Category Archives: medico-legal

Vioxx and the 140,000 MI’s

As I previously noted here, a study by Graham et al, examining the cardiovascular risks of Vioxx, was being considered for publication in the Lancet when it was prematurely published on the FDA’s website, much to the Lancet’s dismay. Today, that same study, with some modifications, has been published online at the Lancet. It is being widely quoted in the press, particularly the assertion that Vioxx is shown to be responsible for 88,000 to 140,000 excess cases of serious coronary heart disease in the United States between 1999 and 2004. Let us take a closer look at this assertion.

The study itself is from Kaiser Permanente. It is a nested case-control study of 1,394,764 persons who were exposed to various NSAIDs between 1999 and 2001. The subset of patients who had myocardial infarction or sudden death from coronary disease were identified and constituted the cases. They were each matched to 4 controls from the overall group (matched for age, sex and health-plan region). In the Lancet study published today, the various types of NSAIDS were then evaluated for the odds-ratio of coronary events compared with remote use of NSAIDS (basically similar to non-users) and compared with celecoxib. This study found that Vioxx users had an increased risk of coronary events of 1.34 compared to remote users, and 1.5 compared to current users of celecoxib. This risk increase was particularly significant for high dose Vioxx (3.00 compared to remote users and 3.58 compared with celecoxib users).

Apart from the the usual caveats that apply to non-randomized cohort studies, I don’t have much of a problem with this part of the study. It becomes more interesting when the excess morbidity from Vioxx is considered.

In the original report published on November 2 at the FDA’s website, the authors state in their discussion:

High-dose rofecoxib conferred a 3.7-fold increase in risk and standard-dose a 1.5-fold increase compared with celecoxib, the most frequently prescribed COX-2 selective agent… From 1999 to 2003, there were an estimated 92,791,000 prescriptions for rofecoxib, of which 17.6% were high-dose. Combining this with data on mean prescription length, we estimate that the increased rofecoxib risk observed in this study would yield an excess of 27,785 cases of AMI and SCD in the US over the years 1999-2003, with 53.4% due to standard-dose use.

Now compare this statement, which estimated an excess of 27,785 cases of AMI and SCD, with the following statement in the conclusion of today’s Lancet paper:

From 1999 to September, 2004, an estimated 106.7 million rofecoxib prescriptions were dispensed in the USA, of which 17.6% were high-dose. In two Merck-sponsored randomised clinical trials relative risks for acute myocardial infarction of 5 for high-dose rofecoxib and 2 for the standard dose were recorded. The background rate for acute myocardial infarction among control groups from studies of cardiovascular risk in NSAID users varied from 7.9 per 1000 person-years in CLASS to 12.4 per 1000 person-years in TennCare. Using the relative risks from the abovementioned randomised clinical trials and the background rates seen in NSAID risk studies, an estimated 88,000–140,000 excess cases of serious coronary heart disease probably occurred in the USA over the market-life of rofecoxib.

Note that here, the authors use relative risks for MI of 5 and 2 for their calculations, which they did not derive from their own data but rather from two trials that have nothing to do with their study. They then use these numbers to come up with estimates of excess cases of serious coronary disease between 88,000 and 140,000, rather than the 27,785 from their original analysis (the slight increase in prescriptions used in the calculations only accounts for a small fraction of the difference).

It is very possible that the latter numbers more accurately reflect the truth than the former ones. And I am quite convinced of the excessive cardiovascular risk of Vioxx. Nevertheless, it seems disingenuous, at best, to publish a large trial whose primary purpose is to estimate the cardiovascular risk from Vioxx, and then, in the conclusion, calculate the number of patients harmed using risk estimates from totally different studies, without even mentioning that this is what is being done. And, of course, the number 140,000 is what gets picked up.

Politics, politics.

