Podcasts about p2y12

N Engl J Med 2024;391:1673-1684Background: Non-ST elevation myocardial infarction (NSTEMI) is the most common acute coronary syndrome subtype in adults over 75 years old. However, these patients were underrepresented in landmark NSTEMI trials. Older adults with multiple comorbidities face an increased risk of mortality. While NSTEMI contributes to this risk, they also have competing risks such as advanced age, frailty, and chronic kidney disease. The presence of competing risks means that aggressively managing one condition may have a smaller impact on overall mortality compared to a younger, otherwise healthy adult with myocardial infarction, whose primary risk of death stems from the myocardial infarction itself. Additionally, comorbid conditions like advanced kidney disease and diffuse atherosclerosis can increase the risks associated with revascularization.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.A patient-level meta-analysis of smaller trials, including 1,479 patients, found that in elderly patients with NSTEMI, an invasive strategy reduced myocardial infarction and urgent revascularization but not mortality.The Older Patients with Non–ST-Segment Elevation Myocardial Infarction Randomized Interventional Treatment (SENRIOR-RITA) trial sought to assess invasive vs conservative management of elderly patients with NSTEMI, in a more pragmatic design.Patients: Eligible patients had to have type I NSTEMI and be 75 years or older.Patients were excluded if they had cardiogenic shock or life expectancy less than 1 year.Baseline characteristics: The trial randomized 1,518 patients from hospitals across England and Scotland – 753 randomized to invasive strategy and 765 to conservative strategy.The average age of patients was 82 years and 55% were men. Approximately 65% had hypertension, 31% had diabetes, 31% had hyperlipidemia, 31% had prior myocardial infarction, 15% had prior stroke or TIA, 21% had kidney disease, 15% had chronic obstructive pulmonary disease, and 5% were current smokers.The average Charlson comorbidity index was 5.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo invasive or conservative strategy.In the invasive strategy, patients underwent coronary angiogram, and revascularization was performed as appropriate. In the conservative arm, patients were treated (unless contraindicated) with aspirin, a P2Y12 receptor antagonist, statin, beta-blocker and an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. Patients in the conservative arm were allowed to have a coronary angiogram if they had worsening clinical status.Endpoints: The primary end point was a composite of cardiovascular death or nonfatal myocardial infarction. Secondary outcomes included all-cause death, subsequent coronary revascularization, hospitalization for heart failure, stroke and bleeding.Analysis was performed based on the intention-to-treat principle. The trial aimed to detect a hazard ratio of 0.78, assuming a 20% risk of the primary outcome in the conservative arm. A sample size of 1,668 patients with at least 688 primary outcome events would provide 90% power at 5% alpha, while 520 events would provide 80% power.Results: Among the patient randomized to the invasive arm, 90% underwent coronary angiography and 50% underwent revascularization. The medium number of days from admission to coronary angiography was 5. Among patients randomized to the conservative arm, 5.6% underwent coronary angiography within 7 days. The median follow-up time was 4.1 years.The primary outcome was not significantly different between both groups (25.6% with invasive vs 26.3% with conservative, HR: 0.94, 95%: 0.77 - 1.14; p= 0.53).There was also no difference in all-cause death (36.1% vs 32.3%), cardiovascular death (15.8% vs 14.2%), stroke (4.2% vs 5.2%), hospitalization for heart failure (10.9% vs 10.7%), or major bleeding (8.2% vs 6.4%) “incidence for invasive mentioned first”. Future coronary revascularization was more frequent in the conservative arm (13.7% vs 3.9%). Non-fatal myocardial infarction was significantly lower with an invasive strategy (11.7% vs 15.0%).Procedural related complications occurred in less than 1% of the patients.There were no significant subgroup interactions for the primary outcome.Conclusion: In older patients with NSTEMI, an invasive strategy compared to conservative strategy, did not reduce the primary composite endpoint of cardiovascular death or nonfatal myocardial infarction, over a median of 4.1 years.The trial enrolled fewer patients than planned, and the lower-than-expected event rate reduced its statistical power. Additionally, the median 5-day delay before coronary angiography may have biased the results toward the conservative strategy.Despite its limitations, this trial demonstrates that a conservative approach is a reasonable option for selected older patients with NSTEMI. It also highlights that, although enrolling older patients with comorbidities in trials is challenging, it is feasible, and greater effort is needed to include more of this population in future trials.Finally, in this trial of patients with myocardial infarction, about one-third died over a median of 4.1 years, with less than half of these deaths attributed to cardiovascular disease. Even if an invasive strategy had reduced cardiovascular mortality, its impact on all-cause mortality would have been less significant. This concept extends beyond this trial; when interventions are applied to older patients with multiple competing risks, their overall benefit diminishes.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

In this episode, we review the new 2025 ACC/AHA Acute Coronary Syndrome (ACS) guidelines, with a particular focus on guideline recommendations for analgesics, P2Y12 inhibitors, parenteral anticoagulation, and lipid management. Key Concepts Nitrates and opioids are recommended for symptomatic relief of chest pain. Some patients may not be appropriate for nitrates (e.g. recent PDE-5 inhibitor use, hypotension, or right ventricular infarction). Opioids are used for nitrate-refractory angina but have a theoretical risk of delaying the effect of oral antiplatelet medications. Prasugrel and ticagrelor are preferred P2Y12 inhibitors over clopidogrel in most patients. Patient-specific factors, including the use of PCI, play a role in P2Y12 inhibitor selection. Anticoagulation with heparin is recommended in nearly all acute coronary syndrome (ACS) scenarios. Alternative anticoagulants may be used depending on whether PCI/CABG is planned and whether the anticoagulant is used prior to PCI/CABG (“upstream”) or during the PCI procedure itself. LDL goals after ACS have changed again. All ACS patients should have an LDL goal < 70 with a consideration of an LDL goal of 55-69. A variety of non-statin therapies may be added to a high intensity statin regimen if LDL is not at goal. References Rao SV, O'Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. Published online February 27, 2025. https://www.ahajournals.org/doi/10.1161/CIR.0000000000001309

This episode of JACC-Baran features a brief discussion on Kendrick Lamar and the history of racial discrimination in the United States. Then Hiroki Ueyama, MD, from Emory University discusses his study on P2Y12 inhibitor pre-treatment in NST-ACS using data from the Chest Pain-MI Registry. The study examines how guideline changes have influenced clinical practice, revealing a decline in pre-treatment rates, significant practice variations, and no major differences in outcomes except for longer hospital stays in CABG patients. Watch the video or listen as a podcast here, then check out the JACC article: https://www.jacc.org/doi/10.1016/j.jacc.2024.09.1227

Será que a recomendação clássica de 12 meses de DAPT após SCA ou angioplastia ainda faz sentido? Neste episódio, exploramos as evidências mais recentes que questionam essa prática tradicional.✅ O que você vai ouvir: • Diferenças entre os principais inibidores do P2Y12 (clopidogrel, prasugrel e ticagrelor) • Quando encurtar, descalonar ou estender a DAPT com base nos principais Trials • Como avaliar o risco de sangramento (Scores PRECISE-DAPT e DAPT)• Terapia tripla em pacientes com fibrilação atrial e necessidade de anticoagulaçãoVamos discutir de forma prática e baseada em evidências quando a DAPT pode ser encurtada ou estendida — e o impacto direto dessas decisões nos desfechos do paciente.

N Engl J Med 2013;369:1587-1597N Engl J Med 2014;371:1111-1120Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Background: In the TAPAS trial, thrombus aspiration in patients with ST elevation myocardial infarction (STEMI) improved coronary reperfusion as evident by coronary blush grade and electrocardiogram. The improvement in these surrogate endpoints was large and generated enthusiasm within the cardiology community regarding the potential of thrombus aspiration. While the trial demonstrated a trend toward improvement in clinical outcomes, this was not statistically significant and the trial was not powered for these clinical outcomes.The Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) trial was designed to assess the impact of thrombus aspiration in patients with STEMI, and was powered to detect differences in clinical endpoints.Patients: Patients were included if they had chest pain suggestive of myocardial ischemia for at least 30 minutes but less than 24 hours before hospital admission, and if the EKG showed new ST-segment elevation or left bundle-branch block.Patients were excluded if they couldn't provide informed consent or if they needed emergency coronary artery bypass grafting.The trial enrolled patients from all 29 PCI centers in Sweden, 1 in Iceland and 1 in Denmark.Baseline characteristics: The trial randomized 7,244 patients – 3,621 randomized to thrombus aspiration and 3,623 randomized to conventional PCI.The average age of patients was 66 years and 75% were men. Approximately 42% had hypertension, 12% had diabetes, 21% had hyperlipidemia, 12% had prior myocardial infarction, and 31% were current smokers.Procedures: Patients were randomly assigned in a 1:1 ratio to undergo thrombus aspiration follow by PCI or conventional PCI. The study was open label.The use of anticoagulants during PCI was left to the discretion of the treating physician. Stenting was encouraged with the type of stent left to the discretion of the physician. The administration of P2Y12 inhibitors was also left to the discretion of the physician. Lifelong treatment with aspirin was recommended in all patients.Endpoints: The primary end point was all-cause death at 30 days. Data on mortality were obtained from the national population registry. The secondary end points, which were obtained from the SWEDEHEART registry and the national discharge registry, included 30-day rates of hospitalization for recurrent myocardial infarction, stent thrombosis, target-vessel revascularization, target-lesion revascularization, and the composite of all-cause mortality or recurrent myocardial infarction.Analysis was performed based on the intention-to-treat principle. To achieve 80% power with a two-sided alpha of 0.05, a total of 4,886 patients would be needed to detect a hazard ratio for death of at least 1.30 with PCI alone as compared with PCI plus thrombus aspiration. This calculation assumed the 30-day mortality with PCI alone to be 6.3%. Due to lower than expected mortality rate, the sample size was increased to 7,138 patients. The new sample size would detect an odds ratio for death with PCI alone as compared with PCI with thrombus aspiration of at least 1.5, assuming the 30-day mortality in the conventional PCI group to be 3.5%.Results: Out of the 11,709 patients with STEMI in Sweden or Iceland, 4,697 (40.1%) were not enrolled in the trial. Of these patients not enrolled, 1,162 (24.7%) underwent thrombus aspiration. The median time from onset of symptoms to PCI was approximately 3 hours. No patients were lost to follow up with respect to the primary outcome. Among patients assigned to thrombus aspiration, 93.9% of the patients underwent the procedure. Among patients assigned to conventional PCI, 4.9% underwent thrombus aspiration.The primary outcome of all-cause death at 30-days was similar between both treatment groups (2.8% with thrombus aspiration vs 3.0% with conventional PCI, HR: 0.94, 95% CI: 0.72 - 1.22; p= 0.63).There were no statistically significant differences in any of the secondary outcomes at 30-days (incidence for thrombus aspiration mentioned first): Hospitalization for recurrent myocardial infarction (0.5% vs 0.9%), stent thrombosis (0.2% vs 0.5%), target-vessel revascularization (1.8% vs 2.2%), target-lesion revascularization (1.2% vs 1.6%), and the composite of all-cause death or recurrent myocardial infarction (3.3% vs 3.9%).There was no difference in the incidence of stroke or neurological complications (0.5% in both groups), and no difference in the incidence of perforation or tamponade (0.4% in both groups).Authors published a 1-year follow up study. At 1-year, there was no significant difference in all-cause death (5.3% with thrombus-aspiration group vs. 5.6% with conventional PCI, HR: 0.94, 95% CI: 0.78 - 1.15; p= 0.57). Similarly, no significant differences were observed for any of the secondary endpoints (incidence for thrombus aspiration mentioned first): Hospitalization for recurrent myocardial infarction (2.7% in both groups), stent thrombosis (0.7% vs 0.9%), target-vessel revascularization (4.4% vs 4.9%), target-lesion revascularization (3.2% vs 3.5%), and the composite of all-cause death or recurrent myocardial infarction (7.7% vs 8.1%).There were no significant subgroup interactions for the primary outcome.Conclusion: In patients with ST elevation myocardial infarction, thrombus aspiration during PCI as compared to conventional PCI, did not improve the primary outcome of all-cause at 30-days. It also did not significantly reduce the secondary outcomes at 30-days which included hospitalization for recurrent myocardial infarction, stent thrombosis, target-vessel revascularization, target-lesion revascularization, and the composite of all-cause death or recurrent myocardial infarction. Results remained unchanged at 1-year.The TAPAS and TASTE trials highlight a critical lesson in research: Reliance on surrogate endpoints to guide medical practice can be misleading, even when surrogate outcomes suggest a substantial benefit, as seen in the TAPAS trial. Therefore, positive findings based on surrogate endpoints should always be validated by larger trials powered to assess clinical outcomes, before adopting them into clinical practice.The TAPAS trial did impact clinical practice, with approximately 1 in 4 patients with STEMI in Sweden during the TASTE study period, who were not enrolled in the TASTE trial, underwent thrombus aspiration.Another key takeaway is that results from smaller trials are not always replicated in larger studies. In TAPAS, thrombus aspiration was associated with a reduction in 30-day mortality, with a number needed to treat of approximately 53 patients. However, this finding was not statistically significant, raising questions about whether a larger sample size could have demonstrated a significant benefit. This assumption was refuted by the TASTE trial, highlighting the potential pitfalls of prematurely adopting interventions without robust evidence from sufficiently large trials.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

In this podcast, Dr. Valentin Fuster discusses a study on the use of P2Y12 inhibitor pretreatment in patients with non-ST elevation acute coronary syndrome, revealing significant variability in its application across institutions and operators. Despite initial hypotheses of benefit, the findings indicate no significant difference in patient outcomes, suggesting that routine pretreatment may not be necessary, especially when treatment is initiated within 24 hours of symptom onset.

In this episode of JACC podcast, Dr. Valentin Fuster highlights key studies from the February 4th, 2025 issue, including the rising prevalence and mortality of coagulase-negative staphylococcal endocarditis and the clinical implications of new diagnostic technologies like photon-counting detector CT for coronary artery disease. Other highlights include discussions on P2Y12 inhibitor pretreatment in acute coronary syndrome, cardiologist integration into hospital systems, and reviews on heart failure medication costs and myocarditis management strategies.

Antiplatelets After Stenting   Guest: Malcolm Bell, M.D. Host: Sharonne Hayes, M.D.   In this podcast, we discuss the rationale for shortening the duration of dual antiplatelet therapy after coronary stenting and continuing P2Y12 inhibitor in preference to continuing aspirin as monotherapy.  With this approach, the risk of significant bleeding is reduced significantly and with no corresponding increase in ischemic or thrombotic events.  This strategy is particularly attractive for patients who are considered to be at high-risk of bleeding or who suffer an actionable bleed. A P2Y12 inhibitor appears to more efficacious for long term secondary prevention than aspirin.   Topics Discussed: Changes in the use of dual antiplatelet therapy for patients undergoing coronary stenting.  Short DAPT and dropping the aspirin. Patient population ideal for monotherapy with a P2Y12 inhibitor. What do you do after 6 or 12 months of monotherapy – continue, or switch back to aspirin? Connect with Mayo Clinic's Cardiovascular Continuing Medical Education online at https://cveducation.mayo.edu or on Twitter @MayoClinicCV and @MayoCVservices. LinkedIn: Mayo Clinic Cardiovascular Services Cardiovascular Education App: The Mayo Clinic Cardiovascular CME App is an innovative educational platform that features cardiology-focused continuing medical education wherever and whenever you need it. Use this app to access other free content and browse upcoming courses. Download it for free in Apple or Google stores today! No CME credit offered for this episode. Podcast episode transcript found here.

