bims-mitost 2019-04-28 papers

bims-mitost

Biomed News

on Mitochondrial toxicity and statins

Issue of 2019–04–28
six papers selected by
Yvonne Will, Scientia-Consultants LLC

Statin-induced myopathy: a case report.
Relative Effect of Current Intensive Lipid-Lowering Drugs on Cardiovascular Outcomes in Secondary Prevention　- A Meta-Analysis of 12 Randomized Trials.
Cost-effectiveness of lipid lowering with statins and ezetimibe in chronic kidney disease.
Statins for primary prevention of cardiovascular disease: modelling guidelines and patient preferences based on an Irish cohort.
Statins for the primary prevention of cardiovascular disease: an overview of systematic reviews.
Anti-arrhythmic and cardio-protective effects of atorvastatin and a potent pyridoindole derivative on isolated hearts from rats with metabolic syndrome.

Eur Heart J Case Rep. 2018 Dec;2(4): yty130

Statin-induced myopathy: a case report.

Emmanuel De Cock, Heidi Hannon, Veronique Moerman, Marie Schurgers.

   Background: Statins are one of the most frequently used drug groups among patients with cardiovascular disease. Muscle pain is very frequent among patients using statins. It is important to distinguish patients with benign muscle pain without significant biochemical correlates from patients with serious myopathies.
Case summary: We present the case of a 68-year-old woman taking atorvastatin in the past 8 months after a coronary bypass grafting, presenting with proximal muscle weakness and pain. Biochemical analysis showed a markedly elevated creatine kinase (CK) (24,159 U/L). Despite discontinuation of the statin and therapy for rhabdomyolysis (IV fluid, mannitol, and sodium bicarbonate), CK levels did not drop as much as expected. Muscle biopsy showed mild inflammatory changes and few necrotic muscle fibres, suggestive for an immune-mediated necrotizing myopathy (IMNM). Serology showed a high anti-HMG-CoA reductase antibody (anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody) titre, diagnostic for an IMNM induced by statins. The patient was treated with corticosteroids and methotrexate. Creatine kinase levels, muscle weakness, and pain gradually improved over the following months.
Discussion: IMNM induced by statins is a relatively new entity. It is important to be recognized because it is not a self-limiting adverse effect such as the frequent benign muscle pains caused by statins. Beside discontinuation of the causative statin, aggressive immunosuppressive therapy is mandatory in IMNM. Therefore, it is important to test for anti-HMGCR antibodies and if necessary perform a muscle biopsy in patients taking statins, presenting with muscle weakness, and CK elevations not improving after discontinuation of the statin.

Keywords:  Anti-HMGCR antibodies; Case report; Immune-mediated necrotizing myopathy; Myopathy; Statin

DOI:  https://doi.org/10.1093/ehjcr/yty130
Circ J. 2019 Apr 19.

Relative Effect of Current Intensive Lipid-Lowering Drugs on Cardiovascular Outcomes in Secondary Prevention　- A Meta-Analysis of 12 Randomized Trials.

Shifei Wang, Jiancheng Xiu, Wangjun Liao, Yulin Liao, Jianping Bin.

   BACKGROUND: We aimed to investigate the comparative cardiovascular benefits of high-dose statin, ezetimibe-statin, and PCSK9 inhibitor-statin treatments in secondary prevention patients.Methods and Results:We selected 12 randomized controlled trials (n=131,978 patients) using PubMed and Embase (inception-June 1, 2018). Subgroup differences were explored by meta-regression and Cochran Q test. The relative effects of high-dose statin, ezetimibe-statin, and PCSK9 inhibitor-statin on major cardiovascular events (MACE), and revascularization were varied and decreased gradually, of which high-dose statin resulted in lower risk of MACE and revascularization than PCSK9 inhibitor-statin per 1 mmol/L reduction of low-density lipoprotein cholesterol (LDL-C): risk ratio (RR) for MACE, 0.86 (95% confidence interval (CI), 0.81-0.90) for high-dose statin, 0.90 (95% CI, 0.83-0.96) for ezetimibe-statin, and 0.94 (95% CI, 0.92-0.96) for PCSK9 inhibitor-statin; RR for revascularization, 0.84 (95% CI, 0.77-0.90) for high-dose statin, 0.91 (95% CI, 0.81-1.00) for ezetimibe-statin, and 0.94 (95% CI, 0.90-0.97) for PCSK9 inhibitor-statin. Similar relative effects of intensive lipid-lowering treatment were also observed in analyses of myocardial infarction and stroke, although no significant difference between groups was identified.
CONCLUSIONS: In secondary prevention patients, the relative benefits of high-dose statin, ezetimibe-statin, and PCSK9 inhibitor-statin treatments were varied and decreased gradually, of which high-dose statin was significantly superior to PCSK9 inhibitor-statin for improving MACE and revascularization per 1 mmol/L reduction of LDL-C.