Six articles on postmarketing drug surveillance from JAMA

The pharmaceutical industry and the FDA are being battered by testimony and discussion in the wake of Vioxx. Presumably this will soon die down: news stories appear, flare up and soon fizzle out when their energy (and the public’s interest) is spent. For now, however, the drug surveillance story is still burning bright. David Graham, the gaunt FDA whistle-blower, is enjoying his Warholian fifteen minutes of fame. And this week’s online edition of JAMA pre-publishes six pieces that will appear in next week’s print edition. These articles are about Baycol (cerivastatin), a drug no longer in the news but relevant to the topic. Very briefly summarized:

  • The FDA’s Graham et al examine the incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs, an inception cohort study of 252,460 patients treated with various statins and fibrates between 1998 and 2001. The number of patients needed to treat for one year to produce one case of severe rhabdomyolysis was roughly 23,000 for monotherapy with atorvastatin, pravastatin or simvastatin; 3500 for monotherapy with a fibrate, 2000 for monotherapy with cerivastatin, 1500 for fibrate plus a statin other than cerivastatin and only about 10 for fibrate plus cerivastatin.
  • Psaty et al discuss the potential for conflict of interest in the evaluation of suspected adverse drug reactions. They discuss the FDA’s regulatory process, noting that: “…the proportion of new molecular entities that are first introduced in the United States has increased from 2-3 % in the early 1980s to 60% in 1998” and “in contrast to the highly structured premarketing evaluation, postmarketing surveillance has little structure” (and is underfunded).
    They describe the information that was publicly available on Baycol, mainly from SADR’s, and contrast this with the information that was available to Bayer but not to the public (which they derive from litigation documents, in which they were expert witnesses for the plaintiffs). They suggest that there was information posessed by the company which should have been made public, but which represented a conflict of interest for Bayer.
    The authors argue that, given the speed with which new agents enter the market, the public is at increased risk due to the lack of resources available for post-marketing surveillance and the conflict of interest inherent in the pharmaceutical companies’ positition. This should be dealt with by strengthening the post-marketing surveillance structures and possibly creating an independent agency to deal with this.
  • Pierkowski responds to this article on behalf of Bayer, emphasizing that Psaty et al were expert witnesses against Bayer. He argues that both the FDA and Bayer took appropriate actions at the appropriate times.
  • Psaty et al then respond to Pierkowski’s points, arguing that whether or not Bayer took appropriate action is less important than whether or not the post-marketing system needs to be dramatically improved.
    “While Piorkowski, as an attorney representing Bayer, properly defends some of the company’s specific actions, the purpose of our article was to raise an important public health issue. For us, the cerivastatin-rhabdomyolysis case report served as an illustration. We were primarily concerned to demonstrate how the current postmarketing surveillance system and the current FDA regulations may not, under certain circumstances, be adequate to protect the health of the public.”
  • Strom reviews the whole post-marketing surveillance system. His manuscript was submitted to JAMA by Bayer. He notes that much data is supplied by the SADR system, but the data itself is, necessarily, of limited quality and must be considered hypothesis generating. It needs to be followed up by appropriate hypothesis testing, which is where the system can and should be improved. He believes that, from a regulatory standpoint, the FDA is up to the task if given the appropriate resources. From a scientific standpoint, other organizations (such as the publicly funded Centers for Education and Research in Therapeutics) need to be developed and strengthened in order to analyze and respond to hypotheses generated from the SADR’s. This cannot be left up to the pharmaceutical industry, given its inherent conflict of interest.
  • Finally, in an excellent editorial, JAMA editors Fontanarosa, Rennie and DeAngelis sum it all up nicely. If you only read one of the six articles, I would suggest reading this one. The authors provide the background to the articles published in this issue, and make several suggestions, including decoupling the drug-approval and post-marketing surveillance processes, since “it is unreasonable to expect that the same agency that was responsible for approval of drug licensing and labeling would also be committed to actively seek evidence to prove itself wrong”. They conclude:
    “The postmarketing surveillance system requires a long overdue major restructuring. Until that occurs—as indicated by the articles in this issue of JAMA, as epitomized by recent evidence of serious harms from widely used and heavily promoted medications, as demonstrated by the influence of industry over postmarketing data, and as illustrated by the lengths to which some manufacturers will go to protect their interests—the United States will still be far short of having an effective, vigilant, and trustworthy system of postmarketing surveillance to protect the public.”

That being the case, what is the practitioner to do? Assuming that there will continue to be delays before adverse drug effects are discovered and publicized, prudence before prescribing the latest “hot” drugs seems warranted, more than ever. About a year ago, the pharmaceutical rep promoting one of the newer statins asked me when I would be comfortable prescribing this particular medication. I said I would wait at least a year. Now that same representative is reminding me that it’s been a year. I’m still not ready.

