What are they thinkin'?
I don't see how anyone could advocate for less aggressive statin therapy with the new data that has come out in the last couple of years. How will you live with yourself if even one patient dies on a 40 mg dose of simva that you could have had on 80 mg of atorva?

I agree
It does seem odd, particularly in light of A to Z, which showed no benefit of high dose simvastatin over low dose, contrasting this to both PROVE-IT and TNT. I hope we know more when we get the results of IDEAL and SEARCH.

therapeutic substitution
I do it all the time. Haven't seen anyone die from it yet. In fact I see patients who are happier because they have more money to spend. I can't prove that this makes them live any longer, but I can prove that it makes them live better. One only has to look at the smiles on their faces. And when 12-15% of our GDP is spent on medical care (and this is outpacing the rate of inflation each year), cost control is something that we will all have to come to grips with. Not everyone makes a Doctor's salary. Remember, everyone pays in the end. We, as taxpayers pay for medicare, we also pay in terms of higher insurance premiums and cost shifting. And let's not forget the people that die from NOT taking their medicines because they are too expensive. (Something like 30% of all patients post-MI stop ALL of their medicines 6 months after the event, and cost is one of the biggest factors. One doesn't have to run a study to figure out that this is bad.) Something to consider while we endlessly debate studies that offer little in terms of absolute risk reduction. P.S. I was unimpressed by the TNT study, but that is just my opinion.

here is something from a different thread
Colin, Consider atorvastatin 80 mg /d. In the Treat to New Target (TNT) trial, atorvastatin 80 mg/d provided a 22% relative risk reduction in major cardiovascular events (HR 0.78, p<.001) compared with atorvastatin 10 mg/d. In the CARDS and ASCOT-LLA trials, atorvastatin 10 mg/d provided a 37% and 36% reduction in CV events (both versus placebo), respectively. Hence to determine the true efficacy of atorvastatin 80 mg/d, one simply multiplies the relative risks, i.e. 0.63 x 0.78 = 0.49, or a 51% reduction in cardiovascular events. I would say that a halving of CV events with high-dose atorvastatin therapy is not bad. Wouldn't you?

Hello Dan.
Good morning. From the TNT trial data/commentary published on this very website (and I will try and quote as best as possible): 1) # of deaths from noncardiovascular causes increased. If this is true, we can prevent heart attacks and strokes and watch our patients die from something else. Having been in medicine for awhile, I can assure you that although CV disease is the #1 killer, there are many, many other ways to die. 2) "while the increase in noncardiovascular events may be due to chance, it is still a matter of concern." (I would like to be able to italicize those last few words, but can't.) 3) "we need further reassurance as to the safety of this approach before a major shift in our current goals for LDL cholesterol levels."

TNT trial
I believe Dave Filips opinion on the TNT trial was echoed by the editorial in the NEJM (which accompanied the TNT trail) which emphasized caution before diving in head first.

cholesterol lowering trialists collaboration
From an individual-patient based meta-analysis of 14 trials of statins covering >90,000 patients: Cause-specific mortality There were a total of 8186 deaths, including 4655 (57%) from vascular causes and 3531 (43%) from non-vascular causes (webtable 2). During the scheduled treatment period, there were 3832 (8·5%) deaths among the 45 054 participants allocated a statin compared with 4354 (9·7%) among the 45 002 controls. This difference represents a 12% proportional reduction in all-cause mortality per mmol/L LDL cholesterol reduction (RR 0·88, 95% CI 0·84–0·91; p0·0001; figure 1). In an unweighted analysis, a slightly larger mortality reduction of 13% (RR 0·87, 0·84–0·91; p0·0001) was found, chiefly because the mean LDL cholesterol reduction at 1 year in these trials was 1·09 mmol/L. And later on.... There were also non-significant reductions in deaths from stroke (RR 0·91, 99% CI 0·74–1·11; p=0·2), from other vascular causes (RR 0·95, 99% CI 0·78–1·16; p=0·5), and from nonvascular causes (RR 0·95, 95% CI 0·90–1·01; p=0·1). Among the non-vascular causes of death, there was no evidence that lowering LDL cholesterol with a statin adversely affected the risk of death from cancer, respiratory disease, trauma, or other or unknown causes (figure 1).

