplants were excluded. Only twopatients in the control group were given cholestyramine, whichfurther reduced their cholesterol levels by 5 percent over athree-month period. No elevated levels of creatine kinase oraminotransferases (i.e., to more than three times the normalvalue), myositis, or rhabdomyolysis was documented in any patient.A minority of patients were weaned from corticosteroids (Table 2).Because the actual corticosteroid-free period was short(one to two months), it is not known whether it had any significanteffect on cholesterol levels.
Figure 1. Mean (±SE) Cholesterol Levels during the First Year after Cardiac Transplantation in the Study Patients.
To convert values for cholesterol to millimoles per liter, multiply by 0.02586.
Cardiac Rejection
The average number of episodes of mild (grade 1A or 1B) or moderate(grade 2, 3A, or 3B) cardiac rejection per patient did not differsignificantly between the two groups (in which the frequencyof biopsy was similar) (Table 3). These results did not changesignificantly when the patients with second transplants wereexcluded from the analysis. Although it was not a primary endpoint in the trial, the development of cardiac rejection accompaniedby hemodynamic compromise was markedly less frequent in thepatients treated with pravastatin than in the control patients(3 vs. 14, P = 0.005) (Table 4). According to the grading ofendomyocardial-biopsy specimens, 65 percent of these 17 patientshad moderate rejection, whereas 35 percent did not, suggestingeither that there was an error in the sampling of endomyocardial-biopsyspecimens or that humoral rejection was involved.16
Table 4. Clinical Characteristics and Outcomes of Patients Presenting with Cardiac Rejection Accompanied by Hemodynamic Compromise.
Survival
One-year survival was significantly greater in the pravastatingroup than in the control group (94 percent vs. 78 percent,P = 0.025) (Figure 2). The differences in survival between thetwo groups did not change significantly when the 10 patientswith second transplants (including 1 patient in the pravastatingroup and 3 patients in the control group who died) were excluded;after these exclusions, survival was 95 percent in the pravastatingroup and 81 percent in the control group (P = 0.037). Duringthe first year after transplantation, three patients in thepravastatin group died, all because of cardiac rejection. Inthe control group, there were 10 deaths and 1 second transplantation(due to severe cardiac dysfunction as a result of coronary vasculopathy)in the first year after transplantation. Of the 10 deaths, 8were due to cardiac rejection, 1 to cancer, and 1 to infection(following antirejection therapy).
Figure 2. Survival during the First Year after Cardiac Transplantation in the Study Patients.
Coronary Vasculopathy
Results of Angiography
Coronary vasculopathy was detected angiographically in threepatients in the pravastatin group and seven patients in thecontrol group at the end of the first year after transplantation.Seven patients did not undergo coronary angiography during thatyear because they died suddenly. All seven were examined atautopsy, and three of them, all in the control group, were foundto have severe coronary vasculopathy in the transplant. Theother four patients died suddenly from cardiac rejection. Therefore,the total number of patients found to have coronary vasculopathyin their transplants by angiography or at autopsy was higherin the control group (10 patients) than in the pravastatin group(3 patients) (P = 0.049). When patients with second transplantswere excluded from the analysis, there were eight patients inthe control group with coronary vasculopathy, as compared withtwo patients in the pravastatin group (P = 0.057).
Results of Intracoronary Ultrasonography
Of the 97 patients randomized, 48 patients had both base-lineand one-year intracoronary ultrasonography. This procedure wasnot performed in the remaining 49 patients because of the unavailabilityof intracoronary ultrasonography (21 patients), safety considerationswith regard to intracoronary ultrasonography at the time ofangiography (5), the terms of the agreement with the healthmaintenance organization (16), or death in the first year, beforethe follow-up intracoronary ultrasonography (7). The demographicvariables (Table 1) and characteristics of immunosuppression(Table 2) of the 27 patients in the pravastatin group and the21 patients in the control group who underwent intracoronaryultrasonography did not differ significantly. After transplantation,more of the control patients who underwent intracoronary ultrasonographyhad cardiac rejection accompanied by hemodynamic compromise(four patients, as compared with one patient in the pravastatingroup). The pravastatin group had significantly less progressionthan the control group with regard to maximal intimal thickness(0.11±0.09 vs. 0.23±0.16 mm, P = 0.002) and theintimal index (0.05±0.03 vs. 0.10±0.10, P = 0.031)(Figure 3). The results of intracoronary ultrasonography didnot change significantly when the five patients with secondtransplants who underwent this procedure (two in the pravastatingroup and three in the control group) were excluded. Of thepatients with coronary vasculopathy in their transplants asconfirmed by angiography or at autopsy, six in the control groupand two in the pravastatin group did not have intracoronaryultrasonography.
