EXTENDING VTE PROPHYLAXIS IN ACUTELY ILL MEDICAL PATIENTS

Transcription

1 EXTENDING VTE PROPHYLAXIS IN ACUTELY ILL MEDICAL PATIENTS Samuel Z. Goldhaber, MD Director, VTE Research Group Cardiovascular Division Brigham and Women s Hospital Professor of Medicine Harvard Medical School October 13, 2012

2 DISCLOSURES Research Support: Eisai; Daiichi; EKOS; Johnson & Johnson; Sanofi-Aventis Consultant: Baxter; Boehringer-Ingelheim; BMS; Daiichi; Eisai; Merck; Pfizer; Portola; Sanofi-Aventis

3 41 Y.O. WOMAN: SUDDEN COLLAPSE

4 ITALIAN PE REGISTRY: MORTALITY RATE N=1,787 (6.7% inhospital mortality) (Casazza F, et al. Thromb Res epub.) 32% in-hospital mortality Unstable 3.4% in-hospital mortality Stable

5 ITALIAN PE REGISTRY: MORTALITY RATE OVER TIME (N=1,787) TIME COURSE OF DEATH DUE TO PE Unstable VERSUS OTHER CAUSES Stable (Casazza F, et al. Thromb Res epub.)

6 BWH Hospital Expenses: Pulmonary Embolism ( ) 250 $2,000,000 $1,800,000 Number of PE patients $1,600,000 $1,400,000 $1,200,000 $1,000,000 $800,000 $600,000 $400,000 $200,000 Annual PE Hospital Expense ($) Year $0 Number of Patients Total Annual Hospital PE Expense PE = Pulmonary embolism (Fanikos J. Am J Med. 2013)

7 CTEPH PATHOPHYSIOLOGY (Piazza G, Goldhaber SZ. N Engl J Med. 2011;364: )

8 POST THROMBOTIC SYNDROME Venous ectasia Hyperpigmentation Venous ulcer Edema Skin induration Venous ectasia

9 VITAE II Status Quo 100% VTE Prophylaxis By preventing PE, We prevent Recurrent VTE, CTEPH, and PTS. (Fanikos J, et al. Thromb Haemost. 2009; 102: )

10 100, ,000 PE-related deaths annually in the U.S. alone PE is the most preventable cause of death among hospitalized patients

11 OPPORTUNITIES/ CHALLENGES VTE prophylaxis reduces PE/ DVT Prophylaxis prevents recurrent VTE, CTEPH, post-thrombotic syndrome Electronic alerts reduce symptomatic DVT and PE Patient education improves medication adherence Failure to identify optimal medical patients for extended outpatient prophylaxis

12 TRIALS OF VTE PROPHYLAXIS IN HOSPITALIZED MEDICAL PATIENTS MEDENOX (enoxaparin 40 mg) Samama MM, et al. N Engl J Med. 1999;341: PREVENT (dalteparin 5000 IU) Leizorovicz A, et al. Circulation. 2004;110: ARTEMIS (fondaparinux 2.5 mg) Cohen AT, et al. BMJ. 2006; 332:

13 3 PHARMACOLOGICAL TRIALS Once daily injected low-dose anticoagulant prophylaxis, in these 3 placebo-controlled trials, reduced DVT/ PE by > ½, without increasing major bleeding.

14 VTE PROPHLAXIS GUIDELINES: HOSPITALIZED MEDICAL PATIENTS 2012 ACCP: Anticoagulant prophylaxis with LMWH, UFH, or fondaparinux for patients at increased risk 2011 ACP: Pharmacologic prophylaxis with heparin or a related drug, unless assessed risk for bleeding outweighs the likely benefits

15 ealert RANDOMIZED TRIAL VTE risk score > 4 No prophylaxis N = 2506 INTERVENTION Single alert n = 1255 CONTROL No alert n = 1251 (Kucher N, et al. N Engl J Med. 2005;352: )

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17 PRIMARY END POINT %Freedom from DVT/ PE Number at risk Time (days) Intervention Control Intervention Control (Kucher N, et al. N Engl J Med. 2005;352: )

18 HOSPITAL AUDITS INCREASE # PROPHYLAXIS PROTOCOLS (Anderson FA, Goldhaber SZ, Tapson VF, et al. Am J Med. 2010; 123: )

19 PATIENT REFUSAL: THE MOST COMMON REASON FOR OMISSION OF ORDERED VTE PROPHYLAXIS LMWH QD UFH BID UFH TID % pts receiving all doses Refusal explains dose omission 78% 54% 45% 39% 59% 42% (Fanikos J, et al. Am J Med. 2010; 123: )

20 PATIENT EDUCATION TRIAL p< p= p= Adherence (%) Proportion receiving 100% of doses (%) Patient refusal (%) Historical Cohort Patient Education Cohort (Piazza G, et al. Am J Med. 2012; 125: )

21 KEY OPPORTUNITIES Electronic alerts and audits improve implementation of VTE prophylaxis By preventing VTE, we prevent recurrent DVT/ PE, CTEPH, PTS Patient education programs improve medication adherence

22 RATIONALE: EXTENDED PROPHYLAXIS Although emphasis has focused on inhospital prophylaxis, 75% of VTEs present in outpatients Of these patients, many have undergone hospitalization (37%) or surgery (23%) in the 3 months preceding the diagnosis of VTE (Arch Intern Med. 2007;167:1471.)