A new patent for an old drug in a new population

In a much discussed (see Kevin MD and Medical rants) study presented at the AHA meetings in New Orleans and just being published in this week’s NEJM, a fixed dose combination of hydralazine and isosorbide dinitrate, BiDil, was found to significantly reduce morbidity and mortality in African American patients with congestive heart failure. BiDil (vs placebo) was added to standard therapy for CHF (including ACE inhibitors or ARB’s, aldactone and beta-blockers). The trial was halted early because of significant benefit of the active medication.

This trial is being actively discussed because it seems to be the first time that a drug is being promoted specifically for use in a racial group. Another aspect of this study which I find fascinating is its financial genesis. My understanding of the course of events is as follows.

Isosorbide dinitrate and hydralazine have been used for the treatment of heart failure in the past. The isosorbide-hydralazine combination pill was patented (in the 1980’s) for the treatment of congestive heart failure, but failed to provide significant benefits in large trials; as a result, the FDA would not approve it as a new medication. Subgroup analysis of the original trials, however, suggested benefit in black patients. The company NitroMed, which had acquired the rights to the combination, then applied for and received a new patent for it specifically for the treatment of heart failure in black patients. Unlike the original patent, which expires in 2007, the new one for the same medication is valid until 2020. Armed with this new patent, NitroMed sponsored the current trial. With the positive results just reported, the FDA is likely to approve BiDil for use in black patients.

My initial reaction to this whole story was that it represents a typical interaction between industry, the patent system and the FDA. There is a one-two punch with the patent system prolonging the drug company’s monopoly by granting a new patent for use in a subpopulation, which the FDA then protects by limiting approval of the medication to that subpopulation.

The other side of this coin, however, is that precisely this system led to a potential profit for NitroMed, which made sponsoring the trial financially attractive. The result is likely to be of benefit to many African Americans. A prime example of the strengths and problems with the pharmaceutical industry’s ties to regulatory agencies.

Medical decision-making competence

This week’s Lancet contains a study by Raymont et al investigating the prevalence of mental incapacity in medical inpatients and associated risk factors (see also this item in Shrinkette’s blog ).

In order to judge medical decision-making competence, the authors used two tools: the MacArthur competence assessment tool for treatment (MacCAT-T), and clinical vignettes (based on something called the “Thinking Rationally About Treatment” research method).

After excluding 143 patients for severe cognitive impairment, altered level of consciousness and refusal to participate, 159 patients were interviewed. Of these, 50 (31%) were deemed lacking in capacity to make medical decisions.

Lack of capacity was correlated with increasing age and with a poor score on the Mini Mental Status Exam. The median MMSE score was 29 (out of a maximum of 30) in patients with capacity and 22 in those without capacity.

Significantly, when the clinical team caring for the patients and close relatives were asked to judge the patients’ capacity, those with capacity were correctly assessed almost 100% of the time, but those deemed lacking in capacity by the authors were judged incompetent only 25% of the time by the physicians and similarly by the relatives.

The conclusion to the abstract: “Mental incapacity is common in acutely ill medical inpatients, and clinicians tend not to recognise it. Screening methods for cognitive impairment could be useful in detecting those with doubtful capacity to consent”.
Are we really underestimating patients’ decision-making capacity as badly as this article suggests? Possibly, but I have a few reservations about the study.

The MacCAT-T tool used to assess medical decision-making capacity is a relatively new one. How valid is it? If three-quarters of physicians caring for the patients and three quarters of their relatives judged the patients who “failed” the MacCAT-T assessment to be competent, it makes me wonder as much about the validity of the tool as about the physicians’ and relatives’ assessments.

According to the authors:

MacCAT-T is a semi-structured interview that measures: (1) understanding of the disorder and its treatment, including associated benefits and risks; (2) appreciation of the disorder and its treatment–ie, how the patient understands they could be specifically affected, which usually entails some level of insight; (3) reasoning, which assesses the processes behind the decision and ability to compare alternatives in view of their consequences; and (4) the ability to express a choice.

I am no expert in such assessment tools, but it seems to me that this sort of assessment might bias, for example, against people who have crackpot medical ideas. Are they necessarily incompetent?

Since the assessment of medical competence correlated well with the MMSE assessment in this study, wouldn’t we be better off relying on the MMSE itself, which is not limited to medical decision making capacity? The determination of a patient’s specific competence to make medical decisions seems somehow more paternalistic and prone to bias than a more general assessment of mental status.