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Ann Thorac Surg 2004;77:925-931
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery

^a University of Auckland, Auckland, New Zealand
^b Department of Anesthesiology, Green Lane Hospital, Auckland, New Zealand
^c Department of Cardiothoracic Surgery, Green Lane Hospital, Auckland, New Zealand
^d Department of Cardiology, Green Lane Hospital, Auckland, New Zealand
^e Department of Medicine, University of Otago, Dunedin, New Zealand

Accepted for publication September 8, 2003.

^* Address reprint requests to Dr Merry, Department of Anaesthesiology, University of Auckland, Mercy Hospital, 98 Mountain Rd, Private Bag 92019, Auckland 1003, New Zealand
e-mail: a.merry{at}auckland.ac.nz

	Abstract

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
BACKGROUND: Bivalirudin is a short-acting direct thrombin inhibitor, with advantages over unfractionated heparin for anticoagulation in cardiac surgery. We hypothesized that bivalirudin is not associated with a clinically important increase in blood loss compared with heparin with protamine reversal in patients undergoing off pump coronary artery bypass (OPCAB) surgery. We also assessed flow with angiography at 3 months using a modified Thombolysis in Myocardial Infarction (TIMI) grade in the grafted coronary arteries.

METHODS: One hundred patients were randomly assigned to receive bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/h infusion) or heparin (150 to 300 U/kg bolus) with protamine reversal.

RESULTS: A median of 3 (range, 1 to 5) grafts were inserted per patient. Blood loss for the 12 hours after study drug initiation in the bivalirudin group (median, 793 mL; interquartile range, 532 to 1,214 mL; range, 320 to 4,909 mL; n = 50) was not significantly greater than in the heparin group (median, 805 mL; interquartile range, 517 to 1,117 mL; range, 201 to 2,567 mL; n = 50; p = 0.165). Median graft flow was 3.0 in the bivalirudin group (n = 40) and 2.67 in the heparin group (n = 39; p = 0.047). The bivalirudin group had more patients with grade 3 (ie, full) flow in at least 1 graft (100% versus 90%; p = 0.04), a trend toward more patients with grade 3 flow in all grafts (60% versus 38%; p = 0.06), and more grafts with grade 3 flow (82% versus 67%; p = 0.03).

CONCLUSIONS: Anticoagulation for OPCAB surgery with bivalirudin was feasible without a clinically important increase in perioperative blood loss. Graft flow was better in the bivalirudin patients; the impact of this on clinical outcomes requires a larger study.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 

Doctor White discloses that he has a financial relationship with The Medicines Company.

 

Controlled anticoagulation is essential for cardiac surgery and unfractionated heparin has almost always been the drug chosen for this purpose. Its advantages include reversibility with protamine, ease of titration and low cost. However, heparin is an animal extract of variable composition and activity and has been associated with platelet activation and dysfunction, the inflammatory response to surgery and cardiopulmonary bypass (CPB) and the formation of antibodies to platelet factor four complex [1] with consequent heparin-induced thrombocytopenia in approximately 3% of these cases [2]. In addition, heparin antibody formation [1, 3] may be an independent risk factor for myocardial infarction [4]. Protamine is also an animal extract, with potential for immune-mediated reactions. Its short half-life (4.5 minutes) may result in unopposed heparin effects postoperatively [5]. The combined adverse effects of heparin and protamine may exacerbate bleeding after cardiac surgery in some patients [6].

Bivalirudin (Angiomax) is a short-acting (plasma half life = 25 minutes), synthetic peptide (20 amino acid) direct thrombin inhibitor (The Medicines Company, Parsippany, NJ). It inhibits both clot-bound and fluid-phase thrombin, inhibits thrombin-mediated platelet aggregation, and has a low propensity for the generation of immune or inflammatory responses [7]. It is less likely to induce thrombocytopenia than heparin. Compared with heparin (without protamine reversal) bivalirudin has been shown to reduce bleeding and ischemic complications in patients with acute coronary syndromes [8] including those undergoing percutaneous coronary interventions (PCI) [9, 10]. This pharmacodynamic and pharmacokinetic profile might be suitable for anticoagulation in cardiac surgery. On the other hand, the possibility of serious postoperative bleeding with an anticoagulant for which there is no reversal agent is a formidable prospect after operations involving CPB. The degree of anticoagulation typically employed in off-pump coronary artery bypass (OPCAB) surgery is less than with CPB and serious postoperative bleeding is less frequent [11, 12]. Furthermore, because OPCAB surgery may produce a postoperative procoagulant state, heparin is only par-tially reversed after these operations in some surgical units (in the interests of graft patency) [11, 13–15].

