A study of size-selective renal elimination using a novel human model.

The recently discovered selective glomerular hypofiltration syndromes have increased interest in the actual elimination of molecules in the human kidney. In the present study, a novel human model was introduced to directly measure the single-pass renal elimination of molecules of increasing size. Plasma concentrations of urea, creatinine, C-peptide, insulin, pro-BNP, ß2-microglobulin, cystatin C, troponin-T, orosomucoid, albumin, and IgG were analysed in arterial and renal venous blood from 45 patients undergoing Transcatheter Aortic Valve Implantation (TAVI). The renal elimination ratio (RER) was calculated as the arteriovenous concentration difference divided by the arterial concentration. Estimated glomerular filtration rate (eGFR) was calculated by the CKD-EPI equations for both creatinine and cystatin C. Creatinine (0.11 kDa) showed the highest RER (21.0 ± 6.3%). With increasing molecular size, the RER gradually decreased, where the RER of cystatin C (13 kDa) was 14.4 ± 5.3% and troponin-T (36 kDa) was 11.3 ± 4.6%. The renal elimination threshold was found between 36 and 44 kDa as the RER of orosomucoid (44 kDa) was -0.2 ± 4.7%. The RER of creatinine and cystatin C showed a significant and moderate positive linear relationship with eGFR (r = 0.48 and 0.40). In conclusion, a novel human model was employed to demonstrate a decline in renal elimination with increasing molecular size. Moreover, RERs of creatinine and cystatin C were found to correlate with eGFR, suggesting the potential of this model to study selective glomerular hypofiltration syndromes.

Routine revascularization with percutaneous coronary intervention in patients with coronary artery disease undergoing transcatheter aortic valve implantation - the third nordic aortic valve intervention trial - NOTION-3.

BACKGROUND: Coronary artery disease (CAD) frequently coexists with severe aortic valve stenosis (AS) in patients planned for transcatheter aortic valve implantation (TAVI). How to manage CAD in this patient population is still an unresolved question. In particular, it is still not known whether fractional flow reserve (FFR) guided revascularization with percutaneous coronary intervention (PCI) is superior to medical treatment for CAD in terms of clinical outcomes. STUDY DESIGN: The third Nordic Aortic Valve Intervention (NOTION-3) Trial is an open-label investigator-initiated, multicenter multinational trial planned to randomize 452 patients with severe AS and significant CAD to either FFR-guided PCI or medical treatment, in addition to TAVI. Patients are eligible for the study in the presence of at least 1 significant PCI-eligible coronary stenosis. A significant stenosis is defined as either FFR ≤0.80 and/or diameter stenosis >90%. The primary end point is a composite of first occurring all-cause mortality, myocardial infarction, or urgent revascularization (PCI or coronary artery bypass graft performed during unplanned hospital admission) until the last included patient have been followed for 1 year after the TAVI. SUMMARY: NOTION-3 is a multicenter, multinational randomized trial aiming at comparing FFR-guided revascularization vs medical treatment of CAD in patients with severe AS planned for TAVI.

Rationale and design of switch Swedeheart: A registry-based, stepped-wedge, cluster-randomized, open-label multicenter trial to compare prasugrel and ticagrelor for treatment of patients with acute coronary syndrome.

BACKGROUND: European treatment guidelines recommend prasugrel over ticagrelor for treating patients with non-ST-elevation acute coronary syndrome (ACS), prompting several Swedish administrative regions to transition from ticagrelor to prasugrel as the preferred treatment for patients with ACS. We aim to systematically evaluate this transition to determine the relative efficacy of prasugrel versus ticagrelor in a real-world cohort of patients with ACS. STUDY DESIGN AND OBJECTIVES: The SWITCH SWEDEHEART trial is a prospective, multicenter, open-label, cross-sectional, stepped-wedge cluster-randomized clinical trial, in which administrative regions in Sweden will constitute the clusters. At the start of the study, all clusters will use ticagrelor as the P2Y12 inhibitor drug of choice for ACS. The order in which the clusters will implement the transition from ticagrelor to prasugrel will be randomly assigned. Every 9 months, 1 cluster will switch from ticagrelor to prasugrel as the P2Y12 inhibitor of choice for patients with ACS. The primary endpoint is the composite 1-year rate of the death, stroke, or myocardial infarction. CONCLUSIONS: The SWITCH SWEDEHEART study will provide an extensive randomized comparison between ticagrelor and prasugrel. Novel therapies are frequently costly and supported by evidence from few or small studies, and systematic evaluation after the introduction is rare. This study will establish an important standard for introducing and evaluating the effects of health care changes within our societies.

