Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial.

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure? METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death. RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant. CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.

The Impact of Ferric Derisomaltose on Cardiovascular and Noncardiovascular Events in Patients With Anemia, Iron Deficiency, and Heart Failure With Reduced Ejection Fraction.

BACKGROUND: In some countries, intravenous ferric derisomaltose (FDI) is only licensed for treating iron deficiency with anemia. Accordingly, we investigated the effects of intravenous FDI in a subgroup of patients with anemia in the IRONMAN (Effectiveness of Intravenous (IV) Iron Treatment Versus Standard Care in Patients With Heart Failure and Iron Deficiency) trial. METHOD AND RESULTS: IRONMAN enrolled patients with heart failure, a left ventricular ejection fraction of ≤45%, and iron deficiency (ferritin <100 µg/L or transferrin saturation of <20%), 771 (68%) of whom had anemia (hemoglobin <12 g/dL for women and <13 g/dL for men). Patients were randomized, open label, to FDI (n = 397) or usual care (n = 374) and followed for a median of 2.6 years. The primary end point, recurrent hospitalization for heart failure and cardiovascular death, occurred less frequently for those assigned to FDI (rate ratio 0.78, 95% confidence interval 0.61-1.01; P = .063). First event analysis for cardiovascular death or hospitalization for heart failure, less affected by the coronavirus disease 2019 pandemic, gave similar results (hazard ratio 0.77, 95% confidence interval 0.62-0.96; P = .022). Patients randomized to FDI reported a better Minnesota Living with Heart Failure quality of life, for overall (P = .013) and physical domain (P = .00093) scores at 4 months. CONCLUSIONS: In patients with iron deficiency anemia and heart failure with reduced left ventricular ejection fraction, intravenous FDI improves quality of life and may decrease cardiovascular events.

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. METHODS: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 µg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. FINDINGS: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8-3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference -7·00% [95% CI -12·69 to -1·32]; p=0·016). INTERPRETATION: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. FUNDING: British Heart Foundation and Pharmacosmos.

Anterior mitral valve perforation in the absence of acute infection: Diagnosis by two-dimensional and three-dimensional transesophageal echocardiography.

Anterior mitral valve leaflet (AMVL) perforation is most commonly seen in the setting of infective endocarditis. We present a case of AMVL perforation in a previously healthy 62-year-old male who presented with a six-month history of worsening dyspnea and peripheral edema. Blood cultures, inflammatory markers, and autoimmune profile were negative. Transthoracic echocardiography demonstrated severe mitral regurgitation (MR) with a possible AMVL perforation, which was confirmed by three-dimensional transesophageal echocardiography as a well-circumscribed hole in the A2 segment. The patient made a successful recovery from mitral valve repair surgery.

Specialist intervention is associated with improved patient outcomes in patients with decompensated heart failure: evaluation of the impact of a multidisciplinary inpatient heart failure team.

OBJECTIVE: The study aimed to evaluate the impact of a multidisciplinary inpatient heart failure team (HFT) on treatment, hospital readmissions and mortality of patients with decompensated heart failure (HF). METHODS: A retrospective service evaluation was undertaken in a UK tertiary centre university hospital comparing 196 patients admitted with HF in the 6 months prior to the introduction of the HFT (pre-HFT) with all 211 patients seen by the HFT (post-HFT) during its first operational year. RESULTS: There were no significant differences in patient baseline characteristics between the groups. Inpatient mortality (22% pre-HFT vs 6% post-HFT; p<0.0001) and 1-year mortality (43% pre-HFT vs 27% post-HFT; p=0.001) were significantly lower in the post-HFT cohort. Post-HFT patients were significantly more likely to be discharged on loop diuretics (84% vs 98%; p=<0.0001), ACE inhibitors (65% vs 76%; p=0.02), ACE inhibitors and/or angiotensin receptor blockers (83% vs 91%; p=0.02), and mineralocorticoid receptor antagonists (44% vs 68%; p<0.0001) pre-HFT versus post-HFT, respectively. There was no difference in discharge prescription rates of beta-blockers (59% pre-HFT vs 63% post-HFT; p=0.45). The mean length of stay (17±19 days pre-HFT vs 19±18 days post-HFT; p=0.06), 1-year all-cause readmission rates (46% pre-HFT vs 47% post-HFT; p=0.82) and HF readmission rates (28% pre-HFT vs 20% post-HFT; p=0.09) were not different between the groups. CONCLUSIONS: The introduction of a specialist inpatient HFT was associated with improved patient outcome. Inpatient and 1-year mortality were significantly reduced. Improved use of evidence-based drug therapies, more intensive diuretic use and multidisciplinary care may contribute to these differences in outcome.

A unique case of "double-orifice aortic valve"-comprehensive assessment by 2-, 3-dimensional, and color Doppler echocardiography.

