Intravenous iron and SGLT2 inhibitors in iron-deficient patients with heart failure and reduced ejection fraction.

AIMS: To explore the potential interaction between use of SGLT2 inhibitors and the increase in haemoglobin in patients randomized to intravenous iron or the control group in the IRONMAN (Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency) trial. METHODS AND RESULTS: This was a post hoc exploratory analysis of the IRONMAN trial which randomized patients with heart failure, a left ventricular ejection fraction (LVEF) ≤ 45% and iron deficiency (transferrin saturation <20% or ferritin <100 µg/L) to open label intravenous ferric derisomaltose or usual care. Of the 1137 randomized patients, 29 (2.6%) were taking an SGLT2 inhibitor at baseline. The mean (SD) change in haemoglobin from baseline at 4 weeks in those taking an SGLT2 inhibitor at baseline was 1.3 (1.2) g/dL in patients randomized to ferric derisomaltose and 0.1 (0.7) g/dL in the usual care group; between-group difference = 1.0 g/dL (95% CI 0.1, 1.8). The equivalent numbers in the no SGLT2 inhibitor group were 0.6 (0.9) g/dL in those randomized to ferric derisomaltose and 0.1 (0.8) g/dL in the usual care group; between-group difference = 0.4 g/dL (95% CI 0.3, 1.6); interaction P value = 0.10. No patient receiving an SGLT2 inhibitor at baseline developed polycythaemia during follow-up (defined as haemoglobin >16.5 g/dL [men] or >16 g/dL [women]). CONCLUSIONS: In the IRONMAN trial, there was a trend to a greater increase in haemoglobin with ferric derisomaltose in iron-deficient patients taking an SGLT2 inhibitor at baseline, as compared with those not taking one.

Allopurinol and cardiovascular outcomes in patients with ischaemic heart disease: the ALL-HEART RCT and economic evaluation.

Background: Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid and is used to prevent acute gout flares in patients with gout. Observational and small interventional studies have suggested beneficial cardiovascular effects of allopurinol. Objective: To determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease. Design: Prospective, randomised, open-label, blinded endpoint multicentre clinical trial. Setting: Four hundred and twenty-four UK primary care practices. Participants: Aged 60 years and over with ischaemic heart disease but no gout. Interventions: Participants were randomised (1 : 1) using a central web-based randomisation system to receive allopurinol up to 600 mg daily that was added to usual care or to continue usual care. Main outcome measures: The primary outcome was the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes were non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, all-cause mortality, hospitalisation for heart failure, hospitalisation for acute coronary syndrome, coronary revascularisation, hospitalisation for acute coronary syndrome or coronary revascularisation, all cardiovascular hospitalisations, quality of life and cost-effectiveness. The hazard ratio (allopurinol vs. usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis. Results: From 7 February 2014 to 2 October 2017, 5937 participants were enrolled and randomised to the allopurinol arm (n = 2979) or the usual care arm (n = 2958). A total of 5721 randomised participants (2853 allopurinol; 2868 usual care) were included in the modified intention-to-treat analysis population (mean age 72.0 years; 75.5% male). There was no difference between the allopurinol and usual care arms in the primary endpoint, 314 (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years), hazard ratio 1.04 (95% confidence interval 0.89 to 1.21); p = 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, hazard ratio 1.02 (95% confidence interval 0.87 to 1.20); p = 0.77. The pre-specified health economic analysis plan was to perform a 'within trial' cost-utility analysis if there was no statistically significant difference in the primary endpoint, so NHS costs and quality-adjusted life-years were estimated over a 5-year period. The difference in costs between treatment arms was +£115 higher for allopurinol (95% confidence interval £17 to £210) with no difference in quality-adjusted life-years (95% confidence interval -0.061 to +0.060). We conclude that there is no evidence that allopurinol used in line with the study protocol is cost-effective. Limitations: The results may not be generalisable to younger populations, other ethnic groups or patients with more acute ischaemic heart disease. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment, but an on-treatment analysis gave similar results to the main analysis. Conclusions: The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve cardiovascular outcomes compared to usual care in patients with ischaemic heart disease. We conclude that allopurinol should not be recommended for the secondary prevention of cardiovascular events in patients with ischaemic heart disease but no gout. Future work: The effects of allopurinol on cardiovascular outcomes in patients with ischaemic heart disease and co-existing hyperuricaemia or clinical gout could be explored in future studies. Trial registration: This trial is registered as EU Clinical Trials Register (EudraCT 2013-003559-39) and ISRCTN (ISRCTN 32017426). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/36/41) and is published in full in Health Technology Assessment; Vol. 28, No. 18. See the NIHR Funding and Awards website for further award information.

