Heparin-Induced Thrombocytopenia. Steven Baroletti, PharmD., M.B.A., BCPS Brigham and Women s Hospital

Transcription

1 Heparin-Induced Thrombocytopenia Steven Baroletti, PharmD., M.B.A., BCPS Brigham and Women s Hospital

2 Heparin-induced thrombocytopenia (HIT) A serious concern associated with thrombosis development following administration of heparins Excessive morbidities and cost are associated with HIT development Perceived increase in the development of HIT Growing concerns in setting of varying qualities of heparin products CHEST 2008;133:340S-380S Thromb Haemost. 2008;100: Clin Appl Thromb Hemost 2009;15:

3 Agenda Provide overview of the development, diagnosis, and treatments for heparininduced thrombocytopenia Discuss approaches to educating practitioners and patients about heparin-induced thrombocytopenia

4 What is Heparin-Induced Thrombocytopenia? Heparin-induced thrombocytopenia (HIT) is an antibody-mediated, adverse effect of heparin that is important because of its strong association with venous and arterial thrombosis CHEST 2008;133:340S-380S

5 Classification of HIT non-immune (formerly Type I HIT) HIT (immune) (formerly Type II HIT) Mild platelet decrease Benign 1-4 day onset No treatment indicated No need to stop heparin Significant platelet decrease Significant sequelae 5-14 day onset Treatment indicated Must stop heparin

6 Pathophysiology of HIT Heparin molecule Heparin molecules bind with PF4 to form a complex Antibodies formed by immune system against Hep-PF4 complex Platelet Factor 4 (PF4) Hep-PF4 Complex Clot Platelet Platelet activation can lead to blood clot formation Antibodies bind to Hep-PF4 Complex that causes platelet activation Adapted from Warkentin Blood 1994; 84:

7 STRUCTURAL CHARACTERISTICS Fractionation UFH 10,000-30,000 D a LMWH 3,000-8,000 D a Chemical synthesis Fondaparinux Adapted from Pharmacy Times 2002: 76-84

8 Incidence of HIT 1 trillion units of heparin are used yearly in the US, 12 million hospitalized patients receive UFH Incidence of HIT: UFH 1-5% Incidence of HIT: LMWH < 1% CHEST 2008;133:340S-380S Warkentin TE, et al. NEJM. 1995;332: Martel N et al. Blood. 2005; 106:

9 Risk of Thrombosis Cumulative Thrombotic Event Rate (%) Days After Isolated HIT Recognized 52.8% Warkentin TE, Kelton JG. Am J Med. 1996;101:

10 HIT + Thrombosis = HITT 1) High morbidity and mortality: ¾ venous thrombosis ¼ arterial thrombosis 2) Paradoxical massive PE, bilateral or multi-limb DVT; mesenteric arterial thrombosis; MI, stroke 3) Venous gangrene, especially extremities (fingers, toes, etc.)

11 BWH HIT Experience 349 patients developed HIT: (75%) with isolated HIT - 87 (24%) with HITT Characteristic Isolated HIT (n=262) HITT (n=87) p-value Age (mean years) 64.1 ± ± Sex (male)- no. % 139 (53.1) 47 (54) 0.9 Avg. length of stay (median) 25 ± ± Kidney disease 60 (22.9) 13 (14.9) 0.13 Liver disease 35 (13.4) 9 (10.3) 0.58 Cancer 50 (19.1) 29 (33.3) 0.01 Hypertension 148 (56.5) 47 (54.0) 0.7 Myocardial infarction 30 (11.5) 2 (2.3) Coronary artery disease 127 (48.5) 31 (25.3) 0.05 Diabetes Mellitus 85 (32.4) 22 (25.3) 0.2 Pulmonary disease 77 (29.4) 26 (29.9) 0.9 Surgery during admission 157(59.9) 61 (70.1) 0.09 Type of Surgery Thromb Haemost. 2008;100:

12 HIT Frequency: UFH vs. LMWH 0.9% p=0.032 p=< % 0.7% p<0.001 UFH LMWH 0.6% Incidence (%) 0.5% 0.4% 0.3% p=< % 0.1% 0.0% All HIT HIT HITT Clinical Presentation Thromb Haemost. 2008;100:

13 UFH vs. LMWH UFH was the presumed causative agent in 82% of patients, LMWH in 7% of patients, and both in 11% of patients Patients who received UFH developed HIT with thrombosis more often than those who received LMWH (27% vs 4%; p=0.01) Thromb Haemost. 2008;100:

14 Mortality as a Function of Platelet Nadir 30 Day Mortality (%) < >150

15 Pharmacoeconomic outcomes Total hospitalization costs were similar for HIT and HITT ($122,191 vs $112,281; p=0.84) Hospital costs were higher in the group exposed to UFH than those treated with LMWH ($113,000 vs $56,352; p < 0.001) Thromb Haemost. 2008;100:

