A prolonged-release formulation of tacrolimus for once-daily administration (tacrolimus QD) has been developed. This phase II, open-label, multicenter, prospective single-arm study compared the ...pharmacokinetics (PK) of tacrolimus in stable heart transplant patients before and after conversion from twice-daily tacrolimus (tacrolimus BID) to tacrolimus QD.
Heart transplant recipients (≥6 months after transplant), previously maintained on tacrolimus BID-based therapy, received tacrolimus BID from Days 1 to 7 and were converted on a 1:1 (mg/mg) basis to tacrolimus QD. Five 24-hour PK profiles were collected (Days 1, 7, 8, 14, 21). Safety parameters were also evaluated.
Of 85 patients, 45 (50.6%) completed all 5 evaluable PK profiles. Steady-state tacrolimus area under the curve, 0 to 24 hours (AUC(0-24)) and minimum concentration (C(min)) were comparable for both formulations, with treatment ratio means of 90.5% (90% confidence intervals CI, 86.4%-94.6%) and 87.4% (95% CI, 82.9%-92.0%), respectively (acceptance interval, 80%-125%). There was good correlation between AUC(0-24) and C(min) for tacrolimus QD (r = 0.94) and BID (r = 0.91). The relationship between these 2 parameters was also similar.
This study provides evidence for successful conversion from tacrolimus BID to QD on a 1:1 (mg/mg) total daily dose basis. Approximately one-third of patients may require dose adjustments. Both formulations were well tolerated, with stable renal function during the study. Adverse events were reported by approximately one-tenth of patients receiving tacrolimus BID and a quarter of those who received QD.
There is an urgent need to assess changes in well-being on a multinational scale during the COVID-19 pandemic, thus culturally valid scales must be available.
With this in mind, this study examined ...the invariance of the WHO well-being index (WHO-5) among a sample of 5183 people from 12 Latin Americans countries (Argentina, Bolivia, Chile, Colombia, Cuba, Ecuador, El Salvador, Guatemala, Mexico, Paraguay, Peru, and Uruguay).
The results of the present study indicate that the WHO-5 is strictly invariant across samples from different Latin American countries. Furthermore, the results of the IRT analysis indicate that all items of the WHO-5 were highly discriminative and that the difficulty required to respond to each of the five items is ascending. Additionally, the results indicated the presence of moderate and small size differences in subjective well-being among most countries.
The WHO-5 is useful for assessing subjective well-being in 12 Latin American countries during the COVID-19 pandemic, since the differences between scores can be attributed to differences in well-being and not in other characteristics of the scale.
Abstract Objective Statins have been shown to reduce the risk of major cardiovascular disease. We recognize that there is a major gap between the use of statins in actual practice and treatment ...guidelines for dyslipidemia. Low adherence to statins may have a significant impact on clinical issues and health-care costs. The objective is to evaluate the impact of low adherence to statins on clinical issues and direct health-care costs. Methods A cohort of 55,134 patients newly treated with statins was reconstructed from the Régie de l'Assurance Maladie du Québec and Med-Echo databases. Subjects included were aged between 45 and 85, initially free of cardiovascular disease, newly treated with statins between 1999 and 2002, and followed-up for a minimum of 3 years. Adherence to statins was measured in terms of the proportion of days' supply of medication dispensed over a defined period, and categorized as ≥80% or <80%. The adjusted odds ratio (OR) of cardiovascular events between the two adherence groups was estimated using a polytomous logistic analysis. The mean costs of direct health-care services were evaluated. A two-part model was applied for hospitalization costs. Results The mean high adherence level to statins was around to 96% during follow-up; and this value was at 42% for the low adherence level. The patients with low adherence to statins were more likely to have coronary artery disease (OR 1.07; 95% confidence interval CI, 1.01–1.13), cerebrovascular disease (OR 1.13; 95% CI 1.03–1.25), and chronic heart failure within 3-year period of follow-up (OR 1.13; 95% CI 1.01–1.26). Low adherence to statins was also associated with an increased risk of hospitalization by 4% (OR 1.04; 95% CI 1.01–1.09). Among patients who were hospitalized, low adherence to statins was significantly associated with increase of hospitalization costs by approximately $1060/patient for a 3-year period. Conclusion Low adherence to statins was correlated with a higher risk of cardiovascular disease, hospitalization rate, and hospitalization costs. An increased level of adherence to statins agents should provide a better health status for individuals and a net economic gain.
