Hokusai-VTE trial: edoxaban equal efficacy and better safety compared to warfarin

In the treatment of venous thromboembolism (VTE), the oral anticoagulant edoxaban resulted in equal efficacy and better safety compared to standard warfarin when either drug was used with initial low molecular weight heparin (LMWH), according to the results of the Hokusai-VTE trial.

VTE is the collective term for potentially fatal blood clots in the legs, deep vein thrombosis (DVT) and in the lungs, pulmonary embolism (PE).

The results from the global phase 3 Hokusai-VTE study of 8,292 patients with either acute symptomatic DVT, PE, or both were presented recently at the European Society of Cardiology (ESC) Congress 2013 in Amsterdam and published online in the New England Journal of Medicine.

Hokusai-VTE was a global, event-driven, randomised, double-blind, parallel-group phase 3 clinical study involving 8,292 patients in 439 clinical sites across 37 countries to evaluate once-daily edoxaban in patients with symptomatic DVT and/or PE. Patients were randomised to one of two different treatment groups. Both groups received open-label enoxaparin or unfractionated heparin for at least five days, and either warfarin or placebo (administered to edoxaban group), followed by double-blind edoxaban 60mg (n=4,118) (edoxaban 30mg for patients with renal impairment or low body weight or p-glycoprotein inhibitor use) or warfarin (n=4,122) for at least three months and up to a maximum of one year (duration of study treatment was determined by the investigator based on the patient's clinical features). Patients were followed for 12 months regardless of treatment duration to provide investigators with a better understanding of outcomes in clinical practice relative to an on-treatment analysis only.


The study found that the investigational, oral, once-daily direct factor Xa-inhibitor edoxaban met the primary efficacy endpoint of non-inferiority compared to warfarin, following initial use of heparin in both arms, for the treatment and prevention of recurrent symptomatic VTE. Once-daily edoxaban also demonstrated superiority compared to warfarin for the principal safety outcome of clinically relevant bleeding (the composite of major or clinically relevant non-major bleeding).

The Hokusai-VTE study was designed to reflect clinical practice using a flexible treatment duration of three to 12 months, including initial heparin treatment, in a broad spectrum of VTE patients, including those with severe PE. For the primary efficacy outcome, edoxaban demonstrated non-inferiority with a numerically lower incidence of recurrent symptomatic VTE compared to warfarin (3.2% versus 3.5%, respectively) (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.70 to 1.13; p<0.001 for noninferiority).

Edoxaban was also found to be superior to warfarin for the pre-specified principal safety outcome of clinically relevant bleeding (8.5% versus 10.3%, respectively) (HR, 0.81; 95% CI, 0.71 to 0.94; p=0.004 for superiority).

Patient specific dosing was applied according to the study protocol. Edoxaban was dosed at 60mg once-daily, except for those patients with clinical factors that commonly impact response to oral anticoagulants (renal impairment, low body weight, or concomitant use of certain glycoprotein inhibitors) who received edoxaban 30mg according to the study protocol. The reduced dose of edoxaban was found to have an efficacy profile consistent with the overall study cohort, with fewer recurrent VTE events in patients receiving 30mg edoxaban (n=733) compared to warfarin (n=719) (VTE recurrence of 3.0% versus 4.2%; HR, 0.73; 95% CI, 0.42 to 1.26). Clinically relevant bleeding in patients receiving edoxaban 30mg was significantly lower compared to warfarin (7.9% versus 12.8%, respectively) (HR, 0.62; 95% CI, 0.44 to 0.86).

Among patients with DVT (n=4,921), VTE recurrence was similar in the edoxaban and warfarin groups (3.4% versus 3.3%, respectively) (HR, 1.02; 95% CI, 0.75 to 1.38), while the incidence of recurrent VTE among patients with PE (n=3,319) was numerically lower for patients treated with once-daily edoxaban compared to warfarin (2.8% versus 3.9%, respectively) (HR, 0.73; 95% CI, 0.50 to 1.06). Additionally, in a sub-group analysis, patients with severe PE and evidence of right ventricular dysfunction (defined as NT pro-BNP ≥ 500 pg/mL, n=938) treated with edoxaban had a 48% lower risk of recurrent symptomatic VTE compared to warfarin (3.3% versus 6.2%, respectively) (HR, 0.52; 95% CI, 0.28 to 0.98).

