Dapagliflozin vs. metolazone in heart failure resistant to loop diuretics.

BACKGROUND AND AIMS: To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. METHODS AND RESULTS: A multi-centre, open-label, randomized, and active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 h). The primary endpoint was a diuretic effect, assessed by change in weight (kg). Secondary endpoints included a change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 h was 977 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 h was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; P = 0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) vs. 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; P = 0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. CONCLUSION: In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04860011.

Risk Stratification Guided by the Index of Microcirculatory Resistance and Left Ventricular End-Diastolic Pressure in Acute Myocardial Infarction.

BACKGROUND: The index of microcirculatory resistance (IMR) of the infarct-related artery and left ventricular end-diastolic pressure (LVEDP) are acute, prognostic biomarkers in patients undergoing primary percutaneous coronary intervention. The clinical significance of IMR and LVEDP in combination is unknown. METHODS: IMR and LVEDP were prospectively measured in a prespecified substudy of the T-TIME clinical trial (Trial of Low Dose Adjunctive Alteplase During Primary PCI). IMR was measured using a pressure- and temperature-sensing guidewire following percutaneous coronary intervention. Prognostically established thresholds for IMR (>32) and LVEDP (>18 mm Hg) were predefined. Contrast-enhanced cardiovascular magnetic resonance imaging (1.5 Tesla) was acquired 2 to 7 days and 3 months postmyocardial infarction. The primary end point was major adverse cardiac events, defined as cardiac death/nonfatal myocardial infarction/heart failure hospitalization at 1 year. RESULTS: IMR and LVEDP were both measured in 131 patients (mean age 59±10.7 years, 103 [78.6%] male, 48 [36.6%] with anterior myocardial infarction). The median IMR was 29 (interquartile range, 17-55), the median LVEDP was 17 mm Hg (interquartile range, 12-21), and the correlation between them was not statistically significant (r=0.15; P=0.087). Fifty-three patients (40%) had low IMR (≤32) and low LVEDP (≤18), 18 (14%) had low IMR and high LVEDP, 31 (24%) had high IMR and low LVEDP, while 29 (22%) had high IMR and high LVEDP. Infarct size (% LV mass), LV ejection fraction, final myocardial perfusion grade ≤1, TIMI (Thrombolysis In Myocardial Infarction) flow grade ≤2, and coronary flow reserve were associated with LVEDP/IMR group, as was hospitalization for heart failure (n=18 events; P=0.045) and major adverse cardiac events (n=21 events; P=0.051). LVEDP>18 and IMR>32 combined was associated with major adverse cardiac events, independent of age, estimated glomerular filtration rate, and infarct-related artery (odds ratio, 5.80 [95% CI, 1.60-21.22] P=0.008). The net reclassification improvement for detecting major adverse cardiac events was 50.6% (95% CI, 2.7-98.2; P=0.033) when LVEDP>18 was added to IMR>32. CONCLUSIONS: IMR and LVEDP in combination have incremental value for risk stratification following primary percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02257294.

Chest pain with less than 20% change in high sensitivity troponin T - a low risk cohort?

Background: Patients with chest pain are risk-stratified using serial high-sensitivity troponin (T) assays (hsTnT). Those with change in (Δ)hsTnT <20% are often categorised as low-risk and are less likely to be managed as acute coronary syndromes (ACS). We sought to characterise such a population of 'low-risk' chest pain presenters.Methods: We performed a retrospective cohort analysis of sequential patients admitted to our centre over a 1-year period with chest pain, absence of ST-elevation, with elevated hsTnT concentrations, and compared demographic, clinical and outcome data according to ΔhsTnT.Results: Three hundred and eleven patients were subdivided by ΔhsTnT [<20% (n = 80), 20-100% (n = 78), >100% (n = 153)]. Baseline demographic data were well-matched across the three subgroups; atrial fibrillation was more common in the two lower magnitude ΔhsTnT groups. Obstructive coronary artery disease (CAD) - while less common in those with ΔhsTnT <20% (66.2%) compared to the 20-100% (73.1%) and >100% (75.9%) groups (p = 0.03) - remained high in this lower risk group, and indeed revascularisation occurred in >60% of patients, equally frequently in all three groups. Using absolute ΔhsTnT ≥9ng/L within the ΔhsTnT <20% group provided incremental value in ruling in ACS, with a positive predictive value of 74.1%. ΔhsTnT was a univariate but not a multivariate predictor of obstructive CAD.Conclusions: Obstructive CAD and need for revascularisation are frequent in chest pain presenters with ΔhsTnT <20%. The increasing focus on hsTnT algorithms to exclude ACS and promote early discharge without adequate clinical risk stratification modelling risks misdiagnosis of patients presenting with acute myocardial ischaemia with a low-level hsTnT rise.

Sacubitril/Valsartan and Mexiletine: A Proarrhythmic Combination?

The uptake of sacubitril/valsartan since the PARADIGM study confirmed its beneficial effects on outcomes over enalapril in chronic systolic heart failure has inevitably led to potential interactions with co-prescribed medications in real-world patients. We report two cases that raise the possibility of an interaction between sacubitril/valsartan and the class Ib anti-arrhythmic mexiletine resulting in proarrhythmic effects. We discuss the pharmacokinetics of both agents and posit potential mechanistic interactions that suggest caution should be used and careful monitoring for (ventricular) arrhythmias applied in patients receiving sacubitril/valsartan and mexiletine.

