Contemporary Coronary Graft Patency: 5-Year Observational Data From a Randomized Trial of Conduits

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1 ADULT CARDIAC SURGERY: The Annals of Thoracic Surgery CME Program is located online at To take the CME activity related to this article, you must have either an STS member or an individual nonmember subscription to the journal. Contemporary Coronary Graft Patency: 5-Year Observational Data From a Randomized Trial of Conduits Philip A. R. Hayward, FRCS, and Brian F. Buxton, FRACS Department of Cardiac Surgery, Austin Hospital, Heidelberg, Melbourne, Australia Background. The Radial Artery Patency and Clinical Outcomes (RAPCO) study has enrolled patients into two trials to compare the radial artery with the free right internal thoracic artery (if age <70 years) or with saphenous vein (if age >70 years) when grafted onto the largest target other than the left anterior descending artery. Patency outcomes in RAPCO will focus only on the trial graft in each case. However, postoperative angiography from this ongoing study has reassessed all coronary grafts, both trial and nontrial: together these offer a valuable observational overview of likely graft patency in the current era in predominately asymptomatic patients, in contrast to symptom-directed studies that may overestimate the incidence of graft failure. Methods. Protocol-directed percutaneous angiography has been performed at intervals weighted toward the end of the study period, or earlier when directed by symptoms. To date, 184 patients have been studied as per protocol, at time points up to 10 years (mean, 3.9), among whom there are 430 nontrial grafts in addition to the 184 trial grafts. Supplementary angiography (percutaneous or computed tomography) was offered at a fixed 5-year time point postoperatively: at this juncture, 193 trial grafts and 469 nontrial grafts have been imaged. Three masked investigators report grafts as angiographically successful if patent from proximal to distal anastomosis inclusive. Failed grafts include greater than 80% stenosis, string sign, or occlusion. Results. In staggered protocol-directed angiography, overall patency of the in-situ internal thoracic artery grafts and free arterial grafts was 95.5% (210 of 220) and 91.4%% (150 of 164), respectively, which did not differ significantly (p 0.13). Saphenous vein graft patency was 83.0% (191 of 230) with a trend to higher failure rate compared with free arterial grafts (p 0.07), and was significantly lower than that of in-situ internal thoracic artery grafts (p 0.01). At the optional 5-year time point, outcomes are similar to the protocol-directed findings, with patency of in-situ left and right internal thoracic artery grafts of 95.8% (204 of 213), which was significantly greater than that of the other two groups (p 0.02 and p < 0.001). Patency of free arterial conduits and saphenous vein grafts was 89.1% (139 of 156) and 82.4% (201 of 244), respectively, which did not differ significantly (p 0.09) at 5 years. Conclusions. Although trending to superior patency compared with vein grafts, free arterial conduits have not matched the gold standard achieved by in-situ internal thoracic arteries at trial midpoint. Until the results from RAPCO are available, which will test types of free arterial graft against each other and will compare radial and vein grafts in the longer term, these observational data justify for now our current practice of maximal use of in-situ conduits supplemented by free radial grafts. (Ann Thorac Surg 2007;84: ) 2007 by The Society of Thoracic Surgeons Accepted for publication April 5, Address correspondence to Dr Buxton, Austin Hospital, PO Box 5555, Heidelberg, Melbourne, Victoria, 3084, Australia; brianbuxton@ oz .com.au. Sustained symptomatic and prognostic benefit from coronary artery revascularization is dependant on graft patency as well as progression of native disease. Numerous historical studies have demonstrated the superiority of internal thoracic artery (ITA) grafts over vein grafts with respect to patency and prognostic benefit [1 7], and the last decade has seen a considerable increase in the use of arterial conduits during coronary surgery. The Radial Artery Patency and Clinical Outcomes (RAPCO) study is one of several trials designed to determine whether the radial artery (RA) was superior or inferior to other conduits in its patency and clinical results [8 