Acute Coronary Syndromes Trial Research Articles

Advances in Clinical Cardiology 2023: A Summary of Key Clinical Trials.

Over the course of 2023, numerous key clinical trials with valuable contributions to clinical cardiology were published or presented at major international conferences. This review seeks to summarise these trials and reflect on their clinical context. The authors collated and reviewed clinical trials presented at major cardiology conferences during 2023 including the American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC), Transcatheter Cardiovascular Therapeutics (TCT), American Heart Association (AHA), European Heart Rhythm Association (EHRA), Society for Cardiovascular Angiography and Interventions (SCAI), TVT-The Heart Summit (TVT) and Cardiovascular Research Technologies (CRT). Trials with a broad relevance to the cardiology community and those with potential to change current practice were included. A total of 80 key cardiology clinical trials were identified for inclusion. Key trials in acute coronary syndrome (ACS) and antiplatelet management such as HOST-IDEA, T-PASS and STOP-DAPT3 were included in addition to several pivotal interventional trials such as ORBITA 2, MULTISTARS-AMI, ILUMIEN-IV, OCTIVUS and OCTOBER. Additionally, several trials evaluated new stent design and technology such as BIOSTEMI, PARTHENOPE and TRANSFORM. Structural intervention trials included long-term data from PARTNER 3, new data on the durability of transcatheter aortic valve intervention (TAVI), in addition to major new trials regarding transcatheter tricuspid valve intervention from TRISCEND II. Heart failure (HF) and prevention covered several key studies including DAPA-MI, STEP-HF, ADVOR, DICTATE HF and CAMEO-DAPA. In cardiac devices and electrophysiology, several trial exploring novel ablation strategies in atrial fibrillation (AF) such as PULSED AF and ADVENT were presented with further data evaluating the efficacy of anticoagulation in subclinical AF in NOAH-AFNET 6, FRAIL AF and AZALEA-TIMI 71. This article presents a summary of key clinical cardiology trials published and presented during the past year and should be of interest to both practising clinicians and researchers.

Impact of Society Guidelines on Trends in Use of Newer P2Y12 Inhibitors for Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention.

Over the past decade, major society guidelines have recommended the use of newer P2Y12 inhibitors over clopidogrel for those undergoing percutaneous coronary intervention for acute coronary syndrome. It is unclear what impact these recommendations had on clinical practice. All percutaneous coronary intervention procedures (n=534 210) for acute coronary syndrome in England and Wales (April 1, 2010, to March 31, 2022) were retrospectively analyzed, stratified by choice of preprocedural P2Y12 inhibitor (clopidogrel, ticagrelor, and prasugrel). Multivariable logistic regression models were used to examine odds ratios of receipt of ticagrelor and prasugrel (versus clopidogrel) over time, and predictors of their receipt. Overall, there was a significant increase in receipt of newer P2Y12 inhibitors from 2010 to 2020 (2022 versus 2010: ticagrelor odds ratio, 8.12 [95% CI, 7.67-8.60]; prasugrel odds ratio, 6.14 [95% CI, 5.53-6.81]), more so in ST-segment-elevation myocardial infarction than non-ST-segment-elevation acute coronary syndrome indication. The most significant increase in odds of receipt of prasugrel was observed between 2020 and 2022 (P<0.001), following a decline/plateau in its use in earlier years (2011-2019). In contrast, the odds of receipt of ticagrelor significantly increased in earlier years (2012-2017, Ptrend<0.001), after which the trend was stable (Ptrend=0.093). Over a 13-year-period, there has been a significant increase in use of newer P2Y12 inhibitors, although uptake of prasugrel use remained significantly lower than ticagrelor. Earlier society guidelines (pre-2017) were associated with the highest rates of ticagrelor use for non-ST-segment-elevation acute coronary syndrome and ST-segment-elevation myocardial infarction cases while the ISAR-REACT 5 (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome) trial and later society guidelines were associated with higher prasugrel use, mainly for ST-segment-elevation myocardial infarction indication.

