Synchrotron yields 'safer' vaccine

27 March 2013 Last updated at 18:00 ET

Fergus Walsh, Medical correspondent Article written by Fergus Walsh Medical correspondent

Diamond Light SourceDiamond is sited on the Harwell science campus just south of Oxford

Producing vaccines against viral threats is a potentially hazardous business and that’s why manufacturers have to operate strict controls to ensure that no pathogens escape.

British scientists have developed a new method to create an entirely synthetic vaccine which doesn’t rely on using live infectious virus, meaning it is much safer.

What’s more the prototype vaccine they have created, for the animal disease foot-and-mouth, has been engineered to make it more stable.

That means it can be kept out of the fridge for many hours before returning to the cold chain – overcoming one of the major hurdles in administering vaccines in the developing world.

The research, published in the journal PLOS pathogens, was a collaboration between scientists at Oxford and Reading Universities, the Pirbright Institute, and the UK’s national synchrotron facility, the Diamond Light Source near Oxford.

virusComputer image of foot-and-mouth virus

Diamond is a particle accelerator which sends electrons round a giant magnetic ring at near light speeds.

The electrons emit energy in the form of intense X-rays which are channelled along “beamlines” – into laboratories where they are used to analyse structures in extraordinary detail.

Infectious

Synchrotrons have been used before to analyse viruses at the atomic level, but the technology has advanced considerably to enable scientists to create a stable synthetic vaccine.

“What we have achieved here is close to the holy grail of foot-and-mouth vaccines.

Unlike traditional vaccines, there is no chance that the empty shell vaccine could revert to an infectious form,” said Dave Stuart, Life Sciences Director at Diamond, and MRC Professor of Structural Biology at the University of Oxford.

“This work will have a broad and enduring impact on vaccine development, and the technology should be transferable to other viruses from the same family, such as poliovirus and hand-foot-and-mouth disease, a human virus which is currently endemic in South-East Asia,”

These human disease threats, like foot-and-mouth, are all picornaviruses.

Viruses are inherently unstable and fragile, but picornaviruses can be studied using X-ray crystallography.

Diamond Light SourceThe Crystal Lab uses robots

This enables the protein shell of the virus to be analysed at the atomic level – something a billion times smaller than a pinhead.

Pathogen

As with any vaccine, the aim is to prompt the immune system to recognise this outer shell and destroy the pathogen before it has time to lock onto cells and infect them with its genetic material.

In this research the scientists created a synthetic viral shell, but lacking its pathogenic RNA interior – the genetic material the virus uses to replicate itself.

Crucially they were able to reinforce the structure of the viral shell to make it stronger, to improve the stability of the vaccine.

Pre-clinical trials have shown it to be stable at temperatures up to 56C for at least two hours. Foot-and-mouth is endemic in central Africa, parts of the Middle East and Asia, so this would be a significant improvement over existing vaccines.

With current foot-and-mouth vaccines it is difficult to distinguish between immunised livestock and those which have been infected.

That proved to be a major hurdle in controlling the foot-and-mouth outbreak in the UK in 2001 because it would have prevented the export of livestock.

Polio

But the synthetic vaccine should allow scientists to show the absence of infection in vaccinated animals.

“The foot-and-mouth-disease virus epidemic in the UK in 2001 was disastrous and cost the economy billions of pounds in control measures and compensation.

“This important work has been a direct result of the additional funding that was provided as a result of the 2001 outbreak to research this highly contagious disease,” explained Dr Bryan Charleston, Head of Livestock Viral Diseases Programme at the Pirbright Institute.

The potential hazards of working with viruses was underlined in 2007 when the Pirbright laboratory site was identified as the source of a leak which led to an outbreak of foot-and-mouth disease.

Polio, another picornavirus, which exclusively affects humans, has been eliminated from nearly every country in the world, although it stubbornly persists in Nigeria, Pakistan and Afghanistan.

The need for secure vaccine production will become even more vital should polio be wiped out.

“Current polio vaccines, which use live virus for their production, pose a potential threat to the long-term success of eradication if they were to re-establish themselves in the population.

