Greater Fibrinolysis Resistance but No Greater Platelet Aggregation in Critically Ill COVID-19 Patients

Background The hemostatic balance in patients with coronavirus disease 2019 (COVID-19) seems to be shifted toward a hypercoagulable state. The aim of the current study was to assess the associated coagulation alterations by point-of-care-diagnostics, focusing on details of clot formation and lysis in these severely affected patients. Methods The authors’ prospective monocentric observational study included critically ill patients diagnosed with COVID-19. Demographics and biochemical data were recorded. To assess the comprehensive hemostatic profile of this patient population, aggregometric (Multiplate) and viscoelastometric (CloPro) measures were performed in the intensive care unit of a university hospital at a single occasion. Coagulation analysis and assessment of coagulation factors were performed. Data were compared to healthy controls. Results In total, 27 patients (21 male; mean age, 60 yr) were included. Impedance aggregometry displayed no greater platelet aggregability in COVID-19 in comparison with healthy controls (area under the curve [AUC] in adenosine diphosphate test, 68 ± 37 U vs. 91 ± 29 U [−27 (Hodges–Lehmann 95% CI, −48 to −1); P = 0.043]; AUC in arachidonic acid test, 102 ± 54 U vs. 115 ± 26 U [−21 (Hodges–Lehmann 95% CI, −51 to 21); P = 0.374]; AUC in thrombin receptor activating peptide 6 test, 114 ± 61 U vs. 144 ± 31 U [−31 (Hodges–Lehmann 95% CI, −69 to −7); P = 0.113]). Comparing the thromboelastometric results of COVID-19 patients to healthy controls, the authors observed significant differences in maximum clot firmness in fibrin contribution to maximum clot firmness assay (37 ± 11 mm vs. 15 ± 4 mm [21 (Hodges–Lehmann 95% CI, 17 to 26); P < 0.001]) and lysis time in extrinsic activation and activation of fibrinolysis by tissue plasminogen activator assay (530 ± 327 s vs. 211 ± 80 s [238 (Hodges–Lehmann 95% CI, 160 to 326); P < 0.001]). Conclusions Thromboelastometry in COVID-19 patients revealed greater fibrinolysis resistance. The authors did not find a greater platelet aggregability based on impedance aggregometric tests. These findings may contribute to our understanding of the hypercoagulable state of critically ill patients with COVID-19. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Abstract 15939: Neither Moderate Consumption of Sugarcane Liquor (“Cachaca”) Nor of Red Wine Affect Cardiovascular Risk Biomarkers in Healthy Individuals

Introduction: It is well established that moderate consumption of red wine is associated with reduced risk of cardiovascular (CV) events. Many observational studies have shown that this same benefit could be seen with other alcohol beverages different from wine. However, the correlation between the Brazilian sugarcane liquor (“cachaca”) and CV benefit has not been demonstrated in human trials. Hypothesis: Cachaca causes changes in biomarkers of CV risk in the same proportion as wine. Methods: In this crossover randomized study, healthy individuals were initially designated to have daily moderate alcohol consumption (MAC) of either cachaca or red wine for a period of 4 weeks. MAC, for both drinks, was denoted as a daily dose equivalent of 28g of alcohol for men and 14g for women. Then, after an abstinence period of 7 days, drink types were switched for more 4 weeks. Analysis of CV risk biomarkers were determined before and after each intervention, and consisted of C-reactive protein, lipid profile, platelet aggregability and glycid profile. (This research was funded by FAPESP 2018/09675-4). Results: Of the 37 individuals originally enrolled, 2 refused to continue the study. The average age of the individuals was 41.7 (±15.3 years) and 43.2% were men. Adherence to the protocol was considered essentially ideal, with 100% of regular use in both interventions and only 3 individuals reporting abuse during the study period. There was no significant variation in anthropometric measurements during the study, except for a weight gain (0.6kg) with red wine (p = 0.011). As seen in the table, no significant changes were noted in the inflammatory markers, lipid profile, platelet aggregability nor glycid profile before and after each intervention. Conclusions: This study shows that in healthy individuals, neither red wine nor cachaca changed CV biomarkers related to atherosclerotic progression after 4 weeks of MAC. However, there was a marked weight gain with daily wine consumption.

