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DVT-WRAP SlideCAST. Optimizing Management of Pulmonary Embolism: From Threat to Therapy. Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School. Learning Objectives. Epidemiology Diagnosis Risk Stratification

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optimizing management of pulmonary embolism from threat to therapy

DVT-WRAP SlideCAST

Optimizing Management of PulmonaryEmbolism: From Threat to Therapy

Samuel Z. Goldhaber, MD

Cardiovascular Division

Brigham and Women’s Hospital

Professor of Medicine

Harvard Medical School

learning objectives
Learning Objectives
  • Epidemiology
  • Diagnosis
  • Risk Stratification
  • Treatment: anticoagulation

thrombolysis

embolectomy

  • Prevention
incidence
Incidence
  • 900,000 PEs/ DVTs in USA in 2002.
  • Estimated 296,000 PE deaths:

7% treated, 34% sudden and fatal, and 59% undetected.

Heit J. ASH Abstract 2005

-----------------------------------------

762,000 PEs/ DVTs in EU in 2004.

Thromb Haemostas 2007; 98: 756

slide6

The high death rate from PE (exceeding acute MI!) and the high frequency of undiagnosed PE causing “sudden cardiac death” emphasize the need for improved preventive efforts.

Failure to institute prophylaxis is a much bigger problem with Medical Service patients than Surgical Service patients.

annual at risk for vte u s hospitals
Annual At-Risk for VTE:U.S. Hospitals
  • 7.7 million Medical Service inpatients
  • 3.4 million Surgical Service inpatients
  • Based upon ACCP guidelines for VTE prophylaxis

Anderson FA Jr, et al. Am J Hematol; 2007; 82: 777-782

outpatient and inpatient vte are linked
Outpatient and Inpatient VTE are Linked
  • 74% of VTEs present in outpatients.
  • 42% of outpatient VTE patients have had recent surgery or hospitalization.
  • Only 40% had received VTE prophylaxis.

Spencer FA, et al. Arch Intern Med 2007; 167: 1471-1475

icoper cumulative mortality

25

20

15

10

5

0

ICOPER Cumulative Mortality

17.5%

Mortality (%)

7

14

30

60

90

Days From Diagnosis

Lancet 1999; 353: 1386-1389

slide11

Progression of

Chronic Venous Insufficiency

From UpToDate 2006

cardiovascular risk factors and vte n 63 552 meta analysis
Cardiovascular Risk Factors and VTE (N=63,552 meta-analysis)

RFRR

Obesity 2.3

Hypertension 1.5

Diabetes 1.4

Cigarettes 1.2

High Cholesterol 1.2

Ageno W. Circulation 2008; 117: 93-102

eat veggies and lower vte risk careful with red meat
Eat Veggies and Lower VTE Risk; Careful with Red Meat

Steffen LM. Circulation2007;115:188-195

dabish 20 year cohort vte subsequent cv events
Dabish 20-Year Cohort: VTE, Subsequent CV Events
  • Assessed risk of MI, Stroke
  • 25,199 with DVT
  • 16,925 with PE
  • 163,566 population controls

Sorensen HT. Lancet 2007; 370: 1773-1779

rr cv event in pe patients
RR CV Event in PE Patients

Sorensen HT. Lancet 2007; 370: 1773-1779

reversible risk factors
Reversible Risk Factors
  • Nutrition: eat fruits, veggies, fish; less red meat
  • Quit cigarettes
  • Lose weight/ exercise
  • Prevent DM/ metabolic syndrome
  • Control hypertension
  • Lower cholesterol
pe sxs signs pioped ii
PE SXS/ Signs (PIOPED II)
  • Dyspnea (79%)
  • Tachypnea (57%)
  • Pleuritic pain (47%)
  • Leg edema, erythema, tenderness, palpable cord (47%)
  • Cough/ hemoptysis (43%)

