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Shortly after the emergence of coronavirus disease 2019 (COVID-19) in late 2019, clinicians rapidly recognized an apparent association between the disease and both arterial and venous thrombotic complications, which was confirmed in epidemiologic studies. Based on these data, hospitals empirically developed and implemented protocols with different strategies for anticoagulation of hospitalized COVID-19 patients. Subsequent randomized controlled trials (RCTs) clarified the role of anticoagulation in patients hospitalized with COVID-19 and recently discharged from the hospital. In this review, we discuss the epidemiology and pathophysiology of thrombosis in patients with COVID-19, observational comparative effectiveness analyses that provided hints of a benefit from anticoagulation, and finally the RCTs that established which patients with COVID-19 benefit from treatment-dose anticoagulation. These RCTs have demonstrated that hospitalized, noncritically ill patients with COVID-19 benefit from treatment-dose anticoagulation, but patients who are hospitalized and critically ill, discharged from the hospital, or not hospitalized do not benefit. [ABSTRACT FROM AUTHOR]

The RCTs of AF-PCI/ACS patients lack such information (Table 1).[[5], [7]] A subgroup analysis of the REDUAL PCI trial showed that only 9.9% of included patients had high-risk procedural factors and only 10% had both high-risk procedural and clinical complexity factors.[13] Although high-risk procedural features were not explicit exclusion criteria, the dearth of procedural details and the absence of statistically powered outcome stratification by PCI complexity prevent generalization of the four RCT results to PCI patients with high ischaemic risk PCI, which may represent up to 60% of cases according to a recent study.[12] Sub-analyses and specific high-risk subgroups. These patients made up only a fraction of the patients enrolled in WOEST (27%), PIONEER AF-PCI (29%), RE-DUAL (50%), AUGUSTUS (51%), and ENTRUST-AF PCI (52%), and individual trials were not powered to detect a treatment by subgroup interaction. The low thrombogenicity of new stent platforms, together with the increasing awareness of the prognostic impact of bleeding events have prompted the design of many RCTs testing a de-escalation or shortening of antithrombotic therapy, aiming at reducing bleeding without any trade-off in ischaemic events (Table 1).[38] Among them, the RCTs including patients with AF-PCI/ACS were the only ones in which: (i) the primary endpoints did not include ischaemic outcomes; (ii) procedural details were not reported; (iii) ACS patients were not well represented, as none focused entirely on the acute setting; (iv) "de-escalation" was started very early after PCI (Table 1). [Extracted from the article]

The authors discuss a study by Saad et al in the issue about the findings of a study on myocardial infarction (MI) during the COVID-19 pandemic. They talk about the limitations which challenge the interpretation of the data, the consistency of the findings of the study with results observed in several registries that have collected detailed clinical data about patients presenting with ST-segment elevation MI (STEMi) in the COVID era, and possible mediators of excess mortality.

Background: The primary goal of phase 2 and 3 clinical trials is to evaluate the safety and effectiveness of therapeutic interventions, and efficient and reproducible ascertainment of important clinical events, either as clinical outcome events (COEs) or adverse events (AEs), is critical. Clinical outcomes require consistency and clinical judgment, so these events are often adjudicated centrally by clinical events classification (CEC) physician reviewers using standardized definitions. In contrast, AEs are reported by sites to the trial coordinating center based on common reporting criteria set by regulatory authorities and trial sponsors. These different requirements have led to the development of separate tracks for COE and AE review.Main Body: Potential COEs that fail to meet standardized definitions for CEC adjudication - i.e. negatively adjudicated events (NAE) - may meet criteria for AEs. Trial oversight practices require the sponsor to process AEs regardless of how the AEs are submitted; therefore, review of NAEs may be necessary to ensure that important AEs do not go unreported. The Duke Clinical Research Institute (DCRI) developed and implemented a process for scrutinizing NAEs to detect potential missed serious AEs. Initial experience with this process across two trials suggests that approximately 0.2% of NAEs are serious unexpected AEs that were not otherwise reported and another 1.5% are serious expected AEs.Conclusions: Given their infrequent concealment of serious AEs in two large trials assessing cardiovascular outcomes, routine scrutiny of NAEs to identify AEs is not recommended at this time, though it may be useful in some trials and should be carefully considered by the trial team. Closer integration of data across safety surveillance and endpoint adjudication systems may enable scrutiny of NAEs when indicated while limiting complexity associated with this process. [ABSTRACT FROM AUTHOR]

