The pioglitazone controversy continues

Pioglitazone (Actose) and rosiglitazone (Avandia) are members of the thiazoladinedione (TZD) class of oral medications for type 2 diabetes. These agents have been surrounded by controversy because their predecessor in the TZD class, troglitazone (Rezulin), was withdrawn from the market because of liver toxicity. Although their beneficial effects on metabolic risk factors for macrovascular disease have long been known, outcome based data regarding protection against such events have been lacking until very recently and the Public Citizen Health Research Group has placed TZD drugs on its “do not use” list.

Recently the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events) demonstrated the efficacy of pioglitazone in preventing macrovascular events. I blogged it here following presentation of the results but shortly after the announcement and before final publication a BMJ opinion piece was harshly critical of the study. My response to the BMJ commentary is here.

Now PROactive has been published in Lancet October 8 along with a commentary by Hannele Yki-Järvinen. Unlike the BMJ editorial the Lancet commentary acknowledges the clinical benefit of pioglitazone in decreasing macrovascular events. The major controversy about the PROactive results concerned the lack of statistical significance for the primary outcome and reliance on the secondary outcome. But Yki-Järvinen points out that inclusion of procedure related endpoints in the primary outcome could have biased the results against pioglitazone and implies (as I said before) that the primary outcome would have reached statistical significance with a longer follow up period, as the curves were diverging at study’s end. The commentary poses questions about the clinical significance of the increase in heart failure and how it might counterbalance the improvement in vascular outcomes.

So is it time for Public Citizen to change its “do not use” recommendation? They defend the recommendation on the basis that the TZDs “may be less effective than other drugs for diabetes and cause liver damage, weight gain, anemia and heart failure.” PROactive and other evidence suggests that this statement may be unfounded. How can the question of effectiveness of TZDs compared to other agents be answered? Because different classes of medication for diabetes have mechanisms of action which are complementary to one another it may be simplistic to ask whether one class of agents is as effective as another. It now appears that pioglitazone can join metformin as another agent capable of improving macrovascular outcomes. As for liver damage, none was found in PROactive. Weight gain (4 kg more than placebo) was seen, but the clinical significance is unknown and anemia was not mentioned. The problem of heart failure remains troubling although no new heart failure concerns were raised by the study.

Why is Alzheimer’s disease getting all the attention?

This study published in Radiology, evaluating structural changes and cerebral blood flow in elderly demented patients compared with age-matched cognitively intact individuals, found reduced cerebral blood flow in the demented patients suggesting that vascular disease is an important factor in dementia in the elderly. We’ve gone through phases in our understanding of dementia. In the nineteenth century dementia was synonymous with general paresis of the insane, later understood to be caused by syphilis. A half century ago dementia was widely believed to be primarily a vascular disease, leading to a proliferation of vasodilators such as ergoloid mesylates, cyclandelate, and papaverine, none of which worked. More recently we’ve better appreciated Alzheimer’s disease. Does the article in Radiology bring us full circle with regard to “vascular dementia?” No, but it suggests that perhaps our emphasis on Alzheimer’s disease has lead to an under appreciation of vascular mechanisms. Here’s info on multi-infarct dementia and Binswanger’s dementia.

Two lessons in the interpretation of medical literature from a fascinating paper in Medscape General Medicine

Anticoagulation Therapy for Venous Thromboembolism, a review in Medscape General Medicine, stunningly concludes: “Anticoagulants have not been shown to be efficacious in reducing morbidity and/or mortality or safe in VTE treatment.”
Lesson one: Evidence based medicine (EBM) doesn’t always give us the answer.
The Medscape review points out that anticoagulant therapy became the standard based on a single small randomized controlled trial published in Lancet in 1960 which would be considered unacceptably flawed by today’s EBM standards. Moreover, subsequent studies in support of anticoagulation for venous thromboembolism (VTE) were of the sort the EBM crowd frowns on (observational studies, comparisons with historical controls, etc.).

