Secondary Prevention Of Atherothrombotic Events Research Articles

Impact of CYP2C19 genotype status on clinical outcomes in patients with symptomatic coronary artery disease, stroke, and peripheral arterial disease

Abstract Background Coronary artery disease (CAD), stroke, and peripheral arterial disease (PAD) are clinical manifestations of atherosclerosis. Clopidogrel is widely used for the secondary prevention of atherothrombotic events in these patients. CYP2C19 plays a pivotal role in the conversion of clopidogrel to its active metabolite. Clopidogrel-treated carriers of a CYP2C19 loss-of-function allele (LOF) may have a higher risk of new atherothrombotic events. Previous studies on genotype-guided treatment were mainly performed in CAD and showed mixed results. Purpose To simultaneously investigate the impact of CYP2C19 genotype status on the rate of atherothrombotic events in the most common types of atherosclerotic disease (CAD, stroke, PAD). Methods A comprehensive search in Pubmed, EMBASE and MEDLINE from their inception to April 8th 2022 was performed. For CAD, randomized controlled trials (RCTs) comparing genotype-guided and standard antithrombotic treatment were included. For stroke and PAD, cohort studies and post-hoc analyses of RCTs concerning the association between CYP2C19 genotype status and clinical outcomes in clopidogrel-treated patients were included. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the safety end point major bleeding. Secondary endpoints were myocardial infarction, stent thrombosis, and ischemic stroke. Results Forty-two studies were identified: 11 studies on CAD, 27 studies on stroke, and 4 studies on PAD. In CAD, genotype-guided therapy significantly reduced the risk of MACE (RR 0.60, 95% CI 0.43 – 0.83), myocardial infarction (RR 0.53, 95% CI 0.42 – 0.68), and stent thrombosis (RR 0.64, 95% CI 0.43 – 0.94) compared to standard antithrombotic treatment. The rate of major bleeding did not differ significantly (RR 0.93, 95% CI 0.70 – 1.23). Most RCTs were performed in patients after percutaneous coronary intervention (9/11). In stroke, LOF carriers had a significantly higher risk of MACE (RR 1.62, 95% CI 1.24 – 2.11) and recurrent ischemic stroke (RR 2.00, 95% CI 1.49 – 2.67) compared to non-carriers. No significant differences were found in major bleeding (RR 0.90, 95% CI 0.43 – 1.89). In the 6955 patients with symptomatic PAD treated with clopidogrel in the EUCLID trial, no differences in MACE or major bleeding were found between LOF carriers and non-carriers. In three smaller studies on patients with PAD treated with clopidogrel after endovascular therapy, CYP2C19 genotype status was significantly associated with atherothrombotic events. Conclusion The available evidence in PAD is too limited to draw meaningful conclusions. In stroke patients, LOF carriers treated with clopidogrel had a higher risk of MACE and recurrent stroke. Genotype-guided treatment significantly decreased the rate of atherothrombotic events in patients with CAD, especially after PCI.

Development of a Novel Apigenin Dosage form as a Substitute for the Modern Triple Antithrombotic Regimen

The simultaneous administration of three antiplatelet agents has been proposed as an efficient strategy for the secondary prevention of atherothrombotic events and is included in the European guidelines. However, this strategy presented an increased risk of bleeding; therefore, the identification of new antiplatelet agents, with improved efficacy and diminished side effects, is of great importance. In silico studies, UPLC/MS Q-TOF plasma stability, in vitro platelet aggregation experiments, and pharmacokinetic studies were exploited. In the present study, it has been predicted that the flavonoid apigenin could target different platelet activation pathways, including P2Y12, protease-activated receptor-1 (PAR-1), and cyclooxygenase 1 (COX-1). To enhance apigenin's potency, hybridization with docosahexaenoic acid (DHA) was performed, as fatty acids have illustrated potent efficacy against cardiovascular diseases (CVDs). The new molecular hybrid, termed 4'-DHA-apigenin, demonstrated enhanced inhibitory activity against platelet aggregation induced by thrombin receptor activator peptide-6 (TRAP-6), adenosine diphosphate (ADP), and arachidonic acid (AA), with respect to the parent apigenin. The 4'-DHA-apigenin hybrid illustrated an almost 2-fold enhanced inhibitory activity, with respect to apigenin, and an almost 3-fold enhanced inhibitory activity, with respect to DHA, for the ADP-induced platelet aggregation. Additionally, the hybrid presented a more than 12-fold enhanced inhibitory activity with respect to DHA for the TRAP-6 induced platelet aggregation. Furthermore, a 2-fold enhanced inhibitory activity was recorded for the 4'-DHA-apigenin hybrid for the AA-induced platelet aggregation with respect to apigenin. To surmount the reduced LC-MS based plasma stability, a novel dosage form in olive oil has been developed. The 4'-DHA-apigenin olive oil-based formulation presented an enhanced antiplatelet inhibitory effect in three activation pathways. To further explore the pharmacokinetic profile of 4'-DHA-apigenin in olive oil formulations, a UPLC/MS Q-TOF protocol has been established to quantify the serum levels of apigenin after oral administration to C57BL/6J wild type mice. The olive oil-based formulation of 4'-DHA-apigenin demonstrated an increase in apigenin bioavailability of 262 %. This study may offer a new therapeutic strategy tailored to improve the treatment of CVDs.

