Patrick, I respectfully disagree. The drug company chose this model for a reason. As Nissen said, if it was positive, they would have gone to the FDA for an indication for atherosclerosis reduction. The Heterozygous FH model is a perfect LDL-driven model of atherosclerosis. IMT changes have already been validated with statins (see ASAP study 1991). Therefore, a drug such as Zetia which is touted to be helpful because it lowers LDL cholesterol is well suited to be tested in this model. It failed.

Thanks for the point Craig, but IDEAL was positive in secondary endpoints, confirming that clinical endpoints can track with CIMT changes. ASAP was simply used as an example to show that in hetero FH, 9% LDL changes can result in measurable CIMT changes. Failure to show such changes as in Enhance which ad 19% LDL reduction, may not mean the drug failed - the trial itself may have failed because of chance, etc... - but it brings up the question again of why we are using a drug for 5 years, $5 billion of revenue / year, with no clinical endpoint data and LDL as the only ' surrogate endpoint'. This comes after another trial showed LDL reduction (with HDL elevation) produced excess mortality (torceptibid). This trial also failed to produce changes in CIMT progression.

Thank you for an excellent review , i feel that we have missed an essential part of the puzzle in the LDL hypothesis. Most of the arguments forget that LDL itself as well as HDL has sub populations, and that the LDL -III or small dense LDL is closely linked to atherogenisis. The problem with Ezetemibe is that there is only two studies looking at these sub populations with Ezetemibe only but the one in greek FH patients show a variable effect on small dense LDL and a reduction in functional HDL. So if ezetemibe does not effect the sub populations that affect atherosclerosis that we would expect the ENHANCE study to be negative and unlikely to affect clinical events because it does not reduce atherogensis. Whats interesting is that limited studies of HRT show a similar picture. The final question that remains is whether torcetrapib had a a pro atherogenic effect do similar issues.

People have to be careful when they compare studies like ASAP and Enhance. You have to look at what baseline IMT the patients started and it was double the thikness in ASAP. Imagery studies are not end point studies. Are we going to throw out 20 years of studies showing that decreasing LDL-C is reducing cardiovasculaires events based on one study in a FH population of 720? I sure hope not and lets leave improve it to answer about Zetia....

http://www.nytimes.com/2008/01/27/opinion/27taubes.html?ref=opinion There have been some great comments posted here. For those interested in this topic, worthwhile to check out the op-ed by Gary Taubes (link above) NY Times, Sunday 26 Jan for yet another point of view

Ralph, No-I don't think this will increase interest in that drug, which had significant untoward effects on the QT interval and HDL. But it will be important to separate inflammation and the LDL story much better in the future. Here is a link to a funny satire of the ads related to ezetimibe (By The Health Ranger) for those interested-- http://www.youtube.com/watch?v=rwendcLch-4

Ezetimibe, to the best of my knowledge, works in exactly the same way as cholestyramine does/did. It is rather easeir to take as you don't have to sprinkle it over your food and suffer a major problem with wind leakage afterwards. However, cholestyramine was found to significantly increase overall mortality in several clinical trials, despite lowering LDL levels.

I note that ezetimibe has no outcome data, and none will be available for many years (let me guess that if things are not looking too good, we may find a rather long delay as the investigators find a sudden overwheliming need to change the primary end-point - or I am being too cynical).

On the basis that we now have data confirming that ezetimibe does not have any benefit on IMT, and that it works in exactly the same way as cholestryamine does/did, should we not be lobbying the FDA to ban its use until we have hard outcome data? Because if it does - as I suspect it will - show an increased overall mortality (as per torcetrapib) then we may be killing rather a lot of people during the next five years or so. And who fancies explaining that away? 'Oh we never would have guessed.....' Not really good enough.

By the way the LDL/cholesterol hypothesis is nonsense. Always was, always will be. And I am just waiting to say 'I told you so.'

Regards 

Malcolm Kendrick

Conflict of interest: I wrote the book 'The Great Cholesterol Con'

Can we really extrapolate the result of ENHANCE to the general population with atherosclerosis? Can we surmised that in FH patients will require longer treatment period before we can see significant reduction in atherosclerosis burden? I dont think the result of ENHANCE is a failed trial in terms of reaching the primary endpoint, it only gives us an insight that atherosclerosis is a difficult disease to treat and not everybody can follow the same pathway of reductions or control as seen in other studies.

I still believed that reducing LDL-C into a more appropiate level we can reduce mortality and morbidity and the results of ENHANCE should not encourage us to see otherwise and I'm pretty sure if the study was done in a regular patients without FH probably we will be looking at a different results.

