Apixaban

Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation

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Abstract

Background

Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit.

Methods

We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason).

Results

We included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P=0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P=0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group.

Conclusions

Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding.

Apixaban for Stroke Prevention in Subclinical AF

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res360

In the ARTESIA trial, how did apixaban compare with aspirin regarding the risk of stroke or systemic embolism?

Healey et al. conducted the ARTESIA trial, which assessed whether apixaban resulted in a lower risk of stroke or systemic embolism than aspirin, with an acceptably low risk of major bleeding, among patients with risk factors for stroke who also had subclinical atrial fibrillation detected by a pacemaker, defibrillator, or implantable cardiac monitor.

Clinical Pearls

Q: What is subclinical atrial fibrillation?

A: The authors proposed the term subclinical atrial fibrillation to describe atrial fibrillation that is asymptomatic or that produces such short-lasting, nonspecific symptoms that it is not readily diagnosed by standard clinical means but is uncovered only with the use of long-term, continuous cardiac rhythm monitoring by an implanted cardiac pacemaker or defibrillator. They reported that subclinical atrial fibrillation was present in more than one third of older patients with hypertension who had received a pacemaker and was associated with an increased risk of ischemic stroke or systemic embolism by a factor of 2.5. However, the absolute increase in stroke risk with subclinical atrial fibrillation was 1 percentage point per year, approximately half the risk increase observed among patients with clinically detected atrial fibrillation.

Q: In the ARTESIA trial, how did apixaban compare with aspirin regarding the risk of stroke or systemic embolism?

A: The trial showed that among patients with episodes of subclinical atrial fibrillation and risk factors for stroke, the risk of stroke or systemic embolism was lower by 37% (95% CI, 12 to 55) with apixaban than with aspirin. Stroke or systemic embolism (primary efficacy outcome) occurred in 55 patients assigned to receive apixaban (0.78% per patient-year) and 86 patients assigned to receive aspirin (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007).

Morning Report Questions

Q: Was the risk of bleeding higher with apixaban than with aspirin in the trial?

A: The risk of major bleeding was 1.71% per patient-year with apixaban and 0.94% per patient-year with aspirin (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). Clinical presentation with hemodynamic instability was uncommon, and most bleeding events responded to supportive care, which could include red-cell transfusion. Fatal bleeding occurred in 5 patients with apixaban and 8 patients with aspirin. Symptomatic intracranial hemorrhage occurred in 12 patients with apixaban and 15 patients with aspirin.

Q: Are the trial findings generalizable to patients without an implanted cardiac electronic device?

A: Although the results of the ARTESIA trial are directly relevant to patients with implanted cardiac electronic devices, one might consider broader implications given the proliferation of implanted and wearable cardiac monitors as well as direct-to-consumer devices used to screen for atrial fibrillation. Although it was initially contemplated that the high prevalence of subclinical atrial fibrillation was confined to patients with pacemakers, subsequent studies involving implantable cardiac monitors showed subclinical atrial fibrillation in many older patients without pacemakers. Some of these patients may also have risk factors for stroke that are similar to those of the patients in the ARTESIA trial. However, the results of the ARTESIA trial apply directly only to patients who are already at increased risk for stroke in whom subclinical atrial fibrillation is detected by an implanted device.

Apixaban for Stroke Prevention in

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Abstract

Background

Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit.

Methods

We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason).

Results

We included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P=0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P=0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group.

Conclusions

Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding.

PPIs Cut Upper GI Bleeds From Anticoagulants

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Bleeding risk was highest with rivaroxaban, lowest with apixaban

Anticoagulation patients at risk for upper gastrointestinal (GI) bleeding saw their risk reduced by more than a third when a proton pump inhibitor (PPI) was added to oral anticoagulant therapy, according to a retrospective analysis of Medicare claims.

In addition, the choice of anticoagulant can be important for outcomes, reported Wayne Ray, PhD, of Vanderbilt University Medical Center in Nashville, and colleagues. During 754,389 person-years of therapy, they found that the highest risk of upper GI hemorrhage was associated with rivaroxaban (Xarelto) but not apixaban (Eliquis), dabigatran (Pradaxa), or warfarin (Coumadin).

