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Thursday, August 16, 2018

Limb Salvage Bests Amputation for Critical Limb Ischemia


Patients with advanced peripheral artery disease had worse survival and higher costs when major amputation was performed as first-line treatment, researchers found in a retrospective analysis.
In a propensity score-matched analysis of Medicare beneficiaries with critical limb ischemia (CLI), 4-year survival rates were 38% with endovascular revascularization as the first-line strategy, 40% with surgical revascularization, and 23% with major amputation (P<0.001 for both versus amputation).
Subsequent major amputation rates over follow-up were 6.5%, 9.6%, and 10.6%, respectively (P<0.001 for all comparisons), according to a group led by Jihad Mustapha, MD, of Advanced Cardiac & Vascular Amputation Prevention Centers in Grand Rapids, Michigan, reporting online in the Journal of the American Heart Association.
In turn, total health costs per patient-year totaled $49,700, $49,200, and $55,700, after endovascular revascularization, surgery, and amputation — a significant difference for both revascularization types versus amputation.
“Primary major amputation portends a poor prognosis even when adjusting for demographics, medical history, and disease severity. Compared with revascularization, primary major amputation is associated with shorter survival time, increased risk of second major amputation, and higher healthcare costs. These results were generally consistent regardless of patient characteristics and clinical presentation,” the authors noted.
“Survival following CLI diagnosis is lower than that of heart failure, stroke, and most cancers. Given that CLI is underdiagnosed, increasing in prevalence, and responsible for significant risk to life and limb, considerable efforts are needed to raise disease awareness, refine diagnostic algorithms, and establish evidence-based treatment pathways,” they wrote.
Whether a surgical or endovascular procedure is better for CLI remains unclear, although the investigators said they were looking to the BEST-CLI trial (slated for completion in 2019 with 2,100 participants) for answers.
In their study, Mustapha and colleagues included Medicare beneficiaries who were first diagnosed with CLI in 2011 (n=72,199). This patient population overall demonstrated 46% survival over 4 years and 87% freedom from major amputation. A subset of 9,942 individuals was used in the propensity-matched analysis.
Not all cases of CLI resulted in major treatment; endovascular revascularization was given to 40%, surgical revascularization to 20%, and major amputation to 6%.
The reliance on administrative claims yielded several limitations to the study. For one, there was the potential for misclassification of patient characteristics and billing codes, as well as the possibility of unmeasured confounders affecting the findings. Moreover, the researchers had no access to more granular wound data.
“Despite these limitations, the present analysis has significant value. CLI remains a disease entity associated with significant morbidity and mortality in elderly patients, with unacceptably high rates of adverse events despite intervention,” commented Javier Valle, MD, and Stephen Waldo, MD, both of Veterans Affairs Eastern Colorado Health Care System in Denver.
In an accompanying editorial, Valle and Waldo noted that 40% of patients in this analysis received a primary treatment strategy other than attempted endovascular or surgical revascularization, and that 30% of patients undergoing primary amputation did not have gangrene. “These findings are surprising given the consensuses recommendations for revascularization as the first-line therapy for this condition,” they said.
There are two important ways to address these problems, Valle and Waldo suggested:
“Unfortunately, adherence to these guidelines remains underwhelming, with only 32% of patients with CLI receiving all guideline-recommended medical therapies in some series. Implementation of programs that increase the adoption of guideline-directed medical therapies is needed,” they wrote.
“Second, it is important to emphasize that urgent revascularization is imperative to improve outcomes in these patients. Prior data suggest that a substantial number of individuals with CLI do not undergo any revascularization attempt before amputation, confirmed in the present analysis,” the editorialists noted. “Education about the importance of revascularization for limb salvage among primary care practitioners and ancillary services, like podiatry, are critical to improve outcomes for this condition.”
The study was funded by CLI Global Society.
Mustapha reported consulting for Abbott Vascular, Bard Peripheral Vascular, Boston Scientific, Cardiovascular Systems, Cook Medical, Medtronic, Spectranetics, and Terumo.
Valle declared no relevant conflicts of interest.
Waldo disclosed unrelated investigator-initiated research support to the Denver Research Institute from Abiomed, Cardiovascular Systems Incorporated, and Merck Pharmaceuticals.
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‘I Didn’t Study Medicine to Prescribe Weed’


