Impacts of high sensitivity troponin T reporting on care and outcomes in clinical practice: Interactions between low troponin concentrations and participant sex within two randomized clinical trials.

BACKGROUND: The impacts of high sensitivity cardiac troponin (hs-cTn) reporting on downstream interventions amongst suspected acute coronary syndrome (ACS) in the emergency department (ED), especially amongst those with newly identified hs-cTn elevations and in consideration of well-established sex-related disparities, has not been critically evaluated to date. This investigation explores the impact of hs-cTnT reporting on care and outcomes, particularly by participant sex. METHODS: Two similarly ED-based randomized controlled trials conducted between July 2011 to March 2013 (n = 1988) and August 2015 to April 2019 (n = 3378) were comparatively evaluated. Clinical outcomes were adjudicated to the Fourth Universal Definition of MI. Changes in practice were assessed at 30 days, and death or MI were explored to 12 months. RESULTS: The HS-Troponin study demonstrated no difference in death or MI with unmasking amongst those with hs-cTnT <30 ng/L, whereas the RAPID TnT study demonstrated a significantly higher rate. In RAPID TnT, there was significant increase in death or MI associated with unmasking for females with hs-cTnT <30 ng/L (masked: 11[1.5%], unmasked: 25[3.4%],HR: 2.27,95%C.I.:1.87-2.77,P < 0.001). Less cardiac stress testing with unmasking amongst those <30 ng/L was observed in males in both studies, which was significant in RAPID TnT (masked: 92[12.0%], unmasked: 55[7.0%], P = 0.008). In RAPID TnT, significantly higher rates of angiography in males were observed with unmasking, with no such changes amongst females <30 ng/L (masked: 28[3.7%], unmasked: 51[6.5%],P = 0.01). CONCLUSION: Compared with males, there were no evident impacts on downstream practices for females with unmasking in RAPID TnT, likely representing missed opportunities to reduce late death or MI.

Twelve-Month Outcomes of Patients With Myocardial Injury not Due to Type-1 Myocardial Infarction.

BACKGROUND: Diagnosis of acute myocardial infarction (AMI) requires a combination of elevated cardiac troponins, and clinical or echocardiographic evidence of coronary ischaemia. Identification of patients with a high likelihood of coronary plaque rupture (Type 1 myocardial infarction [MI]) is crucial as it is these patients for whom coronary intervention has been well-established to provide benefit and reduce subsequent coronary ischemic events. However, high-sensitivity cardiac troponin (hs-cTn) assays have increasingly identified patients with hs-cTn elevations not due to Type 1 MI where recommendations for ongoing care are currently limited. Understanding the profile and clinical outcomes for these patients may inform the development of an emerging evidence-base. METHODS: Using two previously published studies (hs-cTnT study n=1,937, RAPID-TnT study n=3,270) and the Fourth Universal Definition of MI, index presentations of patients to South Australian emergency departments with suspected AMI, defined by high sensitivity cardiac troponin T (hs-cTnT) greater than the upper reference limit (14 ng/L) and without obvious corresponding ischaemia on electrocardiogram (ECG), were classified as either Type 1 MI (T1MI), Type 2 MI (T2MI), acute myocardial injury (AI), or chronic myocardial injury (CI). Patients with non-elevated hs-cTnT (defined as <14 ng/L) were excluded. Outcomes assessed included death, MI, unstable angina, and non-coronary cardiovascular events within 12 months. RESULTS: In total, 1,192 patients comprising 164 (13.8%) T1MI, 173 (14.5%) T2MI/AI, and 855 (71.7%) CI were included. The rate of death or recurrent acute coronary syndrome was greatest in patients with T1MI, but also occurred with moderate frequency in Type 2 MI/AI and CI (T1MI: 32/164 [19.5%]; T2MI/AI: 24/173 [13.1%]; CI:116/885 [13.6%]; p=0.008). Of all the deaths observed, 74% occurred among those with an initial index diagnostic classification of CI. After adjusting for age, gender and baseline comorbidities, the relative hazard ratios for non-coronary cardiovascular readmissions were similar across all groups: Type 2 MI/AI: 1.30 (95% confidence interval 0.99-1.72, p=0.062); CI: 1.10 (95% confidence interval 0.61-2.00, p=0.75). CONCLUSIONS: Non-T1MI accounted for the majority of patients presenting with elevated hs-cTnT without ischaemia on ECG. Patients with T1MI had the highest rates of death or recurrent AMI; however patients with T2MI/AI and CI experienced a substantial rate of non-coronary cardiovascular re-hospitalisations.