The primary efficacy outcome was the recurrence of symptomatic VTE, defined as the composite of recurrent symptomatic DVT, non-fatal symptomatic PE and fatal PE in patients during the 12-month study period. The principal safety outcome was clinically relevant bleeding (major or non-major) occurring during or within three days of interrupting or stopping study treatment. Secondary efficacy outcomes included the composite clinical outcome of symptomatic recurrent DVT, non-fatal symptomatic recurrent PE and all-cause mortality.

Harry Büller, MD, PhD, Professor of Internal Medicine, Chairman of the Department of Vascular Medicine at the Academic Medical Center in Amsterdam, The Netherlands and Chairman of the Hokusai-VTE steering committee, said: "Hokusai-VTE was designed to include a broad range of VTE patients, including those with severe pulmonary embolism, and we are therefore pleased that the study found that edoxaban administered once daily is as efficacious as warfarin for the prevention of recurrent symptomatic VTE while significantly reducing the risk of bleeding. A promising finding was the sizeable reduction in recurrent symptomatic VTE among patients with severe pulmonary embolism who were treated with edoxaban."

The success of edoxaban compared to warfarin is good news in the quest for simplified treatment of VTE, said Dr. Büller. "The problem with warfarin is that food and alcohol and many, many medications interfere with the level and so therefore you're obliged to do careful laboratory testing every three to four weeks or even more frequently to measure the INR (international normalised ratio) and adjust the dose. The great advantage of the new oral anticoagulants is they have very predictable kinetics and dynamics and therefore can be given in a fixed dose and do not need monitoring."

But, along with enthusiasm for oral anticoagulants, there is also growing hope in the field that injectable heparin might also be safely eliminated, thus switching two inconvenient therapies for one pill, said Dr. Büller. "Two previous oral anticoagulant studies have omitted LMWH altogether (EINSTEIN PE and AMPLIFY) and were applauded because of the simplicity of just giving pills. But, both EINSTEIN PE and AMPLIFY were criticised for under-representing the severely ill sub-groups that make up a large part of the Hokusai-VTE population. The whole field was rushing to the conclusion that we could get rid of both heparin, and warfarin, but I think the findings of the Hokusai-VTE study show that in these sub-groups it looks like it would be pretty unwise to omit heparin. Our study adjusts that thinking just a little bit, and may start us reconsidering."

The study is named after the famous Japanese artist and painter Katsushika Hokusai.

AQUARIUS study results

The blood pressure lowering drug aliskiren did not improve coronary artery disease when given to patients who had prehypertension, results of the Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS) reveal.

The findings, reported at the ESC with simultaneous publication in the Journal of the American Medical Association, offer new insight into the value of lowering blood pressure beyond prehypertensive goals.

Lead investigator Stephen Nicholls MBBS, PhD, Deputy Director at the South Australian Health and Medical Research Institute, Professor of Cardiology at the University of Adelaide and Consultant Cardiologist at the Royal Adelaide Hospital in Adelaide, Australia, said: "In the AQUARIUS study, although greater blood pressure lowering was observed in the aliskiren treatment group, we did not observe significant slowing of disease progression. While these findings do not support the use of aliskiren for regression or prevention of progression of coronary atherosclerosis, prespecified exploratory findings in the trial suggests there may be some other potential benefits in patients with pre-existing coronary artery disease and blood pressure levels treated to goal."

AQUARIUS was a prospective, randomised, multicenter, double-blind clinical trial conducted at 103 centers. It included patients aged 35 years or older with angiographic evidence of coronary artery disease, prehypertensive blood pressure at baseline (systolic blood pressure between 125 and 139mmHg and diastolic blood pressure less than 90mmHg) and two additional cardiovascular risk factors.

