Antithrombotic therapy in high-risk patients after percutaneous coronary intervention; study design, cohort profile and incidence of adverse events.

BACKGROUND: Patients with multiple clinical risk factors are a complex group in whom both bleeding and recurrent ischaemic events often occur during treatment with dual/triple antithrombotic therapy after percutaneous coronary intervention. Decisions on optimal antithrombotic treatment in these patients are challenging and not supported by clear guideline recommendations. A prospective observational cohort study was set up to evaluate patient-related factors, platelet reactivity, genetics, and a broad spectrum of biomarkers in predicting adverse events in these high-risk patients. Aim of the current paper is to present the study design, with a detailed description of the cohort as a whole, and evaluation of bleeding and ischaemic outcomes during follow-up, thereby facilitating future research questions focusing on specific data provided by the cohort. METHODS: We included patients with ≥ 3 predefined risk factors who were treated with dual/triple antithrombotic therapy following PCI. We performed a wide range of haemostatic tests and collected all ischaemic and bleeding events during 6-12 months follow-up. RESULTS: We included 524 high-risk patients who underwent PCI within the previous 1-2 months. All patients used a P2Y12 inhibitor (clopidogrel n = 388, prasugrel n = 61, ticagrelor n = 75) in combination with aspirin (n = 397) and/or anticoagulants (n = 160). Bleeding events were reported by 254 patients (48.5%), necessitating intervention or hospital admission in 92 patients (17.5%). Major adverse cardiovascular events (myocardial infarction, stroke, death) occurred in 69 patients (13.2%). CONCLUSION: The high risk for both bleeding and ischaemic events in this cohort of patients with multiple clinical risk factors illustrates the challenges that the cardiologist faces to make a balanced decision on the optimal treatment strategy. This cohort will serve to answer several future research questions about the optimal management of these patients on dual/triple antithrombotic therapy, and the possible value of a wide range of laboratory tests to guide these decisions.

Importance of confirming the underlying diagnosis in patients with myocardial infarction and non-obstructive coronary arteries (MINOCA): a single-centre retrospective cohort study.

BACKGROUND: Many patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) are discharged without a known aetiology for their clinical presentation. This study sought to assess the effect of this 'indeterminate MINOCA' diagnosis on the prevalence of recurrent cardiovascular events and presentations to the Cardiac Emergency Department (CED). METHODS: We retrospectively analysed all patients meeting the diagnostic MINOCA criteria presenting at a large secondary hospital between January 2017 and April 2019. PARTICIPANTS: Patients were divided into the (1) 'indeterminate MINOCA', or (2) 'MINOCA with diagnosis' group. The primary outcome was the occurrence of major adverse cardiac events (MACE) defined as the composite of all-cause mortality, non-fatal myocardial infarction, stroke and any revascularisation procedure. Secondary outcomes were all recurrent visits at the CED, and MACE including unplanned cardiac hospitalisation. RESULTS: In 62/198 (31.3%) MINOCA patients, a conclusive diagnosis was found (myocardial infarction, (peri)myocarditis, cardiomyopathy, or miscellaneous). MINOCA patients with a confirmed diagnosis were younger compared to those with an indeterminate diagnosis (56.7 vs. 62.3 years, p = 0.007), had higher maximum troponin-T [238 ng/L vs. 69 ng/L, p < 0.001] and creatine kinase (CK) levels [212U/L vs. 152U/L, p = 0.007], and presented more frequently with electrocardiographic signs of ischaemia (71.0% vs. 47.1%, p = 0.002). Indeterminate MINOCA patients more often showed recurrent CED presentations (36.8% vs. 22.6%, p = 0.048), however the occurrence of cardiovascular events was equal (8.8 vs. 8.1%, p = 0.86). Multivariable analysis showed that elevated levels of troponin-T and CK, ST-segment deviation on electrocardiography, reduced left ventricular ejection fraction, regional wall motion abnormalities, and performance of additional examination methods were independent predictors for finding the underlying MINOCA cause. CONCLUSIONS: Only in one-third of MINOCA patients a conclusive diagnosis for the acute presentation was identified. Recurrent CED visits were more often observed in the indeterminate MINOCA group, while the occurrence of cardiovascular events was similar across groups. TRIAL REGISTRATION: Retrospectively registered.

