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Research

The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials

Kiranbir Josan, Sumit R. Majumdar and Finlay A. McAlister
CMAJ February 26, 2008 178 (5) 576-584; DOI: https://doi.org/10.1503/cmaj.070675
Kiranbir Josan MD
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Sumit R. Majumdar MD MPH
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Finlay A. McAlister MD MSc
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  • Choice of substance
    Martin Gerken
    Posted on: 05 August 2008
  • Statins - Safe ?
    Dr.Herbert H. Nehrlich
    Posted on: 06 May 2008
  • Statins are safe. So stop checking ALT and AST in asymptomatic patients on statins!
    Kevork M. Peltekian
    Posted on: 23 April 2008
  • Posted on: (5 August 2008)
    Choice of substance
    • Martin Gerken

    You do not comment on the choice of substance: 6 of the 7 trials were comparing 80mg of atorvastatin vs. normal-intensity statin. The only trial of high-dose simvastatin (A-Z) showed no significant benefit. I hope that the SEARCH trial will provide adequate data on simvastatin. I'd suggest a sensitivity analysis using duration of trial as a variable. It seems, that the effect of high-dose atorvastatin is confined to a limit...

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    You do not comment on the choice of substance: 6 of the 7 trials were comparing 80mg of atorvastatin vs. normal-intensity statin. The only trial of high-dose simvastatin (A-Z) showed no significant benefit. I hope that the SEARCH trial will provide adequate data on simvastatin. I'd suggest a sensitivity analysis using duration of trial as a variable. It seems, that the effect of high-dose atorvastatin is confined to a limited period of time after ACS.

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.
  • Posted on: (6 May 2008)
    Statins - Safe ?
    • Dr.Herbert H. Nehrlich

    Dr. Peltekian's headline announces to the readers that STATINS ARE SAFE. We only wish. Statins reduce the body's production of mevalonate through the suppression of a liver enzyme called hydroxymethylglutaryl (HMG) coenzyme A reductase. This enzyme is crucial in enabling the body to synthesize such substances as cholesterol, Co-enzyme Q-10 etc., substances that are essential for every living cell.So, if you reduce the supp...

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    Dr. Peltekian's headline announces to the readers that STATINS ARE SAFE. We only wish. Statins reduce the body's production of mevalonate through the suppression of a liver enzyme called hydroxymethylglutaryl (HMG) coenzyme A reductase. This enzyme is crucial in enabling the body to synthesize such substances as cholesterol, Co-enzyme Q-10 etc., substances that are essential for every living cell.So, if you reduce the supply of mevalonate, the liver can no longer keep up production of sufficient cholesterol and has to slow the shipping of cholesterol from the depot (liver)to the various areas in need of it via the bloodstream. Hence, blood cholesterol will be lower in lab tests.Mevalonate is not just important in this respect but is heavily involved in muscle metabolism as well as in the production of thromboxane. Thromboxane, of course, is the agent responsible for the important stage in healing called clotting and originates in the platelets of our blood. Mitochondria are energy factories that MUST have coenzyme Q- 10, the very substance that is in short supply when people undergo statin treatment.

    Further, since smooth muscles are involved in setting up plaque, a reduction in plaque through enforced "laziness" of smooth muscle cells seems plausible and inevitable.

    However, the dismal success record of statin treatment, combined with their sometimes atrocious side effects (identified and hidden) makes the prescription of statins in humans an assault with unknown and likely dire consequences. Space is always scarce and I will not take the time to go into the pro's and con's of cholesterol and our pre-occupation with it as the Bogeyman. However, people tend to die with low cholesterol blood levels yet we see some sort of necessity in establishing the same scenario. May I ask for the studies that have shown that lowering cholesterol is reasonable and thus good practice? Statins are safe? Let us look at the PROSPER Trial and the all cause mortality. It is not improved by statins.

    I prefer to see cholesterol as an extremely vital substance, essential for good health and indispensable when it comes to repair and maintenance of the body. Yes, statins are now Big Pharma's golden goose and the price of gold is rising.

    If we think of rhabdomyolysis, of transient global amnesia and of the propensity of statins to initiate cancer in many animals, if we consider the truly dismal success of statin treatment then we can skip looking at the plausibility of using these drugs altogether.

