Managing Antithrombotic Therapy in Patients With Both Atrial Fibrillation and Coronary Heart Disease

Purpose

Atrial fibrillation (AF) and coronary heart disease (CHD) commonly occur together. Previous consensus guidelines were published before the wide availability of novel oral anticoagulants (NOACs) and newer P2Y₁₂ antiplatelet agents. We examine recent evidence to guide management in 3 categories of patients with AF and CHD: patients with stable CHD, nonstented patients with recent acute coronary syndrome, and patients with a coronary stent requiring dual-antiplatelet therapy.

Methods

We conducted a literature search by evaluation of PubMed and other data sources including international meeting reports. We critically reviewed recent clinical trial and relevant registry evidence to update European and US consensus documents.

Findings

Oral anticoagulation with warfarin or NOACs is required to prevent embolic stroke in AF, and antiplatelet therapy is insufficient for this purpose. Antiplatelet therapy using monotherapy with aspirin is the standard of care in stable CHD. Dual-antiplatelet therapy with aspirin and clopidogrel or a new P2Y₁₂ inhibitor (dual-antiplatelet therapy) is needed to reduce coronary events after an acute coronary syndrome or after percutaneous coronary intervention. Combinations of these agents increase the risk of bleeding, and limited clinical trial evidence suggests that withdrawal of aspirin may reduce bleeding without increasing coronary events.

Implications

Available clinical trials and registries provide remarkably little evidence to guide difficult clinical decision making in patients with combined AF and CHD. In patients on triple antithrombotic therapy with vitamin K antagonists, aspirin, and clopidogrel, a single clinical trial indicates that withdrawal of aspirin may reduce bleeding risk without increasing the risk of coronary thrombosis. It is unclear whether this evidence applies to combinations of NOACs and newer P2Y₁₂ inhibitors. Clinical trials of combinations of the newer antithrombotic agents are urgently needed to guide clinical care.     

Reversibility of platelet P2Y12 inhibition by platelet supplementation: ex vivo and in vitro comparisons of prasugrel,clopidogrel and ticagrelor

Essentials

• Successful outcome of platelet transfusion depends on specific antiplatelet therapy in use.
• We assessed if ticagrelor, clopidogrel or prasugrel impacts on donor platelet activity ex vivo.
• Ticagrelor and/or its active metabolite in plasma or bound to platelets can inhibit donor platelets.
• This might compromise the effectiveness of platelet transfusion therapy.

Summary

Background

Platelet transfusion is the conventional approach to restore platelet function during acute bleeds or surgery, but successful outcome depends on the specific antiplatelet therapy. Notably ticagrelor is associated with inadequate recovery of platelet function after platelet transfusion. We examined whether plasma and/or platelets from ticagrelor‐treated patients influence donor platelet function, in comparison with clopidogrel and prasugrel.

Methods

Platelet transfusion was mimicked ex vivo by mixing naïve donor platelet‐rich plasma (PRP) or gel‐filtered platelets (GFP) in defined proportions with PRP, plasma or GFP from cardiovascular patients receiving standard care including medication with prasugrel, clopidogrel or ticagrelor (n = 20 each). Blood was taken 4 h after the previous dose. HLA2/HLA28 haplotyping let us distinguish net (all platelet) and individual patient/donor platelet reactivity in mixtures of patient/donor platelets, measured by flow cytometry analysis of ADP‐induced fibrinogen binding and CD62P expression.

Results

ADP responsiveness of donor platelets was dramatically reduced by even low (10%) concentrations of PRP or plasma from ticagrelor‐treated patients. Clopidogrel and prasugrel were associated with more modest donor platelet inhibition. GFP from ticagrelor‐treated patients but not patients receiving clopidogrel or prasugrel also suppressed donor GFP function upon mixing, suggesting the transfer of ticagrelor from patient platelets to donor platelets. This transfer did not lead to recovery of ADP responsiveness of patient's platelets.

Conclusion

Collectively, these observations support the concept that ticagrelor and/or its active metabolite in plasma or bound to platelets can inhibit donor platelets, which might compromise the effectiveness of platelet transfusion therapy.

     

Cost-Effectiveness of 12-Month Treatment With Ticagrelor Compared With Clopidogrel in the Management of Acute Coronary Syndromes

Background

The PLATO (Platelet Inhibition and Patient Outcomes) randomized trial (NCT00391872) in patients with acute coronary syndromes (ACS) reported that ticagrelor (in addition to aspirin) reduced the rate of the composite end point of myocardial infarction (MI), stroke, or cardiovascular death compared with clopidogrel (in addition to aspirin) by 16% over 12 months (P < 0.001). No significant difference in the incidence of major bleeding was noted, but ticagrelor was associated with a higher rate of major bleeding not related to coronary artery bypass grafting.

