Study Shows Local Standards Of Care Affect The Benefits Of Switching To New Treatement Alternatives

An analysis of a trial into how a new drug dabigatran was effective in preventing stroke in patients with atrial fibrillation has shown that local standards of care affect the benefits of switching to new treatments. This analysis of the RELY trial is reported in an Article Online First and in an upcoming Lancet, and is being presented at this week's European Society of Cardiology meeting in Stockholm, Sweden. The Article is by Professor Lars Wallentin, Uppsala University, Sweden, and colleagues.

The RELY study compared standard warfarin treatment with 110mg and 150mg twice daily doses of dabigatran. For warfarin treatment to be both safe and effective, blood tests are used to monitor its effects, which need to be kept within a very narrow window. This requires close monitoring and dose changes. As shown in the study there are large variations in standards of warfarin care between different centres and different countries. The standards of care can be estimated by averaging the time in the therapeutic range (TTR) for all warfarin treated patients in a centre (cTTR).This new analysis looked at whether or not the benefits shown by dabigatran in RELY were consistent even in centres that had poor INR quality control as estimated by cTTR.

The researchers showed there were fewer ischaemic strokes but not fewer occurrences of intracranial bleeding with increasing cTTR in the warfarin group. The value of cTTR had no effect influence on the the effect of dabigatran versus warfarin for preventing stroke. However, concerning cardiovascular mortality, bleeding and all cardiovascular events there risks were higher at centres with lower cTTR. Therefore concerning these events advantages of dabigatran versus warfarin were considerably larger at sites with poor standards of care.

The authors say: "Thus, these findings support the superiority of 150mg dabigatran twice daily and the non-inferiority of 110mg dabigatran twice daily versus warfarin for protection against stroke in atrial fibrillation irrespective of the quality of INR control that a centre can achieve."

But they add: "For secondary outcomes, such as non-haemorrhagic events and mortaility, advantages of dabigatran were reported for sites with poorer INR control, whereas results were comparable in sites with better INR control. Overall, these results show that local standards of care affect the benefits of switching to new treatment alternatives."

In a linked Comment, Dr Deirdre A Lane and Professor Gregory Y H Lip, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK, says the findings mean oral anticoagulants would probably be advocated for an even greater proportion of patients with atrial fibrillation, in view of the future availability of the new oral anticoagulants, such as dabigatran, that overcome the disadvantages of warfarin.

They conclude: "Until the new oral anticoagulants become widely available (a positive advance), we should advocate tight INR control at conventional levels, for which there is a wealth of evidence for benefit, and promote strategies to improve the management of therapy with vitamin K antagonists [such as warfarin]."

Researchers Exploring 'Fusion Strategy' Against E-coli

South Dakota State University research is exploring a "fusion strategy" for making improved vaccines to protect pigs and humans against some strains of E. coli.

The SDSU researchers altered the toxins produced by a form of E. coli and genetically fused the non-poisonous "toxoid" to a protein known to cause an immune reaction. The resulting "fusion protein" could be used to develop a vaccine.

Assistant professor Weiping Zhang in SDSU's Veterinary and Biomedical Sciences Department studies a group of E. coli called enterotoxigenic Escherichia coli, or ETEC. Besides causing diarrheal illness in farm animals such as pigs, ETEC strains are the main source of bacterial-caused diarrhea in human populations in the developing world, and the chief cause of traveler's diarrhea. The World Health Organization estimates that ETEC causes approximately 210 million cases of illness in humans and 380,000 deaths, mostly in children in developing countries.

Enterotoxigenic E. coli produce enterotoxins that affect the tissues lining the intestine and cause the vomiting and diarrhea associated with ETEC.

The research is one of the ongoing projects in SDSU's Center for Infectious Disease Research and Vaccinology, which looks for new ways to diagnose and treat infectious disease in humans and domestic animals.

The ETEC project is innovative in that it uses as vaccine components, the toxins that scientists call "heat-stable enterotoxins," or STs, that are generally harmful to animals and humans and remain active even in a temperature of boiling water.

Zhang said heat-stable enterotoxins can't be used directly as a vaccine component because of their toxicity and because they are poor at causing an immune response unless coupled to a carrier protein. For that reason, many vaccine researchers working with ETEC focus their research on other disease-causing elements - the so-called heat-labile enterotoxins that are destroyed at high temperatures and the fimbriae, or appendages that help the bacteria hold on to the host and cause disease.

However, Zhang said not including STs as a vaccine component poses a problem because more than two-thirds of human ETEC diarrhea cases and more than one-fourth of ETEC diarrhea cases in pigs are caused by ETEC strains that produce a heat-stabile enterotoxin called STa.

"STa antigens must be included for developing broadly effective vaccines against ETEC infection," Zhang said.

The SDSU research explored an approach for using heat-stable enterotoxins.

"Since they are toxic, we cannot use them directly. So we mutated a gene. We only changed one amino acid for each toxin. And that change shifted them from toxic to non-toxic," Zhang said.

In the same way researchers mutated the gene that produces the heat-labile enterotoxin, which is known to produce an immune response. They then fused the two toxoids to produce a fusion protein.

mportantly, by tweaking only a few amino acids, the researchers left the protein structure of the bacterium largely intact. That is important, Zhang said, because just as the toxin has to bind to a receptor in the small intestine in order to cause the disease, the vaccine component must bind to that same receptor in order to cause an immune response.

Zhang and his colleagues published the study of their "fusion strategy" in January 2010 in the journal Infection and Immunity. Zhang's co-authors were Chengxian Zhang, David H. Francis, Ying Fang, and David Knudsen, all of SDSU; James Nataro of the University of Maryland School of Medicine; and Donald C. Robertson of Kansas State University.

In summer 2010 researchers began studying five possible vaccine components using a pig model. Once they select the best vaccine component, they'll move on to larger lab trials and field trials. The possibility of an improved swine vaccine is important because some estimates say swine producers lose $80 million a year because of illness in pigs in North America alone, Zhang said.

Meanwhile, since the toxins produced by ETEC in pigs and humans are nearly identical, Zhang and his colleagues are using the same system they've developed at SDSU for exploring a swine vaccine to explore a possible human vaccine.

Zhang has received $368,000 in grant funds for vaccine research against enterotoxigenic Escherichia coli-associated diarrhea in humans using a pig model that he and SDSU professor David Francis have developed. The research is sponsored by the U.S. Department of Health and Human Services' National Institutes of Health through its National Institute of Allergy and Infectious Diseases.

Zhang and his colleagues at three other institutions also have received about $1 million in support from the Bill & Melinda Gates Foundation for research into strategies for optimizing the vaccine for humans. Right now they have mutated only a single amino acid. The Gates Foundation wants to know if the vaccine components would be even more effective if researchers mutate other amino acids.

If the research leads to an improved vaccine either for pigs or humans, that entire process of developing the vaccine will take about 10 to 15 years, Zhang said.

Source:
South Dakota State University