Optimizing Management of PulmonaryOptimizing Management of PulmonaryEmbolism: From Threat to TherapyEmbolism: From Threat to Therapy

Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDCardiovascular DivisionCardiovascular Division

Brigham and Women’s HospitalBrigham and Women’s HospitalProfessor of MedicineProfessor of Medicine

Harvard Medical SchoolHarvard Medical School

Samuel Z. Goldhaber, MDSamuel Z. Goldhaber, MDCardiovascular DivisionCardiovascular Division

Brigham and Women’s HospitalBrigham and Women’s HospitalProfessor of MedicineProfessor of Medicine

Harvard Medical SchoolHarvard Medical School

DVT-WRAP SlideCASTDVT-WRAP SlideCAST

Learning ObjectivesLearning Objectives

► EpidemiologyEpidemiology► DiagnosisDiagnosis► Risk StratificationRisk Stratification► Treatment: Treatment: anticoagulationanticoagulation

thrombolysisthrombolysis

embolectomyembolectomy► PreventionPrevention

► EpidemiologyEpidemiology► DiagnosisDiagnosis► Risk StratificationRisk Stratification► Treatment: Treatment: anticoagulationanticoagulation

thrombolysisthrombolysis

embolectomyembolectomy► PreventionPrevention

EpidemiologyEpidemiology

IncidenceIncidence

• 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

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

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

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

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

Annual At-Risk for VTE:Annual At-Risk for VTE:U.S. HospitalsU.S. Hospitals

► 7.7 million Medical Service inpatients7.7 million Medical Service inpatients

► 3.4 million Surgical Service inpatients 3.4 million Surgical Service inpatients

► Based upon ACCP guidelines for VTE prophylaxisBased upon ACCP guidelines for VTE prophylaxis

► 7.7 million Medical Service inpatients7.7 million Medical Service inpatients

► 3.4 million Surgical Service inpatients 3.4 million Surgical Service inpatients

► Based upon ACCP guidelines for VTE prophylaxisBased upon ACCP guidelines for VTE prophylaxis

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

Outpatient and Inpatient VTE are LinkedOutpatient and Inpatient VTE are Linked

► 74% of VTEs present in outpatients.74% of VTEs present in outpatients.

► 42% of outpatient VTE patients have had recent 42% of outpatient VTE patients have had recent surgery or hospitalization. surgery or hospitalization.

► Only 40% had received VTE prophylaxis.Only 40% had received VTE prophylaxis.

► 74% of VTEs present in outpatients.74% of VTEs present in outpatients.

► 42% of outpatient VTE patients have had recent 42% of outpatient VTE patients have had recent surgery or hospitalization. surgery or hospitalization.

► Only 40% had received VTE prophylaxis.Only 40% had received VTE prophylaxis.

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

ICOPER Cumulative MortalityICOPER Cumulative MortalityM

ort

alit

y (

%)

Mort

alit

y (

%)

Days From DiagnosisDays From Diagnosis

17.5%17.5%

0

5

10

15

20

25

7 14 30 60 90

Lancet 1999; 353: 1386-1389

Progression of Chronic Venous Insufficiency

From UpToDate 2006

Cardiovascular Risk Factors and VTE Cardiovascular Risk Factors and VTE (N=63,552 meta-analysis)(N=63,552 meta-analysis)

RFRF RRRRObesityObesity 2.32.3

HypertensionHypertension 1.51.5

DiabetesDiabetes 1.41.4

CigarettesCigarettes 1.21.2

High CholesterolHigh Cholesterol 1.21.2

RFRF RRRRObesityObesity 2.32.3

HypertensionHypertension 1.51.5

DiabetesDiabetes 1.41.4

CigarettesCigarettes 1.21.2

High CholesterolHigh Cholesterol 1.21.2

Ageno W. Circulation 2008; 117: 93-102Ageno W. Circulation 2008; 117: 93-102

Steffen LM. CirculationSteffen LM. Circulation 2007;115:188-1952007;115:188-195

Eat Veggies and Lower VTE Risk; Eat Veggies and Lower VTE Risk; Careful with Red MeatCareful with Red Meat

Adjusted Hazard Ratios (Quintiles)2 3 4 5 p

Fruits, veggie

0.73 0.57 0.47 0.59 0.03

Fish 0.58 0.60 0.55 0.70 0.30

Red Meat

1.24 1.21 1.09 2.01 0.02

Dabish 20-Year Cohort: Dabish 20-Year Cohort: VTE, Subsequent CV EventsVTE, Subsequent CV Events