Our initial review of the PLATO trial, published in April 2024, was based on the data available to us at that time. We have since became aware of new information that reduces our confidence in the PLATO results. This new information has major implications for clinical practice. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Despite representing only 6.9% of the total P2Y12 inhibitor prescriptions among Medicare beneficiaries in 2020, Ticagrelor accounted for nearly two-thirds of total Medicare spending on these drugs in the same year. We summarize important points below but you can refer to this investigation at BMJ for more details.1. Unexplained Regional Variation: In our original review, we highlighted the treatment effect interaction based on region of enrollment, where ticagrelor was less effective compared to clopidogrel for patients enrolled in North America. It appeared to be a strong signal and was associated with a p-value for the interaction of 0.05. However, we were cautious in our interpretation since overall, patients enrolled in North America represented a relatively small fraction of total patients and we could not think of a reasonable explanation.Information in the BMJ investigation now sheds new light on these findings. In our review, we only presented data contained in the supplement accompanying the PLATO trial manuscript, which categorized patients based on region of enrollment but did not provide country specific information. The BMJ report notes that in a separate subgroup analysis, based on country of randomization, the primary outcome was numerically higher with ticagrelor in the United States (12.6% vs 10.1%, HR: 1.27, 95% CI: 0.92 – 1.75). This subgroup represented 7.6% of the total trial participants. Overall, 9.7% of trial participants were enrolled from North America. This means the US data drove the findings from the North American subgroup.The explanation provided by AstraZeneca (the manufacturer of ticagrelor) to explain the observed treatment effect heterogeneity was that aspirin dosing in the United States was higher than in other countries. It even led the FDA to issue a black box warning to avoid an aspirin maintenance dose of >100 mg in patients taking ticagrelor. An extensive statistical analysis of the regional variation in PLATO yielded four interesting points. First what was the prior likelihood of observing a ticagrelor vs clopidogrel HR of > 1.25 in the US, when the overall HR was actually equal to 0.84? That probability is ≤ 0.01. This alone suggests more than chance. Second point: a strong US/nonUS interaction was noted for each of the 3 components of the primary endpoint—CV death, MI, stroke. Third: they found a very strong interaction between treatment and median aspirin dose, and, importantly, the aspirin interaction effect was similar in US and nonUS settings. Fourth, an analysis of contract research organization (CRO) vs sponsor monitoring of the site accounted for 61% of the treatment-by- region interaction. The authors downplayed this finding because of the four countries monitored by a CRO (Israel, US, Georgia and Russia), the US made up the majority and thus is confounded by the aspirin interaction. Noteworthy was a lack of direct analysis of CRO vs sponsor test for interaction. One problem though: the BMJ investigation found that the lead author, Kevin Carroll was the head statistician at AstraZeneca and had worked at the company for 20 years. Carroll presented the PLATO results at the FDA advisory meeting. The paper lists Carroll as having no conflicts. Carroll told the BMJ that he had disposed of all conflicts of interest before submitting that analysis. But, in our opinion, the aspirin explanation does not pass muster because of biologic implausibility. See next section: How would a higher dose of aspirin reduce the efficacy of ticagrelor?The primary composite endpoint was vascular death, MI or stroke. If the higher aspirin dose impacted this, we would hypothesize that it caused more major bleeding in the ticagrelor group with some events resulting in vascular death, type 2 MI and hemorrhagic stroke, driving the treatment effect in favor of clopidogrel. But there is no evidence of this.The figure below is from the original subgroup plots provided in the PLATO supplement. The difference in the treatment effect for the primary endpoint for North American patients is striking but there is no difference for major bleeding.In our opinion and the opinion of others, the role of supervision of the centers could be important. Most centers were monitored by the sponsor. Four countries (Israel, US, Georgia and Russia) were monitored by a contract research organization. All four of these countries had numerically higher rates of the primary outcome in the ticagrelor group. This has major implications and we do not take them lightly. Essentially, it suggests malfeasance on the part of the sponsor. So is there anything else to support such a claim? Well, yes. 2. Concerns about event adjudication. Based on a report from Victor Serebruany, an adjunct faculty member at Johns Hopkins University, and the BMJ investigation, FDA records indicated that site reports documented 504 myocardial infarctions in patients who received ticagrelor compared to 548 in patients who received clopidogrel. However, after adjudication, the count increased only for the clopidogrel group, reaching 593. There was also some imbalance among groups in adjudicating death. These imbalances raise concerns about potential unblinding and result tampering. We read many of the authors' replies and we did not find a clear explanation of why all readjudicated extra MIs were in the clopidogrel group (45 clopidogrel; ticagrelor 0). 3. There were also concerns about the accuracy of death records as sites death records did not always match the FDA records.We cite from the BMJ: The BMJ's analysis also found omissions in PLATO's landmark publication. The paper, published in NEJM and reported as an intent-to-treat analysis, reports 905 total deaths from any cause among all randomized patients. An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths “discovered after withdrawal of consent.” The BMJ obtained some records for patients whose deaths were not reported in NEJM (see table 1) and asked the journal for a response.NEJM editor in chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice,” concluding that “it does not appear that correcting this 15-year-old article is going to have any impact.”It is noteworthy that the United States Department of Justice launched a formal investigation into the PLATO trial in 2013; however, the probe was closed in 2014. The BMJ column cited a spokesperson for the US attorney's office who said…”we determined that the allegations lacked sufficient merit such that it was not in the best interests of the US to intervene in the suit.” 4. Mortality reduction in PLATO defies explanation: Shortly after PLATO was published, Drs. Victor Serebruany and Dan Atar wrote an editorial in the European Heart Journal titled: The PLATO trial: do you believe in magic? They noted that the overall HR for all-cause death ticagrelor vs clopidogrel was 0.78 (95% CI: 0.69 - 0.89; p< 0.001). There were 107 more lives saved with ticagrelor vs clopidogrel. To explain the surprise of this massive effect size, they compared it to the COMMIT trial of clopidogrel vs placebo in patients with acute MI. In COMMIT, 119 lives were saved with clopidogrel (vs placebo), but COMMIT had three-fold more patients than PLATO—and the gain was vs placebo. They tempt the reader to ask: how could ticagrelor fare that well against a drug that crushed placebo? We note two other reasons to be concerned about the outsized mortality reduction in PLATO. One is plausibility. The all-cause mortality benefit exceeded the reduction in MI, CV death or stroke. Given the numerically higher rate of bleeding, how else does ticagrelor reduce death vs clopidogrel? The second reason is the lack of such a signal in Phase 2 studies, such as this one. 5. PLATO results are on outlier: Multiple observational studies have failed to replicate the benefits of ticagrelor observed in the PLATO trial. While observational studies are inherently limited by confounding factors and are inferior to randomized trials, their findings warrant a re-evaluation of ticagrelor's benefits. Furthermore, two randomized trials—one conducted predominantly in Japanese patients and another in South Korea—did not demonstrate the superiority of ticagrelor, instead showing higher bleeding rates and a numerical increase in ischemic events.Ticagrelor also significantly underperformed against another new antiplatelet drug, prasugrel. In the non-industry-funded ISAR-REACT 5 trial, which enrolled patients with acute coronary syndrome, the primary event of death, MI, or stroke was 36% higher in the ticagrelor arm (9.3% vs 6.9%, HR 1.36, 95% CI: 1.09 - 1.70). Major bleeding was also numerically higher in the ticagrelor arm. 6. PLATO authors have responded to these arguments.We provide links to four of the authors responses. * Thrombosis and Hemostasis https://www.wellesu.com/10.1160/TH11-03-0162* Stroke https://www.ahajournals.org/doi/10.1161/strokeaha.111.000514* Inter J of Cardiol https://doi.org/10.1016/j.ijcard.2014.06.029* Circulation https://doi.org/10.1161/CIRCULATIONAHA.111.047498Conclusion These are vitally important revelations regarding PLATO and ticagrelor. The FDA advisory committee recommended that FDA require a confirmatory trial. This was not done. As such, ticagrelor gained serious market share in the non-clopidogrel antiplatelet market for more than a decade. Yet no other compelling evidence for its benefit over clopidogrel has come to light. It clearly underperformed vs prasugrel. These old and new revelations have changed our positive view of ticagrelor. We no longer have confidence in this drug. We strongly agree with the recommendation for another properly controlled trial. We also believe this highlights the benefits of having either two regulatory trials or a single regulatory trial combined with a mandated post-approval trial. These revelations also emphasize the benefits of robust critical appraisal and skeptical but not cynical approaches to surprising evidence. Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

JACC Associate Editor Seng Chan You, MD, and author Hiroki Ueyama, MD discuss this study presented at AHA and published in JACC. NCDR study finds a steady decline in P2Y12 inhibitor pretreatment for NSTE-ACS in the US, but significant variability persists among operators, institutions, and regions. This practice was not associated with any benefits but was linked to a longer length of stay among those undergoing CABG, underscoring the importance of maintaining efforts to integrate evidence into clinical practice.

In this episode, we dive into the role of microglial cells, the brain's resident immune defenders, and how their chronic activation at the cellular level contributes to neurodegeneration. We'll explore the cellular mechanisms behind microglial activation, including the involvement of P2Y12 receptors and the release of pro-inflammatory cytokines like IL-1β and TNF-α. Additionally, we'll discuss how everyday environmental toxins and stressors can trigger long-term microglial activity, potentially increasing the risk of conditions like Alzheimer's. Topics: 1. Introduction - Overview: Microglia and neurodegeneration. - Environmental toxins affecting microglia. 2. Brain and Microglial Overview - Brain has neurons and glial cells. - Microglia are the brain's immune cells. - Roles: Immune defense, synaptic pruning, neuroprotection. 3. Microglial Immune Function - Constantly monitor for infection and damage. - Activated microglia perform phagocytosis. - Clear debris and maintain brain health. 4. Cellular Mechanisms of Activation - P2Y12 receptors respond to ATP/ADP. - Microglia shift from resting to activated. - Activated microglia are highly phagocytic. 5. Role in Synaptic Pruning - Microglia help in synaptic pruning. - Remove weak synapses for efficient brain circuits. 6. Microglia in Neurodegeneration - Chronic activation leads to inflammation. - Release of cytokines like IL-1β, TNF-α, IL-6. - Contributes to Alzheimer's, Parkinson's. - MHC molecules 7. Environmental Toxins and Activation - Mycotoxins cross BBB and activate microglia - Heavy metals like lead, aluminum affect neurons - Pesticides/herbicides linked to Parkinson's risk 8. Other Factors Activating Microglia - Industrial chemicals, BPA - Artificial additives, alcohol - Chronic stress 9. Conclusion - Recap: Microglial functions and overactivation. - Lifestyle factors influence microglial health. Thank you to our episode sponsors: 1. Check out ⁠⁠⁠⁠⁠⁠⁠Daily Nouri⁠⁠⁠⁠⁠⁠⁠ and use code ⁠⁠⁠⁠⁠⁠⁠CHLOE20⁠⁠⁠⁠⁠⁠⁠ for 20% off your order. 2. Check out the TruAge ⁠Biological Age Test⁠ from ⁠TruMe Labs⁠. Thanks for tuning in! Get Chloe's Book Today! "⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠75 Gut-Healing Strategies & Biohacks⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠" Follow Chloe on Instagram ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Follow Chloe on TikTok @chloe_c_porter Visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠synthesisofwellness.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to purchase products, subscribe to our mailing list, and more! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support

Dr. Valentin Fuster discusses the Augustus trial's groundbreaking findings on antithrombotic strategies for atrial fibrillation patients post-acute coronary syndrome or PCI. The study reveals that a regimen of apixaban and a P2Y12 inhibitor—without aspirin—offers superior safety and efficacy, challenging traditional triple therapy approaches.

N Engl J Med 2024;390:1372-1381Background: Beta-blockers are prescribed to the majority of patients with acute myocardial infarction. The bulk of evidence supporting this practice comes from trials published in the 1980s - BHAT and ISIS-I. Since the publication of these seminal trials, the care of patients with acute myocardial infarction has significantly changed with improvement in antiplatelet therapy, the addition of high-intensity statins and renin–angiotensin–aldosterone system antagonists in addition to early revascularization for STEMI patients. Furthermore, myocardial injury is now detected based on high-sensitivity troponin assays which can detect smaller myocardial infarctions. Therefore, there is a lack of evidence whether beta-blockers provide benefit for patients with acute myocardial infarction in the current era.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The Randomized Evaluation of Decreased Usage of Beta-Blockers after Acute Myocardial Infarction (REDUCE-AMI) trial sought to assess whether long-term oral beta-blocker treatment improves outcomes in patients with acute myocardial infarction and preserved left ventricular ejection fraction.Patients: Eligible patients were adults, 1 to 7 days after myocardial infarction who underwent coronary angiography and echocardiography. Patients were required to have obstructive coronary artery disease on coronary angiography defined as stenosis of ≥50%, a fractional flow reserve of ≤0.80, or an instantaneous wave-free ratio of ≤0.89 at any time point before randomization. Left ventricular Ejection fraction on echocardiogram had to be ≥50%. Patients were excluded if they had contraindications to beta-blockers or if the treating physician determined that treatment with beta-blockers is indicated for other conditions.Baseline characteristics: The trial randomized 2,508 patients to the beta-blockers group and 2,512 patients to the control group. The average age of patients was 65 years with 78% being men. About 20% were current smokers, 46% had hypertension, 14% had diabetes, 7% had prior myocardial infarction and < 1% had prior heart failure.The index event was STEMI in 35% of the patients. About 96% underwent percutaneous coronary intervention. The median heart rate was 74 bpm and the median systolic blood pressure was 151 mm Hg.Medications at discharge included aspirin in 97% of the patients, P2Y12 inhibitors in 96%, ACEi or ARBs in 80% and statins in 99%.Procedures: Patients were randomized 1:1 to receive metoprolol succinate (first choice), bisoprolol (second choice) or no beta-blockers. The target doses were at least 100 mg daily for metoprolol succinate and at least 5 mg daily for bisoprolol. Patients in the control group were discouraged from using beta-blockers; they did not receive placebo. If a patient was on beta-blocker therapy at the time of enrollment and was randomly assigned to the no–beta-blocker group, the beta-blocker had to tapered off over a period of 2 to 4 weeks.Endpoints: The primary end point was a composite of death from any cause or new myocardial infarction. Secondary end points were death from any cause, death from cardiovascular causes, myocardial infarction, hospitalization for atrial fibrillation as primary diagnosis, and heart failure hospitalization. There were three safety endpoints: 1- Hospitalization for bradycardia, second- or third-degree atrioventricular block, hypotension, syncope, or implantation of a pacemaker, 2- hospitalization for asthma or chronic obstructive pulmonary disease as a primary diagnosis and 3- hospitalization for stroke.Data on clinical end points were not centrally adjudicated but rather obtained from the SWEDEHEART registry and the Swedish Population Registry.Statistical analysis was performed based on the intention-to-treat principle. Before trial initiation, the estimated event rate in the control group was 7.2%/ year and at least 16.7% lower event rate in the beta-blocker group was considered clinically meaningful. During the trial, the actual event rate in control group was 3%/ year. Given this event rate, a 25% lower event rate in the beta-blocker group was considered clinically meaningful. A total of 379 primary end point events were needed in order to have 80% power at a two-sided alpha of 0.05, to detect the 25% lower event rate with beta-blockers. The estimated number of patients needed was about 5,000.Results: Among the patients who attended the SWEDEHEART registry, 1500/1831 (81.9%) of the beta-blocker group were still taking beta-blockers after 11 to 13 months; compared to 269/ 1886 (14.3%) in the no beta-blocker group.After a median follow up time of 3.5 years, beta-blockers did not the reduce the composite primary endpoint compared to no beta-blockers (7.9% vs 8.3%, HR: 0.96; 95% CI, 0.79 - 1.16; p= 0.64). There were no significant differences in death from any cause (3.9% vs 4.1%), death from cardiovascular causes (1.5% vs 1.3%), myocardial infarction (4.5% vs 4.7%), hospitalization for atrial fibrillation (1.1% vs 1.4%) or hospitalization for heart failure (0.8% vs 0.9%).Safety endpoints were also not significantly different between both groups; 3.4% vs 3.2% for the bradyarrhythmia, syncope or hypotension endpoint, 0.6% in both groups for the hospitalization for asthma or COPD endpoint and 1.4% vs 1.8% for hospitalization for stroke.There were no significant subgroup interactions.Conclusion: In patients with acute myocardial infarction who underwent coronary angiography and had preserved left ventricular systolic function, treatment with beta-blockers did not improve outcomes over a 3.5-year follow-up. Events were infrequent in the trial; 1.4% for cardiovascular death, 4.6% for recurrent myocardial infarction and 0.8% for hospitalization for heart failure. The low event rate in this population in the current era makes it difficult to demonstrate additional benefit with more therapies.The open-label design of the study may have introduced performance bias; however, this bias is expected to favor beta-blockers given the superiority design of the study. Another limitation, as noted by the authors, is that outcomes were obtained from the SWEDEHEART registry and the Swedish Population Registry and were not centrally adjudicated. However, this is expected to affect both groups equally.We believe the divergent results between this trial and older beta-blocker trials in myocardial infarction patients such as BHAT and ISIS-1 which were published in the 1980s, is due to the significant improvement in the management of acute myocardial infarction over time including improved medical therapy in addition to early revascularization for STEMI patients. This improved patient care has led to significantly lower mortality rates over time. For instance, all-cause death in the control arm of REDUCE-AMI is significantly lower than that of BHAT and ISIS-1, at 4.1% vs 9.8% and 11.9%, respectively. This is despite REDUCE-AMI having a longer follow-up period of 3.5 years compared to 2.1 years and 1 year in the earlier trials.In conclusion, this study does not provide evidence that beta-blockers improve outcomes for patients with acute myocardial infarction and preserved ejection fraction in the contemporary era.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

