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Re-graft patency and clinical efficacy of aprotinin in elective bypass surgery
PII: S0967-2109(97)00079-3
Cardiovascular Surgery, Vol. 5, No. 6, pp. 604–607, 1997 1997 The International Society for Cardiovascular Surgery Published by Elsevier Science Ltd. Printed in Great Britain 0967–2109/97 $17.00 + 0.00
Re-Graft patency and clinical efficacy of aprotinin in elective bypass surgery M. Lass, O. Simic and J. Ostermeyer
¨ Department of Cardiac Surgery, St. Georg Hospital, Lohmuhlenstrasse 5, 20099 Hamburg, Germany To investigate possible influence of aprotinin on graft patency, a randomized, double-blind group comparative study was carried out in male patients selected for primary bypass surgery. One hundred and ten patients received either placebo treatment or aprotinin according to the Hammersmith Hospital regimen(n = 55 per group). Graft patency was evaluated by angiography in 44 aprotinin and 35 placebo patients between the 18th and 35th day postoperatively. There was no difference in overall graft occlusion. Among the aprotinin patients, 73% (32/44) hsd grafts patent compared with 71% (25/35) of the placebo group. Graft occlusion was not accompanied by signs of myocardial infarction in any case. Blood loss within 6 h postoperatively was reduced by 58.5% in the aprotinin group (P ⬍ 0.001). of these patients 51% (26/51) did not need donor blood compared with 21% (10/47) of the placebo patients (P = 0.003). Mean transfusion requirements per patient were 1.1 and 2.7 units in the aprotinin and placebo groups, respectively. 1997 The International Society for Cardiovascular Surgery Keywords: coronary artery bypass, graft patency, aprotinin
Intraoperative administration of the proteinase inhibitor aprotinin leads to a reduction in postoperative blood loss and transfusion requirements in patients undergoing cardiopulmonary bypass surgery [1–8]. Today, few studies have examined possible side effects, although some authors have claimed an adverse effect on bypass graft patency [9], pointing to aprotinin being a predisposing factor towards early thrombus formation [10]. Others argue against such suspicions in view of the widespread use of aprotinin in cardiac surgery [7]. The influence of aprotinin on early graft patency therefore remains a matter for discussion.
Patients and Methods Patients A randomized, double-blind, placebo-controlled study was carried out between May 1990 and NovCorrespondence to: Dr M. Lass
604
ember 1992 and approved by the Ethical Committee of the University of Ulm, Germany. The exclusion criteria were: age 70 years or more, previous exposure to aprotinin, antiplatelet therapy during the 7 days before operation, obesity (Broca-Index ⬍ 30%), compromised cardiac function (ejection fraction ⬍ 40%), drug-dependent diabetes, elevated serum creatinine ( ⬍ 200 mmol/l), and percutaneous transluminal coronary angioplasty procedure during the proceding 6 months. Some 55 patients received aprotinin during surgery according to the Hammersmith schedule (2 × 106 KIU as loading dose before sternotomy, followed by an infusion of 0.5 × 106 KIU/h until the end of surgery; 2 × 106 KIU added to the prime). In addition, 55 patients received saline solution as a matching placebo in identical form and by the same administration scheme. Surgical technique Sodium-heparin 350 IU/kg intravenous was given before cannulation of the aorta. During extracorCARDIOVASCULAR SURGERY
DECEMBER 1997 VOL 5 NO 6
Aprotinin efficacy in bypass surgery: M. Lass et al.