11]. Patients were randomly assigned to receive either a RA or a free right ITA if aged less than 70 years, and participants older than this were randomly assigned to receive either a RA or saphenous vein. Trial follow-up comprises a 10-year postoperative period with a program of clinical review and staggered angiography by The Society of Thoracic Surgeons /07/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 796 HAYWARD AND BUXTON Ann Thorac Surg FIVE-YEAR PATENCY IN OBSERVATIONAL RAPCO DATA 2007;84: conduit was applied to the best coronary target other than the left anterior descending artery. When the trial reports finally, it will describe only patency of the study graft. Yet patients received on average 3.3 grafts, and the angiograms performed in the RAPCO trial document the patency status of all grafts. Furthermore, the RAPCO angiograms are not biased by the presence of recurrent coronary symptoms, as the vast majority of patients in the trial remain well many years after their surgery. Thus, we may utilize the angiographic findings in patients enrolled in this trial to derive a broad contemporary snapshot of the fate of coronary grafts in primarily well patients in the modern era, with a wider perspective than will ultimately be reflected by the trial results. Fig 1. Five-year patency of three subgroups of conduits. Fisher s exact test: in situ versus free arterial, p 0.02; in situ versus saphenous vein graph (SVG), p ; and free arterial versus SVG, p Our understanding of coronary graft patency is limited in two respects. The routine use after surgery of antiplatelet agents, statins, angiotensin-converting enzyme inhibitors, and beta blockers, added to greater operative awareness of careful conduit handling and anastomotic technique, may collectively influence the long0term patency of grafts, such that historical controls may not be applicable to coronary artery grafts performed in the modern era [12]. Furthermore, many of the data that we do have regarding graft patency are derived from symptom-directed angiography, which tends to overestimate graft failure [13]. In the RAPCO protocol [9], the trial graft was defined as the second graft: that is to say, the randomly selected Material and Methods The protocol of the RAPCO trial has been described elsewhere, as has our technique for minimal conduit handling and use of only gentle dilatation with papaverine diluted in heparinized blood [9, 12]. Ethical approval was granted by the Hospital Board with waiver of consent (approval nos. H95/086 and H2006/02690). The left anterior descending artery (LAD) was revascularized with an in-situ ITA graft in a standard fashion, and the study graft was used for the next best target. This was required by the protocol to have a diameter greater than 1.5 mm and larger than those of other non-lad vessels, to be subtended by a stenosis of at least 70%, and to be free of diffuse disease. The magnitude of runoff could not be quantified. Study grafts were constructed in an aortocoronary configuration to a single target. Third, fourth, or fifth grafts were performed as necessary by any configu- Fig 2. Actuarial graft patency on protocoldirected angiography at 1 month to 10 years. Log-rank test: in situ arterial (red line) versus free arterial (blue line), p 0.14; in situ versus saphenous vein (green line), p ; and free arterial versus saphenous vein, p Patency probability Years In situ arterial Free arterial SV

3 Ann Thorac Surg HAYWARD AND BUXTON 2007;84: FIVE-YEAR PATENCY IN OBSERVATIONAL RAPCO DATA ration to lesser targets, with preference for second free arterial graft or saphenous vein (SV). Postoperative selective coronary angiography was performed for each patient at a single time point during the 10-year follow-up period according to a randomly allocated, staggered program. That was weighted toward the second half of the study, as it was anticipated that the larger number of clinical events would occur in this time frame. By design, therefore, at the 5-year point, fewer than half of the patients had undergone a protocoldirected angiogram. Thus patients were offered, in addition, a voluntary 5-year midtrial angiogram for supplementary data. This could be performed by conventional percutaneous or computed tomography (CT) angiography technique. All the postoperative angiograms were reported by three independent reviewers, including two cardiac surgeons and one cardiologist (or radiologist in