In order to achieve the best outcomes for patients, it is important to leverage the perspective of experts. This expertise comes from clinical experience, research experience, as well as training and education. But, what happens when expertise is influenced by incredible amounts of money, and when carefully selected data is mistaken for evidence? On October 25, 2011, Eli Lilly withdrew Xigris (activated drotrecogin alpha) a drug intended to treat sepsis in high-risk patients from all markets, including the United States, in the wake of a final study known as the PROWESS-SHOCK trial.
Xigris has a sordid history. In 2001, the U.S. Food and Drug Administration approved the use of this drug based upon the evidence of one phase 3 randomized, controlled trial, known as the PROWESS study published in the same year. The adoption of the drug was slow and there were restrictions placed upon its use to include only those severely ill with a high risk of death. In 2002, the Surviving Sepsis Campaign was launched by Eli Lilly to promote the treatment of sepsis, and particularly to promote the use of their drug for sepsis. This drug, Xigris, had a cost of $8,000 per course of therapy and was administered as a continuous intravenous infusion for 96 hours. Use of the drug was part of the bundle of care that was recommended for treating septic patients. Experts in both the US and Europe raised questions about the study design and its outcomes.
Three additional trials (RESOLVE, ADDRESS and ENHANCE—all completed before 2006) failed to show an improvement in the primary end points (outcomes). In fact, one trial showed twice the risk of serious bleeding events with the use of the drug. Despite these new data, the Surviving Sepsis Campaign proceeded along with the support of the Society of Critical Care Medicine, the American College of Chest Physicians, the American Thoracic Society and international critical care societies—all expert-lead organizations focused on the care of critically ill patients. In the initial evaluation for use of the drug, all of these experts were presented with selected data in support of the use of the drug, rather than comprehensive evidence weighing the risks and benefits for its use. Evidence comes through using knowledge and perspective in a careful and thorough comparison of risks and benefits.
My colleagues at the National Institutes of Health (NIH), specifically Drs. Eichacker, Natanson and Danner, were outspoken about the ongoing issues with the use of this drug and did not support its use nor adopt the manufacturer’s policies, as had commonly been the case elsewhere. Worldwide, intensive care units and their medical leadership established policies and protocols for the use of the drug based upon one set of data. The NIH physicians published an editorial in the New England Journal of Medicine in October of 2006 outlining their perspective of what had happened and how the system had failed to remove a dangerous drug from the market. These three physicians, with decades of experience and expertise in critical care, as well as many others, were drowned out by the crowd of other experts willing to adopt the protocols prescribed by Eli Lilly based upon a single set of data, and without comprehensive review of all available information.
As recently as 2009, a clinical therapeutics article in the New England Journal of Medicine recommended the use of Xigris in selected patients. This year, the PROWESS-SHOCK trial was completed and it did not demonstrate a statistically significant difference in survival with the use of Xigris. Finally, Eli Lilly announced the withdrawal of Xigris from the market last month.
As more and more therapies are developed, it will be equally important that each is critically evaluated for their impact by expert review that is not influenced by aggressive marketing campaigns. These evaluations should clearly look at the data, study design and outcomes, and impartial experts should determine whether evidence exists for benefit over the risks. Evidence based medicine is a buzzword today which is supposed to speak to the unquestionable quality of the utility of certain therapies. Evidence for the use of drugs or therapies comes from careful and thorough evaluation of all available data, with a perspective of the disease or illness being treated, and the risks and benefits of the drug or therapy. As Drs. Eichacker, Natanson and Danner suggested, “when properly formulated and applied, practice guidelines and performance standards hold the promise of improving patients’ outcomes. Professional societies and other stakeholders must work together to promote a consistent guideline development process… (without) the intrusion of marketing strategies masquerading as evidence based medicine.”
We see older workers (classified as those over 55 years of age) forgoing retirement for a variety of reasons, including economic instability. Combine that behavior with this group’s inherently large size and it’s no surprise they represent the nation’s fastest growing segment of the working population. So, how is this impacting the health system, particularly workers’ compensation claims? We can look at some of the data produced from the Centers for Disease Control and the Bureau of Labor Statistics regarding their workplace injuries for clues.
The Morbidity and Mortality Weekly Report from April 29, 2011, describes the data and detail around 2009 workplace injuries among these older workers. We find that from 2003 to 2009 there was an absolute 5% increase in work-related injuries resulting in lost time among older workers, increasing from 12% of injuries to 17% of injuries among workers. While the rates for many injuries are lower in the older workers, the median length of time that these workers are absent from work increases with age, which suggests that these older workers take longer to recover from non-fatal injuries than their younger counterparts.
Some other data points are worth mentioning. We see that older workers have the highest fatal injury rates with 31% of all occupational fatalities. However, the rates of many other types of injuries are lower in the older workers, despite their higher rates of falls from the same level, fractures and hip injuries. In addition, back pain constitutes a large percentage of the acute traumatic injuries. Like the increasing problem of chronic pain, these cases have the potential to become long-term problems for injured workers, employers and carriers alike.
Clearly, critical strategies around safety to prevent falls and other injuries are required. We also need clear occupational medicine pathways for these workers to be treated by clinicians familiar with and capable of managing these injuries. Furthermore, these physicians should be vigilant against the development of chronic pain problems. Collectively we have an opportunity to recognize the trend and take steps toward mutual benefits for the injured workers, employers and carriers.