Obesity-induced vena cava compression syndrome: a case report of a rare precipitant of a type 2 myocardial infarction in a patient with critical aortic stenosis.

Background: Obesity is a global health problem of increasing prevalence with a broad range of multisystem complications. An under-recognized complication of severe obesity is the potential haemodynamic compromise that may arise due to pathological external compression of the inferior vena cava whilst lying in the supine position, a phenomenon known as obesity-induced vena cava compression syndrome. Case summary: A 56-year-old independent woman presented to a rural Australian hospital for routine dressing care for bilateral lymphoedema on a background of class III morbid obesity (weight 197 kg, body mass index 68.55 kg/m3) and aortic stenosis. Whilst laid in the supine position with both legs elevated to aid lower limb venous return, the patient developed angina with associated troponin rise (15 to 75 to 332 ng/L) and inferolateral territory ischaemic changes on electrocardiogram. The pain then resolved shortly after restoring the patient to the upright position. A transthoracic echocardiogram showed critical bicuspid aortic stenosis. Computerized tomography coronary angiogram showed no significant coronary artery disease. Following multidisciplinary discussions, a transcatheter aortic valve insertion was performed via a transfemoral approach. Post-procedure, she went into atrial fibrillation, she was cardioverted into a sinus rhythm with new left bundle branch block. There were no complications otherwise, and the patient was discharged home following a brief period of convalescence. Discussion: We describe a case of suspected obesity-induced vena cava compression syndrome precipitating a type 2 myocardial infarction in a pre-load dependent patient with critical bicuspid valve aortic stenosis. This case highlights a potential haemodynamic consequence of morbid obesity in the supine position.

Impact of Surgical and Transcatheter Aortic Valve Replacement on Frailty Score.

OBJECTIVE: Frailty is common in the aortic stenosis (AS) population and impacts outcomes after both transcatheter and surgical aortic valve replacement (TAVR and sAVR, respectively). Frailty can significantly impact the decision regarding the suitability of a patient for aortic valve intervention, with frail patients often excluded. Since many frailty tools use indicators which may be influenced by AS itself, some of which are subjectively symptom driven, we sought to determine the impact of intervention on frailty scores. METHODS: A prospective, observational cohort study included patients being assessed for aortic valve (AV) intervention with either TAVR or sAVR due to severe aortic stenosis. Patients were assessed for symptoms at baseline, and 1- and 6-months post intervention subjectively, using the New York Heart Association (NYHA) class and the Kansas City Cardiomyopathy Questionnaire (KCCQ), and objectively, using a 6-minute walk test (6MWT). These were compared with frailty at baseline and final review using the Fried Frailty Scale (FFS). RESULTS AND CONCLUSIONS: Sixty-six (66) patients completed pre- and post-intervention reviews. The mean FFS score was significantly lower, indicating less frailty, at 6 months relative to pre procedure (1.18 vs 1.73, p=0.002). This correlated with the change in symptoms (p<0.001). Between intervention groups, the final mean FFS of both groups decreased significantly, with TAVR to 1.33 (p=0.030) and sAVR to 0.8 (p=0.015). There was no difference in the degree of improvement between interventions (p=0.517). Aortic valve intervention improves frailty scores in both TAVR and sAVR treated patients.

Impact of increased augmentation index and valvuloarterial impedance on symptom recovery after aortic valve replacement for severe aortic stenosis.

BACKGROUND: Aortic stenosis (AS) is a common valvular disorder with a large symptomatic burden resulting from increased myocardial workload due to valvular obstruction. The contribution of increased afterload from arterial stiffness on symptoms is uncertain. The purpose of this analysis was to determine the symptomatic impact of arterial stiffness as determined by Applanation Tonometry. METHODS: Eighty-eight patients with severe AS undergoing intervention with transcatheter aortic valve replacement (TAVR) (n = 65) or surgical aortic valve replacement (SAVR) (n = 23) were prospectively enrolled. Symptoms were recorded using the NYHA Class, Kansas City Cardiomyopathy Questionnaire (KCCQ) and a 6 min walk test (6MWT) at baseline, and 1- and 6-months post intervention. Pulse Wave Analysis (PWA) using Applanation Tonometry was performed at all reviews, including the augmentation index (AIx). RESULTS: Patients undergoing TAVR were older, with worse renal function and lower aortic valve areas, but were otherwise similar. There was no significant difference between the augmentation index of our AS population compared with an age matched reference population (p = 0.89).Symptoms significantly improved after intervention according to NYHA Class, KCCQ and 6MWT. Additionally, with adjustment, the initial augmentation index correlated with the final KCCQ (Coeff. = -0.383, p = 0.02) and NYHA Class (Coeff. = 0.012, p = 0.03) and a baseline AIx value in the top quartile resulted in a significantly worse final KCCQ (95.1 v 85.2, p = 0.048) relative to the bottom 3 quartiles. CONCLUSIONS: According to our analysis, an elevated baseline AIx is associated with a poorer symptomatic recovery after aortic valve intervention and so is worthy of consideration when assessing potential symptomatic benefit.