23 EXTENDED PROPHYLAXIS: MEDICAL / SURGICAL PATIENTS Several studies have validated extended outof-hospital VTE prophylaxis in orthopedics and abdominal or pelvic cancer surgery Although medical patients have a higher frequency of comorbid conditions and risk factors for VTE, few receive extended duration thromboprophylaxis after hospital discharge (Lancet. 2001;358:9.) (N Engl J Med. 2002;346:975.)

24 EXCLAIM TRIAL: OBJECTIVE AND DESIGN (N=5,963) Evaluate extended VTE prophylaxis in acutely ill medical patients All receive enoxaparin 40 mg/d X 10 days Then randomized to enoxaparin 40 mg/d X 28 more days versus placebo

25 EXCLAIM: Efficacy Endpoints All VTE events Extended prophylaxis N=2485 (%) Placebo N=2510 (%) Absolute Risk reduction (95% CI) 2.5% 4.0% (-2.5% to -0.5%) Sx ic VTE 0.2% 1.0% (-1.2% to -0.3%) (Hull RD, et al. Ann Intern Med. 2010;153: 8-18.)

26 EXCLAIM: Safety Endpoint Major Bleeding Extended Prophylaxis N=2975 (%) Placebo N=2988 (%) Absolute Risk Difference (95% CI) 0.8% 0.3% (0.1% to 0.9%) Net clinical benefit observed in female, older, and sedentary patients (Hull RD, et al. Ann Intern Med. 2010;153: 8-18.)

27 MAGELLAN: Design

28 PRIMARY EFFICACY OUTCOME: Day 35

29 SAFETY OUTCOMES

30 ADOPT Study Design Randomization in a 1:1 ratio to double-blind, doubledummy oral apixaban 2.5 mg BID for 30 days versus subcutaneous enoxaparin 40 mg QD for 6 14 days Day 6 Hospital discharge 14 ± 3 days 30 ± 2 days 60 ± 7 days 90 ± 7 days Hospitalization Enoxaparin Screen Randomize Ultrasound Ultrasound Safety follow-up visits Apixaban (Goldhaber S, et al. N Engl J Med. 2011; 365: )

31 EFFICACY Variable Apixaban n/n (%) Enoxaparin n/n (%) Relative risk (95% CI) Day 30: Primary efficacy outcome (Total VTE/ VTErelated death) 60/2211 (2.71) 70/2284 (3.06) 0.87 (0.62, 1.23) (Goldhaber S, et al. N Engl J Med. 2011; 365: )

32 SYMPTOMATIC VTE after PARENTERAL RX Post- Parenteral RR=0.44 (0.19, 1.00)

33 BLEEDING Variable Apixaban n/n (%) Enoxaparin n/n (%) Relative risk (95% CI) Major bleeding 15/3184 (0.47) 6/3217 (0.19) 2.58 (1.02, 7.24) P=0.04 Major and clinically relevant non-major bleeding 85/3184 (2.67) 67/3217 (2.08) 1.28 (0.93, 1.76) P=0.12

34 CONCLUSIONS: ADOPT TRIAL VTE risk increases after hospital discharge Despite a nonsignificant trend after the parenteral period favoring extended prophylaxis, ADOPT does not provide evidence to justify such a policy in a broad population of medically ill patients We need to identify high-risk subgroups who might benefit from extended VTE prophylaxis

35 EXTENDED VTE PROPHYLAXIS IN MEDICAL PATIENTS Study EXCLAIM (n = 5,963) MAGELLAN (n = 8,101) ADOPT (n = 6,528) Study conclusion VTE Major bleeding VTE Major bleeding VTE Major bleeding Net clinical benefit Marginal No No Ann Intern Med. 2010;153:8-18. myamericanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/ documents/downloadable/ucm_ pdf N Engl J Med. 2011; 365:

36 POST-DISCHARGE VTE IN MEDICAL PATIENTS MAGELLAN Hospital ADOPT Symptoma.c VTE + VTE Death Discharge 10 day Enoxaparin 35 day Apixaban Incidence of VTE related death 10d 35d Enox 10D 0.2% 1.0% The rate of symptomatic VTE > doubles over 21 days post discharge, and the risk of fatal VTE increases 5 fold Riva 35D 0.1% 0.6%

37 CHEST ACCP GUIDELINES 2012: DVT/PE (9 TH EDITION) In acutely ill, hospitalized medical patients who receive initial thromboprophylaxis, we suggest against extended thromboprophylaxis beyond the period of immobilization or acute hospital stay (Grade 2B). (CHEST. 2012; 141: (2) (suppl) e195s-226s.)

