Transcript PE SlideCAST - iQandA-CME
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
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Epidemiology
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Diagnosis
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Risk Stratification
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Treatment: anticoagulation thrombolysis embolectomy
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Prevention
Epidemiology
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
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762,000 PEs/ DVTs in EU in 2004.
Thromb Haemostas 2007; 98: 756
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
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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
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74% of VTEs present in outpatients.
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42% of outpatient VTE patients have had recent surgery or hospitalization.
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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 17.5% 0 7 14 30 Days From Diagnosis 60 Lancet 1999; 353: 1386-1389 90
From UpToDate 2006 Progression of Chronic Venous Insufficiency
Cardiovascular Risk Factors and VTE (N=63,552 meta-analysis)
RF
Obesity Hypertension Diabetes Cigarettes High Cholesterol
RR
2.3
1.5
1.4
1.2
1.2
Ageno W. Circulation 2008; 117: 93-102
Eat Veggies and Lower VTE Risk; Careful with Red Meat
Fruits, veggie Fish Adjusted Hazard Ratios (Quintiles)
2 0.73
3 0.57
4 0.47
5 0.59
p 0.03
0.58
0.60
0.55
0.70
0.30
Red Meat
1.24
1.21
1.09
2.01
0.02
Steffen LM. Circulation 2007;115:188-195
Dabish 20-Year Cohort: VTE, Subsequent CV Events
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Assessed risk of MI, Stroke
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25,199 with DVT
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16,925 with PE
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163,566 population controls Sorensen HT. Lancet 2007; 370: 1773-1779
CV Event Acute MI Stroke RR CV Event in PE Patients 1 Year RR 2.6
2.9
2-20 Year RR 1.3
1.3
Sorensen HT. Lancet 2007; 370: 1773-1779
Reversible Risk Factors 1.
Nutrition: eat fruits, veggies, fish; less red meat 2.
Quit cigarettes 3.
Lose weight/ exercise 4.
Prevent DM/ metabolic syndrome 5.
Control hypertension 6.
Lower cholesterol
DIAGNOSIS
PE SXS/ Signs (PIOPED II)
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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
JAMA 2006; 295: 172-179 Clinical Decision Rule
CT Leg Venography & U/S: Necessary or “Overkill”?
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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)
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Chest CT alone (N=1,819) was noninferior to chest CT plus leg U/S. (Lancet 2008; 371: 1343-1352)
Saddle Embolus
PE Diagnosis
Suspect PE: CXR, ECG, Oximetry CDR < 4 CDR > 4 D-dimer
Chest CT High: get CT Normal: stop W/U Pos: Rx for PE Neg: stop W/U
Risk Stratification
Risk Stratification : PE is essential to decide: 1.
Anticoagulation alone
versus
anticoagulation plus thrombolysis/ embolectomy 2.
Triage to Intensive Care Unit 3.
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)
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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
► ► 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 Circulation 2004; 110: 3276
Treatment
VTE: Immediate Anticoagulation 1.
2.
3.
4.
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
► 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
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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)
47 EMERGENCY EMBOLECTOMIES Survival = 94 %
N=47 J Thorac Cardiovasc Surg 2005;129:1018
Surgical Embolectomy at BWH: Surgeon’s Cell Phone
PE Thrombectomy Device
Dimension: 11 French
Suction Ports Spiral Coil
Heparin “Catches Up” with Lysis: Lung Perfusion Arch Intern Med 1997; 157: 2550
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? (1 st patient enrolled 11/10/2007; 65 th on 8/25/2008)
LYSIS VS. Filter: Massive PE (N=108)
Lysis Filter Lysis Filter
8 YEAR F/U IVC FILTERS: RCT PREPIC. Circulation 2005; 112: 416-422
BARD RECOVERY FILTER
RATE OF RECURRENT VTE
Olmsted County 35% 30% 25% 20% 15% 10% 5% 0% 5% 10% 13% 30%
//
1/12 1/2 1 Number of Years 10
(Arch Intern Med 2000; 160: 761-768)
Risks for Recurrence
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“Unprovoked”
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Strong FH; PMH of VTE
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Antiphospholipid antibody syndrome
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Cancer
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Male (Kyrle PA. NEJM 2004; 350: 2558) (McRae S. Lancet 2006; 368: 371-8)
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Presentation with PE Symptoms Eichinger. Arch Intern Med 2004;164: 92)
TRIAL PREVENT ELATE
Trials of Unprovoked VTE : Favor Indefinite Duration Anticoagulation (NEJM 2003)
THRIVE-3 TAKE-HOME POINT
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Low intensity A/C (INR 1.5-2.0) reduces recurrence rate by 2/3.
Standard A/C (INR 2.0-3.0) is more effective but as safe as low intensity A/C.
Ximelagatran effective, safe.