Effect of Balloon Aortic Valvuloplasty on Mortality in Patients With Severe Aortic Stenosis Prior to Conservative Treatment and Surgical or Transcatheter Aortic Valve Replacement.

BACKGROUND: Outcomes following an initial strategy of balloon aortic valvuloplasty (BAV) prior to medical therapy or intervention with surgical or transcatheter aortic valve replacement (SAVR or TAVR) are unclear in the modern transcatheter intervention era. METHODS: A retrospective, observational cohort study of the echocardiography, cardiothoracic surgery and TAVR databases between 1 January 2006 and 31 December 2016 was performed to compare outcomes between all patients with severe aortic stenosis (AS) treated with or without BAV prior to medical or invasive therapy. RESULTS: 3,142 patients were available for analysis. 223 BAV treated patients had lower mortality relative to medically treated patients, particularly early (20.1% v. 7.6% at 6 months, 58.1% v. 52.5% at 5 years). Over 5 years, the adjusted hazard ratio (HR) was 0.62 (95% CI 0.48-0.80, p < 0.001). Compared with 630 patients proceeding directly to intervention, 75 patients receiving BAV experienced a higher mortality (HR = 2.76, 95% CI 2.07-3.66, p < 0.001). No subsequent excess perioperative mortality was observed with BAV compared with those receiving surgery directly (HR = 1.45, 95% CI 0.91-2.31, p = 0.117). CONCLUSIONS: The risk associated with BAV is low, and improves mortality compared with medical therapy. Balloon aortic valvuloplasty treated patients have poorer outcomes, but treatment with BAV does not increase perioperative mortality and may lessen it.

Sex Differences in Instantaneous Wave-Free Ratio or Fractional Flow Reserve-Guided Revascularization Strategy.

OBJECTIVES: This study sought to evaluate sex differences in procedural characteristics and clinical outcomes of instantaneous wave-free ratio (iFR)- and fractional flow reserve (FFR)-guided revascularization strategies. BACKGROUND: An iFR-guided strategy has shown a lower revascularization rate than an FFR-guided strategy, without differences in clinical outcomes. METHODS: This is a post hoc analysis of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate stenosis to guide Revascularization) study, in which 601 women and 1,891 men were randomized to iFR- or FFR-guided strategy. The primary endpoint was 1-year major adverse cardiac events (MACE), a composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization. RESULTS: Among the entire population, women had a lower number of functionally significant lesions per patient (0.31 ± 0.51 vs. 0.43 ± 0.59; p < 0.001) and less frequently underwent revascularization than men (42.1% vs. 53.1%; p < 0.001). There was no difference in mean iFR value according to sex (0.91 ± 0.09 vs. 0.91 ± 0.10; p = 0.442). However, the mean FFR value was lower in men than in women (0.83 ± 0.09 vs. 0.85 ± 0.10; p = 0.001). In men, an FFR-guided strategy was associated with a higher rate of revascularization than an iFR-guided strategy (57.1% vs. 49.3%; p = 0.001), but this difference was not observed in women (41.4% vs. 42.6%; p = 0.757). There was no difference in MACE rates between iFR- and FFR-guided strategies in both women (5.4% vs. 5.6%, adjusted hazard ratio: 1.10; 95% confidence interval: 0.50 to 2.43; p = 0.805) and men (6.6% vs. 7.0%, adjusted hazard ratio: 0.98; 95% confidence interval: 0.66 to 1.46; p = 0.919). CONCLUSIONS: An FFR-guided strategy was associated with a higher rate of revascularization than iFR-guided strategy in men, but not in women. However, iFR- and FFR-guided strategies showed comparable clinical outcomes, regardless of sex. (Functional Lesion Assessment of Intermediate Stenosis to guide Revascularization [DEFINE-FLAIR]; NCT02053038).

Multidisciplinary transcatheter aortic valve replacement heart team programme improves mortality in aortic stenosis.