► Assessed risk of MI, StrokeAssessed risk of MI, Stroke

► 25,199 with DVT25,199 with DVT

► 16,925 with PE 16,925 with PE

► 163,566 population controls163,566 population controls

► Assessed risk of MI, StrokeAssessed risk of MI, Stroke

► 25,199 with DVT25,199 with DVT

► 16,925 with PE 16,925 with PE

► 163,566 population controls163,566 population controls

Sorensen HT. Lancet 2007; 370: 1773-1779Sorensen HT. Lancet 2007; 370: 1773-1779

RR CV Event in PE PatientsRR CV Event in PE Patients

CV EventCV Event 1 Year RR1 Year RR 2-20 Year RR2-20 Year RR

Acute MIAcute MI 2.62.6 1.31.3

StrokeStroke 2.92.9 1.31.3

Sorensen HT. Lancet 2007; 370: 1773-1779

Reversible Risk FactorsReversible Risk Factors

1.1. Nutrition: eat fruits, veggies, fish; less red meatNutrition: eat fruits, veggies, fish; less red meat

2.2. Quit cigarettesQuit cigarettes

3.3. Lose weight/ exerciseLose weight/ exercise

4.4. Prevent DM/ metabolic syndromePrevent DM/ metabolic syndrome

5.5. Control hypertension Control hypertension

6.6. Lower cholesterolLower cholesterol

1.1. Nutrition: eat fruits, veggies, fish; less red meatNutrition: eat fruits, veggies, fish; less red meat

2.2. Quit cigarettesQuit cigarettes

3.3. Lose weight/ exerciseLose weight/ exercise

4.4. Prevent DM/ metabolic syndromePrevent DM/ metabolic syndrome

5.5. Control hypertension Control hypertension

6.6. Lower cholesterolLower cholesterol

DIAGNOSISDIAGNOSIS

PE SXS/ Signs (PIOPED II)PE SXS/ Signs (PIOPED II)

► Dyspnea (79%)Dyspnea (79%)

► Tachypnea (57%)Tachypnea (57%)

► Pleuritic pain (47%)Pleuritic pain (47%)

► Leg edema, erythema, tenderness, palpable Leg edema, erythema, tenderness, palpable cord (47%)cord (47%)

► Cough/ hemoptysis (43%)Cough/ hemoptysis (43%)

► Dyspnea (79%)Dyspnea (79%)

► Tachypnea (57%)Tachypnea (57%)

► Pleuritic pain (47%)Pleuritic pain (47%)

► Leg edema, erythema, tenderness, palpable Leg edema, erythema, tenderness, palpable cord (47%)cord (47%)

► Cough/ hemoptysis (43%)Cough/ hemoptysis (43%)

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

Clinical Decision RuleClinical Decision Rule

JAMA 2006; 295: 172-179JAMA 2006; 295: 172-179

CT Leg Venography & U/S:CT Leg Venography & U/S:Necessary or “Overkill”?Necessary or “Overkill”?

► Incremental value of CTV (N=829): Incremental value of CTV (N=829):

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

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

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

► Incremental value of CTV (N=829): Incremental value of CTV (N=829):

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

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

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

Saddle EmbolusSaddle Embolus

PE DiagnosisPE Diagnosis

Suspect PE: CXR, ECG, Oximetry

CDR < 4 CDR > 4

Chest CTD-dimer

Pos: Rx for PEHigh: get CT

Neg: stop W/UNormal: stop W/U

Risk StratificationRisk Stratification

Risk StratificationRisk Stratification: PE: PEis is essentialessential to decide: to decide:

1.1. Anticoagulation Anticoagulation alonealone versusversus anticoagulation anticoagulation plusplus thrombolysis/ thrombolysis/ embolectomyembolectomy

2.2. Triage to Intensive Care UnitTriage to Intensive Care Unit

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

Risk StratificationRisk Stratification: PE: PEis is essentialessential to decide: to decide:

1.1. Anticoagulation Anticoagulation alonealone versusversus anticoagulation anticoagulation plusplus thrombolysis/ thrombolysis/ embolectomyembolectomy

2.2. Triage to Intensive Care UnitTriage to Intensive Care Unit

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

Circulation 2008; 117: 1711-1716

TROPONIN META-ANALYSIS: Indicates RV TROPONIN META-ANALYSIS: Indicates RV Micro Infarct (Even “Leaks” Are Important)Micro Infarct (Even “Leaks” Are Important)

► 1,985 patients from 20 PE studies 1,985 patients from 20 PE studies

► 20%20% of 618 with of 618 with elevated levels diedelevated levels died

► 3.7%3.7% of 1,367 with of 1,367 with WNL levels diedWNL levels died

► In hemodynamically stable PE patients, In hemodynamically stable PE patients, elevated troponin levels elevated troponin levels increased mortality increased mortality 6-fold.6-fold.

