Optimizing Management of Pulmonary Embolism: From Threat to Therapy

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Optimizing Management of PulmonaryEmbolism From
Threat to Therapy
DVT-WRAP SlideCAST

• Samuel Z. Goldhaber, MD
• Cardiovascular Division
• Brigham and Womens Hospital
• Professor of Medicine
• Harvard Medical School

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Learning Objectives

• Epidemiology
• Diagnosis
• Risk Stratification
• Treatment anticoagulation
• thrombolysis
• embolectomy
• Prevention

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Epidemiology
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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

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• 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.

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Annual At-Risk for VTEU.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
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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
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ICOPER Cumulative Mortality
17.5
Mortality ()
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14
30
60
90
Days From Diagnosis
Lancet 1999 353 1386-1389
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Progression of Chronic Venous Insufficiency
From UpToDate 2006
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Cardiovascular Risk Factors and VTE (N63,552
meta-analysis)

• RF RR
• Obesity 2.3
• Hypertension 1.5
• Diabetes 1.4
• Cigarettes 1.2
• High Cholesterol 1.2

Ageno W. Circulation 2008 117 93-102
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Eat Veggies and Lower VTE Risk Careful with Red
Meat
Steffen LM. Circulation 2007115188-195
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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
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RR CV Event in PE Patients
Sorensen HT. Lancet 2007 370 1773-1779
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Reversible Risk Factors

• Nutrition eat fruits, veggies, fish less red
  meat
• Quit cigarettes
• Lose weight/ exercise
• Prevent DM/ metabolic syndrome
• Control hypertension
• Lower cholesterol

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DIAGNOSIS
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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
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Clinical Decision Rule
JAMA 2006 295 172-179
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CT Leg Venography U/SNecessary or Overkill?

• Incremental value of CTV (N829)
• 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 (N1,819) was noninferior to chest
  CT plus leg U/S. (Lancet 2008 371 1343-1352)

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• Saddle Embolus

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PE Diagnosis
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Risk Stratification
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• Risk Stratification PE
• is essential to decide
• Anticoagulation alone versus anticoagulation plus
  thrombolysis/ embolectomy
• Triage to Intensive Care Unit
• Consider RFs for fatal PE massive PE,
  immobilization, age gt 75 years, cancer.

Circulation 2008 117 1711-1716
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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
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Risk Stratify PEAssess RV Size, Function

• ECHO RV/LV EDD gt 0.9 predicts increased
  hospital mortality (OR2.6)
• (Fremont B. CHEST 2008133 358) and recurrent
  (often fatal) PE
• (Arch Intern Med 2006 166 2151)
• Chest CT an alternative to ECHO to compare RV/LV
  size

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RV ENLARGEMENT CHEST CT

• Circulation 2004 110 3276

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Treatment
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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

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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 349146)
• (FDA approved May 2007)

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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)
• (Vasc Interv Radiol 2008 19 372-376)

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47 EMERGENCY EMBOLECTOMIES
Survival 94
N47
J Thorac Cardiovasc Surg 20051291018
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Surgical Embolectomy at BWHSurgeons Cell Phone
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PE Thrombectomy Device
Dimension 11 French
Spiral Coil
Suction Ports
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Heparin Catches Up with Lysis Lung Perfusion
Arch Intern Med 1997 157 2550
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• 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)

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LYSIS VS. Filter Massive PE(N108)
Lysis
Filter
Lysis
Filter
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8 YEAR F/U IVC FILTERS RCT
PREPIC. Circulation 2005 112 416-422
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BARDRECOVERY FILTER
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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 2004164 92)
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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-3 Ximelagatran effective, safe.

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Does Thrombophilia Predict Recurrent VTE?

• 474 VTE patients followed for an average of 7
  years.
• Most patients were anticoagulated for lt 12
  months.
• 90 (20) suffered recurrence.
• Thrombophilia did not increase likelihood of
  recurrence.

Christiansen SC. JAMA 2005 293 2352
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How Often and For How Long Does CT Remain
Abnormal After PE?
Nijkeuter M. CHEST 2006 129 192-197
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Warfarin Pharmacogenomics

• 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
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Genotype vs Standard Warfarin Dosing (n206)
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
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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
• Heneghan C. Lancet 2006 367 404-411

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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)

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Novel Oral Anticoagulants

• Dabigatran an oral DTItwice 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)
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Prevention
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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
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EXCLAIM Extended-Duration Enoxaparin Prophylaxis
in High-Risk Medical Patients
Hull RD et al. July 2007 ISTH Geneva
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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 Thromb Haemostas 2007 5 1610-6
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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
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ENDORSE WORLDWIDE (Lancet 2008 371 387-394)
68,183 patients 32 countries 358 sites First
patient enrolled August 2, 2006Last patient
enrolled January 4, 2007
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Worldwide Prophylaxis Status for 68,183 Patients
52 at Risk for VTE (50 receive
ACCPrecommended prophy)
Medical
Surgical
42 at Risk for VTE
64 at Risk for VTE
59 receive ACCPRec. Px
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• We have initiated trials to modify MD behavior
  and improve implementation of VTE prophylaxisnot
  trials of specific types of prophylaxiselectronic
  alerts and human alerts.

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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 (gt 60 minutes)
• Bed rest 1 (bed rest order)
• Advanced age 1 (gt 70 years)
• Obesity 1 (BMI gt 29 kg/m2)
• HRT/OC 1 (order entry)

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Randomization
VTE risk score gt 4 No prophylaxis N 2,506
CONTROL No computer alert N 1,251
INTERVENTION Single alert N 1,255
Kucher N, et al. NEJM 2005352969-977
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90-Day Primary Endpoint

• Intervent. Control Hazard
  Ratio p
• N1255 N1251
  (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 2005352969-977
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Primary End Point
Number at risk
Intervention
1255
977
900
853
Control
1251
976
893
839
Kucher N, et al. NEJM 2005352969-977
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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.

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Which Risk Factor is Most Predictive of Recurrent
VTE (After Stopping Anticoagulation)?

• Factor V Leiden
• Prothrombin gene mutation
• Postoperative state
• Unprovoked, idiopathic VTEetiology unknown
• Birth control or pregnancy associated

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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