Objectives: To analyse the effect of the implementation of a transcatheter aortic valve replacement (TAVR) and multidisciplinary heart team programme on mortality in severe aortic stenosis (AS). Methods: A retrospective, observational cohort study was performed using the echocardiography, cardiothoracic surgery and TAVR databases between 1 January 2006 and 31 December 2016. Outcomes were compared between the pre- and post-TAVR programme eras in a tertiary referral centre providing transcatheter and surgical interventions for AS.All-cause mortality within 5 years from diagnosis was determined for 3399 patients with echocardiographically defined severe AS. Results: Of 3399 patients, there were 210 deaths (6.2%) at 30 days and 1614 deaths (47.5%) at 5 years.Overall, patients diagnosed in the post-TAVR programme era were older, with a lower ejection fraction and more severe AS, but were less comorbid.Among 705 patients undergoing intervention, those in the post-TAVR programme era were older, with a lower ejection fraction and more severe AS but no significant differences in comorbidities.Using an inverse probability weighted cohort and a Cox proportional hazards model, a significant mortality benefit was noted between eras alone (HR=0.86, 95% CI 0.77 to 0.97, p=0.015). When matching for age, comorbidities and valve severity, this benefit was more evident (HR=0.82, 95% CI 0.73 to 0.92, p=0.001).After adjusting for the presence of aortic valve intervention, a significant benefit persisted (HR=0.84, 95% CI 0.75 to 0.95, p=0.005). Conclusion: The implementation of a TAVR programme is associated with a mortality benefit in the population with severe AS, independent of the expansion of access to intervention.

Comparison of Major Adverse Cardiac Events Between Instantaneous Wave-Free Ratio and Fractional Flow Reserve-Guided Strategy in Patients With or Without Type 2 Diabetes: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Invasive physiologic indices such as fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are used in clinical practice. Nevertheless, comparative prognostic outcomes of iFR-guided and FFR-guided treatment in patients with type 2 diabetes have not yet been fully investigated. Objective: To compare 1-year clinical outcomes of iFR-guided or FFR-guided treatment in patients with and without diabetes in the Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularization (DEFINE-FLAIR) trial. Design, Setting, and Participants: The DEFINE-FLAIR trial is a multicenter, international, randomized, double-blinded trial that randomly assigned 2492 patients in a 1:1 ratio to undergo either iFR-guided or FFR-guided coronary revascularization. Patients were eligible for trial inclusion if they had intermediate coronary artery disease (40%-70% diameter stenosis) in at least 1 native coronary artery. Data were analyzed between January 2014 and December 2015. Interventions: According to the study protocol, iFR of 0.89 or less and FFR of 0.80 or less were used as criteria for revascularization. When iFR or FFR was higher than the prespecified threshold, revascularization was deferred. Main Outcomes and Measures: The primary end point was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. The incidence of MACE was compared according to the presence of diabetes in iFR-guided and FFR-guided groups. Results: Among the total trial population (2492 patients), 758 patients (30.4%) had diabetes. Mean age of the patients was 66 years, 76% were men (1868 of 2465), and 80% of patients presented with stable angina (1983 of 2465). In the nondiabetes population (68.5%; 1707 patients), iFR guidance was associated with a significantly higher rate of deferral of revascularization than the FFR-guided group (56.5% [n = 477 of 844] vs 46.6% [n = 402 of 863]; P < .001). However, it was not different between the 2 groups in the diabetes population (42.1% [n = 161 of 382] vs 47.1% [n = 177 of 376]; P = .15). At 1 year, the diabetes population showed a significantly higher rate of MACE than the nondiabetes population (8.6% vs 5.6%; adjusted hazard ratio [HR], 1.88; 95% CI, 1.28-2.64; P < .001). However, there was no significant difference in MACE rates between iFR-guided and FFR-guided groups in both the diabetes (10.0% vs 7.2%; adjusted HR, 1.33; 95% CI, 0.78-2.25; P = .30) and nondiabetes population (4.7% vs 6.4%; HR, 0.83; 95% CI, 0.51-1.35; P = .45) (interaction P = .25). Conclusions and Relevance: The diabetes population showed significantly higher risk of MACE than the nondiabetes population, even with the iFR-guided or FFR-guided treatment. The iFR-guided and FFR-guided treatment showed comparable risk of MACE and provided equal safety in selecting revascularization target among patients with diabetes. Trial Registration: ClinicalTrials.gov identifier: NCT02053038.

Safety of the Deferral of Coronary Revascularization on the Basis of Instantaneous Wave-Free Ratio and Fractional Flow Reserve Measurements in Stable Coronary Artery Disease and Acute Coronary Syndromes.

