Circulation Editors’ Picks

Abstract

HomeCirculationVol. 128, No. 18Circulation Editors’ Picks Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCirculation Editors’ PicksMost Read Articles on the Topic of Biomarkers The Editors The Editors Search for more papers by this author Originally published29 Oct 2013https://doi.org/10.1161/CIRCULATIONAHA.113.006643Circulation. 2013;128:e369–e376Transcriptomic Biomarkers for the Accurate Diagnosis of MyocarditisSummary—New diagnostic tools based on gene signatures derived from the entire complement of messenger RNAs in a cell or tissue have become established in the clinical management of certain disorders, particularly cancer. The comprehensiveness of this approach contributes to its accuracy. Myocarditis is a disorder that causes a substantial proportion of patients presenting with new-onset heart failure and left ventricular dysfunction. Typically diagnosed by endomyocardial biopsy and evaluated with histological criteria called the Dallas criteria, clinical management is hampered by low sensitivity and specificity and the need for multiple cardiac biopsies. The present study suggests that the application of a transcriptomic based biomarker can substantially improve the diagnostic accuracy of heart biopsy for myocarditis. Using endomyocardial biopsy tissue obtained at the time of clinical presentation, we developed a molecular signature comprising 62 genes that predicted with high accuracy the presence of myocarditis in a population of 48 patients. Importantly, this required evaluation of tissue from a single endomyocardial biopsy sample and therefore is clinically practical. The present results could provide treating physicians with important and accurate diagnostic information about individual patients and could provide tools for personalized treatment or monitoring. Given emerging treatment strategies for viral and inflammatory myocarditis, accurate diagnostic tools are of increased importance.Conclusions—Together, these findings demonstrate that transcriptomic biomarkers from a single endomyocardial biopsy can improve the clinical detection of patients with inflammatory diseases of the heart. This approach advances the clinical management and treatment of cardiac disorders with highly variable outcome.1High-Molecular-Weight and Total Adiponectin Levels and Incident Symptomatic Peripheral Artery Disease in Women: A Prospective InvestigationSummary—Lower-extremity peripheral artery disease (PAD) is a manifestation of atherosclerosis that has received considerably less clinical and research attention than coronary or cerebrovascular disease. PAD shares many risk factors with other cardiovascular diseases, including smoking, diabetes mellitus, hypertension, and hyperlipidemia; however, less is known about how PAD differs from atherosclerosis of other vascular territories. Studies of biomarkers and future disease risk can improve our ability to detect patients at heightened risk and our understanding of disease pathogenesis and, by extension, may identify potential novel modalities for treatment. Adiponectin is secreted from adipose tissue and is known to be inversely correlated with future diabetes mellitus risk. It may also be antiatherogenic. This study is the first to examine the relationship between adiponectin and PAD as a specific vascular end point. A large population of initially healthy women aged ≥45 years without existing cardiovascular disease was studied. After traditional cardiovascular risk factors were taken into account, women with high-molecular-weight or total adiponectin levels in the highest tertile had a 59% (high-molecular-weight) or 63% (total) reduced risk for future symptomatic PAD (intermittent claudication or lower-extremity revascularization) compared with women with levels in the lowest tertile. Given the lack of a consistently demonstrated relationship between adiponectin and other cardiovascular end points, this striking result, if confirmed, suggests a unique relationship of adiponectin in PAD development that may reflect a more prominent role of adipokines in peripheral atherosclerosis.Conclusions—Total and HMW adiponectin are inversely associated with incident PAD among initially healthy women. These prospective data support a protective role for this adipokine in peripheral atherosclerosis development.2Growth-Differentiation Factor-15 Is a Robust, Independent Predictor of 11-Year Mortality Risk in Community-Dwelling Older Adults: The Rancho Bernardo StudySummary—The goal of risk stratification for primary prevention of cardiovascular disease is to identify individuals who may be candidates for interventions that could improve outcomes. Current risk stratification tools remain imperfect, and biomarkers that reflect novel pathophysiological pathways could