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Aims/hypothesis The aim of this work was to study the incidence over time of lower extremity amputations and determine variables associated with increased risk of amputations in people with type 1 diabetes. Methods Individuals with type 1 diabetes registered in the Swedish National Diabetes Registry with no previous amputation from 1 January 1998 and followed to 2 October 2019 were included. Time-updated Cox regression and gradient of risk per SD were used to evaluate the impact of risk factors on the incidence of amputation. Age- and sex-adjusted incidences were estimated over time. Results Of 46,088 people with type 1 diabetes with no previous amputation (mean age 32.5 years [SD 14.5], 25,354 [55%] male sex), 1519 (3.3%) underwent amputation. Median follow-up was 12.4 years. The standardised incidence for any amputation in 1998–2001 was 2.84 (95% CI 2.32, 3.36) per 1000 person-years and decreased to 1.64 (95% CI 1.38, 1.90) per 1000 person-years in 2017–2019. The incidence for minor and major amputations showed a similar pattern. Hyperglycaemia and renal dysfunction were the strongest risk factors for amputation, followed by older age, male sex, cardiovascular comorbidities, smoking and hypertension. Glycaemic control and age- and sex-adjusted renal function improved during the corresponding time period as amputations decreased. Conclusions/interpretation The incidence of amputation and of the most prominent risk factors for amputation, including renal dysfunction and hyperglycaemia, has improved considerably during recent years for people with type 1 diabetes. This finding has important implications for quality of life, health economics and prognosis regarding CVD, indicating a trend shift in the treatment of type 1 diabetes. Graphical abstract

Background: Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of all recorded adverse muscle events in large, long-term, randomised, double-blind trials of statin therapy. Methods: Randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years, and involved a double-blind comparison of statin versus placebo or of a more intensive versus a less intensive statin regimen. We analysed individual participant data from 19 double-blind trials of statin versus placebo (n=123 940) and four double-blind trials of a more intensive versus a less intensive statin regimen (n=30 724). Standard inverse-variance-weighted meta-analyses of the effects on muscle outcomes were conducted according to a prespecified protocol. Findings: Among 19 placebo-controlled trials (mean age 63 years [SD 8], with 34 533 [27·9%] women, 59 610 [48·1%] participants with previous vascular disease, and 22 925 [18·5%] participants with diabetes), during a weighted average median follow-up of 4·3 years, 16 835 (27·1%) allocated statin versus 16 446 (26·6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1·03; 95% CI 1·01–1·06). During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04–1·10), corresponding to an absolute excess rate of 11 (6–16) events per 1000 person-years, which indicates that only one in 15 ([1·07–1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin. After year 1, there was no significant excess in first reports of muscle pain or weakness (0·99; 0·96–1·02). For all years combined, more intensive statin regimens (ie, 40–80 mg atorvastatin or 20–40 mg rosuvastatin once per day) yielded a higher RR than less intensive or moderate-intensity regimens (1·08 [1·04–1·13] vs 1·03 [1·00–1·05]) compared with placebo, and a small excess was present (1·05 [0·99–1·12]) for more intensive regimens after year 1. There was no clear evidence that the RR differed for different statins, or in different clinical circumstances. Statin therapy yielded a small, clinically insignificant increase in median creatine kinase values of approximately 0·02 times the upper limit of normal. Interpretation: Statin therapy caused a small excess of mostly mild muscle pain. Most (>90%) of all reports of muscle symptoms by participants allocated statin therapy were not due to the statin. The small risks of muscle symptoms are much lower than the known cardiovascular benefits. There is a need to review the clinical management of muscle symptoms in patients taking a statin. Funding: British Heart Foundation, Medical Research Council, Australian National Health and Medical Research Council.

Background: Historically, life expectancy in persons with type 1 diabetes (T1D) has been shorter than the general population, but earlier studies did not stratify patients according to cardiorenal complications. Methods: T1D persons were identified in the Swedish National Diabetes Registry (n=45,575) and compared with matched controls from the general population (n=220,141) . Mortality rates from 2002 to 20were estimated in persons with T1D overall and after stratification for prevalent cardiovascular and renal disease. Results: In persons with T1D, mean age was 32.4 years and 44.9% were women. Age- and sex- adjusted mortality rates decreased over time in both groups but remained significantly higher in those with T1D during 2017 to 2019. In T1D persons ≥45 years without previous renal or cardiovascular complications (approximately 50% of persons in this age group) similar standardized mortality rates were observed, over time compared with controls, with slightly lower mortality in T1D persons during the last period, 5.55 (95% CI 4.51-6.60) vs. 7. (95% CI 6.75-7.40) deaths per 1,000 person years (Figure) . Conclusion: Excess mortality persisted over time in persons with T1D, largely in patients with cardiorenal complications. Improved secondary prevention with a focus on differentiated treatment is needed to close the gap in mortality for persons with T1D. Disclosure S. Hallström: None. M.O. Wijkman: None. J. Ludvigsson: Advisory Panel; Dompé. Research Support; Diamyd Medical. M.A. Pfeffer: Consultant; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Corvidia Therapeutics, GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Peerbridge, Sanofi. Research Support; Novartis Pharmaceuticals Corporation. Other Relationship; DalCor Pharmaceuticals, National Heart, Lung, and Blood Institute. A. Rosengren: None. M. Lind: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk. Research Support; Eli Lilly and Company, Novo Nordisk. Funding ALF [ALFGBG-717211] and [ALFGBG-966173], grants from the Novo Nordisk foundation, Swedish Heart and Lung Foundation [20180589], [20210679], Swedish Research Council [2018-02527] [VRREG 2019-00193], and the Gothenburg Society of Medicine.

Aims Albuminuria is strongly associated with risk of renal dysfunction, cardiovascular disease and mortality. However, clinical guidelines diverge, and evidence is sparse on what risk factor levels regarding blood pressure, blood lipids and BMI are needed to prevent albuminuria in adolescents and young adults with type 1 diabetes. Methods A total of 9347 children and adults with type 1 diabetes [mean age 15.3 years and mean diabetes duration 1.4 years at start of follow-up] from The Swedish National Diabetes Registry were followed from first registration until end of 2017. Levels for risk factors for a risk increase in nephropathy were evaluated, and the gradient of risk per 1 SD (standard deviation) was estimated to compare the impact of each risk factor. Results During the follow-up period, 8610 (92.1%) remained normoalbuminuric, 737 (7.9%) individuals developed micro- or macroalbuminuria at any time period of whom 132 (17.9% of 737) individuals developed macroalbuminuria. Blood pressure ≥ 140/80 mmHg was associated with increased risk of albuminuria (p ≤ 0.0001), as were triglycerides ≥ 1.0 mmol/L (p = 0.039), total cholesterol ≥ 5.0 mmol/L (p = 0.0003), HDL p = 0.013), LDL 3.5– p = 0.020), and BMI ≥ 30 kg/m2 (p = 0.033). HbA1c was the strongest risk factor for any albuminuria estimated by the measure gradient of risk per 1 SD, followed by diastolic blood pressure, triglycerides, systolic blood pressure, cholesterol and LDL. In patients with HbA1c > 65 mmol/mol (> 8.1%), blood pressure > 140/70 mmHg was associated with increased risk of albuminuria. Conclusions Preventing renal complications in adolescents and young adults with type 1 diabetes need avoidance at relatively high levels of blood pressure, blood lipids and BMI, whereas very tight control is not associated with further risk reduction. For patients with long-term poor glycaemic control, stricter blood pressure control is advocated.

