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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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November 10, 2008

Crestor: Risks Up, Risks Down

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Posted by Derek

AstraZeneca took a pretty big risk in running a trial as big as the JUPITER one, but it seems to have paid off for them. As everyone has been reading, it appears that their Crestor (rosuvastatin), lowers the risk of cardiovascular events in patients with elevated C-reactive protein, even those with reasonable cholesterol numbers. (NEJM paper here).

These patients don’t have an awful lot of heart attacks, but they did have less while on the drug. That’s going to be enough, all by itself, to expand the market for Crestor (and probably the other statins as well). The question is whether the others will have the same effect. You’d think so, especially a similar strong one like Lipitor, but AstraZeneca is the only company with numbers for its own product.

The question will be whether it’s worth treating such a wider patient population at these intent-to-treat numbers, a point made in an accompanying editorial in the New England Journal of Medicine:

The relative risk reductions achieved with the use of statin therapy in JUPITER were clearly significant. However, absolute differences in risk are more clinically important than relative reductions in risk in deciding whether to recommend drug therapy, since the absolute benefits of treatment must be large enough to justify the associated risks and costs. The proportion of participants with hard cardiac events in JUPITER was reduced from 1.8% (157 of 8901 subjects) in the placebo group to 0.9% (83 of the 8901 subjects) in the rosuvastatin group; thus, 120 participants were treated for 1.9 years to prevent one event.

It’s interesting to imagine these numbers flipped over, though – if a drug caused heart attacks at these same statistical levels in these same patients, it would be taken off the market immediately. Look, for example, at the risks of cardiovascular problems with Vioxx. The VIGOR trial showed 17 heart attacks in a group of over 4,000 patients, a rate (at the highest dose) of about four times the naproxen-treated control group. In relative risk terms, that’s a serious alarm bell – but in absolute risk, not so much.

This isn’t a completely fair comparison, of course – in the case of statins, cardiovascular events are what you’re trying to treat for in the first place, as opposed to having them as a totally unrelated side effect in a pain medication. And there were other options than a Cox-2 inhibitor for many (although not for all) of the people taking Vioxx. And there’s the general primum non nocere principle: when we find that a drug is causing actual harm (as opposed to doing nothing), it’s likely to be withdrawn, even if the harm is at very low statistical levels.

But at the same time, not giving people something that could prevent these heart attacks is still rather equivalent to causing said heart attacks – isn’t it? We have to make the call of whether the cost, and the statin side effects, are worth it. That’s not an easy one (for one thing, there was a statistically significant difference in the number of Crestor-treated patients showing diabetic symptoms in this trial). And when a drug shows harmful side effects, we should make the call in the same way. I just don’t see the two situation treated in a similar manner much of the time, though.

Comments (17) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials


COMMENTS

1. carol on November 10, 2008 9:54 AM writes...

I Had a MI in 2005 with high cholestoral and have taken Crestor for the past 3 years. My overall health is better now, my good HDL is 78 which is very good. My heart doctor says I'm in very good health and I only take 5 mg of Crestor.

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2. schinderhannes on November 10, 2008 10:06 AM writes...

The real pity for society is of course, that nobody will ever run such a trial with atorvastation (lipitor) or simvastatin, to see if they too can give you a similar benefit whilst beeing generic pretty soon. So its up to happy guessing....
It´s a dilemma I don´t know a solution to.
And its very good news for AZ :-)

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3. The Pharmacoepidemiologist on November 10, 2008 11:33 AM writes...

Derek

I think it's time for you to take that Epidemiology 101 refresher course whose flyers you've been tossing away in the labs. The situations aren't the same. That's the difference between a safety issue and an efficacy claim. But that they were the same.

Perhaps you should sign up for the Regulatory Affairs 101 refresher too, while you're at it.

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4. Derek Lowe on November 10, 2008 11:47 AM writes...

I sort of figured that you or someone in the field would have a problem with that comparison - and I have some problem with it myself. Efficacy and safety are different - but the ways in which we react to them are spread even wider, I think. And that gets to the Regulatory Affairs question, too - we have to show that we're safe, first.

But is Crestor safe in this patient population, or not? I guess it depends on how you read the glycosylated hemoglobin numbers, or the risks for rhabdomyolysis. The way the story is playing in the news, though, is "Statins for Everyone? Drug Helps People Whether They Have High Cholesterol Or Not!" That's as opposed to the Vioxx coverage, which was more along the lines of "Toxic Drug Kills Its Innocent Users, Company Knew All Along".

