Statin withdrawal: clinical implications and molecular mechanisms

Retrospective analyses of data from the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM), the National Registry of Myocardial Infarction 4, and the Global Registry of Acute Coronary Events (GRACE) trials revealed that the benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) on acute coronary outcomes are rapidly lost and outcomes worsened if statins are discontinued during a patient's hospitalization for an acute coronary syndrome. Withdrawal of statin therapy in the first 24 hours of hospitalization for non-ST-elevation myocardial infarction increased the hospital morbidity and mortality rate versus continued therapy (11.9% vs 5.7%, p<0.01). Data from the Treating New Targets (TNT) study, however, suggested that short-term discontinuation of statin therapy in patients with stable cardiac conditions may not substantially increase the risk of acute coronary syndromes. In patients with acute coronary syndromes who discontinue statins, the rapid increase in risk of an event may result not only from the lost benefits from the therapy, but also from rebound inhibition of vascular protective substances and activation of vascular deleterious substances. Statins inhibit cholesterol synthesis in vascular cells. By reducing levels of isoprenoid intermediates, statins increase the production of nitric oxide and downregulate angiotensin II AT(1) receptors, endothelin-1, vascular inflammatory adhesion molecules, and inflammatory cytokines. These benefits are rapidly lost and often transiently reversed when statins are acutely discontinued. Acute removal of pleiotropic effects and rebound vascular dysfunction may be more important in an acute coronary event, where inflammation promotes rupture of atherosclerotic plaques and inflammatory and prothrombosis markers are present in high concentration, than in stable chronic vascular disease. In the absence of data from randomized controlled trials, current information suggests that statin therapy should be continued, and possibly boosted, during hospitalization for an acute coronary syndrome. Because statins are discontinued during the early hospitalization of many patients, practitioners must ensure that statins are not omitted, unless contraindicated, from the treatment of patients with acute coronary syndromes.     

Expert opinion: the therapeutic challenges faced by statin intolerance

Introduction: Statin intolerance is largely defined by muscle related symptoms, leading to intolerability and cessation. The nocebo effect coupled with the challenges of diagnosing statin myopathy undermines drug adherence that is critical for achieving the benefits of lipid-lowering and cardiovascular risk reduction. A temporal relationship should be made between the initiation of therapy and development of symptoms to aid in diagnosis. The mainstay of treatment is statin cessation or statin dose reduction and evaluation of alternative causes for muscle related symptoms. Most symptoms usually resolve within 2 weeks of discontinuing therapy. The patient can be re-challenged with the same statin at a lower dose or an alternative statin. Non-statin lipid lowering therapies offer an alternative to patients who cannot tolerate statins.

Areas covered: We discuss current guideline-focused management of patients with statin intolerance.

Expert opinion: When initiating statin therapy, attention to risk factors for statin intolerance is strongly recommended. Most patients will tolerate some degree of statin therapy; thus statin re-challenge is advisable. If alternative dosing regimens are not tolerated, non-statin medications are acceptable alternatives. To limit errors in the diagnosis of statin intolerance, improvements in clinician-patient communication about the side effects and benefits of statins should be attempted.     

Statins in acute coronary syndromes

The development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) has been a very significant development in the management of coronary artery disease. Large prospective clinical trials have provided unequivocal evidence that cholesterol lowering therapy with statins reduces all-cause mortality in patients with coronary artery disease. There is now accumulating data indicating that statin treatment should be initiated early after an acute coronary syndrome. This body of evidence is based on large databases in which investigators compared outcomes among patients taking statins with those patients who were not prescribed cholesterol lowering therapy. Prospective, randomized, clinical trials also indicate that early statin therapy reduces recurrent ischemia. Finally, studies examining long-term compliance with statin therapy suggest increased adherence to therapy when statins are prescribed during the initial hospitalization for an acute coronary syndrome. In tandem with these clinical observations, there is a large body of scientific data that highlights many important cellular and molecular mechanisms through which statins may confer early benefit. These effects involve relatively rapid improvement in endothelial function, antiischemic, antithrombotic and antiinflammatory actions of statins.     