► 1,985 patients from 20 PE studies 1,985 patients from 20 PE studies

► 20%20% of 618 with of 618 with elevated levels diedelevated levels died

► 3.7%3.7% of 1,367 with of 1,367 with WNL levels diedWNL levels died

► In hemodynamically stable PE patients, In hemodynamically stable PE patients, elevated troponin levels elevated troponin levels increased mortality increased mortality 6-fold.6-fold.

Circulation 2007; 116: 427-433Circulation 2007; 116: 427-433

Risk Stratify PE:Risk Stratify PE:Assess RV Size, FunctionAssess RV Size, Function

► ECHO:ECHO: RV/LV EDD RV/LV EDD >> 0.9 predicts 0.9 predicts increased hospital mortality (OR=2.6) increased hospital mortality (OR=2.6)

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

(Arch Intern Med 2006; 166: 2151)(Arch Intern Med 2006; 166: 2151)► Chest CT:Chest CT: an alternative to ECHO to an alternative to ECHO to

compare RV/LV sizecompare RV/LV size

► ECHO:ECHO: RV/LV EDD RV/LV EDD >> 0.9 predicts 0.9 predicts increased hospital mortality (OR=2.6) increased hospital mortality (OR=2.6)

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

(Arch Intern Med 2006; 166: 2151)(Arch Intern Med 2006; 166: 2151)► Chest CT:Chest CT: an alternative to ECHO to an alternative to ECHO to

compare RV/LV sizecompare RV/LV size

RV ENLARGEMENT: RV ENLARGEMENT: CHEST CTCHEST CT

Circulation 2004; 110: 3276Circulation 2004; 110: 3276Circulation 2004; 110: 3276Circulation 2004; 110: 3276

TreatmentTreatment

VTE: Immediate AnticoagulationVTE: Immediate Anticoagulation

1.1. Unfractionated heparin: target PTT between Unfractionated heparin: target PTT between 60 to 80 seconds60 to 80 seconds

2.2. Low molecular weight heparins: enoxaparin, Low molecular weight heparins: enoxaparin, dalteparin, tinzaparindalteparin, tinzaparin

3.3. FondaparinuxFondaparinux

4.4. Direct thrombin inhibitors (HIT): argatroban, Direct thrombin inhibitors (HIT): argatroban, lepirudin, bivalirudinlepirudin, bivalirudin

1.1. Unfractionated heparin: target PTT between Unfractionated heparin: target PTT between 60 to 80 seconds60 to 80 seconds

2.2. Low molecular weight heparins: enoxaparin, Low molecular weight heparins: enoxaparin, dalteparin, tinzaparindalteparin, tinzaparin

3.3. FondaparinuxFondaparinux

4.4. Direct thrombin inhibitors (HIT): argatroban, Direct thrombin inhibitors (HIT): argatroban, lepirudin, bivalirudinlepirudin, bivalirudin

Cancer and VTECancer and VTE

► 3-fold higher recurrence and bleeding,3-fold higher recurrence and bleeding, when treating cancer patients (Prandoni. when treating cancer patients (Prandoni. Blood 2002; 100: 3484)Blood 2002; 100: 3484)

► LMWH MonotherapyLMWH Monotherapy halves recurrence, halves recurrence, compared with warfarin. compared with warfarin.

(Lee AYY. NEJM 2003; 349:146)(Lee AYY. NEJM 2003; 349:146)

(FDA approved May 2007)(FDA approved May 2007)

► 3-fold higher recurrence and bleeding,3-fold higher recurrence and bleeding, when treating cancer patients (Prandoni. when treating cancer patients (Prandoni. Blood 2002; 100: 3484)Blood 2002; 100: 3484)

► LMWH MonotherapyLMWH Monotherapy halves recurrence, halves recurrence, compared with warfarin. compared with warfarin.

