Statin therapy for prevention and treatment of acute and chronic cardiovascular disease: update on recent trials and metaanalyses

PURPOSE OF REVIEW: To summarize the evidence from recent clinical trials and metaanalyses on the efficacy of statin therapy to reduce death, myocardial infarction and stroke, and to review the effects of statins in patients with low LDL cholesterol, diabetes, end-stage renal disease, and acute coronary syndrome. RECENT FINDINGS: In large metaanalyses of randomized controlled trials relative risk reductions from statins compared with placebo for patients with manifest or with risk factors for coronary artery disease were 13% for overall mortality, 26% for fatal and nonfatal myocardial infarction, and 18% for fatal and nonfatal stroke. Evidence from large trials suggests that patients with type II diabetes compared with patients without diabetes have similar risk reductions from statins for cardiovascular events, but this benefit is not seen in patients with diabetes and end-stage renal disease. In patients with acute coronary syndrome, early treatment with high-dose atorvastatin reduces cardiovascular morbidity after the first 4 months following the event, but the impact on mortality endpoints remains less clear. Results from recent trials in patients with stable coronary artery disease or type II diabetes suggest that statins provide benefit at considerable low LDL cholesterol levels. Therefore, target values for LDL cholesterol of less than 1.8 mmol/l (<70 mg/dl) should be considered for all patients with coronary artery disease or equivalent coronary risk. SUMMARY: For patients at high risk of coronary artery disease there is growing evidence for the concept of 'the lower, the better' regarding LDL cholesterol levels. Ongoing trials are further investigating the safety of lower target values in patients at various risk of coronary artery disease.     

Fluvastatin in the therapy of acute coronary syndrome: Rationale and design of a multicenter, randomized, double-blind, placebo-controlled trial (The FACS Trial)[ISRCTN81331696

BACKGROUND: Activation of inflammatory pathways plays an important contributory role in coronary plaque instability and subsequent rupture, which can lead to the development of acute coronary syndrome (ACS). Elevated levels of serum inflammatory markers such as C-reactive protein (CRP) represent independent risk factors for further cardiovascular events. Recent evidence indicates that in addition to lowering cholesterol levels, statins also decrease levels of inflammatory markers. Previous controlled clinical trials reporting the positive effects of statins in participants with ACS were designed for very early secondary prevention. To our knowledge, no controlled trials have evaluated the potential benefits of statin therapy, beginning immediately at the time of hospital admission. A previous pilot study performed by our group focused on early initiation of cerivastatin therapy. We demonstrated a highly significant reduction in levels of inflammatory markers (CRP and interleukin-6). Based on these preliminary findings, we are conducting a clinical trial to evaluate the efficacy of another statin, fluvastatin, as an early intervention in patients with ACS. METHODS: The FACS-trial (Fluvastatin in the therapy of Acute Coronary Syndrome) is a multicenter, randomized, double-blind, placebo-controlled study evaluating the effects of fluvastatin therapy initiated at the time of hospital admission. The study will enroll 1,000 participants admitted to hospital for ACS (both with and without ST elevation). The primary endpoint for the study is the influence of fluvastatin therapy on levels of inflammatory markers (CRP and interleukin-6) and on pregnancy associated plasma protein A (PAPP-A). A combined secondary endpoint is 30-day and one-year occurrence of death, nonfatal myocardial infarction, recurrent symptomatic ischemia, urgent revascularization, and cardiac arrest. CONCLUSION: The primary objective of the FACS trial is to demonstrate that statin therapy, when started immediately after hospital admission for ACS, results in reduction of inflammation and improvement of prognosis. This study may contribute to new knowledge regarding therapeutic strategies for patients suffering from ACS and may offer additional clinical indications for the use of statins.     

Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease,and stroke: systematic review and meta-analysis

Objectives To determine by how much statins reduce serum concentrations of low density lipoprotein (LDL) cholesterol and incidence of ischaemic heart disease (IHD) events and stroke, according to drug, dose, and duration of treatment.Design Three meta-analyses: 164 short term randomised placebo controlled trials of six statins and LDL cholesterol reduction; 58 randomised trials of cholesterol lowering by any means and IHD events; and nine cohort studies and the same 58 trials on stoke.Main outcome measures Reductions in LDL cholesterol according to statin and dose; reduction in IHD events and stroke for a specified reduction in LDL cholesterol.Results Reductions in LDL cholesterol (in the 164 trials) were 2.8 mmol/l (60%) with rosuvastatin 80 mg/day, 2.6 mmol/l (55%) with atorvastatin 80 mg/day, 1.8 mmol/l (40%) with atorvastatin 10 mg/day, lovastatin 40 mg/day, simvastatin 40 mg/day, or rosuvastatin 5 mg/day, all from pretreatment concentrations of 4.8 mmol/l. Pravastatin and fluvastatin achieved smaller reductions. In the 58 trials, for an LDL cholesterol reduction of 1.0 mmol/l the risk of IHD events was reduced by 11% in the first year of treatment, 24% in the second year, 33% in years three to five, and by 36% thereafter (P < 0.001 for trend). IHD events were reduced by 20%, 31%, and 51% in trials grouped by LDL cholesterol reduction (means 0.5 mmol/l, 1.0 mmol/l, and 1.6 mmol/l) after results from first two years of treatment were excluded (P < 0.001 for trend). After several years a reduction of 1.8 mmol/l would reduce IHD events by an estimated 61%. Results from the same 58 trials, corroborated by results from the nine cohort studies, show that lowering LDL cholesterol decreases all stroke by 10% for a 1 mmol/l reduction and 17% for a 1.8 mmol/l reduction. Estimates allow for the fact that trials tended to recruit people with vascular disease, among whom the effect of LDL cholesterol reduction on stroke is greater because of their higher risk of thromboembolic stroke (rather than haemorrhagic stroke) compared with people in the general population.Conclusions Statins can lower LDL cholesterol concentration by an average of 1.8 mmol/l which reduces the risk of IHD events by about 60% and stroke by 17%.     

Cardiovascular outcomes among participants with diabetes in the recent large statin trials

PURPOSE OF REVIEW: Despite their increased cardiovascular risk and its continuous relationship with cholesterol, until recently only diabetic patients with marked dyslipidaemia were routinely offered lipid-lowering therapy. The secondary prevention statin trials led to more widespread cholesterol lowering in patients with coronary disease and diabetes. Here we review the results of recent randomized trials, which included substantial numbers of patients with diabetes and no vascular disease. RECENT FINDINGS: The MRC/BHF Heart Protection Study included 5963 participants with diabetes, of whom 2912 had no history of vascular disease at baseline. Patients were randomized to 40 mg simvastatin daily or matching placebo for 5 years, which, on average, reduced LDL by 1.0 mmol/l compared with placebo. Highly significant reductions of about one-quarter in major vascular events were seen both overall and in different types of patient with diabetes, including those with average and below average lipid levels. Recent data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial and the Anglo-Scandinavian Cardiac Outcomes Trial support these findings and are consistent with these effects. SUMMARY: Good quality, randomized trials including substantial numbers of patients with diabetes show that such patients obtain the same proportional benefit as other groups studied. Given their increased cardiovascular risk, these findings argue for a simple strategy of considering routine statin therapy for patients with type 2 diabetes and adult patients with type 1 diabetes, irrespective of lipid levels. As generic statins become available this could have a greater impact on the burden of cardiovascular disease in diabetes than restricted and targeted therapy.     

