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Three Part Question

In [patients undergoing coronary arterial bypass grafting] does [aprotinin] administration [compromise graft patency]?

Clinical Scenario

You have referred a patient with unstable angina who is on aspirin and a heparin infusion. You take him to theatre for CABG and the anaesthetist gives him aprotinin according to Hammersmith Protocol (2 Million KIU as loading dose before sternotomy, followed by infusion of 0.5 million KIU/hour until the end of surgery; 2 million KIU added to the priming volume additionally). After straightforward quadruple bypass grafts he comes off bypass with ease and is transferred to intensive care unit without any inotropic support. Two hours later the patient develops ST elevation in the inferior leads. Though the patients is stable haemodynamically, a balloon pump is inserted and as arrangement is being made to take him back for re-exploration, the ECG changes revert back to normal and remain so subsequently.
Two months later you review this patient who is still getting some angina. An angiogram reveals that 2 of the vein grafts are now blocked. You wonder whether it was the aprotinin that might have caused this complication.

Search Strategy

Medline 1966-07/03 using the OVID interface, Cochrane Database of Systematic Reviews, ACP Journal Club and the Database of Reviews of Effects
Medline: [exp Aprotinin/ OR Aprotinin.mp/ OR Trasylol mp] AND [exp vascular patency/ OR graft patency.mp OR exp Graft occlusion, Vascular/ OR graft occlusion.mp]
Cochrane Database of Systematic Reviews, ACP Journal Club and the Database of Reviews of effects: Aprotinin