Importance: Clinical decisions are ideally based on evidence generated from multiple randomized controlled trials (RCTs) evaluating clinical outcomes, but historically, few clinical guideline recommendations have been based entirely on this type of evidence.Objective: To determine the class and level of evidence (LOE) supporting current major cardiovascular society guideline recommendations, and changes in LOE over time.Data Sources: Current American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology (ESC) clinical guideline documents (2008-2018), as identified on cardiovascular society websites, and immediate predecessors to these guideline documents (1999-2014), as referenced in current guideline documents.Study Selection: Comprehensive guideline documents including recommendations organized by class and LOE.Data Extraction and Synthesis: The number of recommendations and the distribution of LOE (A [supported by data from multiple RCTs or a single, large RCT], B [supported by data from observational studies or a single RCT], and C [supported by expert opinion only]) were determined for each guideline document.Main Outcomes and Measures: The proportion of guideline recommendations supported by evidence from multiple RCTs (LOE A).Results: Across 26 current ACC/AHA guidelines (2930 recommendations; median, 121 recommendations per guideline [25th-75th percentiles, 76-155]), 248 recommendations (8.5%) were classified as LOE A, 1465 (50.0%) as LOE B, and 1217 (41.5%) as LOE C. The median proportion of LOE A recommendations was 7.9% (25th-75th percentiles, 0.9%-15.2%). Across 25 current ESC guideline documents (3399 recommendations; median, 130 recommendations per guideline [25th-75th percentiles, 111-154]), 484 recommendations (14.2%) were classified as LOE A, 1053 (31.0%) as LOE B, and 1862 (54.8%) as LOE C. When comparing current guidelines with prior versions, the proportion of recommendations that were LOE A did not increase in either ACC/AHA (median, 9.0% [current] vs 11.7% [prior]) or ESC guidelines (median, 15.1% [current] vs 17.6% [prior]).Conclusions and Relevance: Among recommendations in major cardiovascular society guidelines, only a small percentage were supported by evidence from multiple RCTs or a single, large RCT. This pattern does not appear to have meaningfully improved from 2008 to 2018. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) increases a patient's stroke risk four- to five-fold. Anticoagulation with the vitamin K antagonist (VKA) warfarin reduces the risk of stroke by 67%, but warfarin carries a significant risk of major bleeding and has unpredictable pharmacodynamics with a narrow therapeutic window, necessitating frequent monitoring of its anticoagulant effect. The non–vitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban provide more predictable anticoagulant activity than warfarin with a lower risk of major bleeding, and each is noninferior to warfarin for the prevention of stroke. All have earned regulatory approval in the past eight years. At least one of the NOACs is approved for use in all patients with AF, except those with mechanical valves and rheumatic mitral valve disease, for whom warfarin remains the only option. Recent clinical trials have shown that antithrombotic regimens including NOACs are safe and effective in patients with AF who need potent antiplatelet therapy. [ABSTRACT FROM AUTHOR]

An editorial is presented on Edoxaban in atrial fibrillation patients with percutaneous coronary intervention by acute or chronic coronary syndrome presentation. Topics include balancing competing risks of bleeding and ischaemic event; providing the best balance of protection from ischaemic events while limiting bleeding in patients; and suggesting a higher rate of ischaemic events with the edoxaban-based regimen in patients.

Real-world data (RWD) has been defined as data generated outside of traditional randomized clinical trials (RCTs). Though RWD has received increasing attention from regulatory authorities and professional societies, dividing evidence into that derived from ‘real-world’ vs. ‘non-real-world’ sources provides only one element of a much larger framework for evidence evaluation. Evidence should be evaluated on the source of the data, the method of treatment allocation (whether any intervention being evaluated was assigned or simply observed as used in practice) and the context in which the evidence was generated (overall study design). Under this framework, RWD refers only to data source, and a study incorporates RWD when it primarily uses data collected for non-research purposes, such as insurance claims data or the electronic health record, regardless of study design. Separation of study design, data source, and context enables parallel evaluation of two critical elements: (i) whether a study can support claims of causal inference, which can be assured with a high degree of confidence only in studies where patients are assigned treatments by protocol; and (ii) whether the study population and clinical context mirror clinical practice, a strength of observational studies using data from clinical practice or administrative claims. In this review, we describe the strengths and weaknesses of observational and non-observational studies, and studies involving RWD and non-RWD, through the lens of anticoagulation for atrial fibrillation (AF). Observational studies employing RWD are useful for describing how oral anticoagulants are used in clinical practice, but generally cannot be used to make claims regarding comparative treatment effects. Questions regarding treatment effect generally are best answered through an RCT, and additional pragmatic RCTs are needed to compare different antithrombotic agents for the prevention of thrombotic events in AF. View large Download slide View large Download slide [ABSTRACT FROM AUTHOR]

