Aprotinin versus ϵ-aminocaproic acid for aortic surgery using deep hypothermic circulatory arrest

Aprotinin Versus c-Aminocaproic Acid for Aortic Surgery Using Deep Hypothermic Circulatory Arrest M i c h a e l P. E a t o n , M D a n d G. M i c h a e l Deeb, M D

Objective: To compare the relative efficacy of aprotinin and ~-aminocaproic acid (EACA) in decreasing blood loss and transfusion requirements after aortic surgery involving deep hypothermic circulatory arrest (DHCA). Design: A retrospective chart review. Setting: A university medical center. Participants: Forty-nine patients who had undergone thoracic aortic surgery with the use of circulatory arrest. Interventions: Charts were examined for variables believed to influence postoperative blood loss, including the use of medications, and for the amount of postoperative chest tube drainage and perioperative transfusion. Measurements and Main Results: Median chest tube output (CTO) at 6 and 12 hours postoperatively was nearly identical in patients treated with aprotinin or EACA (660 and 1,015 v700 and 950 mL for aprotinin and EACA at 6 and 12 hours, respectively), as were total perioperative blood

transfusions. Complications were not significantly different between groups with the exception of a trend toward increased incidence of renal failure in the group receiving EACA. Conclusion: Aprotinin and EACA appear to be equally efficacious in reducing perioperative blood loss and transfusion requirements in patients undergoing aortic surgery involving DHCA. Questions of safety remain about the use of EACA in this setting that could not be addressed by this small retrospective study. A prospective, placebo-controlled study is warranted to confirm the absolute efficacy of these agents and to better define safety issues.

PROTININ, a peptide derived from bovine lung, is a nonspecific serine protease inhibitor that has been shown to decrease blood loss and transfusion requirements in surgery involving the use of cardiopulmonary bypass (CPB).I,2 Whereas some investigators have found aprotinin to be both safe and efficacious in the setting of deep hypothermic circulatory arrest (DHCA), 3 recently, concern has been raised about the use of aprotinin in cases involving DHCA both in terms of an increased incidence of thrombotic events 4 and a reversal of its effect on bleeding? e-Aminocaproic acid (EACA), a synthetic lysine analog, is an inhibitor of fibrinolysis that has also been shown to decrease the incidence of bleeding and transfusion associated with CPB. 6,7 Several studies have compared these two drugs with regard both to efficacy and adverse effects in routine cardiac surgery. 8,9 There is no published experience with the use of EACA in DHCA cases. With the above concerns in mind, the authors retrospectively studied a series of DHCA cases performed at the University of Michigan (Ann Arbor, MI) in which patients received one of these two drugs.

surgeries involved the valve and 24 surgeries did not. One patient had surgery involving the vena cava and was not included in the study. The patients' charts were reviewed, and the following data were obtained. Predictor variables included age, sex, preoperative hematocrit, platelet count, creatinine level, prothrombin time, partial thromboplastin time; aspirin use within 7 days or beparin use within 24 hours; surgeon; type of surgery; duration of surgery, CPB, DHCA, and retrograde cerebral perfusion (RCP); dose of aprotinin or EACA; heparin dosing and activated coagulation times; and intraoperative transfusion of blood products. Outcome variables included chest tube output (CTO) and transfusions of red blood cells (RBCs) and blood products for 48 hours postoperatively; occurrence of re-exploration for bleeding, death, stroke, myocardial infarction (MI), and acute renal failure (ARF), as well as discharge hematocrit. Stroke was defined as a new neurologic deficit that persisted to discharge, when there was physical examination and/or radiologic evidence of an ischemic/embolic event. MI was defined by standard electrocardiogram mid/or enzyme criteria. ARF was defined as the need for dialysis and/or hemofiltration in the intensive care unit. Primary outcomes investigated were cumulative CTO and homologous RBC transfusion at 6 and 12 hours; the occurrence of ARF, new neurologic deficit, MI, re-exploration for bleeding, and death. All statistics were calculated using the JMP (SAS Institute, Inc, Cary, NC) statistical platform. Univariate analysis was performed using the Student's t-test or Wilcoxou's rank sums for normally distributed and non-normally distributed continuous outcomes, respectively. Categoric outcomes were compared using one-way Fisher's exact test. Multivariate analysis was performed on predictor variables as previously listed using stepwise regressions for continuous response variables and multiple logistic regressions for categoric outcomes; p values less than 0.05 were considered significant.