The Emerging Potential of the Apelin-APJ System in Heart Failure.

The apelin-APJ system is a novel neurohormonal pathway, with studies to date suggesting that it may be of pathophysiologic relevance in heart failure and may indeed be a viable therapeutic target in this syndrome. This interest is driven primarily by the demonstration of its vasodilator, inotropic, and aquaretic actions as well as its apparent antagonistic relationship with the renin-angiotensin system. However, its promise is heightened further by the observation that, unlike other and more established cardioprotective pathways, it appears to be down-regulated in heart failure, suggesting that augmentation of this axis may have a powerful effect on the heart failure syndrome. We review the literature regarding the apelin-APJ system in heart failure and suggest areas requiring further research.

Cheating the CHA2DS2-VASc Score: Thromboembolism in Apical Hypertrophic Cardiomyopathy.

Atrial fibrillation increases the risk of systemic thromboembolism in general and stroke in particular. Not all patients who develop atrial fibrillation are at significantly heightened risk of thromboembolic complications, however, with the development of risk scoring systems aiding clinicians in determining whether formal anticoagulation is mandated. The most commonly used contemporary scoring systems-CHADS2 and CHA2DS2-VASc-provide a reliable means of assessing stroke risk, but certain cardiac conditions are associated with an increased incidence of thromboembolism without impacting on these risk scores. Hypertrophic cardiomyopathy, with its apical variant, is such a condition. We present a case of a patient with apical hypertrophic cardiomyopathy and atrial fibrillation who suffered dire thromboembolic consequences despite a reassuringly low CHA2DS2-VASc score and suggest that this scoring system is modified to incorporate the thromboembolic risk inherent to certain cardiomyopathies irrespective of impairment of left ventricular systolic dysfunction or clinical heart failure.

How is dilated cardiomyopathy investigated in Scotland? A contemporary survey.

BACKGROUND AND AIMS: Dilated cardiomyopathy (DCM) is a common cause of heart failure. The underlying aetiology remains poorly characterised, with ca. 50% labelled 'idiopathic'. We assessed the extent to which the aetiology of DCM is investigated in Scotland, in comparison to European Society of Cardiology (ESC) recommendations. METHODS AND RESULTS: Questionnaires regarding the use of coronary angiography, use and availability of cardiac magnetic resonance imaging (CMR) and blood/urine panels to investigate the causes of DCM were sent to the heart failure lead in each of the 23 hospitals across Scotland with an established cardiology department; responses were obtained from 21/23 (91.3%). ESC guidelines regarding coronary angiography were adopted in only 8/21 (38.1%). Only 7/21 (33.3%) had easy access to CMR although 14/21 (66.7%) felt it would be a useful test in DCM. The ESC-recommended blood profile was checked routinely in 7/21 (33.3%). Additional blood tests, many of which not currently recommended, were performed in selected centres. CONCLUSIONS: DCM patients in Scotland are in general unlikely to undergo current ESC-recommended investigation into the underlying aetiology. There is a need for prospective studies to determine the success rate and influence on management and outcome of such multifaceted approaches to investigating the cause of DCM.

Galectin-3 and cardiac function in survivors of acute myocardial infarction.

BACKGROUND: Galectin-3 is a biomarker associated with inflammation and fibrosis that predicts adverse outcome and relates to biomarkers of extracellular matrix turnover in patients with heart failure, particularly when left ventricular (LV) systolic function is preserved. Whether galectin-3 is related to LV remodeling after acute myocardial infarction is unknown. METHODS AND RESULTS: Circulating galectin-3 and various extracellular matrix biomarkers were measured in 100 patients (age, 58.9±12.0 years; 77% men) admitted with acute myocardial infarction and LV dysfunction, at baseline (mean 46 hours) and at 24 weeks, with cardiac MRI at each time-point. LV remodeling was defined as change in LV end-systolic volume index. Relationships among galectin-3, biomarkers, and LV remodeling were analyzed across the entire cohort, then according to median baseline LV ejection fraction. Galectin-3 levels were elevated in 22 patients (22%) at baseline and increased significantly over time from 14.7±5.5 to 16.3±6.6 ng/mL (P=0.007). Baseline galectin-3 did not correlate with any LV parameters at baseline or change in any parameter over time. Galectin-3 was positively associated with remodeling in patients with supramedian baseline LV ejection fraction (ie, >49.2%; r=0.40; P=0.01) but not when LV ejection fraction was ≤49.2%. Galectin-3 correlated significantly with matrix metalloproteinase-3 and monocyte chemoattractant protein-1 at baseline, biomarkers that have been shown to relate to LV remodeling in this cohort. CONCLUSIONS: Galectin-3 correlated significantly with certain biomarkers involved in extracellular matrix turnover, although no definite relationship was identified with LV remodeling. Whether galectin-3 plays a pathological role in remodeling remains unclear but merits further study. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00132093.