the minority of cases in which CT angiography was performed). Simplified definitions of graft outcome were utilized, whereby grafts were defined as either satisfactory or failed if there was occlusion, string sign, or greater than 80% stenosis in the graft. All angiographic data are prospectively entered into a visual FoxPro 5.0 database (Microsoft Corporation, Seattle, Washington), which was used as the source of information for this study. Data were analyzed using SPSS software (SPSS, Chicago, Illinois). Results By August 2006, among the 619 participants in RAPCO, 334 patients had undergone postoperative angiography, yielding patency data for 1,102 coronary grafts. The majority of patients had undergone only either their protocol-directed angiogram or the 5-year optional restudy, but 53 patients had undergone both studies. The 198 angiograms performed under protocol had occurred at a mean of 3.9 years after the coronary surgery (range, 1 month to 10 years). From these studies, patency data could be derived for 184 trial grafts, 198 LAD grafts, and 246 other grafts (with 14 trial grafts missing owing to protocol violations). Similarly, the 189 patients who underwent a 5-year optional re-study provided patency data for 189 trial and LAD grafts and for 276 other grafts. The majority of these were performed by conventional angiography, but 38% of these voluntary re-studies were performed by CT technique. The 14 breaches of protocol, whereby patients did not receive the intended conduit for the second graft, occurred either because the randomized conduit was not suitable for use or because the findings at surgery did not fit the protocol and the surgeon acted according to clinical need. These patients are included in the analysis, however, because the conduit, its target and its patency are all known and thus there is no necessity to analyze by intention to treat. There were no significant differences in the age, sex distribution, urgency, or presence of hypertension, diabetes mellitus, or other comorbidity, among the three Fig 3. Comparative patencies of different in situ and free arterial conduits at 5 years. Fisher s exact test: left internal thoracic artery (LITA) versus right internal thoracic artery (RITA), p 0.7; and radial artery (RA) versus free right ITA (FRITA), p 0.5. (SV saphenous vein.) 797 groups randomized to RA, right ITA, or SV, except that those patients who received a free right ITA as their second graft were younger by definition, as this was inherent in the design of the trial as described above. The distributions of the targets for each conduit varies because the in-situ arterial grafts were placed to the LAD in all but 5 cases, whereas free arterial grafts were placed to the second targets in all but 6 cases. The saphenous vein grafts are spread throughout second to fourth targets. Five-year optional angiography shows patency for the in-situ arterial conduits, free arterial conduits (RA or free right ITA), and reversed SV to be 96%, 89%, and 82%, respectively (see Fig 1). The patency of the in-situ arterial grafts is significantly better than that of the free arterial conduits (p 0.02, Fisher s exact test), and the free arterial conduits trended to superior patency over that of SV (p 0.08, Fisher s exact test). The patency rates for the three different conduit groups were similar irrespective of whether the patient was studied by percutaneous or CT angiography ( 2, p 0.4). The actuarial estimates of graft patency for the in-situ arterial, free arterial, and SV groups derived from protocol-directed angiography are summarized in Figure 2. At these staggered time points, patency of in-situ arterial grafts trended to superiority over that of free arterial grafts (p 0.14, log-rank test), and was highly significantly superior to that of SV grafts (p ). There was a trend to superior patency with free arterial grafts compared with SV grafts that did not achieve significance (p 0.07), although the mean duration of angiographic follow-up at these staggered time points is less than 4 years. Within each category of conduit type (in-situ arterial grafts, free arterial grafts, or SV grafts), the selection of actual conduit did not impact on patency (Fig 3). Thus, the patency for the left and right pedicled ITAs was 96%

