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Hypertension Canada's 2020 guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children provide comprehensive, evidence-based guidance for health care professionals and patients. Hypertension Canada develops the guidelines using rigourous methodology, carefully mitigating the risk of bias in our process. All draft recommendations undergo critical review by expert methodologists without conflict to ensure quality. Our guideline panel is diverse, including multiple health professional groups (nurses, pharmacy, academics, and physicians), and worked in concert with experts in primary care and implementation to ensure optimal usability. The 2020 guidelines include new guidance on the management of resistant hypertension and the management of hypertension in women planning pregnancy.

Author(s): Sukumar, Smrithi; Gulilat, Markus; Linton, Bradley; Gryn, Steven E; Dresser, George K; Alfonsi, Jeffrey E; Schwarz, Ute I; Kim, Richard B; Schwartz, Janice B | Abstract: ObjectivesLower than recommended doses of direct-acting oral anticoagulants are often prescribed to older adults with nonvalvular atrial fibrillation (NVAF). Our goal was to determine the consequences of lower than recommended dosing on plasma apixaban concentrations during the clinical care of older adults with NVAF.DesignConvenience sample of patients receiving anticoagulation during 2017.SettingAcademic medical center.ParticipantsStable adults older than 65 years with NVAF receiving apixaban on a chronic basis.MeasurementsPatient age, weight, creatinine, co-medications, and apixaban concentrations.ResultsA total of 110 older adults with NVAF (mean age = 80.4 y; range = 66-100 y with 45% women) were studied. Overall, 48 patients received recommended dosing of 5 mg twice/day, and 42 received lower than recommended dosing. One patient in each category had concentrations below the expected 5% to 95% range at time of peak concentrations. Differences in proportion of apixaban concentrations within or outside expected ranges were not significant between patients receiving lower than recommended doses and those dosed as recommended at 5 mg twice/day (P = .35). However, in patients dosed as recommended with 5 mg twice/day, four had concentrations above the 5% to 95% range for peak levels expected at 3 to 4 hours after dosing; in two, this occurred around the midpoint of the dosing interval. Twenty patients received 2.5 mg twice/day as recommended. One-third had apixaban concentrations higher than expected peak concentrations compared with the clinical trials, and more than two-thirds had levels above the reported median for peak concentrations.ConclusionsApixaban concentrations in older adults with NVAF seen clinically were higher than expected based on clinical trial data. The findings raise questions about the optimal dosing of apixaban in older adults with NVAF encountered outside of clinical trials and suggest a role for the monitoring of apixaban concentrations during care of patients that differ from those in randomized trials or when considering dosing outside of published guidelines. J Am Geriatr Soc 67:1902-1906, 2019.

Hypertension Canada provides annually-updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension in adults and children. This year, the adult and pediatric guidelines are combined in one document. The new 2018 pregnancy-specific hypertension guidelines are published separately. For 2018, 5 new guidelines were introduced, and one existing guideline on the blood pressure thresholds and targets in the setting of thrombolysis for acute ischemic stroke was revised. The use of validated wrist devices for the estimation of blood pressure in individuals with large arm circumference is now included. Guidance is provided for the follow-up measurements of blood pressure, with the use of standardized methods and electronic (oscillometric) upper arm devices in individuals with hypertension, and either ambulatory blood pressure monitoring or home blood pressure monitoring in individuals with white coat effect. We specify that all individuals with hypertension should have an assessment of global cardiovascular risk to promote health behaviours that lower blood pressure. Finally, an angiotensin receptor-neprilysin inhibitor combination should be used in place of either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in individuals with heart failure (with ejection fraction < 40%) who are symptomatic despite appropriate doses of guideline-directed heart failure therapies. The specific evidence and rationale underlying each of these guidelines are discussed.

Rosuvastatin is commonly prescribed for the treatment of hypercholesterolemia and hepatic transporter-mediated accumulation in the liver enhances its efficacy. Current guidelines indicate no preference for fed or fasted rosuvastatin administration. We investigated the association between food intake and rosuvastatin disposition in healthy subjects and low-density lipoprotein cholesterol (LDL-C)-lowering effects among patients taking rosuvastatin. We demonstrate that administration with food resulted in a near 40% reduction of rosuvastatin exposure in healthy Asian (n = 12) and Caucasian (n = 11) subjects. Higher rosuvastatin concentrations in Asian subjects also correlated with higher allele frequency of ABCG2 c.421C>A. In mice, a greater rosuvastatin liver:plasma ratio was noted when administered with food. Among rosuvastatin patients (n = 156), there was no difference in dose needed to reach target LDL-C, measured LDL-C, or lathosterol concentrations, when administered in a fed or fasting state. Therefore, taking rosuvastatin with food could reduce systemic concentrations, and subsequent myopathy risk, without compromising LDL-C-lowering benefit.

