Every patient wants their doctor to be a professional. But the broader concept of “medical professionalism” is not a cut-and-dry matter, as it opens the door to debates over how physicians interact with politics and society, the regulation of doctors’ ethical and legal behavior, and the role of the physician in the new world of health care. Those are large enough questions to warrant a year of discussion in the MacLean Center for Clinical Medical Ethics Seminar Series, and a centerpiece slot at the 23rd annual Dorothy J. MacLean Fellows Conference, held last week.

“In recent decades, there has been a renewed focus in medical education on professionalism being seen as a way to improve patient care, strengthen the doctor-patient relationship, reduce conflict of interest, improve physician self-regulation and ultimately to strengthen the alliance between medicine, patients, and society,” said Mark Siegler, Director of the MacLean Center, in his opening remarks.

If professionalism is too abstract, the themes on the first day of the conference could be simplified as what a doctor should and should not do in today’s tumultuous health care waters. Driving that instability is the ever-growing chunk of the world economy eaten up by the health care industry, said the conference’s first speaker, Arthur Rubenstein of the University of Pennsylvania (and formerly of UCMC). The United States spent $2.3 trillion on health care in 2009, he said, roughly equivalent to the GDP of France. With economies slowing around the world, those costs are unsustainable, and physicians must come together as a profession to work with patients and policymakers to find solutions that benefit all parties.

“We need to do something about that as a medical profession. If we don’t, the future is going to be quite problematic,” Rubenstein said. “If in the financial crisis which we are now surely in, at both the state and national level, the medical profession puts their own interests before those of patients - particularly the poor and elderly patients - our now privileged position in society will be given up, and our contract with society will be changed for the worse, and we may not recover in the foreseeable future.”

Participation was also one take-home message of Christine Cassel’s talk, which emphasized how the classical definition of the medical professional would have to evolve in the new health care landscape envisioned by last year’s Affordable Care Act. Cassel, the president and CEO of the American Board of Internal Medicine (and another former UChicagoan), said that the three primary goals of health care reforms are affordability, access, and quality. Creating a system that addresses all three will require balancing the intrinsic motivations of physicians to help patients with the extrinsic motivations of financial and regulatory oversight. A new kind of medical professionalism that accepts a health care system based around technology and teamwork will help the field achieve that balance with a minimum of pain, Cassel said.

“To my mind it’s a new kind of professionalism that leaves behind these old ideas of what the nostalgic profession was, and becomes committed to collaboration, evidence, measurement, and transparency so that it’s not at odds with accountability, but in fact becomes accountability,” Cassel said. “This is a challenge for many of us, and it’s going to take change.”

A case study of how that change can happen was presented by Troy Brennan, Chief Medical Officer for the pharmacy chain CVS. Brennan recapped efforts over the last decade to eliminate gifts from pharmaceutical companies to physicians at academic medical centers. While this practice was once thought to be innocuous by many physicians, others argued that it created a conflict of interest. In an example of extrinsic regulation to alter physician behavior, the American Board of Internal Medicine proposed that academic medical centers regulate these interactions between Big Pharma and physicians - an initiative supported by medical students. As a result, physician-industry relationships dropped, though a CVS study is still collecting data on whether that has affected prescription behavior, driving more doctors toward prescribing generics instead of brand name drugs.

Preserving physicians’ integrity and reputation is important for the role of the medical professional proposed by Paul Starr of Princeton University. In a time of ideological polarization and lack of trust in public institutions, it’s important for professionals to bring trustworthy knowledge to the public debate, Starr said, citing the recent Republican debate where candidate Michele Bachmann claimed a link between the HPV vaccine and mental disability.

“When prominent political figures make uninformed statements on national television about the effects of a vaccine, or distort the findings of researchers on a cancer screening test, then politicians may have a real, substantial impact on public understanding,” Starr said. “It is just at those moments when the scientific community should hold its ground and insist on abiding by the evidence.”

read more

Brain surgery remains one of the more complex procedures in the clinical arsenal, an intervention any doctor would like to avoid if possible. But many conditions - a growing brain tumor, a bleeding hemorrhage - require the surgeon to go in, opening the skull, dodging blood vessels, and preserving healthy tissue to correct the problem. If these maladies were somehow preventable or treatable with a medication, it could cut down on the complications and cost of neurosurgery. Even so, you might be surprised to find a surgeon doing the research that could someday reduce his own workload.

