VENOUS THROMBOEMBOLISM PROPHYLAXIS for the Hospitalized Medical Patients Madel Sadili, MD, FCCP, FPCCP.

VENOUS THROMBOEMBOLISM PROPHYLAXIS for the Hospitalized Medical Patients
Madel Sadili, MD, FCCP, FPCCP

Lecture Outline Arterial & Venous Thrombosis Burden Of Disease (VTE)
Incidence Rationale for Thromboprophylaxis Risk Factors Grading of Recommendations Recommendations Drugs Summary

Venous Thromboembolism (VTE)
DVT : Deep-vein thrombosis PE : Pulmonary Embolism

Arterial Thrombosis Most common cause of MI, stroke, & limb gangrene
Usually is initiated by the spontaneous or mechanical rupture of atherosclerotic plaque Consists of platelet aggregates held together by small amounts of fibrin Strategies to inhibit arterial thrombogenesis focus mainly on drugs that block platelet function but often include anticoagulant agents to prevent fibrin deposition

Venous thrombosis Leads to PE (can be fatal) & to postphlebitic syndrome Occurs when procoagulant stimuli overwhelm natural protective mechanisms, ie, excessive activation of coagulation with thrombophilic abnormalities, vessel wall damage or stasis; inflammatory cytokines generated after trauma, surgery, or medical illness activate endothelial cells that express adhesion molecules that attract leukocytes which elaborate tissue factor & express receptors for factor X & fibrinogen, that promotes coagulation on their surfaces; neutrophils generate O2 free radicals & release hydrolytic enzymes, enhancing local clot formation Venous thrombus is composed mainly of fibrin & RBCs Anticoagulants are the drugs of choice for their prevention & treatment

IMPACT OF VENOUS THROMBOEMBOLISM

Hospitalization for an acute medical illness
Independently associated with ~8fold increase in relative risk for VTE (Heit, et al. Arch Int Med 2000;160) 10-30% of general medical patients may develop VTE (Cohen, et al. Thromb Haemost 2005; 94) 50-70% of symptomatic thromboembolic events, and 70-80% of fatal PEs occur in non-surgical patients (Goldhaber, et al. Chest 2000; 118) ¾ of VTE in hospitalized patients occur in acutely ill nonsurgical patients (Leizorovicz, et al. J Thrombosis & Hemostasis 2003)

PE (postmortem studies) is associated with up to 10% of deaths in hospitalized patients, and only ¼ of these occur following surgery thus… ¾ of hospitalized patients who suffer a fatal PE are in fact medical patients Cohen et al. Thromb Haemost 2005; 94

VTE: Magnitude of the Problem
DVT 2 million cases Post-thrombotic syndrome 800,000 cases PE 600,000 cases Goldhaber has suggested that the true prevalence of DVT is closer to 2 million cases. The scope of the problem goes beyond the morbidity from the DVT itself. Post-thrombotic syndrome and pulmonary hypertension are severe sequelae, which impact on quality of life. Approximately 10% of PE leads to death, accounting for 60,000 deaths per year. Overall, the $1.5 billion dollars per year are spent on venous thrombosis per year. Death 60,000 cases Pulmonary hypertension 30,000 cases Estimated cost of VTE care = US$ 1.5 billion/year Goldhaber SZ et al. Lancet 1999;353:1386–9

Therefore... the appropriate prophylaxis of medical inpatients offers an important opportunity to significantly reduce the burden of disease due to VTE

VENOUS THROMBOEMBOLISM: Philippine AUTOPSY SURVEYS
Samia Reyes Juaneza Pingol INSTITUTION STUH PGH PHC PGH PERIOD STUDY DESIGN CS DS CC DS NUMBER , , AGE ( YEARS ) NB NB - 73 FINDINGS P. Infarct PVO PE / Inf PE / Inf INCIDENCE (%) Villespin, unpublished, 1994

Rationale for Thromboprophylaxis in Hospitalized Patients

Rationale Description High Prevalence of VTE
Adverse Consequences of unprevented VTE Efficacy & Effectiveness of thromboprophylaxis Description Most hospitalized px have risk factors for VTE DVT is common in many hospitalized px Hosp-acquired DVT & PE are usually clinically silent Difficult to predict which at-risk patients will develop symptomatic thromboembolic complications Screening at-risk px using PE or noninvasive testing is neither effective nor cost-effective Symptomatic DVT & PE Fatal PE Costs of investigating symptomatic patients Risks & costs of treating unprevented VTE, esp bleeding Increased future risk of recurrent VTE Chronic post-thrombotic syndrome Thromboprophylaxis is highly efficacious at preventing DVT, proximal DVT, symptomatic VTE, & fatal PE Prevention of DVT also prevents PE Cost-effectiveness of prophylaxis has repeatedly been demonstrated Geerts, et al. Chest 2001; 119:132S-175S

Who are at risk for VTE?

