jeudi 31 mars 2016
VIDEO: Taking control of health spending
3D Printing: Logistics Offset Promise for VAD Planning
In patients with congenital heart disease and heart failure, 3D printing can aid pre-surgical planning for ventricular assist device (VAD) implantation, a review suggested. Cost and accessibility, however, remain barriers to more widespread adoption.
Given the opportunity to "hold physical replicas of a patient's anatomy in our hand before entering the operating room," 3D printing is a "promising" technology, Kanwal M. Farooqi, MD, of Rutgers-New Jersey Medical School in Newark, and colleagues wrote online in JACC: Heart Failure.
But, 3D printing demands substantial logistical considerations in exchange for better device placement in complex anatomy, the authors noted.
Running up the cost of each 3D-printed model are factors such as post-processing software, personnel needed to perform the segmentation, the 3D printer, and material costs, Farooqi's group wrote, noting that the price of 3D printers typically runs the gamut from "a few hundred dollars" to more than $100,000 for industrial-size machinery.
In the authors' previous experiences, "the printer we used was the Mojo, a desktop printer which costs approximately $5,000. The material cost for this printer is typically about $5 per cubic inch for an acrylonitrile butadiene styrene plastic." The authors proposed creating models on a smaller scale to reduce material use, noting that their models were "33% of the full heart size and used a range of 0.4 to 0.7 in3 of material."
In addition, a source image dataset can be compiled via either cardiac CT or MRI, the group noted. At the crux of this decision is the tradeoff between faster scanning by CT and the lack of radiation when imaging by MRI.
Farooqi and colleagues ultimately suggested that while there is little doubt that 3D printing can be helpful in patients with congenital heart disease, the technology is still not quite ready for prime time.
"Considering that the overall response to this technology from the medical community, especially surgeons, has been positive, the main barriers to more widespread use are largely technical (i.e., access to post-processing software, knowledge of skillful post-processing, availability of good image datasets, access to a 3D printer)," they wrote.
"With the enthusiasm for this technology comes the need for standardization of technique, establishment of clinical utility, and increases in accessibility. These are hurdles that are not insignificant," the authors concluded.
Farooqi reported no relevant conflicts of interest.
ACC for the Cath Lab: PARTNER II, Delayed DES, Early Beta-Blockers
The American College of Cardiology (ACC) scientific sessions roll into Chicago this weekend bringing the findings of 24 late-breaking trials and a slew of other highlighted clinical research studies.
For interventional cardiologists, the action starts with PARTNER II in the Saturday morning opening showcase. The trial pits TAVR against surgery for reducing death or stroke for an intermediate surgical risk group. With a follow-up of 2 years, these results will show whether TAVR outcomes in these patients are similar to their high-risk counterparts.
Also in the spotlight are the following trials:
DANAMI-3: Can deferring drug-eluting stent implantation after primary percutaneous coronary intervention (PCI) lower the odds of stent thrombosis in ST-segment elevation myocardial infarction (STEMI) patients? Does postconditioning reduce infarct size in this group? Two presentations from a randomized Danish study attempt to answer these questions.
Early-BAMI: This randomized, double-blind trial will be noteworthy for its data on the impact of early IV beta-blocker treatment before PCI on infarct size for STEMI patients.
Sapien 3: Next-generation TAVR using the Sapien 3 prosthetic goes head to head with PARTNER II Cohort A patients who got surgery. At 1 year, it will be seen if these propensity-matched results match the promising 30-day findings -- in which the Sapien 3 boasted very low adverse event rates -- that were presented at ACC 2015.
FIRE AND ICE: This prospective study comparing cryoballoon and irrigated radiofrequency ablation for paroxysmal atrial fibrillation holds promise for finally pinning down the optimal ablation technology.
INOVATE-HF: Do patients with heart failure benefit from vagal nerve stimulation? Data from this study come 2 years after NECTAR-HF, a negative trial that had a follow-up period of 6 months.
Other buzzworthy late-breakers include a study on patient involvement in discharge decisions for low-risk chest pain and an investigation of the relationship between TAVR procedure volume and patient outcomes. The featured clinical research sessions include 3-year results from CoreValve and a study of valve hemodynamic deterioration after TAVR.
ACC for the Cath Lab: PARTNER II, Delayed DES, Early Beta-BlockersSmoking During Pregnancy Alters Fetal DNA (CME/CE)
Babies born to mothers who smoke during pregnancy show modifications in their DNA that mirror those seen in adult smokers, according to findings from a meta-analysis of DNA methylation studies.
The analysis is the first from the international Pregnancy and Childhood Epigenetics (PACE) consortium, which is studying the impact of in utero and early-life exposures on newborn epigenome by analyzing birth cohorts from the U.S. and Europe using a single DNA methylation platform.
Researchers identified more than 6,000 DNA modifications in babies born to moms who smoked during pregnancy. About half of these modifications corresponded to specific genes, including some linked to lip and cleft palate and asthma. Maternal smoking during pregnancy has been previously implicated as a risk factor for these conditions.
Other identified genes are linked to cancers associated with adult smoking, including lung, colorectal, and liver, researcher Bonnie Joubert, PhD, of the National Institute of Environmental Health Sciences, and colleagues, wrote in the American Journal of Human Genetics, published online March 31.
In an interview with MedPage Today, Joubert said the study is the largest ever to explore the impact of maternal smoking on DNA expression in newborns. Smaller studies have also shown links between in utero exposure to cigarette toxins and DNA methylation.
"These findings re-enforce the known evidence that smoking during pregnancy is harmful to offspring, and it provides additional data on the underlying pathways that could be involved in this," she said.
Maternal smoking during pregnancy has been linked to an increased risk for specific developmental, birth-related disorders, including lip and cleft palate, low-birth weight, reduced pulmonary function, sudden infant death syndrome (SIDS), and asthma.
"Our findings might implicate epigenetic mechanisms in the etiology of these exposure-disease relationships," the researchers wrote.
The analysis included 13 birth cohort studies from the United States and Europe, with a total of 6,685 mother-newborn pairs. In 13% of cases there was sustained (daily) exposure to maternal smoking during pregnancy, and in 25% there was some exposure from mothers who were occasional smokers or who quit smoking early in pregnancy. The rest of the newborns (62%) were born to mothers who did not smoke.
Five of the cohort studies included in the analysis included older children (n=3,187, average age=6.8 years), and 8% of these children were exposed to sustained maternal smoking in utero.
Joubert and colleagues explored the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) using a commercial methylation assay (Illumina 450K BeadChip).
Among the main findings:
- 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation.
- Several of the identified genes were related to diseases previously linked to maternal smoking, including bone morphogenetic protein 4 (BMP4), which is related to lip and cleft palate; and estrogen receptor 1 (ESR1), which is closely linked to breast and hepatocellular cancers and asthma.
- Several differentially methylated CpGs were associated with gene expression, and the researchers observed enrichment in pathways and processes critical to development.
- In the subanalysis of older children, 100% of CpGs showed nominal or greater levels of significance, which the researchers concluded were far more than would be expected by chance (P< 2.2 x 10-16).
Data with repeat measures in the same children were limited, so the researchers were not able to analyze changes in methylation over time.
"Our findings suggest that [in utero] exposure to maternal smoking has lasting effects, but it would certainly be helpful to actually follow children from birth to confirm this," Joubert said.
The researchers concluded that their findings "could provide new insights into the mechanisms involved in the detrimental health outcomes that arise from [maternal smoking] in utero exposure."
"This inaugural paper from the PACE consortium represents a major effort to combine data from many studies in a large-scale meta-analysis of epigenome-wide association studies of maternal smoking in relation to methylation in newborns," they wrote.
Funding for the international PACE consortium is provided by the National Institute of Environmental Health Sciences and others.
Let Primary Care Be Primary Care
I saw a patient yesterday who was coming to see me for what he described as "two reasons."
The first one was kind of silly-sounding. He had changed insurance on Jan. 1, and despite just having had his annual physical a few months ago, his new insurance sent a letter saying he was eligible for a $50 gift card if he had an annual physical before April 1.
Desperate for this gift card (which, like most gift cards in America, will likely go unredeemed), he called immediately (3 days before the deadline) to schedule another annual physical.
Luckily, the second reason he needed to see me actually required me to do an evaluation. This was a preoperative visit for an upcoming cataract procedure. He handed over the multipage form his eye doctor had given him, which required a complete history, physical, some labs, and an electrocardiogram, and then he launched into a series of questions he had about the planned procedure.