That’s the case with Issam Awad, professor of surgery at the University of Chicago Medical Center, and the latest paper in his project studying an abnormality of the brain’s blood vessels. Cerebral cavernous malformation (CCM), alternatively known as cavernous angioma, occurs when the small blood vessels of the brain grow abnormally large. These malformations can occasionally form a dangerous lesion, leading to headaches, bleeding in the brain, or stroke. But it wasn’t until the routine use of MRI technology until clinicians discovered just how commonly CCM can be found - 1 in 500 people - even though it is often non-symptomatic.

The presence of non-symptomatic CCM complicates the matter further for neurosurgeons, who must decide whether to perform surgery to correct the lesion or wait to see if it worsens. This dilemma is especially difficult in patients with a family history of CCM, which makes up about one-third of the cases. Waiting to see if the angioma is going to become problematic enough to require surgery can be a frustrating experience.

“There is currently no treatment in clinical use to either prevent the formation or the maturation of these lesions,” Awad said. “The way we deal with them now is we wait until a lesion gets bad or does something bad, and then we take it out.”

Awad and colleagues Douglas Marchuk from Duke University and Mark Ginsberg at the University of California, San Diego have used those familial CCM cases to find the cause of the condition, focusing on a gene called KRIT1 (or CCM1 for its clinical significance). By knocking down KRIT1, they could create a mouse model that formed CCM lesions, and study the cellular signals that accompany the condition. It turned out that reducing the activity of KRIT1 increased the activity of a signal called ROCK, which made CCM lesions leakier and more severe. CCM lesions removed surgically from human subjects by Awad also tested for high levels of ROCK, suggesting that the mechanism was the same across species.

So the obvious hypothesis to test was whether an inhibitor of ROCK could block the formation of CCM lesions. For a paper published yesterday in Stroke, researchers from the three laboratories performed the experiments in their mouse model of CCM, treating the mice for four months with a ROCK inhibitor drug called fasudil. When they compared the brains of these drug-treated animals to the brains of animals treated with a placebo, they found fewer lesions, smaller lesions, and a reduction in inflammation and hemorrhage after fasudil.

“This animal model and humans have lesions that are aggressive and symptomatic: They leak blood, they show inflammatory properties, and endothelial cells multiply or proliferate,” Awad said. “None of these features were present in the fasudil-treated mice. It was like the lesion was chilled down and shrunk.”

Though promising, this early experiment was performed in only a small number of mice. More extensive testing in animals - and if everything goes well, in human clinical trials - will be required before the drug can be deployed in the neurology practice. Fasudil is also not yet approved for use in the United States, though it is used in Japan for a different neurological condition and has been “clinically well tolerated” there, Awad said.

read more

When the drug ezetimibe was approved in 2002, it was hailed by its makers as a new tool for lowering cholesterol and fighting heart disease in patients. In clinical trials, the drug (marketed by Merck as Zetia) lowered levels of low-density lipoprotein or LDL, the so-called “bad cholesterol” associated with atherosclerosis, the thickening of blood vessels that can lead to stroke and heart attacks. Though LDL was also the target of the highly successful statin drugs, Zetia passed the FDA because it offered an alternative mechanism for reducing cholesterol levels, and soon was making billions of dollars a year for the pharmaceutical company. But as more and more people took the drug and more research was conducted, the scientific data did not match the marketing hype, with large clinical trials failing to find a protective effect against cardiac events and even finding in some cases that it made blood vessels thicker.

Sadly, the story of Zetia is not that unusual. In recent years, other drugs such as Vioxx and Redux have been come under fire when dangerous side effects or underwhelming clinical results became apparent after approval. These high-profile failures (and the inevitable ensuing lawsuits) have threatened to slow drug development, as pharmaceutical companies are understandably nervous about investing big money in a potential dud. Expensive new drugs that offer little to no improvement over pre-existing treatments also cause damage, by needlessly raising health care costs. So what changes can we make to the U.S. health care system to promote the creation of innovative new drugs worth their price tag?

Three authors, including G. Caleb Alexander of the University of Chicago Medical Center, proposed five not-so-easy fixes in a recent issue of Annals of Internal Medicine. Their strategy includes reforms of the FDA’s drug approval process, drug labels, and the payment strategy of insurance companies on the other. For drug companies that may not like the extra squeeze, incentives can be built into the system to sweeten the deal for developing more effective treatments and drugs for currently untreatable diseases. “Despite these challenges, the United States has a long history of successfully improving the safety and value of prescription drugs, and substantial progress can still be made,” the authors write.