Background: Lower extremity amputations in people with diabetes is a major source of disability and distress and it constitutes a significant financial burden for the healthcare system. Risk factors and current risks for amputation in persons with type 1 diabetes have not been extensively studied. Methods: Persons with type 1 diabetes registered in the Swedish National Diabetes Registry with no previous amputation from 1998 and followed until 2019 were included. Time-updated Cox regression and gradient of risk per SD were used to evaluate the impact of risk factors on the incidence of amputation. Age and sex adjusted incidences were estimated over time. Findings: Of 46,008 persons with type 1 diabetes with no previous amputation and a mean age of 32.5 years (SD 14.5) and 25 354 (55%) male, 1,519 (3.3%) underwent amputation. Median follow-up was 12.4 years. The age and sex adjusted incidence for any amputation decreased over time. The standardized incidence was 1998-2001 2.84 (95% CI 2.32-3.36) per 1000 patient years and decreased to 1.64 (95% CI 1.38-1.90) in 2017-2019 along with improved glycaemic control (0.02% [95% CI 0.02-0.02] per year) and renal function (0.23 ml/min/1.73m² [95% CI 0.21-0.24] per year). Risk factors for amputations were hyperglycemia, renal dysfunction, older age, male gender, cardiovascular comorbidities, smoking and hypertension. Interpretation: Prognosis has improved considerably regarding the risk of amputations in persons with type 1 diabetes while glycaemic control and renal function improved which were the most prominent risk factors. Disclosure S. Hallström: None. A. Svensson: None. A. Pivodic: None. A. F. Olafsdottir: None. M. Londahl: Advisory Panel; Self; Abbott, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Sanofi. H. Wedel: None. M. Lind: Consultant; Self; AstraZeneca, Eli Lilly and Company, Other Relationship; Self; Novo Nordisk, Research Support; Self; Dexcom, Inc. Funding Novo Nordisk Foundation; Swedish State

Background: Persons with diabetic nephropathy have an increased risk to progress to severe renal failure and have a high cardiovascular risk. To better understand the impact of risk factors on diabetes complications information from diagnosis and onward is needed. Less focus has been on evaluating other risk factors than HbA1c following large populations from diagnosis with repeated measurements. Therefore, we aimed to evaluate risk factors for albuminuria in children and young adults. Methods: In a population-based cohort study persons with type 1 diabetes (T1D), both children (data from SWEDIABKIDS) and adults (data from Swedish National Diabetes Registry) were included, and followed from January 1, 2001 to December 31, 2017. The association between risk factors and albuminuria was evaluated. The gradient of risk per 1 SD (standard deviation) was estimated to compare the impact of each risk factor. Results: A total of 10398 individuals with T1D were followed, 43.4% female, mean age 14.7 years and mean HbA1c 8.0% (63.4 mmol/mol). HbA1c was the strongest risk factor with an odds ratio (OR) of 1.51 (95% 1.39-1.64, p89 mg/dL (>1.0 mmol/L), total cholesterol >193 mg/dL (>5.0 mmol/L), LDL >135 mg/dL (>3.5 mmol/L) and BMI >30 kg/m2. Smoking showed no association. Conclusion: For individuals with type 1 diabetes, higher HbA1c, blood pressure, triglycerides, LDL and cholesterol were the most prominent risk factors for albuminuria. Blood pressure levels 140/80 mmHg were associated with increased risk of albuminuria. Disclosure S.S. Ahmadi: None. A. Pivodic: None. A. Svensson: None. H. Wedel: None. J. Ludvigsson: None. M. Lind: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk Inc. Consultant; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. Research Support; Self; Dexcom, Inc., Novo Nordisk Inc. Funding Swedish Child Diabetes Foundation

Aims Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40–49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials. Methods and results Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21–33%), including 575 patients with LVEF 40–49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40–49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34–1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24–0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when Conclusion Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF

Type 1 diabetes is associated with an increased risk of developing several cardiovascular complications. To our knowledge, the independent association between type 1 diabetes and atrial fibrillation has not been studied.We did a prospective case-control study of individuals with type 1 diabetes in the Swedish National Diabetes Registry who were each matched with five controls for age, sex, and county of residence who were randomly selected from the Swedish Population Register. Cases of atrial fibrillation were obtained from the Swedish National Patient Registry.We followed up 36 258 patients with type 1 diabetes and 179 980 controls between Jan 1, 2001, and Dec 31, 2013. Median follow-up was 9·7 years (IQR 5·2-13·0) for patients and 10·2 years (5·7-13·0) for controls. 749 (2%) individuals with type 1 diabetes and 2882 (2%) controls were diagnosed with atrial fibrillation, with an adjusted hazard ratio (HR) of 1·13 (95% CI 1·01-1·25; p=0·029) in men and 1·50 (1·30-1·72; p0·0001) in women (p=0·0019 for interaction). The excess risk of atrial fibrillation in individuals with type 1 diabetes increased with worsening glycaemic control and renal complications. Among individuals with normoalbuminuria, no excess risk of atrial fibrillation was noted in men with type 1 diabetes who had HbACompared with the general population, the risk of atrial fibrillation in men with type 1 diabetes was slightly raised, whereas for female patients it was 50% higher. The risk of atrial fibrillation in people with type 1 diabetes increased with renal complications and poor glycaemic control.Novo Nordisk Foundation, Swedish State (ALF agreement), Swedish Research Council (SIMSAM), Swedish Heart and Lung Foundation, Swedish Diabetes Foundation, Diabetes Wellness.

Background The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with second-generation drug eluting stents (DESs) is unclear. Because prolonged DAPT is associated with higher bleeding risk and health care costs, establishing optimal DAPT duration is of paramount importance. No other randomized controlled trials have evaluated the safety of shorter DAPT duration in ST-elevation myocardial infarction (STEMI) patients treated with second-generation DESs and latest P2Y12 platelet receptor inhibitors. Hypothesis Six months of DAPT after Resolute Integrity stent implantation in STEMI patients is not inferior to 12 months of DAPT in clinical outcomes. Study design The Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation In ST-elevation Myocardial Infarction (DAPT-STEMI) trial is a randomized, multicenter, international, open-label trial designed to examine the safety (noninferiority) of 6-month DAPT after Resolute Integrity stent implantation in STEMI patients compared with 12-month DAPT. Event-free patients on DAPT at 6month will be randomized (1:1 fashion) between single (aspirin only) versus DAPT for an additional 6 months and followed until 2 years after primary percutaneous coronary intervention. The primary end point is a patient-oriented composite endpoint of all-cause mortality, any myocardial infarction, any revascularization, stroke, and major bleeding (net adverse clinical events [NACE]) at 18 months after randomization. To achieve a power of 85% for a noninferiority limit of 1.66, a total of 1100 enrolled patients are required. Summary The DAPT-STEMI trial aims to assess in STEMI patients treated with second-generation DESs whether discontinuation of DAPT after 6 months of event-free survival is noninferior to routine 12-month DAPT.

To evaluate the safety and efficacy outcomes after primary percutaneous coronary intervention (pPCI) with second‐generation Resolute™ zotarolimus‐eluting stent (R‐ ZES) in patients enrolled in the DAPT‐STEMI Trial (NCT01459627).Background: R‐ ZES is one of the most used drug eluting stents worldwide. To date, the safety and efficacy data of this stent in setting of STEMI is limited.Methods: The Resolute‐STEMI is a prespecified prospective register that reports the safety and efficacy of R‐ZES in setting of ST‐Elevation Myocardial Infarction (STEMI) at 6 months for the following endpoints: a composite endpoint of all‐cause mortality, any myocardial infarction (MI), any (unscheduled) revascularization, stroke and TIMI major bleeding, as well as target lesion failure and stent thrombosis (ST).Results: From a total of 1,100 STEMI patients enrolled in the trial, 998 received a R‐ZES. At 6 months the PE occurred in 42 (4.2%) patients. All‐cause death, MI, revascularization, stroke and TIMI major bleeding was respectively 8 (0.8%), 9 (0.8%), 34 (3.4%), 2 (0.2%), and 4 (0.4%). The rate of target lesion revascularizations involving the culprit lesion was 1.1%. Target lesion failure was 1.5%. The rate of definite ST was 0.5%. The rate of both definite or probable ST was 0.7%.Conclusions: The present analysis is the largest to date reporting short‐ term and mid‐term clinical outcomes with the R‐ZES stent in setting of STEMI. At 30 days and 6‐months R‐ZES has an outstanding safety and efficacy even in this high‐ risk category of patients.

