Deep Vein Thrombosis and Pulmonary Embolus: Updates From ACCP, AC Forum & ESC

Transcription

1 Deep Vein Thrombosis and Pulmonary Embolus: Updates From ACCP, AC Forum & ESC Steven Deitelzweig, MD, MMM, SFHM, FACC, FACP Professor of Medicine University of Queensland School of Medicine System Chairman Hospital Medicine Medical Director Regional Business Development Ochsner Health System

2 Disclosures Research Funding BMS Optum Insight Novosys Consulting BMS Daiichi-Sankyo Janssen Healthcare Portola Board of Directors Society of Hospital Medicine Anticoagulation Forum American College of Cardiology Accreditation Management Board AMA House of Delegates in behalf of SHM Speaking Honoraria Pfizer, BMS Janssen Portola

3 Adults with VTE (millions) Trends in VTE: Prevalence to Double by 2050 Projected VTE Rates ( ) Total Males Females '06 '08 '10 '15 '20 '25 '30 '35 '40 '45 '50 P < Date Deitelzweig SB, et al. American J Hematology :

4 Putting It Into Perspective PE kills more people each year than HIV, car accidents, and breast cancer combined 1 Up to 300,000 people a year die from PE in the US 2 It is the third most common cardiovascular illness 3 350, , , , , ,000 50,000 0 Annual Deaths in the United States 40,500 Breast Cancer* 9,600 AIDS* 34,500 Car Accidents* 300,000 PE** * CDC 2008 ** Consensus Estimates range from 100,000 to 300, Rathbun S. Circulation. 2009; 119(15) e480-e Tapson VF. N Engl J Med. 2008;358: Goldhaber SZ. J Am Coll Cardiol. 1992, 19: (2): Macdougall DA et al. Am J Health-Syst Pharm. 2006;63(20 suppl 6):S5-S15.

5 PE Is the Most Preventable Cause of Death Among Hospitalized Patients Office of the Surgeon General. The Surgeon General s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism Available: Accessed: October 9, 2017.

6 World Thrombosis Day Facts Annual incidence rate of VTE: 0.75 to 2.69 per 1000 individuals across low-, middle-, and high-income countries Higher rate of VTE for the elderly (_> 70 years): 2-7 per 1000 individuals In the United States, diagnosis and treatment of VTE cost $15.5 billion per year Up to 60% of VTE cases occur are associated with a recent hospital stay, making it a leading preventable cause of hospital death 6 World Thrombosis Day website.

7 VTE After Hospital Discharge Despite in-hospital VTE prophylaxis, 75% of VTEs present out-of-hospital About half occur within 5 to 6 weeks of discharge 37% have been hospitalized within the 3 months preceding the diagnosis of VTE 7 Spencer FA, et al. Arch Intern Med. 2007;167:

8 Risk of VTE Extends Post Hospital Discharge Observational study of >11,000 hospitalized medical patients Thomson Reuters MarketScan Inpatient Drug Link Current 6-14 day Injectable Therapy Targets a Small Proportion of VTE risk >50% of VTE Risk Within 35 days Patients with Cancer CHF Lung disease Infection 3.5% Amin AN. J Hosp Med. 2012;7: PMID:

9 Extended VTE Prophylaxis Medical Patients Study Study Conclusion EXCLAIM -- LMWH VTE (n = 5963) a Major bleeding MAGELLAN -- Rivaroxaban VTE (n = 8101) b Major bleeding ADOPT -- Apixaban VTE (n = 6528) c Major bleeding Net Clinical Benefit Marginal No No 2016: APEX, betrixaban vs. enoxaparin 2018?: MARINER, rivaroxaban vs. enoxaparin a. Hull RD, et al. Ann Intern Med. 2010;153:8-18. b. Cohen AT, et al. N Engl J Med. 2013;368: c. Goldhaber SZ, et al. N Engl J Med. 2011;365:

10 2016 Updated VTE Guidelines/ Guidance Statements

11 HOT TOPICS Risk stratification and Treatment of PE High risk VTE VTE and Cancer Duration of anticoagulation for VTE Anticoagulation after a bleed Management with DOACS on obese patients

12 HOT TOPICS Risk stratification and Treatment of PE

13 CASE #1 A 55 year-old man presents with pleuritic chest pain. His BP is 120/70, HR 105, RR is 18, and his O2 sat is 97%. His physical exam is unremarkable. A chest CT shows multiple pulmonary emboli. ECG is normal.