Thrombin Generation as a Method to Identify the Risk of Bleeding in High Clinical-Risk Patients Using Dual Antiplatelet Therapy.

Background: Patients using dual antiplatelet therapy after percutaneous coronary intervention are at risk for bleeding. It is currently unknown whether thrombin generation can be used to identify patients receiving dual antiplatelet therapy with increased bleeding risk. Objectives: To investigate whether thrombin generation measurement in plasma provides additional insight into the assessment of bleeding risk for high clinical-risk patients using dual antiplatelet therapy. Methods: Coagulation factors and thrombin generation in platelet-poor plasma were measured in 93 high clinical-risk frail patients using dual antiplatelet therapy after percutaneous coronary intervention. During 12-month follow-up, clinically relevant bleedings were reported. Thrombin generation at 1 and 6 months after percutaneous coronary intervention was compared between patients with and without bleeding events. Results: One month after percutaneous coronary intervention, the parameters of thrombin generation, endogenous thrombin potential, peak height, and velocity index were significantly lower in patients with bleeding in the following months compared to patients without bleeding. At 6 months follow-up, endogenous thrombin potential, peak height, and velocity index were still (significantly) decreased in the bleeding group as compared to non-bleeders. Thrombin generation in the patients' plasma was strongly dependent on factor II, V, and VIII activity and fibrinogen. Conclusion: High clinical-risk patients using dual antiplatelet therapy with clinically relevant bleeding during follow-up show reduced and delayed thrombin generation in platelet-poor plasma, possibly due to variation in coagulation factors. Thus, impaired thrombin-generating potential may be a "second hit" on top of dual antiplatelet therapy, increasing the bleeding risk in high clinical-risk patients. Thrombin generation has the potential to improve the identification of patients using dual antiplatelet therapy at increased risk of bleeding.

Gender differences with short-term vs 12 months dual antiplatelet therapy in patients with acute coronary syndrome treated with the COMBO dual therapy stent: 2-years follow-up results of the REDUCE trial.

BACKGROUND: Gender differences in the thrombotic and bleeding risk have been suggested to condition the benefits of antithrombotic therapies in Acute Coronary Syndrome (ACS) patients, and mainly among those undergoing percutaneous coronary interventions with drug eluting stents (DES). The impact of gender on the optimal duration of dual antiplatelet therapy (DAPT) in ACS patients is still unexplored and was, therefore, the aim of the present sub-study. METHODS: REDUCE was a prospective, multicenter, randomized investigator-initiated study designed to enroll 1500 ACS patients after treatment with the COMBO Dual Stent Therapy, based on a noninferiority design. Patients were randomized in a 1:1 fashion to either 3 or 12 months of DAPT. Primary study endpoint was a composite of all-cause mortality, myocardial infarction, definite/probable stent thrombosis (ST), stroke, target-vessel revascularization (TVR) and bleedings (BARC II, III, V) at 12 months. Secondary endpoints were cardiovascular mortality and the individual components of the primary endpoint within 24 months. RESULTS: From June 2014 to May 2016 300 women and 1196 men were included in the study. Among them, 43.7% of females and 51.9% of males were assigned to the 3 months DAPT treatment. Baseline characteristics were well matched between the two arms, with the exception of a lower rate of TIMI flow < 3 (p = 0.04), lower systolic blood pressure (p = 0.05) and use of spironolactone (p = 0.006) among women and a more advanced age (p = 0.05) among men receiving a short-term DAPT. At a mean follow-up of 525 (± 198) days, no difference in the primary endpoint was observed according to DAPT duration in both females [6.9% vs 5.9%, HR (95% CI) = 1.19 (0.48-2.9), p = 0.71] and males [8.2% vs 9%, HR (95% CI) = 0.92 (0.63-1.35), p = 0.67; p INT = 0.20]. Results were confirmed after correction for baseline differences [females: adjusted HR (95% CI) = 1.12 (0.45-2.78), p = 0.81; males: adjusted HR (95% CI) = 0.90 (0.61-1.32), p = 0.60]. Comparable rates of survival, thrombotic (MI, stent thrombosis, TVR, stroke) and bleeding events were observed with the two DAPT strategies, with no impact of gender. CONCLUSIONS: The present study shows that among ACS patients randomized in the REDUCE trial, a 3 months DAPT strategy offers comparable results as compared to a standard 12 months DAPT at 2-years follow-up in both male and female gender.

