Prophylaxis of Venous Thromboembolism Dr Galila Zaher Consultant Hematologist MRCPATH

VTE in medical patients 600,000 patients / year are hospitalized for DVT. symptomatic PE 600,000 patients and causes . contributes to death 200,000 annually. Most fatal PE occur in medical patients. A small number of randomised trials compared with that of surgical patients. Meta-analyses in MI ,stroke and other medical patients have clarified the benefits of thrombo-prophylaxis . Most cases of VTE are triggered by causes other than surgery . Despite this high risk in medical patients, there are a smaller number of medical patients in randomised trials compared with the number of surgical patients.

85% of all medical patients admitted to an acute care hospital are eligible and/or suitable for DVT prophylaxis

ACUTE MYOCARDIAL INFARCTION Prior to the introduction of routine antithrombotic therapy . Acute MI had a risk of asymptomatic DVT of 24%, and PE of 2-9%. The risk increases with age and in the presence of heart failure. Prior to the introduction of routine antithrombotic therapy (aspirin, thrombolysis, anticoagulants)

MECHANICAL PROPHYLAXIS GENERAL MEASURES . Compression stockings especially when heparin prophylaxis is contraindicated. (grade A) GENERAL MEASURES : Early mobilisation appears to reduce mortality in acute MI. RCT of 80 patients with acute MI, all of whom received aspirin, the incidence of asymptomatic DVT was significantly reduced in the stockinged leg compared with the other (control) leg.164 Taken in conjunction with good evidence for the efficacy of compression stockings in prevention of asymptomatic DVT and PE in surgical patients,72,73 there is evidence to support the use of compression stockings in patients with MI. :Evidence level 1+

ASPIRIN AND THROMBOLYTIC THERAPY Strongly recommended that all patients with acute MI should be given aspirin (150-300 mg) . (grade A) Strongly recommended that all patients with acute MI should be considered for thrombolytic therapy. (grade A) 1. Evidence level 1++ all patients with clinically suspected evolving acute MI who are not already receiving aspirin should be given aspirin

ANTICOAGULANTS Heparin not routinely in addition to aspirin in acute MI, but reserved for patients at increased thromboembolic risk (grade A) The SIGN guideline . 1. Evidence level 1++

High risk of thromboembolism Large anterior Q-wave infarction. Severe left ventricular dysfunction. Congestive heart failure. History of systemic or PE or thrombophilia. Echo evidence of mural thrombus. Persistent AF. Prolonged immobilization. Marked obesity (grade A)

ANTICOAGULANTS Full-dose heparin , followed with warfarin for up to three months. Bleeding risks outweigh the benefits, thrombo-prophylaxis low-dose SC heparin (7,500 IU 12-hourly) for seven days or until ambulant. (grade A) Full-dose heparin , followed (if indicated by continuing risk) with warfarin for up to three months, depending upon the physician's estimate of the risk: benefit ratio in the individual patient.

Acute stroke Asymptomatic DVT 50% of acute hemiplegic stroke. Clinically apparent DVT or PE <5%. PE may account for up to 25% of early

General measures Early mobilization and hydration . Meta-analysis of haemodilution : VTE was reduced, despite lack of overall benefit. Early mobilisation and hydration should, in theory, reduce the risk of thrombosis, although no studies have been performed to evaluate the impact of these interventions on VTE. There is evidence from one RCT that early intravenous fluids improve stroke outcome,167 perhaps by maintaining homeostasis.168 A meta-analysis of RCTs of haemodilution showed that VTE was reduced, despite overall lack of benefit.169

MECHANICAL PROPHYLAXIS Graduated compression stockings justified for high risk patients. (grade C) Compression stockings are preferred haemorrhagic stroke. (grade D) Intermittent pneumatic compression no evidence effective . Intermittent pneumatic compression is effective in patients undergoing neurosurgery . In small trials :acute stroke, the incidence of asymptomatic DVT was significantly reduced by GECS Taken in conjunction with good evidence for the efficacy of compression stockings in prevention of asymptomatic DVT and PE in surgical patients,72,73 they may therefore be effective in VTE reduction after stroke, although no large RCTs have evaluated their use in this context. Evidence level 1+