The purpose of the ALL-HEART study was to determine whether giving allopurinol to people with ischaemic heart disease (also commonly known as coronary heart disease) would reduce their risk of having a heart attack, stroke or of dying from cardiovascular disease. Allopurinol is a medication usually given to patients with gout to prevent acute gout flares. It is not currently used to treat ischaemic heart disease. We randomly allocated people aged over 60 years with ischaemic heart disease to take up to 600 mg of allopurinol daily (in addition to their usual care) or to continue with their usual care. We then monitored participants for several years and recorded any major health events such as heart attacks, strokes and deaths. We obtained most of the follow-up data from centrally held electronic hospital admissions and death records, making the study easier for participants and more cost-efficient. We asked participants in both groups to complete questionnaires to assess their quality of life during the study. We also collected data to determine whether there was any economic benefit to the NHS of using allopurinol in patients with ischaemic heart disease. There was no difference in the risk of heart attacks, strokes or death from cardiovascular disease between the participants given allopurinol and those in the group continuing their usual care. We also found no difference in the risks of other cardiovascular events, deaths from any cause or quality-of-life measurements between the allopurinol and usual care groups. The results of the ALL-HEART study suggest that we should not recommend that allopurinol be given to people with ischaemic heart disease to prevent further cardiovascular events or deaths.

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.

Clinical outcomes and adverse events of bariatric surgery in adults with severe obesity in Scotland: the SCOTS observational cohort study.

Background: Bariatric surgery is a common procedure worldwide for the treatment of severe obesity and associated comorbid conditions but there is a lack of evidence as to medium-term safety and effectiveness outcomes in a United Kingdom setting. Objective: To establish the clinical outcomes and adverse events of different bariatric surgical procedures, their impact on quality of life and the effect on comorbidities. Design: Prospective observational cohort study. Setting: National Health Service secondary care and private practice in Scotland, United Kingdom. Participants: Adults (age >16 years) undergoing their first bariatric surgery procedure. Main outcome measures: Change in weight, hospital length of stay, readmission and reoperation rate, mortality, diabetes outcomes (HbA1c, medications), quality of life, anxiety, depression. Data sources: Patient-reported outcome measures, hospital records, national electronic health records (Scottish Morbidity Record 01, Scottish Care Information Diabetes, National Records Scotland, Prescription Information System). Results: Between December 2013 and February 2017, 548 eligible patients were approached and 445 participants were enrolled in the study. Of those, 335 had bariatric surgery and 1 withdrew from the study. Mean age was 46.0 (9.2) years, 74.7% were female and the median body mass index was 46.4 (42.4; 52.0) kg/m2. Weight was available for 128 participants at 3 years: mean change was -19.0% (±14.1) from the operation and -24.2% (±12.8) from the start of the preoperative weight-management programme. One hundred and thirty-nine (41.4%) participants were readmitted to hospital in the same or subsequent 35 months post surgery, 18 (5.4% of the operated cohort) had a reoperation or procedure considered to be related to bariatric surgery gastrointestinal complications or revisions. Fewer than five participants (<2%) died during follow-up. HbA1c was available for 93/182 and diabetes medications for 139/182 participants who had type 2 diabetes prior to surgery; HbA1c mean change was -5.72 (±16.71) (p = 0.001) mmol/mol and 65.5% required no diabetes medications (p < 0.001) at 3 years post surgery. Physical quality of life, available for 101/335 participants, improved in the 3 years post surgery, mean change in Rand 12-item Short Form Survey physical component score 8.32 (±8.95) (p < 0.001); however, there was no change in the prevalence of anxiety or depression. Limitations: Due to low numbers of bariatric surgery procedures in Scotland, recruitment was stopped before achieving the intended 2000 participants and follow-up was reduced from 10 years to 3 years. Conclusions: Bariatric surgery is a safe and effective treatment for obesity. Patients in Scotland, UK, appear to be older and have higher body mass than international comparators, which may be due to the small number of procedures performed. Future work: Intervention studies are required to identify the optimal pre- and post surgery pathway to maximise safety and cost-effectiveness. Study registration: This study is registered as ISRCTN47072588. Funding details: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 10/42/02) and is published in full in Health Technology Assessment; Vol. 28, No. 7. See the NIHR Funding and Awards website for further award information.