Aims The AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator‐activated receptor‐αγ agonist aleglitazar in patients with type 2 diabetes mellitus and acute coronary syndrome. The trial terminated early because of futility and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar. Materials and Methods The AleCardio trial enrolled 7226 patients to receive aleglitazar 150 μg or matching placebo on top of standard care. A population pharmacokinetic analysis was conducted in a pharmacokinetic substudy to identify covariates that explained interindividual variability in exposure. Subsequently, the effect of these covariates on surrogate and clinical outcomes was assessed in the full patient population. Results Concomitant administration of clopidogrel was identified as a covariate that influenced the apparent clearance of aleglitazar. Patients using clopidogrel had a mean predicted area under the plasma‐concentration‐time curve (AUC0–24) of 174.7 ng h/mL (SD: ±112.9 ng h/mL) versus 142.2 ng h/mL (SD: ±92.6 ng h/mL) in patients without clopidogrel. The effect of aleglitazar compared with placebo on HbA1c, haemoglobin, serum creatinine and adiponectin was modified by concomitant clopidogrel use (P for interaction 0.007, 0.002

Background:\ud Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy.\ud \ud Objectives:\ud This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR).\ud \ud Methods:\ud Analysis of 16,740 individual patients with left ventricular ejection fraction

ObjectiveTo evaluate if the lowest target level for glycated haemoglobin (HbA1c) of DesignPopulation based cohort study.SettingSwedish National Diabetes Registry, 1 January 1998 to 31 December 2017.Participants10 398 children and adults with type 1 diabetes followed from diagnosis, or close thereafter, until end of 2017.Main outcome measuresRelative risk (odds ratios) for retinopathy and nephropathy for different mean levels of HbA1c.ResultsMean age of participants was 14.7 years (43.4% female), mean duration of diabetes was 1.3 years, and mean HbA1c level was 8.0% (63.4 mmol/mol). After adjustment for age, sex, duration of diabetes, blood pressure, blood lipid levels, body mass index, and smoking, the odds ratio for mean HbA1c 1c levels 6.5-6.9%, HbA1c levels 7.0-7.4% (53-57 mmol/mol) were associated with an increased risk of any retinopathy (1.31, 1.05 to 1.64, P=0.02) and microalbuminuria (1.55, 1.03 to 2.32, P=0.03). The risk for proliferative retinopathy (5.98, 2.10 to 17.06, P1c levels >8.6% (>70 mmol/mol). The risk for severe hypoglycaemia was increased at mean HbA1c ConclusionsRisk of retinopathy and nephropathy did not differ at HbA1c levels 1c levels 6.5-6.9%. The risk for severe complications mainly occurred at HbA1c levels >8.6%, but for milder complications was increased at HbA1c levels >7.0%.

ObjectiveThis study investigates how the excess risk of lower extremity amputations (amputations) in people with type 1 diabetes mellitus (DM) differs from the general population by diabetes duration, glycemic control, and renal complications.Research design and methodsWe analyzed data from people with type 1 DM from the Swedish National Diabetes Register without prior amputation from January 1998 to December 2013. Each person (n=36 872) was randomly matched with five controls by sex, age, and county (n=184 360) from the population without diabetes. All were followed until first amputation, death or end of follow-up.ResultsThe overall adjusted HR for all amputation was 40.1 (95% CI 32.8 to 49.1) for type 1 DM versus controls. HR increased with longer diabetes duration. The incidence of amputation/1000 patient-years was 3.18 (95% CI 2.99 to 3.38) for type 1 DM and 0.07 (95% CI 0.05 to 0.08) for controls. The incidence decreased from 1998–2001 (3.09, 95% CI 2.56 to 3.62) to 2011–2013 (2.64, 95% CI 2.31 to 2.98). The HR for major amputations was lower than for minor amputations and decreased over the time period (p=0.0045). Worsening in glycemic control among patients with diabetes led to increased risk for amputation with an HR of 1.80 (95% CI 1.72 to 1.88) per 10 mmol/mol (1%) increase in hemoglobin A1c.ConclusionsAlthough the absolute risk of amputation is relatively low, the overall excess risk was 40 times that of controls. Excess risk was substantially lower for those with good glycemic control and without renal complications, but excess risk still existed and is greatest for minor amputations.

Aims: We hypothesised that the expected increase in insulin resistance over three years’ time in individuals with impaired glucose tolerance (IGT) and/or impaired fasting glucose could be attenuated by an intervention with focus on physical activity in ordinary primary care. Methods: We conducted a randomised controlled trial with 96 participants over three years. Examination of the participants included anthropometric measures, blood pressure, body weight and height, blood samples, an oral glucose tolerance test, and questionnaires about diet and lifestyle. The study subjects were randomised to either an intense intervention with information, group sessions, referral to physical activity and a step-counter ( n = 31), a less intense intervention without the group sessions ( n = 35), or care as usual group (CAUG) ( n = 30). Differences between the groups were analysed with general linear models adjusted for age, gender, baseline values and time in the intervention. Results: Individual insulin resistance increased in the CAUG. Due to having a similar effect, we combined the two intervention groups into a combined intervention group (CIG; n = 66) in the analyses. In individuals with IGT, the increase in the homeostatic model assessment-insulin resistance differed significantly between those in the CAUG and the CIG (Δ = 0.8; CI: 0.1–1.6; p = 0.034). Likewise, diastolic blood pressure decreased more in the CIG than in the CAUG (Δ = 5.1; CI: 0.1–10.0; p = 0.047). A total of 17 individuals developed Type 2 diabetes, 23% were in the CIG and 33% in the CAUG; so there was a 32% reduced risk in the intervention group. Conclusions: A lifestyle intervention focused on physical activity is feasible in ordinary primary care and prevents deterioration in insulin sensitivity in individuals with IGT over a three-year period.

Objectives The aim of this study was to determine the prognostic impact of chronic total occlusion (CTO) on long-term mortality in a large prospective cohort. Background CTO is present in many patients with coronary artery disease and is difficult to treat with percutaneous coronary intervention. Methods The study population consisted of all consecutive patients who underwent coronary angiography in Sweden between January 1, 2005 and January 1, 2012, who were registered in SCAAR (Swedish Coronary Angiography and Angioplasty Registry). The patient population was heterogeneous with regard to indication for angiography (stable angina, ST-segment elevation myocardial infarction [STEMI], unstable angina or non-STEMI, and other) and treatment options. The long-term mortality rates of patients with and without CTO were compared by using shared frailty Cox proportional hazards regression adjusted for confounders. Tests were conducted for interactions between CTO and several pre-specified characteristics: indication for angiography and percutaneous coronary intervention (stable angina, STEMI, unstable angina or non-STEMI, and other), severity of coronary artery disease (1-, 2-, and 3-vessel and/or left main coronary artery disease), age, sex, and diabetes. Results During the study period, 14,441 patients with CTO and 75,431 patients without CTO were registered in SCAAR. CTO was associated with higher mortality (hazard ratio: 1.29; 95% confidence interval: 1.22 to 1.37; p Conclusions In this large prospective observational study of patients with coronary artery disease, CTO was associated with increased mortality. This association was most prominent in younger patients and in those with acute coronary syndromes.

Background: A substantial excess risk of mortality still exists in persons with type 1 diabetes. The aim of this study was to evaluate the excess risk of mortality in persons with type 1 diabetes without renal complications who target goals for glycemic control and are nonsmokers. Furthermore, we evaluated risk factors of death due to hypoglycemia or ketoacidosis in young adults with type 1 diabetes. Methods: We evaluated a cohort based on 33 915 persons with type 1 diabetes and 169 249 randomly selected controls from the general population matched on age, sex, and county followed over a mean of 8.0 and 8.3 years, respectively. Hazard ratios (HRs) for all-cause and cardiovascular disease (CVD) mortality for persons with type 1 diabetes versus controls were estimated. Results: The adjusted HRs for all-cause and CVD mortality for persons with type 1 diabetes without renal complications (normoalbuminuria and eGFR ≥ 60 ml/min) and HbA1c ≤ 6.9% (52 mmol/mol) compared to controls were 1.22 (95% CI 0.98-1.52) and 1.03 (95% CI 0.66-1.60), respectively. The HRs increased with higher updated mean HbA1c. For nonsmokers in this group, the HRs for all-cause and CVD mortality were somewhat lower: 1.11 (95% CI 0.87-1.42) and 0.89 (95% CI 0.53-1.48) at updated mean HbA1c ≤ 6.9% (52 mmol/mol). HRs for significant predictors for deaths due to hypoglycemia or ketoacidosis in persons < 50 years were male sex 2.40 (95% CI 1.27-4.52), smoking 2.86 (95% CI 1.57-5.22), lower educational level 3.01 (95% CI 1.26-7.22), albuminuria or advanced kidney disease 2.83 (95% CI 1.63-4.93), earlier hospital diagnosis of hypoglycemia or ketoacidosis 2.30 (95% CI 1.20-4.42), and earlier diagnosis of intoxication 2.53 (95% CI 1.06-6.04). Conclusions: If currently recommended HbA1c targets can be reached, renal complications and smoking avoided in persons with type 1 diabetes, the excess risk of mortality will likely converge substantially to that of the general population.

