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Ann Thorac Surg 2005;80:922-927
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Aprotinin Reduces Bleeding and Blood Product Use in Patients Treated With Clopidogrel Before Coronary Artery Bypass Grafting

Department of Cardiothoracic Surgery and Anesthesiology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden

Accepted for publication March 18, 2005.

^_* Address reprint requests to Dr van der Linden, Karolinska Institute, Dept. of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, S-171 76 Stockholm, Sweden (Email: janvan{at}ki.se).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
BACKGROUND: An increased proportion of patients undergoing urgent coronary artery bypass graft surgery (CABG) is being treated with clopidogrel, an irreversible platelet inhibitor. Clopidogrel in combination with aspirin is known to augment bleeding, transfusion requirements, and reoperation rates after CABG. Aprotinin, a protease inhibitor, is approved for use in cardiac surgery to reduce bleeding. The aim of this study was to investigate whether or not intraoperative use of aprotinin decreases bleeding and number of transfusions after CABG in patients treated with clopidogrel less than 5 days before surgery.

METHODS: We retrospectively reviewed the medical records of all consecutive patients, with preoperative clopidogrel exposure less than 5 days before surgery, who underwent urgent CABG at our institution during 1 year (n = 33). Eighteen patients received a full-dose aprotinin regime intraoperatively whereas 15 patients not receiving aprotinin served as a control group.

RESULTS: The two groups were comparable with respect to baseline characteristics and operative data. Mean postoperative bleeding was 710 mL (95% confidence interval [CI]: 560 to 860) in the aprotinin group versus 1,210 mL (95% CI: 860 to 1550) in the control group (p = 0.004). The aprotinin group received fewer transfusions of packed red blood cells (0.9 U, 95% CI: 0.1 to 1.7, versus 2.7 U, 95% CI: 1.4 to 4.1; p = 0.01), platelets (0.1 U, 95% CI: 0 to 0.3, versus 0.6 U, 0.2 to 0.9; p = 0.02), and fewer blood product units (1.1 U, 95% CI: 0.1 to 2.0, versus 3.7 U, 95% CI: 2.1 to 5.4; p = 0.002). There were 3 reoperations for bleeding, all in the control group (p = 0.05).

CONCLUSIONS: Aprotinin reduces bleeding, transfusion requirements of packed red blood cells, platelets, and total blood units in patients on clopidogrel undergoing urgent CABG.

	Introduction

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
When patients are referred to coronary artery bypass grafting surgery (CABG) after first having been subjected to modern aggressive interventional cardiology and pharmacotherapy, the after-effects of that therapy often cause great concern. Especially dreaded is the continued effect of clopidogrel, an irreversible platelet inhibitor, routinely used in patients with unstable angina, as well as in connection with percutaneous coronary interventions [1, 2]. These potent antiplatelet drugs will continue to affect bleeding when the patients undergo CABG.

Recent studies have indeed shown that clopidogrel treatment in combination with aspirin before CABG is associated with increased postoperative bleeding, transfusion, and reexploration rates [3, 4]. Reexploration due to bleeding may not only lengthen the hospital stay, but has also been associated with an increase in mortality [5]. Since clopidogrel is often given before angiography and percutaneous coronary interventions, the patient may later be referred to surgery with the additional handicap of an irreversible platelet inhibition that lasts about 5 days. Thus, the surgical team is facing the question whether the patient should have surgery delayed for 5 days at the risk of acute ischemic events, or should be operated upon earlier at the risk of increased bleeding and morbidity.

Aprotinin, a serine protease inhibitor with antifibrinolytic activity, has successfully been used in cardiac surgery to reduce overall bleeding and transfusion requirements in patients exposed to aspirin [6, 7]. Aprotinin is appealing as it not only reduces overall bleeding in cardiac surgery but also appears to preserve platelet function during cardiopulmonary bypass (CPB) [8, 9]. Moreover, in animals, aprotinin has been shown to shorten prolonged bleeding induced by clopidogrel [10]. The clinical effects of aprotinin in patients receiving clopidogrel are therefore of interest.

