NEUROLOGY

Different strategies to prevent and treat VTE in stroke patients

Arrhythmias – often described as ‘hijackers’ of the heart’s rhythm and pump functions, cause the heart to either beat too fast (tachycardia), too slow (bradycardia), or too irregular (atrial fibrillation [AFib]). AFib is the most frequent form of arrythmia and is associated with an increased risk of stroke, dementia and heart failure (HF). 1,2

Over the past two decades, the prevalence of AFib has increased worldwide by 33%. Currently an estimated 37 million people have been diagnosed with the condition. However, some studies suggest that the prevalence is likely underestimated as a large proportion of asymptomatic individuals, and those who have transient symptoms, remain undiagnosed. It is predicted that the prevalence of AFib will double by 2030. 2,3

AFib, stroke and DVT

Risk factors for AFib include congestive HF, hypertension, increasing age and diabetes. Many of these factors also increase the risk for venous thromboembolism (VTE) and ischaemic stroke in AFib patients. 5

VTE is globally the third most frequent acute cardiovascular syndrome behind myocardial infarction and stroke. Cross-sectional data show that the incidence of VTE is almost eight times higher in individuals aged ≥80 years than in those in their 50s. 13

According to the American Heart Association, there are two forms of VTE: 6 » Deep vein thrombosis (DVT): A blood clot forms in a vein, usually in the deep veins of the legs or pelvis » Pulmonary embolism (PE): The blood clot can dislodge and travel in the blood, particularly to the pulmonary arteries.

Risk of DVT in stroke patients

In immobilised post-stroke patients, the incidences of DVTs vary from 10%-75%. Asymptomatic DVT and clinically evident DVT vary in their prevalence, the latter being 2%-10% after an acute stroke. 5

The risk factors for DVT in acute stroke are advanced age, high stroke scale score, hemiparesis, immobility, female gender, AFib, receipt of intravenous or intra-arterial tissue plasminogen activator, and admission to hospital. Hospitalised patients are at increased risk of developing DVT (about 50%), and this increases the risk of PE. 5,10

The onset of a DVT after acute stroke can be as early as the second day, peaking between days two and seven. If left untreated, proximal DVT have a 15% risk of death. 5

The most common cause of mortality from a DVT after a stroke is a PE, accounting for 13%-25% of early deaths, and their incidence usually ranges from 1%-3% in the first few months after a stroke. 5

Yet, only 50% of the hospitalised patients receive DVT prophylaxis. Prevention of DVT in hospitalised patients decreases the risk of DVT and PE, which in turn decreases mortality and morbidity. 10

DVT prophylaxis can be primary or secondary. Primary prophylaxis is the preferred method with the use of medications and mechanical methods to prevent DVT. Secondary prophylaxis is a less commonly used method that includes early detection with screening methods and the treatment of subclinical DVT. 10

Preventing VTE in ischaemic stroke patients

Khan et al conducted a systematic review examining prophylaxis DVT in patients following an acute stroke.

Initial diagnostic test

The initial test for diagnosing peripheral venous thrombosis is ultrasound. The test is accurate, cost effective, safe, and portable. In addition, Doppler techniques provide direct information regarding flow physiology. 5

Either computed tomography or magnetic resonance imaging can be used. Particularly when studying central veins. Other screening tests employed are 125-I fibrinogen scanning and contrast venography. A 16-point early clinical prediction scale has been suggested to identify patients at high risk for DVT after an ischaemic stroke but needs further study and validation.

New DVTs increased the risk of three-month mortality significantly with no influence on the combined risk of death and dependency. Increased serum C-reactive protein (CRP) levels, alongside a normal fibrinogen level, can predict the development of a new DVT. Such patients may then be reasonably protected with further DVT prophylaxis.

According to the authors, in patients with acute ischaemic stroke (AIS), a reduction of VTE events, death and disability rates was noted when low-molecular-weight heparin (LMWH) were used. However, this slightly increased the risk of extracranial bleeding.

Another study found that compared with standard unfractionated heparin (UFH), low dose LMWH or heparinoid decreases the risk of both DVT and PE without a clear increase in intracranial haemorrhage. Based on these studies, the conclusion was that UFH and LMWH are both effective in reducing DVT and PE in patients with stroke at the cost of a slightly increased risk of haemorrhage (intracerebral [ICH] and extracranial [ECH]).

