The Netherlands Sports Cardiology Map: a step towards sports cardiology network medicine for patient and athlete care.

Sports cardiology is a rapidly evolving subspecialty of cardiology, with a growing demand for expertise. To improve patient care, clinicians, patients, and athletes (recreational to elite) should be able to easily identify specialised care pathways, expertise centres and clinicians with sports cardiology expertise. To this purpose, several international societies and organisations recommend establishing a local and national sports cardiology infrastructure. We therefore aimed to establish The Netherlands Sports Cardiology Map. We conducted a web-based survey, which was published on the Netherlands Society of Cardiology home page (2019-2020) and in which each cardiology department or clinic was asked to provide information on sports cardiology expertise and the current infrastructure. Of the 46 respondent centres, 28 (61%) reported that they had expertise in sports cardiology, of which 22 (79%) had specific expertise in one or more specific types of sports. Integrated multidisciplinary meetings were reported by 43% of the centres (n = 12/28). Only two centres reported ongoing research projects that had been approved by an institutional review board. The Netherlands Sports Cardiology Map is an important step towards improving the existing infrastructure and developing network medicine for sports cardiology.

Guideline compliance for bridging anticoagulation use in vitamin-K antagonist patients; practice variation and factors associated with non-compliance.

BACKGROUND: Bridging anticoagulation is used in vitamin-K antagonist (VKA) patients undergoing invasive procedures and involves complex risk assessment in order to prevent thromboembolic and bleeding outcomes. OBJECTIVES: Our aim was to assess guideline compliance and identify factors associated with bridging and especially, non-compliant bridging. METHODS: A retrospective review of 256 patient records in 13 Dutch hospitals was performed. Demographic, clinical, surgical and care delivery characteristics were collected. Compliance to the American College of Chest Physicians ninth edition guideline (AT9) was assessed. Multilevel regression models were built to explain bridging use and predict non-compliance. RESULTS: Bridging use varied from 15.0 to 83.3% (mean = 41.8%) of patients per hospital, whereas guideline compliance varied from 20.0 to 88.2% (mean = 68.5%) per hospital. Both established thromboembolic risk factors and characteristics outside thromboembolic risk assessment were associated with bridging use. Predictors for overuse were gastrointestinal surgery (OR 14.85, 95% CI 2.69-81.99), vascular surgery (OR 13.01, 95% CI 1.83-92.30), non-elective surgery (OR 8.67, 95% CI 1.67-45.14), lowest 25th percentile socioeconomic status (OR 0.33, 95% CI 0.11-1.02) and use of VKA reversal agents (OR 0.22, 95% CI 0.04-1.16). CONCLUSION: Bridging anticoagulation practice was not compliant with the AT9 in 31.5% of patients. The aggregated AT9 thromboembolic risk was inferior to individual thromboembolic risk factors and other characteristics in explaining bridging use. Therefor the AT9 risk seems less important for the decision making in everyday practice. Additionally, a heterogeneous implementation of the guideline between hospitals was found. Further research and interventions are needed to improve bridging anticoagulation practice in VKA patients.

Defibrillation threshold in elective subcutaneous implantable defibrillator generator replacements: Time to reduce the size of the pulse generator?

