Thromboprophylaxis

From Ganfyd

Contents 1 Introduction 2 Assessment 2.1 Serious Risk Factors 2.2 Other Risk Factors 3 Context 4 Therapy 4.1 Non-pharmacological 4.1.1 Early mobilisation 4.1.2 Hydration 4.1.3 Elastic Support Stockings 4.1.4 Mechanical 4.2 Pharmacological 4.2.1 Aspirin 4.2.2 Heparin 4.2.2.1 Post discharge and prolonged thromboprophylaxis 4.2.3 Warfarin 4.2.4 Fondaparinux 4.2.5 Ximelagatran 4.2.6 Dabigatran etexilate‎ 4.2.6.1 Cautions with drug therapy 4.2.7 Rivaroxaban 4.2.7.1 Cautions with drug therapy 4.2.8 Apixaban 4.3 Comparison between agents 5 Current controversies 6 Other context 7 External Links 8 References

Introduction

Thromboprophylaxis is the prevention of thromboembolic disease. Thrombus formation is favoured by changes in Virchow's triad: blood stasis, increased coagulability of blood and damage to vessel wall. The risk of thromboembolic disease is elevated in the peri-operative period and in several medical conditions such as malignancy as well.

There are increasingly strong grounds for assessing all medical and surgical inpatients for risk routinely, as without a structured approach to such assessment, risk factors and appropriate thromboprophylaxis will be overlooked. In England this has been made a nationally measured process measure and in due course this live experiment in social engineering of clinical staff will be evaluated. There is good evidence that forcing the risk assessment increases the rate of guideline compliant thromboprophylaxis so any real impact on outcomes might be detectable in national mortality data. However a legacy remains of the issue long being regarded as too complex and of too low an absolute risk to patients to be prioritised by a one size fits all approach. A restricted number of good evidence-based guidelines exist, with occasional interesting cultural variation in interpretation of the same evidence base. The quite rapid development of the evidence base is also important, with in particular new drugs and devices constantly coming on to the market, and some opinions not being based on full knowledge of an ever increasing evidence base.

As the trend to eject people from hospital early or attempt to manage them at home without admission continues, more people who are ill but not in hospital will have significant risk of thrombosis and embolism. Considering prophylaxis in such circumstances may be worthwhile.

Assessment

Serious Risk Factors

A patient with any one of the following serious risk factors is 'High Risk':

• Lower limb orthopaedic surgery > 30 minutes
• Pelvic/abdominal surgery for malignancy
• Any surgery > 30 minutes if there is a history of DVT/PE or known thrombophilia
• Paralysis or immobilisation of lower limbs
• Patients admitted for a medical illness requiring thromboprophylaxis (see other risk factors) and who subsequently develop a surgical complication

Other Risk Factors

Any one makes patient 'Moderate Risk', three puts patient in 'High Risk' category:

• Any surgery > 30 minutes
• Age > 40 years
• Obesity ( wt > 80kg)
• History of DVT/PE or known thrombophilia
• Strong family history of DVT/PE
• Prolonged immobility prior to surgery
• Current medical illness eg major lung or heart disease, malignancy, nephrotic syndrome, inflammatory bowel disease. However stroke is a qualified exception for certain forms of thromboprophylaxis and many conditions associated with haemorrhage are absolute or relative contra-indications to some forms of thromboprophylaxis
• Pregnancy & postpartum
• Concomitant Oestrogen, HRT or Combined Oral Contraceptive, tamoxifen, raloxifene

Context

The risk context for thromboembolism is:

• Age: Exponential increase in risk with age.
  • <40 years annual risk - 1/10,000
  • 60-69 years annual risk - 1/1,000
  • >80 years annual risk - 1/100
• Obesity - 3 x risk if obese (body mass index >30 kg/m2)
• Varicose veins - 1.5 x risk after major general / orthopaedic surgery. But low risk after varicose vein surgery
• Previous VTE - Recurrence rate 5 / year, increased by surgery
• Thrombophilias
  • Low coagulation inhibitors (antithrombin, protein C or protein S)
  • Activated protein C resistance (e.g. factor V Leiden)
  • High coagulation factors (I, II, VIII, IX, XI)
  • Antiphospholipid syndrome
  • High homocysteine
• Malignancy - 7 x risk
• Hormone therapy
  • Oral combined contraceptives, HRT, raloxifene, tamoxifen - 3 x risk
  • High-dose progestogens - 6 x risk
• Pregnancy, puerperium - 10 x risk
• immobility( Bedrest >3 days, plaster cast, paralysis) - 10 x risk; increases with duration
• Hospitalisation for acute trauma, acute illness, surgery - 10 x risk
• Anaesthesia - 2x general vs spinal / epidural
• Antipsychotics - 2x if elderly and atypicals ^[1]

Therapy

All therapy should be offered in the context of a patient specific risk assessment and as appropriate reassessment. This risk assessment is easy to both trivialize and be seen as identical to offering chemothromboprophylaxis.