Throughout most of the 20th century, neuroscientists believed that brain structure was relatively immutable after a critical period during childhood. It is only recently that neuroplasticity, the capacity of the brain to change with experience, has been shown to persist throughout adulthood. Norman Doidge, MD, in his 2007 book The Brain That Changes Itself: Stories of Personal Triumph from the Frontiers of Brain Science, provides numerous examples of how resilient and plastic the brain can be. As substantial work continues on utilizing neuroplasticity to supplement lost function in the injured brain, rehabilitation programs increasingly leverage the ability of the brain to develop new pathways based upon stimulation and feedback loops.
Neuroplasticity results from repetitive stimulation of new neuronal pathways. As we process information, our brains utilize the fastest and most regularly used nerve pathways. If those pathways are damaged, and we wish to retain that function, we need the remainder of our brain to find a way to process the information and achieve the same outcome. That involves creating new pathways to achieve a similar functional outcome.
The ability to leverage the neuroplasticity of our brains can positively influence both how we manage the problems of a damaged brain, and how we improve cognitive function and prevent cognitive decline as a normal brain ages. This latter ability, to leverage neuroplasticity in a normally aging brain, was highlighted by Abhilash K. Desai, MD, in an article appearing in a recent issue of Medical Clinic of North America. Dr. Desai describes how older adults “maintain social connectedness, an ongoing sense of purpose, and the abilities to function independently, to permit functional recovery from illness or injury, and to cope with residual functional deficits.” His research is also applicable to rehabilitation and highlights the critical need to engage in activities that enhance brain health. Specifically, he found that “as the brain networks and neurons get activated repetitively, they become more efficient and can process faster,” and that they also “require less initial stimulus to fire up the action potential.” Dr. Desai identified some common factors that can influence neuroplasticity:
One of the tools used to treat both damaged and normal brains is technology known as the brain-computer interface (BCI). These devices receive input from receptors on the body that transmit signals to a device that then produces an action. The devices can provide different forms of output, which become sensory input to the person using the device. There are adaptive changes that occur in neurons and synapses throughout the central nervous system as a result of using these devices that support learning new information and acquiring new skills. These devices help a damaged nervous system find alternative pathways to deliver the same function, and they help healthy, aging brains improve cognitive function and slow cognitive decline. As the technology improves, it will be exciting to see the benefits to a wider range of individuals beyond the currently limited scope of neuro-rehab.
Telemedicine intervention may improve outcomes in the intensive care unit, according to a study that will appear in the June 1 issue of the Journal of the American Medical Association.
This technology is designed to provide remote access, monitoring and a safety net to ICUs that do not have around-the-clock intensivists. The system implements a remote facility with a clinical team of nurses and intensivists who have immediate access to vital signs, electronic medical records (including labs and radiology studies), as well as communication equipment within the patients room. This allows for visualization and communication with nursing and other staff in the ICU. The leader in eICU technology has been VISICU, a Baltimore-based company that is now subsidiary of Philips. The company was founded by two ICU doctors at John Hopkins Hospital in Baltimore, Dr. Brian Rosenfeld and Dr. Michael Breslow, after they initially developed the technology in 1998. For more information on eICU technology, refer to the Philips Website.
The goal of the study, conducted over two years from 2005 to 2007, was to quantify the telemedicine intervention in the ICU with in-hospital death, duration of hospitalization and complications. The investigators in the study utilized the remote monitoring features of the system and concurrently supported and monitored for adherence to best practices, care plan creation, and clinician response times to alarms.
The main study endpoints were hospital mortality adjusted for case-mix and severity. Other endpoints were length of hospitalization and ICU stay, best practice adherence, and complication rates. The study found that the hospital mortality rate decreased from 13.6% to 11.8% when telemedicine intervention was used.
As might be expected, there was increased adherence to clinical practice guidelines designed to prevent ICU complications. For example, the use of medications in the prevention of deep vein thrombosis increased from 85% to 99% and the use of appropriate stress ulcer prophylaxis medication increased from 83% to 96%. In addition, there were decreases in preventable complications of ventilator-associated pneumonia from 13% to 1.6% and catheter-related bloodstream infection from 1.0% to 0.6%.
These are impressive results. However, from a technical standpoint, there are numerous limitations of this study, including the inability to generalize the improvements to other centers as well as the lack of randomization and blinding.
What are the real benefits?
Jeremy M. Kahn, MD, MS, from the University of Pittsburgh in Pittsburgh, Pennsylvania, wrote in his editorial accompanying the study that telemedicine is “merely a tool for quality improvement.” Having seen the eICU functioning, I would agree with Dr.Kahn. The real benefit of this technology is to allow an alarm system to be built into ICUs. This brings expert attention in a timely fashion to any changes in vital signs or critical lab values, for example, or new findings on radiology studies.
I believe the other aspects of the reported better outcomes are due simply to adherence to best practices via a Hawthorne effect—a form of reactivity whereby subjects improve or modify an aspect of their behavior being experimentally measured simply in response to the fact that they are being studied. Dr. Kahn summarizes the best use of this technology: “to define specific quality deficiencies in the target ICUs, and then design the telemedicine intervention specifically to address those deficiencies, akin to other types of quality improvement.”
In the end, the technology itself is not the solution, but rather a tool to change practice that will achieve target outcomes.