Association of magnesium and vitamin D status with grip strength and fatigue in older adults: a 4-week observational study of geriatric participants undergoing rehabilitation.

BACKGROUND: Low magnesium and vitamin D levels negatively affect individuals' health. AIMS: We aimed to investigate the association of magnesium status with grip strength and fatigue scores, and evaluate whether this association differs by vitamin D status among older participants undergoing geriatric rehabilitation. METHODS: This is a 4-week observational study of participants aged ≥ 65 years undergoing rehabilitation. The outcomes were baseline grip strength and fatigue scores, and 4-week change from baseline in grip strength and fatigue scores. The exposures were baseline magnesium tertiles and achieved magnesium tertiles at week 4. Pre-defined subgroup analyses by vitamin D status (25[OH]D < 50 nmol/l = deficient) were performed. RESULTS: At baseline, participants (N = 253, mean age 75.7 years, 49.4% women) in the first magnesium tertile had lower mean grip strength compared to participants in the third tertile (25.99 [95% CI 24.28-27.70] vs. 30.1 [95% CI 28.26-31.69] kg). Similar results were observed among vitamin D sufficient participants (25.54 [95% CI 22.65-28.43] kg in the first magnesium tertile vs. 30.91 [27.97-33.86] kg in the third tertile). This association was not significant among vitamin D deficient participants. At week 4, no significant associations were observed between achieved magnesium tertiles and change in grip strength, overall and by vitamin D status. For fatigue, no significant associations were observed. CONCLUSIONS: Among older participants undergoing rehabilitation, magnesium status may be relevant for grip strength, particularly among vitamin D sufficient individuals. Magnesium status was not associated with fatigue, regardless of vitamin D status. STUDY REGISTRATION: Clinicaltrials.gov, NCT03422263; registered February 5, 2018.

Physical performance and glycemic control under SGLT-2-inhibitors in patients with type 2 diabetes and established atherosclerotic cardiovascular diseases or high cardiovascular risk (PUSH): Design of a 4-week prospective observational study.

Background: Type 2 diabetes (T2D) is associated with limitation in physical performance. Results from animal studies report enhancement of physical performance in T2D rodents treated with sodium glucose cotransporter 2 inhibitors (SGLT2is). However, in human patients with T2D and established atherosclerotic cardiovascular disease (ASCVD) or high cardiovascular risk, the impact of guideline directed SGLT2i medication on physical performance has not been sufficiently examined. Objectives: The main objectives of this study are thus firstly, to assess the changes in physical performance after 4 weeks of exercise therapy in patients with established ASCVD or high cardiovascular risk categorized into three groups according to their glycemic control at baseline. Secondly, to investigate the association of glycemic control at baseline and new guideline directed antidiabetic treatment (inadequate glycemic control and diabetes + new SGLT2i vs. adequate glycemic control and diabetes vs. no diabetes) with change in physical performance. Methods and design: This is a 4-week prospective observational study of 450 participants with established ASCVD or high cardiovascular risk with or without T2D and without previous SGLT2i medication undergoing exercise therapy during inpatient rehabilitation in a single center in Switzerland. Upon admission, participants are categorized into 3 groups of 150 participants each according to their glycemic control. Group I consisting of participants with inadequately controlled T2D defined as mean fasting plasma glucose (FPG) of ≥7 mmol/L, who are consequently administered new treatment with an SGLT2i. Group II comprises of participants with adequately controlled T2D with mean FPG of <7 mmol/L requiring no antidiabetic medication change. Group III consists of participants with no diabetes and mean FPG of ≤ 5.5 mmol/L. Primary outcomes are 6-min walk distance and rate of perceived exertion. Secondary outcomes are echocardiographic parameters (left ventricular mass index; global longitudinal strain average; end-diastolic volume), fatigue, muscle, metabolic, and anthropometric measures. Ethics and dissemination: This study is conducted in accordance with the Declaration of Helsinki with ethical approval from the Cantonal Ethical Commission of Bern, Switzerland. The results will be published in a peer-reviewed journal. The implementation and reporting will be according to the SPIRIT guidelines. Study protocol registration: https://www.clinicaltrials.gov/, identifier: NCT03422263.

Impact of cytochrome P450 3A4-metabolized statins on the antiplatelet effect of a 600-mg loading dose clopidogrel and on clinical outcome in patients undergoing elective coronary stent placement.

