Optimizing post-acute coronary syndrome (ACS) dyslipidemia management: Insights from the North American Acute Coronary Syndrome ACS Reflective III.

BACKGROUND: Despite contemporary practice guidelines, a substantial number of post-acute coronary syndrome (ACS) patients fail to achieve guideline-recommended LDL-C thresholds. Our study aims to objectively investigate this evidence-to-practice care gap. Specifically, we aim to identify opportunities where additional lipid-lowering therapies are indicated and explore reasons for the non-prescription of guideline-recommended therapies. METHODS: ACS patients with LDL-C ≥1.81 mmol/L (70 mg/dL) despite maximally tolerated statin ± ezetimibe therapy (including those intolerant of ≥2 statins) were enrolled 1-12 months post-event from 27 Canadian and United States (U.S.) sites from September 2018 to October 2020 and followed up for three visits during the 12 months post-event. We determined the proportion of patients who did not achieve Canadian/U.S. guideline-recommended LDL-C thresholds, the number of patients who would have been eligible for additional lipid-lowering therapies, and reasons behind lack of escalation in lipid-lowering therapies when indicated. Individual patient and aggregate practice feedback, including guideline-recommended intensification suggestions were provided to each physician. RESULTS: Of the 248 patients enrolled in the pilot study (median age 64 [57, 73] years, 31.5% ¬¬¬¬-female and STEMI 27.4%), 75.4% were on high-intensity statins on the first visit. 18.5% of those who attended all 3 visits had an LDL-C measured only at the first visit which was above the threshold. After one year of follow-up, 51.9% of patients achieved LDL-C thresholds at either visit 2 or 3. In the context of feedback reminding physicians about guideline-directed LDL-C-modifying therapy in their individual participating patients, we observed an increase in the use of ezetimibe and PCSK9 inhibitor therapy at 3-12 months. This was associated with a significant lowering of the mean LDL-C (from 2.93 mmol/L [baseline] to 2.09 mmol/L [3-6 months] to 1.87 mmol/L [6-12 months]) and a significantly greater proportion of patients (from 0% [baseline] to 38.6% [3-6 months] to 53.4% [6-12 months]) achieving guideline-recommended LDL-C thresholds. The most prevalent reasons behind the non-intensification of LDL-C lowering therapy with ezetimibe and/or PCSK9i were LDL-C levels being close to target, the pre-existing use of other lipid-lowering therapies, patient refusal, and cost. CONCLUSION: Although most patients post-ACS are on high-intensity statin therapy, almost 50% failed to achieve guideline-recommended LDL-C thresholds by 1-year follow-up. Furthermore, additional lipid-lowering therapies in this high-risk group were underprescribed, and this may be linked to several factors including potential gaps in physician knowledge, treatment inertia, patient refusal, and cost.

Contemporary use of guideline-based higher potency P2Y12 receptor inhibitor therapy in patients with moderate-to-high risk non-ST-segment elevation myocardial infarction: Results from the Canadian ACS reflective II cross-sectional study.

BACKGROUND: After myocardial infarction, guidelines recommend higher-potency P2Y12 receptor inhibitors, namely ticagrelor and prasugrel, over clopidogrel. HYPOTHESIS: We aimed to determine the contemporary use of higher-potency antiplatelet therapy in Canadian patients with non-ST-elevation myocardial infarction (NSTEMI). METHODS: A total of 684 moderate-to-high risk NSTEMI patients were enrolled in the prospective Canadian ACS Reflective II registry at 12 Canadian hospitals and three clinics in five provinces between July 2016 and May 2018. Multivariable logistic regression modeling was performed to assess factors independently associated with higher-potency P2Y12 receptor inhibitor use at discharge. RESULTS: At hospital discharge, 78.3% of patients were treated with a P2Y12 receptor inhibitor. Among patients discharged on a P2Y12 receptor inhibitor, use of higher-potency P2Y12 receptor inhibitor was 61.4%. After adjustment, treatment in-hospital with PCI (OR 4.48, 95%CI 3.34-6.03, p < .0001) was most strongly associated with higher use of higher-potency P2Y12 receptor inhibitor, while oral anticoagulant use at discharge (OR 0.03, 95%CI 0.01-0.12, p < .0001), and atrial fibrillation (OR 0.40, 95%CI 0.17-0.98, p = .046) were most strongly associated with lower use of higher-potency P2Y12 receptor inhibitor. Use of higher-potency P2Y12 receptor inhibitor varied across provinces (range, 21.6%-78.9%). DISCUSSION: In contemporary Canadian practice, approximately 60% of moderate-to-high risk NSTEMI patients discharged on a P2Y12 receptor inhibitor are treated with a higher-potency P2Y12 receptor inhibitor. In addition to factors that increase risk of bleeding, interprovincial differences in practice patterns were associated with use of higher-potency P2Y12 receptor inhibitor at discharge. Opportunities remain for further optimization of evidence-based, guideline-recommended antiplatelet therapy use.

