Adherence to and dosing of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors in the general population differs according to apolipoprotein E-genotypes

Discontinuation and poor adherence to therapy are major problems during long-term treatment, particularly with cholesterol lowering drugs. Several studies have indicated that the cholesterol lowering effect of statins differs according to apolipoprotein (apo)E genotypes. Low-density lipoprotein-cholesterol lowering capacity appears to be smaller in subjects with the epsilon(4) allele. To assess whether the use of statins in daily practice differs according to apoE genotypes, we used data from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, which started in 1990 and included 7983 subjects aged 55 years or more. During follow-up, there were 798 subjects who started to use statins. We used a Cox proportional hazard model to determine the rate of discontinuation in the first 3 years of statin use. Subjects on statin therapy with epsilon(2)epsilon(2) and epsilon(4)epsilon(4) genotypes showed a trend towards higher dosages than subjects with the other genotypes. Relative to subjects with the epsilon(2)epsilon(3) genotype, those with the epsilon(4)epsilon(4) genotype had a risk of 2.28 [95% confidence interval (CI) 1.02-5.12] to discontinue statins within 3 years. In women, this relative risk was 1.70 (CI 0.53-5.42) versus 3.18 (CI 1.01-10.03) in men. The apoE genotype is associated with discontinuation of statins. This suggests that subjects who are genetically prone to develop hypercholesterolemia show the highest risk of discontinuation of treatment.     

Use of statins in primary and secondary prevention of coronary heart disease and ischemic stroke. Meta-analysis of randomized trials

OBJECTIVE: To estimate the relative risk reduction of the clinical outcomes (coronary events, strokes, cardiovascular, non-cardiovascular and all-cause mortality) associated with statin therapy in primary and secondary prevention. DATA SOURCES: A literature search of the Medline and Cohrane databases for articles published from 1985 to July 2002 was performed. The data on systematic reviews and preliminary reports were also included in this study. Primary and secondary prevention trials and regression trials were eligible. DATA EXTRACTION AND STATISTICAL METHOD: Data were extracted by 2 authors according to the defined inclusion criteria. Disagreements were resolved by consensus or by a third reviewer. Testing for heterogeneity was applied and on the basis of these results a fixed effect model or a random effect model was used for calculation of relative risk values (RR) and 95% confidence intervals (95% CI). Sensitivity analysis tested the impact of the individual study--duration of study, type of statin therapy and study size. The number of patients needed to treat was calculated as an absolute measure of clinical effectiveness of statin therapy when appropriate. RESULTS: Data from 15 trials with 63,410 participants and mean duration of treatment of 3.6 years, were included in this overview. Tests for heterogeneity showed that the variability between study estimates is sufficiently small to assume that they are estimating the same underlying treatment effect. Statin therapy was associated with a 22% reduction in total cholesterol, 29% reduction in LDL cholesterol, 12% reduction in triglycerides and 6% increase in HDL cholesterol. Overall (primary and secondary studies) statin therapy significantly reduces relative risk of coronary events (RR, 0.73, 95% CI, 0.68, 0.77, *p < 0.0001), relative risk of cardiovascular disease mortality (RR, 0.78, 95% CI, 0.73, 0.84, *p < 0.0001), relative risk of non-fatal stroke (RR, 0.74, 95% CI, 0.67, 0.82, *p < 0.0001), relative risk of total (fatal and non-fatal) stroke (RR, 0.77, 95% CI, 0.70, 0.84, *p < 0.001) and relative risk of all-cause death (RR, 0.85, 95% CI, 0.81, 0.89, *p < 0.0001). There was a slight and insignificant reduction of relative risk in non-cardiovascular mortality (RR, 0.94, 95% CI, 0.86, 1.03, p = 0.1677) and fatal strokes (RR, 0.86, 95% CI, 0.70, 1.07, p = 0.1912). Sensitivity analysis showed the robustness of our results for all outcomes. The results were not altered if an individual study was removed from meta-analysis. CONCLUSIONS: This overview indicates that statin treatment reduces the relative risk of occurrence of coronary events, cardiovascular disease mortality, non-fatal strokes and all-cause mortality. While secondary prevention with statins provides considerable improvement of cardiovascular morbidity/mortality, primary prevention with statins provides only small and clinically hardly relevant improvement of cardiovascular morbidity/mortality.     