38 DISCHARGE ALERT TRIAL: OBJECTIVES To determine whether physician notification prior to discharge of medical patients at high-risk for VTE will: 1. Increase thromboprophylaxis utilization after discharge AND 2. Reduce the incidence of symptomatic VTE after hospital discharge (Piazza G, et al. Am J Med; April 2013)

39 INTERVENTION Intervention within 48 hours of planned hospital discharge For patients randomized to the alert group, the responsible physician is notified by direct page that: 1) his/ her patient is at high risk for VTE AND 2) VTE prophylaxis should be considered in the discharge orders

40 DISCHARGE ALERT TRIAL: Overview PLANNED DISCHARGE WITHIN 48 HOURS RISK SCORE 4 ALERT (N=1,252) NO ALERT (N=1,261) INTERVENTION CONTROL ALERT Physician Check for Prophylaxis Order (within 48 hours of ALERT) 90-DAY FOLLOW UP (performed days )

41 BASELINE CHARACTERISTICS Baseline Characteristics Alert (N = 1252) Control (N=1261) Age, years, mean ± SD 70 ± ± Male gender, n (%) 592 (47) 600 (48) 0.88 Body mass index (BMI), mean ± SD 30 ± ± Bed rest/immobilization, n (%) 386 (31) 454 (36) Cancer, n (%) 936 (75) 928 (74) 0.50 History of VTE, n (%) 357 (29) 370 (29) 0.65 Receiving inpatient prophylaxis, n (%) Pharmacological only Mechanical only Both 781 (63) 588 (76) 146 (19) 43 (5.5) 810 (65) 567 (70) 159 (20) 79 (9.8) P

42 VTE PROPHYLAXIS AT DISCHARGE Prophylactic Measures Alert Control p-value Any prophylaxis, n (%) 278 (22) 122 (9.7) <.0001 Mechanical, n (%) Pneumatic compression device Graduated compression stockings Inferior vena cava filter 46 (3.7) 6 (13) 29 (63) 13 (28) 31 (2.5) 2 (6.5) 7 (23) 22 (71) < < Pharmacological, n (%) Unfractionated heparin Enoxaparin Warfarin 234 (19) 15 (6.4) 130 (56) 123 (53) 8 (3.4) 97 (7.7) 12 (12) 52 (54) 29 (30) 3 (3.1) < <

43 STUDY END POINTS Efficacy End Point at 90 days Alert Control Hazard Ratio [95% CI] VTE, n (%) DVT only PE only DVT and PE 48 (4.5) 30 (63) 13 (27) 5 (10) 43 (4.0) 32 (74) 6 (14) 2 (4.7) 1.12 (0.74, 1.69) 0.94 (0.57, 1.55) 2.17 (0.83, 5.72) 2.51 (0.49, 12.93) Safety End Point Death at 90d, n (%) 236 (19) 259 (21) 0.91 (0.76, 1.08) Bleed at 30d, n (%) 13 (1.2) 14 (1.2) 0.94 (0.44, 2.01)

44 SYMPTOMATIC VTE: 90 DAYS Cumulative rate log-rank p = (Am J Med; April 2013) Days from discharge to VTE, starting clock at randomization Alert No Yes

45 DISCUSSION We observed no difference in symptomatic VTE at 90 days Physician alerts doubled the prescription of VTE prophylaxis at hospital discharge However, nearly 80% of alerted physicians did not follow the recommendation to continue VTE prophylaxis after hospital discharge

46 DISCUSSION We focused our intervention on clinician behavior, by encouraging thromboprophylaxis after discharge, but allowing the provider to tailor VTE prevention efforts Even this personalized, individualized strategy failed to demonstrate a net clinic benefit

47 BETRIXABAN 23 hours half life 17% renal clearance Antidote

48 APEX TRIAL (N=6,850) Extended prophylaxis megatrial in high risk, immobilized Medical Patients with CHF, respiratory failure, infection, stroke A higher risk population is targeted than in prior extended prophylaxis megatrials Double-blind RCT: 35 days of oral betrixaban 80 mg daily versus injected enoxaparin 40 mg daily for 6-10 days Endpoint: VTE plus VTE Death Results in 2015

49 APEX Study Design Day days 65+5 days Hospitalization Screen R Randomize Enoxaparin Ultrasound Safety follow- up visits Betrixaban Note: No ultrasound is required at hospital discharge. Only 1 Ultrasound is required at 35 day follow up

50 CONCLUSIONS 1. PE is the #1 cause of preventable death among hospitalized patients 2. Survivors of VTE are at risk for recurrent DVT/ PE, CTEPH, and PTS 3. VTE prophylaxis in-hospital halves the VTE rate, without increasing major bleeding 4. Failure to implement inpatient prophylaxis remains problematic 5. Electronic alerts and audits improve VTE prophylaxis rates and reduce DVT/PE

51 CONCLUSIONS 6. Patient education improves compliance with in-hospital VTE prophylaxis 7. High risk medically ill patients are not receiving prophylaxis at hospital discharge. 8. EXCLAIM suggests that female, older, and immobile patients as those who will benefit the most 9. MAGELLAN, ADOPT, DISCHARGE ALERT: no net clinical benefit of extended prophylaxis 10. Stay tuned for the APEX Trial (n=6,850) with betrixaban: results expected in 2015