Surgery Trauma (major or lower extremity) Immobility, paresis Malignancy Cancer therapy (hormonal, chemotx, radiotx) Previous VTE Increasing age Pregnancy & the postpartum period Estrogen-containing oral contraception or HRT Selective estrogen receptor modulators Acute medical illness Heart or respiratory failure Inflammatory bowel disease Nephrotic syndrome Myeloproliferative disease Paroxysmal nocturnal hemoglobinuria Obesity Smoking Varicose veins Central venous catheterization Inherited or acquired thrombophilia Heit, et al. Arch Int Med 2002; 162:

Absolute risk of DVT in Hospitalized Patients
Medical px % General surgery 15-40 Major gyne surgery Major urologic surgery 15-40 Neurosurgery Stroke Hip or knee arthroplasty; hip fracture surgery 40-60 Major trauma Spinal cord injury 60-80 Critical care patients 10-80 Geerts, et al. Chest 2001; 119:132S-175S

Despite consensus-group recommendations that at-risk medical patients should receive thromboprophylaxis, there is NO CONSENSUS as to which patients are at risk, thus, many patients may not receive appropriate thromboprophylaxis Cohen, et al. Thromb Haemost 2005: 94

Cohen, p 9. Fig. 2

Thromboprophylaxis in Acutely Ill Patients
MEDENOX (1999) Prophylaxis of VTE in MEDical Patients with ENOXaparin 40mg, 20mg enoxaparin vs placebo OD x 6-14 days 866 patients with heart failure, respiratory, & infectious disease Primary outcome – VTE between days 1-14 – DVT detected by bilateral venography (or duplex utz) between days 6-14 (or earlier if clinically indicated) or documented PE Duration of ff-up – 3 months Samama MM et al. N Engl J Med 1999;341:793–800

MEDENOX: Incidence of VTE at Day 14
P = RRR = -63% P = 0.037 RRR = -65% The incidence of total, proximal and distal DVT was significantly reduced with enoxaparin 40 mg compared with placebo. By day 14, the incidence of VTE was 14.9% in the placebo group and 5.5% in the enoxaparin 40 mg group, representing a significant 63% relative risk reduction (97% CI: 37-78%; P = ). Outcomes in the enoxaparin 20 mg group were not significantly different from placebo. A total of four symptomatic non-fatal PE occurred, three in the placebo group and one in the enoxaparin 20 mg group. By day 110, 798 patients had been assessed for secondary efficacy. The significant reduction in total VTE and proximal and distal DVT observed in the enoxaparin 40 mg group was maintained at the 3-month follow-up. Relative risk reduction at 3-month follow-up: all VTE 59% and proximal DVT 66%. Four additional fatal PE occurred during follow-up, one in the placebo group (3 weeks after the treatment period ended) and one and two in the enoxaparin 20 mg and 40 mg groups, respectively (2 months after the treatment period ended). NS NS = not significant Samama MM et al. N Engl J Med 1999;341:793–800

MEDENOX The incidence of VTE was significantly lower in the 40mg enoxaparin group (5.5%) than in the placebo (14.9%) The benefit was maintained at 3 months

PREVENT (2003) Prospective evaluation of Dalteparin efficacy for the prevention of VTE in immobilized patients Largest trial (radomized, double-blind, palacebo-controlled) comparing a LMWH with placebo – Dalteparin 5000 IU OD x 14 days 3706 acutely ill medical patients – CHF, acute respiratory failure, or infectious disease Primary endpoint – clinically important VTE defined as objectively verified symptomatic DVT, PE, sudden death, & objectively verified asymptomatic proximal DVT. Compression UTZ done in all patients who had not reached an endpoint by day 21 Leizorovicz, et al. J Thrombosis & Haemostasis. July 2003

PREVENT: Results Medically ill patients 52% CHF
30% respiratory failure Also, infection without septic shock, rheumatic disorders, arthritis of the legs, or inflammatory bowel disease P=0.0015 Leizorovicz A. et al J Thromb Haemost 2003; 1 (Suppl 1):)OC396

PREVENT The incidence of the composite primary outcome was 2.77% in the dalteparin group and 4.96% in the placebo group, a risk reduction of 45%

