reinvent primary prevention lipid goals?
the pulling apart of the lipid data from the crp data in the study will be interesting!

sameer

Agreed
Can't wait to see these data.

Great news
We had been asked to be part of this study and opted not to expose those 'low' risk patients to placebo. Confirmed by the results. How sweet it is. Now with Asteroid QCA, IVUS and METEOR CIMT. great news for the best statin on the market for lipoprotein changes.

what's in YOUR wallet??? (Kidding, kidding kidding)
Michael, With rousing commentary like that, I MUST ask if you have any disclosures!!!!
(Kidding!)
I agree, see ACC 2008 post.
Melissa

crestor 20 mg (JUPITER) vs crestor 10 mg (CORONA)
Yes it's not good to make inter-trial comparisons, but it makes one think! Perhaps crestor should be initially dosed at 20 mg/d as per JUPITER rather than 10 mg/d as per CORONA. I know that this indirect comparison will change my practice for this drug (I will not initiate at less than 20 mg/d, unless the patient is Asian or an elderly woman).

Best statin on the market??
Dr. Cobble, isn't it a little short-sided to say that crestor is the best statin on the market? With 10 outcomes trials and years of excellent safety info. shouldn't lipitor be used before crestor?

Why not Lipitor as a comparator?
I believe the reason that Lipitor is not used as a comparator is that they know that Lipitor outcomes will not be exceeded. With Lipitor Generic coming in a few short years they don’t want to give up the smoke and mirrors so they can keep a small part of the market share.

best statin on the market
the full comments I made were 'best statin on the market for lipoprotein changes" and that cannot be debated for LDL reduction, NHDL reduction and HDL elevation compared to all other monostatins on the market. That doesn't mean anyone need write crestor, they can write whatever statin they want - assuming one reaches ldl, nhdl goals as rec. by ncep - we don't have a preference. I just think it is funny or not so funny that mkr/sgp and pfe have both picked on rosuva and now the evidence is in - as if it would be a surprise. It's business at usual in our office writing all statins including fluvastatin, atorvatstatin, simvastatin, pravastatin, lovastatin and rosuvatatin and yes simva/eze when needed. STELLER has shown that rosuv is best as montherapy for lipoprot goal achivement. My commentary is not meant to pursuade on to prescribe rosuva. Goals are KING.

Is this a surprise?
Is this outcome a surprise? The only surprise to me is that they used as weak a predictor of CAD as CRP. Coronary artery calcium is about 10 times more predictive of coronary events as HS-CRP. Additionally, why follow the plaque with something as invasive and expensive as IVUS? Plaque area by ultrasound or EBT calcium progression are more proven outcomes than IVUS plus safer and much less expensive.

When did true science give way to profit making for the Ivory Tower CRP and IVUS folks? I think the Crestor marketing department knows that to get sales, they must pay homage to Nissen and The Brigham; no better way to do that than to play with their toys and send lots of money.

William
It will be interesting to see the publication 'reduces cv morbitiy and mortality' and see if it statistically lowers both and to what degree in a 'low' risk population with LDL < 130 and HSRCP > 2-3.

I'm sure a lot of these people would have had EBCT positive scans and more likely those that benefited???

Toys and money and ivory....... well crp is cheap, IVUS isn't but technology is king.

EBCT isn't cheap and radiative etc.. that does not diminish it's risk prediction in models and the utility of it's use (which i think no one questions) - Question has there been a study published that shows following EBCT and treating lipids based on EBCT has confirmed morbidity and mortality reduction singly or independently of LDL goals?

If this data on JUPITER is published and does truly show morbidity and mortality reduction for low risk people with LDL under 130, yet elevated CRP that would be guideline changing.