Provision of a DAPT Score to Cardiologists and Extension of Dual Antiplatelet Therapy Beyond 1 Year After ACS: Randomized Substudy of the Prospective Canadian ACS Reflective II Study.

BACKGROUND: Extension of dual antiplatelet therapy (DAPT) beyond 1 year after acute coronary syndrome is associated with a reduction in ischemic events but also increased bleeding. The DAPT score identifies individuals likely to derive overall benefit or harm from DAPT extension. We sought to evaluate the impact of providing the DAPT score to treating physicians on the decision to extend DAPT beyond 1 year after non-ST-segment elevation myocardial infarction. METHODS: Moderate to high-risk non-ST-segment elevation myocardial infarction patients were enrolled from July 2016 to May 2018 in 13 Canadian hospitals by 52 cardiologists. Participating cardiologists were randomly assigned 1:1 to receive their individual patients' DAPT scores before the 1-year follow-up visit vs not receiving their patients' DAPT scores. Rates of DAPT extension were compared among the randomized groups. RESULTS: At 1 year, 370 of the 585 (63.2%) patients discharged on DAPT were receiving DAPT. Among patients on DAPT at 1 year, the median (25th, 75th percentile) DAPT score was 2 (1,3). DAPT was extended beyond 1 year in 36.2% randomly assigned to provision of DAPT score vs 35.7% in the control group (P = 0.93). In the subgroup of patients with DAPT score ≥ 2, DAPT extension was 49.5% in the DAPT score provision arm vs 40.4% in the control arm (P = 0.22); among patients with DAPT score < 2, DAPT termination was 78.6% in the DAPT score provision arm vs 70.6% in the control arm (P = 0.26) (P value for interaction = 0.1). CONCLUSIONS: In this exploratory randomized trial, provision of the DAPT score to treating physicians had no impact on the duration of DAPT treatment beyond 1 year.

INTRODUCTION: La prolongation de la bithérapie antiplaquettaire au-delà d'un an après un syndrome coronarien aigu est associée à la réduction des accidents ischémiques, mais aussi à l'augmentation des hémorragies. Le score de bithérapie antiplaquettaire permet de déterminer les individus susceptibles d'obtenir des avantages globaux ou des inconvénients de la prolongation de la bithérapie antiplaquettaire. Nous avons cherché à évaluer les répercussions de l'obtention du score de bithérapie antiplaquettaire par les médecins traitants sur la décision quant à la prolongation de la bithérapie antiplaquettaire au-delà d'un an après l'infarctus du myocarde sans élévation du segment ST. MÉTHODES: De juillet 2016 à mai 2018, 52 cardiologues de 13 hôpitaux du Canada ont inscrit des patients exposés à un risque modéré à élevé d'infarctus du myocarde sans élévation du segment ST. Nous avons réparti de façon aléatoire selon un rapport 1:1 les cardiologues participants qui recevaient les scores de bithérapie antiplaquettaire individuels de leurs patients avant la consultation de suivi après un an vs ceux qui ne recevaient pas les scores de bithérapie antiplaquettaire de leurs patients. Nous avons comparé les taux de prolongation de la bithérapie antiplaquettaire des groupes répartis de façon aléatoire. RÉSULTATS: Après un an, 370 (63,2 %) patients sur 585 qui avaient eu à la sortie de l'hôpital une bithérapie antiplaquettaire recevaient la bithérapie antiplaquettaire. Parmi les patients qui prenaient la bithérapie antiplaquettaire après un an, le score médian de bithérapie antiplaquettaire (25e, 75e percentiles) était de 2 (1, 3). La bithérapie antiplaquettaire était prolongée au-delà d'un an chez 36,2 % des patients répartis de façon aléatoire qui avaient un score de bithérapie antiplaquettaire vs 35,7 % dans le groupe témoin (P = 0,93). Dans le sous-groupe de patients qui avaient un score de bithérapie antiplaquettaire ≥ 2, la prolongation de la bithérapie antiplaquettaire était de 49,5 % dans le bras qui avait un score de bithérapie antiplaquettaire vs 40,4 % dans le bras témoin (P = 0,22); parmi les patients qui avaient un score de bithérapie antiplaquettaire < 2, la cessation de la bithérapie antiplaquettaire était de 78,6 % dans le bras qui avait un score de bithérapie antiplaquettaire vs 70,6 % dans le bras témoin (P = 0,26) (valeur P pour l'interaction = 0,1). CONCLUSIONS: Dans cet essai exploratoire à répartition aléatoire, l'obtention du score de la bithérapie antiplaquettaire par les médecins traitants n'a pas engendré de répercussions sur la durée de la bithérapie antiplaquettaire au-delà d'un an.