1. Raise the Bar

One way to prevent surprises when new drugs are transferred from clinical trials to the real world is to require that higher standards are met before approval. Instead of just demonstrating the drug’s superiority to a placebo treatment, researchers could be required to prove that the new drug is better than the current standard of care. Clinical trials should also be designed to measure effects on clinical outcomes, such as atherosclerosis, rather than physiological measures, such as LDL.

2. Semi-Approval

For an FDA approval process that some already criticize as to slow, these additional requirements could further gum up the works. To allow time for this more thorough review, the authors suggest a more nuanced FDA approval, adding a new “conditional” approval stage where the drug could be available with strings attached. For instance, direct-to-consumer advertising could be restricted while more data is collected on the drug’s effects in a larger, more diverse population.

3. The Patent Carrot for the Regulatory Stick

For the pharmaceutical companies, all of the above is a nightmare that would extend the cost and time it takes to bring a new drug to market. As an olive branch, the paper suggests extending the patent exclusivity for new drugs that meet these most stringent standards, giving the pharmaceutical company more time to collect profits before generics are allowed to reach the market. One suggestion is to start the patent clock when the drug is approved, so that the FDA process does not eat up valuable months and years of exclusivity for the drug’s developer. Such a measure would also ease up the pressure on the regulators, reducing “the tension between the ticking clock of patent protection and drug safety,” the authors write.

read more

A large portion of medical research is dedicated to designing and testing new and better drugs for treating disease. But what if we could improve treatments with the drugs we already have - and potentially cut costs at the same time? That’s the proposal made in an editorial this week in the Journal of the American Medical Association written by the Medical Center’s M. Eileen Dolan and Vanderbilt University’s Russell Wilke. Their article, “Genetics and Variable Drug Response,” is an optimistic snapshot of the current state of pharmacogenetics, the use of genetic information to improve the use of pharmaceuticals.

Though individualized or personalized medicine has been a goal of physicians and researchers for several years, the science (as it tends to do) is moving slowly. But as Dolan and Wilke write, promising pharmacogenetics examples are beginning to accumulate, from genes for enzymes found to influence the metabolism of chemotherapy and anti-clotting drugs to genetic variants that predict severe side effects from various agents. Some of these discoveries have already made it to the clinic, such as the genetic test (developed at the University of Chicago by Mark Ratain) for a variant that affects the response to the cancer drug irinotecan. Physicians can use the test to lower the dose in patients found to carry the variant associated with severe side effects at the normal dose.

Dolan and Wilke dream even bigger about pharmacogenetics. Currently, the standard drug dose is set by the average response of a large population, hoping to capture a level where people get the most benefit at the least risk. But as more information about the genetics of drug response are revealed, those doses can be better shaped to each patient according to their own personal risk-benefit. This could bring some drugs deemed “too dangerous” back to common use, if some patients have a genetic profile that enables them to endure the treatment safely.

“For drugs with a narrow therapeutic index, pharmacogenetic studies may hold the potential to resurrect treatments previously withdrawn from the market, particularly for agents designed to fill underserved clinical niches,” they write.

If smarter dosing can truly bring effectiveness up and toxicity down, it would be a benefit to both patients and the health care system in general. One suggestion by the authors is to start building gene-based drug dosing into electronic medical records, creating alerts for doctors about “drug-gene interactions” similar to current alarms for potentially dangerous drug-drug interactions. The future of medication may be more complicated than “take two of these,” but smart implementation may save dollars and lives.

Cohen Video

The American Society of Clinical Oncology recently filmed a short video with Medical Center associate professor of medicine Ezra Cohen, where he talks about how he decided to treat cancer patients while working as a small-town family physician. It’s a nice piece about how doctors are inspired to do their work and the connection between laboratory research and clinical care. If you want to see more videos with Dr. Cohen, he discussed head-and-neck cancer with ScienceLife almost exactly one year ago.

Elsewhere…

Right after his very cool study on the genetic origins of limb development was published, evolutionary biologist Neil Shubin departed for his annual expedition to the Canadian Arctic in search of fossils from the earliest limbed creatures. If you want to follow along with the hunt, Shubin’s teammate (and Tiktaalik co-discoverer) Ted Daeschler is blogging from the dig for the Philadelphia Inquirer! Read about how their remote site on Devon Island is “almost like Mars,” and how the expedition is already finding interesting fossils two days into the trip.

read more

By John Easton

In most clinical trials the targets are patients, volunteers with a disease who sign up for a study to help advance medical knowledge and perhaps lead to better treatments for what ails them. But this week a report in the Archives of Internal Medicine revealed that sometimes the real targets are not so much the patients as the physicians who treat them.

