Contemporary guideline-directed medical therapy in de novo, chronic, and worsening heart failure patients: First data from the TITRATE-HF study.

AIMS: Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers. METHODS AND RESULTS: TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range [IQR] 63-78), 29% were female, and median ejection fraction was 35% (IQR 25-40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF. CONCLUSION: This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management.

Orally Inhaled Flecainide for Conversion of Atrial Fibrillation to Sinus Rhythm: INSTANT Phase 2 Trial.

BACKGROUND: INSTANT (INhalation of flecainide to convert recent-onset SympTomatic Atrial fibrillatioN to sinus rhyThm) was a multicenter, open-label, single-arm study of flecainide acetate oral inhalation solution (FlecIH) for acute conversion of recent-onset (≤48 hours) symptomatic atrial fibrillation (AF) to sinus rhythm. OBJECTIVES: This study investigated the efficacy and safety in 98 patients receiving a single dose of FlecIH delivered via oral inhalation. METHODS: Patients self-administered FlecIH over 8 minutes in a supervised medical setting using a breath-actuated nebulizer and were continuously monitored for 90 minutes using a 12-lead Holter. RESULTS: Mean age was 60.5 years, mean body mass index was 27.0 kg/m2, and 34.7% of the patients were women. All patients had ≥1 AF-related symptoms at baseline, and 87.8% had AF symptoms for ≤24 hours. The conversion rate was 42.6% (95% CI: 33.0%-52.6%) with a median time to conversion of 14.6 minutes. The conversion rate was 46.9% (95% CI: 36.4%-57.7%) in a subpopulation that excluded predose flecainide exposure for the current AF episode. Median time to discharge among patients who converted was 2.5 hours, and only 2 patients had experienced AF recurrence by day 5. In the conversion-no group, 44 (81.5%) patients underwent electrical cardioversion by day 5. The most common adverse events were related to oral inhalation of flecainide (eg, cough, oropharyngeal irritation/pain), which were mostly of mild intensity and limited duration. CONCLUSIONS: The risk-benefit of orally inhaled FlecIH for acute cardioversion of recent-onset AF appears favorable. FlecIH could provide a safe, effective, and convenient first-line therapeutic option. (INhalation of Flecainide to Convert Recent Onset SympTomatic Atrial Fibrillation to siNus rhyThm [INSTANT]; NCT03539302).

Comparison of two algorithms to support medication surveillance for drug-drug interactions between QTc-prolonging drugs.

BACKGROUND: QTc-prolongation is an independent risk factor for developing life-threatening arrhythmias. Risk management of drug-induced QTc-prolongation is complex and digital support tools could be of assistance. Bindraban et al. and Berger et al. developed two algorithms to identify patients at risk for QTc-prolongation. OBJECTIVE: The main aim of this study was to compare the performances of these algorithms for managing QTc-prolonging drug-drug interactions (QT-DDIs). MATERIALS AND METHODS: A retrospective data analysis was performed. A dataset was created from QT-DDI alerts generated for in- and outpatients at a general teaching hospital between November 2016 and March 2018. ECGs recorded within 7 days of the QT-DDI alert were collected. Main outcomes were the performance characteristics of both algorithms. QTc-intervals of > 500 ms on the first ECG after the alert were taken as outcome parameter, to which the performances were compared. Secondary outcome was the distribution of risk scores in the study cohort. RESULTS: In total, 10,870 QT-DDI alerts of 4987 patients were included. ECGs were recorded in 26.2 % of the QT-DDI alerts. Application of the algorithms resulted in area under the ROC-curves of 0.81 (95 % CI 0.79-0.84) for Bindraban et al. and 0.73 (0.70-0.75) for Berger et al. Cut-off values of ≥ 3 and ≥ 6 led to sensitivities of 85.7 % and 89.1 %, and specificities of 60.8 % and 44.3 % respectively. CONCLUSIONS: Both algorithms showed good discriminative abilities to identify patients at risk for QTc-prolongation when using ≥ 2 QTc-prolonging drugs. Implementation of digital algorithms in clinical decision support systems could support the risk management of QT-DDIs.

Colchicine in Patients with Chronic Coronary Disease.

BACKGROUND: Evidence from a recent trial has shown that the antiinflammatory effects of colchicine reduce the risk of cardiovascular events in patients with recent myocardial infarction, but evidence of such a risk reduction in patients with chronic coronary disease is limited. METHODS: In a randomized, controlled, double-blind trial, we assigned patients with chronic coronary disease to receive 0.5 mg of colchicine once daily or matching placebo. The primary end point was a composite of cardiovascular death, spontaneous (nonprocedural) myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization. The key secondary end point was a composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke. RESULTS: A total of 5522 patients underwent randomization; 2762 were assigned to the colchicine group and 2760 to the placebo group. The median duration of follow-up was 28.6 months. A primary end-point event occurred in 187 patients (6.8%) in the colchicine group and in 264 patients (9.6%) in the placebo group (incidence, 2.5 vs. 3.6 events per 100 person-years; hazard ratio, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P<0.001). A key secondary end-point event occurred in 115 patients (4.2%) in the colchicine group and in 157 patients (5.7%) in the placebo group (incidence, 1.5 vs. 2.1 events per 100 person-years; hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.007). The incidence rates of spontaneous myocardial infarction or ischemia-driven coronary revascularization (composite end point), cardiovascular death or spontaneous myocardial infarction (composite end point), ischemia-driven coronary revascularization, and spontaneous myocardial infarction were also significantly lower with colchicine than with placebo. The incidence of death from noncardiovascular causes was higher in the colchicine group than in the placebo group (incidence, 0.7 vs. 0.5 events per 100 person-years; hazard ratio, 1.51; 95% CI, 0.99 to 2.31). CONCLUSIONS: In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than among those who received placebo. (Funded by the National Health Medical Research Council of Australia and others; LoDoCo2 Australian New Zealand Clinical Trials Registry number, ACTRN12614000093684.).

