Lars Wallentin

Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis.

Background— Aspirin and clopidogrel are recommended for patients with acute coronary syndromes (ACS) or undergoing coronary stenting. Ticagrelor, a reversible oral P2Y12-receptor antagonist, provides faster, greater, and more consistent platelet inhibition than clopidogrel and may be useful for patients with acute ST-segment elevation (STE) ACS and planned primary percutaneous coronary intervention. Methods and Result— Platelet Inhibition and Patient Outcomes (PLATO), a randomized, double-blind trial, compared ticagrelor with clopidogrel for the prevention of vascular events in 18 624 ACS patients. This report concerns the 7544 ACS patients with STE or left bundle-branch block allocated to either ticagrelor 180-mg loading dose followed by 90 mg twice daily or clopidogrel 300-mg loading dose (with provision for 300 mg clopidogrel at percutaneous coronary intervention) followed by 75 mg daily for 6 to 12 months. The reduction of the primary end point (myocardial infarction, stroke, or cardiovascular death) with ticagrelor versus clopidogrel (10.8% versus 9.4%; hazard ratio [HR], 0.87; 95% confidence interval, 0.75 to 1.01; P=0.07) was consistent with the overall PLATO results. There was no interaction between presentation with STE/left bundle-branch block and randomized treatment (interaction P=0.29). Ticagrelor reduced several secondary end points, including myocardial infarction alone (HR, 0.80; P=0.03), total mortality (HR, 0.82; P=0.05), and definite stent thrombosis (HR, 0.66; P=0.03). The risk of stroke, low in both groups, was higher with ticagrelor (1.7% versus 1.0%; HR,1.63; 95% confidence interval, 1.07 to 2.48; P=0.02). Ticagrelor did not affect major bleeding (HR, 0.98; P=0.76). Conclusion— In patients with STE-ACS and planned primary percutaneous coronary intervention, the effects of ticagrelor were consistent with those observed in the overall PLATO trial. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00391872.

Influence of Renal Function on the Effects of Early Revascularization in Non-ST-Elevation Myocardial Infarction Data From the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART)

Background— It is unknown whether patients with non–ST-elevation myocardial infarction derive a similar benefit from an early invasive therapy at different levels of renal function. Methods and Results— A total of 23 262 consecutive non–ST-elevation myocardial infarction patients ≤80 years old were included in a nationwide coronary care unit register between 2003 and 2006. Glomerular filtration rate (eGFR) was estimated with the Modification of Diet in Renal Disease Study formula. Patients were divided into medically or invasively treated groups if revascularized within 14 days of admission. A propensity score for the likelihood of invasive therapy was calculated. A Cox regression model with adjustment for propensity score and discharge medication was used to assess the association between early revascularization and 1-year mortality across renal function stages. There was a gradient, with significantly fewer patients treated invasively with declining renal function: eGFR ≥90 mL · min−1 · 1.73 m−2, 62%; eGFR 60 to 89 mL · min−1 · 1.73 m−2, 55%; eGFR 30 to 59 mL · min−1 · 1.73 m−2, 36%; eGFR 15 to 29 mL · min−1 · 1.73 m−2, 14%; and eGFR <15 mL · min−1 · 1.73 m−2/dialysis, 15% (P<0.001). After adjustment, the overall 1-year mortality was 36% lower (hazard ratio 0.64, 95% confidence interval 0.56 to 0.73, P<0.001) with an invasive strategy. The magnitude of survival difference was similar in normal-to-moderate renal function groups. The lower mortality observed with invasive therapy declined with lower renal function, with no difference in mortality in patients with kidney failure (eGFR <15 mL · min−1 · 1.73 m−2) or in those receiving dialysis (hazard ratio 1.61, 95% confidence interval 0.84 to 3.09, P=0.15). Conclusions— Early invasive therapy is associated with greater 1-year survival in patients with non–ST-elevation myocardial infarction and mild-to-moderate renal insufficiency, but the benefit declines with lower renal function, and is less certain in those with renal failure or on dialysis.

Improving clinical outcomes by reducing bleeding in patients with non-ST-elevation acute coronary syndromes.

