Ezetimibe use and mortality after myocardial infarction: A nationwide cohort study.

Background: The inhibition of intestinal cholesterol absorption by ezetimibe improves outcomes after myocardial infarction (MI), yet real-world data on ezetimibe is scarce. We studied the usage of ezetimibe and association with outcome after MI. Methods: Consecutive MI patients in Finland (2010-2018) were retrospectively studied (N = 57,505; 65 % men; mean age 69 years). The study data were collected from national registries. The median follow-up was 4.5 (IQR 2.8-7.1) years. Between-group differences were adjusted for using multivariable regression. Ezetimibe use was studied with competing risk analyses. Results: The cumulative incidence of ezetimibe use was 3.7 % at 90 days, 13.4 % at 5 years, and 19.8 % at 10 years. Younger age was one of the strongest predictors of ezetimibe use (adj.sHR 6.67; CI 5.88-7.69 for patients aged <60 vs ≥80 years). Women were more likely to use ezetimibe during follow-up than men. The average proportion of patients using ezetimibe during follow-up was 6.8 %. (11.7 % at 10 years). Ezetimibe was discontinued by 43.6 % of patients during follow-up. Patients with early ezetimibe therapy after MI had lower all-cause mortality during follow-up (33.6% vs 45.1 %; adj.HR 0.77; CI 0.69-0.86; P < 0.0001). Early ezetimibe use was associated with lower mortality irrespective of sex, age, atrial fibrillation, diabetes, heart failure, malignancy, revascularization, or statin use. Ongoing ezetimibe therapy during follow-up was associated with lower mortality in a time-dependent analysis (adj.HR 0.53; CI 0.48-0.59; P < 0.0001). Conclusions: Ezetimibe is associated with a lower risk of death after MI, yet its therapeutic use is limited, and discontinuation is frequent.

Absorption pharmacokinetics and feasibility of intranasal dexmedetomidine in patients under general anaesthesia.

BACKGROUND: The use of intranasal dexmedetomidine is hampered by a limited understanding of its absorption pharmacokinetics. METHODS: We examined the pharmacokinetics and feasibility of intranasal dexmedetomidine administered in the supine position to adult patients undergoing general anaesthesia. Twenty-eight patients between 35 and 80 years of age, ASA 1-3 and weight between 50 and 100 kg, who underwent elective unilateral total hip or knee arthroplasty under general anaesthesia were recruited. All patients received 100 µg of intranasal dexmedetomidine after anaesthesia induction. Six venous blood samples (at 0, 5, 15, 45, 60, 240 min timepoints from dexmedetomidine administration) were collected from each patient and dexmedetomidine plasma concentrations were measured. Concentration-time profiles after nasal administration were pooled with earlier data from a population analysis of intravenous dexmedetomidine (n = 202) in order to estimate absorption parameters using nonlinear mixed effects. Peak concentration (CMAX) and time (TMAX) were estimated using simulation (n = 1000) with parameter estimates and their associated variability. RESULTS: There were 28 adult patients with a mean (SD) age of 66 (8) years and weight of 83 (10) kg. The mean weight-adjusted dose of dexmedetomidine was 1.22 (0.15) µg kg-1. CMAX 0.273 µg L-1 was achieved at 98 min after intranasal administration (TMAX). The relative bioavailability of dexmedetomidine was 80% (95% CI 75-91%). The absorption half-time (TABS = 120 min; 95% CI 90-147 min) was slower than that in previous pharmacokinetic studies on adult patients. Perioperative haemodynamics of all patients remained stable. CONCLUSIONS: Administration of intranasal dexmedetomidine in the supine position during general anaesthesia is feasible with good bioavailability. This administration method has slower absorption when compared to awake patients in upright position, with consequent concentrations attained after TMAX for several hours.

Non-targeted metabolomics for the identification of plasma metabolites associated with organic anion transporting polypeptide 1B1 function.

