Newly diagnosed with inflammatory arthritis (NISMA)-development of a complex self-management intervention.

BACKGROUND: Patients newly diagnosed with inflammatory arthritis (IA) request regular consultations and support from health professionals to manage physiological, emotional, and social challenges. Evidence suggests that providing a tailored multi-component self-management program may benefit disease management. However, there is a lack of evidence of effective interventions with multiple components targeting the needs of this group. Therefore, the aim of this study was to develop a self-management intervention targeting newly diagnosed patients with IA, following the Medical Research Council (MRC) framework for developing complex interventions. METHODS: The development of the complex self-management intervention covered three steps. First, the evidence base was identified through literature reviews, in which we described a preliminary nurse-led intervention. Secondly, we chose Social Cognitive Theory as the underlying theory along with Acceptance and Commitment Theory to support our communication strategy. Thirdly, the preliminary intervention was discussed and further developed in workshops to ensure that the intervention was in accordance with patients' needs and feasible in clinical practice. RESULTS: The developed intervention comprises a 9-month nurse-led intervention (four individual and two group sessions). A physiotherapist and an occupational therapist will attend the group sessions along with the nurse. All sessions should target IA-specific self-management with a particular focus on medical, role, and emotional management. CONCLUSION: Through the workshops, we involved all levels of the organization to optimize the intervention, but also to create ownership and commitment, and to identify barriers and shortcomings of the preliminary intervention. As a result, from the existing evidence, we believe that we have identified effective mechanisms to increase self-management in people newly diagnosed with IA. Further, we believe that the involvement of various stakeholders has contributed significantly to developing a relevant and feasible intervention. The intervention is a nurse-led complex self-management intervention embedded in a multidisciplinary team (named NISMA). The intervention is currently being tested in a feasibility study.

Randomized clinical trial on closure versus non-closure of mesenteric defects during laparoscopic gastric bypass surgery.

BACKGROUND: Internal herniation is a well known and potentially life-threatening complication of laparoscopic Roux-en-Y gastric bypass (LRYGB). The aim of this study was to evaluate the benefit and harm of closing the mesenteric defects with clips during LRYGB to prevent internal herniation. METHODS: This was a single-centre, single-blinded RCT. Patients eligible for LRYGB were randomized to surgery with or without closure of mesenteric defects with clips. The primary endpoint was the incidence of (intermittent) internal herniation after LRYGB with a minimum follow-up of 24 months. Secondary outcomes were duration of surgery, number of clips used, trocars and sutures used, postoperative pain measured by a visual analogue scale (VAS), and postoperative complications. RESULTS: Between 13 August 2012 and 18 May 2017, 401 patients were randomized to closure (201) or non-closure (200) of mesenteric defects. Median follow-up for both groups was 59 months (range 8-67 and 16-67 months in non-closure and closure groups respectively). The cumulated risk of internal herniation after 2 years was 8.0 per cent in the non-closure group compared with 4.5 per cent in the closure group (hazard ratio (HR) 1.81, 95 per cent c.i. 0.80 to 4.12; P = 0.231). At 5 years, rates were 15.5 and 6.5 per cent respectively (HR 2.52, 1.32 to 4.81; P = 0.005). Closure of mesenteric defects increased operating time by a median of 4 min (95 per cent c.i. 52 to 56 min for the non-closure group and 56 to 60 min for the closure group; P = 0.002). There was no difference in postoperative blood transfusion rates and VAS scores between the groups. CONCLUSION: Routine closure of the mesenteric defects in LRYGB with clips is associated with a lower rate of internal herniation. Registration number: NCT01595230 (http://www.clinicaltrials.gov).

The influence of type 2 diabetes on fibrin clot properties in patients with coronary artery disease.

Type 2 diabetes mellitus (T2DM) increases the risk of coronary thrombosis and both conditions are associated with altered fibrin clot properties. However, the influence of T2DM on fibrin clot properties in patients with coronary artery disease (CAD) remains unclear. We aimed to investigate the influence of T2DM on fibrin clot properties in patients with CAD. Fibrin clot structure and fibrinolysis were investigated in 581 CAD patients (148 with T2DM) using turbidimetric assays, confocal and scanning electron microscopy. Clots made from plasma and plasma-purified fibrinogen were studied, and plasma levels of inflammatory markers were analysed. T2DM patients had increased clot maximum absorbance compared with non-diabetic patients (0.36 ± 0.1 vs 0.33 ± 0.1 au; p=0.01), displayed longer lysis time (804 [618;1002] vs 750 [624;906] seconds; p=0.03) and showed more compact fibrin structure assessed by confocal and electron microscopy. Fibrinogen levels were elevated in T2DM (p< 0.001), but clots made from purified fibrinogen showed no differences in fibrin properties in the two populations. Adjusting for fibrinogen levels, T2DM was associated with C-reactive protein and complement C3 plasma levels, with the former correlating with clot maximum absorbance (r=0.24, p< 0.0001) and the latter with lysis time (r=0.30, p< 0.0001). Independent of fibrinogen levels, females had more compact clots with prolonged lysis time compared with males (all p-values< 0.001). In conclusion, T2DM is associated with prothrombotic changes in fibrin clot properties in patients with CAD. This is related to quantitative rather than qualitative changes in fibrinogen with a possible role for inflammatory proteins.

