Effect of Transcatheter Aortic Valve Implantation vs Surgical Aortic Valve Replacement on All-Cause Mortality in Patients With Aortic Stenosis: A Randomized Clinical Trial.

Importance: Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to surgical aortic valve replacement and is the treatment of choice for patients at high operative risk. The role of TAVI in patients at lower risk is unclear. Objective: To determine whether TAVI is noninferior to surgery in patients at moderately increased operative risk. Design, Setting, and Participants: In this randomized clinical trial conducted at 34 UK centers, 913 patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk due to age or comorbidity were enrolled between April 2014 and April 2018 and followed up through April 2019. Interventions: TAVI using any valve with a CE mark (indicating conformity of the valve with all legal and safety requirements for sale throughout the European Economic Area) and any access route (n = 458) or surgical aortic valve replacement (surgery; n = 455). Main Outcomes and Measures: The primary outcome was all-cause mortality at 1 year. The primary hypothesis was that TAVI was noninferior to surgery, with a noninferiority margin of 5% for the upper limit of the 1-sided 97.5% CI for the absolute between-group difference in mortality. There were 36 secondary outcomes (30 reported herein), including duration of hospital stay, major bleeding events, vascular complications, conduction disturbance requiring pacemaker implantation, and aortic regurgitation. Results: Among 913 patients randomized (median age, 81 years [IQR, 78 to 84 years]; 424 [46%] were female; median Society of Thoracic Surgeons mortality risk score, 2.6% [IQR, 2.0% to 3.4%]), 912 (99.9%) completed follow-up and were included in the noninferiority analysis. At 1 year, there were 21 deaths (4.6%) in the TAVI group and 30 deaths (6.6%) in the surgery group, with an adjusted absolute risk difference of -2.0% (1-sided 97.5% CI, -∞ to 1.2%; P < .001 for noninferiority). Of 30 prespecified secondary outcomes reported herein, 24 showed no significant difference at 1 year. TAVI was associated with significantly shorter postprocedural hospitalization (median of 3 days [IQR, 2 to 5 days] vs 8 days [IQR, 6 to 13 days] in the surgery group). At 1 year, there were significantly fewer major bleeding events after TAVI compared with surgery (7.2% vs 20.2%, respectively; adjusted hazard ratio [HR], 0.33 [95% CI, 0.24 to 0.45]) but significantly more vascular complications (10.3% vs 2.4%; adjusted HR, 4.42 [95% CI, 2.54 to 7.71]), conduction disturbances requiring pacemaker implantation (14.2% vs 7.3%; adjusted HR, 2.05 [95% CI, 1.43 to 2.94]), and mild (38.3% vs 11.7%) or moderate (2.3% vs 0.6%) aortic regurgitation (adjusted odds ratio for mild, moderate, or severe [no instance of severe reported] aortic regurgitation combined vs none, 4.89 [95% CI, 3.08 to 7.75]). Conclusions and Relevance: Among patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk, TAVI was noninferior to surgery with respect to all-cause mortality at 1 year. Trial Registration: isrctn.com Identifier: ISRCTN57819173.

Prevalence and Prognostic Significance of Right Ventricular Systolic Dysfunction in Patients Undergoing Transcatheter Aortic Valve Implantation.

BACKGROUND: Cardiovascular magnetic resonance (CMR) can provide important structural information in patients undergoing transcatheter aortic valve implantation. Although CMR is considered the standard of reference for measuring ventricular volumes and mass, the relationship between CMR findings of right ventricular (RV) function and outcomes after transcatheter aortic valve implantation has not previously been reported. METHODS AND RESULTS: A total of 190 patients underwent 1.5 Tesla CMR before transcatheter aortic valve implantation. Steady-state free precession sequences were used for aortic valve planimetry and to assess ventricular volumes and mass. Semiautomated image analysis was performed by 2 specialist reviewers blinded to patient treatment. Patient follow-up was obtained from the Office of National Statistics mortality database. The median age was 81.0 (interquartile range, 74.9-85.5) years; 50.0% were women. Impaired RV function (RV ejection fraction ≤50%) was present in 45 (23.7%) patients. Patients with RV dysfunction had poorer left ventricular ejection fractions (42% versus 69%), higher indexed left ventricular end-systolic volumes (96 versus 40 mL), and greater indexed left ventricular mass (101 versus 85 g/m(2); P<0.01 for all) than those with normal RV function. Median follow-up was 850 days; 21 of 45 (46.7%) patients with RV dysfunction died, compared with 43 of 145 (29.7%) patients with normal RV function (P=0.035). After adjustment for significant baseline variables, both RV ejection fraction ≤50% (hazard ratio, 2.12; P=0.017) and indexed aortic valve area (hazard ratio, 4.16; P=0.025) were independently associated with survival. CONCLUSIONS: RV function, measured on preprocedural CMR, is an independent predictor of mortality after transcatheter aortic valve implantation. CMR assessment of RV function may be important in the risk stratification of patients undergoing transcatheter aortic valve implantation.