Objective To show that limiting dual antiplatelet therapy (DAPT) to six months in patients with event-free ST-elevation myocardial infarction (STEMI) results in a non-inferior clinical outcome versus DAPT for 12 months. Design Prospective, randomised, multicentre, non-inferiority trial. Setting Patients with STEMI treated with primary percutaneous coronary intervention (PCI) and second generation zotarolimus-eluting stent. Participants Patients with STEMI aged 18 to 85 that underwent a primary PCI with the implantation of second generation drug-eluting stents were enrolled in the trial. Patients that were event-free at six months after primary PCI were randomised at this time point. Interventions Patients that were taking DAPT and were event-free at six months were randomised 1:1 to single antiplatelet therapy (SAPT) (ie, aspirin only) or to DAPT for an additional six months. All patients that were randomised were then followed for another 18 months (ie, 24 months after the primary PCI). Main outcome measures The primary endpoint was a composite of all cause mortality, any myocardial infarction, any revascularisation, stroke, and thrombolysis in myocardial infarction major bleeding at 18 months after randomisation. Results A total of 1100 patients were enrolled in the trial between 19 December 2011 and 30 June 2015. 870 were randomised: 432 to SAPT versus 438 to DAPT. The primary endpoint occurred in 4.8% of patients receiving SAPT versus 6.6% of patients receiving DAPT (hazard ratio 0.73, 95% confidence interval 0.41 to 1.27, P=0.26). Non-inferiority was met (P=0.004 for non-inferiority), as the upper 95% confidence interval of 1.27 was smaller than the prespecified non-inferiority margin of 1.66. Conclusions DAPT to six months was non-inferior to DAPT for 12 months in patients with event-free STEMI at six months after primary PCI with second generation drug-eluting stents. Trial registration Clinicaltrials.gov NCT01459627 .

Late-onset noninfectious pulmonary complications (LONIPCs) affect 6% of allogeneic stem cell transplantation (SCT) recipients within 5 years, conferring subsequent 5-year survival of 50%. Lung transplantation is rarely performed in this setting due to concomitant extrapulmonary morbidity, excessive immunosuppression and concerns about recurring malignancy being considered contraindications. This study assesses survival in highly selected patients undergoing lung transplantation for LONIPCs after SCT.SCT patients undergoing lung transplantation at 20 European centres between 1996 and 2014 were included. Clinical data pre- and post-lung transplantation were reviewed. Propensity score-matched controls were generated from the Eurotransplant and Scandiatransplant registries. Kaplan–Meier survival analysis and Cox proportional hazard regression models evaluating predictors of graft loss were performed.Graft survival at 1, 3 and 5 years of 84%, 72% and 67%, respectively, among the 105 SCT patients proved comparable to controls (p=0.75). Sepsis accounted for 15 out of 37 deaths (41%), with prior mechanical ventilation (HR 6.9, 95% CI 1.0–46.7; pLung transplantation outcomes following SCT were comparable to other end-stage diseases. Lung transplantation should be considered feasible in selected candidates. No SCT-specific factors influencing outcome were identified within this carefully selected patient cohort.

Aim We aimed to study the relationships of loop diuretic dose with renal function and clinical outcomes in patients with chronic heart failure (HF). Methods and results Loop diuretic dose at baseline was recorded in patients included in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). The relationship to change in estimated glomerular filtration rate (eGFR) over time and to the first occurrence of the composite outcome of cardiovascular (CV) death or hospitalization owing to HF was examined in propensity score matched cohorts. Of the 5011 patients, 2550, 745, and 449 were receiving >80 mg (high), 41–80 mg (medium) and ≤40 mg (low) of loop diuretics in furosemide equivalent daily dosages, respectively, which were used to assemble 229, 385, and 1045 pairs of propensity-matched high, medium, and low dose cohorts. Compared with matched no loop diuretic groups, eGFR declined 0.3 ± 0.2, 0.3 ± 0.3 and 1.2 ± 0.5 mL/min/1.73 m2/year in the low-, medium-, and high-dose groups, respectively. Compared with matched no loop diuretic groups, hazard ratios (HR) (95% confidence intervals) for outcome associated with low-, medium- and high-dose groups were 1.71 (1.41–2.06), 1.99 (1.50–2.64), and 2.94 (1.95–4.41), respectively. Higher loop diuretic dose was particularly associated with increased risk for hospitalization owing to HF: HR 4.80 (2.75–8.37), P

Previous studies have established a relationship between socioeconomic status (SES) and survival in coronary heart disease. Acute cardiac care in Sweden is considered to be excellent and independent of SES. We studied the influence of area-level socioeconomic status on mortality after hospitalization for acute myocardial infarction (AMI) between 1995 and 2013 in the Gothenburg metropolitan area, which has little over 800,000 inhabitants and includes three city hospitals.Data were obtained from the SWEDEHEART registry (Swedish Websystem for Enhancement of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) and the Swedish Central Bureau of Statistics for patients hospitalized for ST-elevation myocardial infarction (STEMI) and non-STEMI in the city of Gothenburg in Western Sweden. The groups were compared using Cox proportional hazards regression and logistic regression.10,895 (36% female) patients were hospitalized due to AMI during the study period. Patients residing in areas with lower SES had higher rates of smoking and diabetes (P0.001), and were also at increased risk of developing complications, including heart failure and cardiogenic shock (P0.05). Living in an area with lower SES associated with increased risk of dying after an AMI also in models adjusted for risk factors (P0.05).Also in a country with strong egalitarian traditions, lower SES associates with worse prognosis after AMI, an association that persists after adjustments for differences in traditional cardiovascular risk factors.

AIMS: Leucocyte telomere length is considered a marker of biological ageing and has been suggested to be shorter in patients with CAD and heart failure compared with healthy controls. The aim of this study was to determine whether telomere length is associated with clinical outcomes in patients with ischaemic heart failure and whether this association is superior to chronological age as defined by date of birth. METHODS AND RESULTS: We measured leucocyte telomere length in 3275 patients with chronic ischaemic systolic heart failure participating in the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA) study. The primary composite endpoint was cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, which occurred in 575 patients during follow-up. We observed a significant association of leucocyte telomere lengths with the primary endpoint (hazard ratio 1.10; 95% confidence interval 1.01-1.20; P=0.03). However, this observation was not superior to age as defined by date of birth. The neutral effect of rosuvastatin treatment on clinical outcomes was not modified by baseline telomere length. CONCLUSION: Biological age as defined by leucocyte telomere length was associated with clinical outcomes in patients with ischaemic heart failure, but this association did not add prognostic information above age as defined by date of birth.

