lung transplantation and coronary artery disease
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Lung Transplantation and Coronary Artery DiseaseWilliam Sherman, MD, David G. Rabkin, MD, David Ross, MD, Rajan Saggar, MD,Joseph P. Lynch III, MD, John Belperio, MD, Rajeev Saggar, MD,Michele Hamilton, MD, and Abbas Ardehali, MDDivisions of Cardiothoracic Surgery, Department of Surgery, Pulmonary and Critical Care Medicine, Department of Medicine, and
Cardiology, Department of Medicine, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles,CaliforniaGEN
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Background. Coronary artery disease (CAD) remains arelative contraindication to lung transplantation. We haveoffered lung transplantation and coronary revascularizationto selected patients with discrete CAD and preserved leftventricular function. The purpose of this report is thefollowing: (1) to examine the short-term and medium-termoutcome of patients after coronary revascularization andlung 3transplantation; and (2) to compare the short-termand medium-term outcome of this cohort to a matchedgroup of lung transplant recipients without CAD.
Methods. From January 2000 to March 2010, 27 patientswith CAD underwent coronary revascularization andlung transplantation. The control group was matchedbased on age, diagnosis, lung allocation score, and type
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UCLA, 10833 Le Conte Ave, 62-186 CHS, Los Angeles, CA 90095; e-mail:[email protected].
© 2011 by The Society of Thoracic SurgeonsPublished by Elsevier Inc
Results. Lung transplant recipients with CAD and thecontrol group had similar incidence of primary graftdysfunction (grade III). The duration of mechanical ven-tilation, intensive care unit stay, and hospital stay werethe same. At a mean follow-up of 3 years, the incidence ofcomposite adverse cardiac events was similar in the 2groups.
Conclusions. Lung transplant recipients with CAD andthe control group also had similar medium-term survival.Lung transplantation can be considered in patients withpreexistent CAD with acceptable early and medium-termoutcomes.
(Ann Thorac Surg 2011;92:303–8)
© 2011 by The Society of Thoracic SurgeonsCoronary artery disease (CAD) is considered a relativecontraindication for lung transplantation in many
enters. The rationale for this policy are several: (1)oncern that chronic immunosuppression may accelerateoronary atherosclerosis [1]; (2) concern that patientsith CAD may have a limited short-term and medium-
erm survival due to their atherosclerosis [2]; (3) pre-umption that concomitant lung transplantation andyocardial revascularization may be associated with a
igher surgical risk; and (4) donor shortage.There is a growing body of data suggesting that newer
lasses of immunosuppressive medications and utiliza-ion of statin drugs and antiplatelet agents may have arotective effect on progression of native coronary arteryisease [3, 4]. In addition, multiple reports have demon-trated that coronary revascularization (either by percu-aneous coronary intervention [PCI] or surgical revascu-arization) can lead to event-free, long-term survival [5,]. There are also several reports from experienced cen-ers that concomitant coronary revascularization andung transplantation can be performed with acceptableerioperative outcome [7–10]. Donor shortage remains a
Accepted for publication April 4, 2011.
Address correspondence to Dr Ardehali, Division of CardiothoracicSurgery, Department of Surgery, David Geffen School of Medicine at
ressing issue in the field of lung transplantation. Therere reports that the donor lung pool can be expandedithout any adverse outcome [11–13]. To address donor
hortage and implement a more rational matching-llocation system, some centers have advocated adoptionf an “alternate program” where nonstandard donorrgans are allocated to high-risk recipients after in-ormed consent [14].
Given the increasing number of lung transplant can-idates with CAD, we adopted a policy in 2000 to acceptatients with CAD for lung transplantation provided that
hey had no other contraindications, they had discreteoronary artery lesions, and they had preserved leftentricular function. The purpose of this report is two-old: (1) to report the short-term and medium-termutcome of this cohort of patients after coronary revas-ularization and lung transplantation; and (2) to comparehe short-term and medium-term outcomes of this cohorto a matched group of patients without CAD.