Objective

By extrapolating the key findings of PLATO, we sought to assess the cost-effectiveness of ticagrelor compared with clopidogrel in the management of ACS in a contemporary Australian setting.

Methods

A Markov model with 4 health states (free from further ACS events, MI, stroke, and death) was developed to simulate the long-term costs and outcomes associated with ACS. Event risks were based on data derived directly from PLATO, and costs and utilities were drawn from published sources. A 10-year time horizon was simulated, and future costs and benefits were discounted at a 5% annual rate. However, treatment with ticagrelor and clopidogrel was only assumed for the first 12 months, with no benefits applied beyond drug cessation. Sensitivity analyses were undertaken based on variations to key data inputs. All costs for resource use applied in the analysis were based on published Australian prices (in 2010/2011 dollars [A$]).

Results

Over 10 years, the estimated quality-adjusted life-years lived per-patient were 5.74 and 5.68 for ticagrelor and clopidogrel, respectively. Net costs were A$19,132 for ticagrelor and A$18,428 for clopidogrel. These equated to an incremental cost-effectiveness ratio of A$9031 per quality-adjusted life-year gained for ticagrelor compared with clopidogrel. Sensitivity analyses indicated the result to be robust.

Conclusions

When assessed from the perspective of the Australian health care system, ticagrelor is likely to be cost-effective compared with clopidogrel in preventing downstream morbidity and mortality associated with ACS.     

Randomized Assessment of Ticagrelor Versus Prasugrel Antiplatelet Effects in Patients With Diabetes

OBJECTIVE

It has been postulated that prasugrel might be the preferred treatment option in diabetes mellitus (DM) patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). We aimed to compare the pharmacodynamic action of ticagrelor versus prasugrel.

RESEARCH DESIGN AND METHODS

In a prospective, single-center, single-blind, crossover study, 30 consecutive ACS patients with DM who had been pretreated with clopidogrel were randomized to either 90 mg ticagrelor twice daily or 10 mg prasugrel once daily with a 15-day treatment period. Platelet reactivity (PR) was assessed with the VerifyNow P2Y12 function assay, measured in P2Y12 reaction units (PRU).

RESULTS

PR was significantly lower after ticagrelor (45.2 PRU [95% CI 27.4–63.1]) compared with prasugrel (80.8 PRU [63.0–98.7]), with a least squares mean difference of –35.6 PRU (−55.2 to −15.9, P = 0.001). High PR rate was 0% for ticagrelor and 3.3% for prasugrel (P = 1.0).

CONCLUSIONS

In DM patients with ACS who had been pretreated with clopidogrel and who undergo PCI, ticagrelor achieves a significantly higher platelet inhibition than prasugrel. Both antiplatelet agents effectively treat high PR. The relevance of these findings to the clinical efficacy and safety of ticagrelor and prasugrel in DM patients needs further elucidation.Patients with diabetes mellitus (DM) suffering from acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI) have an increased platelet reactivity (PR) and prothrombotic potential, a lower response to clopidogrel, and a higher risk of cardiovascular complications and recurrent atherothrombotic events than non-DM patients (1–8).Prasugrel and ticagrelor are newer and more potent than clopidogrel antiplatelet agents, which have been introduced recently into our armamentarium while treating ACS patients undergoing PCI (9,10). In the Prasugrel Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS-3) study, in patients with DM and coronary artery disease (CAD), prasugrel provided a higher inhibitory platelet activity than high-dose clopidogrel (11). A prespecified, subgroup analysis of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed that prasugrel significantly reduced the incidence of the composite of cardiovascular death, myocardial infarction, and stroke compared with clopidogrel (12.2 and 17.0%, respectively, HR 0.70; P < 0.001) among DM patients, although without significant DM status-by-treatment interaction (12). Of note, no benefit on mortality was observed with prasugrel over clopidogrel. Furthermore, in the subgroup analyses of the Platelet Inhibition and Patient Outcomes (PLATO) trial, the reduction in the primary composite end point, all-cause mortality, and stent thrombosis with no increase in major bleeding in DM patients by ticagrelor was consistent with the overall cohort (3,13). While interpreting the above subanalyses, it has been proposed that prasugrel may be the preferred treatment option in DM patients (14), although a word of caution has been raised by others for comparison between PLATO and TRITON regarding early ischemic events in such patients (3).There are no direct clinical outcome comparisons of ticagrelor versus prasugrel. In a pharmacodynamic comparison of ticagrelor versus prasugrel in ACS patients undergoing PCI and exhibiting high PR (HPR) while on clopidogrel, ticagrelor reduced PR to a lower level than prasugrel (15). In ST segment elevation myocardial infarction patients undergoing primary PCI, both ticagrelor and prasugrel appeared similarly effective in reducing PR during the first 24 h, with lower PR achieved with ticagrelor than prasugrel at day 5 (16). In the current study, we aimed to compare the pharmacodynamic action of ticagrelor versus prasugrel in DM patients with ACS undergoing PCI who had been pretreated with clopidogrel.     

