VTE Prophylaxis: Duration - NYSPFP · orthopedic surgery, we suggest extending thromboprophylaxis in the outpatient period for up to 35 days from the day of surgery rather than for

VTE Prophylaxis: Duration

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Post Discharge Prophylaxis: Orthopedic Surgery

Guideline: ACCP 20122.4. For patients undergoing major orthopedic surgery, we suggest extending thromboprophylaxis in the outpatient period for up to 35 days from the day of surgery rather than for only 10 to 14 days (Grade 2B)

Guideline: AAOS 2011In the absence of reliable evidence about how long to employ these prophylactic strategies, it is the opinion of this work group that patients and physicians discuss the duration of prophylaxis

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Post Discharge Prophylaxis: Cancer Surgery

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Guideline: ACCP 20123.6.6. For high-VTE-risk patients undergoing abdominal or pelvic surgery for cancer who are not otherwise at high risk for major bleeding complications, we recommend extended duration pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis

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Medically Ill Patients

Thromboprophylaxis Trials in Medically Ill PatientsInpatients, Average duration 7 – 14 d

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1Samama MM, et al. N Engl J Med 1999;341:793–8002Leizorovicz A, et al. Circulation 2004;110:874–93Cohen AT, et al. BMJ 2006;332:325–9

RRR = relative risk reduction

Thromboprophylaxis Trials in Medically Ill Inpatients

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1Samama MM, et al. N Engl J Med 1999;341:793–8002Leizorovicz A, et al. Circulation 2004;110:874–93Cohen AT, et al. BMJ 2006;332:325–9

Average duration of treatment: 7 – 14 d

Post Discharge Prophylaxis: Completing the Primary Course

Clinical Trials: treatment duration: 7- 14 days

vs

2012 Average Hospital LOS 4.5 daysAHRQ CUP data 2012 accessed 7/1/2018

Complete the primary course of treatment

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Extended or Post Discharge Thromboprophylaxisin Medically-Ill

Extended or Post Discharge • Result

Disease burden of VTE is shifting to the OP setting with shortening hospital stays

• LOS 4.5 days• 85% of VTE events are post discharge

What have we learned from prior studies(EXCLAIM, MAGELLAN)

Need to identify highest risk of VTE, but low risk of bleeding

How long to continue prophylaxis? 30 vs 45 days

Can we identify patients at highest risk?• Validated RAMs that address factors that

influence post discharge VTE events• IMPROVE or Padua or other RAM

Can we implement the use of validated clinical VTE RAMs +/- biomarkers

APEX vs MARINER

What are the strategies to strategies to minimize harm (bleeding)

• Active cancer• Renal insufficiency

Does VTE reduction exceed risk of bleeding?• Not for EXCLAIM, MAGELLAN, ADOPT• Possibly for APEX• MARINER results pending (tent’ve Aug 25th)

VTE in Medically Ill is Shifting to Post Discharge Settings

IMPROVE Registry (N = 15,156)• 26 sites from North/South America

and 24 sites from Europe and Australasia (July 2002 – September 2006)

• 184 VTE’s: • Median is 17 days, IQR 6-43 days

• 89 post discharge VTE’s: • Median is 44 days, IQR 25-68 days

Tapson V et al Chest 2007;132:936-45Flanders S et al JAMA Intern Med 2014;174:1577-84

US Hospital Performance Consortium for VTE (N = 20,994)• 35 Michigan hospitals in US (2011 –

2012)• 85.0% of VTE post-discharge

In-Hospital ThromboprophylaxisMay Not Reduce VTE Risk

US CMS claims analysis from 2005 – 2009 (N = 141,628)• LOS, mean (SD) - 4.4 (2.8) days• 3.9% received post-discharge prophylaxis (92% warfarin)• Hospital prophylaxis use did NOT reduce risk of post-discharge VTE (p = 0.398)

US Hospital Performance Consortium for VTE (N = 20,994)• LOS, mean/median – 4.5/3.0 – 4.0 days• Hospitals chrachterized by tertiles of pharmacologic prophylaxis rates: 85.8%,

72.6%, and 55.5%• No difference in hazards of VTE between hospitals

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Mahan C et al Thromb Res 2013;132(5):520-6Flanders S et al JAMA Intern Med 2014;174:1577-84

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EXCLAIM, MAGELLAN, ADOPT Extended Thromboprophylaxis in Medically Ill

1. Hull RD, et al Ann Intern Med. 2010 Jul 6;153(1):8-182. Cohen AT, et al. N Engl J Med 2013; 368: 513–233. Goldhaber SZ, et al. N Engl J Med 2011; 365: 2167–77