meta-analyses
NEJM 1997:337:536 Meta analyses are not predictive 35% of the time. To summarize, they are wrong over 1/3 of the time. Questionable science, at best. The NEJM, to the best of my knowledge, rarely, if ever, publishes a meta analysis.

some NEJM meta-analyses
1: Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GY, Bliss J, Vincent-Salomon A, Pantel K. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005 Aug 25;353(8):793-802. PMID: 16120859 [PubMed - indexed for MEDLINE] 2: Sargent DJ, Goldberg RM, Jacobson SD, Macdonald JS, Labianca R, Haller DG, Shepherd LE, Seitz JF, Francini G. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med. 2001 Oct 11;345(15):1091-7. PMID: 11596588 [PubMed - indexed for MEDLINE] 3: Janowsky EC, Kupper LL, Hulka BS. Meta-analyses of the relation between silicone breast implants and the risk of connective-tissue diseases. N Engl J Med. 2000 Mar 16;342(11):781-90. PMID: 10717013 [PubMed - indexed for MEDLINE] 4: Auperin A, Arriagada R, Pignon JP, Le Pechoux C, Gregor A, Stephens RJ, Kristjansen PE, Johnson BE, Ueoka H, Wagner H, Aisner J. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999 Aug 12;341(7):476-84. PMID: 10441603 [PubMed - indexed for MEDLINE] 5: [No authors listed] The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies. The International Perinatal HIV Group. N Engl J Med. 1999 Apr 1;340(13):977-87. PMID: 10099139 [PubMed - indexed for MEDLINE] 6: He J, Vupputuri S, Allen K, Prerost MR, Hughes J, Whelton PK. Passive smoking and the risk of coronary heart disease--a meta-analysis of epidemiologic studies. N Engl J Med. 1999 Mar 25;340(12):920-6. PMID: 10089185 [PubMed - indexed for MEDLINE] 7: Hunter DJ, Spiegelman D, Adami HO, Beeson L, van den Brandt PA, Folsom AR, Fraser GE, Goldbohm RA, Graham S, Howe GR, et al. Cohort studies of fat intake and the risk of breast cancer--a pooled analysis. N Engl J Med. 1996 Feb 8;334(6):356-61. PMID: 8538706 [PubMed - indexed for MEDLINE] 8: [No authors listed] Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. Early Breast Cancer Trialists' Collaborative Group. N Engl J Med. 1995 Nov 30;333(22):1444-55. Erratum in: N Engl J Med 1996 Apr 11;334(15):1003. PMID: 7477144 [PubMed - indexed for MEDLINE] 9: Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med. 1995 Aug 3;333(5):276-82. PMID: 7596371 [PubMed - indexed for MEDLINE] 10: Pignon JP, Arriagada R, Ihde DC, Johnson DH, Perry MC, Souhami RL, Brodin O, Joss RA, Kies MS, Lebeau B, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med. 1992 Dec 3;327(23):1618-24. PMID: 1331787 [PubMed - indexed for MEDLINE] 11: Poynard T, Cales P, Pasta L, Ideo G, Pascal JP, Pagliaro L, Lebrec D. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-Italian Multicenter Study Group. N Engl J Med. 1991 May 30;324(22):1532-8. PMID: 1674104 [PubMed - indexed for MEDLINE]

touche
touche. but the math stays the same. wrong over 1/3 of the time.

Evidence in the eye of the beholder.
What does this say about "evidence"? Using the same published studies, we come up with such different responses. Evidence it seems is in the eye of the beholder. But it is the best we have, and we have to use it. It is probabilistic, however, and we each take a chance on being somewhat wrong whenever we use evidence. Sometimes it is low probability, sometimes it is high. And sometimes it changes. So whether it is meta analyses or not, or which trial we use or wait for, we know there is sometimes no single right answer. We practice in some uncertainty and some certainty. The patient then takes the risk, after informed discussion, as much as possible, which also has limitations. And then we do as the patient wishes, knowing clearly that there is some uncertainty in the interpretation and use of the evidence, and thus uncertainty in practice. And such is life, and practice - the art and science of dealing with uncertainty, using the evidence the best way we think appropriate. Evidence in the eye of the beholder. VS Rambihar Toronto.

