Could Computed Tomography Coronary Angiography Replace Invasive Coronary Angiography as a First-Line Diagnostic Investigation in Suspected Acute Coronary Syndromes? A Decision-Analytic Model.

BACKGROUND: The implementation of high-sensitivity cardiac troponin (hs-cTn) assays into clinical practice has resulted in the identification of a novel cohort of patients with modestly increased troponin concentrations. Subsequent increases in rates of coronary angiography have been observed, without significant increases in rates of coronary revascularisation. Computed tomography coronary angiography (CTCA) is a non-invasive investigation that offers the opportunity to decouple investigation from the impetus to revascularise, and may provide an alternative, more risk-appropriate initial investigative strategy for the cohort with low to moderate hs-cTn increases. This analysis seeks to define the threshold of pre-test probability of coronary revascularisation in patients with suspected acute coronary syndrome at which a strategy of initial CTCA is safe and a more cost-effective approach than standard invasive coronary angiography (ICA). METHODS: A cost-benefit evaluation was conducted using a decision-analytic model. The primary outcome measure was the incremental cost-effectiveness ratio (ICER) of CTCA in comparison with ICA as an initial diagnostic investigation for patients with hs-cTnT levels between 5 and 100 ng/L. Secondary outcome measures of costs, patient outcomes, and quality-adjusted life years were analysed. RESULTS: Median base case ICER over 1,000 trials was $17,163 AUD but demonstrated large variability. Sensitivity analysis demonstrated that CTCA was cost-effective until the probability of requiring revascularisation was ∼60%, beyond which point CTCA was associated with higher costs and poorer outcomes than ICA. CONCLUSIONS: Computed tomography coronary angiography may be a cost-effective first-line investigation for patients with moderate hs-cTnT rises until/up to a 60% pre-test probability for receiving coronary revascularisation. To objectively assess the optimal circumstances of cost-effectiveness, prospective evaluation incorporating the estimated probability of revascularisation will be required.

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.

Contrasting the potential benefits of early invasive coronary angiography in acute and chronic myocardial injury patterns.

BACKGROUND: In cases of evolving myocardial injury not definitively attributed to coronary ischaemia precipitated by plaque rupture, referral for invasive coronary angiography (ICA) may be influenced by observed troponin profiles. We sought to explore association between early ICA and elevated high-sensitivity troponin T (hs-cTnT) concentrations with and without dynamic changes, to examine if there may be a hs-cTnT threshold associated with benefit from an initial ICA strategy. METHODS: Using published studies (hs-cTnT study n = 1937, RAPID-TnT study n = 3270) and the Fourth Universal Definition of Myocardial Infarction (MI), index presentations of patients with hs-cTnT concentrations 5-14ng/L were classified as 'non-elevated' (NE). Hs-cTnT greater than upper reference limit (14ng/L) were classified as 'elevated hs-cTnT with dynamic change' (encompassing acute myocardial injury, Type 1 MI, and Type 2 MI), or 'non-dynamic hs-cTnT elevation' (chronic myocardial injury). Patients with hs-cTnT <5ng/L and/or eGFR<15mmol/L/1.73m2 were excluded. ICA was performed within 30 days of admission. Primary outcome was defined as composite endpoint of death, MI, or unstable angina at 12 months. RESULTS: Altogether, 3620 patients comprising 837 (23.1%) with non-dynamic hs-cTnT elevations and 332 (9.2%) with dynamic hs-cTnT elevations were included. Primary outcome was significantly higher with dynamic and non-dynamic hs-cTnT elevations (Dynamic: HR: 4.13 95%CI:2.92-5.82; p<0.001 Non-dynamic: HR: 2.39 95% confidence interval [CI]:1.74-3.28, p<0.001). Hs-cTnT thresholds where benefit from initial ICA strategy appeared to emerge was observed at 110ng/L and 50ng/L in dynamic and non-dynamic elevations, respectively. CONCLUSION: Early ICA appears to portend benefit in hs-cTnT elevations with and without dynamic changes, and at lower hs-cTnT threshold in non-dynamic hs-cTnT elevation. Differences compel further investigation.

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.

Troponin elevation pattern and subsequent cardiac and non-cardiac outcomes: Implementing the Fourth Universal Definition of Myocardial Infarction and high-sensitivity troponin at a population level.

