Warfarin in the over-80s: a risk benefit assessment

Most commonly, warfarin is used in elderly persons for prevention of stroke in the setting of atrial fibrillation (AF). The lifetime prevalence of AF is nearly 12% among people over 75 years of age. It is now well established that AF is the most common cause of embolic stroke and is directly responsible for more than one-third of all strokes in persons 80-89 years of age.¹ 

Stroke in patients with AF is also more severe and the outcome markedly poorer than in patients with sinus rhythm.² Thus, anticoagulation therapy to prevent stroke is of paramount importance in patients at high risk for thromboembolic stroke.

Warfarin is the recommended treatment for embolic stroke prophylaxis in AF in intermediate-to-high-risk patients. However, the bleeding risk associated with warfarin therapy has led physicians to be cautious in using (and arguably, to underuse) warfarin in older patients, especially those perceived as being at risk of falls.³

Elderly patients who have the highest risk of stroke and worse outcomes with stroke in the setting of AF, may be frequently undertreated.⁴

The relative benefit of warfarin compared with aspirin in preventing embolic stroke is well known,^5,6 however warfarin therapy is not without risk. The association of haemorrhagic complications with warfarin use is well established, and elderly patients appear to be at higher risk. Among patients ≥ 85 years of age compared with patients aged 70-74 years, the risk of intracerebral haemorrhage (ICH) is substantially increased.⁷

Aim of audit

The aim of this retrospective audit was to assess whether the use of warfarin in elderly patients (≥ 80 years) is well justified or not. Many studies have emphasised the under-use of anticoagulants but the elderly patients involved in this audit were thought to be over-prescribed warfarin. 

Method

Data were retrospectively collected from the medical records of all patients > 80 years of age, who were receiving warfarin for AF or other diagnoses (pulmonary embolism [PE], recurrent deep venous thrombosis [DVT] and ischaemic strokes), in St John’s Hospital, Limerick. 

A purpose-designed data collection form was used to collect the following:

• Demographic data 

• Diagnosis for warfarin use

• Latest epidermal growth factor receptor (EGFR)

• CHADS2 score

• HAS-BLED score

• Use of other medications like aspirin, clopidogrel and dipyridamole

• Amount of weekly alcohol consumption

• Risk and history of falls (postural hypotension)

• Compliance with warfarin use and follow-up for international normalised ratio (INR) check

• Stability of INR. 

A special clinic was organised to collect the missing data. Urea and electrolytes (U&Es) were checked. Assessment of risk of fall was undertaken by reviewing the patients’ history, checking for postural hypotension and the amount of alcohol consumption. 

Results

A total of 56 patients (≥ 80 year) were found to be on warfarin for various diagnoses. Six patients were excluded from the study because of lack of availability of full data. The total number of patients included in the audit was 50. Thirty were male and the remaining 20 were female. The age of included patients was between 80 and 90 years with the average age being 84 years old.

The main reason the patients were on warfarin was to treat AF. Forty-one patients had a diagnosis of AF. Thirty-six patients out of the 41 were on warfarin just for AF, while three patients had both AF and recurrent DVT. Two patients had combined AF and previous ischaemic cerebrovascular accident (CVA). Five patients were on warfarin for recurrent DVT only. Three patients had PE while only one patient was on warfarin for metallic aortic valve replacement (AVR).

CHADS2 score was calculated for all 50 patients to assess risk of thromboembolism. CHADS2 score was ≥ 2 for 43 patients. It was 1 for seven patients only and they were the ones who were on warfarin for recurrent DVT and PE.

HAS-BLED score was also calculated for all 50 patients to assess their risk of bleeding. Forty-six patients scored ≤ 3. Only four patients had HAS-BLED score 4. These four patients had high CHADS2 score at the same time. Two of these four patients had history of falls while none of them showed any postural hypotension. For these patients alcohol intake was ≤ 14 units/week. Their INR was always stable and they were regular attendees of warfarin clinic.

All 50 patients attended warfarin clinic regularly and their INR was found to be quite stable. Risk of fall assessment was done by taking history of falls, alcohol consumption and by checking them for postural hypotension. Eight patients had history of falls, while nine patients showed postural hypotension. Out of these eight patients who had history of falls, only two showed postural hypotension. 

Alcohol consumption was also assessed for all 50 patients and only four patients had high-alcohol intake (≥ 21 units /week). Only eight patients were on aspirin concomitantly while none of these 50 patients was on clopidogrel or dipyridamole. 

Discussion

This audit has revealed that AF is the most common reason to be on warfarin in elderly patients. Prescription of warfarin in these patients was justified by their CHADS2 score. 

However, very few patients had high HAS-BLED score as well as increased risk factors for falls. These patients had high CHADS2 score and benefit of using warfarin in them outweighed the risk of bleeding.

