Effects of icosapent ethyl according to baseline residual risk in patients with atherosclerotic cardiovascular disease: results from REDUCE-IT.

BACKGROUND AND AIMS: Icosapent ethyl lowers triglycerides and significantly reduces major adverse cardiovascular events (MACE), though treatment effects may vary between individuals. This study aimed to determine the relative and absolute effects of icosapent ethyl on MACE according to baseline CVD risk in patients with atherosclerotic cardiovascular disease (ASCVD). METHODS: Participants from REDUCE-IT with ASCVD were included (n = 5,785). The primary outcome was 3-point MACE, i.e. non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. Baseline 5-year risk of MACE was estimated using the ESC guideline-recommended SMART2 risk score. Modification of the relative treatment effects of icosapent ethyl by baseline risk was assessed using Cox proportional hazards models including a treatment-by-risk interaction. Next, treatment effects were assessed stratified by quartiles of baseline risk. RESULTS: During a median follow-up of 4.8 years (interquartile range 3.2-5.3), MACE occurred in 361 vs 489 patients in the icosapent ethyl vs placebo group (95% confidence interval [CI]); hazard ratio (HR) 0.72 (0.63-0.82), absolute risk reduction (ARR) 4.4% (2.6-6.2%), number needed to treat (NNT) 23 (16-38), 5-year Kaplan-Meier estimated cumulative incidence reduction (CIR) 5.7% (3.5-7.9%). Icosapent ethyl significantly reduced MACE in all risk quartiles, with an HR (95% CI) of 0.62 (0.43-0.88), 0.66 (0.48-0.92), 0.69 (0.53-0.90), and 0.78 (0.63-0.96) respectively (p for treatment-by-risk interaction = 0.106). The ARR (95% CI) increased across risk quartiles, i.e. was 3.9% (1.0-6.8%), 4.3% (1.2-7.3%), 5.1% (1.4-8.7%), and 5.6% (1.3-10.0%) respectively. This translates to NNTs (95% CI) of 26 (15-98), 24 (14-84), 20 (11-70), and 18 (10-77). The 5-year CIR (95% CI) was 4.8% (1.3-8.2%), 5.0% (1.3-8.7%), 6.1% (1.7-10.5%), and 7.7% (2.3-13.2%) respectively. Consistent results were obtained for 5-point MACE, additionally including coronary revascularization and unstable angina. CONCLUSIONS: Among patients with ASCVD and elevated triglyceride levels, icosapent ethyl significantly reduces the risk of MACE irrespective of baseline CVD risk, though absolute benefits are largest for patients at the highest risk.

Personalized lifetime prediction of survival and treatment benefit in patients with heart failure with reduced ejection fraction: The LIFE-HF model.

AIMS: Although trials have proven the group-level effectiveness of various therapies for heart failure with reduced ejection fraction (HFrEF), important differences in absolute effectiveness exist between individuals. We developed and validated the LIFEtime-perspective for Heart Failure (LIFE-HF) model for the prediction of individual (lifetime) risk and treatment benefit in patients with HFrEF. METHODS AND RESULTS: Cox proportional hazards functions with age as the time scale were developed in the PARADIGM-HF and ATMOSPHERE trials (n = 15 415). Outcomes were cardiovascular death, heart failure (HF) hospitalization or cardiovascular death, and non-cardiovascular mortality. Predictors were age, sex, New York Heart Association class, prior HF hospitalization, diabetes mellitus, extracardiac vascular disease, systolic blood pressure, left ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide, and glomerular filtration rate. The functions were combined in life-tables to predict individual overall and HF hospitalization-free survival. External validation was performed in the SwedeHF registry, ASIAN-HF registry, and DAPA-HF trial (n = 51 286). Calibration of 2- to 10-year risk was adequate, and c-statistics were 0.65-0.74. An interactive tool was developed combining the model with hazard ratios from trials to allow estimation of an individual's (lifetime) risk and treatment benefit in clinical practice. Applying the tool to the development cohort, combined treatment with a mineralocorticoid receptor antagonist, sodium-glucose cotransporter 2 inhibitor, and angiotensin receptor-neprilysin inhibitor was estimated to afford a median of 2.5 (interquartile range [IQR] 1.7-3.7) and 3.7 (IQR 2.4-5.5) additional years of overall and HF hospitalization-free survival, respectively. CONCLUSION: The LIFE-HF model enables estimation of lifelong overall and HF hospitalization-free survival, and (lifetime) treatment benefit for individual patients with HFrEF. It could serve as a tool to improve the management of HFrEF by facilitating personalized medicine and shared decision-making.

