CON: Low Dose Heparin

Kenichi A. Tanaka, MD; Jerrold H. Levy, MD
Cardiothoracic Anesthesia and Critical Care
Emory Healthcare, Dept. of Anesthesiology
Emory University School of Medicine
Atlanta, Georgia
Introduction

Anticoagulation with high dose heparin (target plasma concentration of >2.5 IU/ml) is the current mainstay during cardiac surgery with cardiopulmonary bypass (CPB). Unfortunately, anticoagulation for off-pump coronary artery bypass (OPCAB) is not standardized.1 Further, heparin dosing rules vary among surgeons and institutions for OPCAB procedures. Low dose heparin regimen is proposed based on the assumption that OPCAB procedure is less prothrombotic because it eliminates the large foreign surface of CPB. For cardiologists, reduced heparin dosing is routine for percutaneous coronary intervention (PCI). Despite theoretical benefits of using low dose heparin, we would like to recommend anticoagulation with high dose heparin by presenting the following key points: (A) clinical experiences; (B) heparin pharmacodynamics and pharmacokinetics; (C) insights from PCI and CABG.

(A) Clinical Experiences

The published literature focusing on hemostatic aspects of OPCAB are minimal. Using heparin at >100 IU/kg to keep ACT <300 seconds, Mariani, et al, found increased prothrombin fragment 1.2 (activation marker of prothrombin) and fibrin degradation product levels, and decreased factor VII levels at 24 hours after OPCAB.2 Further, Cartier, et al reported a 1% incidence of deep venous thrombotic complications in a retrospective review of 500 OPCAB patients who received heparin 100 IU/kg with ACT maintained over 300 sec.3 Subclinical activation of coagulation is a well-known phenomenon during heparin therapy for CPB as well as during acute coronary syndrome.4,5 For coronary interventions, increased incidences of intravascular thromboses after coronary interventions had been found in patients who had ACT <300 sec.6 Tissue injury during OPCAB also increased complement (C3a) levels in patients treated with heparin, 100 IU/kg.7

In the recent clinical trial of OPCAB versus CABG with CPB at our institution, heparin anticoagulation with an initial 180 IU/kg (equivalent to a plasma heparin concentration 2.5 IU/ml assuming blood volume of 70 ml/kg) was used, and 3,000-5,000 IU every 30 min was used to maintain ACT >350. An aspirin suppository (650 mg) was given after anesthesia induction in OPCAB group.8 This regimen achieved peak ACT of 445 ± 73 sec compared to 754 ± 200 sec in CABG with CPB group that received an initial heparin dose of 400 IU/kg. The outcomes of two groups were similar after 30 days.

(B) Heparin - Mechanism of Action

Heparin is composed of sulfated mucopolysaccharides of varying molecular weights and antithrombin binding activity. Heparin catalyzes reaction of antithrombin (AT) and thrombin by 1,000-fold, therefore the efficacy of heparin largely depends on the level of endogenous AT. Acquired heparin resistance due to AT deficiency has been reported in cardiac surgical patients. Because AT levels are not routinely measured in preoperative cardiac patients, full-dose heparin (plasma heparin concentration >2.5 IU/ml) may provide some advantage by showing inability to achieve ACT over 350 sec,9 and ensure prompt conversion to CPB if necessary.

Furthermore, low dose heparin (plasma heparin concentrations approximately 1.0 IU/ml) is known to heighten platelet reactivity.10 Increased platelet activation markers during heparin therapy in cardiac patients have also been reported.11

Theoretical advantage of low dose heparin during OPCAB is that a reversal agent may not be necessary after surgery, and residual heparin may confer some benefit. However, prolonged heparin therapy does not seem to provide benefit in patients undergoing PCI.12 Also, the heparin-protamine complex was associated with mild anti-platelet effects, but its half-life was short (15 min). In OPCAB patients whose platelet counts are relatively well maintained, this effect may not be an important issue.

