Optimal intraoperative anticoagulation strategy in patients undergoing off-pump coronary artery bypass

Abstract

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was what the optimal intraoperative anticoagulation strategy should be in patients undergoing off-pump coronary artery bypass graft (CABG) surgery. A total of 157 papers were identified using the reported search, of which 8 were judged to represent the best evidence. The authors, journal, date, country of publication, study type, patient group studied, relevant outcomes and results were tabulated. The quality of clinical trials was assessed. Off-pump CABG is currently considered as a safe and effective alternative to CABG with the use of cardiopulmonary bypass, especially in the presence of off-pump expertise and certain pathologies. Although most technical steps in off-pump revascularization are standardized, it appears that there is inconsistency in intraoperative anticoagulation practice. Surveys conducted in the USA and Europe confirm the lack of uniform policy, with heparin dose ranging between 70 and 500 U/kg and from full-dose protamine to no reversal of anticoagulation. Although the quality of evidence is low, there is a trend for utilization of heparin at 150 U/kg, followed by half-dose protamine reversal, which appears to provide adequate anticoagulation for the safe conduct of anastomoses and thromboprophylaxis without significantly increasing the risk of postoperative bleeding. However, more research is necessary before firm recommendations can be made.

INTRODUCTION

A best evidence topic was written according to a structured protocol [1].

THREE-PART QUESTION

In patients undergoing [off-pump CABG] which [intraoperative anticoagulation strategy] confers [optimal results]?

CLINICAL SCENARIO

You reviewed a patient with stable angina and distal left main stem disease, and a decision was taken to proceed with inpatient CABG without cardiopulmonary bypass. You inform the duty anaesthetist who is experienced in off-pump surgery, whom you have not worked with before. After you discuss the clinical case and planned revascularization strategy, he asks you about intraoperative anticoagulation. You say that you request for full heparinization (similar to on-pump CABG) followed by complete reversal with protamine. He claims that his anticoagulation strategy is different, since half-dose heparin may be similarly efficacious in preventing graft thrombosis, cause less intraoperative bleeding and avoid the use of protamine with its potential adverse effects. You have decided to look at the available evidence and communicate this further before the procedure.

SEARCH STRATEGY

PubMed search form 1948 to October 2011 using the following criteria (off-pump coronary artery bypass or beating heart coronary artery bypass) and (heparin or anticoagulation or heparinization or protamine).

SEARCH OUTCOME

A total of 157 papers were found, of which 8 were identified to provide the best evidence (Table 1).

Table 1:

