Serial cardiac biomarkers, pulmonary artery pressures and traditional parameters of fluid status in relation to prognosis in patients with chronic heart failure: Design and rationale of the BioMEMS study.

AIMS: Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms. METHODS: The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death. CONCLUSION: Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively.

Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Ethnic minorities treated with new-generation drug-eluting coronary stents in two European randomised clinical trials.

BACKGROUND: Several ethnic minorities have an increased risk of cardiovascular events, but previous European trials that investigated clinical outcome after coronary stenting did not assess the patients' ethnic background. AIMS: To compare ethnic minority and Western European trial participants in terms of both cardiovascular risk profile and 1­year clinical outcome after percutaneous coronary intervention. METHODS: In the BIO-RESORT and BIONYX randomised trials, which assessed new-generation drug-eluting stents, information on patients' self-reported ethnic background was prospectively collected. Pooled patient-level data of 5803 patients, enrolled in the Netherlands and Belgium, were analysed in this prespecified analysis. The main endpoint was target vessel failure after 1 year. RESULTS: Patients were classified as belonging to an ethnic minority (n = 293, 5%) or of Western European origin (n = 5510, 95%). Follow-up data were available in 5772 of 5803 (99.5%) patients. Ethnic minority patients were younger, less often female, more often current smokers, more often medically treated for diabetes, and more often had a positive family history of coronary artery disease. The main endpoint target vessel failure did not differ between ethnic minority and Western European patients (3.5% vs 4.9%, hazard ratio 0.71, 95% confidence interval 0.38-1.33; p = 0.28). There was also no difference in mortality, myocardial infarction, and repeat revascularisation rates. CONCLUSIONS: Despite the unfavourable cardiovascular risk profile of ethnic minority patients, short-term clinical outcome after treatment with contemporary drug-eluting stents was highly similar to that in Western European patients. Further efforts should be made to ensure the enrolment of more ethnic minority patients in future coronary stent trials.

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.

Ten-year mortality after treating obstructive coronary atherosclerosis with contemporary stents in patients with or without concomitant peripheral arterial disease.

BACKGROUND AND AIMS: Previous studies in percutaneous coronary intervention (PCI) patients showed a higher 3-year adverse event risk, including all-cause mortality, in those with concomitant peripheral arterial disease (PADs). Ten-year data of mortality and causes of death are scarce. This analysis assessed PCI patients, treated with contemporary drug-eluting stents, the impact of concomitant PADs on very long-term mortality, and causes of death. METHODS: We assessed PCI all-comers from our center who participated in the TWENTE and DUTCH PEERS trials (clinicaltrials.gov:NCT01066650, NCT01331707), comparing patients with versus without PADs. Life status was checked in the Dutch Personal Records Database; causes of death were obtained from medical records. RESULTS: Of 2705 study patients, 668 (24.7%) died during follow-up: 88/212 (41.5%) patients with PADs and 580/2493 (23.1%) without PADs. In PADs patients, the 10-year rate of all-cause mortality was about twice as high as in patients without PADs (41.5% vs.23.1%, HR: 2.05, 95%-CI: 1.64-2.57, p<0.001). For both groups, the rates of patients dying from various causes of death were: cardiac (14.1% vs.6.8%), vascular (2.8% vs. 1.1%), non-cardiovascular (17.4% vs. 9.8%), and unclear causes (7.1% vs. 5.3%), without a statistically significant between-group difference. When multivariate analysis was adjusted for between-group differences in cardiovascular risk profile, PADs remained predictor of all-cause mortality (adjusted HR: 1.38, 95%-CI: 1.08-1.75, p=0.01). CONCLUSIONS: The 10-year all-cause mortality rate in PCI patients with concomitant PADs was almost twice as high as in those without PADs. Age and other traditional cardiovascular risk factors were higher in patients with PADs, but after correction for these confounders PADs still accounted for almost 40% increase in mortality.

Invasiveness of previous treatment for peripheral arterial disease and risk of adverse cardiac events after coronary stenting.