Our aim was to evaluate biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) function using a hypothesis-free metabolomics approach. We analyzed fasting plasma samples from 356 healthy volunteers using non-targeted metabolite profiling by liquid chromatography high-resolution mass spectrometry. Based on SLCO1B1 genotypes, we stratified the volunteers to poor, decreased, normal, increased, and highly increased OATP1B1 function groups. Linear regression analysis, and random forest (RF) and gradient boosted decision tree (GBDT) regressors were used to investigate associations of plasma metabolite features with OATP1B1 function. Of the 9152 molecular features found, 39 associated with OATP1B1 function either in the linear regression analysis (p < 10-5) or the RF or GBDT regressors (Gini impurity decrease > 0.01). Linear regression analysis showed the strongest associations with two features identified as glycodeoxycholate 3-O-glucuronide (GDCA-3G; p = 1.2 × 10-20 for negative and p = 1.7 × 10-19 for positive electrospray ionization) and one identified as glycochenodeoxycholate 3-O-glucuronide (GCDCA-3G; p = 2.7 × 10-16). In both the RF and GBDT models, the GCDCA-3G feature showed the strongest association with OATP1B1 function, with Gini impurity decreases of 0.40 and 0.17. In RF, this was followed by one GDCA-3G feature, an unidentified feature with a molecular weight of 809.3521, and the second GDCA-3G feature. In GBDT, the second and third strongest associations were observed with the GDCA-3G features. Of the other associated features, we identified with confidence two representing lysophosphatidylethanolamine 22:5. In addition, one feature was putatively identified as pregnanolone sulfate and one as pregnenolone sulfate. These results confirm GCDCA-3G and GDCA-3G as robust OATP1B1 biomarkers in human plasma.

Genome-Wide Association Study of Atorvastatin Pharmacokinetics: Associations With SLCO1B1, UGT1A3, and LPP.

In a genome-wide association study of atorvastatin pharmacokinetics in 158 healthy volunteers, the SLCO1B1 c.521T>C (rs4149056) variant associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) of atorvastatin (P = 1.2 × 10-10), 2-hydroxy atorvastatin (P = 4.0 × 10-8), and 4-hydroxy atorvastatin (P = 2.9 × 10-8). An intronic LPP variant, rs1975991, associated with reduced atorvastatin lactone AUC0-∞ (P = 3.8 × 10-8). Three UGT1A variants linked with UGT1A3*2 associated with increased 2-hydroxy atorvastatin lactone AUC0-∞ (P = 3.9 × 10-8). Furthermore, a candidate gene analysis including 243 participants suggested that increased function SLCO1B1 variants and decreased activity CYP3A4 variants affect atorvastatin pharmacokinetics. Compared with individuals with normal function SLCO1B1 genotype, atorvastatin AUC0-∞ was 145% (90% confidence interval: 98-203%; P = 5.6 × 10-11) larger in individuals with poor function, 24% (9-41%; P = 0.0053) larger in those with decreased function, and 41% (16-59%; P = 0.016) smaller in those with highly increased function SLCO1B1 genotype. Individuals with intermediate metabolizer CYP3A4 genotype (CYP3A4*2 or CYP3A4*22 heterozygotes) had 33% (14-55%; P = 0.022) larger atorvastatin AUC0-∞ than those with normal metabolizer genotype. UGT1A3*2 heterozygotes had 16% (5-25%; P = 0.017) smaller and LPP rs1975991 homozygotes had 34% (22-44%; P = 4.8 × 10-5) smaller atorvastatin AUC0-∞ than noncarriers. These data demonstrate that genetic variation in SLCO1B1, UGT1A3, LPP, and CYP3A4 affects atorvastatin pharmacokinetics. This is the first study to suggest that LPP rs1975991 may reduce atorvastatin exposure. [Correction added on 6 April, after first online publication: An incomplete sentence ("= 0.017) smaller in heterozygotes for UGT1A3*2 and 34% (22%, 44%; P × 10-5) smaller in homozygotes for LPP noncarriers.") has been corrected in this version.].