Anti-atherogenic effects of fibrates in type 2 diabetes

Type 2 diabetes is an increasing cause of premature coronary heart disease. Several trials with lipid-modifying therapy have included sufficient numbers of diabetics to indicate that treatment of diabetic dyslipidaemia with either fibrates or statins reduces the risk of future coronary events in such patients. However, until recently no reported study had been designed specifically to investigate the effects of intervening in patients with type 2 diabetes. The Diabetes Atherosclerosis Intervention Study (DAIS) is an angiographic study in which 418 diabetic subjects were randomized to micronised fenofibrate or placebo groups. After 3 years of treatment, the fenofibrate group had a significantly reduced rate of progression of coronary atherosclerosis. This study, when considered with the results of other studies that have included diabetics, has important implications for the treatment of diabetic dyslipidaemia. The evidence that is currently available supports a place for both fibrates and statins, either as monotherapy or in combination, in the treatment of diabetic dyslipidaemia.     

Role of lipid-modifying therapy in the prevention of initial and recurrent stroke

PURPOSE OF REVIEW: To establish the role of cholesterol-modifying therapy in stroke prevention. RECENT FINDINGS: Population-based observational cohort studies show a variable weak positive relationship between increasing plasma total cholesterol concentrations and an increasing risk of ischaemic stroke, which is partly offset by a weaker negative association between decreasing total cholesterol concentrations and an increasing risk of with haemorrhagic stroke. However, randomized controlled trials show unequivocally that lowering plasma total cholesterol by approximately 1.2 mmol/l (and LDL-cholesterol by 1.0 mmol/l) is associated with a reduced relative risk of stroke and other serious vascular events by at least a quarter, and probably a third, without any increase in haemorrhagic stroke, in a wide range of men and women (including individuals with previous stroke). The proportional reduction in stroke risk is consistent, irrespective of the patient's age, baseline plasma cholesterol concentration, and absolute risk of stroke (although perhaps less in very low-risk individuals), but is increased with greater degrees of cholesterol lowering (15% or more), and thus with statin medications, which are more potent than non-statin interventions in lowering cholesterol levels. The absolute reduction in stroke risk achieved by statins is greatest among individuals at highest risk of stroke. Preliminary evidence suggests that lowering total cholesterol levels by diet may be an effective adjunctive therapy to statins, and raising plasma HDL-cholesterol concentrations among patients with coronary heart disease and low HDL-cholesterol levels ( 1 mmol/l) by means of gemfibrozil may also effectively prevent stroke. SUMMARY: Statin drugs are effective and safe in preventing initial and recurrent stroke. However, because they are costly, they should probably be restricted to individuals with an annual risk of stroke and other serious vascular events of 3% or greater, and possibly as low as 1.5%, because routine monitoring of plasma cholesterol, and liver and muscle enzyme concentrations is probably no longer necessary.     

Early initiation of statin therapy after a coronary event

PURPOSE OF REVIEW: Despite improvements in the early management of acute coronary syndromes, the risk of major cardiovascular complications remains high. Lipid-modifying treatment with statins has the potential to further improve outcomes through improved endothelial function, antithrombotic and antiinflammatory actions. Statins are of proven benefit in patients with stable coronary heart disease. There has been speculation on potential mechanisms of benefit but, until recently, little data on the efficacy and safety of statins in the acute setting. Recent observational studies and randomized trials have addressed some of the questions regarding early initiation of statins in acute coronary syndromes. RECENT FINDINGS: Recent observational and randomized trials have shown that early commencement of statins in acute coronary syndromes is safe as early as 6 hours after the event and is likely to improve longer-term compliance. The current data are not sufficient to draw conclusions about the efficacy of statins early in the course of acute coronary syndromes. SUMMARY: Current management for acute coronary syndromes should include the commencement of statin therapy during initial hospital admission. This recommendation is based on safety and compliance data. More randomized trial evidence is required to determine whether early initiation will produce better outcomes than later initiation after an acute coronary event.     