Guideline changing?
"If this data on JUPITER is published and does truly show morbidity and mortality reduction for low risk people with LDL under 130, yet elevated CRP that would be guideline changing"

change the guideline to revise primary prevention lipid goals to lower levels or advocate the routine use of a marker which is essentially a global marker of risk factor burden.

if we need to use crp as an excuse to drive risk factor levels in our patients to "more optimal " levels than that espoused by "current guidelines"...am all for it......

what happens when the next ncep lowers the "normal ldl level" cut off to say 100 mg/dl....suddenly everyone in JUPITER had an indication for the statin eitherways......crp or not....
let me not even start with the tg and hdl issues and the lack of the true control arm (normal lipid and mormal crp) in JUPITER

sameer

Nail in the coffin
As of the release of the Jupiter results, I will officially stop using placebo in all my CVD patients.

use global risk
I have lots of patients on statins who had starting LDL levels well under the guideline goals and thresholds. This is because their global risk is high - abdominal obesity and/or family history and/or older with risk factors like hypertension, etc. I do not think that JUPITER will change much except lead to more confidence in Crestor - which is useful because of the current absence of hard endpoint data.

EBT is cheap
Crestor costs $100 a month. In addition you have costs of office visits monitoring blood work and subjective symptoms, probably another $400 per year. If I use a weak marker such as CRP to base crestor treatment in otherwise low risk patients, I will be spending 4X the cost of an EBT heart scan every year when a majority of these patients will have no plaque and no reason for taking crestor. If I do a calcium score and find out who truly has disease, I will not be treating very low risk patients unnecessarily.

Regarding radiation, EBT imaging has very low radiation. At 0.7msv radiation, an EBT heart scan has 1/10th to 1/30th the radiation of a 64 slice CT angiogram, and 1/15th the radiation of most nuclear stress tests.

I am investigating whether I could publish my personal results using the presence of plaque by EBT calcium imaging as a basis for treatment. Agreeing with William Dixon, I do not have a placebo arm. Against age/gender/risk factor expectations, my results will look great but will that mean anything in our world of double blind placebo controlled trials?

EBT vs standard risk factor assessment
William B.,

According to a report in the Lancet 1-2 weeks ago, just using standard risk factors plus BMI (and not needing any lipid parameters), you can discriminate risk in about 85% of cases. I admit that this still leaves 15% undiscriminated, and for some endpoints, the AU-ROC was only 78% (not 85%), but with global risk determination based on these equations, clinicians can do quite well.

I do not personally use a calculator, as I have access to ultrasound based carotid plaque area measurements (as distinguished from IMT). The combination of both an imaging tool and the standard risk factors would probably push the AU-ROC closer to 100%, but this has yet to be validated in my view for any tool on the market, including CRP, EBT, or US.

Only half of the equation
Risk factors plus obesity will find 85% of the patients with plaque plus a majority of patients without disease. EBT distinguish which patients have and which do not have disease.

As I practice in one of Americas most health communities, I don't see a lot of obesity. A majority of my CAD patients are fit and a remarkable number of them have no major risk factors. I admit that I see a skewed spectrum however in my world, risk factors plus obesity does not work.

If we identify 85% of heart patients and put them on a statin, we will take heart disease from the leading cause of death in this country and make it the leading cause of death in this country. If we identify who has disease and treat them to the goal of plaque stability, we can take coronary death off the leader board! EBT calcium imaging is currently the best and most proven technology to accomplish this.

Passion
William, no one can fault you for your passion and strong motivation to prevent disease.

"EBT calcium imaging is currently the best and most proven technology to accomplish this."

I would say this is a pretty strong comment, there are MANY vascular imaging modalities that predict risk and add to FRS or other risk models. ABI, Duplex, CIMT, QCA, CTA, etc... You don't sleep on a CT scanner by any chance? :o)

Back to the topic:

I think the enrollement demographics pulished in AJC were pretty impressive and await the final results publication:

Demos:
1. They screened 90,000 to find 18,000
2. TC 185
3. LDL 108
4. HDL 49
5. Women 38%
6. Age 66 no dm or cad/cvd
7. NHDL 134
8. TG's 118
9. hsCRP 4.3
10. Glucose 94
11. A1c 5.7%
12. BMI 28.4
13. BP 134/80
14. Tob 16%
15. Met Syn 32%

It's pretty impressive to me that a company would screen 90,000 patients as part of their clinical research outcome studies to answer a question we all want to know but no one wants to pay for. It would have been really interesting if they had performed UMA, 2 hr OGTT, CIMT and perhaps CACS, LDLp or other density testing on these folks. I would really like to see the percent with 0-1 NCEP, 2 NCEP, > 2 NCEP and FRS and Vascular Risk Scores and the event reductions in each group. Hopefully the publication will dissect groups.

