Differential vascular effects of aspirin in people with Type 2 diabetes without cardiovascular disease and matched controls without diabetes.

AIM: We investigated whether the effect of low-dose aspirin on endothelium-dependent vasodilation and arterial stiffness in people with Type 2 diabetes is different from a matched control group. We examined acute and chronic effects, and effects over the 24h dosing interval. METHODS: In an open-label parallel group intervention study, we included 21 participants with Type 2 diabetes and 21 age- and sex-matched controls. Endothelium-dependent vasodilation was assessed as the reactive hyperaemia index (lnRHI) measured by peripheral arterial tonometry (EndoPAT® ). Arterial stiffness was assessed as pulse wave velocity (PWV) measured by applanation tonometry (SphygmoCor® ). Measurements were performed prior to aspirin intake and 1h after aspirin administration (75 mg). Participants were then treated for 6 days, and measurements were repeated at 24 h and 1 h after aspirin intake. RESULTS: Baseline lnRHI did not differ between groups. The controls had an immediate increase in lnRHI after the first aspirin tablet. This was not observed in participants with diabetes (difference between groups; P < 0.05). After 1 week, both groups demonstrated increased lnRHI compared with baseline (P < 0.01). In participants with diabetes, lnRHI was significantly lower 24 h after aspirin administration compared with 1 h after administration (P < 0.05). This difference was not observed in controls (P = 0.84, difference between groups; P = 0.12). The effect on PWV did not differ between groups. CONCLUSION: Aspirin had a reduced immediate effect on endothelium-dependent vasodilation in participants with diabetes. Both groups had improved endothelial function after 1 week of treatment. Further, the effect of aspirin on endothelial function may be declining during a 24 h dosing interval in people with Type 2 diabetes. (Clinical Trial Registry No: 2016-000515-32).

A changing landscape: Temporal trends in incidence and characteristics of patients hospitalized with venous thromboembolism 2006-2015.

BACKGROUND: Venous thromboembolism (VTE) has major clinical and public health impact. However, only sparse data on calendar time trends in incidence from unselected populations reflecting current clinical practice are available. OBJECTIVES: To examine temporal trends in the incidence and characteristics of patients hospitalized with first-time VTE in Denmark between 2006 and 2015. PATIENTS/METHODS: Using nationwide health care registries, we calculated yearly hospitalization rates for first-time VTE from 2006 to 2015. The rates were standardized to the age and sex distribution in 2006. Based on the hospitalization and prescription history of each patient, we assessed the risk profile and evaluated changes over time. RESULTS: We identified 67,426 patients with a first-time VTE hospitalization. The age- and sex-standardized incidence rate increased from 12.6 (95% CI: 12.3-12.9) per 10,000 person years at risk in 2006 to 15.1 (95% CI: 14.7-15.4) in 2015, corresponding to an increase of 19.8%. The increase was due to a 73.9% increase in the standardized incidence rate of pulmonary embolism (PE), whereas no increase was observed for deep vein thrombosis. The risk profile changed with an increasing proportion of elderly patients and patients with comorbidity (proportion of patients with a Charlson's Comorbidity Index score of ≥1). CONCLUSIONS: The hospitalization rate of first-time VTE, and particularly PE, has increased substantially within the last decade in Denmark. In addition, the risk profile of the VTE population has changed with more elderly and more patients with comorbidity being diagnosed. Further efforts are warranted to explore the changes in VTE epidemiology and the clinical implications.

Preadmission use of selective serotonin reuptake inhibitors and short-term mortality in diabetic patients hospitalized due to stroke.