Ray noted in a Vanderbilt new release that an estimated 1% to 1.5% of patients on oral anticoagulants will experience upper GI bleeds every year, and anticoagulant choice and PPI co-therapy could affect the risk of upper GI tract bleeding, a frequent and potentially serious complication of oral anticoagulant treatment. The study, published online in JAMA, found that adding a PPI reduced overall bleeding across all anticoagulants, for an incidence rate ratio of 0.66 and a risk reduction of 34%.

“For patients starting oral anticoagulant treatment, both PPI co-therapy and anticoagulant choice can materially affect risk of upper gastrointestinal bleeding hospitalization,” Ray told MedPage Today. “These factors are particularly important for patients with elevated gastrointestinal risk and argue for a GI evaluation prior to initiating oral anticoagulant treatment.”

Ray also noted that without an added PPI the incidence of hospitalization for upper GI bleeding was 4% per year, while adding a PPI reduced the rate to 2.8% per year.

The retrospective analysis looked at hospitalizations for upper GI bleeds among Medicare beneficiaries in the period 2011-2015. The researchers identified 1,643,123 patients with 1,713,183 new episodes of oral anticoagulant treatment for conditions such as atrial fibrillation.

The mean age in the cohort was 76.4, and atrial fibrillation accounted for 870,330 person-years (74.9%) of follow-up. Women accounted for 56.1% of person-years of follow-up.

Warfarin was by far the most commonly used anticoagulant, Ray and co-authors found. Overall, 1,058,807 anticoagulation patients had no PPI co-therapy vs 239,672 with co-therapy, for a follow-up of 754,389 person-years without co-therapy.

During no PPI co-therapy, the adjusted incidence of hospitalization for upper GI bleeding (n=119) was 115 per 10,000 person-years (95% CI 112-118).

Comparing PPI co-therapy (264,447 person-years) with no co-therapy, the researchers found the overall risk of upper GI bleeding hospitalizations (n=2,245) was lower with co-therapy, for an incidence rate ratio (IRR) of 0.66 (95% CI 0.62-0.69).

Compared with the results of other anticoagulants without PPI co-therapy, hospitalization per 10,000 person-years was highest for rivaroxaban (n=1278) at 144 (IRR 1.97) and lowest for apixaban (n=279) at 73. “Because rivaroxaban is given as a single daily dose intended to maintain 24-hour therapeutic levels, the relative peak plasma concentrations are higher than those for other oral anticoagulants,” Ray and associates explained.

The corresponding hospitalization incidence for dabigatran (n=629) was 120 per 10,000 person-years and for warfarin (n=4,933), 113 per 10,000 person-years.

The association of anticoagulant choice and PPI co-therapy with hospitalization for upper GI bleeding varied according to patients’ underlying disease, with absolute differences driven by the upper quartile of risk.

“For these patients, the difference in the annual incidence of hospitalization for upper gastrointestinal tract bleeding between the treatment strategies with the lowest and the highest gastrointestinal safety (rivaroxaban treatment without PPI and apixaban treatment with PPI, respectively) was 2.1 hospitalizations per 100 person-years,” the authors wrote. “These findings indicate the potential benefits of a gastrointestinal bleeding risk assessment before initiating anticoagulant treatment.”

Ray noted that oral anticoagulants can be extremely valuable in preventing an ischemic stroke — “which is one thing you really do not want to have happen, and we can’t lose sight of that.”

“On the other hand,” he added, “they have potentially very dangerous side effects. What we’ve done with this study is show that clinicians can focus on a high-risk population and significantly improve care for those patients with the addition of a PPI.”

Important Because of Large Patient Numbers

Asked for his perspective, Suneal K. Agarawal, MD, of Baylor College of Medicine in Houston, who was not involved in the research, said: “This a very important study because it reinforces with large numbers of patients what gastroenterologists have assumed for some time, that PPIs reduce GI bleeding. The COGENT trial showed that a PPI reduced GI bleeding in patients on antiplatelet medication, and now we have data on the role of PPIs in anticoagulant as well as antithrombotic therapy.”

