Stockholm – The effectiveness of dual antiplatelet therapy (DAT) with clopidogrel in cardiovascular (CV) patients is highly variable, and the degree of residual platelet aggregation can significantly influence the prognosis. A number of clinical and genetic risk factors contribute to this observation, and the contribution of genetic polymorphisms has been addressed. To date, however, common genetic clusters have not been identified that reliably predict a patient’s response to antiplatelet therapy. The challenge faced by researchers at University Hospital, Tuebingen in Germany is to determine ways of balancing the thrombotic risk, with the risk of bleeding when using DAT. The outcomes of the research includes a conclusion that platelet function testing (PFT), while an important component in risk evaluation, should not be relied on to adjust antiplatelet therapy regimes.
New antiplatelet agents have been developed – and will continue to be developed – that overcome low responsiveness to clopidogrel. These agents have a higher antiplatelet effect and are less susceptible to genetic inheritance. But, according to Professor Meinrad Gawaz of the University Hospital in Tuebingen, Germany, there are important factors to consider before prescribing them. “These new agents offering higher platelet inhibition come with an increased risk of bleeding,” he says. “So far, these drugs have mostly been studied in patients with acute coronary syndromes, but their role in stable CV patients has yet to be fully characterised.”
It is therefore essential to identify sub-groups of patients who could benefit from novel treatment regimes. Platelet function testing (PFT) can help to monitor and guide antiplatelet therapy for patients in at-risk groups more likely to respond to additional antiplatelet therapy. These groups include diabetics and patients suffering from stent thrombosis. Major concerns have been expressed, however, about the transferability of results obtained by different PFT methodologies. Near-patient testing methods have been evaluated in the clinical setting and show reproducible results, but consensus has to be reached upon the appropriate cut-off values to differentiate between thrombotic and bleeding risk.
The results of ongoing trials will show whether adjustment on behalf of routine PFT will lead to improved outcomes. Until then, PFT represents an important component to evaluate the thrombotic risk but adjustment of antiplatelet therapy based on PFT cannot be recommended in a routine fashion but can only be considered as an off-label indication in individual cases bearing in mind the bleeding risk.
Authors:
Professor Meinrad Gawaz
Tel: + 49 707 129 83688 or +49 172 633 6217
Email: Meinrad.Gawaz@med.uni-tuebingen.de
ESC Press Office
Stockholm – Antithrombotic therapy using antiplatelet and anticoagulant agents is the cornerstone of treatment for acute and chronic coronary artery disease (CAD), yet it is also associated with an increased risk of bleeding. It is paradoxical that elderly patients, the most likely population to develop CAD, are those that suffer most from bleeding complications. Research has been carried out at OLVG Hospital in the Netherlands into the stratification of risk for all patients requiring this type of therapy.
Professor Freek Verheugt led the research. “Until relatively recently, aspirin used to be the only effective antiplatelet drug, but now CAD patients can get increased protection from ADP receptor antagonists added to aspirin,” he said. “Previous studies showed us that, compared to younger patients, the elderly seemed to benefit more from single antiplatelet therapy with aspirin that from dual antiplatelet therapy. This data, however, should be treated with caution since it is derived from post-hoc analysis of randomised control trials.”
The TRITON and PLATO clinical trials demonstrated that newer ADP blockers such as prasugrel and ticagrelor are more effective that clopidogrel. But in both trials, the benefits seemed to reduce in patients over 75 years, although this observation comes from post-hoc analyses of the mega-trials. Other research has also shown that the elderly do not get the full benefit from platelet glycoprotein IIb/IIIa receptors, include abciximab, eptifibatide and tirofiban.
For anticoagulants, there is less data available on the risk of bleeding in relation to age. In elderly patients with fibrinolysis, low molecular weight heparin increases the bleeding risk in the elderly significantly over un-fractionated heparin. So, if chosen as the most effective treatment, low molecular weight heparin should be administered in lower doses for older patients. Bleeding associated with the newer anticoagulant bivalirudin also increased in the elderly, when compared to younger patients.
