VTE-Pulmonary Embolism Contemporary Management Schaefer.pdf · VTE-Pulmonary Embolism Contemporary Management ... Hemoptysis 1 Pain on deep vein ... An algorithm for management

VTE-Pulmonary Embolism Contemporary Management

Saul Schaefer, M.D.Professor of Medicine

University of California DavisChief, Cardiology

VA NCHCS

Disclosures

Investigator:Boehringer-Ingelhiem [RELY]Daiichi Sankyo [ENGAGE]

Speakers Bureau:Janssen

VTE

DefinitionsDiagnosisManagement: Conventional

NOACs

VTE

VTE: Venous thromboembolism – deep vein thrombosis (DVT) to pulmonary embolism (PE)

Note: most patients with PE have DVT…many patients with DVT have asymptomatic PE

DVT DVT died of PE

DVT

PE

200,000 deaths/year

30% mortality if diagnosis is missed

Etiology of VTE

• Immobilization: hospitalized patients• Post operative (esp knee/hip surgery)• Cancer• Genetic (protein C and S deficiency, Factor V Leiden)• Trauma

Virchow’s Triad > thrombus formation

Rudolf Virchow 1856

Diagnosis of VTE

• Clinical suspicion• Clinical exam (unilateral swelling)• D-dimer• Clinical algorithm (Wells, Geneva)• LE Doppler • Imaging: CTA, VQ scan

Diagnosis of DVT

• Clinical exam – swollen leg, cord, Homan’s sign

Diagnosis of DVT

• Clinical exam – swollen leg, cord, Homan’s sign• Venous ultrasound

Compression Augmentation

Pulmonary Emboli

NomenclatureChronicity (Acute, subacute, chronic)Hemodynamic Stability (Submassive vs Massive)Anatomic Location (Saddle, Segmental,

Subsegmental)Symptoms

Diagnosis of PE

• Clinical suspicion• Clinical algorithms• D-Dimer• Imaging

Clinical algorithms

Wells [ < 2 low probability, > 4 PE likely ]

PE more likely than alternatives: 3.0 pointsDeep Vein Thrombosis (DVT) suspected: 3.0 pointsTachycardia (pulse >100 beats per minute): 1.5 pointsSurgery or immobilization in last 4 weeks: 1.5 pointsPrior DVT or Pulmonary Embolism: 1.5 pointsHemoptysis: 1.0 pointsActive malignancy: 1.0 points

Kline, Wells: Ann Emerg Med 2003

Clinical algorithmsSimplified Geneva

Age >65 1Previous DVT or PE 1Surgery or fracture within 1 month 1Active malignancy 1Unilateral lower limb pain 1Hemoptysis 1Pain on deep vein palpation of lower limb and unilateral edema 1

Heart rate 75 to 94 bpm 1Heart rate greater than 94 bpm 2

How good are clinical algorithms?277 patients ER

• Geneva• Wells• Geneva “overridden by implicit clinical judgment” [in 21%

of patients]

• Similar proportion of patients classified as low (53-58%), intermediate (37-41%) and high (4-10%).

• +PE: low = 5-13%, intermediate = 38-40%, high = 67-91%

Chagnon et al, Am J Med 2002

D-Dimer

• use if low probability of PE

• NPV = 99.5% +

• positive D-Dimer does NOT raise probability of PE

• normal < 500 ng/ml, but age-related (higher cutoff if age > 80)

+ Wells, Ann Int Med 2001

CTA

CTA

V/Q scan

Ventilation (V): Xenon [or technetium labelled carbon nanoparticles]Perfusion (Q): technetium or gallium labeled albumin

have a low risk of bleeding (grade2B).21 Patients with a low risk ofbleeding have normal renal function,are not frail, and are not receivingdual-antiplatelet therapy.