Platelet indices are novel predictors of hospital mortality in intensive care unit patients

Background and objective

Platelet volume indices (PVIs) are inexpensive and readily available in intensive care units (ICUs). However, their association with mortality has never been investigated in a critical care setting. Our study aimed to investigate the association of PVI and mortality in unselected ICU patients.

Methods

This was a retrospective study conducted in a mixed 24-bed ICU from September 2010 to December 2012. Platelet indices including mean platelet volume (MPV), platelet distribution width (PDW), platelet count, and plateletcrit were measured on ICU entry. Univariable analyses were performed to screen for variables that were associated with mortality. Variables with P < .1 were incorporated into a regression model to adjust for the odds ratio of platelet indices.

Results

A total of 1556 patients were included during the study period, including 1113 survivors and 443 nonsurvivors (mortality rate: 28.47%). Platelet distribution width and MPV were significantly higher in nonsurvivors than in survivors. Platelet distribution width greater than 17% and MPV greater than 11.3 fL were independent risk factors for mortality (adjusted odds ratio: 1.92 and 1.84, respectively) and survival time (hazards ratio: 1.77 and 1.75, respectively).

Conclusion

Higher MPV and PDW are associated with increased risk of death, whereas the decrease in plateletcrit is associated with increased mortality risk.     

Evaluation of Antiplatelet Agents for Secondary Prevention of Stroke Using Mixed Treatment Comparison Meta-analysis

Background

The current guidelines recommend various antiplatelet agents used alone or in combination for secondary prevention of noncardioembolic stroke.

Objective

The purpose of this study was to conduct a mixed treatment comparison meta-analysis to determine which antiplatelet or combination of antiplatelet agents is most efficacious and tolerable in patients with prior stroke.

Methods

A comprehensive literature search was conducted in MEDLINE (1945 through March 2012), EMBASE (1974 through March 2012), and the Cochrane Controlled Trials Registry (1975 through April 2012) to identify randomized trials evaluating the role of various antiplatelet agents and combinations for the secondary prevention of stroke. Key articles were cross-referenced for additional studies. Data were screened and evaluated to generate direct and indirect comparisons for recurrent stroke and overall hemorrhagic events. Data were reported as rate ratios (RRs) and 95% CIs.

Results

A total of 24 articles were included in the analysis. Eleven antiplatelet regimens were compared in >88,000 patients. The combination of acetylsalicylic acid (ASA) plus dipyridamole (DP) was more protective against recurrent stroke than ASA alone (RR = 0.78; 95% CI, 0.64–0.93), and no differences were found in all other direct and indirect comparisons with active treatment. ASA plus DP was associated with more overall hemorrhagic events than DP (RR = 1.83; 95% CI, 1.17–2.81), cilostazol (RR = 2.12; 95% CI, 1.21–3.48), and triflusal (RR = 1.67; 95% CI, 1.05–2.78) but fewer events than the combination of ASA plus clopidogrel (RR = 0.38; 95% CI, 0.25–0.56). The combination of ASA plus clopidogrel was associated with an excess of overall hemorrhagic events compared with clopidogrel (RR = 2.81; 95% CI, 1.96–4.10), cilostazol (RR = 5.56; 95% CI, 3.03–9.66), DP (RR = 4.78; 95% CI, 2.80–8.21), sarpogrelate (RR = 3.59; 95% CI, 1.96–6.45), terutroban (RR = 2.13; 95% CI, 1.21–3.61), ticlopidine (RR = 2.80; 95% CI, 1.69–5.00), and triflusal (RR = 4.36; 95% CI, 2.62–7.81).

Conclusion

We found that ASA plus DP was more protective than ASA alone for preventing recurrent stroke; however, no difference was found between most direct and indirect comparisons of antiplatelet agents and combinations. More overall hemorrhagic events seemed to occur with the combination of ASA and clopidogrel than with other treatments. Selection of antiplatelet therapy for the secondary prevention of stroke must be individualized according to patient comorbidities, including risk of stroke recurrence and bleeding.     

Acute coronary syndrome remodels the antiplatelet aggregation properties of HDL particle subclasses

Essentials

• HDL subclasses were studied in acute coronary syndrome (ACS).
• HDL2 from ACS patients have better antiplatelet potency than HDL from non ACS subjects.
• ACS remodels the antiplatelet properties of HDL subclasses.
• Oxidized polyunsaturated fatty acids content of HDL is modified by ACS.