The research concludes that the risk of bleeding is increased by antiplatelet and anticoagulant therapy when applied to the treatment of acute and chronic CAD. Professor Verheugt explained the findings, “For aspirin, it was clearly shown that the risk reduction of ischemic endpoints applies equally to the elderly, but for clopidogrel this benefit is less apparent. Neither was it clearly seen from use of newer ADP receptor blockers such as prasugrel and ticagrelor. Additionally, no clear benefit was observed for elderly patients treated with glycoprotein receptor blockers for acute coronary syndromes.”
Antiplatelet therapies carry an increased risk of bleeding, especially in the elderly. This is probably also true for anticoagulant drugs, but data that specifically covers the elderly is relatively scarce.
Authors:
Professor Freek W. A. Verheugt
ESC Press Office
Dabigatran etexilate at the forefront
Ingelheim – The European Society of Cardiology (ESC) today issued revised practice guidelines for the management of atrial fibrillation (AF), including guidance on the role of a novel oral treatment, dabigatran etexilate, for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF).
At the same time, Boehringer Ingelheim confirms that the U.S. Food and Drug Administration (FDA) granted a priority review designation for Boehringer Ingelheim’s novel oral direct thrombin inhibitor dabigatran etexilate for the prevention of stroke in AF. A priority review designation is given to new drugs that are expected to offer major advances in treatment, or provide a treatment where no adequate therapy exists. An FDA advisory committee will meet on Monday, September 20th, to review and discuss dabigatran etexilate data.
In addition to the US, the registration process for dabigatran etexilate is underway in Europe, Japan and other countries. The company expects to receive a marketing authorization for dabigatran etexilate in first countries by end of 2010 or beginning of 2011.
All applications, including the FDA New Drug Application (NDA) are based on the results of the pivotal Phase III RE-LY® study (Randomized Evaluation of Long-term anticoagulant therapY), published in the New England Journal of Medicine in August 2009, comparing the efficacy and safety of two doses of dabigatran etexilate with warfarin (titrated to INR * 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with atrial fibrillation.
Results from RE-LY ®, the largest AF study completed to date, showed that in patients with AF, dabigatran etexilate 150mg b.i.d. significantly reduced the risk of stroke and systemic embolism by 34% compared to warfarin, with comparable rates of major bleeding. Dabigatran etexilate 110mg b.i.d. demonstrated similar reductions in stroke and systemic embolism while delivering a reduction in major bleeding rates compared to warfarin. Additionally, both doses showed a significant reduction in haemorrhagic stroke and a significant reduction in life threatening, intracranial and total bleeding compared to warfarin.
Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim said, “Boehringer Ingelheim has a long term commitment to the treatment and prevention of stroke. The decision by the US FDA to grant a priority designation review is an important step in making dabigatran etexilate available for patients with atrial fibrillation to prevent them from strokes.”
Gregory Lip, Professor of cardiovascular medicine at University of Birmingham Centre for Cardiovascular Sciences, UK and a member of the Task Force writing group for the new ESC Guidelines for the management of atrial fibrillation commented, “The updated guidelines reflect the high need for novel treatments in the prevention of atrial-fibrillation related stroke. Both the personal and economic burden of AF-related stroke is high. Consideration of new prevention therapies will improve the overall standard of care.”
Well-controlled vitamin K antagonist (VKA) therapy (warfarin), currently used for the prevention of stroke in atrial fibrillation, is highly effective in reducing the risk of stroke by approximately two-thirds 2, but is associated with an increased risk of bleeding as well as several limitations. Drug-drug and food interactions as well as the requirement for frequent monitoring result in only about 50% of eligible patients receiving VKA therapy 3 with fewer than half of these controlled within the therapeutic INR range.
Stroke is more likely to be severe and fatal in patients with AF, and those who survive face persistent neurological deficits, persistent disability and poorer functional performance. <
Professor Jonas Oldgren, Associate Professor of Cardiology, Uppsala Clinical Research Centre
According to Professor Jonas Oldgren, Associate Professor of Cardiology, Uppsala Clinical Research Centre (which furthermore was one of the coordinating centres in RE-LY®), “Dabigatran etexilate is the first treatment to significantly reduce stroke in patients with atrial fibrillation across all risk groups, when compared to well-controlled warfarin. This novel direct thrombin inhibitor could represent a very important advance in the prevention of stroke in patients with AF for both healthcare professionals and patients alike.”