The Medicare-based analysis had several limitations, the authors said, including the potential misclassification of anticoagulant treatment, PPI co-therapy, and non-steroidal anti-inflammatory drug use, since these variables were determined from filled prescriptions, and Medicare restricts reimbursement for many over-the-counter drugs. In addition, confounding could also have been present by unmeasured factors, such as aspirin exposure and Helicobacter pylori infection.

Furthermore, bleeding risk was measured with a disease risk score, an internal measure suitable for risk stratification within the Medicare cohort and not studied in other populations, Ray and co-authors noted. In terms of generalizability, the cohort excluded patients previously hospitalized for GI bleeding or who switched to a different anticoagulant during the study period. In addition, its Medicare population had a greater prevalence of anticoagulant treatment and GI bleeding risk compared with younger populations.

What, how, when of using NOACs in practice

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Dr Chan Yi-Hsin

When making practical decision on using non-vitamin K antagonist oral anticoagulants (NOACs), several factors should be considered such as age, renal function, and risk of bleeding, according to a presentation at the APSC Congress 2018.

The Asia Pacific Heart Rhythm Society (APHRS) 2017 consensus paper states that “for Asian patients with nonvalvular atrial fibrillation (AF), standard-dose NOACs are the default doses of choice for stroke prevention unless label guidance recommends low-dose regimens.” [J Arrhythm 2017;33:345-367]

“Aspirin is not recommended solely for stroke prevention in AF,” said Dr Chan Yi-Hsin of Chang Gung Memorial Hospital, Linkou, Taiwan.

The recommendations from APHRS are generally aligned with the ACC* and ESC** guidelines, he noted, which indicate that low-risk patients (defined by a CHAD2DS2-VASc=0 for male and =1 for female) do not require antithrombotics. On the other hand, higher-risk patients (CHAD2DS2-VASc ≥2 for all or =1 for male) were recommended to be further assessed with the SAMeTT2R2 score to guide the choice of anticoagulants — NOACs are preferred if the final score is ≥3. [J Arrhythm 2017;33:345-367]

How and what to select?

In selecting which NOAC to use, clinicians need to consider the CHAD2DS2-VASc score, age, renal and liver function, risk of bleeding, and concurrent medications a patient is receiving, Chan pointed out. [APSC 2018, session S047-04]

If CHAD2DS2-VASc=0/1, dabigatran or apixaban can be considered, based on findings from the RELY and ARISTOTLE trials which involved 30–34 percent of lower-risk patients in the overall study population. [N Engl J Med 2009;361:1139-1151; N Engl J Med 2010;363:1875-1876; N Engl J Med 2011;365:981-992] In higher-risk patients, the ENGAGE AF-TIMI 48 trial involving 77.4 percent of patients with CHAD2DS2-VASc=2 suggests the use of edoxaban in such patients, while the ROCKET AF study comprising 87 percent of patients with CHAD2DS2-VASc ≥3 indicates that rivaroxaban be used in these patients. [N Engl J Med 2011;365:883-891; N Engl J Med 2013;369:2093-2104]

Nonetheless, Chan was quick to point out that there are no head-to-head trials comparing the different NOACs so far, and the above suggestions are based on review of the various randomized controlled trials comparing each NOAC with warfarin.

When selecting NOAC in elderly patients (aged ≥75 years), a review study on phase III randomized clinical trials (RCTs) suggests that the risk of bleeding was reduced with apixaban 5 mg BID vs warfarin but the converse was seen (ie, warfarin was favoured) when compared with rivaroxaban 20 mg QD or dabigatran 110/150 mg BID in elderly patients. [Best Pract Res Clin Haematol 2013;26:215-224]

As different NOAC has different renal excretion rate, AF patients with impaired renal function (eGFR*** <50 mL) can consider dabigatran up to 150 mg with regards to efficacy (in terms of reduction in stroke rates), said Chan. [N Engl J Med 2009;361:1139-1151] However, in terms of safety outcome, apixaban can be considered in these patients as previous finding has shown a greater extent of reduction in major bleeding risk with apixaban vs warfarin. [N Engl J Med 2011;365:981-992]