Summary

Background

Although HDLs have antithrombotic effects by reducing platelet activation, the relationship between HDL levels and the risk of acute coronary syndrome (ACS) is unclear, as HDL particles are heterogeneous in composition and biological properties.

Objective

To characterize the effects of HDL2 and HDL3 subclasses from ACS patients and non‐coronary artery disease (CAD) subjects on platelet activation.

Methods

We measured platelet aggregation and ex vivo thrombus formation, analyzed signaling pathways by flow cytometry, and performed a targeted lipidomics analysis on HDL subclasses.

Results

Analysis of human platelet aggregation in suspension, adhesion on von Willebrand factor and thrombus formation on collagen under arterial shear demonstrated that HDL2 from ACS patients had higher antiplatelet potency than HDL3 from ACS patients and HDL from non‐CAD subjects. HDL binding to scavenger receptor class B type I was essential for this effect. A lipidomics analysis revealed that HDL2 from ACS patients had more oxidized polyunsaturated fatty acids (PUFAs). An inverse correlation between the concentrations of 9‐hydroxyoctadecadienoic acid (9‐HODE), 13‐hydroxyoctadecadienoic acid (13‐HODE), the eicosapentaenoic acid metabolite 18‐hydroxyeicosapentaenoic acid (18‐HEPE) and hydroxyeicosatetraenoic acid isomers in HDL2 and platelet aggregation was observed. This relationship was further demonstrated by the direct inhibitory effects of 18‐HEPE, 9‐HODE, 13‐HODE, 17‐hydroxydocosahexaenoic acid and 14‐hydroxydocosahexaenoic acid on collagen‐related peptide‐induced platelet aggregation, indicating that oxidized PUFAs contribute to the antithrombotic effect of ACS HDL2.

Conclusions

Our data shed new light on the antiplatelet effects of HDL subclasses, and suggest physiological adaptation through the modulation of HDL properties in ACS patients that may limit their platelet‐dependent thrombotic risk.

     

Unmet needs in oral antiplatelet therapy with ADP receptor blocking agents

Antiplatelet agents like aspirin and clopidogrel are treatment cornerstones for acute coronary syndromes (ACS). Drawbacks of dual therapy with these agents include slow onset and offset of effect and wide response variability. Clopidogrel may provide little benefit if administered too close to percutaneous coronary intervention (PCI) and increase major bleeding risk if given too close to coronary artery bypass grafting (CABG) or other surgery. It may not provide sufficient antiplatelet coverage prior to CABG if stopped too long before intervention and leave patients without antiplatelet coverage due to hyporesponsiveness. Prasugrel has made steps towards addressing these limitations by exhibiting more efficient metabolism, more rapid onset of effect, and greater and more consistent platelet inhibition than clopidogrel. The TRITON-TIMI38 trial in ACS patients undergoing PCI showed prasugrel produced greater ischemic event protection than clopidogrel but significantly increased major bleeding risk. AZD6140, the first reversible oral P2Y₁₂ inhibitor, provides more rapid onset of effect and greater and more consistent platelet inhibition than clopidogrel. In DISPERSE2, a phase II trial in ACS patients, AZD6140 did not increase bleeding risk, reduced bleeding risk among CABG patients, and produced numerical reductions in myocardial infarction risk. AZD6140 is being compared with clopidogrel in PLATO, a phase III trial in approximately 18000 ACS patients.     

Prehospital Electrocardiographic Manifestations of Acute Myocardial Ischemia Independently Predict Adverse Hospital Outcomes

Background

Prehospital electrocardiography (PH ECG) is becoming the standard of care for patients activating Emergency Medical Services for symptoms of acute coronary syndrome (ACS). Little is known about the prognostic value of ischemia found on PH ECG.

Objective

The purpose of this study was to determine whether manifestations of acute myocardial ischemia on PH ECG are predictive of adverse hospital outcomes.

Methods

This study was a retrospective analysis of all PH ECGs recorded in 630 patients who called 911 for symptoms of ACS and were enrolled in a prospective clinical trial. ST-segment monitoring software was added to the PH ECG device with automatic storage and transmission of ECGs to the destination Emergency Department. Patient medical records were reviewed for adverse hospital outcomes.

Results

In 630 patients who called 911 for ACS symptoms, 270 (42.9%) had PH ECG evidence of ischemia. Overall, 37% of patients with PH ECG ischemia had adverse hospital outcomes compared with 27% of patients without PH ECG ischemia (p < 0.05). Those with PH ECG ischemia were 1.55 times more likely to have adverse hospital outcomes than those without PH ECG ischemia (95% CI 1.09–2.21; p < 0.05), after controlling for other predictors of adverse hospital outcomes (i.e., age, sex, and medical history).

