The prognostic value of coronary flow reserve in patients with non-obstructive coronary artery disease and microvascular dysfunction: a systematic review and meta-analysis with focus on imaging modality and sex difference.

To clarify prognosis of patients with non-obstructive coronary artery disease (NOCAD) and coronary microvascular disease (CMD) assessed as low coronary flow reserve (CFR) according to imaging modalities and sex difference. Comprehensive systematic literature review and meta-analyses were conducted. Risk of death and major adverse cardiac events (MACE) were pooled and compared in patients with abnormally low versus normal CFR using cut-off limits 2.0-2.5. Random effects model used for estimation of odds ratios (OR) and hazard ratios (HR) with 95% confidence interval (CI). Nineteen eligible observational studies provided data for death and MACE, publication bias was insignificant, p = 0.62. Risk of death and MACE were significantly higher in patients with low (n = 4.612, 29%) than normal CFR (n = 11.367, 71%): using transthoracal echocardiography (TTE) (OR 4.25 (95% CI 2.94, 6.15) p < 0.001) and (OR 6.98 (95% CI 2.56, 19.01) p < 0.001), positron emission tomography (PET) (OR 2.51 (CI 95%: 1.40, 4..49) p = 0.002) and (OR 2.87 (95% CI 2.16, 3.81) p < 0.001), and invasive intracoronary assessment (OR 2.23 (95% CI 1.15, 4.34) p < 0.018), and (OR 4.61 (95% CI 2.51, 8.48) p < 0.001), respectively. Pooled adjusted HR for death and MACE were (HR 2.45(95% CI 1.37, 3.53) p < 0.001) and (HR 2.08 (95% CI 1.54, 2.63) p < 0.001) respectively. Studies comparing men and women with abnormally low CFR demonstrated similar worse prognosis in both sexes. Low CFR is associated with poorer prognosis in patients with NOCAD regardless of sex. TTE may overestimate risk of death and MACE, while PET seems to be more appropriate. Future studies are needed to consolidate the current evidence.

Clinical course and therapy optimization of patients after discharge from a specialized heart failure clinic.

Aim: We aimed to describe the clinical course of patients with heart failure with reduced ejection fraction (HFrEF) after discharge from the heart failure clinics (HFC). Patients & methods: We reviewed the hospital's records of 610 patients that were discharged between 2013 and 2018 from the HFC at a single centre. Patients with no recurrent contact to ambulatory cardiac care were invited to an echocardiographic assessment. Results: Of the survivors, 72% were re-referred after discharge. Nearly 30% of the patients with no recurrent contact with ambulatory cardiac care had persistent HFrEF and further therapeutical optimizations were indicated in half of them. Conclusion: This highlights the importance to identify high-risk patients that would benefit from extended management in the HFC.

What is this summary about? In Denmark, it is standard practice to discharge patients with heart failure from heart failure clinics to primary care after achieving optimized guideline-directed medical therapy. However, little is known about their subsequent clinical course and whether their treatment could be further optimized. To answer that question, we reviewed the hospital's records of heart failure patients that were discharged between 2013 and 2018. What were the results? Of the 610 heart failure patients that were discharged from our clinic, 30% had died; 72% of the survivors were re-referred to cardiac clinics in the interim period. Nearly 30% of the patients with no recurrent contact with cardiac clinics had persistent heart failure and further therapeutical optimizations were indicated in half of them. What do the results mean? Deaths and re-referral to cardiac clinics accounted for the majority of the heart failure patients that were initially discharged; while further intervention was indicated in half of the stable patients that had no recurrent contact with cardiac ambulatory care. This highlights the challenges in identifying high-risk patients that would benefit from an extended management programme in the heart failure clinic and the importance of following up heart failure patients despite initial optimized therapy.

Anomalous origin of the right coronary artery from pulmonary artery in an adult presenting with rapid atrial fibrillation: a case report.

Background: An anomalous origin of the right coronary artery from pulmonary artery (ARCAPA) is a very rare coronary anomaly. Case summary: A 56-year-old man, presenting haemodynamically unstable due to very rapid atrial fibrillation, was found to have ARCAPA by coronary computed tomography angiography. He had normal left ventricular ejection fraction and without reversible ischaemia on an adenosine stress rubidium positron emission tomography. He was treated solely with betablockers and has been well since. Discussion: Numerous case reports on ARCAPA have previously been published, but no previous reports have found rapid atrial fibrillation to be the primary symptom of presentation. Current evidence level concerning the treatment is low; nevertheless, surgical intervention should always be considered to prevent sudden cardiac death. The patient in this case was offered surgical intervention but declined.