AIMSnBleeding in patients with coronary artery disease has been linked with adverse outcomes. We examined the incidence and outcomes after bleeding in 20 078 patients with acute coronary syndromes (ACS) enrolled in the OASIS-5 trial who were treated with fondaparinux or the low-molecular weight heparin, enoxaparin.nnnMETHODS AND RESULTSnNine hundred and ninety (4.9%) patients developed major bleeding and 423 (2.1%) developed minor bleeding. Fondaparinux compared with enoxaparin reduced fatal bleeding [0.07 vs. 0.22%, relative risk (RR) 0.30, 95% CI: 0.13-0.71], non-fatal major bleeding (2.2 vs. 4.2%, RR 0.52, 95% CI: 0.44-0.61), minor bleeding (1.1 vs. 3.2%, RR 0.34, 95% CI: 0.27-0.42), and need for transfusion (1.8 vs. 3.1%, RR 0.56, 95% CI: 0.47-0.61) during the first 9 days. One of every six deaths during the first 30 days occurred in patients who experienced bleeding. Cox proportional hazards model revealed that major bleeding was associated with about a four-fold increased hazard of death, myocardial infarction, or stroke during the first 30 days and about a three-fold increased hazard during 180 days of follow up.nnnCONCLUSIONnBleeding in patients with ACS is a powerful determinant of fatal and non-fatal outcomes. Reducing the risk of bleeding using a safer anticoagulant strategy during the first 9 days is associated with substantial reductions in morbidity and mortality.

Persistent Cardiac Troponin I Elevation in Stabilized Patients After an Episode of Acute Coronary Syndrome Predicts Long-Term Mortality

Background— In patients with non–ST-elevation acute coronary syndrome, any troponin elevation is associated with an increased risk for cardiovascular events. However, the prevalence and prognostic importance of persistent troponin elevation in stabilized patients after an episode of non–ST-elevation acute coronary syndrome are unknown and were therefore assessed in this study. Methods and Results— Cardiac troponin I (cTnI) was measured in 1092 stabilized patients at 6 weeks and 3 and 6 months after enrollment in the FRagmin and Fast Revascularization during InStability in Coronary artery disease (FRISC-II) trial. cTnI was analyzed with the Access AccuTnI assay with the application of different prognostic cutoffs. Outcomes were assessed through 5 years. Elevated cTnI levels >0.01 &mgr;g/L were found in 48% of the study patients at 6 weeks, in 36% at 6 months, and in 26% at all 3 measurements. cTnI elevation was associated with increased age and other cardiovascular high-risk features. The lowest tested cTnI cutoff (0.01 &mgr;g/L) was prognostically most useful and was independently predictive of mortality (hazard ratio, 2.1 [95% confidence interval, 1.3 to 3.3]; P=0.001) on multivariable analysis adjusted for cardiovascular risk factors and randomization to an invasive versus noninvasive treatment strategy, whereas it was related to myocardial infarction only on univariate analysis. Conclusions— Persistent minor cTnI elevation can be detected frequently in patients stabilized after an episode of non–ST-elevation acute coronary syndrome with the use of a sensitive assay. Elevated cTnI levels >0.01 &mgr;g/L predict mortality during long-term follow-up. Our results emphasize the importance of further troponin testing in non–ST-elevation acute coronary syndrome patients after hospital discharge.

Troponin T levels and risk of 30-day outcomes in patients with the acute coronary syndrome: prospective verification in the GUSTO IV trial

BACKGROUND: A third-generation troponin T assay with improved precision and a lower detection limit has been developed. However, the appropriate cutoff for identifying patients with the acute coronary syndrome who are at low risk of subsequent mortality has not been established. METHODS: A retrospective evaluation of data from the Fragmin and fast Revascularization during InStability in Coronary artery disease II (FRISC-II) trial suggested that a cutoff below 0.1 microg/L for troponin T levels might be more useful in risk stratification. A prospective validation of two cutoff levels (0.03 microg/L and 0.01 microg/L) was performed in 7115 patients with non-ST-elevation acute coronary syndrome from the Global Utilization of Strategies To open Occluded arteries IV (GUSTO-IV) trial. RESULTS: Patients with troponin T levels >0.1 microg/L had greater 30-day mortality (5.5% [201/3679]) than did those with levels <or=0.1 microg/L (2.2% [75/3436], P <0.001). A cutoff value of 0.03 microg/L provided better discrimination between high and low risk: 5.1% (234/4552) versus 1.6% (42/2563). However, a cutoff value at the lower limit of detection, 0.01 microg/L, provided the best discrimination: 5.0% (254/5123) versus 1.1% (22/1992) (P<0.001). This cutoff level had the highest negative predictive value; it also discriminated best for the combined endpoint of death and myocardial infarction. CONCLUSION: Using a cutoff of <or=0.01 microg/L for the third-generation troponin T assay, the detection level of the assay, is useful for identifying patients with the acute coronary syndrome who are at low risk of subsequent mortality.