Commentary by Dr. Valentin Fuster

N Engl J Med 2013;369:999-1010Background: Adding P2Y12 inhibitors to aspirin improves outcomes in patients with acute coronary syndrome. Yet, debate persisted regarding the optimal timing for administering these drugs in patients undergoing percutaneous coronary intervention (PCI). The ATLANTIC trial showed that pre-hospital administration of ticagrelor did not improve outcomes compared to in-hospital administration, in patients with ST elevation myocardial infarction.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The ACCOAST trial sought to test the hypothesis that administering the P2Y12 inhibitor, prasugrel, 2-48 hours before angiography in non-ST elevation myocardial infarction patients is superior to administering it during PCI.Patients: Patients were enrolled if they had non-ST elevation myocardial infarction. Patients were scheduled to undergo angiography with possible PCI within 2-48 hours after randomization. Patients were excluded if they had cardiogenic shock, refractory ventricular arrhythmias, prior hemorrhagic or ischemic stroke or TIA, history of intracranial neoplasms, history of intracranial AV malformations or aneurysm, surgery within 4 weeks, active bleeding or history of bleeding diathesis or had high risk of bleeding based on the judgement of the investigator.Baseline characteristics: The average age of patients was 64 years with 72% being men. The average weight was 82 kg. About 20% had diabetes, 45% had hyperlipidemia, 62% had hypertension and 33% were current smokers. Creatinine clearance was ≤ 30 ml/min in 3% of the patients and GRACE score was < 140 in 77% of them. Beta-blockers were given in 84% of the patients, statins in 90%, angiotensin-receptor blockers in 13% and ACE inhibitors in 70%.After randomization, 68.7% of the patients underwent PCI while 25.1% were treated medically. CABG within 7 days was performed in 6.2% of the patients.Procedures: Patients were randomized 1:1 to receive pretreatment with prasugrel or matching placebo (control group). Those in the pretreatment group received a 30 mg loading dose of prasugrel before coronary angiography with an additional 30 mg if angiography confirmed the need for PCI. Patients in the control group received placebo before coronary angiography and a 60 mg loading dose of prasugrel in patients undergoing PCI. Only the initial 30 mg loading dose of prasugrel or placebo were administered, if a decision, after coronary angiography, was made to pursue CABG or medical therapy.Endpoints: The primary efficacy end point was a composite endpoint of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or the need for rescue therapy with glycoprotein IIb/IIIa inhibitors. Follow up for the primary endpoint was 7 days post randomization. Secondary endpoints included death from any cause, stent thrombosis and a composite endpoint of death from cardiovascular causes, myocardial infarction, or stroke.Safety end points were major or minor bleeding according to Thrombolysis in Myocardial Infarction (TIMI) criteria.Statistical analysis was performed on the intention-to-treat principle. To achieve 80% power with two-sided alpha of 0.05 for detecting 24% relative risk reduction in the pretreatment compared to the control group, 400 patients with the primary outcome and approximately 4,100 enrolled patients would be needed.Results: The trial randomized 2,037 patients to the pre-treatment group and 1,996 to the control group. The median time from the initial loading dose to PCI was 4.3 hours.The incidence of the composite primary end point was similar between both treatment groups (10.0% in the pre-treatment group vs 9.8% in the control group, HR: 1.02, 95% CI: 0.84 – 1.25; p= 0.81). There was no significant difference between both treatment groups in any of the components of the primary end point, death from any cause, or stent thrombosis. Results were similar for patients who underwent PCI (about two thirds of study participants).There were more major bleeding events at 7 days in the pretreatment group (2.6% vs 1.4%, HR: 1.90, 95%: 1.19 – 3.02; p= 0.006). Major bleeding events not related to CABG were also higher in the pre-treatment group (1.3% vs 0.5%; p= 0.003). In the PCI cohort, 12 patients in the pre-treatment group had life-threatening bleeding compared to 2 in the control group. Most bleedings in this cohort were access site bleeding, pericardial bleeding and retroperitoneal bleeding.Subgroup analysis for the primary efficacy endpoint did not identify any subgroup who would benefit from pre-treatment with prasugrel.Conclusion: In patients with non-ST elevation myocardial infarction undergoing coronary angiography within 48 hours of admission, pre-treatment with prasugrel did not improve ischemic events and resulted in more major bleeding.The results of this trial led to the recommendation that prasugrel should be used after coronary anatomy is defined and PCI is chosen as the treatment strategy. This approach will reduce the risk of bleeding complications without increasing the risk of ischemic events.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

N Engl J Med 2014;371:1016-1027Background: Prior trials have demonstrated that combining P2Y12 inhibitors with aspirin in patients with acute coronary syndrome reduces cardiovascular events. Prasugrel, in the TRITON-TIMI 38 trial, and ticagrelor, in the PLATO trial, were administered in the hospital.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.Older trials had suggested that early administration of glycoprotein IIb/IIIa inhibitors improves outcomes in patients with ST elevation myocardial infarction (STEMI).The ATLANTIC trial sought to test the hypothesis that pre-hospital compared to in-hospital administration of the P2Y12 inhibitor, ticagrelor, improves outcomes in patients with STEMI.Patients: Patients were enrolled if they had STEMI and had experienced symptoms for at least 30 minutes but no longer than 6 hours, and were expected to have EKG to balloon inflation of less than 120 minutes. Patients were excluded if they had prior intracranial bleeding, moderate to severe liver disease, gastrointestinal bleeding within 6 months, planned fibrinolytic therapy or required dialysis.Baseline characteristics: The average age of patients was 61 years with 80% being men. The average weight was 80 kg. About 14% had diabetes, 9% had prior myocardial infarction, 4% had chronic obstructive pulmonary disease and 2% had chronic renal failure. TIMI risk score was 0-2 in 61% of the patients. About 90% had Killip class I. Coronary angiography was performed in 98% of the patients and percutaneous coronary intervention (PCI) with stent placement was performed in 82%. The use of glycoprotein IIb/IIIa inhibitors was high in the study and was administered before percutaneous coronary intervention in 29% of the patients.Procedures: Patients were randomized 1:1 to receive ticagrelor en route to the hospital/ catheterization lab (group 1) or at the catheterization lab (group 2). In group 1, patients received ticagrelor 180mg en route to the hospital and placebo in the catheterization lab. In group 2, patients received placebo en route to the hospital and ticagrelor 180mg in the catheterization lab. Following that, all patients received ticagrelor 90mg twice daily for at least 30 days and the treatment was recommended to continue for 12 months. Clinical endpoints were adjudicated up to 30-days post randomization.Endpoints: There were two coprimary endpoints – proportion of patients who did not have 70% or greater resolution in their ST-segment elevation before PCI and proportion of patients without TIMI grade III flow in the infarcted artery before PCI. Review of EKG and angiographic data was blinded.A secondary prespecified endpoint included the composite of all-cause death, myocardial infarction, stent thrombosis, stroke or urgent revascularization at 30 days.Analysis was performed based on the modified intention-to-treat principle, defined as patients who received at least one loading dose of the study drug. Patients with missing EKG or angiographic data were excluded from the primary endpoint analysis.The sample size estimate was based on an anticipated event rate of 15% in the control group for the EKG endpoint. They estimated that 779 patients would be needed in each group to show a 6% absolute difference with 80% power and an alpha of 2.5%.Results: The trial randomized 1,862 patients, 909 patients to the prehospital group and 953 to the in-hospital group. The median time from randomization to angiography was 48 minutes and the median time between the two loading doses was 31 minutes.There was no significant difference in the proportion of patients who did not have 70% or more ST segment resolution before PCI (86.8% for the pre-hospital group vs 87.6% for the in-hospital group, OR: 0.93, 95% CI: 0.69 – 1.25; p= 0.63) or the proportion of patients who did not have TIMI III flow in the infarcted artery before PCI (82.6% for the pre-hospital group vs 83.1% for the in-hospital group, OR: 0.97, 95% CI: 0.75 – 1.25; p= 0.82).There was also no significant difference for the secondary composite endpoint (4.5% vs 4.4%, OR: 1.03, 95% CI: 0.66 – 1.60; p= 0.91). Stent thrombosis at 30-days was lower in the pre-hospital group (0.2% vs 1.2%, OR: 0.19, 95% CI: 0.04 – 0.86; p= 0.02). Myocardial infarction was not significantly different between both groups (0.8% vs 1.1%; p= 0.53). All-cause death was numerically higher in the pre-hospital group (3.3% vs 2.0%, OR: 1.68, 95% CI: 0.94 – 3.01; p= 0.08).Major bleeding not related to CABG was not significantly different between both treatment groups (1.3% in both groups using the TIMI criteria and 2.9% in the pre-hospital group vs 2.5% in the in-hospital group, using the STEEPLE criteria).Conclusion: In patients with STEMI, pre-hospital administration of ticagrelor did not improve outcomes compared to in-hospital administration. Although pre-hospital administration of ticagrelor reduced stent thrombosis at 30-days, this did not reduce all-cause mortality. In fact, all-cause mortality was numerically higher in the pre-hospital group.A notable finding is that within the in-hospital group, definite stent thrombosis occurred in 1.2% of patients while 1.1% were adjudicated to have myocardial infarction. Stent thrombosis is a serious condition that leads to myocardial infarction. The trial protocol used many definitions for myocardial infarction. This underscores the complexity of counting and adjudicating events in clinical trials and highlights the importance of relying on outcomes less susceptible to bias, such as mortality.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Get full access to Cardiology Trial's Substack at cardiologytrials.substack.com/subscribe

Commentary by Dr. Valentin Fuster

N Engl J Med 2009;361:1045-57.Background Similar to Prasugrel, Ticagrelor is a direct-acting oral antagonist of the adenosine diphosphate receptor P2Y12. Unlike clopidogrel that requires transformation of the prodrug to the active metabolite, Ticagrelor provides faster and more consistent P2Y12 inhibition.In the TRITON-TIMI 38 trial, Prasugrel compared to clopidogrel reduced myocardial infarction in patients with ACS but was associated with more major bleeding and subgroup interactions were evident for patients who were older, had a history of stroke or risk factors for bleeding and who were generally at higher risk for recurrent events.The Study of Platelet Inhibition and Patient Outcomes (PLATO) sought to test the hypothesis that Ticagrelor is superior to clopidogrel for the prevention of vascular events and death in patients presenting with ACS.Cardiology Trial's Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients Eligible patients were hospitalized for ACS, with or without ST-segment elevation (STE), whose onset of symptoms occurred within the previous 24 hours. For patients without STE, at least 2 of the following criteria were required: 1) ST-segment changes on ECG indicating ischemia, 2) a positive biomarker indicating myocardial necrosis, or 3) one or more risk factors including age ≥60 years, previous MI or CABG, CAD with stenosis of ≥50% in at least 2 vessels, history of ischemic stroke, TIA, carotid stenosis, cerebral revascularization, diabetes, peripheral arterial disease or CKD based on creatinine clearance

In our latest episode, we venture into the heart of cardiology innovation, exploring groundbreaking studies that are reshaping how we approach common cardiovascular conditions.   STUDY #1: Our journey begins with a Lancet paper that looks at a potential alternative for treating supraventricular tachycardias (SVTs). Imagine a world where the distress of SVTs can be alleviated without ablation, a rush to the emergency department or the complexities of intravenous therapy. An intranasal medication might be the key, offering a beacon of hope for patients seeking simpler, yet effective solutions. But how effective is this approach, and what does it mean for the future of SVT management? Stambler, BS, Camm, AJ, Alings, M, et al. 2023. Self-administered intranasal etripamil using a symptom-prompted, repeat-dose regimen for atrioventricular-nodal-dependent supraventricular tachycardia (RAPID): A multicentre, randomized trial. Lancet. 10396: 118–128. (https://doi.org/10.1016/S0140-6736(23)00776-6)   STUDY #2: Transitioning to the realm of antiplatelet therapy, we confront the longstanding question of P2Y12 inhibitors versus aspirin. Will these new findings tilt the balance and shift our approach to secondary coronary prevention? The nuances of this study prompt a deeper reflection on patient-centric care and the economics of new-generation medications.  Gragnano, F, Cao, D, Pirondini, L, et al. 2023. P2Y12 inhibitor or aspirin monotherapy for secondary prevention of coronary events. J Am Coll Cardiol. 2: 89–105. (https://doi.org/10.1016/j.jacc.2023.04.051)   STUDY #3: Lastly, we explore the potential of bempedoic acid in the landscape of cholesterol management, particularly for patients who are intolerant to statins. With cardiovascular diseases looming as a pervasive threat, the quest for alternative treatments is critical. We see if bempedoic acid could play a potential role in reducing major cardiovascular events, either alongside, or perhaps in lieu of, traditional statin therapy. Nissen, SE, Menon, V, Nicholls, SJ, et al. 2023. Bempedoic acid for primary prevention of cardiovascular events in statin-intolerant patients. JAMA. 2: 131–140. (https://doi.org/10.1001/jama.2023.9696) Kazi, DS. 2023. Bempedoic acid for high-risk primary prevention of cardiovascular disease: Not a statin substitute but a good plan B. JAMA. 2: 123–125. (https://doi.org/10.1001/jama.2023.9854)   Each study we discuss brings its own set of questions, implications, and possibilities for the future of cardiology. From the practicalities of new drug administrations to the cost and effectiveness of established therapies, this episode will get you up to speed!  For show notes, visit us at https://www.medmastery.com/podcasts/cardiology-podcast.

CardioNerds co-founder Dr. Amit Goyal, series co-chair Dr. Colin Blumenthal, and episode lead Dr. Anushka Tandon to discuss pharmacologic anticoagulation options in atrial fibrillation with Drs. Ashley Lochman and Chris Domenico. The case-based review helps clarify some key concepts, such as when warfarin is preferred for anticoagulation, who may be a good DOAC (direct-acting oral anticoagulant) candidate, how to choose an appropriate DOAC agent, and how to manage anticoagulation therapy in patients already on antiplatelet therapies. Notes were drafted by Dr. Anushka Tandon. The episode audio was edited by student Dr. Shivani Reddy. This CardioNerds Atrial Fibrillation series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Kelly Arps and Dr. Colin Blumenthal. This episode was planned and recorded prior to the release of the 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation. Please refer to this guideline document for the most updated recommendations. We have collaborated with VCU Health to provide CME. Claim free CME here! CardioNerds Atrial Fibrillation PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes - Anticoagulation Pharmacology Avoid potentially fatal errors with this terminology tip for correctly referencing non-warfarin oral anticoagulant agents: it's DOAC (like, please DO use AntiCoagulation), not NOAC (imagine someone interpreting that as “NO AntiCoagulation for this patient” at discharge – yikes)! Sometimes, an oldie really is a goodie – warfarin is recommended over DOACs for patients with mechanical heart valves, moderate-to-severe mitral stenosis, anti-phospholipid antibody syndrome (APLS), left ventricular (LV) thrombus, higher INR goals, or DOAC failure. Patient preference and medication costs should also be considered – at the end of the day, “the best drug is the drug that a patient is willing to take!” Standard-dose rivaroxaban or apixaban may be considered for use in patients weighing >120kg or with BMI >40; use of other DOACs should be limited to pts weighing =/< 120kg or with BMI =/< 40. The pharmacists involved in this podcast promise they don't have stock in apixaban! It just often happens to be the preferred DOAC option in certain scenarios – think patients with severe renal impairment (including ESRD) or with an increased risk for bleeding events (including older adults, those with a history of GI bleed, etc). In general, dual therapy (DOAC or warfarin + P2Y12 inhibitor) is non-inferior to triple therapy (oral anticoagulant + P2Y12 inhibitor + aspirin) at preventing thrombotic events but is associated with a lower risk of bleeding events. Most patients can be transitioned to dual therapy after 7-30 days on triple therapy post-percutaneous coronary intervention. What's that on the horizon? Factor XI inhibitors may become the breakout stars of anticoagulation – multiple investigational agents are being studied for their potential to reduce thrombotic risk without significantly increasing bleeding risk in patients with indications for anticoagulation therapy…at least that's the theorize hope. Watch this space! Notes - Anticoagulation Pharmacology In which cases is warfarin preferred over DOACs in patients with atrial fibrillation? Long-term anticoagulation with warfarin is indicated in patients with atrial fibrillation and either a mechanical valve or moderate-to-severe mitral stenosis (i.e., valvular atrial fibrillation as defined in the 2019 AHA/ACC/HRS guidelines on atrial fibrillation [1]). The REALIGN trial [2] showed increased rates of thromboembolic and bleeding complications with dabigatran vs.

Case Discussion 99: P2Y12 choice for PCI after fibrinolytic Tx

Acute Coronary Syndromes (ACS) Special Guest: Nick Servati, PharmD, BCCP 04:55 – Pathophysiology/Clinical presentation 12:40 – “MONA” myths 20:05 – P2Y12 pretreatment 24:25 – Thrombolytics in ACS 30:35 – Anticoagulation 38:55 – Vasopressors/Inotropes 49:50 – IV antiplatelet agents 60:10 – STEMI pharmacotherapy checklist 66:00 – Future research/Take-home points Reference List: https://pharmacytodose.files.wordpress.com/2023/09/acute-coronary-syndromes-references.pdf PharmacyToDose.Com  @PharmacyToDose  PharmacyToDose@Gmail.com Learn more about your ad choices. Visit megaphone.fm/adchoices

Marco Valgimigli and C. Michael Gibson discuss the PANTHER trial, which compared P2Y12 inhibitor monotherapy with aspririn monotherapy in patients with coronary artery disease.