ASPIRIN Significant decrease in death or dependency. Aspirin significantly reduced PE from 0.5% to 0.3%. Aspirin is started as soon as ICH is excluded by CT or MRI. (grade A) Aspirin can be given by NG tube or rectally : unable to swallow. Eight trials involving 41,325 patients were included in a systematic review of the effect of aspirin on clinical outcome after acute stroke.172 .Evidence level 1++ . Aspirin significantly reduced PE from 0.5% in controls to 0.3%. Evidence level 2+ (150-300 mg/day)

ANTICOAGULANTS Systematic reviews RCTs . Heparin reduces asymptomatic DVT after stroke. Prevention of DVT& PE is offset by an increase in haemorrhagic complications. The bleeding risk is dose-related. If heparins are to be used , low dose should be selected LMWH preferred due to a lower risk of bleeding. UFH (5,000 IU SC BID) . LMWH . Systematic reviews of RCTs of low dose subcutaneous heparins (including heparinoids and LMWHs) have shown that heparin reduces the risk of asymptomatic DVT after stroke.160,161 It is less certain whether clinically apparent DVT is prevented by such regimens. Any benefit in terms of prevention of DVT, PE and early recurrence of ischaemic stroke is offset by an increase in haemorrhagic complications.160,161,172 Routine heparin use in the first two weeks after a presumed ischaemic stroke has not been associated with any net reduction in the proportion of patients who are dead or dependent at six months.160,161 The bleeding risk with UFH and LMWH is dose-related. Since there is no evidence of greater net benefit from higher dose regimens, if heparins are to be used after stroke, low dose regimens should be selected,160,161 and LMWH may be preferred due to a lower risk of bleeding in medical patients.5 Systematic reviews RCTs of low dose subcutaneous heparins (including heparinoids and LMWHs) . heparin reduces the risk of asymptomatic DVT after stroke. Any benefit in terms of prevention of DVT, PE and early recurrence of ischaemic stroke is offset by an increase in haemorrhagic complications. Routine heparin use in the first two weeks after a presumed ischaemic stroke has not been associated with any net reduction in the proportion of patients who are dead or dependent at six months.160,161 The bleeding risk with UFH and LMWH is dose-related. Since there is no evidence of greater net benefit from higher dose regimens, if heparins are to be used after stroke, low dose regimens should be selected,160,161 and LMWH may be preferred due to a lower risk of bleeding in medical patients.5

ACUTE MYOCARDIAL INFARCTION aspirin (150-300 mg).grade A thrombolytic therapy. Grade A. Heparin should not be used routinely but reserved for patients at increased thromboembolic risk grade A. Compression stockings especially when heparin prophylaxis is contraindicated grade A

Acute stroke graduated compression stockings may be justified for some high risk patients. Grade C Compression stockings are preferred for patients with haemorrhagic grade D Aspirin as soon as intracranial haemorrhage is excluded by CT or MR brain scanning. Grade A Aspirin can be given by nasogastric tube or rectally for those who are unable to swallow. UFH or a LMWH at higher than average risk of VTE . Grade A

Other medical patients low dose UFH or LMWH should be considered. grade A LMWH carries a lower risk of bleeding. grade A heparin prophylaxis is contraindicated, GECS may be considered grade C

Cancer patients Minidose warfarin (1 mg/day, no INR monitoring) with central venous catheters. Grade A Low-dose warfarin (target INR 1.6, range 1.3-1.9) during chemotherapy in stage IV breast cancer. Grade A

ANTICOAGULANTS In patients with ischaemic stroke at higher than average risk of VTE : History of previous VTE. known thrombophilia . Active cancer. Lower than average risk of haemorrhagic complications. (grade A)