OBJECTIVES: The aim of this study was to investigate the clinical outcomes of patients deferred from coronary revascularization on the basis of instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements in stable angina pectoris (SAP) and acute coronary syndromes (ACS). BACKGROUND: Assessment of coronary stenosis severity with pressure guidewires is recommended to determine the need for myocardial revascularization. METHODS: The safety of deferral of coronary revascularization in the pooled per-protocol population (n = 4,486) of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trials was investigated. Patients were stratified according to revascularization decision making on the basis of iFR or FFR and to clinical presentation (SAP or ACS). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. RESULTS: Coronary revascularization was deferred in 2,130 patients. Deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group (p < 0.01). At 1 year, the MACE rate in the deferred population was similar between the iFR and FFR groups (4.12% vs. 4.05%; fully adjusted hazard ratio: 1.13; 95% confidence interval: 0.72 to 1.79; p = 0.60). A clinical presentation with ACS was associated with a higher MACE rate compared with SAP in deferred patients (5.91% vs. 3.64% in ACS and SAP, respectively; fully adjusted hazard ratio: 0.61 in favor of SAP; 95% confidence interval: 0.38 to 0.99; p = 0.04). CONCLUSIONS: Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year.

Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI.

BACKGROUND: Coronary revascularization guided by fractional flow reserve (FFR) is associated with better patient outcomes after the procedure than revascularization guided by angiography alone. It is unknown whether the instantaneous wave-free ratio (iFR), an alternative measure that does not require the administration of adenosine, will offer benefits similar to those of FFR. METHODS: We randomly assigned 2492 patients with coronary artery disease, in a 1:1 ratio, to undergo either iFR-guided or FFR-guided coronary revascularization. The primary end point was the 1-year risk of major adverse cardiac events, which were a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization. The trial was designed to show the noninferiority of iFR to FFR, with a margin of 3.4 percentage points for the difference in risk. RESULTS: At 1 year, the primary end point had occurred in 78 of 1148 patients (6.8%) in the iFR group and in 83 of 1182 patients (7.0%) in the FFR group (difference in risk, -0.2 percentage points; 95% confidence interval [CI], -2.3 to 1.8; P<0.001 for noninferiority; hazard ratio, 0.95; 95% CI, 0.68 to 1.33; P=0.78). The risk of each component of the primary end point and of death from cardiovascular or noncardiovascular causes did not differ significantly between the groups. The number of patients who had adverse procedural symptoms and clinical signs was significantly lower in the iFR group than in the FFR group (39 patients [3.1%] vs. 385 patients [30.8%], P<0.001), and the median procedural time was significantly shorter (40.5 minutes vs. 45.0 minutes, P=0.001). CONCLUSIONS: Coronary revascularization guided by iFR was noninferior to revascularization guided by FFR with respect to the risk of major adverse cardiac events at 1 year. The rate of adverse procedural signs and symptoms was lower and the procedural time was shorter with iFR than with FFR. (Funded by Philips Volcano; DEFINE-FLAIR ClinicalTrials.gov number, NCT02053038 .).

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial.

IMPORTANCE: Muscle-related statin intolerance is reported by 5% to 20% of patients. OBJECTIVE: To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. DESIGN, SETTING, AND PARTICIPANTS: Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. INTERVENTIONS: Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). MAIN OUTCOME AND MEASURES: Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. RESULTS: Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7% (95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5% (95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8 mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). CONCLUSIONS AND RELEVANCE: Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01984424.

Correlation of concentrations of high-sensitivity troponin T and high-sensitivity C-reactive protein with plaque progression as measured by CT coronary angiography.

BACKGROUND: Elevated levels of inflammatory biomarkers are associated with increased cardiovascular morbidity and mortality. OBJECTIVE: We sought to determine whether elevated concentrations of high-sensitivity troponin T (hs-TnT) and high-sensitivity C-reactive protein (hs-CRP) predict progression of coronary artery disease (CAD) as determined by coronary CT angiography (coronary CTA). METHODS: Patients presenting to the emergency department with acute chest pain who initially showed no evidence of an acute coronary syndrome underwent baseline and follow-up coronary CTA (median follow-up, 23.9 months) using identical acquisition and reconstruction parameters. Coronary CTA data of each major coronary artery were co-registered. Cross-sections were assessed for the presence of calcified and noncalcified plaques. Progression of atherosclerotic plaque and change of plaque composition from noncalcified to calcified plaque was evaluated and correlated to levels of hs-TnT and hs-CRP at the time of the baseline CT. RESULTS: Fifty-four patients (mean age, 54.1 years; 59% male) were included, and 6775 cross-sections were compared. CAD was detected in 12.2 ± 21.2 cross-sections per patient at baseline. Prevalence of calcified plaque increased by 1.5 ± 2.4 slices per patient (P < .0001) over the follow-up period. On average, 1.6 ± 3.6 slices with new noncalcified plaque were found per patient (P < .0001) and 0.7 ± 1.7 slices with pre-existing noncalcified plaque had progressed to calcified plaque (P < .0001). After multivariate adjustment, change of overall CAD burden was predicted by baseline hs-TnT and hs-CRP (r = 0.29; P = .039 and r = 0.40; P = .004). Change of plaque composition was associated with baseline hs-TnT (r = 0.29; P = .03). CONCLUSION: Concentrations of hs-TnT and hs-CRP are weakly associated with a significant increase in CAD burden and change in plaque composition over 24 months independent of baseline risk factors.