Herkese merhaba. Bildiğiniz üzere ESC (Avrupa Kardiyoloji Cemiyeti) Akut Koroner Sendrom Kılavuzu'nu geçtiğimiz hafta yayınlandı ve biz de çok hızlıca çevirisine başladık. ESC bu kez eski kılavuzlarından farklı olarak NSTEMI VE STEMI'yi tek bir kılavuz halinde yayımladı. ESC, NSTEMI klavuzunu en son 2020 yılında yayımlamışken, STEMI kılavuzunu ise 2017 yılında yayımlamıştı. Şimdi gelin beraber bu yepyeni 2023 AKS kılavuzunu incelemeye kaldığımız yerden devam edelim. Kısaltmalar Konuya geçmeden önce yazı içindeki bazı kısaltmalar: AKS: Akut koroner sendrom STEMI: ST yükselmeli miyokard enfarktüsü NSTEMI : ST yükselmesi olmayan miyokard enfarktüsü PKG / PPKG: Perkutan koroner girişim / Primer perkutan koroner girişim NSTE-AKS: ST yükselmesi olmayan akut koroner sendrom LD: yükleme dozu MD: idame dozu HBR: yüksek kanama riski DAPT: ikili antiplatelet tedavisi UFH: fraksiyone olmamış heparin OAK: Oral antikoagulanlar NOAK: Yeni nesil antikoagulanlar VKA: vitamin k antagonisti DAT: İkili antitrombotik tedavi TAT: Üçlü antitrombotik tedavi SAPT: Aspirin yerine P2Y12 reseptör inhibitörünün (genellikle klopidogrel) tercih edilmesi MACE: majör olumsuz kardiyovasküler olaylar CABG:Koroner arter bypass greftleme Sınıflar ve Düzeyler Kılavuzda geçen öneri sınıf tanımları ve kanıt düzey tanımlamaları aşağıdaki gibidir. Sınıf tanımlamaları Kanıt düzeyi tanımlamaları ANTİTROMBOTİK TEDAVİ AKS yönetiminde ve tedavisinde antitrombotik tedavi büyük önem taşımaktadır. Tedavide spesifik seçim ve kombinasyon, başlama zamanı ve süresi ise hastaya ve çeşitli faktörlere bağlıdır. Antitrombotik tedavinin faydaları olduğu gibi, ciddi veya yaşamı tehdit edebilecek kanama riski de mevcut olduğundan; kar-zarar oranına göre karar tartışılarak verilmelidir. Önerilen antikoagülan ve antiplatelet ilaçlar ve bunların dozları (AKS sırasında ve sonrasında kullanım için) Tablo 1'de özetlenmiştir. Tablo-1. AKS'de antiplatelet ve antikoagülan ilaçlar ve doz rejimi Erken dönemde antiplatelet tedavi Oral antiplatelet tedavi Antiplatelet ilaçlar AKS tedavisinin ilk ve erken döneminde önemli bir rol oynar. Mevcut oral ve iv formlarına üstteki tablo 1'den bakabilirsiniz. Antiplatelet seçiminde hastanın kanama riski de dikkate alınmalıdır. Yüksek kanama riskiyle ilişkili faktörler, Yüksek Kanama Riski Akademik Araştırma Konsorsiyumu (ARC-HBR) tarafından ayrıntılı olarak açıklanmıştır. Tablo 2'de olan bir majör veya iki minör ARC-HBR risk faktörünün varlığı yüksek kanama riskini (HBR) gösterir. Çoklu majör risk faktörlerinin varlığının ise kanama riskinde ilerleyici bir artışla ilişkili olduğuna dikkat edilmelidir. Tablo-2. PKG'de HBR için Majör ve Minör Kriterler  Aspirin tedavisine mümkün olan en kısa sürede başlanır. Tablo 1'de de gördüğümüz gibi LD 150- 300 mg oral olarak verilir ve ardından idameye geçilir.  MD olarak günde bir kez 75-100 mg oral tercih edilir. AKS hastalarında ikili antiplatelet tedavisi, aspirin ve P2Y12 reseptör inhibitor (prasugrel veya tikagrelor), yapılan çalışmalar ile önerilmektedir. Yine yapılan çalışmalarda PKG'ye gidecek AKS hastalarında tikagrelor yerine prasugreli önermiştir. Daha az etkili ve daha fazla değişken trombosit inhibisyonu ile karakterize klopidogrel ise yalnızca prasugrel veya tikagrelorun kontrendike olduğu/mevcut olmadığı durumlarda veya HBR mevcutsa (≥1 majör kriter veya ≥2 minör kriter) kullanılmalıdır. Ayrıca yaşlı hastalarda (≥70 yaş) klopidogrel kullanımı da düşünülebilir. Oral antiplatelet tedavide ön tedavi Hem aspirin hem de oral P2Y12 inhibitörleri, oral LD'yi takiben trombosit inhibisyonunu daha hızlı sağlar. Ön tedavi, koroner anjiyografiden önce ve dolayısıyla koroner anatomi bilinmeden önce genellikle bir P2Y12 reseptör inhibitörü olan bir antitrombosit ilacın verildiği bir yaklaşımı ifade eder. Her ne kadar AKS'de ön tedavinin potansiyel bir faydası olduğu varsayılsa da,

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.24.550176v1?rss=1 Authors: Ma, C., Li, B., Silverman, D., Ding, X., Li, A., Xiao, C., Huang, G., Worden, K., Muroy, S., Chen, W., Xu, Z., Tso, C. F., Huang, Y., Zhang, Y., Luo, Q., Saijo, K., Dan, Y. Abstract: Sleep interacts reciprocally with immune system activity, but its specific relationship with microglia - the resident immune cells in the brain - remains poorly understood. Here we show that microglia can regulate sleep through a mechanism involving Gi-coupled GPCRs, intracellular Ca2+ signaling, and suppression of norepinephrine transmission. Chemogenetic activation of microglia Gi signaling strongly promoted sleep, whereas pharmacological blockade of Gi-coupled P2Y12 receptors decreased sleep. Two-photon imaging showed that P2Y12/Gi activation elevated microglia intracellular Ca2+, and blockade of this Ca2+ elevation largely abolished the Gi-induced sleep increase. Microglia Ca2+ level also increased at natural wake-to-sleep transitions, caused partly by reduced norepinephrine. Furthermore, imaging of norepinephrine activity with its biosensor showed that microglia P2Y12/Gi activation significantly reduced norepinephrine, partly by increasing the adenosine concentration. Thus, microglia can regulate sleep through reciprocal interactions with norepinephrine transmission. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Commentary by Dr. Valentin Fuster

⁠DozeNews PRIME⁠: as melhores e mais didáticas revisões de cardiologia direto na sua caixa de entrada! Assine agora e tenha acesso à todo material já produzido! - ⁠https://dozeporoito.substack.com/

In this week's View, Dr. Eagle discusses P2Y12 inhibitor monotherapy or dual antiplatelet therapy after complex percutaneous coronary interventions, then looks at practical approaches to genetic screening in cardiomyopathies. Finally, Dr. Eagle explores long-term outcomes of perioperative myocardial infarction or injury after non-cardiac surgery.   Subscribe to Eagle's Eye View  

Commentary by Dr. Valentin Fuster

Please join author Pieter Martens and Associate Editor Justin Grodin as they discuss the article "Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Prespecified Analysis From the ADVOR Trial." Dr. Greg Hundley: Welcome listeners to this January 17th issue of Circulation on the Run. And I am Dr. Greg Hundley, Director at the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: And I'm Dr. Peder Myhre from Akershus University Hospital and University of Oslo, in Norway. And today, Greg, we have such an exciting feature paper. It comes to us from the ADVOR trialists. And the ADVOR trial examined the effect of acetazolamide in acute decompensated heart failure. And in this paper we're going to discuss how that treatment effect was across the left ventricular ejection fraction, across the spectrum. Greg, what do you think? Dr. Greg Hundley: Oh, wow. Sounds very interesting. But we might have some other articles in the issue. How about we grab a cup of coffee and Peder maybe this week, I'll go first and we'll start with preclinical science. How about that? Dr. Peder Myhre: Let's do preclinical science, Greg. Dr. Greg Hundley: Well, Peder, this particular paper focuses on the relationship between cardiac fibroblasts and cardiomyocytes. Remember that myocytes sit on a lattice of network of fibroblasts. And when the myocytes die, the fibroblasts then proliferates, secrete collagen and form this thick scar. Now, if we're going to try to regenerate, how are we going to get myocytes to get back into that thick scar when there's really a complete absence? And so as adult cardiomyocytes have little regenerative capacity, resident cardiac fibroblasts synthesize extracellular matrix, post myocardial infarction to form fibrosis, leading to cardiac dysfunction and heart failure. And therapies that can regenerate the myocardium and reverse fibrosis in the setting of a chronic myocardial infarction are lacking. Now, these investigators led by Professor Masaki Ieda from University of Tsukuba, were going to evaluate this process. The overexpression of cardiac transcription factors, including Mef2c, Gata4, Tbx5, Han2, all combined as MGTH. They can directly reprogram cardiac fibroblasts into induced cardiomyocytes and improve cardiac function in and under the setting of an acute myocardial infarction. However, the ability of an in vivo cardiac reprogramming to repair chronic myocardial infarction with established scars, well, that is really undetermined. Dr. Peder Myhre: Oh, what a wonderful introduction, Greg. And the way you described to us how cardiomyocytes and fibroblasts interact was really fascinating. Thank you. And now let's hear what the authors found and don't forget the clinical implications. Dr. Greg Hundley: Thanks, Peder. So these authors developed a novel transgenic mouse system where cardiac reprogramming and fibroblasts lineage tracing could be regulated spatiotemporally with tamoxifen treatment to analyze in vivo cardiac reprogramming in the setting of chronic MI. Then with this new model, the authors found in vivo cardiac reprogramming generates new induced cardiomyocytes from resident cardiac fibroblasts that improves cardiac function and reduces fibrosis in chronic myocardial infarction in mice. Wow. And additionally, they found that overexpression of cardiac reprogramming factors converts profibrotic cardio fibroblasts to a quiescent state, and that reverses fibrosis in chronic myocardial infarction. And therefore, Peder, direct cardiac reprogramming may be a promising therapy for chronic ischemic cardiomyopathies and heart failure. Really exciting work, converting scar tissue to actual functional cardiomyocytes. Dr. Peder Myhre: That was such a fantastic summary, Greg, and a very interesting paper. And I'm now going to take us back to clinical science and epidemiology. Because Greg, we all know that social and psychosocial factors are associated with cardiovascular disease risk. But the relative contributions of these factors to racial and ethnic differences in cardiovascular health has not been quantified. So these authors, led by the corresponding author, Nilay Shah from Northwestern University Feinberg School of Medicine in Chicago, used data from NHANES to examine the contributions of individual level social and psychosocial factors to racial and ethnic differences in population cardiovascular health. And that was measured by something called the cardiovascular health score, CVH score, which ranges from zero to 14, and it counts for diet, smoking, physical activity, body mass index, blood pressure, cholesterol, and blood glucose. Dr. Greg Hundley: Wow, really interesting, Peder. So what did they find here? Dr. Peder Myhre: So Greg, among males, the mean cardiovascular health score was 7.5 in Hispanic, 8.7 in non-Hispanic Asian, 7.5 in non-Hispanic black, and 7.6 in non-Hispanic white adults. And the authors found that the education explained the largest component of cardiovascular health differences among males. And now what about females? In females, the mean score was 8.0 in Hispanic, 9.3 in non-Hispanic Asian, 7.4 in non-Hispanic black, and 8.0 in non-Hispanic white adults. And for women, education explained the largest competence of cardiovascular health difference in non-Hispanic black. And place of birth, and that is US born versus born outside the US, explained the largest component of cardiovascular health difference in Hispanic and non-Hispanic Asian females. So Greg, the authors conclude that education and place of birth conferred the largest statistical contributions to the racial and ethnic differences in cardiovascular health among US adults. Dr. Greg Hundley: Very nice, Peder. What a beautiful description and outline that so well highlighting the differences in men versus women. Well, now we're going to turn back to the world of preclinical science, listeners. And we will continue with the paper by Dr. Amit Khera from Verve Therapeutics. Now, Peder, VERVE-101, this is an investigational in vivo CRISPR base editing medicine designed to alter a single DNA base in the PCSK9 gene. And that permanently turns off hepatic protein production and thereby, durably lowers LDL cholesterol. In this study, the investigators tested the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of non-human primates and also in a murine F1 progeny study. Dr. Peder Myhre: So more on PCSK9s, and this time CRISPR technology. Very exciting. Greg, what did they find? Dr. Greg Hundley: Right, Peder. So VERVE-101 was well tolerated in non-human primates and led to, listen to this, an 83% lower blood PCSK9 protein and 69% lowering of LDL-C with durable effects up to 476 days following the dosing. These results have supported initiation of a first inhuman clinical trial. That's what needs to come next in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease. Wow. Dr. Peder Myhre: Even greater reductions from this therapy on PCSK9 than the previous PCSK9 inhibitor therapies. Wow. Okay, Greg, and now we go from one fascinating study to another. And this time we actually have the primary results from a large randomized clinical trial, Greg. Isn't that exciting? Dr. Greg Hundley: Yes. Dr. Peder Myhre: And this paper describes the primary results of a trial testing in Indobufen versus aspirin on top of clopidogrel in patients undergoing PCI with drug-eluting stent DES who did not have elevated troponin. So that is patients without mycardial infarction. And in fact, fact, this is the first large randomized control trial to explore the efficacy and safety of aspirin replacement on top of P2Y12 inhibitor in patients receiving PCI with death. And Greg, I suppose you like I wonder what Indobufen is, and I just learned that that is a reversible inhibitor of platelet Cox-1 activity and it has comparable biochemical and functional effects to dose of aspirin. And previous data indicate that Indobufen could lessen the unwanted side effects of aspirin and that includes allergy intolerance and most importantly, aspirin resistance, while it retains the antithrombotic efficacy. Dr. Greg Hundley: Wow, Peder. Really interesting and great explanation. Indobufen. So how did they design this trial and what were the primary results? Dr. Peder Myhre: So Greg, the investigators of this trial, called OPTION, led by corresponding authors, Drs. Ge, Quian, and Wu from Fudan University in Shanghai, randomized 4,551 patients from 103 center to either indobufen based DAPT or conventional, and that is aspirin based DAPT for 12 months after DES implementation. And the trial was open label and with a non-inferiority design, which is important to keep in mind. And the primary endpoint was a one year composite of cardiovascular death, non-fatal MI, ischemic stroke, definite or probable stent thrombosis or bleeding, defined as BARC criteria type 2, 3, or 5. And now Greg, the primary endpoint occurred in 101, that is 4.5% of patients in the indobufen based DAPT group compared to 140, that is 6.1% patients, in the conventional DAPT group. And that yields an absolute difference of 1.6%. And the P for non-inferiority was less than 0.01. And the hazard ratio was 0.73 with confidence intervals ranging from 0.56 to 0.94. And Greg, the occurrence of bleeding was particularly interesting and that was also lower in the indobufen based DAPT group compared to the conventional DAPT group. And that was 3.0% versus 4.0% with the hazard ratio of 0.63. And that was primarily driven by a decrease in BARC type two bleeding. So Greg, the authors conclude that in Chinese patients with negative cardiac troponin undergoing DES implementation, indobufen plus clopidogrel DAPT compared with aspirin plus clopidogrel DAPT significantly reduced the risk of one year net clinical outcomes, which was mainly driven by reduction in bleeding events without an increase in ischemic events. Dr. Greg Hundley: Very nice, Peder. So another reversible inhibitor of platelet COX-1 activity, indobufen. And seems to be very, have high utility in individuals of Chinese ethnicity and Asian race. Well, perhaps more to come on that particular drug. Peder, how about we dive into some of the other articles in the issue? And I'll go first. So first, there's a Frontiers article by Professor Beatty entitled “A New Era and Cardiac Rehabilitation Delivery: Research Gaps, Questions, Strategies and Priorities.” And then there's a Research Letter by Professor Zuurbier entitled, “SGLT-2 inhibitor, Empagliflozin, reduces Infarct Size Independent of SGLT-2.” Dr. Peder Myhre: And then Greg, we have a new ECG challenge by Drs. Haghighat, Goldschlager and Oesterle entitled, “AV Block or Something Else?” And then there is a Perspective piece by Dr. Patrick Lawler entitled, “Models for Evidence Generation During the COVID-19 Pandemic: New Opportunities for Clinical Trials in Cardiovascular Medicine.” And Greg, there's definitely so much to learn from all the research that has been done through the pandemic. And finally, we have our own Molly Robbins giving us Highlights from the Circulation Family of Journals. And first, there is a paper describing the characteristics of postoperative heart block in patients undergoing congenital heart surgery described in Circulation: Arrhythmia Electrophysiology. Next, the impact of socioeconomic disadvantages on heart failure outcomes reported in Circulation: Heart Failure. Then there is social and physical barriers to healthy food explored in circulation, cardiovascular quality and outcomes. And then there is the association of culprit-plaque morphology with varying degrees of infarct, myocardial injury size reported in Circulation: Cardiovascular Imaging. And finally, the impact of optical coherence tomography on PCI decisions reported in circulation cardiovascular interventions. Dr. Greg Hundley: Fantastic, Peder. Well, how about we get off to that feature discussion? Dr. Peder Myhre: Let's go. Dr. Mercedes Carnethon: Well, thank you and welcome to this episode of the Circulation on the Run Podcast. I'm really excited today to host this show. My name is Mercedes Carnethon. I'm an associate editor at Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine. I'm really excited to learn from the lead author of a new study on decongestion with Acetazolamide and acute decompensated heart failure across the spectrum of LV ejection fraction. And I've got the lead author with me today, Pieter Martens, as well as my colleague and associate editor Justin Grodin, who handled the paper. So I'd love to start off with just welcoming you, Dr. Martens. Dr. Pieter Martens: Thank you for having me. It's a pleasure to be here today. Dr. Mercedes Carnethon: Yes. And thank you so much for submitting your important work to the journal, Circulation. I'd love to start to hear a little bit about what was your rationale for carrying out this trial and tell us a little bit about what you found. Dr. Pieter Martens: So the ADVOR trial was a double blind placebo controlled randomized trial, which was performed in Belgium. And it set out to assess the effect of acetazolamide in acute decompensated heart failure and this on top of standardized loop diuretic therapy and patients with heart failure. And the goal of the current analysis was to assess whether the treatment effect of acetazolamide in acute heart failure differs amongst patients with a different ejection fraction at baseline at randomization. So we looked specifically at patients with heart failure, reduced, mildly reduced and preserved ejection fraction to determine whether acetazolamide works equally well in those patients. Dr. Mercedes Carnethon: Well, thank you so much. Tell me a little more. What did you find? Did your findings surprise you? Dr. Pieter Martens: All patients that were randomized in the ADVOR trial, we registered a baseline left ventricular ejection fraction at baseline. And what we saw was at the multiple endpoints that we collected in the ADVOR trial, that randomization towards acetazolamide was associated with a pronounced and preserved treatment effect. And different endpoints that we looked at was a primary endpoint which was successful, which is an important endpoint, which we all strive towards in acute decompensated heart failure. And we saw that irrespective of what your baseline ejection fraction was, that randomization towards acetazolamide was associated with a higher odds ratio for having successful decongestion. And also looking at other endpoints which we find important in the treatment of patients with acute compensated heart failure, such as renal endpoints such as the diuresis, the amount of urine that they make, or the natruresis, the amount of sodium that they excrete, we again saw that randomization towards acetazolamide was associated with a higher treatment effect, so more diuresis, more natruresis, which was not effective, whether you had heart failure, reduced, mildly reduced or preserved eject fraction. We did see a slight increase in the creatinine, which was a little bit more pronounced in patients with heart failure with reduced ejection fraction. Dr. Mercedes Carnethon: Thank you so much for that excellent summary. I'm an epidemiologist, so I'm certainly aware that of the cardiovascular diseases and their changes over time, heart failure is one that is going up over time and affecting more of the population. So I know I really enjoyed hearing about an additional therapy that helps to improve quality of life and improve clinical outcomes in individuals who are experiencing heart failure. And I'm really curious as I turn to you, Justin, what attracted you to this particular article and why did you find it to be such a good fit for our audience here at Circulation? Dr. Justin Grodin: Well, Mercedes, I mean, I think you hit the nail on the head with your comment. And clearly when we look at Medicare beneficiaries in the United States, hospitalization for decompensated heart failure is the number one or most common cause for hospitalization. And up to this time, we really haven't had any multi-center randomized control clinical trials that have really informed clinical care with a positive result or a novel strategy that says, "Hey, this might be a better way to treat someone in comparison with something else." And so when we have a clinical trial like ADVOR, one of the crucial things that we want to understand is how does this work and does it work for everybody? And now when we look at the population hospitalized with heart failure, we know that approximately half of them have a weak heart or low ejection fraction, and the other half have a stiff heart, a normal ejection fraction. And so since we've got this 50/50 makeup, it is a crucially important question to understand if we have an important study like ADVOR, does this apply? Are these benefits enjoyed by all these individuals across the spectrum? Dr. Mercedes Carnethon: Thank you so much for really putting that in context. And I believe you had some additional questions for Dr. Martens. Dr. Justin Grodin: Yes. Yeah, thank you. So Pieter, I mean obviously this was a terrific study. One question I had for you guys is, you and your colleagues and the ADVOR research team is whether you had expected these results. Because we know at least historically, that there might be different cardiorenal implications for individuals that have a weak heart or heart failure with reduced ejection fraction in comparison with a stiff heart or heart failure with preserved ejection fraction. Dr. Pieter Martens: Thank you for that comment. And thank you also for the nice feedback on the paper. I think we were not really completely surprised by the results. I think from a pathophysiologic perspective, we do wonder whether heart failure with reduced ejection fraction from a kind of renal perspective is different from heart failure with preserved ejection fraction. Clearly, there are a lot of pathophysiological differences between heart failure with reduced, mildly reduced and preserved ejection fraction. But when it comes to congestion and acute heart failure, they seem to behave, or at least similarly in terms of response to acetazolamide, which was very interesting. We do think there are neurohormonal differences between heart failure reduced ejection fraction, preserved ejection fraction. But at least how acetazolamide works seems relatively unaffected by the ejection fraction. Dr. Justin Grodin: And Pieter, another question that comes to mind, and this is getting a little bit technical, but there have been studies that have shown that people that present to the hospital with decompensated heart failure, that have HFpEF, have a very different perhaps congestion phenotype where they might not have as much blood volume expansion. And so I, for one, was pretty curious as to how these results were going to play out. And I wonder what your thoughts are on that, or maybe that's perhaps more niche and less widely applicable than what you observed. Dr. Pieter Martens: Now, I can completely agree that when we are thinking about congestion, the congestion itself is a sort of pressure based phenomenon. And the pressure based phenomenon is based on what your volume is and the compliance within your cardiovascular system. But I think one of the important things to remember is that how we enrolled patients in the ADVOR trial was that we enrolled patients who had clear signs of volume overload. Remember, we used a volume score to assess clinical decongestion or actually getting rid of the volume. Volume assessment isn't really necessarily a pressure based assessment. And pressures might be the genesis of elevated pressures might be different amongst heart failure with reduced versus preserved ejection fraction. But what was really clear was that all these patients were volume overloaded. And when you think about the volume axis, then it's really about getting rid of that additional sodium, water, and that's where really acetazolamide works. So I do think we differ a little bit from historical acute decompensated heart failure trials in which they sometimes use signs and symptoms of more congestion, a pressure based phenomenon, where our endpoint was truly at volume endpoint. And we do believe that diuretics work really on a volume component of heart failure. Dr. Mercedes Carnethon: Thank you so much, especially for explaining that in a way that even non-clinicians such as myself can understand the potential implications. A big picture question that I have, and I really enjoy these discussions because they give us an opportunity to speculate beyond what we read in the paper. And that question is we do clinical trials and we identify effective therapies. And one of the bigger challenges we often face is getting those therapies out to the people who need them. Do you perceive any barriers in uptake of the use of acetazolamide in clinical practice? Dr. Pieter Martens: That's an excellent question. So one of the, I think beauties about acetazolamide is that this drug has been on the market for about 70 years. So I think everybody has access to it. This is not a novel compound which needs to go through different steps of getting marketing approval and getting a sort of reimbursement before it becomes available in clinical practice. And in theory, everybody should have access to this relatively cheap agent and can use it in its clinical practice. And I think it was very interested when we came out with the initial paper. I think already the day afterwards, we were getting messages from across the world that people have been using acetazolamide. So I think it is an agent which is available in current clinical practice and should not be too many barriers to its current implementation and clinical practice. Dr. Mercedes Carnethon: Well, that's fantastic to hear. So I hope Justin, that you will certainly help to ring the bell to get the information out about this wonderful study. I do want to turn to you, Pieter, to find out whether or not there are any final points that you didn't have an opportunity to discuss with us today. Dr. Pieter Martens: Think some of the other end points we didn't discuss were the effect, for instance, on length of stay. I think length of stay is a very important endpoint because hospital admissions, like Justin said, heart failure is the number one reason why elderly patients are being admitted. And just shortening the length of stay from a financial perspective might be important. So it was also very interesting to see that the use of acetazolamide in the study also translated into a shorter length of stay, which was also was unaffected, whether you had heart failure, reduced, mildly reduced or preserved ejection fraction, Dr. Mercedes Carnethon: Well, I certainly know people appreciate being in their own homes and being able to discharge is certainly a major benefit. So thank you so much for sharing that final point. I really want to thank you so much for a stimulating discussion today. I know that I learned a lot from you, Pieter, and the hard work of your research team as well as from you, Justin, for putting these findings in context and really helping our listeners and the readers of our journal understand why this paper is so important and how it's really moving the field forward for a clinically important problem. So thank you both so much for joining us here today on Circulation on the Run. Dr. Justin Grodin: Thank you. Dr. Pieter Martens: Thank you for having me. Dr. Mercedes Carnethon: I really want to thank our listeners for joining us today for this episode of Circulation on the Run. I hope you will join us again next week for more exciting discussions with our authors. Dr. Greg Hundley: This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Jo Ann Leal, PharmD (Twitter: @jojopharmd) describes the implications of various CYP2C19 phenotypes on clopidogrel metabolism and activity, analyzes the available literature evaluating outcomes of clopidogrel versus ticagrelor in ischemic stroke patients based on CYP2C19 metabolizer status and selects a preferred antiplatelet agent and dose for secondary prevention of ischemic stroke given patient specific pharmacogenomic information. For more pharmacy content, follow Mayo Clinic Pharmacy Residency Programs @MayoPharmRes or the host, Garrett E. Schramm, Pharm.D., @garrett_schramm on Twitter! You can also connect with the Mayo Clinic's School of Continuous Professional Development online at https://ce.mayo.edu/ or on Twitter @MayoMedEd. 