Other medical patients Autopsy : PE cause of deaths in immobilized patients in medical wards. Heparin :56% decrease in asymptomatic DVT &PE The reduction in mortality was not statistically significant . The risk of major bleeding was higher LMWH as effective as UFH in reducing DVT, PE and mortality; lower risk of major bleeding. A recent meta-analysis of : seven trials of heparin versus control : 56% decrease in asymptomatic DVT &PE with heparins. eight trials of LMWH versus UFH: LMWH as effective as UFH in reducing DVT, PE and mortality; but had a 55% lower risk of major bleeding.:

Thrombo-prophylaxis in medical patients Heart failure. Respiratory failure . Infections. (chest infections). Diabetic coma. Inflammatory bowel disease. Nephrotic syndrome. Intensive care patients. Low dose UFH or LMWH . LMWH lower risk of bleeding. (grade A) medical conditions associated with at least one additional risk factor for VTE .Evidence level 1++ In general medical patients who are immobilised in hospital due to acute illness, especially those with heart failure, respiratory failure infections, diabetic coma, inflammatory bowel disease, nephrotic syndrome, or in intensive care, prophylaxis of VTE with low doseUFH or LMWH should be considered. LMWH carries a lower risk of bleeding. (grade A) In 1999 Medenox . Efficacy of a high-dose, prophylactic LMWH in DVT or one of the following

MECHANICAL METHODS Significant risk of VTE :prophylaxis is contraindicated, GECS may be considered.  (grade C) No trials were identified. In medical patients at risk of VTE, graduated compression stockings may be considered (especially if heparin prophylaxis is contraindicated), extrapolating from a meta-analysis of trials in all groups of patients, including medical patients with acute myocardial infarction.164 Evidence level 1+

Cancer patients Cancer patients have an increased risk of VTE. Central venous line thrombosis . Chemotherapy-induced thrombosis. Immobilised cancer in medical or surgical wards should be considered for prophylaxis.

ANTICOAGULANTS Minidose warfarin: (1 mg/day, no INR monitoring) in cancer patients with central venous catheters. (grade A) Low-dose warfarin (target INR 1.6) during chemotherapy stage IV breast cancer. Patients receiving antipsychotic drugs

The Medenox study clearly showed a dose-effect relationship with enoxaparin and the ineffectiveness of the lower prophylactic dose trend toward mortality reduction with enoxaparin. did not reach statistical significance. Efficacy of a high-dose, prophylactic LMWH in preventing venographically evaluated deep-vein thrombosis (DVT) Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341:793-800.

CONCLUSIONS : Enoxaparin, given once daily at a dose of 40 mg subq once daily for 6-14 days reduces the risk of VTE by 63%, without increasing the frequency of hemorrhage. Enoxaparin is the only LMWH with an approved, FDA indication for prophylaxis of DVT in medical patients. should be maintained for at least 7 days,

The majority of fatal PE have not undergone recent surgery.

In PRIME: enoxaparin versus heparin new VTE 0.2% and 1.4% . MEDENOX :confirmed the effectiveness of enoxaparin in preventing VTED in medical patients. In PRIME: enoxaparin versus heparin new VTE 0.2% and 1.4% . In PRIME, a multicentre, randomized, double-blinded comparison of enoxaparin (40 mg) versus heparin (5000 U TID) in deep vein thrombosis prophylaxis,

only 46.4% received thromboprophylactic treatment. Ageno et al. 112 patients with clinical indications for VTE prophylaxis without contraindications to anticoagulation prophylaxis was underprescribed. only 46.4% received thromboprophylactic treatment. retrospectively studied 165 patients with clinical indications for VTE prophylaxis from one teaching and one non-teaching hospital. Their data suggest that among the 112 patients without clinical contraindications to anticoagulation and without oral anticoagulant treatment prior to hospital admission (e.g. for atrial fibrillation), prophylaxis was underprescribed: even though all the 112 patients met consensus guidelines for the use of antithrombotic therapy, only 52 patients (46.4%) actually received thromboprophylactic treatment.