improve risk assessment as well as provide insight into potential therapeutic targets. Growth differentiation factor-15 (GDF-15) is a divergent member of the transforming growth factor-β cytokine superfamily that is upregulated in the myocardium after ischemic injury. Previous community-based studies have shown that higher levels of GDF-15 are associated with prevalent cardiovascular disease. The present study of older community-dwelling adults free of known cardiovascular disease from the Rancho Bernardo Study evaluated the association of GDF-15 levels with cardiovascular outcomes and mortality and found that GDF-15 was a robust predictor of all-cause, cardiovascular, and noncardiovascular mortality even after adjustment for traditional cardiovascular disease risk factors, renal function, and body size. In models containing all 3 markers, both GDF-15 and N-terminal pro-B-type natriuretic peptide, but not C-reactive protein, added incremental value for prediction of cardiovascular and all-cause mortality. When associations are confirmed in other cohorts and when further studies clarify the mechanism of action, GDF-15 may ultimately be a worthy target for therapeutic interventions to prevent cardiovascular and all-cause death.Conclusions—Growth differentiation factor-15 is a strong predictor of all-cause, cardiovascular, and noncardiovascular mortality in community-dwelling older individuals, adding incremental value to traditional risk factors and to NT-proBNP and C-reactive protein levels.3Myocardial Infarction After Carotid Stenting and Endarterectomy: Results From the Carotid Revascularization Endarterectomy Versus Stenting TrialSummary—The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) showed no difference in the composite end point of stroke, myocardial infarction (MI), or death during the periprocedural period and ipsilateral stroke during follow-up. The higher risk of stroke with carotid artery stenting and higher risk of periprocedural myocardial infarction after carotid endarterectomy underscore the need for detailed analysis of the MI end point. Among 2502 patients, 14 MIs occurred in carotid artery stenting and 28 MIs in carotid endarterectomy (hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.94; P=0.032), with a median biomarker ratio of 40 times the upper limit of normal. An additional 8 carotid artery stenting and 12 carotid endarterectomy patients had biomarker positivity only (hazard ratio, 0.66; 95% confidence interval, 0.27 to 1.61; P=0.36), and their median biomarker ratio was 14 times the upper limit of normal. Compared with patients without biomarker elevation, mortality was higher over 4 years for those with MI (hazard ratio, 3.40; 95% confidence interval, 1.67 to 6.92) or biomarker positivity only (hazard ratio, 3.57; 95% confidence interval, 1.46 to 8.68). After adjustment for baseline risk factors, both MI and biomarker positivity only remained independently associated with increased mortality. In the randomized CREST trial, both MI and biomarker positivity without symptoms or ECG changes were more common with carotid endarterectomy than carotid artery stenting. Both events were associated with increased long-term mortality in unadjusted and risk-adjusted analyses, suggesting that the occurrence of periprocedural MI or biomarker positivity only identifies a population of patients at greater risk of death in longer-term follow-up. The findings also suggest that individualized patient risk for such events may be an important consideration in the choice of carotid artery stenting or carotid endarterectomy and the choice of carotid revascularization or medical therapy.Conclusions—In patients randomized to carotid endarterectomy versus carotid artery stenting, both MI and biomarker+ only were more common with carotid endarterectomy. Although the levels of biomarker elevation were modest, both events were independently associated with increased future mortality and remain an important consideration in choosing the mode of carotid revascularization or medical therapy.4Twenty-Two–Year Trends in Incidence of Myocardial Infarction, Coronary Heart Disease Mortality, and Case Fatality in 4 US Communities, 1987–2008Summary—Community-level event rates are the ultimate measures of successful clinical and public health efforts to reduce major causes of mortality. Studies of acute myocardial infarction (AMI) incidence and survival after AMI provide insight into the relative contribution of prevention and treatment to the decline in coronary heart disease death rates. Evidence of community-level impact on disease occurrence and survival is relevant to practicing physicians who treat patients’ elevated risk factors, provide education on avoiding risk through healthy lifestyles and behaviors, and treat AMI events with surgical