Prognostic value of coronary computed tomography angiographic derived fractional flow reserve: a systematic review and meta-analysis.

OBJECTIVES: To obtain more powerful assessment of the prognostic value of fractional flow reserveCT testing we performed a systematic literature review and collaborative meta-analysis of studies that assessed clinical outcomes of CT-derived calculation of FFR (FFRCT) (HeartFlow) analysis in patients with stable coronary artery disease (CAD). METHODS: We searched PubMed and Web of Science electronic databases for published studies that evaluated clinical outcomes following fractional flow reserveCT testing between 1 January 2010 and 31 December 2020. The primary endpoint was defined as 'all-cause mortality (ACM) or myocardial infarction (MI)' at 12-month follow-up. Exploratory analyses were performed using major adverse cardiovascular events (MACEs, ACM+MI+unplanned revascularisation), ACM, MI, spontaneous MI or unplanned (>3 months) revascularisation as the endpoint. RESULTS: Five studies were identified including a total of 5460 patients eligible for meta-analyses. The primary endpoint occurred in 60 (1.1%) patients, 0.6% (13/2126) with FFRCT>0.80% and 1.4% (47/3334) with FFRCT ≤0.80 (relative risk (RR) 2.31 (95% CI 1.29 to 4.13), p=0.005). Likewise, MACE, MI, spontaneous MI or unplanned revascularisation occurred more frequently in patients with FFRCT ≤0.80 versus patients with FFRCT >0.80. Each 0.10-unit FFRCT reduction was associated with a greater risk of the primary endpoint (RR 1.67 (95% CI 1.47 to 1.87), p<0.001). CONCLUSIONS: The 12-month outcomes in patients with stable CAD show low rates of events in those with a negative FFRCT result, and lower risk of an unfavourable outcome in patients with a negative test result compared with patients with a positive test result. Moreover, the FFRCT numerical value was inversely associated with outcomes.

Importance of Risk Assessment in Timing of Invasive Coronary Evaluation and Treatment of Patients With Non-ST-Segment-Elevation Acute Coronary Syndrome: Insights From the VERDICT Trial.

Background The optimal timing of invasive examination and treatment of high-risk patients with non-ST-segment-elevation acute coronary syndrome has not been established. We investigated the efficacy of early invasive coronary angiography compared with standard-care invasive coronary angiography on the risk of all-cause mortality according to the GRACE (Global Registry of Acute Coronary Events) risk score in a predefined subgroup analysis of the VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography) trial. Methods and Results Patients with clinical suspicion of non-ST-segment-elevation acute coronary syndrome with ECG changes indicating new ischemia and/or elevated troponin, in whom invasive coronary angiography was clinically indicated and deemed logistically feasible within 12 hours, were eligible for inclusion. Patients were randomized 1:1 to an early (≤12 hours) or standard (48-72 hours) invasive strategy. The primary outcome of the present study was all-cause mortality. Of 2147 patients randomized in the VERDICT trial, 2092 patients had an available GRACE risk score. Of these, 1021 (48.8%) patients had a GRACE score >140. During a median follow-up of 4.1 years, 192 (18.8%) and 54 (5.0%) patients died in the high and low GRACE score groups, respectively. The risk of death with the early invasive strategy was increased in patients with a GRACE score ≤140 (hazard ratio [HR], 2.04 [95% CI, 1.16-3.59]), whereas there was a trend toward a decreased risk of death with the early invasive strategy in patients with a GRACE score >140 (HR, 0.83 [95% CI, 0.63-1.10]) (Pinteraction=0.006). Conclusions In patients with non-ST-segment-elevation acute coronary syndrome, we found a significant interaction between timing of invasive coronary angiography and GRACE score on the risk of death. Randomized clinical trials are warranted to establish the efficacy and safety among high-risk and low-risk patients with non-ST-segment-elevation acute coronary syndrome. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02061891.

Prognostic Value of Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes.