ACE inhibitors and statins acutely improve endothelial dysfunction of human coronary arterioles

Long-term treatment with angiotensin-converting enzyme (ACE) inhibitors as well as angiotensin II type 1 (AT(1)) receptor antagonists and statins reduces cardiovascular mortality in patients with coronary artery disease as well as chronic heart failure. Little is known about the acute effects of these compounds on vascular reactivity of coronary resistance vessels. Coronary arterioles were obtained from patients undergoing coronary bypass operation (atherosclerosis group) or valve replacement (control group). Responses to endothelium-dependent agonists (histamine, serotonin, and acetylcholine) as well as to the endothelium-independent agonist sodium nitroprusside (SNP) were investigated under baseline conditions and after incubation (15 min) with lisinopril (ACE inhibitor), candesartan (AT(1) receptor antagonist), or fluvastatin. In atherosclerotic vessels, vasorelaxation was significantly reduced to all endothelium-dependent agonists but not, however, to SNP (77 +/- 8, -24 +/- 16, -46 +/- 24, and 98 +/- 8% relaxation for histamine, serotonin, acetylcholine, and SNP, respectively). Lisinopril and fluvastatin but not candesartan significantly improved the responses to the endothelium-dependent agonists (lisinopril: 94 +/- 4, 17 +/- 22, and -20 +/- 13%; fluvastatin: 96 +/- 8, 23 +/- 21, and -25 +/- 18% relaxation for histamine, serotonin, and acetylcholine, respectively). The effect of lisinopril was prevented by pretreatment with a bradykinin antagonist (HOE-130) and dichloroisocoumarine, an inhibitor of kinine-forming enzymes. Pretreatment with a nitric oxide (NO) synthase inhibitor abolished the improvement of endothelial function by lisinopril and fluvastatin. Vascular reactivity in the control group was not influenced by any of the pharmacological interventions. The data demonstrate that in atherosclerosis, endothelium-dependent relaxation of coronary resistance arteries is severely compromised. The impairment can acutely be reversed by ACE inhibitors and statins via increasing the availability of NO.     

血清尿酸、同型半胱氨酸、白细胞介素-6与冠心病患者肠道菌群和主要不良心血管事件的关系研究

摘要 目的：研究血清尿酸（UA）、同型半胱氨酸（Hcy）、白细胞介素-6（IL-6）与冠心病患者肠道菌群和主要不良心血管事件（MACE）的关系。方法：选取2018年5月~2020年12月期间在中国人民解放军联勤保障部队第九八九医院行经皮冠状动脉介入术（PCI）的冠心病患者120例作为冠心病组,选取同期来中国人民解放军联勤保障部队第九八九医院体检的健康志愿者80例作为对照组。对比对照组、冠心病组的血清IL-6、Hcy、UA水平和乳酸杆菌、双歧杆菌、大肠杆菌。Pearson相关性分析IL-6、Hcy、UA和乳酸杆菌、双歧杆菌、大肠杆菌的相关性。记录冠心病组PCI术后随访1年MACE的发生率,并采用多因素Logistic回归分析MACE发生的影响因素。结果：冠心病组的血清IL-6、Hcy、UA水平高于对照组（P<0.05）。冠心病组的乳酸杆菌、双歧杆菌、大肠杆菌数量少于对照组（P<0.05）。Pearson相关性分析结果显示,IL-6、Hcy、UA均与乳酸杆菌、双歧杆菌、大肠杆菌呈负相关（P<0.05）。所有患者均完成随访,无失访患者。随访过程中发现有32例患者发生MACE,发生率为26.67%。根据是否发生MACE分为MACE组（n=32）和无MACE组（n=88）。单因素分析结果显示,MACE的发生与病程、吸烟史、合并高血压、合并糖尿病、置入支架数目、IL-6、Hcy、UA、乳酸杆菌、双歧杆菌、大肠杆菌有关（P<0.05）。多因素Logistic回归分析结果显示：病程偏长、吸烟史、合并高血压、合并糖尿病、置入支架数目更多、IL-6偏高、Hcy偏高、UA偏高是冠心病患者MACE发生的危险因素（P<0.05）。结论：冠心病患者体内IL-6、Hcy、UA水平升高,肠道菌群紊乱,且肠道菌群紊乱与IL-6、Hcy、UA水平相关。此外,冠心病PCI术后MACE发生不可避免,且受到病程、吸烟史、合并高血压等多种因素的影响。     