“Non-infectious vaccines would clearly provide a safeguard against this risk”, said Dr Andrew Macadam, a virologist specialising in polio at the National Institute for Biological Standards and Control in Hertfordshire.

“This technology has great potential in terms of cost and biosafety.

“Any design strategy that minimises the chances of accidental virus release would not only make the world a safer place but would lower the bio-containment barriers to production allowing vaccines to be made more cheaply all over the world.”

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Synchrotron yields ‘safer’ vaccine

27 March 2013 Last updated at 18:00 ET

Fergus Walsh, Medical correspondent Article written by Fergus Walsh Medical correspondent

Diamond Light SourceDiamond is sited on the Harwell science campus just south of Oxford

Producing vaccines against viral threats is a potentially hazardous business and that’s why manufacturers have to operate strict controls to ensure that no pathogens escape.

British scientists have developed a new method to create an entirely synthetic vaccine which doesn’t rely on using live infectious virus, meaning it is much safer.

What’s more the prototype vaccine they have created, for the animal disease foot-and-mouth, has been engineered to make it more stable.

That means it can be kept out of the fridge for many hours before returning to the cold chain – overcoming one of the major hurdles in administering vaccines in the developing world.

The research, published in the journal PLOS pathogens, was a collaboration between scientists at Oxford and Reading Universities, the Pirbright Institute, and the UK’s national synchrotron facility, the Diamond Light Source near Oxford.

virusComputer image of foot-and-mouth virus

Diamond is a particle accelerator which sends electrons round a giant magnetic ring at near light speeds.

The electrons emit energy in the form of intense X-rays which are channelled along “beamlines” – into laboratories where they are used to analyse structures in extraordinary detail.

Infectious

Synchrotrons have been used before to analyse viruses at the atomic level, but the technology has advanced considerably to enable scientists to create a stable synthetic vaccine.

“What we have achieved here is close to the holy grail of foot-and-mouth vaccines.

Unlike traditional vaccines, there is no chance that the empty shell vaccine could revert to an infectious form,” said Dave Stuart, Life Sciences Director at Diamond, and MRC Professor of Structural Biology at the University of Oxford.

“This work will have a broad and enduring impact on vaccine development, and the technology should be transferable to other viruses from the same family, such as poliovirus and hand-foot-and-mouth disease, a human virus which is currently endemic in South-East Asia,”

These human disease threats, like foot-and-mouth, are all picornaviruses.

Viruses are inherently unstable and fragile, but picornaviruses can be studied using X-ray crystallography.

Diamond Light SourceThe Crystal Lab uses robots

This enables the protein shell of the virus to be analysed at the atomic level – something a billion times smaller than a pinhead.

Pathogen

As with any vaccine, the aim is to prompt the immune system to recognise this outer shell and destroy the pathogen before it has time to lock onto cells and infect them with its genetic material.

In this research the scientists created a synthetic viral shell, but lacking its pathogenic RNA interior – the genetic material the virus uses to replicate itself.

Crucially they were able to reinforce the structure of the viral shell to make it stronger, to improve the stability of the vaccine.

Pre-clinical trials have shown it to be stable at temperatures up to 56C for at least two hours. Foot-and-mouth is endemic in central Africa, parts of the Middle East and Asia, so this would be a significant improvement over existing vaccines.

With current foot-and-mouth vaccines it is difficult to distinguish between immunised livestock and those which have been infected.

That proved to be a major hurdle in controlling the foot-and-mouth outbreak in the UK in 2001 because it would have prevented the export of livestock.

Polio

But the synthetic vaccine should allow scientists to show the absence of infection in vaccinated animals.

“The foot-and-mouth-disease virus epidemic in the UK in 2001 was disastrous and cost the economy billions of pounds in control measures and compensation.

“This important work has been a direct result of the additional funding that was provided as a result of the 2001 outbreak to research this highly contagious disease,” explained Dr Bryan Charleston, Head of Livestock Viral Diseases Programme at the Pirbright Institute.