Quantitative Modeling of the Mitral Valve by Three-Dimensional Transesophageal Echocardiography in Patients Undergoing Mitral Valve Repair: Correlation with Intraoperative Surgical Technique.

BACKGROUND: Mitral valve (MV) repair is the procedure of choice for patients with degenerative MV disease (DMVD) with severe mitral regurgitation. The aim of this study was to identify specific quantitative MV parameters from preoperative three-dimensional (3D) transesophageal echocardiography that are associated with the length of the mitral annuloplasty band implanted and the performance of leaflet resection in patients with DMVD undergoing MV repair. METHODS: Ninety-four patients (mean age, 60 ± 11 years; 68% men) referred for MV surgery with adequate-quality preoperative 3D transesophageal echocardiographic studies were retrospectively identified. Parametric maps of the MV were generated using semiautomated MV modeling software. Annular and valvular parameters were measured and indexed to body surface area. The implanted annuloplasty band size and leaflet resection were determined on the basis of surgical reports. RESULTS: Three-dimensional annular circumference correlated best (r = 0.74) with the implanted annuloplasty band length and remained an independent predictor on multivariate linear regression analysis. A third of our cohort (n = 33) had posterior leaflet resection. On receiver operating characteristic curve analysis, P2 segment length ≥ 20 mm (area under the curve, 0.86; sensitivity, 88%; specificity, 74%) and P2 leaflet area ≥ 3.4 cm(2) (area under the curve, 0.84; sensitivity, 85%; specificity, 74%) best discriminated the need for leaflet resection. CONCLUSIONS: In DMVD, quantitative 3D annular circumference obtained from semiautomatically generated parametric maps of the MV from 3D transesophageal echocardiographic data was associated with the surgically implanted annuloplasty band length, while P2 leaflet length ≥ 20 mm and area ≥ 3.4 cm(2) were associated with the performance of leaflet resection. These parameters should be further investigated for preoperative planning in patients with DMVD undergoing MV repair.

Acute and chronic effects of glyceryl trinitrate therapy on insulin and glucose regulation in humans.