Long-term mortality in patients with ischaemic heart failure revascularized with coronary artery bypass grafting or percutaneous coronary intervention: insights from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR).

AIMS: To compare coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for treatment of patients with heart failure due to ischaemic heart disease. METHODS AND RESULTS: We analysed all-cause mortality following CABG or PCI in patients with heart failure with reduced ejection fraction and multivessel disease (coronary artery stenosis >50% in ≥2 vessels or left main) who underwent coronary angiography between 2000 and 2018 in Sweden. We used a propensity score-adjusted logistic and Cox proportional-hazards regressions and instrumental variable model to adjust for known and unknown confounders. Multilevel modelling was used to adjust for the clustering of observations in a hierarchical database. In total, 2509 patients (82.9% men) were included; 35.8% had diabetes and 34.7% had a previous myocardial infarction. The mean age was 68.1 ± 9.4 years (47.8% were >70 years old), and 64.9% had three-vessel or left main disease. Primary designated therapy was PCI in 56.2% and CABG in 43.8%. Median follow-up time was 3.9 years (range 1 day to 10 years). There were 1010 deaths. Risk of death was lower after CABG than after PCI [odds ratio (OR) 0.62; 95% confidence interval (CI) 0.41-0.96; P = 0.031]. The risk of death increased linearly with quintiles of hospitals in which PCI was the preferred method for revascularization (OR 1.27, 95% CI 1.17-1.38, Ptrend < 0.001). CONCLUSION: In patients with ischaemic heart failure, long-term survival was greater after CABG than after PCI.

Assessing the external validity of the VALIDATE-SWEDEHEART trial.

AIMS: The VALIDATE-SWEDEHEART trial was a registry-based randomized trial comparing bivalirudin and heparin in patients with acute myocardial infarction undergoing percutaneous coronary intervention. It showed no differences in mortality at 30 or 180 days. This study examines how well the trial population results may generalize to the population of all screened patients with fulfilled inclusion criteria in regard to mortality at 30 and 180 days. METHODS: The standardized difference in the mean propensity score for trial inclusion between trial population and the screened not-enrolled with fulfilled inclusion criteria was calculated as a metric of similarity. Propensity scores were then used in an inverse-probability weighted Cox regression analysis using the trial population only to estimate the difference in mortality as it would have been had the trial included all screened patients with fulfilled inclusion criteria. Patients who were very likely to be included were weighted down and those who had a very low probability of being in the trial were weighted up. RESULTS: The propensity score difference was 0.61. There were no significant differences in mortality between bivalirudin and heparin in the inverse-probability weighted analysis (hazard ratio 1.11, 95% confidence interval (0.73, 1.68)) at 30 days or 180 days (hazard ratio 0.98, 95% confidence interval (0.70, 1.36)). CONCLUSION: The propensity score difference demonstrated that the screened not-enrolled with fulfilled inclusion criteria and trial population were not similar. The inverse-probability weighted analysis showed no significant differences in mortality. From this, we conclude that the VALIDATE results may be generalized to the screened not-enrolled with fulfilled inclusion criteria.

Bivalirudin versus Heparin Monotherapy in Myocardial Infarction.