Parenteral anticoagulants in heart disease: current status and perspectives (Section II). Position paper of the ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease.

Anticoagulants are a mainstay of cardiovascular therapy, and parenteral anticoagulants have widespread use in cardiology, especially in acute situations. Parenteral anticoagulants include unfractionated heparin, low-molecular-weight heparins, the synthetic pentasaccharides fondaparinux, idraparinux and idrabiotaparinux, and parenteral direct thrombin inhibitors. The several shortcomings of unfractionated heparin and of low-molecular-weight heparins have prompted the development of the other newer agents. Here we review the mechanisms of action, pharmacological properties and side effects of parenteral anticoagulants used in the management of coronary heart disease treated with or without percutaneous coronary interventions, cardioversion for atrial fibrillation, and prosthetic heart valves and valve repair. Using an evidence-based approach, we describe the results of completed clinical trials, highlight ongoing research with currently available agents, and recommend therapeutic options for specific heart diseases.

Reduced antiplatelet effect of aspirin is associated with low-grade inflammation in patients with coronary artery disease.

Inflammation has been proposed to modify platelet function. This may lead to increased platelet reactivity and reduced antiplatelet drug efficacy in patients with coronary artery disease (CAD). However, this hypothesis has not been investigated in stable CAD patients receiving aspirin as mono antiplatelet therapy. It was the objective of this study to investigate the association between platelet reactivity, the inflammatory markers high-sensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6), and platelet activation. We performed a cross-sectional study on 524 stable high-risk CAD patients. Among these, 91% had a history of myocardial infarction, 23% had type 2 diabetes, and 13% had both. All patients received 75 mg aspirin daily as mono antiplatelet therapy. Platelet reactivity was assessed by multiple electrode aggregometry (Multiplate®, MEA) and VerifyNow®. Inflammation was evaluated by hs-CRP and IL-6. Platelet activation was assessed by soluble P-selectin (sP-selectin), and cyclooxygenase-1 inhibition was evaluated by measurement of serum thromboxane B2. Hs-CRP levels were significantly higher in upper platelet reactivity tertile patients than in lower platelet reactivity tertile patients (p≤0.02). Similar results were obtained with IL-6, though not statististically significant (p≥0.15). Platelet activation evaluated by sP-selectin was significantly higher in patients with MEA reactivity levels in the upper tertile than in the lower tertile (p=0.0001). Optimal compliance was confirmed by low serum thromboxane B2 levels in all patients. In conclusion, increased levels of hs-CRP were associated with augmented platelet reactivity in stable high-risk CAD patients receiving aspirin as mono antiplatelet therapy. These findings may suggest that chronic low-grade inflammation reduce the antiplatelet effect of aspirin.

High on-treatment platelet reactivity and P2Y12 antagonists in clinical trials.

Dual antiplatelet therapy with aspirin and clopidogrel in patients undergoing percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes (ACS) has substantially decreased the rate of cardiovascular events. Within the past decade, the variability in pharmacodynamic response as well as the moderate antiplatelet efficacy of clopidogrel has raised major concerns, since high on-clopidogrel platelet reactivity has consistently been associated with increased risk for ischaemic events in PCI patients. The variability in response could be linked to genetic polymorphisms impacting on activity of cytochrome P450 enzymes as well as clinical and demographic variables, but, taken together, factors identified so far can explain only up to approximately 12% of this variability in adenosine diphosphate-induced platelet aggregation on clopidogrel. Regulatory agencies as well as major cardiac societies suggest the use of other anti-platelet medications or alternative dosing strategies for clopidogrel in patients with reduced effectiveness of clopidogrel. This review will focus on the current status of alternate strategies for more sufficient suppression of high platelet reactivity.

Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease.