Patients with peripheral arterial disease (PADs), undergoing percutaneous coronary intervention (PCI), have higher adverse event risks. The effect of invasiveness of PADs treatment on PCI outcome is unknown. This study assessed the impact of the invasiveness of previous PADs treatment (invasive or non-invasive) on event risks after PCI with contemporary drug-eluting stents. This post-hoc analysis pooled 3-year patient-level data of PCI all-comer patients living in the eastern Netherlands, previously treated for PADs. PADs included symptomatic atherosclerotic lesion in the lower or upper extremities; carotid or vertebral arteries; mesenteric arteries or aorta. Invasive PADs treatment comprised endarterectomy, bypass surgery, percutaneous transluminal angioplasty, stenting or amputation; non-invasive treatment consisted of medication and participation in exercise programs. Primary endpoint was (coronary) target vessel failure: composite of cardiac mortality, target vessel-related myocardial infarction, or clinically indicated target vessel revascularization. Of 461 PCI patients with PADs, information on PADs treatment was available in 357 (77.4%) patients; 249 (69.7%) were treated invasively and 108 (30.3%) non-invasively. Baseline and PCI procedural characteristics showed no between-group difference. Invasiveness of PADs treatment was not associated with adverse event risks, including target vessel failure (20.5% vs. 16.0%; HR: 1.30, 95%-CI 0.75-2.26, p = 0.35), major adverse cardiac events (23.3% vs. 20.4%; HR: 1.16, 95%-CI 0.71-1.90, p = 0.55), and all-cause mortality (12.1% vs. 8.3%; HR: 1.48, 95%-CI 0.70-3.13, p = 0.30). In PADs patients participating in PCI trials, we found no significant relation between the invasiveness of previous PADs treatment and 3-year outcome after PCI. Consequently, high-risk PCI patients can be identified by consulting medical records, searching for PADs, irrespective of the invasiveness of PADs treatment.

Guideline implementation, drug sequencing, and quality of care in heart failure: design and rationale of TITRATE-HF.

AIMS: Current heart failure (HF) guidelines recommend to prescribe four drug classes in patients with HF with reduced ejection fraction (HFrEF). A clear challenge exists to adequately implement guideline-directed medical therapy (GDMT) regarding the sequencing of drugs and timely reaching target dose. It is largely unknown how the paradigm shift from a serial and sequential approach for drug therapy to early parallel application of the four drug classes will be executed in daily clinical practice, as well as the reason clinicians may not adhere to new guidelines. We present the design and rationale for the real-world TITRATE-HF study, which aims to assess sequencing strategies for GDMT initiation, dose titration patterns (order and speed), intolerance for GDMT, barriers for implementation, and long-term outcomes in patients with de novo, chronic, and worsening HF. METHODS AND RESULTS: A total of 4000 patients with HFrEF, HF with mildly reduced ejection fraction, and HF with improved ejection fraction will be enrolled in >40 Dutch centres with a follow-up of at least 3 years. Data collection will include demographics, physical examination and vital parameters, electrocardiogram, laboratory measurements, echocardiogram, medication, and quality of life. Detailed information on titration steps will be collected for the four GDMT drug classes. Information will include date, primary reason for change, and potential intolerances. The primary clinical endpoints are HF-related hospitalizations, HF-related urgent visits with a need for intravenous diuretics, all-cause mortality, and cardiovascular mortality. CONCLUSIONS: TITRATE-HF is a real-world multicentre longitudinal registry that will provide unique information on contemporary GDMT implementation, sequencing strategies (order and speed), and prognosis in de novo, worsening, and chronic HF patients.

Use of loop diuretics in patients with chronic heart failure: an observational overview.