Long-Term Benefit of Statin Therapy Initiated during Hospitalization for an Acute Coronary Syndrome

OBJECTIVE: This study sought to determine if the initiation of statin (HMG-CoA reductase inhibitor) therapy during acute coronary syndromes reduces long-term mortality and other adverse cardiac outcomes. BACKGROUND: Initiation of statin therapy during acute coronary syndromes has not been shown to reduce mortality, myocardial infarction or stroke within 4 months of follow-up. METHODS: Clinical trials that randomized patients with acute coronary syndromes to early statin therapy compared with less intensive lipid reduction (placebo/lower-dose statin/usual care), and reported long-term outcomes were included for analysis. RESULTS: In all, there were seven studies (L-CAD, PTT, FLORIDA, Colivicchi et al., PROVE-IT, ESTABLISH, and A-to-Z) with 9553 patients who started statin therapy within 12 days of hospital presentation. The incidence of all-cause mortality was 3.4% in the statin group versus 4.6% in the less intensive lipid reduction group over a weighted mean follow-up of 22.9 months (relative risk [RR] 0.74; 95% CI 0.61, 0.90; p = 0.003). The number of patients needed to treat to prevent one death was 84 patients. Similarly, the incidence of cardiovascular mortality in the statin versus the less intensive lipid reduction group was 2.4% versus 3.3% (RR 0.74; 95% CI 0.58, 0.93; p = 0.010), unstable angina 4.1% versus 5.0% (RR 0.81; 95% CI 0.68, 0.98; p = 0.027), revascularization 11.2% versus 12.9% (RR 0.86; 95% CI 0.78, 0.96; p = 0.006), stroke 1.1% versus 1.2% (RR 0.90; 95% CI 0.62, 1.30; p = 0.56), and myocardial infarction 6.6% versus 7.0% (RR 0.94; 95% CI 0.81, 1.09; p = 0.41). CONCLUSIONS: The benefit of early initiation of statin therapy during acute coronary syndromes slowly accrues over time so that a survival advantage is seen around 24 months. Relatively few patients need to be treated to prevent one death over this time period. Furthermore, this approach significantly reduces unstable angina and the need for revascularization.     

Meta-analysis of large randomized controlled trials to evaluate the impact of statins on cardiovascular outcomes

AIMS: Since 2002, there have been five major outcome trials of statins reporting findings from more than 47,000 subjects. As individual trial results differed, we performed a meta-analysis to ascertain the effectiveness and safety of statins overall and in subgroups. The aim of the study was to estimate the effect of statins on major coronary events and strokes, all-cause mortality and noncardiovascular mortality, and in different subgroups. METHODS: PubMed was searched for trials published in English. Randomized placebo-controlled statin trials with an average follow up of at least 3 years and at least 100 major coronary events were included. For each trial, the statin used, number and type of subjects, proportion of women, mean age and follow up, baseline and change in lipid profile, cardiovascular and non-cardiovascular outcomes were recorded. RESULTS: Ten trials involving 79,494 subjects were included in the meta-analysis. Due to heterogeneity, ALLHAT-LLT was excluded from some analyses. Statin therapy reduced major coronary events by 27% (95%CI 23, 30%), stroke by 18% (95%CI 10, 25%) and all-cause mortality by 15% (95%CI 8, 21%). There was a 4% (95%CI -10, 3%) nonsignificant reduction in noncardiovascular mortality. The reduction in major coronary events is independent of gender and presence of hypertension or diabetes. The risk reduction was greater in smokers (P < 0.05). Coronary events were reduced by 23% (95%CI 18, 29%) in pravastatin trials and 29% (95%CI 25, 33%) in five trials using other statins. Pravastatin reduced strokes by 12% (95%CI 1, 21%) whilst other statins reduced strokes by 24% (95%CI 16, 32%) (P = 0.04). CONCLUSIONS: Statins reduce coronary events, strokes and all-cause mortality without increasing noncoronary mortality. The benefits accrue in men and women, hypertensives and normotensives, diabetics and nondiabetics, and particularly in smokers. Pravastatin appears to have less impact on strokes.     

