Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non–ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization

Wallentin, Lars; Lindholm, Daniel; Siegbahn, Agneta; Wernroth, Lisa; Becker, Richard C.; Cannon, Christopher P.; Cornel, Jan H.; Himmelmänn, Anders; Giannitsis, Evangelos; Harrington, Robert A.; Held, Claes; Husted, Steen; Katus, Hugo A.; Mahaffey, Kenneth W.; Steg, Philippe Gabriel; Storey, Robert F.; James, Stefan

doi:10.1161/circulationaha.113.004420

Cited by 106 publications

(80 citation statements)

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“…GDF‐15 was measured with a precommercial assay (Roche Diagnostics) using a monoclonal mouse antibody for capture and a monoclonal mouse antibody fragment for detection in a sandwich assay format. The results of these analyses in relation to outcomes and effects of study treatment have previously been reported 8, 9, 10…”

Section: Methodsmentioning

confidence: 90%

“…Several biomarkers, on admission for ACS, provide clinically important information on risk for cardiovascular morbidity and mortality, including NT‐proBNP (myocardial dysfunction),9, 10 cardiac troponins (myocardial necrosis),29 and cystatin C (kidney function) 7, 11. Circulating osteoprotegerin has been reported to be associated with cardiovascular outcomes, including mortality, MI, and incident heart failure, in several ACS cohorts 16, 17, 18, 19.…”

Section: Discussionmentioning

confidence: 99%

“…Circulating osteoprotegerin has been reported to be associated with cardiovascular outcomes, including mortality, MI, and incident heart failure, in several ACS cohorts 16, 17, 18, 19. However, although most of these studies include natriuretic peptides,16, 17, 19 troponins,16, 17, 18 and CRP16, 17, 18 in their adjustment strategy, none include GDF‐15, which increases in response to myocardial stress associated with inflammation and tissue damage30 and is becoming a recognized biomarker in ACS 9, 10, 14. In this large study population, the association between high osteoprotegerin levels at admission and risk of the primary end point or cardiovascular death was markedly attenuated and no longer significant after addition of NT‐proBNP, hs‐TnT, and GDF‐15 to the model that included clinical variables and inflammatory biomarkers.…”

Section: Discussionmentioning

confidence: 99%

“…Circulating biomarkers provide independent information on risk for adverse outcomes on top of established demographic and clinical variables in patients with acute coronary syndromes (ACSs) 7, 8, 9, 10, 11. In addition to the established natriuretic peptides and cardiac troponins, which have been extensively evaluated and shown to be suitable biomarkers for prognosis and/or risk stratification of ACS,12, 13 the recently characterized inflammatory marker, growth differentiation factor‐15 (GDF‐15), may also provide additional clinically useful prognostic information in ACS 14.…”

mentioning

confidence: 99%

“…Also, cystatin C, a marker of kidney function, has recently gained increasing relevance as an independent marker of mortality in ACS 15. Accordingly, we have recently shown that NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide),9, 10 high‐sensitivity troponin T (hs‐TnT),9, 10 GDF‐15,8, 9, 10 and cystatin C7 display independent associations with cardiovascular outcomes, including cardiovascular death, in the PLATO (Platelet Inhibition and Patient Outcomes) trial. Therefore, they represent important adjustment variables for evaluating the independent contribution of new biomarkers to prognosis.…”

mentioning

confidence: 99%

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Osteoprotegerin Is Associated With Major Bleeding But Not With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes: Insights From the PLATO (Platelet Inhibition and Patient Outcomes) Trial

Ueland

Åkerblom

Ghukasyan

et al. 2018

JAHA

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BackgroundElevated levels of osteoprotegerin, a secreted tumor necrosis factor–related molecule, might be associated with adverse outcomes in patients with coronary artery disease. We measured plasma osteoprotegerin concentrations on hospital admission, at discharge, and at 1 and 6 months after discharge in a predefined subset (n=5135) of patients with acute coronary syndromes in the PLATO (Platelet Inhibition and Patient Outcomes) trial.Methods and ResultsThe associations between osteoprotegerin and the composite end point of cardiovascular death, nonprocedural spontaneous myocardial infarction or stroke, and non–coronary artery bypass grafting major bleeding during 1 year of follow‐up were assessed by Cox proportional hazards models. Event rates of the composite end point per increasing quartile groups at baseline were 5.2%, 7.5%, 9.2%, and 11.9%. A 50% increase in osteoprotegerin level was associated with a hazard ratio (HR) of 1.31 (95% confidence interval [CI], 1.21–1.42) for the composite end point but was not significant in adjusted analysis (ie, clinical characteristics and levels of C‐reactive protein, troponin T, NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide], and growth differentiation factor‐15). The corresponding rates of non–coronary artery bypass grafting major bleeding were 2.4%, 2.2%, 3.8%, and 7.2%, with an unadjusted HR of 1.52 (95% CI, 1.36–1.69), and a fully adjusted HR of 1.26 (95% CI, 1.09–1.46). The multivariable association between the osteoprotegerin concentrations and the primary end point after 1 month resulted in an HR of 1.09 (95% CI, 0.89–1.33); for major bleeding after 1 month, the HR was 1.33 (95% CI, 0.91–1.96).ConclusionsIn patients with acute coronary syndrome treated with dual antiplatelet therapy, osteoprotegerin was an independent marker of major bleeding but not of ischemic cardiovascular events. Thus, high osteoprotegerin levels may be useful in increasing awareness of increased bleeding risk in patients with acute coronary syndrome receiving antithrombotic therapy.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

