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PubMed2005

The effect of six different statins on the proliferation, migration, and invasion of human smooth muscle cells.

Intimal hyperplasia (IH) can occur after any vascular injury and results from smooth muscle cells (SMC) proliferation, migration, and invasion into the subintimal space. The purpose of this study was to investigate the effect of six different statins on the proliferation, migration, and invasion of human venous SMC. The statins were all used at their Cmax concentrations. SMCs were used to construct growth curves in the presence of 10% fetal calf serum or 10% fetal calf serum supplemented with the six statins. Migration and invasion experiments were performed using modified Boyden chambers. The invasion experiments were performed using Matrigel coated plates. We found that all of the statins significantly inhibited SMC proliferation compared to the platelet-derived growth factor control (ranging from fluvastatin 33% of control to pravastatin 72% of control, P = 0.03). SMC migration through uncoated polycarbonate membranes in presence of the six statins was significantly reduced (ranging from lovastatin 43% to pravastatin 57% of control, P = 0.006). All six statins also significantly reduced SMC invasion (ranging from fluvastatin 65% to simvastatin 87% of control, P = 0.002). We conclude that the inhibitory effect of statins on SMC proliferation, migration, and invasion is a class, rather than drug specific effect.

Atorvastatin↗
PubMed2006

Preoperative statin treatment is associated with reduced postoperative mortality and morbidity in patients undergoing cardiac surgery: an 8-year retrospective cohort study.

BACKGROUND: Cardiac surgical procedures can be associated with significant morbidity and mortality. Recently, it has been recognized that statins might induce multiple biologic effects independent of lipid lowering that could potentially ameliorate adverse surgical outcomes. Accordingly, this study tested the central hypothesis that pretreatment with statins before cardiac surgery would reduce adverse postoperative surgical outcomes. METHODS: Demographic and outcomes data were collected retrospectively for 3829 patients admitted for planned cardiac surgery between February 1994 and December 2002. Statin pretreatment occurred in 1044 patients who were comparable with non-statin-pretreated (n = 2785) patients with regard to sex, race, and age. Primary outcomes examined included postoperative mortality (30-day) and a composite morbidity variable. RESULTS: The odds of experiencing 30-day mortality and morbidity were significantly less in the statin-pretreated group, with unadjusted odds ratios of 0.43 (95% confidence interval [CI], 0.28-0.66) and 0.72 (95% CI, 0.61-0.86), respectively. Risk-adjusted odds ratios for mortality and morbidity were 0.55 (95% CI, 0.32-0.93) and 0.76 (95% CI, 0.62-0.94), respectively, by using a logistic regression model and 0.51 (95% CI, 0.27-0.94) and 0.71 (95% CI, 0.55-0.92), respectively, in the propensity-matched model, demonstrating significant reductions in 30-day morbidity and mortality. In a subsample of patients undergoing valve-only surgery (n = 716), fewer valve-only patients treated with statins experienced mortality, although these results were not statistically significant (1.96% vs 7.5%). CONCLUSIONS: These findings indicate that statin pretreatment before cardiac surgery confers a protective effect with respect to postoperative outcomes.

Cardiac Surgical Procedures↗
PubMed2004

Statin therapy is associated with improved patency of autogenous infrainguinal bypass grafts.

