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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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Elderly heart failure (HF) patients frequently have multiple comorbidities. The prognostic impact of combined comorbidities is poorly quantified in these patients. We assessed the impact of comorbidities on 3-year mortality in geriatric outpatients with newly diagnosed HF. Methods and Results: Of 93 geriatric outpatients with HF (mean age 82.7 years, 36.6% men), 52 patients (55.9%) died within 3 years after HF was diagnosed. Comorbidity was measured with the Charlson Comorbidity Index (CCI). Age- and gender-adjusted hazard ratio (HR) for 3-year mortality was 1.6 (95% confidence interval [CI] 0.9–3.2) for patients with 3–4 CCI points and 3.2 (95% CI 1.5–6.8) for those with >4 CCI points, compared with 1–2 CCI points. After adjustment for age, gender, left ventricular ejection fraction (LVEF), and N-terminal pro–B-type natriuretic peptide, CCI remained predictive of death (CCI 3–4: HR 1.5 (95% CI 0.7–2.9); CCI >4: HR 4.0 (95% CI 1.9–8.8)). In addition to age and gender, the c-statistics for CCI and LVEF were similar (0.63 [95% CI 0.55–0.70] and 0.64 [95% CI 0.56–0.72], respectively). Conclusions: The majority of geriatric outpatients with new HF die within 3 years. Comorbidity, summarized in the CCI, is the strongest independent predictor of mortality. [Copyright &y& Elsevier]

Abstract: Objective: The objective of this study is to evaluate the incidence, predictors, and outcome of complete ST-segment resolution (STR) during transportation after pretreatment with dual or triple antiplatelet therapy in the Ongoing Tirofiban in Myocardial Infarction Evaluation (On-TIME) 2 trial. Methods: Patients with ST-segment elevation myocardial infarction were randomized in the ambulance to pretreatment with high-dose tirofiban (HDT) or to a control pretreatment (placebo or no HDT) on top of 600-mg clopidogrel, 500-mg aspirin, and 5000-IU unfractionated heparin. Complete STR was defined as ≥70% STR on the electrocardiogram obtained before percutaneous coronary intervention (PCI) as compared with the inclusion electrocardiogram. Results: Complete STR before PCI occurred in 16.8% (n = 188/1121) and more frequently in the HDT group (19.0% vs 14.6%, P = .05). Independent predictors for complete STR before PCI were younger age (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.70-0.96, P = .01 per 10 year increase), fast diagnosis (OR, 0.97; 95% CI, 0.97-1.0, P = .004 per 15-minute increase time from symptom onset to diagnosis), longer pretreatment time (OR, 1.09; 95% CI, 1.03-1.16, P = .003 per 15-minute increase time start study medication to angiography), and randomization to HDT (OR, 1.39; 95% CI, 1.0-1.9, P = .05). Complete STR before PCI was associated with very low 30-day (0.5% vs 2.8%, P = .07) and 1-year (1.1% vs 5.0%, P = .019) mortality. Conclusions: Dual or triple antiplatelet pretreatment in the ambulance results in complete STR before PCI in 17% of patients. Fast ST-segment elevation myocardial infarction diagnosis, prehospital initiation of pretreatment early after symptom onset, and HDT independently predicted STR before PCI. Complete STR is associated with improved clinical outcome. [Copyright &y& Elsevier]