Management of concomitant coronary artery disease in patients undergoing transcatheter aortic valve implantation: the United Kingdom TAVI Registry.

BACKGROUND: The management and impact of concomitant coronary artery disease in patients referred for TAVI remains contentious. We describe the prevalence, clinical impact and management of coronary artery disease (CAD) in patients in the United Kingdom TAVI Registry. METHODS: All-inclusive study of patients undergoing TAVI in the United Kingdom (excluding Northern Ireland) from January 2007 to December 2011. Coronary artery disease at the time of TAVI was demonstrated on invasive angiography. RESULTS: 2588 consecutive patients were entered in the U.K. TAVI Registry. CAD was reported in 1171 pts with left main stem involvement in 12.4% of this cohort (n=145). Most patients were free of chest pain, but limited by dyspnoea (NYHA Class III & IV 81.9%). Angina was however more prevalent in those patients with CAD (p<0.0001). Hybrid PCI was uncommon, performed in only 14.7% of the CAD cohort (n=172). Survival at 30days, 1year, and 4years was 93.7%, 81.4% and 72.0% respectively. Adjusting for confounders in a multivariate model the presence and extent of CAD was not associated with early (30-days, p=0.36) or late (4years, p=0.10) survival. CONCLUSIONS: This contemporary study of coronary artery disease management in an "all-comers" patient population undergoing TAVI demonstrates that whilst often an indicator of significant underlying comorbidity coronary artery disease is not associated with decreased short or long-term survival. The majority of patients with aortic stenosis and concomitant CAD can be managed effectively by TAVI alone. However, the importance of the Heart Team in making decisions on individual patients must not be underestimated.

Clinical and economic consequences of non-cardiac incidental findings detected on cardiovascular computed tomography performed prior to transcatheter aortic valve implantation (TAVI).

Transcatheter aortic valve implantation (TAVI) is an effective treatment option for patients with severe degenerative aortic valve stenosis who are high risk for conventional surgery. Computed tomography (CT) performed prior to TAVI can detect pathologies that could influence outcomes following the procedure, however the incidence, cost, and clinical impact of incidental findings has not previously been investigated. 279 patients underwent CT; 188 subsequently had TAVI and 91 were declined. Incidental findings were classified as clinically significant (requiring treatment), indeterminate (requiring further assessment), or clinically insignificant. The primary outcome measure was all-cause mortality up to 3 years. Costs incurred by additional investigations resultant to incidental findings were estimated using the UK Department of Health Payment Tariff. Incidental findings were common in both the TAVI and medical therapy cohorts (54.8 vs. 70.3%; P = 0.014). Subsequently, 45 extra investigations were recommended for the TAVI cohort, at an overall average cost of £32.69 per TAVI patient. In a univariate model, survival was significantly associated with the presence of a clinically significant or indeterminate finding (HR 1.61; P = 0.021). However, on multivariate analysis outcomes after TAVI were not influenced by any category of incidental finding. Incidental findings are common on CT scans performed prior to TAVI. However, the total cost involved in investigating these findings is low, and incidental findings do not independently identify patients with poorer outcomes after TAVI. The discovery of an incidental finding on CT should not necessarily influence or delay the decision to perform TAVI.

Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry.

OBJECTIVES: The objective was to define the characteristics of a real-world patient population treated with transcatheter aortic valve implantation (TAVI), regardless of technology or access route, and to evaluate their clinical outcome over the mid to long term. BACKGROUND: Although a substantial body of data exists in relation to early clinical outcomes after TAVI, there are few data on outcomes beyond 1 year in any notable number of patients. METHODS: The U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry was established to report outcomes of all TAVI procedures performed within the United Kingdom. Data were collected prospectively on 870 patients undergoing 877 TAVI procedures up until December 31, 2009. Mortality tracking was achieved in 100% of patients with mortality status reported as of December 2010. RESULTS: Survival at 30 days was 92.9%, and it was 78.6% and 73.7% at 1 year and 2 years, respectively. There was a marked attrition in survival between 30 days and 1 year. In a univariate model, survival was significantly adversely affected by renal dysfunction, the presence of coronary artery disease, and a nontransfemoral approach; whereas left ventricular function (ejection fraction <30%), the presence of moderate/severe aortic regurgitation, and chronic obstructive pulmonary disease remained the only independent predictors of mortality in the multivariate model. CONCLUSIONS: Midterm to long-term survival after TAVI was encouraging in this high-risk patient population, although a substantial proportion of patients died within the first year.