Kamphuizen and Agnelli 7 compared the early administration of either LMWH or UFH in the prevention of VTE in patients (n=23 043) with AIS. Endpoints included objectively diagnosed DVT, PE, ICH and ECH. Low-dose UFH was arbitrarily defined as ≤15 000 IU/day, low-dose LMWH as ≤6000 IU/day or weight-adjusted dose of ≤86 IU/kg/day.

Compared to control, high-dose UFH was associated with a reduction in PE, but also with an increased risk of ICH (odds ration [OR] = 3.86) and ECH (OR = 4.74). Low-dose UFH decreased the thrombosis risk (OR = 0.17) but had no influence on PE (OR = 0.83). The risk of ICH or ECH was not statistically significant increased (OR = 1.67 for ICH and OR = 1.58 for ECH).

High-dose LMWH decreased both DVT (OR = 0.07) and PE (0.44), but this benefit was offset by an increased risk for ICH (OR = 2.01) and ECH (OR = 1.78). Low-dose LMWH reduced the incidence of both DVT (OR = 0.34) and PE (OR = 0.36), without an increased risk of ICH (OR = 1.39) or ECH (OR = 1.44). For low–dose LMWH, the numbers needed to treat were seven and 38 for DVT and PE, respectively.

The authors concluded that indirect comparison of low and high doses of UFH and LMWH suggests that low-dose LMWH have the best benefit/risk ratio in patients with AIS by decreasing the risk of both DVT and PE, without a clear increase in ICH or ECH.

In McCarthy and Turner’s study 8 , elderly participants were randomly allocated to either control (n=161) or treatment (n=144) with 5000 units calcium heparin subcutaneously eighthourly for two weeks.

The authors reported a reduction in DVT rate from 72.7% in the control group to 22.2% in treatment patients. In patients who died, post-mortem examination to look for PE was performed. Comparison between treated and untreated patients showed significantly fewer deaths and PE in the treated group.

Most of the beneficial effect on mortality was seen in patients with lighter strokes. When patients with PE at post-mortem were excluded, there was no significant difference in the death rate in the treatment and control groups. At post-mortem, 9.9% of the strokes were haemorrhagic (four in the treatment and three in the control group).

The concluded that low-dose calcium heparin given subcutaneously following AIS reduced the number of DVTs, PE and deaths without increasing the number of haemorrhagic strokes in this study.

In the International Stroke Trial, VTE was investigated as a secondary outcome. In this trial, more than 19 000 patients were allocated to subcutaneous unfractionated heparin treatment (12 500 IU twice daily or 5 000 IU twice daily) versus no heparin and aspirin (300mg daily), versus no aspirin. 5

The heparin treatment group showed a decline in the frequency of fatal or nonfatal PE when compared with the group not treated with heparin (0.8% versus 0.5%), but the reduction was significant only in patients also given aspirin daily. Heparin therapy was also associated with a significantly increased risk of ICH compared with no heparin (1.2% versus 0.3%) in those patients who did not receive aspirin.

Sherman et al 9 compared the efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of VTE after AIS (PREVAIL Study). Patients with AIS (n=1762) who were unable to walk unassisted were randomly assigned within 48 hours of symptoms to receive either enoxaparin 40mg subcutaneously once daily or unfractionated heparin 5000 IU subcutaneously every 12 hours for 10 days. Patients were stratified by National Institutes of Health Stroke Scale (NIHSS) score (severe stroke > or =14, less severe stroke <14).

The primary efficacy endpoint was the composite of symptomatic or asymptomatic DVT, symptomatic PE, or fatal PE. Primary safety endpoints were symptomatic ICH, major ECH and all-cause mortality. In the efficacy group (eg one or more dose received, presence of DVT or PE, or assessment for VTE, enoxaparin (n=666) and unfractionated heparin (n=669) were given for 10.5 days.

Enoxaparin reduced the risk of VTE by 43% compared with unfractionated heparin. This reduction was consistent for patients with an NIHSS score of 14 or more (16% vs 30%) or less than 14 (8% vs 14%).