Dr. Oldgren referred to a sub-group analysis presented at this year’s American College of Cardiology’s annual congress in March, which assessed the rate of stroke and systemic embolism in patients defined as being at low, moderate or high risk of such events by the validated stroke risk stratification score, CHADS 2** . The results of this analysis showed that dabigatran etexilate 150mg significantly reduced the number of strokes in patients with AF, irrespective of a patient’s risk profile. Dabigatran etexilate 110mg b.i.d. was associated with significantly lower major bleeding events and both dabigatran doses showed significantly lower intracranial bleeding rates when compared to well-controlled warfarin.
RE-LY® is the largest AF study ever completed (18,113 patients) investigating dabigatran etexilate vs. well controlled warfarin. RE-LY® included patients with at least one risk factor of stroke, representative of a real-world setting. In addition, 50% of enrolled patients were naïve to previous oral anticoagulants, a population who may reflect a more realistic experience with anticoagulants, as they are more likely to represent the patient group with the highest percentages outside of the therapeutic INR range.
Up to three million people worldwide suffer strokes related to AF each year,9-11 which tend to be especially severe and disabling,10 with half of people dying within one year.12 Therefore, there is an clear medical need for an effective and safe anticoagulant, without the multiple limitations of VKA therapy.
CHADS 2 risk score: Congestive heart failure, hypertension: blood pressure consistently above 140/90 mmHg (or treated hypertension on medication), age >75 years, diabetes mellitus, prior stroke or TIA
Press Release Boehringer Ingelheim
Stockholm – Oral rivaroxaban versus standard therapy in the initial treatment of symptomatic deep vein thrombosis and long-term prevention of recurrent venous thromboembolism
Results of the Phase III EINSTEIN-DVT study show that the oral anticoagulant rivaroxaban achieved the primary efficacy and safety outcomes in the treatment of patients with acute, symptomatic deep vein thrombosis (DVT).
The study showed that rivaroxaban demonstrated non-inferior efficacy in the treatment of DVT compared with initial enoxaparin treatment followed by a vitamin K antagonist (VKA), the current standard therapy for the treatment of DVT. Recurrent symptomatic venous thromboembolism (ie, the composite of recurrent DVT, non-fatal or fatal pulmonary embolism) occurred in 2.1% of the rivaroxaban recipients and 3.0% of the subjects receiving standard therapy (p<0.0001 for non-inferiority).
The EINSTEIN-DVT study also demonstrated similar rates of major and clinically relevant non-major bleeding, the principal safety outcome, for rivaroxaban compared with the current standard therapy (8.1% vs. 8.1%, respectively). No liver signal attributable to rivaroxaban was observed in the study.
“The results of the EINSTEIN-DVT trial indicate that rivaroxaban is an effective and safe treatment for acute symptomatic DVT,” said principal investigator, Professor Harry R. Büller, Academic Medical Center, Amsterdam, the Netherlands. “The single-drug approach with rivaroxaban will provide clinicians and patients with an attractive, simple, alternative regimen for the initial and long-term treatment of deep vein thrombosis.”
The multinational EINSTEIN-DVT study was designed to investigate a new single-drug approach with rivaroxaban in comparison to standard therapy in a randomised, open-label, non-inferiority study. The trial involved more than 3,400 patients with acute symptomatic DVT, but without any symptoms of pulmonary embolism, across 253 sites in 32 countries worldwide. Patients received either oral rivaroxaban (15 mg twice-daily for the first three weeks, followed by 20 mg once daily) or body weight-adjusted subcutaneous enoxaparin followed by warfarin or acenocoumarol (dose adjusted to maintain a therapeutic normalised ratio) for three, six or 12 months, based on the attending physician’s assessment at baseline.
The primary efficacy outcome was the cumulative incidence of symptomatic recurrent venous thromboembolism (non-fatal or fatal). The principal safety outcome was the composite of major and clinically relevant non-major bleeding.
* The EINSTEIN DVT study was sponsored by Bayer Schering Pharma
Prof. BULLER Harry
ESC Press Office
