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Aims: A genotype-guided P2Y12-inhibitor de-escalation strategy, switching acute coronary syndrome (ACS) patients without a CYP2C19 loss-of-function allele from ticagrelor or prasugrel to clopidogrel, has shown to reduce bleeding risk without affecting effectivity of therapy by increasing ischemic risk. We estimated the cost-effectiveness of this personalized approach compared to standard dual antiplatelet therapy (DAPT; aspirin plus ticagrelor/prasugrel) in the Netherlands., Methods and Results: We developed a one-year decision tree based on results of the FORCE-ACS registry, comparing a cohort of ACS patients who underwent genotyping with a cohort of ACS patients treated with standard DAPT. This was followed by a lifelong Markov model to compare lifetime costs, and quality-adjusted life years (QALYs) for a fictional cohort of 1000 patients. The cost-effectiveness analysis was performed from the perspective of the Dutch healthcare system. A genotype-guided de-escalation strategy led to anincrease of 55.30 QALYs and saved €698,286 compared to standard DAPT based on a lifetime horizon. Probabilistic sensitivity analysis showed that the genotype-guided strategy was cost-saving in 93% and increased QALYs in 86% of simulations. The intervention remained cost-effective in the scenario where prices for all P2Y12-inhibitors were equalized. The genotype-guided strategy remained dominant in various other scenario and sensitivity analyses., Conclusion: A genotype-guided de-escalation strategy in patients with ACS was both cost-saving and yielded higher QALYs compared to standard DAPT, highlighting its potential for implementation in clinical practice. Trial registration: ClinicalTrials.gov identifier: NCT03823547., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims:  Patients presenting with acute coronary syndrome (ACS) are frequently treated with the P2Y 12 -inhibitor ticagrelor. Some patients prematurely discontinue ticagrelor, but the incidence of reasons for and clinical implications of treatment modification are relatively unknown., Methods and Results:  Data from 4,278 ACS patients (mean age: 63.6 years, 26.1% women) who were discharged on ticagrelor and enrolled in the FORCE-ACS registry between 2015 and 2020 were used. Treatment modifications were categorized as physician-recommended discontinuation, alteration, interruption, or disruption and occurred in 26.7, 20.1, 2.8, and 3.1% of patients within 12 months of follow-up (VISUAL SUMMARY: ). Underlying reasons for treatment modification differed per type of modification. Overall, the rate of ischemic events defined as all-cause death, myocardial infarction, or stroke was 6.6% at 12 months of follow-up. Cox regression analysis using time-updated modification variables as independent variables showed that treatment interruption (adjusted hazard ratio [HR]: 2.93, 95% confidence interval [CI]: 1.48-5.79, p  < 0.01) and disruption (adjusted HR: 2.33, 95% CI: 1.07-5.07, p  = 0.03) were associated with an increased risk of ischemic events even after adjustment for relevant confounders. Discontinuation and alteration were not associated with increased ischemic risk., Conclusion:  In clinical practice, treatment modifications in ACS patients discharged on ticagrelor are common, although type and reasons for modification are heterogeneous. Treatment interruption and disruption are associated with excess cardiovascular risk., Competing Interests: G.J.V. has received institutional research grants from MicroPort and Ferrer and personal fees from Terumo and AstraZeneca. Y.A. has received an institutional research from the Dutch Heart Foundation. J.P.S.H. has received institutional research grants from Abbott Vascular, AstraZeneca, B. Braun, Getinge, Ferrer, Infraredx, and ZonMw. W.J.K. has received an institutional research grant from AstraZeneca. J.M.T.B. has received institutional research grants from AstraZeneca, Daiichi Sankyo, and ZonMw and personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, CeleCor Therapeutics, Daiichi Sankyo, Eli Lilly, Ferrer, and Idorsia. All other authors have no relationships with industry to disclose., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Background: CYP2C19 genotype-guided de-escalation from ticagrelor or prasugrel to clopidogrel may optimize the balance between ischemic and bleeding risk in patients with acute coronary syndrome (ACS)., Objectives: This study sought to compare bleeding and ischemic event rates in genotyped patients vs standard care., Methods: Since 2015, ACS patients in the multicenter FORCE-ACS (Future Optimal Research and Care Evaluation in Patients with Acute Coronary Syndrome) registry received standard dual antiplatelet therapy (DAPT). Since 2021, genotype-guided P2Y 12 inhibitor de-escalation was recommended at a single center, switching noncarriers of the loss-of-function allele CYP2C19∗3 or CYP2C19∗2 from ticagrelor or prasugrel to clopidogrel, whereas loss-of-function carriers remained on ticagrelor or prasugrel. The primary ischemic endpoint, a composite of cardiovascular mortality, myocardial infarction, or stroke, and the primary bleeding endpoint, Bleeding Academic Research Consortium 2, 3, or 5 