INTRODUCTION: This study aimed to evaluate the use and dose of loop diuretics (LDs) across the entire ejection fraction (EF) spectrum in a large, 'real-world' cohort of chronic heart failure (HF) patients. METHODS: A total of 10 366 patients with chronic HF from 34 Dutch outpatient HF clinics were analysed regarding diuretic use and diuretic dose. Data regarding daily diuretic dose were stratified by furosemide dose equivalent (FDE)>80 mg or ≤80 mg. Multivariable logistic regression models were used to assess the association between diuretic dose and clinical features. RESULTS: In this cohort, 8512 (82.1%) patients used diuretics, of which 8179 (96.1%) used LDs. LD use was highest among HF with reduced EF (HFrEF) patients (81.1%) followed by HF with mild-reduced EF (76.1%) and HF with preserved ejection fraction EF (73.8%, p<0.001). Among all LDs users, the median FDE was 40 mg (IQR: 40-80). The results of the multivariable analysis showed that New York Heart Association classes III and IV and diabetes mellitus were one of the strongest determinants of an FDE >80 mg, across all HF categories. Renal impairment was associated with a higher FDE across the entire EF spectrum. CONCLUSION: In this large registry of real-world HF patients, LD use was highest among HFrEF patients. Advanced symptoms, diabetes mellitus and worse renal function were significantly associated with a higher diuretic dose regardless of left ventricular ejection fraction.

Outcome of percutaneous coronary intervention using ultrathin-strut biodegradable polymer sirolimus-eluting versus thin-strut durable polymer zotarolimus-eluting stents in patients with comorbid peripheral arterial disease: a post-hoc analysis from two randomized trials.

Background: In patients with peripheral arterial disease (PADs), who underwent percutaneous coronary intervention (PCI), little is known about the potential impact of using different new-generation drug-eluting stents (DES) on outcome. In PCI all-comers, the results of most between-stent comparisons-stratified by strut thickness-suggested some advantage of coronary stents with ultrathin-struts. The current post-hoc analysis aimed to assess outcomes of PCI with ultrathin-strut biodegradable polymer sirolimus-eluting stents (BP-SES) vs. thin-strut durable polymer zotarolimus-eluting stents (DP-ZES) in patients with PADs. Methods: We pooled 3-year patient-level data from two large-scale randomized all-comer trials to compare Orsiro ultrathin-strut BP-SES vs. Resolute-type thin-strut DP-ZES in trial participants with concomitant PADs. BIO-RESORT (December 2012 to August 2015) and BIONYX (October 2015 to December 2016) included all-comer patients who were aged 18 years or older, capable of providing informed consent, and required a PCI. The trials had web-based randomization, with block sizes of 4 and 8, performed in a 1:1:1 or 1:1 fashion. Assessors, research staff, and patients were blinded to the type of stent used. We assessed the composite main clinical endpoint target vessel failure [TVF: cardiac death, target vessel related myocardial infarction (MI), or clinically indicated target vessel revascularization (TVR)], its components, and stent thrombosis. Results: Of 4,830 trial participants, 360 had PADs: 177 (49.2%) were treated with BP-SES and 183 (50.8%) with DP-ZES. Baseline characteristics were similar. For BP-SES, the 3-year TVF rate was 11.0% and for DP-ZES 17.9% [hazard ratio (HR): 0.59, 95% CI: 0.33-1.04; P=0.07]. For BP-SES, the TVR rate was lower than for DP-ZES (4.1% vs. 11.0%; HR: 0.36, 95% CI: 0.15-0.86; P=0.016), but this did not translate into between-group differences in cardiac death or MI. In small vessels (<2.75 mm), the TVR rate was also lower in BP-SES (5.6% vs. 13.9%; HR: 0.32, 95% CI: 0.11-0.91; P=0.024). Definite-or-probable stent thrombosis rates were 1.2% and 2.3% (P=0.43). Conclusions: In PCI patients with PADs, the 3-year TVF incidence was numerically lower in the ultrathin-strut BP-SES vs. the thin-strut DP-ZES group. Furthermore, TVR risk was significantly lower in ultrathin-strut BP-SES, mainly driven by a lower TVR rate in small vessels. Trial Registration: BIO-RESORT trial: clinicaltrials.gov (NCT01674803); BIONYX trial: clinicaltrials.gov (NCT02508714).

Impact of premature coronary artery disease on adverse event risk following first percutaneous coronary intervention.

