Gerard C.M. Linssen

The Na+/H+exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction: Results of the evaluation of the safety and cardioprotective effects of eniporide in acute myocardial infarction (ESCAMI) trial

OBJECTIVES We conducted an international, prospective, randomized, double-blind, placebo-controlled phase 2 trial in patients undergoing thrombolytic therapy or primary angioplasty for acute ST-elevation myocardial infarction (MI) to investigate the effect of eniporide on infarct size and clinical outcome. BACKGROUND Experimental studies suggest that the activity of the Na(+)/H(+) exchange (NHE) plays an important role in the unfavorable sequels of myocardial ischemia and reperfusion. Eniporide specifically inhibits the NHE-1 isoform and has been shown to limit infarct size in experimental models. METHODS The primary efficacy end point was the infarct size measured by the cumulative release of alpha-hydroxybutyrate dehydrogenase (alpha-HDBH) (area under the curve [AUC] 0 to 72 h). In stage 1, 50, 100, 150 or 200 mg eniporide given as a 10-min infusion before start of reperfusion therapy were compared with placebo in 430 patients, and in stage 2, 100 and 150 mg eniporide were compared with placebo in 959 patients. RESULTS In stage 1, the administration of 100 mg and 150 mg eniporide resulted in smaller infarct sizes (mean alpha-HBDH AUC in U/ml x h, placebo: 44.2, 100 mg eniporide: 40.2, 150 mg eniporide: 33.9), especially in the angioplasty group. In contrast, in stage 2 there was no difference in the enzymatic infarct size between the three groups (placebo: 41.2, 100 mg eniporide: 43.0, 150 mg eniporide: 41.5). Overall there was no effect of eniporide on clinical outcome (death, cardiogenic shock, heart failure, life-threatening arrhythmias). However, there was a significant reduction of the incidence of heart failure in patients reperfused late (>4 h). CONCLUSIONS In this large study administration of the NHE-1 inhibitor eniporide, before reperfusion therapy in patients with acute ST elevation MI, did not limit infarct size or improve clinical outcome.

B-Type Natriuretic Peptide and Prognosis in Heart Failure Patients With Preserved and Reduced Ejection Fraction

OBJECTIVES This study sought to determine the prognostic value of B-type natriuretic peptide (BNP) in patients with heart failure with preserved ejection fraction (HFPEF), in comparison to data in HF patients with reduced left ventricular (LV) EF (≤40%). BACKGROUND Management of patients with HFPEF is difficult. BNP is a useful biomarker in patients with reduced LVEF, but data in HFPEF are scarce. METHODS In this study, 615 patients with mild to moderate HF (mean age 70 years, LVEF 33%) were followed for 18 months. BNP concentrations were measured at baseline and were related to the primary outcome, that is, a composite of all-cause mortality and HF hospitalization, and to mortality alone. The population was divided in quintiles, according to LVEF, and patients with reduced LVEF were compared with those with HFPEF. RESULTS There were 257 patients (42%) who had a primary endpoint and 171 (28%) who died. BNP levels were significantly higher in patients with reduced LVEF than in those with HFPEF (p < 0.001). BNP was a strong predictor of outcome, but LVEF was not. Importantly, if similar levels of BNP were compared across the whole spectrum of LVEF, and for different cutoff levels of LVEF, the associated risk of adverse outcome was similar in HFPEF patients as in those with reduced LVEF. CONCLUSIONS BNP levels are lower in patients with HFPEF than in patients with HF with reduced LVEF, but for a given BNP level, the prognosis in patients with HFPEF is as poor as in those with reduced LVEF.

Third-generation zotarolimus-eluting and everolimus-eluting stents in all-comer patients requiring a percutaneous coronary intervention (DUTCH PEERS): a randomised, single-blind, multicentre, non-inferiority trial