Kudos to research....

Passion
The statement is indeed strong and impassioned. It is strengthened by the mostly ignored clinical DATA in the cardiology literature and impassioned by the fact that I have lost many good friends and relatives to this disease. I have stumbled upon a technology that works! What is not to be impassioned about?

I have read much of the literature about other atherosclerotic imaging technologies in addition to advanced lipid analysis and plaque instability markers. I stand by my statement, EBT calciuim imaging is the best predictor of coronary risk.

standing
Well, can't argue with that. I have multivessel athero age 43 with an LDL of 90-118, NHDL 110-130, ApoB 85-118, HDL 34-53 (avg 40) - no risk factors except HDL close to under 40 and Dad with 5 v cabg age 53. Both GF's died of CAD age 67 and 71, GM with DM and CAD, CVD and CABG.

I have utilized every imaging technique on myself and would get a mammogram to look for breast calcification if my insurance would pay for it :o).

Had a CACS of 2 in the LAD 5 yrs ago not exciting but put me in 75-90% percentile. Had a 1.7 mm soft plaque in my right carotid last year (cimt was age congruent), 3 months later it showed calcification and thus niaspan was added to my statin. Recent abdominal CT for genetic kidney stones showed right renal art calcification and subtle small vessel and aortic calcification (radiologist wanted to know if I had DM with waist of 30 and BMI under 25, glucose normal, prehtn 134/84 now on acei some years). My new CIMT showed regression by 4 years from prior, plaque stable. Will see if I can remove it over the next 1-2 years on combination therapy.

I don't want any more radation unless perhaps a 320 ct spinner.

My only regret is that I didn't start high dose statin and niaspan a long time ago. OF course my lipoproteins based on guidelines DID NOT recommend treatment. But ALL imaging techniques directed otherwise. Duplex would have been no help in early disease for me nor would ABI have been of help.

Keep up the great work. mc

William B, Michael C., etc
Anyone know if there is a large outcomes-driven trial looking at EBT vs standard risk factor screening to determine if the former improves cardiovascular events? I think this would sway many people towards use of this technology.

That's interesting Michael..........
Michael,
Is that why you've been shopping at Victoria's secret lately? :)
Sorry to hear about your athero, but with the positive Rosuvastatin studies, I think folks like you and I have Hope!!! (I have a small plaque in my left common carotid and plan to get back on my crestor next week...nauseated since surgery until the last week or so, now I'm ready to get going again!

still prefer lipitor
Unless the JUPITER trial is a groundbreaker and we see risk reductions >50%, I still favour lipitor:

-CARDS
-ASCOT-LLA
-SAGE
-TNT
-PROVE-IT TIMI-22
-AVERT
-MIRACL
-GREACE
-IDEAL
-SPARCL
-and others I have failed to remember.

Disclosures: None

Dan
You've gotta love a guy with NO disclosures!!!
I find that Lipitor is a bit more difficult to tolerate, how about you?
Melissa

atorvastatin 80
Melissa,

Thanks for the feedback.

I find the problem comes with the dose escalation - going from 40 to 80 mg (or 10 to 80 mg). I am interested to know if Crestor has better tolerability at equipotent dosing; I know that pravachol probably does, but it is too wimpy now to use (post PROVE-IT, REVERSAL, etc).

I've seen a study suggesting that 50% of patients with statin-associated myalgias respond favourably to statin switching, without re-commencement of their symptoms. This was published in Archives of Internal Medicine a year or two ago and picked up by THO.