Keywords:  Ezetimibe; Lipid-lowering drugs; PCSK9 inhibitor; Secondary prevention; Statins

DOI:  https://doi.org/10.1253/circj.CJ-18-1321
Kidney Int. 2019 Mar 12. pii: S0085-2538(19)30171-1. [Epub ahead of print]

Cost-effectiveness of lipid lowering with statins and ezetimibe in chronic kidney disease.

SHARP Collaborative Group

  Statin-based treatments reduce cardiovascular disease (CVD) risk in patients with non-dialysis chronic kidney disease (CKD), but it is unclear which regimen is the most cost-effective. We used the Study of Heart and Renal Protection (SHARP) CKD-CVD policy model to evaluate the effect of statins and ezetimibe on quality-adjusted life years (QALYs) and health care costs in the United States (US) and the United Kingdom (UK). Net costs below $100,000/QALY (US) or £20,000/QALY (UK) were considered cost-effective. We investigated statin regimens with or without ezetimibe 10 mg. Treatment effects on cardiovascular risk were estimated per 1-mmol/L reduction in low-density lipoprotein (LDL) cholesterol as reported in the Cholesterol Treatment Trialists' Collaboration meta-analysis, and reductions in LDL cholesterol were estimated for each statin/ezetimibe regimen. In the US, atorvastatin 40 mg ($0.103/day as of January 2019) increased life expectancy by 0.23 to 0.31 QALYs in non-dialysis patients with stages 3B to 5 CKD, at a net cost of $20,300 to $78,200/QALY. Adding ezetimibe 10 mg ($0.203/day) increased life expectancy by an additional 0.05 to 0.07 QALYs, at a net cost of $43,600 to $91,500/QALY. The cost-effectiveness findings and policy implications in the UK were similar. In summary, in patients with non-dialysis-dependent CKD, the evidence suggests that statin/ezetimibe combination therapy is a cost-effective treatment to reduce the risk of CVD.

Keywords:  chronic kidney disease; cost-effectiveness; ezetimibe; health care costs; quality-adjusted life years; statin

DOI:  https://doi.org/10.1016/j.kint.2019.01.028
Br J Gen Pract. 2019 Apr 23. pii: bjgp19X702701. [Epub ahead of print]

Statins for primary prevention of cardiovascular disease: modelling guidelines and patient preferences based on an Irish cohort.

Paula Byrne, John Cullinan, Paddy Gillespie, Rafael Perera, Susan M Smith.

   BACKGROUND: Changes in clinical guidelines for primary prevention of cardiovascular disease (CVD) have widened eligibility for statin therapy.
AIM: To illustrate the potential impacts of changes in clinical guidelines.
DESIGN AND SETTING: Modelling the impacts of seven consecutive European guidelines based on a cohort of people aged ≥50 years from the Irish Longitudinal Study on Ageing.
METHOD: The eligibility for statin therapy of a sample of people without a history of CVD was established, according to changing guideline recommendations and modelled associated potential costs. The authors calculated the numbers needed to treat (NNT) to prevent one major vascular event in patients at the lowest baseline risk for which each of the seven guidelines recommended treatment, and for those at low, medium, high, and very-high risk according to 2016 guidelines. These were compared with the NNT that patients reported as required to justify taking a daily medicine.
RESULTS: The proportion of patients eligible for statins increased from approximately 8% in 1987 to 61% in 2016; associated costs rose from €13.9 million to €107.1 million per annum. The NNT for those at the lowest risk for which each guideline recommended treatment rose from 40 to 400. By 2016, the NNT for low-risk patients was 400 compared to ≤25 very-high risk patients. The proportion of patients eligible for statins achieving NNT levels that patients regarded as justified to taking a daily medicine fell as guidelines changed over time.
CONCLUSION: Increased eligibility for statin therapy impacts large proportions of the present population and healthcare budgets. Decisions to take and reimburse statins should be considered on the basis of expected cost-effectiveness and acceptability to patients.