INTRODUCTION: The first step-down defibrillation studies in the subcutaneous implantable cardioverter-defibrillator (S-ICD) described a defibrillation threshold (DFT) of 32.5 ± 17.0 J and 36.6 ± 19.8 J. Therefore, the default shock output of the S-ICD was set at 80 J. In de novo implants, the DFT is lower in optimally positioned S-ICDs. However, a retrospective analysis raised concerns about a high DFT in S-ICD replacements, possibly related to fibrosis. OBJECTIVE: We aimed to find the DFT in patients undergoing S-ICD generator replacement. METHODS: This prospective study enrolled patients who underwent S-ICD generator replacement with subsequent defibrillation testing. A pre-specified defibrillation testing protocol was used to determine the DFT, defined as the lowest shock output that effectively terminated the induced ventricular arrhythmia. RESULTS: A total of 45 patients were enrolled, 6.0 ± 2.1 years after initial implant. Mean DFT during replacement in the total cohort was 27.4 ± 14.3 J. In patients with a body mass index (BMI) 18.5-25 kg/m2 (N = 22, BMI 22.5 ± 1.6), median DFT was 20 J (IQR 17.5-30). In 18/22 patients, the DFT was ≤30 J and 5/22 patients were successfully defibrillated at 10 J. One patient with hypertrophic cardiomyopathy had a DFT of 65 J. In patients with a BMI >25 kg/m2 (N = 23, BMI 29.5 ± 4.2), median DFT was 30 J (IQR 20-40). In 15/23 patients, the DFT was ≤30 J and 4/23 patients had a successful defibrillation test at 10 J. CONCLUSIONS: This study eases concerns about a high DFT after S-ICD generator replacement. The majority of patients had a DFT ≤30 J, regardless of BMI, suggesting that the shock output of the S-ICD could be safely reduced.

Genetic variation in coagulation and fibrinolytic proteins and their relation with acute myocardial infarction: a systematic review.

BACKGROUND: It is pathophysiologically conceivable that genetic variations in coagulation and fibrinolytic proteins are associated with the risk of myocardial infarction. Methods and Results- We performed a literature search to identify published case-control studies correlating the factor V Leiden or prothrombin G20210A mutations or fibrinogen G-455A or plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms with the risk of myocardial infarction. Studies were included only if they used solid diagnostic criteria and complied with published methodological criteria. A common OR with corresponding 95% CI was calculated for the risk of myocardial infarction in a fixed-effect model according to Mantel-Haenszel. The factor V Leiden and prothrombin G20201A mutations did not significantly correlate with myocardial infarction (OR 1.26, 95% CI 0.94 to 1.67, P=0.12 and OR 0.89, 95% CI 0.59 to 1.35, P=0.6, respectively). Inclusion of the studies that investigated young patients (<55 years) made the association significant for factor V Leiden (OR 1.29, 95% CI 1.03 to 1.61, P=0.02). Homozygosity for the fibrinogen -455A allele was significantly associated with a decreased risk of myocardial infarction (OR 0.66, 95% CI 0.44 to 0.99, P=0.04), whereas the PAI-1 4G4G genotype was significantly associated with increased risk (OR 1.20, 95% CI 1.04 to 1.39, P=0.04). CONCLUSIONS: Associations between these genetic variations and myocardial infarction were weak or absent. In the absence of clinical implications, our results indicate that screening of patients with myocardial infarction for these genetic variations is not warranted.

Recombinant factor VIIa as an antidote for anticoagulant treatment.

Increasing knowledge on the function of the hemostatic system in vivo and limitations of currently available anticoagulant agents have led to the development of a new generation of anticoagulants. These new agents have a greater specificity towards activated coagulation pathways and factors and are presently being evaluated in clinical studies. The new generation anticoagulants include specific inhibitors of factor IIa (melagatran), factor Xa (pentasaccharides), and agents that interfere with tissue factor (TF) activity. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs. Recombinant factor VIIa (rFVIIa) is a potent prohemostatic agent and may represent an interesting option for consideration when an antidote is required. Indeed, rFVIIa has proven to be efficacious in the reversal of anticoagulant treatment with vitamin K antagonists. Studies in healthy subjects have also revealed that rFVIIa administration corrects coagulation time and can induce thrombin generation during anticoagulation with pentasaccharides or TF-inhibiting therapy. These results indicate that rFVIIa infusion results in a prohemostatic response in vivo in patients receiving treatment with factor Xa- or TF-specific anticoagulants. This suggests that rFVIIa may be a good candidate as an antidote for new anticoagulants in cases of (severe) bleeding or in patients scheduled for emergency surgery.

Recombinant factor VIIa reverses the in vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux.