Bariatric surgery is performed on the stomach and small bowel to help people living with obesity lose weight. Our research study has looked at who is getting bariatric surgery, if they are having problems afterwards, how much weight they lose and if their medical conditions improve. A total of 444 people who were attending bariatric surgery services in Scotland, UK, agreed to take part and 336 had surgery. One hundred and eighty-nine of them completed a questionnaire before their surgery and 85 of them after 3 years, to tell us about how they were feeling physically and mentally. We looked at their computer hospital records to see how long they spent in hospital, any medical problems and changes to diabetes medicines and tests. One in five people taking part did not have surgery after all; they changed their mind or the hospital teams did not think it would be safe or work well for the patient. Those who had surgery lost 19% of their body weight and those with type 2 diabetes needed less or no medication 3 years after the surgery. The effect of physical symptoms on day-to-day activities improved but mental health did not. Compared to other countries, the people taking part were older, heavier and sicker. They spent longer in hospital after surgery and were more likely to be readmitted to hospital. How many appointments they had or what type of health professional they saw before or after surgery did not change these results. We had hoped to have far more people in this study and be able to answer more questions, but not enough people were getting bariatric surgery in Scotland for us to ask them to take part. Further research is needed to find the best ways to care for people living with obesity who would benefit from bariatric surgery.

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 iron in patients with heart failure and iron deficiency: an updated meta-analysis.

AIMS: For patients with heart failure (HF) and iron deficiency (ID), randomized trials suggest that intravenous (IV) iron reduces hospitalizations for heart failure (HHF), but uncertainty exists about the effects in subgroups and the impact on mortality. We conducted a meta-analysis of randomized trials investigating the effect of IV iron on clinical outcomes in patients with HF. METHODS AND RESULTS: We identified randomized trials published between 1 January 2000 and 5 November 2022 investigating the effect of IV iron versus standard care/placebo in patients with HF and ID in any clinical setting, regardless of HF phenotype. Trials of oral iron or not in English were not included. The main outcomes of interest were a composite of HHF and cardiovascular death (CVD), on HHF alone and on cardiovascular and all-cause mortality. Ten trials were identified with 3373 participants, of whom 1759 were assigned to IV iron. IV iron reduced the composite of recurrent HHF and CVD (rate ratio 0.75, 95% confidence interval [CI] 0.61-0.93; p < 0.01) and first HHF or CVD (odds ratio [OR] 0.72, 95% CI 0.53-0.99; p = 0.04). Effects on cardiovascular (OR 0.86, 95% CI 0.70-1.05; p = 0.14) and all-cause mortality (OR 0.93, 95% CI 0.78-1.12; p = 0.47) were inconclusive. Results were similar in analyses confined to the first year of follow-up, which was less disrupted by the COVID-19 pandemic. Subgroup analyses found little evidence of heterogeneity for the effect on the primary endpoint, although patients with transferrin saturation <20% (OR 0.67, 95% CI 0.49-0.92) may have benefited more than those with values ≥20% (OR 0.99, 95% CI 0.74-1.30) (heterogeneity p = 0.07). CONCLUSION: In patients with HF and ID, this meta-analysis suggests that IV iron reduces the risk of HHF but whether this is associated with a reduction in cardiovascular or all-cause mortality remains inconclusive.