Platelet reactivity among patients with acute coronary syndromes and multivessel coronary artery disease

Background Patients with multivessel or complex coronary artery disease (CAD) are at increased risk of atherothrombotic events. It has been suggested that these patients may derive an incremental benefit with more intense antiplatelet strategies, according to prior subgroup analyses from randomized clinical trials. However, whether there is any association between the presence and extension of multivessel CAD and platelet aggregability (PA) in patients with acute coronary syndromes (ACS) is unknown. Purpose To analyze the independent association between PA and presence of multivessel CAD in patients with ACS. Methods Patients with ACS on dual antiplatelet therapy (aspirin plus clopidogrel) were included in this study. Multivessel CAD was defined as the presence of significant ≥50% stenosis at two or more major epicardic vessels. Platelet aggregability was assessed by VerifyNow P2Y12 assay expressed in P2Y12 Reactivity Units (PRU) on the day of discharge from the coronary care unit. High On-treatment platelet reactivity (HPR) was defined as PRU ≥208. Stepwise linear and logistic regression models were applied to adjust for confounders. Models were adjusted for: age, sex, race, diabetes, hypertension, smoking, dyslipidemia, prior MI, prior PCI, prior CABG, prior HF, prior stroke and ACS phenotype (STEMI vs. Non-ST-segment elevation ACS). Results A total of 237 patients were included, among whom 143 (60.3%) had multivessel CAD at the coronary angiogram and 175 (73.8%) were submitted to PCI during index hospitalization. Patients with multivessel disease were older (mean age 64.8±12.1 vs. 58.9±11.2 years; p<0.001) and more likely to have a history of diabetes (47.6% vs. 29.8%; p=0.006) and non-ST-segment elevation ACS as the index event (55.2% vs. 28.7%; p<0.001), compared to patients without multivessel CAD. After adjustments, presence of multivessel CAD was associated with higher PA (mean 161.4±74 PRU in patients with versus 140.3±70.9 PRU in patients without multivessel CAD; adjusted mean difference 23.7 PRU; 95% CI 4.8 to 42.5; p=0.014). Additionally, there was an incremental of 12.5 PRU (95% CI 2.8 to 22.3; adj p=0.012) for each diseased vessel and of 4.67 PRU (95% CI 0.11 to 9.22; adj p=0.045) for each diseased coronary segment. Compared to patients with single-vessel disease, patients with three-vessel disease had higher rates of HPR. (Figure). Conclusion In patients with ACS, the presence and extension of multivessel CAD were associated with higher levels of platelet aggregability and higher rates of high on-treatment platelet reactivity with clopidogrel. This finding may explain the incremental benefit with more intense antiplatelet therapies seen in this particular subgroup in prior clinical trials. Prevalence of HPR and extension of CAD Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Sao Paulo Research Foundation (FAPESP)

Economic analysis of platelet aggregability-guided surgical revascularization compared with standard of care in ACS patients: subanalysis from PLAT-CABG randomized clinical trial

Background Dual antiplatelet therapy (DAPT) is recommended for patients with acute coronary syndromes (ACS). Up to 15% are submitted to coronary artery bypass graft (CABG) during the hospitalization for the index event. However, as current guidelines recommend withdrawal of clopidogrel at least 5 days prior to CABG, this waiting time may increase hospital length of stay, thus potentially having negative impacts on costs and clinical outcomes. As previously presented at the ESC 2019 Congress, the PLAT-CABG study showed that the strategy to shortening CABG waiting time guided by platelet function test was non-inferior to the standard of care in terms of perioperative bleeding and led to shorter length of hospital stay among ACS patients. In this subanalysis, we present results regarding the in-hospital expenses for the two strategies. Purpose To determine, from the perspective of the Brazilian Government Health System (BGHS), the hospital expenses of patients undergoing CABG guided by platelet aggregability tests in comparison to the standard of care. Methods The PLAT-CABG study was a randomized and open label clinical trial testing a strategy of platelet aggregability-guided CABG after ACS versus standard-of-care. A total of 185 ACS patients on DAPT (aspirin plus clopidogrel) scheduled for on-pump or off-pump CABG were randomized to clopidogrel withdraw 5 to 7 days prior to CABG (control group) vs. daily measurements of platelet aggregability using Multiplate ADP-test (intervention group). Hospital cost (expressed in Brazilian currency - reais) subanalysis was pre-specified in the main trial statistical analysis plan. All patients had their hospital expenses covered by the BGHS and platelet aggregability tests costs were included in the analysis. Patients randomized to intervention group were allowed to undergo CABG when platelet aggregation recovered (pre-defined as Multiplate ≥46 AUC). In per protocol analysis, only patients who underwent CABG on the day after reaching the pre-specified aggregabilty cut point were analyzed. Results The main results are depicted in Figure 1. In the intention-to-treat analysis, median hospital expenses for the intervention group were R$15,202.33 and for the control group R$16,251.37 (mean difference of R$1,049.04, or 6.4%, P=0.014). In per protocol analysis, the mean hospital expenses for the intervention group were R$14,248.41 and for the control group R$ 16,039.55 (difference of R$ 1,791.14 or 11.2%, P=0.003). For an estimated 70,000 CABG procedures/year in Brazil, we estimate that the implementation of this routine would save up to R$125,370,000.00/year. Conclusion In patients with ACS taking DAPT, a strategy of platelet function-guided timing to CABG resulted in lower hospital expenses compared to a standard of care of waiting at least 5 days after clopidogrel withdrawal. Figure 1. Hospital expenses between groups Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Roche Diagnostica Brazil

P331Effect of exercise stress test on platelet function in patients with recent acute myocardial infarction