Sharing primary percutaneous coronary intervention care: first experiences with South Limburg ST-elevation myocardial infarction network.

BACKGROUND: In the region of South Limburg, the Netherlands, a shared ST-elevation myocardial infarction (STEMI) networking system (SLIM network) was implemented. During out-of-office hours, two percutaneous coronary intervention (PCI) centres-Maastricht University Medical Centre and Zuyderland Medical Centre-are supported by the same interventional cardiologist. The aim of this study was to analyse performance indicators within this network and to compare them with contemporary European Society of Cardiology guidelines. METHODS: Key time indicators for an all-comer STEMI population were registered by the emergency medical service and the PCI centres. The time measurements showed a non-Gaussian distribution; they are presented as median with 25th and 75th percentiles. RESULTS: Between 1 February 2018 and 31 March 2019, a total of 570 STEMI patients were admitted to the participating centres. The total system delay (from emergency call to needle time) was 65 min (53-77), with a prehospital system delay of 40 min (34-47) and a door-to-needle time of 22 min (15-34). Compared with in-office hours, out-of-office hours significantly lengthened system delays (55 (47-66) vs 70 min (62-81), p < 0.001), emergency medical service transport times (29 (24-34) vs 35 min (29-40), p < 0.001) and door-to-needle times (17 (14-26) vs 26 min (18-37), p < 0.001). CONCLUSIONS: With its effective patient pathway management, the SLIM network was able to meet the quality criteria set by contemporary European revascularisation guidelines.

Design and rationale of ischaemia-driven complete revascularisation versus usual care in patients with non-ST-elevation myocardial infarction and multivessel coronary disease: the South Limburg Myocardial Infarction (SLIM) trial.

AIMS: To compare ischaemia-driven complete coronary revascularisation by percutaneous coronary intervention (PCI) with usual care in patients with non-ST-elevation myocardial infarction (non-STEMI) and multivessel disease (MVD). METHODS: The South Limburg Myocardial Infarction (SLIM) trial (NCT03562572) is an investigator-initiated, prospective, multicentre, randomised controlled trial that compares fractional flow reserve (FFR)-guided complete revascularisation during the index procedure with usual care in non-STEMI patients with MVD. A total of 414 patients will be randomised in a 1:1 fashion. The primary endpoint is the composite of all-cause mortality, non-fatal myocardial infarction, and any revascularisation and stroke (MACCE) at 12 months. The secondary endpoints are: MACCE at 24 and 36 months, and the composite of cardiac death, myocardial infarction, any revascularisation, stroke, major bleeding and left ventricular ejection fraction below 45% at 12, 24 and 36 months. Furthermore, quality of life will be assessed by the Patient Health Questionnaire (PHQ-9) and the Short Form (36) Health Survey (SF-36) at 1 and 12 months of follow-up. CONCLUSION: The SLIM trial aims to provide evidence whether FFR-guided complete revascularisation by PCI is superior to usual care with respect to clinical outcomes (major adverse cardiovascular events) in non-STEMI patients with MVD.

Instantaneous wave-free ratio and fractional flow reserve in clinical practice.

