Statins for Secondary Prevention of Cardiovascular Disease: The Right Dose

Since the publication of the 4S trial in 1994, there has emerged a consensus that statins save lives and decrease myocardial infarctions and strokes in coronary artery disease (CAD) patients irrespective of baseline serum cholesterol. However, there is controversy over the correct dose and the utility of the treatment-to-goal (cholesterol, low-density lipoprotein) approach. To answer remaining questions about the optimal statin dose in CAD patients, we have performed simple and meta-analyses of 3 large long-term (approx. 5 years) dose-clinical response studies (TNT, IDEAL, and SEARCH) and compared the results with older data including long-term safety data. The results show that raising the dose of simvastatin or atorvastatin to 80 mg confers no mortality advantage, an increase in adverse reactions and only a slight decrease in myocardial infarctions and stroke versus a lower dose. These results suggest a cost-effective approach of a single safe dose (40 mg of inexpensive generic simvastatin or atorvastatin) for almost all CAD patients and makes treatment-to-goal and cholesterol monitoring (except to check Received: August 20, 2010 Accepted after revision: November 19, 2010 Published online: January 11, 2011 Reynold Spector, MD 105 Stone Hill Road Colts Neck, NJ 07722 (USA) Tel./Fax +1 732 780 5762 E-Mail mspec007 @ verizon.net © 2011 S. Karger AG, Basel 0031–7012/11/0872–0063$38.00/0 Accessible online at: www.karger.com/pha D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :3 8: 49 P M Spector /Snapinn Pharmacology 2011;87:63–69 64 benefit of statins in secondary prevention, trials need to last a minimum of 5 years. Based on these statin trials, there was general agreement that all CAD patients (currently approx. 20 million in the United States) should be treated with statins irrespective of their serum cholesterol since CAD patients with lower serum cholesterol also benefit [2–4] . However, 2 treatment approaches emerged: one camp thought that the objective of treatment should be to lower serum cholesterol or low-density lipoprotein (LDL) to a certain goal based, in part, on Framingham risk data [5, 6] . (High serum cholesterol is an unequivocal risk factor in the Framingham score [5, 6] .) The notion of treatment-to-goal (cholesterol) was based on the theory that serum cholesterol, especially LDL, was a major contributory cause of CAD (and ischemic stroke) [5, 6] , but the proponents of this method of treatment could not deny that lowering total serum cholesterol and LDL, independent of initial total cholesterol and LDL levels, was crucial [2–4] . In other words, those with lower initial total serum cholesterol (and LDL) benefited as much as those with higher levels in being treated with statins [2–4] . On the other hand, a smaller group noted that the large long-term statin clinical trials were not based on titration to total cholesterol or LDL goals but were parallel fixed-dose design trials [7–9] . This group argued for giving a fixed statin dose to all CAD patients, but they were somewhat vague about what dose to use [7–10] . They also suggested that the effects of statins may be, in large part, independent of their effect on cholesterol and LDL lowering [9] . Along these lines, we note that statin ‘potency’ is traditionally thought of as dependent on the magnitude of lowering of serum cholesterol and LDL. However, this cholesterol-based definition of potency does not establish that in vivo potency (in preventing clinical events like death, MI or stroke) is related to serum cholesterol or LDL lowering. In the current analysis, we assume there is no difference in the in vivo potency between 80 mg of S and 80 mg of atorvastatin (A) in preventing events, an assumption justified below, notwithstanding the twofold greater ‘potency’ of A over S in lowering serum cholesterol. In clinical pharmacology trials, before using a surrogate like serum cholesterol or LDL, if possible, it is important to first establish the effect of the drug on hard endpoints as a function of dose; in this case, death, MI and stroke in CAD patients [11] . If surrogates can be validated, for example bone mineral density in the treatment of osteoporosis (with bisphosphonates) as a surrogate for fractures, then they may become useful. In many cases, surrogates are unnecessary, for example with proton pump inhibitors you just treat with a fixed dose since basically everyone responds with a reduction in stomach acid. You do not need to measure stomach acid. Finally, in some cases like premature ventricular contractions as a surrogate for cardiac death, suppressing the premature ventricular contractions with drugs was actually harmful [9] . To clarify how best to treat CAD patients with statins, in the following analyses we eschew employing serum cholesterol (total, LDL, high-density lipoprotein) and triglycerides as intermediates and look only at clinical events as a function of dose. (We remain neutral on the role of lipoproteins as a contributory cause of CAD and stroke morbidity and mortality [5, 6, 9] .) This approach is now possible because data from 3 long-term parallelgroup controlled randomized trials of S and A in CAD patients have become available in the last 5 years [12–15] . Unlike the older trials that pit S or A versus placebo [1] , these newer trials (TNT [12] , IDEAL [13] and SEARCH [14, 15] ), analyzed by the intention-to-treat principle, pit 2 doses of these statins, a low dose versus a high dose (80 mg) one against another, in single randomized long-term controlled trials. With these newer data, we can make better judgments of how best to treat CAD patients with S or A. Our hypothesis is that it is now possible to select a single dose of cheap generic S (or A) for almost all patients with CAD using the principles of clinical pharmacology generally employed by the FDA [11] and cost considerations. Obviously, the results and conclusions apply only to S and A, the statins studied in the TNT, IDEAL and SEARCH trials. Extrapolation of these results to other statins would be speculative. Finally, as suggested by others [7–9] , the utility of the treatment-to-goal (cholesterol) approach in secondary prevention [5, 6] is unproven and not required for good care of CAD patients as will be documented below.