The Management Strategies andPrognosis of Pulmonary EmbolismTrial-3 (MAPPET-3) randomized 256patients with submassive PE to receiverecombinant tissue plasminogen activa-

tor (tPA) 100 mg over a 2-hour periodfollowed by unfractionated heparin in-fusion or placebo plus heparin antico-agulation.22 Compared with heparinanticoagulation alone, fibrinolysis re-

Figure 1. The pathophysiology of sub-massive PE. PVR indicates pulmonaryvascular resistance.

Figure 2. An algorithm for managementof patients with submassive PE. CT indi-cates computed tomography.

1126 Circulation September 14, 2010

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Hemodynamic alterations in massive PE (that you need to worry about)

have a low risk of bleeding (grade2B).21 Patients with a low risk ofbleeding have normal renal function,are not frail, and are not receivingdual-antiplatelet therapy.

The Management Strategies andPrognosis of Pulmonary EmbolismTrial-3 (MAPPET-3) randomized 256patients with submassive PE to receiverecombinant tissue plasminogen activa-

tor (tPA) 100 mg over a 2-hour periodfollowed by unfractionated heparin in-fusion or placebo plus heparin antico-agulation.22 Compared with heparinanticoagulation alone, fibrinolysis re-

Figure 1. The pathophysiology of sub-massive PE. PVR indicates pulmonaryvascular resistance.

Figure 2. An algorithm for managementof patients with submassive PE. CT indi-cates computed tomography.

1126 Circulation September 14, 2010

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Fibrinolysis or anti-coagulation in massive/sub-massive PE

JAMA. 2014;311(7):717-728

Treatment of Venous Thromboembolism - acute

Confirmed segmental or > PE or proximal DVT

JAMA. 2014;311(7):717-728


CV compromise orthreatened limb loss tPA

McConnell’s sign

“There is a distinct regional pattern of right ventricular dysfunction, with akinesia of the mid free wall but normal motion at the apex”

McConnell et al: Am J Cardiol. 1996; 78: 469–473

McConnell’s sign

“There is a distinct regional pattern of right ventricular dysfunction, with akinesia of the mid free wall but normal motion at the apex”


McConnell’s sign


Pulmonary EmboliThrombolytic therapy –

• leads to early hemodynamic improvement• increased risk of major bleeding

“Major bleeding” 9.2% - 20%Intracranial bleeding 3% - 5%

2008 American College of Chest Physicians’ guidelines: “ “fibrinolysis as an option for patients with submassive PE who are judged to have a low risk of bleeding (grade 2B)”.

!14 mm Hg; p < 0.0001). The decrease in mean pul-monary artery systolic pressure was sustained frombaseline to 48 " 6 h, as estimated by transthoracicechocardiography (51.4 mm Hg vs. 36.9 mm Hg; meandifference, !14.4; p < 0.0001). Mean modified Millerangiographic obstruction index score decreasedfrom 22.5 at baseline to 15.8 at 48 " 6 h (meandifference, !6.6; p < 0.0001).

An analysis was conducted to determine whetherthere was any difference in the change in RV/LVdiameter ratio between patients who had a follow-up

CT scan performed with the 48 " 6-h window andthose who had a follow-up CT scan performed but itfell outside of the 48 " 6-h window. There was nodifference in the change in RV/LV diameter ratio inpatients who had a follow-up CT scan performedwithin the 48 " 6-h window and those who had afollow-up CT scan performed but it fell outside of the48 " 6-h window (mean percentage of change, !24%vs. !29%; p ¼ 0.29). Similarly, there was no differencein the change in pulmonary artery systolic pressure inpatients who had follow-up echocardiography per-formed within the 48 " 6-h window and thosewho had echocardiography performed outside of the48 " 6-h window (mean percentage of change,!14.4 mm Hg vs. !17.5 mm Hg; p ¼ 0.24).

A random-effects model analysis was performed toassess whether there was significant variance in thechange in RV/LV diameter ratio according to studysite. There was no indication of significant study sitevariance (p ¼ 0.24), and the 2-sided p value forcomparing the mean change in RV/LV diameter ratiowith the pre-specified control value of !0.2 remainedsignificant (p < 0.0001).