Pennsylvania fully implemented its medical marijuana law in 2018 and joined 38 states and the District of Columbia that have authorized medical or recreational marijuana at a state level. In an attempt to regulate medical marijuana as a pharmaceutical medication to the extent possible, Pennsylvania instituted a process for certification of patients by qualified physicians, and those certifications can only be honored by licensed dispensaries supplying cannabis products from approved growers within the state. Similar to other states, the requests are overwhelmingly by patients to treat chronic pain.
At the University of Pittsburgh Medical Center (UPMC) where I practice, we have been inundated with such requests and physicians are scrambling to follow the guidelines in the literature and meet the patient demand for medical marijuana certification. I led the effort to author UPMC specific guidelines for medical marijuana certification and the emailed responses I received from physicians after the rollout ranged from congratulations to “horror” that we would institutionalize a process for such an evil substance outside the scope of medical practice. Every time I consider certifying a patient my brain is flooded by more questions than answers: By giving patients our “approval” to use marijuana for chronic pain are we just catering to consumer demand or are we offering them a reasonable nonopioid option?
Certification
In addition, “certification” is not the same as prescribing, despite the state of Pennsylvania’s attempt to medicalize it as much as possible, and dispensaries are free to sell the patient any amount of different products they wish to, such as vaping oils or THC pills. The dispensaries tell me that, on average, medical marijuana costs the patient $200 per month. What is our role in protecting financially vulnerable patients from potentially wasting their money? Since medical marijuana is so expensive, do we feel comfortable if the patient admits to using recreational marijuana for pain? To what extent will we be liable if we certify a patient and they become addicted or do something terrible under the influence of marijuana, such as killing someone in an auto accident? Should we certify patients who are already prescribed opioids or should we insist that opioids be tapered if they are going to use medical marijuana? How do you determine if the patient is benefiting from medical marijuana primarily because they have improved pain or because they like getting high? Do we even care if they get high or not?
I have heard an administrator ask, “What does it matter if they get high?” What percentage of patients do get high on medical marijuana, even when used at low doses? In fact, what is the right dose and how should it be delivered: vaping, oil under the tongue, or pills? How good are the data that medical marijuana is indeed helpful for chronic pain?
Uncertainty
Many physicians are uncomfortable with such uncertainties, and hence it is very understandable why most physicians in the states with medical marijuana laws have chosen not to participate in certification. Other physicians like myself are eager to take this journey with their patients and figure out over time what the best approaches are. I suppose that each physician’s comfort with uncertainty may make them more or less likely to want to be certifying providers. In this era of healthcare reform, I see these uncertainties as no different than so many of the other uncertainties we face in our practices, such as whether even generic pain medications are going to be covered by insurances, whether we should advocate for low-dose opioids in some of our patients with chronic pain, and whether it is ethical to advise a patient who may have a marginal indication for a nerve block to get it — knowing that it may only work for 2 weeks, and they have to pay a $1,000 deductible?
Obviously, there are no answers to any of these questions, but the more uncertainty the more ethical and moral choices confront a physician. Since in most of the patients, we see there is some degree of complex decision-making, why bother taking on any more complexity? I never went to medical school to learn how to prescribe medical marijuana. Then again, I never thought that rectal exams would stop being a routine part of the complete physical. Now that I see my own doctor every year I am grateful for this evolution in practice!
This is the inaugural entry of the AAPM-Pain Medicine blog and I thought that this was a poignant topic to kick it off. The medical marijuana phenomena may get at the core of what we may like or dislike about our physician responsibilities and the myriad of choices we need to make daily for our patients. For some physicians the vexing decision-making paradoxes are energizing and for others they are draining. Perhaps medical marijuana certification is also a lens into how we see ourselves as physicians.
Ajay D. Wasan, MD, MSc, is a professor at the University of Pittsburgh School of Medicine and vice chair for pain medicine in the anesthesiology department. He is also vice president of scientific affairs for the American Academy of Pain Medicine.
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NYU offers full scholarships for all medical students


