Sunday, November 9, 2008

Jupiter is Out, and the News is Good!

I am writing this within hours of the release of the Jupiter study. Already, this is hitting the media at WSJ and CNN, but expect more because this is big news. Looks like DB beat me to the punch, but he seems equally impressed

We participated in this study, so I may be a little biased, but the results are pretty impressive. The study looked at 17,802 patients from all over the world (including the US). The study gave half the patients 20mg of Crestor and the other half placebo. These patients relatively normal cholesterol levels and normal risk for heart attacks, except for an elevated C-reactive protein, or CRP, which is known to be associated with an increased risk of heart attack and stroke. The study was planned for 4 years, but stopped early at 1.9 years when the found that there was a clear benefit for those taking Crestor, and continuing the study would be unethical. The study was stopped a few months ago but the results were presented today and released ahead of press in the New England Journal.

The study found that Crestor reduced the risk of heart-related death, heart attacks and other serious cardiac problems by 44%. This pretty impressive given that these patients under current guidelines would not normally be candidates for taking cholesterol medication.

As evidenced already by the WSJ and CNN post, the message to the public will be 1) this may expand the use of statin medications for people who would otherwise not take them and 2) we need to be cautious before we do this.

Here's a few interesting things that have/may not come out.

1. Crestor is safe. Crestor, which is the most potent statin available on the market had the misfortune of launching just as Vioxx was pulled from the market. When David Graham from the FDA testified in front of congress, he named 5 drugs to potentially be worried about, Crestor being one of them. Dr. Sidney Wolfe, from Public Citizen had already petitioned the FDA not to approve Crestor, and asked for its immediate withdrawal from the market soon after launch. In a 36 page document, the FDA responded to Dr. Wolfe, essentially stating that Crestor was safe. However, the group continues to list Crestor among the worst pills to take.
If anything, this study clearly shows that Crestor is safe. Despite its potency, in a study of almost 18,000 patients, there were no differences in side effects between those that took 20mg and those taking placebo. You read that correctly, no differences. No differences in myopathy, elevated liver enzymes, kidney problems, etc. There was one patient that died of rhabdomyolysis (a very rare, but severe complication of statin medications). However, this patient was 90-years-old and had influenza, pneumonia, and trauma-induced myopathy; and this occured after the study was over.

2. Benefit of treating CRP alone was substantial. There were 142 heart attacks or cardiovascular related envents in the almost 9000 patients given Crestor 20mg, and 251 in the placebo group. This translates in to a number needed to treat (NNT) of 82. In otherwords, you would have to give Crestor 20mg to 82 patients with normal cholesterol but a high CRP for nearly 2 years in order to prevent one of these events. Some will argue that this impact was not substantial. With Crestor at about $3.45 a day, it would cost almost $200,000 over 2 years to prevent such an event. This may seem like a lot, but for mammography, some have calculated the number needed to screen to prevent one death is 781 women, and at a cost of $150 per mammogram, this comes to almost $120,000 which is not that far off.

3. These patients had a low risk for heart attack or stroke. The patients in this study had about a 6% risk of having a heart attack or stroke in 5 years using Framingham calculations. Indeed, the placebo group was found to have a risk of heart attack of less than 1% in the 1.9 years of the study. The mean LDL at baseline was 108mg/dL and current guidelines would have recommended an LDL less than 130mg/dL, with an option of lower than 100. Most physicians would not treat these patients with a medication. Thus, a 44% reduction (absolute reduction about 4%) is pretty impressive and does indeed suggest an expanded role for statins, or at least the need to check CRP.

4. Would a generic be just a good? One could extrapolate that using a generic statin such as simvastatin (generic for Zocor) could do just as well, but at a lower cost ($1 a day). There are several problems with this. First, patients in the study got a 50% reduction in their LDL cholesterol and a 37% reduction in their CRP with 20mg of Crestor. Best case scenario for simivastatin would be 80mg with up to a 47% reduction. However, one thing to consider is that the higher you go in dose, the more likely you are to get side effects with medicine. 20mg of Crestor is half the maximal dose (much of Dr. Wolfe's concern arose from 80mg of Crestor, which did have some side effects, and is why it is not available). 80mg of simvastatin is the maximal dose and very likely to cause side effects. Interestingly, all the studies looking at CRP and vascular changes seem to be in the studies using the higher doses of the potent statins like Lipitor and Crestor. Thus, though a few dollars might be saved, it is not clear that the benefit would be the same and you would likely end up with more side effects.