So I don't give up - but patients often don't call until their follow-up appt to tell me they d/c'd, which is regrettable!

Statin tolerability
In response to D Hackam's query I find a paper by Charles Glueck of the Cincinatti Jewish Hospital in Clinical Therapeutics, Vol 28 No.6, 2006 of value. Of 61 patients intolerant to other statins, only 1 did not tolerate rosuvastatin 5 or 10mg (unilateral myalgia!). Possibly the hydrophylicity similar to pravastatin without the wimpicity helps.

A very recent paper by Steven Baker of McMaster Univ may be enlightening too.

Dan, Dan, Dan.....
Melissa, I can't afford Victoria Secrets anymore. I buy the bras and then would end up throwing those $60 bras on stage at rock concerts and wonder why I wasted my money. Managed or (mis)managed care has made my budget for bras shrink dramatically.

Dan, when naming the positive don't forget the negative with atorva like ASPEN and I'm sure others.

ALL of the monostatins now have event reduction studies. The key is reaching LDL and NHDL goals (apoB) and meeting secondary goals with HDL and TG when applicable.

I think if simva, prava, lova, atorva, rosuva reach your targets they are ALL worthy. After many years of negative campaigning byt many special interest groups rosuva is getting some respect. Atorva 40 just didn't get my dad's LDL to goal and rosuva 10 did, thankfullly.

Now we have METEOR in a low risk population (CIMT), ASTEROID in a high risk population (IVUS and now QCA), JUPITER in a low risk population (morbidity/mortality reduction announced - waiting on publication data).

I think one can feel confident using any statin. Remember atorva to date has not reduced mortality. This is not meant to be positive or negative just and observation.

small study but reflect my experience
Dan,
Edlyn's paper mirrors my anectdotal experience. Baycol was well tolerated from a myalgia standpoint for the same reasons......at least until the company tried to capture more of the market and pushed to 0.8 mg dosing.

Melissa

Michael, atorva reduces mortality, even at 10 mg/d
European Heart Journal Advance Access originally published online on January 5, 2008
European Heart Journal 2008 29(4):499-508; doi:10.1093/eurheartj/ehm583


Aims: To determine the cardiovascular benefits in those originally assigned atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial—2.2 years after closure of the lipid-lowering arm of the trial (ASCOT-LLA).

Methods and results: The Blood Pressure Lowering Arm of the ASCOT trial (ASCOT-BPLA) compared two different antihypertensive treatment strategies on cardiovascular outcomes. ASCOT-LLA was a double-blind placebo-controlled trial of atorvastatin in those enrolled into ASCOT-BPLA with total cholesterol concentrations at baseline of 6.5 mmol/L.

A total of 19 342 hypertensive patients were enrolled in ASCOT-BPLA and 10 305 were further assigned either atorvastatin, 10 mg, or placebo. ASCOT-LLA was stopped prematurely after a median 3.3 years follow-up because of substantial cardiovascular benefits in those assigned atorvastatin. Trial physicians were invited to offer atorvastatin to all ASCOT-LLA patients until the end of ASCOT-BPLA.

The primary outcome of ASCOT-LLA was combined fatal coronary heart disease (CHD) or non-fatal myocardial infarction.

Secondary outcomes included all coronary events, all cardiovascular events and procedures, fatal and non-fatal stroke, cardiovascular mortality, all cause mortality, development of chronic stable angina, heart failure, and peripheral arterial disease.

By the end of ASCOT-LLA, there was a 36% relative risk reduction in primary events (n = 254) in favour of atorvastatin [hazard ratio (HR) 0.64, 95% CI: 0.50–0.83, P = 0.0005]. At the end of ASCOT-BPLA, 2.2 years later, despite extensive crossovers from and to statin usage, the relative risk reduction in primary events (n = 412) among those originally assigned atorvastatin remained at 36% (HR 0.64, 95% CI: 0.53–0.78, P = 0.0001). For almost all other endpoints, risk reductions also remained essentially unchanged and in the case of all cause mortality, the risk reduction of 15% now achieved borderline statistical significance (P = 0.02).