BACKGROUND: The comparative efficacy of various anticoagulation strategies has not been clearly established in patients with acute myocardial infarction who are undergoing percutaneous coronary intervention (PCI) according to current practice, which includes the use of radial-artery access for PCI and administration of potent P2Y12 inhibitors without the planned use of glycoprotein IIb/IIIa inhibitors. METHODS: In this multicenter, randomized, registry-based, open-label clinical trial, we enrolled patients with either ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) who were undergoing PCI and receiving treatment with a potent P2Y12 inhibitor (ticagrelor, prasugrel, or cangrelor) without the planned use of glycoprotein IIb/IIIa inhibitors. The patients were randomly assigned to receive bivalirudin or heparin during PCI, which was performed predominantly with the use of radial-artery access. The primary end point was a composite of death from any cause, myocardial infarction, or major bleeding during 180 days of follow-up. RESULTS: A total of 6006 patients (3005 with STEMI and 3001 with NSTEMI) were enrolled in the trial. At 180 days, a primary end-point event had occurred in 12.3% of the patients (369 of 3004) in the bivalirudin group and in 12.8% (383 of 3002) in the heparin group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.10; P=0.54). The results were consistent between patients with STEMI and those with NSTEMI and across other major subgroups. Myocardial infarction occurred in 2.0% of the patients in the bivalirudin group and in 2.4% in the heparin group (hazard ratio, 0.84; 95% CI, 0.60 to 1.19; P=0.33), major bleeding in 8.6% and 8.6%, respectively (hazard ratio, 1.00; 95% CI, 0.84 to 1.19; P=0.98), definite stent thrombosis in 0.4% and 0.7%, respectively (hazard ratio, 0.54; 95% CI, 0.27 to 1.10; P=0.09), and death in 2.9% and 2.8%, respectively (hazard ratio, 1.05; 95% CI, 0.78 to 1.41; P=0.76). CONCLUSIONS: Among patients undergoing PCI for myocardial infarction, the rate of the composite of death from any cause, myocardial infarction, or major bleeding was not lower among those who received bivalirudin than among those who received heparin monotherapy. (Funded by the Swedish Heart-Lung Foundation and others; VALIDATE-SWEDEHEART ClinicalTrialsRegister.eu number, 2012-005260-10 ; ClinicalTrials.gov number, NCT02311231 .).

Pretreatment with P2Y12 receptor antagonists in ST-elevation myocardial infarction: a report from the Swedish Coronary Angiography and Angioplasty Registry.

AIMS: Pretreatment of patients with ST-elevation myocardial infarction (STEMI) with P2Y12 receptor antagonists is supported by guidelines and is a common practice despite the lack of definite evidence for its benefit. METHODS AND RESULTS: Using data from the Swedish Coronary Angiography and Angioplasty Registry on procedures between 2005 and 2016, we stratified all patients who underwent primary percutaneous coronary intervention due to STEMI in Sweden by whether or not they were pretreated with P2Y12 receptor antagonists. We investigated associations between pretreatment with P2Y12 receptor antagonists and the risk of adverse outcomes using propensity score-adjusted mixed-effects logistic regression, which accounted for clustering of patients within hospitals. The primary endpoint was all-cause death within 30 days. Secondary endpoints were infarct-related artery (IRA) occlusion, 30-day stent thrombosis, in-hospital bleeding, neurological complications, and cardiogenic shock. In total, 44 804 patients were included. They were treated with clopidogrel (N = 26 136, 58.3%), ticagrelor (N = 15 792, 35.3%), or prasugrel (N = 2352, 5.3%); 37 840 (84.5%) were pretreated, and 30 387 (67.8%) had IRA occlusion. At 30 days, there were 2488 (5.6%) deaths and 267 (0.6%) stent thrombosis. Pretreatment was not associated with better survival at 30 days [odds ratio (OR) 1.08, 95% confidence interval (CI) 0.95-1.24; P = 0.313], reduced IRA occlusion (OR 0.98, 95% CI 0.92-1.05; P = 0.608), decreased stent thrombosis (OR 0.99, 95% CI 0.69-1.43; P = 0.932), higher risk of in-hospital bleeding (OR 1.05, 95% CI 0.89-1.26; P = 0.526), or neurological complications (OR 0.72, 95% CI 0.43-1.21; P = 0.210). CONCLUSION: Pretreatment of STEMI patients with P2Y12 receptor antagonists was not associated with improved clinical outcomes.

Single-center evaluation of a next generation fully repositionable and retrievable transcatheter aortic valve replacement.

