Pravastatin Therapy Research Articles

Pravastatin for Cardiovascular Event Primary Prevention in Patients With Mild-to-Moderate Hypertension in the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study

Lipid-lowering therapy in individuals with high risk of cardiovascular disease reduces the incidence of coronary heart disease. However, few studies have assessed the benefits of cholesterol lowering for primary prevention of coronary heart disease in hypertensive patients with mild dyslipidemia or without conventional dyslipidemia. The large, randomized Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese Study showed a 33% reduction in coronary heart disease incidence with pravastatin as the primary prevention in Japanese patients. We conducted an exploratory analysis of the effect of diet plus pravastatin therapy on the primary prevention of cardiovascular events (coronary heart disease, coronary heart disease plus cerebral infarction, and cardiovascular disease) in the 3277 patients with hypertension during the 5-year follow-up. There were no significant differences in mean baseline total cholesterol, blood pressure levels, or variation in blood pressure during the 5-year period between the diet (n=1664) and diet plus pravastatin (n=1613) groups. In the diet plus pravastatin group, the relative risk of coronary heart disease plus cerebral infarction was reduced by 35% (hazard ratio: 0.65; CI: 0.46 to 0.93; P=0.02), cerebral infarction by 46% (hazard ratio: 0.54; CI: 0.29 to 0.98; P=0.04), and cardiovascular disease by 33% (hazard ratio: 0.67; CI: 0.49 to 0.91; P=0.01). In patients without a history of cardiovascular disease who have hypertension and mildly elevated cholesterol, pravastatin was effective in reducing the incidence of cardiovascular disease, particularly cerebral infarction. Hence, in patients with hypertension with mildly elevated cholesterol levels, treatment with a statin is advisable to reduce the burden of cardiovascular disease.

Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients

Background Lipophilic and hydrophilic statins have different effects on adiponectin and insulin resistance in experimental studies and different effects on the rate of onset of new diabetes in large scale clinical studies. Therefore, we hypothesized that simvastatin and pravastatin may have differential metabolic effects in hypercholesterolemic patients. Methods This was a randomized, single-blind, placebo-controlled, parallel study. Age, gender, and body mass index were matched. Forty-three patients were given placebo, simvastatin 20 mg, or pravastatin 40 mg, respectively once daily for 2 months. Results Simvastatin and pravastatin therapy significantly changed lipoprotein levels and improved flow-mediated dilation after 2 months when compared with baseline ( P < 0.001) or placebo treatment ( P < 0.001 by ANOVA). Simvastatin therapy significantly increased insulin levels (mean % changes; 127%, P = 0.014) and decreased plasma adiponectin levels (10%, P = 0.012) and insulin sensitivity as assessed by QUICKI (6%, P = 0.007) when compared with baseline. By contrast, pravastatin therapy did not significantly change insulin levels (−3%, P = 0.437) but significantly increased plasma adiponectin levels (9%, P = 0.011) and insulin sensitivity (6%, P = 0.008) when compared with baseline. In addition, these effects of simvastatin were significant when compared with pravastatin ( P < 0.001 for insulin levels by ANOVA on Ranks, P < 0.001 for adiponectin and P = 0.001 for QUICKI by ANOVA). When compared with baseline, simvastatin significantly increased plasma leptin levels (35%, P = 0.028), but pravastatin did not (1%, P = 0.822). Conclusions Despite causing comparable changes in lipoprotein and endothelium-dependent dilation, simvastatin and pravastatin therapy had differential metabolic effects in hypercholesterolemic patients that may be clinically relevant.