Optimal or standard control of systolic and diastolic blood pressure across risk factor categories in patients with chronic coronary syndromes.

AIMS: Guidelines have lowered blood pressure (BP) targets to <130/80 mmHg. We examined the benefit of intensive control for each BP component, vs. the burden of other modifiable risk factors, in patients with chronic coronary syndromes (CCS). METHODS AND RESULTS: The CLARIFY registry (ISRCTN43070564) enrolled 32 703 patients with CCS, from 2009 to 2010, with a 5-year follow-up. Patients with either BP component below European guideline safety boundaries (120/70 mmHg) were excluded, leaving 19 167 patients (mean age: 63.8 ± 10.1 years, 78% men) in the present analysis. A multivariable-adjusted Cox proportional hazards model showed a gradual increase in cardiovascular risk (cardiovascular death, myocardial infarction, or stroke) when the number of uncontrolled risk factors (active smoking, no physical activity, low-density lipoprotein cholesterol ≥100 mg/dL, and diabetes with glycated haemoglobin ≥7%) increased [adjusted hazard ratio (HR): 1.34; 95% confidence interval (CI): 1.17-1.52, 1.65 (1.40-1.94), and 2.47 (1.90-3.21) for 1, 2, and 3 or 4 uncontrolled risk factors, respectively, vs. 0], without significant interaction with BP. Although uncontrolled systolic (≥140 mmHg) and diastolic (≥90 mmHg) BP were both associated with higher risk than standard BP, standard BP was associated with higher risk than optimal control for only the diastolic component (adjusted HR: 1.08; 95% CI: 0.94-1.25 for systolic BP 130-139 vs. 120-129 mmHg and 1.43; 95% CI: 1.27-1.62 for diastolic BP 80-89 vs. 70-79 mmHg). CONCLUSIONS: Our results suggest that the optimal BP target in CCS may be ≤139/79 mmHg and that optimizing the burden of other risk factors should be prioritized over the further reduction of systolic BP.

We aimed to compare the benefit associated with strict vs. standard control of blood pressure with the potential benefit of controlling other modifiable risk factors in patients with chronic coronary syndromes (CCS).Our analysis conducted in nearly 20 000 patients from the CLARIFY registry (a prospective international cohort of patients with CCS) showed that the benefit associated with strict blood pressure (BP) control (BP < 130/80 mmHg) was marginal and only driven by the diastolic component of blood pressure, whereas having one or more uncontrolled other risk factors was associated with a gradually increasing risk, for all underlying BP levels.Patients with CCS should be treated to achieve BP <140/80 mmHg. However, our results suggest that optimizing the burden of other risk factors (lipid-lowering therapy, exercise, smoking cessation, diabetes control) may need to be prioritized before considering further reduction of systolic BP.

High-dose intravenous iron reduces myocardial infarction in patients on haemodialysis.