Individual lifetime benefit from low-dose colchicine in patients with chronic coronary artery disease.

AIMS: Low-dose colchicine reduces cardiovascular risk in patients with coronary artery disease (CAD), but absolute benefits may vary between individuals. This study aimed to assess the range of individual absolute benefits from low-dose colchicine according to patient risk profile. METHODS AND RESULTS: The European Society of Cardiology (ESC) guideline-recommended SMART-REACH model was combined with the relative treatment effect of low-dose colchicine and applied to patients with CAD from the Low-Dose Colchicine 2 (LoDoCo2) trial and the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease (UCC-SMART) study (n = 10 830). Individual treatment benefits were expressed as 10-year absolute risk reductions (ARRs) for myocardial infarction, stroke, or cardiovascular death (MACE), and MACE-free life-years gained. Predictions were also performed for MACE plus coronary revascularization (MACE+), using a new lifetime model derived in the REduction of Atherothrombosis for Continued Health (REACH) registry. Colchicine was compared with other ESC guideline-recommended intensified (Step 2) prevention strategies, i.e. LDL cholesterol (LDL-c) reduction to 1.4 mmol/L and systolic blood pressure (SBP) reduction to 130 mmHg. The generalizability to other populations was assessed in patients with CAD from REACH North America and Western Europe (n = 25 812). The median 10-year ARR from low-dose colchicine was 4.6% [interquartile range (IQR) 3.6-6.0%] for MACE and 8.6% (IQR 7.6-9.8%) for MACE+. Lifetime benefit was 2.0 (IQR 1.6-2.5) MACE-free years, and 3.4 (IQR 2.6-4.2) MACE+-free life-years gained. For LDL-c and SBP reduction, respectively, the median 10-year ARR for MACE was 3.0% (IQR 1.5-5.1%) and 1.7% (IQR 0.0-5.7%), and the lifetime benefit was 1.2 (IQR 0.6-2.1) and 0.7 (IQR 0.0-2.3) MACE-free life-years gained. Similar results were obtained for MACE+ and in American and European patients from REACH. CONCLUSION: The absolute benefits of low-dose colchicine vary between individual patients with chronic CAD. They may be expected to be of at least similar magnitude to those of intensified LDL-c and SBP reduction in a majority of patients already on conventional lipid-lowering and blood pressure-lowering therapy.

The long-term benefits of treatment with low-dose colchicine were estimated for 36 642 individuals with coronary heart disease, and compared with those of lipid- and blood pressure­lowering therapy. On average, low-dose colchicine was estimated to lower the risk of cardiovascular disease in the next 10 years from 17.8 to 13.2% (a reduction of 4.6% points) and to afford 2.0 additional years of life without cardiovascular disease.Low-dose colchicine was estimated to be the most effective treatment in 49%, intensive blood pressure­lowering therapy in 28%, and intensive lipid-lowering therapy in 23% of patients.

C-Reactive Protein and Risk of Incident Heart Failure in Patients With Cardiovascular Disease.

BACKGROUND: Patients with established cardiovascular disease (CVD) are at high risk of incident heart failure (HF), which may in part reflect the impact of systemic inflammation. OBJECTIVES: The goal of this study was to determine the association between C-reactive protein (CRP) and incident HF in patients with established CVD. METHODS: Patients from the prospective UCC-SMART (Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease) cohort with established CVD, but without prevalent HF were included (n = 8,089). Incident HF was defined as a first hospitalization for HF. The association between baseline CRP and incident HF was assessed using Cox proportional hazards models adjusted for established risk factors (ie, age, sex, myocardial infarction, smoking, diabetes mellitus, body mass index, blood pressure, cholesterol, and kidney function). RESULTS: During a median follow-up of 9.7 years (IQR 5.4-14.1 years), 810 incident HF cases were observed (incidence rate 1.01/100 person-years). Higher CRP was independently associated with an increased risk of incident HF: HR per 1 mg/L: 1.10 (95% CI: 1.07-1.13), and for last vs first CRP quartile: 2.22 (95% CI: 1.76-2.79). The association was significant for both HF with reduced (HR: 1.09; 95% CI: 1.04-1.14) and preserved ejection fraction (HR: 1.12; 95% CI: 1.07-1.18) (P for difference = 0.137). Additional adjustment for medication use and interim myocardial infarction did not attenuate the association, and the association remained consistent beyond 15 years after the CRP measurement. CONCLUSIONS: In patients with established CVD, CRP is an independent risk marker of incident HF. These data support ongoing trial efforts to assess whether anti-inflammatory agents can reduce the burden of HF.