BACKGROUND: Previous studies have demonstrated considerable variation in the antiplatelet effect of aspirin. OBJECTIVES: To investigate the impact of platelet turnover on the antiplatelet effect of aspirin in patients with stable coronary artery disease (CAD) and to identify determinants of platelet turnover. METHODS: Platelet turnover was evaluated by measurements of immature platelets and thrombopoietin in 177 stable CAD patients on aspirin monotherapy, including 85 type 2 diabetics and 92 non-diabetics. Whole blood platelet aggregation was determined using the VerifyNow(®) Aspirin test and multiple electrode aggregometry (MEA, Multiplate(®) ) induced by arachidonic acid (AA) (1.0 mm), adenosine diphosphate (ADP) (10 µm) and collagen (1.0 µg mL(-1) ). RESULTS: Immature platelet levels significantly correlated with MEA (r = 0.31-0.36, P-values < 0.0001) and the platelet activation marker sP-selectin (r = 0.19, P = 0.014). Contrary to the VerifyNow(®) test, MEA significantly correlated with variations in platelet count (r = 0.45-0.68, P-values < 0.0001). Among patients with residual platelet reactivity according to AA, there were significantly more diabetics (61% vs. 41%, P = 0.027) and higher levels of sP-selectin (77.7 ± 29 vs. 70.2 ± 25 ng mL(-1) , P = 0.070) and serum thromboxane B(2) (0.81 [0.46; 1.70] vs. 0.56 [0.31; 1.12] ng mL(-1) , P = 0.034). In a multivariate regression analysis, immature platelet levels were determined by thrombopoietin levels (P < 0.001), smoking (P = 0.020) and type 2 diabetes (P = 0.042). CONCLUSIONS: The antiplatelet effect of aspirin was reduced in CAD patients with an increased platelet turnover. Once-daily dosing of aspirin might not suffice to adequately inhibit platelet aggregation in patients with an increased platelet turnover.

Reduced platelet response to aspirin in patients with coronary artery disease and type 2 diabetes mellitus.

INTRODUCTION: Diabetes mellitus is complicated by accelerated atherosclerosis, resulting in an increased risk of coronary artery disease (CAD) and thrombosis. Despite the proven benefits of aspirin, previous studies indicate a reduced cardiovascular protection from aspirin in diabetic patients. We aimed to investigate whether diabetes mellitus influenced the platelet response to aspirin in patients with CAD. MATERIALS AND METHODS: Platelet aggregation and activation were evaluated during aspirin treatment in 85 diabetic and 92 non-diabetic patients with CAD. Adherence to aspirin was carefully controlled. All patients had CAD verified by coronary angiography and were taking 75 mg non-enteric coated aspirin daily. RESULTS: Diabetic patients showed significantly higher levels of platelet aggregation compared to non-diabetic patients evaluated by VerifyNow® Aspirin (p=0.03) and Multiplate® aggregometry using arachidonic acid (AA) 0.5 mM (p=0.005) and 1.0 mM (p=0.009). In addition, platelet activation determined by soluble P-selectin was significantly higher in diabetics compared to non-diabetics (p=0.005). The higher AA-induced aggregation was associated with higher levels of HbA(1c). Compliance was confirmed by low levels of serum thromboxane B(2) (below 7.2 ng/mL). Diabetics had significantly higher levels of serum thromboxane B(2) (p<0.0001). CONCLUSIONS: Diabetic patients with CAD had significantly higher levels of both platelet aggregation and activation compared to non-diabetic patients with CAD despite treatment with the same dosage of aspirin. These findings may partly explain the reduced cardiovascular protection from aspirin in diabetic patients.

Primary PCI as the preferred reperfusion therapy in STEMI: it is a matter of time.

There is a continuing controversy about the acceptable time-window for primary percutaneous coronary intervention (PPCI) in patients with ST-elevation myocardial infarction (STEMI). Recent American and European guidelines recommend PPCI if the delay in performing PPCI instead of administering fibrinolysis (PCI-related delay) is <60 min and the presentation delay is more than 3 h. Based on a review of the literature, this viewpoint recommends a revision of the guidelines. The evidence supports an acceptable PCI-related delay of 80-120 min and PPCI as the better reperfusion strategy also in the early incomers. Furthermore, the previous assumption that PPCI is less time-dependent than fibrinolysis is questioned. To maximise the number of patients with STEMI eligible for PPCI the optimal logistic may be to establish the diagnosis in the prehospital phase, to bypass local hospitals and re-route patients directly to catheterisation laboratories running 24/7.

Myocardial infarction centres: the way forward.

In the era of primary PCI, a strategy of admitting patients to the nearest hospital should be obsolete. Instead, a prehospital diagnostic strategy should be implemented in order to: (1) refer patients directly to interventional centres, thereby eliminating delay at local hospitals; (2) alert the interventional centre, thereby reducing door to balloon times; (3) initiate adjunctive medication in the prehospital phase.

The platelet polymorphism PlA2 is a genetic risk factor for myocardial infarction.

