MMP-9 and Its Regulators TIMP-1 and EMMPRIN in Patients with Acute ST-Elevation Myocardial Infarction: A NORDISTEMI Substudy.

OBJECTIVES: The extracellular matrix is involved in wound repair after acute myocardial infarction (AMI). We investigated whether matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and the MMP inducer (EMMPRIN) are associated with infarct size, left ventricular function, and clinical outcome in ST-elevation-MI (STEMI). METHODS: In 243 STEMI patients, circulating EMMPRIN, MMP-9, and TIMP-1 were analyzed 3 days and 3 months post-AMI. Infarct size and left ventricular ejection fraction were assessed by single-photon emission computed tomography (SPECT) (n = 230/226) and MRI (n = 111/167) at 3 months. RESULTS: EMMPRIN, MMP-9, and TIMP-1 levels and the MMP-9/TIMP-1 ratio declined from day 3 to 3 months (p < 0.001, all). TIMP-1 levels at day 3 correlated significantly with SPECT- and MRI-based infarct size, troponin T (p < 0.04, all), and amino-terminal pro-B-type natriuretic peptide (NT-proBNP; p < 0.001). The upper quartile of day 3 TIMP-1 levels showed an adjusted odds ratio of 5.0 (95% confidence interval 1.2-20.6) for having a large infarct size. An insignificant relationship between MMP-9 and clinical events within 1 year (death, AMI, or stroke) (n = 15) was observed, probably due to the lack of statistical power. CONCLUSION: The decline in EMMPRIN, MMP-9, and TIMP-1 3 months after acute STEMI is probably due to initial acute-phase processes. The associations between TIMP-1, infarct size, and NT-proBNP indicate a role for TIMP-1 in cardiac remodeling.

Health-related quality of life after myocardial infarction, does choice of method make a difference?

OBJECTIVES: The aim of this study was to compare health-related quality of life (HRQoL) scores obtained from the instrument Short Form (SF)-36 through the so-called SF-6D utilities, and those obtained from 15D, in patients with ST-elevation myocardial infarction (STEMI), and to evaluate the consequences in estimation of quality adjusted life years (QALYs). DESIGN: This was a sub-study of the Norwegian District Treatment of STEMI, in which patients with STEMI treated with tenecteplase, were randomized to early angioplasty or standard management (n = 266). HRQoL data were collected at all visits (0, 1, 3, 7 and 12 months). All patients with complete data were included (n = 248). RESULTS: The score range was 0.33-1.0 for SF-6D and 0.49-1.0 for 15D. Mean utility scores from 15D were higher and had different distribution compared to scores from SF-6D. Mean QALY for the whole group was higher using 15D than SF-6D (0.89 vs. 0.77). The incremental number of QALYs with early angioplasty compared to standard treatment was 0.005 (95% CI: - 0.018 to 0.028) using SF-6D, and 0.004 (95% CI: - 0.010 to 0.018) using the 15D instrument. CONCLUSIONS: Choice of instrument may influence HRQoL scores, but not necessarily the gain in QALYs.

Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels 3 months after myocardial infarction are more strongly associated with magnetic resonance-determined ejection fraction than NTproBNP levels in the acute phase.

BACKGROUND: The relationship between levels of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and left ventricular function determined by magnetic resonance imaging (MRI) in ST-segment-elevation myocardial infarction (STEMI) is largely unknown. METHODS AND RESULTS: This was a substudy of the Norwegian Study on District Treatment of STEMI, in which patients received thrombolysis followed by early or late invasive strategy. NT-proBNP was measured at 3 days and 3 months after the myocardial infarction, and magnetic resonance imaging was performed after 3 months (n = 160). Log NT-proBNP levels at both time points were significantly associated with ejection fraction (EF) (r(2) values 0.25 and 0.42, respectively) as well as infarct size (r(2) values 0.38 and 0.47, respectively; P < .0001 for all, adjusted for confounders). Furthermore, receiver operating characteristic (ROC) curves used to analyze the ability of NT-proBNP to discriminate long-term low EF (≤40%) and large infarct size (≥15.7%), were significant at both time points (P < .001 for all). Pairwise comparison of the ROC curves showed a significantly better performance of NT-proBNP at 3 months compared with 3 days for discrimination of low EF (P = .023). CONCLUSION: Repeated measurements of NT-proBNP in STEMI patients showed that NT-proBNP levels at 3 months were more strongly associated with long-term EF and infarct size than NT-pro BNP levels after 3 days. Our data suggest that measurement of NT-proBNP 3 months after myocardial infarction is a better indicator of left ventricular function compared with NT-proBNP in the acute phase.