Timing of Complete Multivessel Revascularization in Patients Presenting With Non-ST-Segment Elevation Acute Coronary Syndrome

BackgroundComplete revascularization of the culprit and all significant nonculprit lesions in patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS) and multivessel disease (MVD) reduces major adverse cardiac events, but optimal timing of revascularization remains unclear. ObjectivesThis study aims to compare immediate complete revascularization (ICR) and staged complete revascularization (SCR) in patients presenting with NSTE-ACS and MVD. MethodsThis prespecified substudy of the BIOVASC (Percutaneous Complete Revascularization Strategies Using Sirolimus Eluting Biodegradable Polymer Coated Stents in Patients Presenting With Acute Coronary Syndrome and Multivessel Disease) trial included patients with NSTE-ACS and MVD. Risk differences of the primary composite outcome of all-cause mortality, myocardial infarction (MI), unplanned ischemia-driven revascularization (UIDR), or cerebrovascular events and its individual components were compared between ICR and SCR at 1 year. ResultsThe BIOVASC trial enrolled 1,525 patients; 917 patients presented with NSTE-ACS, of whom 459 were allocated to ICR and 458 to SCR. Incidences of the primary composite outcome were similar in the 2 groups (7.9% vs 10.1%; risk difference 2.2%; 95% CI: −1.5 to 6.0; P = 0.15). ICR was associated with a significant reduction of MIs (2.0% vs 5.3%; risk difference 3.3%; 95% CI: 0.9 to 5.7; P = 0.006), which was maintained after exclusion of procedure-related MIs occurring during the index or staged procedure (2.0% vs 4.4%; risk difference 2.4%; 95% CI: 0.1 to 4.7; P = 0.032). UIDRs were also reduced in the ICR group (4.2% vs 7.8%; risk difference 3.5%; 95% CI: 0.4 to 6.6; P = 0.018). ConclusionsICR is safe in patients with NSTE-ACS and MVD and was associated with a reduction in MIs and UIDRs at 1 year.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition with evolocumab decreases myocardial inflammation in individuals with acute coronary syndrome (ACS)

Abstract Background/Introduction Although inflammation is commonly present and often beneficial in the period following tissue injury, prolonged inflammation may impair healing and repair following acute ischemic injury. In addition to its impact on cholesterol metabolism PCSK9 is elevated in patients with inflammatory diseases and is thought to be a pro-inflammatory mediator. The presence and early trajectory of myocardial inflammation, and the impact of PCSK9 inhibition on that trajectory, in patients with an acute myocardial infarction have not been characterized. Purpose Our goals were to assess myocardial inflammation in patients with an acute myocardial infarction using 18F-FDG-PET scans obtained at the time of hospitalization for the infarction and at 30-days following the infarction and the impact of PCSK9 inhibition with evolocumab on inflammation in a placebo-controlled, randomized trial. Methods Fifty-five participants from the Evolocumab in Acute Coronary Syndrome trials, with a NSTEMI and a troponin-I of &amp;gt; 5 ng/ml or with a STEMI were randomized to placebo (n=30) or to 420 mg SQ of evolocumab (n=25) within 24 hours of admission. 18F-FDG-PET scans were performed within five days (2 [1-4]) of randomization and at 30 days. The myocardial mean Standardized Uptake Value (SUV) in the two randomized groups at baseline and the changes from baseline to 30 days were compared. All participants received guideline-directed therapies for acute infarction. Results Mean±SD age of the cohort was 57±13 years, 22% were African American, and 36% were women. There were no significant differences in demographic or clinical characteristics between the two groups. Mean SUV at baseline did not differ between the placebo (2.4±0.5) and the evolocumab (2.7±0.7) groups, p=0.25 for the between groups comparison. Mean SUV decreased in both groups, from 2.4±0.5 to 2.1±0.7 in the placebo group (p=0.05) and from 2.7±0.7 to 1.9±0.5 in the evolocumab group (p &amp;lt;0.0001), and the decrease was less in the placebo group, p=0.039 for the between groups comparison. The percent-change in the placebo group (-10.4%±36%) was also less than the percent change in the evolocumab group (-26.7%±20%), p = 0.04 for the between groups comparison. In addition, the percent of participants in whom the mean SUV units decreased was lower in the placebo group (60%) than in the evolocumab group (88%,), p=0.03 for the between groups comparison. Conclusion Myocardial inflammation assessed using 18F-FDG-PET decreases but is still present 30 days following an acute myocardial infarction. PCSK9 inhibition with evolocumab given within the first 24 hours of admission improves resolution of the inflammation. In addition to its marked impact on lipid levels, PCSK9 inhibition has significant anti-inflammatory effects in the early post-infarction setting.

Clinical implication of ticagrelor monotherapy in patients with small vessel coronary artery disease: results from the TICO randomized trial.