OBJECTIVES: To compare fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) measurements in an all-comer patient population with moderate coronary artery stenoses. BACKGROUND: Visual assessment of the severity of coronary artery stenoses is often discordant in moderate lesions. FFR allows reliable functional severity assessment in these cases but requires adenosine-induced hyperaemia with associated additional time, costs and side effects. The iFR is a hyperaemia-independent index. METHODS AND RESULTS: Between November 2015 and February 2017, 356 consecutive patients were included in whom 515 coronary stenoses were measured using both iFR and FFR. Mean iFR and FFR were 0.90 ± 0.09 and 0.86 ± 0.08, respectively. iFR correlated well with FFR [r = 0.75; p < 0.001]. Receiver operating characteristic analysis identified an area under the curve of 0.92. An iFR-only strategy with a treatment cut-off ≤0.89 revealed a diagnostic classification agreement with the FFR-only strategy in 420 lesions (82%) with a sensitivity of 87%, a specificity of 80%, a positive predictive value of 56% and a negative predictive value of 96%. CONCLUSIONS: Real-time iFR measurements have good negative predictive value compared to FFR, but moderate diagnostic accuracy (82%). It exposes fewer patients to adenosine, reduces procedure time and costs. Further prospective trials are needed to evaluate specific clinical settings, cut-off values and endpoints.

Multivessel revascularisation versus infarct-related artery only revascularisation during the index primary PCI in STEMI patients with multivessel disease: a meta-analysis.

BACKGROUND: There are controversial data regarding infarct-related artery only (IRA-PCI) revascularisation versus multivessel revascularisation (MV-PCI) in ST-elevation myocardial infarction (STEMI) patients with multivessel disease undergoing primary percutaneous coronary intervention (PCI). We performed a meta-analysis comparing outcome in same stage MV-PCI versus IRA-PCI in STEMI patients with multivessel disease. METHODS: Systematic searches of studies comparing MV-PCI with IRA-PCI in the MEDLINE and the Cochrane Database of systematic reviews were conducted. A meta-analysis was performed of all available studies. Primary outcome was all-cause mortality. Secondary endpoints were re-infarction, revascularisation, bleeding and major adverse cardiac events (MACE). RESULTS: A total of 15 studies were identified with a total number of 35,975 patients. Mortality rate was significantly higher in the MV-PCI group compared with the IRA-PCI group, odds ratio (OR): 1.64 (1.46-1.85). Both the incidence of re-infarction and re-PCI were significantly lower in the MV-PCI group compared with the IRA-PCI group: OR 0.54 (0.34-0.88) and OR 0.67 (0.48-0.93), respectively. Bleeding complications occurred more often in the MV-PCI group as compared with the IRA-PCI group: OR 1.24 (1.08-1.42). Rates of MACE were comparable between the two groups. CONCLUSIONS: MV-PCI during the index of primary PCI in STEMI patients is associated with a higher mortality rate, a higher risk of bleeding complications, but lower risk of re-intervention and re-infarction and comparable rates of MACE.

Easy access echocardiography for the general practitioner: results from the Parkstad area in the Netherlands.

Heart failure has a low incidence in general practice but is not easy to recognize in this setting. Frequently a normal electrocardiogram and a normal level of brain natriuretic peptide can exclude heart failure as a cause for dyspnea. Unfortunately the positive predictive value of both techniques is low. Imaging with echocardiography can then give the clue to the correct diagnosis. Also correct diagnosis of cardiac murmurs is not easy in general practice. Therefore an open access echocardiographic service was established in the south of the Netherlands. According to the existing services in the United Kingdom general practitioners in this area were able to ask for an echocardiogram without referring the patient to the cardiologist. During a period of 19 months 131 patients were referred to the Centre of Medical Diagnostics for an echocardiogram. In 12% of the patients referred for dyspnea a left ventricular ejection fraction lower than 40% was found. Fourty nine percent of the patients had diastolic dysfunction. In 33% heart failure could be excluded. In 62% of the patients referred for a cardiac murmur cardiac pathology could be found. In 38% of the patients the cardiac murmur could be established as a functional murmur. The service was found to improve practice by most of the general practitioners.

Open access echocardiography is feasible in the Netherlands.

