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J Thorac Cardiovasc Surg 1994;107:1146-1153
© 1994 Mosby, Inc.

SURGERY FOR ACQUIRED HEART DISEASE

Effects of antiplatelet therapy with indobufen or aspirin-dipyridamole on graft patency one year after coronary artery bypass grafting

Leeds, Manchester, North Humberside, Hull, Harefield,and St.Albans, United Kingdom

Supported by Farmitalia Carlo Erba.

Received for publication May 11, 1993. Accepted for publication Sept. 27, 1993. Address for reprints: S. M. Rajah, MBBS, MRCP (UK), FRCPE, Killingbeck Hospital, York Rd., Leeds, United Kingdom.

Abstract

Saphenous vein coronary artery bypass graft patency can be increased by antiplatelet therapy. Aspirin plus dipyridamole are effective but are associated with tolerability problems. Indobufen is a possible alternative antiplatelet agent that may be better tolerated. A prospective, randomized, double-blind, parallel-group study was undertaken to compare the efficacy and safety of indobufen 200 mg twice daily with aspirin 300 mg thrice daily plus dipyridamole 75 mg thrice daily in preventing occlusion of autologous saphenous vein coronary artery bypass grafts. A total of 803 patients were randomized in the study, of whom 552 had a follow-up coronary angiogram approximately 1 year after operation. All anastomoses were patent in 56% of indobufen-treated patients and 59% of aspirin-dipyridamole recipients (p = 0.384). The percentage of all anastomoses patent was 82% in the indobufen group and 83% in the aspirin-dipyridamole group (p = 0.297). Mean postoperative blood loss was significantly less in the indobufen group (p = 0.043). Patients who received indobufen also had significantly fewer adverse events considered to be treatment-related compared with aspirin-dipyridamole recipients (p = 0.02). At the doses tested indobufen was as effective as aspirin plus dipyridamole in preventing occlusion of saphenous vein grafts and was better tolerated. Because indobufen was associated with less postoperative blood loss it may be used before operation in coronary artery bypass grafting. (J THORAC CARDIOVASC SURG1994;107:1146-53)

Coronary artery bypass grafting (CABG) is of undoubted benefit in relieving the symptoms of ischemic heart disease and, compared with drug therapy, significantly reduces mortality in high-risk patients. ^1-4 However, the success of CABG is dependent on postoperative graft patency, and pooled data suggest that up to 26% of saphenous vein grafts become stenosed or occluded within 1 year of operation and the cumulative occlusion rate is up to 50% within 10 years of operation. ⁵ Internal mammary artery grafts are more resistant to occlusion, with 10-year patency rates of about 95%, ⁶ but for technical and anatomic reasons, saphenous vein grafts are used either alone or in addition to internal mammary artery grafts in most cases. ⁷

Early and 1-year patency rates of saphenous vein grafts can be increased by antiplatelet therapy, ^8-12 and when this study was designed, the consensus was that preoperative initiation of treatment significantly improved the outcome. ¹³ Perioperative administration of aspirin is effective, but is associated with a significantly greater risk of bleeding complications and reoperation as compared with the risk for placebo. ¹⁰

Indobufen, a phenylbutyric acid derivative, prevents platelet aggregation by reversibly inhibiting platelet cyclooxygenase. ^14,15 In comparison with aspirin, which irreversibly acetylates cyclooxygenase, the effects of indobufen are short-lived and platelet function recovers within 24 hours after cessation of indobufen administration. ¹⁶ Furthermore, indobufen has only a modest effect on bleeding time. ^17,18

METHODS

Study population
From February 1986 to August 1989 patients admitted to four centers in the United Kingdom for CABG were screened to determine their suitability for inclusion in the study. Patients aged between 16 and 70 years who were to receive fresh autologous saphenous vein coronary artery bypass grafts, either alone or with internal mammary artery grafts, were considered.