Conclusion: Carry-over benefits from those originally assigned atorvastatin but no longer taking the drug may account for unchanged relative risk reductions in most cardiovascular endpoints observed 2 years after ASCOT-LLA closed.



Quoting from the text - "Owing to the increase in the number of deaths by the end of the extended period of observation, the risk reduction in all cause mortality associated with assignment to atorvastatin achieved borderline significance (P = 0.02). "

goals vs drugs
Michael,

Furthermore, it's not all about goals. Goals are surrogates which are not validated in RCTs.

Clofibrate and estrogen help patients to reach lipoprotein goals, but they both end up killing people. Ezetimibe helps people to reach goals, and we all know about the paucity of endpoint data for this drug. Baycol helps people to reach goals but causes excess fatal rhabdomyolysis.

Follow the evidence not the surrogate data. Personally, I would have tried to maximize your dad's atorvastatin 40 mg/d per TNT (to 80 mg/d), if he could tolerate it. For a lot of patients, this is a matter of putting up with myalgias for a couple of weeks and education, education, education. You might also try coQ10.

fibromyalgia and statin use
from both a personal and professional stance I am asking this. I did have a really nasty experience with Lipitor and we seem to have quite a few pts with fibro who also have high chol/trig, all saying they are doing their best to watch diet, add fiber, and move around more (I won't say exercise, because I know that there are days it hurts to just get out of bed). With one of the worst side effects of statins being muscle pain etc, what do all of you order for your patients with fibro or any muscle disorder? Thanks!

Edlyn
Thanks for the reference! Steve Baker and I worked together about 8 years ago - I had not heard of this paper before. Steve is a great guy.

I fully agree with you and I am eagerly awaiting the results of JUPITER (hydrophilicity without wimpicity).

Interestingly, at a journal club last week on CORONA, several of the participants said they thought they were getting more myalgias with Crestor in their patients, not less. This is why I am suspicious of anecdotal data - not sure what to believe. I will find the paper you mentioned and contact Steve for further details.

dad
But, you see Dan that is just the issue - WE did optimize him on 40 mg of atorva and that didn't work.

No one debates that statins are a foundation in managing risk for athero and events. NCEP defines goals because the evidence is such. (ADA, AHA, ACC also gives guidelines to treatment mgmt all evidence based) Estrogen is not approved to treat lipids as it has not shown reduce risk through its lipid changes, torcetrapib the same. And that is why people are frustrated with zetia - it lowers ldl, does it lower risk???

ASCOTT-LLA while having 36% RRR only had 1% ARR, thus one would need treat 100 people over the trial period exactly like those enrolled to have combined morb/mort reduction. Irony is there again was not mort reduction and as you have stated in the past - further surrogate endpoints should be viewed with suspicion as you point out in BIP and FIELD etc.. in past.

No one downplays lipitor and the wealth of evidence for risk reduction. It has not shown independent mort reduction however. That may be difficult to do in the current era of medical mgmt.

I have no problem putting every patient initially on lipitor - the evidence would support this as it would with simva, prava, lova, etc....

However,
Simva has shown independent mort reduction in 4s and hps, simva has shown independent CV mort reduction in both. woscops with prava has shown the same (all mort and cv mort reduction) in their 10 yr fu in primary prevention.

with respect to cerivastatin - rhabdo would have been rare if clinicians had followed the PI and not written lopid with this product as black boxed instructions had directed. Clinicians had no excuse for making this mistake that had been well pointed out. But who reads that stuff???

Michael
Are you accusing the authors of the extended ASCOT-LLA of fabricating their mortality data?

Despite the fact there was huge crossover after the trial was stopped at 3 years, the non-significant reduction in mortality at 3 years became statistically significant at 5 years. Since randomization did not change, this must mean that the early event benefits (eg for non-fatal vascular outcomes) eventuated in mortality reductions at 5 years.