and medical interventions. We found that although AMI incidence declined during 1987–2008, the decline was steeper over the past 10 years (1997–2008) than in the preceding 10 years. This is especially true among minority populations. For example, among black men and women, little or no decline in first AMI during 1987–1996 transitioned to statistically significant average annual percent declines in incidence during the more recent period (1997–2008), of −2.5%/y (95% confidence interval, −4.7% to −0.4%) and −3.3%/y (95% confidence interval, −5.8% to −0.8%), respectively. Case-fatality rates after AMI declined steadily for men and women over the past 22 years (−3.9%/y and −2.6%/y average annual change, respectively), suggesting continuing improvements in treatment of AMI patients and/or secular trends toward reduced severity of the AMI itself. Maintaining the decline in AMI incidence that gained momentum in the new millennium will require continued efforts to promote cardiovascular health at the community level.Conclusions—Although these findings from 4 communities may not be directly generalizable to blacks and whites in the entire United States, we observed significant declines in MI incidence, primarily as a result of downward trends in rates between 1997 and 2008.5Profibrinolytic, Antithrombotic, and Antiinflammatory Effects of an Insulin-Sensitizing Strategy in Patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) TrialSummary—Type 2 diabetes mellitus is associated with a 2- to 4-fold increase in the incidence and prevalence of coronary artery disease. Comparable increases occur also with respect to cardiovascular events including death, myocardial infarction, and stroke. Insulin resistance has been implicated strongly in accelerating the pathogenesis of coronary artery disease. Two mechanisms potentially linking insulin resistance to poor prognosis include constraint of fibrinolysis and intensification of inflammation. In this study, 2368 patients with type 2 diabetes mellitus and clinically stable angiographically documented coronary artery disease were treated with either an insulin-sensitizing or insulin-providing strategy for glycemic control targeting hemoglobin A1c to <7.0%. Changes in biomarker profiles during the targeted 5 years of follow-up were consistent with reduction of constraints on fibrinolysis and diminution of the intensity of the inflammatory state with the insulin-sensitizing strategy. These changes were not seen with the insulin-providing strategy. On the contrary, the insulin-providing strategy was associated with an apparently increased constraint of fibrinolysis. Thus, the use of insulin-sensitizing drugs for glycemic control may confer benefit with respect to the balance between fibrinolysis and thrombosis, favoring fibrinolysis in patients with type 2 diabetes mellitus.Conclusions—The insulin-sensitizing treatment strategy led to changes in biomarker profiles indicative of decreased insulin resistance, an altered balance between thrombosis and fibrinolysis favoring fibrinolysis, and diminished intensity of the systemic inflammatory state, factors that have been associated with cardiovascular risk.6Humanized Mouse Model of Thrombosis Is Predictive of the Clinical Efficacy of Antiplatelet AgentsSummary—Platelet adhesion and activation are key events contributing to arterial thrombosis in disease states such as atherosclerosis, the leading cause of morbidity and mortality in industrialized countries. Although our current therapeutic armamentarium for preventing and treating complications associated with atherothrombosis has yielded promising results, there remains an urgent need for more effective drugs and better monitoring of treatment modalities. To expedite this process, it is necessary to develop animal models that more accurately recapitulate the human response to antiplatelet agents. In the present report, we demonstrate how mice bearing a genetically modified form of VWF can serve as a biological platform for predicting the in vivo efficacy of such therapies by enabling human platelet thrombus formation at sites of vascular injury, an event critically reliant on adhesion receptors, secretory products, and activation pathways known to contribute to this process in atherosclerotic coronary arteries (ie, αIIbβ3, ADP, and P2Y12). This is further supported by the ability of the Food and Drug Administration–approved αIIbβ3 blockers abciximab, eptifibatide, and tirofiban to effectively limit human but not mouse platelet-mediated clot formation at doses recommended by the American College of Cardiology/American Heart Association for percutaneous coronary intervention. However, the most beneficial aspect of this model may be its ability to ascertain the inhibitory capacity of antiplatelet agents after