It's another session of CardioNerds Rounds! In these rounds, Dr. Priya Kothapalli (Interventional FIT at University of Texas at Auston, Dell Medical School) joins Dr. Deepak Bhatt (Dr. Valentin Fuster Professor of Medicine and Director of Mount Sinai Heart) to discuss the nuances of antithrombotic therapy. As one of the most prolific cardiovascular researchers, clinicians, and educators, CardioNerds is honored to have Dr. Bhatt on Rounds, especially given that Dr. Bhatt has led numerous breakthroughs in antithrombotic therapy. Come round with us today by listening to the episodes of #CardsRounds! Audio editing by CardioNerds Academy Intern, Dr. Christian Faaborg-Andersen. This episode is supported with unrestricted funding from Zoll LifeVest. A special thank you to Mitzy Applegate and Ivan Chevere for their production skills that help make CardioNerds Rounds such an amazing success. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds. Case details are altered to protect patient health information. CardioNerds Rounds is co-chaired by Dr. Karan Desai and Dr. Natalie Stokes.  Speaker disclosures: None Challenging Cases - Atrial Fibrillation with Dr. Hugh Calkins CardioNerds Rounds PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Show notes - Antithrombotic Management with Dr. Deepak Bhatt Case #1 Synopsis: A woman in her early 70s with a history of hypertension, hyperlipidemia, and paroxysmal atrial fibrillation presented with sudden-onset chest pressure and diaphoresis while at rest and was found to have an acute thrombotic 99% mid-LAD occlusion. The patient received OCT-guided PCI with a single drug-eluting stent. We discussed what the appropriate antithrombotic strategy would be for a patient with recent acute coronary syndrome and atrial fibrillation. Case #1Takeaways According to the recent 2021 revascularization guidelines, in patients with atrial fibrillation undergoing PCI and taking oral anticoagulant therapy, it is recommended to discontinue aspirin after 1 to 4 weeks while maintaining P2Y12 inhibitors in addition to a non-vitamin K oral anticoagulant or warfarin.There are two recent trials – AUGUSTUS and the ENTRUST-AF PCI trial – that evaluated regimens of apixaban and edoxaban, respectively, that support earlier findings reporting lower bleeding rates in patients maintained on oral anticoagulant plus a P2Y12 inhibitor compared to triple therapy.Of note, none of these trials were specifically powered for ischemic endpoints, but when pooling data from these trials, rates of death, MI and stent thrombosis with dual therapy were similar to those seen in patients on triple therapy.Additionally, all of these patients enrolled in these trials were briefly treated with triple therapy after PCI before the aspirin was discontinued. In the 2021 guidelines, it is noted that analyses of stent thrombosis suggest that 80% of events occur within 30 days of PCI. Thus, it is reasonable to consider extending triply therapy to 1 month after PCI in high risk patients to reduce risk of stent thromboses.In AUGUSTUS, 90% of patients received clopidogrel as their P2Y12 inhibitor Case #2 Synopsis: A man in his mid-50s with a history of peripheral vascular disease with prior SFA stent for chronic limb ischemia, hyperlipidemia, tobacco use, diabetes, and chronic kidney disease presented with a two day history of “reflux” that was worse with exertion and that improved with rest and associated with diaphoresis. He was diagnosed with an NSTEMI. His LHC revealed 99% mid-RCA thrombotic occlusion with moderate disease in the LAD. He underwent thrombectomy and PCI with a single drug-eluting stent to the RCA. We discussed his short-term and long-term antithrombotic therapy Case #2 Takeaways

In this week's View, Dr. Eagle discusses the Fitbit Heart Study that examines the detection of atrial fibrillation in a large population using wearable devices, then looks at the long-term effects of P2Y12 inhibitor monotherapy after percutaneous coronary intervention. Finally, Dr. Eagle examines a scientific statement on sex differences in arterial hypertension from the ESC Council on Hypertension, the European Association of Preventive Cardiology, the Association of Cardiovascular Nursing and Allied Professions, the ESC Council for Cardiology Practice, and the ESC Working Group on Cardiovascular Pharmacotherapy. Subscribe to Eagle's Eye View

In this interview, Francesco Franchi, MD and Spencer B. King III, MD, MACC, with Matt A. Cavender MD, MPH, FACC, discuss how to make the best choice when selecting an oral P2Y12 inhibitor post-MI.

In this episode, guest host Deepak Bhatt, MD, MPH, FACC, offers a preview of some of the most important and clinically transformative studies being presented at the ESC 2022 Conference, August 26-29. Day One includes: more data from the EMPEROR trial on the mechanisms and clinical benefits of SGLT2i in heart failure, the TAILOR-PCI randomized trial on genotype-guided oral P2Y12 inhibitor therapy, phase 2 data from the ENTRIGUE study on pegozafermin for the treatment of severe hypertriglyceridemia, and the results of the TIME trial on the timing of morning versus evening medication. Also on Day One, Dr. Valentine Fuster will present the results of the SECURE trial, a polypill strategy in secondary prevention. There will also be a presentation of the ASCEND study on the effects of aspirin and omega−3 fatty acid supplements on heart failure. Dr. Bhatt will present data from the REDUCE-IT trial on the significant reduction in ST-Elevation MI with icosapent ethyl. Day One will also cover the EXHAUSTION project, investigating air temperature and cardiovascular disease, as well as the ADDICT-ICCU study on carbon monoxide and acute cardiac events. Day Two will include: a presentation by Davada Perera on REVIVED, investigating percutaneous revascularization for ischemic ventricular dysfunction, ALL-HEART data on allopurinol and cardiovascular outcomes in ischemic heart disease, and a major presentation by Scott Solomon on the DELIVER trial, examining dapagliflozin in heart failure with mildly reduced and preserved ejection fraction. There will also be a number of pooled analyses on Day Two, including one looking at DAPA-HF and DELIVER, and a pre-specified meta-analysis of DELIVER and EMPEROR-Preserved. Together these studies will firmly cement the concept of the SGLT-2 inhibitors class as a heart failure medication.  Day Three opens with an important presentation on INVICTUS, exploring rivaroxaban versus VKA for rheumatic atrial fibrillation. There will also be a group of presentations on some modest but significant Phase 2 trials on factor XIa inhibitor asundexian. Additionally, Renalto Lopes will present data on the APOLLO trial exploring apixaban for prophylaxis of thromboembolic outcomes in COVID-19, and the five-year data from the MOMENTUM 3 study on LVAD Therapy will be presented.   On the fourth and final day, presentations include the clinical outcomes at 5 years of follow-up in the ISCHEMIA-CKD EXTEND trial, the review of the MASTERDAPT trial data at 15 months, the primary results of FOURIER-OLE, and data from the PANTHER Trial on P2Y12 inhibitor versus aspirin monotherapy in patients with coronary artery disease. ESC 2022 promises to be a rich and rewarding experience for those who can attend in person or participate virtually.