Objectives: We assessed differences in risk profile and 3-year outcome between patients undergoing percutaneous coronary intervention (PCI) for premature and non-premature coronary artery disease (CAD). Background: The prevalence of CAD increases with age, yet some individuals develop obstructive CAD at younger age. Methods: Among participants in four randomized all-comers PCI trials, without previous coronary revascularization or myocardial infarction (MI), we compared patients with premature (men <50 years; women <55 years) and non-premature CAD. Various clinical endpoints were assessed, including multivariate analyses. Results: Of 6,171 patients, 887 (14.4%) suffered from premature CAD. These patients had fewer risk factors than patients with non-premature CAD, but were more often smokers (60.7% vs. 26.4%) and overweight (76.2% vs. 69.8%). In addition, premature CAD patients presented more often with ST-segment elevation MI and underwent less often treatment of multiple vessels, and calcified or bifurcated lesions. Furthermore, premature CAD patients had a lower all-cause mortality risk (adj.HR: 0.23, 95%-CI: 0.10-0.52; p < 0.001), but target vessel revascularization (adj.HR: 1.63, 95%-CI: 1.18-2.26; p = 0.003) and definite stent thrombosis risks (adj.HR: 2.24, 95%-CI: 1.06-4.72; p = 0.034) were higher. MACE rates showed no statistically significant difference (6.6% vs. 9.4%; adj.HR: 0.86, 95%-CI: 0.65-1.16; p = 0.33). Conclusions: About one out of seven PCI patients was treated for premature CAD. These patients had less complex risk profiles than patients with non-premature CAD; yet, their risk of repeated revascularization and stent thrombosis was higher. As lifetime event risk of patients with premature CAD is known to be particularly high, further efforts should be made to improve modifiable risk factors such as smoking and overweight. TWENTE trials: (TWENTE I, clinicaltrials.gov: NCT01066650), DUTCH PEERS (TWENTE II, NCT01331707), BIO-RESORT (TWENTE III, NCT01674803), and BIONYX (TWENTE IV, NCT02508714).

First myocardial infarction in patients with premature coronary artery disease: insights into patient characteristics and outcome after treatment with contemporary stents.

AIMS: Patients with premature coronary artery disease (CAD) have a higher incidence of myocardial infarction (MI) than patients with non-premature CAD. The aim of the present study is to asess differences in clinical outcome after a first acute MI, percutaneously treated with new-generation drug-eluting stents between patients with premature and non-premature CAD. METHODS AND RESULTS: We pooled and analysed the characteristics and clinical outcome of all patients with a first MI (and no previous coronary revascularization) at time of enrolment, in four large-scale drug-eluting stent trials. Coronary artery disease was classified premature in men aged <50 and women <55 years. Myocardial infarction patients with premature and non-premature CAD were compared. The main endpoint was major adverse cardiac events (MACE): all-cause mortality, any MI, emergent coronary artery bypass surgery, or clinically indicated target lesion revascularization. Of 3323 patients with a first MI, 582 (17.5%) had premature CAD. These patients had lower risk profiles and underwent less complex interventional procedures than patients with non-premature CAD. At 30-day follow-up, the rates of MACE [hazard ratio (HR): 0.22, 95% confidence interval (CI): 0.07-0.71; P = 0.005), MI (HR: 0.22, 95% CI: 0.05-0.89; P = 0.020), and target vessel failure (HR: 0.30, 95% CI: 0.11-0.82; P = 0.012) were lower in patients with premature CAD. At 1 year, premature CAD was independently associated with lower rates of MACE (adjusted HR: 0.50, 95% CI: 0.26-0.96; P = 0.037) and all-cause mortality (adjusted HR: 0.24, 95% CI: 0.06-0.98; P = 0.046). At 2 years, premature CAD was independently associated with lower mortality (adjusted HR: 0.16, 95% CI: 0.05-0.50; P = 0.002). CONCLUSIONS: First MI patients with premature CAD, treated with contemporary stents, showed lower rates of MACE and all-cause mortality than patients with non-premature CAD, which is most likely related to differences in cardiovascular risk profile. TWENTE trials: TWENTE I, clinicaltrials.gov: NCT01066650), DUTCH PEERS (TWENTE II, NCT01331707), BIO-RESORT (TWENTE III, NCT01674803), and BIONYX (TWENTE IV, NCT02508714).

