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.

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.

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.

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.

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).

Simple risk models to predict cardiovascular death in patients with stable coronary artery disease.

AIMS: Risk estimation is important to motivate patients to adhere to treatment and to identify those in whom additional treatments may be warranted and expensive treatments might be most cost effective. Our aim was to develop a simple risk model based on readily available risk factors for patients with stable coronary artery disease (CAD). METHODS AND RESULTS: Models were developed in the CLARIFY registry of patients with stable CAD, first incorporating only simple clinical variables and then with the inclusion of assessments of left ventricular function, estimated glomerular filtration rate, and haemoglobin levels. The outcome of cardiovascular death over ∼5 years was analysed using a Cox proportional hazards model. Calibration of the models was assessed in an external study, the CORONOR registry of patients with stable coronary disease. We provide formulae for calculation of the risk score and simple integer points-based versions of the scores with associated look-up risk tables. Only the models based on simple clinical variables provided both good c-statistics (0.74 in CLARIFY and 0.80 or over in CORONOR), with no lack of calibration in the external dataset. CONCLUSION: Our preferred model based on 10 readily available variables [age, diabetes, smoking, heart failure (HF) symptom status and histories of atrial fibrillation or flutter, myocardial infarction, peripheral arterial disease, stroke, percutaneous coronary intervention, and hospitalization for HF] had good discriminatory power and fitted well in an external dataset. STUDY REGISTRATION: The CLARIFY registry is registered in the ISRCTN registry of clinical trials (ISRCTN43070564).

Stroke in Hemodialysis Patients Randomized to Different Intravenous Iron Strategies: A Prespecified Analysis from the PIVOTAL Trial.

Background: People with kidney failure treated with hemodialysis (HD) are at increased risk of stroke compared with similarly aged people with normal kidney function. One concern is that treatment of renal anemia might increase stroke risk. We studied risk factors for stroke in a prespecified secondary analysis of a randomized, controlled trial of intravenous iron treatment strategies in HD. Methods: We analyzed data from the Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial, focusing on variables associated with risk of stroke. The trial randomized 2141 adults who had started HD <12 months earlier and who were receiving an erythropoiesis-stimulating agent (ESA) to high-dose IV iron administered proactively or low-dose IV iron administered reactively in a 1:1 ratio. Possible stroke events were independently adjudicated. We performed analyses to identify variables associated with stroke during follow-up and assessed survival following stroke. Results: During a median 2.1 years of follow-up, 69 (3.2%) patients experienced a first postrandomization stroke. Fifty-seven (82.6%) were ischemic strokes, and 12 (17.4%) were hemorrhagic strokes. There were 34 postrandomization strokes in the proactive arm and 35 postrandomization strokes in the reactive arm (hazard ratio, 0.90; 95% confidence interval, 0.56 to 1.44; P=0.66). In multivariable models, women, diabetes, history of prior stroke at baseline, higher baseline systolic BP, lower serum albumin, and higher C-reactive protein were independently associated with stroke events during follow-up. Hemoglobin, total iron, and ESA dose were not associated with risk of stroke. Fifty-eight percent of patients with a stroke event died during follow-up compared with 23% without a stroke. Conclusions: In patients on HD, stroke risk is broadly associated with risk factors previously described to increase cardiovascular risk in this population. Proactive intravenous iron does not increase stroke risk.Clinical Trial registry name and registration number: Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL), 2013-002267-25.

Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial.

BACKGROUND: Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol. METHODS: We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed. FINDINGS: From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029-2052) and median on-treatment follow-up was 1324 days (IQR 870-1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70-1·03], p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group. INTERPRETATION: Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol. FUNDING: Menarini, Ipsen, and Teijin Pharma Ltd.

Intravenous Iron Dosing and Infection Risk in Patients on Hemodialysis: A Prespecified Secondary Analysis of the PIVOTAL Trial.

BACKGROUND: Experimental and observational studies have raised concerns that giving intravenous (IV) iron to patients, such as individuals receiving maintenance hemodialysis, might increase the risk of infections. The Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial randomized 2141 patients undergoing maintenance hemodialysis for ESKD to a high-dose or a low-dose IV iron regimen, with a primary composite outcome of all-cause death, heart attack, stroke, or hospitalization for heart failure. Comparison of infection rates between the two groups was a prespecified secondary analysis. METHODS: Secondary end points included any infection, hospitalization for infection, and death from infection; we calculated cumulative event rates for these end points. We also interrogated the interaction between iron dose and vascular access (fistula versus catheter). RESULTS: We found no significant difference between the high-dose IV iron group compared with the lose-dose group in event rates for all infections (46.5% versus 45.5%, respectively, which represented incidences of 63.3 versus 69.4 per 100 patient years, respectively); rates of hospitalization for infection (29.6% versus 29.3%, respectively) also did not differ. We did find a significant association between risk of a first cardiovascular event and any infection in the previous 30 days. Compared with patients undergoing dialysis with an arteriovenous fistula, those doing so via a catheter had a higher incidence of having any infection, hospitalization for infection, or fatal infection, but IV iron dosing had no effect on these outcomes. CONCLUSIONS: The high-dose and low-dose IV iron groups exhibited identical infection rates. Risk of a first cardiovascular event strongly associated with a recent infection.

