Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study.

BACKGROUND: Physical activity and exercise training are associated with a lower risk for coronary events. However, cross-sectional studies in middle-aged and older male athletes revealed increased coronary artery calcification (CAC) and atherosclerotic plaques, which were related to the amount and intensity of lifelong exercise. We examined the longitudinal relationship between exercise training characteristics and coronary atherosclerosis. METHODS: Middle-aged and older men from the MARC-1 (Measuring Athlete's Risk of Cardiovascular Events 1) study were invited for follow-up in MARC-2 (Measuring Athlete's Risk of Cardiovascular Events 2) study. The prevalence and severity of CAC and plaques were determined by coronary computed tomography angiography. The volume (metabolic equivalent of task [MET] hours/week) and intensity (moderate [3 to 6 MET hours/week]; vigorous [6 to 9 MET hours/week]; and very vigorous [≥9 MET hours/week]) of exercise training were quantified during follow-up. Linear and logistic regression analyses were performed to determine the association between exercise volume/intensity and markers of coronary atherosclerosis. RESULTS: We included 289 (age, 54 [50 to 60] years [median (Q1 to Q3)]) of the original 318 MARC-1 participants with a follow-up of 6.3±0.5 years (mean±SD). Participants exercised for 41 (25 to 57) MET hours/week during follow-up, of which 0% (0 to 19%) was at moderate intensity, 44% (0 to 84%) was at vigorous intensity, and 34% (0 to 80%) was at very vigorous intensity. Prevalence of CAC and the median CAC score increased from 52% to 71% and 1 (0 to 32) to 31 (0 to 132), respectively. Exercise volume during follow-up was not associated with changes in CAC or plaque. Vigorous intensity exercise (per 10% increase) was associated with a lesser increase in CAC score (ß, -0.05 [-0.09 to -0.01]; P=0.02), whereas very vigorous intensity exercise was associated with a greater increase in CAC score (ß, 0.05 [0.01 to 0.09] per 10%; P=0.01). Very vigorous exercise was also associated with increased odds of dichotomized plaque progression (adjusted odds ratio [aOR], 1.09 [1.01 to 1.18] per 10%; aOR, 2.04 [0.93 to 4.15] for highest versus lowest very vigorous intensity tertiles, respectively), and specifically with increased calcified plaques (aOR, 1.07 [1.00 to 1.15] per 10%; aOR, 2.09 [1.09 to 4.00] for highest versus lowest tertile, respectively). CONCLUSIONS: Exercise intensity but not volume was associated with progression of coronary atherosclerosis during 6-year follow-up. It is intriguing that very vigorous intensity exercise was associated with greater CAC and calcified plaque progression, whereas vigorous intensity exercise was associated with less CAC progression.

Remote haemodynamic monitoring of pulmonary artery pressures in patients with chronic heart failure (MONITOR-HF): a randomised clinical trial.

BACKGROUND: The effect of haemodynamic monitoring of pulmonary artery pressure has predominantly been studied in the USA. There is a clear need for randomised trial data from patients treated with contemporary guideline-directed-medical-therapy with long-term follow-up in a different health-care system. METHODS: MONITOR-HF was an open-label, randomised trial, done in 25 centres in the Netherlands. Eligible patients had chronic heart failure of New York Heart Association class III and a previous heart failure hospitalisation, irrespective of ejection fraction. Patients were randomly assigned (1:1) to haemodynamic monitoring (CardioMEMS-HF system, Abbott Laboratories, Abbott Park, IL, USA) or standard care. All patients were scheduled to be seen by their clinician at 3 months and 6 months, and every 6 months thereafter, up to 48 months. The primary endpoint was the mean difference in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score at 12 months. All analyses were by intention-to-treat. This trial was prospectively registered under the clinical trial registration number NTR7673 (NL7430) on the International Clinical Trials Registry Platform. FINDINGS: Between April 1, 2019, and Jan 14, 2022, we randomly assigned 348 patients to either the CardioMEMS-HF group (n=176 [51%]) or the control group (n=172 [49%]). The median age was 69 years (IQR 61-75) and median ejection fraction was 30% (23-40). The difference in mean change in KCCQ overall summary score at 12 months was 7·13 (95% CI 1·51-12·75; p=0·013) between groups (+7·05 in the CardioMEMS group, p=0·0014, and -0·08 in the standard care group, p=0·97). In the responder analysis, the odds ratio (OR) of an improvement of at least 5 points in KCCQ overall summary score was OR 1·69 (95% CI 1·01-2·83; p=0·046) and the OR of a deterioration of at least 5 points was 0·45 (0·26-0·77; p=0·0035) in the CardioMEMS-HF group compared with in the standard care group. The freedom of device-related or system-related complications and sensor failure were 97·7% and 98·8%, respectively. INTERPRETATION: Haemodynamic monitoring substantially improved quality of life and reduced heart failure hospitalisations in patients with moderate-to-severe heart failure treated according to contemporary guidelines. These findings contribute to the aggregate evidence for this technology and might have implications for guideline recommendations and implementation of remote pulmonary artery pressure monitoring. FUNDING: The Dutch Ministry of Health, Health Care Institute (Zorginstituut), and Abbott Laboratories.