BACKGROUND: The mechanically expandable Lotus Valve System is a fully repositionable and retrievable valve with an adaptive seal to minimize paravalvular leak (PVL). The aim of this study was to evaluate the short- and long-term safety and efficacy of the new device with focus on a new implantation technique to reduce the need for a permanent pacemaker (PPM) post procedure. METHODS: We performed a prospective single-center, non-randomized evaluation of the Lotus Valve System. The first 100 consecutive Lotus Valve implantations were included in the analysis. Outcome was assessed according to VARC2-criteria. Postoperative pacemaker rates were assessed using the national pacemaker registry and electronic medical records. Mortality at 30 days and 12 months were acquired from the national population registry. RESULTS: Mean age was 82.7 ± 5.6 years, mean Euroscore I was 25.3 ± 14.5%, mean STS-score was 6.5 ± 4.1% and mean aortic valve area was 0.6 ± 0.1 cm2. There were no cases of valve embolization, ectopic valve deployment or additional valve implantation. Device success according to the VARC2-criteria was 97%. The 30-day mortality rate was 3%. Two deaths occurred due to stroke and one due to a ventricular rupture. Major stroke rate was 2% and major vascular complication rate was 2%. The 12-month mortality rate was 14%. At discharge 87% of patients had no/trace PVL, 12% had mild PVL and one patient had a moderate PVL. A total of 13% received a new PPM post valve implantation. Among patients who did not have a PPM before the procedure, the PPM rate was 15.3%. CONCLUSIONS: This single-center evaluation of the Lotus Valve System demonstrated a good clinical outcome with a low mortality, in a high-risk population. Introduction of a new implantation technique resulted in lower PPM rates than previously reported without negatively affecting PVL. TRIAL REGISTRATION: Current Controlled Trials ISRCTN14952278 , retrospectively registered 06/11/2017.

Bivalirudin versus heparin with primary percutaneous coronary intervention.

BACKGROUND: Optimal adjunctive therapy in ST-segment elevation myocardial infarction (STEMI) patients treated with primary PCI (PPCI) remains a matter of debate. Our aim was to compare the efficacy and safety of bivalirudin to unfractionated heparin (UFH), with or without glycoprotein IIb/IIIa inhibitors (GPI) in a large real-world population, using data from the Swedish national registry, SWEDEHEART. METHOD: From 2008 to 2014 we identified 23,800 STEMI patients presenting within 12 hours from symptom onset treated with PPCI and UFH ±â€¯GPI or bivalirudin±GPI. Primary outcomes included 30-day all-cause mortality and major in-hospital bleeding. Multivariable regression models and propensity score modelling were utilized to study adjusted association between treatment and outcome. RESULTS: Treatment with UFH ±â€¯GPI was associated with similar risk of 30-day mortality compared to bivalirudin±GPI (5.3% vs 5.5%, adjusted HR 0.94; 95% CI 0.82-1.07). The adjusted risk for 1-year mortality, 30-day and 1-year stent thrombosis and re-infarction did not differ significantly between UFH ±â€¯GPI and bivalirudin±GPI. In contrast, treatment with UFH ±â€¯GPI was associated with a significant higher risk of major in-hospital bleeding (adjusted OR 1.62; 95% CI 1.30-2.03). When including GPI use in the multivariable analysis, the difference was attenuated and no longer significant (adjusted OR 1.25; 95% CI 0.92-1.70). CONCLUSION: Bivalirudin±GPI was associated with significantly lower risk for major inhospital bleeding but no significant difference in 30-day or one year mortality, stent thrombosis or re-infarction compared with UFH ±â€¯GPI. The bleeding reduction associated with bivalirudin could be explained by the greater GPI use with UFH.

Progressive increase of the Tpeak-Tend interval is associated with ischaemia-induced ventricular fibrillation in a porcine myocardial infarction model.

Aims: Repolarization indices of ECG have been widely assessed as predictors of ventricular arrhythmias. However, little is known of the dynamic changes of these parameters during continuous monitoring in acute ischaemic episodes. The objective of the study was to evaluate repolarization-related predictors of ventricular fibrillation (VF) during progression of experimental myocardial infarction. Methods and results: Myocardial infarction was induced in 27 pigs by 40-min balloon inflation in the left anterior descending coronary artery, and 12-lead ECG was continuously recorded. Rate-corrected durations of the total Tpeak-Tend intervals measured from the earliest T-wave peak to the latest T-wave end in any lead were determined at baseline and at minute 1, 2, 5, and then every 5th minute of occlusion. There were 7 early (1-3 min) and 10 delayed (15-30 min) VFs in 16 pigs. Baseline Tpeak-Tend did not differ between animals with and without VF. Tpeak-Tend interval rapidly increased immediately after balloon inflation and was greater in VF-susceptible animals at 2-15 min compared with the animals that never developed VF (P < 0.05). Tpeak-Tend was tested as a predictor of delayed VFs. Median Tpeak-Tend at 10th min of occlusion was higher in delayed VF group (n = 10) than in animals without VF (n = 11): 138 [IQR 121-148] ms vs. 111 [IQR 106-127] ms, P = 0.02. Tpeak-Tend ≥123 ms (10th min) predicted delayed VF episodes with HR = 4.5 95% CI 1.1-17.8, P = 0.031. Conclusion: Tpeak-Tend prolongation during ischaemia progression predicts VF in the experimental porcine myocardial infarction model and warrants further testing in clinical settings of acute coronary syndromes.