The doctors who agree to participate as investigators in such a trial almost never find out that that they are the trial’s subjects, the ones being studied. Studies of this sort are known as “seeding” trials–kind of like seeding a cloud with particles in order to produce precipitation. The goals of a seeding trial extend beyond measuring the safety or efficacy of a drug to persuading - some would say hoodwinking - the hundreds of doctors who take part in the study to prescribe the drug and become rainmakers for a drug company. So much for informed consent.

Such matters “seldom see the light of day,” explained Caleb Alexander, associate professor of medicine at the Medical Center, who wrote a commentary to accompany the Archives paper, which was authored by researchers at Brown and Yale Universities. “One might think that seeding trials should be illegal,” he said. “They are unethical. They are not illegal.”

No one knows how often this happens. There is only one other recent, well-documented case and it required a lawsuit to come to light.

In this case, the lawsuit was triggered by accusations that the drug gabapentin - AKA Neurontin, approved by the FDA in 1994 for use to control seizures and in 2002 for nerve-related pain - was being marketed for off-label uses, such as for psychiatric disorders. The suit opened the vaults, allowing plaintiff’s lawyers broad access to the drug makers’ marketing plans, eventually resulting in hundreds of millions of dollars in fines.

One small part of the drug’s history was the STEPS trial, short for Study of Neurontin: Titrate to Effect, Profile of Safety. This was an uncontrolled, unblinded trial, launched after FDA approval. It enlisted 772 investigators, many with little or no clinical-trial experience, and 2,759 patients. Even before it began, there were questions about the design. After it was completed, there was the lawsuit, and then there were documents - more than 3,000 of them - correspondence, memos, presentations, market research. The researchers focused on about 400.

What they found met all the requirements for a seeding trial, as spelled out in a 1994 article in the New England Journal of Medicine (PDF) by former FDA commissioner David Kessler and colleagues. “Some company-sponsored trials of approved drugs appear to serve little or no scientific purpose,” they wrote. They are, instead, “thinly veiled attempts to entice doctors to prescribe a new drug being marketed by the company.”

read more

More Honors for Shubin

In 1863, in the midst of the Civil War, Abraham Lincoln signed an order creating the National Academy of Sciences, an organization bringing together the country’s most esteemed scientists to “investigate, examine, experiment, and report upon any subject of science or art.” From the original 50 members, the group has blossomed to 2,100 today, with roughly 200 of those Nobel Laureates. Any club with a 10 percent Nobel ratio is pretty exclusive, so being elected to the Academy’s lifetime membership is a thrilling honor for a scientist.

This week, evolutionary biologist Neil Shubin was the latest UChicago scientist given the honor of NAS membership, part of this year’s class of 72 new members and 18 “foreign associates.” Shubin becomes the 40th current member of the NAS located at the University of Chicago, and joins Medical Center faculty such as Janet Rowley, Martin Weigert, Donald Steiner, Bernard Roizman, Robert Haselkorn, and David Jablonski, who was elected last year (Fermilab director and professor of physics Pier Oddone was also elected in this year’s class). Election is no simple matter - each new member must pass a 10-step process [pdf] and be voted in to the academy by their potential peers.

Shubin is most famous for the discovery of the pivotal fossil named Tiktaalik roseae, a transitional species between ancient fish and the first limbed creatures to walk the land. But Shubin’s research is more than just fossil-hunting, as he studies the genetic programs that control development of limbs in the embryos of species such as sharks and salamanders. On the blog, we recently featured a paper by Shubin and former graduate student Andrew Gillis, where the embryos of strange creatures called holocephalons revealed some of the earliest steps in limb evolution.

In all likelihood, Shubin’s election was helped by his scientific communication skills as well. From his book about the discovery of Tiktaalik and the story of human evolution, Your Inner Fish: A Journey Through the 3.5-Billion-Year History of the Human Body, to his appearances as a correspondent on WTTW, to his anatomy teaching duties at Pritzker Medical School, Shubin has proven himself eager to educate the public at large about science. Appropriately enough, a second honor announced for Shubin this week was the Distinguished Service Award for Enhancing Education through Biological Research from the National Association of Biology Teachers. Once again, he finds himself in good company, as previous recipients include James Watson, Stephen Jay Gould, and Richard Dawkins.