BACKGROUND: Severity and extent of coronary artery disease (CAD) assessed by invasive coronary angiography (ICA) guide treatment and may predict clinical outcome in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). OBJECTIVES: This study tested the hypothesis that coronary computed tomography angiography (CTA) is equivalent to ICA for risk assessment in patients with NSTEACS. METHODS: The VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes) trial evaluated timing of treatment in relation to outcome in patients with NSTEACS and included a clinically blinded coronary CTA conducted prior to ICA. Severity of CAD was defined as obstructive (coronary stenosis ≥50%) or nonobstructive. Extent of CAD was defined as high risk (obstructive left main or proximal left anterior descending artery stenosis and/or multivessel disease) or non-high risk. The primary endpoint was a composite of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or heart failure. RESULTS: Coronary CTA and ICA were conducted in 978 patients. During a median follow-up time of 4.2 years (interquartile range: 2.7 to 5.5 years), the primary endpoint occurred in 208 patients (21.3%). The rate of the primary endpoint was up to 1.7-fold higher in patients with obstructive CAD compared with in patients with nonobstructive CAD as defined by coronary CTA (hazard ratio [HR]: 1.74; 95% confidence interval [CI]: 1.22 to 2.49; p = 0.002) or ICA (HR: 1.54; 95% CI: 1.13 to 2.11; p = 0.007). In patients with high-risk CAD, the rate of the primary endpoint was 1.5-fold higher compared with the rate in those with non-high-risk CAD as defined by coronary CTA (HR: 1.56; 95% CI: 1.18 to 2.07; p = 0.002). A similar trend was noted for ICA (HR: 1.28; 95% CI: 0.98 to 1.69; p = 0.07). CONCLUSIONS: Coronary CTA is equivalent to ICA for the assessment of long-term risk in patients with NSTEACS. (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes [VERDICT]; NCT02061891).

The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT).

OBJECTIVES: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT). METHODS: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years. RESULTS: As of May 2020, 296 patients have been randomized at 20 centers in Denmark. CONCLUSION: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

Incidence of Ischemic Stroke in Individuals With and Without Aortic Valve Stenosis: A Danish Retrospective Cohort Study.

Background and Purpose- Aortic valve stenosis may lead to atrial and ventricular remodeling, predisposes to atrial fibrillation, and may also be an independent risk factor of ischemic stroke. However, information on stroke rates among persons with aortic valve stenosis are sparse. We aimed to determine the incidence rates and relative risks of ischemic stroke in individuals with diagnosed aortic valve stenosis compared with age- and sex-matched controls. Methods- All patients with incident aortic valve stenosis aged >18 years (n=79 310) and age- and sex-matched controls were identified using the Danish nationwide registries (1997-2017). Incidence rates per 1000 person-years (PY) and multivariable adjusted hazard ratios with 95% CIs were reported. Results- In total, 873 373 individuals (median age 77 years, 51.5% men, 9.1% with aortic valve stenosis) were included. Ischemic stroke occurred in 70 205 (8.0%) individuals during 4 880 862 PY of follow-up. Incidence rates of ischemic stroke were 13.3/1000 PY among the controls compared with 30.4/1000 PY in patients with aortic valve stenosis, corresponding to a hazard ratio of 1.31 (95% CI, 1.28-1.34). In all age-groups, the incidence rates and relative risks were significantly increased in patients with aortic valve stenosis compared with controls, but the relative risk was greater for younger individuals (eg, age group, 18-45 years: hazard ratio, 5.94 [95% CI, 4.10-8.36]). In patients with aortic valve stenosis above 65 years of age, the risk of ischemic stroke was markedly lower after aortic valve replacement (30.3 versus 19.6/1000 PY before and after valve replacement). Among people with atrial fibrillation the incidence rate of ischemic stroke was 1.5 times higher when aortic valve stenosis was present (33.0/1000 PY versus 49.9/1000 PY). Conclusions- People with aortic valve stenosis have a significantly increased risk of ischemic stroke compared with age- and sex-matched controls. Future studies are warranted to explore whether antithrombotic therapy may be beneficial in some individuals.

Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: In patients with non-ST-segment elevation acute coronary syndrome (NSTEACS), coronary pathology may range from structurally normal vessels to severe coronary artery disease. OBJECTIVES: The purpose of this study was to test if coronary computed tomography angiography (CTA) may be used to exclude coronary artery stenosis ≥50% in patients with NSTEACS. METHODS: The VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes) trial (NCT02061891) evaluated the outcome of patients with confirmed NSTEACS randomized 1:1 to very early (within 12 h) or standard (48 to 72 h) invasive coronary angiography (ICA). As an observational component of the trial, a clinically blinded coronary CTA was conducted prior to ICA in both groups. The primary endpoint was the ability of coronary CTA to rule out coronary artery stenosis (≥50% stenosis) in the entire population, expressed as the negative predictive value (NPV), using ICA as the reference standard. RESULTS: Coronary CTA was conducted in 1,023 patients-very early, 2.5 h (interquartile range [IQR]: 1.8 to 4.2 h), n = 583; and standard, 59.9 h (IQR: 38.9 to 86.7 h); n = 440 after the diagnosis of NSTEACS was made. A coronary stenosis ≥50% was found by coronary CTA in 68.9% and by ICA in 67.4% of the patients. Per-patient NPV of coronary CTA was 90.9% (95% confidence interval [CI]: 86.8% to 94.1%) and the positive predictive value, sensitivity, and specificity were 87.9% (95% CI: 85.3% to 90.1%), 96.5% (95% CI: 94.9% to 97.8%) and 72.4% (95% CI: 67.2% to 77.1%), respectively. NPV was not influenced by patient characteristics or clinical risk profile and was similar in the very early and the standard strategy group. CONCLUSIONS: Coronary CTA has a high diagnostic accuracy to rule out clinically significant coronary artery disease in patients with NSTEACS.

Quantification of mitral valve regurgitation by 2D and 3D echocardiography compared with cardiac magnetic resonance a systematic review and meta-analysis.

By means of systematic literature review and meta-analysis, we compared results of studies examining different echocardiographic methods assessing severity of mitral valve regurgitation volume (MVR) with cardiac magnetic resonance imaging (CMR) as standard reference. A systematic search of electronic databases revealed twenty studies eligible for meta-analysis. Results of 2D- and 3D-trans-thoracic (TTE) and trans-esophageal echocardiographic (TEE) proximal isovelocity surface area (PISA) and volumetric methods were compared with CMR. Mean differences (ml) with 95% limits of agreement (LoA) derived from Bland-Altman tests and correlations coefficients [(R) 95% confidence interval (CI)] were pooled together. Overall 1187 patients [mean age = 59 ± 13 years and 678(57%) males] with primary or secondary mild to severe MVR were included. Comparing all echocardiographic methods with CMR showed an overestimation and moderate agreement with difference and 95% LoA of 8.05(- 3.40, 19.49) ml, R = 0.73(95% CI 0.71-0.76) p < 0.001. 3D-PISA followed by 3D-volumetric methods showed the better agreement with an underestimation of - 3.20(- 12.33, 5.92) ml, R = 0.84(95% CI 0.78-0.89) p < 0.001 and overestimation of 3.73(- 9.17, 16.61) ml, R = 0.90(95% CI 0.87, 0.94) p < 0.001, respectively. 2D-volumetric method showed the poorest agreement with difference and 95% LoA of 23.56(- 4.19, 51.31) ml, R = 0.64(95% CI 0.54-0.73) p < 0.001. In patients (n = 280) with severe MVR, 2D technique incorrectly estimated regurgitation volume severity in 106 (38%) compared to 4(14%) patients using 3D technique. Among echocardiographic methods 3D-PISA agreed best with CMR as reference, making 3D-PISA the most reliable method to quantify MVR. CMR can be considered in severe MVR where uncertainties arise and a decision-making prior valve surgery is required. Further powerful studies are needed to assess the accuracy of different echocardiographic methods.

Coronary Artery Disease Assessed by Computed Tomography in Patients with Psoriasis: A Systematic Review and Meta-Analysis.

BACKGROUND: Patients with psoriasis have an increased risk of coronary artery disease (CAD) but data on coronary calcium score (CCS) and cardiac computed tomography angiography (CCTA) are inconsistent. OBJECTIVES: The present study quantitatively summarizes the literature data on the prevalence and burden of CAD in patients with psoriasis compared with controls using CCS and CCTA. METHODS: A systematic review and meta-analysis was conducted. The search included all studies examining CAD prevalence and burden detected by CCS with or without CCTA in patients with psoriasis without prior CAD compared with controls, between the year 2000 and May 30, 2018. RESULTS: Fourteen eligible studies provided data on 1,427 patients with psoriasis and 9,670 controls. Pooled data provided the estimated risk ratio (RR) of CAD and weighted mean differences of CCS in psoriasis patients versus controls. Meta-analysis of the prevalence and burden of CCS showed that patients with psoriasis had an increased risk of CAD (RR 1.14, 95% CI 1.04-1.26; p = 0.004), and for more severe CAD (CCS >100) the risk was further increased (RR 1.71, 95% CI 1.28-2.30; p < 0.001) compared with controls. Weighted mean difference for CCS was significantly higher in patients with psoriasis (12.74, 95% CI 10.70-14.78; p < 0.001). The risk of high-risk coronary plaques identified by CCTA was also significantly higher in psoriasis patients compared with controls (RR 1.77, 95% CI 1.37-2.28; p < 0.001). CONCLUSIONS: Patients with psoriasis have a higher prevalence of subclinical CAD, a higher burden of the disease, and more high-risk coronary plaques compared with controls without psoriasis.