OBJECTIVE: HMG-CoA reductase inhibitors (statins) broadly reduce cardiovascular events, effects that are only partly related to cholesterol lowering. Recent studies suggest important anti-inflammatory and antiproliferative properties of these drugs. The purpose of this study was to determine the influence of statin therapy on graft patency after autogenous infrainguinal arterial reconstructions. METHODS: A retrospective analysis of consecutive patients (1999-2001) who underwent primary autogenous infrainguinal reconstructions with a single segment of greater saphenous vein was performed. Patients were categorized according to concurrent use of a statin. Graft lesions (identified by duplex surveillance) and interventions were tabulated. Comparisons between groups were made by using the Fisher exact test for categorical variables and the Student t test for continuous variables. Patency, limb salvage, and survival were compared by log rank test. A stepwise Cox proportional hazards analysis was then employed to ascertain the relative importance of factors influencing graft patency. RESULTS: A total of 172 patients underwent 189 primary autogenous infrainguinal arterial reconstructions (94 statin, 95 control) during the study period. The groups were well matched for age, indication, and atherosclerotic risk factors. Procedures were performed primarily for limb salvage (92%), with 65% to an infrapopliteal target. Perioperative mortality (2.6%) and major morbidity (3.2%) were not different between groups. There was no difference in primary patency (74% +/- 5% vs 69% +/- 6%; P =.25), limb salvage (92% +/- 3% vs 90% +/- 4%; P =.37), or survival (69% +/- 5% vs 63% +/- 5%; P =.20) at 2 years. However, patients on statins had higher primary-revised (94% +/- 2% vs 83% +/- 5%; P <.02) and secondary (97% +/- 2% vs 87% +/- 4%; P <.02) graft patency rates at 2 years. Of all factors studied by univariate analysis, only statin use was associated with improved secondary patency (P =.03) at 2 years. This was confirmed by multivariate analysis. The risk of graft failure was 3.2-fold higher (95% confidence interval, 1.04-10.04) for the control group. Perioperative cholesterol levels (available in 47% of patients) were not statistically different between groups. CONCLUSIONS: Statin therapy is associated with improved graft patency after infrainguinal bypass grafting with saphenous vein.

Aged↗
PubMed2006

Statins and tissue mineralization: putative involvement of alkaline phosphatase.

Many clinical trials have clearly demonstrated the benefit of statins in the prevention of coronary heart disease. Although other effects have subsequently been described, the so-called pleiotropic effects of statins, there is a tendency to relate all those effects, more or less directly, to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A. Several clinical and laboratory studies show an association between statins and increased bone formation and/or density, but no clear explanation for that statin effect has emerged. We therefore hypothetized that statins may have an effect on alkaline phosphatase activity (ALP), an enzyme with an important role in bone mineralization and that may also contribute to pathological mineralization in other tissues, such as vascular calcification. Our experience with drug effects on ALP lead us to admit the possibility of finding a statin with an ALP increasing effect on bone but not on vascular tissue, or with a more marked effect upon one of the ALP isoforms or isoenzymes. That information would allow the design of clinical trials to confirm the suitability of a specific statin to a specific clinical condition.

Alkaline Phosphatase↗
PubMed2006

Effect of statin treatment on oxidative stress and renal function in renal transplantation.

The beneficial action of statins on the lipid profile, cardiovascular disease, and death is well known. Besides their lipid-lowering role, these drugs have pleiotropic action that derive from their prevention of the synthesis of isoprenoids, mediators in cell signaling. Thus, due to their antioxidant capacity, statins can decrease the production of reactive oxygen species by inhibiting NAD(P)H oxidase activity. Previous studies by our group have described increased oxidative stress status in renal transplantation that might benefit from HMG CoA reductase inhibitor therapy. The aim of this study was to assess the influence of statins on stress parameters and their relevance to renal function in kidney transplantation. In 58 transplanted patients a first blood sample was obtained, without statins followed by 21 patients treated with statins (group 1) and 37 patients without drug (group 0) for a 6-month study period. We collected clinical data as well biochemical results on lipid profile, creatinine and oxidative stress. Lipid profile reduction was significant among group 1 compared with group 0. An increased glutathione peroxidase (GPx) among observed in all patients was greater in the statin-treated group (P = .006). No differences in creatinine or Cockroft-Gault values were observed between before versus after drug administration. In conclusion, statin treatment in renal transplantation improves the lipid profile and may increase GPx-measured antioxidant capacity but appears to have no short-term effect on renal function.

Humans↗
PubMed2006

Association of statin use with improved local control in patients treated with selective bladder preservation for muscle-invasive bladder cancer.