Grading of Recommendations

Grade 1A Clear 1C+ 1B 1C Implications Clarity of risk/benefit
Methodological strength of supporting evidence Implications 1A Clear RCTs w/o important limitations Strong recommendation; can apply to most patients in most circumstances without reservation 1C+ No RCTs, but strong RCT results can be unequivocally extrapolated, or overwhelming evidence from observational studies Strong recommendation; can apply to most patients in most circumstances 1B 1C RCTs with important limitations (inconsistent results, methodological flaws) Observational studies Strong recommendation; likely to apply to most patients Intermediate-strength recommendation; may change when stronger evidence is available

Grade 2A Unclear 2C+ 2B 2C Implications Clarity of risk/benefit
Methodological strength of supporting evidence Implications 2A Unclear RCTs without important limitations Intermediate-strength recommendation; best action may differ depending on cirumstances or patients’ or societal values 2C+ No RCTs, but strong RCT results can be unequivocally extrapolated, or overwhelming evidence from observational studies Weak recommendation; best action may differ depending on circumstances or patients’ or societal values 2B RCTs with important limitations Weak recommendation; alternative approaches likely to be better for some patients under some circumstances 2C Observational studies Very weak recommendation; other alternatives may be equally reasonable

Recommendations: Thromboprophylaxis in the Medically Ill
Geerts, et al. Chest Supplement. Sept 2004; 126/3

General Recommendations
It is recommended that mechanical methods of prophylaxis be used primarily in patients who are at high risk of bleeding (Grade 1C+) or as an adjunct to anticoagulant-based prophylaxis (Grade 2A) Careful attention should be directed toward ensuring the proper use of, and optimal compliance with, the mechanical device (Grade 1C+) We recommend against the use of aspirin alone as prophylaxis against VTE for any patient group (Grade 1A) For each of the antithrombotic agents, it is recommended that clinicians consider the manufacturer’s suggested dosing guidelines (Grade 1C)

General Recommendations
We recommend consideration of renal impairment when deciding on doses of LMWH, fondaparinux, the direct thrombin inhibitors, & other antithrombotic drugs that are cleared by the kidneys, particularly in elderly patients and those who are at high risk for bleeding (Grade 1C+) In all patients undergoing neuraxial anesthesia or analgesia, special caution when using anticoagulant prophylaxis is recommended (Grade 1C+)

Medical Conditions In acutely ill medical patients who have been admitted to the hospital with CHF or severe respiratory disease, or who are confined to bed & have 1 or more additional risk factors, including active cancer , previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease, prophylaxis with LDUH or LMWH is recommended (Grade IA) In medical patients with risk factors for VTE, & in whom there is a contraindication to anticoagulant prophylaxis, the use of mechanical prophylaxis with GCS or IPC is recommended (Grade 1C+)

Medical Condition: Acute MI
For all patients at high risk of systemic or venous thromboembolism (anterior MI, pump failure, previous embolus, atrial fibrillation, or LV thrombus), the administration of IV UFH while receiving streptokinase, is recommended (Grade 1C+)

Medical Condition: Acute Ischemic Stroke
For acute stroke patients with restricted mobility, prophylactic low-dose subcutaneous heparin or LMWH or heparinoids is recommended (Grade 1A). *Low-dose heparin should be restricted for 24h after administration of thrombolytic therapy; it may be used safely in combination with aspirin. For patients who have contraindications to anticoagulants, it is recommended that clinicians use intermittent pneumatic compression devices or elastic stockings (Grade 1C)

Medical Conditions: Intracerebral Hemorrhage
We recommend the initial use of intermittent pnuematic compression (Grade 1C+). In stable patients, low-dose SQ heparin may be initiated as soon as the 2nd day after the onset of the hemorrhage (Grade 2C). Underlying values and preferences: the recommendation for SQ heparin assumes a relatively low degree of risk aversion.

Cancer Patients 6-fold increased risk of VTE compared to those without cancer More specific risk estimates of VTE by cancer type, stage, and treatment approaches are still largely unknown High among those with malignant brain tumors and adenocarcinoma of the ovary, pancreas, colon, stomach, lung, prostate, and kidney Cancer patients undergoing surgery have at least 2x the risk of postoperative DVT and more than 3x the risk of fatal PE

Cancer Patients Cancer patients undergoing surgical procedures receive prophylaxis that is appropriate for their current risk state (Grade 1A). Refer to the surgical subsections. Hospitalized cancer patients who are bedridden with an acute medical illness should receive prophylaxis that is appropriate for their current risk state (Grade 1A). Refer to the medical subsection. It is suggested that clinicians not routinely use prophlaxis to try to prevent thrombosis related to long-term indwelling CVCs in cancer patients (Grade 2B).