SAFETY OUTCOMES. Three patients died while hos-pitalized, and 1 patient died after hospital dischargewithin 30 days of the procedure (Table 5). One patientdied of massive PE before the procedure could becompleted; 1 patient changed her code status andelected to receive hospice care after multisystem or-gan failure developed during a prolonged admission;1 patient died of sepsis unrelated to the procedure;and 1 patient died of PE resulting in progressive res-piratory failure. The patient who died before theprocedure could be completed was a 61-year-oldwoman with diabetes, obesity, and recent infectiousillness who presented hemodynamically stable with

FIGURE 2 Efficacy Outcomes

(A) Change in contrast-enhanced CT–determined mean RV/LVdiameter ratio from baseline to 48 " 6 h after initiation of theultrasound-facilitated, catheter-directed, low-dose fibrinolyticprocedure. (B) Change in invasively measured mean systolicpulmonary artery pressure from baseline to completion of theultrasound-facilitated, catheter-directed, low-dose fibrinolysisand to 48 " 6 h after the procedure as estimated by trans-thoracic echocardiogram. (C) Change in contrast-enhancedCT–determined mean modified Miller pulmonary angiographicobstruction index score from baseline to 48 " 6 h after initiationof the ultrasound-facilitated, catheter-directed, low-dose fibri-nolytic procedure. Abbreviations as in Figure 1.

TABLE 5 Safety Outcomes (N ¼ 150)

Length of stay, SD, days 8.8 " 5

In-hospital death 3 (2)

30-day mortality* 4 (2.7)

Serious and severe adverse events potentiallyrelated to device

3 (2)

Serious and severe adverse events potentiallyrelated to t-PA

2 (1.3)

IVC filter placed 24 (16)

Major bleeding within 30 days* 15 (10)

GUSTO moderate* 14 (9.3)

GUSTO severe* 1 (0.7)

Intracranial hemorrhage 0 (0)

Values are mean " SD or n (%). *N ¼ 149 (1 patient lost to follow-up).

GUSTO ¼ Global Utilization of Streptokinase and Tissue Plasminogen Activatorfor Occluded Coronary Arteries; IVC ¼ inferior vena cava; t-PA ¼ tissue-plasminogen activator.

Piazza et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 8 , N O . 1 0 , 2 0 1 5

Ultrasound-Facilitated, Low-Dose Fibrinolysis for Acute PE A U G U S T 2 4 , 2 0 1 5 : 1 3 8 2 – 9 2

1388

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bleeding or high-risk anticoag IVC filter








CV

bleeding

prognosis

poorgood


CV

bleeding

prognosis

poorgood

hospitalization


CV

bleeding

prognosis

poorgood

hospitalizationoutpatient tx


CV

bleeding

prognosis

poorgood

hospitalizationoutpatient txCrCl < 30 ?


CrCl < 30 ?yesno

LMWHfondaparinuxNOAC

UFH

warfarin

Dabigatran

RivaroXabanApiXabanEdoXaban

for reference only….pharmacology of warfarin and NOACs

NOACs - key points

Specific targets (Xa, IIa)Rapid onset, short half-lifePrimary renal excretionNo monitoringNo reversal (coming*)Interactions with CYP3A, Pgp

* NEJM 2015

RCTs: NOACs in treatment of VTE

Switch therapy: Initial heparin [all] followed by warfarin or dabigatran or edoxaban 1

Mono therapy: apixaban or rivaroxaban vs heparin + warfarin 2

1 RE-COVER, RE-COVER II [NEJM 2009]Hokusai-VTE [edoxaban]

2 AMPLIFY EINSTEIN–DVT and EINSTEIN-PE

dabigatran: RE-COVER

49

• N = 2564, Follow-up 6 months, double-blind

• Inclusion: DVT or PE with planned tx for 6 months

• Randomized to 150 mg dabigatran BID vs warfarin

• Primary outcome: symptomatic VTE or death 2/2 VTE

50

RE-COVER outcomes

51

RE-COVER outcomes

December 2010

Rivaroxaban: EINSTEIN-DVT

• N = 3449, most tx for 6 months, open-label

• Inclusion: DVT w/o PE

• Randomized to rivaroxaban at 15 mg BID for 3 weeks then 20 mg daily for 3, 6, or 12 months vs warfarin