Early studies suggested interactions between statins and clopidogrel. Based on the outcome and platelet data, there is now huge evidence of no interactions between statins and 75 to 300 mg clopidogrel; however, data with 600-mg loading are lacking. In a pre-specified analysis of the EXCELSIOR cohort, we investigated the interaction between statins, especially cytochrome P4503A4-metabolized atorvastatin and simvastatin, and the antiplatelet effects of a 600-mg loading dose of clopidogrel. We analyzed 1,395 patients scheduled for coronary angiography (CA). Patients received clopidogrel 600 mg at least two hours before CA and 75 mg daily thereafter in case of percutaneous coronary intervention (PCI). Statin medication on admission was continued unaltered until discharge. Platelet function was assessed by optical aggregometry and flow cytometry of adenosine diphosphate (ADP)-stimulated surface expression of CD62P, CD63 and PAC-1 before clopidogrel and immediately before CA. Residual platelet aggregation (RPA) after addition of ADP 5 muM was similar irrespective of statin treatment at baseline (p = 0.968). RPA at CA was 46.2 +/- 16.8% in patients without statin (n = 682), 45.5 +/- 17.0% in patients with atorvastatin (n = 255), 45.8 +/- 16.3% with simvastatin (n = 335), 47.3 +/- 14.9% with fluvastatin (n = 42) and 45.9 +/- 16.2% with pravastatin (n = 81; p = 0.962). Consistent results were obtained by flow cytometry. In patients with PCI (n = 553), the one-year incidence of death, myocardial infarction and target lesion reintervention did not differ between cohorts stratified according to statin co-medication (p = 0.645). Thus, peri-interventional atorvastatin and simvastatin had no effect on the antiplatelet activity of a loading dose of clopidogrel 600 mg and did not affect clinical outcome after PCI.

Whole blood aggregometry for evaluation of the antiplatelet effects of clopidogrel.

INTRODUCTION: The marked interindividual variability in platelet inhibition even after administration of high loading doses of clopidogrel raised the question whether monitoring of antiplatelet effects in patients undergoing percutaneous coronary intervention (PCI) can improve clinical outcome. Established methods for monitoring antiplatelet drug activity such as optical aggregometry and determination of surface protein expression are not suitable for routine bedside testing. MATERIAL AND METHODS: We therefore compared the applicability of whole blood impedance aggregometry (20 micromol/L ADP) and the whole blood bedside ULTEGRA assay with ADP-cartridges (20 micromol/L) with optical aggregometry in platelet-rich plasma and determination of surface protein expression (P-Selectin and activated GPIIb/IIIa) by flow cytometry. We analyzed samples obtained from 27 patients scheduled for elective PCI who received a loading dose of 600 mg of clopidogrel. Blood samples were withdrawn before clopidogrel, before PCI and 24h thereafter. RESULTS: Platelet aggregation assessed by optical aggregometry (20 micromol/L ADP) declined from 65+/-9% (baseline) to 42+/-12% (PCI) and 45+/-13% (24h; p<0.01). Expression of surface proteins displayed a similar time course. Platelet aggregation determined by impedance aggregometry decreased from 4.6+/-4.0 Omega (baseline) to 0.1+/-0.3 Omega (PCI) and 0.5+/-1.1 Omega (24h) with no detectable residual platelet aggregation during PCI in 88% of patients. The ULTEGRA assay showed only slight changes after administration of clopidogrel. Correlation analysis between the various assays revealed significant correlations only between optical aggregometry and flow cytometry. CONCLUSIONS: The results indicate that both of the whole blood assays cannot substitute for optical aggregometry or determination of surface proteins in the assessment of clopidogrel-induced platelet inhibition.

Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention.

BACKGROUND: Pretreatment with clopidogrel can reduce the risks associated with percutaneous coronary intervention (PCI). To shorten the time for clopidogrel to become effective, a 600-mg loading dose has been used. We sought to validate this regimen in a large cohort and investigated the time dependence of the antiplatelet effect of 600 mg of clopidogrel. METHODS AND RESULTS: Our study included 1001 patients who were scheduled for cardiac catheterization as potential candidates for PCI. We obtained blood samples before administration of 600 mg of clopidogrel and at the time of catheterization, which varied according to logistic needs. We assessed platelet aggregation by optical aggregometry and surface expression of P-selectin and activated glycoprotein IIb/IIIa by flow cytometry. Platelet aggregation induced by 5 micromol/L ADP was 51+/-14% when catheterization was performed at <1 hour, 41+/-14% at 1 to <2 hours, 37+/-15% at 2 to <4 hours, 36+/-13% at 4 to <6 hours, and 35+/-14% at > or =6 hours after clopidogrel administration. After 2 hours (n=718), the level of platelet aggregation and the surface expression of P-selectin and activated glycoprotein IIb/IIIa did not change significantly with time after clopidogrel (P>0.24 by univariate or multivariate regression). Comedication with CYP3A4 metabolized statins did not significantly affect platelet aggregation after clopidogrel (P=0.62). Among the 428 patients undergoing PCI, the 30-day composite rate of major adverse cardiac events was 1.9%, with no significant difference between patients undergoing PCI within 2 hours after clopidogrel loading and those undergoing PCI at a later time point. CONCLUSIONS: After loading with 600 mg of clopidogrel, the full antiplatelet effect of the drug is achieved after 2 hours. Statins do not interfere with the level of platelet inhibition after this dose.