AMPLIFY phase 3 study results

Results from the six month phase 3 AMPLIFY trial of 5,395 patients with acute venous thromboembolism (VTE), which included symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism (PE), have recently been announced.

In this trial, apixaban as a single-agent achieved the primary efficacy endpoint of non-inferiority to conventional therapy (transition from initial parenteral enoxaparin to warfarin therapy) in the reduction of the composite endpoint of recurrent symptomatic VTE or VTE-related death.

Apixaban also met the primary safety endpoint of superiority for major bleeding, with a 69% relative risk reduction (RRR) compared to conventional therapy (absolute risk reduction [ARR] 1.2%; p<0.001 for superiority).

Importantly, AMPLIFY demonstrated comparable results for the primary efficacy and safety endpoints between patients entering the study with a DVT or a PE.

The findings were published online in the New England Journal of Medicine and presented at the 24th Congress of the International Society on Thrombosis and Haemostasis (ISTH).

Dr Alexander Cohen, Honorary Consultant Vascular Physician at King's College Hospital said, "In the AMPLIFY trial apixaban was shown to be effective in the treatment of venous thromboembolism, with the additional benefit of having a significantly lower risk of bleeds compared to current standard therapies, which is positive news for patients and healthcare professionals. Subject to regulatory approval, this improved risk benefit profile will provide clinicians with confidence when considering prescribing this treatment and provide reassurance for patients. The fact it is an oral treatment has additional advantages in terms of convenience for patients and potential cost-savings for hospitals."

Apixaban is not currently licensed for the treatment of venous thromboembolism. Based on the results of AMPLIFY, as well as AMPLIFY-EXT, which were published online on December 8, 2012, in New England Journal of Medicine with simultaneous presentation during a late-breaker session at the 54th Annual Meeting of the American Society of Hematology (ASH), Bristol-Myers Squibb and Pfizer plan to initiate regulatory filings for the initial and long-term treatment of VTE, as well as for extended prevention of recurrent VTE.

Venous thromboembolism, or VTE, is a spectrum of disease that encompasses two serious conditions: deep vein thrombosis (DVT), a blood clot in a deep vein, usually in the leg, that partially or totally blocks the flow of blood; and pulmonary embolism (PE), a blood clot in the pulmonary artery blocking one or more vessels in the lungs. VTE continues to be a major cause of morbidity and mortality, with more than one million VTE events estimated to occur annually across six major EU countries (UK, France, Germany, Italy, Spain and Sweden). Once a VTE has occurred, up to 30% of people may have a VTE recurrence in the long term, some of which could potentially be fatal.



AMPLIFY, (Apixaban for the initial Management of PuLmonary embolIsm and deep vein thrombosis as First-line therapY), a randomised, double-blind, multicentre trial, included 5,395 patients with confirmed symptomatic DVT or PE requiring treatment for six months, and evaluated apixaban as a single-agent (10mg twice daily for seven days followed by 5mg twice daily thereafter) compared to conventional therapy (transition from initial parenteral enoxaparin to warfarin therapy). Approximately one third of patients in the trial had a PE
at the time of enrolment into the study.

The primary efficacy outcome was the composite endpoint of recurrent symptomatic VTE or VTE-related death. (Recurrent VTE included fatal or non fatal PE and nonfatal DVT). For the primary efficacy outcome, apixaban achieved non-inferiority to conventional therapy in the reduction of recurrent symptomatic VTE or VTE-related death. The primary efficacy outcome occurred in 59 patients in the apixaban group (2.3%) and 71 patients (2.7%) receiving conventional therapy (relative risk 0.84; ARR 0.4%; 95% CI, 0.60 to 1.18; p<0.001 for non-inferiority).

Apixaban achieved the primary safety endpoint of superiority for major bleeding. Major bleeding occurred in 0.6% of patients given apixaban and 1.8% of those given conventional therapy (relative risk 0.31; ARR 1.2%; 95% CI, 0.17 to 0.55; p<0.001 for superiority). The composite of major and clinically relevant nonmajor bleeding occurred in 4.3% and 9.7% of patients in the apixaban and conventional-therapy groups, respectively (relative risk 0.44; ARR 5.4%, 95% CI, 0.36 to 0.55; p<0.001). Rates of other adverse events were similar in the
two groups.

AMPLIFY demonstrated comparable results for the primary efficacy and safety endpoints between patients entering the study with a DVT
or a PE.

Ten years of olmesartan symposium

A scientific symposium sponsored by Daiichi Sankyo and the Menarini Group-Ten Years of Olmesartan: Tailoring Patient Care-at the 23rd European Meeting on Hypertension and Cardiovascular Protection highlighted important national initiatives to improve blood pressure control in Europe.