A

METHODS

After approval of the institutional review board, the cardiac surgery database was reviewed for cases involving DHCA. Charts were available on 50 patients who underwent surgery between February 1993 and February 1995. Forty-nine patients had surgery on their ascending aorta and/or aortic arch for aneurysmal disease or dissection; 25

From the University of Rochester School of Medicine, Rochester, NY," and the University of Michigan Medical Center, Ann Arbor, MI. The statistical analysis described in this manuscript was performed in consultation with John Kolassa, PhD, Department of Biostatistics, University of Rochester, Rochester, NY Address reprint requests to Michael P. Eaton, MD, Assistant Professor of Anesthesiology, University of Rochester School of Medicine, Box 604, 601 ElmwoodAve, Rochester, NY 14642. Copyright © 1998 by W.B. Saunders Company 1053-0770/98/1205-001158.00/0

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Copyright© 1998by W.B. Saunders Company KEY WORDS: aprotinin, ~-aminocaproic acid, cardiopulmonary bypass, thoracic aortic aneurysm

RESULTS

Twenty-nine patients received aprotinin; 20 received 2 X 106 kallikrein inactivator units (KIU) as a loading dose, 2 × 106 KIU in the pump prime, and an infusion of 5 × 105 KIU per hour. Nine patients received half this dose. Nineteen patients received only EACA in doses from 5 to 40 g before bypass with a bolus/infusion scheme or boluses before and after CPB and in the pump prime. Five patients who had initially received aprotinin subsequently received EACA during the procedure,

Journal of Cardiothoracic and Vascular Anesthesia, Vo112, No 5 (October), 1998: pp 548-552

APROTININ VEACA FOR DHCA

usually after CPB, at the surgeon's request, in doses from 2.5 to 7 g. When considering blood loss and transfusion, the latter five patients were considered on an intention-to-treat basis as having received aprotinin. For analyzing complications, patients receiving both drugs were considered as a separate group. Drug selection and dose were based on a number of factors, including familiarity of the anesthesiologist and surgeon with each drug, the timing of the case (EACA was more available at night), and date of surgery (one surgeon began to use a 30-g dose of EACA after reading a paper reporting its efficacy). One patient received neither drug and was not included in drng-effect analysis. Two patients were found to have bleeding from a surgical cause at re-exploration and were not included in the analysis of postoperative bleeding or transfusion requirements. Five patients died intraoperatively; these patients were not included in the analysis of postoperative events, but were included in the analysis of intraoperative events and overall mortality. Forty-one patients (16 who received EACA and 25 who received aprotinin) were left for the analysis of postoperative bleeding and transfusion requirements. All patients received heparin, 300 to 500 U/kg, before the initiation of CPB, and the pump prime contained 10,000 U. Additional heparin was administered while undergoing CPB to maintain a kaolin ACT of greater than 600 seconds for aprotinin-treated or greater than 480 seconds for EACA-treated patients, or to maintain an acceptable heparin concentration as determined by the Hepcon HMS (Medtronic Inc, Minneapolis, MN) according to a heparin dose-response curve. Patients were cooled to a bladder temperature of 18°C or less before circulatory arrest. All patients received RCP thi-ough either the superior vena cava cannula or a cannula placed in the right internal jugular vein. Eleven patients also had a period of DHCA without RCP from 2 to 60 minutes. Forty-three procedures were performed by one surgeon and the remaining six were performed by one other surgeon. Demographics, laboratory data, and procedure characteristics were similar between groups except that patients receiving EACA had a greater mean height. There was a trend toward more emergent procedures in the EACA group (p = 0.07; Table 1). Univariate analysis showed no significant difference between groups in CTO or blood transfusion at 6 or 12 hours (Figs 1 and 2). Patients receiving EACA received more platelets intraoperatively than aprotinin-treated patients (p < 0.05), although there was no difference in total platelet transfusion. Other intraoperative RBC and blood product transfusion was not significantly different (Fig 2), nor were total donor exposures (DE; median, 43.5; interquartile range, 36.8 to 107.3 v median, 46; interquartile range, 29.5-72.5 for EACA and aprotinin, respectively). Renal failure was more common in the EACA group (5/16 v 1/21; p < 0.05). This did not maintain significance when the possibly confounding variable of emergent procedures was controlled for, but a trend remained (p = 0.097). When analyzed separately, emergent patients receiving EACA had a higher incidence of ARF than those receiving aprotinin (5/10 v 0/8; p < 0.05). There was no significant difference between groups in the rate of other complications (Table 2).