bleeding, were compared between a genotyped cohort and a cohort treated with standard DAPT after 1 year., Results: Among 5,321 enrolled ACS patients, 406 underwent genotyping compared with 4,915 nongenotyped ACS patients on standard DAPT. In the genotyped cohort, 65.3% (n = 265) were noncarriers, 88.7% (n = 235) of whom were switched to clopidogrel. The primary ischemic endpoint occurred in 5.2% (n = 21) of patients in the genotyped cohort compared to 6.9% (n = 337) in the standard care cohort (adjusted HR: 0.82; 95% CI: 0.53-1.28). The primary bleeding rate was significantly lower in the genotyped cohort compared to the standard care cohort (4.7% vs 9.8%; adjusted HR: 0.47; 95% CI: 0.30-0.76)., Conclusions: The implementation of a CYP2C19 genotype-guided P2Y 12 inhibitor de-escalation strategy in a real-world ACS population resulted in lower bleeding rates without an increase in ischemic events compared to a standard DAPT regimen., Competing Interests: Funding Support and Author Disclosures The FORCE-ACS registry is supported by grants from ZonMw, the St. Antonius Research Fund, and AstraZeneca. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents. Dr Vlachojannis has received institutional research grants from MicroPort and Ferrer; and has received personal fees from Terumo and AstraZeneca. Dr Appelman has received an institutional research grant from the Dutch Heart Foundation. Dr Henriques has received institutional research grants from Abbott Vascular, AstraZeneca, B. Braun, Getinge, Ferrer, Infraredx, and ZonMw. Dr Kikkert has received an institutional research grant from AstraZeneca. Dr ten Berg has received institutional research grants from AstraZeneca, Daiichi Sankyo, and ZonMw; and has received personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, CeleCor Therapeutics, Daiichi Sankyo, Eli Lilly, Ferrer, and Idorsia. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objective: Patients with acute coronary syndrome (ACS) remain at high risk for recurrent ischaemic and bleeding events during follow-up. Our study aimed to quantify and compare the impact of these adverse events on quality of life (QoL)., Methods: Data from patients with ACS prospectively enrolled in the FORCE-ACS registry between January 2015 and December 2019 were used for this study. The primary ischaemic and bleeding events of interest were hospital readmission for ACS and Bleeding Academic Research Consortium type 2 or 3 bleeding during 12 months follow-up. QoL was measured using the EQ-5D Visual Analogue Scale (VAS) score and the 12-item Short Form Survey version 2 derived Physical Component Summary (PCS) and Mental Health Component Summary (MCS) scores at 12 months follow-up., Results: In total, 3339 patients (mean age 66.8 years, 27.9% women) were included. During follow-up, ischaemic events occurred in 202 patients (6.0%) and bleeding events in 565 patients (16.9%). After adjustment for demographic and clinical characteristics, ischaemic events remained independently associated with lower QoL regardless of metric used. Bleeding was also independently associated with lower EQ-5D VAS and PCS scores, but not with a lower MCS score. The QoL decrement associated with ischaemic events was numerically larger than the decrement associated with bleeding., Conclusions: Ischaemic and bleeding events remain prevalent and are independently associated with lower QoL at 12 months follow-up in patients previously admitted for ACS. The incidence and impact of these adverse events should be considered when balancing individual ischaemic and bleeding risks., Competing Interests: Competing interests: WK has received an institutional research grant from AstraZeneca. GJV has received institutional research grants from MicroPort and Ferrer and personal fees from Terumo and AstraZeneca. YA has received an institutional research from the Dutch Heart Foundation. JPSH has received institutional research grants from Abbott Vascular, AstraZeneca, B. Braun, Getinge, Ferrer, Infraredx and ZonMw. JtB has received institutional research grants from AstraZeneca, Daiichi Sankyo and ZonMw and personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, CeleCor Therapeutics, Daiichi Sankyo, Eli Lilly, Ferrer and Idorsia. All other authors have no relationships with industry to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Hyperkalaemia is observed frequently in heart failure (HF) patients and is associated with an impaired prognosis and underuse of mineralocorticoid receptor antagonists (MRAs). However, the effects of serum potassium on prescription of the full guideline recommended daily dose of 50 mg in real-world daily practice are unknown. Therefore, we investigated serum potassium and its association with the prescribed MRA dose in a large cohort of chronic HF patients., Methods and Results: A total of 5346 patients with chronic HF with a left ventricular ejection fraction ≤40% from 34 Dutch outpatient HF clinics between 2013 and 2016 were analysed on serum potassium and MRA (spironolactone and eplenerone) dose. Data were stratified by potassium as a serum potassium level <4.0, 4.0 to 5.0 or >5.0 mmol/L. Multivariable logistic regression models were used to assess the association between serum potassium and