He told me that he had seen the eye doctor just a week before, but that the majority of his visit had been spent with "people other than the doctor" who did the majority of his evaluation. He said the doctor came flying into the exam room for the last few minutes, took a look at his eye, and told him to schedule the procedure.
Talk to the Other Doctor
The issue was, after the doctor had left, he told them he had a number of questions, including why this particular procedure was chosen, was it the best one to do, was it actually necessary to do at this time, was the cheaper procedure not satisfactory, was more the expensive procedure covered by his insurance, and so on.
The ancillary staff who were still with him told him that unfortunately the doctor did not have time to answer these questions, but that he could address these with his primary care doctor during his preoperative visit.
Wait, really? Now I'm answering insurance questions and explaining the risks of someone else's procedure, because they're too busy?
One of the board members of my foundation, at our most recent board meeting, said to me, "The problem with you primary care doctors is, you only see us for about 10 minutes, and every time we have a complaint you send us to someone else. My knee hurts, you send me to me to an orthopedist. I've got a rash, you send me to a dermatologist. Headaches, on to the neurologist. Shortness of breath, a cardiologist and pulmonologist."
The problem is the specialist will then spend a long time sitting and talking to the patient about this one problem, hopefully giving them their undivided attention. And who will the patient feel is really providing them with care?
We are challenged by the limits of time, and all we need to cover. Of necessity, we are responsible for the whole patient, managing their high blood pressure, their diabetes, their depression, their chronic obstructive pulmonary disease, their chronic pain, working to get them to quit smoking, making sure their health maintenance is up to date.
Paying Enough Attention?
Every once in a while, some commentary appears in a major medical journal lambasting us all for not paying attention to a certain problem. Just recently I read an essay about how doctors usually fail to elicit a thorough and adequate military history, when this could be critically important to a patient's overall health and should not be "ignored." The problem is, there are just too many things that everyone thinks we should be putting all our attention on, and that, if we don't, we are missing the big picture to the detriment of our patient's health.
How are we, as primary care providers, with our 15-to-20-minute visits, going to be able to check all the boxes, do all the things we are supposed to do, and spend enough time to really evaluate and assess all of the multiple symptoms and issues our patients bring to us -- especially when we are asked to do someone else's work?
A recent analysis of U.S. healthcare revealed that care by primary care providers accounted for 55% of the healthcare visits in this country, but they received only 5% of the reimbursement of healthcare dollars.
Today I gave a seminar to our medicine interns on their ambulatory block rotation about the primary care evaluation and management of headaches.
We looked at what needs to go into a detailed and thorough evaluation of a patient with headaches. To do it right, I suggested, the evaluation should probably be a dedicated appointment, with no other issues getting in the way. A whole separate visit to really be able to help the patient figure out why they're having pain in their head. But we recognized how difficult this can be to accomplish in the real world.
Is it easier to get an MRI and to send them on to a neurologist? Absolutely.
It takes 3 minutes to do it wrong, and maybe an hour to do it right. You do the math.
Reordering Our Priorities
If we are to return primary care to the center of healthcare, to once again make it primary, we need to reorder our priorities.
There are plenty of times where we need a neurologist to help us figure out someone's complex headache syndrome. That's what they're there for. But they will tell you they're overwhelmed and seeing too many patients that they don't need to seen, routine migraine patients that the primary care doctor should have been able to "handle" and try on a new medicine. And we have trouble getting our patients in to see them, probably because they're filled up with those patients they may not need to see just now.
But since the day when we as internists, pediatricians, gynecologists, and family medicine providers released our control, allowed ourselves to be bullied into the low end of the Relative Value Units, to allow "evaluation and management" codes to be set with rates determined by people with no interest in or respect for what we do, we lost our power.
I'm not saying I need to plan an hour with everybody; most of the time I can't even imagine having that many things I need to talk about with somebody, and they certainly don't want to spend an hour with me. And right now, if I were to set aside that much time for extended visits, very quickly the powers that be in finance would start yelling at me about my productivity.
Let us spend the time we need with our patients, get to know them, listen to their fears and concerns, tackle as many of the issues as we can. Have specialists send patients to us to manage what is outside their realm of expertise, and we will do the same back to them. Given the choice, we can handle of lot of headaches, back pain, rashes, and shortness of breath.
But don't ask us to explain the risks, benefits, and alternatives to someone else's surgery -- we've got enough to do.
Let Primary Care Be Primary CareEnvironmental Factors Tied to PBC (CME/CE)
Environmental factors such as chemicals can trigger primary biliary cholangitis (PBC), according to researchers from China and the University of California Davis.
In a review published in the World Journal of Gastroenterology, the researchers looked at the natural history, genetics, and immunobiology of PBC, with a particular emphasis on data that show how the loss of tolerance to 0-E2 (the major autoantigen of PBC) is the pivotal event in the etiology of PBC.
The review was led by Jinjun Wang, PhD, of Yangzhou University in China. Primary biliary cholangitis (also known as primary biliary cirrhosis) is a chronic cholestatic liver disease that overwhelmingly affects women. It has been suggested that PBC begins with a loss of immune self-tolerance leading to the destruction of small- and medium-sized intrahepatic bile ducts and eventually to the development of fibrosis and biliary cirrhosis.
The fact that most patients with PBC are women (about 8:1 female to male ratio) suggests that there "are significant genetic components" to the disease, wrote Wang and his colleagues. Studies have also established that, in addition to genetic disposition, environmental factors also contribute to the loss of tolerance in PBC.
According to the authors, some of these studies have shown how environmental factors can trigger autoimmunity in PBC through molecular mimicry.
"Although microorganisms are possible candidates for the induction of autoimmune disease by molecular mimicry, there are other potential environmental factors," the authors wrote, "including chemical compounds foreign to living organisms."
They pointed out that PBC is characterized by high titer of antimitochondrial autoantibodies directed against the E2 subunit of pyruvate dehydrogenase (PDC-E2) lipoyl domain.
In the article, Wang and his colleagues hypothesized -- and presented evidence from quantitative structure-activity relationships and animal models -- that "xenobiotic" (i.e., induced by a foreign chemical substance) modification of the PDC-E2 lipoyl domain could lead to a loss of self-tolerance and "is a pivotal event in the initial etiology of PBC in genetically susceptible hosts."
They based this thesis on several findings.
For example, quantitative structure-activity relationship studies suggest that disruption of the lipoyl ring S-S linkage renders the lipoic acid "activated" and receptive for xenobiotic modification and subsequent AMA recognition. Data from immunological characterization of antigen and Ig isotype specificities against one such lipoyl acid mimic SAc and rPDC-E2 strongly support a xenobiotic etiology in PBC.
This is significant, the authors contend, considering the high frequency at which AMAs are found in patients with acute liver failure.
Many, if not most, cases of liver injury are the result of drug overdose, and in this review Wang and his colleagues examined the link between xenobiotics and AMA in acetaminophen induced liver injuries.
In one study an analysis of serum samples from subjects who have experienced acute liver failure found that severe liver injury could lead to AMA production. Specifically, the study found AMA with the same antigen and epitope specificity as patients with PBC in 35% of patients who experienced acetaminophen poisoning, which suggests that the PDC-ED lipoyl domain is likely a target of APAP induced reactive oxygen species.
Furthermore, the authors pointed out that while 85% of acetaminophen (the most widely used prescription drug in the U.S.) is metabolized in the liver to nontoxic compounds, the remaining 15% is converted into a highly-electrophilic metabolite N-acetyl-p-benzoquinoneimine (NAPQI).
According to Wang and his colleagues, a highly reactive electrophilic metabolite such as NAPQI can deplete the intracellular glutathione pool, making PDC-E2 more vulnerable to further modification by electrophiles.
"[I]n genetically susceptible individuals, the prolonged exposure to electrophilic agents such as acetaminophen, may initiate and/or enhance the breakdown of self-tolerance to PDC-E2 and eventually lead to PBC," the authors wrote.
The authors wrote that going forward their work in this field will be "directed at examining the biochemical and immunological mechanisms underlying the breach of tolerance in autoimmunity in PBC by environmental chemicals. Knowledge gained from this model may have significant preventive and therapeutic implications in the clinical management of PBC."
The authors disclosed no relationships with industry.
Heart Failure Risk Rises With CAD Burden Post-MI (CME/CE)
A first heart attack is more likely to lead to heart failure in patients with a high burden of coronary artery disease (CAD), according to a newly published study.