I have a colleague who constantly complains that statins don't reduce the "body count". Such people just don't read the literature. Check the collaborative meta-analysis of 90,000+ patients in 14 statin trials published 3 years ago in the Lancet by the CTT group. Yes there was a significant reduction in all cause mortality in that analysis too!

Second, the NNT in all trials is grossly inflated by the fact that trials tend to enroll healthier patients at lower risk of events (on average, only 15% of patients seen in actual practice would make it into trials, given the extensive list of inclusion and exclusion criteria in most studies). This means that patients in the real world have higher event risk -- no surprise there though!! WHich in turn means that the real-world NNT is substantially lower, and this has been shown in observational data (albeit distorted by lack of randomization).

Therefore, I do not let an NNT of 100 worry me, because I know that in the real world the NNT is about 10. Look at patients even in the HPS randomized trial who were older than 65. NNT in this trial for simva 40 mg/d was only 10. You can imagine it would be an order of magnitude lower in the real world.

Imagination
My imagination to that order of magnitude isn't that dramatic. I do however love Alice in Wonderland and The Wizard of Oz.

No accusation of fabrication at all. I did hear today that the pfizer reps were saying the Jupiter was halted due to safety concerns.......and my response to that was.....that is correct it was safer to BE ON rosuvastatin. Their implication was to the contrary again it seems we are in an election year... :o) PFE reps in our area are quiet creative in spreading misinformation that plays on everyones fears.

Real world: we see many patients that are just like the clinical studies and feel each study reflects patients in our practice.

Your colleague's comments as you know are innacurate.

NNT for CV event reduction in statin secondary studies is ~ 30 over study duration and NNT for Mort reduction in such is ~ 70. NNT in primary prevention studies is ~ 70 of CV event reduction and ~ 250 for mort reduction (the latter is usually never statistical due to low numbers). In the very very high risk people such as people with diabetes or acs, ami etc. the NNT tends to be under 10 for cv event reduction and under 30 for mort reduction. This can also apply to bp studies - HOPE for example acei study not bp NNT for event reduction was 25, NNT for mort reduction was 50 and NNT for mort reduction in DM pop was 32.

ASCOT LLA 3.3 years was a primary prevention study kind of and here are the demographics 10,000 pts:
63 yo, 33% smoked (very high), bp 164/95 (stage 2) end of study 137/78 - my concern is the additive benefit of starting bp and lipid mgmt together to complicate the study, TIA 9-10% of pop, DM 27% of pop, LVH 23% of pop, PVD 5% of pop yet only 18% were on ASA. End of 3.3 years 83-84% were on atorva and in placebo group 8-13% were on statin. FU extra 2.2 years 63-67% of original statin group were on atorva or other statin and placebo grp now had 56-63% on atorva or other.

As stated earlier combined endpoint at 3.3 years was ARR 1%, NNT 100 during that time.

Combined CV events at 5.5 years ARR 1.6% NNT 63 very much like past primary prevention studies although this was really a mix of primary and secondary.
All Mort at 3.3 years ARR 0.5 NS NNT 200
All Mort at 5.5 years ARR 1.2 NNT 82 and even though p was 0.02 it was borderline due to the dilution of this kind of analysis
CV Mort at 3.3 years ARR 0.2 NS NNT 500
CV Mort at 5.5 years ARR 0.5 NS NNT 200 very much like prior primary prevention studies. This again is not intended to take anything from atorva and outcomes.

Woscops 10 year data as you know was published and only had 30% statin penetration after trail completion, yet showed NNT for CV Mort just over 40 and NNT for all cause Mort just over 50 both statistical.

I guess the point would be for those high risk primary prevention patients and those high risk secondary prevention patients - start a statin early most definately. Even more important and Canada is great at this: make sure they are also on asa, acei, bb and other agents to get target bp, glucose and lifestyle to normal levels.

Mike