Another distinct feature in OPCAB patients is the core-body-temperature maintained during surgery. In our recent experience,8 the lowest core temperature was 35.8 ± 0.45°C in OPCAB, and 34.2 ± 1.09°C in CABG with CPB. The heparin dose and body temperature intimately influences the elimination half-life of heparin. When 100 IU, 200 IU, or 400 IU of intravenous heparin is administered at 37°C, the approximate half-life is 60 min, 90 min, and 150 min, respectively.13 Decreases in the body temperature prolong the elimination half-life.14 It is possible that faster thrombin generation and heparin turnover occur in the OPCAB group, necessitating larger heparin dosing to maintain effective heparin concentrations. In the Puskus study,8 the ratio of heparin : protamine dose was 1.7:1 in CABG with CPB and 3.2:1 in OPCAB; thus lower amount of protamine (83 ± 27 mg versus 234 ± 39 mg) required to achieve comparable ACTs suggested a faster heparin turnover.

Maintaining high levels of anticoagulation with heparin titration or supplemental antithrombin have been shown to reduce activation of coagulation.15,16 Clot-bound thrombin is more resistant to heparin-AT complex, thus need for heparin may be increased.17

Lastly, the incidence of heparin-induced thrombocytopenia is the same in OPCAB and CABG with CPB regardless of heparin doses, although porcine heparin was less causative than bovine heparin.18

(C) Insights from PCI and CABG with CPB

Unless endoscopic techniques are used, median sternotomy is necessary, and tissue factor derived from the wound, especially the pleural cavity, may be very potent procoagulant stimuli. During CABG with CPB, it was assumed that tissue factor pathway was the main source of procoagulant response based on the measurement of procoagulant marker (prothrombin fragment 1.2) in patients having defects of intrinsic coagulation pathway.19,20

Improved clinical outcomes have been shown with the addition of a glycoprotein IIb/IIIa inhibitor or clopidogrel to heparin anticoagulation during PCI, and several studies have shown decreased prothrombin activation and 17thrombin generation with increased ACTs in patients receiving abciximab or tirofiban.21-23 This information underscores the importance of platelet activation in thrombotic occlusion of coronary artery and stents. Adding a potent platelet inhibitor to heparin anticoagulation may carry a high risk.24-26 However, early utilization of aspirin therapy may be beneficial in this population.27 In the study by Puskas, et al.,8 aspirin (650 mg) was used routinely in OPCAB group (n=98), which most likely contributed to the low incidence of arterial thromboembolic events (stroke 1/98, TIA 1/98, Q-wave MI 1/98) in 30 days.

One additional consideration to support higher doses of heparin is the fact that coronary rethrombosis after PCI or thrombolytic therapy can occur despite heparin. Heparin is less effective at inhibiting thrombin bound to fibrin because a 20-fold greater concentration is required to block 70% activity of the clot-bound enzyme than is required for equivalent inhibition of fluid-phase thrombin (plasma heparin concentrations of 2.0 IU/ml and 0.1 IU/ml, respectively). To prevent clot-bound thrombin activity, Weitz, et al. suggested plasma heparin concentrations of >2.0 IU/ml should be targeted and these levels can only be achieved with higher dose heparinization.17

Conclusion

In conclusion, we believe the evidence supports the use of higher heparin concentrations during OPCAB procedures. Even in the study described by Puskus from Emory where initial "low dose" was administered, additional heparin was administered every 30 min to maintain circulating levels. Adequate circulating levels can be achieved with higher initial dosing, or supplemental dosing. Heparin has been used in cardiac surgery for more than 50 years, but we do need to realize its limitations as an anticoagulant, and utilize appropriate monitoring. Novel thrombin inhibitors and strategies including bivalirudin (Angiomax) are being evaluated in OPCAB surgery, and represent important approaches for better thrombin modulation during cardiac surgery.

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