BACKGROUND: Patients with diabetes have an increased risk of stroke with a poor prognosis. Moreover, diabetic patients are at increased risk of depression and therefore likely to use selective serotonin reuptake inhibitors (SSRIs). We examined whether preadmission SSRI use was associated with increased mortality in diabetic patients hospitalized due to stroke. METHODS: Population-based medical databases were used to identify all first-time stroke-related hospitalizations and subsequent mortality in diabetic patients in Denmark between 2004 and 2012 (n = 12 620). Based on redeemed prescriptions, SSRI use was categorized as current (new or long term), former or nonuse, and absolute 30-day mortality and mortality rate ratios (MRRs) were computed using Cox regression controlling for confounding factors. RESULTS: Amongst SSRI nonusers, 30-day stroke mortality was 15.8% (10.4% for ischaemic stroke, 41.8% for intracerebral haemorrhage and 27.3% for subarachnoid haemorrhage). Amongst current SSRI users, 30-day stroke mortality was 23.3% (17.1% for ischaemic stroke, 50.7% for intracerebral haemorrhage and 28.6% for subarachnoid haemorrhage). Current SSRI use was associated with increased 30-day stroke mortality compared with nonuse [adjusted MRR 1.3, 95% confidence interval (CI) 1.1-1.5], with the highest risk observed amongst new users (MRR 1.5, 95% CI 1.2-1.8). Overall stroke mortality was driven by increased mortality due to ischaemic stroke, with adjusted MRRs of 1.3 (95% CI 1.1-1.7) for current users and 1.7 (95% CI 1.2-2.4) for new users. Propensity score-matched results were similar and robust across subgroups. CONCLUSION: In patients with diabetes, preadmission SSRI use was associated with increased mortality following ischaemic stroke, compared with nonuse.

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.

New oral anticoagulants: clinical indications, monitoring and treatment of acute bleeding complications.

New oral anticoagulants like the direct thrombin inhibitor, dabigatran (Pradaxa®), and factor Xa-inhibitors, rivaroxaban (Xarelto®) and apixaban (Eliquis®) are available for prophylaxis and treatment of thromboembolic disease. They are emerging alternatives to warfarin and provide equal or better clinical outcome together with reduced need for routine monitoring. Methods for measuring drug concentrations are available, although a correlation between plasma drug concentrations and the risk of bleeding has not been firmly established. Standard laboratory measures like prothrombin time and activated partial thromboplastin time are not sensitive enough to detect thrombin or factor Xa inhibition provided by new oral anticoagulants. Thus, these standard tests may only be used as a crude estimation of the actual anticoagulation status. Further challenges regarding patients receiving new oral anticoagulants who presents with major bleeding or need for emergency surgery pose a unique problem. No established agents are clinically available to reverse the anticoagulant effect, although preclinical data report prothrombin complex concentrate as more efficient than fresh frozen plasma or other prohaemostatic agents. This review summaries current knowledge on approved new oral anticoagulants and discusses clinical aspects of monitoring, with particular focus on the management of the bleeding patient.

Nationwide registry-based analysis of cardiovascular risk factors and adverse outcomes in patients treated with strontium ranelate.

UNLABELLED: National registers showed that a large proportion of patients treated with strontium ranelate have conditions that may now contraindicate use. The risk of death in strontium ranelate-treated patients was significantly higher than that seen in users of other osteoporosis drugs even after adjusting for cardiovascular risk factor profile. INTRODUCTION: The European Medicines Agency (EMA) recently warned that strontium ranelate should be avoided in patients with ischaemic heart disease (IHD), peripheral vascular disease (PVD) or cerebrovascular disease (CVD), and in patients with uncontrolled hypertension. We investigated to what extent patients beginning strontium ranelate had cardiovascular conditions and determined the rates of MI, stroke and death. METHODS: Using the Danish National Prescription Database, we identified all 3,252 patients aged 50+ who began strontium ranelate in 2005-2007 and 35,606 users of other osteoporosis drugs as controls. Hospital contacts and causes of death were retrieved from national registers. RESULTS: Patients starting strontium were older than patients treated with other osteoporosis drugs and more likely to suffer from IHD, PVD or CVD (combined prevalence 19.2 % in female users and 29.5 % in male users). The adjusted risk of MI was not significantly increased (women: HR 1.05 [95 % CI 0.79-1.41, p = 0.73]; men: 1.28 [0.74-2.20, p = 0.38]). For stroke, the adjusted HR was 1.23 (0.98-1.55, p = 0.07) in women and 1.64 (0.99-2.70, p = 0.05) in men. All-cause mortality was higher in strontium users (women: adjusted HR 1.20 [1.10-1.30, p < 0.001]; men: adjusted HR 1.22 [1.03-1.45, p < 0.05]). CONCLUSION: Patients treated with strontium ranelate have an unfavourable cardiovascular risk profile compared with users of other osteoporosis drugs. However, only the risk of death differed significantly from the rates observed in users of other osteoporosis drugs adjusted for risk factor profile. A large proportion of patients currently treated with strontium ranelate have conditions that would now be considered contraindications according to EMA.

