The patient population selected in the ENHANCE study seems an unusual choice given the mode of action of ezetimibe. FH is generally a condition of excess LDL, caused by defective LDL receptors that leads to abnormal LDL handling, and is not due to abnormal intestinal cholesterol absorption. Statins themselves may have specific benefits in these patients due to their ability to upregulate the defective LDL-R. The justification for choosing FH heterozygotes seems driven by the need for a quick outcome study, measuring a surrogate endpoint. Surely a more apt patient group would be high risk individuals who have abnormal intestinal cholesterol absorption e.g. APOE4 carriers with diabetes? However perhaps a study of this kind would struggle to find sufficient numbers to study and, if small, would still require a surrogate endpoint. IMPROVE-IT should be considered the definitive answer to the ezetimibe question.

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.

I have now seen several people pick up on Nissen's comment about ASAP and it seems odd to me that we would choose to use that trial with its CIMT surrogate endpoint to compare simvastatin and atorvastatin when we have the 9,000, 4.8 year IDEAL trial to compare those agents. Given the marginal clinical benefit on hard endpoints of high-dose atorvatatin over moderate dose simvatatin in IDEAL, why are we putting faith in CIMT from ASAP as a meaningful way to try and make sense out of ENHANCE?

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.

I have seen too many Good research articles, solid animal and human studies that show something other than just LDL lowering is going on to reduce the risk of future events. Many early Pravastatin and Lovestatin studies shoed LDL was not the end all be all. There were early studies that despite the lowering of LDL by Lovestatin, there was an increase in the number of heart attacks. In several other studies with Pravastatin, not only did Pravastatin lower LDL, but seemed to have effects on smooth muscle cell proliferation, and capping over the plaque. This lead to decreases in CHD. Pravastatin has been dicounted due to it not being as "potent" as Lipitor or some others, yet there is a huge data base of studies with Pravastatin consitantly reducing the risk of future events. I know the "Prove-it" trial will come up, but let's face it shouldn't that trial have been 80mg of Pravastatin vs 40 of Lipitor. That would have been a real test. Is lowering cholesterol important? YES! But it is not the whole story and I think we will learn that lower is good, but not better and it's with What you lower it that makes a difference. My own 2 cents worth.

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.

Dear Dr. Eric Topol In the Heartwire article "Questioning the importance of LDL cholesterol: The ENHANCE fallout" fro January 22, 2008(http://email.theheart.org/cgi-bin1/DM/z/eBgjQ0N6QSX0Vth0JC6E0EL) you said: ?The idea that you're just going to lower LDL and people are going to get better, that's too simplistic, much too simplistic," We have had published last year an eletter in British Medical Journal entitled "The Cholesterol hypothesis debacle" (1), telling there is compelling justification for a critical look to other hypothesis that explain the formation of atheromas by repeated injury to the artery's wall, which may occur through various mechanisms and that this could provide a solid scientific basis for therapies that are more logical, safer and clinically more effective than those based on cholesterol theory. In our article at BMJ we also have presented a new hypothesis based in the repeated injury concept that was named Acidity Theory of Atherosclerosis. Developed in 2006 this hypothesis places acidity as having an important role in the generator mechanism of atherosclerotic lesions, and giving a new perspective for the understanding of the etiology and pathogenesis of atherosclerosis (2) Carlos Monteiro President Infarct Combat Project 1) "The Cholesterol hypothesis debacle"http://www.bmj.com/cgi/eletters/334/7594/604-b#162886 2) Acidic Environment Evoked by Chronic Stress: A Novel Mechanism to Explain Atherogenesis: a preprint of the manuscript is at http://www.infarctcombat.org/AcidityTheory.pdf

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....

It is interesting that BusinessWeek would target Lipitor in the wake of the ENHANCE trial which doesn't even address statin efficacy. While the NNT in ASCOT is 100, the trial was stopped 2 years earlier than planned by the DSMB due to significant event reductions. Had the DSMB allowed more subjects in the trial to have events by continuing the trial, it is entirely reasonable to expect that the absolute events would have been greater and the NNT significantly lower. However, it would have been unethical to continue to treat the control group with placebo. While NNT is important, the safety of the trial participants is more important.

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

to dr. topol- do you think there will be renewed interest in the old probucol, which was purported to reduce oxidized ldl cholesterol, although it really didn't lower total or ldl to any real significant degree. thanks

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

Great review nad idea for a video blog! But could we please improve the video and audio quality??

Dr Topol certainly deserves a better a/v streaming for his coverage.

Sincerely,

Joao

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'

 

I am a medical anthropologist researching women and statins and the co-author of the Canadian report “Evidence for Caution: Women and Statin Use” (http://www.whp-apsf.ca/en/index.html) published by Women and Health Protection. WHP is a coalition of community groups, researchers, journalists and activists concerned about the safety of prescription drugs. WHP’s “knowledge advocacy” is directed towards making recommendations to the Canadian government to protect women’s health.

 

 Evidence for Caution describes the weak evidence base for statin therapy for women at any age. And it looks at some major risks for women including exercise intolerance, breast cancer, miscarriage and birth defects as well as opening a discussion about the extraordinary stresses faced by women caregivers of statin-impaired family members.