Exclusion criteria comprised previous CABG or other cardiac operation or requirement for cardiac procedures other than CABG; history of major complications at cardiac catheterization; gastrointestinal bleeding or intolerance to aspirin, dipyridamole, or any other nonsteroidal antiinflammatory drug (NSAID); allergy to contrast media; bleeding disorders; any condition necessitating anticoagulant or long-term NSAID treatment; active peptic ulcer; significant renal or hepatic impairment; and women of childbearing potential. Patients undergoing urgent operation or admitted to the hospital too late to take the scheduled preoperative doses of study medication were also excluded.

Informed consent was obtained from all patients before enrollment. The study was done in accordance with the principles of the Declaration of Helsinki and was approved by the local Ethics Committee at each center.

Study treatment and concomitant medication
Patients were randomized to study treatment before operation. Treatment with aspirin or any other platelet-active drug was stopped 2 weeks before operation.

The study treatment regimens were indobufen 200 mg twice daily (I group) and aspirin 300 mg three times daily plus dipyridamole 75 mg three times daily (AD group). Indobufen and dipyridamole therapy was started 24 hours before operation and a single dose of aspirin was administered on the evening before operation. Treatment was administered via a nasogastric tube in the immediate postoperative period if the patient was unable to swallow. Regular study treatment was then continued for 12 months, when follow-up angiography was scheduled. Indobufen, aspirin and dipyridamole, and matching placebo capsules were provided by Farmitalia Carlo Erba Ltd., St. Albans, United Kingdom.

Postoperatively, compliance was assessed at each follow-up visit. Patients who received at least 80% of study medication during the study were considered to be treatment compliant. In the event of suspected intolerance to study treatment, the dose was reduced or the patient switched to another antiplatelet drug. This was an intention-to-treat study so patients changing medication were not withdrawn from the study and were followed up according to the protocol.

Patients were provided with a list of NSAID-containing proprietary preparations to avoid and a supply of acetaminophen for self-medication.

Operation
CABG was done according to the usual procedure of the surgeon. The type of graft (single, Y, or sequential), the site of stenosis bypassed, the site of the distal anastomosis, and the lumen diameter of the grafted vessel at the distal anastomosis were recorded for each graft. Surgical complications were noted and the volume of blood recovered from wound drains from the end of operation until 8:00 AM the next day was measured.

Efficacy evaluation
Angiography was scheduled for 12 months after operation. The techniques used were selective graft injection or digital subtraction angiography with intraarterial injection into the aortic root and selective graft catheterization where necessary. The cardiologists who did the angiograms were blinded as to treatment allocation. Grafts were recorded as either patent or occluded. Single grafts were considered patent if the origin was located and contrast medium was seen to flow through the graft into the distal vessel. For sequential and Y grafts, distal anastomoses were recorded as patent if contrast medium was seen to flow into the grafted arteries; if the graft was occluded at the proximal end, all distal anastomoses were considered to be occluded. Angiograms were reviewed independently by cardiac radiologists (M.R., D.B., J.D., and S.K.) who were blinded to treatment allocation. The New York Heart Association angina grade was recorded at each follow-up visit as a measure of change in angina status after operation.

Safety evaluation
All adverse events that occurred from the first dose of study treatment to the last follow-up visit were recorded, together with their severity and putative relationship to treatment.

Statistical analysis
It was decided to do the primary analysis on the proportion of patients in whom treatment failed (that is, with one or more anastomoses occluded) and the target sample size was calculated to detect a 30% failure rate for indobufen, with a power of 80%, assuming a 20% failure rate for aspirin plus dipyridamole and a one-sided significance level of 5%. On this basis, 250 patients in each arm were required to have follow-up angiography. A final target sample size of 425 patients per arm was chosen, to allow for withdrawals. In fact, two-sided tests were used, reducing the power to 70% (if the failure rates and significance level are unchanged).

Results from all study centers have been pooled for analysis, but statistical comparisons were made with the use of procedures that account for between-center variation. Results of treatment group comparisons are presented as two-sided p values.

Analyses were done on the intention-to-treat population. Secondary analyses were also done on those patients who had follow-up angiography and on those who complied fully with the protocol.