• Primary outcome: symptomatic recurrent VTE

Rivaroxaban: EINSTEIN-DVT

55

EINSTEIN-DVT

Oral Apixaban for the Treatment of Acute Venous Thromboembolism

Giancarlo Agnelli, M.D., Harry R. Buller, M.D., Ph.D., Alexander Cohen, M.D., Madelyn Curto, D.V.M., Alexander S. Gallus, M.D., Margot Johnson, M.D., Urszula

Masiukiewicz, M.D., Raphael Pak, Ph.D., John Thompson, Ph.D., Gary E. Raskob, Ph.D., Jeffrey I. Weitz, M.D., for the AMPLIFY Investigators

N Engl J MedVolume 369(9):799-808

August 29, 2013

Apixaban: AMPLIFY

Agnelli G et al. N Engl J Med 2013;369:799-808

5395 pts

initial Rx – apixaban 10 BID for 7 days, then 5 mg BID or LMWH/warfarin

* Hokusai VTE September 2013

R

edoxaban

warfarin

3 M 6 M 12 M

initial (LMW)Heparinplacebo warfarinplacebo edoxaban

Day 6- 12

Sham INR

INR

Day 1- 5

Symptomatic confirmed VTE event

Hokusai VTE: LMW heparin followed by edoxaban vs. initial LMW heparin followed by warfarin only

60

Hokusai VTE: Primary Efficacy Outcome

1.00 0

0.70 1.130.89

Hazard Ratio

Edoxaban superior Edoxaban non-inferior

1.50

hep / edoxaban(n / N)

hep / warfarin(n / N)

HR(95% CI)

mITTOverall

130 / 4,1183.2%

146 / 4,1223.5%

0.89 (0.70–1.13)

mITTOn-Rx

66 / 4,1181.6%

80 / 4,1221.9%

0.82(0.60-1.14)

Overall

On-Rx

TTR : 63.5%

Hokusai VTE: Bleeding

hep / edoxaban(n / N)

hep / warfarin(n / N)

HR(95% CI)

349 / 4,1188.5%

423 / 4,12210.3%

0.81(0.71–0.94)

warfarin 4122 3757 3627 3522 3313 3218 2979 2165 2007 1883 1754 1613 1212

edoxaban 4118 3840 3695 3587 3382 3308 3038 2192 2043 1904 1767 1650 1241

Number of patients at risk

RCTs: NOACs in acute treatment of VTE

dabigatran: RE-COVER, RE-COVER II edoxaban: Hokusai-VTE apixaban: AMPLIFY rivaroxaban: EINSTEIN–DVT and EINSTEIN-PE

Efficacy = = = =Safety less bleeding less bleeding less bleeding less bleeding

dabigatran rivaroxaban apixaban edoxaban

.

Amin et al J Medical Economics 2014

Evaluation of medical costs associated with use of new oral anticoagulants compared with standard therapy among venous thromboembolism patients

As a result of the reduction in clinical event rates, the overall medical cost differences were:

dabigatran −$146 rivaroxaban −$482, apixaban −$918 edoxaban −$344

for VTE patients vs patients treated with standard therapy.

NOACs in extended treatment of VTE

Problem: recurrent VTE occurs in many patients following discontinuation of anti-thrombotic therapy

Question: Can extended treatment of VTE (>6 months) reduce incidence of recurrent VTE??

Cumulative incidence of recurrent thromboembolism separately in patients with idiopathic (unprovoked) and secondary VTE.