I think there exists far too much "hopeful...
..thinking" when comparing statin mono-therapy #'s. 51% ?? I think not. By my calculation it’s closer to the low 40’s. But, I am no statistician. No mono-therapy trial 'lumping together' large groups of patients; euglycemic, MS/IR, NIDDM, all lipid phenotypes,.. has shown much above 37% reduction in combined endpoints. [continued on thread,..]

Thread continued,... stain/LDL myopia
In one atorvastatin trial the p value was NS for event reduction in women, diabetics, LV dysfunction, etc., etc. ASCOT. yet, redesign w a lipid phenotype 'rarely' seen in NIDDM,.. HDL >52 on average [CARDS],.. and ,.. "low & behold",.. what % of the diabetics that you tx in your practice have HDL’s > 52 ? Half? A third? Why did dialysis patients see their rate of fatal ischemic stroke increase 2.03 times,.. on tx in the 4D trial?? Maybe Lp(a) shouldn’t be treated with certain statins. Any lipid clinic director knows that. But if subfractions were done routinely, everyone would know that. Select a certain phenotype to study & it will influence results,.. sometimes NOT as one had hoped. Diabetics are NOT LDL specific phenotypes: Drexel H et al Diabetes Care 28:1264-1265, 2005. What’s the greatest reduction in events seen in patients w FBG >126 in a mono-therapy lipid trial ?? NO,.. it`s not a statin,.. or a fibrate,.. it`s niacin. 54%. A benchmark. Everyone’s ‘waiting’ for an effective therapy for HDL,.. well,… we already have one; CDP, CLAS-I, CLAS-II, FATS, FATS follow up, HATS, AFREGS, ARBITER .In the CDP [government funded] looking at subsets of glycemic status at baseline, the WORSE the glycemic status at baseline, the greater the 'delta' of the event reduction. All the way to ~70% with niacin. See Dr. Charles Reavens' statement in Atherosclerosis Suppl last month. On the money. Different strokes, for different folks.. Isolated 'high' LDL, with little else?? Atorva Trigs over 800 w mod-low HDL?? Feno & fish oil Trigs < 800 w high LDL & low HDL?? Simva, niacin & fish oil [frozen] NIDDM dyslipidemia, w elevated Lp(a)? Simva /niacin: Only prava & simva are Lp(a) neutral [continued on thread 2]

Thread 2 - Statin/LDL myopia,... end of an era,...
Treat all targets,.. does it make sense that CAD is that simple?? Hypertension is already accepted as a combo-therapy disease state. Why do we think that targeting one surrogate risk marker will solve all our problems. There is NO evidence behind that!! The evidence for 70-95% reductions is there,.. multiple agents, modulating multiple targets; Statins are LDL drugs. Fine’ Niacin has as much pleiotropic effects as any statin,.. possible more; Rosensen et al Atherosclerosis 171 (2003) 87–96 . PON-1 NO We really need to 'get off of this' statin/LDL myopia,... LDL as MOST of us measure it, isn’t even LDL. Calculated LDL = [Real, direct measured] R-LDL & IDL & Lp(a) The last 2 are virtually statin-non-responsive. There goes the potential to reduce calc-LDL more than 65%,… ever. The calculated LDL loses accuracy as it descends; 5% @ 160, 10% @ 130. 15% @ 100 and when the calc-LDL: says it’s “65 mg/dL, it’s actually 19% higher. ALWAYS undertreating with that. So lower may be better, but was it as low as you thought?? That isn’t even factoring in triglycerides, just the Friedewald variance on any LDL. See Drexel’s paper on predicting events in diabetics. LDL is nearly worthless. HDL & pattern “B” are far more predictive. Neither is influenced significantly by statins. Framinham Offspring Study: HDL2 shift of 1 mg/dL changed the probability of CAD 26%. And it’s linear,.. Top to bottom. July 2004 NCEP statement: LDL relationship to events is a log relationship. Still using a calculated panel?? OK. Al-Sheikh AHA Scientific Sessions Nov 2004 Using ‘traditional lipid panel’ components, here is how they rank in predictive power: TC/HDL > HDL > Non-HDL > TC > LDL > TG In studies where a direct LDL was measured, once the IDL component was removed from the LDL,.. It was no longer predictive. It is swiftly becoming a ‘general, non-specific’ surrogate risk marker: One size does not fit all. Would we assess anyone’s risk today based on only a total cholesterol?? ~80% of all known lipid phenotypes can be managed / fully corrected with a low-dose ‘branded’ statin [or 40 mg lovastatin], one gm or > of prescription ER-niacin & 5-7 capsules of fish oil,.. Frozen. Run lipid subfractions prior to treatment & after. Usually a ‘clean slate’. Never happens with statin-mono tx, or ezetimibe-statin. There is nearly always ‘residual risk’ seen as pattern “B” unconverted, low HDL2, elevated Lp(a), etc. That is all cumulatively EXTREMELY significant,.. and virtually statin non-responsive. If you do it right, the 3 components of the calc-LDL prior to tx will tell you the likelihood of statin response or even the need for more ‘horsepower’. Who measures an “iceberg of risk”, by ‘cruising the surface’ glancing at the tips,… never acknowledging the need to actually measure the entire iceberg? The LDL decade is over,.. let’s move on. Castelli was right. Why did we only seize 20% of his data from 3 decades ago, and ignore the remainder? Exit soapbox,.. SMc