“NOACs can [also] be used in patients with mild or moderate liver impairment (Child-Pugh categories A and B), with no dose reduction required for any of the NOAC in AF patients with Child-Pugh category A impairment,” said Chan. “NOACs are not recommended for those in Child-Pugh category C.” [Eur Heart J 2018;39:1330-1393]

One should also consider drug-drug interactions of NOACs with other medications a patient is taking, advised Chan. For example, in AF patients who are also taking HIV protease inhibitor or anti-epileptic drugs (such as carbamazepine, phenobarbital, phenytoin), all NOACs are contraindicated. [J Formos Med Assoc 2016;115:893-952; J Arrhythm 2017;33:345-367]

When to stop and restart?

“Renal function and surgical factors [ie, bleeding risk for surgery] help to determine when to discontinue and restart a NOAC for elective surgery,” said Chan.

According to the APHRS, TSOC, and THRS# guidelines, AF patients with normal renal function can stop any of the NOAC ≥24 hours before an elective surgical intervention classified to be of low bleeding risk and ≥48 hours for high bleeding risk. However, in AF patients with renal impairment, a longer duration of NOAC discontinuation before an elective surgery needs to be considered for those on dabigatran. [J Formos Med Assoc 2016;115:893-952; J Arrhythm 2017;33:345-367]

“Heparin/LMWH## bridging is generally not necessary for NOACs. NOAC is uninterrupted when performing AF catheter ablation,” said Chan.

“Generally, NOACs can be restarted 24 hours post-procedure with low-bleeding risk, and 48–72 hours post-procedure with high-bleeding risk. For procedure in which immediate and complete haemostasis can be achieved (eg, pacemaker implantations and skin surgery), NOACs can be resumed 6–8 hours after the interventions,” he added, citing recommendations from the ESC, APHRS, TSOC, and THRS guidelines. [Eur Heart J 2018;39:1330-1393; J Formos Med Assoc 2016;115:893-952; J Arrhythm 2017;33:345-367]

Bleeding management

“For non-life-threatening major bleeding, reversal agent is generally not necessary … these can be managed with supporting care,” said Chan. [Eur Heart J 2018;39:1330-1393]

For life-threatening major bleeding, idarucizumab is the specific reversal agent for dabigatran while andexanet alpha can be used to reverse factor Xa inhibitors such as apixaban, rivaroxaban, and edoxaban, he stated.

 

*ACC: American College of Cardiology
**ESC: European Society of Cardiology
*** eGFR: estimated glomerular filtration rate
#TSOC and THRS: TSOC=Taiwan Society of Cardiology; THRS=Taiwan Heart Rhythm Society
##LMWH: Low-molecular-weight heparin.

 

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Uninterrupted apixaban therapy vs. warfarin during AF ablation: A question of safety and efficacy

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Catheter ablation is increasingly being performed for patients with paroxysmal and persistent atrial fibrillation (AF). Atrial fibrillation ablation carries a significant risk of thromboembolism and bleeding due to thrombus formation in the left atrium and intraprocedural conversion from AF to sinus rhythm. Multiple strategies are commonly employed peri-AF ablation to reduce the risk of thromboembolic complications, including the use of transesophageal echocardiography, intracardiac echocardiography, irrigated ablation catheters, and intraprocedural anticoagulation. [1]

Historically, patients treated with vitamin k antagonists (VKA) would typically discontinue this medication and be bridged with low-molecular-weight heparin prior to ablation. However, recent recommendations state that patients undergoing an AF ablation can safely undergo the procedure without discontinuation. [1]

Direct oral anticoagulants (DOACs), have emerged as an increasingly common therapy for thromboembolism prevention in AF. However, strategies for its use in the setting of AF ablation have been varied and may be associated with an increased incidence of thromboembolism. [2]

A recent multicenter study published in The American Journal of Cardiology evaluated the safety and efficacy of uninterrupted apixaban versus warfarin anticoagulation in the periprocedural AF ablation setting. [3] There were no thromboembolic events in the apixaban group or the VKA group. There were no significant differences observed in major bleeding endpoints, minor bleeding, pericardial effusion or groin hematoma. Interestingly, the heparin requirement was the same for both warfarin and apixaban; however, while the periprocedural activated clotting time (ACT) in warfarin group was significant, minimum ACT throughout AF ablation was lower. This might suggest that periprocedural apixaban anticoagulation leads to a more consistent ACT in this setting.