Eligibility required a target blood vessel for imaging with at least 20% and less than 50% stenosis. After receiving aliskiren 150mg for one week to assess tolerability a total of 613 participants were randomised to receive either aliskiren 300mg (n=305) or placebo daily (n=308). Baseline intravascular ultrasonography was used to identify a target artery for imaging with the primary endpoint of the study being percent atheroma volume (PAV), and a secondary outcome being total atheroma volume (TAV)-measures of the amount of plaque present in the coronary artery.

Among the 458 participants (74.7%) who remained in the study for more than 72 weeks, there were no statistically significant differences in primary or secondary outcomes between those treated with aliskiren or placebo. PAV decreased by 0.33% in the aliskiren group and increased by 0.11% in the placebo group (p=0.08), and TAV, decreased by 4 versus 2.1mm respectively (p=0.18). Regression of PAV was observed in 56.9% of aliskiren-treated patients and 48.9% of placebo-treated patients (p=0.09), whereas TAV regressed in 64.4% versus 57.5% respectively (p=0.13). However, pre-specified exploratory findings showed significantly greater blood pressure reductions in the aliskiren-treated group (systolic -2.9 versus -0.8mmHg, p=0.007; and diastolic -2.0 versus -0.4mmHg, P=0.003). There were fewer major cardiovascular events (8.5% versus 16.2%, p=0.004), and non-fatal myocardial infarctions (0.3% versus 2.6%, p=0.02) in the aliskiren group).

ARISTOTLE post hoc sub analysis for apixaban

Results of a post-hoc sub analysis from the Phase III ARISTOTLE trial, which was designed to demonstrate the efficacy and safety of apixaban (Eliquis) compared to warfarin for the prevention of stroke or systemic embolism in nonvalvular atrial fibrillation (NVAF) patients were also presented at the ESC.

The ARISTOTLE trial excluded patients with clinically significant mitral stenosis, or a mechanical prosthetic heart valve. This sub analysis evaluated apixaban compared to warfarin in patients with or without other types of valvular heart disease (VHD) who were eligible for enrolment in the ARISTOTLE trial, including mitral regurgitation, mitral stenosis, aortic regurgitation, aortic stenosis, tricuspid regurgitation, or valve surgery. Those 4,808 patients were the focus of this sub analysis.

The results of this sub analysis were consistent with the results of the overall ARISTOTLE trial and demonstrated that apixaban compared with warfarin reduced stroke or systemic embolism, caused fewer major bleeding events, and reduced all-cause mortality in NVAF patients with or without VHD.

"This sub analysis provides better insight into the efficacy and safety of apixaban in nonvalvular atrial fibrillation patients with certain types of valvular heart disease, which are common in an elderly population," said study lead author Dr. Alvaro Avezum of the Dante Pazzanese Institute of Cardiology in San Paulo, Brazil. "These patients are generally older and considered to be at greater risk for clinical events than NVAF patients without VHD."

This sub analysis evaluated data from 4,808 NVAF patients (26.4% of the ARISTOTLE trial population) who had both VHD and NVAF. For the purpose of this analysis, subjects with VHD were identified by any history of at least moderate mitral regurgitation (n=3,526), mitral stenosis (n=131), aortic regurgitation (n=384), aortic stenosis (n=887), tricuspid regurgitation (n=2,124), or valve surgery (n=251). Note that some of these patients had more than one valvular abnormality.

In this sub analysis, overall patients with these types of VHD had higher rates of stroke or systemic embolism and of major bleeding than patients without VHD, regardless of treatment. Moreover, patients randomised to apixaban had lower rates of stroke or systemic embolism and of major bleeding compared with patients randomised to warfarin, both among patients with and without VHD. All p-values for interaction (due to presence or absence of VHD) were non-significant for the major outcomes of stroke and systemic embolism, major bleeding, and death.