Abstract Background The aims of this work were (1) to compare cerebral oxygenation-perfusion (COP), central hemodynamics, and peak oxygen uptake ( V ˙ o2 peak) in heart transplant recipients (HTRs) ...vs age-matched healthy controls (AMHCs) during exercise and recovery and (2) to study the relationships between COP, central hemodynamics, and V ˙ o2 peak in HTRs and AMHCs. Methods Twenty-six HTRs (3 women) and 27 AMHCs (5 women) were recruited. Maximal cardiopulmonary function (gas exchange analysis), cardiac hemodynamics (impedance cardiography), and left frontal COP (near-infrared spectroscopy) were measured continuously during and after a maximal ergocycle (Ergoline 800S, Bitz, Germany) test. Results Compared with AMHCs, HTRs had lower V ˙ o2 peak, maximal cardiac index (CImax), and maximal ventilatory variables ( P < 0.05). COP was lower during exercise (oxyhemoglobin ΔO2 Hb, 50% and 75% of V ˙ O2 peak, total hemoglobin ΔtHb, 100% of V ˙ O2 peak; P < 0.05), and recovery in HTRs (ΔO2 Hb, minutes 2-5; ΔtHb, minutes 1-5; P < 0.05) compared with AMHCs. End-tidal pressure of CO2 was lower during exercise compared with that in AMHCs ( P < 0.0001). In HTRs, CImax was positively correlated with exercise cerebral hemodynamics ( R = 0.54-0.60; P < 0.01). Conclusions In HTRs, COP was reduced during exercise and recovery compared with that in AMHCs, potentially because of a combination of blunted cerebral vasodilation by CO2 , cerebrovascular dysfunction, reduced cardiac function, and medication. The impaired V ˙ O2 peak observed in HTRs was mainly caused by reduced maximal ventilation and CI. In HTRs, COP is impaired and is correlated with cardiac function, potentially impacting cognitive function. Therefore, we need to study which interventions (eg, exercise training) are most effective for improving or normalizing (or both) COP during and after exercise in HTRs.
Aims
Few investigations have been conducted to identify genetic determinants of common, polygenetic forms of heart failure (HF), and only a limited number of these genetic associations have been ...validated by multiple groups.
Methods and results
We performed a case–control study to further investigate the potential impact of 14 previously reported candidate genes on the risk of HF and specific HF sub‐types. We also performed an exploratory genome‐wide study. We included 799 patients with HF and 1529 controls. After adjusting for age, sex, and genetic ancestry, we found that the C allele of rs2234962 in BAG3 was associated with a decreased risk of idiopathic dilated cardiomyopathy (odds ratio 0.42, 95% confidence interval 0.25–0.68, P = 0.0005), consistent with a previous report. No association for the other primary variants or exploratory genome‐wide study was found.
Conclusions
Our findings provide independent replication for the association between a common coding variant (rs2234962) in BAG3 and the risk of idiopathic dilated cardiomyopathy.
The impact of baseline systolic blood pressure (SBP) on outcomes in patients with advanced chronic systolic heart failure (HF) has not been studied using a propensity-matched design. Of the 2,706 ...participants in the Beta-Blocker Evaluation of Survival Trial (BEST) with chronic HF, New York Heart Association class III to IV symptoms and left ventricular ejection fraction ≤35%, 1,751 had SBP ≤120 mm Hg (median 108, range 70 to 120) and 955 had SBP >120 mm Hg (median 134, range 121 to 192). Propensity scores for SBP >120 mm Hg, calculated for each patient, were used to assemble a matched cohort of 545 pairs of patients with SBPs ≤120 and >120 mm Hg who were balanced in 65 baseline characteristics. Matched Cox regression models were used to estimate associations between SBP ≤120 mm Hg and outcomes over 4 years of follow-up. Matched participants had a mean age ± SD of 62 ± 12 years, 24% were women, and 24% were African-American. HF hospitalization occurred in 38% and 32% of patients with SBPs ≤120 and >120 mm Hg, respectively (hazard ratio 1.33 SBP ≤120 was compared to >120 mm Hg, 95% confidence interval 1.04 to 1.69, p = 0.023). All-cause mortality occurred in 28% and 30% of matched patients with SBPs ≤120 and >120 mm Hg, respectively (hazard ratio 1.13 SBP ≤120 compared to >120 mm Hg, 95% confidence interval 0.86 to 1.49, p = 0.369). In conclusion, in patients with advanced chronic systolic HF, baseline SBP ≤120 mm Hg is associated with increased risk of HF hospitalization, but had no association with all-cause mortality.
