A 68-year-old woman presents with palpitations, feeling generally unwell for three days. She denies any chest pain, shortness of breath, or lightheadedness. Past medical history includes hypertension, dyslipidemia, and osteoarthritis with no history of dysrhythmia. Her heart rate is 125 and her remaining vital signs are normal. Her pulse is irregular and her physical exam is otherwise unremarkable. ECG shows atrial fibrillation.
You slow her heart rate using diltiazem. Your workup reveals no sinister causes or complications of her atrial fibrillation. You calculate her CHA2DS2-VASc score to be 3 and talk to the patient about starting stroke prophylaxis. She tells you, “my friend’s husband was put on apixaban and died from bleeding in his brain. Which option gives me the lowest risk of death from bleeding?”
What are the mortality outcomes in patients taking DOACs vs. warfarin for nonvalvular atrial fibrillation (NVAF) and venous thromboembolism (VTE)?
Oral anticoagulation is used for treatment of VTE and in stroke prevention for patients with NVAF. Direct oral anticoagulants (DOACs) are now prescribed more often than warfarin for a number of reasons, including fewer drug interactions, fixed dosing, and lack of monitoring.
The most concerning risk of anticoagulant medications is bleeding, particularly intracranial bleeding. The rate of fatal bleeding is very low.1 A recent systematic review and meta-analysis has estimated the case fatality from bleeding on the DOACs.2
Title: Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials
Reference: Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015; 13: 2012–20.
Population: phase 3 trials; patients ≥ 18 years old; anticoagulation for NVAF or VTE for ≥ 3 months; study reporting fatal bleeding, major bleeding, mortality rated to cardiovascular disease, and all-cause mortality
Intervention: DOACs (rivaroxaban, apixaban, dabigatran, edoxaban, darexaban, betrixaban)
Primary: case fatality rate (mortality per case of major bleeding), rate of fatal bleeding (per 100 Pt-yrs)
Secondary: cardiovascular mortality, all-cause mortality
Data sources: MEDLINE, EMBASE, the Central Register of Controlled Trials databases, ClinicalTrials.gov, and cardiology and hematology conference abstracts up to August 2015.
Study selection: Two authors independently assessed all potential studies for inclusion. Disagreements were resolved by a third author.
Data extraction: Two authors independently extracted the data with a third author resolving disagreements.
Bias was assessed using the Cochrane Risk of Bias tool.
This is a systematic review and meta-analysis of thirteen RCTs published from 2009 to 2015 comparing dabigatran, rivaroxaban, apixaban and edoxaban.
Results and limitations
8/13 studies were considered high quality based on the Cochrane Rik of Bias tool.
12 studies reported death from major bleeding.
- Case fatality rate of bleeding
- On DOACs: 7.57% (95% CI, 6.53–8.68; I2 = 0)
- On warfarin: 11.05% (95% CI, 9.17–13.07; I2 = 33.3%)
- Fatal bleeding incident rate (per 100 Pt-yrs)
- On DOACs: 0.16 (95% CI, 0.12–0.20; I2 = 36.5%)
- On warfarin: 0.32 (95% CI, 0.27–0.37; I2 = 15.0%)
In terms of secondary outcomes, risk of cardiovascular mortality and all-cause mortality were also lower in patients taking DOACs.
- Cardiovascular mortality: RR 0.88 [95% CI, 0.82–0.94], p = 0.0002 (weighted comparison of 1,975/57,940 on DOACs vs. 1,318/44,803 on warfarin).
- In a subgroup analysis, edoxaban was the only drug to show a cardiovascular mortality reduction compared to warfarin.
- Only trials investigating NVAF patients showed that DOACs were associated with a reduction in cardiovascular mortality (not VTE studies).
- All-cause mortality: RR 0.91 [95% CI, 0.87–0.96], p < 0.001 (weighted comparison of 3,921/58,021 on DOACs vs. 2,967/44,822 on warfarin)
- Only trials investigating NVAF patients showed that DOACs were associated with a reduction in all cause mortality.
There are some important limitations to this review. The authors chose to pool patients with NVAF and VTE. Patients with NVAF are typically older with more comorbidities than those with VTE. The significant difference found in primary outcomes, for which no subgroup analysis was done, may be driven by one of these patient populations.
The definition of major and minor bleeding was not standardized between the phase 3 studies, therefore a patient documented to have major bleeding on rivaroxaban may not have been classified as having major bleeding on dabigatran. This could have biased the major bleeding case fatality rate.
This review consists of industry sponsored trials which likely allow for closer INR monitoring for patients on warfarin than occurs in practice. As such, the mortality outcomes for patients taking warfarin may be underestimated.
The phase 3 study populations may have differed from the ‘real world’ patient population who is being prescribed these drugs, including fewer patients in the studies with renal impairment, a younger study population and fewer patients with active cancer.
This systematic review did not compare the bleeding case fatality rate of individual DOACs
The bottom line
DOACs have a lower case fatality rate with major bleeding, lower cardiovascular mortality, and lower all-cause mortality than warfarin in this analysis combining phase-3 studies of NVAF and VTE. Patients who bleed taking DOACs are less likely to die than those who bleed taking warfarin. Patients being started on an oral anticoagulant in the ED should be properly informed of the bleeding risks. Overall, this study adds to mounting evidence that, when starting patients in the ED on anticoagulation, DOACs should be considered first line ahead of warfarin in the absence of valvular AF, significant renal impairment, and cost issues.
You discuss the different options for oral anticoagulants with your patient and inform her as to their safety profiles. You review your list of contraindications to DOACs and confirm that she has none. You suggest starting her on rivaroxaban and she agrees. You write a prescription for rivaroxaban and diltiazem and arrange outpatient follow up for her.
This post was copy-edited by Michael Bravo (@bravbro).
Patients gain knowledge about drugs in many ways. When I tell a patient I would like to start them on an anticoagulant, the reactions are varied. Many of my Canadian patients watch American television and are aware of several contemporary US law suits focusing on DOAC bleeding complications. I have been told by different patients that they don’t want to be prescribed rivaroxaban (Xarelto), dabigatran (Pradaxa) or apixaban (Eliquis) because they believe these are dangerous drugs which should never be taken. I am also told by patients they do not want to be prescribed warfarin as this is ‘rat poison’.
It generally takes me some time to explain that all anticoagulant medications have a small risk of bleeding, but the risk of bleeding is much lower than the benefits of stroke protection or worsening venous thromboembolism. The annual risk of serious bleeding on anticoagulation is 2-3%, however the risk in the young and healthy population is much lower, nearer 0.5%. The overall rate of major bleeding is similar between the all anticoagulants, but the rate of intracranial bleeding is much lower with DOACs compared to warfarin.
This systematic review allows me to tell patients that not only do the DOACs cause less intracranial bleeding than warfarin, but when bleeding occurs, patients do better on DOACs. This is true, even though there is no reversal agent for apixaban or edoxaban. Emergency physicians should have no hesitation in prescribing DOACs over warfarin.