Health and cost consequences of early versus late invasive strategy after thrombolysis for acute myocardial infarction.

UNLABELLED: The NORwegian study on DIstrict treatment of ST-Elevation Myocardial Infarction showed an improved clinical outcome with early transfer for percutaneous coronary intervention (PCI) compared to a more conservative approach after thrombolysis. The aim of this substudy was to compare the 12-month quality-adjusted life years (QALYs) and costs of these alternative strategies. METHODS: Patients with ST-elevation myocardial infarction <6 h duration and >90 min expected delay to PCI, received full-dose tenecteplase and were randomized to either early or late invasive strategy (n = 266). Detailed quality of life and resource use data were registered prospectively for a period of 12 months. Health outcomes were measured as quality of life using a generic instrument (15D). Quality of life scores were translated into QALYs. Unit costs were based on hospital accounts, fee schedules, and market prices. RESULTS: After 12 months of follow-up, patients in the early invasive group had 0.008 (95% CI -0.027 to 0.043) more QALYs compared to the late invasive group. The mean total costs were €18,201 in the early versus €17,643 in the late invasive group, with a mean difference of €558 (95% CI -2258 to 3484). Cost/QALY was €69,750 while cost/avoided clinical endpoint was €5636. CONCLUSION: Early and late invasive strategies after thrombolysis resulted in similar quality of life and similar costs in ST-elevation myocardial infarction patients living far from a PCI centre (NCT00161005).

Left ventricular function in acute myocardial infarction treated with thrombolysis followed by early versus late invasive strategy.

BACKGROUND: Thrombolysis remains the treatment of choice in acute ST-segment elevation myocardial infarction (STEMI) when primary percutaneous coronary intervention (PCI) cannot be performed within 90 to 120 minutes. The optimal treatment after thrombolysis is still debated, but several studies have shown improved clinical outcomes with early transfer for PCI. The aim of this study was to investigate whether an early invasive strategy after thrombolysis preserved left ventricular function better than a late invasive strategy. METHODS: This was a substudy of the NORwegian study on DIstrict treatment of ST-Elevation Myocardial Infarction. Patients with STEMI of <6 hours of duration and >90 minutes of expected transfer delays to PCI were treated with aspirin, tenecteplase, enoxaparin, and clopidogrel and randomized to early or late invasive strategy (N = 266). Left ventricular volumes and ejection fraction were assessed by single-photon emission computed tomography, echocardiography, and magnetic resonance imaging 3 months after the index infarction. RESULTS: Noninvasive imaging was completed in 241 patients (91%). Median end-diastolic and end-systolic volumes after 3 months did not differ between groups. Median ejection fraction was well preserved and also without differences: 63% (interquartile range 51-70) in the early invasive versus 65% (interquartile range 55-71) in the late invasive group when assessed by single-photon emission computed tomography (P = .30), 55% versus 55% when assessed by echocardiography (P = .88), and 57% versus 57% when assessed by magnetic resonance imaging (P = .99). CONCLUSION: In this group of STEMI patients treated with thrombolysis, no difference in left ventricular function after 3 months was found between patients treated with early versus late invasive strategy.

Assessment of left ventricular function with magnetic resonance imaging vs. echocardiography, contrast echocardiography, and single-photon emission computed tomography in patients with recent ST-elevation myocardial infarction.