Clinical perspectives on the role of anti-platelet and statin therapy in patients with vascular diseases

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis and is associated with a several-fold increased risk of cardiovascular morbidity and mortality. Statins and anti-platelet therapy have been unequivocally shown to be beneficial in patients with coronary artery disease, but minimal data exist on the effectiveness of these agents in patients with PAD and those undergoing peripheral vascular interventions. One recent study has demonstrated that statins are very effective as secondary preventive measures in patients with PAD but continue to be underutilized in this cohort. In our institutional peripheral interventional database, after adjustment for demographics and comorbidities, statin therapy (OR=0.21, 95% CI 0.05-0.86, p=0.03) and clopidogrel therapy (OR=0.17, 95% CI 0.04-0.78, p=0.02) were both associated with a significant reduction of the composite event rate of death, myocardial infarction and stroke at 6 months. In this article, we critically review the existing literature on the role of anti-platelet and statin therapy in reducing cardiovascular events in patients with PAD. Appropriate use of these agents may significantly decrease the cardiovascular morbidity and mortality of patients with PAD.     

Impact of gender on statin efficacy

ABSTRACT

Objective: To determine the impact of statin therapy on the combined endpoint of cardiovascular events in women and men separately.

Research design and methods: A systematic literature search through May 2006 was conducted to identify randomized, controlled statin trials evaluating the gender specific incidence of cardiovascular events. Weighted averages were reported as relative risks (RRs) with 95% confidence intervals (CI) calculated via random-effects model.

Main outcome measures: The primary outcome measured was a composite endpoint of all cardiovascular events. Secondary outcomes measured included death, myocardial infarction (MI), and stroke.

Results: Fifteen trials were included in this meta-analysis. Cardiovascular events were reduced in men (RR 0.76 [95% CI 0.70, 0.81]) and women (RR 0.79 [95% CI 0.69, 0.90]). Reductions in mortality, MI, and stroke predominantly contributed to the reduction in cardiovascular events in men taking statins. Women did not have a reduction in mortality or stroke, suggesting that the reductions in cardiac events may have been predominantly due to reductions in need for revascularization and/or unstable angina.

Conclusions: Statins reduced the risk of cardiovascular events in men and women, but women on statins may not have reductions in mortality and stroke like their male counterparts.     

Current use of nonsteroidal antiinflammatory drugs and the risk of acute myocardial infarction

STUDY OBJECTIVE: To evaluate the risk of acute myocardial infarction during current exposure to nonsteroidal antiinflammatory drugs (NSAIDs). DESIGN: Retrospective case-control analysis. SETTING: General practice offices. SUBJECTS: A total of 8688 case patients, aged 89 years or younger, with a first-time acute myocardial infarction and 33,923 control subjects matched on age, sex, calendar time, and general practice attended. INTERVENTION: The United Kingdom General Practice Research Database was searched for potential cases of first-time acute myocardial infarction between January 1995 and April 2001. Control subjects without acute myocardial infarction were identified at random. MEASUREMENTS AND MAIN RESULTS: Exposure to NSAIDs was assessed, and 650 case patients and 2339 control subjects were found to be currently taking NSAIDs. After adjusting for various risk factors for acute myocardial infarction (e.g., hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, body mass index, smoking), the relative risk (expressed as odds ratio [OR]) of acute myocardial infarction was 1.07 (95% confidence interval [CI] 0.96-1.19) for subjects with current NSAID exposure compared with those not taking NSAIDs. The adjusted OR for current diclofenac use was 1.23 (95% CI 1.00-1.51), for current ibuprofen use 1.16 (95% CI 0.92-1.46), and for current naproxen use 0.96 (95% CI 0.66-1.38) compared with those not taking NSAIDs. Current aspirin use combined with current NSAID use was associated with a statistically significant risk reduction (adjusted OR 0.74, 95% CI 0.57-0.97), compared with nonuse of NSAIDs and aspirin. Current use of aspirin together with current use of ibuprofen yielded an adjusted OR of 0.69 (95% CI 0.42-1.15). CONCLUSIONS: Our results provide additional evidence that the risk of first-time acute myocardial infarction during current use of NSAIDs is not materially altered. We found no evidence for a reduced cardioprotective effect of aspirin with concomitant NSAID use.     