The potential hazards of working with viruses was underlined in 2007 when the Pirbright laboratory site was identified as the source of a leak which led to an outbreak of foot-and-mouth disease.

Polio, another picornavirus, which exclusively affects humans, has been eliminated from nearly every country in the world, although it stubbornly persists in Nigeria, Pakistan and Afghanistan.

The need for secure vaccine production will become even more vital should polio be wiped out.

“Current polio vaccines, which use live virus for their production, pose a potential threat to the long-term success of eradication if they were to re-establish themselves in the population.

“Non-infectious vaccines would clearly provide a safeguard against this risk”, said Dr Andrew Macadam, a virologist specialising in polio at the National Institute for Biological Standards and Control in Hertfordshire.

“This technology has great potential in terms of cost and biosafety.

“Any design strategy that minimises the chances of accidental virus release would not only make the world a safer place but would lower the bio-containment barriers to production allowing vaccines to be made more cheaply all over the world.”


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Consultants warn of A&E ‘meltdown’

28 March 2013 Last updated at 02:47 ET

Ambulances queue outside Wrexham Maelor hospitalThese ambulances were queuing outside Wrexham’s Maelor Hospital

A&E departments in Welsh hospitals are at the point of meltdown and patients are dying as a result, say consultants.

Almost half of the country’s A&E consultants have signed a joint letter to new Health Minister Mark Drakeford to express their concerns.

They say serious overcrowding is putting patient safety at risk.

The Welsh government said one of Mr Drakeford’s priorities was to look at ways of easing the pressures on unscheduled healthcare.

The consultants’ letter says pressure on health boards to meet financial targets has led to the closure of short-term hospital beds at the expense of care.

Earlier this month, A&E units were under intense pressure as record numbers of patients attended Welsh hospitals.

But the consultants warn that a lack of beds means serious overcrowding is almost a daily occurrence.

The letter, sent by the College of Emergency Medicine says: “Our emergency departments are at the point of meltdown. Most days, they are seriously overcrowded.

“This jeopardises safety and puts patients at risk: there is clear evidence that death rates go up if patients requiring admission remain in emergency departments for hours whilst they wait for ward beds to become available.

“Each of us has seen standards of care slipping in our departments, as we struggle to look after a dozen or more patients stuck in the emergency departments whilst waiting for ward beds, in addition to our normal workload.”

They point to a number of examples of patients coming to real harm because of overcrowding:

  • A patient with chest pain having a cardiac arrest whilst being seen in the eye examination room (as there was no room in the resuscitation bay)
  • No space in the resuscitation bay to accommodate a baby having a severe seizure
  • Waits for a ward bed of 24-36 hours are now common, and at least one patient spent a three days in an emergency department

In addition, they say that these pressures are having a knock-on effect on the Welsh Ambulance service which is unable to respond to emergencies “when scores of ambulances are queuing outside gridlocked emergency departments”.

Wales’ ambulances have missed a response time target for life-threatening calls for the ninth consecutive month.

Statistics from February show 60.8% of emergency responses arrived within eight minutes, missing the Welsh Ambulance Service target of 65%.

A Welsh government spokesperson said: “The newly appointed Minister for Health and Social Services, Mark Drakeford, has stated that one of his priorities over the next 12 months is to look at ways of easing the pressures on unscheduled healthcare – this includes out of hours services, emergency departments and ambulance services.”

The consultants warn that creating a culture whereby health boards are required to achieve financial balance could lead to the same result as the Mid Staffordshire scandal.

A public inquiry report found that neglect and abuse at Stafford Hospital between 2005 and 2008 had led to needless deaths.

Published at the start of February, the Francis report accused the NHS of putting corporate self-interest ahead of patients.

The consultants say: “The motive behind the financial squeeze affecting hospitals in Wales is different to that underpinning the Mid Staffordshire scandal, but from our perspective, the result is the same: the pursuit of targets and financial balance at the expense of quality of care.”

Wales’ seven health boards are currently in the process of trying to balance their books before the end of the financial year.

