The Story & The Study

Reading the 6 September 2007 Medication Noncompliance blog entry, Pfizer Funded Study Says: Don’t Stop Taking Your Lipitor!,¹ alerted me to an intriguing Pfizer-sponsored statin research project and the presentation of its findings carried in multiple print and internet outlets.

Points of Intrigue

What is there, one might ask, about this study of statins that could be called intriguing?

Well, one intriguing point is that the first dozen or so articles on a Google search for “Pfizer,” “Lipitor,” and “simvastatin” referencing this study contain almost identical text taken from a press release put out by Pfizer - which may explain why Reuters, the first source I found after reading the Medication Noncompliance post, published the article under the title, Patients Who Switched from Established Lipitor Therapy to Simvastatin Experienced a Significant 30 Percent Increase in Relative Risk of Cardiovascular Events or Death, New Observational Study Shows, a rather longish headline that nonetheless effectively conveys the pro-Pfizer interpretation of the results conveniently uncluttered by any messy details and disclaimers.

A second intriguing point is that, although the study would certainly be categorized as medical research, was presented at the European Society of Cardiology Congress, and is to be published in The British Journal of Cardiology, most of these outlets carrying news of the study positioned it in the investment and business divisions of their web sites, as indicated by the domain and subdomain names of the pertinent URLs assigned to the articles, including, among others, biz.yahoo.com, money.cnn.com, www.forbes.com, finance.google.com, today.reuters.com/stocks, news.moneycentral.msn.com/ticker, www.quote.com. The story also received considerable play in the newsletters and sites covering the pharmaceutical industry (e.g., Drug Industry Daily and Pharmaceutical Business Review). Reportage of the study at clinically oriented sites (e.g., WebMD - which did not quote extensively from the press release) was notably less extensive.

Clearly, there is nothing illegitimate about a consideration of the business implications of medical research findings (or, for that matter, distributing press releases on the occasion of favorable news for the sending entity); I only suggest that garnering an understanding of this study and others like it might be abetted if its commercial aspect and its marketing spin are taken into account.

The clinical and marketing motivations for the study almost assuredly originate from the ramifications of the same historical event: Zocor, the branded version of simvastatin, a statin found to have been an effective agent albeit one somewhat less powerful than Lipitor, lost its patent protection in June 2006. Consequently, the price of this medication dropped significantly, causing a significant fraction of Lipitor users to change their medication to generic simvastatin, a shift encouraged and called for by certain third party payers, physicians, and patients themselves.

Pfizer, unsurprisingly, has questioned the clinical wisdom of patients migrating from their product, Lipitor, to a generic drug.² For a congruent but more fiscally eloquent explanation, consider this excerpt from Fighting the Generics Next Door published 7 September 2007 at The Motley Fool:

“Observational study” means the researchers reviewed records of patients who in the past took Lipitor, some of whom switched to simvastatin. Retrospective studies of this sort typically lack certain desirable qualities of prospective studies, such as randomization of patients, control of variables, and complete pertinent information. In this study, as the report notes, “Reasons for why treatment was discontinued were not available from the database, Pfizer indicated, adding that reasons for switching from one drug to the other were also not available. Furthermore, Pfizer explained that patients in the study were not randomised to each arm, which limits the significance of the findings.”

The non-randomized sample means that the two comparison groups, Lipitor-Continuers and Lipitor-Switchers, were not necessarily comparable. One detail , for example, from the poster session that didn’t make its way into the press release is that, as reported in Cholesterol Drug Change May Be Risky, “as a group, the patients who remained on Lipitor also took more heart medications and had better cholesterol control to begin with than the patients who switched to simvastatin,” a fact that could go far to explain the difference in outcomes.

The Patient Compliance Angle

The significance of the conclusions was especially limited for me since my personal interest in this study arose from a secondary finding:

Without knowing why the treatments were discontinued or why the patients were switched, this finding is interesting in a “how about that?” sort of way, but almost worthless for generating hypotheses or useful clinical practices.