PROVE-IT trial: economic analysis

Introduction: the PROVE-IT (“Intensive versus moderate lipid lowering with statins after acute coronary syndromes”) was a comparison of pravastatin 40 mg/die versus atorvastatin 80 mg/die in patients with an acute coronary syndrome (ACS). Aim: our aim was to investigate the economic consequence of high dose of atorvastatin vs usual-dose of pravastatin in Italian patients with a history of acute coronary syndrome. Methods: the analysis is conducted on the basis of clinical outcomes of the PROVE-IT study. We conducted a cost-effectiveness analysis, comparing high dose of atorvastatin (80 mg/die) versus usual-dose of pravastatin (40 mg/die) in the perspective of the Italian National Health Service. We identified and quantified medical costs: drug costs according to the Italian National Therapeutic Formulary and hospitalizations were quantified based on the Italian National Health Service tariffs (2008). Effects were measured in terms of morbidity reduction (number of deaths and frequency of hospitalizations). We considered an observation period of 24 months. The costs borne after the first 12 months were discounted using an annual rate of 3%. We conducted one and multi-way sensitivity analyses on unit cost and effectiveness. Results: the cost of pravastatin or atorvastatin therapy over the 2 years period amounted to approximately 664.684 millions euro and 909.006 euro per 1,000 patients respectively. Atorvastatin was more efficacious compared to pravastatin and the overall cost of care per 1,000 patients over 24 months of follow-up was estimated at 2.58 millions euro in the pravastatin and 2.57 millions euro in the atorvastatin group, resulting into a cost saving of about 11.000 euro. Discussion: this study demonstrates that high dose atorvastatin treatment leads to a reduction of direct costs for the National Health System. Atorvastatin therapy is dominant since it is both less costly and more effective than pravastatin. Results were sensitive to either clinical or economic variables.

Treatment with an apolipoprotein A-1 mimetic peptide in combination with pravastatin inhibits collagen-induced arthritis

To evaluate the therapeutic potential of an apolipoprotein A-1 (apoA-1) mimetic peptide, D-4F, in combination with pravastatin in collagen-induced arthritis (CIA), syngeneic Louvain rats were immunized with type II collagen and randomized to vehicle control, D-4F monotherapy, pravastatin monotherapy, or D-4F + pravastatin combination therapy. Clinical arthritis activity was evaluated and radiographs, type II collagen antibody titers, cytokine/chemokine levels, and HDL function analysis were obtained. There was significant reduction in clinical severity scores in the high and medium dose D-4F + pravastatin groups compared to controls ( p ≤ 0.0001). Reduction in erosive disease occurred in the medium/high dose combination groups compared to non-combination groups ( p ≤ 0.01). Favorable changes in cytokines/chemokines were noted with treatment, and response to combination D-4F/pravastatin therapy was associated with improvement in HDL's anti-inflammatory properties. Combination D-4F/pravastatin significantly reduced clinical disease activity in CIA, and may have dual therapeutic potential in other autoimmune diseases with increased cardiovascular morbidity and mortality.

Effects of pravastatin in prevention of diabetes and mechanism thereof: experiment with non-obese diabetic mice

To explore the effects of pravastatin in prevention of diabetes and mechanisms thereof. 1183 to 4-week-old female non-obese diabetic (NOD) mice were randomly divided into 4 groups: control group (n = 30), fed with regular diet, low-dose pravastatin group (n = 29), fed with 1 mg kg(-1) d(-1) pravastatin via the diet, medium-dose pravastatin group (n =29) fed with 10 mg kg(-1) d(-1) pravastatin via the diet, and high-dose pravastatin group (n = 30), fed with 40 mg kg(-1) d(-1) pravastatin via the diet. The mice were followed up till they were 30-week old. Urine glucose was measured every week. Eight 12-week old mice without onset of DM from each group were killed with the pancreas taken out to undergo insulitis scoring via microscopy. Another 8 12-week old mice without onset of DM from each group were killed with their spleens taken out. Suspension of splenocytes was made, put into a 96-well plate, and stimulated by rGAD65; and [3SH]-thymidine was incorporated. The stimulation index (SI) of the splenocytes was calculated. Flow cytometry was used to observe the population of CD4 CD25+ regulatory T cells. ELISA was used to detect the interferon (IFN)-gamma and interleukin (IL)-4 levels in the supernatants of splenocytes. RT-PCR was used to detect the mRNA expression of IFN-gamma and IL4 in the spleen. At 30 weeks of age, the incidence rate of DM onset of the high-dose pravastatin group was significantly lower than that of the control group (P = 0.003), and the incidence rates of DM onset of the medium and low dose groups were not significantly different from that of the control group (both P >0.05). The severity of insulitis at 12 weeks of age of the high-dose pravastatin group was significantly lower than that of the controls group (P <0.001). There were no significant difference in the SI level and in the percentage of CD4+ CD25+ regulatory T cells among the four groups (all P >0.05). The IFN-gamma level in the supernatant of splenocytes of the high-dose pravastatin group was (42 + 20) pg/ml, significantly lower than that of the control group [(157 + 32) pg/ml, P = 0.000]. The IFN-gamma mRNA expression level in the spleen of the high-dose pravastatin group was 0.24 +/- 0.10, significantly lower than that of the control group (0.81 +/- 0.18, P =0.000). The IL-4 level in the supernatants of splenocytes of the high-dose pravastatin group was S (91 +/- 22) pg/m, significantly higher than that of the control group [(44 +/- 20) pg/ml, P=0.000)]. The IL4 mRNA expression level in spleen of the high-dose pravastatin group was 0.39 +/- 0.18, significantly higher than that of the control group (0.20 +/- 0.08, P = 0.002). However, there were not significant differences in the IFN-gamma and IL-4 levels in the supernatant and the IFN-gamma and IL-4 mRNA expression in spleen among the medium dose, low dose, and control groups (all P >0.05). High-dose pravastatin therapy at early time decreases the IFN-gamma level and increases the IL-4 level, shifts the immune response to the direction of Th2, and subsequently lessens insulitis and prevents DM.