New York University said Thursday that it will cover tuition for all its medical students regardless of their financial situation, a first among the nation’s major medical schools and an attempt to expand career options for graduates who won’t be saddled with six-figure debt.
School officials worry that rising tuition and soaring loan balances are pushing new doctors into high-paying fields and contributing to a shortage of researchers and primary care physicians. Medical schools nationwide have been conducting aggressive fundraising campaigns to compete for top prospects, alleviate the debt burden and give graduates more career choices.
NYU raised more than $450 million of the roughly $600 million it estimates it will need to fund the tuition package in perpetuity, including $100 million from Home Depot founder Kenneth Langone and his wife, Elaine. The school will provide full-tuition scholarships for 92 first-year students—another 10 are already covered through M.D./PhD programs—as well as 350 students already partway through the M.D.-only degree program.
“This is going to be a huge game-changer for us, for our students and for our patients,” said Dr. Rafael Rivera, associate dean for admission and financial aid. The school will refund out-of-pocket tuition payments already made for the current year, and return loans students may have taken out.
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Health Officials Cut Special NIH Gene Therapy Experiment Oversite Rules


As gene therapies have become reality, the U.S. government is removing some special regulations that had been set up long ago over concerns of exotic safety risks.
The Associated Press reported that a National Institutes of Health oversight panel will no longer be called upon to review all gene therapy applications. That panel will now take a broader advisory role, the AP said. The U.S. Food and Drug Administration (FDA) will now look at gene therapy treatments as it down all other types of medications.
In an article penned by NIH Director Francis Collins and FDA Commissioner Scott Gottlieb, the two said the decision to change the NIH oversite role is a good one, as it duplicates the FDA’s regulatory efforts, the AP said. Currently, there are more than 700 gene therapy proposals pending before the FDA. Gottlieb and Collins said the tools currently used to address other areas of science “are now well suited to gene therapy,” the AP reported.
Gene therapies have made significant advancements over the past few years, with some even scoring regulatory approval. For example, in March, the FDA approved Spark Therapeutics’ Luxturna (voretigene neparvovec), a gene therapy for a rare, genetic form of blindness. It was the first time the FDA approved a directly administered gene therapy that targets a disease caused by mutations in a specific gene. Last year the FDA approved the first CAR-T cancer therapies.
At the time of Luxturna’s approval, Gottlieb said he believes gene therapy “will become a mainstay in treating, and maybe curing, many of our most devastating and intractable illnesses.”
The AP noted that the rules being changed only concern gene therapies that alter DNA to treat diseases following birth. The rule changes do not cover embryos, eggs or sperm to correct potential disease. Those kinds of gene therapies are prohibited, the AP said.
The new changes will not go into effect until a period of public comment has passed. There is significant support among the pharma and biotech sectors for the changes, the AP said. Jeffrey Kahn, who heads up the Bioethics Institute at Johns Hopkins University, said the move is “consistent with recommendations from the Institute of Medicine several years ago,” the AP said. Kahn added there are mechanisms in place to protect patients and said gene therapy no longer needs to be treated as a “special case of clinical research.”
Leigh Turner of the University of Minnesota Center for Bioethics told the AP that she agreed the FDA has the tools to handle the regulatory oversite of gene therapies.
“I don’t think this is somehow a massive deregulation. We never want to become blasé or cavalier about gene therapy clinical trials. Careful scrutiny, whether by one body or two, is as important as ever,” Turner said, according to the report.
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FDA Approves Teva Pharma (TEVA) Generic Epipen