OBJECTIVES: To assess whether statin use improves local control (LC) in patients undergoing organ-preserving trimodality therapy for muscle-invasive bladder cancer. METHODS: We retrospectively analyzed the data from 286 patients with muscle-invasive, transitional cell carcinoma of the bladder treated with maximal transurethral resection of the bladder tumor followed by chemoradiotherapy from 1986 to 2003 at the Massachusetts General Hospital. Patients with a complete response after induction chemoradiotherapy received consolidation chemoradiotherapy and those with an incomplete response underwent cystectomy. Of the 286 patients, 35 (12%) were known to be taking a statin during chemoradiotherapy. LC was defined as freedom from the development of muscle-invasive bladder cancer or superficial bladder cancer necessitating cystectomy. RESULTS: The median follow-up time was 2.7 years for all patients and 3.1 years for survivors. The overall 5-year LC rate was 55%. On univariate analysis, tumor stage, completeness of transurethral resection of the bladder tumor, hydronephrosis, chemotherapy type, treatment era, and statin use were significantly associated with LC. The 5-year LC rate for patients taking a statin was 73% versus 52% for patients not taking a statin (P = 0.04). On multivariate analysis incorporating covariates that were statistically significant (P < 0.05) on univariate analysis, only chemotherapy with cisplatin (P = 0.02) and the absence of hydronephrosis (P = 0.01) remained significantly associated with LC. CONCLUSIONS: Statin use was associated with an improvement in LC on univariate analysis but was not found to be independently associated with LC after controlling for known prognostic factors. The potential beneficial interaction between statin use and chemoradiotherapy in bladder cancer warrants further investigation in a prospective study.

Aged↗
PubMed2003

The cholesteryl ester transfer protein Taq1B gene polymorphism predicts clinical benefit of statin therapy in patients with significant coronary artery disease.

BACKGROUND: Cholesteryl ester transfer protein (CETP) regulates plasma lipid distribution. A polymorphism in the CETP gene (Taq1B) is associated with CETP activity, HDL concentration, atherosclerosis progression, and response to statins, and may influence cardiovascular (CV) events. We studied CETP Taq1B genotype, plasma HDL, and clinical events among all patients and patients stratified by statin treatment. METHODS: Consenting patients (n = 2531) with significant coronary artery disease (> or =1 lesion of > or =70% stenosis) undergoing coronary arteriography were genotyped, grouped by statin prescription at hospital discharge, and prospectively followed-up for the outcomes of all-cause mortality and myocardial infarction. RESULTS: CETP Taq1B genotype frequencies were: B1B1, 32.9%; B1B2, 50.3%; and B2B2 16.8%. Plasma HDL was reduced for B1B1 patients (33 +/- 12 mg/dL, vs 36 +/- 13 mg/dL and 36 +/- 13 mg/dL for B1B2 and B2B2, respectively, P for trend =.003). Overall, event rates did not differ between genotypes. Event rates were similar among untreated (24.8%) and statin-treated (24.2%) B1 homozygotes (P = NS); statins significantly reduced events for B1B2 subjects (28.0% vs 21.0%, P =.009) and for B2B2 subjects (26.4% vs 17.4%, P =.048). Therapeutic benefit for B2 carriers remained after adjustment for covariates, and regression interaction analysis showed that B2 carriers experienced reduced events (relative risk [RR] 0.62, 95% CI 0.45-0.86), but statins did not benefit those with B1B1 (RR 1.09, 95% CI 0.70-1.7; P for interaction =.02). Findings were similar for the end point of death alone, although a modest benefit was seen in B1B1 patients (RR 0.67, P =.10), in addition to the strong benefit for B1B2 (RR 0.53, P =.001) and B2B2 (RR 0.28, P =.001). CONCLUSIONS: The CETP Taq1B polymorphism is associated with differential HDL levels but no significant differential in CV risk in the absence of treatment. Importantly, however, CV event reduction by statin therapy is substantially enhanced in the presence of a B2 allele. Our findings suggest, for the first time, the potential of CETP Taq1B genotyping to enable more effective, pharmacogenetically directed therapy.

Aged↗
PubMed1998

Treatment of hyperlipidemia with combined niacin-statin regimens.