(Lee AYY. NEJM 2003; 349:146)(Lee AYY. NEJM 2003; 349:146)

(FDA approved May 2007)(FDA approved May 2007)

Aggressive VTE TherapyAggressive VTE Therapy

► Surgical embolectomySurgical embolectomy

(Stein PD. Am J Cardiol 2007; 99: 421)(Stein PD. Am J Cardiol 2007; 99: 421)► Catheter embolectomyCatheter embolectomy

(Kucher N. CHEST 2007; 132: 657-663)(Kucher N. CHEST 2007; 132: 657-663)► PE ThrombolysisPE Thrombolysis

(Wan S. Circulation 2004; 110: 744)(Wan S. Circulation 2004; 110: 744)► Catheter-based DVT therapiesCatheter-based DVT therapies

(Chang R. Radiology 2008; 246: 619)(Chang R. Radiology 2008; 246: 619)

(Vasc Interv Radiol 2008; 19: 372-376)(Vasc Interv Radiol 2008; 19: 372-376)

► Surgical embolectomySurgical embolectomy

(Stein PD. Am J Cardiol 2007; 99: 421)(Stein PD. Am J Cardiol 2007; 99: 421)► Catheter embolectomyCatheter embolectomy

(Kucher N. CHEST 2007; 132: 657-663)(Kucher N. CHEST 2007; 132: 657-663)► PE ThrombolysisPE Thrombolysis

(Wan S. Circulation 2004; 110: 744)(Wan S. Circulation 2004; 110: 744)► Catheter-based DVT therapiesCatheter-based DVT therapies

(Chang R. Radiology 2008; 246: 619)(Chang R. Radiology 2008; 246: 619)

(Vasc Interv Radiol 2008; 19: 372-376)(Vasc Interv Radiol 2008; 19: 372-376)

47 EMERGENCY EMBOLECTOMIES

Survival = 94 %

J Thorac Cardiovasc Surg 2005;129:1018

N=47

Surgical Embolectomy at BWH:Surgical Embolectomy at BWH:Surgeon’s Cell PhoneSurgeon’s Cell Phone

PE Thrombectomy DevicePE Thrombectomy Device

Dimension: 11 French

Spiral CoilSuction Ports

Heparin “Catches Up” with Lysis: Heparin “Catches Up” with Lysis: Lung PerfusionLung Perfusion

Arch Intern Med 1997; 157: 2550

ThrombolysisThrombolysis in submassive PE remains in submassive PE remains controversial.controversial.

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

(1(1stst patient enrolled 11/10/2007; 65 patient enrolled 11/10/2007; 65 thth on 8/25/2008) on 8/25/2008)

ThrombolysisThrombolysis in submassive PE remains in submassive PE remains controversial.controversial.

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

(1(1stst patient enrolled 11/10/2007; 65 patient enrolled 11/10/2007; 65 thth on 8/25/2008) on 8/25/2008)

LYSIS VS. Filter: Massive PELYSIS VS. Filter: Massive PE(N=108)(N=108)

Lysis

Lysis

Filter

Filter

8 YEAR F/U IVC FILTERS: RCT8 YEAR F/U IVC FILTERS: RCT

PREPIC. Circulation 2005; 112: 416-422PREPIC. Circulation 2005; 112: 416-422

BARDBARDRECOVERY RECOVERY

FILTERFILTER

RATE OF RECURRENT VTE

(Arch Intern Med 2000; 160: 761-768)

Olmsted County

5%

10%13%

30%

0%

5%

10%

15%

20%

25%

30%

35%

1/12 1/2 1 10

Number of Years

//

Risks for Recurrence Risks for Recurrence

► ““Unprovoked”Unprovoked”

► Strong FH; PMH of VTEStrong FH; PMH of VTE

► Antiphospholipid antibody syndromeAntiphospholipid antibody syndrome

► CancerCancer

► Male (Kyrle PA. NEJM 2004; 350: 2558) (McRae S. Male (Kyrle PA. NEJM 2004; 350: 2558) (McRae S. Lancet 2006; 368: 371-8)Lancet 2006; 368: 371-8)

► Presentation with PE Symptoms Presentation with PE Symptoms

► ““Unprovoked”Unprovoked”

► Strong FH; PMH of VTEStrong FH; PMH of VTE

► Antiphospholipid antibody syndromeAntiphospholipid antibody syndrome

► CancerCancer

► Male (Kyrle PA. NEJM 2004; 350: 2558) (McRae S. Male (Kyrle PA. NEJM 2004; 350: 2558) (McRae S. Lancet 2006; 368: 371-8)Lancet 2006; 368: 371-8)

► Presentation with PE Symptoms Presentation with PE Symptoms

Eichinger. Arch Intern Med 2004;164: 92)

Trials of Unprovoked VTE : Favor Indefinite Trials of Unprovoked VTE : Favor Indefinite Duration Anticoagulation (NEJM 2003)Duration Anticoagulation (NEJM 2003)

TRIALTRIAL TAKE-HOME POINT TAKE-HOME POINT ..

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

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

THRIVE-3THRIVE-3 Ximelagatran effective, safe.Ximelagatran effective, safe.

TRIALTRIAL TAKE-HOME POINT TAKE-HOME POINT ..