On Episode 18 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the July 2022 issue of Stroke: “Impact of Shunting Practice Patterns During Carotid Endarterectomy for Symptomatic Carotid Stenosis” and “Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke.” She also interviews Dr. Magdy Selim about his article “Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage: A Post Hoc Analysis of the i-DEF Trial.” Dr. Negar Asdaghi:         Let's start with some questions. 1) Is deferoxamine mesylate yet another failed agent for treatment of patients with intracerebral hemorrhage, or is deferoxamine getting us closer than ever to an approved therapy for this deadly form of stroke? 2) Are different strokes happening to different folks due to their disadvantaged socioeconomic status? 3) And finally, how does a surgeon's personal practice preference to either routinely or selectively use carotid shunting during carotid endarterectomy impact the recurrent risk of stroke or death in patients with symptomatic carotid disease? We'll tackle these questions and a lot more in today's podcast as we continue to cover the cerebrovascular world's latest and greatest because, without a doubt, this is the best in Stroke. Dr. Negar Asdaghi:         Welcome back to the July issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. The July 2022 issue of Stroke contains a range of really interesting papers that I'd like to highlight here. As part of our Cochrane Corner articles, giving us short summaries of the long systematic review of a given topic, we have two short articles, one on the issue of local versus general anesthesia for carotid endarterectomy, where we learn that based on the current evidence, there's no convincing difference between local versus general anesthesia in the risk of stroke and death within 30 days after the procedure. In the second Cochrane Corner article, titled "Information Provision for Stroke Survivors and Their Carers," we learn that stroke survivors and their caregivers routinely report dissatisfaction with information provided to them by their clinicians about their condition and how active approaches to information provision is superior to its passive forms in improving patients' involvement in their care, their satisfaction, and, ultimately and not surprisingly, their stroke outcome. Dr. Negar Asdaghi:         As part of our original contributions in this issue of the journal, we have an important paper titled "The Risk of Early Versus Later Rebleeding From Dural AV Fistulas With Cortical Venous Drainage." We are reminded in this paper that cranial dural arteriovenous fistulas are classified based on their venous drainage into those with or those without cortical venous drainage, or CVD. Dural AV fistulas without CVD rarely cause intracranial bleeding, while those with CVD may cause hemorrhage. In this study, the authors show that the risk of rebleeding of dural AV fistulas with CVD presenting with hemorrhage is increased in the first two weeks after ICH, emphasizing the importance of early detection of these malformations by vascular imaging and early treatment of AV fistulas with cortical drainage. This paper is another analysis from the CONDOR registry. Our devoted Stroke Alert listeners recall that we covered this registry in more detail when we interviewed Dr. Amin-Hanjani last October on the outcomes of intracerebral hemorrhage patients found to have dural AV fistulas. I encourage you to review these articles in addition to listening to our podcast today. Dr. Negar Asdaghi:         Later in the podcast, I have the distinct honor of interviewing Dr. Magdy Selim from Harvard Medical School on a critical analysis from i-DEF trial to examine the long-term outcome of patients with ICH who were randomized to receive deferoxamine versus placebo. As an expert in the field of intracerebral hemorrhage and a member of the recently published American Heart Association Guidelines Committee, Dr. Selim was not fazed at all about the neutral results of the trial. "The future of ICH is bright," he says, and in the interview, he tells us why. But first, with these two articles. Dr. Negar Asdaghi:         Since its first reported successful surgery in 1953, carotid endarterectomy, or CEA, has become a common surgical procedure to prevent ischemic stroke in patients with carotid disease. CEA requires a temporary clamping of the carotid artery that is being worked on. During this time, the ipsilateral hemisphere is, of course, dependent on collateral flow from the posterior circulation or from the contralateral anterior circulation to maintain its perfusion pressure. Intraoperatively, various methods are used to monitor cerebral perfusion, and the risk of clamping-induced hypoperfusion is obviously variable for each patient depending on the patient's specific anatomy, their collateral status, and other risk factors. One way to protect the brain against possible clamp-induced ischemia is to do carotid shunting. The problem is that carotid shunting also comes with its own set of risks and problems. There's the risk of causing carotid dissection, embolization of pieces of the plaque during shunt insertion, or the risk of causing air embolism. Dr. Negar Asdaghi:         There are also other shunt-related local complications that should be noted, such as possibility of causing injuries to the cranial nerves or development of neck hematoma related to the more extensive surgical exposure required for shunting. So, it's not surprising that the practice patterns with regards to shunting is quite variable amongst different surgeons. There are surgeons that are considered routine shunters, and those who are considered selective shunters, meaning that the shunt is inserted only in cases with a particular indication. The question is whether the surgeon's preference for shunting can impact the CEA outcomes. In the current issue of the journal, we have an interesting study led by Dr. Randall DeMartino from the Division of Vascular and Endovascular Surgery at Mayo Clinic, Rochester, where the authors look at the impact of shunting practice patterns during carotid endarterectomy on the following post-CEA outcomes: number one, in-hospital stroke and in-hospital death rates, and number two, combined stroke and death in patients with a recent symptomatic carotid disease, that is, carotid stenosis associated with a history of either ipsilateral stroke or TIA within the past 14 days of endarterectomy. Dr. Negar Asdaghi:         So, the data for the study came from the ongoing Vascular Quality Initiative database, which comprises a network of more than 600 North American academic and community hospitals, and collects data on 12 different vascular procedures, one of which is CEA. The study included over 13,000 carotid endarterectomies performed from 2010 to 2019 for symptomatic carotid patients. This number came after they applied their exclusion criteria to all CEAs performed in the database during this timeframe, importantly excluding any asymptomatic carotid surgeries or those in whom surgery was performed after the two-week mark post qualifying TIA or stroke. Now, before we go over the results, let's go over some definitions used in the study. They had to classify surgeons to be able to do the study into two categories of routine versus selective shunters. So, what they did was to analyze all consecutive CEAs, whether they were done on symptomatic or asymptomatic carotids, in this database, aggregated at the surgeon level. Surgeons routinely shunting in over 95% of their procedures were gauged as routine shunters. Otherwise, they were classified as selective shunters. Dr. Negar Asdaghi:         Now, coming to each case included in this study, each surgical case was, in turn, classified into four categories based on whether or not a shunt was actually used for that particular case: category one, no shunt used; category two, shunt used as a routine procedure; number three, shunt used for a preoperative, mostly anatomical indication; number four, shunt was used for an intraoperative indication, which, as we mentioned before, these are mostly intraoperative hemodynamic compromised situations. And here are the results: In total, 3,186 of surgeries, that is 24% of surgeries, were performed by routine shunters versus 76% by selective shunters. So, most surgeons were selective shunters in this study. The demographic of patients operated by the routine versus selective shunters were more or less similar with regards to the age of the patients, most of their vascular risk factors, and the degree of ipsilateral or contralateral carotid stenosis or occlusion, with a few notable exceptions, in that patients undergoing surgery by routine shunters were more likely White, more likely to have had a prior CABG, more likely to undergo the operation while taking a P2Y12 inhibitor antiplatelet agent, and these patients were more likely to have had a TIA rather than a stroke as their qualifying event, which probably explains why they were more likely to be operated on within 48 hours of symptom onset as well. So, the authors accounted for these differences when they did their multivariate analysis. Dr. Negar Asdaghi:         The other thing to note was that overall, routine shunters used a shunt in 98.1% of their cases, whereas selective shunters used them in 46% of their cases. Now, in terms of their study outcomes, the shunting practice pattern did not impact the primary outcomes of in-hospital stroke or death, or a combination of these two outcomes, or even the odds of development of cranial nerve injuries or hemorrhage in the adjusted model, which is really good news here. But interestingly, in the final adjusted model, whether or not an actual shunt was placed during surgery did significantly increase the risk of postoperative stroke, with the odds ratio of 1.29, an effect that was entirely driven by the use of shunt by a surgeon classified as a selective shunter in this study. Dr. Negar Asdaghi:         So, in simple terms, if a shunt was placed during CEA, it did increase the risk of stroke only if that surgeon was a selective shunter. Another interesting association was that amongst selective shunters, placing a shunt for a patient with a very recent ischemic event, that is, TIA or stroke within the past 48 hours prior to surgery, and placing a shunt for an intraoperative indication, meaning shunt placement was not pre-surgically planned, also significantly increased the risk of postoperative stroke. So, what we learned from the study is that, though a surgeon's shunting practice pattern did not have an impact on the overall postoperative risk of stroke or death, the placement of a shunt did indeed increase the risk of postoperative stroke only if it was placed by a surgeon who is a selective shunter, especially for an intraoperative indication in a patient with a recent ischemic event. Dr. Negar Asdaghi:         So, shunts can be tricky, especially if they're done by a surgeon who doesn't place them routinely. So, my take-home message is that ultimately, like every other procedure in medicine, clinical outcomes are as much operator dependent as they are patient dependent, and for every procedure, it's fair to say that practice makes perfect. Dr. Negar Asdaghi:         It is now more than 25 years since intravenous thrombolytic therapy has been approved for treatment of patients with acute ischemic stroke and more than seven years since randomized control trials demonstrated the efficacy of mechanical thrombectomy to improve clinical outcome in ischemic stroke patients with large vessel occlusions. To date, reperfusion therapies are the only available acute treatments for select patients with ischemic stroke. What do we mean by "select"? "Select" meaning that not all patients will benefit from these therapies, making it absolutely necessary for clinicians to be up to date with various indications and contraindications to use these therapies. Needless to say that the criteria for reperfusion therapies do not and should not consider the socioeconomic status of patients, but sadly, socioeconomic inequalities seem to impact the use of reperfusion therapies. Dr. Negar Asdaghi:         In this issue of the journal, in the study titled "Socioeconomic Inequalities in Reperfusion Therapy for Acute Ischemic Stroke," Dr. Øgendahl Buus from Aarhus University Hospital in Denmark and colleagues studied the impact of the socioeconomic status of stroke patients on the odds of receiving reperfusion therapies in the large nationwide Danish Stroke Registry, or DSR. Now a bit about the registry: DSR contains prospectively collected nationwide data on all stroke patients admitted to Danish hospitals. It's interesting to note that in Denmark, stroke patients are exclusively admitted to public hospitals, and all departments treating stroke patients are obligated to report data to DSR. Now, for this study, they included over 63,000 stroke patients from 2013 to 2018. After excluding hemorrhagic stroke, TIAs, and other exclusion criteria of the study, they arrived at their sample size of 37,187 patients that were included in this study. Dr. Negar Asdaghi:         Now, a few definitions. The socioeconomic status of each patient was determined based on three parameters. Parameter number one, their educational level. It was categorized into three levels of low, medium, or high levels of education. Category number two, income level. This was calculated based on the average family equivalent disposable income, or FED income, during five years prior to stroke onset, again classified into three categories of high, medium, or low income. And the third factor was the employment status of the patient during the calendar year prior to the stroke onset, also categorized into three categories of employed, unemployed, and retired. And, of course, the authors used various definitions to be able to fit special situations into these categories. For instance, a person who is temporarily unemployed due to illness or other special situation was still categorized under the employed category. So, that gave them, in total, nine groups to analyze across these three categories. Dr. Negar Asdaghi:         And here are their findings. The median age of total stroke patients in the cohort was 73.2 years, 44.1% were women, 41% categorized under low educational level, 68% retired, and 33.3% had low income levels. Not surprisingly, patients and hospital characteristics varied tremendously across these nine groups of education, employment, and income, and a univariate analysis in general, low socioeconomic status was associated with more severe strokes, living alone, living at an assisted living residency, having had prior stroke, high comorbidity index score, hypertension, and late hospital arrival. So, they accounted for these differences in their multivariate analysis. Dr. Negar Asdaghi:         Now, overall, the treatment rates of IV thrombolysis was 17.6%, which is actually considered a very high percentage as compared to other registry-based studies, but the percentage of IV thrombolytic use dramatically varied based on the different socioeconomic designation. So, let's look at this. In the univariate analysis, for education, intravenous thrombolysis rates were 19.3% among patients with high educational level compared to 16.2% among patients with low educational level. Let's look at income. For income, IV thrombolytic treatment rates reach 20.7% for high-income patients compared to 14.8% for low-income patients. For employment status, thrombolytic rates were 23.7% among employed patients compared to 15.7% for unemployed patients. In their fully adjusted models, unemployed patients were less likely to receive IV lytics as compared to their employed counterparts. Dr. Negar Asdaghi:         Now, for thrombectomy, socioeconomic gradients were also noted for these three categories. For education, thrombectomy rates were 4.5% among patients with high education level compared to 3.6% among patients with low educational level. For income, treatment rates were 3.2% among low-income patients compared to 4.7% among high-income patients. But arguably, the most robust differences were noted again across the category of employment. Employed patients were nearly twice more likely to receive thrombectomy as compared to unemployed patients, rates being 5.1% versus 2.8%, respectively. Now, when they adjusted their analysis to only those patients presenting within the reperfusion time windows in the fully adjusted models, unemployment and low income remain significant negative predictors of receiving both of these reperfusion therapies. So, what we learned from this study is that stroke patients who were unemployed, earned a relatively low income, or had fewer years of formal education were less likely to receive life-saving reperfusion therapies despite potentially being eligible for these treatments. Dr. Negar Asdaghi:         Now, let's take a moment to really understand that data presented here are in the context of a tax-funded, universal healthcare offered across Denmark, where we can at least make the assumption that financial constraints potentially preventing access to therapies are likely minimized. There are many countries around the globe where patients or family members have to pay for these therapies before even receiving them. So, these findings from the current study from Denmark are alarming in that they point to possibly more robust inequalities across the globe in other healthcare systems. Dr. Negar Asdaghi:         Intracerebral hemorrhage, or ICH, is an aggressive form of stroke, typically carrying a higher morbidity and mortality than its ischemic counterpart. Yet much of the research in the field of intracerebral hemorrhage has followed the ischemic stroke footsteps, including defining the optimal primary outcome for the randomized trials of ICH. For ischemic stroke, the 90-day functional outcome, as measured by the modified Rankin Scale, is commonly used as a primary outcome in clinical trials. There are many reasons for this selection, including the ease of use and the fact that the majority of functional recovery post-ischemic stroke occurs during the first 90-day time period. But time to maximum recovery and, importantly, the trajectory of recovery may be different in hemorrhagic as compared to ischemic stroke. Defining the long-term outcomes and longitudinal trajectory of recovery in ICH is, therefore, important to better understand its prognosis and, of course, selecting the appropriate primary outcome measure for future randomized trials of ICH. Dr. Negar Asdaghi:         In the recent years, the safety and efficacy of various agents to improve ICH outcomes have been tested. Deferoxamine mesylate, an iron-chelating agent, is one such agent that was recently studied as part of the i-DEF multicenter randomized trial, and the main results of the study were published in Lancet Neurology in 2019. In the current issue of the journal, in the study titled "Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage," we learn about the results of a post hoc analysis of i-DEF that looks at the trajectory of functional outcome in patients enrolled in the trial with a special attention on their continued recovery after the 90-day post-ICH mark. Dr. Negar Asdaghi:         Joining me now is the senior author of this paper, Dr. Magdy Selim, who's also one of the primary investigators of i-DEF trial. Dr. Selim is a Professor of Neurology at Harvard Medical School and Chief of Stroke Division at Beth Israel Deaconess Medical Center in Boston. He's a world renowned researcher in the field of cerebrovascular disorders with special focus on treatment of patients with intracerebral hemorrhage. Dr. Selim has led and currently leads multiple National Institutes of Health-funded clinical trials of intracerebral hemorrhage, including the ongoing SATURN trial. I'm delighted to welcome him to our podcast today. Good afternoon, Magdy. Thank you for joining us today. Dr. Magdy Selim:             Thank you, Dr. Asdaghi. It's really my pleasure to be here with you, and I'm certainly honored to do this today. Dr. Negar Asdaghi:         That's great. Thank you. So, let's start with some background on deferoxamine and the literature supporting the use of deferoxamine before i-DEF. Dr. Magdy Selim:             So, as you mentioned, deferoxamine is an iron chelator; it binds to iron and removes excess iron from the body. The unique thing about it is that it has other neuroprotective properties, which are good for hemorrhagic stroke and ischemic stroke. It also has anti-inflammatory and anti-apoptotic effects. It even lowers the blood pressure, which we know sometimes is helpful in intracerebral hemorrhage. The rationale behind this or why this would be effective really comes from animal studies. After you have a hemorrhage, there is hemolysis of the red blood cells, there is a release of hemoglobin degradation products, in particular, iron, and the accumulation of iron in the hematoma and the surrounding tissue triggers a cascade of molecular and cellular events that lead to what we call secondary injury, characterized by inflammation, hydroxyl radical formation, and cell death. And many animal studies, animal models of intracerebral hemorrhage, whether in pigs or in rats, young or aged rats, have shown that treatment with deferoxamine can reduce iron in the brain after intracerebral hemorrhage and also results in improved performance on behavioral tests. And that was the reason why we moved into clinical testing. Dr. Negar Asdaghi:         So, a lot of encouraging data before the trial. Can we hear a little bit about the trial, its design, and inclusion criteria, please? Dr. Magdy Selim:             Sure. So i-DEF was a phase 2 study, and actually it started as Hi-DEF, which was high dose deferoxamine, and then became i-DEF, which intermediate dose deferoxamine. So, it's a randomized, double blind, placebo control trial. We used something called futility design, which is actually sort of new in the stroke field. And we had 294 patients who had supratentorial hemorrhage that were randomized within 24 hours to either get placebo or deferoxamine. And deferoxamine initially was given at 62 mg per day for three days, but then we ran into some safety issues with this high dose, and that's why we lowered it to 32, and that became the intermediate dose, or the i-DEF. So, the only kind of thing unique about inclusion/exclusion criteria was that there was an age cutoff, patients had to be 80 or younger. They needed to have some deficit on the exam, so their NIH Stroke Scale had to be 6 or greater, and their GCS had to be greater than 6, and their modified Rankin before the onset of the hemorrhage had to be less than 1. Dr. Negar Asdaghi:         And so, what were the primary and secondary outcomes in i-DEF? Dr. Magdy Selim:             The primary outcome was twofold actually. One of them was safety. One of the issues we ran into with the high dose is that the drug is associated with increased risk for adult respiratory distress syndrome, ARDS. So, we wanted to make sure that this lower dose was safe, and it does not increase the instance of ARDS. The second thing was, as I said, we used something called the futility design, and we wanted to compare the outcome of patients treated with deferoxamine versus placebo to determine whether it's futile to move to a large phase 3 trial or not. And what we were looking at is a difference in outcome and modified Rankin 0 to 2 at 90 days, and the difference would be at least 12% in favor of deferoxamine in order for us to move forward. You asked about the secondary outcomes as well? Dr. Negar Asdaghi:         Yes. Dr. Magdy Selim:             So, actually, the secondary outcomes, they're relevant because they're relevant to the study that we just published. So, the secondary outcomes was also to look at modified Rankin 0 to 3, instead of 0 to 2, at 90 days and the difference between the two treatment groups. We wanted to look at the ordinal distribution of the Rankin at the same time point. And we also wanted to look at all the outcomes at six months, 180 days. And that came a little bit later in the course of the study because there was some evidence emerging at that time that maybe assessment of outcome later in intracerebral hemorrhage would be more accurate than assessing it early on. Dr. Negar Asdaghi:         So, I want to come back to the secondary outcome, of course, that's sort of the topic of your current paper in this issue of the journal, but can you just briefly tell us, please, the primary outcome and the sort of results of what was published in 2019 with i-DEF before we move on to the current paper? Dr. Magdy Selim:             Yeah. So, as I said, the primary outcome was the difference in the proportion of patients that achieved modified Rankin 0 to 2 at 90 days, and what we wanted to see is a difference of around 12%. Unfortunately, the primary outcome was neutral, we did not see that. But what we saw actually, almost all the secondary outcomes were positive, except for the primary outcome. So, when we looked at the secondary outcome using modified Rankin 0 to 3, instead of 0 to 2, the difference was 12.1%. When we looked at the difference in the modified Rankin 0 to 2 at six months, the difference was 15.6% in favor of deferoxamine, but these were secondary outcomes and not the primary outcomes. Dr. Negar Asdaghi:         So, the trial is almost positive. It just depends on how you define the primary outcome, which is really a nice segue to your current study. In the current study, you looked at this secondary outcome in a longitudinal way and looked at the mRS of 0 to 2 at six months from ICH. Can you please tell us about this current paper? Dr. Magdy Selim:             Yeah. So, one of the things that we did with i-DEF is that we were checking the modified Rankin at different time points for all the patients. So, we had it after one week, after one month, after two months, after three months, and after six months. And what we wanted really was a couple of things, just in patients with intracerebral hemorrhage without any treatment, what's the natural course of recovery? And the interesting thing we found out is that patients actually continue to improve over time, and that's what you expect, but what we didn't expect is that they even continue to improve after 90 days. Dr. Magdy Selim:             We always used to think that maximum recovery is around 90 days from ischemic stroke literature, but we saw a lot of patients getting better after 90 days. And this turns out to be also the case with deferoxamine, but the interesting thing is that the percentage of patients that had a good outcome, modified Rankin 0 to 2, was higher with deferoxamine at day seven, at day 30, at day 60, not at 90 days, but again at six months. So, actually, it was higher at all time points except our primary endpoint. Dr. Negar Asdaghi:         So, Magdy, you've already answered my next question, which is exactly what you alluded to, deferoxamine seemed to have improved the outcomes at all of those time points, except for the 90 day, which was the primary outcome of your trial. Why do you think the magic was lost at 90 days? Dr. Magdy Selim:             This is really the million-dollar question. I think we obviously struggled over this. And we went back, we thought maybe there was misrating of the modified Rankin in some of the patients. We tried to correct for this. The difference was bigger, but still not significant. So, we don't really have a good reason to tell you why, at this particular time point, we didn't see the difference except bad luck, I think. But I mean, there are reasons, I think, the question that people actually ask me is the opposite, is why do you think a drug that you give for three days early on is going to make a difference after six months? And I think there are biological reasons to explain this. Dr. Magdy Selim:             So, what happened is that those hemorrhage patients have a lot of other problems. They have increased ICP, they have hydrocephalus, they have intraventricular hemorrhage, and actually iron has been implicated in the development of hydrocephalus in chronic white matter injury. So, my explanation is that you start early on with the treatment, it does help, but it takes a while for it to kick in and for this kind of medical complication to resolve until actually you see the true effect of the drug. And maybe that's why you see the unmasking at the end between the two groups. Dr. Negar Asdaghi:         Yeah, I think I want to recap this for our listeners. Very important to, again, think about those things that some of the acute therapies that we offer the patients may not have a measurable improvement outcome difference early on, certainly with intravenous thrombolysis, we saw that, whereas we saw measurable outcome difference at 90 days, or maybe in this case at six months, but not quite early on. So, it doesn't mean that they don't work. We just are unable to measure that difference and improvement early on. So, what do you think the future holds for deferoxamine? Are we going to see another trial? Dr. Magdy Selim:             Well, I certainly hope so. We're working on some few ideas for that. A lot of people think that maybe we should just do the same thing, but look at six months as the primary outcome. But I think we're actually, that's probably not our primary thinking at this point in time. So, we have published other papers, other analysis, to show that the effect of deferoxamine actually relates to the volume of the hemorrhage. So, if the hemorrhage is very small, there is very minimal benefit. If the hemorrhage is very large, also there is very minimal benefit. And that's really to get kind of the big bang for your buck. You really want people who have mild-to-moderate size hemorrhages. So, we're thinking of a couple of ways to go about deferoxamine with this, whether alone or in combination with other interventions. So, hopefully, we'll have some stuff to share with you in the coming few years, two or three. Dr. Negar Asdaghi:         We'll definitely look forward to reading about those or being involved in the trials as a site, but there's a great way of just actually talking about my next question. It's just completely different than the current paper. I wanted to digress a bit and talk about the recently published intracerebral hemorrhage guidelines, which just published a few months ago. You were part of the guidelines committee. Can you give us a little bit of your point of view of what are the top two most important updates from the guidelines in ICH treatment? Dr. Magdy Selim:             Actually, the guidelines, for the first time this year, in the first page, they have the top 10 take-home messages or top 10 new ones. So, in my opinion, the most important ones, we usually tell you what to do, but here we tell you what not to do because we think it's not good for the patients. So, for example, using steroids just as a prophylactic therapy is actually not recommended. The same thing, we see a lot of people put patients with hemorrhage on hypertonic saline, hyperosmolar therapy, just prophylactically. I don't think there's any benefit that this helps as well, and the same thing for antiepileptic drugs. So, that was one important point. The second one was blood pressure lowering, and there is emphasis now that whatever you use to lower the blood pressure, you want to make sure that the blood pressure variability is very minimal and that there is a smooth kind of control over blood pressure that has been shown to be actually important in terms of help. I'm going to make them three, not two, because I think the third one is important. Dr. Negar Asdaghi:         Okay. I'll give you one more then. Dr. Magdy Selim:             Which is the first time we include this in the guideline, and with emphasis on the role of the home caregiver for hemorrhage patients and the psychological support, the education that they need, and the training that they need to actually care for these patients and how to improve their quality of life. So, I think that's an important aspect that we didn't touch upon before, and obviously very important. Dr. Negar Asdaghi:         Very important points. Let me just review them again for our listeners. So, don't do steroids, hypertonics, and preemptive antiepileptic therapies. They don't work. The second point that you raise is reduction of blood pressure, important to keep that in mind, but paying attention to blood pressure variability. And the third one, the importance of social aspect of care of patients with intracerebral hemorrhage. That's great for us. Let me just end with one last question. Magdy, thank you so much for all of this wonderful take-home messages from the current study from i-DEF and also the guidelines. There's been a lot of excitement in the field of ischemic stroke with the success of reperfusion therapies, and yet not much for intracerebral hemorrhage. What is your hope in terms of future therapies for ICH? Dr. Magdy Selim:             So, I happen to be one of the people who is very optimistic about the future of ICH. I think it's just a matter of time. But I think we need to make some changes. We need to really treat ICH as an emergency, so time is really important. And I think right now, you see a hemorrhage patient, they just put them on the side because they think that there's nothing to do. But the way I see the future evolving, and probably the breaking point to be, is that we can diagnose ICH in the field. You immediately lower the blood pressure, reverse coagulopathy if you can, and even kind of use hemostatic agents, if the FASTEST trial shows evidence to support that, and then you take them to the hospital where there might be some role for hematoma reduction using minimally invasive therapy and some other treatments like deferoxamine, or there are a lot of other agents to target the secondary injury at the same time. So, I think it's going to be a combination of things, and they need to happen in tandem and continuously, but we need to start quickly on these patients. Dr. Negar Asdaghi:         Dr. Magdy Selim, it's been a pleasure interviewing you on the podcast. We look forward to having you back and covering more of your work. Thank you for joining us. Dr. Magdy Selim:             Thank you very much for having me. Dr. Negar Asdaghi:         And this concludes our podcast for the July 2022 issue of Stroke. Please be sure to check out this month's table of contents for a full list of publications, including a series of Focus Updates on the very topic of, you guessed it, intracerebral hemorrhage. These updates are great complements to the newly published American Heart Association guidelines for the management of patients with spontaneous intracerebral hemorrhage in May 2022. Dr. Negar Asdaghi:         And with this, we end our July podcast and draw inspiration from one particular July story, which unfolded on July 20. In 1969, on this day, Commander Neil Armstrong and lunar module pilot Buzz Aldrin landed on the moon, and Armstrong became the first person to walk on the moon. The crew of Apollo 11 changed the course of history, landing humanity on another celestial body for the first time and later safely returning everyone back to earth. Armstrong, an experienced naval aviator, a test pilot, a decorated veteran, astronaut, and university professor, passed away in 2012 from complications of coronary artery disease, reminding us that every step we take in understanding, diagnosing, and treating vascular disorders is truly part of that giant leap to save the mankind. And what better way to do this than to stay alert with Stroke Alert. Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