14 CASE #1 What is this patient's risk of early mortality related to PE? A) 1% B) 10% C) 20%

15 Pulmonary Embolism Severity Index Estimates the risk of 30-day mortality from PE Class (Risk) Score/Po ints I (Very Low) <66 0% II (Low) % 30-Day Mortality III (Intermed) % IV (High) % V (Very High) > % Aujesky D et al, Eur Heart J 2006; 27: Total point score obtained by summing patients age in years and the points for each applicable characteristic

16 Simplified Version (Score > 1 = high risk) - age > 80 y - history of cancer - COPD - pulse 110 bpm - BP < 100 mmhg - art O2 sat < 90% Patients in Simplified PESI: Low risk 30-day mortality of 1% High risk 30-day mortality of 10.9% Estimates the risk of 30-day mortality from PE Arch Intern Med 2010; 170: 1383

17 ACCP 2016: Choice of Long Term (1 st 3 Months) & Extended Anticoagulant Therapy In patients with DVT of the leg or PE (w/o active cancer): DOAC s are preferred over warfarin (Grade 2B) Warfarin preferred over LMWH (Grade 2C) No one DOAC is preferred over the other Extended treatment w/ DOACs reduces recurrent VTE and is associated with less bleeding risks Kearon C, et al. CHEST Guideline, Chest

18 Comparison of NOAC Trials in DVT/PE Treatment: Study Designs XARELTO (rivaroxaban) ELIQUIS (apixaban) PRADAXA (dabigatran) LIXIANA (edoxaban) Trials EINSTEIN DVT & PE AMPLIFY RECOVER I & II HOKUSAI VTE Sample size, n (%) N=8282 N=5395 N=5107 N=8240 PE patients, n (%) 4832 (58) 1836 (34) ~31% 3319 (40) Active cancer**, n (%) 430 (5.3) 143 (2.7) ~4.7% 208 (2.5) Unprovoked, n (%) 5255 (63) 4845 (90) N/A 5410 (66) Regimen Single oral agent concept Single oral agent concept Initial Heparin Bridge Required Initial Heparin Bridge Required Dosing 15mg bid x 21 d, then 20 mg qd [3, 6, or 12 mo] 10 mg bid x 7 d, then 5 mg bid [6 mo] LMWH/UFH x 5-10 d, then 150 mg bid [6 mo] LMWH/UFH x 5-12 d, then 60 mg qd [3, 6, or 12 mo] *Postrandomization. **At baseline. Double-dummy period oral drug only, dabigatran vs warfarin. HOKUSAI enrolled 771(9.3%) patients with cancer listed as the cause of DVT or PE. For Presentation Only Not intended for data comparison.

19 When should you use a new oral anticoagulant? Your patient is adherent Your patient has a poor INR control (TTR < 60%) Your patient has good renal function (creatinine clearance 50 ml/min or better) Your patient has good hepatic function (AST/ALT and bilirubin normal or < 2x ULN)

20 ACCP 2016: Outpatient Treatment of Low Risk PE Suitable for outpatient treatment: 1. No contraindications (recent bleeding, severe renal/liver disease, or severe thrombocytopenia) 2. Expected to be compliant with treatment 3. Feels well enough to be treated at home Clinical prediction rules such as PESI (<85 or simplified score 0) can identify low-risk patients Echo and biomarkers not routinely recommended If noted, RV dysfunction or increased biomarker levels should discourage home treatment Kearon C, et al. CHEST Guideline, Chest

21 Echocardiogram and PE Prognosis Meta-analysis - RV dysfunction as a prognostic factor in stable patients with PE 12 trials, 3283 hemodynamically stable patients with acute PE 1223 patients (37.3%) RVD patients (62.7%) RVD- MORTALITY 167/1223 (13.7%) 134/2060 (6.5%) Cho JH, et al. BMC Cardiovascular Disorders. 2014;14:64.