Patients and Methods
This study was approved by the Institutional ReviewBoard. The records of all patients who underwent lungtransplantation at the University of California-Los Ange-les from January 2000 to March 2010 were reviewed.During this period, 27 patients underwent lung trans-plantation and coronary revascularization and are the
subject of this study.0003-4975/$36.00doi:10.1016/j.athoracsur.2011.04.021
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Coronary Artery Screening Protocol in LungTransplant CandidatesMale candidates over the age of 40, female candidatesover the age of 45, or younger candidates with symptomssuggestive of ischemic heart disease were routinelyscreened for CAD by coronary angiography. Myocardialstress studies were not performed as a screening tool orconfirmatory study.
Selection Criteria for Lung Transplant CandidatesWith CADPatients with diffuse CAD or patients with an ejectionfraction of less than 0.50 and concomitant CAD wererejected for transplantation. Patients with discrete coro-nary lesions (�50% in the left main coronary artery or�70% in other major vessels) and preserved ejectionfraction (who were otherwise acceptable candidates)were accepted for lung transplantation. It should be
Fig 1. Coronary revascularization protocolamong the accepted lung transplant candi-dates with coronary artery disease. († � crite-ria for acceptance of lung transplant candi-dates with CAD: discrete coronary arterylesions with preserved ventricular functionwho are otherwise acceptable candidates. * �criteria for single lung transplantation: age �60, no evidence of septic lung disease, and[or] pulmonary hypertension; CABG � coro-nary artery bypass grafting; CAD � coronaryartery disease; PCI � percutaneous coronaryintervention.)
Abbreviation and Acronyms
BMS � bare metal stentBOS � bronchiolitis obliterans syndromeCABG � coronary artery bypass graftCAD � coronary artery diseaseCVA � cerebral vascular accidentDES � drug eluting stentICU � intensive care unitLAS � lung allocation scorePCI � percutaneous coronary interventionPGD � primary graft dysfunction
emphasized that this cohort had no other relative contra-indication and were otherwise deemed to be good can-didates for lung transplantation.
Coronary Revascularization ProtocolAll patients with CAD as described above, who weredeemed a candidate for single lung transplantation (age�60, no evidence of septic lung disease, and [or] pulmo-nary hypertension) were considered for PCI or coronaryartery bypass grafting (CABG), depending on their anat-omy (Fig 1). Patients with left main CAD, or whoseanatomy was not suitable for PCI, were referred forconcomitant CABG and single lung transplant. All otherswere referred for PCI followed by single lung transplan-tation. Bare metal stents were used as clinically indicated.These patients were kept on clopidogrel bisulfate (BristolMeyers Squibb, New York, NY) for 1 month. Starting in2004, drug eluting stents were used selectively. Thesepatients were kept on clopidogrel from 6 to 12 monthsand underwent the transplant procedure on clopidogrel.
Patients in need of double lung transplantation werescheduled for concomitant CABG at the time of lungtransplantation. Coronary artery bypass grafting andlung transplantation were performed on cardiopulmo-nary bypass. Saphenous vein grafts were used as con-duits as clamshell incision and transverse sternotomyprecluded use of internal mammary arteries.
Control GroupEach lung transplant recipient with CAD was matched to alung transplant recipient without CAD (1:3 ratio). Matching
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algorithms were based on age, diagnosis, lung allocationscore, and type of procedure.
Perioperative CareThe criteria for single versus double lung transplantation inthe control and the CAD groups were identical. All patientsunder 60 years of age were offered double lung transplan-tation. Other patients (�60 years of age, no evidence ofseptic lung disease, and [or] pulmonary hypertension) wereoffered single lung transplantation. Selected patients be-tween the ages of 60 to 70 years with pulmonary hyperten-sion and (or) septic lung diseases were offered double lungtransplantation. All double lung transplants were per-formed on cardiopulmonary bypass. Coronary revascular-ization was performed first, followed by implantation of theallografts. Modified controlled reperfusion protocol wasused in all lung transplant procedures [15].
