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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: Twitter: Dereklowe

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November 12, 2008

Crestor: Would It Save Any Lives?

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Posted by Derek

Should millions more people be taking Crestor? That’s a real balancing act. You have a decrease in heart attacks, but from a fairly small incidence rate. So at a minimum, you’ll need to balance the costs of those coronary events versus the cost of paying for all that Crestor. And statins are not without side effects themselves, so you’ll need to adjust your figures for the incidence of rhabdomyolosis, among other things. (For example, is the increased evidence of high blood sugar in the Crestor treatment group a real effect, or not? If so, you’ll need to add a bit of diabetes cost to the spreadsheet). In any case, the cost of getting all these people screened for C-reactive protein levels in the first place needs to be added in as well.

Naturally, as in any of these calculations, you’re going to have to figure how much should be spent to prevent each excess death, once you’ve decided that these deaths can indeed be considered excess. (Unfortunately, the answer cannot always be “as much as it takes”, since there is not enough money in the world to treat everyone for everything, forever). And that brings up another key question: would putting high-CRP patients on Crestor save lives at all?

Well, you’d think so, what with lowering the incidence of those coronary events. But mortality figures are tricky. In all the graphs presented in the NEJM paper, the “deaths from all causes” one is the least compelling. That shouldn’t be a real surprise, since cutting something down in the 1% range isn’t going to bend the curve very much on its own. But if you look closer at the data, things are even fuzzier.

As pointed out to me by a correspondent, the Crestor-treated group for some reason showed a lower death rate from cancer (35 deaths versus 58). It doesn’t seem particularly likely that this is a real effect – I’ve never heard of statins showing a protective effect like this, although if someone knows differently, I’d be glad to hear about it. The paper makes nothing of this comparison, at any rate. Minus this effect, though, the death rate between the two groups might well be within the error bars. The argument for Crestor would then have to be made purely on treatment costs, as in the first paragraph, because you’d be saving few, if any, lives at all.

And maybe there’s a case to be made. I’m not a public health expert, so I don’t know what numbers to put into those calculations. But it’s important to realize, contrary to some of the headlines out there, that it’s actually a hard call to make. I note that AstraZeneca is being cautious about what all this means for sales of Crestor. They’re wise to be.

Comments (20) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials


1. Still Scared of Dinosaurs on November 12, 2008 10:02 AM writes...

Save lives compared to what? The paper shows that the drug has protective effects in comparison to placebo, but in the real world the treatment decision would most likely be Crestor vs some other statin. The paper states that the NNT for one year to prevent one occurrence of the primary endpoint is 95 and the estimated 5-year NNT is 25. Given that the comparator is placebo and the primary included events other than death I would expect that the NNT to prevent one death by any cause as compared to a generic statin would be pretty large and the cost of that death prevented would buy an awful lot of mosquito nets and water filters.

As for the cancer rates it's fun to throw out the hypothesis that the inflammation causing the CRP to go up is preventing the immune system from detecting and eliminating the cancer. Remove it and the body wakes up the the presence of the cancer. Probably a garbage idea but it's fun to throw it out because I don't have to prove it. 17K patients, though. That's a lot of power, and the incidence of newly detected cancers was lower in the Crestor group also.

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2. satan on November 12, 2008 1:52 PM writes...

There is a better way- screen people for CRP instead of various cholesterol tests. The majority of people with dyslipidaemia have high CRP levels. Since altering lipids has proven ineffective, maybe lowering CRP levels is a better idea.

In any case insulin resistance, high CRP levels and dyslipidaemia often occur as a triad.

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3. srp on November 12, 2008 8:28 PM writes...

Were any of the people in this trial taking aspirin? My understanding is that the mechanism for aspirin reducing heart attacks is thought to be a reduction in inflammation, though I could be wrong. What I mean is, is Crestor better than aspirin?

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4. Anonymous on November 12, 2008 9:28 PM writes...