Dehydroepiandrosterone therapy in men with angiographically verified coronary heart disease: the effects on plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and fibrinogen plasma concentrations

INTRODUCTION: The aim of this study was to analyze the influence of DHEA therapy on fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) plasma concentrations in men with decreased serum DHEA-S levels and angiographically verified coronary heart disease (CHD). MATERIAL AND METHODS: The study included thirty men aged 41-60 years (mean age 52 +/- 0.90 yr) with serum DHEA-S concentration < 2000 mg/l, who were randomized into a double-blind, placebo-controlled, cross-over trial. Subjects completed the 80 days study of 40 days of 150 mg oral DHEA daily or placebo, and next groups were changed after 30 days of wash-out. Fasting early morning blood samples were obtained at baseline and after each treatment to determine serum hormones levels (testosterone, DHEA-S, LH, FSH and estradiol) and also fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) plasma concentrations. RESULTS: Administration of DHEA was associated with 4.5-fold increase in DHEA-S levels. Estrogen levels significantly increased after DHEA from 22.1 +/- 0.7 pg/ml to 26.4 +/- 1.6 pg/l (mean +/- SEM; p < 0.05), while testosterone levels did not changed. Fibrinogen concentrations significantly decreased in DHEA group from 4.5 +/- 0.3 g/l to 3.83 +/- 0.2 g/l (p < 0.05 vs. placebo). Changes of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) were not statistical significant (respectively: 8.37 +/- 0.4 ng/ml vs. 8.93 +/- 0.5 ng/ml and 82.3 +/- 6.3 ng/ml vs. 92.7 +/- 9.1 ng/ml (mean +/- SEM; NS vs. placebo). Tolerance of the treatment was good and no adverse effects were observed. CONCLUSIONS: DHEA therapy in dose of 150 mg daily during 40 days in men with DHEAS levels < 2000 mg/l and angiographically verified coronary heart disease (CHD) was connected with significant decreasing of fibrinogen concentration and increasing of estradiol levels, and did not influence on plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) plasma concentrations.     

Immediate effect of fluvastatin on lipid levels in acute coronary syndrome

It is widely assumed that acute benefit of statin therapy is mediated especially by non-lipid effects. The immediate influence of statins on lipid levels in patients with acute coronary syndrome (ACS) is, however, not clear. A total of 64 consecutive patients with ACS were randomized at admission to fluvastatin 80 mg (Group 1, N = 32) or standard therapy without statin (Group 2, N = 32). The levels of total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), and triglycerides (TG) were examined at admission and after 24 h. Baseline characteristics were comparable in both groups. In Group 1, fluvastatin significantly decreased the levels of TC by 14.5%, LDL-C by 17.2%, and HDL-C by 10.0% (P < 0.001); TG were not influenced. In Group 2 only marginal reductions in TC (by 4.1%, P = 0.03) and HDL-C (by 7.5%, P < 0.01) were detected; the levels of LDL-C and TG were not changed. As compared with Group 2, in Group 1 the final levels of TC (P = 0.02) and LDL-C (P = 0.01) were significantly lower. Fluvastatin therapy, when started at admission in patients with ACS, significantly reduces TC and LDL-C already after 24 h. We suggest that the lipid-lowering effect of statins in the therapy of ACS is probably as prompt as non-lipid effects.     

Statin Intensity and Clinical Outcome in Patients with Stable Coronary Artery Disease and Very Low LDL-Cholesterol