Non-pharmacological

Early mobilisation

There is no evidence in favour of bed rest from multiple randomised trials in multiple forms of surgery and plenty of evidence for early mobilization.

Hydration

Adequate hydration is theoretically important. There is insufficient evidence to recommend haemodilution or venesection (except in primary polycythaemia).

Elastic Support Stockings

See also compression stockings.

Thigh length graduated compression (TED) stockings (or calf length where patients can not have thigh length) have been proved to reduce DVT in multiple situations other than emergency fracture neck of femur patients. The minimum length of wearing them is 5 days, but benefit may extend for several weeks. The usefulness of calf length stockings in the low risk long haul air travel situation has been demonstrated but there is no consistent data on effectiveness of calf length stockings in surgery patients. Importantly however there is now good evidence that they do not have net benefit in stroke patients^[2] which illustrates the limits of generalization and the strengths of studies to address major gaps in the evidence base.

Mechanical

Selected active mechanical measures may have a role in medium to high risk patients who have not had previous DVT and who cannot have LMWH prophylaxis. The evidence base must be regarded as device specific and it is possible for seemingly minor changes in a device to considerably alter a device's clinical effectiveness. Electrical stimulation devices have a very poor evidence base for effectiveness.

Pharmacological

Aspirin

Although aspirin is a non-steroidal anti-inflammatory drug (NSAID), at small doses of 75-300mg per day, it exerts an anti-thrombotic effect through its anti-platelet effect. Interestingly historic studies did suggest at very high dose it had an anti - thrombotic effect. A dose of at least 150mg daily for 30 plus days reduces PE rate as much as heparin given for a minimum of 5 days in patients with fractured neck of femur in one trial but this has not been reproduced. It does not reduce DVT rate, so patients might develop post-thrombotic syndrome. It can be considered in patients with LMWH intolerance, who refuse injection or after fractured neck of femur but can not be recommended now we have agents with a better overall effectiveness.

Heparin

• Unfractionated
• Low-molecular (LMWH)

British guidelines have been published in 2006^[3] LMWHs at correct dosage are superior to ordinary heparin on clinical effectiveness measures. Cost benefit arguments in favour of unfractionated heparin are increasingly difficult to sustain, but should be considered in health system context (eg in third world public health systems). All published randomised clinical trials have given heparin for a minimum of 5 days. There is increasing evidence that high risk patients may benefit from taking LMWH for up to a month after surgery. While the case for elective surgical patient prophylaxis is strong it is suspected that treatment in medical patients reduces pulmonary embolism to a similar degree to causing major bleeding and there is only a trend towards reduced mortality^[4]. There is doubt as to whether in young medical patients with infection LMWH has any advantages over knee length antiembolic stockings^[5]. Monitoring guidelines for heparin-induced thrombocytopenia (HIT) can be less intrusive for LMWH than unfractionated heparin.

Post discharge and prolonged thromboprophylaxis

The results of clinical trials in elective knee and hip surgery have resulted in guideline recommendations for fixed periods of treatment after the surgery. We now know from observational studies that failure to adhere to such guidelines (as is common) and offering no post discharge thromboprophylaxis is associated with a hazard ratio of 2.9 (1.8-5.0) of death at three months which translates into an absolute increased death rate of greater than 1%^[6]. There is now good evidence that post discharge thromboprophylaxis in medical patients will not be effective due to excessive bleeding^[7].

When extended thromboprophylaxis has been tried in medical inpatients the evidence base is suggestive that thromboprophylaxis has little point after three weeks^[8]. Such issues are rarely considered in clinical guidelines, yet alone by clinicians unfamiliar with the full evidence base.

Warfarin

In patients already on warfarin at therapeutic INR it should be used. The place in other indications is selective, as the induction phase could theoretically increase the risk of VTE if it is used alone and the risk benefit evaluation is complex.