Stein PD. Am J Med 2007; 120: 871-879

clinical decision rule
Clinical Decision Rule

JAMA 2006; 295: 172-179

ct leg venography u s necessary or overkill
CT Leg Venography & U/S:Necessary or “Overkill”?
  • Incremental value of CTV (N=829):

0.7% in low-risk patients and 2.6% in high risk patients (prior VTE, cancer). CTV more than doubles radiation dose

(Hunsaker. AJR 2008; 190: 322-328)

  • Chest CT alone (N=1,819) was noninferior to chest CT plus leg U/S. (Lancet 2008; 371: 1343-1352)
slide25

Risk Stratification: PE

is essential to decide:

Anticoagulation aloneversus anticoagulation plusthrombolysis/ embolectomy

Triage to Intensive Care Unit

Consider RFs for fatal PE: massive PE, immobilization, age > 75 years, cancer.

Circulation 2008; 117: 1711-1716

troponin meta analysis indicates rv micro infarct even leaks are important
TROPONIN META-ANALYSIS: Indicates RV Micro Infarct (Even “Leaks” Are Important)
  • 1,985 patients from 20 PE studies
  • 20% of 618 with elevated levels died
  • 3.7% of 1,367 with WNL levels died
  • In hemodynamically stable PE patients, elevated troponin levels increased mortality 6-fold.

Circulation 2007; 116: 427-433

risk stratify pe assess rv size function
Risk Stratify PE:Assess RV Size, Function
  • ECHO: RV/LV EDD > 0.9 predicts increased hospital mortality (OR=2.6)

(Fremont B. CHEST 2008;133: 358) and recurrent (often fatal) PE

(Arch Intern Med 2006; 166: 2151)

  • Chest CT: an alternative to ECHO to compare RV/LV size
rv enlargement chest ct
RV ENLARGEMENT: CHEST CT

Circulation 2004; 110: 3276

vte immediate anticoagulation
VTE: Immediate Anticoagulation
  • Unfractionated heparin: target PTT between 60 to 80 seconds
  • Low molecular weight heparins: enoxaparin, dalteparin, tinzaparin
  • Fondaparinux
  • Direct thrombin inhibitors (HIT): argatroban, lepirudin, bivalirudin
cancer and vte
Cancer and VTE
  • 3-fold higher recurrence and bleeding, when treating cancer patients (Prandoni. Blood 2002; 100: 3484)
  • LMWH Monotherapy halves recurrence, compared with warfarin.

(Lee AYY. NEJM 2003; 349:146)

(FDA approved May 2007)

aggressive vte therapy
Aggressive VTE Therapy
  • Surgical embolectomy

(Stein PD. Am J Cardiol 2007; 99: 421)

  • Catheter embolectomy

(Kucher N. CHEST 2007; 132: 657-663)

  • PE Thrombolysis

(Wan S. Circulation 2004; 110: 744)

  • Catheter-based DVT therapies

(Chang R. Radiology 2008; 246: 619)

(VascIntervRadiol 2008; 19: 372-376)

slide33

47 EMERGENCY EMBOLECTOMIES

Survival = 94 %

N=47

J Thorac Cardiovasc Surg 2005;129:1018

slide35

PE Thrombectomy Device

Dimension: 11 French

SuctionPorts

Spiral Coil

slide41

Thrombolysis in submassive PE remains controversial.

A multinational European clinical trial (85 centers/ 12 countries) will enroll about 1,100 submassive PE patients with normal BP, elevated Troponin, and RV enlargement on ECHO. Reduce death/ CV collapse from 12.9% to 7.6% in 1 week?

(1st patient enrolled 11/10/2007; 65th on 8/25/2008)

8 year f u ivc filters rct
8 YEAR F/U IVC FILTERS: RCT

PREPIC. Circulation 2005; 112: 416-422

risks for recurrence
Risks for Recurrence
  • “Unprovoked”
  • Strong FH; PMH of VTE
  • Antiphospholipid antibody syndrome
  • Cancer
  • Male (Kyrle PA. NEJM 2004; 350: 2558) (McRae S. Lancet 2006; 368: 371-8)
  • Presentation with PE Symptoms

Eichinger. Arch Intern Med 2004;164: 92)

trials of unprovoked vte favor indefinite duration anticoagulation nejm 2003
Trials of Unprovoked VTE : Favor Indefinite Duration Anticoagulation (NEJM 2003)

TRIAL TAKE-HOME POINT .