Combined use of niacin with a statin is an attractive option, since these types of medication have the best records in clinical trials for reduction in cardiovascular events and improvement in progression/regression of coronary lesions. In early use, the niacin-statin combination generated a few case reports documenting severe myopathy and rhabdomyolysis. Subsequent prospective trials in >400 patients, however, have not encountered myopathy. This experience includes 165 patients who took a statin in combination with Niaspan, a new, extended-release niacin administered once nightly. Hepatic toxicity with immediate-release niacin and with Niaspan used in combination with statins has been minimal. However, substantial transaminase elevations occurred with the use of a sustained-release niacin (Nicobid) given twice daily. The niacin-statin treatment regimens gave augmented low-density lipoprotein (LDL)-cholesterol reduction along with favorable changes in high-density lipoprotein (HDL) cholesterol, lipoprotein(a), and triglycerides. This combination therapy can be used safely as long as (1) careful attention is given to niacin formulation and dosing; (2) liver functions are monitored; and (3) patients are educated to recognize symptoms of myopathy. However, special caution should apply to use of niacin in combination with high doses of statins, or with statins introduced into clinical practice in 1997 or later, since little experience has accumulated in these circumstances.

Anticholesteremic Agents↗
PubMed2002

Statins do not meet expectations for lowering low-density lipoprotein cholesterol levels when used in clinical practice.

BACKGROUND: Statins have become a mainstay in the treatment of hyperlipidemia, based on their potency and favorable side-effect profile. Drug choice is presumed to be guided by the estimated degree of low-density lipoprotein (LDL) cholesterol lowering required in a particular patient and the projected efficacy of any drug-dose combination, as contained in the package inserts for each medication. We investigated whether these expectations were met in a clinical practice. METHODS: Data were analyzed for 367 hyperlipidemic patients in a preventive cardiology practice who were not taking statins at entry, who were given a standard statin dose at their first visit, and who had at least one follow-up visit on the same drug/dose. Expected LDL cholesterol reductions were calculated for each patient based on guidelines in the package inserts for each drug. RESULTS: The mean (+/-SD) observed LDL cholesterol reduction of 26% +/- 20% was significantly less than expected (34% +/- 7%, P < 0.001). The ratio of observed to expected reduction was not different for the three statins used (atorvastatin, 0.79 +/- 0.48; simvastatin, 0.88 +/- 0.61; pravastatin, 0.75 +/- 0.69; P = 0.39). CONCLUSIONS: The use of statins in a clinical practice led to observed reductions in LDL cholesterol level that were significantly less than those projected by package insert guidelines. We believe this gap reflects the reduced patient compliance frequently observed in clinical practice settings, rather than any inherent difference in statin responsiveness of a practice versus a trial population. Physicians should be aware of this disparity when using statins in the clinical setting.

Aged↗
PubMed2001

Statins inhibit oxidized-LDL-mediated LOX-1 expression, uptake of oxidized-LDL and reduction in PKB phosphorylation.

OBJECTIVES: LOX-1, a lectin-like receptor on endothelial cells, facilitates the uptake of oxidized-LDL. Expression of LOX-1 is involved in the pathobiological effects of oxidized-LDL in endothelial cells, including apoptosis, suppression of cNOS activity and cell adhesion. Recent studies show that intracellular signal protein kinase B (PKB) is involved in the regulation of cNOS. Further, HMG CoA reductase inhibitors (statins) may affect LOX-1 expression. In this study, we examined the modulation of LOX-1 expression and PKB activity in response to oxidized-LDL by two different statins (simvastatin and atorvastatin). METHODS AND RESULTS: Cultured human coronary artery endothelial cells (HCAECs) were used in this study. Oxidized-LDL (40 microg/ml) was found to upregulate the expression of LOX-1 (mRNA and protein), enhance [125I]-ox-LDL uptake and to reduce the phosphorylation of PKB (p-PKB). Two different statins, simvastatin and atorvastatin (each 1 and 10 microM), upregulated the activity of PKB and decreased LOX-1 expression and [125I]-ox-LDL uptake. A high concentration of statins (10 microM) gave a more potent effect than the low concentration (1 microM). The effects of the two different statins were similar. CONCLUSIONS: These observations show that statins decrease LOX-1 expression, a novel oxidized-LDL endothelial receptor, and uptake of oxidized-LDL in HCAECs. The effect of statins on LOX-1 expression is associated with an increase in PKB activity in HCAECs.