BACKGROUND Third-generation, permanent-polymer-based drug-eluting stents with novel, flexible designs might be more easily delivered than previous generations of stents in complex coronary lesions, but might be less longitudinally stable. We aimed to assess the safety and efficacy in all-comer patients of two third-generation stents that are often used clinically, but that have not yet been compared, and one of which has not previously been assessed in a randomised trial. METHODS In this investigator-initiated, single-blind, multicentre, randomised, two-arm, non-inferiority trial, patients aged 18 years and older who required a percutaneous coronary intervention with implantation of a drug-eluting stent were recruited from four study sites in the Netherlands. We randomly assigned patients by independently managed computer-generated allocation sequences in a 1:1 ratio to receive either cobalt-chromium-based zotarolimus-eluting stents (Resolute Integrity, Medtronic, Santa Rosa, CA, USA) or platinum-chromium-based everolimus-eluting stents (Promus Element, Boston Scientific, Natick, MA, USA). Patients and analysts were masked to the allocated stent, but treating clinicians were not. The primary endpoint of target-vessel failure was a composite of safety (cardiac death or target-vessel-related myocardial infarction) and efficacy (target-vessel revascularisation) at 12 months, analysed by intention to treat (with a non-inferiority margin of 3·6%). This trial is registered with ClinicalTrials.gov, number NCT01331707. FINDINGS Between Nov 25, 2010, and May 24, 2012, 1811 eligible all-comer patients, with 2371 target lesions, were enrolled in the study. 370 (20%) patients presented with ST-elevation myocardial infarction and 447 (25%) with non-ST-elevation myocardial infarction. 906 patients were assigned to receive zotarolimus-eluting stents and 905 to receive everolimus-eluting stents. Ease of stent delivery was shown by very low numbers of patients requiring treatment other than their assigned study treatment (six [1%] in the zotarolimus-eluting stent group vs five [1%] in the everolimus-eluting stent group; p=0·22). 12-month follow-up results were available for 1810 patients (one patient in the zotarolimus-eluting stent group withdrew consent). The primary endpoint was met by 55 (6%) of 905 patients in the zotarolimus-eluting stent group and 47 (5%) of 905 in the everolimus-eluting stent group. The zotarolimus-eluting stent was non-inferior to the everolimus-eluting stent (absolute risk difference 0·88%, 95% CI -1·24% to 3·01%; upper limit of one-sided 95% CI 2·69%; non-inferiority p=0·006). We noted no significant between-group differences in individual components of the primary endpoint. Definite stent thrombosis occurred in three (0·3%) patients in the zotarolimus-eluting stent group and six (0·7%) patients in the everolimus-eluting stent group (p=0·34). Longitudinal stent deformation was seen only in the everolimus-eluting stent group (nine [1·0%] of 905 vs 0 of 906, p=0·002; nine of 1591 [0·6%] everolimus-eluting stents implanted became deformed), but was not associated with any adverse events. INTERPRETATION Both stents were similarly efficacious and safe, and provided excellent clinical outcomes, especially in view of the large number of patients who presented with acute myocardial infarctions. FUNDING Boston Scientific, Medtronic.

Clinical and prognostic effects of atrial fibrillation in heart failure patients with reduced and preserved left ventricular ejection fraction

Atrial fibrillation (AF) is common in heart failure (HF), but few data regarding the prognostic relevance of AF are available in HF patients with preserved left ventricular ejection fraction (HF‐PEF). We aimed to study the clinical impact of AF vs. sinus rhythm (SR) in stabilized HF patients with reduced left ventricular ejection fraction (HF‐REF) and in those with preserved left ventricular ejection fraction (HF‐PEF).

N-terminal pro-B-type natriuretic peptide is an independent predictor of cardiovascular morbidity and mortality in the general population

AIMS Natriuretic peptides including N-terminal pro-B-type natriuretic peptide (NT-proBNP) are established biomarkers in heart failure. However, their prognostic value in the general population is less well established. The purpose of our study was to investigate the prognostic properties of NT-proBNP for death and cardiovascular (CV) events in the general population. METHODS AND RESULTS In the population-based Prevention of Renal and Vascular End-stage Disease (PREVEND) study, 8383 subjects were prospectively followed for a median period of 7.5 years. There were 4181 (49.9%) males and 4202 (50.1%) females, mean age was 49.3 +/- 12.7 years (range 28-75). Median NT-proBNP at baseline was 37.7 pg/mL (IQR 16.8-73.8). All-cause death occurred in 437 (5.2%) subjects and there were 557 (6.6%) CV events. Higher levels of plasma NT-proBNP were related to higher event rates. When adjusted for age, gender, and other relevant covariates, each doubling of NT-proBNP remained significantly associated with a 22% increased risk for all-cause mortality (P < 0.001) and a 16% increased risk of CV events (P < 0.001). CONCLUSION In this large community-based cohort, plasma NT-proBNP was a strong predictor of death and a wide range of CV events.

Depressive symptoms are prominent among elderly hospitalised heart failure patients

There are limited data on the prevalence of depressive symptoms in hospitalised elderly HF patients and demographic and clinical characteristics associated with depressive symptoms are not known.

The spectrum of death after myocardial infarction: A necropsy study

To determine the relative frequency of the causes of death in the acute (less than 24 hours), early (24 hours to 3 weeks), and chronic (greater than 3 weeks) phases of myocardial infarction, data from all autopsies performed at a university hospital during a 56-month period were reviewed. Autopsies were performed in 56% of in-hospital deaths and 27% of patients dead on arrival in the emergency room (out-of-hospital deaths). In 271 cases of suspected cardiac death, a myocardial infarction of any age was identified. Death had occurred in the acute phase of a first infarction in 19 patients and was most frequently due to pump failure (37%) followed by cardiac rupture (26%) and arrhythmias (21%). Death had occurred 24 hours to 3 weeks after a first infarction in 80 patients and was most frequently due to pump failure (44%), rupture (27%), and arrhythmias (16%). Recurrent acute infarction was found in 32% of patients whose deaths were due to arrhythmias or pump failure and in 19% of those whose deaths were due to rupture. Death had occurred greater than 3 weeks after a first infarction in 172 patients. In 132 (77%) of these patients death was due to a complication of a new acute or recent infarction. Myocardial rupture was a less frequent cause of death in patients with recurrent infarction (8%) than in those dying in the acute or early phase after their first infarction (27%, p = 0.0009). A primary arrhythmia in the absence of recurrent infarction or ischemia accounted for only 14% of out-of-hospital deaths late after an infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary N-Terminal Prohormone Brain Natriuretic Peptide Excretion in Patients With Chronic Heart Failure