Defining the appropriate CTA stenosis threshold for gatekeeping to invasive angiography: 50% or 70%?

There is currently much debate around the limited positive predictive value (PPV) of CT coronary angiography (CTA). There remain no published studies comparing different thresholds to define significant visual stenoses on CTA compared to the gold standard quantitative coronary angiography (QCA). The spatial resolution for ICA is (0.1 mm)(3) compared with (0.5 mm)(3) in clinical CTA and direct comparison introduces a systematic overestimation of stenosis severity by CTCA. Assessing both ≥ 50% and ≥ 70% visual stenoses on CTA with QCA we found that the negative predictive value (NPV) of CTA is equally high for both. The PPV of CTA improves using ≥ 70% but with a loss of sensitivity. Using ≥ 70% stenosis on CTA for referral for ICA would reduce the number of ICA that does not lead to percutaneous intervention (PCI) but a functional test for intermediate lesions (visual stenoses of 50%-69%) on CTA is recommended to overcome the reduction in sensitivity.

The role of cardiovascular magnetic resonance in patients presenting with chest pain, raised troponin, and unobstructed coronary arteries.

AIMS: Troponin measurement is used in the assessment and risk stratification of patients presenting acutely with chest pain when the main cause of elevation is coronary artery disease. However, some patients have no coronary obstruction on angiography, leading to diagnostic uncertainty. We evaluated the incremental diagnostic value of cardiovascular magnetic resonance (CMR) in these patients. METHODS AND RESULTS: Sixty consecutive patients (mean age 44 years, 72% male) with a troponin-positive episode of chest pain and unobstructed coronary arteries were recruited within 3 months of initial presentation. All patients underwent CMR with cine imaging, T2-weighted imaging for detection of inflammation, and late gadolinium enhancement imaging for detection of infarction/fibrosis. An identifiable basis for troponin elevation was established in 65% of patients. The commonest underlying cause was myocarditis (50%), followed by myocardial infarction (11.6%) and cardiomyopathy (3.4%). In the 35% of patients where no clear diagnosis was identified by CMR, significant myocardial infarction/fibrosis was excluded. CONCLUSION: CMR is a valuable adjunct to conventional investigations in a diagnostically challenging and important group of patients with troponin-positive chest pain and unobstructed coronary arteries.

64-multislice computed tomography in consecutive patients with suspected or proven coronary artery disease: initial single center experience.

BACKGROUND: The improved accuracy of 64-multislice CT (MSCT) suggests that this technique may replace other non-invasive methods to detect clinically significant coronary atherosclerosis. The aim of the present study was to assess the clinical usefulness of in consecutive patients with suspected or proven coronary artery disease (CAD). METHODS: 64-MSCT was performed in 56 patients (age 56+/-16 years, 50 male) with suspected or proven CAD (35 patients with chest pain/positive provocative tests/risk factors), 18 with documented significant CAD, CABG surgery or stent implantation, 3 non-assessable with selective angiography because of peripheral vascular disease or large aneurysms of the ascending aorta. RESULTS: One patient was excluded because of contrast extravasation. In 30/55 patients (54%) 64-MSCT excluded significant coronary stenoses; in 13/55 patients (24%) angiography and/or angioplasty were recommended to treat (3) 50% diameter stenoses shown by MSCT, a diagnosis confirmed in 9 (81.8%) of the 11 patients who underwent further investigations; 12/55 patients (22%) needed angiography or other preliminary non-invasive tests because 64-MSCT was of insufficient diagnostic quality. Predictors of a poor diagnostic quality of 64-MSCT were older age (64+/-8 vs. 55+/-11 years, p<0.007), diabetes mellitus (42% vs. 9%, p=0.017), previous angiography, angioplasty or CABG surgery (83% vs. 26%, p<0.0001), Agatston score>400 (75% vs. 21%, p<0.002). CONCLUSION: 64-MSCT provided complete diagnostic coronary images sufficient for clinical decision making in the vast majority (78%) of a consecutive group of patients studied for suspected or proven CAD. Predictors of diagnostic failure were massive calcification, long-standing known coronary atherosclerosis or previous CABG/stent implantation, old age and diabetes mellitus.

Combined coronary and perfusion cardiovascular magnetic resonance for the assessment of coronary artery stenosis.