The occurrence of any bleeding was similar with enoxaparin (8%) or unfractionated heparin. The frequency of the composite of symptomatic ICH and major ECH was small and closely similar between groups (1%).

The authors concluded that for patients with acute AIS, enoxaparin is preferable to unfractionated heparin for VTE prophylaxis in view of its better clinical benefits to risk ratio and convenience of once daily administration. Excellence (NICE) published their draft guideline for the treatment of suspected or confirmed DVT and PE at the end of last year. 11

In terms of anticoagulation treatment for suspected or confirmed DVT or PE, NICE recommends:

» Apixaban » Rivaroxaban » Dabigatran

When using interim therapeutic anticoagulation for suspected proximal DVT or PE offer:

» Apixaban » Rivaroxaban » LMWH Carry out baseline blood tests including full blood count and clotting profile, and tests of renal and hepatic function. Do not wait for the results of baseline blood tests before starting anticoagulation treatment but ensure these tests have been reviewed (and acted upon if necessary) within 24 hours of starting treatment.

For confirmed DVT and PE, the following treatment is recommended:

Offer anticoagulation treatment for at least three months. If not already done, carry out baseline blood tests including full blood count and clotting profile, and tests of renal and hepatic function. Do not wait for the results of baseline blood tests before starting anticoagulation treatment but ensure these tests have been reviewed (and acted upon if necessary) within 24 hours of starting treatment.

When offering anticoagulation treatment for confirmed proximal DVT or PE, consider comorbidities, contraindications, and the person’s preferences. Offer either apixaban or rivaroxaban to people with confirmed proximal DVT or PE unless they have one of the comorbidities (cancer, low body weight, chronic kidney disease).

In addition, the European Heart Rhythm Association 13 recommends against the use of NOACs/DOACs in AFib patients with mechanical prosthetic valves or moderate-severe mitral stenosis (usually of rheumatic origin).

If neither apixaban nor rivaroxaban is suitable offer:

LMWH for five days followed by dabigatran or edoxaban or LMWH concurrently with a vitamin K antagonist (VKA) for at least 11 days, or until the INR is at least 2.0 in two consecutive readings, followed by a VKA on its own.

Do not routinely offer UFH with a VKA to treat confirmed proximal DVT or PE unless the person has established renal failure (estimated creatinine clearance <15ml/min or an increased risk of bleeding.

References available on request. SF

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To reduce the risk of stroke and systemic embolism in patients with AF #

150 mg twice daily Treatment of acute * and prevention of recurrent PE and/or DVT

Prevention of VTE in patients who have undergone hip and knee replacement surgery **

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220 mg once daily

Capsules are not actual size #In patients ≥ 80 years: 110 mg twice daily *Following treatment with a parenteral anticoagulant for at least 5 days **Patients with moderate renal impairment have an increased risk for bleeding. For those patients the recommended dose of Pradaxa ® is 150 mg once daily. For VTE prevention following hip replacement surgery in patients with moderate renal impairment, Pradaxa ® 75 mg capsules should be used instead of the 110 mg capsules. DOAC = direct oral anticoagulant; PE = pulmonary embolism; DVT = deep vein thrombosis; VTE = venous thromboembolism; AF = atrial fibrillation Reference: Pradaxa ® Approved professional information. South Africa. Date of publication 15 July 2019. S4 Pradaxa ® 75 mg. Each capsule contains 110 mg of dabigatran etexilate base (as mesilate salt). Reg. No. 45/8.2/0130. S4 Pradaxa ® 110 mg. Each capsule contains 110 mg of dabigatran etexilate base (as mesilate salt). Reg. No. 42/8.2/0131. S4 Pradaxa ® 150 mg. Each capsule contains 150 mg of dabigatran etexilate base (as mesilate salt). Reg. No. 45/8.2/0162. For full prescribing information refer to the professional information approved by the Regulatory Authority. Applicant details: Ingelheim Pharmaceuticals (Pty) Ltd, 407 Pine Ave, Randburg. Tel: +27 (011) 348-2400. Cpy. Reg. No. 1966/008618/07. BI Ref. No. PC-ZA-100686. Expiry date: June 2022.