The postoperative care of lung transplant recipientswith CAD and the control group was identical. Theimmunosuppressive regimen included induction therapywith Thymoglobulin (Genzyme Corporation, Cambridge,MA) for patients under the age of 60 in the absence ofseptic lung diseases, or basiliximab (Novartis, East Ha-nover, NJ) for all others. All lung transplant recipientsreceived tacrolimus, mycophenolate mofetil, and ste-roids. In addition, all patients were treated with prava-statin and aspirin indefinitely.
Data AnalysesDemographics, diagnoses, coronary anatomy, and the peri-operative characteristics of the 2 groups were collected. Thefollowing clinical endpoints were monitored and comparedin the 2 groups: primary graft dysfunction score (grade III at72 hours), the duration of mechanical ventilation, intensivecare unit stay and hospital stay, incidence of reexplorationfor bleeding, incidence of atrial fibrillation (lasting longerthan 30 minutes and requiring therapy), incidence of cere-brovascular accidents, and a composite cardiac adverseevent index (defined as episodes of acute coronary syn-drome, redo revascularization, or hospital admission forcongestive heart failure). The Kaplan-Meier survival of the2 groups was also compared.
Statistical AnalysesData are presented as mean � standard deviation, or
edian and the range, as appropriate. Survival wasetermined using Kaplan-Meier analysis and log-ranknalysis was utilized for statistical significance. All statis-ical analysis was performed using STATA 6.2 softwareStata Corp, College Station, TX) and a p value less than.05 was considered statistically significant.
Results
Perioperative Characteristics of Patients With CADand the Control GroupDuring the study period, 27 patients with critical coro-nary artery lesions and preserved left ventricular func-
tion underwent lung transplantation and coronary revas-cularization, and are therefore the subjects of this study.The perioperative characteristics of this group of patientsare shown in Table 1. The waiting time for patients withCAD and the control group was similar. Thirteen of 27patients were deemed suitable candidates for single lungtransplantation and were therefore referred for pre-lungtransplant PCI. Ten of 13 patients received bare metalstents. The median number of stents used and thenumber of vessels stented was 1 (range 1 to 2), and 1(range 1 to 2), respectively.
The remaining 14 patients in need of double lungtransplantation were activated on the lung transplantwaiting list for concomitant lung transplantation andCABG. The median number of bypasses performed was1, with a range of 1 to 3. The cardiopulmonary bypasstime and the allograft cold ischemia time for patientsundergoing double lung transplantation and concomi-tant CABG was similar to patients undergoing doublelung transplantation alone (Table 1).
The perioperative characteristics of the control group(matched for age, diagnosis, procedure type, and LAS)are also listed on Table 1. There were no intraoperativemyocardial ischemic events in either the candidates withCAD or the control group.
Postoperative Comparison of Patients With CAD andthe Control GroupPostoperative clinical outcomes are shown in Table 2.The incidence of primary graft dysfunction grade III at 72
Table 1. Perioperative Characteristics of Lung TransplantRecipients With Coronary Artery Disease (CAD) and theControl Group
Characteristic
CADGroup
(n � 27)
ControlGroup
(n � 81) p Value
Age (years)Mean (range) 63 (55–72) 63 (49–74) 0.67
Sex:M/F 24/3 48/33 0.005
DiagnosisRestrictive lung disease 19 57Obstructive lung disease 8 24 0.99
Coronary artery disease1-vessel disease 22 N/A2-vessel disease 2 N/A3-vessel disease 3 N/A
Lung allocation score 41.2 � 8.0 41.4 � 9.2 0.83Waiting time (days) 140 � 185 137 � 195 0.70Lung transplant procedure
Single lung transplant 13 43 0.66Double lung transplant 14 38
Cardiopulmonary bypasstime (double lungtransplant) (minutes)
221 � 46 211 � 79 0.17
Cold ischemia time(minutes)
343 � 69 360 � 83 0.68
N/A � not applicable.