PREVENT Low intensity A/C (INR 1.5-2.0) reduces recurrence rate by 2/3.

ELATE Standard A/C (INR 2.0-3.0) is more effective but as safe as low intensity A/C.

THRIVE-3Ximelagatran effective, safe.

does thrombophilia predict recurrent vte
Does Thrombophilia Predict Recurrent VTE?
  • 474 VTE patients followed for an average of 7 years.
  • Most patients were anticoagulated for < 12 months.
  • 90 (20%) suffered recurrence.
  • Thrombophilia did not increase likelihood of recurrence.

Christiansen SC. JAMA 2005; 293: 2352

warfarin pharmacogenomics
WarfarinPharmacogenomics
  • Cytochrome P450 2C9 genotyping can identify mutations associated with impaired warfarin metabolism.
  • Vitamin K receptor polymorphism testing can identify whether patients require low, intermediate, or high doses of warfarin.

Schwartz UI. NEJM 2008; 358: 999

slide51

Genotype vs Standard Warfarin Dosing (n=206) Couma-Gen Trial

  • Rapid turnaround CYP2C9 and VKORC1 testing vs. “empiric”
  • Primary endpoint: TTR
  • Smaller and fewer dosing changes with genetic testing
  • No difference in TTR

Circulation 2007; 116: 2563-2570

self monitoring inr meta analysis of 14 rcts
Self-Monitoring INR: Meta-Analysis of 14 RCTS
  • Reduced TE events (55% fewer)
  • Reduced all-cause mortality (39% less)
  • Reduced major bleeds (35% fewer)

Benefits increase further with self-dosing

  • 73% fewer TE events
  • 63% lower all-cause mortality

HeneghanC. Lancet 2006; 367: 404-411

march 19 2008 medicare expanded reimbursement for home inr monitoring
March 19, 2008: Medicare Expanded Reimbursement for Home INR Monitoring
  • Medicare used to cover only mechanical heart valves
  • Now will reimburse VTE (after 3 months of warfarin) and chronic atrial fibrillation
  • Aetna follows new Medicare guidelines (and surely others will, too)
novel oral anticoagulants
Novel Oral Anticoagulants
  • Dabigatran: an oral DTI—twice daily fixed dose (renal clearance)
  • Rivaroxaban: direct factor Xa inhibitor (renal clearance)—once daily fixed dose
  • Apixaban: direct factor Xa inhibitor (hepatic clearance)—twice daily fixed dose

Gross PL, Weitz JI; ATVB 2008; 28: 380)

vte prophylaxis in 19 958 medical patients 9 studies meta analysis
VTE Prophylaxis in 19,958 Medical Patients/9 Studies (Meta-Analysis)
  • 62% reduction in fatal PE
  • 57% reduction in fatal or nonfatal PE
  • 53% reduction in DVT

Dentali F, et al. Ann Intern Med 2007; 146: 278-288

exclaim extended duration enoxaparin prophylaxis in high risk medical patients
EXCLAIM: Extended-Duration Enoxaparin Prophylaxis in High-Risk Medical Patients

HullRD et al. July 2007; ISTH; Geneva

the amin report prophylaxis rates in the us
The Amin Report: Prophylaxis Rates in the US
  • Studied 196,104 Medical Service discharges from 227 hospitals (Premier® database).
  • VTE prophylaxis rate was 62%.
  • ACCP-deemed appropriate prophylaxis rate was 34%.