Compared with post-myocardial infarction (MI) patients with no more than one occluded coronary artery, those with two obstructed arteries were 25% more likely to suffer heart failure within 6 years. That risk rose to 75% in patients with three blocked arteries, senior investigator Véronique Roger, MD, of the Mayo Clinic in Rochester, Minn., and colleagues reported online in JAMA Cardiology.
"This study provides important information on the role of the extent of coronary disease at the time of the first MI on the future development of heart failure. The more extensive coronary disease is, the higher the risk of heart failure, regardless of whether or not another infarction occurs," Roger said in an email to MedPage Today.
"These findings underscore the need to examine if complete revascularization strategies would help prevent heart failure after MI," Roger said.
The population-based cohort study included 1,922 patients with incident MI diagnosed from 1990 through 2010 who had no history of heart failure. More than half (65%) were men, and their mean age was 64.
Roger and colleagues followed these patients through early 2013 (mean follow-up 6.7 years). The investigators determined the extent of angiographic CAD at baseline and categorized the disease burden according to the number of major epicardial coronary arteries with 50% or more lumen diameter obstruction.
A total of 588 patients (30.6%) developed heart failure, ascertained by the Framingham criteria, during the follow-up.
With death and recurrent MI modeled as competing risks, the cumulative incidence rates of post-MI heart failure among the patients, categorized according to the number of obstructed arteries, were as follows (P<0.001 for trend):
- 0-1 obstructed artery: 10.7% at 30 days and 14.7% at 5 years
- 2 obstructed arteries: 14.6% at 30 days and 20.6% at 5 years
- 3 obstructed arteries: 23% at 30 days and 29.8% at 5 years
Compared with patients with zero or one blocked artery, those with two blocked arteries had a significantly increased risk for heart failure (hazard ratio 1.25; 95% confidence interval 0.99-1.59; P<0.001). In patients with three blocked arteries, the risk was much higher (HR 1.75; 95% CI 1.40-2.20; P<0.001).
This increased risk occurred independently of recurrent MI, and it did not change with heart failure subtypes (reduced or preserved ejection fraction), Roger and colleagues reported.
"During the past 2 decades, major changes in the epidemiology of MI have occurred. Progress in its acute treatment improved short-term survival, but heart failure remains frequent after MI and leads to excess mortality. Hence, the acute treatment of MI aimed at restoring vessel patency is not sufficient to prevent heart failure, underscoring the importance of understanding the contemporary mechanisms leading to its development," Roger and colleagues said.
In particular, "The mechanisms through which concomitant atherosclerosis in coronary vessels other than the culprit artery adversely affect heart failure risk post-MI need further study," they suggested.
A chief limitation of the study was that the cohort was mostly white, "which may limit the generalizability to groups not adequately represented," the investigators noted.
The study was funded by the National Institutes of Health.
No researchers reported relevant financial relationships with industry.
VIDEO: Greater Manchester: Ditching the lanyards
American Medicine's 'Go to the ER' Mentality
Currently, in American healthcare, experts are wringing their hands in confusion. I mean, people have insurance, right? And yet, healthcare is still expensive and, dang it, people just keep going to the emergency room (ER). Visits are climbing everywhere, and I can speak from personal experience when I say that we're tasked with more and more complex and multi-varied duties in the emergency departments of the 21st century.
I'm not a medical economist. I do have some thoughts on the well-intentioned but deeply flawed Affordable Care Act. However, I won't go there right now. What I do want to address is the "go directly to the ER" mentality of modern American medicine.
Call your physician. If it's after hours, the recording for any physician or practice of any sort in America will have a message: "If this is an emergency, hang up and dial 911." It's a nice idea. But, of course, it presumes that everyone really understands the idea of emergency. In fact, they don't. We understand that, or we try to, but we see lots of things that come in ambulances, or just come to the ER, that really aren't.
"I feel fine, but my blood pressure is up."
"I was bitten by a spider, and I watch nature shows, and I know how dangerous they are."
"I have a bad cold, and I have taken two rounds of antibiotics. I have an appointment with my doctor tomorrow, but I thought I'd just come on in to get checked out."
The list goes on. In part, it's because we do a poor job of educating people about their bodies and their illnesses. Online searches usually result in someone self-diagnosing Ebola or cancer, so that doesn't help much.
But in part it's because the ER, the emergency department (ED), has become the default. Surgical patients are told to have wound rechecks in the emergency department. Kids with fevers are directed there by pediatricians or family doctors or secretaries. People who need to be admitted are sent in "just to get checked before they go upstairs." Or sometimes, so the physician on duty can do the negotiation with the hospitalist, rather than having the primary care physician do so.
Why is the ED the default? In 1986 Reagan championed and Congress passed EMTALA, the Emergency Medical Treatment and Active Labor Act, which says you can't turn anyone away for reasons of nonpayment. Another well-intentioned bit of government meddling, it never provided any funds for its expansive act of compassion, so many emergency departments and trauma centers simply shut their doors. You can't see patients for free all day and still meet your budget. I think something needed to be done, but it probably went too far.
Fast forward. Insurance is expensive even when the government mandates it. Whether for fear of litigation or due to overbooked schedules everyone else can always send patients to the ED day or night for any reason. We still function under EMTALA, and that will never, ever change. Patients have little to no expectation of payment when covered by Medicaid and know it (and thus use the ED for everything, and I mean everything). We are seeing expanding lifespans for the elderly, but with more complex illnesses being treated and "survived." We have fewer and fewer primary care providers.
Who actually thought emergency department visits would decrease, and why? Did they ask anyone who saw patients on a daily basis? Or only lobbyists, administrators and progressive academics with starry-eyed fantasies?
I want to take care of everyone. But the Titanic that is emergency medicine in America is sinking. We really, honestly can't bear the burden for all of the chaos of our national healthcare. And don't tell me that if we have a single-payer system it will change everything, because it won't. EMTALA will go on, and doctors paid by the feds will not be more productive than they are now, so everything will still flow to the emergency departments and trauma centers of the land.
This isn't about rejecting the poor, or even criticizing Obamacare. It isn't about single-payer or Medicare for all. It's about entrenched behaviors and facing the reality of the system we've created, which allows one part of the system to attempt to carry the limitations of the rest.
Herb Stein, father of Ben Stein, famously said: "If a thing can't go on forever, it won't go on forever."
And if it's true anywhere, it's true in the emergency departments of this great land of ours.
Where the answer to every crisis is: "Hang up and dial 911."
Edwin Leap is an emergency physician who blogs at edwinleap.com and is the author of The Practice Test and Life in Emergistan. This post appeared on KevinMD.com.
American Medicine's 'Go to the ER' MentalitySlow Medicine: Force-Feeding Dialysis
How often does a reluctant patient with advanced kidney disease agree to start dialysis at the behest of her doctors? We've seen it many times, and apparently we're not alone.
A new analysis in JAMA Internal Medicine found that whether or not a patient begins dialysis has more to do with physician style, chance, and community standards than with objective clinical measures or patient preferences.
The researchers individually reviewed records from more than 1,600 patients at the VA who initiated dialysis between 2000 and 2009. They concluded that a decision to initiate dialysis was primarily determined by:
- The physician's style, i.e., certain physicians seemed to promote early dialysis initiation more than others
- An acute clinical event, such as a hospitalization, in which the "imperative to treat often seemed to override patient choice"
- Patient-physician discussions. The researchers note that these discussions "were sometimes adversarial, and physician recommendations to initiate dialysis sometimes seemed to conflict with patient priorities"
These findings are especially noteworthy in light of recent data suggesting that earlier dialysis initiation does not improve outcomes.
Most notably, in 2010 the IDEAL trial compared outcomes among more than 800 patients with stage 5 chronic kidney disease who were randomized to either start dialysis once the glomerular filtration rate (GRF) dropped below 15 ml per minute or to a conservative strategy of waiting for a traditional indication for dialysis (i.e., unmanageable electrolyte disturbances, volume overload, or symptoms of uremia).
The trial demonstrated that not only was GFR-based initiation no better than the conservative strategy with respect to mortality, cardiovascular events, and fluid and electrolyte complications, but that the conservative strategy enabled patients to remain off dialysis for an average of six additional months – limiting burdens on patients and reducing wasteful spending.
Even as new research raises questions about the benefits of early dialysis, evidence suggests that nephrologists are starting dialysis at earlier and earlier stages. It is likely that numerous factors – financial and otherwise – have driven this trend.