Exercise-induced cardiac troponin release in athletes with versus without coronary atherosclerosis.

The magnitude of exercise-induced cardiac troponin (cTn) elevations is dependent on cardiovascular health status, and previous studies have shown that occult coronary atherosclerosis is highly prevalent among amateur athletes. We tested the hypothesis that middle-aged and older athletes with coronary atherosclerosis demonstrate greater cTn elevations following a controlled endurance exercise test compared with healthy peers. We included 59 male athletes from the Measuring Athletes' Risk of Cardiovascular events 2 (MARC-2) study and stratified them as controls [coronary artery calcium score (CACS) = 0, n = 20], high CACS [≥300 Agatston units or ≥75th Multi-Ethnic Study of Atherosclerosis (MESA) percentile, n = 20] or significant stenosis (≥50% in any coronary artery, n = 19). Participants performed a cycling test with incremental workload until volitional exhaustion. Serial high-sensitivity cTn (hs-cTn) T and I concentrations were measured (baseline, after 30-min warm-up, and 0, 30, 60, 120, and 180 min postexercise). There were 58 participants (61 [58-69] yr) who completed the exercise test (76 ± 14 min) with a peak heart rate of 97.7 [94.8-101.8]% of their estimated maximum. Exercise duration and workload did not differ across groups. High-sensitivity cardiac troponin T (Hs-cTnT) and high-sensitivity cardiac troponin I (hs-cTnI) concentrations significantly increased (1.55 [1.33-2.14]-fold and 2.76 [1.89-3.86]-fold, respectively) over time, but patterns of cTn changes and the incidence of concentrations >99th percentile did not differ across groups. Serial sampling of hs-cTnT and hs-cTnI concentrations during and following an exhaustive endurance exercise test did not reveal differences in exercise-induced cTn release between athletes with versus without coronary atherosclerosis. These findings suggest that a high CACS or a >50% stenosis in any coronary artery does not aggravate exercise-induced cTn release in middle-aged and older athletes.NEW & NOTEWORTHY Exercise-induced cardiac troponin (cTn) release is considered to be dependent on cardiovascular health status. We tested whether athletes with coronary atherosclerosis demonstrate greater exercise-induced cTn release compared with healthy peers. Athletes with coronary atherosclerosis did not differ in cTn release following exercise compared with healthy peers. Our findings suggest that a high CACS or a >50% stenosis in any coronary artery does not aggravate exercise-induced cTn release in middle-aged and older athletes.

Association of Low-Dose Colchicine With Incidence of Knee and Hip Replacements : Exploratory Analyses From a Randomized, Controlled, Double-Blind Trial.