But the Lancet study, flawed as it was, had striking results in favor of treatment. Anticoagulation became the standard, and it has since been considered unethical to do any more placebo controlled randomized trials. The totality of the subsequent evidence, although low level by EBM standards, is compelling. For me, the treatment of VTE with anticoagulants is justified even though it will probably never be “evidence based.” This thoughtful and thorough review in the Journal of Internal Medicine makes that point better than I can.
Lesson two: Financial conflicts of interest aren’t the only ones that need to be disclosed.
Note the following author information for the Medscape paper.Disclosure: David K. Cundiff has no significant financial interests or relationships to disclose. Mr. Cundiff has disclosed that he withdrew warfarin from a patient with lower limb deep vein thrombosis on the grounds that the risk of bleeding in this case seemed to be higher than the benefit of anticoagulant treatment. The patient later died of pulmonary embolism and Mr. Cundiff subsequently lost his medical license because of this case.
Kind of makes you want to read the paper a little more carefully, eh?

What’s so special about Up to Date?

Wonders The Krafty Librarian, who reports doctors’ reactions when a local health system decided to restrict Up to Date access to on campus users. (Linked at Grand Rounds by Hospital Impact). Up to Date is expensive and very restrictive in its access options. Institutional subscriptions generally only provide on site access. Apparently it’s prohibitively expensive for many institutions to provide home access for all users. Like the Krafty Librarian I wonder why so many folks swear by it.

She writes: “But is UpToDate's content really that much more superior to FirstConsult and eMedicine that doctors are willing to put up with a product that seems to have extremely restrictiveve access policies and is not rapidly expanding into needed areas like the handheld and EMR market? Or are physicians apathetic? They know about UpToDate, they know it is a good product, but they don't care to learn or be bothered with other products because they are sticking with the one that they are familiar with come hell or high water.”

Hmmm--- I have mixed feelings. Apparently, according to one of the links in the post, emedicine has an institutional edition which requires a paid subscription. This is news to me, and I’m struggling to understand how it differs from the free version of emedicine I was already familiar with. So is Up to Date really that much better than the free version of emedicine? Emedicine seems to be a work in progress, and is getting better and better. However, it doesn’t seem as well organized or as extensively linked as Up to Date. It’s a large and growing collection of stand alone monographs. And, if renowned expertise in the authorship is important, Up to Date has the edge with a list of contributors that reads like a parade of stars. Also, it’s advertising free, and the free version of emedicine is not (if that’s important to you).

But Up to Date may be living largely on reputation. As the Krafty Librarian points out, doctors are familiar with it and trust it. I don’t agree with some of my colleagues who think it’s all they need, or that it’s even the best resource. I use it extensively and have a personal subscription so I can access it at home (very important to me), but I find it complementary to many other resources. Disadvantages include imprecise searching (you usually have to combine searching and browsing) and somewhat limited graphics. I think there may be other resources that provide a better bang for the buck.

Warfarin after acute coronary syndrome?

The pendulum has been swinging on this issue for years. A meta-analysis published in the August 16 issue of Annals of Internal Medicine favors warfarin added to aspirin for patients with ACS. Patients who received coronary stents were excluded. Warfarin was associated with decreases in myocardial infarction, ischemic stroke and need for revascularization. Benefits outweighed the bleeding risks in all but those patients stratified as high risk for bleeding. There was no effect on mortality.

For patients with ACS who do not receive stents we now have two antithrombotic agents to consider adding to aspirin, these being clopidogrel and warfarin. Patient selection for treatment with one agent or the other will be complex, and will need to take into account risk factors, cost, and patient preference.

Statins and clopidogrel together: Do we have the final answer?

Not yet, in spite of the profusion of studies that have been published ever since the first report in Circulation of an in vitro interaction between clopidogrel and atorvastatin. Clopidogrel is a pro-drug which is metabolized to the active drug by CYP3A4, while atorvastatin is metabolized by the same enzyme. Atorvastatin attenuated the anti-platelet action of clopidogrel in vitro, in a dose dependent fashion.

