Recognising the superior safety of direct oral anticoagulants (DOACs) over warfarin, and their equivalent or better efficacy in preventing strokes, is the first step in choosing a medication in patients with non-valvular atrial fibrillation (NVAF), according to Dr Christopher Hammett, interventional cardiologist at the Royal Brisbane and Women’s Hospital.

“We need to focus on implementing what we already know to improve the quality of care in our patients with atrial fibrillation,” Dr Hammett told the limbic.

“The fact is that all three DOAC options available in Australia are at least as good as warfarin in preventing stroke, and pose lower bleeding risks,” he says.

“Which DOAC to use can be individualised according to a patient’s needs. Factors that influence which DOAC to choose can include the presence of renal impairment, where the extent to which the medication is excreted by the kidneys and the trial evidence in renal impairment is important.

“Other factors are the identification of those with a genuinely increased risk of gastrointestinal or other haemorrhage, and situations where the consequences of bleeding are likely to be particularly serious, for example in Jehovah’s Witnesses who cannot be treated with blood products.

“In the last two situations, the ability to directly reverse the effect of anticoagulation if bleeding occurs is an important consideration. ”

Guidelines support DOAC efficacy

Guidelines on the management of atrial fibrillation from the European Society of Cardiology¹ highlight the significant reduction in stroke risk identified in the landmark phase III studies comparing apixaban, dabigatran and rivaroxaban with warfarin, without increases in the risk of major bleeding.

Stroke or systemic embolism was reduced by 21% with apixaban 5 mg twice daily in the ARISTOTLE study;² dabigatran 150 mg twice daily reduced stroke and systemic embolism by 34% and dabigatran 110 mg twice daily was non-inferior to warfarin in the RE-LY study;³ and by 21% with rivaroxaban 20 mg once daily (with a dose adjustment to 15 mg daily for those with estimated creatinine clearance of 30-49 mL/min) in the ROCKET AF study.⁴

The ROCKET AF⁴ study included a study population with multiple co-morbidities and an average CHADS2 score of 3.5. Patients in the ARISTOTLE² and RE-LY³ studies had average CHADS2 scores of 2.1.

The ESC guidelines emphasise that risk factors for stroke and bleeding overlap.¹ “For example, older age is one of the most important predictors of both ischaemic stroke and bleeding in AF patients,” they state.

“A high bleeding risk score should generally not result in withholding oral anticoagulation (OAC). Rather, bleeding risk factors should be identified and treatable factors corrected.”

Comparing DOACs and individualising therapy

There is not yet evidence that any one of the DOACs is superior to the others for stroke prevention in NVAF, and indirect comparison are difficult because of differences between patients enrolled in the randomised trials.⁵ For example, patients in the ROCKET AF study of rivaroxaban had a mean CHADS₂ score of 3.5, compared to 2.1 in both the RE-LY study of dabigatran and the ARISTOTLE study of apixaban.

Apart from differences in stroke risk, the trials also varied in the intensity of anticoagulation in warfarin control groups. In ROCKET-AF, patients in the warfarin arm spent a lower mean percentage of time in the therapeutic range of warfarin (59%) compared to those in RE-LY and ARISTOTLE (both >64%).⁵

A 2017 review in the European Heart Journal discussed the principles for choosing a DOAC in patients with NVAF.^6,7 The authors, led by German neurologist Dr Hans-Christoph Diener, said there is no preference for a particular DOAC over another in patients with AF:

• with stable coronary artery disease
• with stable peripheral vascular disease
• undergoing cardioversion (although VKAs remain the standard of care)
• undergoing catheter ablation (although the OAC of choice is uninterrupted warfarin)
• for secondary stroke prevention
• with hypertension.

In patients with a high risk of gastrointestinal bleeding, they said the first choice is apixaban 5 mg twice daily or dabigatran 110 mg twice daily. They added the caveat that GI bleeding, even in the setting of anticoagulation, does usually not cause death or permanent major disability. “Thus, the choice of OAC should be driven mainly by stroke prevention considerations,” they said.

“The label ‘high risk of gastrointestinal bleeding’ is imprecise. For example, patients with H. pylori-related ulcer haemorrhage may no longer be at high risk of bleeding once the infection has been eradicated.”

In patients with stage III chronic kidney disease (creatinine clearance 30-49 mL/min) the first choice is rivaroxaban 15mg daily or apixaban 5 mg twice daily (reduced to 2.5 mg twice daily if patients have one or more additional criteria: age ≥80 years, body weight ≤60 kg, serum creatinine ≥133 mmol/L). Dabigatran 110 mg twice daily is the second choice, the review stated.

Once- or twice-daily dosing is not a primary consideration, but may be a factor in the decision-making process for some patients, for example because of their personal preferences or concerns about polypharmacy, it concluded.

Prospective real-world evidence with rivaroxaban (Xarelto)

The prospective, international XANTUS study enrolled 6,784 patients with NVAF commencing treatment with rivaroxaban and followed them about every 3 months for one year, or for at least 30 days after permanent discontinuation.⁸ Decisions about rivaroxaban prescription, including the dose and duration of therapy, were at the discretion of the treating physician. The average treatment duration was 329 days.

This broad population averaged 71.5 years of age (ranging up to 99 years), and had mean CHADS₂ score of 2.0 compared to 3.5 in the ROCKET AF study. Compared to ROCKET AF, patients in XANTUS more closely resembled those in the RE-LY study of dabigatran and the ARISTOTLE trial of apixaban.