poreal circulation the activated clotting time was maintained at > 400 s. At the end of bypass, heparin was neutralized by an intravenous injection of protamine at a heparin/protamine ratio of 100 IU : 1.0 mg. Myocardial protection was achieved with Bretschneider’s cardioplegic solution injected into the aortic root (30 ml/kg bodyweight within 7 min of infusion time) after cross-clamping. Surgery was carried out under moderate systemic hypothermia (30°). The surgical procedures were performed by five different surgeons under routine clinical conditions. The same standardized technique of anaesthesia was used in all patients. Coronary angiography Graft patency was determined by coronary angiography at 18 to 35 days after operation. Coronary arteriography was performed using the Judkins technique via the femoral artery and selective injection of contrast medium into each coronary artery orifice and each aortic bypass orifice. Identification of left internal mammary artery or right internal mammary artery bypasses was carried out by selective angiography of the subclavian artery with its mammary artery branch. Any bypass was regarded as occluded where a runoff contrast medium of the coronary artery segment could not be proved. Postoperative blood loss and transfusion requirements Postoperative blood loss was measured at regular intervals after chest closure: 0–2 h, 2–6 h, 6–12 h, 12–24 h removal of the drains. Packed red cells were administered under standardized conditions; when the haemoglobin level fell to ⬍ 1.55 mmol/l in the intensive care unit or to 1.1 mmol/l under bypass conditions. Statistical analysis Demographic data were compared for homogeneity using Student’s t-test. Blood loss and transfusion requirements were also evaluated by Student’s t-test. The number of graft occlusions were described by a two-by-two contingency table and tested by X2-test with one degree of freedom.
and placebo groups, respectively. Thirty-five aprotinin patients received 36 internal mammary artery grafts and 37 placebo patients received 39 internal mammary artery grafts. Four aprotinin and eight placebo patients were excluded from the analysis because of acute heart failure, re-thoracotomy after re-animation or bleeding, drug-dependent diabetes mellitus, combined valve and bypass procedure, and postoperative non-compliance. There were two deaths in the placebo group. The hospital mortality rate was 1.8%. Postoperative complications were observed in 12/54 aprotinin and 21/55 placebo patients, all of them within the spectrum observed after open-heart surgery such as mental distress and urogenital infection, but not related to aprotinin. Complications were distributed between the treatment groups except for three acute heart failures, two re-thoracotomies for refixing the sternum, and one Q-wave myocardial infarction which occurred in the placebo group. Operative data Mean operative data are shown in Table 1. Bypass time was shortened by 18 min, aortic cross-clamping time by 10 min and chest closing time (end of bypass until end of operation) by 23 min. Graft patency Graft patency was evaluated in 44 aprotinin patients and 35 placebo patients. The overall patency rate was similar in the treatment groups in the per graft analysis and in the per patient analysis. Whereas the internal mammary artery was found occluded in five patients of aprotinin group — corresponding to a patency rate of 81.4% — there was no internal mammary artery occlusion in the placebo group. In contrast 91.7% of all venous grafts were found patent in the aprotinin group compared with 82.4% in the placebo group. In the per patient analysis venous grafts were patent in 84% of the aprotinin patients and in 70.5% of the placebo patients. Clinical efficacy The postoperative blood loss via thoracic drains was reduced by 58.5% in the aprotinin group during the
Table 1 Operative data (mean min.)
Results
Procedure time
Aprotinin group
Placebo group
Bypass (min) Cross-clamp (min) Chest closure (min)*
92 44 62
110 54 85
Group comparability Both treatment groups were comparable with respect to age, bodyweight, height, preoperative haemoglobin level, and the risk profile for coronary heart disease. The mean total number of grafts implanted was also comparable: 2.87 and 2.85 in the aprotinin CARDIOVASCULAR SURGERY
DECEMBER 1997 VOL 5 NO 6
*
From end of bypass until end of operation
605
Aprotinin efficacy in bypass surgery: M. Lass et al.
first 6 h postoperatively (P ⬍ 0.001), the cumulative drainage volume being significantly different between treatment groups (Figure 1). In the aprotinin group 51% of the patients (26/51) did not require any donor blood compared with 21% (10/47) of the placebo group (P = 0.003). Total transfusion requirements per group were also significantly reduced by aprotinin administration. The mean erythrocyte concentrates needed per patient were 1.1 U in the aprotinin group and 2.7 U in the placebo group (P ⬍ 0.001). With regard to the transfused patients, a trend to less donor blood was observed in the aprotinin group: 2.2 U per patient compared with 3.4 U in the placebo group. Some 22% (11/49) of aprotinin patients required fresh frozen plasma compared with 54% (19/35) of placebo patients (P ⬍ 0.001).