Background: It is known that the efficacy of thrombolytic therapy in ST-segment elevation myocardial infarction (STEMI) is highly time dependent with the best efficacy when given within the so-called golden hour. This analysis from the On-TIME 2 trial evaluated the efficacy of triple antiplatelet therapy on initial patency and ST-segment resolution (STR) in relation to time from symptom onset to first medical contact. Methods: The On-TIME 2 trial included 1,398 consecutive STEMI patients referred for primary percutaneous coronary intervention (PCI). Patients were randomized to dual (500 mg aspirin and 600 mg clopidogrel) or triple antiplatelet (500 mg aspirin, 600 mg clopidogrel, and tirofiban 25 μg/kg bolus and 0.15 μg/kg per minute maintenance infusion for 18 hours) pretreatment in the ambulance. Primary outcome of this sub-analysis was initial patency of the infarct-related vessel and STR before PCI according to time from symptom onset to first medical contact in quartiles. In addition, the incidence of aborted myocardial infarction, defined as the absence of a rise in creatinine kinase, was assessed. Results: Initial patency, STR before PCI, and the incidence of aborted myocardial infarction gradually increased with shorter time from symptom onset to first medical contact. Initial Thrombolysis in Myocardial Infarction flow was present in 21.2% in the total population and 26.2%, 21.5%, 18.1%, and 18.8% in the time quartiles, respectively (P for trend = .01). The incidence of complete STR pre-angiography was 16.6% in the total population and 23.4%, 18.2%, 14.7%, and 9.9% in the 4 quartiles, respectively (P for trend < .001). This was largely driven by the effect of triple antiplatelet therapy, which further improved initial patency and STR and led to a significantly higher incidence of aborted myocardial infarction (13.2% vs 8.7%, P = .011), especially in the patients with short duration of symptoms. Conclusion: Antiplatelet pretreatment before primary PCI, including a glycoprotein IIb/IIIa blocker, seems to be most effective when given shortly after symptom onset. Further studies should be performed to test this hypothesis. [Copyright &y& Elsevier]

• Repurposing approved drugs holds tremendous promise for a wide range of unmet medical needs. • Market conditions, however, are rarely supportive. • Drawing on lessons from the recent approval of colchicine for heart disease, we propose key policy changes to create more reliable yet societally acceptable business models for drug repurposing. [ABSTRACT FROM AUTHOR]

Pseudonormalization of the left ventricular (LV) filling pattern complicates the Doppler echocardiographic assessment of LV diastolic function in patients with heart failure. The Valsalva maneuver is recommended as a method of differentiating between normal and pseudonormal LV filling patterns. However, neither a standardized Valsalva maneuver nor a healthy control population has been studied so far. Therefore, we studied changes in mitral flow velocities in response to a standardized Valsolva maneuver in 55 heart failure patients with LV systolic dysfunction and 35 control subjects. The study subjects were instructed to elevate their intrathoracic airway pressure to 40 mm Hg for 10 seconds. Doppler mitral flow velocities were recorded at rest and during the Valsalva maneuver. All study subjects had comparable decreases in early mitral flow velocity, but mitral flow velocity at atrial contraction increased rather than decreased in patients with a restrictive LV filling pattern. This markedly abnormal response might be useful in detecting elevated filling pressures and pseudonormal filling patterns. Furthermore, in all but 2 patients and all control subjects with an E/A ratio between 1 and 2, inversion of the E/A ratio occurred. This proves that, in contrast to previous beliefs, inversion of the E/A ratio does not differentiate between normal and pseudonormal LV filling patterns. [ABSTRACT FROM AUTHOR]

Abstract Purpose Disease management of stable coronary artery disease consists of controlling hemostasis and lipid regulation. No treatment strategies preventing plaque erosion or rupture are yet available. Cholesterol crystal–induced inflammation leading to plaque destabilization is believed to be an important factor contributing to plaque instability and might well be amenable to treatment with anti-inflammatory drugs. Colchicine has anti-inflammatory properties with the potential to address both the direct and indirect inflammatory mechanisms in the plaque. Methods A literature search was performed in MEDLINE (PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials, as well as in the clinical trial registries, to identify finished and ongoing clinical studies on colchicine in stable coronary artery disease. Findings Preclinical findings of colchicine in stable coronary artery disease have shown protective effects on surrogate outcomes, such as myocardial infarction size and postangioplasty restenosis. Retrospective cohort studies in patients with gout report a lower incidence of combined cardiovascular outcomes in those treated with colchicine. Thus far, one prospective, randomized clinical trial has provided evidence on a possible protective effect of colchicine in stable coronary artery disease. Meta-analysis of trials of colchicine in multiple cardiovascular diseases revealed a decrease in myocardial infarction with varying levels of evidence. Currently, 5 major clinical trials involving >10,000 patients are recruiting patients, all focusing on major cardiovascular outcomes. Implications The body and quality of evidence regarding the efficacy of colchicine for secondary prevention of stable and acute phases of coronary artery disease will be greatly expanded in the upcoming years, providing less biased and more accurate effect estimates. If colchicine's anti-inflammatory characteristics translate to improved event-free cardiovascular survival, this relatively safe, low-cost, and well-known drug may become the third pillar (next to lipid regulation and platelet inhibition) in the medical management of stable coronary artery disease. [ABSTRACT FROM AUTHOR]