Computed tomography stress myocardial perfusion imaging in patients considered for revascularization: a comparison with fractional flow reserve.

AIMS: Adenosine stress computed tomography myocardial perfusion imaging (CTP) is an emerging non-invasive method for detecting myocardial ischaemia. Its value when compared with fractional flow reserve (FFR), a highly accurate index of ischaemia, is unknown. Our aim was to determine the diagnostic accuracy of CTP and its incremental value when used with computed tomography coronary angiography (CTA) for detecting ischaemia compared with FFR. METHODS AND RESULTS: Forty-two patients (126 vessel territories), who had at least one ≥50% angiographic stenosis on invasive angiography considered for non-urgent revascularization, were included and underwent FFR and CT assessment, including CTP, delayed contrast enhancement scan and CTA all acquired using 320-detector row CT, and prospective ECG gating. Fractional flow reserve was determined in 86 territories subtended by vessels with ≥50% stenosis upon visual assessment. Fractional flow reserve ≤0.8 was considered to indicate significant ischaemia. Computed tomography myocardial perfusion imaging correctly identified 31/41 (76%) ischaemic territories and 38/45 (84%) non-ischaemic territories. Per-vessel territory sensitivity, specificity, positive, and negative predictive values of CTP were 76, 84, 82, and 79%, respectively. The combination of a ≥50% stenosis on CTA and perfusion defect on CTP was 98% specific for ischaemia, while the presence of <50% stenosis on CTA and normal perfusion on CTP was 100% specific for exclusion of ischaemia. Mean radiation for CTP and combined CT was 5.3 and 11.3 mSv, respectively. CONCLUSION: Computed tomography myocardial perfusion imaging is moderately accurate in identifying perfusion defects associated with ischaemia as assessed by FFR in patients considered for revascularization. In territories, where CTA and CTP are concordant, CTA/CTP is highly accurate in the detection and exclusion of ischaemia. This is achievable with acceptable radiation exposure using 320-detector row CT and prospective ECG gating.

Prognostic value of CT angiography for major adverse cardiac events in patients with acute chest pain from the emergency department: 2-year outcomes of the ROMICAT trial.

OBJECTIVES: The aim of this study was to determine the 2-year prognostic value of cardiac computed tomography (CT) for predicting major adverse cardiac events (MACE) in patients presenting to the emergency department (ED) with acute chest pain. BACKGROUND: CT has high potential for early triage of acute chest pain patients. However, there is a paucity of data regarding the prognostic value of CT in this ED cohort. METHODS: We followed 368 patients from the ROMICAT (Rule Out Myocardial Infarction Using Computer Assisted Tomography) trial (age 53 ± 12 years; 61% male) who presented to the ED with acute chest pain, negative initial troponin, and a nonischemic electrocardiogram for 2 years. Contrast-enhanced 64-slice CT was obtained during index hospitalization, and caregivers and patients remained blinded to the results. CT was assessed for the presence of plaque, stenosis (>50% luminal narrowing), and left ventricular regional wall motion abnormalities (RWMA). The primary endpoint was MACE, defined as composite cardiac death, nonfatal myocardial infarction, or coronary revascularization. RESULTS: Follow-up was completed in 333 patients (90.5%) with a median follow-up period of 23 months. At the end of the follow-up period, 25 patients (6.8%) experienced 35 MACE (no cardiac deaths, 12 myocardial infarctions, and 23 revascularizations). Cumulative probability of 2-year MACE increased across CT strata for coronary artery disease (CAD) (no CAD 0%; nonobstructive CAD 4.6%; obstructive CAD 30.3%; log-rank p < 0.0001) and across combined CT strata for CAD and RWMA (no stenosis or RWMA 0.9%; 1 feature-either RWMA [15.0%] or stenosis [10.1%], both stenosis and RWMA 62.4%; log-rank p < 0.0001). The c statistic for predicting MACE was 0.61 for clinical Thrombolysis In Myocardial Infarction risk score and improved to 0.84 by adding CT CAD data and improved further to 0.91 by adding RWMA (both p < 0.0001). CONCLUSIONS: CT coronary and functional features predict MACE and have incremental prognostic value beyond clinical risk score in ED patients with acute chest pain. The absence of CAD on CT provides a 2-year MACE-free warranty period, whereas coronary stenosis with RWMA is associated with the highest risk of MACE.