Aspirin, in low doses, prevents clotting by preferentially blocking COX-1 enzymes in platelets. This leads to reduced platelet function and thus reduced clotting. In vascular disease (i.e. heart attack, stroke, peripheral ischemia), atherosclerotic plaques tend to throw clots to various parts of the body. Hence aspirin's effect at low doses. At high doses COX-1 and COX-2 are blocked. COX-2 appears to have a role in anti-coagulation. Hence COX-2 selective inhibitors increase the risk of heart disease. However, I think mortality alone isn't what you want to look at. After all, even if a heart attack/stroke/ischemic colitis doesn't kill you, it does lead to increased medical costs. Besides, policy makers managed to cost-justify the chicken pox vaccine by invoking parents missing work to take care of their kids. You really don't think that you could do that with the costs of treating a vascular event + post-op care + care for eventual heart failure + disability payments?

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5. milkshake on November 12, 2008 9:34 PM writes...

I don't like the side-effect profile of Crestor. First do no harm. Lipitor 10-20 mg or simvastatin 20-40 mg is a far safer preventive measure usable for a wide patient population (40y+ male, overweight, elevated LDL, TG, CRP but no manifest cardiovascular problems). In this age of HMOs one cannot trust that every primary care practicioner will watch for the muscle/liver/kidney damage signs and perform the regular blood tests.

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6. Arethusa on November 12, 2008 10:08 PM writes...

Interestingly there was a sizeable study recently completed in Glasgow (results not yet published) on the beneficial effects of statins in asthma. Perhaps another manifestation of the anti-inflammatory effects of statins.

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7. brian on November 13, 2008 2:45 AM writes...

I was involved with the CARDS Trial (Collaborative Atorvastatin Diabetes Study), which was a primary prevention study, sponsored by Pfizer, which showed reduced CVD event rates (stroke, heart attack, etc.) in Diabetics with no prior history of CVD. As with JUPITER, it was also stopped early due to efficacy.

It also showed a similar reduction in Cancer and Cancer Deaths. In fact, heard it mentioned many times amongst lipidologist circles that many statin studies have demonstrated a reduced risk of cancer, although nobody knows exactly why: reduction in inflamation, perhaps?

Anyway, here is a link to the results:

(you might need to tell it you are a health professional to see the full results.)

As an aside, many statin studies have now demonstrated a reduction in CVD relative risk proportional to the reduction in LDL REGARDLESS OF BASELINE LDL! CARDS showed this, for example.

Therefore, elevated CRP is possibly NOT a precondition to get a reduction in CVD--and it probably DOES NOT MATTER WHICH STATIN GETS YOU THERE. However, in order to get an overall worthwhile cost+risk/benefit ratio, you need to make sure that your treated cohort has a high enough initial risk to balance out the costs and known ADRs.

This is why it would probably be better to built a predictive model that takes into account all these factors, to better inform physicians about optimal treatment options for individual patients. Given enough epidemiological and outcome data, it could be done, and it SHOULD be done. But putting Pharmas in charge of this is like a fox in a hen house.

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8. brian on November 13, 2008 2:58 AM writes...

FYI, here is a study which showed a reduction in cancer rates amongst FH patients treated with Statins. FH is a genetic disease which results in very high LDL levels.

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9. pharmascam on November 13, 2008 8:43 AM writes...

What about spending the money on programs to help people learn to eat better and get more exercise!

OH NO that will never happen

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10. brian on November 13, 2008 11:27 AM writes...

Good diet and exercise will help, but there are many CVD and cancer risk factors that are beyond an individual's direct control.

For example, I've met children whose LDL levels are so high, if they'd been born 20 years earlier, they'd be dead before they graduated from high school. Thank God we have the ability to treat them now.

When I was helping to develope the diagnostic criteria for FH in the UK, I saw a lot of LDL data from FH positive and negatives for males and females from childhood onwards, for several European countries.

The fact is, median LDL levels INCREASE WITH AGE. The ENTIRE DISTRIBUTION CURVE (which is approximately normal) shifts higher with age.

Therefore, if we believe that a given individual's CVD risk is related to his/her LDL level, then the overall CVD risk of the entire population increases with age.

And there are many reasons for this, and most of them cannot be blamed on the individual. For one thing, our bodies just don't work as efficiently as we get older. Our metabolism slows down, our thyroids and livers get 'tired', we tend to put on weight, etc. etc. And, over the course of our lifetimes, we build up plaque and scarring in our circulatory system, include the coronary arteries.

So, of course people should do what they can to stay as healthy as possible, but unfortunately things are not as simple as we would like.

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11. Still Scared of Dinosaurs on November 13, 2008 12:06 PM writes...