Discussion The efficacy of aprotinin in reducing blood loss and transfusion requirements in bypass surgery is beyond discussion after 10 years of experience. In view of the knowledge acquired concerning preservation of platelet function when administering aprotinin during extracorporeal circulation, increasing attention has been paid to its effects on graft patency [9–13]. The study presented here is a controlled trial which used coronary angiography for the evaluation of graft patency after aprotinin treatment in the largest patient population reported so far. Although the invasive method led to a high dropout rate with respect to angiography, 79 patients were catheterized postoperatively. They provide evidence that the overall graft patency is not influenced by aprotinin. Early venous grafts patency was investigated by Bidstrup et al. [11] in 1993 in a prospective randomized trial in 90 patients (43 aprotinin, 47 placebo) by means of magnetic resonance imaging.
,, 1200
1000
Aprotinin (n=51) P < 0.001
Placebo (n=47)
(ml)
800 600 400 200 160 0
0–2
0–6
0–12
[h]
Figure 1 Cu,alative thoracic drainage volume
606
0–24
It was also analysed by Lemmer et al. [5] in 1994 in a randomized, controlled, multicentre US study using ultrafast computed tomography scan for evaluation, the assessment being made on a per graft and per patient analysis in 164 patients (83 aprotinin, 81 placebo) and by Havel et al. [14] using coronary angiography. None of these groups reported an increase in graft occlusion after aprotinin therapy and the present results confirm these previous findings. The results of four independent trials using three methods of assessment of graft patency, therefore, do not provide evidence that patency is influenced by aprotinin in venous grafts. In 1993, Jegaden et al. [12] investigated the influence of aprotinin on graft patency in 52 patients exclusively undergoing arterial revascularization. They reported patent grafts in 99.3% (142/143) and concluded that aprotinin did not influence the patency. In 1992, Cosgrove et al. [9] performed a controlled trial with 169 patients undergoing isolated reoperative myocardial revascularization. They obtained post-mortem examinations in seven patients: four arterial grafts, all in aprotinin-treated patients, were found patent. In contrast, the present authors found internal mammary artery grafts occluded in five of 27 patients of the aprotinin group compared to none of 29 in the placebo group. According to Fishers’s Exact test, this gives a probability value of 5 (11%) and narrowly misses the normal level of significance. In this context the problem of multiple testing has to be addressed, for it requires adjustment of the probability value to a higher threshold of significance. The relevance of this probability value is underlined by the intend-to-treat analysis where internal mammary artery graft occlusions occurred in five of 29 aprotinin an one of 29 placebo patients, giving a P-value of 19 (36%). On the other hand, venous grafts were occluded in 29% (10/35) of placebo patients and in 16% (7/44) of the aprotinin patients, indicating by-chance results in these smallsized groups. It was therefore speculated that the patient numbers were too small to balance centrespecific influences, e.g. the study patients were operated on by five different surgeons. Another specific influence might be a combined revascularization — internal mammary artery on left anterior descending artery, ACB on right diagonalis over left anterior descending artery. This technique might have led to a flow competition which ultimately can be unfavourable for the smaller arterial vessel. LookIng for further explanations, the authors retrospectively analysed all the occluded internal mammary artery grafts and found a poor run-off caused by very small coronary vessels in three patients who also underwent the combined procedure; in one case a non-critical stenosis might have been bypassed and in one case the occlusion remained unclear. HowCARDIOVASCULAR SURGERY
DECEMBER 1997 VOL 5 NO 6
Aprotinin efficacy in bypass surgery: M. Lass et al.
ever, the authors consider this an accidential result due to the small group number which did not balance the individual patient’s conditions against the centre effects. Consequently, they continue to administer aprotinin in all bypass procedures but, as shown by the occluded grafts, the only way to resolve this issue conclusively may be to address this specific problem in a new trial. Bypass and cross-clamping times and the time for chest closure were each shorter in the aprotinin group, indicating a more sufficient effect on haemostasis function. This led to a dry operation field and time-saving chest closure, possibly with less bleeding or complications with canulation and anastomosis. With regard to other efficacy parameters such as blood loss and transfusion requirements of blood and blood products, the present results confirm those in previous reports [1–8]. In addition, it should be mentioned that the transfused patients also required less donor blood when operated on with aprotinin prophylaxis.
