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Alexander KP et al, JAMA 2005;294:3108-16

Excess Dosing of Antiplatelet and Antithrombin Agents in the Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes. Alexander KP et al, JAMA 2005;294:3108-16.

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Alexander KP et al, JAMA 2005;294:3108-16

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  1. Excess Dosing of Antiplatelet and Antithrombin Agents in the Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes Alexander KP et al, JAMA 2005;294:3108-16 CRUSADE is a National Quality Initiative of Duke Clinical Research, funded Schering Corporation. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership provides an unrestricted grant in support of the program.

  2. Background • Anti-platelet and anti-thrombin agents are efficacious and thus recommended treatments for patients with NSTE ACS (AHA/ACC Guidelines) • Current QI efforts focus on increasing their use in this population

  3. Major Bleeding in NSTE ACS Trials (and CRUSADE) % Bleeding per Trial Definition Major Bleeding: ICH + HCT drop >12% or 15% drop ± transfusion Cohen NEJM 1997; Petersen JAMA 2004; PURSUIT NEJM 1998; Boersma Lancet 2002

  4. Purpose • Determine the frequency with which UF heparin, LMWH, and GP IIb/IIIa inhibitors are dosed in accordance with recommendations • Determine patient and hospital factors associated with excess dosing • Determine the associations between excess dosing and risk for major bleeding

  5. Methods • All CRUSADE NSTE ACS pts (n= 30,316 at 384 sites) • January - December 2004 • Excluded if missing dose, creatinine clearance, weight, or transferred prior to discharge • Grouped according to acute therapy • Predictors of excess dose • Relationship btw dose and major bleeding • Transfer and CABG patients excluded • Major bleeding was defined as a drop in Hct ≥ 12%, RBC transfusion, intracranial hemorrhage

  6. Appropriate Dosing of Acute Medications* in CRUSADE • Unfractionated Heparin • Use weight-based dosing • Bolus: 60- 70 U/kg  Infusion: 12-15 U/kg/hr • LMW Heparin: Enoxaparin • Use weight-based dosing (0.95-1.05 mg/kg) • GP IIb-IIIa: Tirofiban •  Bolus to 6 µg/kg, if CrCl < 30 mL/min •  Infusion to 0.05 µg/kg/min, if CrCl < 30 mL/min • GP IIb-IIIa: Eptifibatide •  Infusion to 1.0 µg/kg, if CrCl < 50 mL/min * Dosing information collected in CRUSADE beginning Q1 2004

  7. Characteristics by Acute Antithrombotic Therapy UFH LMWH GP IIb/IIIa (13,298) (12,526) (13,967) Age (median) 65.2 67.1 63.1 Female (%) 35.8 39.5 32.8 Renal Insuff (%) 12.5 10.7 6.8 CrCl (mean) 58.3 57.0 64.1 Weight (median kg) 82 81 84 Diabetes (%) 31.8 32.8 29.3 Signs of CHF (%) 20.4 23.0 15.0 Catheterization (%) 86.7 79.0 90.7 PCI (%) 58.4 47.8 74.3 Cardiac Markers (+) 88.7 89.1 89.9 Academic Center (%) 36 22 30 Cardiologist (%) 64 56 69 Alexander KA, JAMA 2005;294:3108-16

  8. Predictors of Excess Dosing UFH LMWH GP IIb/IIIa Age >75 0.81 0.75 14.39 Renal Insuf. 1.25 0.82 4.12 Female - 0.73 3.74 Weight (per 5kg ↓) 1.28 1.26 1.02 Alexander KA, JAMA 2005;294:3108-16

  9. Excess Dose of GP IIb/IIIa Inhibitors 91% 65% 46% % Excess Dose 26% Age (yrs) Sex Serum Creatinine (if CrCl <50cc/min) Alexander KA, Circulation 2005;17:II-431

  10. Estimated Creatinine Clearance (CrCl)Cockroft-Gault Calculations assuming a 150 pound woman CrCl = (140-age) x weight in kg ---------------------------      X 0.85 (if female) (72 X serum creatinine) 

  11. Antithrombotic Dose and Major BleedingNon-CABG and Non- Transfer Population P<0.0001 P<0.0002 P= NS Major Bleeding (%) 11.5% n=6,924 n=7,484 n=8,085 Treatment Group Alexander KA, JAMA 2005;294:3108-16

  12. Cumulative Effects of Dosing Errors Combined Use of Heparins and GP IIb-IIIa 11.5% n=2,139 (35%) n=419 (7%) n=3,590 (58%) Excess Dose Among Patients Given Two Antithrombotic Agents (n=6,148) Alexander KA, JAMA 2005;294:3108-16

  13. Adjusted Risk of Major Bleeding (age, sex, renal insufficiency, weight, CHF, SBP) Excess vs. No Excess • UFH OR 1.08 (0.94 – 1.26) • LMWH OR 1.39 (1.110 – 1.74) • GP IIb/IIIa OR 1.36 (1.10 – 1.68)

  14. Conclusions • Excess dosing is common for anti-thrombotic therapies • Disproportionately affects the thin, elderly, women, and those with renal failure • After accounting for pt risk, excess dosing remains a significant predictor of bleeding • Particularly when multiple agents in excess or major excess given • Appropriately dosed pts have bleeding rates approaching those in trials and better than average community population

  15. Optimizing Dosing of AnticoagulantsSteps for Improvement • Determine CrCl and weight for all patients upon hospital admission • Link drug dosing with weight and CrCl • Integrate clinical pharmacists into ED and CCU environments to monitor dosing in “real time” • Quality metrics should monitor “how” as well as “if” evidence-based medicines are given • Ideal comparisons between antithrombotic strategies would consider only those patients who receive recommended dosing

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