Critical Care On admission to a critical care unit, all patients should be assessed for their risk of VTE. Accordingly, most patients should receive thromboprophylaxis (Grade 1A) For patients who are at high risk for bleeding, mechanical prophylaxis with GCS &/or IPC is recommended, until the bleeding risk decreases (Grade 1C+) For ICU patients who are at moderate risk for VTE (eg, medically ill or postoperative px), LDUH or LMWH prophylaxis is recommended (Grade 1A) For patients who are at higher risk, such as that following major trauma or orthopedic surgery, LMWH prophylaxis is recommended (Grade 1A)

BURNS Burn patients with additional risk factors for VTE, including one or more of the ff: advanced age, morbid obesity, extensive or lower extremity burns, concomitant lower extremity trauma, use of a femoral venous catheter, &/or prolonged immobility (Grade 1C+) If there are no contraindications, the use of either LDUH or LMWH is recommended, starting as soon as it is considered safe to do so (Grade 1C+)

Long Distance Travel For long-distance travelers (ie, flights of >6h duration): avoidance of constrictive clothing around the lower extremities or waist; avoidance of dehydration & frequent calf muscle stretching (Grade 1C) For long-distance travelers with additional risk factors for VTE, the general strategies listed above are recommended. If active prophylaxis is considered, because of the perceived increased risk of venous thrombosis, the use of properly fitted, below-knee GCS, providing mmHg of pressure at the ankle (Grade 2B), or a single prophylactic dose of LMWH, injected prior to departure (Grade 2B), is recommended. We recommend against the use of aspirin for VTE prevention associated with travel (Grade 1B)

General Surgery Moderate-risk patients: Higher risk patients:
LDUH 5,000 u bid or LMWH <3,400 u od (Grade 1A) Higher risk patients: LDUH 5,000 u tid or LMWH >3,400 u od (Grade 1A) High-risk patients with multiple risk factors Same as high-risk patients plus the use of GCS &/or IPC (Grade 1C+)

Major Gynecologic & Urologic Surgery
LDUH 5,000u bid to tid (Grade 1A)

Orthopedic Surgery Elective total hip or knee arthroplasty:
LMWH, Fondaparinux, or adjusted-dose vit K antagonist (VKA with INR 2-3 (Grade 1A) Hip fracture surgery (HFS): Fondaparinux (Grade 1A), LMWH (Grade 1C+), VKA (Grade 2B), or LDUH (Grade 1B) Thromboprophylaxis is recommended to be given for at least 10 days (Grade 1A)

Increased Risk of Bleeding
Recent surgery Known bleeding disorder Impaired renal function Uncontrolled hypertension Large ischaemic cerebral infarction Active GI bleeding (peptic/bowel) Use of antiplatelet drugs or NSAIDs

Methods of DVT Prophylaxis
Unfractionated heparin (UFH) Low-molecular-weight heparins (LMWHs) Oral anticoagulants (warfarin) Pentasaccharides (fondaparinux) Antiplatelet therapy Mechanical compression and early ambulation

Unfractionated Heparin
Main anticoagulant action is mediated by the heparin/AT interaction, which inactivates thrombin factor IIa & factors Xa, IXa, & XIIa Increases vessel wall permeability, suppresses proliferation of vascular smooth muscle cells, suppresses osteoblast formation, & activates osteoclasts, promoting bone loss, & HIT IV infusion or SC injection (reduced bioavailabiltiy, thus, 10% higher initial dose) Dose adjustment by monitoring aPTT, or, when very high doses are given, by ACT (activated clotting time)

LMWH Polysulfated glycosaminoglycans about 1/3 the molecular weight of UFH Like heparin, major anticoagulant effect by activating AT Administered in fixed doses, for thromboprophylaxis, or in total body weight (TBW)-adjusted doses, for therapeutic effect

LMWH Reduced binding properties to proteins & cells, explaining all of the anticoagulant, phramacokinetic, & other biological differences between heparin & LMWH: -reduced ability to inactivate thrombin bec the smaller fragments cannot bind simultaneously to AT & thrombin, but, since bridging bet AT & factor Xa is less critical for factor Xa activity, the smaller fragments inactivate factor Xa almost as well as larger molecules -reduced binding to plasma proteins is responsible for the more predictable dose-response relationship of LMWHs -lower binding to macrophages & endothelial cells increases the plasma half-life of LMWHs -reduced binding to platelets & PF4 explains lower incidence of HIT -reduced binding to osteoblasts results in lower incidence of bone loss