MRA dose and to adjust for potential confounders. Mean serum potassium was 4.4 ± 0.5 mmol/L and hyperkalaemia (serum potassium >5.0 mmol/L) was present in 399 patients (7.5%). MRA was used in 3091 patients (58.1%). Patients with hyperkalaemia significantly less often received ≥100% of the target dose (50 mg) compared with patients with a serum potassium between 4.0-5.0 mmol/L and <4.0 mmol/L (7.7% vs. 9.5% vs. 13.6% respectively, P = 0.0078). In the multivariable regression analyses, patients with hyperkalaemia were significantly less likely to receive ≥100% of the target dose compared with patients with serum potassium 4.0-5.0 mmol/L (OR 0.38, 95% CI 0.15-0.97, P = 0.044). Additionally, a one unit increase in serum potassium was significantly associated with a lower odds of receiving ≥100% of the target dose (OR 0.69, 95% CI 0.49-0.98, P = 0.036)., Conclusions: In this large registry of real-world chronic HF patients, both an increase in serum potassium and hyperkalaemia were associated with a lower odds of receiving the guideline-recommended MRA dose., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: To validate the Global Registry of Acute Coronary Events (GRACE) risk score and examine the extent and impact of the risk-treatment paradox in contemporary patients with acute coronary syndrome (ACS)., Methods: Data from 5015 patients with ACS enrolled in the FORCE-ACS registry between January 2015 and December 2019 were used for model validation. The performance of the GRACE risk score for predicting in-hospital and 1-year mortality was evaluated based on indices of model discrimination and calibration. Differences in the delivery of guideline-recommended care among patients who survived hospitalisation (n=4911) per GRACE risk stratum were assessed and the association with postdischarge mortality was examined., Results: Discriminative power of the GRACE risk score was good for predicting in-hospital (c-statistic: 0.86; 95% CI: 0.83 to 0.90) and 1-year mortality (c-statistic: 0.82; 95% CI: 0.79 to 0.84). However, the GRACE risk score overestimated the absolute in-hospital and 1-year mortality risk (Hosmer-Lemeshow goodness-of-fit test p<0.01). Intermediate-risk and high-risk patients were 12% and 29% less likely to receive optimal guideline-recommended care compared with low-risk patients, respectively. Optimal guideline-recommended care was associated with lower mortality in intermediate- and high-risk patients., Conclusions: The GRACE risk score identified patients at higher risk for in-hospital and 1-year mortality, but overestimated absolute risk levels in contemporary patients. Optimal guideline-recommended care was associated with lower mortality in intermediate-risk and high-risk patients, but was less likely to be delivered with increasing mortality risk., Competing Interests: Competing interests: Dr Wouter J Kikkert has received a research grant from AstraZeneca. Dr Georgios J Vlachojannis has research grants from MicroPort and Ferrer and personal fees from Terumo and AstraZeneca. Dr Yolande Appelman has received a research grant from the Dutch Heart Foundation. Professor Dr José PS Henriques has received research grants from Abbott Vascular, AstraZeneca, B. Braun, Getinge, Ferrer, Infraredx and ZonMw. Professor Dr Jurriën M ten Berg has received research grants from AstraZeneca and ZonMw and personal fees from AstraZeneca, Accu-Metrics, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Ferrer, Idorsia, Pfizer and The Medicines Company. All other authors have no relationships with industry to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Diagnostic and treatment strategies for acute coronary syndrome have improved dramatically over the past few decades, but mortality and recurrent myocardial infarction rates remain high. An aging population with increasing co-morbidities heralds new clinical challenges. Therefore, in order to evaluate and improve current treatment strategies, detailed information on clinical presentation, treatment and follow-up in real-world patients is needed. The Future Optimal Research and Care Evaluation in patients with Acute Coronary Syndrome (FORCE-ACS) registry (ClinicalTrials.gov Identifier: NCT03823547) is a multi-center, prospective real-world registry of patients admitted with (suspected) acute coronary syndrome. Both non-interventional and interventional cardiac centers in different regions of the Netherlands are currently participating. Patients are treated according to local protocols, enabling the evaluation of different diagnostic and treatment strategies used in daily practice. Data collection is performed using electronic medical records and quality-of-life questionnaires, which are sent 1, 12, 24 and 36 months after initial admission. Major end points are all-cause mortality, myocardial infarction, stent thrombosis, stroke, revascularization and all bleeding requiring medical attention. Invasive therapy, antithrombotic therapy including patient-tailored strategies, such as the use of risk scores, pharmacogenetic guided antiplatelet therapy and patient reported outcome measures are monitored. The FORCE-ACS registry provides insight into numerous aspects of the (quality of) care for acute coronary syndrome patients.