Studies the usefulness of echocardiography in detecting left ventricular (LV) dysfunction in population-based sample. Common cardiovascular disorder; Benefits of angiotensin-converting enzyme (ACE); Value of 12-lead electrocardiogram versus echocardiography; Use of Rotterdam study; Study limitations; Essential tool in detecting LV dysfunction.

Background: Colchicine reduces risk of cardiovascular events in patients post-myocardial infarction and in patients with chronic coronary disease. It remains unclear whether this effect is related to the time of onset of treatment following an acute coronary syndrome (ACS).Objectives: This study investigates risk for major adverse cardiovascular events in relation to history and timing of prior ACS, to determine whether the benefits of colchicine are consistent independent of prior ACS status.Methods: The LoDoCo2 (Low-Dose Colchicine 2) trial randomly allocated patients with chronic coronary disease to colchicine 0.5 mg once daily or placebo. The rate of the composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was compared between patients with no prior, recent (6-24 months), remote (2-7 years), or very remote (>7 years) ACS; interaction between ACS status and colchicine treatment effect was assessed.Results: In 5,522 randomized patients, risk of the primary endpoint was independent of prior ACS status. Colchicine consistently reduced the primary endpoint in patients with no prior ACS (incidence: 2.8 vs 3.4 events per 100 person-years; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.52-1.27), recent ACS (incidence: 2.4 vs 3.3 events per 100 person-years; HR: 0.75; 95% CI: 0.51-1.10), remote ACS (incidence: 1.8 vs 3.2 events per 100 person-years, HR: 0.55; 95% CI: 0.37-0.82), and very remote ACS (incidence: 3.0 vs 4.3 events per 100 person-years, HR: 0.70; 95% CI: 0.51-0.96) (P for interaction = 0.59).Conclusions: The benefits of colchicine are consistent irrespective of history and timing of prior ACS. (The LoDoCo2 Trial: Low Dose Colchicine for secondary prevention of cardiovascular disease [LoDoCo2] ACTRN12614000093684). [ABSTRACT FROM AUTHOR]

Assessment of both coronary artery calcium(CAC) scores and myocardial perfusion imaging(MPI) in patients suspected of coronary artery disease(CAD) provides incremental prognostic information. We used an automated method to determine CAC scores on low-dose attenuation correction CT(LDACT) images gathered during MPI in one single assessment. The prognostic value of this automated CAC score is unknown, we therefore investigated the association of this automated CAC scores and major adverse cardiovascular events(MACE) in a large chest-pain cohort. We analyzed 747 symptomatic patients referred for 82RubidiumPET/CT, without a history of coronary revascularization. Ischemia was defined as a summed difference score≥2. We used a validated deep learning(DL) method to determine CAC scores. For survival analysis CAC scores were dichotomized as low(<400) and high(≥400). MACE was defined as all cause death, late revascularization (>90 days after scanning) or nonfatal myocardial infarction. Cox proportional hazard analysis were performed to identify predictors of MACE. During 4 years follow-up, 115 MACEs were observed. High CAC scores showed higher cumulative event rates, irrespective of ischemia (nonischemic: 25.8% vs 11.9% and ischemic: 57.6% vs 23.4%, P -values <0.001). Multivariable cox regression revealed both high CAC scores (HR 2.19 95%CI 1.43–3.35) and ischemia (HR 2.56 95%CI 1.71–3.35) as independent predictors of MACE. Addition of automated CAC scores showed a net reclassification improvement of 0.13(0.022–0.245). Automatically derived CAC scores determined during a single imaging session are independently associated with MACE. This validated DL method could improve risk stratification and subsequently lead to more personalized treatment in patients suspected of CAD. • Combined assessment of CAC scores and perfusion data provide additional information. • We show a validated DL-method to determine CAC scores on CT images required during MPI. • No additional radiation exposure and manual scoring of a physician is needed. • We showed that this automated CAC score was independently associated with MACE. • If confirmed externally this could lead to better risk stratification in patients suspected of CCS. [ABSTRACT FROM AUTHOR]