The latest offering is a recent study in the European Journal of Clinical Investigation in which the effect of clopidogrel on platelet function was tested during concomitant administration of several statins in healthy subjects. Simvastatin and fluvastatin, but not atorvastatin, pravastatin or rosuvastatin, attenuated the effect of clopidogrel. The dose of atorvastatin was only 20mg daily.

An earlier study had concluded that none of five statins, including atorvastatin, attenuated the anti-platelet effect of clopidogrel. The range of atorvastatin doses in that study was 10-40mg.

The clinical significance of the interaction is controversial, with this recent outcome based study suggesting no significant clinical effect, but with other evidence suggesting the interaction may indeed be clinically adverse.

Despite several studies and substantial expert opinion pointing to the safety of concomitant use of statins and clopidogrel I remain concerned because of a lack of data concerning statin dosage effects. My specific concern is that the in vitro evidence suggests that the interaction is dose dependent, and the highest atorvastatin dose purportedly shown to be safe with clopidogrel was 40mg. This is particularly important in view of recent recommendations that 80mg atorvastatin be initiated in the early period following acute coronary syndrome.

Government run health agencies would prefer a double standard

And apparently they have been enjoying one for some time, at least when it comes to reporting malpractice awards and settlements to the National Practitioner Data Bank., as reported here in the New York Times. The law requiring reporting to the Data Bank explicitly applies to federal government health services as well as the private sector. However, the new inspector general has found that non-compliance on the part of government health services is routine. The excuses cited by the federal agencies, such as the NIH and the Indian Health Service, are that sometimes the records get lost, or that they just plain don’t think they should have to comply.

What’s being done about it? The Times piece concludes with:
“Betty James Duke, administrator of the health services agency, said she would soon recommend changes to ‘ensure greater compliance’ with the reporting requirements. But in discussions with the inspector general's staff, federal agencies did not make any firm commitments. ‘It was not clear whether they would fully comply,’ Mr. Levinson wrote.”

Non medical

A blog devoted to cool stuff about Google maps.

Intensive glycemic control in critical illness

This is a hot topic in hospital medicine. I’ve discussed the tension between “patient oriented” and “disease oriented” medical literature. In my opinion we need to read both. Here’s a patient oriented review of intensive in patient insulin therapy from last October’s Cleveland Clinic Journal of Medicine. Here is a disease oriented study and an accompanying editorial from a recent issue of the Journal of Clinical Investigation.

For me, empirical evidence is more interesting and meaningful when coupled with pathophysiologic rationale. (I hope the EBM Mafia isn’t watching).

Stephen Barrett takes courageous stand against Institute of Medicine Report

Stephen Barrett wrote this critical review (via Medscape) of the Institute of Medicine (IOM) book on complementary and alternative medicine (CAM). The National Center for Complementary and Alternative Medicine (NCCAM), a subsidiary of the NIH, commissioned the IOM to write the report. Barrett accuses both the NCCAM and the IOM of promoting unsound health claims. The report, Barrett says, uncritically accepts implausible health methods. In my opinion he nails the issue in stating “Methods that are plausible should be tested with well-designed clinical trials. The rest should be discarded” (Italics mine). I have previously argued that it is wasteful to study scientifically implausible treatments. He goes on: “Despite all the alleged experts involved in its preparation, the IOM report does not contain a single word of criticism against methods that are sufficiently irrational to be discarded now. Instead, it makes broad, sweeping generalizations and attempts to set an agenda for the widespread adoption of ‘CAM’ research and teaching.”

And, concerning CAM teaching, Barrett points out the increasing uncritical adoption of unscientific claims in medical school curricula. He cites this paper by Stanford professor of medicine Wallace Sampson, M.D. on medical school teaching of alternative medicine. Sampson’s survey indicates that medical schools often present baseless alternative medicine claims uncritically or, worse, actively promote them. This open access full text article is worth reading in its entirety. Sampson writes “With inadequate approaches that fail to uphold criteria for validity and plausibility, so called ‘evidence-based’ medicine remains fluid and loses its value to help physicians discern what is truly useful.” Bingo! Sampson makes valid suggestions for reform of the medical school curriculum.