Association of Central Nervous System-Affecting Medications With Occurrence and Short-Term Mortality of Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: The use of medications commonly prescribed after traumatic brain injury (TBI) has been little studied before TBI. This study examined the association between the use of medications that affect the central nervous system (CNS) and the occurrence and short-term mortality of TBI. METHODS: Mandatory Finnish registries were used to identify TBI admissions, fatal TBIs, and drug purchases during 2005-2018. Patients with TBI were 1:1 matched to nontrauma control patients to investigate the association between medications and the occurrence of TBI and 30-day mortality after TBI. Number needed to harm (NNH) was calculated for all medications. RESULTS: The cohort included 59 606 patients with TBI and a similar number of control patients. CNS-affecting drugs were more common in patients with TBI than in controls [odds ratio = 2.07 (2.02-2.13), P < .001)]. Benzodiazepines were the most common type of medications in patients with TBI (17%) and in controls (11%). The lowest NNH for the occurrence of TBI was associated with benzodiazepines (15.4), selective serotonin uptake inhibitors (18.5), and second-generation antipsychotics (25.8). Eight percent of the patients with TBI died within 30 days. The highest hazard ratios (HR) and lowest NNHs associated with short-term mortality were observed with strong opioids [HR = 1.41 (1.26-1.59), NNH = 33.1], second-generation antipsychotics [HR = 1.36 (1.23-1.50), NNH = 37.1], and atypical antidepressants [HR = 1.17 (1.04-1.31), NNH = 77.7]. CONCLUSION: Thirty-seven percent of patients with TBI used at least 1 CNS-affecting drug. This proportion was significantly higher than in the control population (24%). The highest risk and lowest NNH for short-term mortality were observed with strong opioids, second-generation antipsychotics, and atypical antidepressants. The current risks underscore the importance of weighing the benefits and risks before prescribing CNS-affecting drugs in patients at risk of head injury.

Posaconazole-ibrutinib interaction cannot be avoided by staggered dosing: How to optimize ibrutinib dose during posaconazole treatment.

AIMS: Ibrutinib is used in the treatment of certain B-cell malignancies. Due to its CYP3A4-mediated metabolism and highly variable pharmacokinetics, it is prone to potentially harmful drug-drug interactions. METHODS: In a randomized, placebo-controlled, three-phase crossover study, we examined the effect of the CYP3A4-inhibiting antifungal posaconazole on ibrutinib pharmacokinetics. Eleven healthy participants ingested repeated doses of 300 mg of posaconazole either in the morning or in the evening, or placebo. A single dose of ibrutinib (30, 70 or 140 mg, respectively) was administered at 9 AM, 1 or 12 h after the preceding posaconazole/placebo dose. RESULTS: On average, morning posaconazole increased the dose-adjusted geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0-∞ ) and peak plasma concentration (Cmax ) of ibrutinib 9.5-fold (90% confidence interval [CI] 6.3-14.3, P < 0.001) and 8.5-fold (90% CI 5.7-12.8, P < 0.001), respectively, while evening posaconazole increased those 10.3-fold (90% CI 6.7-16.0, P < 0.001) and 8.2-fold (90% CI 5.2-13.2, P < 0.001), respectively. Posaconazole had no significant effect on the half-life of ibrutinib, but substantially reduced the metabolite PCI-45227 to ibrutinib AUC0-∞ ratio. There were no significant differences in ibrutinib pharmacokinetics between morning and evening posaconazole phases. CONCLUSIONS: Posaconazole increases ibrutinib exposure substantially, by about 10-fold. This interaction cannot be avoided by dosing the drugs 12 h apart. In general, a 70-mg daily dose of ibrutinib should not be exceeded during posaconazole treatment to avoid potentially toxic systemic ibrutinib concentrations.

Real-world pharmacogenetics of statin intolerance: effects of SLCO1B1, ABCG2 , and CYP2C9 variants.

OBJECTIVE: The association of SLCO1B1 c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport also by other proteins exhibiting clinically meaningful genetic variation. Our aim was to investigate associations of SLCO1B1 c.521T>C with intolerance to atorvastatin, fluvastatin, pravastatin, rosuvastatin, or simvastatin, those of ABCG2 c.421C>A with intolerance to atorvastatin, fluvastatin, or rosuvastatin, and that of CYP2C9*2 and *3 alleles with intolerance to fluvastatin. METHODS: We studied the associations of these variants with statin intolerance in 2042 patients initiating statin therapy by combining genetic data from samples from the Helsinki Biobank to clinical chemistry and statin purchase data. RESULTS: We confirmed the association of SLCO1B1 c.521C/C genotype with simvastatin intolerance both by using phenotype of switching initial statin to another as a marker of statin intolerance [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.08-3.25, P  = 0.025] and statin switching along with creatine kinase measurement (HR 5.44, 95% CI 1.49-19.9, P  = 0.011). No significant association was observed with atorvastatin and rosuvastatin. The sample sizes for fluvastatin and pravastatin were relatively small, but SLCO1B1 c.521T>C carriers had an increased risk of pravastatin intolerance defined by statin switching when compared to homozygous reference T/T genotype (HR 2.11, 95% CI 1.01-4.39, P  = 0.047). CONCLUSION: The current results can inform pharmacogenetic statin prescribing guidelines and show feasibility for the methodology to be used in larger future studies.