Go online to PeerView.com/SPE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The latest stroke statistics estimate that about 800,000 individuals in the United States experience a stroke each year. Furthermore, about 20% of all strokes are recurrent, and many of these patients previously experienced a minor stroke or transient ischemic attack (TIA). Recurrence is greatest within the first 24 to 48 hours, but the risk remains elevated for months, even years, after the initial event. The American Heart Association (AHA) and American Stroke Association (ASA) recently updated their guidelines for stroke prevention to include expanded and detailed recommendations for the use of dual antiplatelet therapy (DAPT), the combination of aspirin and clopidogrel or ticagrelor, to further reduce the risk of stroke. These guidelines also include specific recommendations for individuals with minor acute ischemic stroke (AIS) or a TIA. In this activity based on a recent satellite symposium in New Orleans, leading experts on stroke management highlight the current guideline recommendations and discuss the latest perspectives on DAPT before transitioning to patient case scenarios where each expert demonstrates how these advances can be translated into clinical practice to improve outcomes and reduce the risk of recurrent stroke, while accounting for bleeding risks, antiplatelet resistance, and patient adherence. Upon completion of this CE activity, participants will be able to: Identify individuals with AIS or TIA who are appropriate candidates for treatment with antiplatelet therapy to reduce the risk of recurrent stroke, Assess the benefits and risks of using P2Y12 inhibitors with aspirin as DAPT for the prevention of recurrent stroke, Apply DAPT with P2Y12 inhibitors in appropriate patients following symptom onset to reduce the risk of recurrent stroke, Employ patient-centered communication strategies to facilitate adherence to DAPT with P2Y12 inhibitors in appropriate patients with AIS or TIA to reduce the risk of recurrent stroke.

Go online to PeerView.com/SPE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The latest stroke statistics estimate that about 800,000 individuals in the United States experience a stroke each year. Furthermore, about 20% of all strokes are recurrent, and many of these patients previously experienced a minor stroke or transient ischemic attack (TIA). Recurrence is greatest within the first 24 to 48 hours, but the risk remains elevated for months, even years, after the initial event. The American Heart Association (AHA) and American Stroke Association (ASA) recently updated their guidelines for stroke prevention to include expanded and detailed recommendations for the use of dual antiplatelet therapy (DAPT), the combination of aspirin and clopidogrel or ticagrelor, to further reduce the risk of stroke. These guidelines also include specific recommendations for individuals with minor acute ischemic stroke (AIS) or a TIA. In this activity based on a recent satellite symposium in New Orleans, leading experts on stroke management highlight the current guideline recommendations and discuss the latest perspectives on DAPT before transitioning to patient case scenarios where each expert demonstrates how these advances can be translated into clinical practice to improve outcomes and reduce the risk of recurrent stroke, while accounting for bleeding risks, antiplatelet resistance, and patient adherence. Upon completion of this CE activity, participants will be able to: Identify individuals with AIS or TIA who are appropriate candidates for treatment with antiplatelet therapy to reduce the risk of recurrent stroke, Assess the benefits and risks of using P2Y12 inhibitors with aspirin as DAPT for the prevention of recurrent stroke, Apply DAPT with P2Y12 inhibitors in appropriate patients following symptom onset to reduce the risk of recurrent stroke, Employ patient-centered communication strategies to facilitate adherence to DAPT with P2Y12 inhibitors in appropriate patients with AIS or TIA to reduce the risk of recurrent stroke.

Go online to PeerView.com/SPE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The latest stroke statistics estimate that about 800,000 individuals in the United States experience a stroke each year. Furthermore, about 20% of all strokes are recurrent, and many of these patients previously experienced a minor stroke or transient ischemic attack (TIA). Recurrence is greatest within the first 24 to 48 hours, but the risk remains elevated for months, even years, after the initial event. The American Heart Association (AHA) and American Stroke Association (ASA) recently updated their guidelines for stroke prevention to include expanded and detailed recommendations for the use of dual antiplatelet therapy (DAPT), the combination of aspirin and clopidogrel or ticagrelor, to further reduce the risk of stroke. These guidelines also include specific recommendations for individuals with minor acute ischemic stroke (AIS) or a TIA. In this activity based on a recent satellite symposium in New Orleans, leading experts on stroke management highlight the current guideline recommendations and discuss the latest perspectives on DAPT before transitioning to patient case scenarios where each expert demonstrates how these advances can be translated into clinical practice to improve outcomes and reduce the risk of recurrent stroke, while accounting for bleeding risks, antiplatelet resistance, and patient adherence. Upon completion of this CE activity, participants will be able to: Identify individuals with AIS or TIA who are appropriate candidates for treatment with antiplatelet therapy to reduce the risk of recurrent stroke, Assess the benefits and risks of using P2Y12 inhibitors with aspirin as DAPT for the prevention of recurrent stroke, Apply DAPT with P2Y12 inhibitors in appropriate patients following symptom onset to reduce the risk of recurrent stroke, Employ patient-centered communication strategies to facilitate adherence to DAPT with P2Y12 inhibitors in appropriate patients with AIS or TIA to reduce the risk of recurrent stroke.

Go online to PeerView.com/SPE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The latest stroke statistics estimate that about 800,000 individuals in the United States experience a stroke each year. Furthermore, about 20% of all strokes are recurrent, and many of these patients previously experienced a minor stroke or transient ischemic attack (TIA). Recurrence is greatest within the first 24 to 48 hours, but the risk remains elevated for months, even years, after the initial event. The American Heart Association (AHA) and American Stroke Association (ASA) recently updated their guidelines for stroke prevention to include expanded and detailed recommendations for the use of dual antiplatelet therapy (DAPT), the combination of aspirin and clopidogrel or ticagrelor, to further reduce the risk of stroke. These guidelines also include specific recommendations for individuals with minor acute ischemic stroke (AIS) or a TIA. In this activity based on a recent satellite symposium in New Orleans, leading experts on stroke management highlight the current guideline recommendations and discuss the latest perspectives on DAPT before transitioning to patient case scenarios where each expert demonstrates how these advances can be translated into clinical practice to improve outcomes and reduce the risk of recurrent stroke, while accounting for bleeding risks, antiplatelet resistance, and patient adherence. Upon completion of this CE activity, participants will be able to: Identify individuals with AIS or TIA who are appropriate candidates for treatment with antiplatelet therapy to reduce the risk of recurrent stroke, Assess the benefits and risks of using P2Y12 inhibitors with aspirin as DAPT for the prevention of recurrent stroke, Apply DAPT with P2Y12 inhibitors in appropriate patients following symptom onset to reduce the risk of recurrent stroke, Employ patient-centered communication strategies to facilitate adherence to DAPT with P2Y12 inhibitors in appropriate patients with AIS or TIA to reduce the risk of recurrent stroke.

Go online to PeerView.com/SPE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The latest stroke statistics estimate that about 800,000 individuals in the United States experience a stroke each year. Furthermore, about 20% of all strokes are recurrent, and many of these patients previously experienced a minor stroke or transient ischemic attack (TIA). Recurrence is greatest within the first 24 to 48 hours, but the risk remains elevated for months, even years, after the initial event. The American Heart Association (AHA) and American Stroke Association (ASA) recently updated their guidelines for stroke prevention to include expanded and detailed recommendations for the use of dual antiplatelet therapy (DAPT), the combination of aspirin and clopidogrel or ticagrelor, to further reduce the risk of stroke. These guidelines also include specific recommendations for individuals with minor acute ischemic stroke (AIS) or a TIA. In this activity based on a recent satellite symposium in New Orleans, leading experts on stroke management highlight the current guideline recommendations and discuss the latest perspectives on DAPT before transitioning to patient case scenarios where each expert demonstrates how these advances can be translated into clinical practice to improve outcomes and reduce the risk of recurrent stroke, while accounting for bleeding risks, antiplatelet resistance, and patient adherence. Upon completion of this CE activity, participants will be able to: Identify individuals with AIS or TIA who are appropriate candidates for treatment with antiplatelet therapy to reduce the risk of recurrent stroke, Assess the benefits and risks of using P2Y12 inhibitors with aspirin as DAPT for the prevention of recurrent stroke, Apply DAPT with P2Y12 inhibitors in appropriate patients following symptom onset to reduce the risk of recurrent stroke, Employ patient-centered communication strategies to facilitate adherence to DAPT with P2Y12 inhibitors in appropriate patients with AIS or TIA to reduce the risk of recurrent stroke.

Go online to PeerView.com/SPE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The latest stroke statistics estimate that about 800,000 individuals in the United States experience a stroke each year. Furthermore, about 20% of all strokes are recurrent, and many of these patients previously experienced a minor stroke or transient ischemic attack (TIA). Recurrence is greatest within the first 24 to 48 hours, but the risk remains elevated for months, even years, after the initial event. The American Heart Association (AHA) and American Stroke Association (ASA) recently updated their guidelines for stroke prevention to include expanded and detailed recommendations for the use of dual antiplatelet therapy (DAPT), the combination of aspirin and clopidogrel or ticagrelor, to further reduce the risk of stroke. These guidelines also include specific recommendations for individuals with minor acute ischemic stroke (AIS) or a TIA. In this activity based on a recent satellite symposium in New Orleans, leading experts on stroke management highlight the current guideline recommendations and discuss the latest perspectives on DAPT before transitioning to patient case scenarios where each expert demonstrates how these advances can be translated into clinical practice to improve outcomes and reduce the risk of recurrent stroke, while accounting for bleeding risks, antiplatelet resistance, and patient adherence. Upon completion of this CE activity, participants will be able to: Identify individuals with AIS or TIA who are appropriate candidates for treatment with antiplatelet therapy to reduce the risk of recurrent stroke, Assess the benefits and risks of using P2Y12 inhibitors with aspirin as DAPT for the prevention of recurrent stroke, Apply DAPT with P2Y12 inhibitors in appropriate patients following symptom onset to reduce the risk of recurrent stroke, Employ patient-centered communication strategies to facilitate adherence to DAPT with P2Y12 inhibitors in appropriate patients with AIS or TIA to reduce the risk of recurrent stroke.