The purpose of this study was to evaluate the feasibility and accuracy of combined coronary and perfusion cardiovascular magnetic resonance (CMR) in the assessment of coronary artery stenosis. Thirty-five consecutive patients (27 men, eight women, age range 34-81 years), undergoing cardiac catheterization, were assessed with 3D coronary CMR and rest-stress perfusion CMR. Significant coronary stenosis was determined by vessel narrowing or signal loss with coronary CMR, and by abnormal contrast enhancement with perfusion CMR. Coronary artery diameter stenosis greater than 50% was considered significant with conventional cardiac catheterization. Seventeen patients had significant coronary artery disease, and in these there were 35 significant stenoses on cardiac catheterization. All left main stem arteries were normal on both cardiac catheterization and coronary CMR. For the diagnosis of coronary artery stenosis, coronary CMR had a sensitivity of 92% for the left anterior descending artery (LAD), 79% for the right coronary artery (RCA), but only 13% for the circumflex coronary artery (LCX). Perfusion CMR had corresponding sensitivities of 69%, 86%, and 63%, respectively. For all arteries the accuracies for coronary and perfusion CMR were 67% and 72%, respectively. Combining coronary and perfusion CMR improved the accuracy to 77%. These data demonstrate that in patients with suspected coronary artery disease, combined coronary and perfusion CMR is feasible, increases the accuracy of detection of significant coronary stenosis, and offers the possibility of combined anatomical and hemodynamic assessment of coronary artery stenosis.

Two novel missense mutations in ABCA1 result in altered trafficking and cause severe autosomal recessive HDL deficiency.

Extremely low concentrations of high density lipoprotein (HDL)-cholesterol and apolipoprotein (apo) AI are features of Tangier disease caused by autosomal recessive mutations in ATP-binding cassette transporter A1 (ABCA1). Less deleterious, but dominantly inherited mutations cause HDL deficiency. We investigated causes of severe HDL deficiency in a 42-year-old female with progressive coronary disease. ApoAI-mediated efflux of cholesterol from the proband's fibroblasts was less than 10% of normal and nucleotide sequencing revealed inheritance of two novel mutations in ABCAI, V1704D and L1379F. ABCA1 mRNA was approximately 3-fold higher in the proband's cells than in control cells; preincubation with cholesterol increased it 5-fold in control and 8-fold in the proband's cells, but similar amounts of ABCA1 protein were present in control and mutant cells. When transiently transfected into HEK293 cells, confocal microscopy revealed that both mutant proteins were retained in the endoplasmic reticulum, while wild-type ABCA1 was located at the plasma membrane. Severe HDL deficiency in the proband was caused by two novel autosomal recessive mutations in ABCA1, one (V1704D) predicted to lie in a transmembrane segment and the other (L1379F) in a large extracellular loop. Both mutations prevent normal trafficking of ABCA1, thereby explaining their inability to mediate apoA1-dependent lipid efflux.

Abciximab is rapidly effective in preventing and arresting established platelet aggregation.

BACKGROUND: Abciximab reduces the thrombotic complications of angioplasty. It is also used, as a 'bail out' treatment when angioplasty is complicated by thrombus but its speed of action is not known. This study sought to establish how quickly abciximab blocks the aggregation of both quiescent and activated platelets to explain this rapid efficacy. METHODS: Optical aggregometry (OA) and whole blood electrical impedance platelet aggregometry (WBEA) were performed with blood from 10 healthy volunteers. Abciximab 5 microg/ml was added in each case with saline control 5 minutes before agonist, 10 seconds before agonist and during aggregation. RESULTS: (1) Abciximab administered 5 minutes before agonist, completely inhibited aggregation with OA: (medians and ranges) 0% (all 0), control: 71% (50-95%) p < 0.001. and with WBEA: 0 omega (all 0 omega), control: 7.5 omega (4.8-12.5 omega) p = 0.016. (2) When administered 10 s before agonist with OA a small initial degree of aggregation occurred but this was rapidly reversed (time to reversal: 2 mins (1-4.5 mins) to low levels of aggregation 16.5% (0-22%), control 72.5% (55-95%) p = 0.002. With WBEA aggregation was completely inhibited: 0 omega (all 0 omega), control: 7.5 omega (4.8-12.3 omega) p = 0.016. (3) When administered during aggregation, with OA the rise in the aggregometry tracing was rapidly arrested (time to arrest: 1.5 mins (0.1-3 mins)) with no further aggregation occurring: 42% (30-57%), control: 80% (60-100%) p = 0.002. With WBEA the findings were similar: (time to arrest 1.5 mins (1-2 mins)) 6.3 omega (1.5-11.3 omega), control: 10 omega (3-12 omega) p = 0.031. CONCLUSIONS: These data suggest that when administered during a procedure in which thrombus has occurred, aggregation may be rapidly arrested. This applies to quiescent platelets but also activated platelets undergoing aggregation.