“I am deeply honored to receive the NABT Distinguished Service Award. In an age where the ideas and tools of biology are increasingly playing a role in our lives, it is a deep honor to be recognized by those who are at the front lines of educating the next generation,” Shubin said.

The Science of Killing Bin Laden

A news story as big as the killing of Osama Bin Laden spares no beats, and there were plenty of science stories written this week in the aftermath of Sunday night’s surprise news. The most direct scientific angle was in the identification of the terrorist leader’s body, a step U.S. officials wanted to prove beyond a doubt before going public with the news. Like many of the events surrounding the raid, many of the details remain classified. But that hasn’t stopped science writers from writing explainers on how biometrics and DNA matching likely would have been used to make sure the Navy SEALS really had killed Bin Laden. President Obama himself confirmed that DNA testing was used to confirm they had the right body, but one fascinating mystery is where the DNA used to make the comparison was gathered. Nature blog The Great Beyond describes the candidates - from Bin Laden’s half-brothers and half-sister to one of his purported 26 children - and talks a bit about the recent history of using DNA identification techniques in criminal matters, including one crook busted by DNA he left on a slice of pizza.

Elsewhere…

The creation of new drugs, and the death of old drugs - Medical Center researchers commented on both sides of the pharmaceutical life cycle in newspaper stories this week. In the New York Times blog Fixes, reporter David Bornstein looks at the “valley of death” in developing new drugs for less-than-common diseases, and focused on the Myelin Repair Foundation and researchers such as Brian Popko (who we have featured twice). Then yesterday, the Chicago Tribune’s Bruce Japsen wrote about the upcoming patent expirations on the popular drugs Plavix, Lipitor, and Actos, and talks to our Caleb Alexander about the implications for health care.

How do you make a new species in the lab? It’s easier if you find a lizard species that is entirely female and can reproduce by cloning. Ed Yong at Not Exactly Rocket Science describes genome mash-ups, asexual reproduction, and the trickiness of species-naming in this great post.

A retired nurse and research coordinator at the Medical Center talks with Dawn Turner Trice about her experiences working with a small rural clinic in Ghana.

Tablets of olanzopine, an atypical antipsychotic drug (from Wikimedia Commons)

If you watch enough football games, you might come away with the impression that today’s most profitable drugs are for erectile dysfunction, cholesterol, and allergies. But far less public attention is paid to one of the most expensive classes of drugs : the antipsychotics, drugs designed to treat certain mental disorders. From 1995 to 2006, the number of doctor visits where antipsychotics were prescribed or continued tripled from 6.2 million to 16.7 million, reflecting a nearly $10 billion chunk of the industry. What’s more, the majority of those prescriptions and dollars result from off-label uses of the drugs to treat illnesses where the clinical evidence of their effectiveness and safety is not crystal clear.

Those astonishing figures come from a new study by University of Chicago and Stanford University researchers, published earlier this month in Pharmacoepidemiology and Drug Safety. In the paper, a team led by G. Caleb Alexander, assistant professor of medicine at the University of Chicago Medical Center, used physician survey data to determine the trends and costs of antipsychotic use from 1995 to 2008. The results portray a corner of the pharmaceutical industry that has evolved at a much faster pace than regulatory agencies and the best scientific evidence can keep up with.

The history of antipsychotic medications stretches back more than 50 years to the first wave of agents, now called the “typical” antipsychotics. These drugs, with names such as haloperidol and chlorpromazine (more commonly known as Thorazine), were originally developed to treat the psychotic symptoms of schizophrenia. The typical antipsychotics led the field until the mid-1990’s, when a new class of “atypical” antipsychotics with a slightly different mechanism began to appear on the market for the treatment of schizophrenia, boasting of fewer motor side effects than the older drugs.

Despite the higher cost of atypical agents - typically 5 to 10 times that of the generic, typical agents - they quickly overtook their predecessors despite unconvincing evidence that they were safer or more effective. Though the atypical agents largely avoided the short-term dyskinesia seen with older antipsychotics, longer-term studies found effects upon weight gain and other metabolic conditions, leading to diabetes in some cases. Furthermore, when directly compared against the typical agents for treatment of symptoms such as mania in bipolar syndrome, atypical drugs were no more effective than the cheaper, older medications.