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

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

THRIVE-3THRIVE-3 Ximelagatran effective, safe.Ximelagatran effective, safe.

Does Thrombophilia Predict Recurrent VTE?Does Thrombophilia Predict Recurrent VTE?

► 474 VTE patients followed for an average of 7 years.474 VTE patients followed for an average of 7 years.

► Most patients were anticoagulated for Most patients were anticoagulated for << 12 months. 12 months.

► 90 (20%) suffered recurrence.90 (20%) suffered recurrence.

► Thrombophilia did Thrombophilia did notnot increase likelihood of increase likelihood of

recurrencerecurrence..

► 474 VTE patients followed for an average of 7 years.474 VTE patients followed for an average of 7 years.

► Most patients were anticoagulated for Most patients were anticoagulated for << 12 months. 12 months.

► 90 (20%) suffered recurrence.90 (20%) suffered recurrence.

► Thrombophilia did Thrombophilia did notnot increase likelihood of increase likelihood of

recurrencerecurrence..

Christiansen SC. JAMA 2005; 293: 2352Christiansen SC. JAMA 2005; 293: 2352

How Often and For How Long Does How Often and For How Long Does CT Remain Abnormal After PE?CT Remain Abnormal After PE?

F/U ABNORMAL

6 Weeks 68%

3 Months 65%

6 Months 57%

11 Months 52%

Nijkeuter M. CHEST 2006; 129: 192-197Nijkeuter M. CHEST 2006; 129: 192-197

Warfarin PharmacogenomicsWarfarin Pharmacogenomics

1.1. Cytochrome P450 2C9 genotyping can identify Cytochrome P450 2C9 genotyping can identify mutations associated with impaired warfarin mutations associated with impaired warfarin metabolism.metabolism.

2.2. Vitamin K receptor polymorphism testing can Vitamin K receptor polymorphism testing can identify whether patients require low, intermediate, identify whether patients require low, intermediate,

or high doses of warfarinor high doses of warfarin..

1.1. Cytochrome P450 2C9 genotyping can identify Cytochrome P450 2C9 genotyping can identify mutations associated with impaired warfarin mutations associated with impaired warfarin metabolism.metabolism.

2.2. Vitamin K receptor polymorphism testing can Vitamin K receptor polymorphism testing can identify whether patients require low, intermediate, identify whether patients require low, intermediate,

or high doses of warfarinor high doses of warfarin..

Schwartz UI. NEJM 2008; 358: 999Schwartz UI. NEJM 2008; 358: 999

► Rapid turnaround CYP2C9 and VKORC1 testing Rapid turnaround CYP2C9 and VKORC1 testing vs. “empiric”vs. “empiric”

► Primary endpoint: TTR Primary endpoint: TTR

► Smaller and fewer dosing changes with genetic Smaller and fewer dosing changes with genetic testing testing

► No difference in TTRNo difference in TTR

► Rapid turnaround CYP2C9 and VKORC1 testing Rapid turnaround CYP2C9 and VKORC1 testing vs. “empiric”vs. “empiric”

► Primary endpoint: TTR Primary endpoint: TTR

► Smaller and fewer dosing changes with genetic Smaller and fewer dosing changes with genetic testing testing

► No difference in TTRNo difference in TTR

Genotype vs Standard Warfarin Dosing Genotype vs Standard Warfarin Dosing (n=206) (n=206)

Couma-Gen TrialCouma-Gen Trial

Circulation 2007; 116: 2563-2570Circulation 2007; 116: 2563-2570

Self-Monitoring INR: Meta-Analysis of 14 RCTSSelf-Monitoring INR: Meta-Analysis of 14 RCTS

► Reduced TE events (55% fewer)Reduced TE events (55% fewer)► Reduced all-cause mortality (39% less)Reduced all-cause mortality (39% less)► Reduced major bleeds (35% fewer)Reduced major bleeds (35% fewer)

Benefits increase further with self-dosingBenefits increase further with self-dosing► 73% fewer TE events73% fewer TE events► 63% lower all-cause mortality63% lower all-cause mortality

Heneghan C. Lancet 2006; 367: 404-411Heneghan C. Lancet 2006; 367: 404-411

► Reduced TE events (55% fewer)Reduced TE events (55% fewer)► Reduced all-cause mortality (39% less)Reduced all-cause mortality (39% less)► Reduced major bleeds (35% fewer)Reduced major bleeds (35% fewer)

Benefits increase further with self-dosingBenefits increase further with self-dosing► 73% fewer TE events73% fewer TE events► 63% lower all-cause mortality63% lower all-cause mortality