16 How to Diagnosis HIT: Four T s Thrombocytopenia: (platelet count <150,000*) while receiving UFH or LMWH or Patients with >50% drop in platelet count Timing: typical onset 5-14 days following heparin exposure (Immediate to days following re-exposure) Thrombosis: New onset thrombosis and/or enlarging of existing thrombosis, or venous limb ischemia or gangrene Absence of other explanations: sepsis, hemodilution, Intra-aortic balloon pumps, CVVH, drug- Induced: linezolid, sulfa antibiotics, rifampin, IIB/IIIa Warkentin TE. Circulation.2004:110:e454-e458

17 Therapeutic Management Direct Thrombin Inhibitors (DTI) Lepirudin (FDA-approved) Argatroban (FDA-approved) Bivalirudin (non-fda approved for HIT) Pentasaccharide Fondaparinux (non-fda approved for HIT) CHEST 2008;133:340S-380S

18 General Principles of DTI Therapy Monitoring: PTT (non-pci) and ACT (PCI) No antidote for reversal Caution in renal or hepatic insufficiency False INR elevations, but INR is not monitoring parameter More expensive than heparin Potential for more adverse effects than heparin CHEST 2008;133:340S-380S

19 Fondaparinux Anti-Xa Inhibitor (pentasaccharide) Subcutaneous administration Renal elimination Long-acting = Once daily dosing Monitoring Labs: none recommended Caution: pts going to procedures or surgery

20 Fondaparinux use in HIT In a small case series 6 of 7 patients received fondaparinux successfully as a bridge to warfarin following the diagnosis of HIT. We observed this in 8 patients. When fondaparinux was used for prophylaxis, 94% of patients had a documentation of HIT Thromb Haemost 2008; 99: Thromb Haemost 2009 (in press)

21 Duration of Treatment DTI or fondaparinux until at least platelets recover (> 100,000) If therapeutic reason for anticoagulation, then continue treatment If only for acute HIT, then treatment can end once platelets recover CHEST 2008;133:340S-380S

22 Educational Approaches to HIT Multi-disciplinary task force Guidelines Algorithms (clinical pathways) Technology Patient Understanding/Advocacy

23 Make Guidelines Accessible Approach to the patient with suspected heparin induced thrombocytopenia Clinical setting: Patients on heparin for more than 4 days o r patients restarted on heparin after recent exposure Platelet decrease of >50% from baseline, or absolute platelet count New unexpected drops to below 100,000 o r inflammatory or necrotic lesions at heparin thrombotic event while on injection sites (If platelet count decreases but not by >50%, monitor heparin platelet count daily) Presume HIT with thrombosis (HITT) Stop ALL heparin (including catheter based); Measure PF4- heparin antibody test BUT do NOT wait for antibody test. Treat immediately with direct thrombin inhibitor (DTI). If suspicion for HIT is high Positive PF4-heparin antibody assay - Continue heparin. - Measure PF4-heparin antibody assay (if possible, send early morning) - Evaluate other causes of thrombocytopenia as indicated: Medications (antibiotics, antiarrhythmics, chemotherapy, etc.), intraaortic balloon - Review peripheral smear to rule out TTP, platelet clumping - Rule out DIC Negative PF4-heparin antibody assay Review other causes of thrombocytopenia. If there is no other explanation, presume HIT. HIT can be ruled out. May resume heparin. HITT or HIT requiring anticoagulation as a continuous infusion agent (e.g., likely upcoming surgery, ICU patient): Give DTI (argatroban/lepirudin /bivalirudin) until platelet count rises to at least 100,000 or for 3-5 days. HIT and the patient does not need continuous infusion agent (e.g, not preoperative, does not require rapidly cleared anticoagulation agent) Give fondaparinux SC once daily until platelet count rises to at least 100,000 or for 3-5 days. Transition to warfarin when appropriate (see below). Transition to warfarin when appropriate (see below). If the patient requires continued anticoagulation then transition to warfarin as follows: - Confirm platelet count rise to 100,000 or for 3-5 days and th e n*: - Begin warfarin - Overlap DTI or fondaparinux with warfarin until INR is clearly therapeutic [Note that argatroban will raise the INR to a range of 2.0 to 4.0 without any warfarin administration. Therefore, when bridging with argatroban to warfarin, the INR should be determined on the 4 th or 5th day of argatroban infusion after temporarily discontinuing argatroban for at least 6 hours]. - * Starting warfarin within the first few days after HIT diagnosis (even if on DTI) may cause or exacerbate thrombosis and should be avoided. Most consultants advise waiting for resolution of thrombocytopenia before starting warfarin.

24 CPOE Intervention

25 CPOE Intervention

26 Patient Education

27 Discharge Alert for HIT Heparin Induced Thrombocytopenia Alert Patient Name: Date of Birth: I was diagnosed with Heparin -Induced Thrombocytopenia (HIT) on (date) at Hospital/Office, while under the care of MD. I am currently taking Warfarin (Coumadin). I am currently on NO blood thinners (anticoagulation). My history of heparin -induced thrombocytopenia should be taken into consideration if I require anti -coagulation. An alternative medication other than heparin and low molecular weight heparin may be required.

28 CONCLUSIONS HIT remains an important clinical problem with a high complication rate and economic burden Early identification and appropriate determination of true HIT are crucial to optimal management Various approaches and tools exist to educate practitioners and patients about HIT

29 Thank you for your time