Pharmacogenomics in cardiovascular disease: focus on aspirin and ADP receptor antagonists.

Antiplatelet agents like aspirin and adenosine diphosphate receptor antagonists are effective in reducing recurrent ischemic events. Considerable inter-individual variability in the platelet inhibition obtained with these drugs has initiated a search for explanatory mechanisms and ways to improve treatment. In recent years, numerous genetic polymorphisms have been linked with reduced platelet inhibition and lack of clinical efficacy of antiplatelet drugs, particularly clopidogrel and aspirin. Consequently, attempts to adjust antiplatelet treatment according to genotype have been made, but the clinical benefit has been modest in studies performed so far. The progress in genome science over the last decade and the declining cost of sequencing technologies hold the promise of enabling genetically tailored antiplatelet therapy. However, more evidence is needed to clarify which polymorphisms may serve as targets to improve treatment. The present review outlines the panel of polymorphisms affecting the benefit of aspirin and adenosine diphosphate receptor antagonists, including novel and ongoing studies evaluating whether genotyping may be beneficial in tailoring antiplatelet therapy.

Heart failure in patients treated with bisphosphonates.

OBJECTIVES: The aim of this study was to investigate the occurrence of heart failure in patients treated with bisphosphonates. DESIGN: In this nationwide retrospective cohort study from Denmark, all users of bisphosphonates and raloxifene between 1996 and 2006 (n = 102 342) were included in the 'exposed' group and three age- and gender-matched subjects (n = 307.026) from the general population comprised the control group. The risk of heart failure was estimated by Cox proportional hazard analyses. RESULTS: The mean follow-up times were 2.8, 5.5 and 4.9 years for alendronate-, etidronate- and raloxifene-treated patients, respectively. The absolute risk of heart failure was 4.4% in the exposed group and 3.7% in the control group (P < 0.01). The relative risk (RR) of heart failure was significantly increased in users of bisphophonates: crude RR 1.71 [95% confidence interval (CI) 1.63-1.79]; adjusted hazard ratio (HR) 1.41 (95% CI 1.34-1.48). By comparison, raloxifene, which is used for the same indication but has a different mechanism of action, was not associated with an increased risk of heart failure: adjusted HR 1.07 (95% CI 0.76-1.50). When the two most commonly used bisphosphonates, alendronate and etidronate, were analysed separately, significant trends in the risk of heart failure were observed across refill compliance strata. The risk of heart failure increased significantly with increasing refill compliance for etidronate (P for trend < 0.01), whereas it decreased for alendronate (P for trend < 0.01). CONCLUSIONS: Bisphosphonate users were at increased risk of heart failure compared to age- and gender-matched control subjects. However, users of alendronate showed a dose-dependent reduction in this risk, suggesting that alendronate may reduce the risk of heart failure.

Platelet function testing and prediction of procedural bleeding risk.