The aim of this study was to evaluate the efficacy and safety of ticagrelor monotherapy in patients with small vessel disease compared with ticagrelor-based DAPT within the Ticagrelor Monotherapy after 3 Months in the Patients Treated with New Generation Sirolimus Eluting Stent for Acute Coronary Syndrome (TICO) trial population. Reference vessel diameter ≤2.5 mm was considered as small vessel disease. We conducted a comparison of the incidence of target lesion failure (TLF) and Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding. TLF was defined as a composite of cardiac death, target lesion myocardial infarction, stent thrombosis, and target lesion revascularization. 652 patients among 3,056 TICO population (21.3%) had small vessel disease. Patients with small vessel disease showed a higher rate of TLF compared to those without small vessel disease (2.9% vs. 1.0%, log-rank p < 0.001). The presence of small vessel disease emerged as an independent predictor for 1-year TLF (HR 2.84, 95% CI 1.54-5.25), while it did not show a significant association with bleeding complications. The 12-month TLF rate was 1.6% for ticagrelor monotherapy after 3-month DAPT, and 4.2% for ticagrelor-based 12-month DAPT (p = 0.059) in patients with small vessel disease (HR 0.38, 95% CI 0.14-1.04, p for interaction = 0.261). The incidence of BARC type 3 or 5 bleeding rate 2.5% for ticagrelor monotherapy after 3-month DAPT, and 5.6% for ticagrelor-based 12-month DAPT (p = 0.052) in patients with small vessel disease (HR 0.44, 95% CI 0.19-1.01, p for interaction = 0.322). In the 3-month landmark analysis, ticagrelor monotherapy significantly reduced BARC type 3 or 5 bleeding in patients with small vessel disease (HR 0.09, 95% CI 0.01-0.69, log-rank p = 0.005) while demonstrating a similar incidence of TLF compared to ticagrelor based 12-month DAPT during the 3-12 months period. There are no significant interactions between the antiplatelet strategy regarding the 12-month incidence of ischemic and bleeding complications. Ticagrelor monotherapy demonstrated a reduction in bleeding complications after a 3-month period of DAPT without increasing the rate of TLF, when compared to ticagrelor-based 12-month DAPT, specifically in patients with small vessel disease. Clinical Trial Registration: www.ClinicalTrials.gov, identifier, NCT02494895.

Platelet activation and endothelial dysfunction biomarkers in acute coronary syndrome: the impact of PCSK9 inhibition.

Platelet activation and endothelial dysfunction contribute to adverse outcomes in patients with acute coronary syndromes (ACS). The goals of this study were to assess the impact of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition on markers of platelet activation and endothelial dysfunction in ACS patients and the interaction among PCSK9, platelets, and endothelial cells (ECs) on left internal mammary artery (LIMA) vascular endothelium using specimens obtained during coronary artery bypass surgery (CABG). Acute coronary syndromes patients enrolled in the Evolocumab in ACS trials were randomized to placebo or a single dose of 420mg evolocumab within 24 h of hospitalization. Serum samples for analysis of platelet factor 4 (PF4) and P-selectin, markers of platelet activation, and von Willebrand factor (vWF), a marker of endothelial dysfunction, were obtained at baseline and 30 days. Additionally, LIMA segments obtained during CABG from patients who were and were not receiving evolocumab were immunostained with PCSK9; CD61, a platelet-specific marker; and CD31, an endothelial cell-specific marker. Forty-six participants were randomized to placebo or to evolocumab. Controlling for baseline levels, PF4 and vWF were significantly lower in the evolocumab, than in the placebo, group at 30 days. Immunostaining of LIMA specimens from twelve participants undergoing CABG revealed colocalization of PCSK9, CD61, and CD31 at the vascular endothelium. Administration of evolocumab was associated with decreased overlap of PCSK9, CD61, and CD31. Proprotein Convertase Subtilisin/Kexin 9 inhibition decreases markers of platelet activation and endothelial dysfunction in ACS patients. PCSK9 is associated with platelets and vascular ECs in LIMA segments and PCSK9 inhibition decreases that interaction.

A randomized controlled trial to investigate the use of acute coronary syndrome therapy in patients hospitalized with COVID-19: the COVID-19 Acute Coronary Syndrome trial

