Toxicokinetics of ibogaine and noribogaine in a patient with prolonged multiple cardiac arrhythmias after ingestion of internet purchased ibogaine

Background: Ibogaine is an agent that has been evaluated as an unapproved anti-addictive agent for the management of drug dependence. Sudden cardiac death has been described to occur secondary to its use. We describe the clinical effects and toxicokinetics of ibogaine and noribogaine in a single patient. For this purpose, we developed a LC-MS/MS-method to measure ibogaine and noribogaine plasma-concentrations. We used two compartments with first order absorption. Case details: The maximum concentration of ibogaine was 1.45 mg/L. Our patient developed markedly prolonged QTc interval of 647ms maximum, several multiple cardiac arrhythmias (i.e., atrial tachycardia and ventricular tachycardia and Torsades des Pointes). QTc-prolongation remained present until 12 days after ingestion, several days after ibogaine plasma-levels were low, implicating clinically relevant noribogaine concentrations long after ibogaine had been cleared from the plasma. The ratio k12/k21 for noribogaine was 21.5 and 4.28 for ibogaine, implicating a lower distribution of noribogaine from the peripheral compartment into the central compartment compared to ibogaine. Conclusions: We demonstrated a linear relationship between the concentration of the metabolite and long duration of action, rather than with parent ibogaine. Therefore, after (prolonged) ibogaine ingestion, clinicians should beware of long-term effects due to its metabolite

Accuracy of oscillometric blood pressure measurement in atrial fibrillation

The primary aim of this study was to assess the accuracy of automated oscillometry (AO) in outpatients with atrial fibrillation (AF). The secondary aim was to explore whether AO accuracy is influenced by beat-to-beat blood pressure (BP) variability or heart frequency (HF). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by AO and beat-to-beat BP using a validated Volume Clamp Method (VCM) technique. AO accuracy was analyzed separately in tertiles of beat-to-beat BP variability and HF. The main study included 58 AF and 38 sinus rhythm (SR) patients in whom the Welch Allyn Spot Vital Signs (WASVS) was used. An auxiliary study in 23 AF patients used the Philips M3002A IntelliVue ×2. For AF and SR patients, respectively, SBP by WASVS deviated by +0.1 (±14.8) mmHg and -7.9 (±15.7) mmHg from VCM. WASVS-DBP was higher than VCM in AF and SR by 6.3 (±9.2) mmHg and 5.0 (±7.7) mmHg, respectively. High beat-to-beat BP variability and high HF decreased WASVS accuracy for both SBP and DBP. SBP and DBP measurements by Philips M3002A IntelliVue ×2 deviated by -6.8 (±13.2) mmHg and 9.4 (±8.1) mmHg, respectively. Overall, AO accuracy in AF is limited; in individual patients, AO inaccuracy may be considerable. AO accuracy is especially reduced in patients showing large beat-to-beat BP variability or high H

Accuracy of oscillometric blood pressure measurement in atrial fibrillation

OBJECTIVE: The primary aim of this study was to assess the accuracy of automated oscillometry (AO) in outpatients with atrial fibrillation (AF). The secondary aim was to explore whether AO accuracy is influenced by beat-to-beat blood pressure (BP) variability or heart frequency (HF). METHODS: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by AO and beat-to-beat BP using a validated Volume Clamp Method (VCM) technique. AO accuracy was analyzed separately in tertiles of beat-to-beat BP variability and HF. RESULTS: The main study included 58 AF and 38 sinus rhythm (SR) patients in whom the Welch Allyn Spot Vital Signs (WASVS) was used. An auxiliary study in 23 AF patients used the Philips M3002A IntelliVue ×2. For AF and SR patients, respectively, SBP by WASVS deviated by +0.1 (±14.8) mmHg and -7.9 (±15.7) mmHg from VCM. WASVS-DBP was higher than VCM in AF and SR by 6.3 (±9.2) mmHg and 5.0 (±7.7) mmHg, respectively. High beat-to-beat BP variability and high HF decreased WASVS accuracy for both SBP and DBP. SBP and DBP measurements by Philips M3002A IntelliVue ×2 deviated by -6.8 (±13.2) mmHg and 9.4 (±8.1) mmHg, respectively. CONCLUSION: Overall, AO accuracy in AF is limited; in individual patients, AO inaccuracy may be considerable. AO accuracy is especially reduced in patients showing large beat-to-beat BP variability or high HF

Trimetazidine in heart failure with preserved ejection fraction: a randomized controlled cross‐over trial