AIMS: Magnetic resonance imaging (MRI) is often considered to be the gold standard in measuring left ventricular function and volumes. The aim of this study was to assess the agreements between standard echocardiography (standard echo), contrast echocardiography (contrast echo), single-photon emission computed tomography (SPECT), and MRI in the determination of left ventricular ejection fraction (EF) and end-diastolic volumes (EDV) in patients treated for acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Standard echo, contrast echo, SPECT and MRI were performed on the same day, 3 months after STEMI in 150 patients participating in the NORwegian Study on District Treatment of ST-Elevation Myocardial Infarction (NORDISTEMI). Bland-Altman analysis of EF measured by all four imaging modalities showed generally low mean differences but wide limits of agreement. The mean EDV difference, however, was consistently higher when MRI was compared with standard echo (54.9 mL), contrast echo (41.7 mL) and SPECT (54.6 mL), and the limits of agreement were wider. The mean EDV differences between contrast echo vs. standard echo, SPECT vs. standard echo and contrast echo vs. SPECT were small. CONCLUSION: Our data suggest that all four imaging modalities measured EF closely similar after STEMI as demonstrated by a very small bias. The limits of agreement were however wide. EDV measured by MRI was consistently higher when compared with the other methods which may be caused by different tracing-methods and imaging principles. As echocardiography is preferable from a cost-benefit point of view, further analysis would be needed to clarify the nature of such differences.

The association between metabolic syndrome and infarct size in patients with acute myocardial infarction.

BACKGROUND: In patients with the metabolic syndrome, the prevalence of cardiovascular disease, disease-related morbidity and mortality are reported to be significantly higher than in a population without the metabolic syndrome. We investigated the role of metabolic syndrome and related biomarkers as predictors of infarct size in patients with their first myocardial infarction. METHODS: This was a cross-sectional sub-study from the 3 months follow-up in the NORwegian Study of DIstrict treatment of ST-Elevation Myocardial Infarction (NORDISTEMI), including 152 consecutive patients, all initially treated with thrombolysis. Infarct size after 3 months was determined by late gadolinium enhanced magnetic resonance imaging, measuring ventricular infarct volume in absolute and relative terms. RESULTS: At 3 months, 33 patients (22%) were categorized as having metabolic syndrome. There was no significant difference in median infarct size between those presenting with and without the metabolic syndrome [relative infarct volume 9.0 (4.8, 15.1) % vs. 8.3 (2.9, 13.6)%, p = 0.34]. Adjusting for possible confounders did not alter the results essentially. Circulating levels of IL-18, CRP and PAI-I activity were significantly higher in patients with the metabolic syndrome while adiponectin concentrations were significantly lower (p < or = 0.01 for all). None of these variables were associated with myocardial infarct size. CONCLUSIONS: No association between the presence of metabolic syndrome and related biomarkers, and the size of the myocardial infarction was apparent in this study population.

Troponin T concentration 3 days after acute ST-elevation myocardial infarction predicts infarct size and cardiac function at 3 months.

OBJECTIVES: The evaluation of infarct size and left ventricular function after acute myocardial infarction is important for predicting the subsequent clinical course. This assessment can be achieved by non-invasive imaging methods, but biochemical assays are frequently used as an alternative. We investigated the ability of a single measurement of cardiac troponin T (cTnT) the third morning after onset of ST-segment elevation myocardial infarction (STEMI) to predict infarct size and left ventricular ejection fraction (LVEF). METHODS: The study population consisted of 103 patients with their first STEMI treated with thrombolysis. Blood samples for determination of cTnT were drawn the third morning after onset of symptoms. Infarct size and LVEF were assessed by magnetic resonance imaging 3 months later. RESULTS: Linear regression analysis showed a strong, significant correlation between third-day cTnT and infarct size at 3 months (r = 0.84, p < 0.0001). A significant but inverse and weaker correlation was obtained between third-day cTnT and LVEF (r = -0.63, p < 0.0001). Adjusting for age, gender, infarct location and medication changed the results marginally. CONCLUSIONS: A single cTnT value the third morning after onset of STEMI predicted the final infarct size in this group of patients with their first STEMI, and might be useful for ruling out impaired LVEF.

Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study.