Analysis of Variance↗
PubMed2003

An analysis of cholesterol control and statin use in the Losartan Intervention for Endpoint Reduction in Hypertension Study.

BACKGROUND: There is general agreement that patients who have elevated lipid levels and/or risk factors for or existing cardiovascular disease should receive aggressive cholesterol-lowering therapy. However, it is not clear whether patients are receiving the recommended treatment. OBJECTIVE: This study evaluated cholesterol control and statin use in the setting of a large, long-term cardiovascular end point trial. METHODS: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was conducted between 1995 and 2001 to compare the incidence of cardiovascular morbidity and mortality with losartan- or atenolol-based treatment in 9193 patients aged 55 to 80 years with hypertension and left ventricular hypertrophy. The mean (SD) duration of follow-up was 4.8 (0.9) years. Use of lipid-lowering therapy was at the discretion of the investigator. In the present study, analyses of baseline and end-of-study mean total cholesterol (TC) and high-density lipoprotein cholesterol levels and statin use were performed for the combined treatment groups. Based on generally accepted guidelines, achievement of a TC level <5.0 mmol/L (193.5 mg/dL) was used as the treatment target for the purpose of these analyses. The proportions of patients with TC levels above this cutoff were calculated at baseline and at the final visit. RESULTS: A total of 8653 patients had baseline and end-of-study cholesterol measurements and were included in this analysis. At baseline, 528 (6.1%) patients were receiving statins; TC levels were above the cutoff in 381 (72.2%) of these patients, who had a mean TC level of 6.07 mmol/L (234.7 mg/dL). Of 8125 (93.9%) patients who were not receiving statins at baseline, TC levels were above the cutoff in 6859 (84.4%), with a mean TC level of 6.37 mmol/L (246.4 mg/dL). At the end of the study, 1892 (21.9%) patients were receiving a statin; TC levels were above the cutoff in 1096 (57.9%) of these patients, who had a mean TC level of 5.99 mmol/: (231.6 mg/dL). Of 6761 (78.1%) patients who were not receiving statins at the end of the study, TC levels were above the cutoff in 5316 (78.6%), with a mean TC level of 6.24 mmol/L (241.4 mg/dL). CONCLUSIONS: In this long-term cardiovascular end point study in patients with moderate to severe hypertension and left ventricular hypertrophy, statins were not optimally administered and cholesterol levels were poorly controlled.

Aged↗
PubMed1999

New insights into the pharmacodynamic and pharmacokinetic properties of statins.

The beneficial effects of statins are assumed to result from their ability to reduce cholesterol biosynthesis. However, because mevalonic acid is the precursor not only of cholesterol, but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase may result in pleiotropic effects. It has been shown that several statins decrease smooth muscle cell migration and proliferation and that sera from fluvastatin-treated patients interfere with its proliferation. Cholesterol accumulation in macrophages can be inhibited by different statins, while both fluvastatin and simvastatin inhibit secretion of metalloproteinases by human monocyte-derived macrophages. The antiatherosclerotic effects of statins may be achieved by modifying hypercholesterolemia and the arterial wall environment as well. Although statins rarely have severe adverse effects, interactions with other drugs deserve attention. Simvastatin, lovastatin, cerivastatin, and atorvastatin are biotransformed in the liver primarily by cytochrome P450-3A4, and are susceptible to drug interactions when co-administered with potential inhibitors of this enzyme. Indeed, pharmacokinetic interactions (e.g., increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of simvastatin or lovastatin and cyclosporine A, mibefradil, or nefazodone. In contrast, fluvastatin (mainly metabolized by cytochrome P450-2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, a 5- to 23-fold increase in pravastatin bioavailability has been reported in the presence of cyclosporine A. In summary, statins may have direct effects on the arterial wall, which may contribute to their antiatherosclerotic actions. Furthermore, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy.