Causes of fatal traumatic brain injury in Finland.

OBJECTIVE: The phenotype of patients who suffer fatal traumatic brain injury (TBI) is poorly characterized. The authors examined the external causes, contributing diseases, and preinjury medication in adult patients with fatal TBI in a nationwide Finnish cohort. METHODS: Deaths caused by TBIs in Finland were examined among decedents aged ≥ 16 years during 2005-2020 from the national Cause of Death Registry. Usage of prescription medications prior to TBI was studied using medication purchase data from the Social Insurance Institution of Finland. RESULTS: The cohort consisted of 71,488,347 person-years, 821,259 total deaths, and 14,630 TBI-related deaths during 2005-2020, of which 67% (n = 9792) occurred in men. Women were older than men among those who suffered TBI-related death (mean age 77.2 ± 17.1 vs 64.5 ± 19.5 years, p < 0.0001). The overall crude incidence rate of fatal TBIs was 20.5/100,000 person-years (28.1/100,000 in men and 13.2/100,000 in women). TBI was the cause of death in 1.8% of all deaths in the Finnish population during the study years, but in patients aged 16-19 years, TBIs caused more than 17% of all deaths. The most common external cause of fatal TBI was a fall (70%), followed by poisoning or toxic effects (20%) and violence or self-harm (15%) overall. In men, the order of the most common causes of fatal TBI was similar to overall results (64%, 25%, and 19%, respectively), while in women, the most common cause was a fall (82%), followed by complications in healthcare (10%) and poisoning or toxic effects (9%). Cardiovascular diseases, psychiatric diseases, and infections were the most common diseases contributing to death. Blood pressure (lowering) medications were the most common type of medications used before fatal TBI. CNS medications were the second most common medication group. In the context of fatal TBI in Europe, Finland remains at the upper end of fatal TBI incidence. CONCLUSIONS: TBI is a common cause of death in young adults, whereas the incidence of fatal TBI becomes increasingly higher with age in Finland. Cardiovascular diseases and psychiatric conditions were the most common diseases related to death, with opposite age trends. Healthcare facility complications were an alarmingly common cause of death in women with fatal TBI.

Maternal SSRI use during pregnancy and offspring depression or anxiety disorders: A review of the literature and description of a study protocol for a register-based cohort study.

Previous studies examining the relationship between in utero exposure to selective serotonin reuptake inhibitors (SSRI) and long-term offspring depressive or anxiety behaviors are inconclusive. We aimed to critically review the findings of previous studies and describe a new study protocol to investigate the association of prenatal SSRI exposure and offspring depression or anxiety using data from several Finnish national registers. The study includes 1,266,473 mothers and their live-born singleton offspring, born in 1996-2018. The study cohorts include the prenatally SSRI exposed group and three comparison groups: 1) depression exposed/antidepressants unexposed, 2) unexposed to antidepressants or antipsychotics and depression, and 3) discordant siblings. We aim to examine whether depression in prenatally SSRI exposed children is more common or severe than depression in the offspring of mothers with depression but without SSRI exposure. We aim to disambiguate the effects of maternal SSRI from the effects of maternal depression, severity of maternal depression and familial loading history of psychiatric disorders by including data from first-degree relatives of prenatally SSRI exposed and unexposed children. Associations between exposure and outcome are assessed by statistical modeling, accounting for within-family correlation. The study has potential public health significance and in guiding clinicians in considering treatment options for pregnant women.

The cholesterol-lowering effect of statins is modified by LILRB5 intolerance genotype: Results from a recruit-by-genotype clinical trial.

