Sunday, July 31, 2005

Detailing, samples, prescribing, and outcomes

Kevin MD and Blogborygmi cited this article about the influence of drug sampling on residents’ prescribing behavior. There have been numerous articles of this sort, showing various effects of detailing and sampling by pharmaceutical companies, and considerable controversy has been fueled. Many of the citations have been compiled at No Free Lunch and Healthy Skepticism, organizations which are critical of pharmaceutical industry marketing. Some would like to see marketing disappear as we now know it, and are calling on physicians to refuse to accept literature or even small gifts from drug sales representatives. Others would reduce or curtail the pharmaceutical industry’s support of physician CME.

Most all the critics cite the studies as evidence to back up their recommendation to drastically change the landscape of drug company promotion. But is this evidence strong enough to warrant such a recommendation? Check the above web sites, link to the articles and decide for yourself. At the risk of oversimplification the gist of the studies is that physicians’ prescribing behavior is influenced by pharmaceutical industry promotion. That is, marketing works. Some of the studies suggest that the promotions even influence doctors to prescribe outside established guidelines.

But as I browse this extensive collection of links I discover a weakness. I can not find one study about patient outcomes. Only the surrogate endpoints are examined. So, we can learn a lot from these studies about the effect of marketing on doctors’ attitudes and prescribing behaviors, and it’s all very interesting---indeed fascinating---but what about the clinical bottom line? Unfortunately, research to date provides no answers.

Our adventure in evidence-based medicine has taught us about the hazard of reliance on surrogate endpoints. In the 1970s we knew that surrogate hemodynamic endpoints in heart failure were adversely affected by beta blockade, and were taught that beta blockers were bad for heart failure. Only after years of outcome based studies did we realize we were wrong. We also knew that ventricular arrhythmias were harmful, and that since the surrogate endpoint of frequency of ventricular arrhythmias could be decreased by treatment with Class I-C antiarrhythmic drugs, such treatment must be a good thing. Not until completion of the first adequately powered outcome based study, CAST, did we know how tragic such thinking was.

So while the science concerning the effect of drug company promotion is soft, many observers still think the impact on patient outcomes is negative. Although promotions are certainly biased and the material can be deceptive, the information doctors receive is a mixture of good and bad. Must we assume that the bad influence outweighs the good, or is the reverse equally plausible? We must resist simplistic assumptions. Out in the real world varied and sometimes opposing factors are at play. For example, although Vioxx was heavily promoted and associated with harm there are other examples in which drug companies promote numerous beneficial therapies that are evidence-based and known to be under-utilized such as beta blockers and ACE inhibitors for heart failure and low molecular weight heparins for deep vein thrombosis prophylaxis [1] [2] [3]. [4] [5] [6] [7] Who knows how it all balances out?

I don’t rely on drug reps or promotional material to keep current, nor should anyone. There’s no need. Present day information technology makes it unnecessary. We can easily get good quality unbiased information at the point of care. However, a sweeping prohibition against drug reps, samples and industry supported CME is not supported by high level evidence. The jury is still out.

Thursday, July 28, 2005

Patient participation in medical decisions: Is it evidence-based?

Yesterday DB of DB’s Medical Rants blogged about patients participating in treatment decisions, citing this article in the Journal of General Internal Medicine. Interestingly, the study found that about half of patients surveyed would rather the physician make final decisions. He makes the point, and I agree, that we should allow patients to be involved to the extent they wish. But I would caution that unless we apply rigorous principles of evidence-based medicine to the discussion with the patient, the decision making process becomes flawed. So if patients’ decisions need to be evidence-based just as doctors’ decisions do how do we bring that about? Is there enough time in our busy practices to do it?

