New Heparin Dosing Regimen for Diabetics Undergoing Percutaneous Coronary Intervention
May 2005
Unfractionated heparin is the primary anticoagulant administered prior to percutaneous coronary intervention (PCI) to prevent the generation of thrombin at the site of balloon-induced arterial injury and to reduce the thrombogenicity of the various types of equipment used during PCI.1 Although glycoprotein IIb/IIIa receptor antagonists are proven to improve outcomes of PCI, approximately 50% of PCIs are performed only with heparin and without glycoprotein IIb/IIIa receptor antagonists in the United States.2 Several clinical studies have demonstrated a strong inverse relationship between the degree of anticoagulation with heparin defined by the activated clotting time (ACT) and abrupt vessel closure.3–7 The narrow window of therapeutic efficacy of heparin in patients undergoing PCI mandates that anticoagulation with heparin be administered accurately. Thus, achievement of an optimal ACT is needed to minimize the risk of ischemic and bleeding complications. Current PCI guidelines recommend an initial 70 IU/kg intravenous dose of heparin to reach an ACT of 300 to 350 seconds with the Hemochron® device (International Technidyne Corporation, Edison, New Jersey).8
Although newer antithrombotic agents such as low-molecular weight heparin (LMWH) and direct thrombin inhibitors are currently available, heparin continues to be an attractive agent because it is an inexpensive, rapid bedside point-of-care ACT test, and has an antagonist that promptly reverses its antithrombin effect.
It is well-established that adverse clinical outcomes and complications of PCI are more common in diabetics than in non-diabetics. It has been previously demonstrated that diabetics are less sensitive to heparin compared to non-diabetics.9 We hypothesized that an initial heparin dose of 80 IU/kg administered to diabetics might yield a more optimal initial ACT in patients undergoing PCI where no glycoprotein IIb/IIIa receptor antagonist was administered.
Methods
All patients who underwent elective PCI between November 2002 and May 2003 at our institution were eligible for the study. Demographic and procedural data were prospectively collected in our study database. Selection for PCI was based on > 70% stenosis in one or more coronary arteries or bypass grafts, with anatomy amenable for PCI. We prospectively studied 130 elective PCI patients without diabetes treated by intention to receive 70 IU/kg of heparin and 81 elective PCI patients with diabetes treated by intention to receive 80 IU/kg, and compared the initially achieved ACT. Patients treated with heparin, warfarin, or glycoprotein IIb/IIIa receptor antagonist and patients with acute coronary syndromes were excluded.
Elective PCI was performed according to standard techniques. The femoral approach using 6 Fr sheaths and guiding catheters in conjunction with rapid exchange coronary balloons and stents were used. The contrast agent was uniformly nonionic iopromide (Ultravist® 370, Berlex Imaging, Montville, New Jersey). All patients received aspirin and clopidogrel after PCI. ACTs were determined in the cardiac catheterization laboratory. Two milliliters of blood was collected from the sheath into a FTCA 510 tube (International Technidyne Corp.) with the activator Celite three minutes after heparin was administered through the sheath.10–12 The tube was placed inside the Hemochron device after vigorous shaking.
Baseline characteristics are expressed as percentages for discrete variables or as mean ± SD for continuous variables. Discrete variables presented were compared by the chi-square or Fisher’s exact tests. Continuous variables were compared by the Student’s t-test. Statistical analysis was performed using SPSS version 10.0. A p-value 300 seconds. Of the 36 patients who received 80 IU/kg, only 3 patients had an ACT > 350 seconds (ACT were 352, 353, and 356 seconds, respectively).
The heparin response index (HRI), which is the ratio of ACT to heparin units/body weight, is significantly lower in diabetics when compared to non-diabetics (Figure 1) (3.6 ± 0.5 versus 4.4 ± 1.1, p 350 seconds. Although this new dosing regimen leads to a more optimal initial ACT in the target range, the majority of diabetics were still below target range. An initial heparin dose of 85 IU/kg in diabetics might yield a more optimal initial ACT than the dose used in this current study.
The current data suggest that a lower ACT range of 200 to 250 seconds during PCI may minimize the incidence of bleeding complications when heparin is used in conjunction with glycoprotein IIb/IIIa receptor antagonists.13,14 This lower ACT range, however, does not come at the expense of increased incidence of ischemic complications.15
In patients who undergo PCI using anticoagulation with heparin alone, it appears that more robust levels of anticoagulation are required to prevent ischemic complications. Chew et al., in a meta-analysis of six randomized, controlled trials to determine the optimal ACT range for the suppression of peri-procedural ischemic and bleeding events among PCI patients not receiving glycoprotein IIb/IIIa receptor antagonists, reported that the risk of ischemic endpoints progressively decreased as the ACT levels increased, with no upper limit of efficacy.7 This supports previous studies which reported an inverse relationship between the probability of ischemic events and the initial ACT level achieved after the administration of heparin.4,6 Furthermore, the lowest bleeding rate was observed with ACT in the range of 325 to 350 seconds.7 In addition, it was also demonstrated that diabetics had a significantly lower ischemic event rate with an ACT in the range of 350 to 375 seconds compared to diabetics with ACT in the range of 275 to 300 seconds. Kleinman et al. demonstrated that diabetics undergoing PCI benefit from higher doses of heparin despite the use of abciximab.16 Given this, current PCI guidelines of an initial 70 IU/kg of heparin would grossly under-dose diabetics and subject them to increased peri-procedural ischemic events.
The HRI, which is a measure of sensitivity to heparin, showed that diabetics have a different dose response to heparin than non-diabetics. It is not clear why diabetics are less sensitive to heparin, but it may be due to heparin-antithrombin binding kinetics and heparin-antithrombin complex binding to coagulation proteins in patients with hyperglycemia or overt diabetes. In addition, a high glucose environment or advanced glycosylation endproducts (AGEs) may influence this phenomenon.
Study limitations. Our institution measures ACT with the Hemochron system, which yields different values to those of the HemoTec® system (Medtronic, Parker, Colorado). These data cannot be extrapolated to the HemoTec system, which implements different reagents and measurements. This prospective study only assessed the achievement of target ACT in the elective PCI population in a single-center experience. We do not have clinical outcomes related to the different heparin dosing for the two groups. Our dosing regimen does not apply to patients who receive glycoprotein IIb/IIIa receptor antagonists. The sample size of our study is too small to assess for outliers of ACT values in diabetics who were given 80 IU/kg of heparin. The conclusive answer with respect to the optimal heparin-dosing regimen in diabetics warrants a multi-center prospective randomized trial looking at endpoints of death, non-fatal myocardial infarction, bleeding, vascular, and thrombotic complications, especially with the expanded use of drug-eluting stents. However, this may be difficult to do, as it will require a large study population to demonstrate a difference in clinical events and significant funding to carry out the clinical trial.
Adequate levels of anticoagulation with heparin are required to minimize ischemic event rates, especially in diabetics. Administration of a higher dose of 80 IU/kg of heparin for PCI leads to a more optimal initial ACT in diabetics when glycoprotein IIb/IIIa receptor antagonists are not used. The higher dose of 80 IU/kg of heparin is safe, with only a small percentage of patients above the target ACT range of 300 to 350 seconds. The results support the use of a higher initial heparin dose in diabetics versus non-diabetics to attain a more optimal ACT during elective PCI. Further prospective investigation is warranted to determine optimal combinations of antithrombotic and antiplatelet therapies, especially in diabetics.
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