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hours (defined as arterial difference in partial pressure ofoxygen/fraction of inspired oxygen � 200 with a radio-graphic infiltrate) was 4% and 12% in the lung transplantrecipients with CAD and the control group, respectively(p � 0.20). The duration of mechanical ventilation, inten-ive care unit stay, and hospital stay were similar amonghe groups. One patient who underwent a single lungransplant, 2 of the recipients with concomitant CABG,nd 7 of the patients in the control group requiredeexploration for bleeding (11% vs 9%, p � 0.70). Thencidence of perioperative atrial fibrillation (atrial fibril-ation episode � 30 minutes requiring therapy) wasimilar (44% vs 37%, p � 0.49). There were no episodes of
Fig 2. The survival curves of lung transplantrecipients with CAD and the control groupwere similar up to 5 years posttransplanta-tion. (--- � coronary artery disease [CAD]group; — � control group.)
Table 2. Postoperative Clinical Outcomes
Variable
CADGroup
(n � 27)
ControlGroup
(n � 81) p Value
PGD score, grade III (at 72hours)
Number of patients 1 10 0.20Duration of mechanical
ventilation (days)2.1 � 1.4 5.1 � 13.5 0.40
Length of ICU stay (days) 5.3 � 2.2 8.2 � 14.6 0.28Length of hospital stay (days) 15.3 � 7.0 19.3 � 16.2 0.67
Perioperative complicationsReexploration for bleeding 3 7 0.70Incidence of atrial fibrillation
(�30 minutes requiringtherapy)
12 30 0.49
Cerebrovascular accidents 0 2 0.41Myocardial infarction 0 2 0.41
Composite adverse cardiacevents
Acute coronary syndromeepisodes
0 2 0.41
Coronary revascularization 2 1 0.09Congestive heart failure
episodes0 2 0.41
CAD � coronary artery disease; ICU � intensive care unit; PGD �primary graft dysfunction.
erebrovascular accidents or myocardial infarctions inung transplant recipients with CAD. However, in theontrol group, 2 patients had cerebrovascular accidentsnd 2 different patients developed a perioperative myo-ardial infarction.
We also compared the incidence of composite adverseardiac events (defined as acute coronary syndromevents, redo revascularization, and admissions for con-estive heart failure) in the CAD group and the controlroup. At a mean follow-up period of 3 years, there waso statistically significant difference between the 2roups (p � 0.80).The Kaplan-Meier survival curves for patients with
AD and the matched control group are depicted inigure 2. There is no statistically significant differenceetween the 2 survival curves (p � 0.16). The causes ofeath among the 2 groups are listed in Table 3. It is of
nterest that none of the deaths in the lung transplantecipients with CAD was related to a cardiovascularvent. As expected, bronchiolitis obliterans syndromend infections were the leading causes of death amongoth groups.
Table 3. Causes of Death in Lung Transplant RecipientsWith Coronary Artery Disease (CAD) and Control Group
Numbers of Deaths
Cause of DeathCAD Group
(n � 27)Control Group
(n � 81)
Bronchiolitis obliteranssyndrome
4 10
Malignancy 1 5Infections 2 10Suicide 1 0Acute rejection 0 1Acute myocardial infarction 0 1Unknown 1 1Total 9 28
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Comment
The findings of this study demonstrate that selectedpatients with CAD can undergo coronary revasculariza-tion and lung transplantation with acceptable short-termand medium- term outcomes. Our results are compara-ble with lung transplant recipients without CAD.