Background: Elderly heart failure (HF) patients are underrepresented in clinical trials, though are a large proportion of patients in real-world practice. We investigated practice-based, secondary care HF management in a large group of chronic HF patients aged ≥ 80 years (octogenarians)., Methods: We analyzed electronic health records of 3490 octogenarians with chronic HF at 34 Dutch outpatient clinics in the period between 2013 and 2016 , 49% women. Study patients were divided into HFpEF [LVEF ≥ 50%; n = 911 (26.1%)], HFrEF [LVEF < 40%; n = 2009 (57.6%)] and HF with mid-range EF [HFmrEF: LVEF 40-49%; n = 570 (16.3%)]., Results: Most HFrEF patients aged ≥ 80 years received a beta blocker and a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker), i.e. 78.3% and 72.8% respectively, and a mineralocorticoid receptor antagonist (MRA) was prescribed in 52.0% of patients. All three of these guideline-recommended medications (triple therapy) were given in only 29.9% of octogenarians with HFrEF, and at least 50% of target doses of triple therapy, beta blockers, RAS inhibitor and MRA, were prescribed in 43.8%, 62.2% and 53.5% of the total group of HFrEF patients. Contraindications or intolerance for beta blockers was present in 3.5% of the patients, for RAS inhibitors and MRAs in, 7.2% and 6.1% CONCLUSIONS: The majority of octogenarians with HFrEF received one or more guideline-recommended HF medications. However, triple therapy or target doses of the medications were prescribed in a minority. Comorbidities and reported contraindications and tolerances did not fully explain underuse of recommended HF therapies.

Aims: Left atrial (LA) stretch-associated electrophysiological changes in patients with mitral stenosis (MS) predispose to atrial fibrillation. We hypothesized that the normalization of the pressure gradient by percutaneous transvenous mitral balloon valvotomy (PTMV) affects LA but not right atrial (RA) conduction, depending on the site of stimulation. Because direction-dependent (asymmetric) changes of conduction may contribute to arrhythmogenesis, we assessed conduction symmetry in MS patients and tested whether it is restored by PTMV., Methods and Results: In nine patients with MS, atrial effective refractory period and local activation times (ATs) were determined during stimulation before and after PTMV, with up to four decapolar catheters (LA and RA). Eight patients with ventricular pre-excitation served as controls. ATs at basic cycle length were similar before and after PTMV. With stimulation from either atrium, they were about 45 ms in the ipsilateral atrium and about 115 ms in the contralateral atrium. With premature stimulation, ATs increased dramatically. The shortest ATs were found in the RA with RA stimulation (78 +/- 9 and 80 +/- 6 ns, before and after PTMV). PTMV caused a shortening in LA-ATs (following LA stimulation) from 118 +/- 14 to 82 +/- 5 ms (before and after; P < 0.05). Asymmetry in conduction properties was therefore normalized by PTMV. PTMV led to a decrease in RA-ATs (following LA stimulation) from 196 +/- 11 to 174 +/- 13 ms (P < 0.02). In addition, following RA stimulation, the dispersion in ATs in the LA decreased significantly by PTMV (from 66 +/- 10 to 34 +/- 7 ms; P < 0.02)., Conclusion: MS is associated with LA conduction delay, increased LA dispersion of conduction, and conduction asymmetry. These changes are immediately reversible by PTMV.