AIMS: To investigate the effect of high-dose iron vs. low-dose intravenous (IV) iron on myocardial infarction (MI) in patients on maintenance haemodialysis. METHODS AND RESULTS: This was a pre-specified analysis of secondary endpoints of the Proactive IV Iron Therapy in Hemodialysis Patients trial (PIVOTAL) randomized, controlled clinical trial. Adults who had started haemodialysis within the previous year, who had a ferritin concentration <400 µg per litre and a transferrin saturation <30% were randomized to high-dose or low-dose IV iron. The main outcome measure for this analysis was fatal or non-fatal MI. Over a median of 2.1 years of follow-up, 8.4% experienced a MI. Rates of type 1 MIs (3.2/100 patient-years) were 2.5 times higher than type 2 MIs (1.3/100 patient-years). Non-ST-elevation MIs (3.3/100 patient-years) were 6 times more common than ST-elevation MIs (0.5/100 patient-years). Mortality was high after non-fatal MI (1- and 2-year mortality of 40% and 60%, respectively). In time-to-first event analyses, proactive high-dose IV iron reduced the composite endpoint of non-fatal and fatal MI [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.52-0.93, P = 0.01] and non-fatal MI (HR 0.69, 95% CI 0.51-0.93; P = 0.01) when compared with reactive low-dose IV iron. There was less effect of high-dose IV iron on recurrent MI events than on the time-to-first event analysis. CONCLUSION: In total, 8.4% of patients on maintenance haemodialysis had an MI over 2 years. High-dose compared to low-dose IV iron reduced MI in patients receiving haemodialysis. EUDRACT REGISTRATION NUMBER: 2013-002267-25.

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.

The Role of Iron in Calciphylaxis-A Current Review.

Calcific uraemic arteriolopathy (CUA), also known as calciphylaxis, is a rare and often fatal condition, frequently diagnosed in end-stage renal disease (ESRD) patients. Although exact pathogenesis remains unclear, iron supplementation is suggested as a potential risk factor. Iron and erythropoietin are the main stay of treatment for anaemia in ESRD patients. Few observational studies support the role of iron in the pathogenesis of calciphylaxis although data from the pivotal trial was not strongly supportive of this argument, i.e., no difference in incidence of calciphylaxis between the low-dose and high-dose iron treatment arms. Elevated levels of vascular cell adhesion molecules in association with iron excess were postulated to the pathogenesis of CUA by causing inflammation and calcification within the microvasculature. In-addition, oxidative stress generated because of iron deposition in cases of systemic inflammation, such as those seen in ESRD, may play a role in vascular calcification. Despite these arguments, a direct correlation between cumulative iron exposure with CUA incidence is not clearly demonstrated in the literature. Consequently, we do not have evidence to recommend iron reduction or cessation in ESRD patients that develop CUA.

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. METHODS: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. FINDINGS: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89-1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87-1·20], p=0·77). INTERPRETATION: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. FUNDING: UK National Institute for Health and Care Research.

An Analysis of Vascular Access Thrombosis Events From the Proactive IV irOn Therapy in hemodiALysis Patients Trial.

Introduction: Treatment of anemia in dialysis patients has been associated with increased risk of vascular access thrombosis (VAT). Proactive IV irOn Therapy in hemodiALysis Patients (PIVOTAL) was a clinical trial of proactive compared with reactive i.v. iron therapy in patients requiring hemodialysis. We analyzed the trial data to determine whether randomized treatment arm, alongside other clinical and laboratory variables, independently associated with VAT. Methods: In PIVOTAL, 2141 adult patients were randomized. The type of vascular access (arteriovenous fistula [AVF], arteriovenous graft [AVG], or central venous catheter [CVC]) was recorded at baseline and every month after randomization. The associations between clinical and laboratory data and first VAT were evaluated in a multivariate analysis. Results: A total of 480 (22.4%) participants experienced VAT in a median of 2.1 years of follow-up. In multivariable analyses, treatment arm (proactive vs. reactive) was not an independent predictor of VAT (hazard ratio [HR] 1.13, P = 0.18). Diabetic kidney disease (HR 1.45, P < 0.001), AVG use (HR 2.29, P < 0.001), digoxin use (HR 2.48, P < 0.001), diuretic use (HR 1.25, P = 0.02), female sex (HR 1.33, P = 0.002), and previous/current smoker (HR 1.47, P = 0.004) were independently associated with a higher risk of VAT. Angiotensin receptor blocker (ARB) use (HR 0.66, P = 0.01) was independently associated with a lower risk of VAT. Conclusion: In PIVOTAL, VAT occurred in nearly 1 quarter of participants in a median of just >2 years. In this post hoc analysis, randomization to proactive i.v. iron treatment arms did not increase the risk of VAT.