Demographic and background characteristics and surgical details of the two treatment groups were compared by the Mantel-Haenszel test, the extended Mantel-Haenszel test, and the van Elteren test. ¹⁹ Between-group comparison of graft patency rates at the patient level (proportion of patients with all anastomoses patent) was done by the Mantel-Haenszel test. A subsidiary analysis of grafts at the anastomosis level (proportion of all anastomoses patent) was also done by the Mantel-Haenszel test.

The effects on graft patency of various prognostic factors (impaired left ventricular function, smoking habit, previous myocardial infarction, patient weight on admission, site of stenosis, and lumen diameter of the recipient artery) and their possible interaction with treatment were determined by logistic regression analysis. The prevalence of adverse events in the two treatment groups was compared by either the Mantel-Haenszel test or Fisher's exact test.

RESULTS

Patient data
A total of 1776 patients were screened for eligibility to enter the study and 803 (45%) of these were randomized and provided data for analysis. For 17 patients, graft data were not available; the remaining 786 patients received 2408 grafts.

The demographic and background characteristics of the patients available for analysis are presented in Table I.

Results of follow-up angiography were available for 278 patients in the I group and 274 patients in the AD group, that is, for 69% of randomized patients in both treatment groups. Of those patients who underwent follow-up angiography, three in each group violated the study protocol and 135 in the I group and 141 in the AD group were not treatment-compliant.

Graft occlusion data
Angiography was done 44 to 60 weeks after operation in 169 patients in the I group and 159 patients in the AD group (61% and 58%, respectively, of those with angiographic results); 107 patients in the I group (38%) and 112 in the AD group (41%) had angiograms more than 60 weeks after operation. The longest interval between operation and angiography was 98 weeks. Only three patients (one I group, two AD group) underwent angiography before 44 weeks. The time from operation to angiography was not recorded for one patient in each treatment group.

All anastomoses (saphenous vein or internal mammary artery) were patent in 155 patients (56%) in the I group and 162 (59%) in the AD group (odds ratio 1.2; 95% confidence limits [CI] 0.8 to 0.16; p = 0.38; Table II). When saphenous vein grafts alone were considered, 158 patients (58%) in the I group had no occluded anastomoses compared with 170 (63%) in the AD group (odds ratio 1.2; 95% CI 0.9 to 1.7; p = 0.23; Table III). The percentage of patients with all grafts patent decreased with increasing number of anastomoses, whether all grafts or saphenous vein grafts only are considered (Tables II and III).

Within the population of patients assessed angiographically, a total of 883 anastomoses were done in patients in the I group and 870 in patients in the AD group. The overall anastomosis patency rates at follow-up were 82% in the I group and 83% in the AD group (odds ratio 1.1; 95% CI 0.9 to 1.5; p = 0.297). Anastomosis patency rates did not differ between treatment arms with type of conduit, site of graft, or size of recipient vessel (Table IV).

Perioperative complications
There were 27 perioperative deaths (17 I group, 10 AD group) and 67 patients (30 I group, 37 AD group) had life-threatening events during the perioperative period. All were of cardiovascular origin.

The volume of blood recovered in operative wound drains from the end of operation to 8:00 AM on the following day was significantly lower in the I group than in the AD group (mean plus or minus standard deviation of 814.4 ± 543.1 ml versus 898.0 ± 649.3 ml; p = 0.043).

Treatment compliance
During the perioperative period, 67% of patients in both treatment groups received at least 80% of the scheduled doses of study medication. During the period from before operation until 44 weeks afterwards, 141 patients (51%) in the I group were treatment-compliant, compared with 132 patients (48%) in the AD group. The study treatment was replaced by alternative antithrombotic therapy in 127 patients (31%) randomized to the I arm and 125 patients (40%) randomized to the AD arm.

Only five patients in each treatment arm had the study medication reduced for the duration of the study after suspected intolerance.

Adverse events
Throughout the study, 152 patients treated with indobufen (38%) had 233 adverse events that were considered to be potentially treatment-related; in the AD group, 180 patients (45%) reported 309 events (p = 0.02). The prevalence of the most frequent drug-related events is summarized in Table V and a summary of all adverse events that were considered to be related to treatment is given in Table VI.