AIMS: To assess tolerability and optimal time point for initiation of sacubitril/valsartan in patients stabilised after acute heart failure (AHF). METHODS AND RESULTS: TRANSITION was a randomised, multicentre, open-label study comparing two treatment initiation modalities of sacubitril/valsartan. Patients aged ≥ 18 years, hospitalised for AHF were stratified according to pre-admission use of renin-angiotensin-aldosterone system inhibitors and randomised (n = 1002) after stabilisation to initiate sacubitril/valsartan either ≥ 12-h pre-discharge or between Days 1-14 post-discharge. Starting dose (as per label) was 24/26 mg or 49/51 mg bid with up- or down-titration based on tolerability. The primary endpoint was the proportion of patients attaining 97/103 mg bid target dose after 10 weeks. Median time of first dose of sacubitril/valsartan from the day of discharge was Day -1 and Day +1 in the pre-discharge group and the post-discharge group, respectively. Comparable proportions of patients in the pre- and post-discharge initiation groups met the primary endpoint [45.4% vs. 50.7%; risk ratio (RR) 0.90; 95% confidence interval (CI) 0.79-1.02]. The proportion of patients who achieved and maintained for ≥ 2 weeks leading to Week 10, either 49/51 or 97/103 mg bid was 62.1% vs. 68.5% (RR 0.91; 95% CI 0.83-0.99); or any dose was 86.0% vs. 89.6% (RR 0.96; 95% CI 0.92-1.01). Discontinuation due to adverse events occurred in 7.3% vs. 4.9% of patients (RR 1.49; 95% CI 0.90-2.46). CONCLUSIONS: Initiation of sacubitril/valsartan in a wide range of heart failure with reduced ejection fraction patients stabilised after an AHF event, either in hospital or shortly after discharge, is feasible with about half of the patients achieving target dose within 10 weeks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02661217.

Myocardial perfusion grade predicts final infarct size and left ventricular function in patients with ST-elevation myocardial infarction treated with a pharmaco-invasive strategy (thrombolysis and early angioplasty).

AIMS: Primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) usually restores TIMI 3 flow in the occluded artery, but microvascular impairment may persist in >30% of patients. Less is known about microvascular reperfusion in STEMI patients treated with thrombolysis followed by early PCI. We aimed to assess the association between TIMI myocardial perfusion (TMP) at the end of the PCI procedure and left ventricular function (LVEF) and infarct size after three months in such patients. METHODS AND RESULTS: Patients with STEMI treated with thrombolysis and early PCI were included. TMP grade was assessed at the end of the PCI procedure, and MRI was performed after three months. Of the 89 patients included, 92% (n=82) had TIMI 3 flow at the end of the PCI procedure, while only 62% (n=55) had TMP grade 2 or 3. Patients with TMP grade 2-3 had significantly higher LVEF (59% [53-67] vs. 50% [41-56], p<0.0001) and smaller infarct size (8.3 ml [2.7-15.5] vs. 20.7 ml [13.0-36.0], p<0,0001) after three months. CONCLUSIONS: In STEMI patients treated with thrombolysis and early PCI, the TMP grade at the end of the PCI procedure was significantly associated with LVEF and infarct size after three months.

Inflammatory and thrombotic markers in patients with ST-elevation myocardial infarction treated with thrombolysis and early PCI: a NORDISTEMI substudy.