Atherogenic Lipoprotein Particle Size and Concentrations and the Effect of Pravastatin in Children with Familial Hypercholesterolemia

To determine lipoprotein particle concentrations and size in children with familial hypercholesterolemia (FH) and investigate the effect of pravastatin therapy on these measures. Lipoprotein particle concentrations and sizes were examined by nuclear magnetic resonance (NMR) spectroscopy in 144 children with FH and 45 unaffected siblings. The effect of pravastatin therapy (20 to 40 mg) on lipoprotein particle concentration and size were compared with placebo after 1 year of treatment, using analysis of covariance. Compared with the unaffected siblings, the children with FH had significantly higher concentrations of very-low-density lipoprotein (VLDL) particles (115.6 nmol/L vs 51.2 nmol/L; P < .001) and low-density lipoprotein (LDL) particles (1726.8 nmol/L vs 955.3 nmol/L; P < .001), and lower concentrations of high-density lipoprotein (HDL) particles (23.2 micromol/L vs 26.9 micromol/L; P < .001). Compared with placebo, pravastatin therapy decreased the concentration of VLDL particles by 35.9 nmol/L (P < .001), of total LDL particles by 342.7 nmol/L (P < .001), of large LDL particles by 189.5 nmol/L (P < .001), and of small LDL particles by 156.2 nmol/L (P = .152), but increased the concentration of total HDL particles by 2.2 micromol/L (P < .001), of large HDL particles by 1.0 micromol/L (P = .006), and of medium HDL particles by 1.1 micromol/L (P = .003). VLDL particle size increased by 1.0 nm (P = .032). Compared with their healthy siblings, children with FH have an atherogenic lipoprotein profile based on their lipoprotein distribution and lipoprotein particle diameter. Pravastatin therapy can improve, but not fully restore, these lipoprotein abnormalities toward normal levels in these children.

Usefulness of Pravastatin in Primary Prevention of Cardiovascular Events in Women

It is well known that statins reduce the risk of cardiovascular disease. However, the effect of statins in women for the primary prevention of cardiovascular disease has not been determined. We conducted an exploratory analysis of the effect of diet plus pravastatin therapy on the primary prevention of cardiovascular events in women with data from a large-scale primary prevention trial with pravastatin. Patients with hypercholesterolemia (5.7 to 7.0 mmol/L) and no history of coronary heart disease or stroke were randomized to diet or diet plus pravastatin 10 to 20 mg/d and followed up for > or = 5 years. We investigated the effect of diet plus pravastatin treatment on cardiovascular events in 5356 women during the 5-year follow-up. The incidence of cardiovascular events in the women was 2 to 3 times lower than that in men. The occurrence of cardiovascular events was 26% to 37% lower in the diet plus pravastatin treatment group than in the diet alone group. Although these differences did not reach statistical significance, the overall risk reductions were similar to those in men. Notably, women > or = 60 years of age treated with diet plus pravastatin had markedly higher risk reductions for coronary heart disease (45%), coronary heart disease plus cerebral infarction (50%), and stroke (64%) than did women treated with diet alone. Treatment with pravastatin in women with elevated cholesterol but no history of cardiovascular disease provides a benefit similar to that seen in men, and this benefit is more marked in older women. This treatment should be considered routinely for primary cardiovascular protection in women with elevated cholesterol levels.