BACKGROUND: Fondaparinux is a synthetic pentasaccharide, which selectively inhibits coagulation factor (F) Xa, and is registered for prevention of venous thromboembolism following hip fracture, hip replacement, and knee replacement surgery. Recently, it was shown that recombinant FVIIa (rFVIIa) reverses anticoagulant effects of fondaparinux in healthy volunteers. OBJECTIVES: In this study, we have explored the in vitro and ex vivo effects of rFVIIa on clot formation and thrombin-activatable fibrinolysis inhibitor (TAFI)-mediated down-regulation of fibrinolysis after fondaparinux administration. METHODS: In vitro clot lysis assays were performed in pooled normal plasma from healthy volunteers to which fondaparinux was added, and in serial samples from healthy volunteers who received a single bolus dose of fondaparinux, a single bolus dose of rFVIIa, or both. RESULTS AND CONCLUSIONS: Fondaparinux significantly delayed clot formation, and clot lysis was significantly increased due to decreased activation of TAFI. Addition of recombinant FVIIa corrected the inhibited clot formation induced by fondaparinux, and the acceleration of clot lysis was partially reversed. In vivo administration of fondaparinux (10 mg) to healthy volunteers similarly resulted in accelerated plasma clot lysis. Subsequent administration of rFVIIa (90 microg kg(-1)) normalized the clot lysis time up to 6 h postadministration. rFVIIa might be a good therapeutic option in patients treated with fondaparinux who develop bleeding complications, since both clot formation as well as fibrinolytic resistance are improved.

Low-molecular weight heparins in venous and arterial thrombotic disease.

INTRODUCTION: Since the introduction of low-molecular-weight heparins (LMWHs) in the early 1980's, the use of these compounds has been extensively investigated as a substitute for unfractionated heparin (UFH) in patients with venous and arterial thrombotic diseases. LMWHs have several advantages as compared to UFH, such as the subcutaneous route of administration, the predictable anticoagulant response and the lack of the need for laboratory monitoring. The present systematic review evaluates randomised clinical trials which investigated the efficacy and safety of LMWH in the acute treatment of venous thromboembolism, myocardial infarction, unstable coronary syndromes and ischemic stroke. METHODS: A computerised and manual search was performed to identify all relevant clinical trials. All randomised studies, with an a priori defined study population, clinical outcome measurement and adequate follow-up, were reviewed by two independent assessors. Whenever possible a common effect estimate of the included studies was calculated. RESULTS: Thirteen studies in approximately 4000 patients with acute venous thromboembolism revealed an odds ratio for the 3-month recurrent thromboembolism rate and major bleeding complications during exposure of 0.77 (C.I. 0.57-1.04) and 0.61 (C.I. 0.39-0.95), respectively, in favour of LMWH as compared to UFH. In patients with acute myocardial infarction, one study suggested a reduction in the incidence of reinfarction and cardiac death in LMWH recipients compared to UFH, while a placebo-controlled study revealed no beneficial effect of LMWH on these outcomes. In six studies including over 7000 patients with acute unstable coronary syndromes, there was an odds ratio for recurrent angina, myocardial infarction, urgent revascularisation and major bleedings of 0.88 (C.I. 0.76-1.01), 0.84 (C.I. 0.69-1.01), 0.83 (C.I. 0.70-0.99), 1.09 (C.I. 0.70-1.70), respectively, in favour of LMWH compared to UFH. The three studies comparing LMWH treatment with placebo in approximately 1000 patients with acute ischemic stroke revealed an odds ratio for the 10-day recurrent stroke, death or disability after 3 months and major bleeding complications of 0.68 (C.I. 0.41-1.13), 0.94 (C.I. 0.78-1.15), 2.92 (C.I. 1.88-4.55), respectively. CONCLUSION: Fixed-dose subcutaneous LMWH appears to be a safe and effective alternative for dose-adjusted intravenous heparin in the treatment of patients with acute venous thrombotic disease as well as in patients with acute unstable coronary syndromes. The effectiveness of LMWH in patients with acute myocardial infarction remains unclear. There seems to be no beneficial effect of LMWH treatment as compared to placebo in patients with acute ischemic stroke, while the risk of major bleeding was clearly increased.

Inhibition of the tissue factor pathway of coagulation by recombinant nematode anticoagulant protein c2 during elective coronary stent implantation.