BACKGROUND: Osteoarthritis is a major contributor to pain and disability worldwide. Given that inflammation plays an important role in the development of osteoarthritis, anti-inflammatory drugs may slow disease progression. OBJECTIVE: To examine whether colchicine, 0.5 mg daily, reduces incident total knee replacements (TKRs) and total hip replacements (THRs). DESIGN: Exploratory analysis of the LoDoCo2 (Low-Dose Colchicine 2) randomized, controlled, double-blind trial. (Australian New Zealand Clinical Trials Registry: ACTRN12614000093684). SETTING: 43 centers in Australia and the Netherlands. PATIENTS: 5522 patients with chronic coronary artery disease. INTERVENTION: Colchicine, 0.5 mg, or placebo once daily. MEASUREMENTS: The primary outcome was time to first TKR or THR since randomization. All analyses were performed on an intention-to-treat basis. RESULTS: A total of 2762 patients received colchicine and 2760 received placebo during a median follow-up of 28.6 months. During the trial, TKR or THR was performed in 68 patients (2.5%) in the colchicine group and 97 (3.5%) in the placebo group (incidence rate, 0.90 vs. 1.30 per 100 person-years; incidence rate difference, -0.40 [95% CI, -0.74 to -0.06] per 100 person-years; hazard ratio, 0.69 [CI, 0.51 to 0.95]). In sensitivity analyses, similar results were obtained when patients with gout at baseline were excluded and when joint replacements that occurred in the first 3 and 6 months of follow-up were omitted. LIMITATION: LoDoCo2 was not designed to investigate the effect of colchicine in osteoarthritis of the knee or hip and did not collect information specifically on osteoarthritis. CONCLUSION: In this exploratory analysis of the LoDoCo2 trial, use of colchicine, 0.5 mg daily, was associated with a lower incidence of TKR and THR. Further investigation of colchicine therapy to slow disease progression in osteoarthritis is warranted. PRIMARY FUNDING SOURCE: None.

Colchicine in Patients with Chronic Coronary Disease.

BACKGROUND: Evidence from a recent trial has shown that the antiinflammatory effects of colchicine reduce the risk of cardiovascular events in patients with recent myocardial infarction, but evidence of such a risk reduction in patients with chronic coronary disease is limited. METHODS: In a randomized, controlled, double-blind trial, we assigned patients with chronic coronary disease to receive 0.5 mg of colchicine once daily or matching placebo. The primary end point was a composite of cardiovascular death, spontaneous (nonprocedural) myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization. The key secondary end point was a composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke. RESULTS: A total of 5522 patients underwent randomization; 2762 were assigned to the colchicine group and 2760 to the placebo group. The median duration of follow-up was 28.6 months. A primary end-point event occurred in 187 patients (6.8%) in the colchicine group and in 264 patients (9.6%) in the placebo group (incidence, 2.5 vs. 3.6 events per 100 person-years; hazard ratio, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P<0.001). A key secondary end-point event occurred in 115 patients (4.2%) in the colchicine group and in 157 patients (5.7%) in the placebo group (incidence, 1.5 vs. 2.1 events per 100 person-years; hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.007). The incidence rates of spontaneous myocardial infarction or ischemia-driven coronary revascularization (composite end point), cardiovascular death or spontaneous myocardial infarction (composite end point), ischemia-driven coronary revascularization, and spontaneous myocardial infarction were also significantly lower with colchicine than with placebo. The incidence of death from noncardiovascular causes was higher in the colchicine group than in the placebo group (incidence, 0.7 vs. 0.5 events per 100 person-years; hazard ratio, 1.51; 95% CI, 0.99 to 2.31). CONCLUSIONS: In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than among those who received placebo. (Funded by the National Health Medical Research Council of Australia and others; LoDoCo2 Australian New Zealand Clinical Trials Registry number, ACTRN12614000093684.).

A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI.

BACKGROUND: It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y12 inhibitors. METHODS: We conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events - defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria - at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome). RESULTS: For the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.0 to 0.7; P<0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P = 0.04). CONCLUSIONS: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy for selection of oral P2Y12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.).

Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials.