Hypertension is a major risk factor for cardiovascular disease, which is Europe's most frequent cause of death and premature death. Hypertension can be treated effectively, but blood pressure levels remain uncontrolled (≥140/90 mmHg) in more than 50% of treated patients in many European countries.

"In order to tackle this challenge Italy and France have committed to the ambitious goal of achieving blood pressure control for at least 70% of hypertension patients by 2015", said Professor Josep Redón, President of the European Society of Hypertension (ESH), "The European Society of Hypertension fully supports initiatives like this and we will be meeting with more local European hypertension societies to secure their support and work to make this a common goal."

The Daiichi Sankyo and the Menarini Group symposium focused on aspects of patient care that are key to the French and Italian plans, in particular by showing that use of effective, simple treatments like single-pill fixed-dose combinations improves adherence and therefore goal rate achievement.

This tied in with another of the symposium's aims-to mark olmesartan's 10th anniversary -and showed how olmesartan has been combined with other well-known anti-hypertensive drugs to create safe and more effective combinations for patients who need stronger treatments. The availability of different options based on olmesartan, which includes dual and triple combinations, means that treatment can be adapted to individuals' requirements allowing blood pressure to be controlled with a single pill.

The triple-combination therapy Sevikar HCT® provides olmesartan plus two other widely used antihypertensive drugs (amlodipine and hydrochlorothiazide) in a single pill. Sevikar HCT® has an EU-wide label of add-on therapy in patients whose blood pressure is not adequately controlled on the combination of olmesartan medoxomil and amlodipine taken as a dual-component formulation.

To support physicians in their quest to help patients achieve target blood pressure goals, Daiichi Sankyo continues to fund research into antihypertensive treatments, including fixed-dose combinations. In this regard, new data from a Phase IV study revealed at an ESH 2013 poster session showed the superior efficacy on central blood pressure of Sevikar® (a combination of olmesartan+amlodipine) compared with the combination of perindopril and amlodipine. This result was confirmed by superior efficacy in 24 hour ABPM and conventional BP results of the olmesartan combination.

ESH/ESC guidelines for the management of arterial hypertension

Landmark clinical guidelines were introduced recently at Europe's biggest blood pressure conference in Milan.

Lifestyle factors, lack of awareness by both patients and physicians, hesitancy in initiating and intensifying drug treatment, and healthcare structural deficiencies are amongst the reasons for the increasing problem of high blood pressure in Europe, according to new joint Guidelines issued by the European Society of Hypertension (ESH)
and the European Society of Cardiology (ESC).

The Guidelines, which recommend several significant changes to hypertension treatment, were launched at the ESH with simultaneous online publication in the peer-reviewed journals Journal of Hypertension, the European Heart Journal, and Blood Pressure.

First produced in 2003, the original version of the joint ESH/ESC Guidelines for the management of arterial hypertension became one of the most highly-cited medical papers in the world. The 2013 Guidelines -which replace the 2007 edition-give state of the science recommendations which show how the hypertension landscape has changed, and indicate what needs to be done to reduce mortality and morbidity from high blood pressure and associated conditions.

Hypertension has been described as "the leading global risk for mortality in the world". It continues to affect between 30 and 45% of the European population. The authors of the Guidelines express disappointment that this figure has remained high since the 2003 edition. "We really need to raise awareness of the condition", said Professor Giuseppe Mancia (Milan, Italy). "This is a condition that can be controlled if treated properly."

According to the report, "lifestyle changes are the cornerstone for the prevention of hypertension", including reduction of salt (to roughly half present levels) and alcohol, as well as maintaining a healthy body weight, regular exercise, and the elimination of smoking.

Additionally, patients and doctors must be aware that once hypertension has developed, it can be treated with drug therapy. The Guidelines highlight the lack of awareness of the potential problems of hypertension amongst patients, with poor long-term adherence to treatment, and the "inertia" of doctors, who don't take appropriate action when confronted with patients with uncontrolled blood pressure.

The authors state that "despite overwhelming evidence that hypertension is a major cardiovascular risk, studies show that many are still unaware of the condition, that target blood pressure levels are seldom achieved". They also note that there are wide variations in hypertension care in Europe, but that team-based care, with greater nurse involvement, has a better record of success than more standard care.

The 2013 Task Force reviewed all relevant data since the last revision (in 2007), with 18 specific diagnostic and therapeutic areas identified as containing significant change.