Spending less?? by all means,..
500 mg maintenance dose of Neptune Krill oil 20-40 mg of generic lovastatin 1-2 gms Rx ER niacin costs less than most 40-80 mg dose of a branded statin; Covers WAY more risk, costs less, a lot less, no gemfib/low dose statin = less myalgia,.. evidence based medicine,.. albeit mostly government funded; Not really in-line with the LDL-Mafia guidelines,... SMc

Studer et al ARCH INTERN MED/VOL 165, APR 11, 2005
Which class of lipid agent/therapy [incl. diet] has the 'best' reductions in CV nmortality vs. NON-CV mortality and ALL CAUSE mortality?? Fish Oil Worst?? ...the entire fibrate class,...

Brevity and honey-easier to swallow
Stephen, Although tempted to not read this long and winding post, I actually did, cutting you some slack as the early morning hour at which you posted may have actually been responsible for your ramblings. Most of which made sense,however, but I beg of you to err on the side of brevity next time. (I forgive you as I tend to get a little manic at 3 am as well.) None the less, the only problem with becoming Niacin Myopic is that many folks cannot tolerate niacin, having experienced this personally in a long line of flunking lipid therapies. I did exactly as recommended, took it at night, ate half an apple, took a baby aspirin and hung with it through horrible flushing, but big deal I knew I could take it. Then, at week 3 and 1/2, began to itch until I dug hunks of flesh out of my ankles and arms while I slept and bled. Then, I promptly developed symptoms of an ulcer from the aspirin for which I had to buy a bottle of Protonix and take for a month until the searing post prandial pain in my abdomen that radiated into my back cleared up. So, I'm a little more sympathetic with the niacin intolerant than I used to be. Might just try it again sometime though. Already take fish oil, and I agree with the fishoil statements. We shouldn't be treating LPa with statins, because it doesn't work and should be treated with Niacin anyway. I've seen some Lpa levels plummet on Zetia, for reasons unclear and cannot get the time to sit down and look over the data we've accumulated thus far. So, Brevity my dear Stephen will attract more flies than carb-laden honey to this discussion. Your thoughts are appreciated, albeit in abbreviated form anytime here. Melissa

rebuttal
Steve Nissen was able to show - in the aptly named REVERSAL trial - that high dose atorvastatin (that is, 80 mg/d) effectively retards the progression of coronary atherosclerosis. 6 years earlier, atorvastatin was shown to be as good as, if not better than, angioplasty in a study by Pitt in the New England. Atorvastatin 80 mg/d has never been compared with usual care, but if you compare the risk reductions of atorvastatin 10 mg/d vs placebo, and atorvastatin 80 mg/d vs 10 mg/d, the risk reduction for high dose atorvastatin is more than 50%, which means a halving of cardiovascular events. Fish oils, niacin, fibrates, etc ... none of these drug classes have anything close to the evidentiary track record of statins, which is why the title of the article was "billion-dollar battle for statin market share". Incidentally, I have no conflicts of interest or ties to industry.