Cardiac perfusion and function after high-intensity exercise training in late premenopausal and recent postmenopausal women: an MRI study.

We examined the influence of recent menopause and aerobic exercise training in women on myocardial perfusion, left ventricular (LV) dimension, and function. Two groups (n = 14 each) of healthy late premenopausal (50.2 ± 2.1 yr) and recent postmenopausal (54.2 ± 2.8 yr) women underwent cardiac magnetic resonance imaging (cMRI) at baseline and after 12 wk of high-intensity aerobic training. Measurements included LV morphology, systolic function, and myocardial perfusion at rest and during an adenosine stress test. At baseline, resting myocardial perfusion was lower in the postmenopausal than the premenopausal group (77 ± 3 vs. 89 ± 3 ml·100 g-1·min-1; P = 0.01), while adenosine-induced myocardial perfusion was not different (P = 0.81). After exercise training, resting myocardial perfusion was lower in both groups (66 ± 2; P = 0.002 vs. 81 ± 3 ml·100 g-1·min-1; P = 0.03). The adenosine-induced change in myocardial perfusion was lower in the groups combined (by 402 ± 17 ml·100 g-1·min-1; P = 0.02), and the adenosine-induced increase in heart rate was 10 ± 2 beats/min lower (P < 0.0001) in both groups after training. Normalization of myocardial perfusion using an estimate of cardiac work eliminated the differences in perfusion between the premenopausal and postmenopausal groups and the effect of training. Left ventricle mass was higher in both groups (P = 0.03; P = 0.006), whereas LV end-diastolic (P = 0.02) and stroke (P = 0.045) volumes were higher in the postmenopausal group after training. Twelve weeks of exercise training increased left ventricle mass and lowered resting and adenosine-induced myocardial perfusion, an effect that was likely related to cardiac work. The current data also suggest that the early menopausal transition has limited impact on cardiac function and structure. NEW & NOTEWORTHY This study provides for the first time estimates of myocardial perfusion in late premenopausal and recent postmenopausal women before and after a period of intense aerobic training. Resting myocardial perfusion was lower in postmenopausal than premenopausal women. Training lowered myocardial resting and stress perfusion in both groups, an effect that was likely influenced by the lower heart rate.

Rheumatoid arthritis patients have higher prevalence and burden of asymptomatic coronary artery disease assessed by coronary computed tomography: A systematic literature review and meta-analysis.

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased risk of coronary artery disease (CAD) and studies with coronary computed tomography have suggested increased rates of asymptomatic CAD determined by the coronary calcium score (CCS) in these patients. To synthesize the evidence on this topic, we conducted a systematic review and meta-analysis of the literature. METHODS: A systematic review was performed of data comparing the prevalence and burden of asymptomatic CAD in RA and controls using CCS with or without coronary computed tomographic angiography (CCTA). For the meta-analysis, pooled data provided the estimated risk ratio (RR) of CAD and weighted mean differences of CCS in patients with RA compared to controls. RESULTS: The search revealed 1841 results of which 1083 were screened and 26 full text papers were evaluated. Eight studies were included with data on 788 patients with RA and 1641 controls. Patients with RA had significantly increased risk of CAD (RR = 1.26 [95% CI 1.04-1.52]; p = .021) and increased weighted mean differences for CCS (48.25 [95% CI 26.97-69.53]; p < .001) compared to controls. Limited evidence suggested that patients with RA had a higher prevalence of moderate-severe (CCS > 100) CAD and more multivessel CAD, and RA duration and disease activity were associated with higher CCS, RA disease activity was linked with presence of high risk (non-calcified or mixed) coronary plaques, and treatment with methotrexate was tied to absence of CAD, respectively. CONCLUSIONS: In patients with RA, asymptomatic CAD is more prevalent, with higher mean CCS, more multivessel disease, and more high-risk plaques compared to controls.

