The latest guidelines for the management of venous thromboembolism. Includes introduction and management both.

1. MANAGEMENT OF
VENOUS
THROMBOEMBOLISM
Speaker: Abhishek Agrawal Moderator: Dr. Dharmendra Jain

2. Introduction
Pulmonary Embolism and Deep
Venous Thrombosis are a part of
the larger entity ‘Venous
Thromboembolism’.
VTE = DVT + PE
Pulmonary Embolism is known
as The Great Masquerader.

3. Epidemiology
Incidence of VTE is 1.5 per 1000 person years.
Incidence of DVT is approximately twice as that of Pulmonary
Embolism.
Pulmonary embolism is the third most common cause of
hospital-related death and the most common preventable
cause of hospital-related death.
About half the cases of VTE are idiopathic in nature.
Lindblad B, Eriksson A, Bergqvist D: Autopsy-verified pulmonary embolism in a surgical department: Analysis
of the period from 1951 to 1988. Br J Surg 1991;78(7):849-852.
Braunwald 10th edition
Braunwald 10th edition

4. Modifiable Risk Factors
• Obesity
• Metabolic syndrome
• Cigarette smoking
• Hypertension
• Abnormal lipid profile
• High consumption of red meat and
• low consumption of fish, fruits, and
• vegetables

5. Risk Factors
• Advancing age
• Arterial disease, including carotid and coronary disease
• Personal or family history of venous thromboembolism
• Recent surgery, trauma, or immobility, including stroke
• Congestive heart failure
• Chronic obstructive pulmonary disease
• Acute infection
• Air pollution
• Long-haul air travel
• Pregnancy, oral contraceptive pills, or postmenopausal hormone
replacement therapy
• Pacemaker, implantable cardiac defibrillator leads, or indwelling central
• venous catheter
• Hypercoagulable states
• Factor V Leiden resulting in activated protein C resistance
• Prothrombin gene mutation 20210
• Antithrombin deficiency
• Protein C deficiency
• Protein S deficiency Antiphospholipid antibody syndrome

6. DVT
• Distal (calf vein) DVT
• Most DVT starts in the calf. In surgical patients, thrombi often begin intraoperatively. In about half
of patients, they resolve spontaneously within 72 hours, but in onesixth of patients they extend to
involve the proximal veins.5 Isolated calf DVT is usually asymptomatic and does not commonly
cause clinically significant PE. Proximal extension of thrombus is more common in patients with
symptomatic (compared with asymptomatic) calf vein thrombus and occurs in a quarter of
patients within 1 week of presentation.5 The presence of symptoms, and the extent of proximal
progression are harbingers for an increased risk of PE.
• Proximal (popliteal and thigh) DVT
• Symptoms of DVT (pain, swelling, tenderness, and redness) generally do not develop until there is
involvement of the proximal leg veins.5 Massive thrombosis can result in vascular compromise
and venous gangrene.
• About half of patients with symptomatic proximal DVT have clinically silent PE at the time of
diagnosis,6 and 10% have symptomatic PE.7,8 The prevalence of PE increases with age,
particularly above 70 years.7,8
• Without treatment, a quarter of proximal DVT will propagate during the first 30 days, onefifth
regress, and the rest will remain unchanged.6 Without adequate treatment, half the patients will
experience recurrent symptomatic VTE within 3 months.9
• With adequate treatment, regression of thrombus occurs during the first week, and recanalisation
and resolution of thrombus occurs in about half the patients, generally within the first 3
months.10,11 Resolution of thrombus is less likely in patients with extensive initial thrombosis or
cancer. In some cases, thrombus extends into previously unaffected vein segments despite
adequate anticoagulation, but this is usually not associated with an increased risk of PE and is of
uncertain clinical relevance.

