Online Material for the following JACC article
TITLE: Radial Artery and Saphenous Vein Patency More Than 5 Years After Coronary
Artery Bypass Surgery: Results From the Randomized Multicenter Radial Artery Patency
Study (RAPS)
AUTHORS: Saswata Deb, MD, Eric A. Cohen, MD, Steve K. Singh, MD, Dai Une,
MD, Andreas Laupacis, MD, Stephen E. Fremes, MD, for the Radial Artery Patency
Study Investigators
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METHODS:
Study Population
Patients with a dominant circumflex coronary artery were eligible if they had
sequential high grade lesions in the circumflex and graftable obtuse marginal and
posterior descending coronary arteries. Patients were screened preoperatively with a
modified Allen’s test and non-invasive duplex studies to ensure adequate collateral
circulation of the hand. Patients with a history of vasculitis, Raynaud’s syndrome,
bilateral varicose vein stripping or varicose veins were excluded from the study.
Additional exclusion criteria for the study included: a)renal insufficiency (creatinine
greater than 180 umol/L) b)severe peripheral vascular disease precluding femoral access
c)coagulopathy or obligatory uninterrupted use of anticoagulants d)known allergy to
radiographic contrast media d)women of childbearing potential e)co-morbid illness which
precludes the use of follow-up angiography f)geographically inaccessible for follow-up
angiography. Patients who developed any of the preoperative exclusion criteria following
surgery were excluded from late angiography.
Surgical Technique
The non-dominant arm was used for radial artery harvesting. The RA was dilated
in situ by a slow intraluminal injection of 4–5 mL of a dilute solution of verapamil and
papaverine (5 mg verapamil and 65 mg papaverine in 16 mL lactated Ringer’s solution.
All of the participating centres were university centres. The requirement for surgeon
eligibility was that each of the participating surgeons had to perform the procedure in
three patients in their respective institutions prior to recruiting patients for the study, as
we considered that the technique of radial harvesting, preparation and anastomosis to be
fairly simple for experienced surgeons familiar with standard CABG techniques using
ITAs and saphenous veins. A 2-day workshop was held at Sunnybrook Health Science
Centre in July 1996 for training the original surgical co-applicants in the techniques of
radial grafting. Instructional videos were provided to the centers that joined the study
afterward.1
Postoperative Management
Patients received 325 mg of aspirin within six hours postoperatively and daily
thereafter – a lower dose of aspirin was used long term according to institutional practice.
Intravenous nitroglycerin was administered during the first 24 hours postoperatively and
vasopressors were avoided. Oral calcium-channel blockade was initiated on the first
postoperative day and continued for at least six months. Patients were interviewed by
telephone at one month, three months, six months, and yearly thereafter for a maximum
of 10 years postoperatively. If the patient had been hospitalized for cardiac reasons
between interviews, in-patient records were obtained.
Patients had serial perioperative electrocardiograms (ECG, preoperative, and on
the first and fifth postoperative day) which were stripped of patient identifiers and read
centrally by a core ECG committee, consisting of three cardiologists not otherwise
associated with the study. The ECGs were read centrally in a blinded fashion and without
any details of the perioperative course of the patient. Perioperative cardiac enzymes were
measured according to the routine institutional practice but the results were not reviewed
by the ECG committee. A perioperative MI was diagnosed when persistent new
pathological Q waves were present on the postoperative electrocardiograms. A diagnosis
of a perioperative myocardial infarction required a decision of 2 of the 3 reviewing
cardiologists.
Follow-up Angiography
Patients were approached to undergo invasive angiography at least 5 years
postoperatively. The follow-up study was not performed if any of the conditions listed as
exclusions developed since the time of surgery. Patients in whom both study grafts were
identified to be completely occluded at earlier angiography were not eligible for late
protocol directed angiography. All participating sites acquired angiograms digitally, the
image sequences were transferred to CD, and the CDs transferred to the core centre for
centralized reading. The angiogram was performed in accordance with the following
protocol: 1) 6 French diagnostic catheters were used 2) the order of graft and native
vessel injections was at the discretion of the operator 3) 50-100 micrograms of
nitroglycerin were injected into each graft before filming injections and indicated on the
film with a marker 4) at least 2 orthogonal views of each graft including the internal
thoracic artery were obtained 5)panning and continued exposure was used as required to
visualize distal runoff and the size of the target bed 6) injection of native vessels was
performed in addition to injection of the grafts 7) an aortic root angiogram was performed
if the status of any graft could not be determined by graft or stump injection.
Outcome Measures
Because randomization was performed on the basis of graft and territory rather
than per patient, precise allocation to clinical events to study graft was not possible. In a
descriptive manner, the adjudicating committee attempted to allocate clinical events to
the territory of one or other study graft, a non-study graft or progression of native
coronary disease. The committee used a 5 point scale (very unlikely, unlikely, possibly,
probably, likely) considering the totality of the evidence. The 5 point scale was
dichotomized to assess reviewer agreement: “possibly”, “probably”, or “likely” were
considered as “yes”; “very unlikely” or “unlikely” were considered as “no”.