Early Versus Standard Care Invasive Examination and Treatment of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: The optimal timing of invasive coronary angiography (ICA) and revascularization in patients with non-ST-segment elevation acute coronary syndrome is not well defined. We tested the hypothesis that a strategy of very early ICA and possible revascularization within 12 hours of diagnosis is superior to an invasive strategy performed within 48 to 72 hours in terms of clinical outcomes. METHODS: Patients admitted with clinical suspicion of non-ST-segment elevation acute coronary syndrome in the Capital Region of Copenhagen, Denmark, were screened for inclusion in the VERDICT trial (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography) ( ClinicalTrials.gov NCT02061891). Patients with ECG changes indicating new ischemia or elevated troponin, in whom ICA was clinically indicated and deemed logistically feasible within 12 hours, were randomized 1:1 to ICA within 12 hours or standard invasive care within 48 to 72 hours. The primary end point was a combination of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or hospital admission for heart failure. RESULTS: A total of 2147 patients were randomized; 1075 patients allocated to very early invasive evaluation had ICA performed at a median of 4.7 hours after randomization, whereas 1072 patients assigned to standard invasive care had ICA performed 61.6 hours after randomization. Among patients with significant coronary artery disease identified by ICA, coronary revascularization was performed in 88.4% (very early ICA) and 83.1% (standard invasive care). Within a median follow-up time of 4.3 (interquartile range, 4.1-4.4) years, the primary end point occurred in 296 (27.5%) of participants in the very early ICA group and 316 (29.5%) in the standard care group (hazard ratio, 0.92; 95% CI, 0.78-1.08). Among patients with a GRACE risk score (Global Registry of Acute Coronary Events) >140, a very early invasive treatment strategy improved the primary outcome compared with the standard invasive treatment (hazard ratio, 0.81; 95% CI, 0.67-1.01; P value for interaction=0.023). CONCLUSIONS: A strategy of very early invasive coronary evaluation does not improve overall long-term clinical outcome compared with an invasive strategy conducted within 2 to 3 days in patients with non-ST-segment elevation acute coronary syndrome. However, in patients with the highest risk, very early invasive therapy improves long-term outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02061891.

Association of Timing of Aortic Valve Replacement Surgery After Stroke With Risk of Recurrent Stroke and Mortality.

Importance: Timing of surgical aortic valve replacement (SAVR) in patients with aortic valve stenosis and previous stroke for the risk of recurrent stroke is insufficiently investigated. Objective: To evaluate the association of time elapsed between previous stroke and SAVR with the risk of recurrent perioperative stroke, major adverse cardiovascular events (MACE), and mortality among patients with aortic valve stenosis. Design, Setting, and Participants: This cohort study using data from Danish administrative registries included all patients with aortic valve stenosis older than 18 years who underwent SAVR between 1996 and 2014 (n = 14 030). Patients who received simultaneous mitral, tricuspid, or pulmonary valve surgery and patients with endocarditis 1 year prior to surgery were excluded. Data were analyzed from March 2017 to January 2018. Exposures: Time elapsed between prior stroke and SAVR (<3 months, 3-<12 months, ≥12 months, and no prior stroke). Main Outcomes and Measures: Thirty-day risks of MACE, ischemic stroke, and all-cause mortality reported as absolute events and multivariable adjusted odds ratios with 95% confidence intervals. Restricted cubic spline regression models were additionally applied on the subgroup with prior stroke. Results: Of the 14 030 included patients, 616 patients (190 [30.8%] women; mean [SD] age, 72.0 [9.1] years) with prior stroke underwent surgery, and 13 414 (4837 [36.1%] women; mean [SD] age, 69.8 [10.8] years) without prior stroke underwent surgery. The absolute risk of ischemic stroke was significantly increased in patients with stroke less than 3 months prior to surgery compared with patients with no prior stroke (18.4% [37 of 201] vs 1.2% [160 of 13 219]; odds ratio, 14.69; 95% CI, 9.69-22.27). Likewise, compared with patients without stroke, patients with stroke less than 3 months prior surgery were at significantly increased risk of MACE (23.3% [53 of 227] vs 5.7% [768 of 13 414]; odds ratio, 4.57; 95% CI, 3.24-6.44) but not all-cause mortality (6.8% [50 of 730] vs 3.6% [374 of 10 370]; odds ratio, 1.45; 95% CI, 0.83-2.54). Spline analyses supported a declining risk over time, reaching nadir after 2 to 4 months. Conclusions and Relevance: Previous stroke is a major risk factor of recurrent ischemic stroke and MACE in patients undergoing SAVR, especially if time elapsed between previous stroke and surgery is less than 3 months.