Background/Aims: Statin intolerance leads to poor adherence to statin therapy, resulting in a failure to achieve desired cholesterol reduction and adverse outcomes. The LILRB5 Asp247Gly genotype has been identified as being associated with statin intolerance and statin-induced myalgia. We conducted a randomized clinical trial to examine its role in immune response through T regulatory cell aggregation and in achieving cholesterol reduction targets. Methods: A double-blind, cross-over, recruit-by-genotype trial was undertaken. A total of 18 participants who had either the Asp247Asp (T/T) genotype or the Gly247Gly (C/C) genotype were recruited to the study. Participants were randomised to receive placebo or atorvastatin 80 mg daily for 28 days. Following a washout period of 3 weeks, they were then switched to the opposite treatment. Biochemical and immunological measurements as well as interviews were performed prior to and after both treatment periods. Within genotype group comparisons were performed using repeated measures Wilcoxon tests. Two-way repeated measures ANOVA with genotype and treatment as factors were used to compare changes in biochemical parameters between groups during placebo and atorvastatin periods. Results: Individuals with the Asp247Asp genotype had a greater increase in creatine kinase (CK) compared to those with Gly247Gly genotype in response to atorvastatin (p = 0.03). Those with Gly247Gly genotype had a mean non-HDL cholesterol reduction of 2.44 (95% CI:1.59 - 3.29) mmol/L while in Asp247Asp genotype group the mean reduction was 1.28 (95%CI: 0.48 - 2.07) mmol/L. The interaction between the genotype and atorvastatin treatment for total cholesterol (p = 0.007) and non-HDL cholesterol response was significant (p = 0.025). Immunological assessment showed no significant changes in aggregation of T regulatory cells by genotype. Conclusion: The Asp247Gly variant in LILRB5, previously associated with statin intolerance, was associated with differential increases in creatine kinase and total cholesterol and non-HDL cholesterol-lowering response to atorvastatin. Taken together, these results suggest that this variant could have utility in precision cardiovascular therapy.

Lack of Statin Therapy and Outcomes After Ischemic Stroke: A Population-Based Study.

BACKGROUND: Statin treatment is effective at preventing adverse vascular events after ischemic stroke (IS). However, many patients fail to use statins after IS. We studied the impact of not using statins after IS on adverse outcomes. METHODS: IS patients (n=59 588) admitted to 20 Finnish hospitals were retrospectively studied. Study data were combined from national registries on hospital admissions, mortality, cancer diagnoses, prescription medication purchases, and permissions for special reimbursements for medications. Usage of prescription medication was defined as drug purchase within 90 days after hospital discharge. Ongoing statin use during follow-up was analyzed in 90-day intervals. Differences in baseline features, comorbidities, other medications, and recanalization therapies were balanced with inverse probability of treatment weighting. Median follow-up was 5.7 years. RESULTS: Statin therapy was not used by 27.1% of patients within 90 days after IS discharge, with women and older patients using statins less frequently. The average proportion of patients without ongoing statin during the 12-year follow-up was 36.0%. Patients without early statins had higher all-cause mortality at 1 year (7.5% versus 4.4% in patients who did use statins; hazard ratio [HR], 1.74 [CI, 1.61-1.87]) and 12 years (56.8% versus 48.6%; HR, 1.37 [CI, 1.33-1.41]). Cumulative incidence of major adverse cerebrovascular or cardiovascular event was higher at 1 year (subdistribution HR, 1.36 [CI, 1.29-1.43]) and 12 years (subdistribution HR, 1.21 [CI, 1.18-1.25]) without early statin use. Cardiovascular death, recurrent IS, and myocardial infarction were more frequent without early statin use. Early statin use was not associated with hemorrhagic stroke during follow-up. Lack of ongoing statin during follow-up was associated with risk of death in time-dependent analysis (adjusted HR, 3.03 [CI, 2.96-3.23]). CONCLUSIONS: Lack of statin treatment after IS is associated with adverse long-term outcomes. Measures to further improve timely statin use after IS are needed.

Initial statin dose after myocardial infarction and long-term cardiovascular outcomes.