One such factor has been a push for earlier referral to nephrologists among patients with chronic kidney disease. While we do support referral to nephrologists for most younger patients with stage 4 chronic kidney disease (GFR 15-30 mL per minute) who are at high risk of ultimately requiring dialysis – a practice that helps prepare these patient for dialysis and has been associated with improved outcomes – this does not mean these patients should actually initiate dialysis until it is clearly necessary.
Moreover, in certain patients -- frail elderly patients or those with limited life expectancies -- nephrology referral for stage 4 disease often does not make sense. Many such patients may not end up requiring dialysis due to their limited life expectancy, and evidence suggests that frail elderly experience little benefit from the procedure. In our experience, early nephrology referral among such patients often just leads to uncertainty and anxiety.
The decision about when – or if -- someone with advanced kidney disease should embark on dialysis is complex. For some, dialysis can serve as a bridge to transplant or may offer an opportunity to meaningfully extend life; for others, it may simply prolong suffering. Such a situation calls for careful consideration of an individual patient's goals and values. The fact that so frequently dialysis initiation is affected by physician-centric rather than patient-centric factors is cause for great concern.
"Updates in Slow Medicine" applies the latest medical research to support a thoughtful approach to clinical care. It is produced by Pieter Cohen, MD, of Harvard Medical School, and Michael Hochman, MD, of AltaMed Health System in Los Angeles. Rachael Bedard, MD, is a palliative care fellow at the Mount Sinai Hospital in New York. To learn more, visit their Facebook page.
Slow Medicine: Force-Feeding DialysisACP Calls on Government to Curb Drug Prices
Reining in the cost of prescription drugs in the U.S. will mean going beyond setting list prices, and looking at issues of regulatory approval, patents and intellectual property, assessment of value and cost-effectiveness, and health plan drug benefits, according to the American College of Physicians (ACP).
In a position paper in the Annals of Internal Medicine, ACP argued that increasing price transparency, curbing patent extensions, and enabling Medicare to negotiate volume discounts are essential strategies for keeping the rising cost of prescription drugs in check.
They issued seven recommendations for addressing mounting drug costs, based on a comprehensive literature review of the evidence for the high costs of drugs and potential solutions. The recommendations were endorsed by the ACP Board of Regents earlier in 2016.
Thomas Tape, MD, of the University of Nebraska Medical Center in Omaha, and chair elect of the ACP's Board of Regents told MedPage Today that when he prescribes a medication for a patient with a particular drug insurance plan, the cost of that drug is essentially hidden.
"I can't call the pharmacy up and say 'Tell me the price for this patient of these five cholesterol-lowering medications,'" he explained, adding that he cannot help his patient choose a reasonable, affordable drug from a set of options. "And I find that extremely challenging on day-to-day basis," he said.
A 'Pragmatic' Proposal?
Not surprisingly, the recommendations were not met with enthusiasm by the pharmaceutical industry. In an email to MedPage Today, a spokesperson for the Pharmaceutical Research and Manufacturers of America (PhRMA) called the recommendations "far-reaching," and "driven by the false notion that spending on medicines is fueling overall healthcare cost growth."
The spokesperson went on to say that the recommendations "[ignore] how the competitive marketplace for medicines helps keep spending in check."
Instead, discussions about the cost and affordability of medicines should focus on "pragmatic proposals that increase competition, modernize the FDA, remove barriers that limit paying for value, address market distorting programs like 340B, and empower and engage consumers with information to make better informed healthcare decisions," according to the PhRMA spokesperson. "If we focus on these issues, we can enhance the private market and improve patient access to high quality, patient-centered care."
Tape responded to PhRMA's comment via email, saying, "ACP concurs with PhRMA's assertion that a 'competitive marketplace for medicines helps keep spending in check.'"
But Tape stressed that common practices within the pharmaceutical industry such as extending market exclusivity periods, product evergreening, and pay for delay measures actually diminish market competition and drive drug prices higher.
He also noted that the lack of transparency around true out-of-pocket costs to patients for prescription medications prevents them from making informed purchasing decisions and the market from curbing spending.
"Based on a careful review of the available evidence, ACP found that lack of affordability is a major barrier to the 'better use' of medicines that PhRMA calls for. The fact remains that despite discounts, rebates, coupons, and assistance programs, high and increasing drug prices still threaten to keep patients from getting the medications they need."
The goal with the recommendations is to lay out "a set of items for discussion that will hopefully drive the public debate, and the legislative debate, and add some momentum to the work that's already started in Congress around this issue," Tape said.
The ACP recommendations are:
- Requiring pharmaceutical companies to share the "actual material and production costs" to regulators and cost of research and development (R&D) that factored into drug pricing (including drugs previously licensed by another company or research paid for by tax dollars)
- Scrapping the ban on using quality adjusted life-years in studies funded through the Patient-Centered Outcomes Research Institute (PCORI)
- Allowing Medicare to negotiate bulk purchasing agreements and volume discounts on prescription drug prices; contemplating legislative or regulatory strategies for reimporting drugs
- Preventing any extension of market or data exclusivity beyond the current time-frame for small molecule, generic, orphan, and biologic drugs
- Supporting value-based decision making including bundled payment options, indication-specific pricing, value frameworks, and evidence-based benefit design
- Ensuring that tiered or restrictive formularies don't place specialty drugs out of reach for patients through high cost-sharing
- Eliminating confusion between biologics and biosimilar products, and ensuring that physicians are consulted about biosimilar substitutions
Tape emphasized the need for access to research around the comparative value of pharmaceutical products. Most industry research looks at one drug's effectiveness in relation to a placebo and not to other drugs.
"If we're trying to decide what treatment is going to provide the most value for our patients, that information is really important," he stated.
Moreover, ACP would like to see the ban that bars PCORI from using cost as a factor when interpreting a drug's value abolished, "so we can actually determine the relative values of the different treatments, not just the relative effectiveness," Tape said.
Bipartisan Support
John Rother, JD, executive director of the Campaign for Sustainable Rx Pricing and president of the National Coalition on Health Care, told MedPage Today that most of these ideas have bipartisan support, particularly those measures focused on limiting patent extensions to increase competition.
"Competition is a word that both liberals and conservatives can get behind," he said.
Transparency is also key. "We have to know more about what is the basis for a drug's price; how it compares to other drugs already on the market, that's pretty essential information," he said.
However, the ACP proposal to allow Medicare to negotiate drug prices is more controversial.
Unlike the private sector, Medicare Part D, the benefit program focused on prescription drugs, is currently prohibited from using formularies to enable it to negotiate with drug companies via pharmacy benefit managers.
Such changes would require legislation. This leaves increasing transparency and competition as the most practical strategies in the short-term.
"We take these first steps and then we see what happens, if the rate of price increase is reasonable, that may delay further action in the Congress," and if prices continue their steep rise Congress may have to consider "more forceful changes," Rother said.
'Largely Symbolic'
Rena Conti, PhD, associate professor of health policy and economist at the University of Chicago, views the majority or recommendations as "largely symbolic."
Overall, Conti said the recommendations serve as evidence that physicians are being squeezed by new payment reforms, and believe that pharma should also bear some of the burden.
The recommendations around reimportation of drugs, for example aren't "legitimate." For reasons of safety, most proponents of reimportation look to Canada as a key supplier. But if the U.S begins importing low-priced drugs from one place, the manufacturer will simply raise prices in that country, she said.
"Canadians would never support a policy that would make them worse off over time," she said.
The proposals related to transparency around R&D costs are also symbolic, and primarily intended to "shame the industry for purchasing knowledge capital," Conti noted.
Lastly, allowing Medicare to negotiate volume discounts would mean companies could invest as much as they want in new drugs, and the government could decide to pay as little as it wants. "It's like making a public utility out of pharmaceutical companies," she said.
Taking such a step would negatively impact investments in innovation as well as high-scale employment, Conti said, adding "I don't think we would want to do that."