Development of a risk model for predicting QTc interval prolongation in patients using QTc-prolonging drugs.

Background Numerous drugs prolong the QTc interval on the ECG and potentially increase the risk of cardiac arrhythmia. This risk is clinically relevant in patients with additional risk factors. Objective The objective was to develop and validate a risk model to predict QTc interval prolongation of eligible ECGs. Setting Spaarne Gasthuis (Haarlem/Hoofddorp, The Netherlands). Method A dataset was created from ECGs recorded in patients using one or more QTc prolonging drugs, in the period January 2013 and October 2016. In the development set, independent risk factors for QTc interval prolongation were determined using binary logistic regression. Risk scores were assigned based on the beta coefficient. In the risk-score validation set, the area under the ROC-curve, sensitivity and specificity were calculated. Main outcome measure QTc interval prolongation, defined as a QTc interval > 500 ms. Results In the development set 12,949 ECGs were included and in the risk-score validation set 6391 ECGs. The proportion of ECGs with a prolonged QTc interval in patients with no risk factors in the risk-score validation set was 2.7%, while in patients with a high risk score the proportion was 26.1%. The area under the ROC curve was 0.71 (95% CI 0.68-0.73). The sensitivity and specificity were 0.81 and 0.48, respectively. Conclusion A risk model was developed and validated for the prediction of QTc interval prolongation. This risk model can be implemented in a clinical decision support system, supporting the management of the risks involved with QTc interval prolonging drugs.

Risk factors for QTc interval prolongation.

PURPOSE: Prolongation of the QTc interval may result in Torsade de Pointes, a ventricular arrhythmia. Numerous risk factors for QTc interval prolongation have been described, including the use of certain drugs. In clinical practice, there is much debate about the management of the risks involved. In this study, we quantified the effect of these risk factors on the length of the QTc interval. METHODS: We analyzed all ECGs that were taken during routine practice between January 2013 and October 2016 in the Spaarne Gasthuis, a general teaching hospital in the Netherlands. We collected laboratory values in the week before the ECG recording and the drugs prescribed. For the identification of risk factors, we used multilevel linear regression analysis to correct for multiple ECG recordings per patient. RESULTS: We included 133,359 ECGs in our study, taken in 40,037 patients. Patients using one QT-prolonging drug had a 11.08 ms (95% CI 10.63-11.52; p < 0.001) longer QTc interval. Patients using two QT-prolonging drugs had a 3.04 ms (95% CI 2.06-4.02; p < 0.001) increase in the QTc interval compared to patients using one QT-prolonging drug. Women had a longer QTc interval compared to men (16.30 ms 95% CI 14.59-18.01; p < 0.001). The QTc interval increased with increasing age, but the difference between men and women diminished. Other independent risk factors that significantly prolonged the QTc interval with at least 10 ms were hypokalemia, hypocalcemia, and the use of loop diuretics. CONCLUSION: We identified and quantified various risk factors for QTc interval prolongation.

Is subendocardial ischaemia present in patients with chest pain and normal coronary angiograms? A cardiovascular MR study.

AIMS: On the basis of an MRI study it has been suggested that subendocardial hypoperfusion is present in patients with cardiac syndrome X. However, further work is required to test whether these findings can be generalized. METHODS AND RESULTS: MRI was used to visually and semi-quantitatively assess subendocardial and subepicardial perfusion, at rest and during an infusion of adenosine, in 20 patients with angina pectoris and normal coronary angiograms. A myocardial perfusion index (MPI) was calculated using the normalized upslope of myocardial signal enhancement. An index for myocardial perfusion reserve (MPRI) was calculated by dividing the MPI values at maximal vasodilatation by the values at rest. The MPI in our study population increased significantly during adenosine infusion in both the subendocardium (from 0.091 +/- 0.020 to 0.143 +/- 0.030; P < 0.001) and the subepicardium (from 0.074 +/- 0.017 to 0.135 +/- 0.03; P < 0.001). The overall MPRI was 1.83 +/- 0.50. CONCLUSION: The results show that patients with chest pain and normal coronary angiograms had significant perfusion responses to adenosine in both the subendocardium and subepicardium. In the present study we found no evidence for subendocardial hypoperfusion in these patients.