Longitudinal Studies 1: Determinants of Risk.

Longitudinal or observational study designs are important methodologies to investigate potential associations that may not be amenable to randomized controlled trials. In many cases, they may be performed using existing data and are often cost-effective ways of addressing important questions. The major disadvantage of observational studies is the potential for bias. The absence of randomization means that one can never be certain that unknown confounders are present, and specific studies designs have their own inherent forms of bias. Careful study design may minimize bias. Establishing casual association based on observational methods requires due consideration of the quality of the individual study and knowledge of their limitations.

Costs Associated With Intravenous Darbepoetin Versus Epoetin Therapy in Hemodialysis Patients: A Randomized Controlled Trial.

BACKGROUND: Anemia of chronic kidney disease is associated with adverse outcomes and a reduced quality of life. Erythropoiesis-stimulating agents (ESAs) have improved anemia management, and 2 agents are available in Canada, epoetin alfa (EPO) and darbepoetin alfa (DA). EPO and DA are considered equally effective in achieving target hemoglobin (Hb), but it is not clear whether there is a cost difference. There have been few head-to-head comparisons; most published studies are observational switch studies. OBJECTIVE: To compare the cost of DA and EPO and to determine the dose conversion ratio over a 12-month period. DESIGN: Randomized controlled trial. SETTING: Canadian outpatient hemodialysis center. PATIENTS: Eligible patients were adult hemodialysis patients requiring ESA therapy. MEASUREMENTS: The primary outcome was ESA cost (Can$) per patient over 12 months. Secondary outcomes included the dose conversion ratio, deviation from target ranges in anemia indices, iron dose and cost, and time and number of dose changes. METHODS: An open-label randomized controlled trial of intravenous (IV) DA versus EPO was conducted in 50 hemodialysis patients. Participants underwent a minimum 6-week run-in phase followed by a 12-month active study phase. ESA and iron were dosed using a study algorithm. RESULTS: The median cost was $4179 (interquartile range [IQR]: $2416-$5955) for EPO and $2303 (IQR: $1178-$4219) for DA with a difference of $1876 (P = .02). The dose conversion ratio was 280:1 (95% confidence interval [CI]: 197-362:1) at the end of the run-in phase, 360:1 (95% CI: 262-457:1) at the 3-month point of the active phase, and 382:1 (95% CI: 235-529:1) at the 6-month point of the active phase. There were no significant differences between the 2 groups in weekly iron dose, Hb, serum ferritin, or transferrin saturation. The number of dose changes and the time to Hb stability were similar. LIMITATIONS: Results may not be generalizable to hemodialysis units without algorithm-based anemia management, with subcutaneous ESA administration, or to the nondialysis chronic kidney disease population. The effective conversion ratio between EPO and DA is known to increase at higher doses; the Hb targets used in the study were slightly higher than those recommended today so it is possible that the doses used were also higher. Because of this, the cost savings estimated for DA could differ somewhat from the savings realizable in current practice. CONCLUSIONS: In this study of hemodialysis patients with comparable anemia management, IV DA cost $1876 less per year per patient than IV EPO. The dose conversion ratio was greater than 350:1 by the 3-month point. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02817555).

CONTEXTE: L'anémie qui résulte de l'insuffisance rénale chronique est associée à des conséquences défavorables sur la santé du patient et par conséquent, à une diminution de sa qualité de vie. Le recours à des agents stimulants l'érythropoïèse (ASE) a permis d'améliorer considérablement le traitement de ce type d'anémie. Deux de ces agents sont disponibles au Canada: l'époétine alfa (EPO) et la darbépoétine alfa (DA). L'efficacité de ces deux molécules à cibler l'hémoglobine (Hb) est considérée comme équivalente, mais la différence de coût de leur utilisation reste à déterminer. Il existe très peu d'études de comparaison directe entre l'EPO et la DA, et la plupart des études publiées consistent en des études observationnelles de transition. OBJECTIFS DE L'ÉTUDE: Comparer les coûts d'utilisation de la DA et de l'EPO et déterminer le ratio de conversion de dose sur une période de 12 mois. TYPE D'ÉTUDE: Il s'agit d'un essai contrôlé randomisé. CADRE DE L'ÉTUDE: Un centre d'hémodialyse ambulatoire canadien. PATIENTS: Les patients admissibles étaient des patients adultes sous hémodialyse et nécessitant un traitement par les ASE. MESURES: Le principal critère évalué était le coût (en dollars canadiens) d'un traitement par les ASE pour chaque patient sur une période de 12 mois. Parmi les résultats secondaires figuraient le ratio de conversion de dose, l'écart de déviation par rapport à la cible pour les indicateurs de l'anémie, la dose de fer et son coût, de même que le temps de stabilisation de la dose et le nombre de changements de dose. MÉTHODOLOGIE: Un essai ouvert, contrôlé et randomisé a été mené auprès de 50 patients en hémodialyse afin de comparer les traitements intraveineux (IV) par la DA et l'EPO. Les participants ont été suivis pour une phase préalable d'une durée minimale de six semaines avant la phase de l'étude active qui s'est étalée sur 12 mois. Les doses de l'ASE et du fer ont été établies à partir d'un algorithme. RÉSULTATS: Le coût médian était de 4 179 $ (Écart interquartile: 2 416 à 5 955 $) pour l'EPO et de 2 303 $ (EI: 1 178 à 4 219 $) pour la DA, soit une différence de 1 876 $ (P = 0,02). Le ratio de conversion de dose était de 280:1 (IC95: 197:1-362:1) à la fin de la phase préalable, de 360:1 (IC à 95%: 262:1-457:1) après trois mois écoulés dans la phase active et de 382:1 (IC95: 235:1-529:1) après 6 mois de phase active. Aucune différence significative n'a été observée entre les deux groupes en ce qui concerne les doses hebdomadaires de fer, les taux d'hémoglobine et de ferritine sérique ou le coefficient de la saturation de la transferrine (TSAT). Enfin, le nombre de modifications de la dose et le temps de stabilisation de l'hémoglobine se sont avérés similaires. LIMITES DE L'ÉTUDE: Il est possible que l'on ne puisse étendre ces résultats aux unités d'hémodialyse où la gestion de l'anémie ne repose pas sur un algorithme. Il est également hasardeux de généraliser ces résultats aux cas où les traitements par un ASE sont administrés par voie sous-cutanée, de même qu'au sein d'une population de patients non-dialysés. Il est connu que le ratio de conversion optimal entre l'EPO et la DA augmente pour les doses élevées. De plus, les cibles d'hémoglobine utilisées dans l'étude étaient légèrement supérieures à celles qui sont recommandées aujourd'hui, il est donc possible que les doses utilisées aient été elles aussi plus élevées. Par conséquent, les économies estimées pour l'administration de DA pourraient différer légèrement des économies réalisables dans la pratique courante. CONCLUSIONS: Cette étude, réalisée auprès de patients hémodialysés dont les traitements de l'anémie par voie intraveineuse étaient comparables, conclut que l'utilisation de la DA permet une économie annuelle de 1 876 $ par rapport à l'utilisation de l'EPO. De plus, le ratio de conversion de dose s'est avéré supérieur à 350:1 après trois mois écoulés dans la phase active de l'étude.