The aim of this study was to determine whether aprotinin decreases bleeding and transfusion requirements in patients undergoing urgent CABG and treated with clopidogrel less than 5 days before the operation.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The medical records of all patients who underwent urgent and acute on-pump CABG operations at our institution between July 2001 and July 2002 were reviewed. We included only patients treated with clopidogrel, which had been discontinued less than 5 days before surgery (n = 33). All patients were initially loaded with 300 mg of clopidogrel followed by a daily intake of 75 mg, and all patients were first time cardiac surgery candidates. The regional Human Research Ethics Committee, Stockholm, Sweden, approved the study (112303).

Preoperative patient characteristics and perioperative and postoperative data were collected from patient records and our institution’s database. During the postoperative period, patients received transfusions of packed red blood cells, platelets, and plasma at the discretion of the surgeon or the intensive care unit (ICU) physician. The policy of the department was to aim for a hemoglobin value of 85 g/L or more. We recorded number and type of transfusions given during surgery, postoperatively, and during the total hospital stay, as well as use of aspirin, clopidogrel, and low-molecular-weight heparin during the 5 days before surgery. Postoperative (<30 days) survival data were collected from the Total Register of the Swedish Population, Statistics Sweden. There was no loss to follow-up. Hemoglobin concentration was measured the day before surgery, after induction of anesthesia, every 30 minutes during CPB, at end of surgery, at arrival to the ICU, every 2 hours during the first 10 hours in the ICU, postoperatively day 2 and 4, and additionally at the discretion of the attending physician. Chest tube output was measured at hourly intervals in the ICU and autotransfused hourly during the first 4 hours in the ICU if the output exceeded 100 mL per hour. Autotransfusion was avoided if hemolysis was present, namely, if the urine was discolored.

Anesthetic and CPB management were similar for all patients. Cardiopulmonary bypass was performed with a flow rate of 2.4 L/m² or more, mild hypothermia at 34°C, a hollow fiber membrane oxygenator (Dideco Simplex D708; Dideco, Mirandola, Italy), and a roller pump perfusion system (Stöckert Instrumente GmbH, München, Germany). The CPB circuit was primed with Ringer’s acetate and 300 mL of mannitol 10%. Cardiac arrest was induced by antegrade or retrograde cold blood cardioplegia, or both, and maintained during cross-clamping with intermittent doses of cardioplegia. Anticoagulation was achieved with sodium heparin (400 IU/kg) intravenously and 7,500 IU in the CPB prime, and monitored with serial measurements of the activated clotting time (ACT) performed with a kaolin-activated Hemotec device (Medtronic Hemotec, Englewood, Colorado). The ACT was maintained above 400 seconds at all times during CPB. At completion of CPB, heparin was reversed with protamine sulfate given in a 1:1.3 ratio. After this dose, a further dose of 100 mg of protamine was administered if the ACT remained above 140 seconds.

Eighteen patients received aprotinin (Trasylol; Bayer AG, Leverkusen, Germany) 2 million KIU before start of surgery, 500 000 KIU/h during surgery, with an additional 2 million KIU in the CPB prime. None of the patients continued with aprotinin after completion of surgery. Before this study, it was the policy of the department to restrict the use of aprotinin to repeat CABG. Since bleeding in patients on clopidogrel undergoing CABG became a clinical problem, some of the surgeons were persuaded by one of the anesthetists (J.v.d.L.) to use aprotinin, while others adhered to the policy of the department. The final decision to administer aprotinin was at the discretion of the operating surgeon (n = 9).