BackgroundPatients hospitalized with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease. ObjectivesTo investigate the efficacy of an acute coronary syndrome regimen in patients hospitalized with COVID-19 and coronary disease risk factors. MethodsA randomized controlled, open-label trial across acute hospitals (United Kingdom and Brazil) added aspirin, clopidogrel, low-dose rivaroxaban, atorvastatin, and omeprazole to standard care for 28 days. Primary efficacy and safety outcomes were 30-day mortality and bleeding. The key secondary outcome was a daily clinical status (at home, in hospital, on intensive therapy unit admission, or death). ResultsThree hundred twenty patients from 9 centers were randomized. The trial terminated early due to low recruitment. At 30 days, there was no significant difference in mortality (intervention vs control, 11.5% vs 15%; unadjusted odds ratio [OR], 0.73; 95% CI, 0.38-1.41; p = .355). Significant bleeds were infrequent and were not significantly different between the arms (intervention vs control, 1.9% vs 1.9%; p > .999). Using a Bayesian Markov longitudinal ordinal model, it was 93% probable that intervention arm participants were more likely to transition to a better clinical state each day (OR, 1.46; 95% credible interval [CrI], 0.88-2.37; Pr [beta > 0], 93%; adjusted OR, 1.50; 95% CrI, 0.91-2.45; Pr [beta > 0], 95%) and median time to discharge to home was 2 days shorter (95% CrI, −4 to 0; 2% probability that it was worse). ConclusionAcute coronary syndrome treatment regimen was associated with a reduction in the length of hospital stay without an excess in major bleeding. A larger trial is needed to evaluate mortality.

Advances in Clinical Cardiology 2022: A Summary of Key Clinical Trials.

Over the course of 2022, numerous key clinical trials with valuable contributions to clinical cardiology were published or presented at major international conferences. This review seeks to summarise these trials and to reflect on their clinical context. The authors reviewed clinical trials presented at major cardiology conferences during 2022, including the American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC), Transcatheter Cardiovascular Therapeutics (TCT), American Heart Association (AHA), European Heart Rhythm Association (EHRA), Society for Cardiovascular Angiography and Interventions (SCAI), TVT-The Heart Summit (TVT) and Cardiovascular Research Technologies (CRT). Trials with a broad relevance to the cardiology community and those with potential to change current practice were included. A total of 93 key cardiology clinical trials were identified for inclusion. Interventional cardiology data included trials evaluating the use of new generation novel stent technology and new intravascular physiology strategies such as quantitative flow ratio (QFR) to guide revascularisation in stable and unstable coronary artery disease. New trials in acute coronary syndromes and intervention focused on long-term outcomes of optimal medical therapy (OMT), revascularisation in ischaemic dysfunction and left main (LM) intervention. Structural intervention trials included latest data on optimal timing and anticoagulation strategies in transcatheter aortic valve replacement (TAVR), in addition to expanding evidence in mitral and tricuspid valve interventions. Heart failure data included trials with sodium-glucose cotransporter 2 (SGLT2) inhibitors, iron replacement and novel drugs such as omecamtiv. Prevention trials included new data on proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and polypill strategies. In electrophysiology, new data regarding optimal timing of ablative therapy for atrial fibrillation (AF) in addition to novel screening strategies were evaluated. This article presents a summary of key clinical cardiology trials published and presented during the past year and should be of interest to both practising clinicians and researchers.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), platelet activation and interaction with the vascular endothelium: the impact of PCSK9 inhibition with evolocumab in acute coronary syndrome

Abstract Background/Introduction Platelet activation and endothelial dysfunction may contribute to adverse outcomes in patients with acute myocardial infarction. Pre-clinical studies indicate PCSK9 enhances platelet activation. Purpose Our goals were (1) to examine the role of PCSK9 as a potential mediator of platelet activation in patients with acute coronary syndrome (ACS) and (2) to perform immunohistochemical studies of left internal mammary artery (LIMA) specimens to examine interactions among PCSK9, platelets, and endothelial cells in specimens obtained during coronary bypass surgery. Methods Participants from the Evolocumab in Acute Coronary Syndrome trials (EVACS; NCT03515304, NCT04082442), with a NSTEMI and a troponin-I of &amp;gt;5 ng/ml or a STEMI were randomized to placebo or to 420 mg SC of evolocumab, a monoclonal anti-PCSK9 antibody, within 24 hours of hospitalization. We performed serial ex vivo analysis of PF4, a marker of platelet activation, in serum samples obtained at baseline (prior to study drug administration) and at day 30. PF4 values were normalized to total platelet count. All of the participants were on guideline-directed therapies for ACS. Additionally, LIMA samples from patients undergoing coronary bypass surgery were immunostained with PCSK9, the endothelial cell transmembrane glycoprotein CD31 (platelet endothelial cell adhesion molecule-1) and the platelet surface marker CD61 (integrin beta-3). Outcome data were summarized using medians and interquartile ranges. Results Forty-six participants were randomized in a 1:1 fashion to placebo or to evolocumab. Mean (±SD) age of the cohort was 60±13 years, 48% were women and 22% were African American. Baseline PF4 levels (expressed as ng/1k platelets) were similar between the two groups (placebo: 9.3 [4–12] vs evolocumab 8.0 [4–12], p=0.8). In the placebo group, there was a significant increase in PF4 at 30 days to 13.1 [11–14], p&amp;lt;0.01 (baseline vs 30 days). In contrast, there was no significant change from baseline in the evolocumab group at 30 days (10.7 [6–13]), which was significantly lower than the placebo group (p=0.04). Furthermore, immunostaining of LIMA specimens obtained from patients during coronary artery bypass surgery revealed colocalization of PCSK9, CD31, and CD61 on the vascular endothelial cell surface (see Figure). Conclusion PCSK9 inhibition with evolocumab decreases platelet activation in ACS patients on dual anti-platelet therapy. PCSK9 is associated with platelets and endothelial cells at the vascular endothelium. PCSK9 is a potential mediator of the interaction between platelets and vascular endothelial cells in patients with coronary artery disease. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Amgen