Diagnostic accuracy of noninvasive coronary angiography with 320-detector row computed tomography.

We sought to evaluate the diagnostic accuracy of noninvasive coronary angiography using 320-detector row computed tomography, which provides 16-cm craniocaudal coverage in 350 ms and can image the entire coronary tree in a single heartbeat, representing a significant advance from previous-generation scanners. We evaluated 63 consecutive patients who underwent 320-detector row computed tomography and invasive coronary angiography for the investigation of suspected coronary artery disease. Patients with known coronary artery disease were excluded. Computed tomographic (CT) studies were assessed by 2 independent observers blinded to results of invasive coronary angiography. A single observer unaware of CT results assessed invasive coronary angiographic images quantitatively. All available coronary segments were included in the analysis, regardless of size or image quality. Lesions with >50% diameter stenoses were considered significant. Mean heart rate was 63 ± 7 beats/min, with 6 patients (10%) in atrial fibrillation during image acquisition. Thirty-three patients (52%) and 70 of 973 segments (7%) had significant coronary stenoses on invasive coronary angiogram. Seventeen segments (2%) were nondiagnostic on computed tomogram and were assumed to contain significant stenoses on an "intention-to-diagnose" analysis. Sensitivity, specificity, and positive and negative predictive values of computed tomography for detecting significant stenoses were 94%, 87%, 88%, and 93%, respectively, by patient (n = 63), 89%, 95%, 82%, and 97%, respectively, by artery (n = 260), and 87%, 97%, 73%, and 99%, respectively, by segment (n = 973). In conclusion, noninvasive 320-detector row CT coronary angiography provides high diagnostic accuracy across all coronary segments, regardless of size, cardiac rhythm, or image quality.

Periaortic fat deposition is associated with peripheral arterial disease: the Framingham heart study.

BACKGROUND: Central obesity is associated with peripheral arterial disease, suggesting that ectopic fat depots may be associated with localized diseases of the aorta and lower-extremity arteries. We hypothesized that persons with greater amounts of periaortic fat are more likely to have clinical PAD and a low ankle-brachial index. METHODS AND RESULTS: We quantified periaortic fat surrounding the thoracic aorta using a novel volumetric quantitative approach in 1205 participants from the Framingham Heart Study Offspring cohort (mean age, 65.9 years; women, 54%); visceral abdominal fat also was measured. Clinical peripheral arterial disease was defined as a history of intermittent claudication, and ankle-brachial index was dichotomized as low ( ≤ 0.9) or lower-extremity revascularization versus normal (> 0.9 to < 1.4). Regression models were created to examine the association between periaortic fat and intermittent claudication or low ankle-brachial index (n = 66). In multivariable logistic regression, per 1 SD increase in periaortic fat, the odds ratio for the combined end point was 1.52 (P = 0.004); these results were strengthened with additional adjustment for body mass index (odds ratio, 1.69; P = 0.002) or visceral abdominal fat (odds ratio, 1.67; P = 0.009), whereas no association was observed for visceral abdominal fat (P = 0.16). Similarly, per SD increase in body mass index or waist circumference, no association was observed after accounting for visceral abdominal fat (body mass index, P = 0.35; waist circumference, P=0.49). CONCLUSIONS: Periaortic fat is associated with low ABI and intermittent claudication.

Peri-aortic fat, cardiovascular disease risk factors, and aortic calcification: the Framingham Heart Study.

OBJECTIVE: Perivascular fat through the secretion of paracrine and pro-inflammatory mediators may play a role in obesity-mediated vascular disease. We sought to examine associations between adipose tissue depots immediately surrounding the thoracic aorta, metabolic risk factors, and vascular calcification. METHODS: In participants free of cardiovascular disease (CVD) from the Framingham Heart Study Offspring cohort who underwent computed tomography (n=1067, mean age 59 years, 56.1% women), thoracic peri-aortic fat depots were quantified. Visceral abdominal tissue (VAT) and calcification of the thoracic and abdominal aorta were also measured. RESULTS: Peri-aortic fat depots were correlated with body mass index, waist circumference (WC), VAT (all p<0.0001), hypertension (p=0.007), low HDL (p<0.0001), serum triglycerides (p<0.0001), impaired fasting glucose (p=0.005), and diabetes (p=0.02). These associations generally remained significant after adjustment for BMI and WC (all p-values<0.05), but not after VAT adjustment. Thoracic aortic fat was associated with thoracic calcification in models containing VAT (OR 1.31, 95% CI 1.01-1.71, p=0.04), but was not significant after adjustment for CVD risk factors (OR 1.16, 95% CI 0.88-1.51, p=0.30). Thoracic aortic fat, however, was associated with abdominal aortic calcification (OR 1.48, 95% CI 1.11-1.98, p=0.008) and coronary artery calcification (OR 1.47, 95% CI 1.09-1.98, p=0.001) even in models including CVD risk factors and VAT. CONCLUSIONS: Thoracic peri-aortic fat is associated with measures of adiposity, metabolic risk factors, and coronary and abdominal aortic calcification.