Several reports have examined the role of coronaryrevascularization in lung transplant recipients with CAD[7–10]. Snell and colleagues [7] were the first group toreport on 5 patients with clinically significant CAD whounderwent lung transplantation: 2 patients underwentPCI followed by lung transplantation (both alive at dis-charge), and 3 patients had concomitant CABG and lungtransplantation (2 died in the first postoperative year).Lee and colleagues [8] reported on 4 patients who under-
ent concomitant coronary revascularization and lungransplantation (2 with the assistance of cardiopulmo-ary bypass and 2 without cardiopulmonary bypass). Allatients were discharged from the hospital. There wasne death at 8 months posttransplantation due to chronicejection. Patel and colleagues [9] reviewed their experi-nce with 18 lung transplant recipients with clinicallyignificant CAD. Six patients had undergone PCI andhen lung transplantation. The remaining 12 patients hadoncomitant CABG and lung transplantation. There were
deaths in the first posttransplant year in this groupfrom adenoviral and respiratory syncytial viral pneumo-ia). The 1-year survival of lung transplant recipientsith CAD was similar to their non-revascularized cohort.eoane and colleagues [10] reported that the survival of 7atients with CAD who had undergone revascularization
6 with PCI and 1 with CABG) was similar to the survivalf their control group at 5 years. Our study expands theurrent body of knowledge and provides medium-termardiac-related and survival outcomes in lung transplantecipients with CAD.
All of the cited studies and our study have examinedhe role of coronary revascularization in patients withritical CAD (�50% lesion in the left main coronaryrtery or �70% lesions in other vessels). Choong andolleagues [16] have shown that presence of mild oroderate CAD (�50% lesion) in lung transplant recipi-
nts does not affect short-term or long-term survivalhen compared with recipients with CAD. Eighteenercent of patients with moderate CAD developed late
schemic events requiring coronary revascularizationith no effect on mortality. These studies collectivelyrovide some framework for management of lung trans-lant recipients with any extent of CAD.The findings of this study are based on several caveats.
atients with CAD were highly selected. These patientsad discrete coronary lesions with preserved LV func-
ion. Moreover, these patients lack any other significantomorbidity. Patients with CAD and another significantelative contraindication were deemed poor candidatesor concomitant coronary revascularization and lungransplantation. Another feature unique to this report ishe coronary revascularization strategy: we offered pre-
ransplant percutaneous coronary revascularization toatients who were candidates for single lung transplan-ation due to inability to access all coronary territoriesolely from a right or left thoracotomy. This strategyommits patients with a drug-eluting stent to a minimumf 6 months of clopidogrel and a higher risk of peritrans-lant bleeding. This strategy may also delay activatingatients on the waiting list until recovery from coronary
ntervention. Patients who were candidates for doubleung transplantation were offered concomitant CABGhrough the clamshell incision.
The choice of conduits for surgical revascularization ofung transplant candidates is controversial. Given the
edian survival of lung transplant recipients is 48 to 60onths [17], saphenous vein grafts may be a reasonable
onduit. However, with improvements in long-term sur-ival of lung transplant recipients, and the possiblempact of the immunosuppressive medications on therogression of metabolic syndrome and graft atheroscle-osis, use of arterial conduits may also be justified.lthough we used saphenous vein conduits in concomi-
ant procedures, it is encouraging to note that we did notbserve an increase in the incidence of cardiac-relatedomplications and clinical sequelae of vein graft failure.
This study has several limitations. (1) It is a retrospec-ive analysis with all of its inherent limitations. (2) Al-hough this is the largest reported series, the number ofatients in this study is small. (3) This study reports on
he 5-year survival of patients with CAD who underwentung transplantation. The long-term (10-year) survival ofhis cohort is of clinical interest.
In conclusion, lung transplantation can be consideredn patients with preexistent CAD. Selected patients canndergo both procedures (in tandem or concomitant)ith acceptable early and medium-term survival andutcomes. The impact of widespread application of thistrategy on donor pool and long-term recipient survivals unknown.
This study was supported by a Marvin and Ann Browder TrustFund.