Therefore, we hypothesized that anticoagulation for OPCAB surgery with bivalirudin could be provided without a clinically important increase in perioperative blood loss in comparison to heparin with protamine reversal. Our major secondary objective was to compare graft flow between the two regimens 3 months after surgery using angiography.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Patients
We screened patients between November 2000 and May 2002 at Green Lane, Ascot and Mercy Hospitals, Auckland, New Zealand. Patients were eligible if considered suitable for OPCAB. Exclusion criteria were stroke within 2 years, intracranial neoplasm, arteriovenous malformation or aneurysm, on renal dialysis or estimated creatinine clearance of less than 30 mL/min, current warfarin therapy, low-molecular-weight heparin therapy less than 24 hours, abciximab less than 7 days, tirofiban or eptifibatide less than 48 hours, or an activated partial thromboplastin time 50 seconds or longer in patients who had previously received heparin. Aspirin was stopped at least 24 hours before surgery. The study was approved by the Auckland Ethics Committee and all patients gave written informed consent.

Design and procedures
Patients were randomly assigned to receive either bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/h infusion), or heparin (originally 150 U/kg, amended to 150 to 300 U/kg) bolus. Additional rebolus or infusion adjustments were permitted to achieve and maintain an activated clotting time (ACT) of 300 to 350 seconds [13, 15] during coronary grafting until the time protamine reversal was requested by the surgeon. At this stage in the bivalirudin group the infusion was stopped and in the heparin group 1 mg of protamine was administered for every 100 U of the initial dose of heparin, with supplemental doses at the discretion of the anesthetists (who were guided by the ACT). The surgeon was masked to treatment allocation during surgery, until chest closure. The administration of blood products was at the discretion of the surgeons, anesthetists, and intensivists.

The primary endpoint was perioperative blood loss defined as total blood loss from the time of chest incision to 12 hours after study drug initiation. This included blood collected in the discard suction and drains as well as blood absorbed into the surgical swabs (estimated by weighing). The volume of saline added to the surgical field intraoperatively was subtracted from the total. Secondary endpoints included coronary graft flow at 3 months, activated clotting time, ischemic complications, postoperative bleeding events, and adverse events.

Creatine kinase MB (CKMB) and troponin-T were measured at baseline; between 6 and 12 hours; 20 and 24 hours; and at 4 days postoperatively or discharge. Electrocardiograms were obtained at baseline; between 20 and 24 hours; on day 4; and at 3 months postoperatively and were read masked to treatment allocation. In-hospital myocardial infarction was defined as a new significant Q-wave of 0.03 ms or longer duration with a depth of one quarter or greater of the corresponding R-wave amplitude in two or more contiguous leads; or new left bundle branch block; or CKMB or troponin-T of at least 10 times the upper limit of normal. Posthospitalization myocardial infarction was defined as the above electrocardiographic changes or CKMB or troponin-T concentration of at least twice the upper limit of normal.

Postoperative bleeding was classified as severe (life-threatening: requiring reoperation or intracranial), major (overt bleeding associated with a decrease in hemoglobin 50 g/L), moderate (overt bleeding associated with a decrease in hemoglobin 30 g/L) or minor (overt bleeding less than the above).

Angiography was performed with multiple orthogonal views. Graft insertion sites were profiled using large field sizes and appropriate panning and acquisition times to allow assessment of coronary flow. All patients received intracoronary or sublingual nitroglycerine before angiography.

All angiograms were analyzed by one radiographer (BJW) who was blinded to treatment allocation. Coronary graft flow into the native coronary arteries was assessed according to a schema modified from the Thombolysis in Myocardial Infarction (TIMI) criteria for assessment of coronary artery flow in patients with acute coronary syndromes [16]. The grades were defined as follows: grade 0, no antegrade flow down the graft and across the anastomosis into the native coronary artery; grade 1, contrast passes across the anastomosis of the graft into the native coronary artery but fails to opacify the entire coronary bed distal to the graft anastomosis for the duration of the cineangiographic filming sequence; grade 2, contrast passes across the graft anastomosis and opacifies the coronary bed distal to the anastomosis; however, the rate of entry of contrast into the native coronary artery vessel distal to the anastomosis is perceptibly slower than its entry into comparable areas not perfused by the grafted coronary artery; and grade 3, antegrade flow into the bed distal to the anastomosis occurs as promptly as antegrade flow into the opposite artery.