    Statins are mayhem to Coenzyme Q-10 and it follows that statins may thus weaken the heart.They may cause cancer in humans.

    I often wonder what our great-grandparents did without statins. Many did live to a ripe old age.

    There is no evidence that statins are safe and Dr.Peltekian has not provided any for that very reason.A belief, based on clinical observation is often a cousin to bias.As the disclaimer on the Lipitor label says: Lipitor has not been shown to.....

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    None declared

    Show Less
    Competing Interests: None declared.
  • Posted on: (23 April 2008)
    Statins are safe. So stop checking ALT and AST in asymptomatic patients on statins!
    • Kevork M. Peltekian

    I read with interest the meta-analysis by Josan et al [1] on the safety of intensive statin therapy but was disappointed with their avoidance of commenting on the need to monitor hepatotoxicity. In their analysis, even with the intensive statin therapy only 1.5% showed elevations in serum aminotransferase (ALT) levels [1]. Unfortunately, most subjects starting statins get their ALT levels tested and retested unnecessaril...

    Show More

    I read with interest the meta-analysis by Josan et al [1] on the safety of intensive statin therapy but was disappointed with their avoidance of commenting on the need to monitor hepatotoxicity. In their analysis, even with the intensive statin therapy only 1.5% showed elevations in serum aminotransferase (ALT) levels [1]. Unfortunately, most subjects starting statins get their ALT levels tested and retested unnecessarily.

    Randomized controlled trials have shown no difference between placebo and statin groups in withdrawals due to raised ALT levels [2]. Tolman [3] has reviewed the literature for lovastatin, which has been in use since 1986 with 24 million patient-years of clinical experience. Elevated ALT was documented at the rate of 2.6% and 5% for lovastatin doses of 20 mg/day and 80 mg/day, respectively. In many, the elevation in liver enzymes were transient and improved even with continuing therapy. Acute liver failure occurred in 1 per 1.14 million patient-treatment years. This is equivalent to background rate of acute liver failure in the general population.

    Minor elevations in ALT are poorly predictive of hepatotoxicity and hence ineffective in preventing serious liver disease [4]. Furthermore, in a review from primary care setting to determine the value of routine monitoring of enzyme levels (ALT and CK) in over 1000 patients taking statins [5] only 1% had significant elevation in ALT. None appeared to be related to statin use. Similar results were obtained for the analysis of CK levels. They questioned the usefulness of routine monitoring in all patients taking statins. ALT elevations due to statin therapy will almost always resolve within 6 weeks of discontinuation. The decision to reinstitute therapy should be based on an individualized risk versus benefit analysis [6]. Signs and symptoms of hepatic failure (especially jaundice) should prompt immediate discontinuation of therapy and referral to a specialist.

    There is a need to review and change the old published guidelines recommending initial screening laboratory testing as well as ongoing monitoring of liver enzymes during therapy. Judicious use of laboratory testing will minimize needless evaluation and premature discontinuation of statin therapy.

    References 1. Josan K, Majumdar SR, McAlister FA. The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. CMAJ 2008; 178:576-84. 2. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22. 3. Tolman KG. The liver and lovastatin. Am J Cardiol 2002; 89: 1374-1380. 4. Bolego C, Baetta R, Bellosta S, Corsini A, Paoletti R. Safety considerations for statins. Curr Opin Lipidol 2002;13:637-644 5. Smith CC, Bernstein LI, Davis RB, Rind DM, Shmerling RH. Screening for statin-related toxicity: the yield of transaminase and creatine kinase measurements in a primary care setting. Arch Intern Med 2003;163:688-92. 6. Gotto AM Jr. Safety and statin therapy: reconsidering the risks and benefits. Arch Intern Med 2003; 163:657-659.

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.
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Canadian Medical Association Journal: 178 (5)
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Vol. 178, Issue 5
26 Feb 2008
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The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials
Kiranbir Josan, Sumit R. Majumdar, Finlay A. McAlister
CMAJ Feb 2008, 178 (5) 576-584; DOI: 10.1503/cmaj.070675

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The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials
Kiranbir Josan, Sumit R. Majumdar, Finlay A. McAlister
CMAJ Feb 2008, 178 (5) 576-584; DOI: 10.1503/cmaj.070675
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