Conclusions

Evidence of ischemia on PH ECG is an independent predictor of adverse hospital outcomes. ST-segment monitoring in the prehospital setting can identify high-risk patients with symptoms of ACS and provide important prognostic information at presentation to the Emergency Department.     

Dual antiplatelet therapy unmasks distinct platelet reactivity in patients with coronary artery disease

Summary. Background: Platelet‐induced thrombosis is a major risk factor for recurrent ischemic events, although platelet function in patients with cardiovascular disease taking aspirin and clopidogrel is very poorly characterized. The aim of this study was to assess platelet reactivity in patients with cardiovascular disease taking aspirin and clopidogrel. Methods: We developed a rapid assay to measure platelet aggregation in response to arachidonic acid, collagen, adenosine diphosphate (ADP), epinephrine and thrombin receptor activating peptide (TRAP) in 80 healthy volunteers. We then recruited 200 consecutive patients from outpatient clinics and the cardiac catheterization laboratory and tested platelet function. Platelet aggregation induced by epinephrine is a marker of global platelet reactivity. We tested platelet function in 146 patients compliant with antiplatelet therapy. Platelet aggregation to epinephrine was divided into quartiles. The platelet response to the other agonists was analysed based on the response to epinephrine. Results: Platelet reactivity increased significantly across the quartiles in response to epinephrine in healthy volunteers and patients (P < 0.0001). A significant increase in response across quartiles was seen with all agonists in healthy volunteers (P < 0.001). In contrast, a significant increase in response across quartiles was only seen with ADP in patients (P < 0.0001). Hypertension, smoking and diabetes were significantly associated with increasing platelet reactivity to epinephrine (P < 0.05). Conclusion: This study shows that platelet response differs between healthy volunteers and patients on dual antiplatelet therapy. In patients with cardiovascular disease, dual antiplatelet therapy unmasks a distinct type of platelet reactivity in response to epinephrine and ADP but not other agonists.     

Recombinant human thrombopoietin improves platelet counts and reduces platelet transfusion possibility among patients with severe sepsis and thrombocytopenia: A prospective study

Introduction

Thrombocytopenia is prevalent in patients with severe sepsis, and it is associated with mortalities. Effectively adjunctive treatment might be needed to reverse low platelet counts (PCs). With a growing understanding of thrombocytopenia, recombinant human thrombopoietin (rhTPO) is considered a promising beneficial drug. The present study was dedicated to evaluate the efficiency of rhTPO in improving PCs in patients with severe sepsis.

Materials and Methods

We performed a prospective study in patients with severe sepsis between March 2012 and February 2013. All enrolled patients were divided into rhTPO group and control group, depending on whether rhTPO was prescribed or not. Platelet counts and other parameters were measured initially and in the following 15 days.

Results

Totally, 72 patients (38 in the rhTPO group and 34 in the control group) were included. All enrolled parameters exhibited no significant differences between groups at the baseline. Platelet counts showed a significant increase over time in both groups. Faster improvement of PCs in the rhTPO group was observed with a significant difference. Less platelet transfusion occurred in patients who received rhTPO in our study, as well. No drug-related adverse event during the rhTPO therapy was recorded.

Conclusion

The use of rhTPO in combination with conventional medical therapies could significantly improve the PCs in patients with severe sepsis and thrombocytopenia and effectively reduce the platelet transfusion possibility.     

Antiplatelet function variability in clopidogrel-treated patients: need for new antiplatelet agents

Antiplatelet therapy is obligatory in patients with coronary artery disease (CAD) both in acute coronary syndromes (ACS) and in secondary prevention. Aspirin in combination with clopidogrel has been recommended as the main therapeutic regimen for many years. However, the high inter-individual variability of platelet aggregation seen with clopidogrel, caused by the underlying disease (more pronounced in diabetic patients and patients with ACS), drug interactions as well as by genetic variants leading to a reduced formation of the active metabolite of the prodrug clopidogrel, has confronted clinical practice with increasing numbers of adverse clinical events in patients following an ACS. Therefore, new antiplatelet agents have been investigated showing a more favorable efficacy/safety profile. Prasugrel as well as ticagrelor are meanwhile part of the recently published revascularization guidelines of the European Society of Cardiology based on their favorable results with respect to reducing a combined ischemic efficacy endpoint in patients with ACS in the TRITON-TIMI-38 (prasugrel) and PLATO (ticagrelor) trials. Different to clopidogrel, their effects are independent of genetic variants and also drug interactions seem neglectable. This article discusses the reasons for antiplatelet function variability of clopidogrel and presents clinical data of the new ADP-receptor inhibitors by reviewing the recently published trials and prespecified post hoc analyses of these trials as well as the potential use of the new antiplatelet agents in the near future.     