The saga of the pulmonary artery catheter

Medpundit posted about this the other day. Here’s my perspective.

Bedside pulmonary artery catheterization, more commonly known as Swan-Ganz catheterization, began life around 1970. As an internal medicine house officer in the late 70s I watched it come into vogue long before the rigors of evidence based medicine. Offered initially as a tool for management of myocardial infarction it soon enjoyed a broader range of use in critically ill medical patients. In the 1980s papers by Shoemaker and colleagues [1] [2] suggested that aggressive protocol driven therapy guided by the pulmonary artery catheter (PAC) improved outcomes in high risk surgical patients.

In the 1990s several papers addressed PAC guided therapy to maximize oxygen delivery in septic patients, with negative results [3] [4]. In 1996 the SUPPORT investigators published a prospective cohort study of outcomes associated with the use of the PAC in a variety of critically ill patients. This oft-quoted and controversial study suggested harmful effects of the PAC and was followed by editorial commentary suggesting that it was time to pull the catheter. Many writers called for prospective randomized trials of PAC and the American College of Cardiology and other professional societies published guidelines for use of the catheter based on the best evidence at the time.

Subsequently, higher level studies have failed to show benefits of the PAC. Finally, in the October 5 issue of JAMA are two studies and an editorial which suggest we may be approaching the final chapter of the PAC saga. The ESCAPE trial, looking at severely ill patients with heart failure, was a bust. In the same JAMA issue this meta-analysis showed no benefit of the PAC across a spectrum of critical illness. An accompanying editorial is linked here.

It’s been a long and interesting ride. If the ongoing FACTT study fails to show benefits of the PAC in patients with ARDS it may indeed be time to pull the catheter.

Should metformin’s contraindications be contraindicated?

The real test of a drug’s safety is to get it out to the market and into the hands of providers who ignore the labeling and contraindications. Some drugs, like cisapride, prove to be unforgiving of such indiscretions and are taken off the market. That’s the situation that gets most of the attention. Metformin may be different. It seems to be a more forgiving drug. The biguanides, of which metformin is a member, are well known to precipitate lactic acidosis, yet the condition has been difficult to attribute to metformin in the post marketing experience despite widespread contraindicated prescribing. Here’s a point- counter point on the question in a recent issue of CMAJ.

Will the labeling be relaxed for metformin? I don’t know. For now I’ll continue to observe the labeling.

Remembering Hemo the Magnificent

Longer ago than I care to admit a popular educational resource for kids was a series of Bell Telephone sponsored films on a variety of science topics. The series was made for TV in the mid to late 50s and later distributed to schools. The one I remember best was Hemo the Magnificent. It combined humorous Disney style animation with human actors to take the student on a virtual tour of the circulatory system. Clever production elements and analogies (such as nervous pathways illustrated by telephone lines and little men operating levers representing pre-capillary sphincters) held us baby boomers in rapt attention and indelibly etched the circulatory system in our minds.

Fast forward to generation X and this paper in Advances in Physiology Education. The survey of undergraduate students found a high rate of misconceptions about circulatory function and offers fascinating insight about how we learn. When asked to trace the flow of blood a student might draw a path around the perimeter of the body. When asked about the principal function of the lungs some students said it was to filter the blood, others said to convert oxygen into carbon dioxide. There was confusion about distinctions between arteries, veins and capillaries. Worse, these college students were pursuing a career in elementary education.

Despite improvements over time major misconceptions persisted through the end of the course. Equally concerning was the fact that one on one interviews with students uncovered many more misconceptions about the circulation than standard tests, suggesting that students can conceal major areas of misunderstanding on routine testing.