Effect of Early Use of Low-Dose Pravastatin on Major Adverse Cardiac Events in Patients With Acute Myocardial Infarction

It is unclear whether early initiation of low-dose pravastatin therapy can reduce the occurrence of major adverse cardiac events after acute myocardial infarction (AMI). The study group comprised 353 patients with AMI who had plasma total cholesterol levels of 200-250 mg/dl and triglyceride levels <300 mg/dl. The patients were randomly assigned to either receive pravastatin (10 mg/daily, n=176) or not (n=177). The primary endpoint was a composite of death, nonfatal myocardial infarction (MI), unstable angina (UA), stroke, revascularization, and rehospitalization because of other cardiovascular disease. The follow-up period was 9 months. The primary endpoint occurred in 31 patients (17.9%) in the pravastatin group and 55 patients (31.4%) in the non-pravastatin group (relative risk, 0.56; 95% confidence interval, 0.36-0.87). There were no significant differences in the risk of death, nonfatal MI, UA, and stroke between the 2 groups, although the pravastatin group had a lower risk of need for revascularization. For patients with AMI, early and low-dose pravastatin therapy (10 mg/daily) reduces recurrent major adverse cardiac events, mostly the requirement for revascularization.

Biological effects of acute pravastatin treatment in patients after aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled trial

The authors previously demonstrated that acute pravastatin therapy in patients after aneurysmal subarachnoid hemorrhage (SAH) ameliorates vasospasm-related delayed ischemic neurological deficits. The object of this study was to continue to examine potential mechanisms of these beneficial effects. Eighty patients with aneurysmal SAH (age range 18-84 years; time to onset 1.8 +/- 1.3 days) were enrolled in a double-blind study and randomized to receive 40 mg of oral pravastatin or placebo daily for as long as 14 days. Daily transcranial Doppler ultrasonography and blood tests every 3 days (including full blood cell counts, coagulation profiles, fasting glucose and lipid profiles, and serum biochemistry) were performed during the trial period. No significant differences were found in baseline laboratory data between the trial groups. Subsequent measurements during the 14-day trial showed reduced low-density lipoprotein (LDL) cholesterol levels and total/high-density lipoprotein cholesterol ratios between Days 3 and 15 (p < 0.05), and increased D-dimer levels (p < 0.05) on Day 6, in the pravastatin group. Patients who received pravastatin but developed vasospasm had significantly lower baseline LDL cholesterol levels or a less extensive reduction in LDL cholesterol levels (p < 0.05), and greater increases in plasma fibrinogen (p = 0.009) and serum C-reactive protein on Day 3 (p = 0.007), compared with those patients without vasospasm. The reduction in LDL cholesterol levels on Day 3 in the placebo group correlated with the duration of normal cerebral autoregulation on the ipsilateral side of the ruptured aneurysm (p = 0.002). In addition to functioning through a cholesterol-independent pathway, cerebrovascular protection from acute statin therapy following aneurysmal SAH may also function through cholesterol-dependent mechanisms.

Effect of Withdrawal of Pravastatin Therapy on C-Reactive Protein and Low-Density Lipoprotein Cholesterol

In addition to lowering cholesterol, statins effectively lower C-reactive protein (CRP) levels. The effects of withdrawal from long-term statin therapy on CRP are unknown. This study examined the effect of withdrawal from 4 years of statin treatment on CRP. We prospectively evaluated the effects of withdrawal from pravastatin (40 mg) treatment on CRP levels in 566 subjects who participated in a randomized, placebo-controlled trial. Median (interquartile range) CRP levels before randomization were 1.29 mg/L (0.63 to 2.73) and mean low-density lipoprotein (LDL) cholesterol was 4.06 +/- 0.92 mmol/L. Four years after randomization, placebo-treated patients (n = 266) had a nonsignificant 9% increase in CRP, whereas there was a 12% decrease (p = 0.001) in the pravastatin-treated patients (n = 300). LDL cholesterol only decreased in pravastatin-treated patients (-27%; p <0.001). Withdrawal from pravastatin led to a significant increase in both CRP and LDL cholesterol to approximately pretreatment levels (p <0.05 and <0.001, respectively). Changes in CRP after withdrawal from pravastatin could not be predicted by the change in LDL cholesterol. The difference between the pravastatin and placebo groups in terms of change in CRP by withdrawal was consistent and persisted in analysis corrected for body mass index, smoking status, blood pressure, and baseline levels of total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, or triglycerides. In conclusion, withdrawal from pravastatin treatment resulted in an increase in CRP to approximately baseline levels, which is not related to the increase in LDL cholesterol.

Is there life after plaque rupture?