Preoperative platelet transfusions to reverse antiplatelet therapy for urgent non‐cardiac surgery: an observational cohort study

Essentials

• An increasing number of patients requiring surgery receive antiplatelet therapy (APT).
• We analyzed 181 patients receiving presurgery platelet transfusions to reverse APT.
• No coronary thrombosis occurred after platelet transfusion.
• This justifies a prospective trial to test preoperative platelet transfusions to reverse APT.

Summary

Background

Patients receiving antiplatelet therapy (APT) have an increased risk of perioperative bleeding and cardiac adverse events (CAE). Preoperative platelet transfusions may reduce the bleeding risk but may also increase the risk of CAE, particularly coronary thrombosis in patients after recent stent implantation.

Objectives

To analyze the incidence of perioperative CAE and bleeding in patients undergoing non‐cardiac surgery using a standardized management of transfusing two platelet concentrates preoperatively and restart of APT within 24–72 h after surgery.

Methods

A cohort of consecutive patients on APT treated with two platelet concentrates before non‐cardiac surgery between January 2012 and December 2014 was retrospectively identified. Patients were stratified by the risk of major adverse cardiac and cerebrovascular events (MACCE). The primary objective was the incidence of CAE (myocardial infarction, acute heart failure and cardiac troponine T increase). Secondary objectives were incidences of other thromboembolic events, bleedings, transfusions and mortality.

Results

Among 181 patients, 88 received aspirin, 21 clopidogrel and 72 dual APT. MACCE risk was high in 63, moderate in 103 and low in 15 patients; 67 had cardiac stents. Ten patients (5.5%; 95% CI, 3.0–9.9%) developed a CAE (three myocardial infarctions, four cardiac failures and three troponin T increases). None was caused by coronary thrombosis. Surgery‐related bleeding occurred in 22 patients (12.2%; 95% CI, 8.2–17.7%), making 12 re‐interventions necessary (6.6%; 95% CI, 3.8–11.2%).

Conclusion

Preoperative platelet transfusions and early restart of APT allowed urgent surgery and did not cause coronary thromboses, but non‐thrombotic CAEs and re‐bleeding occurred. Randomized trials are warranted to test platelet transfusion against other management strategies.

     

Assessing post-treatment platelet reactivity: a focus on patient selection and setting

Dual antiplatelet therapy is critical to inhibit platelet reactivity in order to prevent ischemic reccurences in stented patients. However, studies have observed a variable blockade of the P2Y12 adenosine diphosphate receptor between patients following clopidogrel intake. This interindividual variability in the biological response is not uncommon with clopidogrel (about 50%) and even prasugrel (20%). High on-treatment platelet reactivity (HTPR) is correlated with thrombotic events following percutaneous coronary intervention. Several studies suggested that tailoring of antiplatelet therapy based on platelet reactivity (PR) monitoring could safely reduce the rate of major adverse cardiovascular events in HTPR patients. In addition, low on-treatment PR was recently associated with bleeding events both in patients treated with prasugrel and clopidogrel. Of importance, bleedings are associated with a poor prognosis in stented patients. Overall, the potential of PR monitoring to individualize antiplatelet therapy might benefit stented patients by reducing both ischemic and bleeding risks. However, such strategies remain to be evaluated in adequately designed large-scale randomized clinical trials.     

Clopidogrel discontinuation and platelet reactivity following coronary stenting

See also Lordkipanidzé M, Harrison P. Beware of being caught on the rebound. This issue, pp 21–3. Summary. Aims: Antiplatelet therapy with aspirin and clopidogrel is recommended for 1 year after drug‐eluting stent (DES) implantation or myocardial infarction. However, the discontinuation of antiplatelet therapy has become an important issue as recent studies have suggested a clustering of ischemic events within 90 days of clopidogrel withdrawal. The objective of this investigation was to explore the hypothesis that there is a transient ‘rebound’ increase in platelet reactivity within 3 months of clopidogrel discontinuation. Methods and Results: In this prospective study, platelet function was assessed in patients taking aspirin and clopidogrel for at least 1 year following DES implantation. Platelet aggregation was measured using a modification of light transmission aggregometry in response to multiple concentrations of adenosine diphosphate (ADP), epinephrine, arachidonic acid, thrombin receptor activating peptide and collagen. Clopidogrel was stopped and platelet function was reassessed 1 week, 1 month and 3 months later. Thirty‐two patients on dual antiplatelet therapy were recruited. Discontinuation of clopidogrel increased platelet aggregation to all agonists, except arachidonic acid. Platelet aggregation in response to ADP (2.5, 5, 10, and 20 μm ) and epinephrine (5 and 20 μm ) was significantly increased at 1 month compared with 3 months following clopidogrel withdrawal. Thus, a transient period of increased platelet reactivity to both ADP and epinephrine was observed 1 month after clopidogrel discontinuation. Conclusions: This study demonstrates a transient increase in platelet reactivity 1 month after clopidogrel withdrawal. This phenomenon may, in part, explain the known clustering of thrombotic events observed after clopidogrel discontinuation. This observation requires confirmation in larger populations.     

