Steen Husted

Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis.

Background— Aspirin and clopidogrel are recommended for patients with acute coronary syndromes (ACS) or undergoing coronary stenting. Ticagrelor, a reversible oral P2Y12-receptor antagonist, provides faster, greater, and more consistent platelet inhibition than clopidogrel and may be useful for patients with acute ST-segment elevation (STE) ACS and planned primary percutaneous coronary intervention. Methods and Result— Platelet Inhibition and Patient Outcomes (PLATO), a randomized, double-blind trial, compared ticagrelor with clopidogrel for the prevention of vascular events in 18 624 ACS patients. This report concerns the 7544 ACS patients with STE or left bundle-branch block allocated to either ticagrelor 180-mg loading dose followed by 90 mg twice daily or clopidogrel 300-mg loading dose (with provision for 300 mg clopidogrel at percutaneous coronary intervention) followed by 75 mg daily for 6 to 12 months. The reduction of the primary end point (myocardial infarction, stroke, or cardiovascular death) with ticagrelor versus clopidogrel (10.8% versus 9.4%; hazard ratio [HR], 0.87; 95% confidence interval, 0.75 to 1.01; P=0.07) was consistent with the overall PLATO results. There was no interaction between presentation with STE/left bundle-branch block and randomized treatment (interaction P=0.29). Ticagrelor reduced several secondary end points, including myocardial infarction alone (HR, 0.80; P=0.03), total mortality (HR, 0.82; P=0.05), and definite stent thrombosis (HR, 0.66; P=0.03). The risk of stroke, low in both groups, was higher with ticagrelor (1.7% versus 1.0%; HR,1.63; 95% confidence interval, 1.07 to 2.48; P=0.02). Ticagrelor did not affect major bleeding (HR, 0.98; P=0.76). Conclusion— In patients with STE-ACS and planned primary percutaneous coronary intervention, the effects of ticagrelor were consistent with those observed in the overall PLATO trial. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00391872.

Vitamin K antagonists in heart disease: Current status and perspectives (Section III)

Oral anticoagulants are a mainstay of cardiovascular therapy, and for over 60 years vitamin K antagonists (VKAs) were the only available agents for long-term use. VKAs interfere with the cyclic inter-conversion of vitamin K and its 2,3 epoxide, thus inhibiting γ-carboxylation of glutamate residues at the amino-termini of vitamin K-dependent proteins, including the coagulation factors (F) II (prothrombin), VII, IX and X, as well as of the anticoagulant proteins C, S and Z. The overall effect of such interference is a dose-dependent anticoagulant effect, which has been therapeutically exploited in heart disease since the early 1950s. In this position paper, we review the mechanisms of action, pharmacological properties and side effects of VKAs, which are used in the management of cardiovascular diseases, including coronary heart disease (where their use is limited), stroke prevention in atrial fibrillation, heart valves and/or chronic heart failure. Using an evidence-based approach, we describe the results of completed clinical trials, highlight areas of uncertainty, and recommend therapeutic options for specific disorders. Although VKAs are being increasingly replaced in most patients with non-valvular atrial fibrillation by the new oral anticoagulants, which target either thrombin or FXa, the VKAs remain the agents of choice for patients with atrial fibrillation in the setting of rheumatic valvular disease and for those with mechanical heart valves.

Ticagrelor: The First Reversibly Binding Oral P2Y12 Receptor Antagonist

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y12 receptor antagonist that blocks ADP-induced platelet aggregation. Unlike thienopyridines, which irreversibly bind to the P2Y12 receptor for the lifetime of the platelet, ticagrelor binds reversibly to the receptor and exhibits rapid onset and offset of effect, which closely follow drug exposure levels. Animal models indicate greater separation between antithrombotic effects and bleeding effects with ticagrelor than with thienopyridines. Unlike the thienopyridines, ticagrelor does not require metabolic activation. It is quickly absorbed and exhibits a rapid antiplatelet effect, with higher and more consistent levels of inhibition of platelet aggregation (IPA) being maintained across the dosing interval than with clopidogrel. IPA levels decline with plasma drug levels after discontinuation of dosing. In the phase II DISPERSE-2 trial of 990 patients with non-ST-elevation acute coronary syndromes (ACS), ticagrelor treatment with 90 mg and 180 mg twice daily showed comparable rates of major and minor bleeding compared with clopidogrel 75 mg while there were numerically fewer myocardial infarctions. Ticagrelor resulted in greater IPA in clopidogrel-naïve patients and produced substantial additional reductions in platelet aggregation activity in patients pretreated with clopidogrel. Ticagrelor treatment was well tolerated in DISPERSE-2, and discontinuation rates were comparable to those observed for clopidogrel. An increased risk of mild to moderate dyspnea and mostly asymptomatic ventricular pauses were observed in phase II studies. The mechanisms for these effects are currently being investigated. The efficacy and safety of ticagrelor are being further evaluated in the phase III PLATO trial, involving approximately 18,000 patients with ACS, including both ST-elevation and non-ST-elevation ACS.