Experimental validation of contrast-enhanced SSFP cine CMR for quantification of myocardium at risk in acute myocardial infarction.

BACKGROUND: Accurate assessment of myocardium at risk (MaR) after acute myocardial infarction (AMI) is necessary when assessing myocardial salvage. Contrast-enhanced steady-state free precession (CE-SSFP) is a recently developed cardiovascular magnetic resonance (CMR) method for assessment of MaR up to 1 week after AMI. Our aim was to validate CE-SSFP for determination of MaR in an experimental porcine model using myocardial perfusion single-photon emission computed tomography (MPS) as a reference standard and to test the stability of MaR-quantification over time after injecting gadolinium-based contrast. METHODS: Eleven pigs were subjected to either 35 or 40 min occlusion of the left anterior descending artery followed by six hours of reperfusion. A technetium-based perfusion tracer was administered intravenously ten minutes before reperfusion. In-vivo and ex-vivo CE-SSFP CMR was performed followed by ex-vivo MPS imaging. MaR was expressed as % of left ventricular mass (LVM). RESULTS: There was good agreement between MaR by ex-vivo CMR and MaR by MPS (bias: 1 ± 3% LVM, r 2 = 0.92, p < 0.001), between ex-vivo and in-vivo CMR (bias 0 ± 2% LVM, r 2 = 0.94, p < 0.001) and between in-vivo CMR and MPS (bias -2 ± 3% LVM, r 2 = 0.87, p < 0.001. No change in MaR was seen over the first 30 min after contrast injection (p = 0.95). CONCLUSIONS: Contrast-enhanced SSFP cine CMR can be used to measure MaR, both in vivo and ex vivo, in a porcine model with good accuracy and precision over the first 30 min after contrast injection. This offers the option to use the less complex ex-vivo imaging when determining myocardial salvage in experimental studies.

The safety of introducing a new generation TAVR device: one departments experience from introducing a second generation repositionable TAVR.

BACKGROUND: In the evolving field of transcatheter aortic valve replacements a new generation of valves have been introduced to clinical practice. With the complexity of the TAVR procedure and the unique aspects of each TAVR device, there is a perceived risk that changing or adding a new valve in a department could lead to a worse outcome for patients, especially during the learning phase. The objective was to study the safety aspect of introducing a second generation repositionable transcatheter valve (Boston Scientific Lotus valve besides Edwards Sapien valve) in a department. METHODS: In a retrospective study, 53 patients receiving the Lotus system, and 47 patients receiving the Sapien system over a period of three years were compared for short-term outcome according to VARC-2 definitions and 1-year survival. RESULTS: Outcome in terms VARC-2 criteria for early safety and clinical efficacy, stroke rate, and survival at 30 days and at 1 year were similar. The Lotus valve had less paravalvular leakage, where 90% had none or trace aortic insufficiency as compared to only 48% for the Sapien system. CONCLUSIONS: Introduction of a new generation valve can be done with early device success and safety, and without jeopardizing the outcome for patients up to one year. We found no adverse effects by changing valve type and observed improved outcome in terms of lower PVL-rates. Both existing and new centers starting a TAVR program can benefit from the use of a new generation device.

Cangrelor in combination with ticagrelor provides consistent and potent P2Y12-inhibition during and after primary percutaneous coronary intervention in real-world patients with ST-segment-elevation myocardial infarction.

Patients pretreated with ticagrelor with less than 1 hour from percutaneous coronary intervention (PCI) or receiving ticagrelor in cath lab were prospectively included and received cangrelor. Cangrelor was infused for 2 hours and platelet function was assessed as P2Y12 reactivity units (PRU) with the VerifyNow P2Y12 function assay before start of infusion, 15 min after the start of infusion, and 30 min after the end of infusion. A total of n = 32 patients with an average age of 68 (±13) years with n = 22 (69%) males were included. The level of P2Y12 inhibition before cangrelor infusion was started was 249 PRU (IQR 221-271). After 15 min of cangrelor infusion the P2Y12 reactivity was markedly decreased to 71 PRU (IQR 52-104, p < 0.001). At 30 min after end of infusion PRU remained within the therapeutic range, 89 PRU (IQR 50-178; p < 0.001 for comparison with preinfusion) with only n = 4 (12.5%) patients with PRU >225. Results were consistent between patients receiving ticagrelor prehospital or in the cath lab and no statistical differences in PRU were noted between the two groups in any of the three measurements. In conclusion, cangrelor in combination with ticagrelor results in consistent and strong P2Y12 inhibition during and after infusion and cangrelor may bridge the gap until oral P2Y12 inhibitors achieve effect in real-world STEMI patients undergoing primary PCI.