Transesophageal echocardiography (TEE) is a powerful imaging tool for the comprehensive assessment of valvular structure and function. TEE may be of added benefit when anatomy is difficult to delineate accurately by transthoracic echocardiography. In this article, we present 2-, 3-dimensional, and color Doppler TEE images from a male patient with aortic stenosis. A highly unusual and complex pattern of valvular calcification created a functionally "double-orifice" valve. Such an abnormality may have implications for the accuracy of continuous-wave Doppler echocardiography, which assumes a single orifice valve in native aortic valves.

Anemia and its association with clinical outcome in heart failure patients undergoing cardiac resynchronization therapy.

PURPOSE: Although a substantial proportion of patients with heart failure (HF) have anemia, there is a paucity of data evaluating the impact of anemia on clinical outcome in CRT patients. Our goal was to examine the ability of baseline hemoglobin (Hb) level and change in Hb level over time to predict clinical 2-year outcome and echocardiographic response to CRT. METHODS: Three hundred consecutive CRT patients (median 72 years [interquartile range (IQR) 16 years], 19% female) with baseline and follow-up hematological profiles available were examined. Baseline anemia was defined as Hb <12 g/dL in women and <13 g/dL in men, and patients were grouped into equal quartiles based on change in Hb. Two-year clinical outcome was determined using a composite endpoint that included HF hospitalization, left ventricular assist device (LVAD) placement, heart transplantation, and all-cause mortality. Echocardiographic reverse remodeling was examined at 6-month follow-up. RESULTS: One hundred fifty-one anemic patients were compared to 149 non-anemic patients. Changes in left ventricular dimensions and ejection fraction were similar for both groups. Univariate predictors of 2-year clinical outcome included baseline creatinine level, diuretic usage, and anemia; in multivariable regression, baseline anemia was an independent predictor for outcome (hazard ratio [HR] 1.79, 95% confidence interval [CI] [1.22-2.63], p = 0.003). The quartile with the most negative change in Hb concentration over time (≤-1.00 g/dL) had poorer event-free 2-year survival (HR 1.84, CI [1.13-3.00], p = 0.014). CONCLUSIONS: Baseline anemia and early postimplantation decline in Hb levels are associated with a worse 2-year prognosis in CRT patients, even though the magnitude of left ventricular reverse remodeling is similar compared to non-anemic patients.

How to improve outcomes with cardiac resynchronisation therapy: importance of lead positioning.

Cardiac resynchronisation therapy (CRT), by retiming the failing heart, improves symptoms, reduces hospitalisations and improves survival in patients with left ventricular dysfunction and QRS prolongation. However, not all patients "respond" to CRT. Successful CRT depends on appropriate patient selection, optimal lead positioning, device programming/optimisation and optimal medical therapy. This review article focuses on the importance of lead positioning in improving outcomes.

UK guidelines for referral and assessment of adults for heart transplantation.

Patients with advanced heart failure have a dismal prognosis and poor quality of life. Heart transplantation provides an effective treatment for a subset of these patients. This article provides cardiologists with up-to-date information about referral for transplantation, the role of left ventricular assist devices prior to transplant, patient selection, waiting-list management and donor heart availability. Timing is of central importance; patients should be referred before complications (eg, cardiorenal syndrome or secondary pulmonary hypertension) have developed that will increase the risk of, or potentially contraindicate, transplantation. Issues related to heart failure aetiology, comorbidity and adherence to medical treatment are reviewed. Finally, the positive role that cardiologists can play in promoting and facilitating organ donation is discussed.

Heart failure: the challenge of selecting patients for implantable cardioverter defibrillator therapy.

Patients with heart failure die predominantly of progressive pump failure or sudden cardiac death. Therefore, it is attractive to believe that an implantable cardioverter defibrillator (ICD) will dramatically reduce mortality by reducing sudden death. However, unfortunately it is not that simple; sudden death is not the same as ICD-preventable death. While ICD prophylaxis always reduces arrhythmic death, it does not always reduce all-cause mortality due to competing risks. Importantly, an arrhythmia may be a marker for heart failure decompensation, with patients at increased risk of heart failure death following shock therapy. Randomized trials have now demonstrated the potential benefits of ICDs in selected patients with left ventricular dysfunction, yet they have also failed to demonstrate benefit in populations where one might have expected to see benefit (e.g., early post-myocardial infarction). Device therapy can offer heart failure patients much more than just a simple shock box. The addition of a left ventricular lead to allow biventricular pacing (cardiac resynchronization therapy) improves symptoms and prolongs life in selected patients with QRS prolongation. Newer technologies allow remote monitoring through the device, which offers the potential to recognize heart failure decompensation or arrhythmias early so that appropriate treatment can be instituted. However, deciding which patient should receive an ICD remains one of the most challenging questions in cardiovascular medicine.

Contrast nephropathy post cardiac resynchronization therapy: an under-recognized complication with important morbidity.