Antiplatelet agents for the treatment and prevention of atherothrombosis

The clinical pharmacology of antiplatelet drugs has been reviewed previously by the European Society of Cardiology (ESC) Task force and by the 8th American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines. Moreover, information on the efficacy and safety of antiplatelet drugs in the treatment and prevention of atherothrombosis is provided by collaborative meta-analyses of 287 secondary prevention trials and 6 primary prevention trials. The present document intends to provide practicing physicians with an updated instrument to guide their choice of the most suitable antiplatelet strategy for the individual patient at risk, or with different clinical manifestations, of atherothrombosis.

Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention

Optimizing outcomes after percutaneous coronary intervention (PCI) requires balancing between the risks of thrombotic and bleeding events in individual patients.1–3 However, finding the optimal balance is not always straightforward since the risks of thrombotic and bleeding complications may differ extremely between individuals. In addition, the individual effects of anticoagulant and antiplatelet drugs are not uniform in patients.4 Recent European guidelines1,3 recommend the use of prasugrel or ticagrelor instead of clopidogrel in all PCI-treated acute coronary syndrome (ACS) patients without contraindication, acknowledging that laboratory assessment of P2Y12-receptor inhibition may be considered only in selected cases when clopidogrel is used.1 However, there is no guidance with respect to the appropriate methodology and the suggested interpretation of results. The Working Group on Thrombosis of the European Society of Cardiology aimed to review the available evidence and the clinical relevance of platelet function testing in order to reach a consensus regarding the methodology, evaluation, and clinical interpretation of platelet function in patients undergoing PCI. Regarding the choice between available P2Y12-inhibitors, the 2011 ESC guidelines on non-ST segment elevation acute coronary syndromes (NSTE-ACS)1 and the 2012 guidelines on ST-segment elevation myocardial infarction3 recommend prasugrel and ticagrelor for all ACS patients without contraindication, and clopidogrel is only recommended if these agents are not available. Despite the restrictive recommendations for clopidogrel, it still holds a class I indication in ACS due to the large differences in the availability of the new-generation P2Y12-inhibitors among European countries. According to the 2011 ACCF/AHA/SCAI guidelines for PCI,5 a P2Y12-inhibitor should be given for ACS patients without preferring novel P2Y12-inhibitors over clopidogrel. Similarly, the 2012 ACCF/AHA unstable angina/non-ST-segment elevation myocardial infarction guidelines6 and the 2013 ACCF/AHA ST-elevation myocardial infarction guidelines …

Ticagrelor Versus Clopidogrel in Elderly Patients With Acute Coronary Syndromes A Substudy From the Prospective Randomized PLATelet Inhibition and Patient Outcomes (PLATO) Trial

Background—Elderly patients with acute coronary syndrome are at high risk of recurrent ischemic events and death, and for both antithrombotic therapy and catheter-based complications. This prespecified analysis investigates the effect and treatment-related complications of ticagrelor versus clopidogrel in elderly patients (≥75 years of age) with acute coronary syndrome compared with those <75 years of age. Methods and Results—The association between age and the primary composite outcome, as well as major bleeding were evaluated in the PLATelet inhibition and patient Outcomes (PLATO) trial using Cox proportional hazards. Similar models were used to evaluate the interaction of age with treatment effects. Hazard ratios were adjusted for baseline characteristics. The clinical benefit of ticagrelor over clopidogrel was not significantly different between patients aged ≥75 years of age (n=2878) and those <75 years of age (n=15 744) with respect to the composite of cardiovascular death, myocardial infarction, or stroke (interaction P=0.56), myocardial infarction (P=0.33), cardiovascular death (P=0.47), definite stent thrombosis (P=0.81), or all-cause mortality (P=0.76). No increase in PLATO-defined overall major bleeding with ticagrelor versus clopidogrel was observed in patients aged ≥75 years (hazard ratio, 1.02; 95% confidence interval, 0.82–1.27) or patients aged <75 years (hazard ratio, 1.04; 95% confidence interval, 0.94–1.15). Dyspnea and ventricular pauses were more common during ticagrelor than clopidogrel treatment, with no evidence of an age-by-treatment interaction. Conclusions—The significant clinical benefit and overall safety of ticagrelor compared with clopidogrel in acute coronary syndrome patients in the PLATO cohort were not found to depend on age. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

FRISC score for selection of patients for an early invasive treatment strategy in unstable coronary artery disease