Dear Ms M. Point(s) well taken,...
Zetia lowered Lp(a),... hmmm. We / I sympathize with your intolerance to niacin. I myself wish it were more tolerant as it tragically seems, those who need it the worst [low HDL2, Lp(a), etc.], always seem to be the least tolerant. We have done due-diligence to develop “THE” method to overcome flushing & maximize compliance,.. but the wheel had already been invented, so once discovered we ‘rolled-with-it’ as is. Dr. Wm. Castelli can be thanked for choosing a ‘round wheel ‘ 1st ~40 years ago. We merely substituted the 72 tablet box of EQUAATE @ WalMart to save $ & added a Walmart jar of applesauce; Whoilla,..The “Alka-Sauce” drill. Dr. Varveris in Naples Florida and many others have interesting twists to this based on their fervor to keep max % on niacin: Dissolve 1-2 tabs of Alka,… swallow 3 TBS applesauce,… wash down niacin w Alka. Some like Varveris add a small benadryl dose to it the 1st few days. It is amazing how MORE tolerant the QHS Rx ER-niacin form is vs. IR crystalline & how badly someone can react the 1st 3-7 days & still ‘tachyphylax’ down to complete tolerance @ 90 days. We have a refill rate, on treatment @ 90 days, of just over 90%. Belief in the benefit of the med is key. But to believe, one must 1st fully appreciate how it benefits the patient via ALL the available literature and witnessing the correction of 27 ‘check marks’ on a VAP test not possible with a statin, fenofib or anything else. Those with the worst compliance in their practices, usually do not challenge or educate their patients on niacin properly,.. or sometimes themselves. Yet, they could experience what we see & many other clinics see,.. 2-3 weeks in a row with no patient call backs; approx. 65-75 starts per 3 weeks. 90 % on tx @ 90 days. Comments on 4D re; Lp(a)?? Exit soapbox,.. SMc

Confession, good for the soul
Stephen, Enjoying your commentary, but to be fair to our forum participants, I might smell an industry rat here. Nothing wrong with being in industry, but would certainly step up to the plate and reveal my affiliation if I were you. As a matter of fact, knowing that you are Niacin myopic just makes you a better resource for any niacin questions that we might have. So, confession is good for the soul. Heck, it might even raise your HDL. Having said that, I think the entire hemodialysis/statin question is fascinating, but produces more questions than answers. It's such a pharmacological quagmire when as a practitioner, I try to choose ANY new medication for my HD pts. I usually just punt, take the lazy way out and call the nephrologist. When designing these studies, avoiding the p450 metabolized meds is the easier way out, but since the atorvastatin folks stuck their neck out, I do wonder if the "failed" pts. were not on p450 inducing meds and the others weren't? I wonder why atorvastatin has been shown to reduce bioinflammatory markers (crp) in other trials and no reduction in diabetic HD pts CV endpoints, with a higher CVA risk in subgroups. (But exercise caution in looking at SMALL subgroups-wasn't it colestid that increased suicide! -maybe it was the constipation, oh well I digress). in 4D, Maybe it WAS the dosing. As far as the comment that so many pts. did not finish the trial, just analyze the data in those that did. (I didn't see this information). As far as LPA, we don't even know what to do with it in the non-uremic population. Fun to lower it, when I can, makes me feel like a better doctor, but as far as what that translates into, I guess I'm just banking on the benefit of lowering all the other stuff as well. And I'll thank you to know that my HDL just returned at 62 (up from 25 just 12 years ago while still in my couch potato state)-LDL still stinks-160's. Having said that, it's time to wind this up and hit the old exercise bike. Hey, Maybe we need a study of exercise impact on the lipid profile of the HD pt. Good old weight loss and exercise. We are obsessed with "buying it in a bottle" aren't we? Melissa