Fondaparinux New parenteral indirect factor Xa inhibitor, with no activity against thrombin Excellent bioavailability after SQ injection with a plasma half-life of 17h, thus given OD Does not bind to platelets or PF4 (no heparin/PF4 complex), thus, no HIT Phase III trial for thromboprophylaxis at 2.5mg OD

THE-PRINCE Study: Incidence of VTE with Enoxaparin and UFH
Thromboembolism Prevention in Heart Failure or Severe Respiratory Disease with Enoxaparin (THE-PRINCE) All evaluable patients Patients with heart failure P=0.0139 18 18 P=0.0146 16.1 16 16 14 14 12 10.4 12 9.7 10 Patients (%) 10 The optimal management of UA/NSTEMI has two goals: the immediate relief of ischaemia and the prevention of serious adverse outcomes, such as death or myocardial infarction/reinfarction. According to the American College of Cardiology (ACC) / American Heart Association (AHA) guidelines, this is best achieved with an approach that includes anti-ischaemic therapy, antiplatelet and antithrombotic therapy, ongoing risk stratification, and the use of invasive procedures as warranted. Query to author: We have added the graph on the left-hand side as in the version we received this was missing. Is this the information that you wanted to display here? 8.4 Patients (%) 8 8 6 6 4 4 2 2 Enoxaparin UFH Enoxaparin UFH Kleber FX et al. Am Heart J 2003;145:614–21

VTE Prevention Non-Pharmacologic Methods
Ambulation Elastic or Graduated compression stockings (GCS) Intermittent pneumatic compression (IPC) devices Arteriovenous foot pumps (VFP)

Mechanical Methods of Prophylaxis
Increase venous outflow and/or reduce stasis within the leg veins Primary attraction is the lack of bleeding potential, therefore, are considered for patients with high bleeding risks Must select the correct size of the device, must properly apply them, and must ensure that they are removed for only a short time each day, and that they do not impede ambulation

Recommendation: Mechanical Methods of Prophylaxis
Should be used primarily in patients who are at high risk of bleeding (Grade 1C+), or an an adjunct to anticoagulant-based prophylaxis (Grade 2A) Careful attention must be directed toward ensuring the proper use of, and optimal compliance with, the mechanical device (Grace 1C+)

Summary VTE is an important clinical problem worldwide
Thromboprophylaxis for the medically-ill patients who are at risk for VTE is effective & safe The concensus recommends against the use of aspirin alone for thromoprophylaxis LDUH, LMWH, VKA, Fondaparinux, and mechanical devices are recommended for thromboprophylaxis.

Thromboprophylaxis in Internal Medicine: a Meta-analysis
19,764 patients UFH or LMWH versus control

Thromboprophylaxis in Internal Medicine: LMWH vs. UFH
4,469 patients LMWH vs. UFH

General Medical Patients: LDUH Versus No Prophylaxis*
Intervention DVT, % (n/N) Study Control LDUH Control LDUH Gallus et al No prophylaxis t.i.d. 22.5 (9/40) 2.6 (1/38) Belch et al. 1981 No prophylaxis t.i.d. 26.0 (13/50) 4.0 (2/50) Query to author: Numbers 22.5 (9/40) and 2.6 (1/38) were changed to the ones mentioned in the reference. Is this okay? Cade 1982 Placebo b.i.d. 10.4 (7/67) 1.6 (1/64) *Includes randomized trials in which routine screening with an objective diagnostic test for DVT was used Gallus AS et al. N Engl J Med 1973;288:545–51 Belch JJ et al. Scott J Med 1981;26:115–7 Cade JF. Crit Care Med 1982;10:448–50 b.i.d., twice a day; t.i.d., 3 times a day

General Medical Patients: LDUH Versus LMWH* (1)
Intervention DVT, % (n/N) Study LDUH LMWH LDUH LMWH Bergmann & Neuhart 1996 5,000 IU b.i.d. Enoxaparin 20 mg o.d. 4.6 (10/216) 4.8 (10/207) Harenberg et al. 1996 5,000 IU t.i.d. Nadroparin 36 mg o.d. 0.5 (4/780) 0.7 (6/810) Lechler et al. 1996 Query to author: We have included intention-to-treat data for Lechler. Is this okay? 5,000 IU t.i.d. Enoxaparin 40 mg o.d. 1.4 (6/443) 0.2 (1/442) *Includes randomized trials in which LDUH and LMWH were compared and routine screening with an objective diagnostic test for DVT was used Bergmann J-F & Neuhart E. Thromb Haemost 1996;76:529–34 Harenberg J et al. Haemostasis 1996;26:127–39 Lechler E et al. Haemostasis 1996;26(Suppl 2):49–56