Genetic variation at the SLCO1B1 gene locus and low density lipoprotein cholesterol lowering response to pravastatin in the elderly.

Our goal was to determine whether genetic variation at genes affecting statin metabolism or targets of statin therapy would influence low density lipoprotein (LDL) cholesterol lowering with pravastatin, baseline heart disease, or cardiac endpoints on trial. We examined associations of single nucleotide polymorphisms (SNPs) at the liver X receptor alpha (LXRA, rs12221497), and the solute carrier organic anion transporter (SLCO1B1, rs4149056 and rs2306283) gene loci with these variables. We studied 5411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. No relationships between genetic variation at the LXRA gene locus with statin induced LDL lowering response or other parameters were noted. Both the SLCO1B1 rs4149056 (valine for alanine at 174) and the rs2306283 (asparagine for aspartic acid at 130) SNPs affect the amino acid sequence of the SLCO1B1 gene product. No effect of the rs2306283 SNP on any of the variables was noted. However the presence of the rs4149056 SNP was associated with significantly less LDL cholesterol lowering response to pravastatin (wildtype, 71.5% of the population, -37.0%; heterozygotes, 25.8% of the population, -36.0%; and homozygotes, 2.7% of the population, -31.8%, p=0.003 at 6 months, and p=0.022 at 12 months). Our data indicate that the presence of the rs4149056 non-synonymous SNP at the SLCO1B1 gene locus can significantly decrease the pravastatin induced LDL cholesterol lowering response.

Adipocytokines and risk of stroke in older people: a nested case-control study.

BACKGROUND: Inflammation may play an important role in atherothrombosis and in promoting cerebral damage after stroke. We hypothesized that plasma adipocytokine concentrations would be associated with risk of stroke in older people. METHODS: Nested case-control study from the Prospective Study of Pravastatin in the Elderly (PROSPER). Subjects were aged 70-82 years and followed up for a mean of 3.2 years: 266 incident stroke cases (179 confirmed as ischaemic) were compared with 532 controls matched for age, gender and treatment allocation (pravastatin or placebo). Adipocytokines [adiponectin, interleukin- (IL-)18 and tumour necrosis factor (TNF)alpha] were measured on stored baseline plasma samples. RESULTS: Elevated plasma adiponectin was associated with lower risk of ischaemic stroke on univariate analysis: odds ratio (OR) 0.78 per 1 SD increase (95% CI 0.62-0.97). There were no associations of IL-18 or TNFalpha with risk for ischaemic or total strokes. In multivariate models the independent predictors of ischaemic stroke were prior cerebrovascular accident (OR 2.68, 95% CI 1.60-4.50), any alcohol use (1.98, 1.33-2.94), triglycerides (1.40, 1.11-1.77), Barthel score (0.75, 0.58-0.96) and known diabetes (1.72, 1.04-2.83); adiponectin, IL-18 and TNFalpha did not contribute. A similar pattern of risk was seen for total stroke. CONCLUSIONS: Reduced adiponectin may have a modest role in the aetiology of ischaemic stroke in older people, however IL-18 and TNFalpha are unlikely to play any important part. These adipocytokines do not have clinical predictive utility; history of prior cerebrovascular accident, known diabetes mellitus, prior disability and higher alcohol intake explain much of the stroke risk.

Recent life problems and non-fatal overdose among heroin users entering treatment.

AIMS: To investigate the role of recent life problems in non-fatal overdose among heroin users entering various drug treatment settings. DESIGN: Cross-sectional data from a longitudinal study investigating drug treatment effectiveness. SETTING: Five prison drug treatment services, three residential rehabilitation units, three residential detoxification units and 21 community drug treatment services located in rural, urban and inner-city areas of Scotland. PARTICIPANTS: Of a total of 793 primary heroin users commencing drug treatment during 2001-02, 337 (42.5%) were prison drug service clients; 91 (11.5%) were residential rehabilitation clients; 97 (12.2%) were residential detoxification clients; and 268 (33.8%) were community drug treatment clients. MEASUREMENTS: Univariate and stepwise multivariate logistic regression analyses examined associations between overdosing in the 90 days prior to treatment entry and basic demographic characteristics, recent drug use and recent life problems. FINDINGS: Ninety-one study participants (11.5%) reported at least one overdose and 19 (2.4%) reported more than one overdose in the 90 days prior to treatment entry. A chi2 test revealed no significant difference in rates of recent overdosing between the four treatment settings (P = 0.650). Recent drug use and recent life problems-but not demographic characteristics-were associated independently with recent overdosing. However, recent life problems were not associated independently with recent overdosing among clients entering prison, clients entering residential rehabilitation or with multiple recent overdosing. CONCLUSIONS: Associations between recent life problems and recent overdose were evident, but varied by treatment setting. Treatment providers should identify and address heroin users' life problems as part of a broad strategy of overdose prevention.