Animals↗
PubMed2002

Statin treatment following coronary artery stenting and one-year survival.

OBJECTIVES: We assessed the influence of statin therapy given after the procedure on one-year survival of patients treated with coronary artery stenting. BACKGROUND: Coronary artery stenting is currently a common treatment option for patients with symptomatic coronary artery disease (CAD). Although several secondary prevention trials have demonstrated improved survival achieved with statin therapy in conservatively treated patients with CAD, it is not known whether this benefit can also be expected in patients undergoing percutaneous coronary interventions with intraluminal stenting. METHODS: This study included 4,520 patients younger than 80 years who underwent coronary artery stenting and were discharged from the hospital in the period October 1995 through September 1999. We compared one-year mortality of 3,585 patients who received statins after stenting with that of 935 patients who did not. RESULTS: The mortality rate at one year was 2.6% among patients who received statins and 5.6% among those who did not. Thus, statin therapy at discharge was associated with an unadjusted odds ratio (OR) of 0.46 (95% confidence interval [CI], 0.33 to 0.65), indicating a 54% reduction in the risk of death at one year. After adjusting for other covariates, the risk reduction associated with statin therapy was 49%, OR 0.51 (95% CI, 0.36 to 0.71). This reduction was observable in most of the subgroups of patients. CONCLUSIONS: The results of this nonrandomized study show that statin therapy improves survival after coronary artery stenting independent of patient characteristics recorded on the day of the intervention.

Coronary Artery Disease↗
PubMed2004

[The interest of statins in nephrology].

STATINS IN THE CASE OF CHRONIC RENAL DISEASE: Data of several large clinical trials in the general population demonstrated that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) are effective in cardiovascular disease prevention with a relatively safe profile. Patients with chronic kidney disease (CKD) are at high risk for developing premature cardiovascular disease, so the benefits of statin therapy might be expected to be substantial in this population. Adjusted dose of statins to calcinurine inhibitors and renal function seem to exhibit a favorable risk/benefit ratio in CKD patients. STUDY RESULTS: Statin use is CKD patients has been associated with a certain efficacy of cardiovascular disease prevention in several uncontrolled trials, and one randomized trial in renal transplant recipients. Several other large-scale randomized trials in CKD patients [4D (atorvastatin), AURORA (rosuvastatin) and SHARP (simvastatin/ezetimib) are currently underway. The results of these trials will permit evidence-based medicinal arguments justifying life-long clinical use of statins for cardiovascular prevention in CKD patients with progressive renal dysfunction, but data are inconclusive. OTHER POSSIBLE EFFECTS: Clinically relevant plethoric effects associated with statin therapy in CKD patients might be restricted to the decrease of inflammation and oxidative stress.

Chronic Disease↗
PubMed2006

Statin wars following coronary revascularization--evidence-based clinical practice?

BACKGROUND: Randomized clinical trials (RCTs) have shown that statins provide substantial heath benefits. Pharmaceutical companies spend enormous amounts of money on both clinical trials and marketing. The relative influence of information from clinical trials on physician prescription patterns for statins is unknown. OBJECTIVE: To examine the correlation between statin prescription patterns and the quality of evidence from RCTs. METHODS: Using the computerized administrative databases of the Quebec Health Insurance Board, the choice of statin for elderly patients (older than 65 years of age) following a coronary revascularization procedure (percutaneous coronary intervention or coronary artery bypass graft surgery) performed between January 1, 1994, and June 30, 2003, was examined. Prescriptions for each statin were compared with their evidence base obtained from a cumulative systematic literature review of RCTs that recorded mortality as an outcome and were published before December 31, 2002. RESULTS: The study cohort comprised 27,979 elderly revascularized patients who received at least one statin prescription. In 1996, the year atorvastatin was introduced, simvastatin and pravastatin had 38.3% and 37.1% of the market share, respectively. By 2003, atorvastatin had 44% of the market share, compared with 29.9% and 24.1% for simvastatin and pravastatin, respectively. In contrast, RCTs published up to the end of 2002 had culminated in 133,341 and 140,565 patient-years of follow-up for simvastatin and pravastatin, respectively, and only 1459 patient-years for atorvastatin. CONCLUSIONS: Prescription patterns regarding the choice of statin do not appear to be determined uniquely from high-quality RCTs. Further research into the other possible determinants of physician prescription patterns is necessary.