Alexander’s study shows the magnitude of that turnover: in 1995, 84 percent of antipsychotics used were from the typical group; in 2008, just 7 percent were typical therapies. Furthermore, the shift wasn’t simply a one-for-one replacement. From 2002 to 2006, the overall use of antipsychotics soared, with atypical agents leading the expansion into new uses of the drugs. Ironically, there was a return to using typical agents to treat schizophrenia over the 1995-2008 period studied, while atypical antipsychotics became popular for the treatment of bipolar disorder, depression, and other disorders that were beyond the scope of the original FDA approval.

“We saw remarkable changes over time,” Alexander said. “We know from other prescription drugs that uses change or evolve over time, and one reason is clinical innovation, but there’s also substantial over-use and over-adoption of therapies beyond the evidence base.”

read more

When Eugene Goldwasser launched the project that would become his life’s work, he thought it would only take a matter of months. Since the early 20th century, biologists had predicted that a hormone they named erythropoietin must exist to promote the production of red blood cells when the body was running low. But in 1955, nobody had found it. Working at the University of Chicago after World War II, Goldwasser was challenged by his mentor, Leon Jacobson, to find erythropoietin, or Epo as it would come to be known.

“Very few biochemists were foolhardy enough to commit themselves to working on this seemingly intractable protein,” wrote Goldwasser, who passed away last week at the age of 88. “My thought was that any reasonably good biochemist ought to be able, in a relatively short time, to purify a hormone with a measurable biological effect.”

It took 22 years. But the purification of Epo, and the hormone’s eventual commercialization as the drug Epogen, ended up being one of the most significant discoveries of its time. A godsend for people struggling with anemia, either directly or as a consequence of kidney failure, cancer, or AIDS, Epo has helped millions of patients avoid blood transfusions that were once a regular part of their disease. A less savory use of Epo, as a performance-boosting drug, led to widespread controversy in the Tour de France in the late 1990’s. The billions of dollars made off of Epogen, and the legal and political battles over that windfall, also made it an important landmark (for better and worse) in the early days of the biotechnology industry.

Goldwasser himself was the recipient of almost none of that fortune, having failed to pursue a patent on the hormone when his purification experiments finally reached fruition in 1977. For him, the pursuit of Epo was pure basic science, and the potential for clinical application, never mind the money to be made off that translation, was a low priority. In a 1996 essay for the journal Perspectives in Biology and Medicine (not online, sadly), Goldwasser wrote about how he was so unconcerned with patenting his discovery, he forgot that he had even tried until discovering an unanswered disclosure form in his files decades later.

“After submitting the form I promptly forgot about it, since nothing was ever done about filing for a patent,” Goldwasser wrote. When the hormones was eventually patented and sold by the company Amgen, Epo brought them well over a billion dollars a year in revenue.

Even in the midst of this boom, Goldwasser was more interested in the scientific history of Epo than its profitability and legal wrangling. The 1996 essay is a gripping narrative of a scientific hunt, riddled with pitfalls and obstacles that Goldwasser and his collaborators were forced to navigate in order to grab hold of the elusive Epo. The biggest obstacle was the hormone itself, which is so effective in promoting red blood cell production that it is only secreted for brief periods and in very small amounts to produce millions of cells. As Merrill Goozner, author of “The $800 Million Pill,” wrote: “the amount of Epo needed to produce that lifetime supply could be dried and formed into a tablet no larger than an aspirin.” Finding such an ephemeral factor and then gathering a quantity large enough to study and replicate it was a gargantuan task, despite Goldwasser’s early confidence.

When Goldwasser began his search, scientists weren’t even sure which organ secreted Epo. So they started with a crude experiment: removing different organs from rats and injecting them with a salt known to induce red blood cell production. When the kidneys were removed, the salt had no effect, leading the researchers to believe they had found their organ (another clue was the anemia often seen in people with chronic kidney disease).

read more

Originally developed in 1897 as a painkiller, aspirin has become a valuable cardiology tool in the 21st century for preventing and treating cardiovascular disease. Because of the drug’s ability to reduce blood clotting, doctors commonly recommend a daily aspirin to patients at high risk or with a history of heart attacks, strokes, and other cardiovascular ailments. Extensive research has largely supported the drug as a cheap and effective way to prevent these life-threatening events and to help nullify what remains the leading cause of death in the United States.