The largest, Betsi Cadwaladr, predicts it may be £3.9m in debt by the end of the financial year, despite £15m of extra funding from the Welsh government.

Analysis by BBC Wales indicates other health boards are also facing similar challenges, but some are predicting they will succeed to stay within budget.

Darren Millar AM, Conservative health spokesperson, said: “This is a dire warning from Welsh NHS emergency consultants that patient safety is being dangerously compromised as a result of financial pressures.

“Axing inpatient bed numbers to save money is leading to overcrowded A&E departments, which cause ambulance queues outside our hospitals and delay them from being able to get back on the road to emergencies.”


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Health Highlights: March 27, 2013

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Study: Antidepressant Use in Pregnancy May Not Affect Baby's Growth

WEDNESDAY, March 20 (HealthDay News) — Taking antidepressants during pregnancy does not have an impact on an infant’s growth during the first year of life, a new study says.

Previous research suggested that depression during pregnancy could slow infant growth, but there were concerns that prescribing antidepressants to pregnant women might also hinder a baby’s physical development.

In this study, Northwestern University researchers found that infants born to mothers who took selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy had a similar weight, length and head circumference over the first year as babies born to mothers who did not have depression and did not take antidepressants during pregnancy.

The infants whose mothers took antidepressants were shorter at birth, but that difference vanished by the time they were 2 weeks old, the study authors reported.

The investigators also found that the growth of infants born to depressed women who did not take SSRIs was similar to infants in the general population.

The study was released online March 20 in advance of publication in an upcoming print issue of the American Journal of Psychiatry.

“Most women want to know about the effect of their depressive illness or the medication they take during pregnancy not only on the infant at birth, but also on the baby’s longer-term growth and development,” lead author Dr. Katherine Wisner said in a university news release. “This information may help women balance the risks and benefits of continuing their antidepressant treatment during pregnancy.”

Depression can harm both a mother’s and infant’s health, noted Wisner, director of Northwestern’s Asher Center for the Study and Treatment of Depressive Disorders, and a professor of psychiatry and behavioral sciences and of obstetrics and gynecology at Northwestern University Feinberg School of Medicine.

Depression in mothers is associated with premature birth and low infant birth weight, which increases the child’s risk of heart disease. Depression also affects the mother’s appetite, nutrition and prenatal care, and is associated with increased alcohol and drug use, Wisner said.

More information

The U.S. Office on Women’s Health has more about pregnancy and depression.

Visit the Source Site

Study: Antidepressant Use in Pregnancy May Not Affect Baby’s Growth

WEDNESDAY, March 20 (HealthDay News) — Taking antidepressants during pregnancy does not have an impact on an infant’s growth during the first year of life, a new study says.

Previous research suggested that depression during pregnancy could slow infant growth, but there were concerns that prescribing antidepressants to pregnant women might also hinder a baby’s physical development.

In this study, Northwestern University researchers found that infants born to mothers who took selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy had a similar weight, length and head circumference over the first year as babies born to mothers who did not have depression and did not take antidepressants during pregnancy.

The infants whose mothers took antidepressants were shorter at birth, but that difference vanished by the time they were 2 weeks old, the study authors reported.

The investigators also found that the growth of infants born to depressed women who did not take SSRIs was similar to infants in the general population.

The study was released online March 20 in advance of publication in an upcoming print issue of the American Journal of Psychiatry.

“Most women want to know about the effect of their depressive illness or the medication they take during pregnancy not only on the infant at birth, but also on the baby’s longer-term growth and development,” lead author Dr. Katherine Wisner said in a university news release. “This information may help women balance the risks and benefits of continuing their antidepressant treatment during pregnancy.”

Depression can harm both a mother’s and infant’s health, noted Wisner, director of Northwestern’s Asher Center for the Study and Treatment of Depressive Disorders, and a professor of psychiatry and behavioral sciences and of obstetrics and gynecology at Northwestern University Feinberg School of Medicine.

Depression in mothers is associated with premature birth and low infant birth weight, which increases the child’s risk of heart disease. Depression also affects the mother’s appetite, nutrition and prenatal care, and is associated with increased alcohol and drug use, Wisner said.