Summary of best evidence papers

Author, date and country Study type	Patient group	Outcomes	Key results	Comments
D'Ancona et al., 2001, Heart Surgery Forum [5], USA Postal survey questionnaire study	Postal survey sent to 800 randomly chosen cardiac surgeons in the USA and Canada—38% responded	Anticoagulation protocol in OPCAB	28% full-dose heparin, 54% half-dose, 13% one-third dose and 5% variable doses	OPCAB anticoagulation practice appeared highly variable. Majority of surgeons use half-dose heparin and 80% maintain ACT levels ≥300 s. Majority (60%) use full-protamine dose for reversal of heparin effect
		Target ACT	10% maintain ACT ≥400 s, 70% between 300 s and 400 s
		Thrombosis risk	12% reported coronary thrombosis
		Perioperative bleeding	Average intraoperative bleeding was 500 ml (range: 200 ml–1.5 l) and postop at 600 ml (range: 300 ml and 1 l)
		Protamine reversal	40% use half-dose protamine; 60% use full-dose
			84% believe that partial heparinization is associated with reduced bleeding
Gatti et al., 2002, Cardiovasc Surg [6], Italy Randomized trial Jadad: 1	60 consecutive patients undergoing OPCAB with heparin 150 U/kg Group A (n = 20): 1 mg protamine/100 U heparin Group B (n = 20): 0.5 mg protamine/100 U heparin Group C (n = 20): no protamine	Partial and total postoperative chest drainage Blood product use	Pleural drainage at 12 h and total: Significant between Groups A and C (326 vs. 676 ml P = 0.01 and 538 vs. 952 ml, P = 0.04, respectively) Significant between Groups A and C (RBC units: 0.5 ± 1.1 vs. 1.9 ± 2.6, P = 0.03)	Heparin should be reversed as it reduces postoperative bleeding and transfusion requirements. Reversal can be partial as it does not significantly increase bleeding while it may eliminate protamine-related adverse effects
Donias et al., (2003), Heart Surg Forum [7], USA	152 consecutive patients undergoing OPCAB	Additional heparin	Low dose (Group 1) required more additional heparin bolus than patients on high dose (2.8 vs. 1.5, P < 0.05).	Heparin dose 150 U/kg is insufficient and can lead to a higher bleeding and thrombotic complications rate. This study provides support for using high-dose heparin
Randomized trial Jadad: 2	Anticogulation protocol: Group 1 (n = 76) received heparin dose 150 U/kg, and given additional 5000 U as required bolus during the procedure to maintain the ACT of >300 s	ACT levels	Greater standard deviation from the mean for ACT in low- vs. high-dose patients (95 s vs. 55 s).
	Group 2 (n = 76) received heparin dose 300 U/kg, and additional heparin 5000 U as required bolus to maintain the ACT of >400 s	Graft revision	Less graft revisions in high dose than low dose (1.3 vs. 5.2%, P < 0.05)
		Intraoperative bleeding and transfusion rates	Higher intraoperative bleeding in low dose than high dose  (800 vs. 650 ml). Higher rate of transfusion in low dose than in high dose (34 vs. 28%) Bleeding requiring re-exploration 1.3% in low dose and 0% in high dose
		Complications	Myocardial infarction 1.3%, both groups 6.6%,  non-coronary thrombotic complications in low-dose group only
Woo et al., 2004, Heart Surgery Forum [8], USA	80 consecutive patients undergoing OPCAB Performed by a single surgeon	ACT levels	Peak ACT 440 ± 9 s; After protamine ACT 125 ± 2 s	50% protamine reversal achieves satisfactory ACT normalization without increasing the risk of bleeding
Retrospective analysis		Protamine dose	95% of patients achieved baseline ACT with 50% protamine dose
	Patients received full heparinization and 50% protamine dose for reversal		Chest drain output at 8 h: 424 ± 24 ml at 12 h: 806 ± 38 Red cell transfusion 1.7 ± 0.2 U
		Blood loss and transfusion