BackgroundAlthough intensive statin therapy is recommended for high risk patients, evidence of its benefit in patients with stable coronary artery disease (CAD) and very low low-density lipoprotein-cholesterol (LDL-C) has been very rare. In this study, we investigated whether higher statin intensity reduces cardiovascular risks in this population.MethodsIn this retrospective study, a total of 5234 patients with stable CAD were screened at three tertiary hospitals in Korea; 449 patients (mean age: 65 years, male: 69%) with LDL-C <80 mg/dL were finally analyzed. The statin intensities were classified according to the 2013 American College of Cardiology/American Heart Association guidelines. Patients who received statins equivalent to or weaker than atorvastatin 10 mg (group 1) were compared with those who took statins equivalent to or stronger than atorvastatin 20 mg (group 2). The impact of statin intensity on major adverse cardiac events (MACE) was evaluated during follow-up.ResultsGroup 1 and group 2 consisted of 181 patients (40.3%) and 268 patients (59.7%), respectively. The mean LDL-C level decreased to 52 and 57 mg/dL in group 1 and group 2, respectively, during follow-up. In a median follow-up of 4.5 years, patients of group 2 had a lower incidence of MACE (30 [16.6%] vs. 12 [4.5%], p <0.001), which were mostly related to a lower incidence of coronary revascularization. Cox proportional hazard analyses identified the statin intensity of group 2 (adjusted hazard ratio: 0.25, confidence interval: 0.11–0.55, p <0.001) and the baseline high-density lipoprotein-cholesterol level as independent determinants of MACE.ConclusionThis study provides evidence that higher intensity statins are beneficial for cardiovascular outcomes in patients with stable CAD and very low LDL-C. Statins equivalent to or stronger than atorvastatin 20 mg are more effective than lower intensity statins.     

不同剂量氟伐他汀对冠心病伴血脂增高患者的临床作用研究

目的:观察不同剂量氟伐他汀对冠心病伴血脂增高患者的临床效果及安全性,为临床治疗提供依据。方法:选择我院2010年5月~2013年2月收治的96例冠心病伴高脂血症患者并将其进行随机分组,即20 mg及40 mg氟伐他汀治疗组各48例,观察和比较两组的临床疗效及不良反应的发生情况。结果:经4周、8周治疗后,两组患者的总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、甘油三酯(TG)的水平均较同组治疗前显著降低,差异均具有统计学意义(P0.05);高密度脂蛋白胆固醇(HDL-C)均较同组治疗前明显升高,差异有统计学意义(P0.05);40 mg组hs-CRP含量下降,较20mg组显著,差异明显具有统计学意义(P0.05)。结论:对于冠心病伴血脂增高患者,采用高剂量氟伐他汀进行降脂治疗临床疗效较好,且安全性高,建议推广应用。     

Familial defective apolipoprotein B-100: a lesson from homozygous and heterozygous patients

Familial defective apolipoprotein B-100 (FDB) is a genetic disorder caused by a substitution of glutamine for arginine at residue 3500 of the apolipoprotein B-100 molecule. We have identified 23 heterozygotes and one homozygote for FDB (frequency 1:20) in a group of 510 patients with hypercholesterolemia. Mean age of the patients (18 females and 6 males) was 46 years. The diagnosis of FDB was based on point mutation PCR analysis of exon 26 of the apo B gene. Plasma lipids in heterozygous patients were: total cholesterol 8.76+/-1.2 mmol/l, triglycerides 1.42+/-0.5 mmol/l, HDL-cholesterol 1.43+/-0.3 mmol/l, LDL-cholesterol 6.69+/-1.2 mmol/l, apoB 1.69+/-0.4 g/l, Lp(a) 0.26+/-0.2 g/l. The most frequent apoE genotype was 3/3 (19 patients), apoE 3/4 genotype was found in 3 patients and one person had apoE 2/3. Xanthelasma palpebrarum was present in 4 patients and tendon xanthomas in 3 patients including the homozygote. Premature manifestation of coronary heart disease was revealed in 3 patients. Sixteen patients were treated with statins, a combination of statin and resin was used in 2 patients (including the homozygote), whereas six patients were treated with the diet only. We conclude that although the plasma lipid levels of total and LDL cholesterol in FDB patients are lower than in patients with familial hypercholesterolemia, the patients with FDB suffer from premature atherosclerosis. The therapeutic approach to FDB individuals and patients with familial hypercholesterolemia is very similar.     

Statin therapy and stroke prevention: what was known, what is new and what is next?

