[PCSK9 inhibitors; who benefits from these new cholesterol-lowering drugs?] / PCSK9-remmers.

PCSK9 inhibitors are monoclonal antibodies that target the protein PCSK9. These drugs (alirocumab and evolcumab) are a new generation of cholesterol-lowering agents for patients with a very high risk of cardiovascular disease. They lower the LDL cholesterol concentration by approximately 50% in comparison with placebo, thereby lowering the risk of myocardial infarction, stroke and cardiovascular death in high-risk patients. Due to their high cost and the cost-effectiveness, there are strict conditions for reimbursement for these agents in the Netherlands. PCSK9 inhibitors can be given to high-risk patients in whom, despite maximal medicinal therapy with statins and ezetimibe, the target level of LDL cholesterol cannot be reached. This article gives an overview of the efficacy and the safety of PCSK9 inhibitors, and of their use in the Netherlands.

Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine.

OBJECTIVE: To identify a plasma metabolomic biomarker signature for migraine. METHODS: Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a 1H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses. RESULTS: Decreases in the level of apolipoprotein A1 (ß -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (ß -0.10; 95% CI -0.15, -0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (ß -0.24; 95% CI -0.36, -0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status. CONCLUSIONS: Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.

Labtracker+, a medical smartphone app for the interpretation of consecutive laboratory results: an external validation study.

OBJECTIVES: When monitoring patients over time, clinicians may struggle to distinguish 'real changes' in consecutive blood parameters from so-called natural fluctuations. In practice, they have to do so by relying on their clinical experience and intuition. We developed Labtracker+, a medical app that calculates the probability that an increase or decrease over time in a specific blood parameter is real, given the time between measurements. DESIGN: We presented patient cases to 135 participants to examine whether there is a difference between medical students, residents and experienced clinicians when it comes to interpreting changes between consecutive laboratory results. Participants were asked to interpret if changes in consecutive laboratory values were likely to be 'real' or rather due to natural fluctuations. The answers of the study participants were compared with the calculated probabilities by the app Labtracker+ and the concordance rates were assessed. SETTING AND PARTICIPANTS: Medical students (n=92), medical residents from the department of internal medicine (n=19) and internists (n=24) at a Dutch University Medical Centre. PRIMARY AND SECONDARY OUTCOME MEASURES: Concordance rates between the study participants and the calculated probabilities by the app Labtracker+ were compared. Besides, we tested whether physicians with clinical experience scored better concordance rates with the app Labtracker+ than inexperienced clinicians. RESULTS: Medical residents and internists showed significantly better concordance rates with the calculated probabilities by the app Labtracker+ than medical students, regarding their interpretation of differences between consecutive laboratory results (p=0.009 and p<0.001, respectively). CONCLUSION: The app Labtracker+ could serve as a clinical decision tool in the interpretation of consecutive laboratory test results and could contribute to rapid recognition of parameter changes by physicians.

A control systems approach to quantify wall shear stress normalization by flow-mediated dilation in the brachial artery.

Flow-mediated dilation is aimed at normalization of local wall shear stress under varying blood flow conditions. Blood flow velocity and vessel diameter are continuous and opposing influences that modulate wall shear stress. We derived an index FMDv to quantify wall shear stress normalization performance by flow-mediated dilation in the brachial artery. In 22 fasting presumed healthy men, we first assessed intra- and inter-session reproducibilities of two indices pFMDv and mFMDv, which consider the relative peak and relative mean hyperemic change in flow velocity, respectively. Second, utilizing oral glucose loading, we evaluated the tracking performance of both FMDv indices, in comparison with existing indices [i.e., the relative peak diameter increase (%FMD), the peak to baseline diameter ratio (Dpeak/Dbase), and the relative peak diameter increase normalized to the full area under the curve of blood flow velocity with hyperemia (FMD/shearAUC) or with area integrated to peak hyperemia (FMD/shearAUC_peak)]. Inter-session and intra-session reproducibilities for pFMDv, mFMDv and %FMD were comparable (intra-class correlation coefficients within 0.521-0.677 range). Both pFMDv and mFMDv showed more clearly a reduction after glucose loading (reduction of ~45%, p≤0.001) than the other indices (% given are relative reductions): %FMD (~11%, p≥0.074); Dpeak/Dbase (~11%, p≥0.074); FMD/shearAUC_peak (~20%, p≥0.016) and FMD/shearAUC (~38%, p≤0.038). Further analysis indicated that wall shear stress normalization under normal (fasting) conditions is already far from ideal (FMDv << 1), which (therefore) does not materially change with glucose loading. Our approach might be useful in intervention studies to detect intrinsic changes in shear stress normalization performance in conduit arteries.