Aged↗
PubMed2004

Stroke prevention, blood cholesterol, and statins.

The risk of stroke increases with age, and hence the disease particularly affects the elderly, who are also at high risk for coronary heart disease. Epidemiological and observational studies have not shown a clear association between cholesterol concentrations and all causes of stroke. Large, long-term statin trials in patients with established or high risk for coronary heart disease have shown that statins decrease stroke incidence. These statin trials in a combined total of 70,020 patients indicate relative and absolute risk reductions for stroke of 21% and 0.9%, respectively. By comparison, the number of strokes prevented per 1000 patients treated for 5 years in patients with coronary heart disease is nine for statins versus 17.3 for antiplatelet drugs and 17 for antihypertensive drugs. Although the Heart Protection Study showed that statins lower the risk of major coronary events in patients with a previous stroke, statins may not lower stroke recurrence in these patients. In this review, we discuss the potential reasons for the effects of statins on stroke and the mechanisms of action. Treatment strategies on the basis of global cardiovascular risk may be most effective. Additional studies in patients representative of the typical stroke population are needed.

Anticholesteremic Agents↗
PubMed2003

Long-term statin safety and efficacy in secondary prevention: can combination therapy improve outcomes?

The use of statins has been associated with substantial reductions in vascular morbidity and mortality. The Prospective Pravastatin Pooling Project (PPP) looked at the long-term safety and efficacy of statins in secondary prevention, based on pooled results from three key statin trials. PPP revealed a highly significant relative risk reduction in total mortality, and demonstrated that pravastatin has a similar incidence of muscle-related side effects as placebo. It has been speculated that treatment with statins in combination with other cardiovascular drugs may have a synergistic effect on reduction of cardiovascular complications. However, for ethical reasons, evidence can only ever be sought from sub-group analyses or meta-analyses of existing studies. Recent studies have focused on statins plus acetyl- salicylic acid (ASA, aspirin). Evidence suggests that a combination of statins with ASA provides a cardiovascular risk reduction that is superior to the respective monotherapy. Thus, statins effectively reduce further cardiovascular morbidity and mortality as well as total mortality in patients with manifest coronary artery disease (CAD) or at high risk, also they act in synergy with ASA and they are safe.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Binding thermodynamics of statins to HMG-CoA reductase.

The statins are powerful inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoA reductase), the key enzyme in the cholesterol biosynthetic pathway, and are among the most widely prescribed drugs in the world. Despite their clinical importance, little is known about the binding thermodynamics of statins to HMG-CoA reductase. In this paper, we report the results of inhibition kinetics and microcalorimetric analysis of a representative type I statin (pravastatin) and four type II statins (fluvastatin, cerivastatin, atorvastatin, and rosuvastatin). Inhibition constants (K(i)) range from 2 to 250 nM for the different statins. Isothermal titration calorimetry (ITC) experiments yield binding enthalpies (DeltaH(binding)) ranging between zero and -9.3 kcal/mol at 25 degrees C. There is a clear correlation between binding affinity and binding enthalpy: the most powerful statins bind with the strongest enthalpies. The proportion by which the binding enthalpy contributes to the binding affinity is not the same for all statins, indicating that the balance among hydrogen bonding, van der Waals, and hydrophobic interactions is not the same for all of them. At 25 degrees C, the dominant contribution to the binding affinity of fluvastatin, pravastatin, cerivastatin, and atorvastatin is the entropy change. Only for rosuvastatin does the enthalpy change contribute more than 50% of the total binding energy (76%). Since the enthalpic and entropic contributions to binding originate from different types of interactions, the thermodynamic dissection presented here provides a way to identify interactions that are critical for affinity and specificity.

Atorvastatin↗