Room for improvement: diagnosing and managing acute coronary syndromes in persons with reduced eGFR

Cardiovascular events are the leading cause of death in chronic kidney disease. A recent analysis from the High-Sensitivity Troponin in the Evaluation of Patients With Suspected Acute Coronary Syndrome trial focused on results in those with reduced estimated glomerular filtration rate. This commentary discusses aspects of acute coronary syndrome diagnosis in this group and the differential approach to acute coronary syndrome management that was observed between those with normal and reduced kidney function.

162-LB: Cardiovascular Outcomes in People with Type 2 Diabetes and Acute Coronary Syndrome—The ELIXA Biomarker Study

Adding novel protein biomarkers to routine clinical risk factors may identify people with type 2 diabetes and acute coronary syndrome who are at highest risk for cardiovascular (CV) outcomes and death. Methods: Bio-banked baseline serum from 5128 of 6069 ELIXA (Evaluating Lixisenatide in Acute Coronary Syndrome) trial (NCT 01147250) participants was analyzed to identify independent risk factors for incident major adverse CV events (MACE, defined as a nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) , and death. A multiplex analysis of 1.8 ml of serum measured the concentration of 49 proteins. Forward-selection Cox models that identified proteins that independently predicted these outcomes were compared to previously validated biomarkers identified in the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) trial data (NCT00069784) . Results: Forty-two proteins were analyzed in 4957 participants who had 630 (12.7%) MACE outcomes and 349 (7.0%) deaths during a median follow-up period of 2.1 years. When added to clinical risk factors, the independent hazard ratios (HR; 95% confidence intervals) of MACE per standard deviation (SD) were NT-proBNP (1.54; 1,41, 1.68) , osteoprotegerin (1.18; 1.08, 1.30) and trefoil factor 3 (1.18, 1.08, 1.29) . HRs per SD for death were NT-proBNP (2.01; 1.78, 2.29) , osteoprotegerin (1.34; 1.18, 2.52) and angiopoietin-2 (1.28; 1.15, 1.44) . C statistics for MACE and death were 0.70 (0,68, 0.72) and 0.79 (0.76, 0.81) respectively compared to 0.63 (0.61, 0.65) and 0.66 (0.63, 0.69) for clinical variables alone. These proteins had all been previously identified and validated in ORIGIN. Notably, NT-proBNP alone plus clinical risk factors yielded C statistics of 0.69 (0.67, 0.71) and 0.78 (0.75, 0.80) for MACE and death respectively. Conclusion: NT-proBNP and other proteins independently predict CV outcomes in people with type 2 diabetes following acute coronary syndrome. Adding other biomarkers only marginally increased NT-proBNP's prognostic value. Disclosure H. C. Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk, Sanofi. S. Hess: Employee; Sanofi. B. Claggett: Consultant; Amgen Inc., Biogen, Cardurion, Corvia, MyoKardia, Novartis AG. J. Tardif: Consultant; AstraZeneca, DalCor Pharmaceuticals, HLS Therapeutics Inc., Pendopharm, Other Relationship; DalCor Pharmaceuticals, Research Support; Amarin Corporation, AstraZeneca, Ceapro Inc., DalCor Pharmaceuticals, ESPERION Therapeutics, Inc., Ionis Pharmaceuticals, Novartis Pharmaceuticals Corporation, Pfizer Inc., REGENXBIO Inc., Sanofi. M. A. Pfeffer: Consultant; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Corvidia Therapeutics, GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Peerbridge, Sanofi, Other Relationship; DalCor Pharmaceuticals, National Heart, Lung, and Blood Institute, Research Support; Novartis Pharmaceuticals Corporation. Funding Sanofi

Podocan and Adverse Clinical Outcome in Patients Admitted With Suspected Acute Coronary Syndromes.