administration to patients. As such, it may aid in correlating values obtained by function monitoring devices with the thrombogenic capacity of platelets when exposed to sites of vascular damage in a living animal, thus providing new insights into this highly debated area of clinical research.Conclusions—The ability of αIIbβ3 and P2Y12 inhibitors to limit human platelet clot formation at doses recommended by the American College of Cardiology/American Heart Association suggests that VWFR1326H mutant mice can serve as both a pharmacodynamic and a functional response biomarker, attributes essential for not only expediting drug development but also designing clinical studies.7Evaluation of Multiple Biomarkers of Cardiovascular Stress for Risk Prediction and Guiding Medical Therapy in Patients With Stable Coronary DiseaseSummary—The benefit of angiotensin-converting enzyme inhibitors in low-risk patients with stable coronary artery disease without heart failure remains controversial, and current practice guidelines note that it is reasonable but not recommended to use angiotensin-converting enzyme inhibitors when cardiovascular risk factors are well controlled and revascularization has been performed. We now demonstrate that elevated levels of 3 novel biomarkers of cardiovascular stress, midregional pro-atrial natriuretic peptide, midregional pro-adrenomedullin, and C-terminal pro-endothelin-1, are associated with the subsequent risk of cardiovascular death and heart failure independently of clinical factors (adjusted hazard ratios per 1-SD increase of 1.97, 1.48, and 1.47, respectively; P≤0.002 for each biomarker). Furthermore, elevated levels of these biomarkers identified patients in whom therapy with an angiotensin-converting enzyme inhibitor resulted in a significant reduction in the risk of cardiovascular death or heart failure. Specifically, trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of ≥2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36–0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74–1.59; Pinteraction=0.012). Thus, in patients with stable coronary artery disease and preserved left ventricular ejection fraction, elevated levels of novel biomarkers of cardiovascular stress identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy.Conclusions—In patients with stable coronary artery disease and preserved left ventricular ejection fraction, our results suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy.8Preoperative Serum Brain Natriuretic Peptide and Risk of Acute Kidney Injury After Cardiac SurgerySummary—Cardiovascular disease and heart failure are highly prevalent among those who undergo cardiac surgery, contributing to hemodynamic stress that may be poorly characterized by clinical history. Consequently, natriuretic peptide biomarkers that better characterize this underlying physiology have become well established in the diagnosis and management of patients with heart failure. In this study, 1139 adults who underwent cardiac surgery were evaluated from 6 centers to establish whether preoperative brain natriuretic peptide (BNP) levels predict postoperative acute kidney injury (AKI; defined by Acute Kidney Injury Network definitions; at least mild AKI was a >0.3-mg/dL [26 μmol/L] or 50% rise in creatinine, and severe AKI was either a doubling of creatinine or the requirement of acute renal replacement therapy). In this high-risk cohort, AKI was common (at least mild AKI, n=407 [36%]; severe AKI, n=58 [5.1%]). After adjustment for different preoperative characteristics, preoperative BNP was a strong and independent predictor of mild and severe AKI. Compared with the lowest BNP quintile, the highest quintile had significantly higher risk of at least mild AKI (risk ratio, 1.87) and severe AKI (risk ratio, 3.17). After adjustment for clinical predictors, the addition of BNP improved the area under the curve to predict at least mild AKI and severe AKI. Compared with clinical parameters alone, BNP also improved risk prediction of AKI cases into lower and higher risk. Preoperative BNP level is associated with postoperative AKI in high-risk patients undergoing cardiac surgery and may be a valuable component of future efforts to improve preoperative risk stratification among surgical candidates.Conclusions—Preoperative BNP level is associated with postoperative AKI in high-risk patients undergoing cardiac surgery. If confirmed in other types of patients and surgeries, preoperative BNP may be a valuable component of future efforts to improve preoperative risk stratification and discrimination among surgical candidates.9Childhood Air Pollutant Exposure and Carotid Artery Intima-Media Thickness in Young AdultsSummary—The atherogenic process has important determinants early in life. Childhood exposure to ozone may be a novel risk factor for carotid artery intima-media thickness in young adults. Exposure to ambient air pollutants increases risk for cardiovascular health outcomes in adults. Early life exposure to ozone has been associated with childhood lung function development. Systemic inflammation induced first in the lung may be propagated throughout the body to target other organ systems. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals to potentially reduce atherosclerotic burden and its consequences.Conclusions—Childhood exposure to O3 may be a novel risk factor for CIMT in a healthy population of college students. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals.10Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): A Phase 2 Trial of Intracoronary Gene Therapy of Sarcoplasmic Reticulum Ca2+-ATPase in Patients With Advanced Heart FailureSummary—The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) phase 2 randomized, double-blind trial evaluated adeno-associated virus type 1 (AAV1)/sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) versus placebo in 39 patients. A deficiency in SERCA2a has been identified in cardiomyocytes from failing human hearts. AAV1/SERCA2a is a viral vector delivering the deficient SERCA2a gene by intracoronary infusion into patients with advanced heart failure. AAV1/SERCA2a in this study population demonstrated no untoward safety findings; there appeared to be fewer cardiovascular adverse events in the high-dose group compared with placebo. The study met the prospectively defined efficacy end points comprising 7 different parameters in 5 clinically relevant domains. All 3 predefined analyses were met at the individual-level, group-level (in functional and left ventricular function/remodeling domains), and clinical outcomes (duration of cardiovascular hospitalizations). High-dose AAV1/SERCA2a compared with placebo also demonstrated significantly delayed and reduced frequency of adverse cardiovascular events per patient, reaching statistical significance at 12 months (P=0.003). The positive signals across 5 domains support the contention that high-dose AAV1/SERCA2a induced meaningful biological activity. Results from this small study indicate a decrease in symptoms of heart failure, augmented functional status, a decrease in natriuretic peptide levels, beneficial ventricular reverse remodeling, and a significant increase in time to and decreased frequency of adjudicated cardiovascular events in the high-dose group versus placebo. The totality of the data, limited by the small study size, strongly supports moving forward with confirmatory clinical studies of AAV1/SERCA2a for patients with severe heart failure. This CUPID trial represents a new approach to the treatment of heart failure with enzyme replacement via gene therapy.Conclusions—The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study demonstrated safety and suggested benefit of adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase in advanced heart failure, supporting larger confirmatory trials.11The Diagnostic Value of Physical Examination and Additional Testing in Primary Care Patients With Suspected Heart FailureSummary—The initial diagnosis of new nonacute heart failure is as difficult as it is important, especially in settings where more advanced diagnostic tests, notably echocardiography, are not readily available. This diagnostic study demonstrates the importance of history taking and, in particular, physical examination in a large cohort of 721 patients suspected of having nonacute heart failure, 207 (28.7%) of whom were diagnosed with heart failure. When a primary care physician is confronted with a patient suspected of having nonacute heart failure, a diagnostic rule including age, objective evidence of prior coronary artery disease, use of a loop diuretic, displaced apex beat, basal or more pulmonary rales, irregularly irregular pulse, heart murmur suggestive of mitral regurgitation, pulse rate, and elevated jugular venous pressure, plus a single additional test, the NT-proBNP plasma level, can accurately predict the presence or absence of heart failure numerically. The rule had comparable performance in 2 validation datasets. Chest x-ray or ECG can be used in addition to or instead of the NT-proBNP measurement depending on local availability and other patient characteristics. It remains important for diagnosticians to maintain basic physical examination skill.Conclusions—In this study, we estimated the quantitative diagnostic contribution of elements of the history and physical examination in the diagnosis of heart failure in primary care outpatients, which may help to improve clinical decision making. The largest additional quantitative diagnostic contribution to those elements was provided by measurement of NT-proBNP. For