General Medical Patients: LDUH Versus LMWH* (2)
Intervention DVT, % (n/N) Study LDUH LMWH LDUH LMWH Harenberg et al. 1999† 5,000 IU t.i.d. Enoxaparin 40 mg o.d. 22.1 (67/303) 15.6 (51/327) Kleber et al. 2003 5,000 IU t.i.d. Enoxaparin 40 mg o.d. 10.4 (22/212) 8.4 (20/239) *Includes randomized trials in which LDUH and LMWH were compared and routine screening with an objective diagnostic test for DVT was used †This study has been presented only in abstract form to date Harenberg J et al. Blood 1999;94(Suppl 1):399A Kleber FX et al. Am Heart J 2003;145:614–21

Prophylaxis of VTE in Medical Patients
RR of DVT in studies comparing heparins with no treatment Heparin better Heparin worse Surgery n=12,550 RR=0.43 (95% CI, 0.37–0.50) General medicine n= RR=0.44 (95% CI, 0.29–0.64) Stroke n= RR=0.43 (95% CI, 0.26–0.73) Query to author: please suggest a reference for this slide? Also, please could you confirm how the x axis should be labelled? – if it is RR then the box plots and stated values do not match. Acute MI n= RR=0.32 (95% CI, 0.20–0.61) 0.5 1 1.5 RR CI, confidence interval; MI, myocardial infarction

Thromboprophylaxis in Internal Medicine: Risk:Benefit Ratio
Risk:benefit ratio of heparins vs. controls 50% reduction in risk of symptomatic PE 2-fold increase in major bleeding Risk:benefit ratio of LMWH versus UFH Similar effect on symptomatic PE 50% reduction in risk of major bleeding LMWHs are effective and safe

Incidence of VTE in Heart Failure Patients in THE-PRINCE and MEDENOX studies
20 16 12 8 4 MEDENOX Placebo (n=96) Enoxaparin 40 mg o.d. (n=98) THE-PRINCE (n=113) THE-PRINCE UFH 5,000 IU t.i.d. (n=93) 14.6 4.0 9.7 16.1 Incidence of VTE (%) Kleber FX et al. Am Heart J 2003;145:614–21 Samama MM et al. N Engl J Med 1999;341:793–800 UFH, unfractionated heparin

PREVENT: Study Design Dalteparin vs. Placebo in medically ill patients (n=3,706) Primary endpoint: reduction in clinically important VTE Objectively verified symptomatic DVT Objectively verified asymptomatic proximal DVT Fatal and non-fatal PE Sudden death Selection of Patients: Day 3 Randomizations: Day 1 Bilateral ultrasonography Treatment Period Follow-up period PREVENT, Prospective Evaluation of Dalteparin Efficacy In Immobilized Patients Trial Vaitkus PT et al Vasc Med 2002;7:269-73

PREVENT: Incidence of VTE on Day 21
Incidence of VTE (%) Difference in Risk Dalteparin Placebo incidence ratio (n=1,518) (n=1,473) (–3.57 to –0.81) (0.38–0.80) Query to author: okay to write Day 21 instead of 21+3 (in ISTH abstract)? P= (Cochran-Mantel-Haenszel test) Leizorovicz A et al. J Thromb Haemost 2003;1(Suppl 1):OC396

EXCLAIM: Extended Clinical Prophylaxis in Acutely ill Medical Patients

Thromboprophylaxis in Medical Patients: Real World Data
DVT Free Routine preventive efforts among inpatients are not widely practiced, especially among acutely ill medical patients IMPROVE2 International Medical Prevention Registry on Venous Thromboembolism Most acutely ill medical patients do not receive thromboprophylaxis during hospitalization Goldhaber SZ & Tapson VF. J Thromb Haemost 2003; 1 (Suppl 1):P1470 Anderson FA et al. J Thromb Haemost 2003; 1 (Suppl 1):P1438

DVT FREE Registry (1) Of the 5,451 patients, 50% (n=2,725) were diagnosed with DVT as outpatients or in the emergency department and 50% (n=2,726) were diagnosed as inpatients Overall, 71% (n=3,894) of patients received no prophylaxis for DVT within 30 days prior to diagnosis Of the 29% (n=1,557) of patients who did receive prophylaxis, 30% (n=410) were diagnosed with DVT as outpatients and 70% (n=1,147) as inpatients Query to author: We have altered this slide using data from the reference shown. Is this updated slide okay? Goldhaber SZ & Tapson VF. J Thromb Haemost 2003;1(Suppl 1):P1470