Background— Urinary excretion is currently regarded as the main mechanism of elimination of N-terminal prohormone brain natriuretic peptide (NT-proBNP). The clinical implications and the value of measurement of urinary NT-proBNP in patients with heart failure are largely unknown. Methods and Results— We studied 94 patients (age, 58±11 years; 79% men) with chronic heart failure (CHF) and 20 age- and sex-matched healthy control subjects. Glomerular filtration rate and effective renal plasma flow were measured as clearance of 125I-iothalamate and 131I-hippuran, respectively. NT-proBNP levels were determined in both plasma and 24-hour urine collections. Mean left ventricular ejection fraction of CHF patients was 0.28±0.09. Plasma NT-proBNP levels were higher in CHF patients compared with control subjects (median, 547 versus 41 pg/mL; P<0.001). Urinary NT-proBNP excretion, however, was substantially lower in CHF patients (median, 0.13 versus 2.3 mL/min; P<0.001). Urinary NT-proBNP excretion was independent of estimated glomerular filtration rate. In both CHF patients and control subjects, there was a strong and inverse relation between plasma NT-proBNP concentrations and urinary NT-proBNP excretion (r=−0.72 and r=−0.65 respectively; both P<0.001). Decreased renal plasma flow in CHF was significantly associated with a lower excretion of NT-proBNP (P=0.026). Conclusions— Urinary NT-proBNP excretion is lower in patients with CHF compared with control subjects and is inversely related to plasma NT-proBNP. Urinary NT-proBNP is associated with renal plasma flow but not with estimated glomerular filtration rate. Elevated levels of plasma NT-proBNP in patients with CHF might be explained not only by myocardial stress but also by a marked decrease in urinary excretion.

Clinical Events and Patient-Reported Chest Pain in All-Comers Treated With Resolute Integrity and Promus Element Stents : 2-Year Follow-Up of the DUTCH PEERS (DUrable Polymer-Based STent CHallenge of Promus ElemEnt Versus ReSolute Integrity) Randomized Trial (TWENTE II)

OBJECTIVES This study assessed clinical events and patient-reported chest pain 2 years after treatment of all-comers with Resolute Integrity zotarolimus-eluting stents (Medtronic Vascular, Santa Rosa, California) and Promus Element everolimus-eluting stents (Boston Scientific, Natick, Massachusetts). BACKGROUND For both drug-eluting stents (DES), no all-comer outcome data from >12 months of follow-up have been published. Although there is increasing interest in patient-reported chest pain following stenting, data with novel DES are scarce. METHODS The DUTCH PEERS multicenter trial (TWENTE II) (DUrable Polymer-Based STent CHallenge of Promus ElemEnt Versus ReSolute Integrity) Randomized Trial [TWENTE II]) randomized 1,811 all-comer patients to treatment with 1 type of DES. Monitoring and event adjudication were performed by independent contract research organizations. RESULTS The 2-year follow-up of 1,810 patients (99.9%) was available. The primary composite endpoint target vessel failure occurred in 8.6% and 7.8% of patients treated with zotarolimus- and everolimus-eluting stents, respectively (p = 0.55). Rates of components of target vessel failure were: cardiac death (2.4% vs. 1.9%, p = 0.42); target vessel-related myocardial infarction (2.4% vs. 1.8%, p = 0.33); clinically-indicated target vessel revascularization (4.6% vs. 4.9%, p = 0.83). At 1- and 2-year follow-up, >80% of patients were free from chest pain (no between-stent difference). In addition, >87% of patients were either free from chest pain or experienced pain only at maximal physical exertion, but not during normal daily activities. Patients with chest pain after 12 months at no more than moderate physical effort had a higher risk of target vessel revascularization during the following year (hazard ratio: 1.89 [95% confidence interval: 1.05 to 3.39], p = 0.03). CONCLUSIONS During the second year of follow-up, the incidence of adverse clinical endpoints remained similar and low for both DES. The vast majority of patients were free from chest pain.

Long-term follow-up in optimally treated and stable heart failure patients: primary care vs. heart failure clinic. Results of the COACH-2 study.

It has been suggested that home‐based heart failure (HF) management in primary care may be an alternative to clinic‐based management in HF patients. However, little is known about adherence to HF guidelines and adherence to the medication regimen in these home‐based programmes. The aim of the current study was to determine whether long‐term follow‐up and treatment in primary care is equally effective as follow‐up at a specialized HF clinic in terms of guideline adherence and patient adherence, in HF patients initially managed and up‐titrated to optimal treatment at a specialized HF clinic.