References 1. Bistrup, B. P., Royston, D., Sapsford, R. N., Taylor, K. M. and Cosgrove, D. M., Reduction in blood loss and blood use after cardiopulmonary bypass with high-dose aprotinin. Journal of Thoracic and Cardiovascular Surgery,, 1989, 97, 369–372. 2. Bidstrup, B. P., Harrison, J., Royston, D., Taylor, K. M. and Treasure, T., Aprotinin therapy in cardiac operations: a report on use in 41 cardiac centres in the United Kingdom. Annals of Thoracic Surgery,, 1993, 55, 971–976. 3. Blauhut, B., Boss, C., Necek, S., Doran, J. E., Spath, P. and Hansen, P. L., Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement and renal function after cardiopulmonary bypass. Journal of Thoracic Cardiovascular Surgery,, 1991, 101, 958–967.
CARDIOVASCULAR SURGERY
DECEMBER 1997 VOL 5 NO 6
4. Dietrich, W., Barakay, A., Dilthey, G., Henze, R., Niekau, E., Sebening, F. and Richter, J. A., Reduction of homologous blood requirement in cardiac surgery by intraoperative aprotinin application. Thoracic and Cardiovascular Surgeon,, 1989, 37, 92–98. 5. Lemmer, J. H., Stanford, W. and Bonney, S. L. et al., Aprotinin for coronary bypass operations: efficacy, safety and influence on early saphenous vein graft patency. Journal of Thoracic Cardiovascular Surgery,, 1994, 107, 543–553. 6. Royston, D., The serine antiprotease aprotinin (Trasylol): a novel approach to reducing postoperative bleeding. Blood Coagulation and Fibrinolysis,, 1990, 1, 55–59. 7. Royston, D., High-dose aprotinin therapy: a review of the first five year’s experience. Journal of Cardiothoracic Anesthesiology,, 1992, 16, 76–100. 8. Van Oeveren, W., Hansen, J. G. and Bidstrup, B. P., Effects of aprotinin on hemostatic mechanism during cardiopulmonary bypass. Annals of Thoracic Surgery,, 1987, 44, 640–645. 9. Cosgrove, D. M., Heric, B., Lytle, B. W., Taylor, P. C., Novoa, R., Golding, L. A. R., Steward, R. W., McCarthy, P. M. and Loop, F. D., Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Annals of Thoracic Surgery,, 1992, 54, 1031–1038. 10. Bohrer, H., Fleisher, F. and Lang, J., Early formation of thrombi on pulmonary artery catheters in cardiac surgical patients receiving high dose aprotinin. Journal of Cardiothoracic Anesthesiology,, 1990, 4, 222–225. 11. Bidstrup, B. P., Underwood, R. S. and Sapsford, R. N., Effect of aprotinin on aortocoronary bypass graft patency. Journal of Thoracic Cardiovascular Surgery,, 1993, 105((1)), 147–153. 12. Jegaden, O., Vedrinne, C. and Rossi, R., Aprotinin does not compromise arterial graft patency in coronary bypass operation. Journal of Thoracic Cardiovascular Surgery,, 1993, 106, 180–181. 13. Ollivier, J. P. and the EPPAC group, Patency of aortocoronary bypass grafts at 6 months: a French multicentre study. Archives des Maladies du Coeur et des Vaisseaux, 1991, 84, 537–542. ¨ 14. Havel, M., Grabenwoger, F., Schneider, J., Laufer, G., Wollenek, B., Owen, A., Simon, P., Teufelsbauer, H. and Wolner, E., Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood. Journal of Thoracic Cardiovascular Surgergy,, 1994, 107, 807–810. Paper accepted 12 June 1997
607
Cardiovascular Surgery, Vol. 5, No. 6, pp. 604–607, 1997 1997 The International Society for Cardiovascular Surgery Published by Elsevier Science Ltd. Printed in Great Britain 0967–2109/97 $17.00 + 0.00