8. Pathophysiology cont..
PE has the following pathophysiological effects:-
Increased pulmonary vascular resistance
Impaired gas exchange and hypoxemia
Alveolar hyperventilation
Increased airway resistance
Decreased pulmonary compliance

10. Clinical Features
• Most common symptom – Dyspnea
• Most common sign – Tachycardia
• Otherwise unexplained dyspnea
• Chest pain, either pleuritic or “atypical”
• Anxiety
• Cough
• Tachypnea
• Tachycardia
• Low-grade fever
• Left parasternal lift
• Tricuspid regurgitant murmur Accentuated P2
• Hemoptysis
• Leg edema, erythema, tenderness
SYMPTOMS
SIGNS

11. PULOMONARY
EMBOLISM
MASSIVE PE
SUBMASSIVE PE
MILD PE
i. Sustained hypotension (systolic blood
pressure 90 mm Hg for at least 15
minutes or requiring inotropic
support, not due to a cause other than
PE
ii. Pulselessness or
iii. Persistent profound bradycardia (heart
rate 40 bpm with signs or symptoms of
shock).
i. Without systemic hypotension
(systolic blood pressure 􏰋90 mm Hg)
ii. With either RV dysfunction or
myocardial necrosis.
Acute PE and the absence of the clinical
markers of adverse prognosis that define
massive or submassive PE.
Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and
Chronic Thromboembolic Pulmonary Hypertension - A Scientific Statement From the American Heart
Association
Troponin I > 0.9 ng/mL or troponin T > 0.1 ng/mL
BNP > 90 pg/mL or pro-NT BNP > 500 pg/mL

12. Modified from Piazza G, Goldhaber SZ. Management of submassive pulmonary embolism.
Circulation 2010;122:1124-9

13. Chest X-Ray
HAMPTON HUMP
WESTERMARK SIGN
PALLA’s
SIGN

14. Electrocardiogram

15. D-dimer
 The sensitivity of the d-dimer is >80% for DVT (including
isolated calf DVT) and >95% for PE.
 A normal d-dimer is a useful “rule out” test.
Other causes of raised D-dimer
o Myocardial infarction
o Pneumonia
o Sepsis
o Cancer
o Postoperative state
o Second and Third trimester of pregnancy.

16. CT ANGIOGRAPHY
 The overall negative predictive value of a chest CT scan was
99.4%
 The CT scan serves as a prognostic and diagnostic test .
 Right ventricular enlargement on CT portends a complicated
hospital course.
 The chest CT scan can also detect other pulmonary diseases
that are present in conjunction with PE or that explain a
clinical presentation that mimics PE.

17. When reviewing results of CT, the clinician should look for
the following:
• Size, location, and extent of thrombus.
• Other diagnoses that may coexist with PE or explain PE symptoms:
• Pneumonia
• Atelectasis
• Pericardial effusion/Pneumothorax
• Left ventricular enlargement
• Pulmonary artery enlargement, suggestive of pulmonary
hypertension
• Age of thrombus: acute, subacute, chronic
• Location of thrombus: pulmonary arteries, pelvic veins, deep leg
veins, upper extremity veins
• Right ventricular enlargement
• Contour of the interventricular septum: whether it bulges toward
the left ventricle, thus indicating right ventricular pressure overload
Incidental masses or nodules in lung

18. Echocardiogram
Right ventricular enlargement or hypokinesis, especially free
wall hypokinesis, with sparing of the apex (the McConnell
sign)
Interventricular septal flattening and paradoxical motion
toward the left ventricle, resulting in a D-shaped left ventricle
in cross section
Tricuspid regurgitation
Pulmonary hypertension with a tricuspid regurgitant jet
velocity >2.6 m/sec.
Loss of respiratory-phasic collapse of the inferior vena cava
with inspiration
Dilated inferior vena cava without physiologic inspiratory
collapse
Direct visualization of thrombus (more likely with
transesophageal echocardiography)

21. Venous Ultrasonography
 DVT ----- loss of vein compressibility.
 If PE is suspected, DVT can be considered a surrogate for PE.
 At least half of patients with PE have no imaging evidence of
DVT because the original thrombus may have completely
embolised leaving no residue at the original site.
 A negative result does not rule out the possibility of PE

22. Other Modalities
 Ventilation Perfusion Scanning
 Pulmonary Angiography
 Contrast Venography

23. Differential Diagnosis
 Anxiety
 Pleurisy
 Costochondritis
 Pneumonia, bronchitis, asthma, COPD
 Myocardial infarction
 Pericarditis
 Congestive heart failure
 Idiopathic pulmonary hypertension

24. Clinical Decision Rules
Low Clinical Likelihood of DVT if Point Score Is Zero or Less; Moderate
Likelihood if Score Is 1 to 2; High Likelihood if Score Is 3 or Greater
Clinical Variable DVT Score
Active cancer 1
Paralysis, paresis, or recent cast 1
Bedridden for >3 days; major surgery <12 weeks 1
Tenderness along distribution of deep veins 1
Entire leg swelling 1
Unilateral calf swelling >3 cm 1
Pitting edema 1
Collateral superficial nonvaricose veins 1
Alternative diagnosis at least as likely as DVT –2

25. Wells Criteria for clinical
likelihood of PE
High Probability if >4 score points
Clinical Variable PE Score
Signs and symptoms of DVT 3.0
Alternative diagnosis less likely than PE 3.0
Heart rate >100/min 1.5
Immobilization >3 days or surgery within
4 weeks
1.5
Prior PE or DVT 1.5
Hemoptysis 1.0
Cancer 1.0

26. WELLS Criteria for
likelihood of PE
DVT - 3
Cancer - 1
Immobilization >3 days or
surgery within 4 weeks - 1.5
Prior PE or DVT – 1.5
Tachycardia – 1.5
Diagnosis other than PE - 3
Hemoptysis - 1
High Probability if >4 score points
Low Probability if <=4 score points

29. TREATMENT
 Oxygenation
 Hemodynamic stability
 Anticoagulation
 Fibrinolysis
 IVC filter
 Catheter Embolectomy
 Surgical Embolectomy

30. Anticoagulation
Heparin is the corner stone of anticoagulation.
Heparin at its pentasaccharide sulfation sequence binds to the
enzyme inhibitor antithrombin III (AT), causing a conformational
change that results in its activation through an increase in the
flexibility of its reactive site loop.
The activated AT then inactivates coagulation factors thrombin
(factor IIa), Xa, IXa, XIa, and XIIa.
Target the aPTT between 1.5 and 2.5 times the control value.The
therapeutic range of aPTT is 60 to 80 seconds.
shorter half-life of UFH is advantageous for patients who might
require insertion of an inferior vena caval filter, thrombolysis, or
embolectomy.

32. Low Molecular Weight Heparin
LMWHs consist of short chains of polysaccharide
(fragments of UFH).
It also binds to AT-III to inhibit Factor Xa but it has no
effect on Factor II (Thrombin)
LMWH therapy is monitored by the anti-factor Xa assay,
measuring anti-factor Xa activity.

33. Heparin and LMWH - MOA

34. Difference LMWH and UFH
UFH LMWH
Unpredicatable response
 Significant protein binding
 Saturable clearance mechanism
 Inactivation by platelet factor 4
Predictable response
 Less protein binding
 Less inactivation by platelet factor 4
Less bioavailability More bioavailability
Short half life Long half life
Need of regular monitoring No need of regular monitoring
Risk of HIT Less risk of HIT

35. LMWH
 In a trial of 672 patients with VTE and cancer, those randomized to
dalteparin monotherapy had a much lower VTE recurrence rate than did
patients receiving dalteparin as a “bridge” to warfarin: 8.8% versus 17.4%.
Lee AY, Levine MN, Baker RI, et al: Low-molecular-weight heparin versus a coumarin for the
prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med
349:146, 2003.

36. When monitoring needed in LMWH
 The plasma anti-Xa level may be useful in five situations:
(1) UFH anticoagulation with baseline elevated aPTT
caused by a lupus anticoagulant or anticardiolipin
antibodies
(2) LMWH dosing in obese patients
(3) LMWH dosing in patients with renal dysfunction
(4) pregnancy
(5) determination of the origin of an unexpected
bleeding or clotting problem in patients receiving what
appeared to be appropriate anticoagulant dosing.

37. FONDAPARINUX
• Fondaparinux is an anticoagulant pentasaccharide that
specifically inhibits activated factor X. By selectively binding to
anti- thrombin, fondaparinux potentiates (about 300 times)
the neutralization of factor Xa by antithrombin
• Fixed-dose, once-daily subcutaneous injection, without the
need for coagulation laboratory monitoring or dose adjust-
ment.

38. FONDAPARINUX - MOA

39. • Uses:-
① The FDA has approved fondaparinux for initial treatment of
acute PE and acute DVT as a bridge to oral anticoagulation with
warfarin.
② Fondaparinux is often used off label for the management of
suspected or proven heparin-induced thrombocytopenia89
(see later).
③ At times, fondaparinux is used off label as monotherapy
without warfarin to treat VTE patients without cancer who
cannot tolerate warfarin or who suffer recurrent VTE despite
warfarin.
The dose for VTE prophylaxis is a fixed low dose of 2.5 mg once daily,
regardless of body weight.

40. WARFARIN
• Warfarin is a vitamin K antagonist that prevents gamma-
carboxylation activation of coagulation factors II, VII, IX, and X.
• Half life of factor VII is 6 hours whereas half life of factor II is 5
days.
• Its activity is measured by Prothrombin Time.
• The full anticoagulant effect of warfarin may not be apparent
for 5 to 7 days, even if the prothrombin time, used to monitor
warfarin’s effect, becomes elevated more rapidly.
• For VTE patients, the usual target INR range is between 2.0
and 3.0.

41. Warfarin - MOA

42. Overlap of Warfarin and LMWH
• Warfarin monotherapy decreases the levels of two
endogenous anticoagulants, proteins C and S, thus increasing
thrombogenic potential.
• Warfarin should be overlapped with LMWH to counteract the
procoagulant state for at least 5 days, and preferably till the
target INR is achieved 2 times 24 hours apart.

43. Starting dose
• Warfarin is traditionally dosed by an “educated guess”
coupled with trial and error.
• One open-label, randomized trial compared two warfarin ini-
tiation nomograms (5 mg versus 10 mg) in 50 patients with
acute VTE.95 The median time to two consecutive target INRs
was 5 days in both groups (P = 0.69).
• Computer-assisted warfarin dosing can be used for better
results.
Quiroz R, Gerhard-Herman M, Kosowsky JM, et al: Comparison of a single end point to
determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism.
Am J Cardiol 98:535, 2006.

44. Warfarin Interactions

45. Novel Anticoagulants
• Immediate onset of action
• Short half life
• Administration in fixed doses without routine laboratory
coagulation monitoring.
• Few drug-drug or drug-food interactions
• No bridging is needed with a parenteral anticoagulant when
they have to be stopped for any diagnostic or surgical
procedure.

46. Dabigatran
• It is a direct thrombin inhibitor.
• It has been proven noninferior to enoxaparin in three major
orthopedic surgery trials of total knee or hip arthroplasty.
• In a large-scale trial of acute VTE, dabigatran was noninferior
to warfarin.
Wolowacz SE, Roskell NS, Plumb JM, et al: Efficacy and safety of dabigatran etexilate for the
prevention of venous thromboembolism following total hip or knee arthroplasty. A
meta-analysis. Thromb Haemost 101:77, 2009.

47. Rivaroxaban
• Rivaroxaban is a factor Xa inhibitor.
• It has 80% bioavailability.
• Half life is 5 to 9 hours.
• It is approved for treatment of acute DVT and acute PE as
monotherapy .
• Its efficacy has proven superior to enoxaparin to prevent VTE
after total knee and hip arthroplasty.
• Both dabigatran and rivaroxaban are approved in Canada and
Europe for VTE prevention after knee or hip arthroplasty.
Eriksson BI, Borris LC, Friedman RJ, et al: Rivaroxaban versus enoxaparin for
thromboprophylaxis after hip arthroplasty. N Engl J Med 358:2765, 2008.
Lassen MR, Ageno W, Borris LC, et al: Rivaroxaban versus enoxaparin for thromboprophylaxis
after total knee arthroplasty. N Engl J Med 358:2776, 2008.

48. RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN
MODE Oral Oral Oral Oral
MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor
Dose
VTE
Prophylaxis
20 mg OD 2.5 mg BD - 110 mg on day
1 ➡️ 220mg OD
Dose VTE
Treatment
15 mg BD X
3wks ➡️ 20 mg
OD
10 mg BD X
1wk ➡️ 5 mg
BD
60 mg OD 150 mg BD
Antidote ANDEXANAT
ALFA
ANDEXANAT
ALFA
ANDEXANAT
ALFA
IDARUCIZUMA
B

49. Cancer and VTE – LMWH should be used as monotherapy
Unprovoked PE/Proximal leg DVT - Anticoagulation for an indefinite
duration with a target INR between 2 and 3.
An alternative approach after the first 6 months of anticoagulation is
to reduce the intensity of anticoagulation and to lower the target INR
range to between 1.5 and 2.
Optimal Duration of Anticoagulation
CLINICAL SETTING RECOMMENDATION
First provoked PE/proximal leg DVT 3 to 6 months
First provoked upper extremity DVT or
isolated calf DVT
3 months
Second provoked VTE Uncertain
Second VTE Indefinite duration
Cancer and VTE Consider indefinite duration or until
cancer is resolved
Unprovoked PE/Proximal leg DVT Consider indefinite duration
First unprovoked calf DVT 3 months
Second unprovoked calf DVT Uncertain

51. Recurrent VTE
• Recurrent VTE has a high fatality rate, especially when it
occurs despite ongoing anticoagulation within the first week
of diagnosis.115
• Even after completion of a 6-month course of anticoagulation,
the case fatality rate for recurrent PE remains high.116

52. D-dimer in Recurrent VTE
• In the placebo group of the PREVENT trial, D-dimer was
measured 7 weeks after discontinuation of warfarin in
patients with unprovoked VTE.126 The subsequent recurrence
rate was twice as high in those with elevated D-dimer levels.
• However,an overview of 1888 patients who had unprovoked
VTE showed that they had a high 3.5% annual risk of
recurrence despite normal D-dimer levels after stopping of
anticoagulation.127
Shrivastava S, Ridker PM, Glynn RJ, et al: D-dimer, factor VIII coagulant activity, low-intensity
warfarin and the risk of recurrent venous thromboembolism. J Thromb Haemost 4:1208, 2006.
Verhovsek M, Douketis JD, Yi Q, et al: Systematic review: D-dimer to predict recurrent disease
after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern
Med 149:481, W494, 2008.

53. • In a separate meta-analysis of patients with idiopathic VTE,
those with normal D-dimer levels measured 1 month after
discontinuation of oral anticoagulation had a clinically
important 7.2% recurrence rate.
• No guideline committee has endorsed the use of D-dimer
levels to direct the optimal duration of anticoagulation.
Bruinstroop E, Klok FA, Van De Ree MA, et al: Elevated D-dimer levels predict recurrence in
patients with idiopathic venous thromboembolism: A meta-analysis. J Thromb Haemost 7:611,
2009.

54. FIBRINOLYSIS
• Successful fibrinolysis reverses right heart failure and may
result in a lower rate of death and recurrent PE by
① Dissolving much of the anatomically obstructing pulmonary
arterial thrombus
② Preventing the continued release of serotonin and other
neurohumoral factors that exacerbate pulmonary
hypertension
③ Lysing much of the source of the thrombus in the pelvic or
deep leg veins, thereby decreasing the likelihood of
recurrent PE.
• Wide window
• Patients who receive thrombolysis up to 14 days after new
symptoms or signs maintain an effective response.

56. Fibrinolytic Agents

57. Fibrinolytic Agents
Fibrinolytic FDA
Indication for
PE
Direct
Plasminogen
Activator
Dosage Fibrin
Specificity
PAI
Resistance
Streptokinase Yes No 250 000-IU IV bolus followed
by
100 000-IU/h infusion for 12–
24 h
- -
Urokinase Yes No 4400-IU/kg bolus, followed by
4400
IU 􏰋 kg􏰋1 􏰋 h􏰋1 for 12–24 h
- -
Alteplase Yes Yes 100-mg IV infusion over 2
h
++ ++
Reteplase No Yes Double 10-U IV bolus† 30
min apart
+ +
Tenecteplase No Yes Weight-adjusted IV bolus over
5 s (30–50 mg with a 5-mg
step every 10 kg from 􏰋60 to 􏰋
90 kg)
+++ +++

58. Use of Heparin before and after
Thrombolysis
1. Discontinue the continuous infusion of intravenous UFH as soon
as the decision has been made to administer thrombolysis.
2. Proceed to order thrombolysis. Use the U.S. Food and Drug
Administration–approved regimen of alteplase 100 mg as a
continuous infusion during 2 hours.
3. Do not delay the thrombolysis infusion by obtaining an activated
partial thromboplastin time (aPTT).
4. Infuse thrombolysis as soon as it becomes available.
5. At the conclusion of the 2-hour infusion, obtain a stat aPTT.
6. If the aPTT is 80 seconds or less (which is almost always the case),
7. resume UFH as a continuous infusion without a bolus.
8. If the aPTT exceeds 80 seconds, hold off from resuming heparin
for 4 hours and repeat the aPTT. At this time, the aPTT has
virtually always declined to <80 seconds. If this is the case, resume
continuous infusion of intravenous UFH without a bolus.