The primary angiographic outcome variable was graft flow, defined as the mean flow grade for each patient. For comparison with other studies grafts were defined as patent if contrast passed across the anastamosis. The presence of thrombus was also evaluated [17].

The study statistician created a random allocation list in permuted blocks of 4 or 6, stratified by the two surgeons, using computer-generated numbers. The randomization envelope was opened when the surgeon confirmed OPCAB surgery was feasible (namely after sternotomy and examination of the heart). Safety and angiographic data were reviewed by an independent safety committee after 10, 25, and 50 patients had been studied.

Statistics
We defined a clinically important increase in blood loss as a 25% increase in the bivalirudin arm compared with the heparin arm. Fifty patients in each group provided more than 80% power to detect a 25% excess in the bivalirudin arm (we assumed a mean 12-hour blood loss of 1,000 mL in the heparin group and a pooled standard deviation of 400 mL). We also predefined a composite endpoint of death, myocardial infarction, repeat revascularization, or severe bleeding. Analysis was on an intention to treat basis. Mann-Whitney tests were used for data which were continuous but not normally distributed and, ² tests were used for categorical data. Two-sided tests were used throughout except for blood loss, for which a one-sided test was used.

	Results

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Patients
Out of 226 patients screened, 100 were randomized (Fig 1). The baseline characteristics of the two groups were similar except that in the bivalirudin group more patients were current smokers, had diabetes, or had had a previous myocardial infarction (Table 1). The median number of grafts per patient was 3 (range, 1 to 5).

View larger version (35K): [in this window] [in a new window]   Fig 1. Trial profile. (ITT = intent to treat.)

View larger version (17K): [in this window] [in a new window]   Fig 2. Activated clotting time (ACT; mean, SE) by study drug. (Heavy line = bivalirudin; light line = heparin plus protamine.)

Bleeding
Perioperative blood loss (Fig 3) in the bivalirudin group (median, 793 mL; interquartile range, 532 to 1,214 mL; range, 320 to 4,909 mL; n = 50) was not significantly greater than in the heparin group (median, 805 mL; interquartile range, 517 to 1,117 mL; range, 201 to 2,567 mL; n = 50; Mann-Whitney test, p = 0.165). There were no significant differences in median blood loss in the 22 patients who received aspirin within the blood collection period postoperatively (bivalirudin 718 mL and heparin 800 mL) or in the 78 patients who did not (bivalirudin 807 mL and heparin 810 mL). Two patients in the heparin group and 1 in the bivalirudin group had incomplete blood loss data for logistical reasons. Exclusion of these 3 patients produced similar results (bivalirudin 778 mL; heparin 805; Mann-Whitney test, p = 0.205).

View larger version (21K): [in this window] [in a new window]   Fig 3. Perioperative blood loss: box plots showing the median, interquartile range, range, and outliers. The top two outliers in the bivalirudin group relate to patients who were converted to cardiopulmonary bypass and administered heparin.

View larger version (18K): [in this window] [in a new window]   Fig 4. Graft flow by patient at 3 months: box plots showing the median, interquartile range, range, and outliers. The median graft flow grades were 3.0 (bivalirudin) and 2.67 (heparin): Mann-Whitney test, p = 0.047.

View larger version (21K): [in this window] [in a new window]   Fig 5. Mean graft flow by patient: the proportion of patients with no impaired grafts was higher in the bivalirudin group: 2 test, p = 0.06. Hatched bars = bivalirudin (n = 40); open bars = heparin plus protamine (n = 39).

	Comment

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
This is the first randomized comparison of a new anticoagulant with heparin and protamine reversal for anticoagulation during cardiac surgery. Our results show that anticoagulation for off-pump surgery is feasible with bivalirudin without a clinically important increase in perioperative blood loss. In addition, patients who received bivalirudin had better mean flows in their grafted arteries than those who received heparin (Fig 4), the clinical value of which manifested as a trend towards complete flow in all the grafts of more patients in the bivalirudin group than in the heparin group (Fig 5). This suggests that bivalirudin may have the potential to improve outcome after coronary surgery, as it has done in the settings of acute coronary syndromes [8], percutanious coronary intervention [9, 10], and acute myocardial infarction [18].