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Section: Methodsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Osteoprotegerin Is Associated With Major Bleeding But Not With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes: Insights From the PLATO (Platelet Inhibition and Patient Outcomes) Trial

Ueland

Åkerblom

Ghukasyan

et al. 2018

JAHA

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Antiretroviral Drug Recommendations for HIV Treatment and Prevention

Shalev

Brudney

Scherer

2021

JAMA

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In Reply We agree with Dr Donzelli that reforming health care payment is an essential step in reducing the delivery of lowvalue services. This is core to our argument around the economic forces that guide the de-adoption of low-value care. 1 Within this realm of economic levers, Donzelli makes an important distinction between pay-for-performance and payfor-health models, noting some inconsistent results from the former. Although there is evidence that targeted payment policies can reduce the provision of low-value care, 2 we agree that more holistic value-based payment models are needed. Our understanding of how to best pay for health continues to evolve and requires precise measurement of and alignment around the definition of health. One approach raised by Donzelli is to move toward risk-adjusted capitated payments, an approach already used at scale within the Medicare Advantage program. There is also some evidence to suggest that other global payment structures influence the provision of low-value services. 3 As the adoption of value-based payment continues to grow, it will be important to rigorously evaluate the impact on low-value care.Donzelli states that "low-value care for patients and society can be high value for the producers, hospitals, and physicians selling it." This important point is sometimes left unacknowledged and identifies trade-offs that must be addressed when seeking widespread de-adoption of low-value care. Here, value-based payment can also play an important role by allocating health care spending to the highest-value services and offsetting potential financial losses. In our own efforts, we have found that value-based payment redirects attention to highvalue services, reallocates savings to increase benefits and reduce out-of-pocket costs for patients, and can actually increase payments to primary care providers. 4 Donzelli also notes that "health authorities should…issue firm recommendations highlighting the health risks and costs of low-value services" instead of simply noting that there is insufficient evidence to cover a service. We agree that when evidence is conclusive, it is essential to clearly communicate health risks and costs. Unfortunately, there is often truly insufficient evidence on the value of many common clinical services. 5 Increased attention to building an evidence base around low-value care is a prerequisite for the effective use of downstream economic levers. 1

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Ticagrelor vs Clopidogrel for Patients With Acute Coronary Syndrome Undergoing Percutaneous Intervention

Kim

Kubica

Jeong

2021

JAMA

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To the Editor A recent retrospective cohort analysis by Dr You and colleagues 1 demonstrated that compared with clopidogrel, ticagrelor was not associated with better outcomes in patients from the US and South Korea with acute coronary syndrome (ACS) undergoing percutaneous intervention (PCI). However, there are several important discrepancies between this cohort analysis and the randomized Platelet Inhibition and Patient Outcomes (PLATO) trial. 2 First, this large-scale retrospective cohort analysis included ACS patients who were considered to be at relatively low risk compared with PLATO. Approximately 80% of patients enrolled in PLATO had acute myocardial infarction (AMI), whereas the proportion of patients with AMI was more limited in this cohort analysis of databases (approximately 20% in the IQVIA Hospital, approximately 50% in the Optum EHR, and approximately 65% in the Health Insurance Review and Assessment service [HIRA]). Compared with clopidogrel, potent P2Y12 inhibitors such as ticagrelor have shown more clinical benefit in high-risk patients with enhanced thrombogenic milieu. 3 In the PLATO trial, there was no definite clinical benefit of ticagrelor vs clopidogrel in ACS patients with a normal cardiac troponin level.Second, important clinical and laboratory covariates reflecting clinical risk of patients with ACS were not included in You and colleagues' 1 propensity score model, unlike the Korea Acute Myocardial Infarction Registry-National Institutes of Health in Dual Anti-Platelet Therapy (KAMIR-NIH-DAPT) score, which uses clinical and laboratory covariates to weigh net ischemic and bleeding risks in patients with AMI. Variables in this model included cardiogenic shock, left ventricular ejection fraction less than 30%, creatinine, anemia, atrial fibrillation, multivessel disease, and complete revascularization. In patients with a KAMIR-NIH-DAPT score of 3 or higher, the use of a potent P2Y12 inhibitor showed an overall clinical benefit compared with clopidogrel without increasing bleeding events. 4 Third, the study by You and colleagues 1 did not provide sufficient data regarding coronary arterial lesional characteristics and procedural interventions; we are concerned that despite statistical adjustment, this study may not have uncovered critical confounders such as disease activity and lesion complexity. Because clopidogrel has limited antiplatelet effect to prevent atherothrombotic event occurrence in patients with AMI, potent P2Y12 inhibitors may have more clinical benefit than clopidogrel in patients treated with complex interventions or who have remnant coronary artery lesions. Recent evidence has suggested a benefit of ticagrelor vs clopidogrel for cardiac protection in high-risk patients with AMI. 5

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Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non–ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization

Cited by 106 publications

References 35 publications

Osteoprotegerin Is Associated With Major Bleeding But Not With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes: Insights From the PLATO (Platelet Inhibition and Patient Outcomes) Trial

Osteoprotegerin Is Associated With Major Bleeding But Not With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes: Insights From the PLATO (Platelet Inhibition and Patient Outcomes) Trial

Antiretroviral Drug Recommendations for HIV Treatment and Prevention

Ticagrelor vs Clopidogrel for Patients With Acute Coronary Syndrome Undergoing Percutaneous Intervention

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