22 Hospitalizations and Other Healthcare Resource Utilization among Patients with Deep Vein Thrombosis Treated with Rivaroxaban versus Low- Molecular Weight Heparin and Warfarin in the Outpatient Setting Deitelzweig S, Laliberté F, Crivera C, et al. Hospitalizations and Utilization of Other Healthcare Resources among Patients with Deep Vein Thrombosis Treated with Rivaroxaban versus Low-Molecular-Weight Heparin and Warfarin in the Outpatient Setting. Clinical Therapeutics. 2016;

23 Premier Hospital Database Analysis Study Design of Premier Hospital Database Analysis: Hospital Readmissions in VTE Patients in the US Data source: Premier hospital database Patient identification period: 8/1/2014 5/31/2016 Included: Hospitalized patients* with primary discharge diagnosis of VTE Patients who received apixaban or warfarin during any time of the hospitalization (from admission to discharge) Apixaban n=2554 Warfarin n=26,522 Excluded: Patients receiving both apixaban and warfarin or any other DOAC, including rivaroxaban, dabigatran, and edoxaban during the index hospitalizations Evidence of AF or atrial flutter (AFL) during the entire study period Primary Outcomes: Hospital length of stay (LOS) for initial hospitalization for VTE Costs of hospitalization during the initial hospitalization for VTE Secondary Outcomes: All-cause, clinically relevant bleeding-related hospital readmissions Major bleeding-related hospital readmissions Major bleeding-related, clinically relevant bleeding-related, VTErelated, and all-cause readmissions and associated LOS and costs * Inpatient admissions or ED admissions for either index admissions or readmissions. 23 Statistical Methods: Descriptive statistics will be utilized to describe demographics, clinical characteristics, hospital characteristics, treatment-related information, hospital LOS, costs, and readmission rates Multivariable generalized linear models were carried out to compare hospital LOS and cost, while controlling for key differences in patient and hospital characteristics Lin A et al. To be presented at: American College of Cardiology Scientific Session 2018; March 10-12, 2018; Orlando, FL, USA.

24 Premier Hospital Database Analysis Mean Index Hospitalization LOS Hospital Cost Hospitalization Length of Stay (LOS) and Cost 5 4 Hospital LOS* Per Patient for Index Hospitalization P<0.001 $9000 Hospital Cost P< $ $ Apixaban n=2554 Warfarin n=26,522 $0 $6713 $7754 Apixaban n=2554 Warfarin n=26,522 Mean Difference: * After controlling for key patient and hospital characteristics. Error bars represent 95% CI. 24 Lin A, et al. Presented at: American College of Cardiology Scientific Session 2018; March 10-12, 2018; Orlando, FL, USA.

25 Premier Hospital Database Analysis Hospital Readmission Rates Apixaban (n=2554) Warfarin (n=26,522) P value All-cause readmission, n (%) 196 (7.67%) 2650 (9.99%) Major bleeding-related readmission, n (%) 8 (0.31%) 197 (0.74%) VTE-related readmission, n (%) 196 (7.67%) 2642 (9.96%) Lin A et al. Presented at: American College of Cardiology Scientific Session 2018; March 10-12, 2018; Orlando, FL, USA.