More information

The U.S. Office on Women’s Health has more about pregnancy and depression.


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Prebiotics in baby formula and eczema: mixed picture

By Andrew M. Seaman

NEW YORK | Thu Mar 28, 2013 3:16pm EDT

NEW YORK (Reuters Health) – There’s some evidence to suggest that putting prebiotics in baby formula protects children against the skin condition eczema, according to a fresh look at past research.

The theory is that babies who can’t breastfeed can drink formula fortified with prebiotics, which are food particles that promote the growth of healthy gut bacteria or flora, and build immunity against some allergens.

“When you change the gut flora your immunity changes as well,” said Dr. John Sinn, the review’s senior author from The University of Sydney’s Royal North Shore Hospital in Australia.

The analysis, published on Thursday by the Cochrane Collaboration, an international organization that evaluates medical research, is an update to a previous review from 2007 that did not find enough evidence to say whether putting prebiotics in baby formula had any benefits.

Previous research had found that about 8 percent of children will develop a food allergy, 20 percent will develop eczema and up to about 34 percent will develop wheezing or asthma.

For the new analysis, the researchers were able to include four studies that randomly assigned a total of 1,428 babies to either regular formula or formula fortified with prebiotics.

The studies reported whether or not the children developed allergic reactions, such as asthma, eczema or hives between four months and two years of age.

Overall, the prebiotic formula did not prevent babies from developing asthma or hives compared to babies fed regular formula, but there was evidence to suggest it may protect against eczema.

Specifically, about 8 percent of 634 babies fed formula with prebiotics developed eczema, compared to about 12 percent of 586 babies fed regular formula.

According to the authors, 25 babies would need to be fed formula with prebiotics to prevent one from developing eczema.

However, the researchers warn that the evidence behind this finding is weak, because it’s only based on four studies that were different from each other. Also, they cannot say whether any benefit from prebiotics would last beyond infancy.

Dr. Frank Greer, a professor of pediatrics at Meriter Hospital’s Wisconsin Perinatal Center in Madison, said he was not “very impressed” with the evidence.

Greer, who co-authored the American Academy of Pediatrics’ (AAP) clinical report on probiotics and prebiotics, said the only strategy they found to possibly prevent eczema was four months of exclusive breastfeeding.

“My basic recommendation for parents is if your child is at risk for allergies the best thing you can do is exclusively breastfeed for four months. And if you have to supplement, supplement with hydrolyzed formula,” said Greer, who was not involved with the new analysis.

He said hydrolyzed formulas don’t carry the same risk of allergic reactions as formulas that use cow’s milk. And while he said prebiotics don’t hurt, he can’t say that they offer any real protection.

The AAP currently recommends women breastfeed their newborns exclusively for about the first six months of life, after which some foods can be added along with continued breastfeeding.

SOURCE: bit.ly/14yoLHR The Cochrane Library, online March 28, 2013.

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Scientists criticize Italy for allowing unproven stem cell therapy

By Catherine Hornby

ROME | Thu Mar 28, 2013 3:13pm EDT

ROME (Reuters) – Scientists have criticized an Italian government decree allowing a group of terminally-ill patients to continue using an unproven stem cell treatment, saying such therapies may cause harm and risk exploiting desperate people.

The treatment, created by the privately-owned Stamina Foundation, was banned by Italian medicines regulator AIFA last year after it inspected their laboratories, leading to a series of legal challenges by families of patients.

In early March, Health Minister Renato Balduzzi allowed a terminally ill child to continue using the Stamina treatment after hearing the emotional pleas of her parents.

The Health Ministry then issued an official decree on March 21 allowing 32 patients, mainly children, already using the treatment to continue it.

Scientists from around Europe released a statement on Thursday criticizing the decree, warning that Balduzzi was “riding roughshod over existing European licensing criteria”, failing to protect patients from exploitation and ignoring the need for sound evidence that therapies are effective.