Re-Graft patency and clinical efficacy of aprotinin in elective bypass surgery M. Lass, O. Simic and J. Ostermeyer
¨ Department of Cardiac Surgery, St. Georg Hospital, Lohmuhlenstrasse 5, 20099 Hamburg, Germany To investigate possible influence of aprotinin on graft patency, a randomized, double-blind group comparative study was carried out in male patients selected for primary bypass surgery. One hundred and ten patients received either placebo treatment or aprotinin according to the Hammersmith Hospital regimen(n = 55 per group). Graft patency was evaluated by angiography in 44 aprotinin and 35 placebo patients between the 18th and 35th day postoperatively. There was no difference in overall graft occlusion. Among the aprotinin patients, 73% (32/44) hsd grafts patent compared with 71% (25/35) of the placebo group. Graft occlusion was not accompanied by signs of myocardial infarction in any case. Blood loss within 6 h postoperatively was reduced by 58.5% in the aprotinin group (P ⬍ 0.001). of these patients 51% (26/51) did not need donor blood compared with 21% (10/47) of the placebo patients (P = 0.003). Mean transfusion requirements per patient were 1.1 and 2.7 units in the aprotinin and placebo groups, respectively. 1997 The International Society for Cardiovascular Surgery Keywords: coronary artery bypass, graft patency, aprotinin
Intraoperative administration of the proteinase inhibitor aprotinin leads to a reduction in postoperative blood loss and transfusion requirements in patients undergoing cardiopulmonary bypass surgery [1–8]. Today, few studies have examined possible side effects, although some authors have claimed an adverse effect on bypass graft patency [9], pointing to aprotinin being a predisposing factor towards early thrombus formation [10]. Others argue against such suspicions in view of the widespread use of aprotinin in cardiac surgery [7]. The influence of aprotinin on early graft patency therefore remains a matter for discussion.
Patients and Methods Patients A randomized, double-blind, placebo-controlled study was carried out between May 1990 and NovCorrespondence to: Dr M. Lass
604
ember 1992 and approved by the Ethical Committee of the University of Ulm, Germany. The exclusion criteria were: age 70 years or more, previous exposure to aprotinin, antiplatelet therapy during the 7 days before operation, obesity (Broca-Index ⬍ 30%), compromised cardiac function (ejection fraction ⬍ 40%), drug-dependent diabetes, elevated serum creatinine ( ⬍ 200 mmol/l), and percutaneous transluminal coronary angioplasty procedure during the proceding 6 months. Some 55 patients received aprotinin during surgery according to the Hammersmith schedule (2 × 106 KIU as loading dose before sternotomy, followed by an infusion of 0.5 × 106 KIU/h until the end of surgery; 2 × 106 KIU added to the prime). In addition, 55 patients received saline solution as a matching placebo in identical form and by the same administration scheme. Surgical technique Sodium-heparin 350 IU/kg intravenous was given before cannulation of the aorta. During extracorCARDIOVASCULAR SURGERY
DECEMBER 1997 VOL 5 NO 6
Aprotinin efficacy in bypass surgery: M. Lass et al.