Introduction: Statins are beneficial for both primary and secondary prevention of cardiovascular disease in many patients at elevated risk. However, selection of patients most likely to respond and least likely to have adverse effects can benefit from refinement. While pharmacogenomic aspects of statins have been thoroughly evaluated, as yet there has been no major impact on patient care, although there is great potential that a precision medicine approach might one day enhance patient care.Areas covered: This paper provides a brief overview of genetic variants that influence statin responsiveness, together with newer information on genetic risk scores that combine numerous common DNA variants into a stronger prediction of cardiovascular risk reduction from statins. We also discuss a pharmacokinetic-based approach to aid in prediction and prevention of statin adverse effects.Expert commentary: While individual genetic variants appear to have statistically significant effects on lipid lowering by s...

We provide an overview of orally administered lipid-lowering therapies under development.Recent data support statins for intermediate risk primary prevention, and ezetimibe for high-risk secondary prevention. Novel agents in development include bempedoic acid and gemcabene, and work continues on one remaining cholesteryl ester transfer protein inhibitor, anacetrapib, to determine whether this class can reduce cardiovascular risk. Selective peroxisome proliferator-activated receptor modulators such as K-877 are under study to determine whether they have an advantage over older fibrates. Diacylglycerol transferase inhibitors such as pradigastat appear to have potent triglyceride-lowering effects, even for patients with familial chylomicronemia syndrome. Finally, novel ω-3 preparations are available with significant triglyceride lowering, although their role in therapy remains unclear.Statins will remain the backbone of lipid-lowering therapy, although several novel oral agents are promising. The common theme across drugs in development is the demonstration of good lipid-lowering effect, although lacking cardiovascular outcomes data, which will likely be necessary before any of them, can be recommended or approved for widespread use.

Background Direct-acting oral anticoagulants (DOACs) are widely prescribed for stroke prevention in patients with atrial fibrillation (AF). An important advantage of DOACs is that routine monitoring of an anticoagulation response is not necessary. Nevertheless, because of their mechanism of action, a DOAC anticoagulation effect can be inferred based on the observed plasma concentration. However, there is a paucity of data relating to observed interpatient variation in DOAC plasma concentrations in the postmarket clinical setting. Methods We determined rivaroxaban and apixaban plasma concentrations in patients with AF during routine clinic visits. Results Among 243 patients (rivaroxaban, n = 94; apixaban, n = 149) enrolled in this study, a 60- and 50-fold interpatient variation in plasma concentration was observed for rivaroxaban and apixaban, respectively. Approximately 12% of patients receiving rivaroxaban and 13% of patients receiving apixaban exceeded the 95th percentile for predicted maximum plasma concentration observed in clinical trials. Conclusions In this routine-care setting, rivaroxaban and apixaban plasma concentrations tended to be more variable than those observed in clinical trials. Identification of additional clinical and molecular determinants that more fully predict patients at risk for excessively high or low DOAC concentrations may enable a more precise DOAC dosing regimen for the individual patient.

Due to high basal interindividual variation in cytochrome P450 3A (CYP3A) activity and susceptibility to drug interactions, there has been interest in the application of efficient probe drug phenotyping strategies, as well as endogenous biomarkers for assessment of in vivo CYP3A activity. The biomarkers 4β-hydroxycholesterol (4βHC) and 6β-hydroxycortisol (6βHCL) are sensitive to CYP3A induction and inhibition. However, their utility for the assessment of constitutive CYP3A activity remains uncertain. We investigated whether endogenous plasma biomarkers (4βHC and 6βHCL) are associated with basal CYP3A metabolic activity in healthy subjects assessed by a convenient single-time-point oral midazolam (MDZ) phenotyping strategy. Plasma 4βHC and 6βHCL metabolic ratios (MRs) were analysed in 51 healthy adult participants. CYP3A activity was determined after administration of an oral MDZ microdose (100 μg). Simple linear and multiple linear regression analyses were performed to assess relationships between MDZ oral clearance, biomarkers and subject covariates. Among study subjects, basal MDZ oral clearance, 4βHC and 6βHCL MRs ranged 6.5-, 10- and 13-fold, respectively. Participant age and alcohol consumption were negatively associated with MDZ oral clearance (p = 0.03 and p = 0.045, respectively), while weight and female sex were associated with lower plasma 4βHC MR (p = 0.0003 and p = 0.032, respectively). Neither 4βHC nor 6βHCL MRs were associated with MDZ oral clearance. Plasma 4βHC and 6βHCL MRs do not relate to MDZ single-time-point metabolic phenotype in the assessment of constitutive CYP3A activity among healthy individuals.

Lipid-lowering medications, particularly statins, have been a popular target for pharmacogenetic studies. A handful of genes have shown promise for predicting response to therapy from the perspective of lipid lowering, as well as myopathy. A number of genes have been implicated and have biological plausibility based on their involvement with the pharmacokinetics or pharmacodynamics of statins or other lipid-lowering medications. The level of confidence and replication of these findings varies, although several associations are likely true. Novel classes of lipid-lowering therapy have opened up new possibilities in the treatment of severe inherited forms of dyslipidemia, making the identification of such mutations an important pharmacogenetic predictor of failure of standard therapy, with potential response to novel therapy. Advances in next-generation sequencing technology bring the application of pharmacogenetics even closer to routine clinical practice.