心房颤动采用三联疗法和双重抗血小板疗法抗血栓治疗策略对卒中、主要不良心脑血管事件、出血事件、全因病死率影响的Meta分析

目的 综合评价三联疗法(TT)和双重抗血小板治疗(DAPT)的策略在心房颤动(AF)病人接受经皮冠状动脉介入治疗(PCI)后对卒中、主要不良心脑血管事件(MCAE)、出血事件、全因病死率的影响.方法 检索PubMed,Embase,Web of Science数据库中2000―2018年的文章.根据纳入和排除标准进行筛...     

Incremental Effect of Clopidogrel on Important Outcomes in Patients with Cardiovascular Disease

OBJECTIVES: To quantify the impact of clopidogrel plus aspirin on the individual outcomes of death, myocardial infarction, or stroke in patients with established cardiovascular disease, or in patients with multiple risk factors for vascular disease. BACKGROUND: Randomized trials have demonstrated a reduction in composite outcomes when clopidogrel is added to aspirin therapy in patients with coronary artery disease; however, the magnitude of benefit on individual outcomes is unknown. METHODS: We conducted a meta-analysis on randomized, controlled trials that compared aspirin plus clopidogrel with aspirin plus placebo for the treatment of coronary artery disease. RESULTS: This analysis included five randomized trials (CURE, CREDO, CLARITY, COMMIT, and CHARISMA) in 79 624 patients. The incidence of all-cause mortality was 6.3% in the aspirin plus clopidogrel group versus 6.7% in the aspirin group (odds ratio [OR] 0.94; 95% CI 0.89, 0.99; p = 0.026). The incidence of myocardial infarction was 2.7% and 3.3% (OR 0.82; 95% CI 0.75, 0.89; p < 0.0001), and stroke was 1.2% and 1.4% (OR 0.82; 95% CI 0.73, 0.93; p = 0.002). Similarly, the incidence of major bleeding was 1.6% and 1.3% (OR 1.26; 95% CI 1.11, 1.41; p < 0.0001), and fatal bleeding was 0.28% and 0.27% (OR 1.04; 95% CI 0.76, 1.43; p = 0.79). CONCLUSION: The addition of clopidogrel to aspirin results in a small reduction in all-cause mortality in patients with ST-elevation myocardial infarction and a modest reduction in myocardial infarction and stroke in patients with cardiovascular disease. The overall incidence of major bleeding however is increased, although there is no excess of fatal bleeds or hemorrhagic strokes.     