AIMS: Effective statin therapy is a cornerstone of secondary prevention after myocardial infarction (MI). Real-life statin dosing is nevertheless suboptimal and largely determined early after MI. We studied long-term outcome impact of initial statin dose after MI. METHODS AND RESULTS: Consecutive MI patients treated in Finland who used statins early after index event were retrospectively studied (N = 72 401; 67% men; mean age 68 years) using national registries. High-dose statin therapy was used by 26.3%, moderate dose by 69.2%, and low dose by 4.5%. Differences in baseline features, comorbidities, revascularisation, and usage of other evidence-based medications were adjusted for with multivariable regression. The primary outcome was major adverse cardiovascular or cerebrovascular event (MACCE) within 10 years. Median follow-up was 4.9 years. MACCE was less frequent in high-dose group compared with moderate dose [adjusted hazard ratio (HR) 0.92; P < 0.0001; number needed to treat (NNT) 34.1] and to low dose [adj.HR 0.81; P < 0.001; NNT 13.4] as well as in moderate-dose group compared with low dose (adj.HR 0.88; P < 0.0001; NNT 23.4). Death (adj.HR 0.87; P < 0.0001; NNT 23.6), recurrent MI (adj.sHR 0.91; P = 0.0001), and stroke (adj.sHR 0.86; P < 0.0001) were less frequent with a high- vs. moderate-dose statin. Higher initial statin dose after MI was associated with better long-term outcomes in subgroups by age, sex, atrial fibrillation, dementia, diabetes, heart failure, revascularisation, prior statin usage, or usage of other evidence-based medications. CONCLUSION: Higher initial statin dose after MI is dose-dependently associated with better long-term cardiovascular outcomes. These results underline the importance of using a high statin dose early after MI.

A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics.

AIMS: The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin. METHODS: We conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n = 159) and a cohort of previously published studies (n = 88). RESULTS: In a genome-wide association meta-analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.521 T > C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration-time curve (AUC) and peak plasma concentration of rosuvastatin (P = 1.8 × 10-12 and P = 3.2 × 10-15 ). The candidate gene analysis suggested that the ABCG2 c.421C > A (rs2231142) SNV associates with increased rosuvastatin AUC (P = .0079), while the SLCO1B1 c.388A > G (rs2306283) and SLCO2B1 c.1457C > T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P = .0041 and P = .0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased and highly increased organic anion transporting polypeptide (OATP) 1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1-fold (90% confidence interval 1.6-2.8, P = 4.69 × 10-5 ) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16-62%; P = .019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2-fold (1.5-3.0; P = 2.6 × 10-4 ) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11-42%; P = .01). CONCLUSION: These data suggest roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin-induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.

Early statin use and cardiovascular outcomes after myocardial infarction: A population-based case-control study.

BACKGROUND AND AIMS: Statin therapy is a cornerstone of secondary prevention after myocardial infarction (MI). However, many patients do not use statins. We studied the association of not using statin early after MI with adverse outcomes. METHODS: Consecutive MI patients admitted to 20 Finnish hospitals (n = 64,401; median age 71) were retrospectively studied. Statin was not used by 17.1% within 90 days after MI discharge (exposure). Differences in baseline features, comorbidities, revascularization, and other evidence-based medications were balanced with propensity score matching, resulting in 10,051 pairs of patients with and without statin. Median follow-up was 5.9 years. RESULTS: Patients not using statin early after MI had higher all-cause mortality in 1-year (15.8% vs. 11.9%; HR 1.38; CI 1.30-1.46; p < 0.0001) and 10-year follow-up (71.1% vs. 65.2%; HR 1.34; CI 1.30-1.39; p < 0.0001) in the matched cohort. The number needed to harm by not using statin was 24.1 at 1-year and 9.5 at 10-years. The cumulative incidence of major adverse cardiovascular event was higher at 1- and 10-years in matched patients not using statins (sHR 1.15; p < 0.0001 for both). Cardiovascular death, new MI, and ischemic stroke were more frequent without early statin. A lack of statin was associated with outcomes regardless of sex, age, atrial fibrillation, dementia, diabetes, heart failure, revascularization, or usage of other evidence-based secondary preventive medications in subgroup analyses. CONCLUSIONS: Lack of statin therapy early after MI is associated with adverse outcomes across the spectrum of MI patients. Results underline the importance of timely statin use after MI.

Genomewide Association Study of Simvastatin Pharmacokinetics.