Background: To evaluate the effects of continuous glucose monitoring (CGM) on nocturnal and daytime hypoglycemia in persons with type 1 diabetes treated with multiple daily insulin injections (MDI); we also evaluated factors related to differences in hypoglycemia confidence in this population. Methods: Evaluations were performed from the GOLD randomized trial, an open-label multicenter crossover randomized clinical trial (n = 161) over 69 weeks comparing CGM to self-measurement of blood glucose (SMBG) in persons with type 1 diabetes treated with MDI. Masked CGM and the hypoglycemia confidence questionnaire were used for evaluations. Results: Time with nocturnal hypoglycemia, glucose levels

Background— International geographic differences in outcomes may exist for clinical trials of heart failure and reduced ejection fraction (HF-REF), but there are few data for those with preserved ejection fraction (HF-PEF). Methods and Results— We analyzed outcomes by international geographic region in the Irbesartan in Heart Failure with Preserved systolic function trial (I-Preserve), the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved trial, the CHARM-Alternative and CHARM–Added HF-REF trials, and the Controlled Rosuvastatin Multinational Trial in HF-REF (CORONA). Crude rates of heart failure hospitalization varied by geographic region, and more so for HF-PEF than for HF-REF. Rates in patients with HF-PEF were highest in the United States/Canada (HF hospitalization rate 7.6 per 100 patient-years in I-Preserve; 8.8 in CHARM-Preserved), intermediate in Western Europe (4.8/100 and 4.7/100), and lowest in Eastern Europe/Russia (3.3/100 and 2.8/100). The difference between the United States/Canada versus Eastern Europe/Russia persisted after adjustment for key prognostic variables: adjusted hazard ratios 1.34 (95% confidence interval, 1.01–1.74; P =0.04) in I-Preserve and 1.85 (95% confidence interval, 1.17–2.91; P =0.01) in CHARM-Preserved. In HF-REF, rates of HF hospitalization were slightly lower in Western Europe compared with other regions. For both HF-REF and HF-PEF, there were few regional differences in rates of all-cause or cardiovascular mortality. Conclusions— The differences in event rates observed suggest there is international geographic variation in 1 or more of the definition and diagnosis of HF-PEF, the risk profile of patients enrolled, and the threshold for hospitalization, which has implications for the conduct of future global trials.

Objective Insulin resistance has been linked to development and progression of atherosclerosis and is present in most patients with type 2 diabetes. Whether the degree of insulin resistance predicts adverse outcomes in patients with type 2 diabetes and acute coronary syndrome (ACS) is uncertain. Design The Effect of Aleglitazar on Cardiovascular Outcomes after Acute Coronary Syndrome in Patients with Type 2 Diabetes Mellitus trial compared the peroxisome proliferator-activated receptor-α/γ agonist aleglitazar with placebo in patients with type 2 diabetes and recent ACS. In participants not treated with insulin, we determined whether baseline homeostasis model assessment of insulin resistance (HOMA-IR; n = 4303) or the change in HOMA-IR on assigned study treatment (n = 3568) was related to the risk of death or major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in unadjusted and adjusted models. Because an inverse association of HOMA-IR with N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been described, we specifically examined effects of adjustment for the latter. Results In unadjusted analysis, twofold higher baseline HOMA-IR was associated with lower risk of death [hazard ratio (HR): 0.79, 95% CI: 0.68 to 0.91, P = 0.002]. Adjustment for 24 standard demographic and clinical variables had minimal effect on this association. However, after further adjustment for NT-proBNP, the association of HOMA-IR with death was no longer present (adjusted HR: 0.99, 95% CI: 0.83 to 1.19, P = 0.94). Baseline HOMA-IR was not associated with major adverse cardiovascular events, nor was the change in HOMA-IR on study treatment associated with death or major adverse cardiovascular events. Conclusions After accounting for levels of NT-proBNP, insulin resistance assessed by HOMA-IR is not related to the risk of death or major adverse cardiovascular events in patients with type 2 diabetes and ACS.

Importance Oral glucocorticoid treatment increases fracture risk, and evidence is lacking regarding the efficacy of alendronate to protect against hip fracture in older patients using glucocorticoids. Objective To investigate whether alendronate treatment in older patients using oral prednisolone is associated with decreased hip fracture risk and adverse effects. Design, Setting, and Participants Retrospective cohort study using a national database (N = 433 195) of patients aged 65 years or older undergoing a health evaluation (baseline) at Swedish health care facilities; 1802 patients who were prescribed alendronate after at least 3 months of oral prednisolone treatment (≥5 mg/d) were identified. Propensity score matching was used to select 1802 patients without alendronate use from 6076 patients taking prednisolone with the same dose and treatment time criteria. Follow-up occurred between January 2008 and December 2014. Exposures Alendronate vs no alendronate use; no patients had previously taken alendronate at the time of prednisolone initiation. Main Outcomes and Measures The primary outcome was incident hip fracture. Results Of the 3604 included patients, the mean age was 79.9 (SD, 7.5) years, and 2524 (70%) were women. After a median follow-up of 1.32 years (interquartile range, 0.57-2.34 years), there were 27 hip fractures in the alendronate group and 73 in the no-alendronate group, corresponding to incidence rates of 9.5 (95% CI, 6.5-13.9) and 27.2 (95% CI, 21.6-34.2) fractures per 1000 person-years, with an absolute rate difference of −17.6 (95% CI, −24.8 to −10.4). The use of alendronate was associated with a lower risk of hip fracture in a multivariable-adjusted Cox model (hazard ratio, 0.35; 95% CI, 0.22-0.54). Alendronate treatment was not associated with increased risk of mild upper gastrointestinal tract symptoms (alendronate vs no alendronate, 15.6 [95% CI, 11.6-21.0] vs 12.9 [95% CI, 9.3-18.0] per 1000 person-years; P = .40) or peptic ulcers (10.9 [95% CI, 7.7-15.5] vs 11.4 [95% CI, 8.0-16.2] per 1000 person-years; P = .86). There were no cases of incident drug-induced osteonecrosis and only 1 case of femoral shaft fracture in each group. Conclusions and Relevance Among older patients using medium to high doses of prednisolone, alendronate treatment was associated with a significantly lower risk of hip fracture over a median of 1.32 years. Although the findings are limited by the observational study design and the small number of events, these results support the use of alendronate in this patient group.

BACKGROUND The relationship between mortality and heart rate remains unclear for patients with heart failure with reduced ejection fraction in either sinus rhythm or atrial fibrillation (AF).OBJECTIVES This analysis explored the prognostic importance of heart rate in patients with heart failure with reduced ejection fraction in randomized controlled trials comparing beta-blockers and placebo.METHODS The Beta-Blockers in Heart Failure Collaborative Group performed a meta-analysis of harmonized individual patient data from 11 double-blind randomized controlled trials. The primary outcome was all-cause mortality, analyzed with Cox proportional hazard ratios (HR) modeling heart rate measured at baseline and approximately 6 months post-randomization.RESULTS A higher heart rate at baseline was associated with greater all-cause mortality for patients in sinus rhythm (n = 14,166; adjusted HR: 1.11 per 10 beats/min; 95% confidence interval [CI]: 1.07 to 1.15; p CONCLUSIONS Regardless of pre-treatment heart rate, beta-blockers reduce mortality in patients with heart failure with reduced ejection fraction in sinus rhythm. Achieving a lower heart rate is associated with better prognosis, but only for those in sinus rhythm. (C) 2017 by the American College of Cardiology Foundation.

Aims To investigate the prognostic significance of hospitalization for worsening heart failure (WHF), myocardial infarction (MI), and stroke in patients with chronic heart failure (HF). Methods and results We studied 5011 patients with HF and reduced EF (HF-REF) in the CORONA trial and 4128 patients with HF and preserved EF (HF-PEF) in the I-Preserve trial. Adjusted hazard ratios (HRs) for death were estimated for 0–30 days and ≥31 days after first post-randomization WHF, MI, or stroke used as a time-dependent variable, compared with patients with none of these events. In CORONA, 1616 patients (32%) had post-randomization first events (1223 WHF, 216 MI, 177 stroke), and the adjusted HR for mortality ≤30 days after an event was: WHF 7.21 [95% confidence interval (CI) 2.05–25.40], MI 23.08 (95% CI 6.44–82.71), and stroke 32.15 (95% CI 8.93–115.83). The HR for mortality at >30 days was: WHF 3.62 (95% CI 3.11–4.21), MI 4.41 (95% CI 3.23–6.02), and stroke 3.19 (95% CI 2.21–4.61). In I-Preserve, 896 patients (22%) experienced a post-randomization event (638 WHF, 111 MI, 147 stroke). The HR for mortality ≤30 days was WHF 31.77 (95% CI 7.60–132.81), MI 154.77 (95% CI 34.21–700.17), and stroke 223.30 (95% CI 51.42–969.78); for >30 days it was WHF 3.36 (95% CI 2.79–4.05), MI 3.29 (95% CI 2.14–5.06), and stroke 5.13 (95% CI 3.61–7.29). Conclusions In patients with both HF-REF and HF-PEF, hospitalization for WHF was associated with high early and late mortality. The early relative risk of death was not as great as following MI or stroke, but the longer term relative risk of death was similar following all three types of event. Numerically, more deaths occurred following WHF because it was a much more common event.