There were 142 treatment-emergent major bleeding events in 128 patients (2.1 events per 100 patient-years), 118 died (1.9 events per 100 patient-years), and 43 suffered a stroke (0.7 events per 100 patient-years). The incidence of major gastrointestinal bleeding was 0.9 events per 100 patient-years.

“Rates of stroke and major bleeding were low in patients receiving rivaroxaban in routine clinical practice,” the researchers concluded.

Dr Hammett, writing in a 2016 review, said the XANTUS study filled an important gap in understanding the use of rivaroxaban.⁹

“ROCKET-AF, studied a particularly high-risk group of patients,” he said. Their median age was 73 years, 90% were hypertensive, and more than 55% had a history of prior stroke, systemic embolus or transient ischaemic attack.

“These are risk factors not just for stroke, but also for bleeding,” he said. “Given this, the major bleeding rate in ROCKET-AF was reassuringly low (3.6%/100 patient-years).”

An important remaining question was the outcomes with rivaroxaban in lower-risk patients.

“The unselected prospective cohort in XANTUS is more representative of the patients we see in everyday practice,” he said. “The event rates were low, with 96.1% of patients having no major adverse events over the 1-year follow-up. The rate of stroke/systemic embolisation was only 0.8%, and major bleeding 2.1%.

“The XANTUS trial provides reassurance that the results from ROCKET-AF are reproducible in everyday practice, and are generalisable to a broader patient cohort.

“Stroke and major bleeding rates were … comparable to or better than those seen in the randomised trials for both dabigatran and apixaban.”

The results of XANTUS have been complemented by an analysis based on nearly 10 million electronic medical records from the United States Department of Defense healthcare system, used to identify major bleeding among patients taking rivaroxaban for NVAF.¹⁰

A total of 44,793 patients received rivaroxaban. The risk of bleeding was higher in the 26.9% of patients who also had diabetes, but fatal outcomes associated with major bleeding were rare.

Incidence rates per 100 person years (diabetes vs no diabetes) were: major bleeding 3.68 vs 2.12, gastrointestinal bleeding 3.30 vs 2.12, intracranial bleeding 0.19 vs 0.25, other/unspecified bleeding 0.20 vs 0.14. The mortality rate associated with bleeding was 0.09 per 100 person years in both people with and without diabetes.

Treatment of bleeding complications: haemostasis vs thrombosis risk

Strategies for managing bleeding in patients treated with the direct-acting factor Xa inhibitors rivaroxaban and apixaban include activated charcoal and circulatory support until the anticoagulant is no longer active. Options in more severe bleeding include non-activated prothrombin complex concentrates (PCCs), activated prothrombin complex concentrates (aPCCs) and recombinant factor VIIa.

A study in patients treated at Swedish hospitals identified 84 patients receiving rivaroxaban or apixaban who were treated with PCCs for major bleeding events.¹¹. Intracranial haemorrhage was the most common site of bleeding requiring reversal (59 cases), followed by gastrointestinal bleeding in 13 patients. The study used 4-factor PCC which is not available in Australia. Australia has 3-factor PCC.

Management with PCCs was assessed as effective in 58 patients (69%) and ineffective in 26 patients (31%, 16 of whom had intracranial haemorrhage). Only two patients developed an ischaemic stroke, occurring 5 and 10 days after treatment with PCC.

“The administration of PCCs for the management of major bleeding events associated with rivaroxaban or apixaban is effective in most cases and is associated with a low risk of thromboembolism,” the researchers concluded. “Our findings are limited by the absence of a control group in the study.”

The study claimed to be the first to assess the use of PCCs in patients rather than healthy volunteers, and address the challenge of balancing control of haemorrhage with an increased risk of thromboembolism in this challenging group.

A practical guide on the use of DOACs in patients with atrial fibrillation¹² published by the European Heart Rhythm Association said clinical trials and registry data with DOACs had shown that the administration of coagulation factor was rarely needed.

“Indeed, any NOAC-antagonizing effect has to be balanced carefully against the potential prothrombotic effect,” stated the guide which was published in the European Heart Journal.

The guide, written by a team of European and UK experts advised that the administration of PCCs or aPCCs should be considered in a patient with life-threatening bleeding if immediate haemostatic support was required, particularly in situations where a specific reversal agent was not available.

“The choice between PCC and aPCC may depend on their availability and the experience of the treatment centre. Particularly aPCC induces a strong pro-coagulant effect and should only be used by physicians experienced in their use,” it said.

It also noted that PCC and aPCC were preferred over recombinant activated factor VIIa (NovoSeven, 90 mg/kg) given the absence of any outcome data and its pronounced pro-coagulant effect.

References

1. Kirchhof P et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37: 2893-2962.
2. Granger CB et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-92.
3. Connolly SJ et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
4. Patel MR et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-91.
5. Shields AM, Lip GY. Choosing the right drug to fit the patient when selecting oral anticoagulation for stroke prevention in atrial fibrillation. J Intern Med 2015; 278: 1-18.
6. Diener HC et al. Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 1. Eur Heart J 2017; 38: 852-859.
7. Diener HC et al. Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 2. Eur Heart J 2017; 38: 860-868.
8. Camm AJ et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 2016; 37: 1145-53.
9. The XANTUS study: real-world evidence on the use of rivaroxaban for stroke prevention in atrial fibrillation. Research Review. 2016.
10. Peacock WF et al. Comparison of the incidence of major bleeding with rivaroxaban use among nonvalvular atrial fibrillation patients with versus without diabetes mellitus.Am J Cardiol2017; 119: 753-759.
11. Majeed A et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood 2017; 130: 1706-1712.
12. Steffel, J et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J (2018) 00, 1-64.