BackgroundMarkers of bone and extracellular matrix (ECM) remodeling may be associated with adverse outcomes in atherosclerotic cardiovascular disease. Podocan is a newly discovered ECM glycoprotein, previously not studied in a chest pain population. We wanted to study the association between Podocan levels on admission and the risk of adverse outcomes in a chest pain population with suspected acute coronary syndromes.MethodsA total of 815 patients from the Risk markers in Acute Coronary Syndrome (RACS) trial with suspected coronary chest pain were followed for 7 years. Blood samples were taken immediately after inclusion and stored in the biobank. Associations between Podocan and endpoints were assessed with Cox proportional hazards analyses.ResultsThe median admission level of Podocan was 0.674 ng/ml (0.566–0.908 ng/ml). No significant association was found between Podocan quartile levels and all-cause death, neither at 1 year nor 2- or 7-years follow-up (p > 0.05 for all). Furthermore, no significant association could be shown between Podocan and cardiac death, myocardial infarction (MI), stroke, or the composites of all-cause death/MI/stroke or cardiac death/MI/stroke (p > 0.05 for all). Similarly, in a subgroup of patients with Troponin T-positive (n = 432) there was no significant association between Podocan and any of the outcome measures (p > 0.05 for all endpoints and points in time).ConclusionPodocan, a novel ECM biomarker, is not associated with all-cause mortality or other major cardiovascular adverse events in patients admitted with acute chest pain suspected to be of coronary origin.Clinical Trials.gov Identifier:NCT00521976.

EP News: Allied Professionals

In this nonprespecified, post hoc analysis of the AUGUSTUS (An Open-Label, 2 × 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention) trial, Harskamp et al (J Am Coll Cardiol 2022;79:417, PMID 35115097) sought to evaluate whether the risk of bleeding or stroke as assessed by baseline HAS-BLED and CHA2DS2-VASc scores affected the results of the trial.

Advances in Clinical Cardiology 2021: A Summary of Key Clinical Trials

IntroductionOver the course of 2021, numerous key clinical trials with valuable contributions to clinical cardiology were published or presented at major international conferences. This review seeks to summarise these trials and reflect on their clinical context.MethodsThe authors reviewed clinical trials presented at major cardiology conferences during 2021 including the American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC), Transcatheter Cardiovascular Therapeutics (TCT), American Heart Association (AHA), European Heart Rhythm Association (EHRA), Society for Cardiovascular Angiography and Interventions (SCAI), TVT-The Heart Summit (TVT) and Cardiovascular Research Technologies (CRT). Trials with a broad relevance to the cardiology community and those with potential to change current practice were included.ResultsA total of 150 key cardiology clinical trials were identified for inclusion. Interventional cardiology data included trials evaluating the use of new generation novel stent technology and new intravascular physiology strategies such as quantitative flow ratio (QFR) to guide revascularisation in stable and unstable coronary artery disease. New trials in acute coronary syndromes focused on shock, out of hospital cardiac arrest (OOHCA), the impact of COVID-19 on ST-elevation myocardial infarction (STEMI) networks and optimal duration/type of antiplatelet treatment. Structural intervention trials included latest data on transcatheter aortic valve replacement (TAVR) and mitral, tricuspid and pulmonary valve interventions. Heart failure data included trials with sodium-glucose cotransporter 2 (SGLT2) inhibitors, sacubitril/valsartan and novel drugs such as mavacamten for hypertrophic cardiomyopathy (HCM). Prevention trials included new data on proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In electrophysiology, new data regarding atrial fibrillation (AF) screening and new evidence for rhythm vs. rate control strategies were evaluated.ConclusionThis article presents a summary of key clinical cardiology trials published and presented during the past year and should be of interest to both practising clinicians and researchers.

Blood and Urine Biomarkers Predicting Worsening Kidney Function in Patients with Type 2 Diabetes Post-Acute Coronary Syndrome: An Analysis from the EXAMINE Trial