Rationale and design of a randomised trial of intravenous iron in patients with heart failure.

OBJECTIVES: For patients with a reduced left ventricular ejection fraction (LVEF) heart failure with reduced ejection fraction (HFrEF) and iron deficiency, administration of intravenous iron improves symptoms, exercise capacity and may in the following 12 months, reduce hospitalisations for heart failure. The Effectiveness of Intravenous iron treatment versus standard care in patients with heart failure and iron deficiency (IRONMAN) trial evaluated whether the benefits of intravenous iron persist in the longer term and impact on morbidity and mortality. METHODS: IRONMAN is a prospective, randomised, open-label, blinded endpoint (PROBE) event-driven trial. Patients aged ≥18 years with HFrEF (LVEF ≤45%) and evidence of iron deficiency (ferritin <100 µg/L and/or TSAT <20%) were enrolled if they had either a current or recent hospitalisation for heart failure or elevated plasma concentrations of a natriuretic peptide. Participants were randomised to receive, or not to receive, intravenous ferric derisomaltose in addition to guideline-recommended therapy for HFrEF. Every 4 months, intravenous iron was administered if either ferritin was <100 µg/L or, provided ferritin was ≤400 µg/L, TSAT was <25%. The primary endpoint is a composite of total hospitalisations for heart failure and cardiovascular death. Hospitalisation and deaths due to infection are safety endpoints. RESULTS: Trial recruitment was completed across 70 UK hospital sites in October 2021. Participants were followed until the end of March 2022. We plan to report the results by November 2022. CONCLUSIONS: IRONMAN will determine whether repeated doses of intravenous ferric derisomaltose are beneficial and safe for the long-term treatment of a broad range of patients with HFrEF and iron deficiency. TRIAL REGISTRATION NUMBER: NCT02642562.

Impact of smoking on cardiovascular outcomes in patients with stable coronary artery disease.

AIMS: Smoking is a major preventable risk factor for cardiovascular disease and mortality. However, the 'smoker's paradox' suggests that it is associated with better survival after acute myocardial infarction. We aimed to investigate the impact of smoking on mortality and cardiovascular outcomes in patients with stable coronary artery disease. METHODS: The international CLARIFY registry included 32,703 patients with stable coronary artery disease between 2009 and 2010. Among the 32,378 patients included in the present analysis, Cox proportional hazards models (adjusted for age, sex, geographic region, prior myocardial infarction, and revascularization status) were used to estimate associations between smoking status and outcomes. Patients were stratified as follows: 41.3% of patients never smoked, 12.5% were current smokers and 46.2% were former smokers. RESULTS: Current smokers were younger than never-smokers and former smokers (59 vs. 66 and 64 years old, respectively, p < 0.0001). There were more men among current or former smokers compared with never-smokers. Compared with never-smokers, both current and former smokers were at higher risk of all-cause death (hazard ratio = 1.96 and 1.37) and cardiovascular death (hazard ratio = 1.92 and 1.38) within five years (all p < 0.05). Similarly graded and increased risks were present for myocardial infarction and the composite of cardiovascular death, myocardial infarction and stroke (all p < 0.05). CONCLUSION: In contrast to the 'smoker's paradox', current smokers with stable coronary artery disease have a greatly increased risk of future cardiovascular events, including mortality, compared with never-smokers. In former smokers, cardiovascular risk remains elevated albeit at an intermediate level between that of current and never-smokers, reinforcing the importance of smoking cessation. (ISRCTN43070564).

SurgiCal Obesity Treatment Study (SCOTS): a prospective, observational cohort study on health and socioeconomic burden in treatment-seeking individuals with severe obesity in Scotland, UK.