A major development is the decision to recommend a single systolic blood pressure target of 140mmHg for almost all patients. This contrasts with the 2007 version which recommended a 140/90mmHg target for moderate to low risk patients, and 130/80mmHg target for high risk patients. "There was not enough evidence to justify two targets" said Professor Robert Fagard (Leuven, Belgium).

Other changes include:

• An increasing role for home blood pressure monitoring, alongside ambulatory blood pressure monitoring

• A greater emphasis on assessing the totality of risk factors for cardiovascular and other diseases. For example, most people with hypertension also have additional risk factors such as organ damage, diabetes, and other cardiovascular risk factors. These need to be considered together before initiating treatment, and during the follow-up

• Special emphasis on specific groups, eg. diabetics, the young, the elderly, and drug treatment of the over 80s. Women are also considered separately, eg. during pregnancy. Special consideration is given to new treatments such as renal denervation for resistant hypertension-which is described as "promising", although more trials are
called for

• New guidance on how and when to take anti-hypertensive drugs.

The report indicated no treatment for high normal blood pressure, no specific preference for single drug therapy, and an updated protocol for drugs taken in combination. The guidance takes a liberal attitude to choice of first step drugs, noting the evidence that the beneficial effect of hypertension depends largely on blood pressure lowering. Rather than presenting a hierarchy of drugs (a generic 1st, 2nd, 3rd choice and so on), the approach taken promotes individualised treatment, ie. to help physicians to decide which drugs to give in which clinical/demographic condition.

Empagliflozin: new phase III results

Findings from a series of pivotal phase III clinical trials of the investigational compound, empagliflozin were announced recently at the American Diabetes Association (ADA) meeting. The findings demonstrate significant reductions in blood glucose and body weight in adults with type 2 diabetes. The research includes analyses of empagliflozin monotherapy, as add on to metformin with or without a sulphonylurea, and as add-on to basal insulin.

Professor Clifford Bailey, (Professor of Clinical Science), Aston University, Birmingham, UK, said: "Recent clinical studies with empagliflozin have been very encouraging. Empagliflozin belongs to a new class of treatment for type 2 diabetes called sodium-glucose co-transporter 2 (SGLT2) inhibitors. These inhibitors reduce the amount of glucose reabsorbed back into the bloodstream via the kidney. This leads to urinary glucose excretion and caloric loss.

"Although several differently acting treatments are currently available to help control blood glucose for people with type 2 diabetes, many patients do not achieve their glycaemic goals. SGLT2 inhibition offers a new approach to improve glycaemic control independently of beta-cell function and insulin resistance."

Pivotal phase III results of the investigational compound empagliflozin added to metformin, with or without a sulphonylurea, showed significant improvements in blood glucose control and weight reductions in adults with type 2 diabetes. Similar results were demonstrated when empagliflozin was used as add-on to basal insulin.

Dr Charles de Wet, Medical Director, Boehringer Ingelheim said: "These positive phase III trial results in people with type 2 diabetes provide us with confidence for our ambitious phase III clinical trial programme for empagliflozin. Treating type 2 diabetes is complex and with the growing burden of the condition in the UK, it is important to continue our commitment to diabetes patients by developing innovative medicines that work in novel ways to help tackle the problem now and in the near future."

Motivating patients to make lifestyle changes

Previous research has shown that lifestyle changes such as increasing exercise and making better food choices can help people lose weight, and prevent diabetes and its complications. But until now, those studies have focused on highly motivated individuals who volunteered to be part of the research. The same could hold true for patients told by their healthcare providers to make changes, according to research presented at the ADA sessions.

The landmark NIH Diabetes Prevention Program (DPP) has previously shown that intensive, one-on-one lifestyle intervention could help people lose weight and dramatically reduce their risk for developing type 2 diabetes. Out of this research, a template for similar interventions to be used in less expensive group settings was developed. Several smaller, community-based studies have proven successful using this model, but these have all been conducted with participants who volunteered for the research, suggesting a high level of motivation. This study, using participants from VA Medical Centers across the country, looks at what happens when patients are told by their healthcare providers that they need to make changes.

"We wanted to see how effective a lifestyle change program would be for patients in a national health care system," said Sandra L. Jackson, MPH, a PhD candidate in Nutrition and Health Sciences at Emory University in Atlanta, whose dissertation research focuses on this question. "In order to achieve wide-scale results in reducing the prevalence of diabetes in this country, we need to get to patients who are at risk. "

The records of 400,000 patients in a VA program known as MOVE! (Managing Obesity and Overweight in Veterans Everywhere) were analysed. Among all participants, the researchers found weight loss of 1.3% of body weight, on average, was maintained over a three-year period.