This study examined the effect of acute and sustained transdermal glyceryl trinitrate (GTN) therapy on insulin and glucose regulation. Totally, 12 males (18-30 years) underwent a glucose tolerance test at baseline (visit 1), 90 minutes after acute transdermal GTN 0.6 mg/h (visit 2), following 7 days of continuous GTN (visit 3), and 2 to 3 days after stopping GTN (visit 4). At each visit, plasma glucose and insulin concentrations were measured before and 30, 60, 90, and 120 minutes after a 75-g oral glucose load. Indices of glucose metabolism that were examined included the insulin sensitivity index, the homeostasis model assessment of insulin resistance (HOMA-IR), and the insulinogenic index. The acute administration of GTN had no effect on glucose and insulin responses (visit 2). However, after 7 days of GTN exposure (visit 3) there was an increase in the mean glucose concentration measured after the oral glucose load. On visit 1, the mean glucose concentration (± standard deviation) following the 75 g oral glucose challenge was 5.7 ± 0.5 µmol/L. On visit 3, after 7 days of transdermal GTN therapy, the mean glucose concentration after the oral glucose was significantly higher; 6.2 ± 0.5 µmol/L (P < .015; 95% confidence intervals 0.25-0.77). There was also an increase in the HOMA-IR index; on visit 1, the median HOMA-IR (interquartile range) was 5.2 (3.9) versus 6.9 (6.8) on visit 3 (P < .015). Other indices of glucose metabolism did not change. These observations document that GTN therapy modifies glucose metabolism causing evidence of increased insulin resistance during sustained therapy in normal humans.

Quantification of mitral valve anatomy by three-dimensional transesophageal echocardiography in mitral valve prolapse predicts surgical anatomy and the complexity of mitral valve repair.

BACKGROUND: Three-dimensional (3D) transesophageal echocardiography (TEE) is more accurate than two-dimensional (2D) TEE in the qualitative assessment of mitral valve (MV) prolapse (MVP). However, the accuracy of 3D TEE in quantifying MV anatomy is less well studied, and its clinical relevance for MV repair is unknown. METHODS: The number of prolapsed segments, leaflet heights, and annular dimensions were assessed using 2D and 3D TEE and compared with surgical measurements in 50 patients (mean age, 61 ± 11 years) who underwent MV repair for mainly advanced MVP. RESULTS: Three-dimensional TEE was more accurate (92%-100%) than 2D TEE (80%-96%) in identifying prolapsed segments. Three-dimensional TEE and intraoperative measurements of leaflet height did not differ significantly, while 2D TEE significantly overestimated the height of the posterior segment P1 and the anterior segment A2. Three-dimensional TEE quantitative MV measurements were related to surgical technique: patients with more complex MVP (one vs two to four vs five or more prolapsed segments) showed progressive enlargement of annular anteroposterior (31 ± 5 vs 34 ± 4 vs 37 ± 6 mm, respectively, P = .02) and commissural diameters (40 ± 6 vs 44 ± 5 vs 50 ± 10 mm, respectively, P = .04) and needed increasingly complex MV repair with larger annuloplasty bands (60 ± 13 vs 67 ± 9 vs 72 ± 10 mm, P = .02) and more neochordae (7 ± 3 vs 12 ± 5 vs 26 ± 6, P < .01). CONCLUSIONS: Measurements of MV anatomy on 3D TEE are accurate compared with surgical measurements. Quantitative MV characteristics, as assessed by 3D TEE, determined the complexity of MV repair.

Daily low-dose folic acid supplementation does not prevent nitroglycerin-induced nitric oxide synthase dysfunction and tolerance: a human in vivo study.

INTRODUCTION: Continuous treatment with nitroglycerin (GTN) causes tolerance and endothelial dysfunction, both of which may involve endothelial nitric oxide synthase (eNOS) dysfunction. eNOS dysfunction may be linked to depletion of tetrahydrobiopterin, and folic acid may be involved in the regeneration of this cofactor. It has been demonstrated that 10 mg/day folic acid supplementation prevents the development of GTN tolerance and GTN-induced endothelial dysfunction. However, the efficacy of daily lower-dose folic acid supplementation for preventing these phenomena has not been investigated. OBJECTIVE: To determine the effect of 1 mg/day folic acid supplementation on responses to sustained GTN therapy. METHODS AND RESULTS: On visit 1, 20 healthy male volunteers were randomly assigned to receive either oral folic acid (1 mg/day) or placebo for one week in a double- blind study. All subjects also received continuous transdermal GTN (0.6 mg/h). On visit 2, forearm blood flow was measured using venous occlusion strain-gauge plethysmography in response to incremental intra-arterial infusions of acetylcholine, N-monomethyl-L-arginine and GTN. Subjects in both groups displayed significantly decreased responses to acetylcholine and N-monomethyl-L-arginine infusions compared with a control group that received no treatment. Responses to GTN were also significantly diminished in both groups (P<0.05 for all). DISCUSSION: The present data demonstrate that daily supplementation with 1 mg folic acid does not prevent the development of GTN-induced eNOS dysfunction or tolerance.

