Oral Apixaban for the Treatment of Acute Venous Thromboembolism.


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

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


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.


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

AMPLIFY: Apixaban in Acute VTE as Effective But Safer Than Standard Anticoagulation.


The oral factor Xa inhibitorapixaban (Eliquis, Pfizer/Bristol-Myers Squibb) was as effective as standard enoxaparin plus warfarin in treating acute venous thromboembolism (VTE) in a large randomized trial, one in which treatment with apixaban also led to a 69% drop in risk of major bleeding complications[1].

“The efficacy of apixaban in the patients with pulmonary embolism was similar to that in patients with deep vein thrombosis [DVT], and the relative effect was maintained in the approximately 40% of patients who presented with extensive disease,” write Dr Giancarlo Agnelli (University of Perugia, Italy) and associates, in the New England Journal of Medicine.

Their report on the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial, conducted at 358 centers in 28 countries, was slated for publication July 1, 2013 in conjunction with the study’s scheduled presentation here at the 2013 Congress of the International Society on Thrombosis and Haemostasis. The New England Journal of Medicine lifted its embargo on AMPLIFY coverage on June 30, following, it said, an embargo break by Reuters

“After 60 years of warfarin, it is an exciting time in thrombosis care,” writes Dr Mary Cushman(University of Vermont, Burlington) in an accompanying editorial [2]. However, “shifting with care to new treatments is essential to safe and effective practice.” She cautions that “new anticoagulants are not for every patient” and notes developments that have helped make warfarin management less burdensome, including the advent of prothrombin-time self-testing, anticoagulation clinics, and reduced monitoring frequency for some patients.

Also, she notes, a lot remains to be learned about the new oral agents, apixaban along with dabigatran(Pradaxa, Boehringer Ingelheim) and rivaroxaban (Xarelto, Bayer/Johnson & Johnson), including reversal strategies, monitoring (eg, in the presence of interacting drugs, extremes of patient weight, or bleeding or thrombosis complications), [and] approaches to treatment failure.”

The trial randomized 5395 patients with acute, symptomatic proximal VTE and/or pulmonary embolism (PE) to receive, with double blinding, either apixaban (n=2691) or subcutaneous enoxaparin followed by warfarin (n=2704). The factor Xa inhibitor was given as 10 mg twice daily for seven days followed by 5 mg twice daily for six months; enoxaparin was given for at least five days (median 6.5 days), with warfarin continued for six months.

The primary efficacy outcome was seen in 2.3% of patients taking apixaban and 2.7% of those on conventional therapy, which handily met the prespecified criteria for apixaban noninferiority (p<0.001). The results were nearly identical in each of the two VTE subgroups: those who entered with DVT and those who had PE.

Major bleeding occurred in 0.6% of the apixaban and 1.8% of the conventional-therapy groups, for a 69% drop in relative risk with the factor Xa inhibitor (p<0.001 for superiority). The composite of major bleeding or clinically relevant nonmajor bleeding fell by 56% (p<0.001 for superiority). VTE recurred within 30 days in 0.2% and 0.3%, respectively.

Relative Risk (95% CI) for Outcomes Apixaban vs Conventional Therapy

End points RR (95% CI)
First recurrent VTE or VTE-related death* 0.84 (0.60–1.18)
Major bleeding 0.31 (0.17–0.55)
Major or clinically relevant nonmajor bleeding 0.44 (0.36–0.55)
Death during treatment period 0.79 (0.53–1.19)
VTE or CV death 0.80 (0.57–1.11)
VTE, VTE-related death, or major bleeding 0.62 (0.47–0.83)

*Primary efficacy outcome

“The efficacy and safety of apixaban were consistent across a broad range of subgroups, including those based on clinically important features such as an age of more than 75 years, a body weight of more than 100 kg, use of parenteral anticoagulant treatment before randomization, and the duration of such treatment,” suggesting that the findings are likely generalizable across a broad spectrum of patients, according to the group. The findings at participating centers where warfarin-treated patients were more often maintained in a therapeutic INR range were also consistent with trial’s overall results, they write.

“On the basis of the results of this trial, together with those of the [AMPLIFY-EXT] trial, apixaban provided a simple, effective, and safe regimen for the initial and long-term treatment of venous thromboembolism.”

In AMPLIFY-EXT, as heartwire reported late last year, the risk of recurrent VTE or death was significantly reduced among patients who completed a full six-month course of anticoagulation for VTE and then stayed on apixaban another six to 12 months, so-called extended therapy for VTE, compared with anticoagulated patients who were then given placebo.

The trial was funded by Pfizer and Bristol-Myers Squibb. Agnelli discloses receiving personal fees from Pfizer in relation to the conduct of the trial, and other personal fees from Boehringer Ingelheim, Sanofi, Daiichi-Sankyo, and Bayer Healthcare. Disclosures for the coauthors are listed on the journal’s website. Cushman had no disclosures.

http://www.medscape.com

 

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Source: Mayo clinic

 

 

white�pn�t� X1� font-size:9.0pt;font-family:”Arial”,”sans-serif”;color:#666666′>And, I’ll tell you right now, after this last year, leaving Waiheke Island, going to Hawaii (as detailed in Going Out On A Limb), well… I feel freer, happier, more peaceful and more my true self than I ever have in 35 years and I categorically COULD NOT have done it if I had not reached out for support.

 

So, I implore you, if you are someone who is afraid to reach out for support, please… for the love of all things… swallow your fears, your negative self-talk, your pride or whatever is keeping you stuck and please, please put your freaking hand up! The Universe will deliver what you need if you will only step up to help yourself. People will materialise to support you. Information will find its way to you when you move forward to open your arms to receive it. You will find help in the most unlikely of places if you are willing to step outside your comfort zone. Do not judge how things may have gone before… perhaps once before you reached out and you didn’t get the response and support you needed. The past is gone and it has no bearing now. Life is short, don’t waste one second of it when the support you need lies all around you, beckoning you to call upon it.