ACP Calls on Government to Curb Drug PricesOncoBreak: Growing Nipples, Areolas; 'Charities' Busted; Instructive Physical Exams
A reality TV show provided the inspiration for a company that is developing stem cell-derived nipple and areola tissue for reconstructive procedures for breast cancer survivors. (NOLA.com)
The European Medicines Agency has taken a preliminary step toward expanding approval of the PD-1 inhibitor nivolumab (Opdivo) to include treatment of classical Hodgkin lymphoma. (Business Wire)
Two Tennessee-based "charities" have agreed to disband and pay $76 million in fines and restitution to settle a federal lawsuit alleging that charity organizers spent most of the donations on themselves -- but wish the feds luck in collecting any of the money. (New York Times)
A whistleblower in Turkey has accused drugmaker Novartis of bribing Turkish healthcare providers to make formulary decisions favorable to the company's drugs. (Reuters via Fierce Pharma)
An oncologist-blogger suggests medical educators should send students on rounds with oncologists to learn about the value of the old-fashioned physical exam in the era of high-tech medicine. (ASCO)
Laboratory analysis of 200 cans of prepared foods showed that two-thirds of the containers had traces of a suspected cancer-causing chemical, according to a consortium of environmental and health groups. (Environment News Service)
Researchers have uncovered another small piece of the lung cancer puzzle, identifying a potentially targetable mutation that occurred in more than 5% of tissue samples analyzed. (The Oncologist)
Laboratory studies have provided clues to how cancer stem cells thrive in a low-oxygen environment (hypoxia), allowing them to proliferate and spread to distant sites in the body. (PNAS)
Almost as soon as new cancer drugs become available, tumors develop new ways to evade the drugs' anticancer activity, in this case, drugs targeting the CDK4/6 pathway. (Cancer Research)
More evidence links the diabetes drug pioglitazone (Actos) to bladder cancer. MedPage Today has the details.
OncoBreak: Growing Nipples, Areolas; 'Charities' Busted; Instructive Physical ExamsENDO to Celebrate 100 Years at Boston Meeting
BOSTON -- Women's health and endocrine disrupting chemicals will be in the spotlight at this year's meeting of the Endocrine Society, which is celebrating its 100 year anniversary.
The Society said they plan on releasing a scientific statement on bioidentical hormone therapy used to treat menopausal symptoms and other conditions. In addition, new research looking at the link between polycystic ovary syndrome and asthma will be released at the conference, which will be held at the Boston Convention and Exhibition Center from April 1-4.
As in previous years, researchers will be presenting new research on how endocrine disrupting chemicals affect health; this year there's a focus on how exposure to these chemicals interacts with the microbiome, male fertility, cancer risk, and risk of attention deficit disorders in children.
"We have strategically highlighted landmark work in our history over our first 100 years that have shaped and guided the Society across the basic-translational-clinical spectra of endocrine science and clinical care," wrote Gary Hammer, MD, PhD, who is the clinical science chair of the society's annual meeting steering committee, in an email to MedPage Today. "Research and associated discoveries are increasingly improving patient outcome, optimizing care and bringing personalized medicine to the forefront of endocrine care -- transforming the landscape of endocrinology."
Technology
The Society will not only be reflecting on the past, though; they'll also be taking a look at some promising new technologies. Not to be outdone by other meetings that have featured the bionic pancreas, Edward Damiano, PhD, the developer of a prototype now undergoing testing, will share the latest data from his research. And Douglas Melton, PhD, at Harvard University, will be talking about transplantation of insulin producing cells for treating diabetes and sharing results from his lab in a presidential plenary session.
Two other researchers will be talking about how to use big data to propel clinical advances in adrenal disease, and another pair of researchers will be talking about new ways of treating metabolic bone disease.
One of those researchers, Michael McClung, MD, at the Oregon Osteoporosis Center, will be looking at how the safety profile of those new treatments has changed. "Physicians should notice an increase in presented work that highlights the important translation of science discovery, evidence–based guidelines and specifically genetics into clinical practice," wrote Hammer. "Such work is the cornerstone of the rise of personalized medicine that ill increasingly shape how we care for our endocrine patients."
And on the Society's centennial theme, D. Lynn Loriaux, MD, PhD, at Oregon Health Sciences Center in Portland, will give the Clark T. Sawin presentation with a lecture on the history of endocrinology.
ENDO to Celebrate 100 Years at Boston MeetingIntracoronary Gene Therapy Appears Safe in HF Patients (CME/CE)
A gene transfer therapy that delivers the adenylyl cyclase type 6 (AC6) protein via a modified adenovirus into the coronary artery showed early promise as a novel treatment for heart failure, according to a phase II trial.
In 56 patients, intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) was found to have a dose-related beneficial effect on cardiac function, including improvements in left ventricular function beyond standard therapy in a subset of patients with nonischemic heart failure monitored for up to 1 year versus placebo, wrote H. Kirk Hammond, MD, of the University of California San Diego and the VA San Diego Healthcare System, and colleagues.
AC6 gene transfer was not associated with increased adverse events, they wrote in JAMA Cardiology.
"Heart function improved considerably in at least a subset of patients, and at the highest dose we saw no increase in serious adverse events, " Hammond told MedPage Today. "There also appeared to be no ceiling on dose response."
The hospital admission rate among patients who received the AC6 gene transfer was just 9.5% (four of 42) during the trial, compared with 28.6% (four of 14) in the placebo group, but Hammond noted that the study was not powered to show this outcome (relative risk 0.33, 95% 0.08-1.36, P=0.10).
"This finding was encouraging, but for outcomes such as mortality and rehospitalization for heart failure, much larger studies will be needed," he said.
AC6 is a protein found in cardiac muscle cells which is key for regulating heart function. The protein appears to be down-regulated in heart failure patients, Hammond added.
The trial included heart failure patients treated at seven medical centers in the U.S. (one VA medical center, five academic centers, one community hospital) between mid-July 2010 and late October 2014. All patients had an ejection fraction (EF) of 40% or less when screened, and they were randomized to receive one of five doses of intracoronary Ad5.hAC6 or placebo.
In addition to baseline cardiac catheterization, the study participants underwent a second catheterization 4 weeks after treatment to measure left ventricular pressure development (+dP/dt) and decline (-dP/dt). Exercise testing and EF were assessed 4 and 12 weeks after randomization.
A total of 14 patients were randomized to receive placebo and 42 patients received a single administration of intracoronary Ad5.hAC5 at one of five ascending doses (3.2 x 109 to 1012 virus particles). Nitroprusside sodium was used to increase gene transfer efficiency.
Primary endpoints included exercise duration and EF before and at 4 and 12 weeks after randomization and peak rates of +dP/dt and -dP/dt before and 4 weeks after randomization. Mean EF at randomization was low (31%) among participants in all arms of the study.
Exercise duration showed no significant group differences at 4 weeks (P=0.27) and 12 weeks (P=0.47). AC6 gene transfer patients had increased EF at 4 weeks (+6.0 [1.7] EF units, n=21, P<0.004), but not 12 weeks (+3.0 [2.4] EF units, n=21, P=0.16). Placebo participants showed no increase in EF at 4 weeks or 12 weeks.
AC6 gene transfer increased LV peak -dP/dt (P<0.03) and AC6 gene transfer also increased EF in study participants with nonischemic heart failure (P=0.02).
Only nonischemic AC6 gene transfer patients showed a significant increase in EF at 12 weeks: EF fell by 0.8 (3.0) EF units in ischemic etiology patients, and increased by 8.2 (3.3) EF units in nonischemic patients. Repeat analysis confirmed this finding, the authors noted.
"Why would individuals with nonischemic heart failure have a superior response,?" the researchers wrote. "Perhaps reduced viable myocardium in those with ischemic heart failure impedes the response to AC6 gene transfer. Alternatively, because ischemia affects endothelial function, its presence may impede transvascular movement of the vector into the cardiac interstitium and thereby may curtail gene response."
The start-up biotechnology company Renova Therapeutics, which was founded by Hammond and colleagues, is in the planning phase of a larger study of the gene transfer therapy to confirm its safety and efficacy in patients with heart failure. The Renova-funded trial will likely include about 1,500 patients and will begin enrolling patients in about a year, he added.
This study was funded by the National Heart, Lung, and Blood Institute Gene Therapy Resource Program and Renova Therapeutics via an NIH Public Private Partnership.
The Belfer Gene Therapy Core Facility at Weill-Cornell manufactured Ad5.hAC6.
Hammond and some co-authors disclosed relevant relationships with Renova Therapeutics. One co-author disclosed relevant relationships with Topera, Abbott, Medtronic, Boston Scientific, St Jude Medical, and Biotronik.
Morning Break: Publicity Bonanza for Anti-Vax Film; Trumped Abortion; Medical Drones
Andrew Wakefield's film that supposedly exposes CDC skullduggery related to vaccines and autism -- which scored global headlines after getting the boot from the Tribeca Film Festival -- will be screened elsewhere in New York on Friday. (New York Times)
Donald Trump said abortion should be outlawed and women should be punished for having one; he later walked that back. (Reuters)
A special House panel seeking names of fetal tissue researchers issued subpoenas to eight medical organizations (The New York Times). Take MedPage Today's survey on this issue.