The authors point out that faulty preconceptions about course material hinder learning. Learning is a synthesis of new content and what the student thought before. If the student’s prior thoughts are flawed the learning is less effective. The discipline of physiology, the study of how the body works, may be uniquely susceptible to prior thinking. Early on children begin to develop a mental model based on their interpretations of body sensations. Although the model becomes more sophisticated over time it remains flawed. The teaching of physiology might be more effective if teachers could identify student misconceptions, then employ means to help students unlearn or modify them. The authors conclude that new methods of assessment and teaching are needed. I would add that perhaps we should resurrect Hemo the Magnificent.

Dialysis for dummies

Hospitalists are increasingly called on to participate in the care of dialysis patients. Now it’s more important than ever for us to know a little about dialysis. Here’s a nice review from Southern Medical Journal with the basics.

Hepatoadrenal syndrome

This paper in Critical Care Medicine is noteworthy because it demonstrates an unexpectedly high rate of adrenal insufficiency in patients with severe acute and chronic liver failure, and suggests that treatment with hydrocortisone improves outcome in those patients demonstrated to have adrenal insufficiency. Perhaps we should be doing rapid cortrosyn stimulation tests on these patients at hospital admission. This is useful information with the potential to change hospital practice.

Furosemide and albumin administration in acute lung injury

A recent paper in Critical Care Medicine adds another piece to our understanding of the controversy surrounding fluid management in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In patients with ALI/ARDS and low total serum protein (<6g/dl) the investigators compared furosemide with albumin to furosemide with placebo. The albumin group had better outcomes in terms of oxygenation and hemodynamic stability. The use of albumin was associated with less shock, the need for fewer fluid boluses, and consequently better ability to maintain negative fluid balance.

Historically the controversy has centered around two related questions, one being whether it’s better to maintain positive or negative fluid balance in ARDS (the “wet vs. dry” debate) and the other issue being the use of albumin in general.

Evidence to date seems to favor the dry school (patients with negative fluid balance and who lost weight did better in this study and those who dropped their wedge pressure did better in this one). The level of evidence in these studies is somewhat low, and better answers await completion of FACTT, an ARDSnet sponsored study prospectively comparing wet and dry strategies. (The study also has arms comparing central venous catheter vs. pulmonary artery catheter monitoring).

The albumin controversy has an interesting history. Used indiscriminately in the past, it fell into disfavor after this meta-analysis of albumin use in a variety of critical illnesses including ARDS. Survival differences in this analysis were not significantly different but the point estimates suggested harm with albumin administration.

I can remember when it was popular to administer albumin with loop diuretics for ARDS based on little more than physiologic plausibility. People began to decry the use of albumin when evidence based medicine came on the scene. This study in Critical Care Medicine suggests an evidentiary basis for albumin, but the authors caution that more studies, looking at more meaningful outcomes, are needed. I look forward to knowing whether patients have fewer days of mechanical ventillation, shorter ICU stays and better survival.

Hormone replacement hype

A recent issue of The American Journal of Obstetrics and Gynecology reports that doctors have an inflated perception of the risks of hormone replacement therapy (HRT). The survey of Florida physicians found that primary care doctors were more likely to overestimate the risk than Ob-Gyns. The authors felt the respondents were confused between relative risk difference and absolute risk difference.

This is illustrated by data from the Women’s Health Initiative (WHI) study of estrogen and progesterone in which the relative risk numbers, when considered alone, exaggerate the perception of harm from HRT. This may have resulted in distorted media reporting of the study. For example, considering only the relative risks, there was a 29% increase in coronary heart disease events, a 26% increase in breast cancer, a 41% increase in stroke, and a doubling of pulmonary embolism. Unfortunately these figures are deceptive because they ignore the low baseline rate of events. Translated into absolute risk, HRT was associated with only 7 excess coronary heart disease events per 10,000 patient years, 8 more breast cancers, 8 more strokes, and 8 more PEs. These numbers represented the true magnitude of harm but seemed to be buried in the fine print of much of the popular reporting. An editorial in the same issue of JAMA cautioned against taking relative risk out of context, correctly pointing out that absolute risk data provided the true measure of effect. Although the editorial put the study in perspective it was given little notice in popular reporting.

