Friday, April 13, 2007

A Dire Warning Arrives in the Mail: Evidence or Pseudoevidence?

I get all sorts of letters, but this one was striking. It was in an envelope from /alert Marketing, a company which promises to "target physicians by therapy area or by specialty with the #1 rated M.D./alert mail programs." In the envelope was a "dear healthcare provider" letter from one Dan MacDonald, VP for managed healthcare operations from Forest Pharmaceuticals. The letter contained this dire warning:
certain managed care organizations have instituted initiatives attempting to switch patients from Lexapro .. to a generic SSRI, including citalopram. However, well-controlled Lexapro patients should not be switched, unless switched for a medical circumstance..

Then, in a black box, it stated (the bold font was in the original):

The clinical profile of Lexapro and citalopram are distinct, as illustrated by the following:

- Lexapro is effective in the treatment of major depressive disorder (MD) and generalized anxiety disorder (GAD). In contrast, citalopram is not indicated for GAD, or for any other anxiety disorder. [citations were two the respective drug labels.]

- There is clinical evidence for the greater efficacy of Lexapro vs. Celexa

- In a prospective, randomized double-blind trial in MDD patients, Lexapro 20 mg/day was significantly superior to Celexa 40 mg/day in both response (p<0.01)>

- In a pooled analysis of three randomized, double-blind comparison trials, Lexapro 10-20 mg/day led to significantly greater improvement in MADRS scores of severely depressed patients then citalopram 20-40 mg/day at endpoint.(4)

- In the overall population (moderately to severely depressed patients) in the pooled analysis of these same three trials, Lexapro 10-20 mg/day showed a significant improvement in MADRS vs placebo at week 1, whereas citalopram was not significantly different from placebo until week 6.(4)

There is currently no generic equivalent for Lexapro.

And there it was, the dread managed care companies were trying to bludgeon us poor "healthcare providers" into switching patients to less effective medicine. And the warning was in a black box.

Of course, I have not always been a big fan of how many managed care companies have operated. (See, for example, this post.)

But is it really so bad to switch a patient from escitalopram (Lexapro) to citalopram? Let's have a look at the evidence.

First, it is true that citalopram does not have an indication for generalized anxiety disorder. But that is because Forest Pharmaceuticals did not go to the effort to try to secure one before its patent ran out.

Let us then look at References 3 and 4:
3. Moore N, Verdoux H, Fantino B. Prospective, multicentre, randomized double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. Int Clin Psychopharmacol 2005; 20: 131-137.
4. Gorman JM, Korotzer A, Su G. Efficacy comparison of escitalorpram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. CNS Spectrums 2002; 7(suppl 1): 40-44.

Reference 3 turns out to be a short-term (8 week) trial. Thus the importance of its results are questionable because treating major depression usually involves treatment for considerably longer than 8 weeks. It showed at best a two-point difference on the 60 point MADRS scale in favor of escitalopram, which does not suggest much of an advantage to this non-psychiatrist.

Reference 4 was a pooled analysis. It turns out it was the main focus of a 2004 article which assessed claims of the superiority of escitalopram over citalopram in Sweden. [ Svensson S, Mansfield PR. Escitalopram: superior to citalopram or a chiral chimera? Psychother Psychosom 2004: 73: 10-16.]

The main points made by Svensson and Mansfield were that:
  • Most chiral drugs (like escitalopram) have not proven superior to the racemic mixtures from which they were derived (like citalopram).
  • Escitalopram (Cipralex in Sweden) was heavily promoted by H Lundbeck A/S, its Swedish manufacturer as its patent on citalopram (Cipramil in Sweden) was ready to run out.
  • "The advertisements published so far do not claim less adverse effects but do claim superior efficacy. These efficiacy cliams, however, are not supported by evaluations from the Swedish MPA [Medical Products Agency] and the Institute for Rational Pharmacotherapy (IRP) attached to the Danish Medicines Agency."
  • All the trials and the pooled analysis were sponsored by Lundbeck
  • In the best single analysis from the study by Gorman et al, a pooled analysis most compatible with the intention-to-treat principle, comparing the change in MADRS scores at 8 weeks, there were no significant differences between escitalopram and citalopram.

Thus the claims made in the letter sent to me above based on the study by Gorman et al apparently referred to an analysis that was less compatible with the intention-to-treat principle, or to the one-week results. The intention-to-treat principle is that patients should be analyzed in the groups to which they were initially assigned, even if they drop out of the study. Failing to follow this principle risks biasing the results, since patients who drop out may do so because they did not get good results with the study drug. The one-week results mean little, since, again, depression usually is a problem that lasts much longer than one week.

So in summary the dire warnings sent to many "healthcare providers" about switching from Lexapro to citalopram do not appear to be based on very strong evidence. In fact, it puts enough of a spin on the existing evidence to qualify as an example of pseudoevidence (see post here). But physicians and other health care professionals receive lots of letters, and few have the time to analyze the claims made in each one. However, the pharmaceutical (and biotechnology and device) companies and their marketing and "medical education" company partners appear to have huge resources to devote to spinning the evidence into pseudoevidence to support their products.

If only there were equal resources devoted to a truly evidence-based approach to the relevant clinical research.

Meanwhile, fellow "healthcare providers," be very skeptical of dire but self-serving warnings from pharmaceutical/ biotechnology/ device companies and their marketing and "medical education" allies.

1 comment:

Paul said...

As a long term patient, I've come to take a broad, almost presidential perspective on these matters.

My motto is that managed care and the drug companies are workin' hard for nothing but the betterment of the human condition.