Statin Drugs - A Critical Review of the Risk/Benefit Clinical Research

Many well-funded sources attempt to justify the wide use of the statin drugs to lower TC and LDL by citing references in support of the claims that high levels of TC and LDL have been correlated with cardiovascular disease. Such claims are unfounded, since high TC and LDL are well-correlated with age, which is a risk factor.[1,2]  With age removed, there is almost no correlation, and certainly none that allows a worthwhile prediction of risk for a given individual. The rare familial hypercholesterolemia (FH), in which TC > 400 mg/dL, is usually represented as more deadly than it really is, when the sales of statin drugs are at stake. Moreover, the removal of those with FH from the high TC and LDL groups in epidemiological studies also removes any predictive ability.[1] 

The supposed benefits of the statins, beyond a large, but meaningless lowering of TC and LDL, long recognized as a worthless surrogate endpoint,[3] are usually given as lowered relative risks (RR) of mostly non-fatal heart attacks without the slightest indication of the low magnitude of the more meaningful reduction of absolute risk or of all-cause death rates. This misrepresentation has been noted.[1,4]  So the usual tout of pravastatin in the WOSCOPS trial, based on a 22% drop in all-cause mortality, was given without the information that this was only a 0.9% drop absolute in the 5-year trial period, or 0.18% per year. The higher all-cause death rates in 2 of the big trials of lovastatin were ignored, as was the higher breast cancer rate (RR = 1500%) in the CARE trial with pravastatin.[1]  Furthermore, it is also known that studies of drugs sponsored by their maker are often biased or selected, so even the 0.9% was probably exaggerated.[5-7]

Besides cancer, the other side effects of statins listed were incomplete, and should have included constipation, myalgia, myopathy, polyneuropathy, liver and kidney damage, congestive heart failure and amnesia. Side-effects are usually said to affect 2-6% of patients. In fact, a recent meta-analysis noted side-effects in 20% of patients above the placebo rate (65% vs. 45%), and no change whatever in the all-cause death rate for atorvastatin. [8] The PROSPER trial on pravastatin showed no change in the all-cause death rate, and increased cancer and stroke rates. 9 Statins are commonly used at a dose to lower TC to < 160 mg/dL, a level noted in the report of a NHLBI conference to be associated with higher cancer rates.[10]

Statins decrease the body’s production of the essential coenzyme Q-10 and dolichol, among other things. Low Q-10 levels are strongly associated with congestive heart failure.[10a]

There is some recognition that statins operate to lower non-fatal heart attack rates by mechanisms other than cholesterol lowering, but none that their desirable effect on thromboxane A2 is less than men can obtain with buffered aspirin,[11] or that the desirable effect of raising nitric oxide (NO) levels is less than one can obtain with the supplement L-arginine with no side-effects. These effects of statins are independent of initial or final TC or LDL levels,[12] and thus there is no way to determine who “should be treated” with statins, or what the dose should be.

Since the use of statins for primary prevention of CVD has been shown to increase all-cause mortality by 1% over a 10-year period,13 and has very little to no effect in secondary prevention of death,[9,11,14,15] it would seem that there is no cost-benefit in primary prevention, and very little for secondary prevention.

The most favorable trial with seemingly impeccable reporting and minimal financial conflict of interest was the Heart Protection Study (HPS), on simvastatin for 5 years, in which secondary prevention in men (86% of patients) of any unwanted vascular event gave a RR = 0.76 (5.5% absolute, 1.1% per year), and an all-cause death rate drop of 0.38% per year.16 Since this performance is inferior to that of either Bufferin™ in men [11] or omega-3 fatty acid supplements,[17] both of which have lesser side-effects, and are far less expensive, the logic of prescribing simvastatin seems faulty.

In another example, total cardiovascular events and procedures were 2% absolute lower with atorvastatin than with placebo after 3.5 years, giving RR = 0.79. This is a poorer performance than that of Bufferin™ for which RR = 0.31 for non-fatal MI in men during 7 years.[11]  With omega-3 fatty acid supplements during 3.5 years, total cardiovascular events had RR = 0.80, and for all fatal events in this period RR = 0.7917 vs. about 1.0 for atorvastatin.[8]

Atorvastatin and simvastatin are the statin drugs most likely to cause memory loss.[18]

In the ASCOT-LLA trial19 on hypertensive subjects with average or lower TC, there was no change in the all-cause death rate vs. placebo after 3.5 years; however there was a higher incidence of the arbitrarily defined primary endpoint of non-fatal MI plus fatal CVD among the 19% women in the trial, similar to the effect of aspirin in women.[20]

Careful examination of the literature on statin drugs reveals false premises, minimal to no benefits, serious side-effects leading to very low adherence rates,[8,21] and safer, low-cost alternatives for prevention of CVD deaths.