The Center for Investigative Reporting reviews thousands of criminal court records and finds that profiteering often masquerades as medical care for injured Californians.
Valeant asks its lenders for some slack. (Wall Street Journal)
How to recover from soul-sucking med school, from the physician-author of How to Get Naked with Your Doctor. (KevinMD)
Nestlé, maker of KitKat and Häagen-Dazs, is invading big pharma territory. (STAT News)
An investigational test to detect Zika virus in donated blood is now available, the FDA said.
On another front, should we load mosquitoes up with destructive payloads? (New Scientist)
Shots fired: An Indian psychiatry journal points out what looks like serial plagiarism in its pages. (Discover)
Ready or not, here come the medical drones. (Telemedicine Magazine)
An Italian nurse was arrested and charged with murdering 13 hospital patients. (Reuters)
Which politician called the GOP vow to repeal ObamaCare "a stupid promise"? (The Hill)
Boost your Tinder appeal with one simple change, research dollars hard at work. (NPR)
27 million -- that's the latest count of uninsured Americans under Obamacare through 2019 according to the Congressional Budget Office.
Does Ebola hide itself inside peoples' eyes? (The Atlantic)
The FTC shut down a fake cancer charity. (Washington Post)
A familiar name in biotech investment circles, G. Steven Burrill, will pay a $5.8-million fine and withdraw from the securities business, after the SEC found that he had spent investors' money on his lavish personal lifestyle. (Reuters)
Could an optimized microbiome mix help in stroke recovery? (Scientific American)
Medical marijuana gets a celebrity makeover from Whoopi Goldberg, who thinks it's good for menstrual cramps. (People)
Morning Break is a daily guide to what's new and interesting on the Web for healthcare professionals, powered by the MedPage Today community. Got a tip? Send it to us: MPT_editorial@everydayhealthinc.com.
Morning Break: Publicity Bonanza for Anti-Vax Film; Trumped Abortion; Medical DronesOrencia: Try Again in Lupus? (CME/CE)
The T cell-inhibiting antibody abatacept (Orencia) may help patients with refractory systemic lupus erythematosus (SLE), especially those with articular involvement, according to a small retrospective study.
In the first assessment of the drug for refractory SLE in routine clinical practice, more than half of patients using abatacept for 6 months reduced their SLE Disease Activity Index (SLEDAI) by at least 4 points, and 70% improved according to physician assessment. The treatment was well tolerated overall, according to Raphaele Seror, MD, of Hopitaux universitaires Paris-Sud, Le Kremlin Bicetre in France, and associates.
"These data support conducting new controlled trials of abatacept in SLE patients," the researchers wrote online in Lupus.
Seror and co-authors noted that even with the approval of belimumab (Benlysta), the anti-B lymphocyte stimulator, therapeutic SLE options, and in particular biologics, remain limited.
The study included 11 SLE patients drawn from a French rheumatology network and treated with abatacept for active refractory disease. The primary endpoint was the change in SLEDAI score at 6 months, with response defined as a SLEDAI decrease of 4 or more points. Ten (91%) patients were women, the median age was 44 years, and the median disease duration was 12.5 years.
The indications for abatacept therapy were articular involvement in eight patients, renal or cutaneous involvement in one patient each, and autoimmune thrombocytopenia in one patient. Treatment lasted for a median duration of 7 months. Ten of the patients were positive for anti-double stranded DNA antibodies, and 10 were taking concomitant oral steroids. Seven had had previous biologic exposure.
Five discontinuations at a median treatment duration of 6 months included two for a lack of efficacy (one each primary failure and lupus flare), two for adverse events, and one for intention to conceive.
The median SLEDAI decreased from a baseline score of 6 to 4 (P=0.031), while the median prednisone dose fell only slightly, from 10 mg/day to 9.5 mg/day (P=0.25), but increased in four patients.
The median Disease Activity Score in 28 joints dropped in the eight articular patients from 5.7 to 3.9 (P=0.039), decreasing in seven out of eight cases, and 38% had a complete remission.
Among five patients with cutaneous involvement, three experienced complete remission on abatacept, and one had a partial response. A patient with stage IV lupus nephritis experienced a complete response with no other treatment.
Four adverse events occurred in three patients, but none were severe infections. In the six evaluable participants with elevated anti-DNA antibody levels at baseline, serum levels decreased in four and returned to the normal range in one.
This suggestion of promise provides a counterpart to the somewhat disappointing results from previous trials of abatacept in lupus nephritis. Seror and associates called for further evaluation of abatacept specifically in SLE subgroups with articular and cutaneous manifestations.
The researchers pointed out that changing the response criteria might transform negative results into positive ones since in non-renal lupus, the British Isles Lupus Activity Group response is frequently too stringent a standard to show efficacy. Among suggested new definitions of response is the SLE Responder Index (SRI), which showed belimumab to be effective in two phase III trials.
The SRI includes an efficacy endpoint based on a 4-point SLEDAI improvement, which in the current study showed abatacept to be effective in 50%.
"The authors' findings correlate with some of the findings – especially the response of lupus arthritis – of a previous abatacept clinical trial that, unfortunately, did not meet its primary endpoint," said Petros Efthimiou, MD, of Weill Cornell Medical College in New York, who was not involved in the study.
Interestingly, some of abatacept's effect may be due to cross-talk between T and B cells in SLE, Efthimiou told MedPage Today.
A new randomized placebo-controlled trial of abatacept in polyarticular SLE is under way and incorporates some of the newer clinical endpoints and response criteria. "Hopefully, this ongoing trial will shed some light on efficacy for lupus rash," Efthimiou said.
Among the study's limitations were its retrospective design, its small sample size, and the preponderance of patients with articular SLE.
The authors reported financial relationships with Sanofi, Merck Sharp & Dohme, AbbVie, Bristol-Myers Squibb, Actelion, Pfizer, UCB, Biogen, Roche, Novartis, and GlaxoSmithKline.
Cancer Death Does not Come Sooner When it Comes at Home (CME/CE)
Despite possible concerns about its quality, receiving palliative care and dying at home did not have a detrimental effect on the survival of end-stage cancer patients, according to results of a Japanese multicenter study.
Patients who died at home had significantly longer survival in unadjusted models (HR 0.86, 95% CI 0.78-0.96, P<0.01) and in models adjusted for age (per decade), sex, primary cancer site, presence of metastasis, anticancer therapy within 1 month, presence of delirium, and palliative performance scale category (HR 0.87, 95% CI 0.77-0.97; P=0.01), reported Jun Hamano MD, of the University of Tsukuba in Japan, and colleagues.
Dying at home significantly enhanced survival of patients in their last weeks or days of life compared with those who died in hospital, they wrote in Cancer.
"The most important finding of this study is that patients who died at home had a survival time similar to or significantly longer than that of patients who died in a hospital, after adjustments for background factors with the proven prognostic classification Prognosis in Palliative Care Study model A (PiPS-A)," the authors wrote.
Previous research has shown that place of death does affect the quality of end of life experience, and that more than 50% of people would prefer to be cared for and die at home.
Despite this preference, death at home is not achieved in many countries or is achieved only at a very late stage of the disease, often due to lack of caregivers and/or resources, or because of concerns that survival may be shortened because of less effective medical care at-home compared to in-hospital, the authors noted.
Hamano told MedPage Today that "while we don't have any data as to whether the quality of those extra days at end of life was better at home than in hospital, I think both patient and family could be more comfortable at home."
The study corroborated findings of a preliminary single-center study showed that patients receiving home-based palliative care had a median survival time of 67 days significantly longer than the 33 days observed with hospital-based palliative care. However, the study was limited by lack of adjustment for sufficient prognostic factors.
Hamano and colleagues analyzed data analysis from 2,069 cancer patients in the care of 58 participating palliative care services from September 2012 to April 2014. Most were referred for symptom control (pain, delirium, and dyspnea) and care during dying.
Eligible patients had a mean age of 69.4, and had locally advanced or metastatic cancer (including hematopoietic neoplasms). The most frequent site of primary cancer was gastrointestinal tract, followed by respiratory tract/intrathoracic cancer. Patients dying at long-term care facilities were excluded.