In one study by Gage et al, patients at risk for falls but with concomitant increased stroke risk as manifested by a CHADS2 score of ≥ 2 would benefit overall from anticoagulation, specifically, warfarin therapy, even in the setting of an increased risk of haemorrhage.¹¹

Few studies have addressed the relationship of falls or predicted fall risk with bleeding in the setting of anticoagulation for AF. 

A meta-analysis of antithrombotic therapy in elderly patients at risk for falls concluded that the propensity for falling in elderly patients should not be an important factor when deciding whether or not a patient is a good candidate for anticoagulation for AF.⁸  

In a study by Fang MC et al, it appears that an INR of 2.0-3.0 provides the best balance between bleeding risk and stroke prevention benefit.⁷

In analyses from the SPORTIF III and SPORTIF V trials, rates of bleeding were higher among patients who had poor INR control compared with those with good control (goal INR 2.0-3.0).⁹ All of the patients included in the audit had good INR control. They were regularly monitored in a pharmacist-led warfarin clinic.  

Among the patients > 75 years of age in the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial, there was no difference in the rates of ICH between aspirin and warfarin-treated groups with a goal INR of 2.0-3.0.¹⁰

In various popular studies warfarin has been found to be superior to aspirin alone for the prevention of thromboembolic stroke in the setting of AF. In the Atrial Fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W) trial, warfarin was found to be superior to combination of aspirin and clopidogrel.¹²

A recent analysis was undertaken of the net clinical benefit (balancing ischaemic stroke and ICH) of warfarin in a real-world nationwide Danish cohort of > 130,000 people, in whom stroke risk was assessed by both CHADS2 and CHA2DS2-VASc and bleeding by HAS-BLED. 

This analysis revealed that there was a positive net clinical benefit with warfarin alone in patients with CHADS2 ≥ 1 and a CHA2DS2-VASc score ≥ 2. The net clinical benefit with warfarin was higher in patients with a high risk of bleeding (HAS-BLED score ≥ 3).¹³

Future directions

Several novel oral anticoagulants are expected to shift the balance of benefit and risk in anticoagulation for AF. 

In the RELY trial, the oral direct thrombin inhibitor dabigatran was compared at two doses with warfarin to a target INR of 2.0-3.0.¹⁴

In this trial, low-dose dabigatran (110mg twice daily) was non-inferior to warfarin in preventing stroke or systemic embolism and exhibited a better bleeding profile than warfarin. 

High-dose dabigatran (150mg twice daily) was superior to warfarin in preventing stroke. Importantly, both the high-dose and low-dose dabigatran groups had significantly lower rates of ICH compared with the warfarin group.

In the ARISTOTLE trial, apixaban (an oral factor Xa antagonist) was compared with warfarin in patients with AF. Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding and resulted in lower mortality.¹⁵

In the ROCKET AF trial, rivaroxaban (oral factor Xa inhibitor) was found non-inferior to warfarin for the prevention of stroke or systemic embolism. Intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. 

All three novel oral anticoagulants – dabigatran, rivaroxaban and apixaban – appear to offer superior net clinical benefit over warfarin in patients with a CHADS2 score ≥ 1 or CHA2DS2-VASc score ≥ 2, regardless of bleeding risk. When the risks of stroke and bleeding are both elevated, dabigatran, rivaroxaban and apixaban appear to have a greater net clinical benefit than warfarin.¹⁷ 

Conclusion

The population of elderly patients presents challenges with regard to the decision to provide anticoagulation treatment. 

The available data suggest warfarin appears to be generally underused in the treatment of elderly patients with AF. There is fairly clear evidence that warfarin reduces embolic and ischaemic events, benefits that outweigh bleeding risk. 

In a recent consensus conference organised by the Royal College of Physicians of Edinburgh in 2012, it was highlighted that all patients with AF should have a formal stroke risk assessment with a scoring tool such as CHA2DS2-VASc. It also states that the use of the HAS-BLED score can help to identify bleeding risks but emphasises that it should not be used on its own to exclude patients from anticoagulation therapy.¹⁸

This audit showed that CHADS2 score was appropriately used for assessment of stroke risk in patients with AF. HAS-BLED score for most of our patients showed low risk of bleeding. Only four patients had a high HAS-BLED score but at the same time they had a high CHADS2 score. 

So the use of warfarin in these patients was justified. These patients were monitored more closely but could now be considered potential candidates for new oral anticoagulants. 

Finally, the pharmacist-led warfarin clinic is providing an excellent and efficient service. Physicians appear to be competently following all the latest guidelines for the use of anticoagulants. It will be of better value to conduct this sort of audit in a primary care set-up, where patients are usually lost to regular follow-up.

References

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