Consider these case examples. You are counselling your patient about upcoming knee replacement. You plan to give enoxeparin for DVT prophylaxis. How do you inform the patient? Sure, you know that it’s the right thing to do and all the experts recommend it, but the patient deserves evidence. So, you do a Pub Med search (or, somewhat more easily, consult a filtered resource such as Up To Date) and cull out the studies you critically appraise as valid and applicable to your patient. In order to advise your patient on the magnitude of benefit of the proposed treatment you look for, or calculate the absolute risk reduction (ARR) for the proposed treatment as well as the absolute risk increase (ARI) for bleeding. In order to translate this into language the patient can understand you then, from the absolute risk reduction for DVT and the absolute risk increase for bleeding, calculate the number needed to treat (NNT) and number needed to harm (NNH) respectively. You then have the discussion with the patient, modifying it as necessary to take into account any unique attributes of your patient which might increase bleeding risk. If the patient is to be discharged early after the surgery you must also provide information concerning the cost of continued enoxeparin at home, taking into account the patient’s financial condition and payer sources. Then you ask the patient and any concerned family members if they have questions, answer them as they arise, and document your discussion in the medical record. Time consuming, eh?

Of course if this is not your first patient to receive enoxeparin for orthopedic prophylaxis maybe you’ve done the drill before, but the discussion still takes a lot of time. And your next patient may present a clinical problem you haven’t researched in the last couple of months. Let’s say you’re discharging a patient after an acute coronary syndrome (ACS). You want to put the patient on a statin drug because you know it’s a good thing to do and you are going to explain it to the patient. To merely say “this is good for you” or “here, take this pill because it will decrease your risk of another heart attack” might sound paternalistic in this day of medical consumerism. So, again, you must present the patient with evidence. You do the search and find a raft of studies, from which you choose the ones of the highest level of evidence and applicability to your patient. As you critically appraise the studies you ask how the study in question applies to your patient. How do the lipid entry criteria and average lipid levels of the study patients match up with your patient’s lipid results? What is the number needed to treat and the number needed to harm (your patient tells you a friend of hers heard that cholesterol lowering medications could destroy the kidneys)?

Your next patient arrives from the nursing home with severe sepsis. As multiple concerned family members attend the patient and ask numerous questions you are considering whether to give activated protein C. You are aware of the positive results of the PROWESS study, but are concerned about the risks of serious bleeding. You are aware of the strict and very detailed inclusion criteria for patient selection, and you’ve heard of some recent controversy that has arisen concerning the use of activated protein C, and you need to explain it all to the family. You are already behind schedule after the long discussion with your previous patient about statin drugs.

What’s a doctor to do? I have no pat answer. Our patients deserve to be included in decision making but if they participate they must have the high quality and specificity of information they need to make valid choices.

Wednesday, July 27, 2005

An under-appreciated cause of dilated cardiomyopathy

The current issue of Annals of Internal Medicine contains a paper highlighting the importance of familial dilated cardiomyopathy. In a series of “idiopathic” dilated cardiomyopathy (DCM) the investigators found evidence of DCM or subclinical abnormalities in left ventricular function in relatives of about one third of patients. Previous estimates have cited similar or even higher prevalence of familial etiology of DCM. This points out that familial DCM is a very important etiology of heart failure and may be the most common cause of idiopathic DCM.

In my experience, when we encounter a new case of DCM we do the standard work up to screen for valve disease, coronary disease, thyroid disease, hemochromatosis as well as toxins (particularly ethanol) and if that screen is negative we say “it must have been a viral myocarditis.” I always wonder if that diagnosis is correct. I have no doubt it exists but I think it tends to be overdiagnosed.

That raises the question of just how common viral myocarditis really is as a cause of DCM. Controversy surrounds the issue of how many patients actually have myocarditis, and how many cases of myocarditis are actually viral. This small series found a viral etiology in around 20% to 30% of DCM, all Coxsackie B.

So, what can we make of this? Here are some key points.
1) Familial cardiomyopathy is a common cause of DCM.
2) Familial DCM is important to recognize because family members may benefit from screening via electrocardiography and echocardiography.
3) Gene testing in DCM should be limited to specific (and infrequent) situations. This review of the genetics of cardiomyopathy discusses genetic testing and makes some useful practical points.
4) Viral myocarditis is a known cause of cardiomyopathy but its relative importance is controversial. The American College of Cardiology Guidelines state that myocardial biopsy is indicated only in unusual specific circumstances, and the guidelines do not recommend viral serologic testing.