Characterization of the acetylation of cyclooxygenase-isozymes and targeted lipidomics of eicosanoids in serum and colon cancer cells by the new aspirin formulation IP1867B versus aspirin in vitro.

Background: Aspirin(acetylsalicylic acid, ASA) is recommended for the secondary prevention of atherothrombotic events and has shown anticancer effects. The current enteric-coated drug formulation may reduce aspirin bioavailability. Liquid formulations could improve aspirin pharmacokinetics and pharmacodynamics. IP1867B is a liquid-aspirin formulation that combines three ingredients, ASA/triacetin/saccharin. Methods: ASA and IP1867B(L-ASA) were assessed in human serum(obtained by allowing to clot human whole blood at 37 °C for 1h), washed platelets, and colonic adenocarcinoma HCA7 cells on eicosanoid generation and COX-isozyme acetylation at Serine529 and 516 by LC-MS/MS. Results: In serum, ASA and L-ASA acted by selectively affecting COX-1-derived eicosanoids, including thromboxane(TX)B2. L-ASA was more potent in inhibiting serum TXB2, a known biomarker of aspirin antiplatelet effect, than ASA. However, ASA and L-ASA were equipotent to acetylate COX-1 in washed platelets and COX-2 in HCA7 cells. In HCA7 cells, ASA and L-ASA acted by inhibiting prostaglandin(PG)E2(the most abundant prostanoid) and TXB2 biosynthesis. In the presence of a high arachidonic acid concentration(100μM), 15R-hydroxyeicosatetraenoic acid(HETE) was generated at baseline by cancer cell COX-2 and was only slightly enhanced by supratherapeutic concentrations of ASA(1mM). In whole blood and HCA7 cells treated with ASA or L-ASA, 15-epi-lipoxin(LX)A4 were undetectable. Conclusion: IP1867B was more potent in affecting serum TXB2 generation than ASA. The relevance of this finding deserves evaluation in vivo in humans. In cancer cells, ASA and IP1867B acted by inhibiting PGE2 and TXB2 generation via the acetylation of COX-2. ASA and IP867B at clinically relevant concentrations did not substantially induce the biosynthesis of 15R-HETE and 15-epi-LXA4.

Long-term dual antiplatelet therapy and nuisance bleeding: impact on quality of life.

Long term dual antiplatelet therapy (LTDAPT), with ticagrelor 60 mg and low-dose aspirin, is indicated after acute coronary syndrome (ACS) for the secondary prevention of atherothrombotic events in high-risk patients with a history of ACS of at least 1 year. LTDAPT had a good tolerability and safety profile, but the risk of TIMI major bleeding was increased. However, even non-significant bleeding may be important because it has an effect on the quality of life and therefore may lead to treatment discontinuation. We, therefore, evaluated patients' experiences with LTDAPT and the impact of nuisance bleeding on quality of life and treatment adherence. We retrospectively reviewed 225 patients in follow-up after ACS with at least one high-risk condition, treated with ticagrelor 60 mg twice daily (after 90 mg twice daily for 12 months). The outpatient follow-up program after hospitalization provides a visit on day 30 after discharge, then after 3 months, continuing with six-monthly checks. We assessed the presence and intensity of bleeding, as well as health-related quality of life (HRQoL), at each visit. The TIMI score was used to determine the severity of the bleeding. Any overt bleeding event that did not meet the major and minor criteria was labeled "minimal" and could be framed as "nuisance bleeding." The HRQoL was assessed by the EuroQol-5 and Dimension (EQ-5D) visual analog scale (VAS) score. Minimal bleedings were present in 49 patients (21%), but only in one case (by decision of the patient) there was a cause for discontinuation of therapy. However, 39 (79%) subjects had asked for opinions on stopping the therapy during the telephone consultation. Factors influencing LTDAPT knowledge included access to medication counselling, engaging with information communicated during medication counselling, and access to timely, relevant and expert information and advice after discharge from the hospital. All adverse events, judged to be "not serious" in trials, may have an effect on the quality of life and therefore may lead to treatment discontinuation. The authors underline the importance of careful outpatient follow-up and ongoing counselling, to check out compliance and possible adverse effect of LTDAPT.