Introduction: Worsening kidney function (WKF) is frequent among patients with type 2 diabetes (T2D) and a recent acute coronary syndrome (ACS) and is associated with a poor prognosis. An accurate prediction of WKF is clinically important. Aims: Using data from the Cardiovascular Outcomes Study of Alogliptin in Patients with Type 2 Diabetes and Acute Coronary Syndrome trial including patients with T2D and a recent ACS, and a large biomarker panel incorporating proteins measured both in blood and urine, we aim to determine those with best performance for WKF prediction. Methods: WKF was defined as a ≥40% estimated glomerular filtration rate (eGFR) drop from baseline, eGFR <15 mL/min, or dialysis. Mixed-effects and time-updated Cox models were used. Results: 5,131 patients were included from whom 222 (4.3%) developed at least one WKF episode over a median follow-up of 18 months. Patients who developed WKF were more frequently women, had longer diabetes duration, a more frequent heart failure history, higher anemia prevalence, and impaired kidney function. In multivariable models including all variables (clinical and biomarkers) independently associated with WKF with a p value ≤0.0001, blood kidney injury molecule 1 (KIM-1) was (by far) the variable with strongest WKF association, followed by anemia. KIM-1 alone provided good discrimination for WKF prediction (area under the curve = 0.73). Patients in the high KIM-1-derived risk tertile had a 6.7-fold higher risk of any WKF than patients classified as low risk. In time-updated Cox models, the occurrence of WKF was independently associated with a higher risk of death: adjusted hazard ratio = 4.93 (3.06–7.96), p value <0.0001. Conclusion: Blood KIM-1 was the biomarker with the strongest association with WKF. The occurrence of WKF was independently associated with a higher risk of subsequent cardiovascular events and mortality.

Abstract 12563: The Trajectory of Platelet Factor 4 in Acute Myocardial Infarction and the Impact of PCSK9-Inhibition

Introduction: Increased platelet activity during the peri- and early post-infarction period may contribute to adverse outcomes during that time. Platelet factor 4 (PF4) promotes coagulation and inflammation. The trajectory of PF4 and the impact of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition on that trajectory are unknown. Hypothesis: Early administration of the PCSK9 inhibitor evulocumab, added to dual anti-platelet therapy, inhibits a rise in PF4 during the early post-infarction period. Methods: Participants from the Evolocumab in Acute Coronary Syndrome trials (EVACS; NCT03515304, NCT04082442), with a NSTEMI and a troponin-I of &gt; 5 ng/ml or a STEMI were randomized to placebo or to 420 mg SQ of evolocumab within 24 hours of hospitalization. We performed serial ex vivo serum PF4 levels obtained at baseline (prior to study drug administration), and at days 1 and 30 and PF4 values were normalized to total platelet count. Normally distributed data were summarized using means and standard deviations and non-normally distributed data using medians and interquartile ranges. Results: Twenty-three participants were randomized to placebo and 23 to evolocumab. Mean age was 60±13 years, 48% were women, 22% were African American and 96% were on dual anti platelet therapy. Baseline PF4 concentrations (expressed as ng/1k platelets) did not differ between the two groups (placebo: 9.3 [4-12] vs evolocumab 8.0 [4-12], p=0.8). There was no significant change in PF4 in the placebo group from baseline to day 1 but a significant increase to 13.0 [11-14], p&lt;0.01 (baseline vs 30 days) at 30 days (+32%). In contrast, there were no significant changes from baseline in the evolocumab group at either of the timepoints. At 30 days PF4 was higher in the placebo group 13.06 [11-14] than the evolocumab group 10.7 [6-13], p=0.04. Further analysis of results in the evolocumab group did not show any significant changes in PF4 based on the type of P2Y12 inhibitor used and no association with the change in LDL-cholesterol. Conclusion: A rise in PF4 levels was observed during the early post-infarction period in acute myocardial infarction patients. This rise was reversed by a single 420 mg SQ dose of evolocumab administered within 24 hours of hospital admission.

Comparison of ticagrelor with clopidogrel on quality of life in patients with acute coronary syndrome

BackgroundTicagrelor has a Class I recommendation for use following percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS). However, ticagrelor needs to be taken twice a day, as compared to clopidogrel. Its adverse effects, such as dyspnea or bleeding, are known to be more common than with clopidogrel. Dyspnea may tend to be uncomfortable and limit activity. Major bleeding often leads to hospitalization or transfusions, and frequent minor bleeding, which might not result in patients seeking medical care, can make ACS patients feel unhealthy. Thus, these characteristics may affect the health-related quality of life (HQOL).MethodsIn the PLEIO (comParison of ticagreLor and clopidogrEl on mIcrocirculation in patients with acute cOronary syndrome) trial, we randomized 120 participants to receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for at least 12 months. We carried out an HQOL assessment with the Short Form 36 Health Survey (SF-36) questionnaire on the day of discharge following PCI, as well as six months later.ResultsAt discharge, the HQOL measures were similar in the ticagrelor and clopidogrel groups, both having a physical component summary (PCS) and a mental component summary (MCS) score. A six-month HQOL follow-up assessment showed that there were no differences between the two study groups in either the PCS or the MCS scores. In both groups, the PCS scores significantly increased over six months of treatment (both p < 0.01). However, the MCS score did not differ significantly. A baseline MCS score is an independent predictor of better physical and mental health status at six months.ConclusionsTicagrelor, as compared to clopidogrel, did not significantly reduce the HQOL during the six months following PCI in patients with ACS.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02618733.