A retrospective study: Factors associated with the risk of abdominal aortic aneurysm rupture

IntroductionLiterature regarding pharmacological manipulation of aneurysm development and progression is abundant; however studies looking at preventing rupture are sparse. Moreover, best medical therapy is ill-instituted, and continued in this high-risk cohort. This paper aims to identify factors which affect the risk of AAA-rupture.Materials & methodsA retrospective review of patients undergoing non-screen detected AAA-repair at a single tertiary-referral centre was performed. Age, cardiovascular history, medication use and the nature of surgical repair (elective or emergency) were converted to binary characteristics and a binomial logistic regression performed.ResultsWe included 315 admissions for ruptured AAA, and 668 referrals for elective repair of large aneurysms (n = 983). Multifactorial analysis showed that the cohort which was prescribed statins experienced fewer ruptured AAA ([OR] 0.50, [95% CI] 0.32–0.77). Factors associated with increased risk of rupture include female gender (2.49, 1.63–3.80), history of hypertension (3.5, 1.6–3.8) or renal failure (8.08, 4.15–15.4), age over 80 (2.77, 1.79–4.27) and current smoking (1.80, 1.09–2.96).Discussion and conclusionsThis is the largest study, interrogating individual patient data, to suggest an association between statins and prevention of large AAA-rupture. As patients with AAA are at high risk of cardiovascular events, and statins may decrease the risk of the devastating consequence of the condition, healthcare teams should maintain pharmaco-vigilance in instituting and continuing best medical therapy, including a statin.     

Managing hyperlipidemia: current and future roles of HMG-CoA reductase inhibitors.

The current and future roles of statins as antilipemic agents for the prevention and management of coronary artery disease (CAD) are reviewed. Therapy with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) substantially reduces total cholesterol and low-density-lipoprotein (LDL) cholesterol concentrations. Large clinical trials have documented the efficacy of statin therapy for both primary and secondary prevention of CAD. Nevertheless, many eligible patients are either untreated or inadequately treated with these agents. In one study, 61% of patients with documented CAD were not treated with a lipid-lowering agent. Large percentages of high-risk patients receiving such agents are not meeting cholesterol goals set by the National Cholesterol Education Program (NCEP). Populations at increased risk for coronary events include patients with diabetes, women, the elderly, and patients with established CAD. Comparative studies have not shown any one agent as clearly superior to the others. Future possibilities for statin use include early treatment of hypercholesterolemia and acute coronary syndromes consistent with guidelines established by NCEP. Many clinicians now believe that an aggressive approach to lowering LDL cholesterol may yield even greater reductions in coronary events. Treatment may reduce the risk of recurrent ischemic events when initiated within 96 hours of hospitalization for acute myocardial infarction or unstable angina and continued for up to four months. Another use may be the management of atherosclerotic cerebrovascular disease. Closer attention to potential adverse effects will be necessary before any expansion in statin use. Statins are highly effective for improving cardiovascular outcomes in high-risk patients but are frequently underused. Pharmacists can help extend the benefits of statins to more patients.     

Effects of statins on all-cause mortality at different low-density-lipoprotein cholesterol levels in Asian patients with type 2 diabetes

Objective: To investigate the effects of statins on all-cause mortality risk at different low-density lipoprotein cholesterol (LDL-C) levels, and to compare the mortality risk between statin users and non-users with identical LDL-C levels in a type 2 diabetes cohort.

Methods: In total, 10,582 outpatients aged ≥18 years with type 2 diabetes mellitus (T2DM) between 2009 and 2012 were enrolled in this retrospective cohort study in central Taiwan. All-cause mortality events were followed up until the end of 2014. According to the medical records during the follow-up period, the patients were classified into statin (+) and statin (?) groups. Patients were categorized into different LDL-C segments based on their mean LDL-C levels during the 2.8-year follow-up.

Results: Non-cardiovascular mortality accounted for more than half the deaths. Overall, statin therapy significantly reduced the all-cause mortality risk in both univariable and multivariable models (hazard ratios?=?0.39 and 0.38, respectively). Sub-group analyses showed that the lowest mortality risk occurred in the 80–89?mg/dL segment in the statin (?) group and in the 90–99?mg/dL segment in the statin (+) group. Statin therapy significantly reduced the mortality risk at all LDL-C levels except for low LDL-C (<60?mg/dL).

Conclusions: In addition to reducing LDL-C levels, statin therapy reduced all-cause mortality risk in Taiwanese patients with T2DM. Statins further reduced the mortality risk at most LDL levels. However, at low LDL-C levels, the positive effects of statins may have been nullified.     