poreal circulation the activated clotting time was maintained at > 400 s. At the end of bypass, heparin was neutralized by an intravenous injection of protamine at a heparin/protamine ratio of 100 IU : 1.0 mg. Myocardial protection was achieved with Bretschneider’s cardioplegic solution injected into the aortic root (30 ml/kg bodyweight within 7 min of infusion time) after cross-clamping. Surgery was carried out under moderate systemic hypothermia (30°). The surgical procedures were performed by five different surgeons under routine clinical conditions. The same standardized technique of anaesthesia was used in all patients. Coronary angiography Graft patency was determined by coronary angiography at 18 to 35 days after operation. Coronary arteriography was performed using the Judkins technique via the femoral artery and selective injection of contrast medium into each coronary artery orifice and each aortic bypass orifice. Identification of left internal mammary artery or right internal mammary artery bypasses was carried out by selective angiography of the subclavian artery with its mammary artery branch. Any bypass was regarded as occluded where a runoff contrast medium of the coronary artery segment could not be proved. Postoperative blood loss and transfusion requirements Postoperative blood loss was measured at regular intervals after chest closure: 0–2 h, 2–6 h, 6–12 h, 12–24 h removal of the drains. Packed red cells were administered under standardized conditions; when the haemoglobin level fell to ⬍ 1.55 mmol/l in the intensive care unit or to 1.1 mmol/l under bypass conditions. Statistical analysis Demographic data were compared for homogeneity using Student’s t-test. Blood loss and transfusion requirements were also evaluated by Student’s t-test. The number of graft occlusions were described by a two-by-two contingency table and tested by X2-test with one degree of freedom.
and placebo groups, respectively. Thirty-five aprotinin patients received 36 internal mammary artery grafts and 37 placebo patients received 39 internal mammary artery grafts. Four aprotinin and eight placebo patients were excluded from the analysis because of acute heart failure, re-thoracotomy after re-animation or bleeding, drug-dependent diabetes mellitus, combined valve and bypass procedure, and postoperative non-compliance. There were two deaths in the placebo group. The hospital mortality rate was 1.8%. Postoperative complications were observed in 12/54 aprotinin and 21/55 placebo patients, all of them within the spectrum observed after open-heart surgery such as mental distress and urogenital infection, but not related to aprotinin. Complications were distributed between the treatment groups except for three acute heart failures, two re-thoracotomies for refixing the sternum, and one Q-wave myocardial infarction which occurred in the placebo group. Operative data Mean operative data are shown in Table 1. Bypass time was shortened by 18 min, aortic cross-clamping time by 10 min and chest closing time (end of bypass until end of operation) by 23 min. Graft patency Graft patency was evaluated in 44 aprotinin patients and 35 placebo patients. The overall patency rate was similar in the treatment groups in the per graft analysis and in the per patient analysis. Whereas the internal mammary artery was found occluded in five patients of aprotinin group — corresponding to a patency rate of 81.4% — there was no internal mammary artery occlusion in the placebo group. In contrast 91.7% of all venous grafts were found patent in the aprotinin group compared with 82.4% in the placebo group. In the per patient analysis venous grafts were patent in 84% of the aprotinin patients and in 70.5% of the placebo patients. Clinical efficacy The postoperative blood loss via thoracic drains was reduced by 58.5% in the aprotinin group during the
Table 1 Operative data (mean min.)
Results
Procedure time
Aprotinin group
Placebo group
Bypass (min) Cross-clamp (min) Chest closure (min)*
92 44 62
110 54 85
Group comparability Both treatment groups were comparable with respect to age, bodyweight, height, preoperative haemoglobin level, and the risk profile for coronary heart disease. The mean total number of grafts implanted was also comparable: 2.87 and 2.85 in the aprotinin CARDIOVASCULAR SURGERY
DECEMBER 1997 VOL 5 NO 6
*
From end of bypass until end of operation
605
Aprotinin efficacy in bypass surgery: M. Lass et al.
first 6 h postoperatively (P ⬍ 0.001), the cumulative drainage volume being significantly different between treatment groups (Figure 1). In the aprotinin group 51% of the patients (26/51) did not require any donor blood compared with 21% (10/47) of the placebo group (P = 0.003). Total transfusion requirements per group were also significantly reduced by aprotinin administration. The mean erythrocyte concentrates needed per patient were 1.1 U in the aprotinin group and 2.7 U in the placebo group (P ⬍ 0.001). With regard to the transfused patients, a trend to less donor blood was observed in the aprotinin group: 2.2 U per patient compared with 3.4 U in the placebo group. Some 22% (11/49) of aprotinin patients required fresh frozen plasma compared with 54% (19/35) of placebo patients (P ⬍ 0.001).