>> What about spending the money on programs to help people learn to eat better and get more exercise!


How much do you have to spend to get people to LEARN this? To do it, maybe, but anyone who hasn't learned this by now is actively avoiding the information.

And, again, I would say the the overall benefit to humanity of any such money spent would be greater if it went to water treatment systems and mosquito nets.


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12. ShunMadmen on November 13, 2008 2:43 PM writes...

I am baffled by Derek and the commenters lukewarm repose to these trial results. It doesn't get much better than this for a big outcomes trial.

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13. Cathy on November 13, 2008 3:46 PM writes...

I too was concerned about the way the study was reported. Out of nearly 18,000 people,393 had serious cardiac events: 142 on Crestor, 251 on placebo, a difference of 109. But 54 more people on Crestor got diabetes compared to those who took placebos. Unless some also had serious cardiac
events, the net "saving" now is 55 people. Diabetes is also a serious disease that increases likelihood of future problems after the study is over.

So just under 400 people had cardiac events worth mentioning. Over 2600 had "serious" side effects. Over 2600 had "muscle weakness." We don't know if there's an overlap. But how serious are these effects? If you're too weak to exercise, aren't you at increased risk for more illness? And what about quality of life, expense and increased stress on medical facilities?

And what are the statistics on these 400 people? The study just says they were over 50 (male) or over 60 (female). If those who suffered severe episodes are mostly in their seventies and eighties, we have to ask what's next. I forget who pointed out that a decline in geriatric heart disease means an increase in geriatric dementia.

Anyway, I'm not a statistician. But with a huge sample like this, won't you get some significat effects by chance?

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14. Still Scared of Dinosaurs on November 13, 2008 3:52 PM writes...


Maybe we've become too jaded by the "death by all causes in the only endpoint" mentality that is the norm in cancer trials. I recognize that preventing a heart attack is clearly a greater beneft than temporarily shrinking a tumor, but Derek's original question was whether Crestor would save any lives. If so, what would the cost per life be?

I stand by the assertion that if the alternative is a generic statin you'd probably have to treat a lot of people to save a life. The cost may still be less if the costs of the events prevented pay for the Crestor - and I'm sure if those numbers look good AZ will let us know.

You're right about how this fits in the universe of outcomes trials. It's just that the outcome of this trial is not the one Derek asked about.

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15. brian on November 14, 2008 3:27 AM writes...

I think the potential anti-cancer effect really needs to be taken seriously.

Its been seen, to my personal knowledge, in both a Crestor and Lipitor study. And, in the European Heart Study with the FH patients, it was aparently not specific to any particular statin, but to the whole class (again

The FH study is particularily compelling, as untreated FH subjects have a relatively high early mortality rate. Therefore, you would expect to see LESS cancers in untreated versus treated patients. But, in fact, the opposite is true. And it was with a relatively large cohort of subjects (>3000) over many years (>20).

These are patients who generally take statins from puberty, FYI.

There may be other explanations for this finding, but the simplest one is mostly likely correct:

Statins *may*, by some mechanism, have an anti-cancer effect!

Isn't that fascinating if true? Perhaps there is some hidden gold here?

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16. Percy on November 14, 2008 5:00 AM writes...

It saves lifes do you dare not to take the change, they had to close the study in advance due to ethical reasons its such a good compound. And why try agianst other statins - thats up to other pharma to do this study of there own - its not for free you know

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17. hibob on November 19, 2008 5:35 PM writes...

@still scared of dinosaurs -
Since the patient population being studied is people without elevated LDL/dislipidaemia, it makes sense to compare to placebo: there was no reason to prescribe statins to these people. They wouldn't be on a statin, crestor or otherwise, if it weren't for this study.
I'll agree that this study hasn't shown any benefit for crestor vs any other statin - or that the CV risk being addressed is conclusively tied to high CRP.
It is a big step for increasing the number of prescriptions of statins though, so Astrazeneca got a good bang for its buck.

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18. Dan on December 15, 2008 6:34 PM writes...