Inhibition of capsaicin-induced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK-0974).

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Calcitonin gene-related peptide (CGRP) was first described as a potent vasodilator. * CGRP is also increasingly recognized as a key player in the pathophysiology of migraine, and CGRP receptor antagonists potentially offer a new approach for treating migraine. * A novel pharmacodynamic assay to measure CGRP receptor antagonist activity non-invasively in humans has been developed, which involves measuring the increase in dermal blood flow induced by topical application of capsaicin on the forearm. WHAT THIS STUDY ADDS: * This study shows that the novel oral CGRP receptor antagonist, telcagepant, inhibits the increases in dermal blood flow induced by the topical application of capsaicin on the human forearm. * This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists. AIMS: To evaluate inhibition of capsaicin-induced increase in dermal blood flow (DBF) following telcagepant (MK-0974), a potent and selective orally bioavailable calcitonin gene-related peptide (CGRP) receptor antagonist being developed for the acute treatment of migraine. METHODS: A three-period crossover study in 12 healthy adult men. Each subject received a single oral dose of telcagepant 300 mg, telcagepant 800 mg or placebo at 0 h, followed 0.5 and 3.5 h later by two topical doses of 300 and 1000 microg capsaicin per 20 microl water-ethanol mixture. Capsaicin was applied at two sites on the volar surface of the subjects' left and right forearms. DBF was assessed by laser Doppler perfusion imaging immediately before ('baseline'), and 0.5 h after each capsaicin application at 1 and 4 h. Plasma samples to determine telcagepant concentrations were collected immediately after laser Doppler perfusion imaging. A pharmacodynamic model was developed to explore the relationship between plasma concentration and inhibition of capsaicin-induced increase in DBF. RESULTS: Geometric mean plasma concentrations after dosing with 300 mg and 800 mg telcagepant were 720 and 1146 nm, respectively, at 1 h, vs. 582 and 2548 nm, respectively, at 4 h. The pharmacodynamic model suggested that the EC(90) for telcagepant inhibition of capsaicin-induced increases in DBF was 909 nm. CONCLUSIONS: Telcagepant inhibits the increases in DBF induced by the topical application of capsaicin on the human forearm. This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists.

Acute effects of sumatriptan on aortic blood pressure, stiffness, and pressure waveform.

BACKGROUND AND OBJECTIVES: Sumatriptan, a 5-hydroxytryptamine (HT)(1B/1D) receptor agonist, is an effective acute antimigraine drug. Because of its vasoconstrictor activity, it is contraindicated in patients at high risk for adverse cardiovascular events. Acute antimigraine drugs without vasoconstrictor effects are currently being developed, and sensitive, noninvasive techniques by which to detect drug-induced vascular effects would facilitate their clinical development. The effects of sumatriptan on aortic blood pressure, stiffness, and pressure waveform have not been assessed previously in detail. METHODS: A randomized, placebo-controlled, double-blind, 4-way crossover study was performed in 12 healthy subjects. Each subject received 25, 50, and 100 mg sumatriptan and placebo as single oral doses. Vascular measurements, including oscillometric blood pressure measurement, arterial ultrasound, systolic pulse contour analysis, and aortic pulse wave velocity measurement, were performed at baseline and 30, 90, and 150 minutes after drug administration. RESULTS: Compared with placebo and expressed as weighted mean +/- SD, 100 mg sumatriptan increased aortic systolic blood pressure by 6 +/- 5 mm Hg (P < .01), aortic pulse wave velocity by 0.5 +/- 0.5 m/s (P < .01), and aortic augmentation index by 13% +/- 6% (P < .0001). The increase in aortic systolic blood pressure was larger compared with the increase in brachial systolic blood pressure (P < .0001). Significant vascular effects were already detected after the lowest dose of sumatriptan by systolic pulse contour analysis and arterial ultrasound. CONCLUSION: These findings show that therapeutic doses of sumatriptan acutely increase aortic blood pressure, stiffness, and augmentation index. Noninvasive systolic pulse contour analysis and arterial ultrasound may facilitate detection of drug-induced vascular effects in early clinical trials.

Calcitonin gene-related peptide-induced vasodilation in the human forearm is antagonized by CGRP8-37: evaluation of a human in vivo pharmacodynamic model.