Sample Size
A sample size of 350 patients would provide 80% power to detect a 35% relative
risk reduction from an estimated 23% occlusion rate in saphenous veins to 15% in radial
arteries, assuming a 5% within-patient correlation, for a 2-tailed alpha of 0.05.
Systematic Review
A standardized protocol was used for study identification, inclusion and data
abstraction. We performed a PubMed search of all publications up to April 1, 2011, with
no language restrictions for full articles with the search terms “radial”, “vein”, “veins”
and “patency” in various combinations and restricted our search for studies with
angiographic follow-up greater than 5 years postoperatively. Citations were screened for
inclusion using a hierarchical approach, progressing from title to abstract and then to the
full manuscript. The bibliographies of the identified journal articles were further
reviewed to identify additional relevant studies. In situations where the same cohort of
patients contributed to different reports, we preferentially abstracted data from the most
recent publication in the series. Aggregated results of late graft patency including the
RAPS results were determined using a random effects model and expressed as odds ratios
and 95% confidence intervals (Comprehensive Meta Analysis Version 2.0).
Heterogeneity was assessed using the Q-value.
Statistical Analysis
Univariate comparisons were performed using unpaired t-tests for continuous
variables and Chi-square or Fisher's exact test for categorical variables of baseline
characteristics between patients who did and did not undergo late angiography. MantelHaenszel Chi-square test was used to compare those variables with more than two levels
(CCS Class, Left Ventricular Grade, Proximal Stenosis).
Because radial artery and saphenous vein grafts are clustered within the same
patient, cumulative radial and saphenous vein graft patency was compared statistically
using the sandwich estimator for the variance. Each patient was right censored at their
last angiogram if they did not have an event. Cumulative patency curves for complete
occlusion included any patient that had either early or late angiograms; for functional
occlusion, patients that had either early or late invasive angiograms were included.
Target vessel stenosis was a pre-specified risk variable for graft occlusion. There
was no adjustment for the p value. The effect of target vessel stenosis on late graft
occlusion was determined using Chi-square test of proportional data and log-rank test for
cumulative graft patency.
RESULTS:
Patient population
Of the 510 patients in the 9 centres that participated in late angiography, protocol
violations occurred in 16 patients (1 or both study grafts not performed) – these patients
were not eligible for protocol directed angiography. Medical exclusions were present in
64 patients. The specific reasons for exclusion from late angiography were: new dye
allergy 1, complication from previous angiography 1, renal dysfunction 10, peripheral
vascular disease 3, referring physician refusal 6, and other medical co-morbidities in 43
patients (cancer 10, dementia 3, stroke 2, other neurological 2, psychiatric 2, drug
dependency 1, chronic obstructive lung disease 3, arrhythmia 2, post-trauma 1, and
multiple illness/frailty 17 patients).
In 7 cases, a patient received both radial-artery and control saphenous-vein grafts
but to the territory opposite that randomly allocated. The reasons for such crossovers
were inadvertent or unspecified error by the surgeon in 6 patients and concern about the
size or quality of the radial artery in 1. In the analysis of the primary end point, all these
patients were analyzed according to the intention to treat.
DISCUSSION:
Systematic Review
A single meta-analysis was identified which reported patency results from either
observational or randomized trials beyond 5 years7. Altogether there were 7 studies
included in the analysis. The definition of patency was consistent with our primary
outcome. A more recent publication was identified for one of the included studies6 and a
single additional publication identified8.
The OR for radial patency in 8 studies (both randomized and observational
studies) involving 522 radials and 880 SVGs was 0.504, 95%CI 0.290-0.875, p=0.015.
The benefit of radial grafting appeared stronger (OR 0.327, 95%CI 0.130-0.822,
p=0.017) when the analysis was restricted to the 2 randomized comparisons of radial and
saphenous vein graft patency (RAPCO, RSVP, 110 radials, 103 SVGs in total). The
updated results with the inclusion of the RAPS results are much more strongly
significant, and with narrower confidence intervals. The aggregated data including RAPS
suggests that the use of a radial artery provides an odds reduction in coronary artery graft
patency beyond 5 years of approximately 50% compared to a saphenous vein, but not as
much as previously estimated from randomized trials alone.
Study Limitations
Medical exclusions were present in 64 patients. The protocol stipulated that
research angiography was not to be performed should any condition listed as an exclusion
criteria develop following surgery (i.e. dye allergy, renal insufficiency, severe PVD and
co-morbid illness). Compared to the 269 patients who underwent late angiography, the 64
medical exclusion patients were older (mean age 63.3 + 8.4 vs. 60.4 + 8.0 years, p=0.01),
more likely to be older than 70 years (13/64 (20.3%) vs. 32/269 (11.9%), p=0.08), less
likely to be female (4/64 (6.3%) vs. 41/269 (15.2%), p=0.07), with a greater prevalence
of hypertension (43/64 (67.2%) vs. 121/269 (45.0%), p=0.001) and more peripheral
vascular disease (8/64 (12.5%) vs. 16/269 (5.9%), p=0.07).