5. What about diabetes? Not sure whether the media will pick up on this, but they did find that physician report of diabetes was increased in the Crestor group (270 reports of diabetes, vs. 216 in the placebo group; P=0.01). This might seem a concern; however, these were physician reports without confirmation. When looking at the study lab values, there were no significant differences with respect to the fasting blood glucose level, and the A1c level was pretty much the same (5.9% and 5.8%). There is no biologically plausible reason to suspect Crestor as a cause of diabetes. However, both groups had a 41% prevalence of metabolic syndrome, which is a pre-diabetic state. Thus, it is not surprising to find an increase in diabetes in both groups.

Bottom Line
This is compelling data and will likely change guidelines. The anti-statin, anti-pharma folks will try to shoot this one down, but the data is pretty solid. If you are a man over 50 or a woman over 60, you should definitely ask your doctor to check your CRP if you cholesterol is relatively normal, and you would not otherwise be a candidate for cholesterol lowering medication. If your CRP is elevated, I think Crestor 20mg is a good option, since it is not clear that other medications (specifically simvastatin) would provide similar benefit.


Chus said...

Cholesterol pills may become as ubiquitous as a daily dose of aspirin for middle-aged men and women who have normal levels of artery-clogging fat after a study found the medicine cut their risks of heart attacks, strokes and death by almost half.

Anonymous said...

"There were 142 heart attacks or cardiovascular related envents in the almost 9000 patients given Crestor 20mg, and 251 in the placebo group."

do you know the breakdown of heart attacks in each group? Defined how?

And what was the "cardiovascular related events" breakdown, and what exactly were those events, and how were they defined?

Dr. Matthew Mintz said...

The break down can be found in the article on the NEJM web site.
The best place to look is Table 3
I just tried to post the image in my post, but it wouldn't fit.

Anonymous said...

Take a look here for a critical look at Jupiter.

Dr. Matthew Mintz said...

Andrew, thanks for the link. A few comments on Junk Food Science's criticisms.
1. Stopping the study early ruins the results and is done to make the results look better. Not true. They defined when to stop the study before the study began. They had an independent data safety monitoring board review the data periodically. This is common practice for studies. It would not have been ethical to continue the study when such a huge benefit was seen in the study group. Finally, the results were statistically significant. The power calculation is used to estimate how many patients you would need in a study to show a benefit. Instead of the 25% that they predicted, they found 44% unexpectedly.
2. Study participants were not typical patients, and thus not representative. Not true. It is not unusual to exclude patients with significant illnesses. In a patient that is designed to see if Crestor prevents cardiovascular outcomes in patients with normal cholesterol but high CRP, you would WANT to exclude people that already had cardiovasculr disease. The purpose of a randomized trial is to prove causation. The problem with randomized trials is extrapolation to the general public. Good example of this is Chantix. Patients with mental health disorders were excluded from the study because Chantix was compared to bupropion, which is used to treat depression. However, when Chantix was released to everyone, some potential issues arose in patient with mental health conditions. Smokers are disproportionally represented by patients with mental health disorders, so this is important. Regarding Jupiter, these patients are quite representative of the general public: overweight, at risk for diabetes, mildly hypertensive, etc.
3. An absolute risk difference of about 1% in the endpoints isn't that big a deal. Not true. This group would have had a risk of heart attack alone for 6% in 5 years using mean baseline data and Framingham risk scores. The placebo group had about a 1% rate or heart attack in under 2 years seems compatable with this rate. Thus, in this low risk group, an absolute difference of abou 1% is meaningful. If your risk for heart attack and stroke is 6% (1/17) in 5 years, and can be cut to 3% (1/33), that would be a pretty big deal
4. Results "contradict other rosuvastatin trials done for primary-prevention or for high-risk patients taking the statin for considerably more years." Not false, but does not really apply. This study was done in patients with heart failure to see if more agressive control of cholesterol would improve outcomes. It did not. These results are not surprising because 1) you can have heart failure not as a result of athersosclerosis and 2) if heart failure is a result of atherosclerosis, it's because the arteries are already clogged up. The results of CORONA are dissappointing, but not suprising, and more importantly not applicable to primary prevention of cardiovascular disease.