Diagnostic accuracy of 64-slice multidetector CT for detection of in-stent restenosis in an unselected, consecutive patient population.

OBJECTIVES: To investigate the diagnostic accuracy of 64-slice multidetector computed tomography (64-CT) for detection of in-stent restenosis (ISR) in an unselected, consecutive patient population. BACKGROUND: Detection of in-stent restenosis by cardiac CT would be a major advance for the evaluation of patients suspected of having ISR. However, the diagnostic accuracy of current generation 64-CT in this context is not fully established. METHODS: We conducted a prospective study on patients with stable angina or acute coronary syndrome with no prior history of coronary artery disease. Six months after percutaneous coronary intervention (PCI) with stent placement they underwent a 64-CT scan (Toshiba Multi-Slice Aquilion 64) and consequently a repeat coronary angiography for comparison. Cardiac CT data sets were analyzed for the presence of in-stent restenosis by two independent expert readers blinded to the coronary angiographic data. RESULTS: Ninety-three patients with a total of 140 stents were evaluated. Males comprised 82% of the study group and the mean age was 63±10 years. The mean time from PCI to the repeat coronary angiography was 208±37 days and the mean time from 64-CT to repeat coronary angiography was 3.7±4.9 days. The restenosis rate according to coronary angiography was 26%. Stent diameter, strut thickness, heart rate and body mass index (BMI) significantly affected image quality. The sensitivity, specificity, positive and negative predictive values of 64-CT for detection of in-stent restenosis were 27%, 95%, 67% and 78%, respectively. CONCLUSIONS: Current generation, 64-slice CT, remains limited in its ability to accurately detect in-stent restenosis.

Assessment of coronary plaque progression in coronary computed tomography angiography using a semiquantitative score.

OBJECTIVES: We sought to describe the progression of coronary atherosclerotic plaque over time by computed tomography (CT) angiography stratified by plaque composition and its association with cardiovascular risk profiles. BACKGROUND: Data on the progression of atherosclerosis stratified by plaque composition with the use of noninvasive assessment by CT are limited and hampered by high measurement variability. METHODS: This analysis included patients who presented with acute chest pain to the emergency department but initially showed no evidence of acute coronary syndromes. All patients underwent contrast-enhanced 64-slice CT at baseline and after 2 years with the use of a similar protocol. CT datasets were coregistered and assessed for the presence of calcified and noncalcified plaque at 1 mm cross sections of the proximal 40 mm of each major coronary artery. Plaque progression over time and its association with risk factors were determined. Measurement reproducibility and correlation to plaque volume was performed in a subset of patients. RESULTS: We included 69 patients (mean age 55 +/- 12 years, 59% male patients) and compared 8,311 coregistered cross sections at baseline and follow-up. At baseline, any plaque, calcified plaque, and noncalcified were detected in 12.5%, 10.1%, and 2.4% of cross sections per patient, respectively. There was significant progression in the mean number of cross sections containing any plaque (16.5 +/- 25.3 vs. 18.6 +/- 25.5, p = 0.01) and noncalcified plaque (3.1 +/- 5.8 vs. 4.4 +/- 7.0, p = 0.04) but not calcified plaque (13.3 +/- 23.1 vs. 14.2 +/- 22.0, p = 0.2). In longitudinal regression analysis, the presence of baseline plaque, number of cardiovascular risk factors, and smoking were independently associated with plaque progression after adjustment for age, sex, and follow-up time interval. The semiquantitative score based on cross sections correlated closely with plaque volume progression (r = 0.75, p < 0.0001) and demonstrated an excellent intraobserver and interobserver agreement (kappa = 0.95 and kappa = 0.93, respectively). CONCLUSIONS: Coronary plaque burden of patients with acute chest pain significantly increases during the course of 2 years. Progression over time is dependent on plaque composition and cardiovascular risk profile. Larger studies are needed to confirm these results and to determine the effect of medical treatment on progression.