Go online to PeerView.com/SPE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The latest stroke statistics estimate that about 800,000 individuals in the United States experience a stroke each year. Furthermore, about 20% of all strokes are recurrent, and many of these patients previously experienced a minor stroke or transient ischemic attack (TIA). Recurrence is greatest within the first 24 to 48 hours, but the risk remains elevated for months, even years, after the initial event. The American Heart Association (AHA) and American Stroke Association (ASA) recently updated their guidelines for stroke prevention to include expanded and detailed recommendations for the use of dual antiplatelet therapy (DAPT), the combination of aspirin and clopidogrel or ticagrelor, to further reduce the risk of stroke. These guidelines also include specific recommendations for individuals with minor acute ischemic stroke (AIS) or a TIA. In this activity based on a recent satellite symposium in New Orleans, leading experts on stroke management highlight the current guideline recommendations and discuss the latest perspectives on DAPT before transitioning to patient case scenarios where each expert demonstrates how these advances can be translated into clinical practice to improve outcomes and reduce the risk of recurrent stroke, while accounting for bleeding risks, antiplatelet resistance, and patient adherence. Upon completion of this CE activity, participants will be able to: Identify individuals with AIS or TIA who are appropriate candidates for treatment with antiplatelet therapy to reduce the risk of recurrent stroke, Assess the benefits and risks of using P2Y12 inhibitors with aspirin as DAPT for the prevention of recurrent stroke, Apply DAPT with P2Y12 inhibitors in appropriate patients following symptom onset to reduce the risk of recurrent stroke, Employ patient-centered communication strategies to facilitate adherence to DAPT with P2Y12 inhibitors in appropriate patients with AIS or TIA to reduce the risk of recurrent stroke.

Go online to PeerView.com/SPE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The latest stroke statistics estimate that about 800,000 individuals in the United States experience a stroke each year. Furthermore, about 20% of all strokes are recurrent, and many of these patients previously experienced a minor stroke or transient ischemic attack (TIA). Recurrence is greatest within the first 24 to 48 hours, but the risk remains elevated for months, even years, after the initial event. The American Heart Association (AHA) and American Stroke Association (ASA) recently updated their guidelines for stroke prevention to include expanded and detailed recommendations for the use of dual antiplatelet therapy (DAPT), the combination of aspirin and clopidogrel or ticagrelor, to further reduce the risk of stroke. These guidelines also include specific recommendations for individuals with minor acute ischemic stroke (AIS) or a TIA. In this activity based on a recent satellite symposium in New Orleans, leading experts on stroke management highlight the current guideline recommendations and discuss the latest perspectives on DAPT before transitioning to patient case scenarios where each expert demonstrates how these advances can be translated into clinical practice to improve outcomes and reduce the risk of recurrent stroke, while accounting for bleeding risks, antiplatelet resistance, and patient adherence. Upon completion of this CE activity, participants will be able to: Identify individuals with AIS or TIA who are appropriate candidates for treatment with antiplatelet therapy to reduce the risk of recurrent stroke, Assess the benefits and risks of using P2Y12 inhibitors with aspirin as DAPT for the prevention of recurrent stroke, Apply DAPT with P2Y12 inhibitors in appropriate patients following symptom onset to reduce the risk of recurrent stroke, Employ patient-centered communication strategies to facilitate adherence to DAPT with P2Y12 inhibitors in appropriate patients with AIS or TIA to reduce the risk of recurrent stroke.

Welcome to Ask Stago, the podcast dedicated to provide expert answers to your expert questions in hemostasis. In today's episode, our guest David Courtois will explain further what is platelet aggregometry, how to measure it and in which indications it is useful.   Literature sources: Born GVR. Aggregation of blood platelets by adenosine disphosphate and its reversal. Nature 1962; 194: 927 – 929. O'Brien JR. Platelet aggregation. II. Some results from a new method of study. J Clin Pathol 1962; 15: 452-458. Caen JP, Michel H. Platelet shape change and aggregation. Nature 1972; 240 (5377): 148-149. Holmsen H. Platelet metabolism and activation Semin Hematol. 1985; 22 (3): 2 19-40. Kinlough-Rathbone RL, Packham MA, Mustard JF. Platelet aggregation in Methods in Hematology, Churchill Livingstone, New-York 1983; 8: 64-91. Zhou L, Schmaier AH. Platelet aggregation testing in platelet-rich plasma: description of procedures with the aim to develop standards in the field. Am J Clin Pathol 2005; 123 (2): 172-183. Hvas AM, Favaloro EJ. Platelet function analyzed by light transmission aggregometry. Methods Mol Biol 2017; 1646: 321-331. Christie DJ, Avari T, Carrington LR, Cohen E, DeBiase BA, Harrison P, Kickler TS, Kottke-Marchant K, Ledford-Kraemer M, Rand ML, Schmaier AH, McCabe White M. Platelet function testing by aggregometry: approved guidelines, H58-A. Clinical and Laboratory Standards Institute: Wayne, PA, USA 2008; 28 (31): 1-45. Frontroth, J.P.; Favaloro, E.J. Ristocetin-Induced Platelet Aggregation (RIPA) and RIPA Mixing Studies. Methods Mol. Biol. 2017, 1646, 473–494. Hayward CPM, Pai M, Liu Y, Moffat KA, Seecharan J, Weber KE, Cook RJ, Heddle NM. Diagnostic utility of light transmission platelet aggregometry: results from a prospective study of individuals referred for bleeding disorders assessments. J Throm Haemost 2009; 7 (4): 676-684 Cattaneo M., Hayward CP, Moffat KA, Pugliano MT, Liu Y, Michelson AD. Results of a worldwide survey on the assessment of platelet function by light transmission aggregometry: a report from the platelet physiology subcommittee of the SSCC of the ISTH. J. Thromb Haemost 2009; 7: 1029 Hayward CPM, Moffat KA, Raby A, Israels S, Plumhoff E, Flynn G, Zehnder J.L. Development of North American consensus guidelines for medical laboratories that perform and interpret platelet function testing using light transmission aggregometry. Am J Clin Pathol 2010; 134: 955-963. Harrison P, Mackie I, Mumford A, Briggs C, Liesner R, Winter M, Machin S. British Committee for Standards in Haematology. Guidelines for the laboratory investigation of heritable disorders of platelet function. Br J Haematol 2011; 155: 30-44 Dawood BB, Lowe GC, Lordkipanidze M, Bem D, Daly ME, Makris M, Mumford A, Wilde JT, Watson SP. Evaluation of participants with suspected heritable platelet function disorder including recommendation and validation of a streamlined agonist panel. Blood 2012; 120 (25): 5041-5049. Cattaneo M, Cerletti C, Harrison P, Hayward CPM, Kenny D, Nugent D, Nurden P, Rao KA, Schmaier AH, Watson SP, Lussana F, Pugliano MT. Recommendations for the standardization of light transmission aggregometry: a consensus of the working party from the platelet physiology subcommittee of SSC/ISTH. J Throm Haemost 2013; 11: 1183-1189. Rao AK. Inherited platelet function disorders: overview and disorders of granules, secretion, and signal transduction. Hematol Oncol Clin North Am 2013; 27 (3): 585-611. Nurden AT, Nurden P. Inherited disorders of platelet function: selected updates. J Thromb Haemost 2015; 13 (Suppl 1): 2-9. Frelinger AL 3rd, Gachet C, Mumford AD, Noris P, Mezzano D, Harrison P, Gresele P. Laboratory monitoring P2Y12 inhibitors communication from the SSC of the ISTH. J Throm Haemost 2018; 16 (11): 2341-2346 Podda G, Scavone M, Femia EA, Cattaneo M. Aggregometry in the settings of thrombocytopenia, thrombocytosis and antiplatelet therapy. Platelets 2018; 29 (7): 644-649. Hayward CPM, Moffat KA, Brunet J, Carlino SA, Plumhoff E, Meijer P, Zehnder JL. Update on diagnostic testing for platelet function disorders: What is pratical and useful? Int J Lab Hematol 2019; 41 (Suppl 1): 26-32 Gresele P, Orsini S, Noris P, Falcinelli E, Alleci MC, Bury L, Borhany M, Santoro C, Glembotsky AC, Cid AR, Tosetto A, De Candia E, Fontan P, Guglielmini G, Pecci A, BAT-VAL study investigators (57). Validation of the ISTH/SSC bleeding assessment tool for inherited platelet disorders: A communication from the Platelet Physiology SSC. J Thromb Haemost 2020; 18 (3): 732:739. Rabbolini D, Connor D, Morel-Kopp MC, Donikian D, Kondo M, Chen W, Alessi MC, Stevenson W, Chen V, Joseph J, Brighton C, Ward C, Sydney Platelet Group. An integrated approach to inherited platelet disorders: results from a research collaborative, the Sydney Platelet Group. Pathology 2020; 52 (2): 243-255.   Content is scientific and technical in nature. It is intended as an educational tool for laboratory professionals and topics discussed are not intended as recommendations or as commentary on appropriate clinical practice.

P2Y12 loading dose timing in PCI

No episódio de hoje do check-up semanal, o editor-chefe médico do portal PEBMED, Ronaldo Gismondi, inicia o podcast trazendo novas informações sobre a disseminação da nova variante do SARS-CoV-2, batizada de Ômicron e sobre o novo programa do Governo Federal para combate do Aedes Aegypti. Para os artigos comentados de hoje, serão abordados: síndrome de pernas inquietas, síndrome mão, pé e boca na pediatria e mitos e verdades sobre infecção urinária. Fechando o episódio, confira o resumo sobre inibidores no P12y2 no infarto e apneia do sono. Aperte o play e fique por dentro das últimas da medicina!

The association of genetic polymorphisms and P2Y12 inhibitors in regards to efficacy for patients with ischemic stroke or transient ischemic attack (TIA) remains controversial. Drs. Deepak Bhatt of Brigham and Women's Hospital and Natalie Kreitzer of the University of Cincinnati discuss key perspectives from a neurocritical, emergency medicine, and stroke perspective related to this important area of medicine.

FDA 批准免疫检查点药物联用治疗晚期肝细胞癌NEJM 有胃癌家族史患者幽门螺杆菌治疗可预防胃癌Gut 早期胃癌粘膜下剥离术后出血的预测模型Gastroenterology 大数据计算结直肠癌患者的亲属筛查年龄Nature子刊 β1肾上腺素受体抑制剂奈必洛尔治疗直肠癌、乳腺癌纳武利尤单抗+ 伊匹木单抗（nivolumab+ipilimumab）纳武利尤单抗是一种抗PD-1单抗，2014年上市，目前药物适应症症包括黑色素瘤、肾细胞癌、肺癌、肝癌、食管癌等。在《呼吸科星期二 Episode2》中，已经介绍了纳武利尤单抗+伊匹木单抗（CTLA-4单抗），联合低剂量化疗作为转移或复发的非小细胞肺癌的一线治疗方案。2020年3月，FDA批准纳武利尤单抗+伊匹木单抗用于曾接受过索拉非尼治疗的晚期肝细胞癌的治疗。《CheckMate 040研究：纳武利尤单抗+ 伊匹木单抗对曾接受索拉非尼治疗的晚期肝细胞癌患者的1/2期临床研究》JAMA Oncology，2020年10月 (1)大多数肝细胞癌被诊断时已经是晚期，与纳武利尤单抗单药治疗相比，纳武利尤单抗+ 伊匹木单抗可改善临床疗效。研究旨在评估纳武利尤单抗/伊匹木单抗治疗曾接受索拉非尼治疗的、晚期肝细胞癌患者的疗效和安全性。这项多中心、开放标签、多队列、1/2期研究中，纳入148名患者，81%男性，中位年龄为60岁，给予不同剂量的纳武利尤单抗/伊匹木单抗治疗。A组：纳武利尤单抗1mg/kg和伊匹木单抗3mg/kg q3w，随后纳武利尤单抗240mg q2w；B组：纳武利尤单抗3mg/kg和伊匹木单抗1 mg/kg q3w，随后纳武利尤单抗240mg q2w；C组：纳武利尤单抗3mg/kg和伊匹木单抗1 mg/kg q6w。平均随访30.7个月，A组、B组和C组客观缓解率分别为32%、27%和29%；缓解持续时间分别为未达到、15.2个月和21.7个月；不良事件发生率分别为94%、71%和79%。结论：纳武利尤单抗+ 伊匹木单抗具有可管理的安全性、客观有效。幽门螺杆菌和胃癌的关系约有36%-47%的胃癌归因于幽门螺杆菌感染，机制尚不十分清楚，假说包括：细菌菌株差异；宿主免疫应答的基因差异；宿主上皮细胞凋亡、细胞信号传导的差异；环境因素（饮食、胃酸等）。有研究证实，幽门螺杆菌感染与黏膜相关淋巴组织淋巴瘤相关。《随机对照研究：有胃癌家族史患者的幽门螺杆菌治疗》New England Journal of Medicine，2020年1月 (2)幽门螺杆菌感染和胃癌家族史是胃癌的主要危险因素，研究的目的是评价根除幽门螺杆菌可否降低有胃癌家族史的人患胃癌的风险。这项单中心、双盲、安慰剂对照试验中，筛选了胃癌患者的3100名一级亲属，随机分别接受根除治疗（兰索拉唑+阿莫西林+克拉霉素）或安慰剂治疗。在中位9.2年随访期间，治疗组1.2%和安慰剂组2.7%的参与者发生了胃癌（P=0.03）。治疗组中，发生胃癌的10位参与者中5人有持续幽门螺杆菌感染。根除幽门螺杆菌者中0.8%和持续感染者中2.9%发生胃癌（风险比，0.27）。结论：一级亲属患胃癌的幽门螺杆菌感染者中，根除幽门螺杆菌可降低患胃癌的风险。《回顾性队列研究：幽门螺杆菌感染后胃癌的危险因素与发病率》Gastroenterology，2020年10月 (3)研究只在计算幽门螺杆菌阳性后、非近端胃腺癌的发病率和危险因素。这项回顾性队列研究，收集了371,813名患者的数据，中位年龄62岁，92.3%男性被诊断为幽门螺杆菌感染。幽门螺杆菌感染后5年、10年和20年的远端胃腺癌累计发病率分别为0.37%、0.5%和0.65%。与癌症相关的因素包括发现幽门螺杆菌感染时的年龄较大（风险比 1.13），非裔美国人（风险比 2.00），亚裔（风险比 2.52），拉丁裔（风险比 1.59），吸烟史（风险比 1.38）。与男性相比，女性患胃腺癌的风险降低（风险比 0.52），血清抗体阳性的、幽门螺杆菌感染者癌症风险也降低（风险比 0.74）。证实治疗后根除幽门螺杆菌可降低胃癌风险（风险比 0.24）。结论：幽门螺杆菌感染的的少数民族和吸烟者患胃癌的风险明显更高。只有在根除成功的情况下，幽门螺杆菌感染的治疗才能降低风险。《马祖群岛的长期队列研究：大规模根除幽门螺杆菌降低胃癌发病率和死亡率》Gut，2020年8月 (4)胃癌的大规模根除幽门螺杆菌已被提出，但其长期效果尚不清楚。来自台湾大学的研究人员针对居住在台湾马祖群岛、幽门螺杆菌普遍感染的、≥30岁的、高风险人群进行筛查，呼吸试验阳性患者均接受幽门螺杆菌的根除治疗。评估了在2016年年底和2018年之前，大规模根除幽门螺杆菌对降低胃癌发病率和死亡率这两种主要结果的有效性。经6轮大规模筛查和根除，覆盖率达85.5%，转诊率为93.5%。幽门螺杆菌的患病率从64.2%下降到15.0%，再感染率低于1%。萎缩性胃炎和肠上皮化生的出现和严重程度也随时间而减少。与1995 - 2003年历史对照相比，降低胃癌发病率和死亡率的有效性分别为53%（p30mm、肿瘤位于胃的下1/3、存在多发性肿瘤、各类抗血栓药物阻断剂使用）。内镜粘膜下剥离术后低危（0-1分）、中危（2分）、高危（3 ~ 4分）、极高危（≥5分）的出血概率分别为2.8%、6.1%、11.4%、29.7%。在外部验证队列中，模型显示了良好的鉴别能力，一致性指数（C-statisic）为0.70，校准度很好。结论:在这项全国性的多中心研究中，推导并外部验证了粘膜下切除术后出血的预测模型。该模型可作为早期胃癌患者黏膜下切除的临床决策支持工具。《系统综述和荟萃分析：早期胃癌非治疗性内镜切除术后淋巴结转移的患病率和危险因素》Journal of Gastroenterology，2020年10月 (7)早期胃癌内镜粘膜下切除，如果未达到根治，则需要额外手术。该系统性回顾的目的是评价淋巴结转移的发生风险相关因素。研究纳入24项研究，包括3877例患者，其中311例患有淋巴结转移（合并患病率 8.1%）。淋巴结转移的风险高的因素包括：淋巴侵犯（风险比 4.22）、淋巴血管侵犯（风险比4.17）、血管侵犯（风险比2.38）、垂直切缘阳性（风险比2.16）、粘膜下侵犯深度≥500μm（风险比2.14）、肿瘤大小>30mm（风险比1.77）。结论：一些病理因素，最明显的是淋巴侵犯和淋巴血管侵犯，与发生在粘膜下切除后、早期胃癌的、淋巴结转移相关。结直肠癌的危险因素结直肠癌（colorectal cancer，CRC）的危险因素包括环境和遗传因素。遗传因素包括：遗传性结肠癌综合征、结直肠癌或腺瘤的个人史或家族史、有炎症性肠病，以及接受过腹部放疗。潜在可纠正的危险因素包括：肥胖、糖尿病、吸烟、过量饮酒、过度摄入加工肉类以及缺乏体力活动。《病例对照：早发结直肠癌的危险因素》Gastroenterology，2020年8月 (8)研究旨在分析早发性结直肠癌相关的危险因素。研究对1999-2014年接受结肠镜检查的、18至49岁的、退伍军人进行了病例对照研究，包括了651例早发结直肠癌病例和67,416例对照，中位年龄为45.3岁，男性占82.3%，随访3年。与对照组相比，年龄较大、男性、吸烟者、非阿司匹林使用者的病例比例较高，且BMI较低（P