Background: Although most patients in the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial had mild symptoms, there is a poor correlation between reported functional limitation and prognosis in heart failure.Objectives: The aim of this study was to examine the spectrum of risk in PARADIGM-HF and the effect of LCZ696 across that spectrum.Methods: This study analyzed rates of the primary composite outcome of cardiovascular death or heart failure hospitalization, its components, and all-cause mortality using the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) risk scores to categorize patients. The authors determined whether risk, on the basis of these scores, modified the treatment effect of LCZ696.Results: The complete MAGGIC risk score was available for 8,375 of the 8,399 patients in PARADIGM-HF. The median MAGGIC score was 20 (IQR: 16 to 24). An increase of 1 point was associated with a 6% increased risk for the primary endpoint (p < 0.001) and a 7% increased risk for cardiovascular death (p < 0.001). The benefit of LCZ696 over enalapril for the primary endpoint was similar across the spectrum of risk (p = 0.159). Treating 100 patients for 2 years with LCZ696 instead of enalapril led to 7 fewer patients in the highest quintile of risk experiencing primary outcomes, compared with 3 in the lowest quintile. Analyses using the EMPHASIS-HF risk score gave similar findings.Conclusions: Although most PARADIGM-HF patients had mild symptoms, many were at high risk for adverse outcomes and obtained a large absolute benefit from LCZ696, compared with enalapril, over a relatively short treatment period. LCZ696's benefit was consistent across the spectrum of risk. (PARADIGM-HF trial [Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure]; NCT01035255). [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this trial was to study the effect of a high bolus dose (HBD) of tirofiban on clinical outcome in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI). Background: The On-TIME 2 (Ongoing Tirofiban In Myocardial infarction Evaluation 2) placebo-controlled, double-blind, randomized trial showed that early administration of HBD tirofiban in the ambulance improves ST-segment resolution in patients with STEMI undergoing primary percutaneous coronary intervention. The effect of early tirofiban treatment on clinical outcome is unclear. Methods: The On-TIME 2 trial consisted of 2 phases: an open-label phase, followed by a double-blind, placebo-controlled phase. STEMI patients were randomized to either HBD tirofiban or no tirofiban (phase 1) or placebo (phase 2) in addition to aspirin, heparin, and high-dose clopidogrel. The protocol pre-specified a pooled analysis of the 2 study phases to assess the incidence of major adverse cardiac events at the 30-day follow-up and on total mortality at the 1-year follow-up. Results: During a 3-year period, 1,398 patients were randomized, 414 in phase 1 and 984 in phase 2. Major adverse cardiac events at 30 days were significantly reduced (5.8% vs. 8.6%, p = 0.043). There was a strong trend toward a decrease in mortality (2.2% vs. 4.1%, p = 0.051) in patients who were randomized to tirofiban pre-treatment, which was maintained during the 1-year follow-up (3.7% vs. 5.8%, p = 0.08). No clinically relevant difference in bleeding was observed. Conclusions: Early, pre-hospital initiation of HBD tirofiban, in addition to high-dose clopidogrel, improves the clinical outcome after primary percutaneous coronary intervention in patients with STEMI. (Ongoing 2b/3a inhibition In Myocardial infarction Evaluation; ISRCTN06195297) [Copyright &y& Elsevier]