Operations were performed through a standard midline sternotomy; the left internal thoracic artery was harvested as a pedicle and used as an in situ graft in all cases. The saphenous vein and the radial artery were harvested when needed. Cardiopulmonary bypass was instituted in a routine fashion, and CABG was then conducted using saphenous and arterial grafts as specified in Table 1. Two 32F chest tubes (Argyle; Tyco Health Care, Tullamore, Ireland), inserted through separate skin incisions, were positioned in the left pleura and mediastinum, respectively, and connected to the vein reservoir from the CPB circuit at a negative pressure of 15 cm H₂O. Tranexamic acid was given at the discretion of the surgeon after reversal of heparin with protamine sulphate if clots were absent in the wound or in the chest tubes. The intraoperative volume of bleeding was estimated from the intraoperative net volume in the suction reservoirs and the net weight of the surgical dressings.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
None of the patients died during the 30-day study period. Eighteen patients received a full-dose regimen of aprotinin intraoperatively (aprotinin group), whereas 15 patients were not treated with aprotinin (control group). Baseline characteristics and operative data of the two groups are summarized in Table 1. No statistically significant differences were found for clinical parameters, including duration of CPB and cross-clamping, and number of distal anastomoses. The exception was duration of surgery, which on average was almost 1 hour longer in the control group (p = 0.05). The mean time between the last administration of clopidogrel and surgery was 1.1 days (95% CI: 0.7 to 2.5) in the aprotinin group and 1.6 days (95% CI: 0.7 to 2.5) in the control group (p = 0.38). Postoperative data and bleeding and transfusion requirements are summarized in Tables 2 and 3, respectively. Patients in the aprotinin group stayed a significantly shorter time in the ICU and in the hospital. No reoperations for bleeding occurred in the aprotinin group, compared with 3 in the control group (p = 0.05). On the first postoperative day, troponin-T levels were lower in the aprotinin group (p = 0.05). Hemolysis was not present in any of the patients. Two patients in the control group versus 6 patients in the aprotinin group did not receive autotransfusion since the drainage output was less than 100 mL per hour (p = 0.12).

View larger version (24K): [in this window] [in a new window]   Fig 1. Average bleeding (mL) in the operating room (OR), intensive care unit (ICU), and total bleeding in the OR and ICU (Total) in the aprotinin group and the control group.

View larger version (19K): [in this window] [in a new window]   Fig 2. Average blood product use (Units) in the aprotinin group and the control group. (PRBC =packed red blood cells).

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The main finding of this study was that aprotinin decreases bleeding and transfusion requirements during CABG in patients treated with clopidogrel less than 5 days earlier.

Several recent studies have demonstrated that clopidogrel treatment within 4 days of CABG significantly increases blood loss, requires more reoperations for bleeding, and has greater transfusion requirements for red blood cells (6 to 11 times), plasma (2 to 4 times), and platelets (2 to 45 times) [3, 4, 11, 12]. Furthermore, the usual combination of aspirin and clopidogrel has synergistic antiplatelet effects, because each agent affects platelet aggregation by different mechanisms. Thus, Yende and Wunderink [3] found that the reoperation rate in patients undergoing CABG increased from 2.3% to 10.4% when the patients were treated with aspirin only and with the combination aspirin/clopidogrel, respectively. In comparison, their reoperation rate was 0% for patients who received neither aspirin nor clopidogrel. It is thus not surprising that the American College of Cardiology/American Heart Association 2004 guideline update for CABG surgery [13], states that "If clinical circumstances permit, clopidogrel should be withheld for 5 days before performance of CABG surgery" (class I recommendation, level of evidence: B). This recommendation will most certainly be followed in patients who are to undergo elective CABG. However, recent data indicate that as many as 5% of patients presenting for CABG may require urgent or acute surgery after clopidogrel administration [11]. In these clinical circumstances surgeons will not easily delay surgery, as that may lead to acute ischemic events. Clearly, if excessive bleeding could be avoided the decision to commence surgery would be much easier. This study indicates that a significant reduction of clopidogrel-induced bleeding and transfusion requirements can be achieved with full-dose aprotinin treatment.