Figure 3. Results of intracoronary Ultrasonography.
As compared with the pravastatin group, the control group had significantly greater increases in maximal intimal thickness (P = 0.002) and the intimal index (P = 0.031) during the first year after cardiac transplantation. Maximal intimal thickness represents the thickness of the most severely atherosclerotic area, and the intimal index the ratio of the area of plaque to the total vessel area. Values obtained at one year are expressed as means ±SE.
Relation to Cholesterol Levels within Study Groups
There was no correlation between higher cholesterol levels andthe development of either cardiac rejection accompanied by hemodynamiccompromise or coronary vasculopathy in the transplant (as detectedby angiography or at autopsy). Among the patients who underwentintracoronary ultrasonography in both study groups, there wasno correlation between cholesterol levels and the progressionof intimal thickness (measured as either maximal intimal thicknessor the intimal index).
Natural-Killer-Cell Activity
A subgroup of 20 consecutive patients, 9 in the pravastatingroup and 11 in the control group, were assessed for natural-killer-cellcytotoxicity. The base-line characteristics and postoperativecharacteristics of immunosuppression (including cyclosporinetrough levels) of these patients were similar to those of thecorresponding study groups as a whole. Among the patients inthe subgroup, there was only one infectious episode requiringantibiotic therapy (in a patient assigned to receive pravastatin).
Peripheral-blood samples were obtained for the assessment ofnatural-killer-cell cytotoxicity during a six-month period.An average of 4.8 samples per patient were collected in thepravastatin group, and 4.7 samples per patient were collectedin the control group. Blood samples taken during episodes ofcardiac rejection (as confirmed by endomyocardial biopsy) orinfection were excluded, and all data on one control patientwith severe rejection were excluded. There was significantlylower natural-killer-cell cytotoxicity in the weighted averageof multiple samples collected over time in the pravastatin groupthan in the control group (9.8 percent vs. 22.2 percent specificlysis, P = 0.014).
Discussion
The results of this randomized study suggest that the earlyuse of pravastatin after cardiac transplantation safely lowerscholesterol levels, decreases the incidence of major rejection,improves one-year survival, and reduces the development of coronaryvasculopathy. These benefits may result from a direct reductionof cholesterol, an effect of lower cholesterol levels on immunefunction, a cholesterol-independent effect of pravastatin onimmune function, or another cause as yet unknown.
Pravastatin did not change the overall incidence of cardiacrejection, but it decreased the rate of rejection accompaniedby hemodynamic compromise, resulting in better survival. Rejectionaccompanied by hemodynamic compromise has often been associatedwith humoral rejection16,17 (i.e., that occurring without producingmarked lymphocytic infiltration in endomyocardial-biopsy specimens),an observation that agrees with our findings. In the first yearafter transplantation, death due to cardiac rejection was relativelycommon in the control group, occurring in eight patients. Fourof these patients had concomitant infection (due to antirejectiontherapy) but were not reported as having died of infection,which could explain the higher rates of rejection and lowerinfection-related mortality in this study.
In a multinational study of patients with hyperlipidemia,18pravastatin reduced total cholesterol levels and rates of allcardiovascular events beginning six months after the start ofthe study. In our study, the drug appeared to reduce the developmentof coronary vasculopathy as diagnosed by coronary angiography,at autopsy, or by intracoronary ultrasonography (the last ofwhich is more sensitive in measuring the early presence of suchvasculopathy). Maximal intimal thickness (the measurement ofthe most severely atherosclerotic area) and the intimal index(the ratio of the area of plaque to the total vessel area),which together provide a description of the plaque burden inrelation to coronary-artery size, were the two measurementsmade by intracoronary ultrasonography. Pathological specimensfrom patients with cardiac transplants who have severe coronaryvasculopathy have been reported to have a high cholesterol content.19Therefore, early cholesterol lowering with pravastatin may playa part in decreasing the incorporation of cholesterol into thecoronary arteries of the donor heart.