Aim: Angina pectoris is common in patients with heart failure and reduced ejection fraction (HF-REF) but its relationship with outcomes has not been well defined. This relationship was investigated further in a retrospective analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Methods and results: Four thousand, eight hundred and seventy-eight patients were divided into three categories: no history of angina and no chest pain at baseline (Group A; n = 1240), past history of angina but no chest pain at baseline (Group B; n = 1353) and both a history of angina and chest pain at baseline (Group C; n = 2285). Outcomes were examined using Kaplan–Meier and Cox regression survival analysis. Compared with Group A, Group C had a higher risk of non-fatal myocardial infarction or unstable angina (HR: 2.36, 1.54–3.61; P < 0.001), this composite plus coronary revascularization (HR: 2.54, 1.76–3.68; P < 0.001), as well as HF hospitalization (HR: 1.35, 1.13–1.63; P = 0.001), over a median follow-up period of 33 months. There was no difference in cardiovascular or all-cause mortality. Group B had a smaller increase in risk of coronary events but not of heart failure hospitalization. Conclusion: Patients with HF-REF and ongoing angina are at an increased risk of acute coronary syndrome and HF hospitalization. Whether these patients would benefit from more aggressive medical therapy or percutaneous revascularization is not known and merits further investigation.

Summary Background The benefits of intensified glycaemic control after acute myocardial infarction are uncertain. We report the 20 year follow-up results of the first Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI 1) trial. Methods DIGAMI 1 was a prospective, randomised, open-label trial with blinded endpoint evaluation (PROBE) done at coronary care units in 19 Swedish hospitals between Jan 1, 1990 and Dec 31, 1993. Patients with and without previously diagnosed diabetes and with blood glucose concentrations of more than 11 mmol/L who had had a suspected acute myocardial infarction in the previous 24 h were randomly assigned (1:1), with sealed envelopes, to intensified insulin-based glycaemic control for at least 3 months, or to a control group prescribed conventional glucose-lowering treatment. Masking was not considered feasible or safe on the basis of insulin use. The primary endpoint was mortality, in both the original study and the present follow-up analysis. Analysis was by intention to treat. Findings 620 patients were randomised to intensified insulin-based glycaemic control (n=306) or the control group (n=314). During a mean follow-up period of 7·3 years (SD 6·6; range 0·0–21·8) years, 271 patients (89%) died in the intensified glycaemic control group and 285 (91%) patients died in the standard glycaemic control group. Median survival time was 7·0 years (IQR 1·8–12·4) in patients in the intensified glycaemic control group and 4·7 (1·0–11·4) in those in the standard group (hazard ratio 0·83, 95% CI 0·70–0·98; p=0·027). The effect of intensified glycaemic control was apparent during 8 years after randomisation, increasing survival by 2·3 years. Interpretation Intensified insulin-based glycaemic control after acute myocardial infarction in patients with diabetes and hyperglycaemia at admission had a long-lasting effect on longevity. Although the effect of glucose lowering might be less apparent with presently available, more effective lipid-lowering and blood-pressure-lowering drugs, improved glycaemic control might still be important for longevity after acute myocardial infarction. Funding Swedish Heart-Lung Foundation, Kronoberg County Council.

Objectives This study sought to examine the effect of statin therapy hospitalizations for heart failure (HFH) in patients in the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) trial. Background HFH is an important, frequently recurrent event. Conventional time-to-first event analyses do not take account repeat events. We used a number of statistical approaches to examine the effect of treatment on first and repeat HFH in the CORONA trial. Methods In the CORONA trial, 5,011 patients ≥60 years of age with chronic New York Heart Association functional classes II to IV systolic heart failure resulting from ischemia were randomized to receive rosuvastatin or placebo. Poisson, Andersen-Gill, and negative binomial methods (NB) were used to analyze the effect of rosuvastatin on HFH, and the NB and a parametric joint frailty model (JF) were used to examine this effect while accounting for the competing risk of cardiovascular (CV) death. Rosuvastatin/placebo rate ratios were calculated, both unadjusted and adjusted. Results A total of 1,291 patients had 1 or more HFH (750 of these had a single HFH only), and there were a total of 2,408 HFHs. The hazard ratio for the conventional time-to-first event analysis for HFH was 0.91 (95% confidence interval [CI]: 0.82 to 1.02, p = 0.105). In contrast, the NB on repeat hospitalizations gave an unadjusted RR (RR) for HFH of 0.86 (95% CI: 0.75 to 0.99, p = 0.030), adjusted 0.82 (95% CI: 0.72 to 0.92, p = 0.001), and after including CV death as the last event, adjusted RR of 0.85 (95% CI: 0.77 to 0.94, p = 0.001). The JF gave an adjusted RR of 0.82 (95% CI: 0.73 to 0.92, p = 0.001). Similar results were found in analyses of all CV hospitalizations and all-cause hospitalizations. Conclusions When repeat events were included, rosuvastatin was shown to reduce the risk of HFH by approximately 15% to 20%, equating to approximately 76 fewer admissions per 1,000 patients treated over a median 33 months of follow-up. Including repeat events could increase the ability to detect treatment effects in heart failure trials.

Background: This study aimed to explore the feasibility and effect of an intervention in clinical practice with isolated physical activity in individuals with IGT, recruited by the FINDRISC questionnaire. Methods: The questionnaire was sent to a population of 9734 individuals, 35–75 years old, in Sweden. Those with a risk score ≥15 were encouraged to perform an oral glucose tolerance test. Individuals with IGT were invited to participate in a randomized controlled trial with a focus on physical activity. The participants were allocated to one of three arms; basic intervention, intensive intervention or to care as usual. A total of 52 individuals were carefully examined and questionnaires about diet and lifestyle were completed at baseline and after one year. All analyses were adjusted for differences in age and sex, and calorie intake when relevant. Results :The prevalence of chronic diseases in the study population was high, creating considerable difficulties in conducting a standardized test for fitness. Waist circumference ( p=0.020), sagittal diameter ( p=0.035), body weight ( p=0.038) and BMI ( p=0.043) decreased significantly more in the intensive care group than in care as usual and the basic care group. However, the significance was abolished when differences in energy intake were accounted for. Conclusions: In an intention to treat, prospective lifestyle interventions with physical activity are feasible, but a high prevalence of comorbidities needs to be considered. Also, an intervention focused on isolated physical activity inevitably led to changes in diet with weight loss and significant improvement of essential risk factors in spite of the participants’ burden of chronic diseases.

ObjectiveThe purpose of the study was to investigate the excess risk of acute myocardial infarction (AMI) and death from coronary artery disease (coronary heart disease, CHD) in relation to age, level of glycaemic control and renal complications in patients with type 2 diabetes.MethodsA total of 431 579 patients with type 2 diabetes mellitus registered in the Swedish National Diabetes Register from 1 January 1998 to 31 December 2012, and 2 173 620 controls from the general population were included. Cox regression was used to study the excess risk of AMI and CHD.ResultsDuring follow-up of 5.1 years in the diabetes group and 5.4 years in the control group, 36 124 (8.4%) and 115 712 (5.3%) CHD events were registered, with corresponding incidence rates/1000 person-years of 14.64 (95% CI 14.49 to 14.79) and 8.73 (95% CI 8.68 to 8.78), respectively. The HR after adjustment for sex and age was 1.67 (1.65–1.69) which was reduced to 1.42 (1.41–1.44) with further adjustment for level of education, country of birth, diabetes duration and comorbidities. The multivariable-adjusted HR for AMI and CHD death with a time-updated glycated haemoglobin level of 6.9% or lower (≤52 mmol/mol) together with normoalbuminuria and estimated glomerular filtration rate ≥60 mL/min for patients with diabetes compared with controls was 0.95 (95% CI 0.92 to 0.98, pConclusionsIn this study, the excess risk of AMI and CHD death was higher for patients with type 2 diabetes compared with controls but converged to that in the general population in patients with on-target HbA1c levels and without renal complications.