BACKGROUND: The Fourth Universal Definition of Myocardial Infarction (MI) differentiates MI from myocardial injury. We characterised the temporal course of cardiac and non-cardiac outcomes associated with MI, acute and chronic myocardial injury. METHODS: We included all patients presenting to public emergency departments in South Australia between June 2011-Sept 2019. Episodes of care (EOCs) were classified into 5 groups based on high-sensitivity troponin-T (hs-cTnT) and diagnostic codes: 1) Acute MI [rise/fall in hs-cTnT and primary diagnosis of acute coronary syndrome], 2) Acute myocardial injury with coronary artery disease (CAD) [rise/fall in hs-cTnT and diagnosis of CAD], 3) Acute myocardial injury without CAD [rise/fall in hs-cTnT without diagnosis of CAD], 4) Chronic myocardial injury [elevated hs-cTnT without rise/fall], and 5) No myocardial injury. Multivariable flexible parametric models were used to characterize the temporal hazard of death, MI, heart failure (HF), and ventricular arrhythmia. RESULTS: 372,310 EOCs (218,878 individuals) were included: acute MI (19,052 [5.12%]), acute myocardial injury with CAD (6,928 [1.86%]), acute myocardial injury without CAD (32,231 [8.66%]), chronic myocardial injury (55,056 [14.79%]), and no myocardial injury (259,043 [69.58%]). We observed an early hazard of MI and HF after acute MI and acute myocardial injury with CAD. In contrast, subsequent MI risk was lower and more constant in patients with acute injury without CAD or chronic injury. All patterns of myocardial injury were associated with significantly higher risk of all-cause mortality and ventricular arrhythmia. CONCLUSIONS: Different patterns of myocardial injury were associated with divergent profiles of subsequent cardiac and non-cardiac risk. The therapeutic approach and modifiability of such excess risks require further research.

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.

High-sensitivity troponin in chronic kidney disease: Considerations in myocardial infarction and beyond.

Acute myocardial infarction (MI) represents one of the most common hospital encounters, with significant short-term and long-term morbidity and mortality, and frequently occurs in patients with chronic kidney disease (CKD). Cardiac troponin is an exquisitely sensitive biomarker for myocardial injury and plays an essential role in the diagnosis, risk-stratification, and management of MI. In 2017, the United States Food and Drug Administration approved Roche Diagnostics' 5th generation high-sensitivity cardiac troponin (hs-cTn) for clinical use. Whilst the improved analytical sensitivity of these new high-sensitivity troponin assays facilitate early diagnosis of MI, it also frequently identifies troponin elevations above the conventional reference threshold in the context of non-coronary conditions such as renal dysfunction, and can represent a major diagnostic challenge to clinicians. Furthermore, the optimal management strategy of patients with troponin elevation and high comorbidity burden, a common issue in patients with CKD, remains undefined. In recent years, there has been substantial research and progress undertaken in this rapidly evolving area. In this review, we aim to provide clinicians with an overview of hs-cTn in the setting of CKD as well as an update on its application and the particular considerations involved in the management of myocardial infarction, stable coronary artery disease and myocardial injury in this high risk population.

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.

Clinical Events After Deferral of LAD Revascularization Following Physiological Coronary Assessment.

BACKGROUND: Physicians are not always comfortable deferring treatment of a stenosis in the left anterior descending (LAD) artery because of the perception that there is a high risk of major adverse cardiac events (MACE). The authors describe, using the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) trial, MACE rates when LAD lesions are deferred, guided by physiological assessment using fractional flow reserve (FFR) or the instantaneous wave-free ratio (iFR). OBJECTIVES: The purpose of this study was to establish the safety of deferring treatment in the LAD using FFR or iFR within the DEFINE-FLAIR trial. METHODS: MACE rates at 1 year were compared between groups (iFR and FFR) in patients whose physiological assessment led to LAD lesions being deferred. MACE was defined as a composite of cardiovascular death, myocardial infarction (MI), and unplanned revascularization at 1 year. Patients, and staff performing follow-up, were blinded to whether the decision was made with FFR or iFR. Outcomes were adjusted for age and sex. RESULTS: A total of 872 patients had lesions deferred in the LAD (421 guided by FFR, 451 guided by iFR). The event rate with iFR was significantly lower than with FFR (2.44% vs. 5.26%; adjusted HR: 0.46; 95% confidence interval [CI]: 0.22 to 0.95; p = 0.04). This was driven by significantly lower unplanned revascularization with iFR and numerically lower MI (unplanned revascularization: 2.22% iFR vs. 4.99% FFR; adjusted HR: 0.44; 95% CI: 0.21 to 0.93; p = 0.03; MI: 0.44% iFR vs. 2.14% FFR; adjusted HR: 0.23; 95% CI: 0.05 to 1.07; p = 0.06). CONCLUSIONS: iFR-guided deferral appears to be safe for patients with LAD lesions. Patients in whom iFR-guided deferral was performed had statistically significantly lower event rates than those with FFR-guided deferral.

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.