Discussion The efficacy of aprotinin in reducing blood loss and transfusion requirements in bypass surgery is beyond discussion after 10 years of experience. In view of the knowledge acquired concerning preservation of platelet function when administering aprotinin during extracorporeal circulation, increasing attention has been paid to its effects on graft patency [9–13]. The study presented here is a controlled trial which used coronary angiography for the evaluation of graft patency after aprotinin treatment in the largest patient population reported so far. Although the invasive method led to a high dropout rate with respect to angiography, 79 patients were catheterized postoperatively. They provide evidence that the overall graft patency is not influenced by aprotinin. Early venous grafts patency was investigated by Bidstrup et al. [11] in 1993 in a prospective randomized trial in 90 patients (43 aprotinin, 47 placebo) by means of magnetic resonance imaging.
,, 1200
1000
Aprotinin (n=51) P < 0.001
Placebo (n=47)
(ml)
800 600 400 200 160 0
0–2
0–6
0–12
[h]
Figure 1 Cu,alative thoracic drainage volume
606
0–24
It was also analysed by Lemmer et al. [5] in 1994 in a randomized, controlled, multicentre US study using ultrafast computed tomography scan for evaluation, the assessment being made on a per graft and per patient analysis in 164 patients (83 aprotinin, 81 placebo) and by Havel et al. [14] using coronary angiography. None of these groups reported an increase in graft occlusion after aprotinin therapy and the present results confirm these previous findings. The results of four independent trials using three methods of assessment of graft patency, therefore, do not provide evidence that patency is influenced by aprotinin in venous grafts. In 1993, Jegaden et al. [12] investigated the influence of aprotinin on graft patency in 52 patients exclusively undergoing arterial revascularization. They reported patent grafts in 99.3% (142/143) and concluded that aprotinin did not influence the patency. In 1992, Cosgrove et al. [9] performed a controlled trial with 169 patients undergoing isolated reoperative myocardial revascularization. They obtained post-mortem examinations in seven patients: four arterial grafts, all in aprotinin-treated patients, were found patent. In contrast, the present authors found internal mammary artery grafts occluded in five of 27 patients of the aprotinin group compared to none of 29 in the placebo group. According to Fishers’s Exact test, this gives a probability value of 5 (11%) and narrowly misses the normal level of significance. In this context the problem of multiple testing has to be addressed, for it requires adjustment of the probability value to a higher threshold of significance. The relevance of this probability value is underlined by the intend-to-treat analysis where internal mammary artery graft occlusions occurred in five of 29 aprotinin an one of 29 placebo patients, giving a P-value of 19 (36%). On the other hand, venous grafts were occluded in 29% (10/35) of placebo patients and in 16% (7/44) of the aprotinin patients, indicating by-chance results in these smallsized groups. It was therefore speculated that the patient numbers were too small to balance centrespecific influences, e.g. the study patients were operated on by five different surgeons. Another specific influence might be a combined revascularization — internal mammary artery on left anterior descending artery, ACB on right diagonalis over left anterior descending artery. This technique might have led to a flow competition which ultimately can be unfavourable for the smaller arterial vessel. LookIng for further explanations, the authors retrospectively analysed all the occluded internal mammary artery grafts and found a poor run-off caused by very small coronary vessels in three patients who also underwent the combined procedure; in one case a non-critical stenosis might have been bypassed and in one case the occlusion remained unclear. HowCARDIOVASCULAR SURGERY
DECEMBER 1997 VOL 5 NO 6
Aprotinin efficacy in bypass surgery: M. Lass et al.
ever, the authors consider this an accidential result due to the small group number which did not balance the individual patient’s conditions against the centre effects. Consequently, they continue to administer aprotinin in all bypass procedures but, as shown by the occluded grafts, the only way to resolve this issue conclusively may be to address this specific problem in a new trial. Bypass and cross-clamping times and the time for chest closure were each shorter in the aprotinin group, indicating a more sufficient effect on haemostasis function. This led to a dry operation field and time-saving chest closure, possibly with less bleeding or complications with canulation and anastomosis. With regard to other efficacy parameters such as blood loss and transfusion requirements of blood and blood products, the present results confirm those in previous reports [1–8]. In addition, it should be mentioned that the transfused patients also required less donor blood when operated on with aprotinin prophylaxis.