DVT FREE Registry (2) Surgical patients (those with a history of surgery within 3 months prior to diagnosis) were far more likely to receive DVT prophylaxis than non-surgical patients The vast majority of non-surgical patients (80%; n=2,295) received no prophylaxis within 30 days before diagnosis Query to author: We have altered this slide using data from the reference shown. Is this updated slide okay? Goldhaber SZ & Tapson VF. J Thromb Haemost 2003;1(Suppl 1):P1470

IMPROVE: Prophylaxis According to Primary-admission Category
60 50 46 45 40 thromboprophylaxis (%) Patients receiving 24 20 Cardiac Pulmonary Neurological Cancer (n=254) (n=348) (n=208) (n=104) Primary-admission category

IMPROVE: Prophylaxis According to Number of Risk Factors
80 64 60 51 thromboprophylaxis (%) Patients receiving 40 31 29 \ 20 (n=86) 1–2 (n=826) 3–4 (n=605) 5 (n=77) Number of VTE risk factors

Thromboprophylaxis in Medical Patients: Heparins (UFH and LMWH) versus Control
Heparins better Heparins worse DVT PE Death Major haemorrhage RR=0.44 (0.29–0.64) P<0.001 RR=0.48 (0.34–0.68) P<0.001 P=NS Note to author: this slide has been redrawn as the values did not match those shown in the reference. 0.5 1 1.5 2.0 2.5 3.0 3.5 RR Mismetti P et al. Thromb Haemost 2000;83:14–19

Thromboprophylaxis in Medical Patients: LMWH versus UFH
LMWH better UFH better DVT PE Death Major haemorrhage P=NS RR=0.48 (0.23–1.0) P=0.049 RR Mismetti P et al. Thromb Haemost 2000;83:14–19

SAFETY of THROMBOPROPHYLAXIS

MEDENOX: Summary of haemorrhage during the treatment period
NS n = 5 n = 4 n = 36 n = 34 n = 27 These slides summarize safety outcomes during the treatment period. There were no significant differences between the groups in the frequency of major or minor haemorrhage, thrombocytopenia or any other adverse event. Major haemorrhage occurred in 11 patients during the treatment period; the fatal haemorrhage in the enoxaparin 40 mg group was considered unrelated to the study treatment by the investigators. Two additional fatal haemorrhages occurred during follow-up, one in the enoxaparin 20 mg group and one in the enoxaparin 40 mg group, 8 and 3 weeks after discontinuation of the study medication, respectively. n = 1 n = 6 n = 4 Placebo Enoxaparin 20 mg Enoxaparin 40 mg NS = not significant

THE-PRINCE Study: Adverse-event Analysis
Overall adverse events Injection-site haematoma P<0.004 P<0.027 15 60 53.8 12.6 50 45.8 10 40 Patients (%) 7.2 Patients (%) 30 The optimal management of UA/NSTEMI has two goals: the immediate relief of ischaemia and the prevention of serious adverse outcomes, such as death or myocardial infarction/reinfarction. According to the American college of Cardiology (ACC) / American Heart Association (AHA) guidelines, this is best achieved with an approach that includes anti-ischaemic therapy, antiplatelet and antithrombotic therapy, ongoing risk stratification, and the use of invasive procedures as warranted. 5 20 10 Enoxaparin Enoxaparin UFH UFH Kleber FX et al. Am Heart J 2003;145:614–21

RIETE: Does VTE Outcome Differ in Surgical and Medical Patients?
RIETE: computerized registry of patients with VTE Consecutive, current and symptomatic VTE 3-month outcome Surgical Medical (n=672) (n=1,286) Thromboprophylaxis 454 (68%) 312 (24%) Query to author: Please suggest a full reference for this slide or confirm that the ISTH abstract shown is okay. Monreal M et al. J Thromb Haemost 2003;1(Suppl 1):P1398

RIETE: VTE Characteristics
Surgical Medical P value (n=671) (n=1,286) Distal DVT (17%) (9%) 0.001 Proximal DVT 295 (44%) 645 (50%) 0.009 PE 259 (39%) 526 (41%) NS Note to author: 295 (45%) is not correct – please could you provide the reference so that this can be double checked (data not in ISTH abstract)? Monreal M et al. J Thromb Haemost 2003;1(Suppl 1):P1398