Prandoni P et al. Haematologica 2007;92:199-205


dabigatran: vs warfarin or placebo 1

rivaroxaban: vs placebo 2

apixaban: vs placebo 3

1 RE-MEDY, RE-SONATE []2 EINSTEIN-Extension3 AMPLIFY-EXT

Dabigatran:

Cumulative Risk of Recurrent Venous Thromboembolism or Related Death (or Unexplained Death in the Placebo-Control Study).

Schulman S et al. N Engl J Med 2013;368:709-718.

vs warfarin

vs placebo

Dabigatran:

Cumulative Risk of Any Bleeding.

Schulman S et al. N Engl J Med 2013;368:709-718.

vs warfarin

vs placebo

EINSTEIN-Extension: Primary Efficacy Outcome Analysis

Rivaroxaban (n=602)

n (%)

Placebo(n=594)

n (%)Hazard ratio

(95% CI) p-valueSymptomatic recurrent VTE 8 (1.3) 42 (7.1)* 0.18

(0.09–0.39)

<0.001†

Recurrent DVT 5 31 ----- -----Non-fatal PE 2 13 ----- -----Fatal PE 0 1 ----- -----PE cannot be ruled out 1 0 ----- -----

*Some patients experienced more than 1 event†p<0.001 for superiority

Bauersachs R, et al. N Engl J Med. 2010;363(26):2499-2510.

CI=confidence interval; DVT=deep vein thrombosis; ITT=intent-to-treat; PE=pulmonary embolism; VTE=venous thromboembolism

ITT population


dabigatran: 95% reduction vs placebo 1

rivaroxaban: 82% reduction vs placebo 2

apixaban: 67% reduction vs placebo 3


Evaluation of Oral Anticoagulants for the Extended Treatment of Venous Thromboembolism Using a Mixed-Treatment Comparison, Meta-Analytic Approach

Rollins et al: Clinical Therapeutics, 2014

.

“In the present meta-analysis, efficacy end points in the extended treatment of VTE with apixaban, dabigatran, rivaroxaban, warfarin (conventional and low dose)…were not significantly different.”

Rollins et al Clin Therapeutics 2014

Evaluation of Oral Anticoagulants for the Extended Treatment of Venous Thromboembolism Using a Mixed-Treatment Comparison, Meta-Analytic Approach

The assessment of non-major or clinically relevant bleeding did not identify any meaningful differences between these agents

.Comparative efficacy and safety of anticoagulants and aspirin for extended treatment of venous thromboembolism: A network meta-analysis

Thrombosis Research 2015

Extended treatment of VTE – NOACS, warfarin and aspirin

.Comparative efficacy and safety of anticoagulants and aspirin for extended treatment of venous thromboembolism: A network meta-analysis

Thrombosis Research 2015

Extended treatment of VTE – NOACS, warfarin and aspirin

ASA

Treatment of Venous Thromboembolism – long-term

JAMA. 2014;311(7):717-728

NOACs in prophylaxis of VTE for knee/hip surgery

dabigatran: vs warfarin or placebo 1

rivaroxaban: vs placebo 2

apixaban: vs placebo 3


Comparative Effectiveness of New Oral Anticoagulants and Standard Thromboprophylaxis in Patients Having Total Hip or Knee Replacement: A Systematic Review

Ann Intern Med. 2013;159(4):275-284. doi:10.7326/0003-4819-159-4- 201308200-00008

Summary

VTE diagnosis relies on clinical suspicion, exam, assessment of risk (D-dimer, Geneva or Wells score), imaging

VTE treatment depends on risk, including concurrent conditions, thrombus burden, and hemodynamics

NOACs can safely treat VTE with reduced bleeding, and will likely, IMHO, replace heparin/warfarin

Hanging chads (with apologies to Kathleen Harris)

Role of NOACs in massive PE ?

Extended treatment (> 6 months) for some/all ?

Documents

VTE-Pulmonary Embolism Contemporary Management Schaefer.pdf · VTE-Pulmonary Embolism Contemporary Management ... Hemoptysis 1 Pain on deep vein ... An algorithm for management