Aprotinin, a serine protease inhibitor, has hitherto been used prophylactically to reduce blood loss, transfusion requirements, reoperations for bleeding, and the systemic inflammatory response associated with CABG and the use of CPB. A recent meta-analysis of 35 randomized trials, involving 3,879 patients [14], showed that aprotinin use was associated with significantly reduced perioperative transfusion and stroke rates, as well as a trend toward a lower incidence of postoperative atrial fibrillation. The full-dose aprotinin regimen will cause anti-inflammatory and kallikrein inhibitory effects as well as plasmin inhibition, whereas the half-dose regimen achieves only plasmin inhibition, and hence this dose has primarily only antifibrinolytic activity [15]. In patients on aspirin therapy before CABG, clinical studies have shown that full-dose aprotinin significantly reduces blood loss and transfusion requirements [7]. Although aprotinin is indicated for primary and repeat CABG patients at high risk for surgical bleeding, data evaluating the use of aprotinin in clopiogrel-treated patients undergoing CABG have been sparse. In an animal model, the administration of aprotinin has been shown to shorten the prolonged bleeding time induced by clopidogrel treatment [10].

As aprotinin is a foreign protein, hypersensitivity reactions are possible, with an increased risk in patients reexposed to aprotinin-containing products, in particular within a 6-month interval [15]. Although uncommon, severe and fatal adverse events associated with extensive venous and arterial thromboses have been reported, both with the United States Food and Drug Administration–approved full-dose regimen and with variations on the recommended dose. However, in the only multicenter trial [16] that used postoperative coronary angiographic assessment and the recommended full dose in CABG patients, the incidence of saphenous vein graft thrombosis was not significantly higher in the treated group than in the placebo group when adjusted for risk factors associated with vein graft occlusion (aprotinin versus placebo risk ratio 1.05, 90% CI: 0.6 to 1.8). Aprotinin did not affect the occurrence of myocardial infarction or mortality [17]. The newly published meta-analysis of 35 randomized controlled trials revealed no increased risk of mortality, myocardial infarction, or renal failure in patients undergoing CABG who received aprotinin [14]. Instead, apart from less bleeding and transfusion requirements, our data indicate that the duration of the operation could be shortened with the use of aprotinin in clopidogrel treated patients. This effect is most likely due to shortened hemostatic measures at the end of the operation, since there were no differences in duration of CPB and cross-clamping time. Moreover, we observed lower troponin-T values postoperatively in the aprotinin group, which is in accordance with the study by Taggart and coworkers [18]. These findings may be explained by the antithrombotic and antinflammatory mechanisms of action of aprotinin [19].

Although this study is a retrospective nonrandomized study, the study data were prospectively gathered in our institution’s database, which includes all patients operated at our institution. Still, the inevitable drawbacks of a nonrandomized study like this have motivated us to follow up with a prospective randomized clinical trial. As we did not measure platelet function preoperatively, the groups may not have been comparable in that respect. However, resistance to clopidogrel is reported to be in the range of 5% to 15% [20, 21], and even if some of the patients in the aprotinin group were resistant, it can not explain the large differences in blood loss and transfusion requirements. Tranexamic acid was almost never used intraoperatively, but sometimes was used postoperatively if excessive bleeding occurred and no clots were noted in the drains. However, because tranexamic acic was used more often in the control group, it can not explain our findings. Finally, to eliminate any remaining doubt about a possible influence of tranexamic acid, we excluded patients who received tranexamic acid from the comparison. In spite of the small numbers, we still found significant differences between the aprotinin group (n = 15) and the control group (n = 8) regarding total bleeding (p < 0.01) and total number of transfusions (p = 0.05). Hence, the effects must be attributed to aprotinin. Thus, the only remaining alternative explanation for the difference is some form of unknown patient selection, a drawback that is inherent in our study’s nature, namely, a retrospective review of data concerning what probably is a first-time observation.

In conclusion, full-dose aprotinin reduces bleeding, transfusion requirements of packed red blood cells, platelets, and total number of blood units in patients on clopidogrel undergoing urgent CABG.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Ulrik Sartipy Jan van der Linden Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lindvall, G. Articles by van der Linden, J. Search for Related Content PubMed PubMed Citation Articles by Lindvall, G. Articles by van der Linden, J.