In the present study, there did not appear to be a correlationbetween cholesterol levels and the development of coronary vasculopathyone year after transplantation. The absence of correlation maybe due to the relatively small number of patients in each studygroup, the need for longer follow-up, or both. It also suggeststhat pravastatin may slow the progression of coronary vasculopathyby an effect independent of cholesterol reduction. Immunologiceffects of HMG-CoA reductase inhibitors have been reported invitro and may result from changes in circulating lipids or othereffects. These reported immunologic effects include the regulationof DNA in cycling cells,20 the inhibition of chemotaxis by monocytes,21the regulation of natural-killer-cell cytotoxicity,10,11,22and the inhibition of antibody-dependent cellular cytotoxicity.11
The decrease in natural-killer-cell cytotoxicity in the pravastatingroup in this study suggests that pravastatin may cause an increasedstate of immunosuppression. HMG-CoA reductase inhibitors havebeen shown to decrease antibody-dependent cellular cytotoxicityand natural-killer-cell function, which have been implicatedin the clinical rejection of renal allografts.23,24 In an invitro study, natural-killer-cell cytotoxicity was inhibitedby as much as 95 percent by the HMG-CoA reductase inhibitormevastatin and was restored by the addition of mevalonate, theproduct of the reductase enzyme, but not by cholesterol or dolichol.Cutts et al.10 have postulated the existence of a metaboliteof mevalonate that restores natural-killer-cell cytotoxicity,possibly through a modulation of the glycoprotein compositionof a natural-killer-cell receptor or a requirement for a mevalonate-modifiedreceptor component. the finding of decreased natural-killer-cellcytotoxicity in the pravastatin-treated patients we studiedmay itself be important or may be only a marker for other immunosuppressiveeffects possibly responsible both for the benefits seen in termsof survival and for the development of coronary vasculopathy.
Pravastatin may interact with cyclosporine, which blocks thesynthesis of interleukin-2 in stimulated T lymphocytes. Theaddition of interleukin-2 restored the natural-killer-cell cytotoxicityand partly restored the antibody-dependent cytotoxicity thatwere inhibited in lovastatin-treated in vitro cell cultures,as reported by Cutts and Bankhurst.11 A synergy between cyclosporineand pravastatin could explain increased immunosuppression inrecipients of cardiac transplants, whereas patients withouttransplants who receive HMG-CoA reductase inhibitors for hypercholesterolemiado not have clinical immunosuppression.25
The number of patients in this study was relatively small, andthe study was not blinded. However, survival was an objectiveend point and the findings on intracoronary ultrasonographywere interpreted blindly. Intracoronary ultrasonography wasnot performed in all patients both at base line and after oneyear of follow-up; however, demographic data on the subgroupof patients in the pravastatin and control groups who underwentthe procedure suggest they were comparable to the overall groups.Eight patients with coronary vasculopathy in their transplantsdiagnosed by angiography or at autopsy did not undergo intracoronaryultrasonography, and six of them were in the control group.Because the progression of intimal thickening seen on intracoronaryultrasonography in these patients would be expected to be considerable,the true means for the intimal changes may be even greater,leading to an underestimation of the differences in intimalthickening between the groups.
This study suggests that pravastatin lowers cholesterol levels;reduces the incidence of cardiac rejection accompanied by hemodynamiccompromise, thereby increasing first-year survival; and reducesthe development of coronary vasculopathy in the first year aftercardiac transplantation. The inhibition of natural killer cellsin pravastatin-treated patients suggests that pravastatin hasan increased immunosuppressive effect in cyclosporine-treatedpatients with cardiac transplants. Long-term follow-up willbe needed to determine whether pravastatin continues to havebeneficial effects after one year.
Supported in part by an unrestricted grant from Bristol-MyersSquibb.
We are indebted to Bonnie Anderson and Judy Neary for theirdedication in preparing the manuscript and to Mikki Ozawa, HuiPing Zhong, and Dr. Masaru Hirata of the UCLA tissue-typinglaboratory for performing the natural-killer-cell assays.
Source Information
From the Divisions of Cardiology (J.A.K., S.K., J.A.J., L.Y., A.S., G.A.C., K.T., M.A.H., J.D.M., N.K., A.H.) and Cardiothoracic Surgery (H.L., X.M.W., D.C., P.I.T., D.C.D.), University of California at Los Angeles School of Medicine, Los Angeles; and Brigham and Women's Hospital, Boston (L.W.S.).
Address reprint requests to Dr. Kobashigawa at the UCLA Medical Center, CHS 47-123, Los Angeles, CA 90024.
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Drugs in Cardiac Transplantation
Ballantyne C. M., von Moltke L. L., Greenblatt D. J., Kobashigawa J., Keogh A. M., Spratt P., Valantine H. A.
Extract |
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N Engl J Med 1996;
334:400-402, Feb 8, 1996.
Correspondence
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