Background Exercise-based cardiac rehabilitation for coronary artery disease (CAD) is associated with lower cardiovascular mortality. On the other hand, acute strenuous exercise has been linked to cardiovascular complications such as acute myocardial infarction (AMI) and sudden cardiac death. One of the pathophysiological mechanisms involved in these outcomes might be an increase in platelet aggregability after exercise. Although previous studies showed higher platelet aggregability after exercise among stable CAD patients on aspirin treatment, there is no data regarding the effect of exercise on platelet activity in post-AMI patients on dual anti-platelet therapy (DAPT). Purpose To evaluate the effect of high-intensity exercise on platelet aggregability in sedentary post-AMI patients on DAPT. Methods Platelet function was analyzed immediately before and after maximal cardiopulmonary exercise test (CPET) on cycle ergometer utilizing a personalized ramp protocol and aiming to achieving peak exercise in around 10 min. The CPET was done within 31±4 days after uncomplicated AMI. Platelet aggregability was assessed by Multiplate®ADPtest (MP-ADP) and Multiplate® ASPItest (MP-ASPI) measured as area under the curve (AUC). Reticulated platelets were measured concomitantly to MP-ADP e MP-ASPI using a fully automated flow cytometer (Sysmex XN-2000®) to determine absolute immature platelet count (IPC) per 103/microliter. Continuous variables were expressed as means ±standard deviation or as median and 25th–75th percentiles if not Gaussian distributed. Comparisons between the pre- and post-CPET assessments were performed using Wilcoxon signed rank test. Results We analyzed 81 sedentary patients (mean age 58.3±10.1 years-old, 76.5% men) after AMI (50.6% with ST-elevation myocardial infarction, mean left ventricular ejection fraction after index event 55±11.7%, 98.8% on statin and 85.5% on beta-blocker treatment). Platelet aggregability, either by MP-ADP or MP-ASPI, and IPC were significantly increased after CPET (table). Platelet function after CPET Before CPET After CPET p-value Multiplate® ADPtest (AUC) – median (25th–75th percentiles) 32.0 (22.0–48.5) 37.0 (26.0–55.2) 0.003 Multiplate® ASPItest (AUC) – median (25th–75th percentiles) 17.0 (12.7–22.0) 22.0 (16.7–28.0) <0.001 Immature platelet count (103/microliter) – median (25th–75th percentiles) 9.5 (6.8–13.8) 9.6 (6.6–16.5) 0.006 CPET: cardiopulmonary exercise test; AUC: area under the curve. Conclusion On this post-AMI population, platelet was hyperactivated after exercise stress test despite the use of DAPT. These findings suggest that, even when properly treated, post-AMI patients might be at higher risk of ischemic complications after high-intensity exercises, reinforcing the importance of tailoring exercise prescription in this population. Acknowledgement/Funding Sao Paulo Research Foundation, FAPESP

P1839Platelet aggregability evaluation in patients with acute coronary syndromes scheduled for coronary artery bypass graft. The PLAT-CABG study

Background Dual antiplatelet therapy is recommended for patients (pts) with acute coronary syndromes (ACS). However, 10–15% of pts have indication of coronary artery bypass graft (CABG) for the index event and current guidelines recommend stopping clopidogrel at least 5 days prior to CABG. This waiting time could increase hospital length of stay, thus having negative impacts on costs and clinical complications. Purpose To evaluate if release to CABG based on platelet aggregability by Multiplate AnalyzerTM would be non-inferior in comparison with common practice (5 days) in terms of 24-hours post-CABG bleeding. Methods The PLAT-CABG (NCT 02516267) is a randomized, open label, non-inferiority trial (boundary 25%) testing a strategy of platelet aggregability-guided release to CABG versus standard-of-care on the primary endpoint of chest tube drainage in the first 24 hours post CABG. A total of 190 pts admitted with ACS, treated with aspirin + clopidogrel and with indication for CABG, were assigned to clopidogrel discontinued 5 days prior to CABG (control group) vs. daily measurements of platelet aggregability to ADP using Multiplate AnalyzerTM (intervention group) with CABG occurring after recovering from platelet inhibition (pre-defined as a threshold of 46 AU). Results The main results are depicted in the table Main results of PLAT-CABG study Variables Control Group (n=95) Intervention Group (n=95) P-value for superiority P-value for non-inferiority Chest tube drainage (mL), Median (25th–75th) 350 (250–500) 350 (250–500) 0.680 0.001 Time symptom to CABG (hours), Median (25th–75th) 191 (150–281) 166 (119–225) <0.001 NA Time surgery indication to CABG (hours), Median (25th–75th) 136 (112–161) 112 (66–142) <0.001 NA CABG = coronary artery bypass graft. Conclusion Platelet-aggregability guided release to CABG is non-inferior to standard of care in ACS patients awaiting CABG in terms of peri-operative bleeding and significantly shortens the time to CABG. Acknowledgement/Funding Roche Diagnostica Brazil