26 CASE #2 Hot Topic: High Risk VTE 48 year old male presents to local hospital with acute SOB. His vitals: 87% on room air, initially required 15 L NC oxygen, HR 150, RR 30, BP 140/79. CTA showed extensive bilateral PE and RV/LV ratio >1. ECHO: RV dilated, hypokinetic, septal flattening, RVSP 54 mm Hg. Elevated troponin and BNP He was administered one dose lovenox and sent to you.

27 What would you do? CASE #2 A. Unfractionated heparin and observe B. Systemic thrombolysis with 100 mg tpa C. Surgical thrombectomy D. Catheter directed thrombolysis E. Catheter thrombectomy of PE F. Do you have the experts cell phone that gave us the last grand rounds on this topic

28 CASE #2 52.4%* 15% Kucher et al Massive PE Circulation 2006.

29 ESC 2014 guideline recommendations Clinical suspicion of PE Shock / hypotension? YES NO Diagnostic algorithm Diagnostic algorithm PE confirmed Assess clinical risk (PESI or spesi) PE confirmed Intermediate risk PESI class III-V or spesi 1 PESI class I-II or spesi = 0 Consider further risk stratification Both positive RV function (echo or CT) a Laboratory testing b One positive or both negative High risk Intermediate high risk Intermediate low risk Low risk Primary reperfusion AVC monitoring: consider rescue reperfusion Hospitalisation; A/C Consider early discharge and home treatment, if feasible Konstantinides S, Eur Heart J 2014

30 Thrombolytics for intermediate risk PE Konstantinides S, Eur Heart J 2014

31 Catheter-Based Thrombus Removal for the Initial Treatment of PE Evidence for the use of CDT compared with anticoagulation alone, CDT compared to systemic thrombolytic therapy, and catheter-based treatment without thrombolytic therapy is low quality and recommendations made are weak. CDT may be more effective than systemic thrombolysis: Achieves a higher local concentration of thrombolytic drug by infusing the drug directly into the PE itself. Fragmentation of the thrombus due to the placement of the catheter may enhance pharmacologic or endogenous thrombolysis

32 ESC Reperfusion for acute PE Konstantinides S, Eur Heart J 2014

33 Pulmonary Embolism: Which Therapy To Use Best treatment unknown - no standard approach as strategies all over the map Varies by medical service, location, size and threat to patient, etc. etc. No consistency in decision-making No single team or clearing-house No accepted algorithm No centralized location for care No systematic evaluation of results

34 Pulmonary Embolism Response Team (PERT) A Multidisciplinary Pulmonary Embolism Response Team : Initial 30-Month Experience With a Novel Approach to Delivery of Care to Patients With Submassive and Massive Pulmonary Embolism. Kabrhel C, Rosovsky R, Channick R, et al. Chest 2016; 150:384

35 Case 29 yo with extensive DVT No phlegmasia (alba or cerulea) dolens No increase risk of bleeding Would you use thrombolysis? A. Yes B. No

36 ATTRACT Trial Question: does pharmacomechanical thrombolysis prevent postthrombotic syndrome in DVT? Design: RCT, open-label, assessor-blinded Patients: 692 patients with acute proximal DVT Intervention: pharmacomechanical thrombolysis + anticoagulation + compression stockings Comparison: anticoagulation + compression stockings Outcome: Primary efficacy: post-thrombotic syndrome Safety: bleeding, recurrent VTE, death Timeframe: 2 years Vedantham S. N Engl J Med Dec 7;377(23): PMID:

37 ATTRACT Trial Vedantham S. N Engl J Med Dec 7;377(23): PMID:

38 Hot Topic VTE and Cancer 65 year old male with PE Prostate cancer, hormonal deprivation therapy Low intermediate risk, normal kidney and liver What would you treat with A. LMWH B. LMWH/warfarin C. Rivaroxaban D. Apixaban E. LMWH/edoxaban