 

The report also examines the many difficulties in figuring out how to accurately assess harm: an issue which applies to all potential users, both male and female. Our concerns are framed within the context of the women’s health movement and address its fundamental goals---full disclosure and informed consent.

 

Statin users cannot make an informed decision about benefits vs. risks because, despite repeated requests by researchers, the majority of trials have not fully released their non-cardiac serious adverse event data.

 The inability of independent researchers to examine all relevant evidence, coupled with the reluctance of many physicians to hear and follow-up on reports of pain and impairment, and the seeming incapacity of regulatory bodies to swiftly identify dangers in the post-marketing period add up to an urgent need to rethink the “so safe it should be in the drinking water” message.

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.

 

Dr. Topol's discussion about whether the lack of effects by ezetimibe on oxidize-LDL particles could be the possible biological or pathophysiological cause for the enhance trial outcome is interesting, although of secondary importance. To date, despite the intense research effort, no trial have been able to prove the value of modyfing and/or reducing oxidized LDL-C particles vs. significantly and profoundly reducing LDL-C levels (please refer to definitive analysis by the Oxford-University-led meta-analyses).  The latter, with all possible and plausible biological imperfections, is a proven hypothesis with 100th+ of thousand patients' data.  A trial like enhance, while raising important questions about whether Rx tools/strategies to reduce LDL-C achieve similar results, cannot confute 'a' proven hypothesis.  Undoubtedly, while statin Rx is proven, other lipid altering approaches (i.e., fibrates, nicotinic acid, ppar, cetp-i) yelded inconsistent results.   With enhance, it is rather difficult to exclude, until the full scientific and medical dataset is properly released beyond a financial analyst press release, whether methodological issues, i.e., measurement variability beyond those assumed, compromised the validity of the experiment.  The imaging-based enhance will not be the first nor the last trial yielding inconclusive results.  Disclosing all the measurement variability including their changes overtime, i.e., sonographer, reader and their interaction, is critical to understand to what extent VYTORIN does not offer benefit in reducing the progression of IMT over simvastatin alone in the population of patients studied in enhance. I/the scientific medical community look forward to the properly presenting/discussion data at ACC and to the more definitive larger outcome trials' data.

Congratulations for embracing an effective medium to stimulate scientific/medical debate.

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. 

It would nice to see the work of Drs Superko, B. Greg Brown, A. Taylor, etc., be given 10% of the "noise-level" as the LDL Mafia. The NCEP panel seems to be devoid of any sensitivity to lipidology beyond LDL.

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.

 

The controversy as to aggressive lipid reduction in those at relatively low risk and no coronary disease is real and should be better studied.  However, the news media does enormous damange in an article such the business week issue cited when it mixes statin treatment of all elevated ldl's as well as those with severe cad.  Patients believe that statins are harmful to all.  Those who have had severe cad have clearly benefited based in multiple studies.  Sensational reporting can cause those who need statins to discontinue them.  Evidence based cardiology practice is important, but much of what we believe to be true based on large studies is seldom seen in an individual practice due to relatively small sample size of one practioner.  Yet, in 20 years of cardiology I have seen in my practice a significant decrease in cardiac morbidity with aggressive lipid reduction in those w/cad, above and beyond the advances in CABG and PTCA.  The ACC and AHA should be more aggressive in responding to the media in print and TV when data is presented so sensationally that people that clearly benefit from a particular approach are frightened from pursuing treatment.

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. 

Enhance was a superiority trial with the hypothesis that Simvistatin/Ezetimibe was superior to Simvistatin in reducing LDL-C which it did and slowing the progression of atherosclerosis using the validated surrogate CIMT which it didn't. So just because you lower LDL-C to a greater extent with Simvistatin/Ezetimbe vs Simvistatin does not mean you slow the progression of  atherosclerosis as this trial clearly shows. The concern with Ezetimibe is that it reduces HDL2b and only reduces large LDL particles leaving small dense LDL uneffected. This would result in in a larger reduction in LDL-C but greater progession in atherosclerosis which this trial trended toward. But remember it was not statistically significant so it could have resulted by chance. The true outcomes study IMPROVE-IT uses patients with ACS so the HDL2b issue may not be so important but the LDL particle number and size issue with Ezetimibe is still there. Finally,Enhance was not powered for CVD outcomes.

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.

The question I have is why was ezetimibe approved by FDA on  lowering a surrogate biomaker LDL while torceptrapib which raised another biomarker HDL had to do an outcomes trial before FDA would consider approval. Both were novel new classes of drugs. Was LDL  lowering so much more important than raising HDL in predicting CVD events or CIMT progression? Obviously not for CIMT progression. So we await Improve IT to answer the events question a mear 10 years after the drug was introduced to the public. Is the FDA really protecting us? Should it be required that a company start a events trial either before or at the introduction of a new CV agent?  If this were the case we wouldn't even be discussing  this rather unremarkable study. Big Pharma spend more on events trials and less on marketing and you won't get in this PR mess. And please stop marketing this drug directly to consumers until the Improve IT trial is done. And Dr Topol all general IM docs are not idiots regarding ezetimibe. This drugs has always been a drug of last resort for me. But it's very hard to convince patients of that when they've seen those slick Madison Ave. commercials. The myth of the temple of LDL is hard to break.

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?

Your blog is interesting! Keep up the good work!