daily practice, a diagnostic rule was derived that may be useful to quantify the probability of heart failure in patients with new symptoms suggestive of heart failure.12Dipeptidyl Peptidase-4 Modulates Left Ventricular Dysfunction in Chronic Heart Failure via Angiogenesis-Dependent and -Independent ActionsSummary—Dipeptidyl peptidase-4 (DPP4) is a serine protease with a primary function of truncating various bioactive molecules such as incretin hormones, angiogenic chemokines, inflammatory cytokines, denatured collagen, and brain natriuretic peptide. To date, the pathophysiological significance of DPP4 in the processes of diabetes mellitus, malignancy, and inflammation has been well recognized and well established; however, the role of DPP4 in the pathogenesis of cardiovascular disease remained unclear until as recently as several years ago, when the first report demonstrated the protective role of DPP4 inhibition in acute myocardial infarction. The present study highlights a novel pathophysiological role for DPP4 in diastolic left ventricular dysfunction and raises the possibility of using DPP4 as a diagnostic surrogate and a therapeutic target for chronic heart failure. One of the primary interpretations drawn from the present study is that the coronary microcirculation is essential for diastolic left ventricular dysfunction development, in which DPP4 may play a pathophysiological role by regulating coronary angiogenesis. Diabetes mellitus has been postulated to exacerbate heart failure, and the comorbidity of diabetic retinopathy, ie, diabetic microvasculopathy, has been suggested to be associated with the increased incidence of heart failure in patients with diabetes mellitus. Thus, the present study proposes another therapeutic benefit of the small-molecule DPP4 inhibitors in reducing the incidence of heart failure in patients with diabetes mellitus.Conclusions—DPP4 inhibition reverses DHF via membrane-bound DPP4/stromal cell-derived factor-1α–dependent local actions on angiogenesis and circulating DPP4/glucagon-like peptide-1–mediated inotropic actions. Myocardium-derived DPP4 activity in coronary sinus can be monitored by peripheral vein sampling, which partly correlates with DHF index; thus, circulating DPP4 may potentially serve as a biomarker for monitoring DHF.13Multiple Biomarkers and Risk of Clinical and Subclinical Vascular Brain Injury: The Framingham Offspring StudySummary—Numerous biomarkers representing various biological pathways have been independently implicated in cerebrovascular disease, but their relative contribution to the prediction of clinical cerebrovascular disease is uncertain. In a middle-aged community sample, we used a multimarker approach to identify plausible biomarkers associated with clinical and subclinical vascular brain injury. This approach also permitted us to assess the contribution of each biomarker to clinical risk reclassification after accounting for standard vascular risk factors that comprise the Framingham Stroke Risk Profile. In analyses adjusted for traditional risk factors, we observed an association between an aggregate panel of biomarkers, including markers of inflammation (C-reactive protein), hemostasis (D-dimer and plasminogen activator inhibitor-1), neurohormonal activity (aldosterone-to-renin ratio, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptides), and endothelial function (plasma homocysteine and urinary albumin/creatinine ratio), and the risk of stroke/transient ischemic attack and with magnetic resonance imaging brain volumes. In further analyses, we identified that higher B-type natriuretic peptide levels and albuminuria were associated with the risk of stroke/transient ischemic attack and that the addition of these biomarker data provided incremental information over clinical risk factors predicting stroke. We further indentified that albuminuria (but not B-type natriuretic peptide) was also associated with smaller brain volume, as were higher C-reactive protein, D-dimer, and plasma homocysteine levels. Our findings are consistent with prior observations that alterations in several different biological pathways may underlie the pathophysiology of clinical and subclinical brain disease. However, whether the knowledge of B-type natriuretic peptide and albuminuria may be used to target individuals at risk of stroke for more intense primary prevention or monitoring requires further investigation.Conclusions—In a middle-aged community sample, we identified multiple biomarkers that were associated with clinical and subclinical vascular brain injury and could improve risk stratification.14Cardiac Biomarkers Are Associated With an Increased Risk of Stroke and Death in Patients With Atrial Fibrillation: A Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) SubstudySu