Effect of oral anticoagulant therapy on mortality in end-stage renal disease patients with atrial fibrillation: a prospective study.

BACKGROUND: The aim of this study was to evaluate, in a cohort of haemodialysis patients with atrial fibrillation (AF), the relationship between oral anticoagulant therapy (OAT) and mortality, thromboembolic events and haemorrhage. METHODS: Two hundred and ninety patients with AF were prospectively followed for 4 years. Warfarin and antiplatelet intake, age, dialytic age, comorbidities, CHA2DS2-VASc and HAS-BLED scores were considered as predictors of risk of death, thromboembolism and bleeding events. In patients taking OAT, the international normalized ratio (INR) was assessed and the percentage time in the target therapeutic range (TTR) was calculated. RESULTS: At recruitment, 134/290 patients were taking warfarin. During follow-up there were 170 deaths, 28 thromboembolic events and 95 bleedings. After balancing for treatment propensity, intention-to-treat analysis on OAT intake at recruitment did not show differences in total mortality, thromboembolic events and bleedings, while the as-treated analysis, accounting for treatment switch, showed that patients taking OAT at recruitment had a significantly lower mortality than those not taking it [hazard ratio, HR 0.53 (95% confidence interval 0.28-0.90), p = 0.04], with a decrease of thromboembolic events [HR 0.36 (0.13-1.05), p = 0.06], and an increase of bleedings [HR 1.79 (0.72-4.39), p = 0.20], both non-significant. Among patients taking OAT at recruitment, those continuing to take warfarin had a significant reduction in the risk of total [HR 0.28 (0.14-0.53), p < 0.001] and cardiovascular [HR 0.21 (0.11-0.40), p < 0.001] mortality compared to patients stopping OAT. CONCLUSIONS: In haemodialysis patients with AF, continuously taking warfarin is associated with a reduction of the risk of total and cardiovascular mortality.

Warfarin use, mortality, bleeding and stroke in haemodialysis patients with atrial fibrillation.

BACKGROUND: Oral anticoagulation therapy (OAT) is the choice treatment for thromboembolism prevention in atrial fibrillation (AF), although data about OAT use in haemodialysis (HD) patients with AF are contradictory. METHODS: The effect of OAT on the risk of mortality, stroke and bleeding was prospectively evaluated in a population of HD patients with AF. All the patients of 10 HD Italian centres alive on 31 October 2010 with documented AF episode(s) were recruited and followed-up for 2 years. OAT and antiplatelet intake, age, dialytic age, comorbidities and percentage time in the target international normalized ratio (INR) range (target therapeutic range; TTR) were considered as predictors of hazard of death, thromboembolic and bleeding events. RESULTS: At recruitment, 134 patients out of 290 were taking OAT. During the follow-up, 115 patients died (4 strokes, 3 haemorrhagic and 1 thromboembolic). Antiplatelet therapy, but not OAT, was associated with increased mortality (HR 1.71, CI 1.10-2.64, P = 0.02). The estimated survival of patients always taking OAT tended to be higher than that of patients who stopped taking (68.6 versus 49.6%, P = 0.07). OAT was not correlated to a significant decreased risk of thromboembolic events (HR 0.12, CI 0.00-3.59, P = 0.20), while it was associated with an increased risk of bleeding (HR 3.96, CI 1.15-13.68, P = 0.03). Higher TTR was associated with a reduced bleeding risk (HR 0.09, CI 0.01-0.76, P = 0.03), while previous haemorrhagic events were associated with higher haemorrhagic risk (HR 2.17, CI 1.09-4.35, P = 0.03). CONCLUSIONS: In our population of HD patients with AF, the mortality is very high. OAT is not associated with increased mortality, while antiplatelet drugs are. OAT seems, on the contrary, associated with a better survival; however, it does not decrease the incidence of ischaemic stroke, whereas it increases the incidence of bleeding. Bleeding risk is lower in subjects in whom the INR is kept within the therapeutic range.

Calcium profiling in hemodiafiltration: a new way to reduce the calcium overload risk without compromising cardiovascular stability.

BACKGROUND: Low and high dialysate calcium (Ca²âº) content may have positive and harmful effects depending on the considered pathological aspect: hemodynamic instability, cardiac arrhythmias, parathormone release, adynamic bone disease, cardio-vascular calcifications. We hypothesized that a time-profiled Ca²âº concentration would keep the cardiovascular advantages of high Ca²âº but would reduce the risk of calcium overload. METHODS: A prospective, multicenter study using a particular hemodiafiltration technique that allows the profiling of electrolytes was designed. Patients (n = 22) underwent randomly a 3-week dialysis session with low and high constant dialysate Ca²âº (Ld(Ca,), 1.25 mM and Hd(Ca,), 2 mM) and profiled Ca²âº (Pd(Ca)), respectively. Plasma and spent dialysate Ca²âº, systolic and diastolic arterial pressure (SAP, DAP) and QT interval corrected for heart rate (QTc) were analyzed. RESULTS: Plasma Ca²âº concentration decreased in Ld(Ca), whereas it increased in Hd(Ca) and to a lesser extent, in Pd(Ca). Total amount of Ca²âº given to the patient in Pd(Ca) (15.5 ± 1.0 mmol) was higher than in Ld(Ca) (4.3 ± 1.6 mmol) but lower than in Hd(Ca) (21.9 ± 3.3 mmol). SAP and DAP decreased in Ld(Ca), whereas it was almost constant in both Hd(Ca) and Pd(Ca·). QTc significantly increased, up to critical values (>460 msec), only during Ld(Ca·). CONCLUSIONS: Pd(Ca) seems to retain the advantages of high Ca²âº in terms of hemodynamic stability and modification of QTc while reducing the excessive positive calcium balance typical of dialysis with high Ca²âº content.

The nephrologist's anticoagulation treatment patterns/regimens in chronic hemodialysis patients with atrial fibrillation.

BACKGROUND: The prevalence of atrial fibrillation (AF) is high in hemodialysis (HD) patients. It was suggested that oral anticoagulant therapy (OAT), the choice treatment for reducing the thromboembolic risk in AF patients, increases the incidence of both ischemic and hemorrhagic strokes in the HD population. Moreover, the therapy-related bleeding risk is particularly high in these patients. For these reasons there is no agreement on the use of OAT in HD patients with AF. The aim of this study was to evaluate the criteria adopted by nephrologists in prescribing OAT in HD patients with AF. METHODS: All the patients presenting AF (paroxysmal, persistent or permanent) at 31/10/2010 (n = 290) were recruited from 1529 HD patients from ten Italian HD centres. To detect factors related to OAT administration the main clinical features, CHADS2 and HASBLED scores were evaluated in logistic regression models. RESULTS: The presence of permanent AF (OR = 4.28, p < 0.0001) was the only clinical factor directly associated to OAT administration, while previous bleedings (OR = 0.35, p = 0.004) were inversely related. The CHADS2 score was not associated with OAT prescription (OR = 0.85, p = 0.08), while an inverse relation was found with the hemorrhagic risk score (OR = 0.74, p = 0.03). CONCLUSION: A high AF prevalence was observed in our HD population, but less than 50 % of these patients received OAT. Patients with permanent AF were more frequently treated with warfarin, while OAT administration was uncommon in those with previous bleedings. The thromboembolic risk score was not associated with warfarin prescription, while there was an inverse relation with the hemorrhagic risk score.

Model-based analysis of potassium removal during hemodialysis.

Potassium ion (K(+)) kinetics in intra- and extracellular compartments during dialysis was studied by means of a double-pool computer model, which included potassium-dependent active transport (Na-K-ATPase pump) in 38 patients undergoing chronic hemodialysis. Each patient was treated for 2 weeks with a constant K(+) dialysate concentration (K(+)(CONST) therapy) and afterward for 2 weeks with a time-varying (profiled) K(+) dialysate concentration (K(+)(PROF) therapy). The two therapies induced different levels of K(+) plasma concentration (K(+)(CONST): 3.71 +/- 0.88 mmol/L vs. K(+)(PROF): 3.97 +/- 0.64 mmol/L, time-averaged values, P < 0.01). The computer model was tuned to accurately fit plasmatic K(+) measured in the course and 1 h after K(+)(CONST) and K(+)(PROF) therapies and was then used to simulate the kinetics of intra- and extracellular K(+). Model-based analysis showed that almost all the K(+) removal in the first 90 min of dialysis was derived from the extracellular compartment. The different K(+) time course in the dialysate and the consequently different Na-K pump activity resulted in a different sharing of removed potassium mass at the end of dialysis: 56% +/- 17% from the extracellular compartment in K(+)(PROF) versus 41% +/- 14% in K(+)(CONST). At the end of both therapies, the K(+) distribution was largely unbalanced, and, in the next 3 h, K(+) continued to flow in the extracellular space (about 24 mmol). After rebalancing, about 80% of the K(+) mass that was removed derived from the intracellular compartment. In conclusion, the Na-K pump plays a major role in K(+) apportionment between extracellular and intracellular compartments, and potassium dialysate concentration strongly influences pump activity.

Calcium and potassium changes during haemodialysis alter ventricular repolarization duration: in vivo and in silico analysis.