Monday, July 25, 2005

The Hospitalist Movement

There was some blogging this weekend about the movement. Kevin MD linked an article from the Chicago Tribune about hospitalists. I found the article accurate except for its negative portrayal of patient acceptance of hospitalist care. “So if the system is so great, why don't patients appreciate it?” the author asks. Mainly anecdotes and a sampling of opinion back up the author’s negative assessment of patient satisfaction. At least some research evidence paints a brighter picture. Wachter’s textbook Hospital Medicine 2nd ed. p.4 cites two studies [1] [2] showing patient satisfaction with the hospitalist model to be no worse than that of the traditional primary care system.
Retired doc shared his impressions of the annual meeting of the Society of Hospital Medicine, (the national hospitalist organization), wondered if it’s largely about money, and drew some lively reader comments.

Disclosure: I’m a hospitalist enjoying the success of the movement.

Saturday, July 23, 2005

Doctors get bad grades in antithrombotics 101

In the July 11 issue of Archives of Internal Medicine is a survey from the National Anticoagulation Benchmark and Outcomes Report Steering Committee showing poor adherence to guidelines for antithrombotic therapies in a variety of clinical settings. Aspirin for myocardial infarction, warfarin for atrial fibrillation, treatment of venous thromboembolism (VTE) and prophylaxis for orthopedic procedures were evaluated.

Although practice patterns were found lacking in all areas one finding concerning treatment of VTE was particularly interesting. Almost half of patients with acute VTE had unfractionated or low molecular weight heparin discontinued too soon (before the INR was at least 2.0 for two consecutive days). As pointed out in the Archives article, the guidelines call for continuation of some form of heparin (unfractionated or low molecular weight) for at least four days AND until the INR is at least 2.0 for two consecutive days.

I suspect this failure of adherence is driven by pressure to discharge patients quickly and by a popular misconception that patients are adequately anticoagulated with warfarin as soon as the INR reaches 2.0. Such an approach is not only outside the guidelines but also pharmacologically irrational. The vitamin K dependent factors decay at different rates following the initiation of warfarin. Although factor VII, with the shortest half-life, is the major determinant of the INR the patient’s state of anticoagulation is determined by the other factors which have longer half lives. Put another way, when warfarin is initiated the initial rise in INR does not reflect anticoagulation of the patient. Worse yet, protein C, a vitamin K dependent anticoagulant has a short half-life similar to that of factor VII, thus rendering the patient hypercoagulable when the INR first rises. Here is a nice little review of the acute effects of warfarin from the Cleveland Clinic Journal of Medicine.

Atorvastatin in end stage renal disease

This week's New England Journal of Medicine reported a study of atorvastatin treatment for patients with type 2 diabetes undergoing hemodialysis. There was no difference from placebo in the primary composite endpoint, a relative risk of .82 for combined cardiac events, and a relative risk of 2.03 for fatal stroke. There was no difference in non-fatal stroke or all cause mortality.

The media are already hyping this study, citing the “surprising” findings and highlighting a “two fold increase in deadly stroke” due to the statin. So, let’s take a moment for a sober assessment.

The results are disappointing, but how surprising, really? The attributes of the study population suggest that the principal dyslipidemia was the metabolic syndrome, characterized by high triglycerides, low HDL, and presumably small dense LDL particles. (The mean pre-treatment LDL cholesterol was 126 and the mean triglyceride level was around 265). It has long been known that statins are of limited effectiveness in treating the metabolic syndrome. Multiple other atherogenic factors are known to be associated with end stage renal disease including hypercoagulability, elevated levels of lipoprotein (a), elevated homocysteine, elevated angiotensin II, and disturbances in calcium and phosphate metabolism. Such factors are not mitigated by statin treatment. We would not expect LDLC to be the principal player in the vast atherogenic milieu of ESRD.

The finding regarding fatal stroke is unexplained. The authors point out in the discussion section of the paper that it could be due to chance. True to form, the popular media have cited only the more sensational increase in relative risk. The actual absolute excess in stroke mortality, though not trivial, was somewhat less impressive (2%, number needed to harm 50).

An essential tenet of evidence-based medicine is critical appraisal the literature, something we don't usually find in the lay press.