“These unproven and ill-prepared stem cell therapies, for which there is no scientific basis, will do nothing for patients and their families except make them poorer,” said Charles French-Constant from the University of Edinburgh’s Center for Regenerative Medicine.

“DANGEROUS PRECEDENT”

Advocates of the therapy say strict regulations work in favor of big drug companies with their portfolio of blockbuster treatments, reducing the pool of potential competitors. But scientists said Stamina’s treatment was unproven and risky.

“There is no rationale for this and no evidence that these procedures are not dangerous for patients,” said Professor Michele De Luca of the University of Modena.

“This creates a dangerous precedent,” he said, adding that anyone could use media pressure and take advantage of patients’ hopes of skirting normal evidence-based procedures.

Stem cells are the body’s mother cells and can self-renew or multiply while maintaining the ability to transform into any type of cell.

Stem cell therapy involves introducing new adult stem cells into damaged tissue to treat disease. A number of therapies exist but many remain at the experimental stage.

Several judges presiding over the cases brought by patients’ families ruled the Stamina treatment should be available under a law that permits the use of unproven therapies for patients who are dying and have no other options.

Supporters of the therapy have held rallies calling for it to be made available to anyone with an incurable disease. One woman staging a near-naked protest in a Rome square with “yes to life, yes to Stamina” scrawled on her body.

Scientists warned that a complication or death as a result of such an untested therapy could become an obstacle for the advancement of all stem cell therapies.

“This would include some of the more promising therapies that have a strong scientific rationale for working in patients with certain types of disorders such as Parkinson’s disease,” said Roger Barker, Professor of Clinical Neuroscience at the University of Cambridge.

(Editing by Rosalind Russell)

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Devices Coated with Paclitaxel Help Leg Arteries

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38125

Peripheral Artery Disease

Latest News| Videos

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By Chris Kaiser, Cardiology Editor, MedPage Today

Published: March 27, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Action Points

  • Note that in these two studies of patients with in-stent restenosis after femoropopliteal stenting, the use of paclitaxel-containing devices led to favorable outcomes.
  • Be aware that neither study enrolled a control group, limiting the ability to draw firm conclusions about the role of paclitaxel-eluting devices in this population.

The drug paclitaxel may be the answer for device success in the tortuous femoropopliteal arteries, two studies suggested.

In one study, the use of a paclitaxel-eluting balloon was associated with an 83.7% primary patency rate at 1 year that was maintained in 72.4% at 2 years, according to Antonio Micari, MD, of Maria Eleonora Hospital in Palermo, Italy, and colleagues.

In the second study, a paclitaxel-eluting stent was associated with a 78.8% primary patency rate at 1 year for opening stented lesions that had restenosed, with an 81% rate of freedom from target lesion revascularization at 1 year, according to Thomas Zeller, MD, of the University Heart Center Freiburg–Bad Krozingen in Germany, and colleagues.

Both studies appeared in the latest issue of JACC: Cardiovascular Interventions.

Micari and colleagues noted that the secondary patency rate in 89 cases was 85%, and repeat revascularization was needed in only 14.3% of patients.

They concluded that “primary patency was favorably maintained in most patients despite a low [provisional] stenting rate during the index procedure.”

They also pointed out that these outcomes were accompanied by “similarly favorable results” on ankle-brachial index (0.56 at baseline versus 0.88 at 2 years), absolute claudication distance (418 m at follow-up of 27 months versus 316 m at 12 months and 111 m at baseline), Rutherford class (65% were class 3 at baseline versus 1% at 2 years), and quality of life (significant improvements in mobility, usual activity, pain/discomfort at 2 years). All changes from baseline to 2 years were significant at P<0.001.

Paclitaxel-eluting balloons may be an option over drug-eluting stents, particularly because they are “less likely to impact future interventions when compared with any first-line stent strategy,” Micari and colleagues concluded.

Because the femoropopliteal artery undergoes “significant torsion, extension, and flexion during daily activity, femoropopliteal stent fractures have been reported that are associated with restenosis and potential distal embolization of stent fragments,” wrote Ehtisham Mahmud, MD, of the University of California San Diego, in an accompanying commentary.