To adjust for patient factors that might affect survival, the investigators classified patients according to the modified PiPS-A survival groups: patients surviving for days (0-13 days), weeks (14-55 days), and months (>55 days). Survival time was measured from the day of referral to the date of death, up to 180 days, after which time survivors were censored.
Of the 1,582 patients receiving care in hospital and 487 receiving care at home, a total of 1,607 patients died in hospital, and 462 patients died at home.
A significantly longer survival time was seen among patients who died at home versus those who died in hospital with an estimated median survival time of 13 days (95% CI 10.3-15.7 days) versus 9 days (95% CI 8.0-10.0 days, P=0.006) in the days' prognosis group, and 36 days (95% CI 29.9-42.1 days) versus 29 days (95% CI, 26.5-31.5 days, P=0.007) in the weeks' prognosis group. No significant difference was seen in the months' prognosis group.
Survival time was significantly influenced by age (per decade), sex, palliative performance scale category, lung cancer, gastrointestinal cancer, breast cancer, delirium, and modified PiPS-A group.
The study also compared survival effects related to life-sustaining treatment -- parenteral hydration during the 48-72 hours before death and antibiotic therapy during the initial 3-week period after enrollment -- that was used in a significantly higher percentage of patients dying in hospital.
Home-based care was associated with extended survival, although this effect was significant only in the PiPS-A days' prognosis group (P=0.039). The authors noted that the survival benefit seen despite less use of life-sustaining treatment could indicate that these treatments were not effective for prolonging survival in this patient population.
Study limitations included data lost to follow-up on 63 participants, and potential selection biases in terms of the characteristics of patients referred for palliation at home versus hospital.
Stephanie Blank, MD, of NYU Langone Medical Center in New York City noted that U.S. home- and hospital-based hospice care are likely to differ from Japan's care.
But she pointed out that "this research highlights the importance of listening to patients and not assuming more medical care is necessarily better."
The study was supported by the National Cancer Center (Japan).
Hamano and co-authors disclosed no relevant relationships with industry.
mercredi 30 mars 2016
Pioglitazone Bladder Cancer Link Seen Again (CME/CE)
Pioglitazone (Actos) was associated with a higher risk of bladder cancer than other diabetes drugs in a large population-based cohort study.
Researchers looked at about 146,000 patients in the U.K. who had recently started taking an anti-diabetic drug; those on pioglitazone faced an increased risk of bladder cancer of 121.0 versus 88.9 per 100,000 person-years among those on other diabetes drugs (hazard ratio 1.63, 95% CI 1.22-2.19). Fifty-four patients receiving pioglitazone were diagnosed with cancer after a mean follow-up of 4.7 years.
But those on rosiglitazone (Avandia) didn't see an increased risk of bladder cancer (HR 1.10, 95% CI 0.83-1.47), according to lead author Marco Tuccori, PhD, at the Jewish General Hospital in Montreal, Canada, suggesting that the increased risk was not a class effect. Tuccori and colleagues published their findings on Wednesday in The BMJ.
In 2015, Actos manufacturer Takeda agreed to pay $2.4 billion to settle lawsuits alleging that it hid bladder cancer risks associated with the drug from patients.
Where the Evidence Fits In
The new study is the latest in a long-running seesaw drama, with one study identifying an increased bladder cancer risk with the drug, only to be followed by another showing no link.
The latest results support findings from a 2005 trial that found a heightened risk of bladder cancer for those on pioglitazone versus placebo. But last year, a study published in the Journal of the American Medical Association found no association between the two, for example.
Silvio Inzucchi, MD, at the Yale School of Medicine, said he still considers that JAMA study to be the definitive one in this area.
"It's interesting to note that the sum total of bladder cancer events in the pioglitazone-treated patients was only 54" in the BMJ study, he told MedPage Today in an email. "Given such small numbers any modest changes in the underlying risk for bladder cancer could have a big impact on measured incidence rates."
The JAMA study, on the other hand, analyzed a larger number of cases (n=1,261) and had a longer duration of follow-up (with a median of 7.3 years), he pointed out.
Inzucchi noted that in the BMJ study, pioglitazone patients "tended to be older, had worse diabetes control, had a greater likelihood of previous bladder conditions, and had more urine testing." He added that those factors, rather than the drug itself, could have been determining factors in bladder cancer diagnosis. (Tuccori and colleagues adjusted for age, HbA1c, and presence of bladder conditions, as well as certain other factors, in their statistical analyses.)
But there's still a "substantial and fairly consistent body of evidence" that supports the link between bladder cancer and pioglitazone, according to Victor Montori, MD, at the Mayo Clinic in Rochester, Minn. "By some accounts the association between pioglitazone and bladder cancer should be added to the long list of suppressed information about harm that would have affected the informed use of a drug during its patent protected life," he wrote in an accompanying editorial.
And David Nathan, MD, at Massachusetts General Hospital, told MedPage Today that the findings were not surprising. "This study is simply better (and larger) than many of the older observational studies," he wrote in an email. "What needs to be emphasized is that the absolute risk for bladder cancer, which is quite small, adds to the potentially deleterious effects of the thiazolidinediones, such as volume retention and bone loss, which are more common."
He added that he agreed with the editors that some of the contradictory earlier findings may have been due to methodological shortcomings of those trials.
Study Details
Data were taken from the U.K. Clinical Practice Research Datalink. Overall, 622 patients received a diagnosis of bladder cancer, with a crude incidence rate of 90.2 per 100,000 person-years (95% CI 83.2-97.6). The median time between starting a drug and getting diagnosed with bladder cancer was 4.4 years.
Patients who received a prescription for any non-insulin anti-diabetic drug -- including metformin, sulfonylureas, prandial glucose regulators, thiazolidinediones, acarbose, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide (GLP-1) agonists, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors -- between 1998 and 2013 were included. All patients were at least 40 years old.
The authors adjusted for several variables that were recorded at cohort entry, including age, sex, year of entry, body mass index, smoking status, alcohol use status, and the presence of some disorders. They also controlled for duration of treated diabetes.
Compared with those on other anti-diabetic medications, those on pioglitazone were less likely to be obese but more likely to have higher HbA1c levels, have undergone urine protein testing before cohort entry, have a longer duration of treated diabetes, and have previous bladder conditions.
Limitations of the study include the possibility of residual confounding from unmeasured variables like diet, physical activity, family history of cancer, or race. There's also the possibility of misclassification of drug use or of bladder cancer status.
Treating Patients
The absolute risk of bladder cancer for patients on pioglitazone is about three extra cases per 10,000 patients exposed for 1 year, according to Inzucchi. "This risk would need to be considered in the context of the known benefits of the drug, which is now generically available and extremely inexpensive compared to many other diabetes drugs, at less than $10/month in the U.S.," he wrote.
"The problem now is whether the increased likelihood and undesirability of bladder cancer (which remains rare) justify withholding pioglitazone from adults with type 2 diabetes, given the benefits (such as stroke prevention) and potential harms (such as weight gain, heart failure, bone fractures) associated with its use, and the relative efficacy and safety of alternatives," added Montori. "This is the kind of consideration that complicates the treatment of diabetes and demands reliable evidence of comparative effectiveness and safety."
Nathan said doctors need to carefully consider the advantages and disadvantages of different classes of diabetes treatments. Empagliflozin (Jardiance) was found to lower risk of cardiovascular disease last year, raising questions about where other treatments still fit in.
But Inzucchi, who was an investigator on the trial that discovered the CV benefit, said he still thinks there's room for pioglitazone -- particularly when it's paired with empagliflozin. "I actually believe that the pioglitazone-empagliflozin tandem could be quite powerful combination – pioglitazone to prevent or slow the development of atherosclerosis and then empagliflozin to reduce complications from coronary artery disease once it occurs," he wrote. In addition, empagliflozin could reduce fluid retention that is sometimes associated with thiazolidinediones.
But he added that we need more studies to test that and develop evidence-based guidelines. "We've certainly come a long way in less than a year in understanding the CV effects of diabetes therapies and even more information will be forthcoming over the next 1-2 years," he wrote.
The study by Tuccori et al was funded by the Canadian Institutes of Health Research. The authors disclosed no relationships with industry.
Montori disclosed no relationships with industry.
Inzucchi disclosed serving as an expert witness for Takeda, which markets Actos, in a patent suit and receiving clinical study drugs from the company. He also disclosed ties with Merck, Janssen, Sanofi/Regeneron, Poxel, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Intarcia, and Abbott.