OBJECTIVES: There is a lack of evidence to inform the delivery and follow-up of bariatric surgery for people with severe obesity. The SurgiCal Obesity Treatment Study (SCOTS) is a national longitudinal cohort of people undergoing bariatric surgery. Here, we describe characteristics of the recruited SCOTS cohort, and the relationship between health and socioeconomic status with body mass index (BMI) and age. PARTICIPANTS/METHODS: 445 participants scheduled for bariatric surgery at any of 14 centres in Scotland, UK, were recruited between 2013 and 2016 for this longitudinal cohort study (1 withdrawal); 249 completed health-related preoperative patient-reported outcome measures. Regression models were used to estimate the effect of a 10-unit increase in age or BMI, adjusting for sex, smoking and socioeconomic status. RESULTS: Mean age was 46 years and median BMI was 47 kg/m2. For each 10 kg/m2 higher BMI, there was a change of -5.2 (95% CI -6.9 to -3.5; p<0.0001) in Rand 12-item Short Form Survey Physical Component Summary (SF-12 PCS), -0.1 (95% CI -0.2 to -0.1; p<0.0001) in EuroQoL 5-level EQ-5D version index score and 14.2 (95% CI 10.7 to 17.7; p<0.0001) in Impact of Weight on Quality of Life-Lite Physical Function Score. We observed a 3.1 times higher use of specialist aids and equipment at home (OR: 3.1, 95% CI 1.9 to 5.0; p<0.0001). Broadly, similar results were seen for each 10-year higher age, including a change of -2.1 (95% CI -3.7 to -0.5; p<0.01) in SF-12 PCS. CONCLUSIONS: A higher BMI combined with older age is associated with poor physical functioning and quality of life in people seeking bariatric surgery treatment. Policy-makers must consider the health and care needs of these individuals and invest to provide increased access to effective weight management. TRIAL REGISTRATION NUMBER: ISRCTN47072588.

Heart Failure Hospitalization in Adults Receiving Hemodialysis and the Effect of Intravenous Iron Therapy.

OBJECTIVES: This study sought to examine the effect of intravenous iron on heart failure events in hemodialysis patients. BACKGROUND: Heart failure is a common and deadly complication in patients receiving hemodialysis and is difficult to diagnose and treat. METHODS: The study analyzed heart failure events in the PIVOTAL (Proactive IV Iron Therapy in Hemodialysis Patients) trial, which compared intravenous iron administered proactively in a high-dose regimen with a low-dose regimen administered reactively. Heart failure hospitalization was an adjudicated outcome, a component of the primary composite outcome, and a prespecified secondary endpoint in the trial. RESULTS: Overall, 2,141 participants were followed for a median of 2.1 years. A first fatal or nonfatal heart failure event occurred in 51 (4.7%) of 1,093 patients in the high-dose iron group and in 70 (6.7%) of 1,048 patients in the low-dose group (HR: 0.66; 95% CI: 0.46-0.94; P = 0.023). There was a total of 63 heart failure events (including first and recurrent events) in the high-dose iron group and 98 in the low-dose group, giving a rate ratio of 0.59 (95% CI: 0.40-0.87; P = 0.0084). Most patients presented with pulmonary edema and were mainly treated by mechanical removal of fluid. History of heart failure and diabetes were independent predictors of a heart failure event. CONCLUSIONS: Compared with a lower-dose regimen, high-dose intravenous iron decreased the occurrence of first and recurrent heart failure events in patients undergoing hemodialysis, with large relative and absolute risk reductions. (UK Multicentre Open-label Randomised Controlled Trial Of IV Iron Therapy In Incident Haemodialysis Patients; 2013-002267-25).

Intravenous iron for heart failure with evidence of iron deficiency: a meta-analysis of randomised trials.