Remote haemodynamic monitoring of pulmonary artery pressures in patients with chronic heart failure (MONITOR-HF): a randomised clinical trial.

BACKGROUND: The effect of haemodynamic monitoring of pulmonary artery pressure has predominantly been studied in the USA. There is a clear need for randomised trial data from patients treated with contemporary guideline-directed-medical-therapy with long-term follow-up in a different health-care system. METHODS: MONITOR-HF was an open-label, randomised trial, done in 25 centres in the Netherlands. Eligible patients had chronic heart failure of New York Heart Association class III and a previous heart failure hospitalisation, irrespective of ejection fraction. Patients were randomly assigned (1:1) to haemodynamic monitoring (CardioMEMS-HF system, Abbott Laboratories, Abbott Park, IL, USA) or standard care. All patients were scheduled to be seen by their clinician at 3 months and 6 months, and every 6 months thereafter, up to 48 months. The primary endpoint was the mean difference in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score at 12 months. All analyses were by intention-to-treat. This trial was prospectively registered under the clinical trial registration number NTR7673 (NL7430) on the International Clinical Trials Registry Platform. FINDINGS: Between April 1, 2019, and Jan 14, 2022, we randomly assigned 348 patients to either the CardioMEMS-HF group (n=176 [51%]) or the control group (n=172 [49%]). The median age was 69 years (IQR 61-75) and median ejection fraction was 30% (23-40). The difference in mean change in KCCQ overall summary score at 12 months was 7·13 (95% CI 1·51-12·75; p=0·013) between groups (+7·05 in the CardioMEMS group, p=0·0014, and -0·08 in the standard care group, p=0·97). In the responder analysis, the odds ratio (OR) of an improvement of at least 5 points in KCCQ overall summary score was OR 1·69 (95% CI 1·01-2·83; p=0·046) and the OR of a deterioration of at least 5 points was 0·45 (0·26-0·77; p=0·0035) in the CardioMEMS-HF group compared with in the standard care group. The freedom of device-related or system-related complications and sensor failure were 97·7% and 98·8%, respectively. INTERPRETATION: Haemodynamic monitoring substantially improved quality of life and reduced heart failure hospitalisations in patients with moderate-to-severe heart failure treated according to contemporary guidelines. These findings contribute to the aggregate evidence for this technology and might have implications for guideline recommendations and implementation of remote pulmonary artery pressure monitoring. FUNDING: The Dutch Ministry of Health, Health Care Institute (Zorginstituut), and Abbott Laboratories.

Identifying distinct clinical clusters in heart failure with mildly reduced ejection fraction.

INTRODUCTION: Heart failure (HF) is a heterogeneous syndrome, and the specific sub-category HF with mildly reduced ejection fraction (EF) range (HFmrEF; 41-49% EF) is only recently recognised as a distinct entity. Cluster analysis can characterise heterogeneous patient populations and could serve as a stratification tool in clinical trials and for prognostication. The aim of this study was to identify clusters in HFmrEF and compare cluster prognosis. METHODS AND RESULTS: Latent class analysis to cluster HFmrEF patients based on their characteristics was performed in the Swedish HF registry (n = 7316). Identified clusters were validated in a Dutch cross-sectional HF registry-based dataset CHECK-HF (n = 1536). In Sweden, mortality and hospitalisation across the clusters were compared using a Cox proportional hazard model, with a Fine-Gray sub-distribution for competing risks and adjustment for age and sex. Six clusters were discovered with the following prevalence and hazard ratio with 95% confidence intervals (HR [95%CI]) vs. cluster 1: 1) low-comorbidity (17%, reference), 2) ischaemic-male (13%, HR 0.9 [95% CI 0.7-1.1]), 3) atrial fibrillation (20%, HR 1.5 [95% CI 1.2-1.9]), 4) device/wide QRS (9%, HR 2.7 [95% CI 2.2-3.4]), 5) metabolic (19%, HR 3.1 [95% CI 2.5-3.7]) and 6) cardio-renal phenotype (22%, HR 2.8 [95% CI 2.2-3.6]). The cluster model was robust between both datasets. CONCLUSION: We found robust clusters with potential clinical meaning and differences in mortality and hospitalisation. Our clustering model could be valuable as a clinical differentiation support and prognostic tool in clinical trial design.