Impact of statin therapy on coronary plaque burden and composition assessed by coronary computed tomographic angiography: a systematic review and meta-analysis.

Aim: To clarify the potential role of coronary computed tomographic angiography (CCTA) in assessing the remodelling impact of statin therapy on plaque burden and compositions. Methods and results: A systematic literature review and meta-analysis were conducted to examine the effect of statin therapy on different plaque volumes assessed by serial CCTA. Twelve studies were included with a mean (±standard deviation) follow-up period of 14.5 ± 9.5 months. Data on plaque volume were pooled using weighted mean difference method. Available data on a total of 199 intensive statin therapy receivers, 404 moderate statin therapy receivers and 189 controls (mean age = 62 ± 5 years, male gender = 78%) were meta-analysed. Intensive statin therapy reduced total plaque volume (TPV) by -20.87 [95% confidence interval (CI) -31.17, -10.56; P < 0.001] mm3, while moderate statin therapy reduced it by -1.67 (95% CI -9.99, 6.65; P = 0.69) mm3. In contrast TPV increased significantly in controls by 14.96 (95% CI 5.28, 24.64; P = 0.002) mm3. Percents of mean volume regression were -3.6% and -0.7% in intensive and moderate statin receivers, respectively, vs. +5.8% progression in controls. Statin therapy decreased non-calcified plaque volume by -7.62 (95% CI -17.38, 2.13; P = 0.124) mm3 and low attenuation plaque volume by -5.84 (95% CI -8.02, -3.66; P < 0.001) mm3. In statin therapy receivers, calcified plaque volume increased by 11.83 (95% CI 3.37, 20.29; P = 0.006) mm3 and calcium signal intensity increased by 21.99 (95% CI 9.2, 34.8; P < 0.001) Hounsfield units. Conclusions: Initial studies demonstrated CCTA's possible role in evaluating the effect of statin therapy on plaque volume and composition. Further studies are warranted to delineate the mechanisms behind plaque changes.

Characteristics and long-term prognosis of patients with heart failure and mid-range ejection fraction compared with reduced and preserved ejection fraction: a systematic review and meta-analysis.

AIMS: This study aimed to assess by a meta-analysis the clinical characteristics, all-cause and cardiovascular mortality, and hospitalization of patients with heart failure (HF) with mid-range ejection fraction (HFmrEF) compared with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Data from 12 eligible observational studies including 109 257 patients were pooled. HFmrEF patients were significantly different and occupied a mid-position between HFrEF and HFpEF: mean age 73.6 ± 9.8 vs. 72.6 ± 9.8 and 77.6 ± 7.2 years, male gender 59% vs. 68.5% and 40%, ischaemic heart disease 49% vs. 52.6% and 39.4%, hypertension 67.3% vs. 61.5% and 76.5%, atrial fibrillation 45.2% vs. 39.6% and 46%, chronic obstructive pulmonary disease 26.4% vs. 24.9% and 30.5%, estimated glomerular filtration rate 62 ± 30 vs. 63.3 ± 23 and 59 ± 22.5, use of renin-angiotensin system inhibitors 79.6% vs. 90.1% and 68.7%, beta-blockers 82% vs. 89% and 73.5%, and aldosterone antagonists 20.3 vs. 31.5% and 26%, P-values < 0.05. After a mean follow-up of 31 ± 5 months, all-cause mortality was significantly lower in HFmrEF than in HFrEF and HFpEF (26.8% vs. 29.5% and 31%): risk ratio (RR) 0.95 [0.93-0.98; 95% confidence interval (CI)], P < 0.001, and 0.97 (0.94-0.99; 95% CI), P = 0.014, respectively. Cardiovascular mortality was lowest in HFmrEF (9.7% vs. 13% and 12.8%): RR = 0.81 (0.73-0.91), P < 0.001, and 1.10 (0.97-1.24; 95% CI), P = 0.13, respectively. HF hospitalization in HFmrEF compared to that in HFrEF and HFpEF was 23.9% vs. 27.6% and 23.3% with RR = 0.89 (0.85-0.93), P < 0.001, and RR = 1.12 (1.07-1.17), P < 0.001, respectively. CONCLUSIONS: The results of this study support that HFmrEF is a distinct category characterized by a mid-position between HFrEF and HFpEF and with the lowest all-cause and cardiovascular mortality.