VIDEO: Hopes for new child cancer test
HRT Slows Atherosclerosis Progression in Early Menopause (CME/CE)
Oral estradiol therapy appeared to improved indications of cardiovascular disease in women in the early stages of menopause, a randomized trial found.
Age had a significant impact on the effects of estradiol, as women who were less than 6 years past menopause ("early menopause") experienced a lower rate of increase in carotid-artery intima-media thickness (CIMT) after 5 years of follow-up versus women who were classified as "late menopause" (P=0.007 for interaction), reported Howard N. Hodis, MD, of the University of Southern California in Los Angeles, and colleagues.
The early menopause group also had a statistically significant reduced rate of CIMT increase than women in the placebo group (0.0044 mm increase vs 0.0078 mm increase, respectively, P=0.008), they wrote in the New England Journal of Medicine.
These findings are in line with prior observational studies, which have shown inverse associations between postmenopausal hormone replacement therapy (HRT) and risk of cardiovascular disease. A subanalysis of the Women's Health Initiative (WHI) data 13 years later showed an age-related trend, where HRT was not associated with the same cardiovascular risk for women earlier in menopause compared with later in menopause.
Hodis and colleagues discussed a "timing hypothesis," which suggests HRT is associated with beneficial effects on atherosclerosis and coronary heart disease when women are first going through menopause, but not more than 10 years past menopause.
"Since the subanalysis of the WHI, there has been an appreciation that initiation of hormone therapy early after the menopause transition has a different impact than 10 years after," commented Lauren Streicher, MD, of Northwestern University in Chicago.
"There is relatively little information about the specifics of this 'critical window.' While the current recommendation is to offer hormone therapy for relief of symptoms only, this information builds the case that early initiation of therapy will have a positive impact on cardiovascular health," Streicher, who was not involved with the study, wrote in an email to MedPage Today.
Hodis and colleagues found no significant differences in the rates of carotid-artery intima-media thickness for women in the late menopause (≥10 years) group who were given estradiol versus placebo (P=0.29).
The Early versus Late Intervention Trial with Estradiol (ELITE) trial was comprised of 643 women stratified by age according to time since menopause. Each group was split into estradiol and placebo. The estradiol group received 1 mg of 17β estradiol, plus 45 mg progesterone vaginal gel for women with a uterus, while the control group received placebo pills and gel. Carotid-artery intima-media thickness was measured via cardiac CT every 6 months.
There were serious adverse events in 45 women in the placebo group and 43 in the estradiol group. The estradiol group had one death (from glioblastoma), 10 women with breast cancer, one woman with myocardial infarction, and three women with deep vein thrombosis, but the difference between the estradiol and placebo groups was not statistically significant, the authors reported.
Examining secondary outcomes, there were no significant differences between women in the estradiol group (either early or late menopause) and the placebo group for coronary atherosclerosis following their treatment regimen. However, measures of coronary atherosclerosis, such as coronary artery calcium scores, were much higher in the late menopause group compared to the early menopause group.
Judy Hannah, MD, of the National Institute on Aging in Bethesda, Md., which funded the study, said that there should now be less concern among clinicians about prescribing HRT to relieve menopausal symptoms in these younger women.
"A physician knows a patient and knows her risk factors -- whether she has a history of breast cancer, cardiovascular disease, or a history of smoking," she told MedPage Today. "But physicians should be more open to considering hormone replacement therapy, and whether it's an option for their patient."
But in an accompanying editorial, John F. Keaney Jr., MD, of University of Massachusetts Medical School in Worcester, and Caren G. Solomon, MD, of Brigham and Women's Hospital in Boston, said that the actual relevance of these results to clinical coronary heart disease remains questionable, in part due to the measures used.
"The trial assessed only surrogate measures of coronary heart disease and was not designed or powered to assess clinical events," Keaney and Solomon wrote. "The occurrence of myocardial infarction and stroke involves not only atherosclerotic plaque formation but also plaque rupture and thrombosis [and] any changes in these latter two phenomena would not be captured by the CIMT measurements."
Hodis' group acknowledged these limitations, and added that the sample size and duration of follow-up may have been insufficient to allow for the detection in between-group differences of coronary artery outcomes.
The editorialists also pointed out that the current clinical data that supports the timing hypothesis are "suggestive but inconsistent."
Finally, they said the trial results did not warrant straying from current clinical guidelines, which caution against using postmenopausal hormone therapy for the purpose of preventing cardiovascular events."
Hannah said it would be ideal to have a large database of women who were taking HRT hormone replacement therapy whose outcomes could be tracked. But she conceded that such an enterprise would require considerable resources.
"Electronic health records and large healthcare systems have the ability to mine data, so they may be able to gain some important information; they'll have how long the woman took the hormone therapy, the doses and type, and they may be able to see relationships between cardiovascular and other diseases and use of menopausal hormone products," she said. "But that would be a large database, and it would take a long time."
This study was supported by grants from the National Institute on Aging (NIA) and the NIH.
Hodis disclosed support from NIA. Co-authors disclosed relevant relationships with the NIH, GE, and TherapeuticsMD.
Keaney is associate editor of New England Journal of Medicine (NEJM). Solomon is a NEJM deputy editor.
Guidance on Same-Day Discharge After PCI too Strict? (CME/CE)
Same-day discharge after percutaneous coronary intervention (PCI) generally saves healthcare dollars without hurting patient outcomes, a literature review found.
Arguing against the many exclusions for same-day discharge recommended in the 2009 Society for Cardiovascular Angiography and Interventions (SCAI) consensus statement, the totality of "the available evidence supports the safety of same-day discharge in selected patients after PCI," Adhir Shroff, MD, MPH, of the University of Illinois at Chicago, and colleagues wrote online in JAMA Cardiology.
"Greater adoption of same-day discharge programs after PCI has the potential to improve patient satisfaction, increase bed availability, and reduce hospital costs without increasing adverse patient outcomes," they wrote.
And those goals, it seems, may be increasingly within reach for many PCI scenarios.
"Due to advancements in technique, pharmacology, and technology, PCI is much safer and is commonly practiced throughout the world," they wrote. What's more, according to Shroff's group, a prior estimate had predicted that the U.S. health care system would save $200-$500 million per year if half of the patients undergoing PCI were discharged the same day.
Ian C. Gilchrist, MD, of Hershey Medical Center in Hershey, Pa., and a co-author of the review, agreed that "a lot has changed in the way care can be delivered." Unlike bypass surgery, which used to require weeks or months of recovery, "PCI can be done during the daylight hours," he told MedPage Today in a phone interview.
"That pretty much can be done on most routine patients across the spectrum. I think that's something that not all clinicians, especially those outside of the interventional field, understand. They're still thinking back to last decade's approach," Gilchrist said.
One particular barrier to widespread early release is "physician inertia," according to the authors. Given the hazards of staying in the hospital, however -- where infection, accidents, drug errors have been commonly reported -- they suggested that clinicians might overcome this by realizing that "the patient may be safer at home than in the hospital."
Currently, the authors wrote, SCAI's "conservative recommendations would exclude most patients now undergoing PCI regardless of their procedural outcome from same-day discharge. Indeed, the limitations of these exclusion criteria were illustrated in a case series of 100 consecutive patients discharged safely on the same day as their PCI during a period just predating the publication of the 2009 guidelines. Only 15% of these patients actually fit the definitions for appropriate same-day discharge, with most having features considered higher risk by the consensus document."
Shroff's literature review was performed on studies published between 1995 and 2015.
Nowadays, "a priori factors based on age and other preexisting conditions should not necessarily present a barrier to same-day discharge unless those conditions necessitate hospitalization," the authors wrote.
Gilchrist added that "the paper also highlights that just because you can send a patient home earlier doesn't mean that the care of the person is done earlier. All the places that send patients home quickly typically have safety nets set up: patient are contacted the following day, and instructions given on what to do."
Shroff's group suggested that key to every successful same-day discharge are: the accurate assessment of suitability for early release, excellent procedural outcomes, rapid and reliable stabilization of vascular access, reliable provision of dual antiplatelet therapy, and postprocedural patient education (including routine early follow-up and tracking).
Overnight observation can still be appropriate in a situation where the patient has "no social support at home," where no one to take care of them or look in on them, Gilchrist said.
The same goes for patients in whom complications arose during PCI and those who may have heart attacks, he noted.
The authors concluded that "promoting early discharge for stable PCI recipients will benefit patients, caregivers, medical centers, and payers. Same-day discharge after low-risk cases is the next step in the evolution of PCI."
Shroff and Gilchrist cited no relevant relationships with industry.
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