Abstract Aims Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF. Methods and results The DoPING‐HFpEF trial was a phase II single‐centre, double‐blind, placebo‐controlled, randomized cross‐over trial. Patients were randomized to trimetazidine treatment or placebo for 3 months and switched after a 2‐week wash‐out period. The primary endpoint was change in pulmonary capillary wedge pressure, measured with right heart catheterization at multiple stages of bicycling exercise. Secondary endpoint was change in myocardial phosphocreatine/adenosine triphosphate, an index of the myocardial energy status, measured with phosphorus‐31 magnetic resonance spectroscopy. The study included 25 patients (10/15 males/females; mean (standard deviation) age, 66 (10) years; body mass index, 29.8 (4.5) kg/m2); with the diagnosis of HFpEF confirmed with (exercise) right heart catheterization either before or during the trial. There was no effect of trimetazidine on the primary outcome pulmonary capillary wedge pressure at multiple levels of exercise (mean change 0 [95% confidence interval, 95% CI −2, 2] mmHg over multiple levels of exercise, P = 0.60). Myocardial phosphocreatine/adenosine triphosphate in the trimetazidine arm was similar to placebo (1.08 [0.76, 1.76] vs. 1.30 [0.95, 1.86], P = 0.08). There was no change by trimetazidine compared with placebo in the exploratory parameters: 6‐min walking distance (mean change of −6 [95% CI −18, 7] m vs. −5 [95% CI −22, 22] m, respectively, P = 0.93), N‐terminal pro‐B‐type natriuretic peptide (5 (−156, 166) ng/L vs. −13 (−172, 147) ng/L, P = 0.70), overall quality‐of‐life (KCCQ and EQ‐5D‐5L, P = 0.78 and P = 0.51, respectively), parameters for diastolic function measured with echocardiography and cardiac magnetic resonance, or metabolic parameters. Conclusions Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF

AV junction ablation and cardiac resynchronization for patients with permanent atrial fibrillation and narrow QRS: the APAF-CRT mortality trial

International audienceAbstract Aims In patients with atrial fibrillation (AF) and heart failure (HF), strict and regular rate control with atrioventricular junction ablation and biventricular pacemaker (Ablation + CRT) has been shown to be superior to pharmacological rate control in reducing HF hospitalizations. However, whether it also improves survival is unknown. Methods and results In this international, open-label, blinded outcome trial, we randomly assigned patients with severely symptomatic permanent AF >6 months, narrow QRS (≤110 ms) and at least one HF hospitalization in the previous year to Ablation + CRT or to pharmacological rate control. We hypothesized that Ablation + CRT is superior in reducing the primary endpoint of all-cause mortality. A total of 133 patients were randomized. The mean age was 73 ± 10 years, and 62 (47%) were females. The trial was stopped for efficacy at interim analysis after a median of 29 months of follow-up per patient. The primary endpoint occurred in 7 patients (11%) in the Ablation + CRT arm and in 20 patients (29%) in the Drug arm [hazard ratio (HR) 0.26, 95% confidence interval (CI) 0.10–0.65; P = 0.004]. The estimated death rates at 2 years were 5% and 21%, respectively; at 4 years, 14% and 41%. The benefit of Ablation + CRT of all-cause mortality was similar in patients with ejection fraction (EF) ≤35% and in those with >35%. The secondary endpoint combining all-cause mortality or HF hospitalization was significantly lower in the Ablation + CRT arm [18 (29%) vs. 36 (51%); HR 0.40, 95% CI 0.22–0.73; P = 0.002]. Conclusions Ablation + CRT was superior to pharmacological therapy in reducing mortality in patients with permanent AF and narrow QRS who were hospitalized for HF, irrespective of their baseline EF. Study registration ClinicalTrials.gov Identifier: NCT02137187

AV junction ablation and cardiac resynchronization for patients with permanent atrial fibrillation and narrow QRS: The APAF-CRT mortality trial

Aims : In patients with atrial fibrillation (AF) and heart failure (HF), strict and regular rate control with atrioventricular junction ablation and biventricular pacemaker (Ablation + CRT) has been shown to be superior to pharmacological rate control in reducing HF hospitalizations. However, whether it also improves survival is unknown. Methods and results : In this international, open-label, blinded outcome trial, we randomly assigned patients with severely symptomatic permanent AF >6 months, narrow QRS (≤110 ms) and at least one HF hospitalization in the previous year to Ablation + CRT or to pharmacological rate control. We hypothesized that Ablation + CRT is superior in reducing the primary endpoint of all-cause mortality. A total of 133 patients were randomized. The mean age was 73 ± 10 years, and 62 (47%) were females. The trial was stopped for efficacy at interim analysis after a median of 29 months of follow-up per patient. The primary endpoint occurred in 7 patients (11%) in the Ablation + CRT arm and in 20 patients (29%) in the Drug arm [hazard ratio (HR) 0.26, 95% confidence interval (CI) 0.10-0.65; P = 0.004]. The estimated death rates at 2 years were 5% and 21%, respectively; at 4 years, 14% and 41%. The benefit of Ablation + CRT of all-cause mortality was similar in patients with ejection fraction (EF) ≤35% and in those with >35%. The secondary endpoint combining all-cause mortality or HF hospitalization was significantly lower in the Ablation + CRT arm [18 (29%) vs. 36 (51%); HR 0.40, 95% CI 0.22-0.73; P = 0.002]. Conclusions : Ablation + CRT was superior to pharmacological therapy in reducing mortality in patients with permanent AF and narrow QRS who were hospitalized for HF, irrespective of their baseline EF. Study registration: ClinicalTrials.gov Identifier: NCT02137187