The U.S. Food and Drug Administration today approved the first generic version of EpiPen and EpiPen Jr (epinephrine) auto-injector for the emergency treatment of allergic reactions, including those that are life-threatening (anaphylaxis), in adults and pediatric patients who weigh more than 33 pounds. Teva Pharmaceuticals USA gained approval to market its generic epinephrine auto-injector in 0.3 mg and 0.15 mg strengths.
“Today’s approval of the first generic version of the most-widely prescribed epinephrine auto-injector in the U.S. is part of our longstanding commitment to advance access to lower cost, safe and effective generic alternatives once patents and other exclusivities no longer prevent approval,” said FDA Commissioner Scott Gottlieb, M.D. “This approval means patients living with severe allergies who require constant access to life-saving epinephrine should have a lower-cost option, as well as another approved product to help protect against potential drug shortages. The path to developing generic drug-device combination products like this one is challenging. We remain committed to doing our part to provide scientific and regulatory clarity for sponsors seeking to develop complex generics, as well as prioritize the approval of medicines with little or no generic competition as part of our overarching effort to remove barriers to generic development and market entry of critically important medicines. Many of these steps were outlined in our Drug Competition Action Plan, announced last year. We’re especially committed to the development of generic copies of complex products. These products can be hard to copy, and therefore sometimes don’t face timely generic competition once patents and exclusivities are no longer a block to approval. We’re advancing new guidance for sponsors to make the development of generic versions of complex products more efficient, and we’re prioritizing review of many complex generic drug applications.”
Life-threatening allergies can include reactions to insect bites or stings, foods, medications, latex or other causes. Anaphylaxis is a medical emergency that affects the whole body and, in some cases, leads to death. Anaphylaxis occurs in approximately one in 50 Americans. People who have had an anaphylaxis episode always face the risk of another one. Because of this risk, they must carry an emergency dose of epinephrine at all times. Many must keep more than one dose at hand.
The EpiPen is intended to automatically inject a dose of epinephrine into a person’s thigh to stop an allergic reaction. The FDA has approved several epinephrine auto-injector products under new drug applications to treat anaphylaxis, including EpiPen, Adrenaclick and Auvi-Q. In addition, “authorized generic” versions of EpiPen and Adrenaclick are marketed without the brand names. An authorized generic is made under the brand name’s existing new drug application using the same formulation, process and manufacturing facilities that are used by the brand name manufacturer. The labeling or packaging is, however, changed to remove the brand name or other trade dress. In some cases, a company may choose to sell an authorized generic at a lower cost than the brand-name drug product.
Epinephrine auto-injector products are known as “combination products” because they consist of a drug (epinephrine) and a device (the auto-injector). The development of generic combination products can be more challenging than typical drug products, and the FDA regularly takes steps to help guide industry through the process. The agency works with individual companies to support their development of such complex products, and creates publicly available guidance describing the steps the FDA recommends companies take to submit complete, approvable applications for various types of medical products. In this case, the FDA has published three draft or final guidances since 2009 related to the development of generic epinephrine auto-injectors. In addition, as with brand-name drugs, the FDA inspects manufacturing and packaging facilities for generic drugs to ensure that they are capable of consistently producing quality products.
This epinephrine injection (auto-injector) is intended for immediate administration to patients. When given intramuscularly or subcutaneously, it has a rapid onset and short duration of action. Epinephrine works by reducing swelling in the airway and increasing blood flow in the veins.
The most common side effects associated with epinephrine injection are anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache and/or respiratory difficulties. Rare cases of serious skin and soft tissue infections have been reported following use of the drug. In patients with heart disease, use of epinephrine injection may cause chest pain (angina pectoris) or abnormal heart beats (ventricular arrhythmias). Following use of epinephrine injection, patients should seek immediate medical or hospital care. Epinephrine should not be injected into the vein, buttock, fingers, hands or feet. To minimize risk of injection-site injury, movement of the leg should be limited during injection.
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China FDA ex-head booted in vaccine scandal; leaders set ‘severe punishment’


The former head of China’s Drug Administration has been forced to resign in the aftermath of a vaccine scandal that rocked the country.