急性冠状动脉综合征患者介入术后抗血小板药物抵抗的临床研究

目的 探讨急性冠状动脉综合征(ACS)患者经皮冠状动脉介入术(PCI)后阿司匹林和氯吡格雷抵抗的发生率及相关影响因素;根据血栓弹力图(TEG)结果指导ACS患者抗血小板药物的使用.方法 用TEG方法检测ACS患者服用阿司匹林和氯吡格雷的血小板抑制率.比较性别、年龄、吸烟、家族史、使用质子泵抑制剂(PPI)、高血压病、高脂血症、糖尿病等对PCI术后阿司匹林和氯吡格雷抵抗的影响,以及对阿司匹林和氯吡格雷抵抗的预测意义.结果 67例ACS患者中13例(19.4％)存在阿司匹林反应低下,9例(13.4％)患者存在氯吡格雷反应低下,3例(4.5％)同时存在阿司匹林反应低下和氯吡格雷反应低下.血小板药物反应低下者44.0％(11/25)合并糖尿病,血小板药物反应正常者11.9％(5/42)合并糖尿病,两者比较差异有统计学意义(P＜0.05);血小板药物反应正常者女性比例(60.0％)明显高于血小板药物反应低下者(19.1％),两者比较差异有统计学意义(P＜0.05).随着年龄的增长抗血小板药物的反应性会降低(P＜0.05).而两者在吸烟、家族史、使用PPI、合并高血压病、高脂血症比例等方面比较差异无统计学意义(P＞0.05).二分变量线性回归分析结果表明,PCI术后阿司匹林和氯吡格雷抵抗的影响因素包括性别、年龄、糖尿病.结论 对不同性别、年龄的ACS合并糖尿病的患者采用个性化抗血小板治疗,可以减少临床缺血事件的发生.     

Antiplatelet therapy for secondary prevention of acute coronary syndrome, transient ischemic attack, and noncardioembolic stroke in an era of cost containment

Physicians are aware of the profound impact of oral antiplatelet therapy for secondary prevention of acute coronary syndrome (ACS), transient ischemic attack, and noncardioembolic stroke. Numerous clinical studies have compared the benefits of aspirin (ASA) alone with those of combination therapy with extended-release dipyridamole or with those of clopidogrel, with or without ASA, for secondary stroke prevention; and of ASA monotherapy compared with ASA plus clopidogrel combination therapy for secondary prevention in various ACS populations. More recently, ASA plus prasugrel has been compared with ASA plus clopidogrel in a high-risk ACS population. However, given the different treatment modalities and methods used in the various trials, it is difficult to make generalizations as to which therapy is most effective with the lowest risk of bleeding. Further complicating physician's decision making are cost considerations, particularly with the newer oral antiplatelet agents, which are considerably more expensive than ASA. This review provides a brief overview of the clinical data on each of the currently marketed oral antiplatelet agents and the available data on cost-effectiveness for the secondary prevention of ACS, transient ischemic attack, and noncardioembolic stroke.     

The future of platelet function testing to guide therapy in clopidogrel low and enhanced responders

Dual oral antiplatelet therapy with aspirin and clopidogrel is the therapy of choice in patients with acute coronary syndromes and in patients undergoing coronary stent placement to lower the risk of thrombotic events. Responsiveness to aspirin and especially to clopidogrel is not uniform and is subject to considerable interindividual variability. Furthermore, there is a broad consensus that clopidogrel low response or so-called high on-treatment platelet reactivity is linked to the occurrence of ischemic events. On the other hand, evidence is accumulating that enhanced clopidogrel responders are at increased risk of bleeding. Newer antiplatelet drugs, such as prasugrel and ticagrelor, are more potent and produce more consistent inhibition of platelet aggregation via the P2Y(12) ADP platelet receptor. A variety of methods of platelet function testing are available for evaluating platelet inhibition in percutaneous coronary intervention-treated patients in order to help determine the individual risk for ischemic and bleeding complications. Although not yet routinely undertaken, platelet function testing offers the potential to tailor antiplatelet therapy for individual patients. Whether alteration of therapy based on platelet function testing improves patients' outcomes remains unclear and is currently under investigation. This article reviews the impact of antiplatelet drug responsiveness on clinical outcomes with a focus on P2Y(12) receptor inhibition as well as on current and future concepts for personalized antiplatelet strategies.     