BACKGROUND: The recent AFFIRM-AHF trial assessing the effect of intravenous (IV) iron on outcomes in patients hospitalised with worsening heart failure who had iron deficiency (ID) narrowly missed its primary efficacy endpoint of recurrent hospitalisations for heart failure (HHF) or cardiovascular (CV) death. We conducted a meta-analysis to determine whether these results were consistent with previous trials. METHODS: We searched for randomised trials of patients with heart failure investigating the effect of IV iron vs placebo/control groups that reported HHF and CV mortality from 1st January 2000 to 5th December 2020. Seven trials were identified and included in this analysis. A fixed effect model was applied to assess the effects of IV iron on the composite of first HHF or CV mortality and individual components of these. RESULTS: Altogether, 2,166 patients were included (n = 1168 assigned to IV iron; n = 998 assigned to control). IV iron reduced the composite of HHF or CV mortality substantially [OR 0.73; (95% confidence interval 0.59-0.90); p = 0.003]. Outcomes were consistent for the pooled trials prior to AFFIRM-AHF. Whereas first HHF were reduced substantially [OR 0.67; (0.54-0.85); p = 0.0007], the effect on CV mortality was uncertain but appeared smaller [OR 0.89; (0.66-1.21); p = 0.47]. CONCLUSION: Administration of IV iron to patients with heart failure and ID reduces the risk of the composite outcome of first heart failure hospitalisation or cardiovascular mortality, but this outcome may be driven predominantly by an effect on HHF. At least three more substantial trials of intravenous iron are underway.

Invasive versus medically managed acute coronary syndromes with prior bypass (CABG-ACS): insights into the registry versus randomised trial populations.

BACKGROUND: Coronary artery bypass graft (CABG) patients are under-represented in acute coronary syndrome (ACS) trials. We compared characteristics and outcomes for patients who did and did not participate in a randomised trial of invasive versus non-invasive management (CABG-ACS). METHODS: ACS patients with prior CABG in four hospitals were randomised to invasive or non-invasive management. Non-randomised patients entered a registry. Primary efficacy (composite of all-cause mortality, rehospitalisation for refractory ischaemia/angina, myocardial infarction (MI), heart failure) and safety outcomes (composite of bleeding, stroke, procedure-related MI, worsening renal function) were independently adjudicated. RESULTS: Of 217 patients screened, 84 (39%) screenfailed, of whom 24 (29%) did not consent and 60 (71%) were ineligible. Of 133 (61%) eligible, 60 (mean±SD age, 71±9 years, 72% male) entered the trial and 73 (age, 72±10 years, 73% male) entered a registry (preferences: physician (79%), patient (38%), both (21%)).Compared with trial participants, registry patients had more valve disease, lower haemoglobin, worse New York Heart Association class and higher frailty.At baseline, invasive management was performed in 52% and 49% trial and registry patients, respectively, of whom 32% and 36% had percutaneous coronary intervention at baseline, respectively (p=0.800). After 2 years follow-up (694 (median, IQR 558-841) days), primary efficacy (43% trial vs 49% registry (HR 1.14, 95% CI 0.69 to 1.89)) and safety outcomes (28% trial vs 22% registry (HR 0.74, 95% CI 0.37 to 1.46)) were similar. EuroQol was lower in registry patients at 1 year. CONCLUSIONS: Compared with trial participants, registry participants had excess morbidity, but longer-term outcomes were similar. TRIAL REGISTRATION NUMBER: NCT01895751.

Metformin and carotid intima-media thickness in never-smokers with type 1 diabetes: The REMOVAL trial.

AIM: To determine whether metformin's effects on carotid artery intima-media thickness (cIMT) in type 1 diabetes differ according to smoking status. METHODS: Regression model effect estimates for the effect of metformin versus placebo (double-blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial. RESULTS: In 428 randomized participants (227 never-smokers, 201 ever-smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.012 mm, 95% CI -0.021 to -0.002; p = .0137) but not in ever-smokers (0.003 mm, 95% CI -0.008 to 0.014; p = .5767); and similarly in non-current smokers (-0.008 mm, 95% CI -0.015 to -0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI -0.007 to 0.032; p = .1887). Three-way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non-current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.020 mm, 95% CI -0.034 to -0.006; p = .0067) but not in ever-smokers (-0.006 mm, 95% CI -0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three-way interaction term. CONCLUSIONS: This subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes.