Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF.

Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n = 161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral one-compartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24 hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (Emax ) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF.

Effect of hemodialysis on the signal-averaged electrocardiogram.

The presence of late potentials (LPs) on signal-averaged electrocardiography (SAECG) is predictive of ventricular tachycardia. The effect of hemodialysis (HD) on SAECG has not been well studied. SAECG was evaluated in 28 patients with chronic renal failure immediately before and after HD. In each SAECG, QRS duration, low-amplitude signal duration (LASd), and root-mean-square voltage of the terminal 40 milliseconds of the QRS (RMS40) were measured. To evaluate the effect of fluid removal on SAECG, the last 12 patients were studied during two different HD sessions, one with and one without fluid removal. Two-dimensional echocardiography was performed before and after HD on these 12 patients. At baseline, four patients met the criteria for LPs on SAECG. Only one patient met the criteria for LPs on SAECG after HD. After HD, the mean LASd decreased (28.3 +/- 12.9 to 24.9 +/- 10.1 milliseconds; P = 0.041) and RMS40 increased (63.0 +/- 56.9 to 79.0 +/- 59.2 microV; P = 0. 006). Among the 12 patients who underwent HD with and without fluid removal, left ventricular end-diastolic dimension decreased with (5. 4 +/- 0.6 to 5.1 +/- 0.6 cm; P = 0.024) but not without fluid removal (5.2 +/- 0.3 to 5.1 +/- 0.4 cm; P = not significant [NS]). RMS40 improved with (43.8 +/- 23.1 to 53.2 +/- 22.6 microV; P = 0. 03) but not without fluid removal (51.0 +/- 26.5 to 51.5 +/- 24.2 microV; P = NS). A significant negative correlation was found between change in body weight and change in RMS40 parameter (r = 0. 456; P = 0.0381). SAECG parameters are abnormal in a significant proportion of patients with chronic renal failure and improve with HD despite electrolyte and other proarrhythmic changes. Decreased left ventricular dimension because of fluid removal during HD is one possible explanation for this improvement.

Cycling of inducibility of paroxysmal supraventricular tachycardia in women and its implications for timing of electrophysiologic procedures.

Arrhythmias in women may be affected by phases of the menstrual cycle. This study was designed to determine the prevalence of perimenstrual clustering of spontaneous episodes of paroxysmal supraventricular tachycardia (SVT) in women. It also tested the hypothesis that women with this temporal pattern of events have an altered probability of induction of paroxysmal SVT during electrophysiologic testing at higher estrogen states (midcycle or with estrogen replacement therapy) than at low estrogen states (perimenstrual or without estrogen replacement). A structured history of the relation of spontaneous paroxysmal SVTs to phases of the menstrual cycle was obtained prospectively among 42 women referred during a 3-year period. Patients with cyclical patterns of spontaneous tachycardias, who had had negative electrophysiologic studies at midcycle or while receiving estrogen replacement therapy, had repeat procedures (1) when premenstrual or at the onset of menses, or (2) after stopping estrogen replacement therapy. Seventeen of 42 consecutive female patients (40%) had histories of perimenstrual clustering of arrhythmias. Six women (4 with normal menstrual cycles, 2 on estrogen replacement therapy), who qualified for paired electrophysiologic studies because of a negative initial electrophysiologic study that included provocation with isoproterenol, had inducibility into SVTs during the second study. All 6 had dual atrioventricular (AV) nodal pathway physiology, 4 had AV nodal reentrant tachycardia (AVNRT) induced, 1 had both AVNRT and reciprocating AV tachycardias, and 1 had nonsustained AVNRT and an atrial tachycardia induced. Successful ablation procedures were performed in 5 of the 6 patients. Thus, among women with a history of perimenstrual clustering of paroxysmal SVT and among those receiving estrogen replacement therapy, scheduling of elective electrophysiologic procedures at times of low estrogen levels (premenstrual or off estrogen replacement therapy) may facilitate the probability of a successful procedure.

Effect of clonidine on heart rate variability in congestive heart failure.

In patients with congestive heart failure, abnormal heart rate variability is a predictor of total mortality and sudden cardiac death. Drugs that improve heart rate variability may have a potential role for improving the survival among these patients. The effects of clonidine were studied in 24 patients with congestive heart failure, sinus rhythm, a left ventricular ejection fraction <0.40, and systolic blood pressure > 115 mm Hg. A 6-minute corridor walk test and 24-hour Holter monitoring were performed before and 42+/-24 days after initiation of clonidine therapy (Catapres-TTS patch, mean dose: 0.33+/-0.21 mg). Changes in other medications used at baseline were not allowed. One patient died suddenly. Two patients did not complete the protocol due to worsening congestive heart failure, which required changes in medications, 1 patient discontinued due to hypotension, and 2 for personal reasons. Among the 18 patients who completed the protocol, the mean RR interval of sinus beats increased from 760+/-106 to 822+/-125 ms (p=0.001) and the distance covered during the 6-minute walk test increased from 1,148+/-277 to 1,255+/-359 feet (p=0.042). Systolic blood pressure decreased from 139+/-15 to 119+/-10 mm Hg (p <0.0001). The following increases were noted in the heart rate variability measurements: high-frequency power in 0.15 to 0.40 Hz: 4.58+/-1.07 to 4.94+/-1.17 In (ms), p=0.002; SD: 47.0+/-16.9 to 52.5+/-18.4 ms, p=0.034; SD of the mean of all RR intervals in 24 hours: 116+/-94 to 130+/-19 ms, p=0.033; SD of all 5-minute mean RR intervals: 106+/-44 to 124+/-66 ms, p=0.042; root-mean square of difference of successive RR intervals: 28.8+/-10.7 to 34.1+/-14.2 ms, p=0.017. Clonidine improves heart rate variability in the patients with congestive heart failure by increasing the parasympathetic tone. It is well tolerated by most patients with heart failure and may have a beneficial effect on exercise capacity.

A prospective study of the effect of I.V. pentamidine therapy on ventricular arrhythmias and QTc prolongation in HIV-infected patients.

STUDY OBJECTIVES: I.V. pentamidine therapy in HIV-infected patients has been associated in case reports and one uncontrolled prospective series with frequent prolongation of the rate-corrected QT interval (QTc) and a high risk for potentially lethal ventricular arrhythmias, especially torsade de pointes. The aim of this study was to prospectively examine in a controlled manner the effect of I.V. pentamidine therapy on the QT interval and the incidence of ventricular arrhythmias. DESIGN: Open, nonrandomized, prospective evaluation of ventricular arrhythmia incidence in HIV-infected patients receiving pentamidine or trimethoprim-sulfamethoxazole (TMP-SMX) utilizing Holter monitoring prior to and during therapy with these agents. SETTING: Staten Island University Hospital, Staten Island, NY. PATIENTS: Twenty-seven HIV-infected patients, of whom 16 received I.V. pentamidine and 11 received I.V. TMP-SMX. MEASUREMENTS AND RESULTS: Study patients underwent Holter monitoring prior to therapy and during the first 3 days and last 2 days of therapy with pentamidine or TMP-SMX, 12-lead ECG prior to and every 24 to 48 h, serum electrolytes prior to and on days 3, 6, 9, and 12 of therapy, and baseline transthoracic two-dimensional and Doppler echocardiography. In the pentamidine group, the results for each monitoring period were as follows (means are presented +/- SEM): pretherapy, 1.66+/-1.03 (median=0) premature ventricular complexes (PVCs) per hour, zero nonsustained ventricular tachycardia (NSVT), zero sustained ventricular tachycardia (VT); early therapy, 1.55+/-0.91 (median=0.04) PVCs per hour, two NSVT (both < or = 5 complexes), zero sustained VT; late therapy, 1.69+/-1.17 (median=0.08) PVCs per hour, zero NSVT, zero sustained VT (p value not significant for early or late therapy as compared to pretherapy for PVCs per hour, NSVT, or sustained VT). In the TMP-SMX group, the Holter monitoring results were as follows: pretherapy, 1.36+/-1.27 (median=0) PVCs per hour, zero NSVT, zero sustained VT; early therapy, 0.71+/-0.53 (median=0.03) PVCs per hour, two NSVT, zero sustained VT; late therapy, 0.56+/-0.51 (median=0) PVCs per hour, zero NSVT, zero sustained VT (p value not significant for pretherapy, early therapy, or late therapy with TMP-SMX as compared to pentamidine for PVCs per hour, NSVT, or VT). The QTc also did not significantly differ during therapy with pentamidine as compared to TMP-SMX. The mean QTc in the pentamidine group decreased during therapy as compared to pretherapy with the difference approaching significance for days 2, 4, and 6 with pentamidine (p<0.06). CONCLUSIONS: QTc prolongation during therapy with pentamidine in HIV-infected patients is not as frequent an occurrence as has been reported previously. In the absence of QTc prolongation, pentamidine therapy was not associated with a significant increase in PVCs, NSVT, or sustained VT as compared to pretherapy recordings or as compared to therapy with TMP-SMX.

Effects of hemodialysis on left ventricular diastolic filling.

Diastolic Doppler filling parameters were measured before and after hemodialyses, performed once with and once without fluid removal. Changes occurred only with fluid removal and correlated with weight loss, indicating that they are the result of reduction in preload.

Irreducible talar dislocation with entrapment by the tibialis posterior and the flexor digitorum longus tendons. A case report.

Complete open-talar dislocation irreducible by virtue of entrapment by the tibialis posterior and flexor digitorum longus tendons occurred in a 41-year-old woman. Two-year follow-up examination revealed no evidence of avascular necrosis. A cursory review of the literature suggests that recovery of a complete range of motion is unusual.