Phenotypic patient profiling for improved implementation of guideline-directed medical therapy: An exploratory analysis in a large real-world chronic heart failure cohort.

Aims: Implementation of guideline-recommended pharmacological treatment in heart failure (HF) patients remains challenging. In 2021, the European Heart Failure Association (HFA) published a consensus document in which patient profiles were created based on readily available patient characteristics and suggested that treatment adjusted to patient profile may result in better individualized treatment and improved guideline adherence. This study aimed to assess the distribution of these patient profiles and their treatment in a large real-world chronic HF cohort. Methods and results: The HFA combined categories of heart rate, blood pressure, presence of atrial fibrillation, chronic kidney disease, and hyperkalemia into eleven phenotypic patient profiles. A total of 4,455 patients with chronic HF and a left ventricular ejection fraction ≤40% with complete information on all characteristics were distributed over these profiles. In total, 1,640 patients (36.8%) could be classified into one of the HFA profiles. Three of these each comprised >5% of the population and consisted of patients with a heart rate >60 beats per minute with normal blood pressure (>90/60 mmHg) and no hyperkalemia. Conclusion: Nearly forty percent of a real-world chronic HF population could be distributed over the eleven patient profiles as suggested by the HFA. Phenotype-specific treatment recommendations are clinically relevant and important to further improve guideline implementation.

Serum potassium level and mineralocorticoid receptor antagonist dose in a large cohort of chronic heart failure patients.

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.

Risk of bleeding after percutaneous coronary intervention and its impact on further adverse events in clinical trial participants with comorbid peripheral arterial disease.

BACKGROUND: Both patients with obstructive coronary artery disease (CAD) and patients with peripheral arterial disease (PADs) have an increased bleeding risk. Information is scarce on bleeding in CAD patients, treated with percutaneous coronary intervention (PCI), who have comorbid PADs. We assessed whether PCI patients with PADs have a higher bleeding risk than PCI patients without PADs. Furthermore, in PCI patients with PADs we evaluated the extent by which bleeding increased the risk of further adverse events. METHODS: Three-year pooled patient-level data of two randomized PCI trials (BIO-RESORT, BIONYX) with drug-eluting stents were analyzed to assess mortality and the composite endpoint major adverse cardiac events (MACE: all-cause mortality, any myocardial infarction, emergent coronary artery bypass surgery, or target lesion revascularization). RESULTS: Among 5989 all-comer patients, followed for 3 years, bleeding occurred in 7.7% (34/440) with comorbid PADs and 5.0% (279/5549) without PADs (HR: 1.59, 95%CI: 1.11-2.23, p = 0.010). Of all PADs patients, those with a bleeding had significantly higher rates of all-cause mortality (HR: 4.70, 95%CI: 2.37-9.33, p < 0.001) and MACE (HR: 2.39, 95%CI: 1.23-4.31, p = 0.003). Furthermore, PADs patients with a bleeding were older (74.4 ± 6.9 vs. 67.4 ± 9.5, p < 0.001). After correction for age and other potential confounders, bleeding remained independently associated with all-cause mortality (adj.HR: 2.97, 95%CI: 1.37-6.43, p = 0.006) while the relation of bleeding with MACE became borderline non-significant (adj.HR: 1.85, 95%CI: 0.97-3.55, p = 0.06). CONCLUSION: PCI patients with PADs had a higher bleeding risk than PCI patients without PADs. In PADs patients, bleeding was associated with all-cause mortality, even after adjustment for potential confounders.