4 798 HAYWARD AND BUXTON Ann Thorac Surg FIVE-YEAR PATENCY IN OBSERVATIONAL RAPCO DATA 2007;84: Fig 4. Influence of target runoff on graft patency. Fisher s exact test: saphenous vein (SV), p 0.31; and radial artery (RA), p and 100%, respectively, at 5 years, and that of the subtypes of free arterial graft was 90% and 88% for RAs and free right ITAs, respectively. Data regarding the source of the SV were not available, but overall patency with SV was 82% at 5 years when grafted to second to fourth targets. The magnitude of the vascular bed for run-off of the coronary graft may also influence long-term patency. In this regard, the in-situ ITA grafts were favored by their anastomosis almost entirely to the LAD. The RAPCO study graft was placed to the largest target other than the LAD, whereas the third and fourth grafts were placed to vessels that were either smaller in caliber or in their distal distribution. Figure 4 demonstrates that on 5-year re-studies, the patency of vein grafts placed to study and nonstudy targets was more than 80% at 5 years and was not significantly different between second versus third or fourth grafts (Fisher s exact test, p 0.31). By contrast, only 6 RAs were placed to the third and fourth coronary targets but in these few grafts, patency could be demonstrated only in half, which was significantly worse than the patency of the study RA graft to the second best target, which was 94.6%. Despite the very small sample size, this difference was statistically significant (Fisher s exact test, p 0.01). Comment Failure of coronary artery grafts may be multifactorial, and may be influenced by the choice of conduit, the degree of competitive flow from the native vessels [3, 4], the magnitude of the vascular bed for run-off [4], and by technical failure of proximal or distal anastomoses. In this series, failure of in-situ ITA grafts is a rare event, as described elsewhere [4 6]; and the 5-year patency of the left and right ITA grafts at 96% and 100%, respectively, is in line with other published series [4 6, 14 17] even though this is elective angiography in well patients rather than re-study mandated by symptoms. These in-situ grafts are, of course, favored both by their magnitude of vascular run-off, being placed usually to the left anterior descending branch or occasionally to large circumflex branches, and by the absence of proximal anastomoses, which may render them less liable to technical failures than free grafts. The patency of RA grafts in our series compares favorably with that described elsewhere [18 24], and is similar to that described by Possati and coworkers [24] who described patency of 88% in a series of 91 RA grafts, 92% of which were re-studied with follow-up of mean duration 8.8 years. Other series, although larger in patient numbers, have re-studied only a minority of RA grafts with mean follow-up varying from 1.2 to 5.6 years. The data presented in our series, although relating only to 98 RA grafts, benefit from the duration of follow-up at 3.9 and 5.0 years for the protocol-directed and elective angiography, respectively, from the absence of patient symptomatology acting as a confounding bias in estimations of graft failure [13], and from its unique 100% rate of graft reassessment. Of concern, however, was the poor patency of RAs grafted to the third and fourth targets (Fig 4). We reiterate that this observation pertains to 6 cases only, and the numbers are too small for conclusions to be drawn, but clearly this merits further investigation. Because only 6 such grafts were performed, their performance does not alter the overall excellent patency of free arterial grafts, however. The 82% patency of vein grafts at 5 years is gratifying, given that it includes poorer targets (such as fourth grafts) than does the free arterial cohort, and it is superior to that described in many historical series [3 7]. As with the radial artery data, our venous patency has the benefits of 100% angiographic follow-up, an acceptable midterm duration of review, and the absence of symptoms in most patients, thereby avoiding overestimation of graft failure and making this representative of outcomes in good clinical practice. It is noteworthy that the patency of vein grafts when placed to the third and fourth position is 80%, compared with 90% when a vein is used as the study graft to the second best target; and this insignificant difference contrasts with the wide discrepancy in patency noted with in the small proportion of RA conduits used for nonstudy targets. Data on more such RA grafts, placed to the lesser targets, are