This means that patients in the ARISTOTLE trial had similar outcomes with apixaban regardless of whether they had VHD, and that the results of this sub analysis were consistent with the overall results of the trial.

PARIS study: results in PCI

Among patients undergoing percutaneous coronary intervention (PCI) with stents, the risk of cardiovascular complications after stopping dual antiplatelet therapy (DAPT) is highly variable depending on the context, and some patients experience no complications at all, according to the results of the Patterns of Non-Adherence to Anti-Platelet Regimens In Stented Patients (PARIS) study.

Results from the PARIS study, which is a prospective, international, multicenter, observational registry trial, enrolled more than 5,000 patients with coronary artery disease undergoing PCI with stent implantation at 15 clinical sites in five countries between July, 2009 and December, 2010, were presented at the ESC. Follow-up at 30 days, six months, one and two years determined whether patients had discontinued, interrupted or disrupted antiplatelet therapy and whether this resulted in any major adverse cardiovascular events (MACE).

Roxana Mehran, Professor of Medicine and Director of Interventional Cardiovascular Research and Clinical Trials, Icahn School of Medicine at Mount Sinai, New York, said: "Our findings challenge existing paradigms for prolonging antiplatelet therapy in otherwise stable patients after PCI, and show that in a real-world setting physicians are making appropriate decisions in selecting low-risk patients for discontinuation. Conversely, when patients simply don't comply or are forced off antiplatelet therapy because they are bleeding, their risk is significantly elevated."

Discontinuation was defined as a physician-recommended cessation of medication for subjects believed to no longer need it, while interruption was defined as temporary (up to 14 days) due to surgical necessity, and disruption was due to bleeding or non-compliance. In a final analysis of 5,018 patients at two years, the study showed a cumulative incidence of discontinuation, interruption and disruption of 40.8%, 10.5% and 14.4%, respectively, while the cumulative incidence of MACE was 11.5%.

At one year, which is the duration currently recommended for antiplatelet therapy, the cumulative incidence of discontinuation, interruption and disruption was 11.5%, 4.6% and 9.8% respectively, with a 7.4% cumulative incidence of MACE. The majority of MACE (74%) occurred in patients who had remained on their recommended antiplatelet therapy, but among those who had not, there was a 50% increased risk of MACE associated with disrupting compared to staying on medication, and a 37% decreased risk associated with discontinuation compared to staying on. In contrast, brief interruptions did not increase risk for thrombotic events such as stent thrombosis or myocardial infarction.

For the latter group, a novel finding was that the risk of MACE was highest in the first seven days of disruption (when there was a seven-fold increase), after which it decreased. Importantly, the study also showed that sustained antiplatelet therapy was not associated with reduced thrombotic risk compared to recommended discontinuation-a finding that goes against common assumption.

TASTE trial: results

Aspiration of the blood clot or "thrombus" that causes a heart attack before re-opening a patient's artery with a balloon catheter does not improve survival compared to performing balloon dilation and stenting alone according to the results of the Thrombus Aspiration in ST- Elevation myocardial infarction in Scandinavia (TASTE) trial presented at the ESC.

The multicentre, prospective, randomised, controlled open-label trial enrolled 7244 patients with STEMI from Sweden, Denmark and Iceland who had a diagnosis of ST-elevation myocardial infarction (STEMI). Half of the patients were assigned to balloon treatment only (known as percutaneous coronary intervention, or PCI) and the other half had their blood clot aspirated before PCI.

The mortality rate at 30 days post-procedure was not statistically different between the groups (3.0% versus 2.8% respectively). Similarly, there was no difference between the two groups for secondary endpoints including risk of new heart attack, stroke and complications related to the treatment. Even high risk groups such as smokers, patients with diabetes or patients with large clots had similar results with either approach.

The TASTE trial is the first large-scale randomised trial of thrombus aspiration for STEMI to be large enough to reveal meaningful findings on mortality and morbidity. It enrolled more patients than all previous randomised trials combined and included a much broader range of patients.