BACKGROUND: Alterations of ventricular repolarization duration, as measured by the QT interval, are frequently observed in haemodialysis (HD) patients. The nature and the sign of these changes are not yet fully understood. METHODS: Different dialysate K(+) and Ca(2+) levels, leading to different end-HD plasma concentrations in the patient, have been tested in the present study in terms of their impact on QTc. A model of the human cardiomyocyte action potential (AP) has been used to assess in silico whether the changes in Ca(2+) and K(+) were able to justify at the cellular level the observed alterations of QTc. RESULTS: QTc was prolonged in HDs with low (1.25 mM) versus high (2 mM) Ca(2+) (424 +/- 33 versus 400 +/- 28 ms, P < 0.05) and in HDs with low (2 mM) versus high (3 mM) K(+) (420 +/- 35 versus 399 +/- 36 ms, P < 0.05). These alterations were confirmed at the cellular level by computational analysis showing prolongation of ventricular AP at low K(+) and low Ca(2+) at the same extent of the measured QTc variations. Numerical simulation predicted a critically long AP (and QT) when considering low K(+) and Ca(2+) simultaneously, suggesting the concurrent lowering of Ca(2+) and K(+) as a potential arrhythmogenic factor. CONCLUSIONS: Numerical simulations of the ventricular AP may be useful to quantitatively predict the complex dependence of AP duration on simultaneous changes in Ca(2+) and K(+). Moreover, Ca(2+) content in the dialysate should be designed not to critically lower serum Ca(2+), especially in sessions at risk of end-dialysis hypokalaemia.

Cardiac response to hemodialysis with different cardiovascular tolerance: heart rate variability and QT interval analysis.

A therapy-specific worsening of cardiovascular stability during bicarbonate dialysis (BD) with respect to acetate-free biofiltration (AFB) have been previously reported. We further investigated the impact of the 2 therapies on electrocardiographic parameters in order to gain novel insight into the cardiac responses. Holter ECG acquired during hypotension-free sessions (12 BD + 12 AFB) were retrospectively analyzed. R-R intervals were extracted from ECG recordings. An autoregressive spectral technique was used to compute low- and high-frequency (LF and HF) components of heart rate variability (HRV). QT interval duration was measured with a computer-assisted technique and corrected for HR. In BD the LF component of HRV after an initial increase was slowly depressed with respect to AFB (p < 0.05). QT duration showed a significant (p < 0.01) hemodialysis-induced reduction. QT shortening was more pronounced (p < 0.05) in BD than in AFB (-31 vs. -10 ms), even after correction for HR (p < 0.05). Cardiac electrical activity is significantly affected by the hemodialysis technique. The decrease in the LF component of HRV and the QT shortening are coherent with the worse cardiovascular tolerance observed in BD and with the hypothesis of an enhanced production of endogenous nitric oxide.

Model-based study of the effects of the hemodialysis technique on the compensatory response to hypovolemia.

BACKGROUND: Hemodialysis technique (dialysate composition, filter, convection/diffusion ratio, etc.) can have an impact on the patient's tendency to acute hypotension. We have examined the hypothesis that the dialysis technique affects the hypotension risk by altering the cardiovascular compensatory response to hemodialysis-induced hypovolemia. METHODS: Twelve hypotension-prone subjects were studied during six sessions of conventional bicarbonate dialysis (BD) and six sessions of acetate-free biofiltration (AFB). Blood volume (BV) control system was used in AFB to provide a BV change equivalent to the BV change observed in BD. The efficacy of reflex compensatory mechanisms was assessed by a model-based computer analysis of the BD and AFB sessions. RESULTS: BD sessions were complicated by hypotension more frequently than the AFB ones (34/66 BD vs. 18/66 AFB). Hypotension arose about 60 minutes earlier in BD (123 +/- 41 minutes in BD vs. 183 +/- 25 minutes in AFB, P < 0.01), and after a smaller BV reduction (hypotension BV 7.9%+/- 2.0% in BD vs. 10.9%+/- 2.6% in AFB, P < 0.05). Model-based computer analysis of the sessions without hypotension revealed differences in peripheral resistance adaptation (9%+/- 9% BD vs. 19%+/- 7% AFB, P < 0.05) as well as in the stroke volume reduction (19%+/- 8% BD vs. 10%+/- 8% AFB, P < 0.001). Model analysis of sessions with hypotension indicated that compensatory mechanisms were almost inoperative in BD, whereas a residual capacity to control peripheral resistance and cardiac contractility was present in AFB. Model simulations demonstrated that hypotension occurred later in AFB since the residual compensatory capacity in AFB was able to sustain the arterial pressure for larger BV reductions (8.3% BD vs. 11.2% AFB). CONCLUSION: The increased risk of acute hypotension in BD compared to AFB is caused by a therapy-induced inhibition of reflex compensatory response to hypovolemia.