Does Thrombophilia Predict Recurrent VTE?
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474 VTE patients followed for an average of 7 years.
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Most patients were anticoagulated for < 12 months.
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90 (20%) suffered recurrence.
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Thrombophilia did
not
increase likelihood of recurrence
.
Christiansen SC. JAMA 2005; 293: 2352
How Often and For How Long Does CT Remain Abnormal After PE?
F/U 6 Weeks 3 Months 6 Months 11 Months ABNORMAL 68% 65% 57% 52% Nijkeuter M. CHEST 2006; 129: 192-197
Warfarin Pharmacogenomics 1.
Cytochrome P450 2C9 genotyping can identify mutations associated with impaired warfarin metabolism.
2.
Vitamin K receptor polymorphism testing can identify whether patients require low, intermediate, or high doses of warfarin .
Schwartz UI. NEJM 2008; 358: 999
Genotype vs Standard Warfarin Dosing (n=206) Couma-Gen Trial
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Rapid turnaround CYP2C9 and VKORC1 testing vs. “empiric”
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Primary endpoint: TTR
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Smaller and fewer dosing changes with genetic testing
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No difference in TTR Circulation 2007; 116: 2563-2570
Self-Monitoring INR: Meta-Analysis of 14 RCTS
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Reduced TE events (55% fewer) Reduced all-cause mortality (39% less) Reduced major bleeds (35% fewer) Benefits increase further with self-dosing
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73% fewer TE events
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63% lower all-cause mortality Heneghan C. Lancet 2006; 367: 404-411
March 19, 2008: Medicare Expanded Reimbursement for Home INR Monitoring
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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 1.
Dabigatran: an oral DTI —twice daily fixed dose (renal clearance) 2.
Rivaroxaban: direct factor Xa inhibitor (renal clearance) —once daily fixed dose 3.
Apixaban: direct factor Xa inhibitor (hepatic clearance) —twice daily fixed dose Gross PL, Weitz JI; ATVB 2008; 28: 380)
Prevention
VTE Prophylaxis in 19,958 Medical Patients/ 9 Studies (Meta-Analysis)
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62% reduction in fatal PE
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57% reduction in fatal or nonfatal PE
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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 End points Outcome, extended prophylaxis, n=2052 (%) Outcome, placebo, n=2062 (%) RR reduction (%) p VTE events Symptomatic No Sxs Hull RD et al. July 2007; ISTH; Geneva 2.8
0.3
2.5
4.9
1.1
3.7
44% 73% 34% 0.001
0.004
0.032
The Amin Report: Prophylaxis Rates in the US
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Studied 196,104 Medical Service discharges from 227 hospitals (Premier ® database).
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VTE prophylaxis rate was 62%.
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ACCP-deemed appropriate prophylaxis rate was 34%.
J Thromb Haemostas 2007; 5: 1610-6
Medical Patient Prophylaxis in Canada
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Studied 1,894 Medical Service discharges from 29 hospitals.
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VTE prophylaxis was indicated in 90% of patients.
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ACCP-deemed appropriate prophylaxis rate was 16%.
Thrombosis Research 2007; 119: 145-155
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 52% at Risk for VTE (50% receive ACCP recommended prophy) Surgical 64% at Risk for VTE 59% receive ACCP Rec. Px Medical 42% at Risk for VTE 40% receive ACCP Rec. Px
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” VTE risk score ≥ 4 points:
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Cancer 3 (ICD codes)
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Prior VTE Hypercoagulability Major surgery Bed rest Advanced age Obesity HRT/OC 3 3 (ICD codes) (Leiden, ACLA) 2 (> 60 minutes) 1 (“bed rest” order) 1 (> 70 years) 1 (BMI > 29 kg/m 2 ) 1 (order entry)
INTERVENTION: Single alert N = 1,255
Kucher N, et al. NEJM 2005;352:969-977 Randomization
VTE risk score > 4 No prophylaxis N = 2,506 CONTROL No computer alert N = 1,251
90-Day Primary Endpoint Intervent. Control Hazard Ratio
p
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 96 94 92 90 0 Number at risk Intervention Control 1255 1251 Kucher N, et al. NEJM 2005;352:969-977 Intervention 30 60 Time (days) 977 976 900 893 Control 853 839 90
“Take Home” Points 1.
2.
3.
4.
5.
6.
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)?
1.
Factor V Leiden 2.
Prothrombin gene mutation 3.
Postoperative state 4.
Unprovoked, idiopathic VTE —etiology unknown 5.
Birth control or pregnancy associated
Which Parameter is Most Predictive of a Benign Clinical Course After Diagnosis of PE?
1.
Systolic BP between 110-130 mm Hg 2.
HR between 60-80 bpm 3.
RR between 12-16/minute 4.
Normal right ventricular size and function on ECHO or CT 5.
Absence of dyspnea or chest pain