OBJECTIVES: The aim of the study was to define the incidence of contrast nephropathy in patients undergoing cardiac resynchronization therapy (CRT). BACKGROUND: CRT is a promising new treatment for advanced heart failure. It is a technically demanding procedure with a recognized failure/complication rate. Contrast nephropathy is a well-recognized complication of coronary angiography/intervention, but has not been described following CRT. METHODS: We performed a retrospective chart review of patients who had undergone CRT at Mount Sinai Hospital, a tertiary referral center for heart failure management, to define the incidence of contrast nephropathy in patients undergoing CRT. Contrast nephropathy was defined as the occurrence of a 25% or greater increase in serum creatinine within 48 h after contrast administration. RESULTS: Sixty-eight patients underwent a total of seventy-three procedures between October 1st 2000 and December 31st 2003. Ten patients (14%) developed contrast nephropathy. Three of these patients (4%) required hemofiltration and one died. Patients with creatinine > or = 200 micromol/l (2.26 mg/dl) were more likely to develop contrast nephropathy than those with creatinine < 200 micromol/l (6/14 patients [43%] v 4/59 patients [7%], p<0.01). The mean length of hospital stay post-procedure in patients developing contrast nephropathy was 19+/-18 (SD) days versus 4+/-5 days for those patients with stable renal function (p<0.01). CONCLUSIONS: Contrast nephropathy is a frequent, but under-recognized complication of CRT with important morbidity/mortality. The extended hospital stay associated with contrast nephropathy has important clinical and health care implications. Patients and physicians need to be aware of this potential risk.

Cardiac resynchronization therapy: retiming the failing right ventricle.

Cardiac resynchronization therapy (CRT) improves symptoms, reduces hospitalization, and may decrease mortality in patients with moderate/severe heart failure and left bundle branch block. Whether CRT may have a role in the management of patients with adult congenital heart disease and a failing right (systemic) ventricle is unknown. We report the case of an adult patient with transposition of the great arteries and previous Mustard's repair, who successfully underwent CRT using a hybrid transvenous/epicardial approach. Exercise tolerance improved, right ventricular (systemic) ejection fraction improved, diuretic requirements reduced, and renal function improved. CRT may offer a new therapeutic option for this patient population.

Cardiac resynchronization therapy: an option for inotrope-supported patients with end-stage heart failure?

BACKGROUND: Patients with refractory heart failure requiring inotropic support have a very poor prognosis. Cardiac resynchronization therapy (CRT) offers symptomatic and possibly a survival benefit for patients with stable chronic heart failure (CHF) and a prolonged QRS, but its role in the management of end-stage heart failure requiring inotropic support has not been evaluated. METHODS: We performed a retrospective observational study of patients undergoing CRT at our institution. RESULTS: We identified 10 patients who required inotropic support for refractory CHF and who underwent CRT while on intravenous inotropic agents. Patients had been in hospital for 30+/-29 days and had received inotropic support for 11+/-6 days prior to CRT. All patients were weaned from inotropic support (2+/-2 days post-CRT) and all patients survived to hospital discharge (12+/-13 days post-CRT). Furosemide dose fell from 160+/-38 mg on admission to 108+/-53 mg on discharge (p<0.01). Serum creatinine fell from 192+/-34 micromol/l prior to CRT to 160+/-37 micromol/l on discharge (p<0.05). Serum sodium was 131+/-4 mmol/l prior to CRT and remained low at 132+/-5 mmol/l on discharge. At short-term follow up (mean 47 days), all patients were alive; mean furosemide dose was 130+/-53 mg (p=0.056 versus pre-CRT). Serum creatinine was 157+/-36 micromol/l and serum sodium had increased to 138+/-6 mmol/l (p<0.05 and p<0.01, respectively, versus pre-CRT). CONCLUSION: CRT may offer a new therapeutic option for inotrope-supported CHF patients with a prolonged QRS.

Comparison of selective ET(A) and ET(B) receptor antagonists in patients with chronic heart failure.

BACKGROUND: The vasoconstrictor action of endothelin-1 (ET-1) is mediated through ET(A) and ET(B) receptor subtypes on vascular smooth muscle. ET(B) receptors are also present on the vascular endothelium where they mediate vasodilation. Animal studies suggest that the ET(B) receptor also acts as a clearance receptor for endothelin. AIMS: To investigate the effects of a selective ET(A) and a selective ET(B) receptor antagonist alone and in combination on haemodynamics and circulating concentrations of ET-1 in patients with chronic heart failure. RESULTS: Infusion of BQ-123 (n=10), a selective ET(A) receptor antagonist, led to systemic vasodilation and did not change plasma ET-1 concentrations (1.38+/-0.82 to 1.38+/-0.91 fmol/ml, ns). Infusion of BQ-788 (n=8) led to systemic vasoconstriction with a rise in plasma ET-1 (1.84+/-1.06 to 2.73+/-0.99 fmol/ml, p<0.01). The addition of BQ-123 to BQ-788 led to systemic and pulmonary vasodilation with no further increase in plasma ET-1 concentrations (2.80+/-1.14 to 2.90+/-1.20 fmol/ml, ns). CONCLUSION: The rise in plasma ET-1 concentrations in response to selective blockade of ET(B) receptors and the associated adverse haemodynamic effects suggest that ET(B) receptors have a role in the clearance of ET-1 in man and that their blockade may not be advantageous for patients with heart failure.