Hansen et al., 2005, Sand Cardiovascular J [9] Denmark Postal survey questionnaire	Postal questionnaires sent to all departments of cardiothoracic  surgery in Nordic countries, including Norway, Finland, Sweden, Denmark and Iceland	Heparin dosing Target ACT results	24% use heparin dose 300 U/kg 32% use heparin dose 150 U/kg 28% use heparin dose 100 U/kg 16% use variable other dosing 21% maintain ACT levels ≥400 s 37.5% maintain ACT levels ≥300 s 37.5% maintain ACT ≥200 s	Anticoagulation protocol varies widely in Nordic countries. Majority use half-dose heparin. Up to 58% aim for ACT ≥300 s. Most protamine reversal is performed with full dose
		Protamine reversal	38% give full-dose protamine (1 mg protamine/100 U heparin)
			29% use half dose 8% use one-third dose 25% use variable dose protamine
Tanaka et al., 2007, J Anesth [2] Randomized trial	200 patients were randomized to conventional CABG or OPCAB	Heparin dose	OPCAB vs. conventional CABG	Heparin dose of 180 U/kg in OPCAB is not associated with hypercoagulable state. Residual heparin effect in early postoperative period in OPCAB may be protective against thrombo-embolic events
Jadad:1	OPCAB patients: heparin 180 U/kg plus 3000 U bolus every 30 min to maintain ACT ≥350 s	Protamine dose	Total heparin dose: 25 399 ± 7355 vs. 38 364 + 8505 (P < 0.001)
	Protamine reversal: 50–75 mg to return ACT to <150 s, additional protamine if ACT ≥200 s	ACT levels	Protamine 83 ± 27 vs. 234 ± 39 (P< 0.001)
	In on-pump CABG–heparin dose of 400 U/kg and ACT ≥400 s	Bleeding, chest drain and transfusion requirements	Peak ACT: 445 ± 73 vs. 754 ± 200 (P < 0.001)
	Heparin reversal with protamine 200–250 mg	Residual heparin activity	Post protamine ACT 131 ± 12 vs. 129 ± 11
			Total intraoperative cell saver: 644 ± 370 ml vs. 805 ± 433 ml
			Re-exploration for bleeding: 2 in 99 vs. 1 in 98
			Chest drain output and transfusion requirements-NS
			Significantly increased in OPCAB
Englberger et al., 2008, Interac CardioVasc Thorac Surg [10], Switzerland	15 question survey emailed to 750 cardio-thoracic surgeons across Europe. Response rate valid for analysis—325/750	Heparin dose	Ranged between 70–500 U/kg 60% use low-dose regimen (<150 U/kg) and 18% use a higher dose (>200 U/kg)	Perioperative anticoagulation strategies vary widely among European cardiothoracic surgeons. Lower heparin dose is most widely used. Majority of surgeons use full-dose protamine reversal
Questionnaire survey		ACT levels	68% accept ACT level of <300
		Protamine dose	52% use full protamine reversal and 38% use half dose and the remaining use two-third reversal or alternative dose
		Experience of thrombosis	97% have not notice higher incidence of DVT or PE in OPCAB
			34% respondents consider OPCAB as a risk factor for early graft occlusion, 33% attributed this risk to a procoagulant state
Paparella et al., 2010, Ann Thorac Surg [11], Italy Randomized trial Jadad:2	42 patients undergoing off-pump CABG were randomized to: high-dose heparin (300 U/kg; n = 21) or low-dose heparin (150 U/kg;  n = 21)	ACT levels	Higher 3 min ACT in high dose than low dose (504 ± 34 vs. 376 ± 18, P < 0.001) Higher peak ACT in high dose than low dose (522 ± 31 vs. 405 ± 16, P < 0.001)	Both high- and low-dose heparin have a similar effect on in vivo clotting activation; therefore, a higher heparin dose does not produce better control of clotting in off-pump CABG. More patients in the low-dose group required additional heparin bolus
	Additional heparin bolus (5000 U) was given if ACT <300 s in low dose or <400 s in high dose	Heparin dose	Eight patients in low-dose group and four patients in high-dose group received additional heparin bolus
		Coagulation markers	The difference between intraoperative and postoperative markers of coagulation and fibrinolysis were not significantly different between the two groups