C-Reactive Protein and Risk of Cardiovascular Events and Mortality in Patients with Various Cardiovascular Disease Locations.

Anti-inflammatory drugs reduce the risk of cardiovascular events in patients with coronary artery disease (CAD), but less is known about the relation between inflammation and outcomes in patients with cerebrovascular disease (CeVD), peripheral artery disease (PAD), and abdominal aortic aneurysm (AAA). This study assessed the association between C-reactive protein (CRP) and clinical outcomes in patients with CAD (n = 4,517), CeVD (n = 2,154), PAD (n = 1,154), and AAA (n = 424) from the prospective Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease study. The primary outcome was recurrent cardiovascular disease (CVD), defined as myocardial infarction, ischemic stroke, or cardiovascular death. Secondary outcomes were major adverse limb events and all-cause mortality. Associations between baseline CRP and outcomes were assessed using Cox proportional hazards models adjusted for age, sex, smoking, diabetes mellitus, body mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, and glomerular filtration rate. Results were stratified by CVD location. During a median follow-up of 9.5 years, 1,877 recurrent CVD events, 887 major adverse limb events, and 2,341 deaths were observed. CRP was independently associated with recurrent CVD (hazard ratio [HR] per 1 mg/L 1.08, 95% confidence interval [CI] 1.05 to 1.10), and all secondary outcomes. Compared with the first quintile of CRP, HRs for recurrent CVD were 1.60 (95% CI 1.35 to 1.89) for the last quintile ≤10 mg/L and 1.90 (95% CI 1.58 to 2.29) for the subgroup with CRP >10 mg/L. CRP was associated with recurrent CVD in patients with CAD (HR per 1 mg/L 1.08, 95% CI 1.04 to 1.11), CeVD (HR 1.05, 95% CI 1.01 to 1.10), PAD (HR 1.08, 95% CI 1.03 to 1.13), and AAA (HR 1.08, 95% CI 1.01 to 1.15). The association between CRP and all-cause mortality was stronger for patients with CAD (HR 1.13, 95% CI 1.09 to 1.16) than for patients with other CVD locations (HRs 1.06 to 1.08; p = 0.002). Associations remained consistent beyond 15 years after the CRP measurement. In conclusion, greater CRP is independently associated with an increased risk of recurrent CVD and mortality, irrespective of previous CVD location.

Metabolic syndrome and risk of incident heart failure in non-diabetic patients with established cardiovascular disease.

BACKGROUND: In patients with established cardiovascular disease (CVD), the relation between metabolic syndrome (MetS) and incident heart failure (HF) in the absence of diabetes mellitus (DM) is largely unknown. This study assessed this relation in non-diabetic patients with established CVD. METHODS: Patients from the prospective UCC-SMART cohort with established CVD, but without DM or HF at baseline were included (n = 4653). MetS was defined according to the Adult Treatment Panel III criteria. Insulin resistance was quantified using the homeostasis model of insulin resistance (HOMA-IR). The outcome was a first hospitalization for HF. Relations were assessed using Cox proportional hazards models adjusted for established risk factors: age, sex, prior myocardial infarction (MI), smoking, cholesterol, and kidney function. RESULTS: During a median follow-up of 8.0 years, 290 cases of incident HF were observed (0.81/100 person years). MetS was significantly related to an increased risk of incident HF independent of established risk factors (hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.04-1.68, HR per criterion 1.17; 95% CI 1.06-1.29), as was HOMA-IR (HR per standard deviation [SD] 1.15; 95% CI 1.03-1.29). Of the individual MetS components, only higher waist circumference independently increased the risk of HF (HR per SD 1.34; 95% CI 1.17-1.53). Relations were independent of the occurrence of interim DM and MI, and were not significantly different for HF with reduced vs preserved ejection fraction. CONCLUSION: In CVD patients without a current diagnosis of DM, MetS and insulin resistance increase the risk of incident HF independent of established risk factors.