Little is known of the relationship between plaque rupture and adaptive geometric remodelling, especially in the context of unstable atherosclerosis. We have assessed remodelling in the proximal brachiocephalic arteries of fat-fed apoE (apolipoprotein E)-knockout mice. The rate of vessel expansive remodelling is similar in vessels with plaques and without plaques, suggesting that the presence of plaque is not necessary for remodelling to occur. In vessels with plaques, the degree of expansive remodelling was strongly associated with the stability of the plaque. Vessels with stable plaques (i.e. with neither buried fibrous caps nor acute plaque ruptures) showed no expansion, whereas those with evidence of plaque rupture expanded at a significant rate. Vessels with stable plaques suffered significant loss of lumen over time, but those with unstable plaques maintained lumen area over time. Pravastatin treatment of male apoE-knockout mice caused a 5-fold increase in fibrous cap thickness and, although it did not influence overall rates of vessel remodelling, it significantly increased both the amount of vessel expansion and the period of time between plaque ruptures, suggesting that it increases the ability of the plaque to resist the rupturing force caused by vessel expansion. These results suggest that vessel expansion in brachiocephalic arteries of fat-fed apoE-knockout mouse does not require the presence of plaque. When a plaque is present, the outward remodelling force is exerted across its cap: vessels with smaller outward remodelling forces cannot overcome the strength of the cap, and the plaque remains stable. When the remodelling force is greater than the strength of the cap, the plaque ruptures. Thus plaque rupture can be viewed as a consequence of vessel remodelling. Interventions that strengthen the plaque, such as pravastatin therapy, do not alter remodelling parameters but instead allow for more outward remodelling before a rupture is caused.

Abstract 2373: Diet Plus Pravastatin Treatment Reduces The Risk Of Cardiovascular Disease And Total Mortality In Patients With Metabolic Syndrome: Sub-analysis From A Large-scale Primary Prevention Trial With Pravastatin (MEGA Study)

Background: The metabolic syndrome is related to an increased risk of cardiovascular disease (CVD), as reported by numerous studies. In this analysis, we investigated the relationship between the metabolic syndrome (MetSyn) and CVD risk in hypercholesterolemic patients and the effect of pravastatin treatment in the MEGA Study population. Methods: The MetSyn was defined according to modified National Cholesterol Education Program (NCEP) criteria, namely, the presence of three or more risk factors: 1)obesity (body mass index ≥25 kg/m 2 ), 2)hypertriglyceridemia (≥150 mg/dL), 3)low HDL cholesterol (&lt;40 mg/dL in men and &lt;50 mg/dL in women), 4)hypertension (SBP≥130 mmHg and/or DBP≥85 mmHg), 5)hyperglycemia (fasting glucose ≥100 mg/dL). The risk of CVD and total mortality was compared in patients with and without MetSyn. The effect of pravastatin plus diet therapy in the patients with MetSyn was compared to those without MetSyn, and moreover these comparisons were conducted in two groups, divided according to their LDL cholesterol levels (cut point: 156.9 mg/dL). Results: A total of 2,636 (33.7%) of the 7,832 hypercholesterolemic patients enrolled in MEGA had MetSyn. A 1.9 times higher incidence of CVD was found in the patients with, compared to those without, MetSyn. The risk of CVD in patients with MetSyn was very similar to that in patients with high LDL cholesterol (≥156.9 mg/dL) and with low LDL cholesterol (&lt;156.9 mg/dL). Notably, a 36% significant risk reduction for CVD and 50% risk reduction for total mortality were observed in the patients with MetSyn treated with pravastatin plus diet treatment compared to diet therapy alone. Moreover, the greatest CVD risk reduction was observed in the high LDL-C group with MetSyn compared to those without MetSyn (Hazard ratio 0.44 vs. 0.56, respectively, interaction p=0.07). Conclusion: Metabolic syndrome increases the risk of CVD regardless of the presence or absence of hypercholesterolemia. Diet plus pravastatin treatment is effective for the prevention of CVD for patients with hypercholesterolemia and MetSyn.