Similar comparisons have been made with other DOACs, although study protocols may differ slightly and there is no direct comparison to assess the role, safety and efficacy of each DOAC. There has been conflicting data, with Steinberg et al, [2] and Sardar et al, [4] demonstrating an increase in neurologic complications with dabigatran compared to VKA. This is contrary to the meta-analysis conducted by Honhloser et al, [5] and Providencia et al, [6] who demonstrated no significant differences in the composite of neurologic and bleeding complications between the dabigatran and uninterrupted VKA groups.

There is even less data for Rivaroxaban, although results of prospective observational [7] and randomised [8] trials with uninterrupted rivaroxaban suggest that this therapy appears to be as safe and efficacious in preventing bleeding and thromboembolic events in patients undergoing AF ablation as uninterrupted warfarin therapy.

More recent data from the RE-CIRCUIT (no increase in thromboembolic endpoints; major bleeding reduction with uninterrupted dabigatran) and AEIOU (no differences in thromboembolic or bleeding endpoints with apixaban-either uninterrupted or interrupted by a single dose- or warfarin) trials are also reassuring, and reinforce that in the near future catheter ablation could possibly move towards uninterrupted DOAC anticoagulation to prevent the difficulties with variable INRs.

However, one must emphasize the need for more information to guide the periprocedural use of both DOACs and VKAs in the real-world setting.

This cardionote was prepared by Dr Amelia Carro-Hevia (Spain) and published simultaneously on Cardio Debate and CardioMaster websites, as part of an ongoing collaboration between the two educational platforms. For more information on Cardiomaster please visit www.cardiomaster.net

REFERENCES:

  1. Calkins H, Hindricks G, Cappato R, Kim YH, Saad EB, Aguinaga L, Akar JG et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythm. 2017;33(5):369-409.
  2. Steinberg BA, Hasselblad V, Atwater BD, Bahnson TD, Washam JB, Alexander JH, et al. Dabigatran for periprocedural anticoagulation following radiofrequency ablation for atrial fibrillation: a meta-analysis of observational studies. J Interv Card Electrophysiol. 2013;37 (3):213–21.
  3. Shah RR, Pillai A, Schafer P, Meggo D, McElderry T, et al. Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation. Am J Cardiol. 2017;120(3):404-407.
  4. Sardar P, Nairooz R, Chatterjee S, Wetterslev J, Ghosh J, Aronow WS. Meta- analysis of risk of stroke or transient ischemic attack with dabigatran for atrial fibrillation ablation. Am J Cardiol. 2014;113(7):1173-7.
  5. Hohnloser SH, Camm AJ. Safety and efficacy of dabigatran etexilate during catheter ablation of atrial fibrillation: a meta-analysis of the literature. Europace. 2013;15(10):1407-11.
  6. Providencia R, Albenque JP, Combes S, Bouzeman A, Casteigt B, Combes N, et al. Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Heart. 2014;100(4):324-35.
  7. Lakkireddy D, Reddy YM, Di Biase L, Vallakati A, Mansour MC, Santangeli P, et al. Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol.2014;63(10):982-8.
  8. Cappato R, Marchlinski FE, Hohnloser SH, Naccarelli GV, Xiang J, Wilber D et al; VENTURE-AF Investigators. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J. 2015;36(28):1805-11.
  9. Calkins H, Willems S, Gerstenfeld EP, Verma A, Schilling R, Hohnloser SH, Okumura K, Serota H, Nordaby M, Guiver K, Biss B, Brouwer MA, Grimaldi M; RE-CIRCUIT Investigators. Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation. N Engl J Med. 2017;376(17):1627-1636.
  10. 10.- Reynolds MR, Allison JS, Natale A, et al. A prospective randomized trial of apixaban dosing during atrial fibrillation of ablation: the AEIOU (Apixaban Evaluation of Interrupted or Uninterrupted Anticoagulation for Ablation of Atrial Fibrillation) Trial. Heart Rhythm Society (HRS) Scientific Sessions 2017; May 11, 2017; Chicago, IL. Abstract C-LBCT01-05

Oral Apixaban for the Treatment of Acute Venous Thromboembolism.