AIMS: Recent randomized trials demonstrated a benefit of low-dose colchicine added to guideline-based treatment in patients with recent myocardial infarction or chronic coronary disease. We performed a systematic review and meta-analysis to obtain best estimates of the effects of colchicine on major adverse cardiovascular events (MACE). METHODS AND RESULTS: We searched the literature for randomized clinical trials of long-term colchicine in patients with atherosclerosis published up to 1 September 2020. The primary efficacy endpoint was MACE, the composite of myocardial infarction, stroke, or cardiovascular death. We combined the results of five trials that included 11 816 patients. The primary endpoint occurred in 578 patients. Colchicine reduced the risk for the primary endpoint by 25% [relative risk (RR) 0.75, 95% confidence interval (CI) 0.61-0.92; P = 0.005], myocardial infarction by 22% (RR 0.78, 95% CI 0.64-0.94; P = 0.010), stroke by 46% (RR 0.54, 95% CI 0.34-0.86; P = 0.009), and coronary revascularization by 23% (RR 0.77, 95% CI 0.66-0.90; P < 0.001). We observed no difference in all-cause death (RR 1.08, 95% CI 0.71-1.62; P = 0.73), with a lower incidence of cardiovascular death (RR 0.82, 95% CI 0.55-1.23; P = 0.34) counterbalanced by a higher incidence of non-cardiovascular death (RR 1.38, 95% CI 0.99-1.92; P = 0.060). CONCLUSION: Our meta-analysis indicates that low-dose colchicine reduced the risk of MACE as well as that of myocardial infarction, stroke, and the need for coronary revascularization in a broad spectrum of patients with coronary disease. There was no difference in all-cause mortality and fewer cardiovascular deaths were counterbalanced by more non-cardiovascular deaths.

Exercise and Coronary Atherosclerosis: Observations, Explanations, Relevance, and Clinical Management.

Physical activity and exercise training are effective strategies for reducing the risk of cardiovascular events, but multiple studies have reported an increased prevalence of coronary atherosclerosis, usually measured as coronary artery calcification, among athletes who are middle-aged and older. Our review of the medical literature demonstrates that the prevalence of coronary artery calcification and atherosclerotic plaques, which are strong predictors for future cardiovascular morbidity and mortality, was higher in athletes compared with controls, and was higher in the most active athletes compared with less active athletes. However, analysis of plaque morphology revealed fewer mixed plaques and more often only calcified plaques among athletes, suggesting a more benign composition of atherosclerotic plaques. This review describes the effects of physical activity and exercise training on coronary atherosclerosis in athletes who are middle-aged and older and aims to contribute to the understanding of the potential adverse effects of the highest doses of exercise training on the coronary arteries. For this purpose, we will review the association between exercise and coronary atherosclerosis measured using computed tomography, discuss the potential underlying mechanisms for exercise-induced coronary atherosclerosis, determine the clinical relevance of coronary atherosclerosis in middle-aged athletes and describe strategies for the clinical management of athletes with coronary atherosclerosis to guide physicians in clinical decision making and treatment of athletes with elevated coronary artery calcification scores.

Clinical Outcome Predictions for the VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) Trial: VICTORIA Outcomes Model.

BACKGROUND: Prediction of outcomes in patients with heart failure (HF) may inform prognosis, clinical decisions regarding treatment selection, and new trial planning. The VICTORIA trial included high-risk patients with HF and reduced ejection fraction and a recent worsening HF event. The study participants had an unusually high event rate despite usage of contemporary guideline-based therapies. To provide generalizable predictive data for a broad population with a recent worsening HF event, we focused on risk prognostication in the placebo group. METHODS: Data from 2524 participants randomized to placebo with chronic HF (New York Heart Association class [NYHA] II-IV) and ejection fraction <45% were studied and backward variable selection was used to create Cox proportional hazards models for clinical endpoints, selecting from 66 candidate predictors. Final model results were produced, accounting for missing data, non-linearities, and interactions with treatment. Optimism-corrected c-indices were calculated using 200 bootstrap samples. RESULTS: During a median follow-up of 10.4 months, the primary outcome of HF hospitalization or cardiovascular death occurred in 972 (38.5%) patients. Independent predictors of increased risk for the primary endpoint included HF characteristics (longer HF duration and worse NYHA class), medical history (prior myocardial infarction), and laboratory values (higher N-terminal pro-hormone B-type natriuretic peptide, bilirubin, urate; lower chloride and albumin). Optimism-corrected c-indices were 0.68 for the HF hospitalization/cardiovascular death model, 0.68 for HF hospitalization/all-cause death, 0.72 for cardiovascular death, and 0.73 for all-cause death. CONCLUSIONS: Predictive models developed in a large diverse clinical trial with comprehensive clinical and laboratory baseline data-including novel measures-performed well in high-risk HF patients who were receiving excellent guideline-based clinical care. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT02861534. LAY SUMMARY: Patients with heart failure may benefit from tools that help clinicians better understand patient's risk for future events like hospitalization. Relatively few risk models have been created after worsening of heart failure in a contemporary cohort. We provide insights on risk factors for clinical events from a recent large, global trial of patients with worsening heart failure to help clinicians better understand and communicate prognosis and select treatment options.