References 1. Bistrup, B. P., Royston, D., Sapsford, R. N., Taylor, K. M. and Cosgrove, D. M., Reduction in blood loss and blood use after cardiopulmonary bypass with high-dose aprotinin. Journal of Thoracic and Cardiovascular Surgery,, 1989, 97, 369–372. 2. Bidstrup, B. P., Harrison, J., Royston, D., Taylor, K. M. and Treasure, T., Aprotinin therapy in cardiac operations: a report on use in 41 cardiac centres in the United Kingdom. Annals of Thoracic Surgery,, 1993, 55, 971–976. 3. Blauhut, B., Boss, C., Necek, S., Doran, J. E., Spath, P. and Hansen, P. L., Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement and renal function after cardiopulmonary bypass. Journal of Thoracic Cardiovascular Surgery,, 1991, 101, 958–967.
CARDIOVASCULAR SURGERY
DECEMBER 1997 VOL 5 NO 6
4. Dietrich, W., Barakay, A., Dilthey, G., Henze, R., Niekau, E., Sebening, F. and Richter, J. A., Reduction of homologous blood requirement in cardiac surgery by intraoperative aprotinin application. Thoracic and Cardiovascular Surgeon,, 1989, 37, 92–98. 5. Lemmer, J. H., Stanford, W. and Bonney, S. L. et al., Aprotinin for coronary bypass operations: efficacy, safety and influence on early saphenous vein graft patency. Journal of Thoracic Cardiovascular Surgery,, 1994, 107, 543–553. 6. Royston, D., The serine antiprotease aprotinin (Trasylol): a novel approach to reducing postoperative bleeding. Blood Coagulation and Fibrinolysis,, 1990, 1, 55–59. 7. Royston, D., High-dose aprotinin therapy: a review of the first five year’s experience. Journal of Cardiothoracic Anesthesiology,, 1992, 16, 76–100. 8. Van Oeveren, W., Hansen, J. G. and Bidstrup, B. P., Effects of aprotinin on hemostatic mechanism during cardiopulmonary bypass. Annals of Thoracic Surgery,, 1987, 44, 640–645. 9. Cosgrove, D. M., Heric, B., Lytle, B. W., Taylor, P. C., Novoa, R., Golding, L. A. R., Steward, R. W., McCarthy, P. M. and Loop, F. D., Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Annals of Thoracic Surgery,, 1992, 54, 1031–1038. 10. Bohrer, H., Fleisher, F. and Lang, J., Early formation of thrombi on pulmonary artery catheters in cardiac surgical patients receiving high dose aprotinin. Journal of Cardiothoracic Anesthesiology,, 1990, 4, 222–225. 11. Bidstrup, B. P., Underwood, R. S. and Sapsford, R. N., Effect of aprotinin on aortocoronary bypass graft patency. Journal of Thoracic Cardiovascular Surgery,, 1993, 105((1)), 147–153. 12. Jegaden, O., Vedrinne, C. and Rossi, R., Aprotinin does not compromise arterial graft patency in coronary bypass operation. Journal of Thoracic Cardiovascular Surgery,, 1993, 106, 180–181. 13. Ollivier, J. P. and the EPPAC group, Patency of aortocoronary bypass grafts at 6 months: a French multicentre study. Archives des Maladies du Coeur et des Vaisseaux, 1991, 84, 537–542. ¨ 14. Havel, M., Grabenwoger, F., Schneider, J., Laufer, G., Wollenek, B., Owen, A., Simon, P., Teufelsbauer, H. and Wolner, E., Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood. Journal of Thoracic Cardiovascular Surgergy,, 1994, 107, 807–810. Paper accepted 12 June 1997
607