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Table 1. Demographics and Procedure Characteristics Aprotinin (n = 29)

Variable

Age (yr) 57 ± 16 Sex: M/F (No.) 17/12 Height (cm) 174 _+ 9 Weight (kg) 78.4 _+ 14.9 Emergent procedure (No.) 11 Procedure (No.) Arch 14 Arch + valve 15 Operative time (min) 571 ± 194 CPB time (rain) 285 -~ 116 DHCAtime(min) 54 + 32 Heparin total dose (units x 103) 60 (44.5-68.5) Intraoperative death (No.) 3 Preoperative Hematocrit (%) 36.1 (33.1-40.1) Creatinine (mg/dL) 0.9 (0.8-1.28) Platelet count (× 103/pL) 212 (164-261) PT (sec) 13.2 (12.5-14.4) P'FF (sec) 25.8 (24.7-29.9)

EACA (n = 19) 58 _+ 18 16/3 180 _+ 10" 84.1 + 11.8 12 11 8 613 ~+ 259 324 _+ 115 50 _+ 19 55 (45-60) 2 40 (34.4-42.7) 1.1 (0.9-1.4) 222 (180-259) 13 (12.2-13.3) 25 (24.1-25.8)

NOTE. Data expressed as mean ± SD, except heparin dose and laboratory values, which are expressed as median (interquartile range). ~p < 0.05. Abbreviations: CPB, cardiopulmonary bypass; DHCA, deep hypothermic circulatory arrest; PT, prothrombin time; PTT, partial thromboplastin time.

Multivariate analysis confirmed the lack of drug effect on indices of bleeding and blood transfusion. Multivariate analysis was performed using all predictor variables previously listed versus CTO and DE. The only multivariate correlates of bleeding and transfusion were weight (inversely correlated, p = 0.0003 for CTO and p = 0.03 for DE) and CPB time (p = 0.006 for CTO and p = 0.0008 for DE). The only significant multivariate correlate of any complication was the positive association of death with emergent procedures ( p = 0.04).

3,00O 2,500 2,000 5" g o o

1,500 1,000 500 0 0

10

20

30

40

50

Time (hr) Fig 1. Cumulative CTO for 48 hours postoperatively, Data points are median milliliters. Error bars represent 25 to 75 percentile range. ©, EACA; II, Aprotinin.

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12 10 == 8 o

4

0

RBC FFP Pits Cryo Intraoperative

RBC FFP Pits Cryo Postoperative

Fig 2. Blood product transfusion intraoperative and postoperative totals at 12 hours. Data expressed as median, error bars represent 25 to 75 percentile range. Abbreviations: EACA, epsilon-aminocaproic acid; RBC, packed red blood cells (units); FFP, fresh frozen plasma (units); Pits, platelets (doses: 1 dose = 6 units); Cryo, cryoprecipitate (doses: 1 dose = 10 units). *Aprotinin less than EACA; p < 0.05 [ ] , Aprotinin; ~3, EACA.