Standardized reporting of co-morbidity outcome after bariatric surgery: low compliance with the ASMBS outcome reporting standards despite ease of use.

BACKGROUND: Despite the publication of the American Society for Metabolic and Bariatric Surgery (ASMBS) Outcome Reporting Standards in 2015, there is still a great variety in definitions used for reporting remission of co-morbidities after bariatric surgery. This hampers meaningful comparison of results. OBJECTIVE: To assess compliance with the ASMBS standards in current literature, and to evaluate use of the standards by applying them in a report on the outcomes of 5 co-morbidities after bariatric surgery. SETTING: Two clinics of the Dutch Obesity Clinic, location Den Haag and Velp, and three affiliated hospitals: Haaglanden Medical Center in Den Haag, Groene Hart Hospital in Gouda, and Vitalys Clinic in Velp. METHODS: A systematic search in PubMed was conducted to identify studies using the ASMBS standards. Besides, the standards were applied to a cohort of patients who underwent a primary bariatric procedure between November 2016 and June 2017. Outcomes of co-morbidities were determined at 6 and 12 months after surgery. RESULTS: Ten previous studies applying ASMBS definitions were identified by the search, including 6 studies using portions of the definitions, and 4 using complete definitions for 3 co-morbidities or in a small population. In this study, the standards were applied to 1064 patients, of whom 796 patients (75%) underwent Roux-en-Y gastric bypass and 268 patients (25%) underwent sleeve gastrectomy. At 12 months, complete remission of diabetes (glycosylated hemoglobin <6%, off medication) was reached in 63%, partial remission (glycosylated hemoglobin 6%-6.4%, off medication) in 7%, and improvement in 28% of patients (n = 232/248, 94%). Complete remission of hypertension (normotensive, off medication) was noted in 8%, partial remission (prehypertensive, off medication) in 23% and improvement in 63% (n = 397/412, 96%). Remission rate for dyslipidemia (normal nonhigh-density lipoprotein, off medication) was 57% and improvement rate was 19% (n = 129/133, 97%). Resolution of gastroesophageal reflux disease (no symptoms, off medication) was observed in 54% (n = 265/265). Obstructive sleep apnea syndrome improved in 90% (n = 157/169, 93%). CONCLUSIONS: Compliance with the ASMBS standards is low, despite ease of use. Standardized definitions provided by the ASMBS guideline could be used in future research to enable comparison of outcomes of different studies and surgical procedures.

Outcomes of second opinions in general internal medicine.

BACKGROUND: To date, the outcomes of second opinions in internal medicine in terms of diagnostic yield and patient benefit have not been studied extensively. This retrospective study explores the outcomes of second opinions at a general internal medicine outpatient clinic in an academic hospital. METHODS: A register of all patients referred to the general internal medicine outpatient clinic of the University Medical Center in Utrecht for a second opinion, was kept. All 173 patients referred between June 2016 and August 2018 were selected. Case records were analyzed for patient characteristics, referring doctor, chief complaint, performed investigations, follow-up time and, established diagnosis, additional diagnoses, initiated treatment and reported benefit. RESULTS: A new diagnosis was established in 13% of all patients. A new treatment was initiated in 56% of all patients: 91% and 51% of patients with and without a new diagnosis respectively (p < 0.001). Of all patients, 19% received an effective treatment (52% vs 14% of patients with vs without a new diagnosis, p < 0.001). Regardless of treatment, resolution or improvement of the chief complaint was achieved in 28% of all patients (52% vs 25% of patients with vs without a new diagnosis, p = 0.006). Regarding diagnostics, 23-33% of radiology, endoscopy and pathology tests performed during second opinion were a repetition of previously conducted investigations. Conventional blood tests were a repetition in 89% of cases. Median time to diagnosis was 64 days (IQR: 25-128 days) and median time to discharge was 75 days (IQR: 31-144 days). CONCLUSION: Second opinions in general internal medicine lead to the establishment of a new diagnosis in a small proportion of patients. However, the value of second opinions may not be limited to the establishment of diagnoses, as new treatments are often initiated and overall patients report improved symptomatology in 28% of cases.