But in 2000, a group of Boston cardiologists trying to identify risk factors that might predict poor outcomes after a heart attack made a strange discovery. Most of the predictive risk factors they discovered and ultimately incorporated into their well-known 7-point “TIMI risk score” made perfect sense. For example, if you came to the emergency room with chest pain and had an abnormal electrocardiogram or elevated levels in the blood signaling heart damage, you were more likely to be at risk for future adverse events. But the team also discovered one risk factor for predicting worse outcomes that was far from expected: the prior use of aspirin. According to their analysis, patients who were taking aspirin to prevent cardiovascular disease actually did worse after suffering a heart attack.

“It seemed to make little sense, because aspirin had clearly proven itself in other settings to be protective against heart attacks,” said Jonathan Rich, an instructor of medicine in the section of cardiology at the University of Chicago Medical Center. “If you suffered a heart attack, to prevent you from having another, your doctor invariably puts you on aspirin. So this unexpected discovery caught everyone’s attention. Did this mean that aspirin use could actually be hurting people?”

Dubbed the “aspirin paradox,” this observation did not deter doctors from continuing to prescribe aspirin for the prevention of cardiovascular disease. But the mystery caused some to wonder whether there was a biological reason for aspirin’s unexpected role as a risk factor, such as “aspirin resistance” in some patients, or if there was instead an epidemiological or statistical explanation. While working in Boston with the TIMI study group, Rich took charge of an effort to comb through the data for a way to explain the paradox.

The research ultimately led to a study, published last month in the Journal of the American College of Cardiology, which seems to take aspirin off the hook. When researchers controlled for a long list of potential confounding variables such as age, sex, smoking, and previous history of cardiovascular events, the association of prior aspirin use with a higher chance of post-event mortality entirely disappeared. Aspirin, they concluded, was not directly causing worse outcomes after a heart attack. Instead, it was simply a common drug that people with previous cardiovascular disease - by definition, a population at high risk for poorer outcomes, were frequently taking.

“Aspirin is probably an innocent bystander,” Rich said. “The reason people who take aspirin do worse than those not taking aspirin is because those taking aspirin have already suffered a heart attack, a stroke, or have heart failure for which they were prescribed the drug. In actuality, when we looked closer at the heart attacks that people suffered, those who were taking aspirin actually had less severe heart attacks than those not taking aspirin, suggesting that perhaps aspirin was indeed beneficial, but simply insufficient to prevent the heart attack entirely.”

read more

When the FDA adds a “Boxed Warning” to a drug - known casually and more dramatically as a “black box” - it can have dramatic consequences. The information is intended to warn physicians of potential adverse effects associated with the drug, issues that are not deemed serious enough to pull the drug from the market but which should prompt extra attention and care. Antidepressants, the diabetes drug Avandia, and Depo-Provera birth control have all received black boxes in recent years, prompting widespread media coverage and medical comment.

Earlier this year, the anticoagulant medication clopidogrel (marketed as Plavix) became the latest drug to be black-boxed by the FDA. The warning fit the purported age of genetic medicine, as it was meant to draw attention to certain patients for whom the anti-clotting drug is less effective due to the presence of a gene variant for an important enzyme. These “poor metabolizers” exhibited reduced ability to convert the drug into its active components, and the black box warned that physicians should run genetic tests and consider alternative treatments in patients with the polymorphism.

But clopidogrel has become an important medical tool, used in millions of patients at high risk for heart attack, stroke, and other cardiovascular events. The drug has increasingly been incorporated into the long-term care of patients with drug-eluting stents - devices implanted to keep arteries open that secrete medication to prevent the vessels from re-narrowing. In patients where genetics renders clopidogrel less effective, the lost protection can lead to a stent thrombosis (where a clot forms on the device and blocks the artery) or other grave problems. Those concerns, and the expense of conducting genetic tests in every patient, have sent ripples through the field of interventional cardiology, said Sandeep Nathan, assistant professor of medicine at the University of Chicago Medical Center.

“There’s a growing recognition that this sort of formulaic approach to anti-platelet therapy is probably not a good idea,” Nathan said. “What has been brewing as a suspicion for well over a decade has come to an explosive head in the past one or two years.”

In response, Nathan has launched a two-pronged research and clinical effort to rethink current use of clopidogrel while seeking the best possible way to address risk in the future. Instead of waiting for a post-stent adverse event to tragically prove a patient’s insensitivity to clopidogrel, Nathan’s group has become one of the first to offer anti-platelet testing before the stent is implanted in patients at high-risk for the drug being ineffective.