Abstract 13362: Increased Bleeding and Poor Outcomes in Patients Who Require Cardiac Procedures While Receiving P2Y12 Inhibitors

Introduction: P2Y12 inhibitors (P2Y12i) reduce thrombotic risk in patients with acute coronary syndrome and in secondary prevention of atherothrombotic events, but dual antiplatelet therapy with a P2Y12i + aspirin increases bleeding risk. P2Y12i washout is recommended prior to procedures, but when procedures cannot be deferred, washout is precluded, thereby increasing periprocedural bleeding risk, with potential negative outcomes. Hypothesis: P2Y12i are associated with increased bleeding risk and poorer clinical and economic outcomes in invasive cardiovascular (CV) procedures. Methods: In a retrospective study of hospital chargemaster data (2017-2019), patients receiving P2Y12i (cangrelor, clopidogrel, prasugrel, ticagrelor, or ticlopidine) or aspirin without P2Y12i (control) prior to an invasive CV procedure were identified from hospital charge and ICD-10 codes. Inpatient bleeding, mortality, length of stay (LOS; days), and intensive care unit (ICU) LOS (days) were assessed. Results: Among 2,996,051 patients with invasive CT procedures, P2Y12i-treated patients had significantly higher bleeding rates versus control patients (4.2% vs 3.1% p<0.05). Coronary artery bypass graft (CABG) procedures were the most common. Heart valve procedures showed the highest bleeding rates. Both CABG and valve procedures showed significant increases in bleeding for patients with P2Y12i versus control patients (CABG 9.2% vs 5.7%; valve 17.2% vs 8.9%; both p<0.05). P2Y12i-treated patients with bleeding versus those without bleeding had significant increases in in-hospital mortality (CABG 5.0% vs 2.1%; valve 12.4% vs 4.8%), LOS (CABG 11.7 vs 10.7; valve 13.0 vs 11.6), and ICU LOS (CABG 8.4 vs 5.5; valve 11.2 vs 8.3) (all p<0.05). Similar findings were observed for other procedures. Conclusions: Invasive CV procedures in patients receiving P2Y12i were associated with increased bleeding rates. Patients with increased bleeding had poorer outcomes, including increased in-hospital mortality. Bleeding avoidance in P2Y12i-treated patients requires an adequate discontinuation period prior to invasive procedures. Delaying CV procedures, however, may result in suboptimal outcomes, highlighting the unmet need for a rapid reversal strategy for P2Y12i.

P99 LONG TERM DUAL ANTIPLATELET THERAPY AFTER MYOCARDIAL INFARCTION IN CLINICAL PRACTICE: IMPACT OF NUISANCE BLEEDING ON MEDICATION ADHERENCE