INTRODUCTION: Both pharmacological and invasive treatment might influence the inflammatory and pro-thrombotic responses observed in acute ST-elevation myocardial infarction (STEMI). We aimed to study whether circulating levels of inflammatory and pro-thrombotic markers differ in STEMI patients treated with early angioplasty compared to standard therapy following thrombolysis. Furthermore, we wanted to study if levels of markers were related to infarct size. MATERIALS AND METHODS: This was a substudy of the NORwegian study on DIstrict treatment of ST-Elevation Myocardial Infarction (NORDISTEMI), in which STEMI patients treated with thrombolysis were randomized to early invasive or standard therapy. Fasting blood samples were collected in the morning 3 days and 3 months after onset of STEMI. Commercially available ELISA methods were used for determination of inflammatory and pro-thrombotic markers. Infarct size was assessed by SPECT after 3 months. RESULTS: 246 patients were included in this substudy. At 3 days, levels of prothrombin fragment 1+2 and D-dimer were higher in the early invasive compared to the standard treatment group, whereas levels of soluble CD40 ligand were lower (p<0.01 for all). No other differences between groups were found in any of the measured markers. Significant, although weak correlations were found between Day 3 levels of C-reactive protein, interleukin-6, prothrombin fragment 1+2 and D-dimer, and infarct size assessed by SPECT after 3 months. CONCLUSIONS: An early invasive strategy following thrombolysis for STEMI was associated with higher subacute levels of D-dimer and prothrombin fragment 1+2, and lower levels of soluble CD40 ligand than standard treatment. Further studies are needed to establish the relation between these changes and clinical outcome. The NORDISTEMI was registered at www.clinicaltrials.gov, NCT00161005.

Efficacy and safety of immediate angioplasty versus ischemia-guided management after thrombolysis in acute myocardial infarction in areas with very long transfer distances results of the NORDISTEMI (NORwegian study on DIstrict treatment of ST-elevation myocardial infarction).

OBJECTIVES: The goal of this study was to compare a strategy of immediate transfer for percutaneous coronary intervention (PCI) with an ischemia-guided approach after thrombolysis in patients with very long transfer distances to PCI. BACKGROUND: Thrombolysis remains the treatment of choice in ST-segment elevation myocardial infarction (STEMI) when primary PCI cannot be performed within 90 to 120 min. The optimal treatment after thrombolysis is still unclear. METHODS: A total of 266 patients with acute STEMI living in rural areas with more than 90-min transfer delays to PCI were treated with tenecteplase, aspirin, enoxaparin, and clopidogrel and randomized to immediate transfer for PCI or to standard management in the local hospitals with early transfer, only if indicated for rescue or clinical deterioration. The primary outcome was a composite of death, reinfarction, stroke, or new ischemia at 12 months, and analysis was by intention to treat. RESULTS: The primary end point was reached in 28 patients (21%) in the early invasive group compared with 36 (27%) in the conservative group (hazard ratio: 0.72, 95% confidence interval: 0.44 to 1.18, p = 0.19). The composite of death, reinfarction, or stroke at 12 months was significantly reduced in the early invasive compared with the conservative group (6% vs. 16%, hazard ratio: 0.36, 95% confidence interval: 0.16 to 0.81, p = 0.01). No significant differences in bleeding or infarct size were observed. CONCLUSIONS: Immediate transfer for PCI did not improve the primary outcome significantly, but reduced the rate of death, reinfarction, or stroke at 12 months in patients with STEMI, treated with thrombolysis and clopidogrel in areas with long transfer distances. (Norwegian Study on District Treatment of ST-Elevation Myocardial Infarction; NCT00161005).

The NORwegian study on DIstrict treatment of ST-elevation myocardial infarction (NORDISTEMI).

OBJECTIVES: Thrombolysis is the treatment of choice for patients with ST-elevation myocardial infarction (STEMI) living in rural areas with long transfer delays to percutaneous coronary intervention (PCI). This trial compares two different strategies following thrombolysis: to transfer all patients for immediate coronary angiography and intervention, or to manage the patients more conservatively. DESIGN: The NORwegian study on DIstrict treatment of STEMI (NORDISTEMI) is an open, prospective, randomized controlled trial in patients with STEMI of less than 6 hours of duration and more than 90 minutes expected time delay to PCI. A total of 266 patients will receive full-dose thrombolysis, preferably pre-hospital, and then be randomized to either strategy. Our primary endpoint is the one year combined incidence of death, reinfarction, stroke or new myocardial ischaemia. The study is registered with ClinicalTrials.gov, number NCT00161005. RESULTS: By April 2006, 109 patients have been randomized. Thrombolysis has been given pre-hospital to 52% of patients. The median transport distance from first medical contact to catheterization laboratory was 155 km (range 90-396 km). Results of the study are expected in 2008.