The magnitude of perioperative blood loss (namely a median of about 800 mL) and the incidence of blood transfusion (namely about 20%) were comparable with previous reports of blood loss (403 to 2,312 mL) and blood transfusion (3.7% to 33%) [11, 19–22] in OPCAB surgery. There was very little difference between treatment groups in the distributions of blood loss data (Fig 3). The 2 bivalirudin patients with the greatest amounts of blood lost were the 2 in whom CPB was needed. It is possible that the administration of both bivalirudin and full dose heparin (followed by the use of CPB) may have contributed to excess anticoagulation and bleeding but this approach was specified in the protocol because we had no information on the management of CPB with bivalirudin.

Our primary analysis of graft flow used a mean flow grade calculated for each patient because grafts are not independent of each other and this approach analyses outcome on a "per patient" basis (namely we randomized and treated patients, not grafts, although a per graft analysis was also significant). We report the group medians of these individual patient means because the distribution of the data was skewed. In this study, we assessed flow from the grafted conduit into the native coronary artery after OPCAB surgery. Previous angiographic analyses have usually measured stenosis (patency) in the grafted conduit or the native artery but have not measured native artery flow [23]. In the first few months after surgery a number of factors can affect flow in the graft, the anastomosis or the native artery. These include stenosis due to neointimal hyperplasia, thrombus formation, technical/surgical factors, spasm, competitive blood flow, the small caliber of the native artery, or supply to an area of myocardial scar. Bivalirudin might be expected to affect thrombus formation and possibly neointimal hyperplasia. There was no difference between the groups in the presence of angiographic thrombus, but angiographic assessment of thrombus is less reliable than angiographic assessment of flow. To know whether our finding of improved graft flow translates into improved clinical outcome will require study in a larger number of patients.

This study included patients with multivessel coronary disease; the mean number of grafts per patient was 3, with 66.3% of grafts being arterial. Definitions of patency vary which makes comparison between studies problematic. Rates of 86.3% at 3 months [22], 98.9% at 1 month [21], and 81.2% at 1 year [15] have been reported. Our result of 91% at 3 months is comparable.

Complete blinding of this study would have been desirable scientifically but because this was the first clinical trial of bivalirudin in cardiac surgery, the safe management of postoperative bleeding was of paramount importance. The interpretation of elevated ACTs, rational protamine administration, and the surgical decision to reopen the chest would have been compromised had the trial been completely blinded. Instead we masked the surgeon intraoperatively and also the angiographic analysis (because we considered these to be the main potential source of bias in the assessment of the blood loss and grafted artery flow).

The longer ACTs in the bivalirudin group might explain the better flow seen in the grafted arteries of these patients. This outcome might have been better in patients who received heparin had it been administered at a higher dose and not reversed (or only partially reversed). However, there are no randomized data to define optimal levels of anticoagulation during and after OPCAB surgery.

It is possible that some form of systematic bias distinguished those patients who returned for angiography from those who did not. However,our follow-up rate (79%) was comparable with other studies [11, 15, 21] and a similar number of patients in each group (10 bivalirudin and 11 heparin) did not return.

The bivalirudin group contained more patients with diabetes, who were smokers or who had had a previous myocardial infarction but the influence of these factors would be unlikely to favor bivalirudin in terms of the bleeding or the angiographic outcomes.

In conclusion, this study has demonstrated the feasibility of using bivalirudin in OPCAB surgery. Blood loss was comparable with that seen with heparin and protamine reversal. This information may be of particular value for patients in whom heparin or protamine is contraindicated (for example, those with heparin-induced thrombocytopenia or allergy to protamine) and in whom OPCAB surgery is feasible. Hirudin is another option in these patients but has a much longer duration of action and has recently been associated with anaphylaxis [24]. Our data also suggest that bivalirudin may provide an advantage over heparin with protamine reversal in respect to flow through grafted arteries. The impact of this on clinical outcomes will require further study. Our conclusions should not be extrapolated to the management of patients undergoing CPB although others have now reported the use of bivalirudin in this setting (in patients with contraindications to heparin or protamine) [25, 26].

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
We would like to thank Drs Cheuk-Kit Wong, John French, Ralph Stewart, Christopher Occleshaw, Mark Webster, Ivor Gerber, Chris Hammett, John Edmond, Barry Snow, and Loretta Bush for their assistance with the study; and Mr Alan Kerr, Dr Warren Smith, and Dr Toby Whitlock for serving on the Safety Committee. This trial was funded by a research grant from The Medicines Company.

	References

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 

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