J ThrombHaemostas 2007; 5: 1610-6

medical patient prophylaxis in canada
Medical Patient Prophylaxis in Canada
  • Studied 1,894 Medical Service discharges from 29 hospitals.
  • VTE prophylaxis was indicated in 90% of patients.
  • ACCP-deemed appropriate prophylaxis rate was 16%.

Thrombosis Research 2007; 119: 145-155

endorse worldwide lancet 2008 371 387 394
ENDORSE : WORLDWIDE (Lancet 2008; 371: 387-394)

68,183 patients; 32 countries; 358 sites

First patient enrolled August 2, 2006;Last patient enrolled January 4, 2007

worldwide prophylaxis status for 68 183 patients

40% receive ACCPRec. Px

Worldwide Prophylaxis Status for 68,183 Patients

52% at Risk for VTE

(50% receive ACCPrecommended prophy)

Surgical

Medical

64% at Risk for VTE

42% at Risk for VTE

59% receive ACCPRec. Px

slide62

We have initiated trials to modify MD behavior and improve implementation of VTE prophylaxis—not trials of specific types of prophylaxis—electronic alerts and human alerts.

definition of high risk
Definition of “High Risk”

VTE risk score ≥ 4 points:

  • Cancer 3 (ICD codes)
  • Prior VTE 3 (ICD codes)
  • Hypercoagulability 3 (Leiden, ACLA)
  • Major surgery 2 (> 60 minutes)
  • Bed rest 1 (“bed rest” order)
  • Advanced age 1 (> 70 years)
  • Obesity 1 (BMI > 29 kg/m2)
  • HRT/OC 1 (order entry)
randomization

VTE risk score > 4

No prophylaxis

N = 2,506

Randomization

CONTROL

No computer alert

N = 1,251

INTERVENTION:

Single alert

N = 1,255

Kucher N, et al. NEJM 2005;352:969-977

90 day primary endpoint
90-Day Primary Endpoint

Intervent.ControlHazard Ratiop

N=1255 N=1251 (95% CI)

Total VTE 61 (4.9) 103 (8.2) 0.59 (0.43-0.81) 0.001

Acute PE 14 (1.1) 35 (2.8) 0.40 (0.21-0.74) 0.004

Proximal DVT 10 (0.8) 23 (1.8) 0.47 (0.20-1.09) 0.08

Distal DVT 5 (0.4) 12 (1.0) 0.42 (0.15-1.18) 0.10

UE DVT 32 (2.5) 33 (2.6) 0.97 (0.60-1.58) 0.90

Kucher N, et al. NEJM 2005;352:969-977

primary end point

100

98

Intervention

96

%Freedom from DVT/PE

94

Control

92

90

0

30

60

90

Time (days)

Primary End Point

Number at risk

Intervention

1255

977

900

853

Control

1251

976

893

839

Kucher N, et al. NEJM 2005;352:969-977

take home points
“Take Home” Points
  • VTE causes CVI, pulmonary hypertension, disability, and death.
  • Diagnose PE: CDR, D-dimer, CT.
  • Risk stratify PE patients: clinical evaluation, biomarkers, RV size/ function (ECHO/ CT)—”window into future,” even if patient appears stable.
  • Thrombolysis remains controversial.
  • Consider indefinite duration anticoagulation for idiopathic VTE
  • Prophylaxis against PE/ DVT is crucial.
which risk factor is most predictive of recurrent vte after stopping anticoagulation
Which Risk Factor is Most Predictive of Recurrent VTE (After Stopping Anticoagulation)?
  • Factor V Leiden
  • Prothrombin gene mutation
  • Postoperative state
  • Unprovoked, idiopathic VTE—etiology unknown
  • Birth control or pregnancy associated
which parameter is most predictive of a benign clinical course after diagnosis of pe
Which Parameter is Most Predictive of a Benign Clinical Course After Diagnosis of PE?
  • Systolic BP between 110-130 mm Hg
  • HR between 60-80 bpm
  • RR between 12-16/minute
  • Normal right ventricular size and function on ECHO or CT
  • Absence of dyspnea or chest pain