Heneghan C. Lancet 2006; 367: 404-411Heneghan C. Lancet 2006; 367: 404-411

March 19, 2008: Medicare Expanded March 19, 2008: Medicare Expanded Reimbursement for Home INR MonitoringReimbursement for Home INR Monitoring

► Medicare used to cover only mechanical Medicare used to cover only mechanical heart valvesheart valves

► Now will reimburse VTE (after 3 months Now will reimburse VTE (after 3 months of warfarin) and chronic atrial fibrillationof warfarin) and chronic atrial fibrillation

► Aetna follows new Medicare guidelines Aetna follows new Medicare guidelines (and surely others will, too) (and surely others will, too)

► Medicare used to cover only mechanical Medicare used to cover only mechanical heart valvesheart valves

► Now will reimburse VTE (after 3 months Now will reimburse VTE (after 3 months of warfarin) and chronic atrial fibrillationof warfarin) and chronic atrial fibrillation

► Aetna follows new Medicare guidelines Aetna follows new Medicare guidelines (and surely others will, too) (and surely others will, too)

Novel Oral AnticoagulantsNovel Oral Anticoagulants

1.1. Dabigatran:Dabigatran: an oral DTI—twice daily fixed dose an oral DTI—twice daily fixed dose (renal clearance)(renal clearance)

2.2. Rivaroxaban:Rivaroxaban: direct factor Xa inhibitor (renal direct factor Xa inhibitor (renal clearance)—once daily fixed doseclearance)—once daily fixed dose

3.3. Apixaban:Apixaban: direct factor Xa inhibitor (hepatic direct factor Xa inhibitor (hepatic clearance)—twice daily fixed doseclearance)—twice daily fixed dose

1.1. Dabigatran:Dabigatran: an oral DTI—twice daily fixed dose an oral DTI—twice daily fixed dose (renal clearance)(renal clearance)

2.2. Rivaroxaban:Rivaroxaban: direct factor Xa inhibitor (renal direct factor Xa inhibitor (renal clearance)—once daily fixed doseclearance)—once daily fixed dose

3.3. Apixaban:Apixaban: direct factor Xa inhibitor (hepatic direct factor Xa inhibitor (hepatic clearance)—twice daily fixed doseclearance)—twice daily fixed dose

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

PreventionPrevention

VTE Prophylaxis in 19,958 Medical Patients/VTE Prophylaxis in 19,958 Medical Patients/9 Studies (Meta-Analysis)9 Studies (Meta-Analysis)

► 62% reduction in fatal PE62% reduction in fatal PE

► 57% reduction in fatal or nonfatal PE57% reduction in fatal or nonfatal PE

► 53% reduction in DVT53% reduction in DVT

► 62% reduction in fatal PE62% reduction in fatal PE

► 57% reduction in fatal or nonfatal PE57% reduction in fatal or nonfatal PE

► 53% reduction in DVT53% reduction in DVT

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

Hull RD et al. July 2007; ISTH; Geneva

EXCLAIM: Extended-Duration Enoxaparin EXCLAIM: Extended-Duration Enoxaparin Prophylaxis in High-Risk Medical PatientsProphylaxis in High-Risk Medical Patients

End pointsEnd points Outcome, Outcome, extended extended

prophylaxis, prophylaxis, n=2052 (%)n=2052 (%)

Outcome, Outcome, placebo, placebo, n=2062 n=2062

(%)(%)

RR RR reduction reduction

(%)(%)

pp

VTE eventsVTE events 2.82.8 4.94.9 44%44% 0.0010.001

SymptomaticSymptomatic 0.30.3 1.11.1 73%73% 0.0040.004

No SxsNo Sxs 2.52.5 3.73.7 34%34% 0.0320.032

The Amin Report: The Amin Report: Prophylaxis Rates in the USProphylaxis Rates in the US

► Studied 196,104 Medical Service discharges from Studied 196,104 Medical Service discharges from 227 hospitals (Premier227 hospitals (Premier® database)® database)..

► VTE prophylaxis rate was 62%.VTE prophylaxis rate was 62%.

► ACCP-deemed appropriate prophylaxis rate was ACCP-deemed appropriate prophylaxis rate was 34%.34%.

► Studied 196,104 Medical Service discharges from Studied 196,104 Medical Service discharges from 227 hospitals (Premier227 hospitals (Premier® database)® database)..

► VTE prophylaxis rate was 62%.VTE prophylaxis rate was 62%.

► ACCP-deemed appropriate prophylaxis rate was ACCP-deemed appropriate prophylaxis rate was 34%.34%.