他汀类药物在急性冠脉综合征住院患者应用现状调查

目的 调查他汀类药物在急性冠脉综合征患者住院期间的应用情况。方法 调查2012年7月—2013年5月所有ACS患者452例,调查其他汀类药物的应用情况。结果 452例患者中有425例（94％）应用他汀类药物,最常用的他汀是阿托伐他汀,平均剂量16mg／d。15例（3．5％）患者应用强化剂量的他汀,96．5％患者接受标准剂量的他汀。27例没有应用他汀类药物患者中,7例有他汀禁忌症,20例没有禁忌症。住院期间应用他汀类药物与入院时LDL—C水平无关。结论 在冠脉综合征住院患者中,接受他汀类药物的比例较高,但剂量不足,与指南推荐存在较大差距,需要加强对医生的教育。     

Secondary prevention of coronary heart disease in elderly patients following myocardial infarction: are all HMG-CoA reductase inhibitors alike?

Cardiovascular disease remains the leading cause of mortality in elderly patients. While coronary heart disease (CHD) morbidity and mortality have decreased over the last 25 years, the percentage reduction in elderly patients is nearly 50% lower than that for the general adult population. Therefore, aggressive primary and secondary prevention of CHD is imperative for our society, and hyperlipidaemia remains the major modifiable risk factor in the elderly population. However, there appears to be a reluctance among practitioners to treat hyperlipidaemia in elderly patients, a bias that is particularly important given the absolute benefits of treating such patients. While many of the major clinical trials involving HMG-CoA reductase inhibitors (statins) in patients with CHD focused on younger individuals, subsequent subgroup analyses of elderly patients have shown consistent reductions in all-cause mortality, major CHD events and numbers of revascularization procedures. Intensive statin therapy in the setting of acute myocardial infarction (MI) has also been shown to reduce the risk of death, MI, unstable angina, revascularization and stroke in elderly patients. Furthermore, three recent articles that have evaluated intensive lipid-lowering in the elderly population have extended the known benefits of such therapy to elderly patients with acute coronary syndrome and stable CHD.Elderly patients often take multiple medications and are at significant risk of drug-drug interactions. Several available statin medications are metabolized by cytochrome P450 (CYP) 3A4 and can therefore interact with commonly used medications such as amiodarone, macrolide antibacterials, calcium channel antagonists, fibric acid derivatives and ciclosporin. These interactions can result in an increased frequency of statin-related hepatotoxicity and myopathy.There are currently six commercially available statin medications on the US market, three of which, lovastatin, simvastatin and pravastatin, are available in generic formulations, and are thus less expensive. Of the commercially available statins, rosuvastatin, atorvastatin and simvastatin have the highest potency. While rosuvastatin currently lacks clinical event data, atorvastatin has the most clinical event data for CHD and even stroke prevention. Although pravastatin has lower potency than other described statins, it also has the lowest risk of drug-drug interactions involving CYP.     

Drug costs associated with non-adherence to cholesterol management guidelines for primary prevention of cardiovascular disease in an elderly population: the Rotterdam study

BACKGROUND: In The Netherlands, costs of HMG-CoA reductase inhibitor (statin) use have recently increased sharply compared with costs of other drugs. However, several studies have established both undertreatment and non-guidelines-indicated treatment with statins, suggesting a suboptimal use of resources. OBJECTIVE: To estimate the drug costs associated with non-guidelines-indicated treatment and undertreatment with statins in an elderly population. PATIENTS AND SETTING: Data were obtained from the Rotterdam Study, a population-based prospective cohort study which began in 1990 with 7983 participants aged > or =55 years. Subjects with a history of cardiovascular disease (CVD) were excluded. Pharmacy records were used to assess patterns of medication use in daily medical practice. MAIN OUTCOME MEASURE: Non-guidelines-indicated treatment and undertreatment with statins were established in relation to Dutch cholesterol management guidelines for all participants. We calculated the costs of statin therapy associated with non-guidelines-indicated treatment, and the costs of statins if all those undertreated were to receive statins. The results were projected on to the Dutch population to determine the economic implications of non-adherence to cholesterol management guidelines in the elderly. RESULTS: Of the participants who started treatment with statins for the primary prevention of CVD during follow-up, 69% received non-guidelines-indicated treatment. More men (7.5%) were undertreated than women (1.6%) and more women (6.2%) received non-guidelines-indicated treatment than men (1.5%). Among the participants without CVD who were still alive at 1 January 2002, 14% were eligible for statin therapy but were untreated. After projection of the prevalence of non-guidelines-indicated treatment and undertreatment to the Dutch population, the absolute costs for non-guidelines-indicated treatment with statins in 2005 were estimated to be approximately 23 million euro(uncertainty limits [UL]: 19-28 million euro), while the cost to eliminate undertreatment was also 23 million euro (UL: 19-28 million euro). CONCLUSION: Reallocation of resources used for statin therapy from those receiving non-guidelines-indicated treatment to those being undertreated could lead to a more efficient use of resources.     