Clinical Outcome Predictions for the VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) Trial.

BACKGROUND: The prediction of outcomes in patients with heart failure (HF) may inform prognosis, clinical decisions regarding treatment selection, and new trial planning. The VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction included high-risk patients with HF with reduced ejection fraction and a recent worsening HF event. The study participants had a high event rate despite the use of contemporary guideline-based therapies. To provide generalizable predictive data for a broad population with a recent worsening HF event, we focused on risk prognostication in the placebo group. METHODS AND RESULTS: Data from 2524 participants randomized to placebo with chronic HF (New York Heart Association functional class II-IV) and an ejection fraction of less than 45% were studied and backward variable selection was used to create Cox proportional hazards models for clinical end points, selecting from 66 candidate predictors. Final model results were produced, accounting for missing data, and nonlinearities. Optimism-corrected c-indices were calculated using 200 bootstrap samples. Over a median follow-up of 10.4 months, the primary outcome of HF hospitalization or cardiovascular death occurred in 972 patients (38.5%). Independent predictors of increased risk for the primary end point included HF characteristics (longer HF duration and worse New York Heart Association functional class), medical history (prior myocardial infarction), and laboratory values (higher N-terminal pro-hormone B-type natriuretic peptide, bilirubin, urate; lower chloride and albumin). Optimism-corrected c-indices were 0.68 for the HF hospitalization/cardiovascular death model, 0.68 for HF hospitalization/all-cause death, 0.72 for cardiovascular death, and 0.73 for all-cause death. CONCLUSIONS: Predictive models developed in a large diverse clinical trial with comprehensive clinical and laboratory baseline data-including novel measures-performed well in high-risk patients with HF who were receiving excellent guideline-based clinical care. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT02861534.Lay Summary: Patients with heart failure may benefit from tools that help clinicians to better understand a patient's risk for future events like hospitalization. Relatively few risk models have been created after the worsening of heart failure in a contemporary cohort. We provide insights on the risk factors for clinical events from a recent, large, global trial of patients with worsening heart failure to help clinicians better understand and communicate prognosis and select treatment options.

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients.

BACKGROUND: Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS: In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTS: At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS: In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients. (Funded by Pfizer; SPIRE-1 and SPIRE-2 ClinicalTrials.gov numbers, NCT01975376 and NCT01975389 .).

The effect of low-dose colchicine in patients with stable coronary artery disease: The LoDoCo2 trial rationale, design, and baseline characteristics.

Because patients with stable coronary artery disease are at continued risk of major atherosclerotic events despite effective secondary prevention strategies, there is a need to continue to develop additional safe, effective and well-tolerated therapies for secondary prevention of cardiovascular disease. RATIONALE AND DESIGN: The LoDoCo (Low Dose Colchicine) pilot trial showed that the anti-inflammatory drug colchicine 0.5 mg once daily appears safe and effective for secondary prevention of cardiovascular disease. Colchicine's low cost and long-term safety suggest that if its efficacy can be confirmed in a rigorous trial, repurposing it for secondary prevention of cardiovascular disease would have the potential to impact the global burden of cardiovascular disease. LoDoCo2 is an investigator-initiated, international, multicentre, double-blind, event driven trial in which 5522 patients with stable coronary artery disease tolerant to colchicine during a 30-day run-in phase have been randomized to colchicine 0.5 mg daily or matching placebo on a background of optimal medical therapy. The study will have 90% power to detect a 30% reduction in the composite primary endpoint: cardiovascular death, myocardial infarction, ischemic stroke and ischemia-driven coronary revascularization. Adverse events potentially related to the use of colchicine will also be collected, including late gastrointestinal intolerance, neuropathy, myopathy, myositis, and neutropenia. CONCLUSION: The LoDoCo2 Trial will provide information on the efficacy and safety of low-dose colchicine for secondary prevention in patients with stable coronary artery disease.