J Thromb Haemostas 2007; 5: 1610-6J Thromb Haemostas 2007; 5: 1610-6

Medical Patient Prophylaxis in CanadaMedical Patient Prophylaxis in Canada

► Studied 1,894 Medical Service discharges from 29 Studied 1,894 Medical Service discharges from 29 hospitals.hospitals.

► VTE prophylaxis was indicated in 90% of patients. VTE prophylaxis was indicated in 90% of patients.

► ACCP-deemed appropriate prophylaxis rate was ACCP-deemed appropriate prophylaxis rate was 16%.16%.

► Studied 1,894 Medical Service discharges from 29 Studied 1,894 Medical Service discharges from 29 hospitals.hospitals.

► VTE prophylaxis was indicated in 90% of patients. VTE prophylaxis was indicated in 90% of patients.

► ACCP-deemed appropriate prophylaxis rate was ACCP-deemed appropriate prophylaxis rate was 16%.16%.

Thrombosis Research 2007; 119: 145-155

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

68,183 patients; 32 countries; 358 sites68,183 patients; 32 countries; 358 sitesFirst patient enrolled August 2, 2006;Last patient enrolled January 4, 2007First patient enrolled August 2, 2006;Last patient enrolled January 4, 2007

42% at Risk for VTE

Medical

40% receive ACCPRec. Px

64% at Risk for VTE

59% receive ACCPRec. Px

Surgical

Worldwide Prophylaxis Status Worldwide Prophylaxis Status for 68,183 Patientsfor 68,183 Patients

52% at Risk for VTE

(50% receive ACCPrecommended prophy)

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

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

Definition of “High Risk”Definition of “High Risk”

VTE risk score ≥ 4 points:VTE risk score ≥ 4 points:► CancerCancer 33 (ICD codes)(ICD codes)► Prior VTEPrior VTE 33 (ICD codes)(ICD codes)► HypercoagulabilityHypercoagulability 33 (Leiden, ACLA)(Leiden, ACLA)► Major surgeryMajor surgery 22 (> 60 minutes)(> 60 minutes)► Bed restBed rest 11 (“bed rest” order)(“bed rest” order)► Advanced ageAdvanced age 11 (> 70 years)(> 70 years)► ObesityObesity 11 (BMI > 29 kg/m(BMI > 29 kg/m22))► HRT/OCHRT/OC 11 (order entry)(order entry)

VTE risk score ≥ 4 points:VTE risk score ≥ 4 points:► CancerCancer 33 (ICD codes)(ICD codes)► Prior VTEPrior VTE 33 (ICD codes)(ICD codes)► HypercoagulabilityHypercoagulability 33 (Leiden, ACLA)(Leiden, ACLA)► Major surgeryMajor surgery 22 (> 60 minutes)(> 60 minutes)► Bed restBed rest 11 (“bed rest” order)(“bed rest” order)► Advanced ageAdvanced age 11 (> 70 years)(> 70 years)► ObesityObesity 11 (BMI > 29 kg/m(BMI > 29 kg/m22))► HRT/OCHRT/OC 11 (order entry)(order entry)

RandomizationRandomization

VTE risk score > 4

No prophylaxis

N = 2,506

INTERVENTION:

Single alert

N = 1,255

CONTROL

No computer alert

N = 1,251

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

90-Day Primary Endpoint90-Day Primary Endpoint

Intervent.Intervent. ControlControl Hazard RatioHazard Ratio pp

N=1255 N=1251 (95% CI)N=1255 N=1251 (95% CI)

Total VTE 61 (4.9) 103 (8.2) Total VTE 61 (4.9) 103 (8.2) 0.590.59 (0.43-0.81) (0.43-0.81) 0.0010.001

Acute PE 14 (1.1) 35 (2.8) Acute PE 14 (1.1) 35 (2.8) 0.400.40 (0.21-0.74) (0.21-0.74) 0.0040.004

Proximal DVT 10 (0.8) 23 (1.8) Proximal DVT 10 (0.8) 23 (1.8) 0.470.47 (0.20-1.09) (0.20-1.09) 0.080.08

Distal DVT 5 (0.4) 12 (1.0) 0.42 (0.15-1.18) 0.10Distal 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) 0.90UE DVT 32 (2.5) 33 (2.6) 0.97 (0.60-1.58) 0.90

Intervent.Intervent. ControlControl Hazard RatioHazard Ratio pp

N=1255 N=1251 (95% CI)N=1255 N=1251 (95% CI)

Total VTE 61 (4.9) 103 (8.2) Total VTE 61 (4.9) 103 (8.2) 0.590.59 (0.43-0.81) (0.43-0.81) 0.0010.001