Aims: The four pivotal beta-blocker trials in heart failure ( HF ) had different inclusion criteria, making comparison difficult without patient stratifying. The aim of this study was to compare, in similar patients, the effects of bisoprolol, metoprolol controlled release/extended release ( CR/XL ), carvedilol and nebivolol on ( i ) total mortality, ( ii ) all-cause mortality or hospitalization due to cardiovascular causes ( time to first event ), ( iii ) all-cause mortality or hospitalization because of HF and ( iv ) tolerability, defined as discontinuation of randomized treatment. Methods: We compared stratified ( s ) subsets in MERIT-HF with patients in CIBIS-II [New York Heart Association ( NYHA ) class III/IV and ejection fraction ( EF ) ≤35%] and COPERNICUS ( NYHA III/IV and EF < 25% ) and in patients with systolic HF in SENIORS-SHF ( age ≥70 years and EF ≤35% ). Results: The annual mortality rates in the placebo and beta-blocker arms were: ( i ) CIBIS-II ( n = 2647 ), 13.2% vs. 8.8% ( relative risk reduction 34%, 95% CI: 19–46, P < 0.0001 ) and MERIT-HFs ( n = 2002 ), 14.8% vs. 8.6% ( relative risk reduction 42%, 95% CI: 24–56, P < 0.0001 ); ( ii ) COPERNICUS ( n = 2289 ), 19.7% vs. 12.8% ( relative risk reduction 35%, 95% CI: 19–48, P = 0.0014 ) and MERIT-HFs ( n = 795 ), 19.1% vs. 11.7% ( relative risk reduction 39%; 95% CI: 11–58, P = 0.0086 ); ( iii ) SENIORS-SHF ( n = 1359 ), 11.3% vs. 9.7% ( relative risk reduction 16%, NS ) and MERIT-HFs ( n = 985 ), 14.8% vs. 10.1% ( relative risk reduction 32%, 95% CI: 2–53, P = 0.038 ). The effects on the other outcomes assessed were similar. Analyses indicated fewer discontinuations from randomized treatment on beta-blockers compared with placebo in COPERNICUS and the MERIT-HFssubsets. Conclusion: The efficacy and tolerability of bisoprolol, carvedilol and metoprolol CR/XL are similar in patients with systolic HF, irrespective of NYHA class or ejection fraction. Nebivolol is less effective and not better tolerated.

Objective Increased sensitivity to alcohol after gastric bypass has been described. The aim of this study was to investigate whether bariatric surgery is associated with alcohol problems. Design and Methods The prospective, controlled Swedish Obese Subjects (SOS) study enrolled 2,010 obese patients who underwent bariatric surgery (68% vertical banded gastroplasty (VBG), 19% banding, and 13% gastric bypass) and 2,037 matched controls. Patients were recruited between 1987 and 2001. Data on alcohol abuse diagnoses, self-reported alcohol consumption, and alcohol problems were obtained from the National Patient Register and questionnaires. Follow-up time was 8-22 years. Results During follow-up, 93.1% of the surgery patients and 96.0% of the controls reported alcohol consumption classified as low risk by the World Health Organization (WHO). However, compared to controls, the gastric bypass group had increased risk of alcohol abuse diagnoses (adjusted hazard ratio [adjHR] = 4.97), alcohol consumption at least at the WHO medium risk level (adjHR = 2.69), and alcohol problems (adjHR = 5.91). VBG increased the risk of these conditions with adjHRs of 2.23, 1.52, and 2.30, respectively, while banding was not different from controls. Conclusions Alcohol consumption, alcohol problems, and alcohol abuse are increased after gastric bypass and VBG.

The excess risk of major coronary events (acute myocardial infarction (AMI) or death from coronary heart disease (CHD)) in individuals with type 1 diabetes (T1D) in relation to glycaemic control and renal complications is not known.Individuals with T1D in the Swedish National Diabetes Registry after 1 January 1998, without a previous MI (n=33 170) and 1 64 698 controls matched on age, sex and county were followed with respect to non-fatal AMI or death from CHD. Data were censored at death due to any cause until 31 December 2011.During median follow-up of 8.3 and 8.9 years for individuals with T1D and controls, respectively, 1500 (4.5%) and 1925 (1.2%), experienced non-fatal AMI or died from CHD, adjusted HR 4.07 (95% CI 3.79 to 4.36). This excess risk increased with younger age, female sex, worse glycaemic control and severity of renal complications.The adjusted HR in men with T1D with updated mean haemoglobin A1c (HbA1c)6.9% (52 mmol/mol) and normoalbuminuria was 1.30 (95% CI 0.90 to 1.88) and in women 3.16 (95% CI 2.14 to 4.65). HRs increased to 10.7 (95% CI 8.0 to 14.3) and 31.8 (95% CI 23.6 to 42.8) in men and women, respectively, with HbA1c9.7% and renal complications.The excess risk of AMI in T1D is substantially lower with good glycaemic control, absence of renal complications and men compared with women. In women, the excess risk of AMI or CHD death persists even among patients with good glycaemic control and no renal complications.

AIMS: To determine the cardiovascular benefits in those originally assigned atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial-2.2 years after closure of the lipid-lowering arm of the trial (ASCOT-LLA). METHODS AND RESULTS: The Blood Pressure Lowering Arm of the ASCOT trial (ASCOT-BPLA) compared two different antihypertensive treatment strategies on cardiovascular outcomes. ASCOT-LLA was a double-blind placebo-controlled trial of atorvastatin in those enrolled into ASCOT-BPLA with total cholesterol concentrations at baseline of < or =6.5 mmol/L. A total of 19 342 hypertensive patients were enrolled in ASCOT-BPLA and 10 305 were further assigned either atorvastatin, 10 mg, or placebo. ASCOT-LLA was stopped prematurely after a median 3.3 years follow-up because of substantial cardiovascular benefits in those assigned atorvastatin. Trial physicians were invited to offer atorvastatin to all ASCOT-LLA patients until the end of ASCOT-BPLA. The primary outcome of ASCOT-LLA was combined fatal coronary heart disease (CHD) or non-fatal myocardial infarction. Secondary outcomes included all coronary events, all cardiovascular events and procedures, fatal and non-fatal stroke, cardiovascular mortality, all cause mortality, development of chronic stable angina, heart failure, and peripheral arterial disease. By the end of ASCOT-LLA, there was a 36% relative risk reduction in primary events (n = 254) in favour of atorvastatin [hazard ratio (HR) 0.64, 95% CI: 0.50-0.83, P = 0.0005]. At the end of ASCOT-BPLA, 2.2 years later, despite extensive crossovers from and to statin usage, the relative risk reduction in primary events (n = 412) among those originally assigned atorvastatin remained at 36% (HR 0.64, 95% CI: 0.53-0.78, P = 0.0001). For almost all other endpoints, risk reductions also remained essentially unchanged and in the case of all cause mortality, the risk reduction of 15% now achieved borderline statistical significance (P = 0.02). CONCLUSION: Carry-over benefits from those originally assigned atorvastatin but no longer taking the drug may account for unchanged relative risk reductions in most cardiovascular endpoints observed 2 years after ASCOT-LLA closed.