Longitudinal studies 1: Determination of risk.

Longitudinal or observational study designs are important methodologies to investigate potential associations that may not be amenable to randomized controlled trials. In many cases they may be performed using existing data and are often cost-effective ways of addressing important questions. The major disadvantage of observational studies is the potential for bias. The absence of randomization means that one can never be certain that unknown confounders are present, and specific studies designs have their own inherent forms of bias. Careful study design may minimize bias. Establishing casual association based on observational methods requires due consideration of the quality of the individual study and knowledge of their limitations.

Longitudinal studies and determination of risk.

Longitudinal and observational study designs are important methodologies to investigate potential associations that may not be amenable to RCTs. In many cases, they may be performed using existing data and are often cost-effective ways of addressing important questions. The major disadvantage of observational studies is the potential for bias. The absence of randomization means that one can never be certain that unknown confounders are present, and specific studies designs have their own inherent forms of bias. Careful study design may minimize bias. Establishing a casual association based on observational methods requires due consideration of the quality of the individual study and knowledge of its limitations.

Diastolic Dysfunction.

Heart failure is a leading cause of hospital admissions in North America. Approximately half of patients with symptoms of heart failure have normal or minimally impaired systolic function and are therefore diagnosed, by exclusion, with diastolic dysfunction. The therapy of diastolic dysfunction to date is largely unsatisfactory. There have been few outcome-based clinical trials to guide clinicians, and most treatments have been empirically derived from the data from systolic heart failure studies. In general, acute management consists of central volume reduction with loop diuretics and long-acting nitrates. In some cases improvement in left ventricular filling can be achieved by reducing heart rate, usually with either beta blockers or calcium channel blockers. The role of digoxin is unclear and it should be used with caution. Theoretically, it has the capacity to further impair ventricular function, but one of the few trials in diastolic heart failure suggested that it improves symptoms and reduces hospitalization. Renin-angiotensin system blockade is a very attractive therapeutic avenue; angiotensin-converting enzyme inhibitors and angiotensin receptor blockers effectively reduce afterload, induce regression of left ventricular hypertrophy in excess of their blood pressure-lowering effect, and confer survival benefits to patients at high risk for cardiovascular death. Although the results of a recent trial using an angiotensin receptor blocker in patients with primarily diastolic heart failure were unimpressive, renin-angiotensin system blockade should still be considered because of its aforementioned benefits. The long-term management of these patients includes a careful assessment for and treatment of myocardial ischemia, treatment of hypertension, and reduction in left ventricular hypertrophy. For the treatment of ischemia, long-acting nitrates and calcium channel blockers may be particularly useful. The results of new trials in this area are expected soon, and hopefully therapy that directly targets the pathophysiologic pathways of this important disease is on the horizon.

Management of heart failure and coronary artery disease in patients with chronic kidney disease.

Cardiovascular disease (CVD) is a major contributor to the mortality and morbidity of patients who suffer from chronic kidney disease (CKD). Heart failure and ischemic heart disease (IHD) are both highly prevalent in this population. The diagnosis of myocardial dysfunction is usually based on echocardiography. As in the general population, systolic dysfunction is treated with a combination of diuretics, renin-angiotensin system blockade, and beta-receptor antagonists. Diastolic dysfunction is best managed by eliminating the cause. Non-invasive tests for coronary artery disease (CAD) may be less reliable in patients with renal disease compared with nonuremic patients. Medical therapy of IHD in this population is generally similar to that for other patient groups, but surgical revascularization appears to carry a higher risk of complications with poorer clinical outcomes. The choice of revascularization procedure (coronary artery bypass grafting versus percutaneous transluminal angioplasty) should be based on the specific coronary anatomy of a given patient as well as a consideration of other comorbid factors.