J-Point Elevation in Survivors of Primary Ventricular Fibrillation and Matched Control Subjects: Incidence and Clinical Significance

https://www.heartrhythmjournal.com/article/S1547-5271(09)01377-0/pdf

J Wave Syndromes

https://www.heartrhythmjournal.com/article/S1547-5271(11)01049-6/pdf

Distinguishing “benign” from “malignant early repolarization”: The value of the ST-segment morphology

Background—The significance of early repolarization, particularly regarding the morphology of the R-wave downslope, has come under question. Methods and Results—We evaluated 29 281 resting ambulatory ECGs from the VA Palo Alto Health Care System. With PR interval as the isoelectric line and amplitude criteria ≥0.1 mV, ST-segment elevation is defined at the end of the QRS, J wave as an upward deflection, and slur as a conduction delay on the QRS downstroke. Associations of ST-segment elevation patterns, J waves, and slurs with cardiovascular mortality were analyzed with Cox analysis. With a median follow-up of 7.6 years, there were 1995 cardiac deaths. Of 29 281 subjects, 87% were male (55±14 years) and 13% were female (56±17 years); 13% were black, 6% were Hispanic, and 81% were white or other. Six hundred sixty-four (2.3%) had inferior or lateral ST-segment elevation: 185 (0.6%) in inferior leads and 479 (1.6%) in lateral leads, 163 (0.6%) in both, and 0.4% had global elevation. A total of 4041 ECGs were...

http://cardiology.org/projects_repolarization_13_2496272416.pdf

Early repolarization in an ambulatory clinical population.

Early repolarization pattern and risk for arrhythmia death: a meta-analysis.

The electrocardiographic (ECG) manifestation of ventricular repolarization includes J (Osborn), T, and U waves. On the basis of biophysical principles of ECG recording, any wave on the body surface ECG represents a coincident voltage gradient generated by cellular electrical activity within the heart. The J wave is a deflection with a dome that appears on the ECG after the QRS complex. A transmural voltage gradient during initial ventricular repolarization, which results from the presence of a prominent action potential notch mediated by the transient outward potassium current (I(to)) in epicardium but not endocardium, is responsible for the registration of the J wave on the ECG. Clinical entities that are associated with J waves (the J-wave syndrome) include the early repolarization syndrome, the Brugada syndrome and idiopathic ventricular fibrillation related to a prominent J wave in the inferior leads. The T wave marks the final phase of ventricular repolarization and is a symbol of transmural dispersion of repolarization (TDR) in the ventricles. An excessively prolonged QT interval with enhanced TDR predisposes people to develop torsade de pointes. The malignant "R-on-T" phenomenon, i.e., an extrasystole that originates on the preceding T wave, is due to transmural propagation of phase 2 reentry or phase 2 early afterdepolarization. A pathological "U" wave as seen with hypokalemia is the consequence of electrical interaction among ventricular myocardial layers at action potential phase 3 of which repolarization slows. A physiological U wave is thought to be due to delayed repolarization of the Purkinje system.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1542-474X.2005.05588.x

ECG Repolarization Waves: Their Genesis and Clinical Implications

Visual Abstract Background and objectives Daprodustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) being investigated for the treatment of anemia of CKD. In this noninferiority trial, we compared daprodustat administered three times weekly with epoetin alfa (epoetin) in patients on prevalent hemodialysis switching from a prior erythropoiesis-stimulating agent (ESA). Design, setting, participants, & measurements Patients on hemodialysis with a baseline hemoglobin of 8–11.5 g/dl receiving an ESA were randomized 2:1 to daprodustat three times weekly (n=270) or conventional epoetin (n=137) for 52 weeks. Dosing algorithms aimed to maintain hemoglobin between 10 and 11 g/dl. The primary end point was mean change in hemoglobin from baseline to the average during the evaluation period (weeks 28–52). The principal secondary end point was average monthly intravenous iron dose. Other secondary end points included BP and hemoglobin variability. Results Daprodustat three times weekly was noninferior to epoetin for mean change in hemoglobin (model-adjusted mean treatment difference [daprodustat-epoetin], −0.05; 95% confidence interval, −0.21 to 0.10). During the evaluation period, mean (SD) hemoglobin values were 10.45 (0.55) and 10.51 (0.85) g/dl for daprodustat and epoetin groups, respectively. Responders (defined as mean hemoglobin during the evaluation period in the analysis range of 10 to 11.5 g/dl) were 80% in the daprodustat group versus 64% in the epoetin group. Proportionately fewer participants in the daprodustat group versus the epoetin group had hemoglobin values either below 10 g/dl or above 11.5 g/dl during the evaluation period. Mean monthly intravenous iron use was not significantly lower with daprodustat versus epoetin. The effect on BP was similar between groups. The percentage of treatment-emergent adverse events was similar between daprodustat (75%) and epoetin (79%). Conclusions Daprodustat was noninferior to epoetin in hemoglobin response and was generally well tolerated. Clinical Trial registry name and registration number: Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat–Three Times Weekly Dosing in Dialysis (ASCEND-TD), NCT03400033

Three Times Weekly Dosing of Daprodustat versus Conventional Epoetin for Treatment of Anemia in Hemodialysis Patients

BACKGROUND
The prespecified on-treatment analysis of ASCEND-ND (NCT02876835) raised concerns about a higher relative risk of cancer-related adverse events (AEs) with daprodustat vs darbepoetin in patients with anaemia of CKD. This concern was not observed in dialysis patients in ASCEND-D (NCT02879305).


METHODS
ASCEND-ND randomized 3 872 patients to daprodustat or darbepoetin. ASCEND-D randomized 2 964 patients to daprodustat or conventional ESAs. In both studies ESA comparators used different dosing intervals (3/week, 1/week, every 2 or every 4 weeks). The prespecified on-treatment approach examined relative risks for cancer AEs up to the last dose date (LDD) +1 day. In these analyses, owing to different dosing intervals between arms, Cox models were used to estimate the daprodustat effect by various follow-up periods (censoring at LDD, LDD + dosing intervals, or end of study).


RESULTS
In ASCEND-ND, the safety of daprodustat vs. darbepoetin on cancer-related AEs depended on the duration of follow-up after LDD: hazard ratio (HR) 1.04 (95%CI 0.77, 1.40) at end of study; HR 1.12 (95%CI 0.81, 1.56) for LDD + dosing interval; HR 1.50 (95%CI 1.04, 2.15) for LDD + 1 day. In ASCEND-D, no excess risk of cancer-related AEs was observed with any model examined.


CONCLUSIONS
Prespecified on-treatment analyses for cancer-related AEs appeared to result in biased risk estimates in ASCEND-ND by preferentially under-counting events from patients assigned to darbepoetin. Analyses accounting for longer darbepoetin dosing intervals, or extending follow-up, resulted in attenuation of effect estimates towards neutrality, similar to ASCEND-D, where ESA comparator dosing intervals are closer to daprodustat.

Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents - post hoc analyses of the ASCEND-ND and ASCEND-D trials.

Tara DiMino

Papers

ECG Repolarization Waves: Their Genesis and Clinical Implications

Three Times Weekly Dosing of Daprodustat versus Conventional Epoetin for Treatment of Anemia in Hemodialysis Patients

Analysis of on-treatment cancer safety events with daprodustat versus conventional erythropoiesis-stimulating agents - post hoc analyses of the ASCEND-ND and ASCEND-D trials.