Undue emphasis on relative risk difference is deceptive. Such emphasis can be used not only to exaggerate harm but also to inflate the apparent effectiveness of treatment, as is sometimes done in pharmaceutical company advertisements.

Why aren’t doctors more savvy about this issue? Maybe we should pay less attention to the popular news reports and concentrate more on the primary sources.

Constrictive pericarditis: the great mimicker

The July issue of the Journal of General Internal Medicine has a case report of constrictive pericarditis presenting as protein-losing enteropathy. This is one of many deceptive presentations of constrictive pericarditis which have been reported including liver disease, Budd Chiari Syndrome, refractory pleural effusions, chylous ascites, chylothorax, and lymphopenia with hypogammaglobulinemia. These unusual manifestations are, in one way or another, consequences of systemic venous hypertension.

Clinically, constrictive pericarditis looks a lot like restrictive cardiomyopathy. Differentiation between the two has been difficult, but is crucial, as constrictive pericarditis is surgically treatable if diagnosed early. Recent advances in echocardiography and cardiac doppler have improved the diagnostic approach which is outlined in this review. The distinction can be made with echo-doppler but it is operator dependent, requiring a focused approach with detailed attention to the respiratory cycle. This isn’t the type of information you’re likely to get from a routine echo report unless you tell the technician exactly what you’re looking for.

Beware of dementia bias

All other things being equal, patients with dementia who are admitted to the ICU do just as well as those without dementia according to this study in the June issue of Critical Care Medicine. A higher percentage of patients in the dementia group (46% vs. 11%) were from nursing homes.

Although there may be legitimate reasons to withhold ICU care in some demented patients (such as advance directives) we can’t base the decision on a presumption of poor clinical outcome.

Computers, evidence based medicine and the problem oriented medical record

After blogging about evidence based medicine (EBM) and the problem oriented medical record (POMR) recently I wondered what Lawrence Weed, originator of the POMR, had been up to lately. It turns out he founded Problem-Knowledge Couplers, the PKC Corporation. They have developed software for medical record keeping and decision support. Concerning EBM and the POMR I opined that we haven’t done a very good job at either. It looks like these folks are on to something that may help us do better at both. Here’s an article about Lawrence Weed in Healthcare Informatics.

Disclosure: I have no interest in PKC.

Watch for major changes in emergency cardiac care

Dr. Gordon Ewy and his group at the University of Arizona are quietly marshalling evidence that challenges the current practice of cardio-pulmonary resuscitation (CPR). One of their latest publications is found here in Circulation. The investigators reviewed resuscitation records of patients experiencing out of hospital cardiac arrest in greater Tucson. Standard automated external defibrillator (AED) protocols were used. This resulted in frequent interruption of chest compressions such that compressions were performed only 43% of the time during resuscitation efforts. Initial defibrillation attempts did not restore perfusing rhythm is any patients, and survival was no better than their historical control.

What is the clinical importance of these observations? Over time following the onset of ventricular fibrillation (VF) myocardial ATP rapidly depletes. The result is that rapidly over time the relative effectiveness of electrical defibrillation diminishes in comparison to chest compressions as the initial modality of treatment, culminating in unresponsiveness to defibrillation unless reperfusion via adequate chest compression (and consequent repletion of myocardial ATP) is accomplished first. [1]

This has lead to the concept of the three phases of CPR: the electrical, the hemodynamic and the metabolic phases. These phases correspond to time periods of roughly 0-5 minutes, 5-10 minutes, and longer, respectively. During the electrical phase initial defibrillation is the most important. That’s in keeping with popular teaching. However, during the hemodynamic phase compression becomes the most important initial intervention, because by that time there is little hope that defibrillation will restore spontaneous circulation unless there is pre-treatment with chest compression to replete myocardial energy stores. The hemodynamic phase is the one often encountered by responders to out of hospital cardiac arrest. (The metabolic phase, during which measures to decrease brain metabolism such as therapeutic hypothermia are of importance, will not be discussed here).