OBJECTIVES: In an urban region in the Netherlands, general practitioners (GPs) were offered an open access echocardiographic service. We report the outcomes of the first two years of this project. METHODS: GPs were given a course on the indications and restrictions for diagnostic referral as well as the interpretation of echocardiographic results. Indications were restricted to `dyspnoea', `cardiac murmur' and `peripheral oedema'. A uniform request form was developed, using ticking boxes for quick completion. The echocardiogram was performed within one week after the request. Results were interpreted by the cardiologist according to the criteria of the Dutch, European and American Societies of Echocardiography. RESULTS: Sixty GPs from 43 general practices participated, covering a practice population of 130,000 persons. During a period of 24 months, 198 patients were referred. Only 1.5% of the workload of the echocardiography department was due to requests from GPs. The GPs kept well to the agreements on indications for echocardiography (91% approved reasons). An abnormal echocardiographic outcome was found in 53% of all patients. For `cardiac murmur' this was 52%, for `dyspnoea' 63%, and for `peripheral oedema' 58%. Left ventricular dysfunction was present in 49 patients (25%); diastolic dysfunction was present in most of them (39 patients, 19%). Systolic dysfunction (LVEF < 40%) was found in 19 patients (10%). Twenty patients (10%) appeared to have relevant aortic or mitral valve disease. CONCLUSION: GPs did not overuse the open access echocardiographic service; they possibly used it conservatively. To prevent underdiagnosis of left ventricular dysfunction, diagnostic strategies in which electrocardiogram, NT-pro-BNP and echocardiography are combined, should be developed.

Determinants and prognostic implications of persistent ST-segment elevation after primary angioplasty for acute myocardial infarction: importance of microvascular reperfusion injury on clinical outcome.

BACKGROUND: Despite early recanalization of an occluded infarct artery, reperfusion at the level of the microcirculation may remain impaired owing to a process of microvascular reperfusion injury. METHODS AND RESULTS: Microvascular reperfusion injury was studied in 91 patients with acute myocardial infarction (AMI) by evaluation of the resolution of ST-segment elevation after successful PTCA. Impaired microvascular reperfusion, defined as the presence of persistent (>/=50% of initial value) ST-segment elevation (ST >/=50%) at the end of coronary intervention, was observed in 33 patients (36%) and was independently correlated with low systolic pressure on admission and high age. Patients >/=55 years of age with systolic pressures /=50% versus ST <50%, P=0.01); nonfatal MI rate, 9% versus 2% (P=0.1); and total major adverse cardiac event (MACE) rate, 45% versus 15% (P<0.005). ST >/=50% was the most important independent determinant of MACE with an adjusted risk ratio of 3.4. CONCLUSIONS: Impaired microvascular reperfusion, as evidenced by ST >/=50% after successful recanalization, occurs in more than one third of our AMI patients, especially in older patients with low systolic pressure. Its detrimental implications on clinical outcome reinforce the need to develop adjunctive agents that attenuate the process of reperfusion injury.

Coxsackievirus B1-based antibody-capture enzyme-linked immunosorbent assay for detection of immunoglobulin G (IgG), IgM, and IgA with broad specificity for enteroviruses.

An antibody-capture enzyme-linked immunosorbent assay (ELISA) with coxsackievirus B1 as the antigen was evaluated for detection of immunoglobulin G (IgG), IgM, and IgA antibodies and showed broad specificity for enteroviruses. In total, 116 serum or cerebrospinal fluid samples from 62 patients were tested by ELISA and the complement fixation test (CFT). Additionally, 15 serum samples that contained poliovirus-specific IgM antibody were tested. Serum samples from 200 healthy blood donors were used for standardization of the assays. The sensitivity of the ELISA varied with time of serum sampling, with a relatively low sensitivity when serum was collected within 3 days after the onset of symptoms (23%; 5 of 22) but good sensitivity when serum was collected later (83%; 20 of 24). The sensitivity was better than that of the CFT. The ELISAs were broadly reactive as concluded from typing of virus isolates that were simultaneously obtained. The assay did, furthermore, detect antibody against poliovirus type 3. Sera that contained rheumatoid factor, antinuclear antibody, or cardiolipin antibody (by the Venereal Disease Research Laboratory test) did not react in this ELISA. Nonspecific reactivity did occur, however, in cases of infectious mononucleosis and in Mycoplasma pneumoniae infection. The enterovirus-specific ELISA is found to be simple to perform, more sensitive than the CFT, and far less laborious than the neutralization test.