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Extended Thromboprophylaxis in Medically IllEXCLAIM, MAGELLAN, ADOPT

1. Hull RD, et al Ann Intern Med. 2010 Jul 6;153(1):8-182. Cohen AT, et al. N Engl J Med 2013; 368: 513–233. Goldhaber SZ, et al. N Engl J Med 2011; 365: 2167–77

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EXCLAIM, MAGELLAN, ADOPT Extended Thromboprophylaxis in Medically Ill

1. Hull RD, et al Ann Intern Med. 2010 Jul 6;153(1):8-182. Cohen AT, et al. N Engl J Med 2013; 368: 513–233. Goldhaber SZ, et al. N Engl J Med 2011; 365: 2167–77

Identifying high VTE risk patients for inclusion:

To be successful with post discharge prophylaxis, we need the ability to identifyHigh VTE Risk patients who are are low bleed risk

VTE RIskBleed Risk

High Low

High * *

Low * *

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Identifying high VTE risk patients for inclusion:Rates of Symptomatic VTE in Hospitalized Medical Patients: Unselected Populations

Study Event Rate (Period in days)

IMPROVE registry 1.0% (90d)

Michigan Consortium 1.28% (90d)

Systematic Review up to ~1.0% (120d)

US Acute Care Hospitals 0.4% (30d)

US Claims Database 1.9% (90d)

Pb arm of extended TP trials 0.56 – 1.1% (~30d)

Identifying high VTE risk patients for inclusion: American College of Chest Physicians ATP Guidelines: 9th Edition (2012)

For the Non-surgical and Non-orthopedic surgical chapters, a primary shift is towards an individualized approach of risk assessing the patients’ bleeding risk factors as well as their VTE risk factors for the appropriate thromboprophylactic strategy

Kahn et al. CHEST 2012; 141:(2 Suppl): e195S-226S

Identifying high VTE risk patients for inclusion: VTE rates by risk score: IMPROVE RAM (n=15,125)

Score Patients,% (n)

3-Month Predicted VTE

Risk*, %

Observed VTE Rate†, % (n)

Observed PE Rate†, % (n)

0 27 (4029) 0.4 0.3 (14) 0.3 (11)

1 42 (6350) 0.6 0.5 (33) 0.3 (19)

2 16 (2420) 1.0 1.3 (31) 0.5 (13)

3 9 (1335) 1.7 1.3 (18) 0.7 (9)

4 5 (729) 2.9 4.1 (30) 2.3 (17)

5-10 2 (262) 7.2 6.5 (17) 2.7 (7)

• c-statistic = 0.69• Overall symptomatic VTE – 1.0%• Patients with a score ≥3 developed a 3-month VTE symptomatic event rate of

2.8% (65/2326) and symptomatic PE event rate of 1.4% (33/2326)

*From the Cox regression model relating VTE to VTE risk score; predicted risks are means for patients in a given risk score group. 31 patients with incomplete covariate information were dropped from the final model †Rates do not consider time to VTE or patient dropout.

Identifying high VTE risk patients for inclusion: IMPROVE RAM Validation-Model Discrimination

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Mahan CE et al Thromb Haemost 2014;112:692-9Rosenberg D et al J Am Heart Assoc. 2014 Nov 17;3(6).pil: e001152

N = 20,321 N = 19,217

Identifying high VTE risk patients for inclusion: IMPROVE RAM Validation –Model Calibration

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Mahan CE et al Thromb Haemost 2014;112:692-9

IMPROVE Score Calibration – VTE VALOUR Study

Add D-Dimer to assess riskHigh D-Dimer = high riskLow D Dimer = low risk

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Identifying high bleeding risk patients for exclusion:Active Malignancy & Chronic Kidney Disease

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APEX: clinical trial design

Clinicaltrials.gov NCT01583218

APEX Trial:

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APEX Trial:

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APEX Trial:

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APEX Trial:

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APEX Trial:

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APEX Trial:

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Betrixaban FDA approval:BEVYXXA is a factor Xa (FXa) inhibitor indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE. (1)

The recommended dose of BEVYXXA is an initial single dose of 160 mg, followed by 80 mg once daily, taken at the same time each day with food.

The recommended duration of treatment is 35 to 42 days

Reduce dose for patients with severe renal impairment.Reduce dose for patients on P-glycoprotein (P-gp) inhibitors.

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MARINER Trial

Primary Endpoint: Composite of Symptomatic VTE or VTE-Related Death

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Thank You

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