Acute PE 14 (1.1) 35 (2.8) Acute PE 14 (1.1) 35 (2.8) 0.400.40 (0.21-0.74) (0.21-0.74) 0.0040.004

Proximal DVT 10 (0.8) 23 (1.8) Proximal DVT 10 (0.8) 23 (1.8) 0.470.47 (0.20-1.09) (0.20-1.09) 0.080.08

Distal DVT 5 (0.4) 12 (1.0) 0.42 (0.15-1.18) 0.10Distal 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) 0.90UE DVT 32 (2.5) 33 (2.6) 0.97 (0.60-1.58) 0.90

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

Primary End PointPrimary End Point

InterventionInterventionControlControl

NNumberumber at risk at risk12551255 977977 900900 85385312511251 976976 893893 839839

InterventionIntervention

Control Control

Time Time ((daysdays))00 3030 6060 9090%

Freedom

fro

m D

VT/

%Fr

eedom

fro

m D

VT/ PEPE

9090

9292

9494

9696

9898

100100

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

““Take Home” PointsTake Home” Points

1.1. VTE causes CVI, pulmonary hypertension, VTE causes CVI, pulmonary hypertension, disability, and death.disability, and death.

2.2. Diagnose PE: CDR, D-dimer, CT. Diagnose PE: CDR, D-dimer, CT.

3.3. Risk stratify PE patients: clinical evaluation, Risk stratify PE patients: clinical evaluation, biomarkers, RV size/ function (ECHO/ CT)biomarkers, RV size/ function (ECHO/ CT)—”window into future,” even if patient appears —”window into future,” even if patient appears stable.stable.

4.4. Thrombolysis remains controversial.Thrombolysis remains controversial.

5.5. Consider indefinite duration anticoagulation for Consider indefinite duration anticoagulation for idiopathic VTEidiopathic VTE

6.6. Prophylaxis against PE/ DVT is crucial.Prophylaxis against PE/ DVT is crucial.

1.1. VTE causes CVI, pulmonary hypertension, VTE causes CVI, pulmonary hypertension, disability, and death.disability, and death.

2.2. Diagnose PE: CDR, D-dimer, CT. Diagnose PE: CDR, D-dimer, CT.

3.3. Risk stratify PE patients: clinical evaluation, Risk stratify PE patients: clinical evaluation, biomarkers, RV size/ function (ECHO/ CT)biomarkers, RV size/ function (ECHO/ CT)—”window into future,” even if patient appears —”window into future,” even if patient appears stable.stable.

4.4. Thrombolysis remains controversial.Thrombolysis remains controversial.

5.5. Consider indefinite duration anticoagulation for Consider indefinite duration anticoagulation for idiopathic VTEidiopathic VTE

6.6. Prophylaxis against PE/ DVT is crucial.Prophylaxis against PE/ DVT is crucial.

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

1.1. Factor V LeidenFactor V Leiden

2.2. Prothrombin gene mutationProthrombin gene mutation

3.3. Postoperative statePostoperative state

4.4. Unprovoked, idiopathic VTE—etiology unknownUnprovoked, idiopathic VTE—etiology unknown

5.5. Birth control or pregnancy associated Birth control or pregnancy associated

1.1. Factor V LeidenFactor V Leiden

2.2. Prothrombin gene mutationProthrombin gene mutation

3.3. Postoperative statePostoperative state

4.4. Unprovoked, idiopathic VTE—etiology unknownUnprovoked, idiopathic VTE—etiology unknown

5.5. Birth control or pregnancy associated Birth control or pregnancy associated

Which Parameter is Most Predictive of a Benign Which Parameter is Most Predictive of a Benign Clinical Course After Diagnosis of PE?Clinical Course After Diagnosis of PE?

1.1. Systolic BP between 110-130 mm HgSystolic BP between 110-130 mm Hg

2.2. HR between 60-80 bpmHR between 60-80 bpm

3.3. RR between 12-16/minuteRR between 12-16/minute

4.4. Normal right ventricular size and function Normal right ventricular size and function on ECHO or CTon ECHO or CT

5.5. Absence of dyspnea or chest painAbsence of dyspnea or chest pain

1.1. Systolic BP between 110-130 mm HgSystolic BP between 110-130 mm Hg

2.2. HR between 60-80 bpmHR between 60-80 bpm

3.3. RR between 12-16/minuteRR between 12-16/minute

4.4. Normal right ventricular size and function Normal right ventricular size and function on ECHO or CTon ECHO or CT

5.5. Absence of dyspnea or chest painAbsence of dyspnea or chest pain