Mahmud noted that the drug paclitaxel seemed better suited for lower-extremity arteries compared with sirolimus-coated devices. Preclinical studies have shown paclitaxel inhibits vascular smooth muscle cell migration and proliferation, which is associated with less restenosis.

He said that both of the studies referenced here “demonstrate that a new paradigm for the treatment of femoropopliteal disease involving local delivery of paclitaxel is emerging.”

Micari and colleagues enrolled 105 patients with 114 lesions and treated them with the In.Pact Admiral paclitaxel-eluting balloon and provisional stenting.

The mean age of patients from the prospective multicenter registry was 68, one-fifth were women, most had hypertension and hyperlipidemia, and half had diabetes, 45% of whom were insulin-dependent. A majority had Rutherford class 3. The mean lesion length was 76 mm, with a 5.2-mm reference vessel diameter.

In the study by Zeller and colleagues, 108 patients with 119 in-stent restenosed lesions of the femoropopliteal artery were treated with the Zilver PTX paclitaxel-eluting stent. The Zilver is a nitinol self-expanding stent that is FDA approved. About 60% of patients were men, most were smokers and had hypertension and hypercholesterolemia. The mean age was 68.

The mean lesion length was 133 mm and about a third were totally occluded at baseline. A total of 8% of lesions had severely fractured stents, another 23% had been previously treated within the last 6 months, and half had undergone at least two previous interventions.

Researchers achieved a 98% procedural success rate (less than 30% restenosis following stent placement). Most of the patients (92%) had one lesion treated. Each lesion required on average 2.1 stents.

Kaplan-Meir estimate of freedom from target lesion revascularization at 24 months was 61%, a drop from 81% at 1 year. About one-third of patients underwent one target lesion revascularization over the course of the study, half of them within the first 12 months of treatment.

The Rutherford class improved from 81% of patients having scores greater than 3 at baseline, to 63% at 1 year; by 2 years, 61% of patients had scores of less than 1.

As in the study by Micari and colleagues, the German investigators also found improvements from baseline to 2 years in ankle brachial index (0.60 to 0.84), walking speed score (from 33 out of 100 to 63), walking distance score (from 27 out of 100 to 63), and climbing score (from 37 out of 100 to 67). All differences were significant at P<0.001.

The Zeller study was limited because it had no control group and there was no core duplex ultrasound laboratory. The researchers said that head-to-head comparisons are needed between the Zilver PTX stent and other endovascular treatments for femoropopliteal in-stent restenosis.

The Micari study was limited by its nonrandomized design, no control group, and a very select group of patients with severe critical limb ischemia.

The study by Zeller and colleagues was sponsored by Cook Medical.

Micari reported a relationship with Medtronic. All other authors have reported that they have no conflicts of interest.

Zeller reported relationships with Cook Medical. Some co-authors reported relationships with Cook Medical, Abbott Vascular, and W.L. Gore. One author is a full-time employee of MED Institute, a Cook Medical Company.

Mahmud reported he has no conflicts of interest.

Primary source: JACC: Cardiovascular Interventions
Source reference:
Micari A, et al “2-year results of paclitaxel-eluting balloons for femoropopliteal artery disease evidence from a multicenter registry” J Am Coll Cardiol Intv 2013; 6: 282-289.

Additional source: JACC: Cardiovascular Interventions
Source reference:
Zeller T, et al “Treatment of femoropopliteal in-stent restenosis with paclitaxel-eluting stents” J Am Coll Cardiol Intv 2013; 6: 274–281.

Additional source: JACC: Cardiovascular Interventions
Source reference:
Mahmud E “Percutaneous revascularization for peripheral arterial disease. Paclitaxel saves the day” J Am Coll Cardiol Intv 2013; 6: 290–292.

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38117

Atherosclerosis

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By Todd Neale, Senior Staff Writer, MedPage Today

Published: March 27, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

  • Note that this systematic review demonstrated improved costs and outcomes among adherent patients in studies of primary or secondary prevention of coronary artery disease.
  • Be aware that few studies contained an adequate control group to adjust for a “healthy adherer” effect.