New LDL-Cholesterol Lowering Therapies: Pharmacology,Clinical Trials,and Relevance to Acute Coronary Syndromes

Background

Reduction in plasma low-density lipoprotein cholesterol (LDL-C) is a fundamental treatment for the prevention of acute coronary syndromes (ACS). Although statin therapy confers significant protection against ACS in both primary and secondary prevention, a considerable residual risk remains after intensive therapy. In addition, a significant proportion of high-risk patients do not achieve the optimal LDL-C goal recommended in the current guidelines (<1.8 mmol/L). Hence, novel LDL-C-lowering agents that act via mechanisms distinct from HMG-CoA reductase inhibition are under investigation.

Objective

We reviewed the recent literature on the development of novel LDL-C–lowering agents that could potentially be used as an alternative or adjunct to statin therapy in high-risk coronary patients.

Methods

PubMed and Scopus databases were searched to retrieve studies on the efficacy and/or tolerability of novel LDL-C-lowering agents in animals and humans.

Results

Agents that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein (apo) B, and microsomal triglyceride transfer protein (MTTP) are the most promising therapies. Inhibition of PCSK9, apoB, and MTTP has been achieved mostly via fully humanized monoclonal antibodies (mAbs), antisense oligonucleotides, and synthetic compounds, respectively. PCSK9 inhibitors increase the hepatic uptake of LDL-C, while apoB and MTTP inhibitors decrease the synthesis and secretion of apoB-containing lipoproteins. These 3 mechanisms lead to marked reductions in plasma LDL-C in patients with hypercholesterolemia at risk for ACS, particularly those with familial hypercholesterolemia. Moreover, these agents can exert additional benefits by decreasing plasma levels of apoB, triglycerides, and lipoprotein(a). Mipomersen and lomitapide have been approved by the United States Food and Drug Administration (US FDA) for use in patients with homozygous familial hypercholesterolemia. PCSK9 inhibitors are currently under final evaluation in clinical outcomes studies and are anticipated to find wide application either as monotherapy or as an adjunct to statins. A main safety concern is the risk for hepatic steatosis with apoB and MTTP inhibitors, which needs to be explored in prospective, long-term trials.

Conclusions

PCSK9, apoB, and MTTP inhibitors can exert potent reductions in plasma LDL-C and apoB concentrations, either as monotherapy or in combination with statins. These effects are particularly relevant to high-risk individuals with marked hypercholesterolemia, such as those with familial hypercholesterolemia. Although the use of mipomersen and lomitapide is limited to severe familial hypercholesterolemia as a replacement for LDL-apheresis, PCSK9 inhibitors are likely to be more widely prescribed in patients at high risk for CVD, especially those who are resistant to or intolerant of high-intensity statin therapy. PCSK9 mAbs are efficacious and have an excellent safety profile, but their long-term impact on cardiovascular events is currently under investigation. Whether PCSK9 mAbs decrease the rates of recurrent cardiovascular events within 3 months following ACS is questionable; however, these agents, unlike statins, may not have pleiotropic benefits on the unstable plaque.     

Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest

Background

The platelet inhibitor clopidogrel is administered to patients treated with therapeutic hypothermia following cardiac arrest due to acute coronary syndromes. Interactions with proton pump inhibitors and genetics are factors with a known potential to attenuate the platelet inhibition of clopidogrel. In patients treated with therapeutic hypothermia, reduced gastrointestinal function and hypothermia may also reduce the effect of clopidogrel. To investigate the net platelet inhibition of clopidogrel, we have measured the platelet reactivity index in patients treated with therapeutic hypothermia.

Methods and results

Twenty-five Caucasian patients treated with clopidogrel and therapeutic hypothermia were prospectively included. Therapeutic hypothermia was defined as 33-34 °C and delivered for 24 h. Clopidogrel loading doses (300-600 mg) were administered enterally the day of admission and followed by 75 mg daily. Blood samples were collected on day 1 (n = 25) and day 3 (n = 16). The samples were analysed for inhibition by clopidogrel with a vasodilator stimulated phosphoprotein phosphorylation kit. On day 1 and day 3, platelet reactivity index was 0.77 ± 0.09 and 0.57 ± 0.16, respectively. The number of patients with a satisfactory antiplatelet effect (defined as platelet reactivity index <0.5) were 0 (0%) and 5 (31%), respectively.

Conclusion

In patients treated with therapeutic hypothermia after cardiac arrest, the effect of clopidogrel on platelets was virtually nonexistent on day 1 after administration, with some improvement on day 3.