REFERENCES

            1. Ravnskov U, The Cholesterol Myths, Washington, DC, New Trends, 2000; www.THINCS.org

            2. Ravnskov U, High cholesterol may protect against infections and atherosclerosis.  Quart J Med 2003;96:927-934.

             3. Fleming TR, DeMets DL.  Surrogate End Points in Clinical Trials: Are We Being Misled? Ann Int Med  1996;125:605-613.

            4. Gigerenzer G, Calculated Risks: How to Know When Numbers Deceive You, New York, NY, Simon & Schuster, 2002.

            5. Krimsky S.  A conflict of interest.  New Scientist  2003;179(2410), online. 

            6. O’Shea, J. C. & DeMets, D. L. ().  Statistical issues relating to international difference in clinical trials.  Am Heart J 2001;142:21-28. 

            7. Mayor S.  Researchers claim clinical trials are reported with misleading statistics. Br Med J  2002;324:1353.

            8. Newman CB, Palmer G, Silbershatz H, Szarek M.  Safety of Atorvastatin Derived from Analysis of 44 Completed Trials in 9,416 Patients.  Am J Cardiol  2003;92:670-6.

            9. Shepherd J, Blauw GJ, Murphy MB et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.  Lancet 2002;360(9346):1623-30.

             10. Jacobs D, Blackburn H, Higgins M et al.  Report of the Conference on Low Blood Cholesterol: Mortality Associations.  Circulation 1992:86:1046-60.

            10a. Mortensen SA.  Perspectives on therapy of cardiovascular diseases with coenzyme Q10 (Ubiquinone). Clin Investig 1993;71:S116-S123.    Langsjoen PH, Langsjoen AM. Coenzyme Q10 In Cardiovascular Disease With Emphasis On Heart Failure and Myocardial Ischaemia. Pacific Heart J 1998;7(3):160-168.

            11. Kauffman, JM.  Bias in Recent Papers on Diets and Drugs in Peer-Reviewed Medical Journals.  J Am Phys Surg 2004;9(1): in press.

            12. Nielsen JV.  Serun lipid lowering and risk reduction? Where is the connection?  Br Med J Rapid Response,  19 Nov 01, to Kmietowicz Z. Statins are the new aspirin, Oxford researchers say.  Br Med J  2001;323:1145.                 

            13. Jackson PR, et al. Statins for primary prevention: at what coronary risk is safety assured? Br J Pharmacology 2001;52:439-446 

            14. Liema AH, van Bovenb AJ, Veegerb NGJM et al.  Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial.  Eur Heart J  2002;23(24):1931-1937.

            15. Kauffman JM, Do Hypolipidemic Drugs Lower Medical Expenses?  Pharmacotherapy  2001;22(12),1583-1586.

            16. HPS Collaborative Group. 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.

            17. Marchioli R, Barzi F, Bomba E et al.  Early Protection Against Sudden Death by n-3 Polyunsaturated Fatty Acids After Myocardial Infarction.  Circulation 2002;105:1897-1903.

             18. Wagstaff LR, Mitton MW, McLendon Arvik B, Doraiswamy PM.  Statin-Associated Memory Loss: Analysis of 60 Case Reports and Review of the Literature.  Pharmacotherapy 2003;23(7):871-880.

             19. Sever PS, Dahlof B, Poulter NR et al. Prevention of coronary and stroke events with atorvastatin in hypertenisve patients who have average or lower-than-average cholesterol concentrations, inthe Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.  Lancet 2003;361:1149-1158.

           20. Kauffman JM, “Aspirin Study Flawed”, Letter to Editor, J. Scientific Exploration 16(2), 247-249 (2002).

            21. Jackevicius CA, Mamdani M, Tu JV. Adherence With Statin Therapy in Elderly Patients With and Without Acute Coronary Syndromes. J Am Med Assoc 2002;288:462-467.

          --Joel M. Kauffman, Ph.D. Professor of Chemistry Emeritus, USP, Philadelphia, PA, USA

Submitted 8 Dec 2003; accepted 9 Dec 2003; published 9 Dec 2003