Heart failure (HF) with reduced ejection fraction represents approximately 50% of the 600,000 Canadians currently living with HF and over 90,000 new cases diagnosed each year. The angiotensin ...receptor neprilysin inhibitor, sacubitril/valsartan, demonstrated superior efficacy in reducing cardiovascular death and HF hospitalization over standard of care therapy.
The potential magnitude of benefit in Canada with respect to preventing or postponing deaths and reducing hospitalizations resulting from its optimal implementation in patients with HF with an ejection fraction <40% was estimated based on published sources.
Of the potentially eligible 225,562 patients, this would amount to the prevention of 4699 cardiovascular deaths and first HF hospitalizations, 3698 thirty-day HF readmissions, and 2820 deaths due to all-cause mortality. The number of patients receiving sacubitril/valsartan nationally in 2018 was 27,267. This represents approximately 12% of the calculated eligible population for this therapy in Canada.
The findings from this analysis suggest that a substantial number of deaths, hospitalizations, and HF readmissions could potentially be avoided by optimal usage of sacubitril/valsartan therapy in Canada. This emphasizes the importance of rapidly and appropriately implementing evidence-based medications into routine clinical practice, to achieve the best possible outcomes for our patients with HF and to reduce the high burden and cost of HF in Canada.
L’insuffisance cardiaque (IC) avec diminution de la fraction d’éjection touche actuellement environ 50 % des 600 000 Canadiens qui sont atteints d’IC, et plus de 90 000 nouveaux cas de cette affection sont diagnostiqués chaque année. L’association sacubitril-valsartan (inhibiteur de la néprilysine et antagoniste des récepteurs de l’angiotensine) a démontré une efficacité supérieure à celle du traitement de référence au chapitre de la réduction de la mortalité d’origine cardiovasculaire et des hospitalisations dues à l’IC.
L’ampleur potentielle des bienfaits du médicament au Canada en matière de prévention ou de report des décès et de réduction des hospitalisations par suite de son utilisation optimale chez les patients atteints d’IC présentant une fraction d’éjection < 40 % a été estimée sur la base de sources publiées.
Chez les 225 562 patients potentiellement admissibles au traitement, le médicament permettrait de prévenir 4 699 décès d’origine cardiovasculaire et premières hospitalisations pour cause d’IC, 3 698 réhospitalisations pour cause d’IC dans les 30 jours suivant la sortie de l’hôpital et 2 820 décès toutes causes confondues. À l’échelle nationale en 2018, 27 267 patients ont été traités par l’association sacubitril-valsartan. Cela représente environ 12 % de la population admissible au traitement selon les calculs s’appliquant au Canada.
Les résultats de cette analyse permettent de penser que beaucoup de décès, d’hospitalisations et de réhospitalisations pour cause d’IC pourraient être évités par suite de la mise en œuvre optimale du traitement par l’association sacubitril-valsartan au Canada. Sous cet éclairage, force est de constater l’importance que revêt l’intégration rapide et appropriée des pharmacothérapies factuelles à la pratique clinique courante, dans l’optique d’une démarche visant à obtenir les meilleurs résultats possible chez nos patients atteints d’IC et à réduire le lourd fardeau de cette affection au Canada.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• The effects of statins may be beneficial to patients with chronic heart failure.
• However, one question that has not yet been answered and that may clarify ...the role of statins in chronic heart failure (CHF) is whether statins prevent the development of CHF in patients with a low risk of cardiovascular disease (CVD)?
WHAT THIS PAPER ADDS
• The study results demonstrate that, in primary prevention, adherence to statins has a positive impact on CHF.
• This study provides evidence of the potential role of statins in CHF.
AIMS
Statins are effective in the prevention of an atherosclerotic event, e.g. coronary artery disease and cerebrovascular disease. Patients at high risk of cardiovascular disease (CVD), such as chronic heart failure (CHF), might benefit from the effects of statin therapy. However, one question that has not yet been answered and that may clarify the role of statins in CHF is whether statins prevent the development of CHF in patients with a low risk of CVD. Our aim was to evaluate the impact of adherence to statins on the incidence of CHF.
METHODS
A cohort of 111 481 patients was reconstructed using the Régie de l'Assurance Maladie du Québec databases. Patients were eligible if they were between 45 and 85 years old, without CVD, and newly treated with statins between 1999 and 2004. A nested case–control design was used to study CHF. Every case of CHF was matched for age and duration of follow‐up in up to 15 randomly selected controls. The adherence level was measured by calculating the medication possession ratio. Rate ratios (RR) of CHF were estimated by conditional logistic regression adjusting for several covariables.