There were no other significant differences between treatment groups apart from cardiovascular events (World Health Organization classification) for which the overall incidence was similar, but the prevalance of events judged to be related to treatment was significantly lower in the I group.

Total study mortality rate was 3.1% and was not significantly different between groups with the majority being perioperative deaths. Three deaths (one in the I group, two in the AD group) were thought to be possibly related to study medication.

The overall incidence of adverse events (regardless of their relationship to operation or study treatment) before the 1-month follow-up was greater in the AD group than in the I group (194 patients [49%] and 416 events versus 170 patients [42%] and 349 events; respectively; p = 0.021).

In both treatment groups, significantly more patients had a lower hemoglobin value after operation than at baseline. This change was more highly statistically significant in the AD group (I group, p = 0.026; AD group, p < 0.001).

DISCUSSION

The results of the primary analyses of this study indicate that the two treatment regimens were equally effective in maintaining the patency of saphenous vein coronary artery bypass grafts, but that indobufen was better tolerated. When subgroup analyses were done there were apparent small differences observed between the treatment groups, most of which were in favor of the aspirin and dipyridamole treatment. These differences were seen in subgroups in which numbers were too small to produce statistical significance and they could therefore have been caused by chance alone.

The proportion of patients with no occluded anastomoses is the most clinically relevant criterion of efficacy, and at 1 year after operation all grafts were patent in 56% of patients treated with indobufen and 59% of patients treated with aspirin-dipyridamole. After adjustment for smoking habit (a variable for which the two groups differed at baseline), the difference between the groups was still not statistically significant (p = 0.460).

An important aim of CABG is to improve the symptoms of angina pectoris, and this was achieved in a large majority of patients, with 87% of those who had angina before operation being symptom-free 1 year later.

The rate of follow-up angiography was close to 70%, a value that Henderson and associates ¹³ considered to be acceptable. The most common reasons for not providing angiographic data were refusal to undergo the examination (44 patients in the I group, 57 in the AD group) and loss to follow-up (13 patients in the I group, 13 in the AD group).

Eighty-two percent and 83% of anastomoses were patent at follow-up angiography in the I and AD groups, respectively; corresponding patency rates for saphenous vein grafts alone were 79% and 81%. In both treatment groups, 92% of internal mammary artery grafts were patent, supporting the recognized superiority of this vessel as a graft conduit. ^6,7,20

These 1-year anastomosis patency rates are within the range (75% to 89%) reported elsewhere for patients receiving antiplatelet therapy after saphenous vein CABG. ²¹ Although the Mayo Clinic study reported apparently superior results at the patient level with 78% of patients who received antiplatelet therapy having all grafts patent at 1 year and a patency rate at the anastomosis level of 89%, ⁹ this may have been the consequence of three important differences between the studies:

1. The present results suggest that a larger number of grafts per patient is associated with a poorer outcome (that is, a greater chance of at least one graft becoming occluded). In this study, the mean number of grafts per patient was 3.1 and the mean number of anastomoses was 3.2 in both treatment groups, whereas in the studies by Chesebro and associates ^8,9patients in the aspirin-dipyridamole group received a mean of 2.1 grafts and 2.8 anastomoses.
   
2. In the present study, the lumen diameter of the recipient vessel was 1.0 mm or less in 16% of anastomoses, compared with less than 5% of anastomoses in the studies by Chesebro and associates ^8,9; this and previous studies (forexample, that of Crosby and colleagues ²¹) have established that occlusion is more likely to occur in smaller grafted vessels.
   
3. Chesebro and associates ^8,9 restricted their investigations to patients with only saphenous vein grafts, whereas more than half of the patients in this study received both saphenous vein and internal mammary artery grafts. When both types of graft are used, the internal mammary artery is commonly used for the left anterior descending artery, a site usually associated with high patency rates for saphenous vein grafts.
   