 

Doctor, how do you account for two separate trials with Lipitor that showed far greater results in the number to treat catagory.  In your pod cast you stated that "statins" only showed 1 in 100 benefit to patients.  Is that fair to "lump" all statins together when talking about number to treat.  Heart Protection Study was 99 to 1, which fits the mold of your premise.  However, with Lipitor:  Cards, Lancet 2004 investigators were told by the data monitoring safety board to halt the trial after 3.3 years due to the benefits of Lipitor.  Reported in the article is a ratio of 27 to 1 for number to treat.  Also in the TNT, NEJM 2005 investigators also found that with Lipitor high dose, number to treat was 30 to 1.  Clearly Pfizer has done the studies as to why Lipitor should be considered as a potent LDL reducer, proven cardiovascular protection for patients, and a proven safety profile at all doses.  ENHANCE has opened many fears with Zetia/Zocor comboination, but again Pfizer also conducted a study called ASAP which yielded much different results.  Would love to hear your comments. 

QUESTION ?

What is the range,.. and average NNT in statin trials,..?

Range = 8 to 100

Average = 27

CLAS-I, CALS-II, USAF-SCOR, FATS, FATS 15 yeareF/U, HATS, AFREGS.

3 TO 11

association,..?

Yes. The only drug with an FDA indication for regression,.. niacin.

Probably about time clinicians were poperly trained in tis use.

 

I have read with interest the many comments on ENHANCE and ASAP. One might include RADIANCE/ILLUSTRATE and ASTEROID. It seems clear... Statins help, others have to be proven. At least 3 other papers on ezetimibe show no change in Endothelial Function and arterial stiffness (Fichtischrer in Eur Hear  jnl 2006, Landmesser Circulation 2005 and Efrati Eur J Clin Pharmacol 2006). If Endothelial function and Atherosclerosis are not affected by ezetimibe and are considered mere surrogate markers and inconclusive we should wind up much of our CV research since a large part of the accepted body count stuff is me-too and marketing driven. Again much of the hype ablout residual risk of 60% beyond statins and LDL lowering considers trials with an LDL Lowering of 25-37%. Much can be said for 1% RRR for 1%LDL Lowering with statins based on meta-analyses but more needs to be said on MR Law's analysis of incremental reductions based on degree of LDL lowering of the likes of 2-3mmol akin to 60% to 80% RRR in the years 3-5 of a 5 year statin trial with the more powerful statins like Rosuvastatin 20/40 and Atorvastatin 80. Again the Atherogenic Lipoprotein Profile and Small Dense LDL reductions are unaccounted for. With statins like rosuvastatin (Caslake and Chapman) showing upto 69% reductions in Small Dense LDLs in patients with TG>2 mmol/L and better HDL increase of 10-15% and Apo-A1 increases do we need billions to be spent on me-too trials? I repeat, if we discard the statin class effect AND atherosclerosis Regression AND Apo-B:Apo-A1 ratio reductions AND CIMT trials and IVUS Trials in favor of body counts and on the other hand defend a new class based on the debateable FH issue then do we need these temples of Atherosclerosis research. 

As noted, ezetimibe has not been shown to improve endothelial function.  Statins have.  Many of the pleiotropic effects of statins are thought to relate to non-LDL effects of inhibition of HMG-CoA reductase, such as reduction in rho-kinase.  It is possible that ezetimibe increases the activity of HMG-CoA reductase as a compensatory effect of cholesterol-lowering.  That could mean that ezetimibe counteracts some of the pleiotropic effects of statins.  It seems prudent to avoid combining the two drugs until outcomes data becomes available.

When most randomized clinical trials of statin use have used fixed dose statins to show benefit in outcomes, why then is treating to target so popular? Is it even evidence based?

If, in case, statins have a dose dependant reduction in cardiovascular outcomes independant of LDL lowering (plaque stabilizatoin, pleiotropic effects), then treating to target would be  wrongly extrapolating the RCT's. Could this be a reason why the LDL target for people with advanced coronary disease seems to get lower every other year - i.e. because irrespective of the LDL level, statins have a dose dependant response to cardiovascular outcomes? And could this also explain studies which show benefits of statins with very low LDL's?

 The popularization of treating LDL to target is what I feel is partly responsible for the rapid adoption of the use of Zetia without any clear primary outcomes trials for that drug. On the other hand, treating to LDL target is the most common medication adjustment in a patient following up with his PCP or cardiologist for chronic CAD. Is this time spent in clinic visits and rechecking lipid levels worth the outcomes or should we just use fixed dose statins?