BACKGROUND: Exposure of tissue factor (TF) to the circulation during coronary stent implantation initiates coagulation activation and may contribute to the risk of thrombotic complications. In this study, we investigated whether inhibition of TF-factor VIIa by recombinant Nematode Anti-coagulant Protein c2 (rNAPc2) is able to suppress haemostatic and inflammatory activity in patients undergoing elective intracoronary stenting. METHODS: In a randomised, double-blind design, 102 patients received either placebo or rNAPc2 (biological half-life >50 hours) at doses of 3.5, 5.0, 7.5 and 10.0 µg/kg as a single subcutaneous administration two to six hours before angioplasty. All patients also received aspirin, clopidogrel and unfractionated heparin (activated clotting time >250 seconds during angioplasty). Serial blood samples were collected before and after the intervention. RESULTS: At 30 hours after stenting, all rNAPc2 treatment groups but not the placebo group demonstrated a reduction from baseline of prothrombin fragment F1+2 and D-dimer plasma levels (to 23 and 12% below baseline values at the highest dose, respectively), which were significantly lower in three rNAPc2 groups compared with placebo (p≤0.03). TF plasma levels were initially reduced in all rNAPc2 groups and returned to baseline values 18 hours after stent implantation. These three markers all increased to above baseline values in the placebo group. Levels of P-selectin, antithrombin III and interleukin-8 were not or only slightly affected by the intervention or by rNAPc2, whereas a significant 2.8 to 4.1 fold increase of C-reactive protein plasma levels was found in all patient groups after the procedure. CONCLUSION: In contrast to the inflammatory response, coagulation activation after elective coronary stent implantation, which is observed in spite of the use of multiple antithrombotic drugs, can be attenuated by inhibition of the TF-factor VIIa complex using rNAPc2. Inhibition of the TF-mediated pathway of coagulation may be an important target to prevent thrombotic complications after coronary stenting.

Monitoring therapy with vitamin K antagonists in patients with lupus anticoagulant: effect on different tests for INR determination.

BACKGROUND: Lupus anticoagulant (antiphospholipid antibodies) is associated with venous and arterial thrombosis in patients with and without autoimmune disorders. Vitamin K antagonists are the treatment of choice in patients with thrombosis, of which the dose is titrated by INR monitoring. Several recent reports suggest that the presence of the lupus anticoagulant disturbs the INR test and may lead to unreliable results with a large variation in INR values, dependent on the reagents used. METHODS: We studied 11 lupus anticoagulant positive patients and 11 lupus anticoagulant negative patients, all using vitamin K antagonists. The INR value was determined using seven different tests and the variation in INR values was compared between the two groups. The amidolytic Factor X levels were used as an phospholipid independent measure for intensity of warfarin therapy. Factor VII and X activity were measured to assess the stability of warfarin therapy. RESULTS: The variation of the results with different INR tests within one patient was minimal and comparable in the two groups for INR's in the therapeutic range. The coefficient of variation for the cases and control group was 10.43 and 9.35, respectively. Variation in both groups increased at supratherapeutic levels of anticoagulation and when the anticoagulation was unstable (measured with Factor X/Factor VII ratio). The relationship between INR values and Factor X analysis revealed no influence of the lupus anticoagulant. CONCLUSIONS: In this study, lupus anticoagulant antibodies do not disturb INR laboratory tests. Differences in INR measurements are seen in patients with a high intensity of anticoagulation and in patients who either just started or in whom no stable anticoagulation has been achieved. Abbreviated Abstract. This study investigates the influence of lupus anticoagulant on INR determination tests in patients treated with warfarin. Eleven cases and eleven lupus anticoagulant negative control patients, also on warfarin therapy, were included. Seven INR results per patient were obtained using different laboratory tests. A factor X assay was performed to obtain an independent measure for the intensity of warfarin therapy. The variation of INR results between the cases and controls revealed no difference in these groups. In addition, the relationship between INR values and Factor X analysis indicated no influence of the lupus anticoagulant. What was observed was an increased difference in INR values in patients with a high intensity of anticoagulation and in patients who either just started or in whom no stable anticoagulation has been achieved