39 Hokusai VTE Cancer Trial Question: is edoxaban as good as LMWH for cancer related VTE? Design: randomized, open-label, non-inferiority trial Patients: 1050 patients with cancer and acute symptomatic or incidental VTE Intervention: LMWH for at least 5 days and then edoxaban 60 mg daily for 6-12 months Comparison: dalteparin 200 u/kg daily for 1 month and then 150 u/kg daily for 6-12 months Outcome at 12 months Recurrent VTE Major bleeding Raskob GE. N Engl J Med Dec 12. [Epub ahead of print] PMID:

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41 HOT TOPICS Duration of anticoagulation for VTE

42 Case 65 year old male with unprovoked proximal DVT 7 months ago On rivaroxaban 20 mg qd Admitted with community acquired pneumonia Normal kidney and liver, no cancer How would you manage his warfarin at discharge A. Stop anticoagulation, has had 6 months of therapy B. Change to ASA C. Continue rivaroxaban, ain t broke, don t fix it D. Decrease rivaroxaban to 10 mg qd E. Change to apixaban 2.5 mg bid

43 EINSTEIN CHOICE Trial Question: is usual or prophylactic dose rivaroxaban better than ASA for extended treatment of VTE? Design: randomized, double-blind, intention to treat trial Patients: 3365 with provoked or unprovoked VTE with equipoise regarding extended treatment who had been treated for 6-12 months Intervention: rivaroxaban 20 mg qd or 10 mg qd for approximately 12 months Comparison: ASA 100 mg qd for approximately 12 months Outcome: Symptomatic VTE or sudden death where PE could not be excluded Major ISTH bleeding Weitz JI. N Engl J Med Mar 30;376(13): PMID:

44 EINSTEIN CHOICE Trial Weitz JI. N Engl J Med Mar 30;376(13): PMID:

45 Case #3:How long will you recommend this patient stay on anticoagulation? 55 yo man with unprovoked PE? a) 3 months b) 6 months c) 12 months d) Indefinitely

46 Cumulative Events (%) The Risk of Recurrence Is Higher With Unprovoked VTE After Discontinuation of Anticoagulation 91 Patients with a first episode of clinically symptomatic proximal DVT and/or PE* (N=1626) Discontinuation of Anticoagulation Unprovoked Provoked Average of 6 months of anticoagulation treatment Patients discontinued anticoagulation and were followed for recurrent DVT/PE 10 0 HR = 2.30; 95% CI: Months After Discontinuation *Excluded patients with active cancer, prior VTE, an indication for indefinite anticoagulation, geographic inaccessibility to followup, or poor life expectancy.

47 Duration of Anticoagulation for VTE: 2016 CHEST and AC Forum Guidelines/Guidance Indication CHEST AC Forum st provoked VTE 3 mo 3 mo (surgical) a 3 mo (medical) 1st unprovoked VTE Extended b Extended 2nd unprovoked VTE Extended b Extended VTE + cancer Extended b Extended a Unless risk factors for recurrence persist b No scheduled stop date, unless high bleeding risk. 1. Kearon C et al. Chest. 2016;149(2): Streiff MB et al. J Thromb Thrombolysis. 2016;41:

48 ACCP Guidelines Regarding Extended Therapy Are Stratified by Bleeding Risk Currently, there is a lack of well-validated tools to stratify the risk of major bleeding during extended anticoagulant therapy in patients with VTE However, the risk of bleeding in patients receiving anticoagulant therapy may increase with the prevalence of certain factors, including: Advanced age Antiplatelet therapy Previous bleeding Cancer Previous stroke Diabetes Kidney or liver failure Anemia Frequent falls Comorbidity and reduced functional capacity Alcohol abuse Poor anticoagulant control Thrombocytopenia Recent surgery

49 Current guidelines recommend extended anticoagulation for most patients with unprovoked DVT/PE and a low to moderate bleeding risk ACCP Guidelines Regarding Extended Therapy Are Stratified by Bleeding Risk Baseline risk of bleeding with no anticoagulation Increased risk with anticoagulation Total risk of bleeding on therapy Estimated Absolute Risk of Major Bleeding After 3 Months of Anticoagulation, % per year Low Risk (0 Risk Factors) Moderate Risk (1 Risk Factor) High Risk ( 2 Risk Factors)