Greater adherence to medications for primary and secondary prevention of coronary artery disease appears to improve outcomes and lower costs, a systematic review showed.

Although medication adherence was measured with various techniques, all primary and secondary prevention studies suggested that patients who were most adherent to their medication regimens had better outcomes compared with their less-adherent counterparts, according to Asaf Bitton, MD, MPH, of Brigham and Women’s Hospital in Boston, and colleagues.

And the studies that evaluated costs showed savings of $294 to $868 per highly adherent patient per year, the researchers reported online in the American Journal of Medicine.

Most of the studies, however, did not take into account the “healthy adherer effect” — the likelihood that adherent patients generally live healthier lifestyles compared with other patients.

“Nonetheless, while the literature is not ideal, and a definitive study has not been performed,” Bitton and colleagues wrote, “there is a preponderance of evidence that suggests the presence of a strong relationship between adherence to essential coronary artery disease prevention medications and both improved health outcomes and cost reductions.”

“Given the pace of delivery innovation throughout the U.S.,” they wrote, “and the magnitude of possible benefits from improved medication adherence, renewed efforts at the private and national levels to better understand and support increases in medication adherence are urgently needed.”

The researchers included 25 studies in the systematic review — five looked at primary prevention of coronary artery disease (all but one involved statins) and 20 looked at secondary prevention (most involved antihypertensives and aspirin).

Most of the studies were retrospective, observational analyses, with some post hoc analyses of randomized controlled trials, and one randomized controlled trial. In general, the studies were determined to be high quality, with adjustment for standard confounding comorbidities and sociodemographic variables.

All of the studies demonstrated better clinical outcomes among patients who were more adherent to their medications.

One study looking at statins for primary prevention, for example, showed that patients with less than 80% adherence were more likely to be hospitalized for coronary heart disease (OR 1.07, 95% CI 1.01 to 1.13), and among those hospitalized, low adherence to statins before admission was associated with significantly higher hospitalization costs.

Three studies looking at statins for secondary prevention showed that high adherence was associated with significantly improved outcomes — fewer hospitalizations and recurrent myocardial infarctions and a lower risk of death. In addition, costs were 10.1% to 17.8% lower among the patients who had high adherence.

In two studies that evaluated adherence to beta-blockers for secondary prevention, low adherence was associated with increased mortality risks. In one, low adherence to propranolol was associated with a 2.4-fold higher mortality risk (RR 2.4, 95% CI 1.1 to 5.6) and in the other, high adherence to beta-blockers was associated with a 63% reduced risk of death (HR 0.37, 95% CI 0.25 to 0.54).

Other studies that included various combination of antihypertensives, statins, and other drugs provided similar results.

The researchers noted that there were several methods used among the studies to measure medication adherence, including medication possession ratio, the proportion of days covered, direct pill counts, and patient survey questions. In addition, multiple techniques were used to adjust for potential confounders and only a few studies adjusted for the healthy adherer effect.

“Thus,” Bitton and colleagues wrote, “there is a critical need for better studies with healthy user controls, especially as payers and purchasers are starting to apply large resources towards adherence improvement and thus need more precise estimates for return on investment analyses.”

Bitton did not receive financial support for work on the study. His co-authors reported support from a research grant from CVS Caremark.

Bitton reported that he had no conflicts of interest. His co-authors reported relationships with Aetna, Express Scripts, Lilly, Teva, the National Association of Chain Drug Stores, UnitedHealthcare, and Mercer. One of the authors is employed by CVS Caremark.

From the American Heart Association:

  • Secondary Prevention & Risk Reduction for Cardiac and Vascular Disease
  • Heart Disease and Stroke 2013 Statistical Update

Primary source: American Journal of Medicine
Source reference:
Bitton A, et al “The impact of medication adherence on coronary artery disease costs and outcomes: a systematic review” Am J Med 2013; DOI: 10.1016/j.amjmed.2012.09.004.

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