PURPOSE OF REVIEW: Randomized trials have shown that statins may reduce the risk of primary stroke. There is no evidence however that statins can reduce recurrent stroke incidence. RECENT FINDINGS: In the SPARCL trial, patients with a recent stroke or transient ischemic attack randomized to atorvastatin 80 mg/day had a significant 16% relative risk reduction of stroke, and a 35% reduction in major coronary events compared with placebo. This was obtained despite 25% of the placebo arm patients receiving a commercially-available statin outside of the trial. Post-hoc analysis used blinded LDL-cholesterol measurements as a marker of adherence to lipid-lowering therapy. Compared with the group with no change or an increase in LDL-cholesterol (the group adherent to placebo or not taking a statin), the group with over 50% reduction in LDL-cholesterol had a significant 31% reduction in stroke. The next step is to define whether achieving LDL-cholesterol below 70 mg/dl is better than a standard dose of statin (LDL around 100-110 mg/dl) in the secondary prevention of stroke. SUMMARY: Statins are effective in reducing both first-ever and recurrent stroke, and this effect seems driven by the extent of LDL-cholesterol lowering.     

Genome-wide study of gene variants associated with differential cardiovascular event reduction by pravastatin therapy

Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8 × 10(-7)). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins.     

The Myocardial Ischemia Reduction with Acute Cholesterol Lowering trial: MIRACuLous or not, it's time to change current practice

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study was the first trial to assess whether statins might be of clinical benefit in those with recently unstable coronary disease. MIRACL found that high-dose atorvastatin was safe and reduced the incidence of the composite endpoint, death, non-fatal myocardial infarction, resuscitated sudden cardiac death or emergent rehospitalization for recurrent ischemia at 16 weeks when compared with placebo. Despite a number of important study limitations, MIRACL's findings and the prior observation that inpatient initiation of lipid-lowering therapy is associated with higher rates of subsequent utilization, suggest that it is prudent to begin statin therapy when patients present with an acute coronary syndrome.     

The Myocardial Ischemia Reduction with Acute Cholesterol Lowering trial: MIRACuLous or not,it's time to change current practice

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study was the first trial to assess whether statins might be of clinical benefit in those with recently unstable coronary disease. MIRACL found that high-dose atorvastatin was safe and reduced the incidence of the composite endpoint, death, non-fatal myocardial infarction, resuscitated sudden cardiac death or emergent rehospitalization for recurrent ischemia at 16 weeks when compared with placebo. Despite a number of important study limitations, MIRACL's findings and the prior observation that inpatient initiation of lipid-lowering therapy is associated with higher rates of subsequent utilization, suggest that it is prudent to begin statin therapy when patients present with an acute coronary syndrome.     

Randomised placebo controlled trial of effect on mood of lowering cholesterol concentration. Oxford Cholesterol Study Group.

OBJECTIVE--To evaluate the effects on mood of a substantial and prolonged reduction in total cholesterol concentration. DESIGN--Randomised placebo controlled comparison of patients who had been allocated to receive simvastatin 20 mg or 40 mg daily versus those allocated matching placebo in a ratio of 2:1. Follow up at an average of 152 weeks after randomisation. SUBJECTS--Men and women aged between 40 and 75 years at entry with blood total cholesterol of 3.5 mmol/l or greater, who were considered to be at higher than average risk of coronary heart disease based on medical history. MAIN OUTCOME MEASURES--The shortened profile of mood states questionnaire, reported use of psychotropic medication, and symptoms possibly related to mood. RESULTS--Simvastatin reduced total cholesterol by 1.9 mmol/l (26.7%) at the time of follow up. Among all 621 patients randomised to simvastatin (414 patients) or placebo (207 patients) there were no significant differences in the use of psychotropic medication or in reports of symptoms possibly related to mood. Of these patients, 491 (334 simvastatin, 157 placebo) completed the mood questionnaire, and there were no significant differences between the treatment groups in total or subscale scores, even when patients with low baseline cholesterol concentrations or elderly subjects were considered separately. CONCLUSION--These results do not support the hypothesis that treatment to lower cholesterol concentration causes mood disturbance.