We investigated genetic determinants of single-dose simvastatin pharmacokinetics in a prospective study of 170 subjects and a retrospective cohort of 59 healthy volunteers. In a microarray-based genomewide association study with the prospective data, the SLCO1B1 c.521T>C (p.Val174Ala, rs4149056) single nucleotide variation showed the strongest, genomewide significant association with the area under the plasma simvastatin acid concentration-time curve (AUC; P = 6.0 × 10-10 ). Meta-analysis with the retrospective cohort strengthened the association (P = 1.6 × 10-17 ). In a stepwise linear regression candidate gene analysis among all 229 participants, SLCO1B1 c.521T>C (P = 1.9 × 10-13 ) and CYP3A4 c.664T>C (p.Ser222Pro, rs55785340, CYP3A4*2, P = 0.023) were associated with increased simvastatin acid AUC. Moreover, the SLCO1B1 c.463C>A (p.Pro155Thr, rs11045819, P = 7.2 × 10-6 ) and c.1929A>C (p.Leu643Phe, rs34671512, P = 5.3 × 10-4 ) variants associated with decreased simvastatin acid AUC. Based on these results and the literature, we classified the volunteers into genotype-predicted OATP1B1 and CYP3A4 phenotype groups. Compared with the normal OATP1B1 function group, simvastatin acid AUC was 273% larger in the poor (90% confidence interval (CI), 137%, 488%; P = 3.1 × 10-6 ), 40% larger in the decreased (90% CI, 8%, 83%; P = 0.036), and 67% smaller in the highly increased function group (90% CI, 46%, 80%; P = 2.4 × 10-4 ). Intermediate CYP3A4 metabolizers (i.e., heterozygous carriers of either CYP3A4*2 or CYP3A4*22 (rs35599367)), had 87% (90% CI, 39%, 152%, P = 6.4 × 10-4 ) larger simvastatin acid AUC than normal metabolizers. These data suggest that in addition to no function SLCO1B1 variants, increased function SLCO1B1 variants and reduced function CYP3A4 variants may affect the pharmacokinetics, efficacy, and safety of simvastatin. Care is warranted if simvastatin is prescribed to patients carrying decreased function SLCO1B1 or CYP3A4 alleles.

Digoxin use and outcomes after myocardial infarction in patients with atrial fibrillation.

Digoxin is used for rate control in atrial fibrillation (AF), but evidence for its efficacy and safety after myocardial infarction (MI) is scarce and mixed. We studied post-MI digoxin use effects on AF patient outcomes in a nationwide registry follow-up study in Finland. Digoxin was used by 18.6% of AF patients after MI, with a decreasing usage trend during 2004-2014. Baseline differences in digoxin users (n = 881) and controls (n = 3898) were balanced with inverse probability of treatment weight adjustment. The median follow-up was 7.4 years. Patients using digoxin after MI had a higher cumulative all-cause mortality (77.4% vs. 72.3%; hazard ratio [HR]: 1.19; confidence interval [CI]: 1.07-1.32; p = 0.001) during a 10-year follow-up. Mortality differences were detected in a subgroup analysis of patients without baseline heart failure (HF) (HR: 1.23; p = 0.019) but not in patients with baseline HF (HR: 1.05; p = 0.413). Cumulative incidences of HF hospitalizations, stroke and new MI were similar between digoxin group and controls. In conclusion, digoxin use after MI is associated with increased mortality but not with HF hospitalizations, new MI or stroke in AF patients. Increased mortality was detected in patients without baseline HF. Results suggest caution with digoxin after MI in AF patients, especially in the absence of HF.

Translational aspects of cytochrome P450-mediated drug-drug interactions: A case study with clopidogrel.

Multimorbidity, polypharmacotherapy and drug interactions are increasingly common in the ageing population. Many drug-drug interactions (DDIs) are caused by perpetrator drugs inhibiting or inducing cytochrome P450 (CYP) enzymes, resulting in alterations of the plasma concentrations of a victim drug. DDIs can have a major negative health impact, and in the past, unrecognized DDIs have resulted in drug withdrawals from the market. Signals to investigate DDIs may emerge from a variety of sources. Nowadays, standard methods are widely available to identify and characterize the mechanisms of CYP-mediated DDIs in vitro. Clinical pharmacokinetic studies, in turn, provide experimental data on pharmacokinetic outcomes of DDIs. Physiologically based pharmacokinetic (PBPK) modelling utilizing both in vitro and in vivo data is a powerful tool to predict different DDI scenarios. Finally, epidemiological studies can provide estimates on the health outcomes of DDIs. Thus, to fully characterize the mechanisms, clinical effects and implications of CYP-mediated DDIs, translational research approaches are required. This minireview provides an overview of translational approaches to study CYP-mediated DDIs, going beyond regulatory DDI guidelines, and an illustrative case study of how the DDI potential of clopidogrel was unveiled by combining these different methods.

Pharmacogenomics of celiprolol - evidence for a role of P-glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics.