Fondaparinux

Fondaparinux may have a role in thromboprophylaxis in those with heparin-induced thrombocytopenia (HIT). It is clinically effective in high risk surgical populations such as those with fracture neck of femur but its cost effectiveness is presently unclear (except in a Swiss subpopulation). Its use is likely to rapidly increase because of convenience.

Ximelagatran

This was withdrawn in February 2006 as it was associated with liver enzyme abnormalities. Further oral thrombin inhibitors (eg SCH 530348) are in phase 2 development.

Dabigatran etexilate‎

Direct thrombin inhibitor. Gained EU licence for thromboprophylaxis following knee and hip joint arthroplasty in 2008.

Cautions with drug therapy

• Severe liver impairment, alcoholism
• Severe kidney impairment (enoxaparin likely to be safe but reduce dose)
• Major trauma or surgery to spine, brain, eye
• Regional/Spinal/epidural block
• Anaemia (Hb <10g/dI)
• Other drugs that increase risk bleeding: Clopidogrel, dipyridamole, NSAIDs (including COX IIs), SSRI antidepressants and calcium channel blockers
• Asthma - aspirin, especially if allergic asthma

Rivaroxaban

Direct Factor Xa inhibitor. Gained EU licence for thromboprophylaxis following knee and hip joint arthroplasty in 2009.

Cautions with drug therapy

• Regional/Spinal/epidural block
• Anaemia
• Severe renal impairment
• Other drugs that increase risk bleeding: Clopidogrel, dipyridamole, NSAIDs (including COX IIs), SSRI antidepressants and calcium channel blockers
• Drugs that interfere strongly with CYP3A4 or P-glycoprotein metabolic pathways

Apixaban

Direct Factor Xa inhibitor. In medically ill patients, an extended course of thromboprophylaxis with apixaban for 30 days was not superior to a shorter course of up to 14 days with enoxaparin^[9].

Comparison between agents

As of 2010 enoxaparin has tended to be used as the standard against which other agents are compared. The multiple meta-analysis that exist comparing various doses of it with various doses of dabigatran etexilate suggest at licensed doses they are effectively equivalent. Rivaroxaban seems superior at licensed doses to enoxaparin in preventing VTE events but causes more minor bleeding, particularly after joint replacement therapy^[11]. NICE in 2010 looked at the various agents used in general surgery and hip replacements. It is apparent that at licensed doses all anticoagulants reduce VTE events by two thirds. It is also apparent that the risk benefit profiles are very indication specific. It seems likely that rivaroxaban is the most clinically effective at licensed dose. The relatively high bleeding rate with this compound is however going to be much more obvious to the surgeon than the benefits since the re-operation rate doubles. Unfractioned heparin was of course compared to the low molecular weight heparins (LMWH). Most published studies favoured LMWH in surgical patients. Medical patients appear to need higher doses of agents than surgical patients^[10]. In some medical indications such as stroke no agent has proved to have a convincing place. In other indications such as myocardial infarction the management of the condition has changed so much with much earlier mobilisation and more PCI, antiplatelet and anticoagulation use that data more than 10 years old is useless.

Current controversies

Most revolve around real world outcomes (as opposed to the surrogate outcomes of investigation determined events such as DVT), individual therapies with benefits/risks for a particular subpopulation and cost benefit issues. The problem can be one of perception:

• The metrics used can be inaccurate and are open to distorting interpretation
• The risk of fatal PE and long term thrombotic morbidity is low enough that the risk of higher and more immediate morbidity associated with thromboprophylaxis can dominate in both patients and clinical staff
• The cut off period of clinical trials and real life follow up can make context difficult
  • A particularly challenging area has proved to be post discharge thromboprophylaxis where inconvenience and selective responsibility has impaired implementation of the trial evidence
• Risk perception varies between patients/surgeons/physicians
• One size fits all recommendations when individualized evidence base interpretation can be challenging and are contra-intuitive to social values(surveys have shown that many clinicians bias thromboprophylaxis towards younger patients and those without advanced dependency/malignancy)
• Selected interpretation of evidence base
• Misquotes of the evidence base (eg by 'Blue Book' UK guidelines on #NOF^[12] versus original Cochrane review^[13]).
• Thromboprophylaxis is far from 100% effective
• There are potential conflicts of interest with the most obvious being the pharmaceutical industry

Other context

External Links

• Thromboprophylaxis During Pregnancy, Labour and after Vaginal Delivery RCOG 2004
• The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Evidence-Based Guidelines 2004 -Note: these are not in the public domain which considerably reduces their usefulness
• Clinical Evidence 2004 on Thromboembolism

References