Final 5-Year Report of the Randomized BIO-RESORT Trial Comparing 3 Contemporary Drug-Eluting Stents in All-Comers.

Background In a previous trial, higher 5-year mortality was observed following treatment with biodegradable polymer Orsiro sirolimus-eluting stents (SES). We assessed 5-year safety and efficacy of all-comers as well as patients with diabetes treated with SES or Synergy everolimus-eluting stents (EES) versus durable polymer Resolute Integrity zotarolimus-eluting stents (ZES). Methods and Results The randomized BIO-RESORT (Comparison of Biodegradable Polymer and Durable Polymer Drug-Eluting Stents in an All Comers Population) trial enrolled 3514 all-comer patients at 4 Dutch cardiac centers. Patients aged ≥18 years who required percutaneous coronary intervention were eligible. Participants were stratified for diabetes and randomized to treatment with SES, EES, or ZES (1:1:1). The main end point was target vessel failure (cardiac mortality, target vessel myocardial infarction, or target vessel revascularization). Five-year follow-up was available in 3183 of 3514 (90.6%) patients. The main end point target vessel failure occurred in 142 of 1169 (12.7%) patients treated with SES, 130 of 1172 (11.6%) treated with EES, versus 157 of 1173 (14.1%) treated with ZES (hazard ratio [HR], 0.89 [95% CI, 0.71-1.12], Plog-rank=0.31; and HR, 0.82 [95% CI, 0.65-1.04], Plog-rank=0.10, respectively). Individual components of target vessel failure showed no significant between-stent difference. Very late definite stent thrombosis rates were low and similar (SES, 1.1%; EES, 0.6%; ZES, 0.9%). In patients with diabetes, target vessel failure did not differ significantly between stent-groups (SES, 19.8%; EES, 19.2%; versus ZES, 21.1% [Plog-rank=0.69 and Plog-rank=0.63]). Conclusions Orsiro SES, Synergy EES, and Resolute Integrity ZES showed similar 5-year outcomes of safety and efficacy, including mortality. A prespecified stent comparison in patients with diabetes also revealed no significant differences in 5-year clinical outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01674803.

Non-cardiovascular medication and readmission for heart failure: an observational cohort study.

Background Among heart failure (HF) patients, hospital readmissions are a major concern. The medication taken by a patient may provide information on comorbidities and conditions and may be used as an indicator to identify populations at an increased risk of HF readmission. Aim This study explored the use of non-cardiovascular medication at hospital discharge from the first HF admission in search of indicators of high risk of readmission for HF. Method The study included 22,476 HF patients from the Dutch PHARMO Database Network at their first HF hospitalization. The data was divided into training and validation sets. A Cox regression model with demographics, date of first HF hospital admission and non-cardiovascular medication present at discharge, adjusted for cardiovascular medication, was developed in the training set and subsequently implemented in the validation set. Results The study included 22,476 patients, mean age 76.7 years (range 18-104) and median follow-up time 2.5 years (range 0-15.7 years). During the study period 6,725 (29.9%) patients were readmitted for HF, with a median time-to-readmission of 7 months (range 0-14.3 years). Non-cardiovascular medication associated with a high risk of readmission for HF were identified as indicators of high risk, with no implied causal relationship. Patients prescribed antigout medications presented a 25% increased risk of readmission (HR 1.25, 95%CI 1.09-1.45, P = 0.002). Patients using insulin had an 18% higher risk of readmission versus patients not using insulin (HR 1.18, 95%CI 1.06-1.32, P = 0.002), but not versus patients treated with other blood-glucose-lowering drugs. No association between the risk of readmission and NSAIDs use was observed. Conclusion The results suggest that diabetes is responsible for the higher HF-readmission risk observed in patients prescribed insulin. The observed risk in users of antigout medication should be further investigated. The absence of an association with the use of NSAIDs should be interpreted with caution.

Thirst in stable heart failure patients; time to reconsider fluid restriction and prescribed diuretics.