RESULTS
The mean patient age was 63 years, 49% had hypertension, 21% had diabetes and 41% were male. A high level of adherence to statins was associated with a reduction of CHF (RR 0.81; 0.71, 0.91). The risks associated with CHF were the development of CVD during follow‐up, being a social‐aid recipient, and suffering from hypertension, diabetes mellitus, or having a higher chronic disease score.
CONCLUSION
Our study indicates that better adherence to statins is associated with a reduced risk of CHF.
We investigated cardiac proinflammatory, mitogenic, and apoptotic signaling events, and plasma biomarkers of inflammation and oxidative stress in de novo adult cardiac transplant (CTX) patients ...receiving tacrolimus (TAC) or cyclosporine A (CsA).
One hundred CTX recipients were randomized 1:1 to TAC/CsA in a prospective, randomized open-label multicenter study. Biomarkers of inflammation, immunity, oxidative stress, and cardiac signaling underlying growth and inflammation (extracellular signal-related kinase 1/2, p38 mitogen-activated protein kinase, mitogen-activated protein kinase kinases MEK 1/2 and 3/6, c-Src), and apoptosis and survival (c-Jun NH2-terminal kinases JNK, Bax/Bcl2, Akt) were assessed at 2, 4, 12, 26, and 52 weeks post-CTX. Plasma from healthy controls (n = 30) and tissue from explanted non-failing hearts (n = 6) were used as controls.
Biomarkers of inflammation/immunity (interleukin -6 and -18, soluble intercellular adhesion molecule, E-selectin, monocyte chemoattractant protein-1, osteopontin, fibrinogen, N-terminal prohormone brain natriuretic peptide, high-sensitive C-reactive protein) and oxidative stress (thiobarbituric acid reactive substances, nitrotyrosine) were increased, and antioxidant capacity was (glutathione/glutathione disulfide) decreased in patients vs healthy controls (p < 0.05). Phosphorylation of mitogen-activated protein kinases and Akt was increased, and Bax/Bcl was decreased in transplanted vs non-transplanted hearts. Except for plasma fibrinogen, which was lower in TAC vs. CsA, (p = 0.01), there were no significant differences in parameters studied between TAC vs CsA immunoprophylaxis.
De novo CTX recipients exhibit significant sub-clinical inflammation and oxidative stress that persists 12 months after transplantation. Associated with this is activation of myocardial growth and inflammatory signaling and decreased apoptosis. Our findings suggest that CTX is an inflammatory condition associated with oxidative stress and myocardial growth regardless of CsA or TAC immunoprophylaxis and independently of rejection status.
Objectives This study sought to assess the prognostic value of physical examination in a modern treated heart failure population. Background The physical examination is the cornerstone of the ...evaluation and monitoring of patients with heart failure. Yet, the prognostic value of congestive signs (i.e., peripheral edema, jugular venous distension, a third heart sound, and pulmonary rales) has not been assessed in the current era. Methods A post-hoc analysis was conducted on all 1,376 patients, 81% male, mean age 67 ± 11 years, with symptomatic left ventricular systolic dysfunction enrolled in the AF-CHF (Atrial Fibrillation and Congestive Heart Failure) trial. The prognostic value of baseline physical examination findings was assessed in univariate and multivariate Cox regression analyses. Results Peripheral edema was observed in 425 (30.9%), jugular venous distension in 297 (21.6%), a third heart sound in 207 (15.0%), and pulmonary rales in 178 (12.9%) patients. Death from cardiovascular causes occurred in 357 (25.9%) patients over a mean follow-up of 37 ± 19 months. All 4 physical examination findings were associated with cardiovascular mortality in univariate analyses (all p values <0.01). In multivariate analyses, taking all 4 signs as potential covariates, only rales (hazard ratio 1.41; 95% confidence interval: 1.07 to 1.86; p = 0.013) and peripheral edema (hazard ratio: 1.25; 95% confidence interval: 1.00 to 1.57; p = 0.048) were associated with cardiovascular mortality, independent of other variables. Conclusions In the modern era, congestive signs on the physical examination (i.e., peripheral edema, jugular venous distension, a third heart sound, and pulmonary rales) continue to provide important prognostic information in patients with congestive heart failure.
PDF