50 HOT TOPICS Anticoagulation after a bleed

51 CASE #4 What To Do After the Bleed 76 y/o man with CAD (NSTEMI 2006), AFIB CHADS-Vasc=4 on warfarin and ASA is admitted with UGIB. INR is 3.0. He requires 3u PRBCs, vit K and FFP. EGD shows peptic ulcer disease. He is started on high dose PPI therapy, bx for H Pylori done. When should his anticoagulation be restarted? a) Never b) In two weeks c) In three months d) Let the primary provider deal with this one

52 CASE #4 What To Do After the Bleed Witt Hematology 2016

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55 CASE #4 What To Do After the Bleed 76 y/o man with CAD (NSTEMI 2006), AFIB CHADS-Vasc=4 on warfarin and ASA is admitted with UGIB. INR is 3.0. He requires 3u PRBCs, vit K and FFP. EGD shows peptic ulcer disease. He is started on high dose PPI therapy, bx for H Pylori done. When should his anticoagulation be restarted? Two weeks may provide the best balance among GI bleed recurrence, thromboembolism and mortality a) Never b) In two weeks c) In three months d) Let the primary provider deal with this one

56 HOT TOPICS Management with DOACS on obese patients

57 CASE #5 DOACs in Extremes of Weight A 56 year old obese man, BMI 42, weight 155 kg presents with bilateral lower extremity swelling. D-Dimer is elevated prompting bilateral lower extremity ultrasound. Ultrasound shows a DVT in LEFT common femoral, superficial femoral and popliteal vein. He is deemed appropriate for outpatient management of this VTE. What anticoagulant regimen do you recommend? a. Rivaroxaban 15 mg BID x21 days then 20 mg daily b. Apixaban 10 mg BID x 7 days then 5 mg BID c. Enoxaparin bridging to warfarin d. Admission for IV heparin bridging to warfarin e. Do you have steve deitelzweig s cell phone number?

58 DOACs in Obesity Reduced exposure, lower peaks, shorter t 1/2 Martin et al Journal of Thrombosis and Haemostasis, :

59 DOACs in Extremes of Weight Systematic review of 6 trials of DOACS vs warfarin n VTE Proportion of patient s classified as high body weight 15-28% Variability may be related to definition (ie > 90kg vs 100kg) Very little information on extreme body weight (eg < 40 kg, > 150 kg Di Minno MN et al. Ann Med Feb;47(1):61-8

60 DOACS AND EXTREMES OF WEIGHT HIGH BODY WEIGHT NORMAL BODY WEIGHT LOW BODY WEIGHT Minno et al Ann Intern Med 2015 Feb;47(1):61-8

61 DOACs in Extremes of Weight ISTH RECOMMENDATIONS: Recommend standard dosing if BMI< 40 and weight < 120 kg. Suggest DOACS not be used if BMI> 40 or weight > 120 kg If DOACs used in BMI > 40 or weight> 120 kg suggest drug specific peak and trough level. If level within expected range continue DOAC; if below suggest warfarin Martin et al. J Thromb Heamost 2016

62 SUMMARY Risk stratify all patients presenting with PE (low, intermediate, or high risk) to determine appropriate disposition Minimum effective duration of therapy for VTE is 3 months. If event is unprovoked consider indefinite anticoagulation if bleeding risk is low Add DOACS as strong evidence based options for VTE treatment and awaiting more data for cancer

63 SUMMARY Consider resuming anticoagulation after a bleed between 7-14 days ISTH Recommends standard dosing DOACS if BMI< 40 and weight < 120 kg and not be use d if BMI> 40 or weight > 120 kg

64 Questions?