The Effect of the Timing of Invasive Management on Cardiac Function in Patients with NSTE-ACS, Insights from the OPTIMA-2 Randomized Controlled Trial.

The timing of coronary angiography in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) remains a matter of debate. The relationship between the timing of invasive management and left ventricular function (LVF) is largely unknown. The An Immediate or Early Invasive Strategy in Non-ST-Elevation Acute Coronary Syndrome trial (OPTIMA-2) was a randomized controlled prospective open-label multicenter trial that randomized 249 NSTE-ACS patients to either an immediate (<3 h) invasive treatment strategy or an early strategy (12–24 h). Patients were pre-treated with a combination of aspirin, ticagrelor and fondaparinux. The aim of this prespecified sub-analysis was to assess (the recovery of) left ventricular function by analysing echocardiography data obtained <72 h after admission and at 30-day follow-up, for patients with a confirmed diagnosis of acute coronary syndrome. LVF was determined using ejection fraction (EF) and global longitudinal strain (GLS). Inter-observer variability was tested. No difference in the recovery of EF was found between an immediate and early strategy if the follow-up echocardiograms were compared to baseline: 2.5% (standard deviation (SD): 7.9) and 3.3% (SD: 8.5), p = 0.51, nor was there any difference in GLS recovery between the study groups: −0.8% (SD: 2.5) vs. −0.7% (SD 2.8) p = 0.82. If baseline and follow-up echocardiograms were compared, there was a similar but significant improvement in both EF and GLS in both separate study groups. An immediate invasive strategy in NSTE-ACS patients did not result in an improved left ventricular EF or GLS recovery compared with an early strategy.

Management of acute coronary syndromes in older adults.

Older patients are underrepresented in prospective studies and randomized clinical trials of acute coronary syndromes (ACS). Over the last decade, a few specific trials have been conducted in this population, allowing more evidence-based management. Older adults are a heterogeneous, complex, and high-risk group whose management requires a multidimensional clinical approach beyond coronary anatomic variables. This review focuses on available data informing evidence-based interventional and pharmacological approaches for older adults with ACS, including guideline-directed management. Overall, an invasive approach appears to demonstrate a better benefit-risk ratio compared to a conservative one across the ACS spectrum, even considering patients' clinical complexity and multiple comorbidities. Conversely, more powerful strategies of antithrombotic therapy for secondary prevention have been associated with increased bleeding events and no benefit in terms of mortality reduction. An interdisciplinary evaluation with geriatric assessment should always be considered to achieve a holistic approach and optimize any treatment on the basis of the underlying biological vulnerability.

Ticagrelor Monotherapy Versus Ticagrelor With Aspirin in Patients With ST-Segment Elevation Myocardial Infarction

The aim of this study was to assess whether the effects of ticagrelor monotherapy after 3-month dual-antiplatelet therapy (DAPT) are consistent among patients presenting with ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction, and unstable angina treated with drug-eluting stents. Ticagrelor monotherapy after short-term DAPT has not been investigated in patients with STEMI. This was a pre-specified, stratified, subgroup analysis of the STEMI cohort from the TICO (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus Stent for Acute Coronary Syndrome) trial, which constituted 36% of the total population. The primary outcome was a composite of major bleeding and major adverse cardiac and cerebrovascular events (MACCE; death, myocardial infarction, stent thrombosis, stroke, or target vessel revascularization). The secondary outcomes were major bleeding and MACCE. The incidence of the primary outcome was 4.4% in patients with STEMI (n=1,103), 6.0% in those with non-ST-segment elevation myocardial infarction (n=1,027), and 4.1% in those with unstable angina (n=926), without statistical significance (p=0.09). Compared with ticagrelor-based 12-month DAPT, ticagrelor monotherapy after 3-month DAPT showed consistent effects on the primary outcome across clinical presentations (p for interaction [pint]=0.64). Furthermore, the effect of ticagrelor monotherapy on the reduction of major bleeding was consistent across clinical presentations (pint=0.36). The effect of ticagrelor monotherapy on MACCE was also consistent in patients with STEMI, without evidence of a higher risk for MACCE (pint=0.14). This pre-specified subgroup analysis revealed no heterogeneity in the effects of ticagrelor monotherapy after 3-month DAPT, compared with 12-month DAPT, for the primary outcome, major bleeding, and MACCE across clinical presentations including STEMI, though larger studies are needed to demonstrate these findings with adequate power. (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus Stent for Acute Coronary Syndrome [TICO Study]; NCT02494895).