BACKGROUND: Atrial fibrillation and heart failure often coexist, causing substantial cardiovascular morbidity and mortality. β blockers are indicated in patients with symptomatic heart failure with reduced ejection fraction; however, the efficacy of these drugs in patients with concomitant atrial fibrillation is uncertain. We therefore meta-analysed individual-patient data to assess the efficacy of β blockers in patients with heart failure and sinus rhythm compared with atrial fibrillation. METHODS: We extracted individual-patient data from ten randomised controlled trials of the comparison of β blockers versus placebo in heart failure. The presence of sinus rhythm or atrial fibrillation was ascertained from the baseline electrocardiograph. The primary outcome was all-cause mortality. Analysis was by intention to treat. Outcome data were meta-analysed with an adjusted Cox proportional hazards regression. The study is registered with Clinicaltrials.gov, number NCT0083244, and PROSPERO, number CRD42014010012. FINDINGS: 18,254 patients were assessed, and of these 13,946 (76%) had sinus rhythm and 3066 (17%) had atrial fibrillation at baseline. Crude death rates over a mean follow-up of 1·5 years (SD 1·1) were 16% (2237 of 13,945) in patients with sinus rhythm and 21% (633 of 3064) in patients with atrial fibrillation. β-blocker therapy led to a significant reduction in all-cause mortality in patients with sinus rhythm (hazard ratio 0·73, 0·67-0·80; p

Objectives: To determine the efficacy and tolerability of β blockers in a broad age range of women and men with heart failure with reduced ejection fraction (HFrEF) by pooling individual patient data from placebo controlled randomised trials.\ud \ud Design: Prospectively designed meta-analysis of individual patient data from patients aged 40-85 in sinus rhythm at baseline, with left ventricular ejection fraction

Diabet. Med. 29, 1501–1505 (2012) Abstract Aim To evaluate the performance of the FINDRISC questionnaire as a tool to recruit individuals with impaired glucose tolerance for lifestyle intervention programmes. Methods A cross-sectional population-based study in primary Health Care Centres in a middle-sized Swedish town. All 9734 individuals, aged 35–75 years, living within a defined area, were invited by mail to fill in and return the FINDRISC questionnaire. Participants with a risk score ≥ 15 (n = 525) were invited to perform an oral glucose tolerance test while those with known diabetes were excluded. Results In total, 5452 questionnaires (58%) were returned and revealed a mean risk-score of 8.5 ± 4.5 (mean ± SD). We found that 525 participants had a risk-score ≥ 15 and 302 (58%) were further examined with an oral glucose tolerance testing (OGTT). Among them we detected 11% with previously undiagnosed Type 2 diabetes, 16% with impaired glucose tolerance and 29% with impaired fasting glucose. A FINDRISC score ≥ 15 was associated with a positive predictive value of 55% for impaired glucose metabolism (impaired fasting glucose + impaired glucose tolerance + Type 2 diabetes) and of 16% for impaired glucose tolerance, respectively. The positive predictive value for impaired glucose tolerance did not increase to more than 17% when choosing the cut-point 17, while there was a significant increase in the positive predictive value for impaired glucose metabolism (70%). Conclusions The FINDRISC questionnaire is a useful instrument for identification of individuals with impaired glucose metabolism but seems less effective for detection of individuals with impaired glucose tolerance. Strategies to find individuals with impaired glucose tolerance for implementation of lifestyle changes in primary care should therefore be developed further.

BACKGROUND Weight loss protects against type 2 diabetes but is hard to maintain with behavioral modification alone. In an analysis of data from a nonrandomized, prospective, controlled study, we examined the effects of bariatric surgery on the prevention of type 2 diabetes. METHODS In this analysis, we included 1658 patients who underwent bariatric surgery and 1771 obese matched controls (with matching performed on a group, rather than individual, level). None of the participants had diabetes at baseline. Patients in the bariatric-surgery cohort underwent banding (19%), vertical banded gastroplasty (69%), or gastric bypass (12%); nonrandomized, matched, prospective controls received usual care. Participants were 37 to 60 years of age, and the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) was 34 or more in men and 38 or more in women. This analysis focused on the rate of incident type 2 diabetes, which was a prespecified secondary end point in the main study. At the time of this analysis (January 1, 2012), participants had been followed for up to 15 years. Despite matching, some baseline characteristics differed significantly between the groups; the baseline body weight was higher and risk factors were more pronounced in the bariatric-surgery group than in the control group. At 15 years, 36.2% of the original participants had dropped out of the study, and 30.9% had not yet reached the time for their 15-year follow-up examination. RESULTS During the follow-up period, type 2 diabetes developed in 392 participants in the control group and in 110 in the bariatric-surgery group, corresponding to incidence rates of 28.4 cases per 1000 person-years and 6.8 cases per 1000 person-years, respectively (adjusted hazard ratio with bariatric surgery, 0.17; 95% confidence interval, 0.13 to 0.21; P

Older patients experience higher rates of cardiovascular disease than younger patients, but may be undertreated with statins due to doubts about efficacy and safety. The Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial allowed an evaluation of the efficacy and safety of atorvastatin among older (≥ 65 years) and younger (65 years) patients with hypertension.A total of 10 305 patients with hypertension, at least three other cardiovascular risk factors, total cholesterol concentrations of 251 mg/dl or less, and no known coronary heart disease (CHD) were randomized to receive atorvastatin 10 mg or placebo. The primary endpoint was a composite of nonfatal myocardial infarction and fatal CHD.There were 4445 patients in the older group (mean 71 years) and 5860 patients (mean 57 years) in the younger group. Among those taking placebo, the older group experienced a higher rate of primary endpoints than the younger group (11.7 vs. 7.6 events per 1000 patient years, respectively). After a median follow-up of 3.3 years, the primary endpoint was reduced by a similar proportion in both older and younger patients (37 vs. 33%, respectively). Although older patients reported more serious adverse events than younger patients, there were no significant differences between atorvastatin and placebo within each age group.Atorvastatin reduced the risk of major cardiovascular events to a similar relative extent in both older and younger patients with treated hypertension. However, given that event rates were higher in older patients, the absolute benefits of atorvastatin were greater for older than younger patients.

Older patients experience higher rates of cardiovascular disease than younger patients, but studies have suggested that relative risk reductions due to antihypertensive therapy are lower in older than younger patients. The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) allowed an evaluation of the efficacy and safety of an amlodipine versus an atenolol-based antihypertensive regimen among older (≥ 65 years) and younger (65 years) patients.In ASCOT-BPLA 19 257 patients (8137 aged ≥ 65 years and 11 02065 years) were randomly assigned to receive amlodipine or atenolol-based antihypertensive therapy. The primary endpoint (nonfatal myocardial infarction and fatal coronary heart disease) and seven secondary endpoints were consistent with the original trial design.All cardiovascular endpoints evaluated favoured the amlodipine-based regimen, significantly so in seven of the 16 age-stratified endpoints. Compared with the atenolol-based regimen, the amlodipine-based regimen reduced the relative risk of cardiovascular events by 17% in older and 15% in younger patients (P0.01). Overall, older patients experienced more cardiovascular events [n = 1625 (20%)] than younger patients [n = 1339 (12%)]. Discontinuations due to serious adverse events were low in both age groups and less frequent in the amlodipine-based versus atenolol-based regimen: 0.6 versus 1.1% among older patients and 0.4 versus 0.8% among younger patients.The amlodipine-based regimen reduced the relative risk of cardiovascular events more effectively than the atenolol-based regimen in both older and younger patients. However, because event rates were higher among older patients, the absolute benefits were greater for older compared with younger patients.

Objectives The purpose of this study was to determine whether coenzyme Q10 is an independent predictor of prognosis in heart failure. Background Blood and tissue concentrations of the essential cofactor coenzyme Q10 are decreased by statins, and this could be harmful in patients with heart failure. Methods We measured serum coenzyme Q10 in 1,191 patients with ischemic systolic heart failure enrolled in CORONA (Controlled Rosuvastatin Multinational Study in Heart Failure) and related this to clinical outcomes. Results Patients with lower coenzyme Q10 concentrations were older and had more advanced heart failure. Mortality was significantly higher among patients in the lowest compared to the highest coenzyme Q10 tertile in a univariate analysis (hazard ratio: 1.50, 95% confidence interval: 1.04 to 2.6, p = 0.03) but not in a multivariable analysis. Coenzyme Q10 was not an independent predictor of any other clinical outcome. Rosuvastatin reduced coenzyme Q10 but there was no interaction between coenzyme Q10 and the effect of rosuvastatin. Conclusions Coenzyme Q10 is not an independent prognostic variable in heart failure. Rosuvastatin reduced coenzyme Q10, but even in patients with a low baseline coenzyme Q10, rosuvastatin treatment was not associated with a significantly worse outcome. (Controlled Rosuvastatin Multinational Study in Heart Failure [CORONA]; NCT00206310 )

3550Background: 5-fluorouracil (5-FU) with the folate pro-drug leucovorin (LV) has long been backbone of chemotherapy for colorectal cancer (CRC). Low expression of folate-related genes may lead to...

Summary Background: Adherence to lipid-lowering therapy in clinical practice is less than ideal. Analysis of registry data has indicated that this is associated with poor outcomes. The objective of the present analysis was to assess the impact of high adherence to drug (defined as > 80% of days covered), compared with low adherence to drug (