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What is Venous Thromboembolism?• When a blood clot (thrombus)

forms in a deep vein, this is called deep vein thrombosis (DVT)– If it happens it happens most

frequently in the leg

• Thromboembolism occurs when part of a clot breaks away and enters the bloodstream– When this happens the blood clot

is called an embolus


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Immediate and long term effects of deep-vein thrombosisSymptoms and risk factorsPreventability of the condition

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VTE: deep vein thrombosis (DVT) andpulmonary embolism (PE)





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What is Pulmonary Embolism?

• Such an embolus can travel via the heart and lodge in an artery in the lungs, blocking blood flow to critical tissues - this is known as pulmonary embolism (PE)

• Venous thromboembolism (VTE) includes DVT and PE


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Andrew Flintoff, cricket

Rebecca Bane, Films

Hilary Clinton, politics

Serena Williams, Tennis



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VTE: Often undetected until too late

Over 70% of fatal PE aredetected post-mortem1,3

Approximately 80% ofDVTs are clinically silent2,3

1. Stein PD, et al. Chest 19952. Lethen H, et al. Am J Cardiol 19973. Sandler DA, et al. J R Soc Med 1989

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VTE is a serious disease that killshundreds of thousands people each year

3rd most common cardiovasculardisease world-wide after ischaemicheart disease and stroke1

Causes ~300,000 deaths in the United States and over 500,000 deaths in Europe per year2,3

In the EU, more than twice as many people die from VTE than from AIDS, breast cancer, prostate cancer and transportation accidents combined3

3.1 billion Euros per year total estimated costs for VTE-associated care4

1.Goldhaber SZ at al; 1992.2.Heit JA,et al; 2005.3.Cohen AT, et al; 2007.4.Cohen AT; 2005

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• VTE is estimated to cause at least 3 million deaths a year worldwide; DVT & PE are common cause of CV mortality & morbidity

• 3rd most common cardiovascular disease worldwide after IHD and stroke• VTE is implicated in every 1 out 10 hospital deaths in the world• Global incidence of VTE : 1 in 1000 people all over the world are affected by VTE

1. Spyropoulos AC. Investigational treatments of venous thromboembolism. Expert Opin Investig Drugs. 2007;16:431-440. 2. Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe. Thromb Haemost. 2007;98:756-764. 3. Parakh R et al., JAPI. 55, Jan 2007; 4. Sharma S et al., IJS.63(2).2001 5. Geerts WH, et al. Chest. 2004;126(3 suppl):338S-400S.


• Post-thrombotic syndrome - occurs in 10% of patients with DVT

• Pulmonary hypertension

occurs in 5% of patients with PE

Burden of VTE

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Virchow‘s Triad of Thrombogenesis

Alterations of vessel wall

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Virchow‘s Triad of Thrombogenesis

Endothelial damageAlterations of vessel wall

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First manifestationmay be fatal PE

of disease

PE contributes to 1 in 10hospital deaths1

PE complications2: Permanent damage to the

lungs and other organs Pulmonary hypertension

Sudden death or cardiac arrest

1. House of Commons Health Committee. Second report of session 2004–05. London: The StationaryOffice; March 2005.2. Goldhaber SZ. N Engl J Med 1998;339:93–104.


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Post Thrombotic Syndrome (PTS) a severelong term complication of DVT

PTS occurs in nearly one-third of patients within 5 years of initial DVT1

DVT-induced valvular incompetence PTS is characterised by3:

Oedema Pain Induration Impaired viability of subcutaneous tissues Ulceration

leads to lower limb hypertension

Severe PTS can lead to intractable, painfulvenous leg ulcers requiringand medical care4

ongoing nursing

© Diepgen TL, et al. DermatologyOnline Atlas (Reprinted with permission).

1. Prandoni P et al. 1996.2. Kahn SR et al. 2004.3. Anderson FA et al. 1998.4. Kahn SR et al. 2000


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• Color Doppler ultrasound in Deep Venous Thrombosis

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ENDORSE- multinational cross sectionalstudy1

Cohen AT et al. Lancet 2008;371:387–94

68 183 patients in 358 hospitals across 32 countries were enrolled:

•30 827 (45%) categorized as surgical

•37 356 (55%) categorized as medical


• The prevalence of VTE risk in the acute hospital care setting

• The proportion of at-risk patients who receive effective thromboprophylaxis

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Mean = 52%

Patients at risk for VTE in 32countries N= 68,183



Cohen AT, et al. Lancet 2008;371: 387-394


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VTE in Asia

Multinational epidemiologic studies

AIDA1 : Assessment of the Incidence of Deep-vein thrombosis in Asia

Local epidemiologic studies


Hong Kong Singapore




South Korea

1 Piovella et al. J Thromb Haemost 2005

Recent evidence from the last two decades suggest the incidence ofVTE in Asians is higher than previously believed

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PE Indian Scenario : PGIMER, Chandigarhstudy

An autopsy study on 1000 medical patients at thePostgraduate Institute of Medical Education and Research(PGIMER), Chandigarh revealed-PE was present in 159 (16%) of 1000 patients who diedhospital —

in the

1.2. In

It was a fatal embolus in 36A major contributor to death in 90 patients.

30 patients, the embolus was an incidental finding atautopsy as death occurred due to some other cause.A clinical (pre-mortem) suspicion of PE was recorded inpatients and a diagnosis of PE could be made in <10%.

30% of


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Research from Kovai medical center and hospitals, Coimbatore reveals

India per se

What is the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) after major spine surgery when no prophylactic measures were used?


Volume Evidence-Based Spine-Care Journal 3/Issue 3 — 2012

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Study at KEM hospital. Mumbai

Methods: A prospective study was performed on 147 patients undergoingmajor orthopaedic surgery for total knee replacement (TKR), total hip replacement (THR), and proximal femur fracture fixation (PFF) without any prophylaxis. These patients were profiled for presence of the known risk factors responsible for development of VTE. A duplex ultrasound on both lower limbs was done 6 to 10 days after surgery.Twenty three patients underwent THR, 22 patients underwent TKR, and 102 underwent surgery for PFF.The patients were assessed clinically for any signs of deep venous thrombosis (DVT) and pulmonaryembolism (PE). A helical CT scan was done in case of suspicion of PE and a duplex ultrasound was done in case of clinical suspicion of DVT irrespective of the stage of study.

Results: The overall incidence of VTE was 6.12% and that of PE was 0.6%. The risk factors that were found to be significantly responsible for development of VTE (p , 0.05) were: immobility greater than 72 hours,malignancy, obesity, surgery lasting more than two hours.

Conclusion: The study reconfirms the belief that DVT has a lower incidenceV Bagaria; PostignradIMned Ja20n06;p82a:1t3i6e–1n39t.sdoia:

1s0.1c13o6/mpgmpj.2a00r5e.0d345w12ithother ethnic groups.

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VTE Indian Scenario: Dr SanjayAgarwala’s Study

A Prospective open randomized study was undertaken to evaluate the incidence ofpost operative DVT in Indian population after lower limb surgery

Incidence of venographically proven DVT in orthopedic population (n=104) wasfound to be72.2% in patients undergoing TKA42.9% in patients undergoing THA

An overall incidence of 60% in the non prophylaxis group

These figures are similar to earlier studies in Asia, Europe and North Americashowing a high frequency of sub-clinical DVT after major joint surgery and need foradequate thromboprophylaxis

S Agarwala et al, Indian Journal Of Orthopedics; 37(2), 2003, 98-104

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• Overall incidence of ~ 60% venographically proven DVT in orthopedic population in the non-prophylaxis group1

• Significant risk of developing PE • In hospital LMWH prophylaxis reduced the overall frequency

of DVT • DVT is currently underestimated in the Indian population• Thromboprophylaxis could prevent morbidity & mortality

1. Agarwala S et al., Indian Journal of Orthopaedics. 37(2), April 2003; 2. AIDA Study J Thromb Haemost.2005 Dec;3(12):2664-704.Fletcher Allen HealthCare: Orthopedics - Length of Stay http://www.fletcherallen.org/about/health_report_cards/quality_of_care_reports/orthopedics/length_of_stay/. Accessed September 4th, 2012





TKR = Total Knee Replacement; THR = Total Hip Replacement

VTE after TKR/THR – Indian Scenario

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Major orthopaedic surgeryincreases the risk of VTE

Slow, turbulent blood flow invalve cusps causes local stasis

Stasis causes thrombus


VTE Most serious frequent complication following total hip replacement (THR)

and TKR surgery Risk increases with the duration of surgery and period of immobility

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VTE occurrence in orthopaedic patientswithout prophylaxis


ProximalVTE (%)

PE (%) Fatal PE (%)

THR 45–57 25–35 7–30 0.1–0.4

Geerts WH et al. Chest 2008;133:381–453S. Demers C, et al. Arch Int Med 1998

TKR 41–85 9–20 2–7 0.2–0.7

Trauma 20–65 – 2–22 –

Arthroscopy 18 – – –

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Objectives: The aim of this work was to study the epidemiology of VTE in Asian patients undergoing orthopedic surgery without thromboprophylaxis. Patients and methods: We performed a prospective observational study of a cohort of consecutive Asian patients hospitalized for total hip or knee replacement or hip fracture surgery without thromboprophylaxis. The primary

Study outcome: was the incidence of the composite of symptomatic VTE or sudden death at hospital discharge. This outcome was also assessed at 1 month’s follow-up.

Results: Between April 2001 and July 2002, 2420 patients were enrolled out of which 403 pts.

Were from 9 centers in India. Median age was 68 years and the median duration of hospitalstay was13 days. The rate of symptomatic VTE or sudden death as notified by investigators was 2.3% [55 patients, 99% confidence interval (CI) 1.6, 3.2] and 1.2% (28 patients, 99% CI0.7, 1.8) after adjudication by an independent committee. Chronic heart failure, varicose veins and a history of VTE were independent risk factors (P < 0.05) for the occurrence of thePrimary endpoint. At 1 month’s follow-up, the incidence of adjudicated symptomatic VTE or sudden death was 1.5% (35/2264 patients).

Conclusion: In Asian patients, the incidence of symptomatic VTE after major orthopedic surgery is not low, consistent with the rates observed in western countries. The use of thromboprophylaxis should be considered in Asian patients undergoing such high-risk surgical procedures

Leizorovicz A, et al SMART Study Group. Epidemiology of venous thromboembolism in Asian patients undergoing major orthopedic surgerywithout thromboprophylaxis. The SMART Study. J Thromb Haemost 2005; 3: 28–34.

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Is routine thromboprophylaxis justified?

A meta-analysis of 10 studies from pubmed and googlescholar regarding VTE in Indian patients post Major orthopedic trauma surgery (hip or proximal femur fracture or spine surgery) a total patient no of 1049 pts revealed

Except 2 studies on spine surgery all the other 8 recommended screening/ thromboprophylaxis for post traumatic patients

Colour doppler was used as the diagnostic/screening toolin 779 pts in the 8 studies The incidence in the thromboprophylaxis receiving group

was 8% and that in the group not receiving any from of thromboprophylaxis was 14.5%

Ramesh K Sen et al; Indian journal of orthopedics; May 2011; Vol 45; Issue 3

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Underuse of VTE prophylaxis- In India

In a study of 100 patients admitted to intensive care units (ICU) in Kolkata, only1 of 2, who should have received thrombo-prophylaxis, actually received it1

Pharmacological prophylaxis was used in only 229 of 466 (47%) patients admitted to an ICU in a hospital in Mumbai who should have received it and the commonest reason cited for not using it was fear of bleeding2

The major reason cited for not using pharmacological thromboprophylaxis is fear of bleeding1,2

The risk of bleeding is however, very small; a meta-analysis revealed that theuse of low dose UFH did not increase the risk of major bleeding3

The risk of facing a medicolegal suit for not using thrombo-prophylaxis when it should have been used seems to be more4

1. Todi SK et al, Indian J Crit Care Med 2003;7:103–5, 2 Ansari K et al J Indian Med Assoc 2007;105:536, 538, 540, 3 Clagett GP etal Ann Surg1988;208:227–40, 4 VK kapoor et al THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 23, NO. 4, 2010

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In spite of all the evidence in its support, VTE prophylaxis remains

grossly underutilizedENDORSE study – India – less than 20% of patients at risk received


Ramakrishna Pinjala, Department of Vascular Surgery, Nizam’s Institute of Medical Sciences, Hyderabad, India

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Points to ponder

•The major reason cited for not using pharmacological thromboprophylaxis is fear of bleeding1,2

Fear of bleeding

•The risk of bleeding is very small; a meta-analysis revealed that the use of low dose UFH did not increase the risk of major bleeding3

Actual risk of bleeding

•The risk of facing a medicolegal suit for not using thrombo-prophylaxis when it should have been used seems to be more4