Objective: To develop a scoring system for risk stratification and evaluation of the effect of an early invasive strategy for treatment of unstable coronary artery disease (CAD). Design: Retrospective analysis of a randomised study (FRISC II; fast revascularisation in instability in coronary disease). Setting: 58 Scandinavian hospitals. Patients: 2457 patients with unstable CAD from the FRISC II study. Main outcome measures: One year rates of mortality and death/myocardial infarction (MI). Methods: Patients were randomly assigned to an early invasive or a non-invasive strategy. From the non-invasive cohort independent variables of death or death/MI were identified. Results: Seven factors, age > 70 years, male sex, diabetes, previous MI, ST depression, and increased concentrations of troponins and markers of inflammation (interleukin 6 or C reactive protein), were associated with an independent increased risk for death or death/MI. In patients with ⩾ 5 of these factors the invasive strategy reduced mortality from 15.4% (20 of 130) to 5.2% (7 of 134) (risk ratio (RR) 0.34, 95% confidence interval (CI) 0.15 to 0.78, p  =  0.006). Death/MI was also reduced in patients with 3–4 factors from 15.7% (80 of 511) to 10.8% (58 of 538) (RR 0.69, 95% CI 0.50 to 0.94, p  =  0.02). Neither death nor death/MI was reduced in patients with 0–2 risk factors. Conclusion: In unstable CAD, this scoring system based on factors independently associated with an adverse outcome can be used shortly after admission to the hospital for risk stratification and for selection of patients to an early invasive treatment strategy.

Silent pulmonary embolism in patients with deep venous thrombosis. Incidence and fate in a randomized, controlled trial of anticoagulation versus no anticoagulation

Abstract. Objectives. A high frequency of asymptomatic pulmonary embolism (PE) in patients with deep venous thrombosis (DVT) has been reported, but information about the outcome of the patients with PE remains sparse. The aims of the present study were to assess the prevalence of silent PE in patients with symptomatic, venographically proven DVT, and to evaluate the natural history of silent PE.

Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy

The ESC NSTEMI and STEMI guidelines1,2 and an ACCF/ACG/AHA consensus document3 recommend treatment with proton pump inhibitors (PPIs) in patients treated with dual antiplatelet treatment (DAPT) during the initial phase of an acute coronary syndrome (ACS) (ESC Class 1A recommendation), particularly in patients with a history of GI bleeding or peptic ulcer. Several studies have raised concerns that many PPIs, especially omeprazole, might diminish the antiplatelet effects of clopidogrel, most likely through inhibition of CYP2C19 and, consequently, the conversion of clopidogrel into its active metabolite.4,5 The aim of this position paper is to review the pharmacokinetic background of the interactions between these drugs, and their consequences on clinical outcomes, and to present suggestions for management of this important issue. Several agents widely used in patients on acetylsalicylic acid (ASA) may interact with the antiplatelet effects of ASA, but none through the CYP2C9 pathway by which ASA is metabolized. Recently, it has been reported that concomitant use of PPIs reduces the protective efficacy of ASA in patients with ischaemic heart disease.6,7 A case–control study investigated the antiplatelet effect of ASA in 418 ASA-treated CVD patients, 54 of whom were also treated with PPIs.7 Patients receiving PPIs had reduced antiplatelet effect of ASA, as shown by greater residual platelet aggregation responses. However, interaction between PPI and ASA is controversial.8 Potential clinical implications of these findings were explored by a registry study in a large population of ASA-treated patients with first time myocardial infarction.6 Even after adjusting for baseline variables with multivariate analysis and propensity score matching, PPI use was still significantly associated with ∼50% more ischaemic cardiovascular events. A sensitivity analysis showed no increase in risk related to the use of H2 receptor blockers.6 Suggested explanations for the …

Incident stroke after discharge from the hospital with a diagnosis of atrial fibrillation

PURPOSE Atrial fibrillation is an important risk factor for stroke. We analyzed stroke risk over time in patients discharged from the hospital with a diagnosis of incident atrial fibrillation as compared with the risk of stroke in the Danish population. SUBJECTS AND METHODS In a random sample of half of the Danish population, we identified 13,625 men and 13,577 women, aged 50 to 89 years, with a hospital diagnosis of atrial fibrillation and no prior diagnosis of stroke during 1980 to 1993. Data on other medical conditions were also available from 1977 to 1993, but medication data were not available. Patients were followed from the diagnosis of atrial fibrillation until the first diagnosis of stroke (nonfatal or fatal cerebral ischemic infarct and cerebral hemorrhage), death, or the end of 1993. The risk of stroke in these patients was compared with the risk in the Danish population using Poisson regression modeling to estimate relative risks (RR) and 95% confidence intervals (CI). RESULTS For men with atrial fibrillation, the stroke rates increased by age, from 13 per 1,000 person-years in those ages 50 to 59 years, to 22 per 1,000 person-years in those ages 60 to 69 years, to 42 per 1,000 person-years in those ages 70 to 79 years, to 51 per 1,000 person-years in those ages 80 to 89 years. Age-specific stroke rates were similar in women with atrial fibrillation. Patients with a hospital diagnosis of atrial fibrillation had an increased risk of stroke (RR = 2.4; 95% CI, 2.3 to 2.5 in men and RR = 3.0; 95% CI, 2.9 to 3.2 in women) compared with the Danish population. Stroke risk was greatest during the first year after discharge and decreased thereafter. Hypertension, diabetes, and peripheral atherosclerosis were also associated with an increased risk of stroke among patients with atrial fibrillation. Ischemic heart disease and heart failure were risk factors in men only. There was no reduction in the risk of stroke from 1980 to 1993. CONCLUSIONS Men and women with atrial fibrillation are at a substantially increased risk of stroke, particularly in the first year after the diagnosis.