The Arizona group has also demonstrated that current practices of rescue breathing may compromise myocardial perfusion due to delays and interruptions in chest compression . This and related evidence, coupled with survey data indicating reluctance of bystanders to perform mouth to mouth rescue breathing has lead these researchers to teach continuous compression CPR to the public and institute local fire department protocol changes in Tucson.

Although the American Heart Association (AHA) and International Liaison Committee on Resuscitation (ILCOR) strive to be evidence based and tend to await high level evidence before recommending changes in emergency cardiac care, expect the following or some semblance thereof to show up eventually in the recommendations: 1) The lay public will be taught compression only CPR; 2) the initial modality for emergency personnel responding to out of hospital cardiac arrest, unless compressions are already in progress, will be a prolonged and continuous series of compressions before defibrillation is attempted.

CAVEATS:

1) For witnessed VT or VF in the health care setting immediate defibrillation remains the initial modality (remember the electrical phase!).

2) This new thinking does NOT apply to pediatric codes or other arrests of suspected respiratory origin. Rescue breathing remains a higher priority in those situations.

Xigris in perspective

The ADDRESS trial of activated protein C (Xigris) was just published in NEJM. Though it was touted in the press as a breaking development it was really nothing new. Maybe September 28 was a slow news day in healthcare. I wouldn’t have bothered posting it here, but now that it’s been hyped some perspective is needed.

ADDRESS is old hat not only because it was announced months ago but also because it merely confirms what we already knew from a subset analysis of the earlier PROWESS trial: that the optimal use of Xigris is exactly according to the way FDA has labeled it and the company (Eli Lilly) has promoted it all along. Specifically, it is indicated as an adjunct to antibiotics and general supportive care in patients with severe sepsis who have an APACHE-2 score of at least 25.

FDA approval of Xigris was based on PROWESS, analysis of which revealed that the benefits of Xigris were confined to the subset of patients with the higher APACHE-2 scores. The FDA restricted its approval to this group of patients and then required Lilly to conduct a randomized controlled trial (ADDRESS) to specifically assess those patients with lower scores. As anticipated from PROWESS, ADDRESS found no overall survival difference. Although there was no overall difference a trend toward increased mortality with Xigris was seen in patients with recent surgery, as had previously been gleaned from PROWESS in the lower risk patients. Increased mortality was also observed with Xigris in the subset of patients who were the first enrollees at their respective research sites, suggesting a learning curve with the drug, and highlighting the importance of experience. This finding bolsters the suggestion of some that the use of Xigris be restricted to intensivists or other designated specialists.

Unfortunately the study was somewhat hyped in the press. Xigris looked like a flop in some reports and like poison in others, not to mention that most of the news reports were just plain confusing.

Finally: Clinical outcome-based data in favor of thiazolidinediones

On September 12 at the 41st European Association for the Study of Diabetes meeting the results of the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) were announced. As reported by Medscape the study of over 5000 type 2 diabetic patients showed a decrease in macrovascular complications in patients treated with pioglitazone (Actose). The 10% relative risk reduction for the primary composite endpoint of seven macrovascular events did not reach statistical significance. However for the composite of stroke, MI and death the 16% reduction was statistically significant.

Other findings included a highly statistically significant >50% reduction in patients needing to add long term insulin. In addition to a significant fall in HbA1C the pioglitazone group experienced a statistically significant rise in HDL and fall in triglyceride levels confirming a beneficial effect on the “metabolic syndrome”, the principal dyslipidemia of type 2 diabetes. No new safety concerns were noted in the study.

This is a significant advance because it has previously been difficult to demonstrate a beneficial effect on macrovascular disease with insulin or oral agents, with the exception of metformin. Pioglitazone and rosiglitazone were reviewed last year in NEJM.

Now will the Public Citizen Health Research Group finally remove Actose from its black list?