Facts Believed to be Associated With All Statin Medications:

Adverse events associated with the statin class of pharmaceuticals are thought to occur more often than they are reported- with high doses of statins prescribed to patients in particular. Since this class of drugs has existed for use for over 20 years, statins are considered safe and effective for enhancing the clearance of LDL noted to be elevated in the lipid profiles of patients..
Additionally, there is no reduction in cardiovascular morbidity or mortality, as well as an increase in a person’s lifespan, if one is on any particular statin medication for their lipid management. So caution should perhaps be considered if one chooses to prescribe such a drug for a patient if they are absent of dyslipidemia to a significant degree, or are under the belief that one statin medication provides a greater cardiovascular benefit over another. In other words, the health care provider should be assured that any statin therapy for their patients is considered reasonable and necessary if the LDL in their patients need to be reduced..
Abstract etiologies for those who prescribe statin drugs on occacsion , such as reducing CRP levels, or for Alzheimer’s treatment, or anything else not involved with LDL reduction is not appropriate prophylaxis at this point for any patient. All other benefits that appear to have favorable effects in such areas are speculative at this point, and require further research for disease states aside from dyslipidemia.
Several risk factors should determine if one is placed on statin therapy, and not just one particular reason. High LDL cholesterol is the apex of rationale for statin therapy, yet other risk factors of the patient should be examined and evaluated as well by their health care provider, perhaps- depending on the patient’s cardiovascular history to determine the appropriate dosage and strength of statin therapy for such patients as it relates to their present LDL level and the reduction that is needed.
Statins do decrease the risk of cardiovascular events significantly, it has been proven. This may be due to the fact that statins improve endothelial function as well as statins having the ability to stabilize coronary artery plaques, which prevents myocardial infarctions. Statins also decrease thrombus formation as well as modulate inflammatory responses. For those patients with dyslipidemia who are placed on a statin, the effects of that statin on reducing a patient’s LDL level can be measured after about five weeks of therapy on a particular statin drug. Liver Function blood tests are recommended for those patients on continued statin therapy, and most are chronically taking statins for the rest of their lives to manage their lipid profile in regards to maintaining the suitable LDL level for a particular patient.
In regards to other uses of statins besides just LDL reduction, there is evidence to suggest that statins have other benefits besides lowering LDL, such as reducing inflammation (CRP) with patients on statin therapy, those patients with dementia or Parkinson's disease may benefit from statin medication, as well as those patients who may have certain types of cancer or even cataracts. Yet again, these other roles for statin therapy have only been minimally explored. Because of the limited evidence regarding additional benefits of statins, the drug should again be prescribed for those with dyslipidemia only at this time involving elevated LDL levels as detected in the patient’s bloodstream.
It appears those statins that are produced specifically by fermentation, such as Zocor and Pravachol, have less incidences of myopathy than the other synthetic statins that exist presently. This may possibly due to the fact that fermented statins are believed to be much more hydrophyllic, which may optimize safety for a patient on a statin medication. Regardless, the lower the dose, the better, with any pharmaceutical prescribed to a patient. All pharmaceuticals have side effects, or they would not be pharmaceuticals. Statin drugs are not an exception.
Yet overall, the existing cholesterol lowering recommendations or guidelines should be re-evaluated, as they may be over-exaggerated upon tacit suggestions from the makers of statins to those who create these current lipid lowering guidelines. This is notable if one chooses to compare these cholesterol guidelines with others in the past. The cholesterol guidelines that exist now are considered by many health care providers and experts to be rather unreasonable, unnecessary, and possibly detrimental to a patient’s health, according to others. Yet statins are beneficial medications for those many people that exist with elevated LDL levels that can cause cardiovascular events to occur because of this abnormality.
Finally, a focus on children and their lifestyles should be amplified so their arteries do not become those of one who is middle-aged, and this may prevent them from being candidates for statin therapy now and in the future.
Dietary management should be the first consideration in regards to correcting lipid dysfunctions,

Dan Abshear

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19. Dave on February 13, 2011 8:35 PM writes...

Perhaps the real question is not mortality, but morbidity. A STEMI vs NSTEMI can mean the difference between an ICD, CHF and sudden cardiac death, vs a relatively good outcome. Have we looked at the morbidity? An example: The recommendation for women not to perform self breast exams... The study stated something to the effect that self breast exams did nothing to prolong life. What about the thought that SBE's may prevent total mastectomies and other sequelae?

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20. Ken on June 24, 2012 12:12 PM writes...

Has there ever been a study of Crestor vs. aspirin or Crestin vs. a plant-based diet?

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