“I view this as testing a parachute. You better be sure that the pack you just strapped on before you jumped out of a plane actually contains a parachute and not camping gear,” Nathan said. “If somebody implanted a drug-eluting stent in me, you better believe that I’m going to want to know if the drug that is my sole protection against a catastrophic, potentially life-ending event, is working.”

read more

A great deal of attention has been paid in recent years to the issue of racial and ethnic health disparities. Statistic after statistic reveals that minorities in the United States, particularly African-American and Hispanic populations, are in poorer health on average compared to American whites. Infant mortality, heart disease, diabetes, obesity, cancer and other maladies appear in often shockingly higher rates in minority populations, reflecting differences frequently attributed to socioeconomic factors and access to quality health care. But a new study by University of Chicago Medical Center researchers finds that a major contributor to those disparities might be traced back to what’s in the medicine cabinet.

The National Social Life, Health, and Aging Project (NSHAP) is a research effort launched out of the University of Chicago to study a large sample of older Americans. In 2005 and 2006, more than 3,000 in-home interviews were conducted across the country with people between the ages of 57 and 85 about their social activity, their health, and their medical care. As part of the interview, researchers not only asked the subject what medications they were currently taking, they looked at the drugs with their own eyes, taking a medication inventory “by direct observation.”

That thorough scan allowed Dima Qato, Caleb Alexander, and colleagues to analyze racial and ethnic patterns of medication use with unprecedented high fidelity. Previous studies which used insurance claims or prescriptions written to measure medication usage missed a key human factor, said Alexander, assistant professor of medicine.

“As we all know from own experience, what you are prescribed and what you take are often quite different,” Alexander said. “This data was unique in that it allowed for us to observe, from a nationally representative sample of individuals, the medicines people were actually taking.”

The analysis focused on medications prescribed to people at high risk for cardiovascular disease, a condition that has seen great progress recently in preventive medicine. Those included both the cholesterol-lowering prescription drug class of statins and the well-known over-the-counter drug aspirin, which is recommended to people at risk of heart attack and stroke for its anti-clotting abilities. Before the researchers even got to comparing different races and ethnicities, a disturbing overall trend appeared regarding use of these medicines.

“We found that across the board, regardless of race, there was evidence of under-use of both stains and aspirin,” said Qato, a research associate in the Department of Obstetrics & Gynecology.

read more

The pharmacy is a service we mostly take for granted in the United States. No matter how tangled our health care system becomes, it’s relatively easy to have a prescription filled when needed, with most people living within a few minutes’ drive of a drug store. Even more than convenience, we’re fortunate to have the reliability of pharmacists, who apply their training to ensuring that people are receiving the correct drug, the proper dose of drug, and that no dangerous drug-drug interactions are risked.

Such routine pharmacy matters rarely cross our mind, but in a post-disaster setting such as Haiti, they are monumental challenges. The good news is that donations of drugs and other medical supplies started to pour into the country soon after the earthquake that killed and injured hundreds of thousands in the Caribbean nation. The bad news was that most of those supplies arrived in the most disorganized fashion possible - giant cardboard boxes and duffel bags haphazardly filled with pills, syringes, bandages and everything else a medical relief effort requires. Each time a doctor needed a particular type of medicine for a patient, they would have to go digging through these boxes for the right drug, like a child searching for the last Snickers bar in a bag of Halloween candy.

So when Dima Awad, a pharmacist at the University of Chicago Medical Center, arrived at the field hospital in Fond Parisien, Haiti, a cheer literally went up among the medical team stationed in the camp. Awad quickly took charge of the mess of medical supplies and set about organizing them into a functional pharmacy, based in one of the rooms of the Love A Child Orphanage unharmed by the earthquake. With the help of a Haitian carpenter who built wooden shelves and a counter using only hand tools, Awad established the first functional post-earthquake pharmacy in all of Haiti. Members of the University of Chicago Haiti Relief team who have returned from the Fond Parisien camp said that this pharmacy may have been the most important contribution the team made to the field hospital.

John Easton and Cheryl Reed (who is in Haiti this week reporting on the Medical Center’s efforts) interviewed Awad last week about her experiences. Awad talks about the challenge of creating a pharmacy from scratch in adverse conditions, how difficult it was to leave her 4-month-old son behind to volunteer in Haiti, the hardships of living in a camp without a shower, and the lasting impact of the relief effort. “After I went through this experience, I truly really feel that the University of Chicago had made a huge difference in Haiti,” Awad said. “We were able to accomplish a lot in just an incredibly short time frame.”

(Previous interviews with Haiti volunteers can be found here and here.)