The aim of this study was to search for associations of genetic variants with celiprolol pharmacokinetics in a large set of pharmacokinetic genes, and, more specifically, in a set of previously identified candidate genes ABCB1, SLCO1A2, and SLCO2B1. To this end, we determined celiprolol single-dose (200 mg) pharmacokinetics and sequenced 379 pharmacokinetic genes in 195 healthy volunteers. Analysis with 46,064 common sequence variants in the 379 genes did not identify any novel genes associated with celiprolol exposure. The candidate gene analysis showed that the ABCB1 c.3435T>C and c.2677T/G>A, and the SLCO1A2 c.516A>C variants were associated with reduced celiprolol area under the plasma concentration-time curve (AUC0-∞ ). An alternative analysis with ABCB1 haplotypes showed that, in addition to SLCO1A2 c.516A>C, three ABCB1 haplotypes were associated with reduced celiprolol AUC0-∞ . A genotype scoring system was developed based on these variants and applied to stratify the participants to low and high celiprolol exposure genotype groups. The mean AUC0-∞ of celiprolol in the low exposure genotype group was 55% of the mean AUC0-∞ in the high exposure group (p = 1.08 × 10-11 ). In addition, the results showed gene-gene interactions in the effects of SLCO1A2 and ABCB1 variants on celiprolol AUC0-∞ (p < 5 × 10-6 ) suggesting an interplay between organic anion transporting polypeptide 1A2 and P-glycoprotein in celiprolol absorption. Taken together, these data indicate that P-glycoprotein and organic anion transporting polypeptide 1A2 play a role in celiprolol pharmacokinetics. Furthermore, patients with ABCB1 and SLCO1A2 genotypes associated with low celiprolol exposure may have an increased risk of poor blood-pressure lowering response to celiprolol.

Common Statin Intolerance Variants in ABCB1 and LILRB5 Show Synergistic Effects on Statin Response: An Observational Study Using Electronic Health Records.

Background: Statin intolerance impacts approximately 10% of statin users, with side effects ranging from mild myalgia to extreme intolerance resulting in myopathy and rhabdomyolysis. Statin intolerance results in poor adherence to therapy and can impact statin efficacy. Many genetic variants are associated with statin intolerance. The effect of these variants on statin efficacy has not been systematically explored. Methods: Using longitudinal electronic health records and genetic biobank data from Tayside, Scotland, we examined the effect of seven genetic variants with previously reported associations with simvastatin or atorvastatin intolerance on the outcome of statin response. Statin response was measured by the reduction achieved when comparing pre- and post-statin non-high-density lipoprotein-cholesterol (non-HDL-C). Post-treatment statin response was limited to non-HDL-C measured within 6months of therapy initiation. Univariate and multivariable linear regression models were used to assess the main and adjusted effect of the variants on statin efficacy. Results: Around 9,401 statin users met study inclusion criteria, of whom 8,843 were first prescribed simvastatin or atorvastatin. The average difference in post-treatment compared to pre-treatment non-HDL-cholesterol was 1.45 (±1.04) mmol/L. In adjusted analyses, only two variants, one in the gene ATP-binding cassette transporter B1 (ABCB1; rs1045642), and one in leukocyte immunoglobulin like receptor B5 (LILRB5; rs12975366), were associated with statin efficacy. In ABCB1, homozygous carriers of the C allele at rs1045642 had 0.06mmol/L better absolute reduction in non-HDL-cholesterol than carriers of the T allele (95% CI: 0.01, 0.1). In LILRB5 (rs12975366), carriers of the C allele had 0.04mmol/L better absolute reduction compared to those homozygous for the T allele (95% CI: 0.004, 0.08). When combined into a two-variant risk score, individuals with both the rs1045642-CC genotype and the rs12975366-TC or CC genotype had a 0.11mmol/L greater absolute reduction in non-HDL-cholesterol compared to those with rs1045642-TC or TT genotype and the rs12975366-TT genotype (95% CI: 0.05, 0.16; p<0.001). Conclusion: We report two genetic variants for statin adverse drug reactions (ADRs) that are associated with statin efficacy. While the ABCB1 variant has been shown to have an association with statin pharmacokinetics, no similar evidence for LILRB5 has been reported. These findings highlight the value of genetic testing to deliver precision therapeutics to statin users.