秋水仙碱与他汀类潜在药物相互作用处方风险分析

目的 分析秋水仙碱与他汀类潜在药物相互作用(potential drug-drug interactions,pDDIs)处方,进行风险评估并制定预防措施。方法 检索知网、维普、万方、PubMed和Elsevier数据库关于秋水仙碱与他汀类相互作用致不良反应的个案和研究报道,进行文献分析;通过医院合理用药软件抽取2020年1月—2022年10月秋水仙碱联合他汀类药物的所有门诊处方,鉴别出潜在药物相互作用并进行严重性分级。结果 检索到该药物相互作用致不良反应个案报道22例,病例对照研究1篇,观察性队列研究2篇;不良反应以老年人居多,男性多于女性;发生时间集中在联合用药21 d内,3例患者死亡;高剂量、高龄、男性和肝/肾功能不全可能增加该pDDIs发生风险;遵义医科大学附属医院共收集到秋水仙碱联合他汀类药物处方72张,其中阿托伐他汀65张,瑞舒伐他汀6张,辛伐他汀1张,危险程度分级均为严重;1例患者联合使用秋水仙碱和阿托伐他汀4个月后出现肌病,1个月后好转;临床药师制定了7项预防措施。结论 遵义医科大学附属医院秋水仙碱与他汀类处方存在pDDIs,需积极实施预防措施并加强监测,尤其是联合用药...     

Effectiveness and hepatotoxicity of statins in men seropositive for hepatitis C virus

STUDY OBJECTIVE: To evaluate the effectiveness and hepatotoxicity of statins in patients who are seropositive for hepatitis C virus (HCV). DESIGN: Retrospective review of a registry of patients with HCV. SETTING: Veterans Affairs Medical Center. PATIENTS: One hundred forty-six male patients who were seropositive for HCV and had received statin therapy between January 1, 1995, and September 9, 2003. MEASUREMENTS AND MAIN RESULTS: Demographic and clinical data were collected for each patient; lipid and alanine aminotransferase (ALT) levels at baseline (within 6 mo of starting a statin), at 3 and 6 months after starting a statin, and at long-term follow-up (mean 22 mo) were also recorded. The primary efficacy end point was a significant decrease from baseline to long-term follow-up low-density lipoprotein cholesterol (LDL) level; the primary safety end point was a significant increase from baseline in ALT level. The mean change in LDL level was a reduction of 22% (p<0.01). No significant increases in ALT levels were observed; only one patient discontinued therapy due to ALT level elevations greater than 3 times the upper limit of normal. CONCLUSION: In men seropositive for HCV, statins were effective in reducing LDL levels and did not result in significant increases in ALT levels from baseline. Thus, statin therapy should be considered for patients with HCV who are at risk for coronary heart disease and do not have significantly elevated serum transaminase levels at baseline.     

Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions

Patients with the metabolic syndrome and/or Type 2 diabetes mellitus continue to have a high risk of coronary heart disease (CHD) and progression of atherosclerotic lesions despite aggressive statin therapy. Although the National Cholesterol Education Programme Adult Treatment Panel III guidelines recommend the use of fibrates in combination with statins in patients at very high risk of CHD (e.g., patients at the low-density lipoprotein cholesterol target with high triglycerides and low high-density lipoprotein cholesterol, many physicians remain reluctant to use these combinations due to concerns of myotoxicity. Recently conducted metabolic and pharmacokinetic drug–drug interaction studies using gemfibrozil or fenofibrate in combination with five commonly used statins demonstrated a widely different drug interaction potential for these two fibrates. Gemfibrozil causes a 2- to 6-fold increase in statin area under the curve and increases the exposure to many recently approved drugs for the treatment of diabetes. Alternatively, fenofibrate does not adversely affect either the metabolism or pharmacokinetics of the statins studied. These pharmacokinetic differences appear to translate into less potential for interactions with fenofibrate/statin combination therapy compared to gemfibrozil/statin co-administration. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study in 10,000 patients with Type 2 diabetes mellitus is testing the efficacy and safety of fenofibrate/statin combination.