Interactions between the single nucleotide polymorphisms in the homocysteine pathway (MTHFR 677C>T, MTHFR 1298 A>C, and CBSins) and the efficacy of HMG-CoA reductase inhibitors in preventing cardiovascular disease in high-risk patients of hypertension: the GenHAT study

BACKGROUND: High homocysteine blood concentrations predispose to coronary artery disease and statins influence homocysteine levels. AIM: To study whether genes that regulate homocysteine metabolism interact with statins to modify the risk of coronary heart disease (CHD) and other cardiovascular outcomes. METHODS: The Genetics of Hypertension Associated Treatment is an ancillary study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The genotyped population in the Lipid-Lowering Trial of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial included 9624 participants randomly assigned to pravastatin or to usual care. The efficacy of pravastatin in reducing risk of all-cause mortality and CHD was compared among genotype strata (MTHFR 677 CC, CT, and TT, MTHFR 1298 AA, AC, and CC, CBSins DD and I) by examining an interaction term in a proportional hazards model. RESULTS: No evidence existed of a pharmacogenetic effect on statins with the MTHFR 1298 A>C genotype for CHD risk. However, in persons with the CC variant for the MTHFR 677 C>T genotype, a significantly protective effect against CHD [0.71 (95% CI 0.58-0.87)] was shown, although in the CT [1.25 (95% CI 0.97-1.61)] and TT groups [0.80 (95% CI 0.50-1.28)] there were no such effects (interaction hazard ratio P=0.004). The CBSins, I+ variant was associated with a significantly reduced risk for CHD among those on statin treatment [0.58 (95% CI 0.44-0.78)] whereas the DD genotype showed no effect of statin therapy [1.01 (95% CI 0.84-1.20; P=0.002 for interaction]. For the endpoint all-cause mortality, no significant differences in efficacy were noted. CONCLUSION: Polymorphisms in genes in the homocysteine pathway (MTHFR 677 C>T and CBSins) appear to modify the efficacy of pravastatin in reducing risk of cardiovascular events.     

Statins do not Increase the Rate of Bleeding Among Warfarin Users

Clinical significance of potential interaction between warfarin and statins is unclear. Our objective was to determine whether use of statins as a class or use of simvastatin modulates the rate of bleeding requiring hospitalization among new warfarin users. Using Finnish healthcare databases, we identified a cohort of 101,588 warfarin initiators between 1 January 2009 and 30 June 2012. By the end of 2012, these patients accumulated 92,695 person‐years of exposure to warfarin‐only and 60,253 years of exposure to warfarin‐with‐statin. The outcome was a composite of gastrointestinal, intracranial or other bleeding leading to hospitalization. A Poisson generalized estimating equation model was employed to estimate rate ratios (RR) and their 95% confidence intervals (CI) for exposure to warfarin‐with‐statin compared to warfarin‐only and to allow multiple episodes per patient and time‐dependent covariates. In multivariable models, we found no difference in the bleeding rate in association with exposure to any statin (multivariable‐adjusted RR = 0.98, 95% CI 0.89–1.07) or to simvastatin (RR = 1.01, 95% CI 0.91–1.11) with warfarin compared to exposure to warfarin‐only. We conclude that concomitant use of statins and warfarin was not associated with an increased rate of bleeding requiring hospitalization.     

Effectiveness of statins in the reduction of the risk of myocardial infarction is modified by the GNB3 C825T variant

INTRODUCTION: The GNB3 C825T polymorphism has been shown to affect lipid parameters, atherosclerosis progression, and incidence of myocardial infarction (MI). Therefore, we assessed whether the effectiveness of statins in reducing the risk of MI was modified by the GNB3 C825T polymorphism. METHODS: In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO), we used a nested case-control design. We selected patients hospitalized for MI as cases if they used antihypertensive drugs and had a diagnosis of hypercholesterolemia before their first MI. Controls met the same eligibility criteria, but were not hospitalized for MI. Logistic regression analysis was used to calculate odds ratios (OR) and synergy index with corresponding 95% confidence intervals (CI), and to adjust for potential confounding factors. RESULTS: We included 459 cases and 1805 controls. The risk of MI was significantly lower among participants exposed to statins compared with participants not exposed to statins (adjusted OR: 0.37, 95% CI: 0.29-0.47). The GNB3T allele was associated with a reduced risk of MI (adjusted OR: 0.74, 95% CI: 0.60-0.92). Among homozygous wild-type (CC) individuals (n=1119), exposure to statins was associated with a lower risk of MI (OR: 0.48, 95% CI: 0.34-0.67). However, T allele carriers (CT and TT) who used statins had an even stronger reduced risk of MI (OR: 0.27, 95% CI: 0.19-0.39). Overall, the interaction between exposure to statins and the GNB3 C825T polymorphism was significantly increased on the multiplicative scale (synergy index: 1.67, 95% CI: 1.06-2.65). CONCLUSION: Our findings show that T allele carriers of the GNB3 C825T polymorphism have less risk of MI and are more likely to benefit from statin therapy in a hypercholesterolemic population of antihypertensive drug users.     