needed before it is clear whether venous conduits are preferable for third and fourth grafts. Although there was a trend to higher patency for free arterial grafts than for vein grafts, the small difference did not achieve statistical significance. That may be because the sample size is too small, or because the follow-up duration is as yet inadequate, and the gap between vein grafts and free arterial grafts might widen beyond 5 years. Alternatively, the difference might be spurious, and may be merely a reflection of greater target heterogeneity with the venous grafts. In conclusion, these unselected patency data compare favorably with other reports of more selective case series. In the modern era of careful conduit tissue handling and optimal use of antiplatelet agents, statins, angiotensin-

5 Ann Thorac Surg HAYWARD AND BUXTON 2007;84: FIVE-YEAR PATENCY IN OBSERVATIONAL RAPCO DATA converting enzyme inhibitors, and beta blockers in the postoperative period, patency results with vein grafts can be achieved that are close of those achieved with free arterial grafts. Nonetheless, there is a trend to superior patency with free arterial grafts particularly when placed to the second best target. Personal experience of use of free arterial grafts may have a role to play in their clinical and angiographic outcome, and the small benefit of free arterial grafts over vein grafts may be negated if the arterial conduit is at all diseased or if the surgical team has much greater experience with vein grafts. The authors are grateful to the following participants: surgeons: A/Prof George Matalanis, Messrs Alexander Rosalion, Siven Seevanayagam, Jai Raman, Julian Gaer, and Masashi Komeda; cardiologists: Prof David L. Hare, Drs George Proimos, Anthony Jackson, Robert Chan, Anthony Dortimer, Mark Horrigan, David Clark, Paul Kertes, Lesley Oliver, and Jennifer Johns; and statistics, database, and editing: Dr Ian Gordon, Mrs Margaret Shaw, Ms Mardi Malone, Ms Rita Pana, Mrs Sandra Gerbo, and Mrs Laura Condillac. References 1. Lytle BW, Blackstone EH, Sabik JF, Houghtaling P, Loop FD, Cosgrove DM. The effect of bilateral internal thoracic artery grafting on survival during 20 postoperative years. Ann Thorac Surg 2004;78: Lytle BW, Sabik JF. Use of multiple arterial grafts and its effect on long-term outcome. Curr Opin Cardiol 2002;17: Shah PJ, Gordon I, Fuller J, Seevanayagam S, et al. Factors affecting saphenous vein graft patency clinical and angiographic study in 1402 symptomatic patients operated on between 1977 and J Thorac Cardiovasc Surg 2003;126: Sabik JF III, Lytle BW, Blackstone EH, Houghtaling PL, Cosgrove DM. 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J Thorac Cardiovasc Surg 1998;116: Iaco AL, Teodori G, Di Giammarco G, et al. Radial artery for myocardial revascularization: long-term clinical and angiographic results, Ann Thorac Surg 2001:72:464 8; discussion Tatoulis J, Royse AG, Buxton BF, et al. The radial artery in coronary surgery: a 5-year experience clinical and angiographic results. Ann Thorac Surg 2002;143: Khot UN, Friedman DT, Pettersson G, Smedira NG, Li J, Ellis SG. Radial artery bypass grafts have an increased occurrence of angiographically severe stenosis and occlusion compared with left internal mammary arteries and saphenous vein grafts. Circulation 2004:109: Possati G, Gaudino M, Prati F, et al. Long-term results of the radial artery used for myocardial revascularization. Circulation 2003;108: INVITED COMMENTARY The Radial Artery Patency and Clinical Outcomes (RAPCO) trial will constitute a landmark in the history of arterial revascularization, and within some years this trial will furnish fundamental answers to the respective role and indications of coronary artery bypass conduits. For these reasons the authors whose dedication and enthusiasm made realization of the RAPCO possible must receive all our gratitude and appreciation. In the present analysis, Hayward and Buxton [1] review the interim RAPCO angiographic database including data from both trial and nontrial grafts and give us an important state of the art overview of the mid-term angiographic patency of arterial and venous conduits. The main findings of this study are the almost perfect results of in situ internal thoracic artery grafts, the 89% 5-year patency of both free right internal thoracic arteries 2007 by The Society of Thoracic Surgeons /07/$32.00 Published by Elsevier Inc doi: /j.athoracsur