OBJECTIVES: The aims of this study were to assess the potential of CGRP8-37, the C-terminal fragment of calcitonin gene-related peptide (CGRP), to inhibit CGRP-induced vasodilation in the human forearm and to evaluate a pharmacodynamic model to aid the clinical development of novel CGRP-receptor antagonists. METHODS: Forearm blood flow (FBF) responses to intra-arterial CGRP infusions were measured via venous occlusion plethysmography in 21 healthy subjects. Dose response to CGRP was assessed during graded infusion of CGRP (1, 3, and 10 ng.min(-1).dL(-1) forearm; n = 6). After a 90-minute washout period, CGRP infusions were repeated during coinfusion of CGRP8-37 (333 ng.min(-1).dL(-1) forearm) to assess inhibition by CGRP8-37. To determine the antagonistic potency of CGRP8-37, a 4-period, placebo-controlled crossover study was conducted in 6 subjects, in which CGRP (10 ng.min(-1).dL(-1) forearm) was infused for 20 minutes together with placebo or CGRP8-37 (300, 600, or 1200 ng.min(-1).dL(-1) forearm). In addition, the effect of each dose of CGRP8-37 on resting FBF was evaluated. RESULTS: CGRP8-37 significantly inhibited the CGRP-induced increase in FBF compared with placebo (from 3.2 +/- 1.1 mL.min(-1).dL(-1) forearm at baseline to 4.8 +/- 1.0, 7.7 +/- 1.9, and 12.3 +/- 3.8 mL.min(-1).dL(-1) forearm versus 3.1 +/- 0.7 mL.min(-1).dL(-1) forearm to 3.8 +/- 0.6, 5.2 +/- 1.5, and 8.5 +/- 3.0 mL.min(-1).dL(-1) forearm for placebo and CGRP8-37, respectively; P < .001). The FBF response during the 20-minute infusion of CGRP was dose-dependently inhibited by CGRP8-37 (area under the curve, 200 +/- 51 mL.dL(-1) forearm for placebo versus 181 +/- 23, 160 +/- 40, and 132 +/- 56 mL.dL(-1) forearm for CGRP8-37, 300, 600, and 1200 ng.min(-1).dL(-1) forearm, respectively; P < .001). CGRP8-37 did not affect resting FBF. CONCLUSIONS: CGRP8-37 inhibits CGRP-induced vasodilation in the human forearm without affecting resting FBF. Venous occlusion plethysmography combined with brachial artery administration of CGRP provides a suitable pharmacodynamic model to aid the clinical development of CGRP-receptor antagonists.

Reproducibility of forearm vasodilator response to intra-arterial infusion of calcitonin gene-related peptide assessed by venous occlusion plethysmography.

AIMS: To assess the reproducibility of the forearm blood flow (FBF) response to intra-arterial infusion of calcitonin-gene related peptide (CGRP), measured by venous occlusion plethysmography. In addition, to compare different ways of expressing the FBF response and perform sample size calculations. METHODS: On two separate visits, CGRP (10 ng min(-1) dl(-1) forearm) was infused for 45 min into the brachial artery of six healthy subjects. Reproducibility was assessed by calculating mean difference, repeatability coefficient, within-subject coefficient of variation (WCV) and intraclass correlation coefficient. RESULTS: CGRP increased FBF from 2.8 +/- 0.4 and 3.2 +/- 0.7 (at baseline) to 15.4 +/- 1.4 and 15.2 +/- 1.5 ml min(-1) dl(-1) forearm (at 45 min) on visits 1 and 2, respectively (P < 0.0001 for both visits). Mean difference in FBF at 45 min between both visits was 0.3 ml min(-1) dl(-1) forearm (repeatability coefficient: 4.1 ml min(-1) dl(-1) forearm). This FBF response appeared to be more reproducible when expressed as absolute FBF in the infused arm (WCV 11%) compared with absolute FBF-ratio between both arms (WCV 37%), percentage change from baseline in FBF in the infused arm (WCV 29%) and percentage change from baseline in FBF-ratio (WCV 40%). When expressed as absolute FBF, a sample size of five (95% confidence interval: 2-12) subjects gives 90% power at a type I error probability of 0.05 to detect a 25% shift in FBF response. CONCLUSIONS: Intra-arterial infusion of CGRP results in a forearm vasodilator response which is reproducible between days. This response is most reproducible when expressed as absolute FBF. The presented methodology provides a suitable pharmacodynamic model to assess the in vivo activity of CGRP-receptor antagonists in a small number of subjects.