Search Outcome

Using Medline 45 papers were found of which 9 were deemed to be relevant. One paper was also found by cross checking reference lists. The Cochrane Database of Systematic reviews search found 14 reviews of which 1 was relevant. The papers are presented in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Henry et al, 2003, UK	Systematic review performed searching for RCTs studying anti-fibrinolytic drugs in adults scheduled for non-urgent surgery 61 studies into aprotinin found (7027 participants). 51 of these trials were in cardiac surgical patients	Systematic Review and Meta-analysis (level 1a)	Incidence of any thrombosis	Data from 15 trials gave a relative risk of thrombosis with aprotinin of 0.64 (95% CI: 0.31 to 1.31)	There was significant heterogeneity in trial outcomes, and some evidence of publication bias Large number of very small studies included in this review This systematic review did not specifically look at graft patency
			Incidence of non-fatal MI	Data from 20 trials gave a relative risk of non-fatal MI of 0.97 (95% CI: 0.69 to 1.36)
			Other thrombosis related outcomes	No significantly elevated risk of stroke, PE or DVT found in this meta-analysis
			Rate of RBC transfusion	Aprotinin reduced the rate of RBC transfusion by a relative 30% (RR=0.70 (95% CI: 0.64 to 0.76)
			Reoperation rate	Aprotinin significantly reduced the need for re-operation due to bleeding RR=0.40 (95% CI: 0.25 to 0.66)
Alderman et al, 1998, USA	436 patients assigned to receive intraoperative aprotinin (Hammersmith regime) 434 patients received placebo ECG, cardiac enzymes, blood loss and replacement evaluated Graft angiography at mean 10.8 days	Double blind PRCT (level 1b)	Percent patients with one or more occluded distal saphenous vein graft	Aprotinin group: 15.4% Placebo group: 10.9% (p=.03)	It is questionable as to whether it is valid to use logistic regression to allow for risk factors when a study is of double blind RCT methodology. However doing this allowed the authors to conclude that there was no significant difference between the groups. Big difference in results between US and non US centers (aprotinin: 9.4% vs 23%; placebo 9.5% vs 12.4%)
			Sub-analysis of the patients from USA (10/13) centers only and thus adjusting for risk factors for SVG occlusion	After adjusting for risk factors for SVG occlusion, the aprotinin vs placebo occlusion risk ratio decreased from 1.7 to 1.05 (90% CI, 0.6 to 1.8)
			Thoracic drainage	43% reduction in aprotinin group (p<.0001)
			Red blood cell requirement	49% reduction in aprotinin group (p<.0001)
Havel et al, 1994, Austria	15 patients assigned to receive high dose aprotinin (2 million KIU before incision, 2 million as infusion in 4 hrs, 2 million in pump) 15 patients received placebo Graft angiography at 7 to 12 days	Double blind PRCT (level 2b)	Graft patency rate (including both IMA and SVG)	All IMA grafts were patent SVG patency was: High dose Aprotinin gp: 93.8%, Low dose Aprotinin gp: 94.5%, Placebo gp: 93.3% Statistically not significant	Significant reduction in thoracic drainage and blood requirement without influencing the early graft patency The number of patients is small
			Post operative blood loss	590ml in high dose and 650ml in low dose group vs 920 ml in placebo (p<.001)
			Post operative transfusion requirement	1.46 units in high and 1.65 in low does group vs 2.43 in placebo (p<.05)
Lemmer Jr et al, 1994, USA	74 patients assigned to receive aprotinin (2 million KIU before incision, 0.5 million KIU/hr, 2 million KIU in pump) 67 patients received placebo Detect perioperative MI by submitting ECG, enzymatic and clinical data to Core ECG lab in blinded fashion Ultrafast CT scan to compare graft patency before discharge or at follow up	Double blind PRCT (level 1b)	Blood product usage	Aprotinin vs placebo Primary CABG: 2.2% vs 5.7% (p=.010) Redo CABG0.0.3% vs 10.7% (p<.001)	Significant reduction in thoracic drainage and blood requirement without influencing the early graft patenc The number of grafts assessed are insufficient to have firm conclusions
			Clinical diagnosis of myocardial infarction	Aprotinin vs placebo Primary CABG: 8.9% vs 5.6% (p=.435) Redo CABG10.3% vs 8.3% (p=NS)
			Early vein graft patency rate	92.0% in aprotinin group vs 95.1% in placebo group
Lass et al, 1995, Germany	55 patients assigned to receive aprotinin (2 million KIU before incision, 0.5 million KIU/hr, 2 million KIU in pump) 55 patients received placebo Graft patency evaluated by angiography in 44 aprotinin and 35 placebo patients between 18th and 35th days	Double blind PRCT (level 1b)	Postoperative blood loss	58.5% reduction in the aprotinin group (p<0.001)	Significant reduction in post operative blood loss No significant adverse affect on graft patency
			Early graft patency	89.5% (111/124) grafts patent in aprotinin vs 87.2%(89/102) in placebo 16% SVG graft (7/44) occluded in aprotinin vs 29% (10/35) in placebo 18.5% IMA graft (5/27) occluded in aprotinin vs 0/27 in placebo (p=0.0511)
Kalangos et al, 1994, Turkey	165 randomised to receive high dose, low dose aprotinin and placebo (55 patients in each group) Graft patency evaluated by angiography at mean of 8.2 days	Double blind PRCT (level 1b)	Early graft patency	High dose aprotinin 140/142 grafts patent Low dose aprotinin 128/128 grafts patent Placebo 138/139 grafts patent (p=NS)	No significant adverse affect on graft patency
Bidstrup et al, 1993, UK	96 adult male patients undergoing first-time isolated coronary bypass by a single surgical team were randomised to either one of two groups: (1) Aprotinin group n=47; (2) Control group (placebo) n=49; Graft patency assessed 9-12 days post operation by MR scanning	Double blind PRCT (level 1b)	No of patients with all vein grafts patent	Aprotinin group 38/43 (88%) Control group 43/47 (91%) p=NS	Angiographical assessment not used 6 patients were excluded from final analysis, 2 died, 4 problems with MR scanning
			No of vein grafts patent	Aprotinin group 126/131 (96%) Control group 134/138 (97%) p=NS
			Transfusion of RBCs	Aprotinin group mean 450mls Control group Mean 795mls P=0.03
van der Meer et al, 1996, Holland	Retrospective analysis of a study looking at various antithrombotic agents after CABG. Of 948 randomized patients, 42 received aprotinin at a single cardiac centre	Retrsopective cohort trial (level 2b)	Graft patency assessed at 1 year by angiography	Aprotinin group 20.5% Non-aprotinin group 12.7% p = 0.091	Non randomized study for the purposes of this analysis Small number receiving aprotinin, from a single centre High occlusion rate all both groups
			Proportions of patients with occluded grafts	Aprotinin group 44.1% Non-aprotinin group 26.3% p=0.029
Laub et al, 1994, USA	47 patients undergoing CABG entered into the study, 32 of these patients received technically adequate ultrafast CT at 6 weeks to assess graft patency 16 patients received aprotinin as per the Hammersmith Regime 16 control patients	Double blind PRCT (Level 2b)	Number of patients with at least 1 occluded graft	Aprotinin group 5/16 pts (31%) Control group 0/16 pts (0%) p = 0.04	7 pts did not receive an adequate CT scan, 2 patients died and 4 patients refused follow up Angiography not used to assess graft patency
			Number of occluded grafts	Aprotinin group 5/43 grafts (12%) Control group 0/38 p=0.057
			Mediastinal and chest drain blood loss	Aprotinin group 722mls Control group 1,540 mls p=0.0006
Jegaden et al, 1993, France	52 patients having aprotinin undergoing total arterial CABG by a single surgeon Used ¾ of the Hammersmith Regime for Aprotinin Angiography performed after 8-21 days	Case-series (level 4)	Patency of arterial grafts post op	142 of 143 arterial grafts in 52 patients remained patent (99.3%) In addition there was 1 anastomotic stenosis and 1 functional stenosis because of flow competition	This report is in the form of a letter and not a full paper and thus omits data such as sample size studies, patient demographics, full description of operative technique etc.
			Complications	1 patient suffered a new Q-wave MI