Ticagrelor Versus Clopidogrel in Elderly Patients With Acute Coronary Syndromes A Substudy From the Prospective Randomized PLATelet Inhibition and Patient Outcomes (PLATO) Trial

Background—Elderly patients with acute coronary syndrome are at high risk of recurrent ischemic events and death, and for both antithrombotic therapy and catheter-based complications. This prespecified analysis investigates the effect and treatment-related complications of ticagrelor versus clopidogrel in elderly patients (≥75 years of age) with acute coronary syndrome compared with those <75 years of age. Methods and Results—The association between age and the primary composite outcome, as well as major bleeding were evaluated in the PLATelet inhibition and patient Outcomes (PLATO) trial using Cox proportional hazards. Similar models were used to evaluate the interaction of age with treatment effects. Hazard ratios were adjusted for baseline characteristics. The clinical benefit of ticagrelor over clopidogrel was not significantly different between patients aged ≥75 years of age (n=2878) and those <75 years of age (n=15 744) with respect to the composite of cardiovascular death, myocardial infarction, or stroke (interaction P=0.56), myocardial infarction (P=0.33), cardiovascular death (P=0.47), definite stent thrombosis (P=0.81), or all-cause mortality (P=0.76). No increase in PLATO-defined overall major bleeding with ticagrelor versus clopidogrel was observed in patients aged ≥75 years (hazard ratio, 1.02; 95% confidence interval, 0.82–1.27) or patients aged <75 years (hazard ratio, 1.04; 95% confidence interval, 0.94–1.15). Dyspnea and ventricular pauses were more common during ticagrelor than clopidogrel treatment, with no evidence of an age-by-treatment interaction. Conclusions—The significant clinical benefit and overall safety of ticagrelor compared with clopidogrel in acute coronary syndrome patients in the PLATO cohort were not found to depend on age. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Quantitative analysis of the admission electrocardiogram identifies patients with unstable coronary artery disease who benefit the most from early invasive treatment

OBJECTIVESnThe aim of the present study was to evaluate whether the effect of an early invasive treatment strategy differed between patients sub-grouped according to their severity of myocardial ischemia, as evaluated by quantitative electrocardiographic (ECG) analysis at the time of presentation. The present study is a sub-study of the previously published Fast Revascularization during InStability in Coronary artery disease trial (FRISC-II).nnnBACKGROUNDnAn early invasive treatment strategy has been shown to be the preferable treatment for non-ST-segment elevation acute coronary syndromes (ACS). The population of patients with unstable coronary artery disease is heterogeneous regarding both the underlying pathology and prognosis. Early risk stratification is important to select patient subgroups that will benefit the most from a given treatment.nnnMETHODSnIn 2,201 patients with non-ST-segment elevation ACS, the ischemic burden at hospital admission was determined by quantitative measurements of ST-T-segment deviations on the ECG. The patients were subsequently sub-grouped in tertiles based on the amount of ST-segment deviation. The primary end point for this analysis was death or myocardial infarction (MI) within one year after study inclusion.nnnRESULTSnThe invasive treatment strategy produced a reduction of approximately 50% in death or MI among the patients with intermediate or major ST-segment deviation. The findings were independent of age, gender, or troponin T status. The patients with confounding factors precluding ST analysis had a poor outcome regardless of the treatment strategy.nnnCONCLUSIONSnIschemic burden on the admission ECG identifies patients with ACS who benefit the most from an invasive treatment strategy. When the standard ECG is scrutinized with complete quantitative measurements, it provides independent information on prognosis and benefit of treatment.

Prognostic value of biomarkers during and after non-ST-segment elevation acute coronary syndrome.