Statins in prevention of repeat revascularization after percutaneous coronary intervention—A meta-analysis of randomized clinical trials

Recent prospective cohort studies have shown that patients discharged on statins after percutaneous coronary intervention (PCI) are at lower risks of repeat revascularization and mortality when compared to those not on statins after discharge. However, few randomized clinical trials among post-PCI patients confirmed these beneficial effects. It is needed to evaluate the effects of post-procedural statin therapy on individual clinical outcomes to facilitate the further investigation on identifying the underlying mechanism(s). A meta-analysis of randomized clinical trials was conducted to examine the effects of statin therapy initiated after coronary angioplasty on repeat revascularization, all-cause mortality and myocardial infarction (MI). From relevant reports on Medline (from inception to October 2009), six randomized clinical trials comprising 2979 patients were included. Relative risks were evaluated for pooled data via random effect models. Compared with controls, post-PCI statin therapy was associated with a significantly decreased risk of repeat revascularization (risk ratio (RR) = 0.73, 95% confidence interval (CI), 0.55–0.98, p = 0.04), nonsignificantly decreased risks of all-cause mortality (RR = 0.88, 95% CI, 0.35–2.21, p = 0.79), MI (RR = 0.76, 95% CI, 0.49–1.18, p = 0.23), and target lesion or target vessel revascularization (RR = 0.58, 95% CI, 0.24–1.39, p = 0.22). In conclusion, statin therapy after PCI can reduce the risk of repeat revascularization. Further investigation is needed to identify the underlying mechanism(s).     

Effect of statins on total cholesterol concentrations and cardiovascular outcomes in patients with diabetes mellitus: a population-based cohort study

Background

In the UK, clinicians usually make treatment decisions based on total cholesterol (TC) at the same time supplemented with high-density lipoprotein cholesterol (HDL-C) measurements. We evaluated statin-associated TC concentration change and its impact on cardiovascular (CV) risk reduction in diabetic patients in the setting of usual care.

Methods

In a population-based cohort study using a record-linkage database in Tayside, Scotland. we studied 6,697 diabetic patients who had at least two separate TC measurements between 1993 and 2007. Patients were categorized into statin-exposed and statin-unexposed groups according to statin use status during the follow-up. The main outcomes were TC concentration change from baseline, CV events, and all-cause mortality during the follow-up. Multivariate Cox regression models with a time-dependent variable for statins were employed to assess outcome risk.

Results

Statin-associated TC concentrations decreased by 1.64 mmol/L (28%) in patients without CV disease (CVD) (5,984) and 1.19 mmol/L (23%) in patients with CVD (713) from 5.90 mmol/L and 5.20 mmol/L at baselines, respectively. Statin use reduced incident and recurrent CV events by 39% and 41%, respectively [adjusted hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.57–0.66; 0.59 95% CI 0.47–0.76) per millimole of TC reduction. For all-cause mortality, the adjusted HRs were 0.39 (95% CI 0.32–0.47) in primary prevention and 0.58 (95% CI 0.42–0.80) in secondary prevention.

Conclusion

Statin use was as effective in diabetic patients in the setting of usual care, as in the clinical trials, in both primary and secondary prevention. TC changes can be used as a measure of statin efficacy in the absence of low-density lipoprotein cholesterol (LDL-C) in diabetic patients.