Comment(s)

Alderman et al presented the IMAGE trial, a study that involved 13 centers with 870 patients. They found a higher occlusion rate in saphenous grafts in the overall study population after aprotinin use, with 15% of patients suffering an occlusion in the Aprotinin group, compared to 11% in the control group. The triallists then adjusted for risk factors even though their study was a randomized controlled trial which should equalize the incidence of risk factors in the two groups. They then concluded that allowing for these risk factors there was no difference in the occlusion rate. One further study found an increased occlusion rate in the aprotinin group. Laub et al found a 30% occlusion rate in the aprotinin group compared to no occlusions in the control group. The numbers in this study was however very small. Of the remaining studies no significant differences were found although Lemmer, Bidstrup and van der Meer found non significant trends towards poorer patency with aprotinin. Due to the differing findings of these studies we combined their data by meta-analysis using a random effects model. We found that the increase in the odds of occlusion was 1.52 (95% C.I. 1.13 – 2.03) and that this result is significant. We therefore conclude that there is a small but significant increase in graft occlusion in patients undergoing CABG with aprotinin. Of note the amount of blood loss and blood product usage is significantly lower in the patients receiving aprotinin in all the studies. The Cochrane review combined the data from 61 studies and found a 30% reduction in blood transfusion, less blood drainage and a significantly lower incidence of reoperation due to bleeding. Finally we found only 1 study that investigated total arterial grafting. Jegaden demonstrated a 99.3% patency rate of arterial grafts in his single series of 52 patients who received 143 arterial anastomoses. This report agrees with the reports of high LIMA patency in the other papers and provides evidence that aprotinin is be safe for total arterial revascularization.

Clinical Bottom Line

Aprotinin clearly reduces blood loss, requirement for blood transfusion, and the risk of reoperation for bleeding, but probably does increase the risk of saphenous vein graft occlusion.

References

1. Henry DA, Moxey AJ, Carless PA, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion (Cochrane Review). In: The Cochrane Library Issue 2, 2004. Chichester, UK: John Wiley & Sons, Ltd.
2. Alderman EL, Levy JH, Rich JB, et al. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998;116(5):716-730.
3. Havel M, Grabenwoger F, Schneider J, et al. Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood. J Thorac Cardiovasc Surg 1994;107(3):807-810.
4. Lemmer JH, Jr., Stanford W, Bonney SL, et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 1994;107(2):543-551.
5. Lass M, Welz A, Kochs M, et al. Aprotinin in elective primary bypass surgery. Graft patency and clinical efficacy. Eur J Cardio-Thorac Surg 1995;9(4):206-210.
6. Kalangos A, Tayyareci G, Pretre R, et al. Influence of aprotinin on early graft thrombosis in patients undergoing myocardial revascularization. Eur J Cardio-Thorac Surg 1994;8(12):651-656.
7. Bidstrup BP, Underwood SR, Sapsford RN, et al. Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac Cardiovasc Surg 1993;105(1):147-152.
8. van der Meer J, Hillege HL, Ascoop CA, et al. Aprotinin in aortocoronary bypass surgery: increased risk of vein-graft occlusion and myocardial infarction? Supportive evidence from a retrospective study. Thromb Haemost 1996;75(1):1-3.
9. Laub GW, Riebman JB, Chen C, et al. The impact of aprotinin on coronary artery bypass graft patency. Chest 1994;106(5):1370-1375.
10. Jegaden O, Vedrinne C, Rossi R. Aprotinin does not compromise arterial graft patency in coronary bypass operations. J Thorac Cardiovasc Surg 1993;106(1):180-181.