DISCUSSION Numerous studies have shown aprotinin to be of value in decreasing bleeding and transfusion requirements associated with routine CPB procedures. 1,2 It is particularly effective for high-risk procedures, such as re-operations, t° The synthetic lysine analogs EACA and tranexamic acid (TEA) have also been shown to decrease blood loss and transfusion associated with cardiac surgery.7,11 Several studies have compared EACA or TEA with aprotinin in patients undergoing primary cardiac surgery for revascularization or valve replacement. Trin-Duc et al, 8 using EACA, and Pugh and Wielogorski, I2 using TEA, found no difference between aprotinin and the synthetic antifibrinolytic in bleeding or transfusion requirements. Menichetti et all3 found aprotinin more effective than EACA or TEA for reducing transfusion requirements, whereas Corbeau et aP 4 found no difference in transfusion requirements between patients receiving aprotinin and TEA, despite lower blood loss in the aprotinin group. A problem with these studies is the study of patients undergoing primary surgery, a group at low risk for bleeding and transfusion, and therefore less likely to benefit from pharmacologic treatment aimed at decreasing bleeding. Van Norman et al9 retrospectively compared aprotinin with EACA in 81 moderate-to-high-risk patients and found a significant benefit of aprotinin over EACA regarding bleeding Table 2. Complications

Aprotinin (n = 24) EACA (n = 19) Both (n = 5)

Re-exposure (surgical cause)

ARF

M]

Stroke

Death (intraoperative)

5 (1) 2(1) 2 (0)

1 5* 0

1 0 0

3 5 1

6 (3) 7(2) 0 (0)

Note, Data are number of patients, *Aprotinin less than EACA; p < 0.05.

and transfusion requirements. The retrospective nature of this study, however, leaves open the possibility of drug selection bias, and the results have not been published in a peer-reviewed journal. In a recent randomized, double-blind, prospective trial, Bennett-Guerrero et aP 5 found a small advantage of aprotinin over EACA with regard to 24-hour CTO and platelet transfusion, but RBC and other component transfusions were not different between groups. Thus, there is limited evidence for a significant benefit of aprotinin over TEA or EACA. No study has been appropriately sized to evaluate safety issues because serious adverse outcomes tend to be relatively rare in routine cardiac surgery. DHCA has enabled surgeons to repair aortic pathology involving the arch vessels in a bloodless, immobile surgical field) 6 One of the drawbacks of this technique, however, is the coagulopathy that predictably develops because of prolonged bypass times and profound hypothermia. Patients undergoing DHCA routinely receive multiple units of blood and blood products to replace oxygen-carrying capacity and restore hemostasis.16 Recently, the use of aprotinin has been extended to the very-high-risk technique of DHCA. 3 Goldstein et al, ? in a retrospective study of 24 patients receiving aprotinin for surgery involving DHCA with age-matched controls, found that aprotinin reduced the need for postoperative RBC transfusion, with no change in perioperative morbidities, including MI, stroke, or renal failure requiring dialysis. Other investigators have impugned the efficacy and safety of aprotinin in conditions of DHCA. Westaby et al,~ in a retrospective study of 80 DHCA cases, found that patients treated with aprotinin had more than double the CTO of historic controls in the first 24 hours postoperatively and suffered an increased incidence of thrombotic cornplications. The latter was believed to be caused by the inhibition of plasmin and protein C, the function of which the investigators believed important in preventing intravascular thrombus formation during arrest states. The ability of aprotinin to influence the protein C system has since been disputed. 17 Sundt et a118 reported a series of 20 patients who underwent aortic surgery with DHCA and aprotinin and compared them with 20 age-matched controls undergoing similar procedures without aprotinin. Patients receiving aprotinin had a higher incidence of postoperative renal failure requiring dialysis, and this group was higher in hospital mortality than controls. Five of the seven aprotinin-treated patients who died perioperatively had postmortem examinations that revealed multiple platelet-fibrin thrombi in the microvasculature of multiple organs, including brain, heart, and kidneys. If, in fact, aprotinin is prothrombotic in the setting of DHCA because of its inhibition of protein C and plasmin, the synthetic lysine analogs would have a theoretic beneft because it is a specific inhibitor of plasmin/plasminogen and should not affect protein C. The authors' results indicate a lack of significant benefit of either EACA or aprotinin, although these data are subject to all the usual limitations of a retrospective study. One major concern is the possibility for bias in drug selection. The main reasons for choosing one or the other drug were not, however, biasing. One was the availability of EACA at any time; this may explain the increased use for emergency cases. Another was the