OBJECTIVES: Platelet glycoprotein (GP) receptor IIb/IIIa plays a key role in the development of myocardial infarction (MI), and Pl(A2) is a polymorphism in the gene encoding this receptor. The prevalence of Pl(A2) shows pronounced geographical variation and has to our knowledge not been presented for a Scandinavian population before. Platelets from Pl(A2)-positive individuals show increased aggregability compared with platelets from Pl(A2)-negative individuals, and Pl(A2) genotypes might be associated with MI. The purpose of this study was to investigate the relation between the Pl(A2) polymorphism and MI in a large Scandinavian population. DESIGN: Case-control study. We included patients with angiographically verified CAD with and without previous MI and a group of healthy individuals matched for age, race, and sex. RESULTS: We studied the frequency of Pl(A2) in 1191 healthy individuals and 1019 patients with coronary artery disease (CAD). Amongst these patients, 529 subjects had suffered an MI previously. Pl(A2) was present in 28% of healthy individuals, 28% of patients with CAD but no MI, and in 35% of patients with CAD and MI. The difference between healthy individuals and MI patients was significant (P = 0.002). Furthermore, a graded relationship between the number of Pl(A2) alleles and the risk of MI was seen (P = 0.011). Associations between Pl(A2) and traditional cardiovascular risk factors as well as mean platelet volume were investigated. We found a significant interaction between Pl(A2) and serum cholesterol. CONCLUSION: In our Scandinavian study population the common platelet polymorphism Pl(A2) is significantly associated with an increased risk of MI, but not of CAD. Clinically, typing for Pl(A2) might have implications for antiplatelet therapy of patients with MI.

Incomplete thromboxane inhibition with 100 mg of intravenous acetylsalicylic acid in patients with acute ST elevation myocardial infarction: a placebo-controlled pilot trial.

BACKGROUND: Acetylsalicylic acid (ASA) is now a standard treatment of acute myocardial infarction (AMI). ASA inhibits thromboxane A(2) (TXA(2)) production by blocking the constitutive cyclooxygenase (COX)-1 enzyme, but only to a small degree the inducible COX-2. COX-2 is induced by increased concentrations of cytokines, which is related to an enhanced inflammatory response. Previously, we have found a complete inhibition of TXA(2) synthesis in healthy volunteers after intravenous administration of 50 mg of ASA. We measured in a randomized, placebo-controlled pilot trial the effect of 100 mg of ASA injected intravenously on TXA(2) synthesis in AMI patients treated with streptokinase. METHODS AND RESULTS: Nineteen patients with AMI treated with streptokinase were randomized to 100 mg of ASA or placebo injected intravenously. Se-TXB(2) and bleeding time were measured before and after drug administration. One hundred and eighty minutes after intravenous ASA administration, treatment with oral ASA was initiated. We found a significant decrease in serum concentrations of TXB(2) after 30, 60 and 180 min following ASA injection compared to placebo, but in none of the patients was complete inhibition of TXA(2) production achieved. No significant change in bleeding time could be demonstrated. CONCLUSION: Intravenous ASA in a dosage of 100 mg did not completely prevent TXA(2) production in AMI patients treated with streptokinase. This may be due to synthesis of TXA(2) by the inducible COX-2 enzyme and/or to a transcellular metabolism in platelets of prostanoids generated by endothelial cells.

[Abciximab (ReoPro) in the treatment of acute coronary syndromes]. / Abciximab (ReoPro) ved behandling af akutte koronare syndromer.

Platelet activation plays a major role in the pathophysiology of acute coronary syndromes (ACS). Inhibition of platelet function is the basic pharmacological treatment of ACS. Platelet membrane glycoprotein IIb/IIIa inhibitors, a new class of potent antiplatelet agents, have been used in the treatment of ACS and in the prevention of complications after percutaneous coronary interventions (PCI). Several large clinical trials have demonstrated the effectiveness of this class of agents. The first of these agents to show beneficial effects after coronary interventions was the mouse/human chimeric Fab fragment antibody c7E3 abciximab (ReoPro). The purpose of this article is to describe the pharmacology of abciximab and to review the results of the clinical trials carried out with the drug in patients with ACS, treated either with or without acute/elective PCI.

n-3 polyunsaturated fatty acids and coronary thrombosis.

Studies of Greenland Eskimos showed that a very high intake of marine n-3 fatty acids markedly inhibited platelet reactivity and suggested that intake of these fatty acids might prevent coronary thrombosis. Later studies with lower, more practical doses of n-3 fatty acids also have shown a platelet inhibitory effect of n-3 fatty acids, albeit fairly marginal. Furthermore, n-3 fatty acids have little effect on measures of blood coagulability and may slightly decrease fibrinolysis. In animal models, n-3 fatty acids often have been shown to inhibit thrombosis, but again the doses have tended to be very high. Finally, there has been little effect of (low-dose) n-3 fatty acids in clinical trials in humans on the incidence of myocardial infarction. Overall, there is little evidence for a major antithrombotic effect of practical doses of n-3 fatty acids on coronary thrombosis. This does not exclude a beneficial effect of n-3 fatty acids on coronary heart disease as suggested from clinical trials, but the major effect may be antiarrhythmic rather than antithrombotic.