Percutaneous transvenous mitral balloon valvotomy (PTMV) has been proven to be an effective and safe method for treatment of patients with severe mitral valve stenosis. This technique has become an accepted alternative for surgical commissurotomy, not only in young patients with pliable valves, but also in selected older patients with extensive valvular pathology. This review highlights the significance of coexisting atrial fibrillation, patient selection and timing of PTMV in patients with mitral valve stenosis.

Three female patients, a 22-year-old Moroccan woman, a 25-year-old Turkish woman and a 35-year-old Iraqi woman, became increasingly dyspnoeic during their pregnancy; this was a symptom of congestive heart failure due to mitral valve stenosis. Since all patients were refractory to medical treatment, they underwent invasive therapy by percutaneous transvenous mitral balloon valvotomy (PTMV). In two patients this therapy was successful, but in one patient a closed mitral valvotomy was needed. All three women delivered healthy infants, two immediately following the PTMV; at follow-up 2-4 years later, the women and infants were all doing well. The prevalence of mitral valve stenosis in the western world is increasing because of changing immigration patterns. When pregnant patients start complaining about dyspnoea, especially if they are immigrants, one should be aware of the possibility of mitral valve stenosis. PTMV is a safe and successful treatment for these patients and is preferred above surgical therapy because of its low morbidity and mortality for both mother and foetus. PTMV must be performed in a thoracic surgery centre by an experienced team and the X-ray exposure should be minimised.

The objective of this study was to validate the additional value of 3-dimensional (3D) transesophageal echocardiography (TEE) for patients with mitral valve stenosis undergoing percutaneous mitral balloon valvotomy (PTMV). Therefore, in a series of 21 patients with severe mitral valve stenosis selected for PTMV, 3D TEE was performed before and after PTMV. The mitral valve area was assessed by planimetry pre- and post-PTMV; the mitral valve volume was assessed and attention was paid to the amount of fusion of the commissures. These results were compared with findings by 2-dimensional transthoracic echocardiography using pressure half-time method for assessment of mitral valve area, and were analyzed for the prediction of successful outcome. Pre-PTMV the mitral valve area assessed by 3D TEE was 1.0 +/- 0.3 cm(2) vs 1.2 +/- 0.4 cm(2) assessed by 2-dimensional transthoracic echocardiography (P =.03) and post-PTMV it was 1.8 +/- 0.5 cm(2) vs 1.9 +/- 0.6 cm(2) (not significant), respectively. The mitral valve volume could be assessed by 3D TEE (mean 2.4 +/- 2.5 cm(3)) and was inversely correlated to a successful PTMV procedure (P <.001). The 3D TEE method enabled a better description of the mitral valvular anatomy, especially post-PTMV. We conclude that 3D TEE will have additional value over 2-dimensional echocardiography in this group of patients, for selection of patients pre-PTMV, and for analyzing pathology of the mitral valve afterward.

Background and Aim of the Study: The predictive value of chronic atrial fibrillation (AF) before percutaneous mitral balloon valvotomy (PMBV) is still under discussion. The effect of the duration of chronic AF on short- or long-term results is not known. Therefore, we analyzed the predictive value of pre-procedural chronic AF and the duration of this rhythm disturbance for short- and long-term outcome after PMBV in patients with mitral valve stenosis., Methods: A total of 140 PMBV procedures was performed in 137 patients with severe mitral stenosis. Sixty-three patients (45%) were in chronic AF; in 40 patients (63%) the AF was of more than one year duration. A successful procedure is defined as PMBV achieved without acute mitral valve replacement, and a mitral valve area after PMBV of > or =1.5 cm2., Results: Patients in chronic AF were significantly older, had a larger left atrial diameter and higher NYHA functional class, compared with patients in sinus rhythm (SR). The success rates of PMBV were 80.5% and 77.6% in patients with SR and AF, respectively (p = NS). Mean follow up was 4.2+/-2.6 years (n = 127). At four years' follow up the event-free survival was 86.5% in patients with SR, and 78.5% in those with chronic AF at baseline (p = 0.031). Multivariate analysis of the entire study population showed the presence of chronic AF to be the only pre-procedural independent predictor for severe mitral regurgitation after PMBV (p = 0.030), as well for an event (p = 0.039) and restenosis (p = 0.034) during follow up. The risk for an event or restenosis during follow up increased seven-fold when chronic AF at baseline was present for more than one year (p = 0.010)., Conclusion: Pre-procedural chronic AF is an independent predictor for unfavorable outcome at short- and long-term follow up after PMBV. A longer duration of AF further increases the risk of an event or restenosis.