OBJECTIVESnThe aim of this study was to assess risk prediction by different biomarkers in patients with an ongoing non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and after clinical stabilization.nnnBACKGROUNDnDifferent biomarkers reflect different aspects of the pathobiology in NSTE-ACS. However, there is little information regarding their relative prognostic value during the time course of disease.nnnMETHODSnThe N-terminal pro-brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), cardiac troponin I (cTnI), and the estimated glomerular filtration rate (eGFR) were measured at randomization and after 6 weeks and 6 months in 877 NSTE-ACS patients included in the FRISC (FRagmin and fast revascularization during InStability in Coronary artery disease) II trial. The biomarkers prognostic value during 5-year follow-up was evaluated by Cox regression models, calculation of the c-statistics, and estimation of the net reclassification improvement (NRI).nnnRESULTSnAmong the biomarkers measured at randomization, NT-proBNP was the strongest predictor for mortality (adjusted hazard ratio [HR]: 1.7; 95% confidence interval [CI]: 1.3 to 2.1; p < 0.001). Even during follow-up, NT-proBNP demonstrated the strongest association to the composite end point of death/myocardial infarction (adjusted HR at 6 weeks: 1.5; 95% CI: 1.3 to 1.7; p < 0.001; adjusted HR at 6 months: 1.4; 95% CI: 1.2 to 1.7; p = 0.001). Even CRP was independently predictive at 6 months for the composite end point (adjusted HR: 1.3; 95% CI: 1.1 to 1.5; p = 0.003). Only 6-week results of NT-proBNP provided significant incremental prognostic value to established risk indicators regarding the composite end point (c-statistics 0.69 [p = 0.03]; NRI 0.11 [p = 0.03]).nnnCONCLUSIONSnThe NT-proBNP is an independent risk predictor in patients with ongoing NSTE-ACS and after clinical stabilization. The CRP exhibits increasing predictive value at later measurements. However, only NT-proBNP provided incremental prognostic value and might therefore be considered as a complement for early follow-up controls after NSTE-ACS.

Growth-Differentiation Factor-15 for Long-Term Risk Prediction in Patients Stabilized After an Episode of Non–ST-Segment–Elevation Acute Coronary Syndrome

Background—Growth-differentiation factor-15 (GDF-15) has emerged as a prognostic biomarker in patients with non–ST-segment–elevation acute coronary syndrome. This study assessed the time course and the long-term prognostic relevance of GDF-15 levels measured repetitively in patients with non–ST-segment–elevation acute coronary syndrome during 6 months after the acute event. Methods and Results—GDF-15 and other biomarkers were measured at randomization, after 6 weeks, and after 3 and 6 months in 950 patients with non–ST-segment–elevation acute coronary syndrome included in the FRagmin and Fast Revascularization during InStability in Coronary artery disease II study. Study end points were death, recurrent myocardial infarction, and their composite during 5-year follow-up. Median GDF-15 levels decreased slightly from 1357 ng/L at randomization to 1302 ng/L at 6 months (P<0.001). GDF-15 was consistently related to cardiovascular risk factors and biochemical markers of hemodynamic stress, renal dysfunction, and inflammation. Moreover, GDF-15 was independently related to the 5-year risk of the composite end point when measured at both 3 months (adjusted hazard ratio, 1.8 [1.0 to 3.0]) and 6 months (adjusted hazard ratio, 2.3 [1.3 to 4.1]). Serial measurements of GDF-15 at randomization and 6 months helped to identify patient cohorts at different levels of risk, with patients with persistently elevated GDF-15 levels >1800 ng/L having the highest rate of the composite end point. Conclusions—GDF-15 is independently related to adverse events in non–ST-segment–elevation acute coronary syndrome both in the acute setting and for at least 6 months after clinical stabilization. Therefore, continued research on GDF-15 should be focused on the usefulness of GDF-15 for support of clinical management in acute and chronic ischemic heart disease.

Growth-differentiation factor-15 for early risk stratification in patients with acute chest pain

Aims Growth-differentiation factor-15 (GDF-15) has emerged as a biomarker of increased mortality and recurrent myocardial infarction (MI) in patients diagnosed with non-ST-elevation acute coronary syndrome. We explored the usefulness of GDF-15 for early risk stratification in 479 unselected patients with acute chest pain. Methods and results Sixty-nine per cent of the patients presented with GDF-15 levels above the previously defined upper reference limit (1200 ng/L). The risks of the composite endpoint of death or (recurrent) MI after 6 months were 1.3, 5.1, and 12.6% in patients with normal (<1200 ng/L), moderately elevated (1200–1800 ng/L), or markedly elevated (>1800 ng/L) levels of GDF-15 on admission, respectively (P < 0.001). By multivariable analysis that included clinical characteristics, ECG findings, peak cardiac troponin I levels within 2 h (cTnI0–2 h), N-terminal pro-B-type natriuretic peptide, C-reactive protein, and cystatin C, GDF-15 remained an independent predictor of the composite endpoint. The ability of the ECG combined with peak cTnI0–2 h to predict the composite endpoint was markedly improved by addition of GDF-15 (c-statistic, 0.74 vs. 0.83; P < 0.001). Conclusion GDF-15 improves risk stratification in unselected patients with acute chest pain and provides prognostic information beyond clinical characteristics, the ECG, and cTnI.