RIETE: Major Outcomes at 3 Months
Surgical (n=671) 46 (7%) 5 (0.8%) 1 (0.1%) 10 (1.5%) Medical (n=1,286) 218 (17%) 43 (3.3%) 17 (1.3%) 52 (4.0%) Odds ratio (95% CI) 0.36 (0.25–0.51) 0.22 (0.08–0.58) 0.11 (0.01–0.79) 0.36 (0.17–0.74) P value 0.0001 0.0004 0.0099 0.002 Death Fatal PE Fatal bleeding Major bleeding Note to author: 46 (6%) and 1 (0.2%) are not correct – please could you provide the reference so that this can be double checked (data not in ISTH abstract)? Monreal M et al. J Thromb Haemost 2003;1(Suppl 1):P1398

Safety of LMWHs in Medical Patients
Hemorrhage Anecdotal reports of ADRs induced by LMWHs In 1997, two cases of fatal bleeding were reported (cancer in one case, morbid obesity and cardiac failure in the other). Patients were over 80 years with worsening renal insufficiency (Hôtel Dieu, Paris, France) Increased bleeding in cardiac patients in trials with a high dose of enoxaparin ADR, adverse drug reaction

Pooled analysis of THE-PRINCE, PRIME and MEDENOX studies
Safety of Enoxaparin Pooled analysis of THE-PRINCE, PRIME and MEDENOX studies Placebo n (%) UFH 5,000 IU TID n(%) Enoxaparin 40 mg OD Total 362 (100) 815 (100) 1,169 (100) Major bleeding* 4 (1.1) 8 (1.0) 9 (0.8) Minor bleeding^ 27 (7.5) 105 (12.9) 89 (7.6) Thrombocytopenia§ 3 (0.8) 5 (0.6) 5 (0.4) *UFH vs. placebo: RR=1.73 (95% CI, ); P=0.009 ^Enoxaparin vs. Placebo: RR=1.02 (95% CI, ); P=NS § Enoxparin vs. UFH: RR= 0.59 (95% CI, ); P=0.0001 Alikhan R. & Cohen AT. Thromb Haemost 2003;89:590-1

Tolerability of LMWHs: Bleeding Events
Patients from medical departments: cardiology, geriatrics, angiology, infectious disease More than 50% of patients received aspirin Prolonged treatment of more than 10 days in 27% of patients Bleeding events observed in 15/334 (4.7%) of patients 7 (7%) during curative treatment 8 (3.4%) during thromboprophylaxis increased bleeding risk when creatinine clearance <20 ml/min Digestive hemorrhage 3 Haematoma 7 Ecchymoses 2 Epistaxis 1 Gingival bleeding 13 cases of thrombocytosis, 4 moderate thrombocytopenia, 1 hepatic cytosis (doubtful causal relationship) Query: Thrombocytopenia okay in final bullet point? Cestac P et al. Drug Saf 2003;26:197–207

LMWHs: Safe and Cost-effective
The good safety profile of LMWHs is an important characteristic of these drugs which allows wide international use and substitution for UFH in most clinical indications Success factor Socio-economic studies have concluded that LMWHs are cost-effective1,2 MEDENOX trial: for patients in a tertiary-care setting, incremental cost-effectiveness of enoxaparin 40 mg versus placebo was US$ 87/VTE avoided1 1Lamy A et al. Can Respir J 2002;9:169–77 2de Lissovoy G & Subedi P. Am J Manag Care 2002;8:1082–8

FDA Approved Indications for Currently Available LMWH
Enoxaparin Dalteparin Tinzaparin Prevention of DVT in Hip Replacement Yes No Extended Prophylaxis Prevention of DVT in Knee Replacement Prevention of DVT in Abdominal Surgery Inpatient treatment of DVT w/wo PE Outpatient treatment of DVT w/o PE ?? Prevention of Ischemia in UA/NSTEMI Prevention of DVT in Medically Ill

SUMMARY and RECOMMENDATIONS

VENOUS THROMBOEMBOLISM PROPHYLAXIS for the Hospitalized Medical Patients Madel Sadili, MD, FCCP, FPCCP.

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VENOUS THROMBOEMBOLISM PROPHYLAXIS for the Hospitalized Medical Patients Madel Sadili, MD, FCCP, FPCCP.

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Presentation on theme: "VENOUS THROMBOEMBOLISM PROPHYLAXIS for the Hospitalized Medical Patients Madel Sadili, MD, FCCP, FPCCP."— Presentation transcript:

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