Evaluation of left ventricular ejection fraction in non-ST-segment elevation acute coronary syndromes and its relationship to treatment.

BACKGROUND: In-hospital assessment of left ventricular ejection fraction (LVEF) in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) is emphasized in current practice guidelines. There are limited data regarding the evaluation of LVEF and clinical characteristics and in-hospital management in the "real world." METHODS: Registries including the Canadian Acute Coronary Syndrome (ACS) I and II, Global Registry of Acute Coronary Events (main GRACE/expanded GRACE(2)), and Canadian Registry of Acute Coronary Events (CANRACE) enrolled 13,703 NSTE-ACS patients across Canada between 1999 and 2008. Patients were stratified by in-hospital LVEF measurement, and LVEF was categorized as normal, mildly, or moderately to severely impaired. We compared clinical characteristics, cardiac procedures, and clinical outcomes across these groups. Multivariable logistic regression identified factors independently associated with the assessment of LVEF. RESULTS: Overall, 8,116 patients (59.2%) had LVEF measurement, and of the 7,667 patients with available LVEF data, 4,470 (58.3%) had normal, 1,916 (25%) mildly impaired, and 1,281 (16.7%) moderately to severely impaired LVEF. Patients with LVEF assessment more frequently (all P < .001) underwent cardiac catheterization, percutaneous coronary intervention or coronary bypass surgery, and had higher (both P < .001) rates of myocardial (re) infarction and heart failure. In-hospital reinfarction, higher Killip class, abnormal biomarker, hospital stay >10 days, and on-site cardiac catheterization facility were independently associated with LVEF assessment. Despite increasing LVEF assessment over time (P for trend < .001), 31.2% of patients in the most recent registry (2008) had no in-hospital LVEF assessment. CONCLUSIONS: In-hospital LVEF assessment is not performed in many NSTE-ACS patients. The LVEF assessment, associated with increased use of evidence-based therapies and invasive cardiac procedures, was obtained more frequently in patients with myocardial (re) infarction, heart failure on presentation, and prolonged hospital stay.

Resident CD8+ T cells suppress CD4+ T cell-dependent late allergic airway responses.

BACKGROUND: The role of CD8+ T cells in the immune response to airway challenge with an allergen is poorly understood. OBJECTIVE: The aim of this study was to test the hypothesis that resident naive CD8+ T cells modulate the magnitude of CD4+ T cell-dependent allergic airway responses. METHODS: Cervical lymph node CD4+ T cells (2 x 10(6)) were harvested from ovalbumin (OVA)- or sham-sensitized rats and injected intraperitoneally into naive Brown Norway recipients. The recipients were treated with a CD8alpha mAb (OX-8) to deplete the resident CD8+ T cells (n = 12) or mouse ascites (n = 12). Two days after adoptive transfer, the recipient animals were OVA challenged, lung resistance was measured for 8 hours, and bronchoalveolar lavage (BAL) was performed. RESULTS: After OVA challenge, primed CD4-transferred CD8-depleted rats had larger early airway responses and late airway responses compared with primed CD4-transferred CD8-nondepleted rats (early airway responses: 158.6% +/- 19.2% vs 115.7% +/- 5.9%, P < .05; late airway responses: 8.5% +/- 1.7% vs 4.4% +/- 0.9%, P < .05). BAL eosinophilia was also greater (4.67% +/- 0.45% vs 2.34 +/- 0.26%, P < .01). The cells in BAL fluid expressing IL-4 mRNA were not significantly changed by CD8 depletion, but IL-5 mRNA+ cells were higher in number, and IFN-gamma mRNA+ cells were fewer in the CD8-depleted group. CONCLUSIONS: Resident CD8+ T cells downregulate the late allergic response and airway inflammation evoked by CD4+ T-cell transfers in Brown Norway rats. This downregulation does not require antigen priming.