AIMS: One of the bothersome symptoms that heart failure (HF) patients can experience is thirst. There are limited data on the association between thirst and fluid intake and clinical variables. Therefore, the aim of this study was to describe severe thirst in stable HF patients and assess factors related to severe thirst, including actual fluid intake and sodium intake. METHODS AND RESULTS: The study had a cross-sectional design. Stable HF patients from two HF clinics in the Netherlands were included and assessed thirst by a visual analogue scale ranging from 0 to 100. They also completed questionnaires on thirst distress, self-care behaviour, and HF symptoms. A 3 day food diary was completed to assess actual fluid intake and sodium intake. Finally, patients collected urine for 24 h. Patients were divided into severe and low thirst based on thirst score and thirst distress. T-tests, Mann-Whitney tests, and χ2 tests were conducted to assess differences between both groups. Multivariable logistic regression analysis was performed to assess factors associated with severe thirst. A total of 100 patients were included (40% female, mean age 72 ± 12) of which 68 completed the food diary. The mean thirst score was 28 ± 25, and 25% experienced severe thirst. The majority of patients (94%) were prescribed a fluid restriction, 37% had a restriction between 1500 and 2000 mL, and 32% a restriction of 1500 mL. Severe thirst in the total group with 100 patients was associated with a higher dose of loop diuretics [odds ratio (OR) 3.25; 95% confidence interval (CI) 1.01-10.45; P = 0.048] and a higher urine output over 24 h (OR 1.002; 95% CI 1.00-1.003; P = 0.010). In the group of patients who completed the food diary (N = 68), severe thirst was associated with a higher sodium intake (OR 1.002; 95% CI 1.001-1.003; P = 0.003), a higher dose of loop diuretics (OR 22.69; 95% CI 2.78-185.04; P = 0.004), and more fatigue (OR 11.2; 95% CI 1.54-82.12; P = 0.017). CONCLUSIONS: A quarter of all stable HF patients experienced severe thirst. A higher dose of loop diuretics was associated with more thirst; therefore, it might be important to review the dose of loop diuretics critically and try to decrease it in order to relieve severe thirst. Because all patients were prescribed a fluid restriction, a reconsideration of this restriction is also suggested.

Outcome after percutaneous coronary intervention with contemporary stents in patients with concomitant peripheral arterial disease: A patient-level pooled analysis of four randomized trials.

BACKGROUND AND AIMS: A considerable number of patients who undergo percutaneous coronary intervention (PCI) also have peripheral arterial disease (PAD) - a signal of more advanced atherosclerosis. After bare metal and early-generation drug-eluting coronary stent implantation, PAD patients showed inferior outcome. As stents and medical treatment were further improved, we aimed to assess the impact of PAD on outcome of PCI with contemporary new-generation stents. METHODS: We analyzed 3-year pooled patient-level data from 4 large-scale randomized new-generation stent trials to compare all-comer patients with and without (core lab-verified) history of symptomatic PAD, defined as obstructive lesions in peripheral locations including lower and upper extremities, carotid, vertebral, mesenteric and renal arteries. Main endpoint was target vessel failure: cardiac death, target vessel-related myocardial infarction, or clinically indicated target vessel revascularization. RESULTS: Of all 9204 patients, 695 (7.6%) had a history of symptomatic PAD. They were older and had more often diabetes, renal failure, hypertension, hypercholesterolemia, and prior stroke. PAD was an independent risk factor for target vessel failure (adjusted-HR:1.42, 95%-CI:1.12-1.73, p = 0.001). Target vessel revascularization (adjusted-HR:1.37, 95%-CI:1.04-1.80, p = 0.026), death (adjusted-HR:1.52, 95%-CI:1.17-1.99, p = 0.002), and major adverse cardiovascular event risks (adjusted-HR:1.36, 95%-CI:1.13-1.64, p = 0.001) were also substantially higher. CONCLUSIONS: A history of symptomatic PAD still allows to simply identify patients with increased risk of unfavorable clinical outcome after PCI, including a higher risk of repeated coronary revascularization, despite using contemporary stents. In clinical practice, this knowledge about higher event risks of PAD patients is helpful both during Heart Team discussions and when informing patients about the procedural risk.