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BACKGROUND

Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism.

METHODS

In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding.

RESULTS

The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], −0.4 percentage points; 95% CI, −1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups.

CONCLUSIONS

A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding

Source: NEJM

Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation.

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Abstract

BACKGROUND:

Anticoagulant treatment with vitamin K antagonists (VKAs) is aimed at preventing thromboembolic complications and has been the therapy of choice for most people with non-valvular atrial fibrillation (AF) for many decades. A new class of anticoagulants, the factor Xa inhibitors, appear to have several pharmacological and practical advantages over VKAs.

OBJECTIVES:

To assess the effectiveness and safety of treatment with factor Xa inhibitors versus VKAs for the prevention of cerebral or systemic embolic events in people with AF.

SEARCH METHODS:

We searched the trials registers of the Cochrane Stroke Group and the Cochrane Heart Group (June 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10), MEDLINE (1950 to April 2013) and EMBASE (1980 to April 2013). In an effort to identify further published, unpublished and ongoing trials we searched trials registers and Google Scholar (July 2012). We also screened reference lists and contacted pharmaceutical companies, authors and sponsors of relevant published trials.

SELECTION CRITERIA:

Randomised controlled trials that directly compared the effects of long-term treatment (more than four weeks) with factor Xa inhibitors and VKAs for the prevention of cerebral and systemic embolism in patients with AF. We included patients with and without a previous stroke or TIA.

DATA COLLECTION AND ANALYSIS:

The primary efficacy outcome was the composite endpoint of all strokes and other systemic embolic events. Two authors independently assessed trial quality and the risk of bias, and extracted data. We calculated a weighted estimate of the typical treatment effect across trials using the odds ratio (OR) with 95% confidence interval (CI) by means of a fixed-effect model. However, in the case of moderate or high heterogeneity of treatment effects, we used a random-effects model to compare the overall treatment effects and performed a pre-specified sensitivity analysis excluding any fully open-label studies.

MAIN RESULTS:

We included data from 42,084 participants randomised into 10 trials. All participants had a confirmed diagnosis of AF (or atrial flutter) and were deemed by the randomising physician to be eligible for long-term anticoagulant treatment with a VKA (warfarin) with a target International Normalised Ratio (INR) of 2.0 to 3.0 in most patients. The included trials directly compared dose-adjusted warfarin with either apixaban, betrixaban, darexaban, edoxaban, idraparinux or rivaroxaban. Four trials were double-masked, five partially-masked (that is different doses of factor Xa inhibitor administered double-masked and warfarin administered open-label) and one was open-label. Median duration of follow-up ranged from 12 weeks to 1.9 years.The composite primary efficacy endpoint of all strokes (both ischaemic and haemorrhagic) and non-central nervous systemic embolic events was reported in nine of the included studies (40,777 participants). Treatment with a factor Xa inhibitor significantly decreased the number of strokes and systemic embolic events compared with dose-adjusted warfarin (OR 0.81, 95% CI 0.72 to 0.91). We also analysed both components of this composite endpoint separately: treatment with a factor Xa inhibitor significantly decreased both the number of ischaemic and haemorrhagic strokes (OR 0.78, 95% CI 0.69 to 0.89) and the number of systemic embolic events (OR 0.53, 95% CI 0.32 to 0.87).All of the included studies (42,078 participants) reported the number of major bleedings. Treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.89, 95% CI 0.81 to 0.98). There was, however, statistically significant and high heterogeneity (I² = 81%) and an analysis using a random-effects model did not show a statistically significant decrease in the number of major bleedings (OR 0.92, 95% CI 0.63 to 1.34). The pre-specified sensitivity analysis excluding open-label studies showed that treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (OR 0.84, 95% CI 0.76 to 0.92) but moderate heterogeneity was still observed (I² = 65%). A similar sensitivity analysis using a random-effects model did not show a statistically significant decrease in the number of major bleedings in patients treated with factor Xa inhibitors (OR 0.78, 95% CI 0.57 to 1.05). Part of the observed heterogeneity can thus be explained by the increased risk of major bleedings in the factor Xa treatment arm in the single included open-label study, which studied idraparinux. Other heterogeneity might be explained by differences in baseline bleeding risks in the two largest trials of apixaban and rivaroxaban that we included in this review.Data on intracranial haemorrhages (ICHs) were reported in eight studies (39,638 participants). Treatment with a factor Xa inhibitor significantly reduced the risk of ICH compared with warfarin (OR 0.56, 95% CI 0.45 to 0.70). Again, we observed statistically significant heterogeneity (I² = 60%). The pre-specified sensitivity analysis excluding the open-label study showed that treatment with a factor Xa inhibitor significantly reduced the number of ICHs compared with warfarin (OR 0.51, 95% CI 0.41 to 0.64), without any sign of statistical heterogeneity (I² = 0%).The number of patients who died from any cause was reported in six studies (38,924 participants). Treatment with a factor Xa inhibitor significantly reduced the number of all-cause deaths compared with warfarin (OR 0.88, 95% 0.81 to 0.97).

AUTHORS’ CONCLUSIONS:

Factor Xa inhibitors significantly reduced the number of strokes and systemic embolic events compared with warfarin in patients with AF. Factor Xa inhibitors also seem to reduce the number of major bleedings and ICHs compared with warfarin, though the evidence for a reduction of major bleedings is somewhat less robust. There is currently no conclusive evidence to determine which factor Xa inhibitor is more effective and safer for long-term anticoagulant treatment of patients with AF as head-to-head studies of the different factor Xa inhibitors have not yet been performed.

Source: PMID

 

For Acute Venous Thromboembolism, Apixaban Compares Favorably with Conventional Treatment.

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Apixaban was as effective as enoxaparin plus warfarin and produced fewer bleeding complications.
Apixaban (Eliquis), a factor Xa inhibitor, is one of several new oral anticoagulation drugs that require no monitoring. In this industry-sponsored, placebo-controlled trial, 5400 patients with acute venous thromboembolism (VTE) received 6-month courses of either apixaban (given twice daily) or conventional treatment with enoxaparin followed by warfarin. The qualifying diagnosis was deep venous thrombosis (DVT) in 65% of patients and pulmonary embolism (with or without DVT) in 35%.

Apixaban was noninferior to conventional therapy at 6 months: The primary efficacy outcome (recurrent symptomatic or fatal VTE) occurred in 2.3% of apixaban recipients and in 2.7% of conventional-therapy recipients. Rates of major bleeding were significantly lower in the apixaban group than in the conventional-therapy group (0.6% vs. 1.8%).

COMMENT

In this study, oral therapy with apixaban was as effective as — and possibly safer than — enoxaparin plus warfarin for patients with acute venous thromboembolism. In another recent trial, apixaban lowered the incidence of recurrent VTE (compared with placebo) in patients who already had completed initial 6- to 12-month course of conventional anticoagulation (NEJM JW Gen Med Jan 3 2013). However, apixaban currently is FDA-approved only for stroke prevention in patients with atrial fibrillation; the only new drug that is FDA-approved for fully oral treatment of acute VTE is another factor Xa inhibitor, rivaroxaban (Xarelto).

Source: NEJM

Oral Apixaban for the Treatment of Acute Venous Thromboembolism.

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BACKGROUND

Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism.

METHODS

In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding.

RESULTS

The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], −0.4 percentage points; 95% CI, −1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups.

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CONCLUSIONS

A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding

Source: NEJM