Possible reasons for the higher noncompliance rates among the patients who switched medications are easy and fun to generate; how about these three for starters:

1. Patients switched because of the cost of medication. Those same patients who switched from Lipitor might well have been those individuals most likely to discontinue medication altogether for financial reasons - even though if the cost of simvastatin were relatively less than that of Lipitor.³
2. Patients switched because of side-effects of Lipitor. Those same patients might well have proved more vulnerable or less able to tolerate side-effects of other statins as well, including simvastatin.
3. Patients switched because of unresponsiveness to Lipitor. The departure of these patients from the Lipitor-taking group would immediately improve the outcome statistics of that category of patients by eliminating their negative results. Moreover, they could well have been more likely to be unresponsive to any statin and thus increase the apparent cardiovascular risk of the “Switched To Simvastatin” group.

Also, while the number of patients who discontinued treatment altogether is given, the actual compliance rates of those who continued treatment with either drug isn’t provided. (In other words, it isn’t known how many patients who continued to be enrolled in treatment with Lipitor, for example, actually took clinically effective doses of that medication, how many took the medication erratically, and how many professed to be taking the medicine but, in fact, were taking none.) Consequently, the effectiveness or ineffectiveness of taking adequate doses of Lipitor and simvastatin is impossible to calculate with confidence.

The Lipitor Challenge

If the study’s design is a researcher’s nightmare, it is a marketer’s delight.

Remember the “Pepsi Challenge” ads that showed blind tastings of Pepsi and Coke by cola drinkers with a stated preference for Coca-Cola? The design of that survey virtually guaranteed a good outcome for Pepsi - if even 10% of those tested, a number probably within the statistical error of the study, had chosen Pepsi, it would have been a triumph for that brand since those were ostensibly hard-core Coke drinkers.

The design of the “Stayed With Lipitor Vs Switched To Simvastatin” study similarly stacks the odds in favor of Lipitor. For one thing, it’s generally acknowledged that Lipitor is more effective than simvastatin; the question is whether the difference justifies the higher cost. So, from the outset, it was clear patients on Lipitor should have had better outcomes. It also seems likely that those patients who remained on Lipitor rather than switching were responding adequately or at least their doctors saw no benefit in moving them to a different drug. As suggested before, patients who switched from Lipitor might well be more likely noncompliant with, vulnerable to side-effects of, or unresponsive to other statins.

But the real clinker to those who don’t follow statin clinical research may be the consensus of earlier studies that discontinuation of any statin increases cardiovascular risk.

For example, New evidence links discontinuation of statin therapy to increased death rates in stroke survivors reports on a study in Stroke: Journal of the American Heart Association that demonstrated that “patients who stop taking cholesterol-lowering drugs within a year of surviving a stroke had a two-fold increased risk of death.”

And Statin Withdrawal Hard on the Heart - Discontinuing Statins Can Lead to Rapid Rise in Cholesterol and C-Reactive Protein notes

So, there would seem to be a reasonable chance that if Merck & Co had sponsored research looking at patients who switched from Zocor (assuming Zocor were still under patent - and incredibly profitable) to a generic form of Lipitor (or any other statin), the headline could have been “Patients Who Switched from Established Zocor Therapy to Atorvastatin Experienced a Significant X Percent Increase in Relative Risk of Cardiovascular Events or Death, New Observational Study Shows.”

Now, that would be an intriguing study, eh?

Conclusions

Maybe there is something especially catastrophic about shifting from Lipitor to simvastatin - or maybe not. In any case, nothing in this research proves either side of the debate. The findings do seem in line with the concept that discontinuing statins places patients at much higher cardiovascular risk, which is helpful but hardly groundbreaking.

The most useful lesson from this study may well be the reminder that certain medical research projects may have as much to do with market share as with morbidity and mortality.

Footnotes

1. I view the take on this study espoused in the Medication Noncompliance post reasonable, informative, and, as always, interesting, but, on the whole, lacking in the kind of embittered cynicism characteristic of the AlignMap perspective. Welcome to the Dark Side. [back]
2. I am not the originator of this concept; The New York Times, for example, in its October 15, 2005 article, Lipitor or Generic? Billion-Dollar Battle Looms, predicted this sort of thing almost a year before Zocor’s patent protection expired. [back]
3. While relative cost of these medications is now a primary issue, this is an unlikely cause of switching in this study, given that the observational period was from October 1997 to June 2005, a period during which Zocor was still under patent and, presumably, did not cost markedly less than Lipitor. [back]

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