Medico legal suit

1. Todi SK et al, Indian J Crit Care Med 2003;7:103–5, 2 Ansari K et al J Indian Med Assoc 2007;105:536, 538, 540, 3 Clagett GP etal Ann Surg 1988;208:227–40, 4 VK kapoor et al THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 23, NO. 4, 2010

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Goals of Therapy

• Diminish the severity and duration of lower extremity symptoms

• Prevent PE• Minimize the risk of recurrent venous

thrombosis• Prevent the post thrombotic syndrome

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Anticoagulant Scenario from 1930’s - 2010

Alban. Eur J Clin Invest 2005














UFH: multiple targets, parenteral

VKAs: multiple targets, oral

LMWHs: multiple targets, parenteral

DTIs: single target, oral and parenteral

Indirect Xa inhibitors:Dual target, parenteral

Direct Xa inhibitors:Single target, oral


DTIs, direct thrombin inhibitors

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Ideal AnticoagulantWarfarin UFH LMWH Fondaparinux Rivaroxaban Dabigatran Apixaban


Once Daily

Predictable effect

Different dosing

Wide Therapeutic


Fast onset of action

No need for monitoring

Risk of HIT Not sure

Drug – drug interactions

Greater efficacy than


Indwelling Epidural catheter

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Rivaroxaban – Direct Factor Xa Inhibitor

• Effective anticoagulation strategy– Factor Xa is the pivotal point for

amplification in the coagulation cascade

– Each molecule of Factor Xa generates ~1,000 molecules of thrombin

– Observed improvement of anticoagulant efficacy with higher selectivity for Factor Xa

• Inhibits thrombin generation– Leaves existing thrombin to

maintain primary haemostasis• Shallower dose–response curve of Factor Xa

compared with thrombin suggests wider therapeutic window

Turpie AGG. Arterioscler Thromb Vasc Biol 2007;27:1238–1247

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Direct Factor Xa inhibitor Oral,administration Fixed dose High oral bioavailability Rapid onset of action Predictable PK and PD No risk of HIT or osteopenia No coagulation monitoring required

Alban S. Eur J Clin Invest. 2005;35(Suppl 1):12.

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Rivaroxaban – Pharmacokinetic Profile

• Terminal half-life: 7 – 11 hrs• Bioavailibility: 80–100 % • Cmax at 2–4 hrs


• Plasma protein binding 92–95%• Moderate volume of distributionDistribution

• ~ two-thirds metabolized• No major or active circulating metabolites Metabolism

• ~ one-third excreted as unchanged active substance in urine

• Of the two-thirds metabolized: half eliminated renally, half eliminated by faecal route


Xarelto Summary of Product Characteristics

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• Rivaroxaban is the only oral anticoagulant which can be safely administered along with indwelling epidural catheter

Last dose of rivaroxaban At least 18 hoursRemoval of catheter

At least 6 hoursNext dose of rivaroxaban

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Rivaroxaban to be Used Without Dose Adjustment Independent of Age, Weight, Gender

No dose adjustment necessary in patients above 65 years

• A higher concentrations in elderly patients are mainly due to reduced renal clearance

No dose adjustment necessary for higher or lower body weights

• Extremes in body weight (<50 kg or >120 kg) had only a small influence on rivaroxaban plasma levels

No dose adjustment necessary for male or female patients

Xarelto®. Summary of Product Characteristics (SPC), May 2009

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Surgical Thrombectomy

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Percutaneous Mechanical Thrombectomy



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Bleed Management in a Nutshell

Bleeding with Newer Oral Anticoagulants

Mild Moderate to severe Life threatening

Delay next doseor discontinuetreatment asappropriate

• Symptomatic treatment• Mechanical compression• Surgical intervention• Fluid replacement• Hemodynamic support• Activated charcoal if

ingested <2 hours prior to presentation

Consider PCCRecombinant FVIIaIn Development –


W. Frank Peacock et al. Clin. Cardiol. DOI:10.1002/clc.22037 © 2012 Wiley Periodicals, Inc.

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Procoagulant Factors for Reversal of Anticoagulants

Fresh Frozen Plasma Cryoprecipitate

Prothrombin complex


Activated Factor VIIa

The Annals of Pharmacotherapy ■ 2013 June, Volume 47

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9/98 medslides.com 43

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