Low real-world early stent thrombosis rates in ST-elevation myocardial infarction patients and the use of bivalirudin, heparin alone or glycoprotein IIb/IIIa inhibitor treatment: A nationwide Swedish registry report.

BACKGROUND: In recent studies of primary percutaneous coronary intervention (PCI), bivalirudin compared with heparin has been associated with increased risk of stent thrombosis (ST). Our aim was to describe incidence and outcome of definite, early ST in a large contemporary primary PCI population divided in antithrombotic therapy subgroups. METHODS AND RESULTS: A prospective, observational cohort study of all 31,258 ST-elevation myocardial infarction patients who received a stent in Sweden from January 2007 to July 2014 in the SWEDEHEART registry was conducted. Patients were divided into 3 groups: bivalirudin, heparin alone, or glycoprotein IIb/IIIa inhibitor treated. Primary outcome measure was incidence of definite early ST (within 30 days of PCI). Secondary outcomes included all-cause mortality. Incidence of early ST was low, regardless of bivalirudin, heparin alone, or glycoprotein IIb/IIIa inhibitor treatment (0.84%, 0.94%, and 0.83%, respectively). All-cause mortality at 1 year was 20.7% for all ST patients (n = 265), compared with 9.1% in those without ST (n = 31,286; P < .001). Patients with ST days 2-30 had numerically higher all-cause mortality at 1 year compared with patients with ST days 0-1 (23% vs 16%, P = .20). CONCLUSION: In this real-world observational study of 31,258 ST-elevation myocardial infarction patients, the incidence of early ST was low, regardless of antithrombotic treatment strategy. Early ST was associated with increased mortality. Numerically higher all-cause mortality at 1 year was noted with ST days 2-30 compared with ST days 0-1 post-PCI.

Bivalirudin versus heparin in non-ST and ST-segment elevation myocardial infarction-a registry-based randomized clinical trial in the SWEDEHEART registry (the VALIDATE-SWEDEHEART trial).

BACKGROUND: The optimal anticoagulant for patients with acute coronary syndrome treated with percutaneous coronary intervention (PCI) has not been validated in current practice of radial approach and pretreatment with potent P2Y12 inhibitors. Several studies have indicated increased bleeding rate and, in some instances, even increased mortality by the routine use of heparin and glycoprotein IIb/IIIa inhibitors compared to bivalirudin. Direct comparison of bivalirudin versus heparin alone has yielded contradictory results depending on study designs. METHODS/DESIGN: The VALIDATE-SWEDEHEART trial is a multicenter, prospective, randomized, registry-based, controlled, and open-label clinical trial in patients with ST-segment elevation myocardial infarction (STEMI) or non-STEMI undergoing PCI pretreated with ticagrelor, prasugrel, or cangrelor. We hypothesize that bivalirudin is superior to heparin alone in reducing death, myocardial infarction, and major bleeding events at 180 days (primary end point). The trial will enroll 3,000 patients with STEMI and 3,000 patients with non-STEMI undergoing PCI. The trial will use a hybrid registry-based randomized clinical trial design where inclusion, randomization, and baseline data collection are performed using The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry. The primary composite end point (death, myocardial infarction, or major bleeding events at 180 days) will be identified through active screening after 7 and 180 days and adjudicated by a blinded central end point committee. Secondary end points and long-term outcomes will be recorded from national registries. CONCLUSION: The VALIDATE-SWEDEHEART trial is founded on a nationwide clinical registry and uses a hybrid registry-based randomized clinical trial (RRCT) design methodology to evaluate efficacy and safety of bivalirudin as compared to heparin alone for acute coronary syndrome, in a large population receiving contemporary recommended therapies including predominantly radial invasive approach and pretreatment with potent P2Y12 inhibitors.

Automatic segmentation of myocardium at risk from contrast enhanced SSFP CMR: validation against expert readers and SPECT.

