Niamh Mullen reports from New Orleans on the drug that could replace warfarin for the treatment of venous thromboembolism
Heralded as the altern-ative to long-term warfarin treatment for venous thromboembolism (VTE), dabigatran etexilate promises patients a fixed dose, no food interactions and no need for monitoring.
The results of the RE-COVER trial, presented by Boehringer Ingelheim at the meeting of the American Society of Haematology (ASH), showed its dabigatran etexilate, called Pradaxa, had equal efficacy compared to well-controlled warfarin at preventing recurrent VTE.
Prof Ajay Kakkar of St Bartholomew’s and the London School of Medicine and Dentistry, said the RE-COVER trial results were very exciting and convincing. “We have the real opportunity; we are in a position now to offer our patients improved clinical outcomes with the ability to replace warfarin with dabigatran for longer-term anticoagulant therapy,” he said.
Prof Kakkar reminded delegates of the difficulties associated with warfarin treatment.
In primary care in the UK, it is one of the classes of medicines most commonly associated with fatal medication errors. In secondary care, it is one of the ten drugs most frequently associated with dispensing errors, and anticoagulants are among the drugs most commonly associated with claims against the NHS.
VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). It is estimated that in the EU, there are approximately 1.5 million episodes of VTE each year and more than 500,000 deaths.
Die within an hour
In the UK alone, there are more VTE deaths each year than from breast cancer, AIDS and traffic accidents combined. Some 10 per cent of those with symptomatic PE die within an hour and for almost a quarter of PE patients, their initial presentation is sudden death. Within two years of PE, 4 per cent develop pulmonary hypertension, which can lead to heart failure.
Professor of Medicine and Biochemistry at McMaster University and Director of the Henderson Research Centre in Ontario, Canada, Jeff Weitz said prevention was important. “The importance of this disorder was highlighted recently by the US Surgeon General’s call to action for prevention of venous pulmonary embolism,” he said. Causes include immobility after surgery or illness, obesity, damage to veins from surgery, chemotherapy or catheters, and hypercoagulable disorders.
For around 50 per cent of individuals, onset is unprovoked — they have not just had surgery or been on a long-haul flight. For the other half who have a well-defined risk factor, treatment with a vitamin K antagonist, such as warfarin, is stopped after three months. “For those patients with unprovoked VTE, we continue because their risk of re-occurance is high. We estimate it is about 10 per cent at one year and 30 per cent at five years. These patients have a chronic disease,” said Prof Weitz.
But long-term warfarin treatment was problematic, he added. Patients have an unpredictable response, it requires monitoring, the dose is variable, it has numerous food and drug interactions and a slow onset and offset of action. Dabigatran, on the other hand, has a rapid onset of action (two or three hours), the dose is fixed, it has no food effect, few drug interactions and no monitoring is required. Prof Sam Schulman, Professor of Medicine at the McMaster University in Canada, added that the drug had great potential to replace warfarin for this group of patients. Outlining the results of the RE-COVER trial, published in the New England Journal of Medicine, he said dabigatran could be very well compared with warfarin for efficacy and safety.
“Regarding safety for clinically relevant bleeding or minor bleeding, there is a reduction of events and therefore dabigatran provides very convenient oral fixed-dose treatment for patients with acute venous thromboembolism.”
The double-blind, double dummy randomised trial recruited patients with a maximum 14 days’ symptoms DVT, PE or both. Participants were initially treated with parenteral therapy (generally heparin) and within 72 hours, had to have a baseline examination to allow inclusion and randomisation to either warfarin or warfarin placebo with parenteral therapy.
After at least two days warfarin treatment was discontinued. Dabigatran was given to those on warfarin placebo and dabigatran placebo was given to those on warfarin. INR (international normalised ratio for reporting the results of blood coagulation tests) was continually monitored.
Of the 2,539 participants treated, 1,274 were treated with dabigatran and 1,265 were treated with warfarin. Those taking part hailed from 200 centres in 209 countries. The average age was 55, while the oldest participant was 97. Females accounted for 42 per cent and a total of 5 per cent had cancer. A quarter had a previous VTE.
Warfarin compliance was higher than normally seen in the clinic at 97.5 per cent. There was 98 per cent compliance with dabigatran.
The 150mg twice-daily dose had equal efficacy compared to warfarin at preventing recurrent VTE. “The difference in risk is 0.4 per cent. We can say with high statistical significance dabigatran is not infer-ior,” said Prof Schulman. There was a 37 per cent reduction in major or clinically relevant non-major bleeding. Major bleeding was comparable between dabigatran (20 patients) and warfarin (24 patients). For any bleeds, dabigatran showed a significant 20 per cent reduction compared to warfarin.
With each drug, there was one fatal bleed. There were 115 patients in the dabigatran group and 86 in the warfarin group who had an adverse event that led to discontinuation of the study drug.
There was no indication of liver problems with dabigatran. A combination of an alanine amino-transferase level exceeding three times the upper limit of normal and bilrubin exceeding twice the upper limit of normal was seen in two patients in the dabigatran group, one of whom had pancreatic cancer and the other had cholangitis.
In the warfarin group, four had these elevated levels. Of those, three had pancreatic cancer and one had uterine cancer with liver metastases.
The results come only months after the publication of the RE-LY study, the largest atrial fibrillation trial to date. It involved 18,113 patients in 900 centres in 44 countries. It found dabigatran etexilate 150mg significantly reduced the risk of stroke and systemic embolism by 34 per cent in patients with atrial fibrillation compared to warfarin without increasing the risk of major bleeding. The 110mg dose demonstrated similar reduction in stroke and systemic embolism compared to warfarin, while delivering a 20 per cent reduction in major bleeding.
Prof Weitz said both doses of dabigatran reduced intra-cranial bleeding — the type of bleeding about which doctors were most concerned in warfarin-treated patients. It also reduced life-threatening and total bleeding compared with warfarin.