We compared the clinical outcomes in the 64 patients who were medical
exclusions and the 269 patients who underwent late angiography. MACE was reduced in
the 64 medical exclusions compared with the patients who underwent angiography. This
was seen for MACE according to the study definition (7/64 (10.9%) vs. 100/465 (21.5%),
p = 0.05) and when perioperative MI was excluded from the definition of MACE (3/64
(4.7%) vs. 55/465 (11.8%), p=0.09). All-cause mortality was increased in the medical
exclusions (15/64 (23.4%) vs. 46/465 (9.9%), p=0.002), while the proportion of cardiac
death was less in the medical exclusions [Cardiac death, 3/15(20.0%) vs. 23/46 (50%),
p=0.04]. The patients who underwent angiography were “healthier” while the medically
excluded patients were more likely to die from non-cardiac causes.
We have reviewed RAPS results according to statin usage, as 23% of patients
were not taking statins as of last follow-up. In patients on statins, functional radial
occlusion was reduced, 25/193 (13.0%) compared to 36/193 (18.7%), p=0.15 with
saphenous veins. Complete radial occlusion was also reduced 21/223 (9.4%) vs. 40/223
(17.9%), p=0.01. In patients not on statins, functional and complete radial occlusion were
reduced compared to saphenous veins [Functional occlusion: 3/41 (7.3%) vs. 10/41
(24.4%), p=0.03; Complete occlusion: 3/46 (6.5%) vs. 10/46 (21.7%), p=0.03].
Acknowledgements
The members of the Radial-Artery Patency Study Group are as follows: Executive
Committee - S.E. Fremes, E.A. Cohen, R. Feder-Elituv, A. Laupacis; Manuscript
Committee –S.E. Fremes, E.A. Cohen, S. Deb, A. Laupacis, S.K. Singh, D. Une;
Steering Committee - S.E. Fremes, E.A. Cohen, A. Laupacis, C. Buller, N.D. Desai, L.
Errett, R. Feder-Elituv, J.F Morin, M.L. Myers, R. Novick, F.D. Rubens, S.K. Singh, T.
Yau, ; Participating Cardiologists - D. Almond (Victoria Hospital, London, Ont.), C.
Buller (University of British Columbia, Vancouver), E.A. Cohen (University of Toronto,
Toronto), L. Dragatakis (McGill University, Montreal), L. Higginson (University of
Ottawa Heart Institute, Ottawa), L. Schwartz (University of Toronto, Toronto), W.
Tymchak (University of Alberta Hospital, Edmonton), R. Watson (University of Toronto,
Toronto); Data Committee - M. Afshar, K. Algarni, S. Deb, R. Feder-Elituv, J. Sever, D.
Une (all at University of Toronto, Toronto); Statisticians - M. Katik, A. Kiss (all at
University of Toronto, Toronto); Angiographic Committee - E.A. Cohen, J. Dubbin, D.
Ko, A. Moody, V. Pen, S. Radhakrishnan, L. Schwartz (all at the University of Toronto,
Toronto); Clinical End-Points Committee - C. Joyner, F. Moussa, M. Myers (all at the
University of Toronto, Toronto); Investigators - Health Sciences Centre, Winnipeg, Man.:
D. Del Rizzo; Institute de Cardiologie de Montreal, Montreal: M. Carrier, R. Cartier, Y.
Leclerc; London Health Sciences Center - University Campus, London, Ont.: D. Boyd,
A. Menkis, R. Novick; London Health Sciences Center - Victoria Campus, London, Ont.:
M.L. Myers; Montreal General Hospital, Montreal: J.F. Morin, D. Shum-Tim; St.
Michael's Hospital, Toronto: D. Bonneau, L. Errett, D. Latter; Sunnybrook Health
Sciences Centre, Toronto: L. Abouzhar, G. Bhatnagar, G.T. Christakis, C. Cutrara, S.E.
Fremes, B. Goldman, ; Toronto General Hospital, Toronto: S. Brister, R.J. Cusimano, C.
Peniston, A. Ralph-Edwards, H. Scully, R. Weisel, T. Yau; University of Alberta
Hospital, Edmonton: E. Gelfand, P. Penkoske; University of Ottawa Heart Institute,
Ottawa: F.D. Rubens; Vancouver Hospital and Health Sciences Centre, Vancouver, B.C.:
L. Burr, G. Fradet, D. Thompson; Site Coordinators - R. Feder-Elituv, S. Finlay, R. Fox,
S. Fox, S. Germain, L. Harris, N. Hsu, MA. James, C. Jesina, M. Keith, R. Mokbel, L.
Montebruno, A. Munoz, C. Nacario, S. Naidoo, R. Sohal, K. Tsang .
e-Figure 1: Meta-Analysis of Randomized and Observational Studies Including RAPS
The results of the meta-analysis of observational and randomized trials comparing radial
artery and saphenous vein occlusion including the RAPS data is presented. An odds ratio
less than 1 indicates lower graft occlusion in the radial artery.
e-Figure 2: Meta-Analysis of Randomized Studies Including RAPS
The results of the meta-analysis of randomized trials comparing radial artery and
saphenous vein occlusion including the RAPS data is presented. An odds ratio less than 1
indicates lower graft occlusion in the radial artery.