Characteristics and prognosis of heart failure with improved compared with persistently reduced ejection fraction: A systematic review and meta-analyses.

Aims We assessed the clinical characteristics and prognosis of chronic heart failure patients with improved ejection fraction (HFIEF) compared with persistently reduced ejection fraction (HFpREF) after evidence-based therapy. Methods and results We performed a meta-analysis including 24 eligible observational studies comparing 2663 HFIEF (≥5% left ventricular ejection fraction (LVEF) improvement) versus 8355 HFpREF patients who received recommended drug therapy, cardiac resynchronization therapy and/or intracardiac defibrillator. LVEF was assessed at baseline and reassessed after 19 ± 19 months. The primary endpoints were all-cause mortality and appropriate shocks. The mean duration of follow-up was 39 ± 12 months. Among HFIEF patients, LVEF improved 16.3 percentage points (95% confidence interval 15.9-16.6, p < 0.0001). Compared with HFpREF patients, HFIEF patients had a comparable mean age (60.9 years vs. 62.4 years, p = 0.11), were more often women (33% vs. 25%), had a higher prevalence of non-ischaemic heart failure (58% vs. 53%), less diabetes (27% vs. 28%), higher systolic blood pressure (127.5 ± 9 vs. 122 ± 12 mmHg) and lower left ventricle end-diastolic diameter (64.1 ± 3.7 vs. 67.4 ± 4.9 mmHg), all p-values < 0.05. Absolute risk of all-cause mortality was lower in HFIEF (5.8%) compared with HFpREF (17.5%) with a risk ratio of 0.34 (95% confidence interval 0.28-0.41), p < 0.001. Risk of appropriate shocks was significantly lower in HFIEF versus HFpREF (risk ratio 0.58 (95% confidence interval 0.46-0.74), p < 0.001). Conclusion In heart failure patients, we identified several baseline characteristics in favour of an improved LVEF, in response to evidence based therapy. Patients with improved LVEF had significantly lower risks of mortality and appropriate shocks compared with patients with persistently reduced LVEF.

Sarcopenia and osteoporosis in older people: a systematic review and meta-analysis.

BACKGROUND: Age-related loss of muscle and bone (sarcopenia and osteoporosis), increases the risk of falls and fractures and consequently leads to a substantial economic burden for the society. The combined condition, osteosarcopenia, may identify patients at a higher risk of those outcomes and could be relevant for assessment and treatment in clinical practice. AIM: To evaluate the current knowledge of the prevalence of osteosarcopenia and the fracture risk in older people. METHOD: A systematic literature review was conducted until 10th March 2018. A total of 1105 papers were detected, whereof 1049 and 29 were excluded by title/abstracts and full-text assessment, respectively. Twenty-seven original papers were included in the systematic review, whereof 17 were suitable for meta-analysis. RESULTS: The prevalence of osteosarcopenia varied (5-37%) depending on the classification of sarcopenia and whether participants were classified initially according to sarcopenia or osteoporosis. In patients with low-energy osteoporotic fractures, sarcopenia was present in 7.8-58% and 1.3-96.3% of the cases, women and men, respectively. The meta-analysis of prevalence of sarcopenia in patients with low-energy fracture (n = 9) was 46% (95% CI 44, 48; p < 0.001). The relative risk of fracture (sarcopenic versus non-sarcopenic) in meta-analysis of four studies was 1.37 (95% CI 1.18, 1.59; p < 0.001). Mean bone mineral density (n = 5) and T-score (n = 3) of femoral neck was significantly lower in sarcopenic participants [- 0.07 g/cm2 (95% CI 0.08, 0.06) and - 0.34 (95% CI - 0.46, - 0.23), respectively]. CONCLUSION: Osteosarcopenia is frequent and the relative risk of fracture is higher among sarcopenic patients. A standard and strict classification of sarcopenia is needed to assess its true relationship and consequences.