The essential role of platelets in haemostasis underlies the relationship between platelet function and spontaneous or procedure-related bleeding, which has important prognostic implications. Although not routinely undertaken, platelet function testing offers the potential to tailor antiplatelet therapy for individual patients. However, uncertainties remain about how well platelet function testing may predict haemostasis and guide management of bleeding risk. Studies of aspirin, P2Y12 inhibitors and other antiplatelet drugs clearly demonstrate how inhibition of platelet function increases bleeding risk. More potent antiplatelet drugs are associated with higher bleeding rates, consistent with the levels of platelet inhibition achieved by these drugs. Studies of patients treated with clopidogrel, which is associated with wide inter-individual variation in antiplatelet effect, suggest that platelet function testing may predict bleeding risk related to coronary artery bypass grafting (CABG) surgery and potentially guide the timing of surgery following discontinuation of clopidogrel. Similarly, some studies have demonstrated a relationship between clopidogrel response and bleeding in patients undergoing percutaneous coronary intervention (PCI), although other studies have not supported this. Carriage of the *17 allele of cytochrome P450 2C19, which is associated with gain of function and enhanced response to clopidogrel, seems to be associated with increased bleeding risk, although studies showing lack of apparent effect of loss-of-function alleles provide contradictory evidence. Further large studies are needed to guide best practice in the application of platelet function testing in the clinical management of patients treated with antiplatelet drugs in order to optimise individual care.

Prolonged outpatient vitamin K antagonist use and risk of venous thromboembolism in patients undergoing total hip or knee replacement.

BACKGROUND: Long-term risk of venous thromboembolism (VTE) following total hip or knee replacement (THR/TKR) compared with controls has not been studied extensively, and the long-term influence of outpatient anticoagulant use on VTE risk remains unknown. The objectives were to evaluate long-term VTE risk following THR/TKR compared with matched controls, and to investigate effect modification by prolonged outpatient vitamin K antagonist use. METHODS: A Danish retrospective nationwide cohort study was conducted. All patients undergoing primary THR/TKR (n = 95,227) between 1998 and 2007 were selected, each matched by age, sex and region with three controls (no THR/TKR). Patients were stratified by prolonged outpatient vitamin K antagonist use in the previous 3 months (in a time-dependent manner). All subjects were followed for VTE, and Cox models were used to calculate disease and medication history adjusted hazard ratios (HRs). RESULTS: Within 6 weeks following surgery, a 13-fold increased risk of VTE was found for THR (adj. HR 12.9; 95% CI 11.2-14.7), and a 14-fold elevated risk for TKR (adj. HR 13.6; 95% CI 11.0-16.7), compared with matched controls. The risk remained substantially increased for at least 4 months following THR/TKR. Within this period, prolonged outpatient vitamin K antagonist use reduced the increase in VTE risk by 69% for THR and 54% for TKR. CONCLUSION: The risk of VTE remains substantially elevated for at least 4 months following THR/TKR; this is well beyond the recommended duration of anticoagulant use. The increase in VTE risk is less pronounced in prolonged outpatient vitamin K antagonist users.

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.

Clopidogrel and the risk of osteoporotic fractures: a nationwide cohort study.

OBJECTIVES: The P2Y(12) inhibitor clopidogrel inhibits platelet aggregation and is used in the treatment and prevention of coronary artery disease. It is widely used and, in combination with acetylsalicylic acid, is the standard of care for acute coronary syndrome and percutaneous coronary intervention. The mode of action of clopidogrel involves pathways that are important to the metabolic activity in bone cells, although to our knowledge whether P2Y(12) receptors are involved in the regulation of bone metabolism has not yet been investigated. Therefore, the objective of the present study was to investigate the association between clopidogrel use and risk of fractures. METHODS: We investigated the association between clopidogrel use and fracture incidence in a nationwide cohort study within the Danish population of approximately 5.3 million individuals. All patients who were prescribed clopidogrel during the years 1996-2008 were included in the study (n = 77 503), and three nonusers were randomly selected, matched for age and gender (n = 232 510), for each clopidogrel-treated subject. RESULTS: Treatment with clopidogrel was associated with both increased overall fracture risk and increased risk of osteoporotic fractures, especially in subjects with a treatment duration of more than 1 year. However, individuals with low exposure to clopidogrel (<0.01 defined daily dose) had a lower risk of fracture than never users. CONCLUSIONS: Use of the P2Y(12) inhibitor clopidogrel is associated with risk of fractures. There seems to be a biphasic relation so that lower doses are associated with decreased fracture risk, whereas higher doses (recommended dose range) are associated with increased risk. More studies are warranted to determine the potential in vivo effect of platelet aggregation inhibitors on bone metabolism.

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.

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.