BACKGROUND: Efficacy of reperfusion therapy can be assessed as myocardial salvage index (MSI) by determining the size of myocardium at risk (MaR) and myocardial infarction (MI), (MSI = 1-MI/MaR). Cardiovascular magnetic resonance (CMR) can be used to assess MI by late gadolinium enhancement (LGE) and MaR by either T2-weighted imaging or contrast enhanced SSFP (CE-SSFP). Automatic segmentation algorithms have been developed and validated for MI by LGE as well as for MaR by T2-weighted imaging. There are, however, no algorithms available for CE-SSFP. Therefore, the aim of this study was to develop and validate automatic segmentation of MaR in CE-SSFP. METHODS: The automatic algorithm applies surface coil intensity correction and classifies myocardial intensities by Expectation Maximization to define a MaR region based on a priori regional criteria, and infarct region from LGE. Automatic segmentation was validated against manual delineation by expert readers in 183 patients with reperfused acute MI from two multi-center randomized clinical trials (RCT) (CHILL-MI and MITOCARE) and against myocardial perfusion SPECT in an additional set (n = 16). Endocardial and epicardial borders were manually delineated at end-diastole and end-systole. Manual delineation of MaR was used as reference and inter-observer variability was assessed for both manual delineation and automatic segmentation of MaR in a subset of patients (n = 15). MaR was expressed as percent of left ventricular mass (%LVM) and analyzed by bias (mean ± standard deviation). Regional agreement was analyzed by Dice Similarity Coefficient (DSC) (mean ± standard deviation). RESULTS: MaR assessed by manual and automatic segmentation were 36 ± 10% and 37 ± 11%LVM respectively with bias 1 ± 6%LVM and regional agreement DSC 0.85 ± 0.08 (n = 183). MaR assessed by SPECT and CE-SSFP automatic segmentation were 27 ± 10%LVM and 29 ± 7%LVM respectively with bias 2 ± 7%LVM. Inter-observer variability was 0 ± 3%LVM for manual delineation and -1 ± 2%LVM for automatic segmentation. CONCLUSIONS: Automatic segmentation of MaR in CE-SSFP was validated against manual delineation in multi-center, multi-vendor studies with low bias and high regional agreement. Bias and variability was similar to inter-observer variability of manual delineation and inter-observer variability was decreased by automatic segmentation. Thus, the proposed automatic segmentation can be used to reduce subjectivity in quantification of MaR in RCT. CLINICAL TRIAL REGISTRATION: NCT01379261. NCT01374321.

QRS broadening due to terminal distortion is associated with the size of myocardial injury in experimental myocardial infarction.

INTRODUCTION: Not only repolarization, but also depolarization ECG indexes reflect the progression of ischemic injury. The aim was to assess the QRS duration and morphology dynamics during the prolonged coronary occlusion and their association with the myocardial area at risk (MaR) and final infarct size (IS). METHODS: In pigs, myocardial infarction was induced by inflation of an angioplasty balloon in the left descending artery (LAD), and ECG was continuously recorded. QRS duration was calculated on a beat-to-beat basis during the occlusion period. Single photon emission computed tomography (SPECT) was performed for the assessment of MaR, and IS was assessed by magnetic resonance imaging (MRI). RESULTS: All animals developed an anteroseptal infarction with MaR 40±9% and IS 23±7%. Two peaks of QRS widening were found in all animals: the early peak immediately after LAD occlusion and the late one 17.7±4.1min later. No association was found between MaR and IS and either QRS width or the degree of QRS widening at the early peak. QRS duration on the late peak correlated with both MaR (r=0.61; p=0.007) and IS (r=0.55; p=0.018). CONCLUSION: The QRS widening at the late peak, but not at the early peak, is associated with the size of myocardial injury, suggesting different underlying mechanisms.

Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results.