59. Use of Heparin before and after Thrombolysis
STOP IV UFH INFUSION
Resume UFH as continous
infusion
APTT > 80 secAPTT < 80 sec (almost always)
Obtain APTT after 2 hours
of infusion
Give ALTEPLASE 100 mg IV
over 2 hour infusion
Proceed to thrombolysis. Do not delay
thrombolysis for obtaining APTT
APTT will be < 80 sec
Hold Heparin for 4 hours
and repeat APTT

61. Fibrinolysis in Submassive PE
• Death or hemodynamic collapse within 7 days of fibrinolysis is
reduced by 56% of patients with submassive PE.
• But risk of hemorrhagic stroke is 2% in firbrinolysed patients
as compared with 0.2% in patients who only receive heparin.
Reference

62. IVC FILTERS
 Indications :-
1) Contraindication to anticoagulation
2) Complication to anticoagulants
3) Failure to achieve target INR inspite of anticoagulation
4) Free floating Ileo-femoral or IVC thrombus
 2 types
1) Permanent
2) Retrievable

63. Normal Venogram Various types of IVC filters

64. Catheter Embolectomy
1) Thrombus fragmentation
2) Rheolytic thrombectomy
3) Suction thrombectomy
4) Rotational thrombectomyC
5) Conventional catheter-directed thrombolysis (CDT)
6) Pharmacomechanical thrombolysis (PMT).

65. Limitations
1. Poor maneuverability
2. Mechanical hemolysis
3. Macroembolization
4. Microembolization.

66. SURGICAL EMBOLECTOMY
• Patients with massive PE and systemic arterial
hypotension or submassive PE with right ventricular
dysfunction in whom contraindications preclude
thrombolysis.
• Acute PE patients who require surgical excision of a right
atrial thrombus or closure of a patent foramen ovale.
• Patients refractory to thrombolysis.

68. Prophylaxis for VTE
• PE is the most preventable cause of in-
hospital death.
• Mechanical Measures – Reduce DVT risk
by 60%
• Intermittent pneumatic compression
devices
• Enhance endogenous fibrinolysis
• Increase venous blood flow, and graduated
compression stockings.
• Graduated compression stockings
Urbankova J, Quiroz R, Kucher N, et al: Intermittent pneumatic
compression and deep vein thrombosis prevention. A meta-analysis in
postoperative patients. Thromb Haemost 94:1181, 2005.

70. Unconventional Approach
• VITAMIN E
• In Women’s Health Study involving 39,876 women
receiving 600 units of vitamin E
• 21% reduction in VTE was seen
• 44% reduction in patients having prior VTE.
• 49% reduction in patients having Factor V Leiden mutation or the
prothrombin gene mutation
• Vitamin E may reduce VTE risk in women, especially
those with a prior history of VTE or with a genetic
predisposition.
Glynn RJ, Ridker PM, Goldhaber SZ, et al: Effects of random allocation to vitamin E supplementation
on the occurrence of venous thromboembolism: Report from the Women’s Health Study.
Circulation 116:1497, 2007.

71. STATINS
• In the JUPITER study, 17802 apparently healthy men and
women with both low-density lipoprotein cholesterol
levels of less than 130 mg/dL and hsCRP levels of 2.0
mg/dL or higher were given Rosuvastatin 20mg/day.
• Symptomatic VTE was reduced by 43% in the
Rosuvastatin group (P = 0.007).
• Thus, Rosuvastatin appears to prevent VTE.
Glynn RJ, Danielson E, Fonseca FA, et al: A randomized trial of rosuvastatin in the prevention of
venous thromboembolism. N Engl J Med 360:1851, 2009.