Valutazione economica dello studio PROVE-IT

Introduction: the PROVE-IT (“Intensive versus moderate lipid lowering with statins after acute coronary syndromes”) was a comparison of pravastatin 40 mg/die versus atorvastatin 80 mg/die in patients with an acute coronary syndrome (ACS). Aim: our aim was to investigate the economic consequence of high dose of atorvastatin vs usual-dose of pravastatin in Italian patients with a history of acute coronary syndrome. Methods: the analysis is conducted on the basis of clinical outcomes of the PROVE-IT study. We conducted a cost-effectiveness analysis, comparing high dose of atorvastatin (80 mg/die) versus usual-dose of pravastatin (40 mg/die) in the perspective of the Italian National Health Service. We identified and quantified medical costs: drug costs according to the Italian National Therapeutic Formulary and hospitalizations were quantified based on the Italian National Health Service tariffs (2006). Effects were measured in terms of mortality and morbidity reduction (number of deaths, life years gained and frequency of hospitalizations). We considered an observation period of 24 months. The costs borne after the first 12 months were discounted using an annual rate of 3%. We conducted one and multi-way sensitivity analyses on unit cost and effectiveness. We also conducted a threshold analysis. Results: the cost of pravastatin or atorvastatin therapy over the 2 years period amounted to approximately 1.3 millions euro and 870,000 euro per 1,000 patients respectively. Atorvastatin was more efficacious compared to pravastatin and the overall cost of care per 1,000 patients over 24 months of follow-up was estimated at 3.2 millions euro in the pravastatin and 2.5 millions euro in the atorvastatin group, resulting into a cost saving of about 700,000 euro that is 27% of total costs occurred in the pravastatin group. Discussion: this study demonstrates that high does atorvastatin treatment leads to a reduction of direct costs for the National Health System. Atorvastatin therapy is dominant since it is both less costly and more effective than pravastatin. Results of sensitivity analysis showed that atorvastatin therapy remains dominant even in the most unfavourable hypotheses.

The Effects of High Dose Pravastatin and Low Dose Pravastatin and Ezetimibe Combination Therapy on Lipid, Glucose Metabolism and Inflammation

Coronary artery disease (CAD) is presently the major cause of mortality and morbidity. Anti-hyperlipidemic treatment is one of the main treatment steps in the management of CAD. Statins are the cornerstones in this treatment. Ezetimibe can be reliably used, when statins prove ineffective in treatment, or to reduce their side effects. In the present study we examined the effects of high-dose pravastatin (40 mg) and low-dose pravastatin (10 mg) + ezetimibe (10 mg) combination therapy on lipid and glucose mechanism, as well as inflammation. This study registered 100 cases. Of the cases, 50 [57.1 +/- 11.1 years (24 (48%) females and 26 (52%) males)] were administered 40 mg/day pravastatin (group 1) and 50 [53.2 +/- 12.2 years (27 (54%) females and 23 (46%) males)] were administered 10 mg pravastatin + 10 mg ezetimibe (group 2). In group 1, total cholesterol fell from 231.1 +/- 83.5 mg/dl to 211.3 +/- 37.2 mg/dl (p = 0.03), triglyceride from 243.5 +/- 96.8 mg/dl to 190.9 +/- 55.2 mg/dl (p = 0.003), and LDL cholesterol from 165.7 +/- 29.7 mg/dl to 133.4 +/- 26.6 mg/dl (p = 0.02). In group 2, total cholesterol dropped from 250.9 +/- 51.8 mg/dl to 187.9 +/- 34.9 mg/dl (p = 0.001), triglyceride from 270.3 +/- 158.9 mg/dl to 154.6 +/- 60.7 mg/dl (p = 0.001), and LDL cholesterol from 158.1 +/- 47.5 mg/dl to 116.9 +/- 26.4 mg/dl (p = 0.001). Insulin resistance decreased from 4.05 +/- 2.31 to 3.16 +/- 1.90 (p = 0.07) in group 1 and from 2.96 +/- 1.50 to 2.05 +/- 0.55 (p = 0.009) in group 2. High sensitive C-reactive protein fell from 6.69 +/- 6.11 mg/l to 3.02 +/- 1.70 mg/l (p = 0.01) in group 1 and from 6.36 +/- 2.06 mg/l to 2.68 +/- 1.69 mg/l (p = 0.001) in group 2. Both therapy regimes are effective. However, we found that low-dose pravastatin and ezetimibe combination therapy is more effective than high-dose pravastatin therapy on lipid metabolism, glucose metabolism and inflammation.