Relationship Between Lifelong Exercise Volume and Coronary Atherosclerosis in Athletes.

BACKGROUND: Higher levels of physical activity are associated with a lower risk of cardiovascular events. Nevertheless, there is debate on the dose-response relationship of exercise and cardiovascular disease outcomes and whether high volumes of exercise may accelerate coronary atherosclerosis. We aimed to determine the relationship between lifelong exercise volumes and coronary atherosclerosis. METHODS: Middle-aged men engaged in competitive or recreational leisure sports underwent a noncontrast and contrast-enhanced computed tomography scan to assess coronary artery calcification (CAC) and plaque characteristics. Participants reported lifelong exercise history patterns. Exercise volumes were multiplied by metabolic equivalent of task (MET) scores to calculate MET-minutes per week. Participants' activity was categorized as <1000, 1000 to 2000, or >2000 MET-min/wk. RESULTS: A total of 284 men (age, 55±7 years) were included. CAC was present in 150 of 284 participants (53%) with a median CAC score of 35.8 (interquartile range, 9.3-145.8). Athletes with a lifelong exercise volume >2000 MET-min/wk (n=75) had a significantly higher CAC score (9.4 [interquartile range, 0-60.9] versus 0 [interquartile range, 0-43.5]; P=0.02) and prevalence of CAC (68%; adjusted odds ratio [ORadjusted]=3.2; 95% confidence interval [CI], 1.6-6.6) and plaque (77%; ORadjusted=3.3; 95% CI, 1.6-7.1) compared with <1000 MET-min/wk (n=88; 43% and 56%, respectively). Very vigorous intensity exercise (≥9 MET) was associated with CAC (ORadjusted=1.47; 95% CI, 1.14-1.91) and plaque (ORadjusted=1.56; 95% CI, 1.17-2.08). Among participants with CAC>0, there was no difference in CAC score (P=0.20), area (P=0.21), density (P=0.25), and regions of interest (P=0.20) across exercise volume groups. Among participants with plaque, the most active group (>2000 MET-min/wk) had a lower prevalence of mixed plaques (48% versus 69%; ORadjusted=0.35; 95% CI, 0.15-0.85) and more often had only calcified plaques (38% versus 16%; ORadjusted=3.57; 95% CI, 1.28-9.97) compared with the least active group (<1000 MET-min/wk). CONCLUSIONS: Participants in the >2000 MET-min/wk group had a higher prevalence of CAC and atherosclerotic plaques. The most active group, however, had a more benign composition of plaques, with fewer mixed plaques and more often only calcified plaques. These observations may explain the increased longevity typical of endurance athletes despite the presence of more coronary atherosclerotic plaque in the most active participants.

The 2017 Dutch Physical Activity Guidelines.

BACKGROUND: The objective of this study was to derive evidence-based physical activity guidelines for the general Dutch population. METHODS: Two systematic reviews were conducted of English language meta-analyses in PubMed summarizing separately randomized controlled trials and prospective cohort studies on the relation between physical activity and sedentary behaviour on the one hand and the risk of all-cause mortality and incidence of 15 major chronic diseases and conditions on the other hand. Other outcome measures were risk factors for cardiovascular disease and type 2 diabetes, physical functioning, and fitness. On the basis of these reviews, an expert committee derived physical activity guidelines. In deriving the guidelines, the committee first selected only experimental and observational prospective findings with a strong level of evidence and then integrated both lines of evidence. RESULTS: The evidence found for beneficial effects on a large number of the outcome measures was sufficiently strong to draw up guidelines to increase physical activity and reduce sedentary behaviour, respectively. At the same time, the current evidence did not provide a sufficient basis for quantifying how much physical activity is minimally needed to achieve beneficial health effects, or at what amount sedentary behaviour becomes detrimental. A general tenet was that at every level of current activity, further increases in physical activity provide additional health benefits, with relatively larger effects among those who are currently not active or active only at light intensity. Three specific guidelines on (1) moderate- and vigorous-intensity physical activity, (2) bone- and muscle-strengthening activities, and (3) sedentary behaviour were formulated separately for adults and children. CONCLUSIONS: There is an unabated need for evidence-based physical activity guidelines that can guide public health policies. Research in which physical activity is measured both objectively (quantity) and subjectively (type and quality) is needed to provide better estimates of the type and actual amount of physical activity required for health.

Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.

BACKGROUND: Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. METHODS AND RESULTS: We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B-type natriuretic peptide and troponin) versus enalapril. CONCLUSIONS: Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Improving usual care after sudden death in the young with focus on inherited cardiac diseases (the CAREFUL study): a community-based intervention study.

AIMS: Inherited cardiac diseases play an important role in sudden death (SD) in the young. Autopsy and cardiogenetic evaluation of relatives of young SD victims identifies relatives at risk. We studied the usual care after SD in the young aimed at identifying inherited cardiac disease, and assessed the efficacy of two interventions to improve this usual care. METHODS AND RESULTS: We conducted a community-based intervention study to increase autopsy rates of young SD victims aged 1-44 years and referral of their relatives to cardiogenetic clinics. In the Amsterdam study region, a 24/7 central telephone number and a website were available to inform general practitioners and coroners. In the Utrecht study region, they were informed by a letter and educational meetings. In two control regions usual care was monitored. Autopsy was performed in 169 of 390 registered SD cases (43.3%). Cardiogenetic evaluation of relatives was indicated in 296 of 390 cases (75.9%), but only 25 of 296 families (8.4%) attended a cardiogenetics clinic. Autopsy rates were 38.7% in the Amsterdam study region, 45.5% in the Utrecht study region, and 49.0% in the control regions. The proportion of families evaluated at cardiogenetics clinics in the Amsterdam study region, the Utrecht study region, and the control regions was 7.3, 9.9, and 8.8%, respectively. CONCLUSIONS: The autopsy rate in young SD cases in the Netherlands is low and few families undergo cardiogenetic evaluation to detect inherited cardiac diseases. Two different interventions did not improve this suboptimal situation substantially.

Assessment of Coronary Artery Calcium on Low-Dose Coronary Computed Tomography Angiography With Iterative Reconstruction.

OBJECTIVE: This study aims to evaluate whether coronary calcium scoring (CCS) is also feasible using low-radiation-dose coronary computed tomography angiography (CCTA) in combination with iterative reconstruction. METHODS: Forty-three individuals without known coronary artery disease underwent both noncontrast CCS (±1 mSv) for reference Agatston scores and low-dose CCTA (±3 mSv). Raw CCTA data were reconstructed with filtered back projection (FBP), hybrid iterative reconstruction (HIR), and model-based iterative reconstruction (MIR). Calcification volumes were derived with thresholds of >351 and >600 Hounsfield units (HU) and converted to proxy Agatston scores with linear regression analysis. RESULTS: Intraclass correlation coefficients for Agatston scores versus CCTA volumes with FBP and iterative reconstruction were excellent (ranges 0.94-0.99 and 0.96-0.99 for >351 HU and >600 HU thresholds, respectively). The >351 HU threshold resulted in higher CCTA volume scores ranging from 65.9 (15.1-347.0) for HIR to 94.8 (42.0-423.0) for MIR (P = 0.001 and <0.001, respectively). The >600 HU threshold scores ranged from 14.1 (0.0-159.3) for HIR to 28.6 (0.0-215.6) for MIR (P = 0.003 and 0.027, respectively). At >351 HU, reclassification occurred in 21 individuals (49%) for FBP and HIR and 25 individuals (58%) for MIR. Reclassifications decreased with >600 HU to 10 (HIR, 23%), 8 (FBP, 19%), and 4 (MIR, 9%). CONCLUSIONS: The CCS is feasible using iteratively reconstructed low-dose CCTA with a calcium threshold of >600 HU. Using MIR, only 9% of individuals were reclassified.

A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure.

AIMS: Although active-controlled trials with renin­angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos. METHODS AND RESULTS: We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34­50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21­44%; P < 0.0001) and heart failure hospitalization (49%, 39­58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15­39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27­48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16­45%; P < 0.0001) for cardiovascular death, 46% (33­56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11­39%; P < 0.0001) for all-cause mortality. CONCLUSION: These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.