Simvastatin Trial

In rodent stroke models, statin pretreatment has been shown to reduce infarct volumes and improve outcomes. Similarly, several clinical studies have shown that prior statin use reduced the severity of acute ischemic stroke and myocardial infarction. Recent studies indicate that beneftt can be achieved even when treatment is initiated after the onset of symptoms. In rodents, atorvastatin and simvastatin have been shown to reduce the growth of ischemic lesions, enhance functional outcome, and induce brain plasticity when administered after stroke onset. A retrospective analysis of the population-based Northern Manhattan Stroke Study (NOMASS) showed that patients using lipid-lowering agents at the time of ischemic stroke have a lower incidence of in-hospital stroke progression and reduced 90-day mortality rates. Retrospective analysis of data of the phase III citicoline trial showed... 

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

Eleart Protection Study Collaborative Group. (2002) MRC/BHF Heart Protection study of cholesterol lowering with simvastatin in 20,506 high-risk individuals a randomized placebo-controlled trial. Lancet, 360, 7-22. 

Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease ... 

Clinical trials with lovastatin (Mevacor), simvastatin (Zocor) and pravastatin (Pravachol) provided much of the evidence supporting the observation that lowering... 

Ezetimibe is the first member of a group of drugs that inhibit intestinal absorption of phytosterols and cholesterol. Its primary clinical effect is reduction of LDL levels. In one trial, patients receiving ezetimibe in combination with simvastatin had marginal, but not statistically significant, increases in carotid intimal-medial thickness (IMT) compared with those... 

Atorvastatin is an HMG Co-A reductase inhibitor. Pooled data from 21 completed and 23 continuing trials representing 3000 patient-years have shown that constipation, flatulence, dyspepsia, abdominal pain, headache, and myalgia occur in 1-3% of patients. Under 2% of atorvastatin-treated patients discontinued treatment because of an adverse event (1). Serious events in this review amounted to one patient with pancreatitis and one with cholestatic jaundice (1). There were no differences in adverse effects in 177 patients randomized for 52 weeks to either simvastatin or atorvastatin (2). 

Some studies have shown increased risks of violent death and depression in subjects with reduced serum cholesterol concentrations. Serum and membrane cholesterol concentrations, the microviscosity of erythrocyte membranes, and platelet serotonin uptake have been determined in 17 patients with hypercholesterolemia (21). There was a significant increase in serotonin transporter activity only during the first month of simvastatin therapy. This suggests that within this period some patients could be vulnerable to depression, violence, or suicide. This is an important paper, in that it explains why mood disorders are not regularly seen in clinical trials with statins, as has been summarized in a recent review (3). 

HMG CoA reductase inhibitors can be associated with small rises in alanine transaminase activity, but have not been definitely associated with severe morbidity involving altered hepatic function. The results of randomized trials do not suggest that statins in standard doses are hepato-toxic. In none of the large randomized studies in which standard doses were assessed (atorvastatin 10 mg/day, fluvastatin 40-80 mg/day, pravastatin 40 mg/day, simvastatin 20-40 mg/day) was there any clear excess risk of hepatitis or any other serious liver-related adverse events. Long-term large randomized trials have confirmed an excess of persistent rises in transaminases with atorvastatin 80 mg/day compared with lower doses or placebo, and similarly some excess with simvastatin 80 mg/day, but hepatitis and liver failure were not reported (4). 

Muldoon MF, Ryan CM, Sereika SM, Flory JD, Manuck SB. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. Am J Med 2004 117(ll) 823-9. 

Recent reports on clinical trials of pravastatin and simvastatin have shown a significant reduction in patient mortality rates for both hypercholesterolemic patients without known coronary heart disease and for those with existing coronary heart disease [7,8], These trials have established cholesterol-lowering agents as an effective treatment for coronary disease and have stimulated the search for new cholesterol-lowering agents with other mechanisms of action. 

TR Pedersen, J Kjekshus, K Berg, T Haghfelt, O Faergeman, G Thorgeirsson, K Pyorala, T Miettinen, AG Olsson, H Wedel, L Wilhelmsen. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease the Scandinavian Simvastatin Survival Study (4S). Lancet 344 1383-1389, 1994. 

Pedersen TR, Faergeman O, KasteleinJJ, etal, High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction the IDEAL study a randomized controlled trial. JAMA 2005 294 2437-2445,... 

Collins R, Armitage J, Parish S, Sleigh P Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes a randomised placebo-controlled trial. Lancet 2003 361 2005-20l 6. 

In the 80-mg simvastatin dose group in the Ato Z trial, CRP levels fell from 20,1 to 1,7 at four months and 1,5 at eight months (P < 0.001) (36). Higher-dose simvastatin resulted in lower CRP levels. In PROVE-IT (35), Ato Z (36), and MIRACL trials (37), higher doses of statin medications resulted in lower low-density cholesterol (LDL) and a better outlook. Higher doses of statin also caused greater falls in CRP levels. This suggests a role for inflammation in these ACS patients (37). 

Today HMG-CoA reductase inhibitors (statins) account for the large majority of prescriptions for lipid-lowering drugs in most countries. As discussed in a subsequent section of this chapter, the widespread acceptance of this drug class is due not only to excellent efficacy and tolerability but also to the publication of several very large intervention trials, which have unequivocally demonstrated the effectiveness of the first three members of the class—lovastatin, simvastatin, and pravastatin—in reducing coronary morbidity and mortality. 

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