Effect of pravastatin on markers of endothelial activation in dialysis patients

The aim of this pilot study was to test the effect of pravastatin on serum levels of high-sensitivity CRP (hs-CRP), IL-6 and the soluble adhesion molecules sVCAM-1, sICAM-1 and sE-selectin in chronic dialysis patients. At the commencement of the study, serum levels of lipids, liver function tests and endothelial markers (CRP, IL-6, sICAM-1, sVCAM-1, sE-selectin) were measured. Patients then commenced 1 month of 10 mg of pravastatin per day, and if tolerated, then 4 months of 40 mg of pravastatin per day. Serum levels of lipids, liver function tests and endothelial markers were repeated after the total of 5 months of pravastatin therapy. Thirty-nine patients were enrolled, and 25 (male/female 17/8; 21 haemodialysis, 4 peritoneal dialysis) patients completed the study. Pravastatin therapy significantly improved the patients' lipid profiles, but had no significant effect on the levels of CRP, IL-6, sICAM-1, sVCAM-1, or sE-selectin. Short-term (5 months) treatment with pravastatin in patients receiving chronic dialysis improved their lipid profile, but had no significant effect on surrogate markers of endothelial activation.

Coronary reactivity, homocysteine and methylenetetrahydrofolate reductase gene variation in young men during pravastatin therapy

High plasma homocysteine (Hcy) has been linked to impaired endothelial function. We investigated whether treatment with pravastatin affects the Hcy levels. Moreover, we studied whether the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism affects coronary vasomotion at baseline and during the treatment with pravastatin. Fifty-one healthy, mildly hypercholesterolemic men (mean age 35 ± 4 years) attended this randomised, double-blind, placebo-controlled study. The volunteers were randomised into groups with 6-month treatment with pravastatin (40 mg/day, n = 25) or placebo ( n = 26). Coronary blood flow measurements with positron emission tomography at rest and during adenosine infusion as well as biochemical analyses were done at baseline and at the end of the treatment period. The Hcy concentration decreased significantly during the pravastatin therapy (− 0.81 ± 1.46 μmol/l, p = 0.01), but not during placebo (0.02 ± 2.39 μmol/l, p = 0.97). The MTHFR polymorphism did not affect the Hcy concentration or coronary flow indices. Neither did the MTHFR polymorphism modulate the effects of pravastatin on coronary vasomotion. In conclusion, a 6-month therapy with pravastatin decreases Hcy concentration in Finnish healthy young men. The MTHFR genotype is neither a determinant of baseline coronary flow indices nor does it modulate the effect of pravastatin on coronary reactivity.

Does pravastatin therapy affect cardiac enzyme levels after percutaneous coronary intervention?

Serum cardiac enzyme elevation after percutaneous coronary intervention (PCI), a relatively common complication, is a prognostic determinant of long-term outcome in patients who undergo these procedures. Statins are postulated to reduce such complications. This study investigated the short-term effects of pravastatin on serum creatine kinase myocardial isoform (CK-MB) and serum cardiac troponin I (cTpI) levels after elective PCI. Of 93 patients studied, 72 (77.4%) were men, and 21 (22.6%) were women (mean age, 58.9+/-11.0 y). Patients were randomly divided into 3 groups before they underwent elective PCI. Preoperatively, group 1 patients (n=30) received pravastatin 10 mg/d, and group 2 patients (n=29) received pravastatin 40 mg/d. Control group patients (n=34) received no lipid-lowering medication. Serum CK-MB and serum cTpI levels were measured preoperatively and then again at 6, 24, and 36 h postoperatively. Demographic features of patients and characteristics of the PCI procedure, including number of vessels/lesions and duration and number of inflations, did not differ among groups (P>.05). Mean serum CK-MB and serum cTpI levels were significantly increased after PCI in all patients (P<.001). When compared with control group patients, those given pravastatin did not experience significantly lowered postprocedural serum CK-MB or serum cTpI levels (P>.05). Preprocedural pravastatin therapy at dosages of 10 mg/d and 40 mg/d seems inadequate for preventing serum cardiac enzyme elevations during short-term follow-up after PCI. Additional research on this topic is recommended.