References
1. Fellström B. Impact and management of hyperlipidemiaposttransplantation. Transplantation 2000;70 (11 Suppl):SS51–7.
2. Boden WE, O’Rourke RA, Teo KK, et al. Impact of optimalmedical therapy with or without percutaneous coronaryintervention on long-term cardiovascular end points in pa-tients with stable coronary artery disease (from the COUR-AGE Trail). Am J Cardiol 2009;104:1–4.
3. Wang TH, Bhatt DL, Fox KA, et al. An analysis of mortalityrates with dual-antiplatelet therapy in the primary preven-tion population of the CHARISMA trial. Eur Heart J 2007;28:2200–7.
4. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterio-scler Thromb Vasc Biol 2001;21:1712–9.
5. Booth J, Clayton T, Pepper J, et al. Randomized controlledtrial of coronary artery bypass surgery versus percutaneouscoronary intervention in patients with multivessel coronaryartery disease: six-year follow-up from the Stent or Surgery
Trial (SoS). Circulation 2008;118:381–8.
308 SHERMAN ET AL Ann Thorac SurgLUNG TRANSPLANTATION AND CAD 2011;92:303–8
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6. Serruys PW, Onuma Y, Garg S, et al. 5-year clinical out-comes of the ARTS II (Arterial Revascularization TherapiesStudy II) of the sirolimus-eluting stent in the treatment ofpatients with multivessel de novo coronary artery lesions.J Am Coll Cardiol 2010;55:1093–101.
7. Snell GI, Richardson M, Griffiths AP, Williams TJ, EsmoreDS. Coronary artery disease in potential lung transplantrecipients � 50 years old: the role of coronary intervention.Chest 1999;116:874–9.
8. Lee R, Meyers BF, Sundt TM, Trulock EP, Patterson GA.Concomitant coronary artery revascularization to allow suc-cessful lung transplantation in selected patients with coro-nary artery disease. J Thorac Cardiovasc Surg 2002;124:1250–1.
9. Patel V, Palmer S, Messier R, Davis RD. Clinical outcomeafter coronary artery revascularization and lung transplan-tation. Ann Thorac Surg 2003;75:372–7.
10. Seoane L, Arcement LM, Valentine VG, McFadden PM.Long-term survival in lung transplant recipients after suc-cessful preoperative coronary revascularization. J ThoracCardiovasc Surg 2005;130:538–41.
Executive Committee 2010–2011
Jennifer Nelson, MD
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use of marginal donor lungs. J Thorac Cardiovasc Surg1995;109:1075–80.
12. Bhorade S, Vigneswaran W, McCabe M, Garrity ER. Liber-alization of donor criteria may expand the donor poolwithout adverse consequence in lung transplantation.J Heart Lung Transplant 2000;19:1199–204.
13. Whiting D, Banerji A, Ross D, et al. Liberalization of donorcriteria in lung transplantation. Am Surg 2003;69:909–12.
14. Laks, H, Marelli D, Fonarow GC, et al. Use of two recipientlists for adults requiring heart transplantation. J ThoracCardiovasc Surg 2003;125:49–59.
15. Schnickel GT, Ross DJ, Beygui R, et al. Modified reperfusionin clinical lung transplantation: the results of 100 consecutivecases. J Thorac Cardiovasc Surg 2006;131:218–23.
16. Choong CK, Meyers BF, Guthrie TJ, Trulock EP, PattersonGA, Moazami N. Does the presence of mild or moderatecoronary artery disease affect the outcomes of lung trans-plantation? Ann Thorac Surg 2006;82:1038–42.
17. Christie JD, Edwards LB, Aurora P, et al. Registry of theInternational Society for Heart and Lung Transplantation:
11. Sundaresan S, Semenkovich J, Ochoa L, et al. Successfuloutcome of lung transplantation is not compromised by the
twenty-fifth official adult lung and heart/lung transplanta-tion report-2008. J Heart Lung Transplant 2008;27:957–69.
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