Bi Jingquan — who presided over China’s drug regulatory agency for three years before a government revamp put him in charge of a market supervision bureau — is stepping down alongside two deputy provincial governors and a mayor in Jilin, where the company at the heart of the scandal is based. Jiao Hong, the current head of the CDA, is being asked to conduct a “deep reflection.”
The news came directly out of a Politburo Standing Committee meeting led by President Xi Jinping, marking exactly a month since the CDA revealed that Changchun Changsheng had falsified records regarding their rabies vaccine, and that their GMP certificate has been revoked.
A few days after that announcement on July 15, Changsheng put out word that they had also been punished for producing substandard DTP vaccines — a mandatory shot for children that prevents diphtheria, tetanus and pertussis (whooping cough).
As public anger erupted, it was further discovered that Changsheng produced and sold close to 500,000 of those problematic doses, almost double the original 250,000 investigators first found.
Concurrent with the Politburo meeting, the State Council has ordered a confiscation of all proceeds that Changsheng has obtained through these illegal activities. And two weeks ago local police filed to arrest 18 staffers involved, including chairwoman Gao Junfang.
The widely reported scandal is a big slap in the face for a drug regulator that’s been branding itself as a beacon of reform, vowing to speed up domestic innovation and facilitate entry of novel foreign drugs while remaining strict on drug safety.
That point is not lost on the Politburo:
[This case] has caused serious adverse impact, both exposing gaps in our monitoring system, and reflecting systemic flaws in the production and distribution of vaccines. We must learn our lesson, be vigilant, clean up the chaos with severe punishment, and accelerate improvement of a longterm mechanism for vaccine and drug regulation.
Severe punishment, of course, is a familiar tactic in Beijing. In 2007, in an effort to demonstrate it’s serious about drug safety, the state executed former drug chief Zheng Xiaoyu on bribery charges.
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Steve Paul reignites xanomeline research as Karuna CEO


Steve Paul has been appointed CEO of US biotech Karuna, to lead development of the psychiatric drug xanomeline, a previously shelved project that he helped to develop at Eli Lilly in the 1990s.
Paul spent 17 years at Eli Lilly, where he held roles including executive vice president for science and technology, and president of Lilly Research Laboratories.
At Lilly, Paul helped develop the company’s mental health blockbusters, Zyprexa and Cymbalta, and helped oversee development of muscarinic cholinergic receptor agonist xanomeline, where its antipsychotic and precognitive properties were first demonstrated.
Karuna hopes that by combining xanomeline with trospium chloride, the safety concerns that caused the drug to be dropped will be overcome.
Paul is chairman at Karuna, but has decided to take the job as CEO after the company completed a $42 million funding round including investment from ARCH Venture Partners, the Wellcome Trust and PureTech Health.
Meanwhile Karuna’s founder Andrew Miller is moving to a new post as chief operating officer of the biotech.
Proceeds of the fundraiser will be used to advance the lead product, now dubbed KarXT (Karuna-xanomeline-trospium chloride).
This includes a phase 2 trial in schizophrenia patients in the third quarter of 2018, and expansion into other therapeutic areas such as Alzheimer’s and pain.
With his appointment Paul brings more than three decades of neuroscience and central nervous system expertise to Karuna.
He is also a co-founder and board member of Sage Therapeutics, and a co-founder of Voyager Therapeutics.
Steve Paul, Karuna, xanomeline
Paul said: “Targeting muscarinic receptors is one of the most promising approaches to treating both the psychosis and cognitive impairment that characterise many disabling neuropsychiatric disorders, including schizophrenia and Alzheimer’s disease, where there is a profound need for more effective treatments.”
“Having been one of the scientists involved in the original work on xanomeline at Lilly, I am excited by the progress that Karuna has made to unlock this important new class of therapeutics.”
“I am looking forward to helping Karuna become a leader in the field and believe in the potential for KarXT to be the first antipsychotic drug with a truly novel mechanism in over 60 years. We are also excited by recent preclinical work suggesting that KarXT may be an effective non-opiate treatment for pain.”
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