When considering sample size calculations and the approach to the statistical analysis at the study outset and before beginning the analysis it was decided to concentrate the main analysis on the patient as the clinical unit. Analyzing grafts or anastomoses is not straightforward because individual grafts within a patient are unlikely to behave independently. ²² Furthermore, we consider that the patient is in fact the most relevant clinical unit. The sample size was therefore calculated to allow for this, assuming that one-tailed significance tests would be used for efficacy analyses. However, before starting the analysis it was decided that two-tailed tests would be more appropriate for demonstrating equivalence of the two treatments, so two-tailed tests were, in fact, used. Although this has reduced the power of the study, examination of the actual p values obtained suggests that the conclusion would have been the same if one-tailed tests had been used.

Fewer treatment-related adverse events were reported by patients randomized to receive indobufen and fewer patients in the I group discontinued study treatment because of unwanted effects. The most frequent adverse effects in both treatment groups were gastrointestinal disorders, usually those well-known to be associated with NSAID administration. It is noteworthy that, because patients who changed to alternative antithrombotic therapy (usually aspirin-based) during the study were included in the safety analysis, some patients in the I group reported adverse events when they were, in fact, taking aspirin. Thus the difference in tolerability of the two regimens may be greater than the data suggest.

The numbers of patients with a complicated postoperative course were similar in the two groups. The mean volume of blood lost postoperatively was significantly less in the I group; interestingly, mean blood loss in the I group was comparable to that reported for patients taking placebo after CABG (805 ml in 35 hours). ¹⁰ Two patients in each group had a fatal hemorrhage (cerebral in one patient treated with indobufen and gastrointestinal in the remaining three cases).

Overall mortality was similar in the two groups and comparable to that of other studies.

When this trial was designed, the dose of aspirin chosen combined with dipyridamole was appropriate for the prevention of coronary artery bypass graft occlusion. ²³ Now a dose of 325 mg/day ofaspirin is recommended ^6,11,24,25 and some advocate 75 mg/day ²⁶ because these lower doses are effective in maintaining graft patency but are better tolerated in terms of gastrointestinal effects and gastrointestinal bleeding. Goldman and associates ¹⁰ still found, however, that mean postoperative blood loss in patients receiving aspirin 325 mg once daily was significantly greater than that in patients treated with placebo. Also, the therapeutic usefulness of dipyridamole in this indication is now in question. ²¹

A recent paper from the veterans group has indicated that, provided aspirin therapy is started promptly after operation, excess bleeding can be avoided without loss of efficacy in respect to early patency. ²⁷ However, the effects on late patency have not yet been reported.

This study is one of the biggest done in the United Kingdom to investigate the effect of antiplatelet treatment in CABG. The results of the primary analyses lead us to conclude that indobufen 200 mg twice daily is as effective as aspirin 300 mg plus dipyridamole 75 mg three times daily in preventing occlusion in saphenous vein grafts and that indobufen is better tolerated than aspirin plus dipyridamole. These results confirm those reported with indobufen in a multicenter study in Italy. ²⁸ Furthermore indobufen may be used before operation because it was associated with less blood loss than was the aspirin plus dipyridamole regimen.

Here is a viable alternative to aspirin for influencing the patency of saphenous vein grafts in CABG.

Acknowledgments

We thank A. F. Mackintosh (Killingbeck Hospital, Leeds, United Kingdom) for valuable advice during the design of the study and to D. Bennett, C. Bray, N. Brooks, and C. Ward (Wythenshawe Hospital, Manchester, United Kingdom) and A. Mitchell (Harefield Hospital, Harefield, United Kingdom) who performed the angiograms for the study. Statistical advice was provided by N. P. Freemantle, MSc, consultant biostatistician, London United Kingdom; J. Smith, BSc, MSc, PhD, Quintiles (UK) Ltd., Reading, United Kingdom; and Professor S. J. Pocock, BA, MSc, PhD, professor of medical statistics, Department of Epidemiology and Population Sciences, London School of Hygiene and Tropical Diseases, London, United Kingdom.

Footnotes

From Killingbeck Hospital, ^a Leeds; Wythenshawe Hospital, ^b Manchester; Castle Hill Hospital, ^c North Humberside; Hull Royal Infirmary, ^d Hull; Harefield Hospital, ^e Harefield; and Farmitalia Carlo Erba Ltd., ^f St. Albans, United Kingdom.

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