Aspirin has been the cornerstone of therapy for the secondary prevention treatment of patients with cardiovascular disease since landmark trials were completed in the late 1970s and early 1980s that demonstrated the efficacy of aspirin for reducing the risk of ischemic events. Notwithstanding the consistent benefits demonstrated with aspirin for both acute and chronic cardiovascular disease, there are a number of toxicities associated with aspirin that have been showcased by recent long-term clinical trials that have included an aspirin monotherapy arm. As an inhibitor of cyclooxygenase (COX), aspirin impairs gastric mucosal protective mechanisms. Previous trials have shown that up to 15-20 % of patients developed gastrointestinal symptoms with aspirin monotherapy, and approximately 1 % of patients per year had a clinically significant bleeding event, including 1 in 1000 patients who suffered an intracranial or fatal bleed. These risks have been shown to be compounded for patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI) who are also treated with other antithrombotic agents during the acute care/procedural period, as well as for an extended time period afterwards. Given observations of substantial increases in bleeding rates from many prior long-term clinical trials that have evaluated aspirin together with other oral platelet inhibitors or oral anticoagulants, the focus of contemporary research has pivoted towards tailored antithrombotic regimens that attempt to either shorten the duration of exposure to aspirin or replace aspirin with an alternative antithrombotic agent. While these shifts are occurring, the safety profile of aspirin when used for the secondary prevention treatment of patients with established cardiovascular disease deserves further consideration. [ABSTRACT FROM AUTHOR]

Importance: About 10% of patients with acute chest pain are ultimately diagnosed with acute coronary syndrome (ACS). Early, accurate estimation of the probability of ACS in these patients using the clinical examination could prevent many hospital admissions among low-risk patients and ensure that high-risk patients are promptly treated.Objective: To review systematically the accuracy of the initial history, physical examination, electrocardiogram, and risk scores incorporating these elements with the first cardiac-specific troponin.Study Selection: MEDLINE and EMBASE were searched (January 1, 1995-July 31, 2015), along with reference lists from retrieved articles, to identify prospective studies of diagnostic test accuracy among patients admitted to the emergency department with symptoms suggesting ACS.Data Extraction and Synthesis: We identified 2992 unique articles; 58 met inclusion criteria.Main Outcomes and Measures: Sensitivity, specificity, and likelihood ratio (LR) of findings for the diagnosis of ACS. The reference standard for ACS was either a final hospital diagnosis of ACS or occurrence of a cardiovascular event within 6 weeks.Results: The clinical findings and risk factors most suggestive of ACS were prior abnormal stress test (specificity, 96%; LR, 3.1 [95% CI, 2.0-4.7]), peripheral arterial disease (specificity, 97%; LR, 2.7 [95% CI, 1.5-4.8]), and pain radiation to both arms (specificity, 96%; LR, 2.6 [95% CI, 1.8-3.7]). The most useful electrocardiogram findings were ST-segment depression (specificity, 95%; LR, 5.3 [95% CI, 2.1-8.6]) and any evidence of ischemia (specificity, 91%; LR, 3.6 [95% CI,1.6-5.7]). Both the History, Electrocardiogram, Age, Risk Factors, Troponin (HEART) and Thrombolysis in Myocardial Infarction (TIMI) risk scores performed well in diagnosing ACS: LR, 13 (95% CI, 7.0-24) for the high-risk range of the HEART score (7-10) and LR, 6.8 (95% CI, 5.2-8.9) for the high-risk range of the TIMI score (5-7). The most useful for identifying patients less likely to have ACS were the low-risk range HEART score (0-3) (LR, 0.20 [95% CI, 0.13-0.30]), low-risk range TIMI score (0-1) (LR, 0.31 [95% CI, 0.23-0.43]), or low to intermediate risk designation by the Heart Foundation of Australia and Cardiac Society of Australia and New Zealand risk algorithm (LR, 0.24 [95% CI, 0.19-0.31]).Conclusions and Relevance: Among patients with suspected ACS presenting to emergency departments, the initial history, physical examination, and electrocardiogram alone did not confirm or exclude the diagnosis of ACS. Instead, the HEART or TIMI risk scores, which incorporate the first cardiac troponin, provided more diagnostic information. [ABSTRACT FROM AUTHOR]