RESULTS

In CABG with the use of cardiopulmonary bypass, routine anticoagulation consists of heparin ≥300 U/kg, aiming at activated clotting time (ACT) of ≥400 s [2, 3]. In addition to the possible procoagulant affliction occurring in the first 24 h following off-pump CABG (OPCAB) [4], the absence of ‘pump effect’ on coagulation means that principles of anticoagulation used for on-pump CABG may not apply in OPCAB. Currently, there are no guidelines for intraoperative coagulation in OPCAB. For this reason, an evidence-based approach to anticoagulation management in OPCAB is essential.

D'Ancona et al. [5] conducted a postal survey in the USA and Canada to determine OPCAB anticoagulation practices. They showed that 54% used half dose with the majority (70%) aiming for ACT levels between 300 and 400 s. Sixty per cent of surgeons used full protamine for reversal. In addition, 84% of surgeons believed that partial heparinization is associated with reduced intraoperative bleeding.

The concept of variable anticoagulation reversal was examined by Gatti and Pugliese [6]. In patients undergoing OPCAB with similar heparin anticoagulation, reversal was performed with three different regimes; full reversal, partial reversal and, lastly, no reversal. The total chest drain output was significantly lower in the full reversal compared with the no protamine group, but there was no significant difference between those who received full and partial protamine reversal. Concurrently, blood transfusion requirements were significantly increased in the no protamine group when compared with the fully reversed group.

Donias et al. [7] investigated the effect of full vs. half-dose heparin on intraoperative graft patency in minimally invasive direct coronary artery bypass. Patients received heparin at 150 U/kg (Group 1) or 300 U/kg (Group 2) with additional boluses to maintain target ACT. Patients in Group 1 had greater variation in the ACT and required more additional heparin. The number of revised grafts was smaller in Group 2 and a thrombus at the site of anastomosis was identified in all of them. Similarly, all non-coronary thrombotic complications occurred solely in Group 1.

An observational study by Woo et al. [8] examined the effect of reduced protamine on clinical outcomes after OPCAB. Full heparin anticoagulation (aiming at an ACT of 400–450 s) was followed by 50% of protamine. This regime normalized the ACT in 95% of patients. The mean chest drain output was comparable with that of other studies where complete protamine was utilized. There was no need for blood or product transfusion, or re-explorations. These data suggest that half-dose protamine safely reverses heparin without increasing postoperative bleeding.

The anticoagulation practice in Nordic countries was assessed in a survey by Hensen et al. [9]. Twenty-four per cent reported using full-dose heparin (≥300 U/kg), 32% used half dose and 28% used one-third dose of heparin. Target intraoperative ACT also varied, with 21% maintaining ACT levels of ≥400 s, 37.5% aiming for ≥300 s and 37.5% for ≥200 s. Complete heparin reversal was used in 38% of cases, half dose in 29% of cases and 25% used variable protamine dose. This study further confirms the lack of standardized anticoagulation pattern in OPCAB, although the majority of surgeons appear to use half-dose heparinization, followed by complete protamine reversal with satisfactory results.

Tanaka et al. [2] assessed the coagulation data in 200 patients who underwent OPCAB or on-pump CABG. Patients received heparin dose 180 U/kg in OPCAB or 400 U/kg for on-pump CABG. Heparin reversal for the OPCAB was protamine 50–75 mg aiming at an ACT of 150 s (with additional 25 mg protamine if ACT > 200 s). The results of this study demonstrated that lower total doses of heparin and protamine can be administered, providing safe conduct of OPCAB, with comparable bleeding and coagulation parameters to conventional on-pump CABG.

Englberger et al. [10] performed a questionnaire survey to determine anticoagulation practice among European surgeons. The intraoperative heparin anticoagulation dose was highly variable and ranged between 70 and 500 U/kg. There was a trend towards a lower dose heparin with 60% using ≤150 U/kg and ACT levels between 200 and 250 s. For protamine reversal, 52% used full-dose protamine. Thirty-four per cent of respondents thought that OPCAB was a risk factor for early graft occlusion but the majority attributed this risk to technical challenges.

Paparella et al. evaluated the effects of half-dose (150 U/kg) vs. high-dose heparin (300 U/kg) on perioperative haemostatic changes in OPCAB [11]. The ACT immediately after heparin administration and peak levels were significantly raised in the high-dose patient group; however, biomarkers of coagulation and fibrinolysis were found to be similar. This suggests that a higher heparin dose does not translate into better control of clotting activation during OPCAB.

CLINICAL BOTTOM LINE

Surveys assessing the patterns of anticoagulation across Europe and North America demonstrate a highly variable practice, with the choice of heparin dose depending on individual or institutional preference. Analysis of the current studies showed a trend towards half-dose heparin with ACT levels of ≥300 s, yielding satisfactory results. Although the majority of surgeons use complete protamine reversal, half-dose protocols have been shown to be equally effective without influencing postoperative bleeding. Evidence from larger randomized studies is needed to further evaluate heparin dosing, target ACT and protamine reversal and formulate robust guidelines.

Conflict of interest: none declared.