Monday, February 4, 2008

KIF6, Jarvik and You

Ok, so today I want to bring up a set of studies which I just finished reviewing extensively. I have to admit, we have some nice trends for genetic and genomic medicine here.

First, KIF 6 is identified as a risk for heart attack. Not super impressive with and Odds Ratio of 1.5. But it is replicated as well.

Second, the "Polymorphism in KIF6 Gene and Benefit From Statins After Acute Coronary Syndromes Results From the PROVE IT-TIMI 22 Study"

This is a good sequencing study of the bigger PROVE IT-TIMI22 study. More importantly it is a great representative of the retrospective analysis we can do on these great pharma based studies. The major limitation is the statistical flaws introduced by the method. So what is the major crux of this study.

The study population for this genetic study was derived from the PROVE IT-TIMI 22 trial, which has been described previously (14). Briefly, the trial comprised 4,162 patients who had been hospitalized for an acute coronary syndrome within 10 days preceding enrollment and who were enrolled while in stable condition and after any planned revascularization.

How well is this patient population a representative?

Because only 10.3% of the patients were nonwhite, which did not provide sufficient power for a separate analysis of ethnic groups, we included only the white patients in this genetic analysis.

If you are not caucasian, these results may not apply to you. The big problem I have with these studies is precisely their lack of diversity. This limits their applicability. But this is still an ok study.

Here is what makes this a good revisit. This study demonstrates a certain population at risk AND a benefit of therapy provided to that group. This is the essence of what pharmacogenomics and personalized medicine will bring to the table. The theory is nice, we will see if it stands

Carriers and noncarriers of KIF6 719Arg received significantly different benefit from high-dose atorvastatin therapy compared with standard-dose pravastatin therapy. Specifically, in carriers of the 719Arg allele, high-dose atorvastatin therapy 80mg, compared with standard-dose pravastatin therapy, reduced the risk of death or major cardiovascular events by 41% (adjusted HR 0.59, 95% confidence interval [CI] 0.45 to 0.77; p <>

This is a pretty good result. Funny how all the cardiologists I know pooh pooh'd the Coumadin genetic testing because there was no clinical outcomes(Not true BTW). Here we have some solid data coming from a cardio study. I maintain that these huge pharma sponsored cardiac studies will be the low-hanging fruit here. They have reams and reams of patients and their data already available, the genotyping should be the easiest part.

So sorry my cardiologist buddies, you got some learin' to do. It's ok, I will help you.

So here's a question. If this benefit is genetically mediated, will the non-carriers of KIF6 719Arg variant have a similar benefit?

In contrast, high-dose atorvastatin, compared with standard-dose pravastatin, was of no significant benefit in noncarriers (adjusted HR 0.94, 95% CI 0.70 to 1.27; p = 0.70) (Table 2). This difference in benefit between carriers and noncarriers was significant (p = 0.018 for interaction between KIF6 719Arg carrier status and treatment)

NOPE. So there you have it, the death knell to one drug fits all! If it stands....

"You hear that Mr Anderson?" (Hat tip Matrix)

Carriers of the 719Arg allele are at increased risk of fatal or nonfatal coronary events when not treated with statins ([8], [9] and [10]), and they clearly benefit from statin therapy, whether it be standard-dose pravastatin compared with placebo (8) or high-dose atorvastatin therapy compared with standard-dose pravastatin. In contrast, noncarriers not only were at lower risk than carriers in the ARIC and WHS trials and in the placebo groups of the CARE and WOSCOPS trials, but noncarriers also received less benefit from statin treatment than did carriers in the CARE, WOSCOPS, and PROVE IT-TIMI 22 trials.

There are some limitations, I agree. Despite the limitations it is the blueprint that matters most. This is the start of the new model! We shall see more of these redux studies shortly.

The Sherpa Says:

One of the biggest sellers in the pharma world, now has a target group that receives maximal benefit. Hey Hank, send me the check in the mail please.....You gotta love Personalized Medicine. Now we need 10 minute genotyping for those patients with chest pain. Or maybe they could use their NAVIGENICS or 23andME screen which their PMD pooh pooh'd? But you would need a
geneticist to interpret that!

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