I just wish that there were some way to have headlines in between those two, and to discuss safety and efficacy as two factors, each with their own weighting. (Throw in cost, and you've got the whole public health argument).

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5. satan on November 10, 2008 6:43 PM writes...

I think that the problem with Vioxx was that Merck knew about the risk, and tried to cover it. Merck also tried to sell Vioxx to the 65+ crowd, knowing that they had the highest risk of 'CV events' from Vioxx.

//That's as opposed to the Vioxx coverage, which was more along the lines of "Toxic Drug Kills Its Innocent Users, Company Knew All Along".//

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6. Malcolm on November 10, 2008 6:56 PM writes...

USD300K to prevent one event, by my back of the envelope scribbling... I shudder to think what the cost/QALY will look like once you factor in adverse events etc.

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7. srp on November 10, 2008 9:21 PM writes...

Interesting question: Would I be willing to pay $300K to avoid a 100% certain upcoming heart attack? What is my maximum willingness to pay for that? I guess if I knew exactly when it would happen and could be ready for it with a team of doctors standing by, I wouldn't pay $300K. But if it could happen just anytime in the next year--I'd have to think about that.

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8. Malcolm on November 10, 2008 10:20 PM writes...

Taking another look at the cost-effectiveness literature for primary prevention with statins, it seems that at least using a generic statin it's not quite bat-shit insane.

This model comes out at about USD50K/QALY for men at a similar level of risk to the JUPITER participants.

That's a lower cost-effectiveness than would merit subsidy under the Australian public formulary (aka PBS) -- about three times too expensive perhaps. And with rosuvastatin at its current price it would look considerably worse.

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9. paul on November 10, 2008 10:33 PM writes...

Cost effectiveness isnt that cut and dried in reality.

First of all - dont you think you may have significantly delayed the onset of disease in many people, despite the fact that they may not have had a CV event in the study period? Isn't that a significant benefit? Sure, its not measured, but I bet its there.

Maybe you are delaying the onset of CV disease when taking a statin by stabilizing your plaques and reducing inflammation - and this benefit might be relatively long lasting.

Also, the cost is for Crestor... realistically, given the large amount of data with other statins, primary prevention, and hs-crp, its not unreasonable to think this may be a class effect. If so, you can get simvastatin (or pravastatin) for four bucks a month.

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10. Malcolm on November 10, 2008 10:50 PM writes...

paul writes:

Maybe you are delaying the onset of CV disease when taking a statin by stabilizing your plaques and reducing inflammation - and this benefit might be relatively long lasting.

Note that the cost-effectiveness modelling I linked to is based on population estimates of event rates, 10 years of treatment, a lifetime time horizon and an overall relative-risk reduction of 30%. Any real benefit is therefore included (which is probably why it looks better than the rough estimate directly from the JUPITER results).

Cost effectiveness isnt that cut and dried in reality.

Yes, and there are wide confidence intervals on these estimates. The 95% CI upper limit of USD250K/QALY might also give you pause before opening your wallet.

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11. DrSnowboard on November 11, 2008 4:19 AM writes...

Wouldn't a gym membership and lifetime Krispy Kreme ban be more efficacious...?

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12. Zachary on November 11, 2008 6:07 AM writes...

It's like a thought experiment I read over at Asymetrical Information one time (not sure I remember it totally correctly, but this is the gist): If a train were hurtling down a track, and you had to choose between it going to track A, hitting one person, and track B, hitting 10 people, everyone chooses track A. However, almost no one claims they would be willing to throw one person in front of a train to derail it to save 10 people it would have otherwise hit. The results are the same, but the act of intervention leading to the lost life seems worse for some reason.

I've always thought that was interesting.

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13. chalker on November 11, 2008 6:54 AM writes...

Just saw the Crestor story on the late news (in Melbourne). According to the story it's the best thing since sliced bread.

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14. Joe the Biologist on November 11, 2008 11:22 AM writes...

Back around '96 and '98, Lipitor was touted in news stories to be efficacious for a large number of conditions as well, including flat feet ;).

Just in time to boost sales it seemed. Must be just a coincidence.

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15. King Cobra on August 14, 2011 9:54 AM writes...

It took just 5 weeks for CRESTOR to KILL my father-in-law!It destroyed his pancreas, liver and kidneys without any warning signs. A search on the internet indicated a non-advertized chance of one in 300,00 of this happening. It is not worth the risk!

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