APROTININ V EACA FOR DHCA

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temporal change in drug preference. At the beginning of the study period, the institution was involved in a study using aprotinin for other, non-DHCA cases. The extension of this drug to these cases seemed logical. Toward the end of the study, the primary surgeon read a paper detailing the successful use of large doses of EACA 6 and adopted this technique. Thus, it is unlikely that drug choice was based on the perception that one drug was better or that any individual patient would be more likely to bleed excessively. Surgical technique, graft, and suture did not change during the study period. The power of this study to detect a clinically important difference in bleeding is limited because of the large interindividual variability, but the complete lack of even a trend toward superior efficacy of either drug is convincing. The virtual identity between groups in median 24-hour CTO (1,240 v 1,262 mL for aprotinin and EACA, respectively) and median total DEs (46 v 43.5) is striking. With such a large variability between patients, it is apparent that factors other than the choice of antihemorrhagic drug therapy are more important in determining blood loss and transfusion requirements after aortic surgery and DHCA. The only factors associated with postoperative bleeding and transfusion were factors commonly accepted to be associated with high risk, long bypass times, and lower patient weight. Although it is impossible to draw any conclusions about the absolute efficacy of either drug in the absence of an untreated control group, it appears difficult to recommend spending the additional several hundred dollars for aprotinin versus EACA, at least based on relative efficacy. Previous studies comparing aprotinin to EACA or TEA have looked primarily at efficacy in decreasing blood loss and transfusion requirements and have not been of sufficient size to have much power to find a significant difference in low probability events, such as stroke, MI, and renal failure. Levy et al, 19 in the largest study attempting to define safety issues related to aprotinin (n = 287), found no increased incidence of thrombotic events in treated patients, with some possible protective effect of aprotinin against stroke. The power of this study to detect differences in low probability complications was limited. The safety of EACA for this indication has not been studied, primarily because of the drug's generic availability. The

power of the authors' study to detect differences in complication rates is small, and the failure to find significant differences between groups in most complications is indicative of little. However, a significantly higher incidence of ARF was found in EACA-treated patients. EACA has been reported to cause ARF, although not in cardiac surgery patients, primarily from inhibition of lysis of thrombi in the collecting system causing obstructive uropathy, but also by producing thi-ombosis in the glomerular capillaries and through rhabdomyolysis and myoglobinuria. 2°-22 Although concerns have been raised about the possible effects of aprotinin on renal function, most evidence suggests that any effects of aprotinin on renal function are minor and transitory and may, in fact, be caused by the effects of CPB rather than any drug effectY It is of interest that all the EACA-treated patients who suffered ARF were undergoing emergency surgery for acute aortic dissection. It may be prudent to assume that patients with compromised renal blood flow are uniquely at risk for renal injury from EACA, whether from sluggish glomerular capillary flow predisposing to thrombosis or slow urine flow predisposing to obstruction. Equally likely is the possibility that the emergency patients receiving EACA simply had already lost renal blood flow because of inclusion of the renal arteries in the dissection. Data on the involvement of renal vessels in the aortic pathology requiring surgery were not usually obtained at the time of surgery. Nevertheless, because of the high mortality associated with postoperative renal failure (50% in the authors' study), the renal effects of EACA in DHCA should be further investigated. In summary, neither aprotinin nor EACA showed a clear relative advantage in efficacy in patients undergoing aortic surgery with DHCA. Although numbers were insufficient to effectively compare safety, a trend toward an increase in ARF was seen in EACA-treated patients that, if confirmed by further study, may contraindicate EACA for surgery involving DHCA. A prospective, randomized trial with a placebo-control group is warranted to show whether either drug has any benefit in DHCA cases, if aprotinin has any benefit to offset its much higher cost, and if EACA truly has negative effects on renal function not seen with aprotinin.

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