Effects of Acute Pravastatin Treatment on Intensity of Rescue Therapy, Length of Inpatient Stay, and 6-Month Outcome in Patients After Aneurysmal Subarachnoid Hemorrhage

We have previously demonstrated that acute pravastatin therapy after aneurysmal subarachnoid hemorrhage ameliorates vasospasm-related delayed ischemic deficits. This study assesses the effects of pravastatin on the frequency and intensity for rescue therapy, length of inpatient stay, and long-term outcome at 6 months. Eighty aneurysmal subarachnoid hemorrhage patients (age 18 to 84 years, onset 1.8+/-1.3 days) were randomized to receive daily oral pravastatin (40 mg) or placebo for up to 14 days. Clinical events were recorded during the trial. Six-month outcome was assessed using the Short Form 36 and the modified Rankin Scale. Although no significant difference in the outcome at discharge was found between the trial groups, multivariate analysis showed pravastatin therapy reduced unfavorable outcome by 73% (P=0.041). The benefit persisted at 6 months (P=0.063) and was notable in the physical (P<0.001) and psychosocial (P<0.001) aspects measured using Short Form 36. Furthermore, the acute pravastatin therapy reduced the requirement for triple-H therapy (hypertensive, hypervolemic, hemodilution; P=0.045) and mortality related to vasospasm (P=0.02) and sepsis (P=0.001); no significant difference was found in the length of inpatient stay between the trial groups. This trial demonstrates that acute statin treatment reduces traditional rescue therapy for vasospasm after aneurysmal subarachnoid hemorrhage. Improvement in early outcome has proved robust at 6 months, particularly in relation to physical and psychosocial (Short Form 36) outcome.

Low HDL‐C predicts the onset of transplant vasculopathy in pediatric cardiac recipients on pravastatin therapy

The levels and protein/lipid compositions of major lipoprotein particles of 19 pediatric cardiac transplant recipients (4-18 yr of age) were studied in this prospective, open clinical follow-up study before and at one yr of pravastatin therapy (10 mg/day). The recipients were grouped into those with (n = 6; group A) and those without (n = 13; group B) angiographically detectable vasculopathy. Twenty-one pediatric non-transplant controls were studied at baseline. At baseline, the group A recipients had 29% lower HDL-C concentrations (p = 0.031) and 29% higher apoB-100/apoA-I ratios (p = 0.034) than the group B recipients. At one yr of pravastatin, the respective figures were 29% (p = 0.013) and 33% (p = 0.005). Compared with the healthy pediatric controls, the transplant recipients had significantly higher serum TG before pravastatin [median (range): 1.3 mmol/L (0.6-3.2) vs. 0.7 mmol/L (0.3-2.4), p = 0.0002] and at one yr [1.3 mmol/L (0.5-3.5) vs. 0.7 mmol/L (0.3-2.4), p = 0.0004]. The baseline apoB-100/apoA1 ratios of the recipients were 33% higher (p = 0.005). In conclusion, low HDL-C and high apoB-100/apoA-I ratio were associated with angiographically detectable vasculopathy. Even though pravastatin effectively lowered the TC and LDL-C and improved compositional properties of LDL and HDL(2) particles, it failed to normalize the elevated TG and, in some patients, to prevent the progression of transplant vasculopathy.

Statin Therapy and the Elderly

In the United States, the prevalence of coronary and other cardiovascular diseases increases with age, reflecting in part the cumulative effect of lifetime exposure to cardiovascular risk factors.1 Coronary and cerebrovascular atherosclerosis in the elderly (≥65 years of age) is a growing clinical problem because of the population’s increasing longevity. Despite this evidence, cardiovascular risk in elderly patients is demonstrably undermanaged according to several epidemiological studies.2–4 In a Canadian study, paradoxically, elderly coronary patients who were at the highest risk for recurrent disease appeared to be the least likely to receive preventive treatment.4 Several factors may contribute to this poor level of management, such as confusion surrounding the relevance of certain modifiable risk factors to this age group, the cost-effectiveness of preventing coronary heart disease (CHD) in older patients, and concerns about the impact of therapies on safety and quality of life. Article p 700 Despite early studies that questioned the association of cholesterol with coronary risk in the elderly, the available epidemiology now favors the perspective that cholesterol remains an important modifiable risk factor in patients ≥65 years of age, especially after adjustment for the presence of comorbid conditions.5 Growing evidence demonstrates the benefit of treating higher-risk older patients. In this issue of Circulation , Deedwania et al6 present the results of the Study Assessing Goals in the Elderly (SAGE), which compares the effect of intensive (atorvastatin 80 mg/d) compared with moderate (pravastatin 40 mg/d) cholesterol lowering with statins in a cohort of 893 men and women 65 to 85 years of age with coronary artery disease. SAGE evaluated the absolute change in total duration of ischemia as measured by 48-hour Holter monitoring from baseline to 1 year. Although total ischemia duration was reduced significantly in both arms compared with baseline, the intensive strategy …