AIM: The MITOCARE study evaluated the efficacy and safety of TRO40303 for the reduction of reperfusion injury in patients undergoing revascularization for ST-elevation myocardial infarction (STEMI). METHODS: Patients presenting with STEMI within 6 h of the onset of pain randomly received TRO40303 (n = 83) or placebo (n = 80) via i.v. bolus injection prior to balloon inflation during primary percutaneous coronary intervention in a double-blind manner. The primary endpoint was infarct size expressed as area under the curve (AUC) for creatine kinase (CK) and for troponin I (TnI) over 3 days. Secondary endpoints included measures of infarct size using cardiac magnetic resonance (CMR) and safety outcomes. RESULTS: The median pain-to-balloon time was 180 min for both groups, and the median (mean) door-to-balloon time was 60 (38) min for all sites. Infarct size, as measured by CK and TnI AUCs at 3 days, was not significantly different between treatment groups. There were no significant differences in the CMR-assessed myocardial salvage index (1-infarct size/myocardium at risk) (mean 52 vs. 58% with placebo, P = 0.1000), mean CMR-assessed infarct size (21.9 g vs. 20.0 g, or 17 vs. 15% of LV-mass) or left ventricular ejection fraction (LVEF) (46 vs. 48%), or in the mean 30-day echocardiographic LVEF (51.5 vs. 52.2%) between TRO40303 and placebo. A greater number of adjudicated safety events occurred in the TRO40303 group for unexplained reasons. CONCLUSION: This study in STEMI patients treated with contemporary mechanical revascularization principles did not show any effect of TRO40303 in limiting reperfusion injury of the ischaemic myocardium.

Anemia in the general population: prevalence, clinical correlates and prognostic impact.

Low hemoglobin concentration is associated with increased mortality, but there is disagreement with regard to the clinical definition of anemia. We aimed to evaluate the prevalence, clinical correlates and association with total and cause-specific long-term mortality across the hemoglobin distribution and for previously proposed definitions of anemia. Blood hemoglobin concentration and mean corpuscular volume was measured in participants of the Malmö diet and cancer study-a prospective cohort study, and related to baseline characteristics and outcomes during follow-up. Primary endpoints were all-cause mortality, cardiovascular mortality and cancer-related mortality. A U-shaped association of hemoglobin with total mortality was observed in spline regression analyses, with nadir at hemoglobin 150 g/L among men and 130 g/L among women. Mortality increased steeply with more strict definitions of anemia, hazard ratio: 1.36, 1.94 and 2.16 for hemoglobin <140/130 (men/women), 132/122 and 130/120 g/L, respectively. Similar trends were seen for both cancer- and cardiovascular mortality. The incidence of coronary disease and cancer did not differ across groups. Erythrocyte volume was an independent predictor of mortality, with the highest mortality observed for macrocytic anemia, which was less prevalent than microcytic and normocytic anemia. Dietary intake of iron and vitamin B12 were significantly lower and use of antithrombotic medications was significantly higher in subjects with anemia. The World Health Organisation definition of anemia was associated with increased mortality (hazard ratio 2.16) but excess mortality was also observed at higher hemoglobin levels. Of morphological subtypes, anemia with macrocytosis was rare but associated with the highest mortality.

A pharmacodynamic comparison of 5 anti-platelet protocols in patients with ST-elevation myocardial infarction undergoing primary PCI.

BACKGROUND: Despite advances in anti-platelet treatments, there still exists an early increase in both ischemic as well as bleeding events following primary PCI in patients with ST-elevation myocardial infarction (STEMI). Platelet inhibition data of different anti-platelet treatments in the acute phase of a myocardial infarction might offer some insight into these problems. The aim of this study was to evaluate the pharmacodynamic profile of 5 different anti-platelet treatments in the acute phase of STEMI in patients undergoing primary PCI. METHODS: A total of 223 STEMI patients undergoing primary PCI were prospectively included. Patients received either pre-hospital clopidogrel only, pre-hospital clopidogrel followed by prasugrel switch in the cath lab, prasugrel treatment only, pre-hospital clopidogrel followed by ticagrelor switch in the cath lab or pre-hospital ticagrelor only. Platelet reactivity was measured serially using vasodilator-stimulated phosphoprotein (VASP). RESULTS: Patients receiving pre-hospital clopidogrel followed by prasugrel switch showed similar platelet inhibition data as patients receiving prasugrel only, with more than 90% being good responders the day after PCI. Average time from prasugrel administration to a VASP value of <50% was 1.5 hours. In patients receiving pre-hospital ticagrelor, 50% were good responders at completion of PCI and average time to a VASP-value of <50% was 2.3 hours. Only 32% of patients receiving clopidogrel only were responders the day after PCI. CONCLUSIONS: Switching from an upstream bolus dose of clopidogrel to prasugrel at the time of PCI, appeared as a safe and feasible option with no tendency for overshoot or attenuation of platelet inhibition. Pre-hospital administration of ticagrelor was associated with a 50% good responder rate at completion of PCI.