Keywords:  drug costs; guideline; hydroxymethylglutaryl-CoA reductase inhibitors, patient preference; primary prevention

DOI:  https://doi.org/10.3399/bjgp19X702701
BMJ Open. 2019 Apr 23. 9(4): e023085

Statins for the primary prevention of cardiovascular disease: an overview of systematic reviews.

Paula Byrne, John Cullinan, Amelia Smith, Susan M Smith.

   OBJECTIVE: To synthesise evidence from exclusively primary prevention data on the effectiveness of statins for prevention of cardiovascular disease (CVD), including stroke, and outcomes stratified by baseline risk and gender.
DESIGN: Overview of systematic reviews (SRs) using Revised-AMSTAR approach to assess quality.
DATA SOURCES: Cochrane Database of Systematic Reviews, MEDLINE, Embase, PubMed, Scopus and PROSPERO to June 2017.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES: SRs of randomised control trials (RCTs) or individual patient data (IPD) from RCTs, examining the effectiveness of statins versus placebo or no treatment on all-cause mortality, coronary heart disease, CVD (including stroke) and composite endpoints, with stratification by baseline risk and gender.
DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed methodological quality. A narrative synthesis was conducted.
RESULTS: Three SRs were included. Quality of included SRs was mixed, and none reported on the risk of bias of included trials.We found trends towards reduced all-cause mortality in all SRs (RR 0.91 [95% CI 0.85 to 0.97]), (RR 0.91 [95% CI 0.83 to 1.01]) and (RR 0.78 [95% CI 0.53 to 1.15]) though it was not statistically significant in two SRs. When stratified by baseline risk, the effect on all-cause mortality was no longer statistically significant except in one medium risk category. One review reported significant reductions (RR 0.85 [95% CI 0.77 to 0.95]) in vascular deaths and non-significant reductions in non-vascular deaths (RR 0.97 [95% CI 0.88 to 1.07]). There were significant reductions in composite outcomes overall, but mixed results were reported in these when stratified by baseline risk. These reviews included studies with participants considered risk equivalent to those with established CVD.
CONCLUSIONS: There is limited evidence on the effectiveness of statins for primary prevention with mixed findings from studies including participants with widely ranging baseline risks. Decision making for the use of statins should consider individual baseline risk, absolute risk reduction and whether risk reduction justifies potential harms and taking a daily medicine for life.
TRIAL REGISTRATION NUMBER: CRD42017064761.

Keywords:  cardiovascular medicine; overview of systematic reviews; preventive medicine; primary prevention; statins

DOI:  https://doi.org/10.1136/bmjopen-2018-023085
Bratisl Lek Listy. 2019 ;120(3): 200-206

Anti-arrhythmic and cardio-protective effects of atorvastatin and a potent pyridoindole derivative on isolated hearts from rats with metabolic syndrome.

B Liptak, V Knezl, Z Gasparova.

   OBJECTIVES: Aims of this study were to investigate the anti-arrhythmic and cardio-protective effect of atorvastatin and of a new pyridoindole derivative (SMe1EC2) on isolated and perfused hearts while following the Langendorff principles.
BACKGROUND: Metabolic syndrome is a widely distributed condition progressing to cardiovascular disease. Many of the metabolic syndrome patients take (HMG)-co-enzyme A (CoA) reductase inhibitors with potential cardio-protective effects. SMe1EC2 is a promising new drug, exerting many positive effects in experimental settings.
METHODS: Rats with induced metabolic syndrome were treated with atorvastatin (25 mg/kg) and SMe1EC2 (25 mg/kg and 0.5 mg/kg, respectively) daily for 3 weeks. After the treatment, the hearts were isolated and perfused according to Langendorff.
RESULTS: Both atorvastatin and SMe1EC2 improved cardiac function by elevating the left ventricular developed pressure (VLDP) and cardiac contractility. Both SMe1EC2-treated groups improved LVDP during reperfusion, significantly increased ‒dP/dt, and moderately elevated +dP/dt values. The treatment with both atorvastatin and SMe1EC2 (25 mg/kg) significantly reduced malignant arrhythmia in comparison to control group and group treated with SMe1EC2 0.5 mg/kg.
CONCLUSIONS: Owing to its anti-arrhythmic and cardio-protective effects, atorvastatin and SMe1EC2 could be of benefit to patients suffering from metabolic syndrome (Tab. 3, Fig. 3, Ref. 41).

Keywords:  Langendorff; hyper-triacylglycerolemic rats; ventricular fibrillation dyslipidemia.

DOI:  https://doi.org/10.4149/BLL_2019_034