Abstract Background Long term dual antiplatelet therapy (LTDAPT) with ticagrelor 60 mg and low–dose aspirin are indicated after acute coronary syndrome (ACS) for the secondary prevention of atherothrombotic events in high–risk patients with a history of ACS of at least 1 year. LTDAPT had a well tolerability and safety profile, but the risk of TIMI major bleeding was increased. However even non significant bleeding may be important because have an effect on quality of life and therefore may lead to treatment discontinuation. Objective To understand the experiences of patients with LTDAPT and nuisance bleeding, and their impact on medication adherence. Methods We retrospectively reviewed 225 patients in follow up after ACS with at least one high risk condition (Fig. 1), treated with ticagrelor 60 mg twice daily (after 90 mg twice daily for 12 months). The outpatient follow–up program after hospitalization provides a visits at day 30 after discharge and subsequently after 3 months, then continuing with six–monthly checks. The intensity of bleeding was assessed according to the TIMI score. Any overt bleeding event that did not meet the criteria of major and minor was defined “minimal”. Results they are shown in Fig. 2. Minmal bleedings were present in 49 patients (21%), but were not a cause for discontinuation of therapy. However 39 (79%) subjects had asked opinion on stop the therapy at the telephone consultation. We found that: (1) participants adhered to treatment when they believed long term DAPT was important to health outcomes; (2) those who experienced nuisance bleeding reported symptoms to be mild and manageable; (3) participants’ and their family’s understanding of LTDAPT risks and benefits, and their ability to manage symptoms, influenced medication adherence. Factors influencing long term DAPT knowledge included access to medication counselling, engaging with information communicated during medication counselling, and access to timely, relevant and expert information and advice after discharge from hospital. Conclusions All adverse events judged to be “not serious” in trials may have an effect on quality of life and therefore may lead to treatment discontinuation. The need to educate the patient in order to improve adherence should therefore be emphasized. The authors underline the importance of careful outpatient follow–up and constant counselling in order to check out compliance and possible adverse effect of long term DAPT risks treatment.

95 Long-term dual antiplatelet therapy after myocardial infarction in clinical practice: impact of nuisance bleeding on medication adherence

Abstract Aims Long-term treatment with ticagrelor 60 mg and low-dose aspirin are indicated after acute coronary syndrome (ACS) for the secondary prevention of atherothrombotic events in high-risk patients with a history of myocardial infarction of at least 1 year. Long-term dual antiplatelet therapy (DAPT) had a well tolerability and safety profile, but the risk of TIMI major bleeding was significantly increased. However even nonsignificant bleeding may be important because have an effect on quality of life and therefore may lead to treatment discontinuation. To understand the experiences of patients with long-term DAPT with ticagrelor 60 mg and low-dose aspirin and nuisance bleeding, and their impact of nuisance bleeding on medication adherence. Methods and results We retrospectively reviewed aggregate data of 187 patients (155 M e 38 F) (mean age 63.8 ± 9 years) in follow-up after ACS with at least one high risk condition (multivessel disease, diabetes, GFR < 60 mL/min, history of prior myocardial infarction, age > 65 years) treated with ticagrelor 60 mg twice daily (after 90 mg twice daily for 12 months). The high risk groups were represented as follows: multivessel disease 105 pts (82%), diabetes 63 pts (33%), GFR< 60 mL/min 27 pts (14%), history of prior MI 33 pts (17%), and >65 year aged 85 pts (45%). The outpatient follow-up programme after hospitalization provides visits at day 30 after discharge and subsequently after 3 months, then continuing with 6-monthly checks. The intensity of bleeding was assessed according to the TIMI score.1 Any overt bleeding event that did not meet the criteria of major and minor was defined ‘minimal’. Treatment was withdrawn in seven patients: three cases showed atrial fibrillation and were placed on oral anticoagulant drugs, one developed intracranial bleeding. In three patients, a temporary withdrawal was due to surgery (one colon polyposis and two cases of bladder papilloma). Minimal bleedings (nasal, gingival, conjunctival, subcutaneous/dermal, rectal and urinary) were present in 31 patients, but were not a cause for discontinuation of therapy. However, 22 (70%) subjects had asked opinion on stop the therapy at the telephone consultation. We found that: (i) participants adhered to treatment when they believed long-term DAPT was important to health outcomes; (ii) those who experienced nuisance bleeding reported symptoms to be mild and manageable; (iii) participants’ and their family’s understanding of long-term DAPT risks and benefits, and their ability to manage symptoms, influenced medication adherence. Factors influencing long-term DAPT knowledge included access to medication counselling, engaging with information communicated during medication counselling, and access to timely, relevant and expert information and advice after discharge from hospital. Conclusions All adverse events judged to be ‘not serious’ in trials may have an effect on quality of life and therefore may lead to treatment discontinuation. The need to educate the patient in order to improve adherence should therefore be emphasized. The authors underline the importance of careful outpatient follow-up and constant counselling in order to check out compliance and possible adverse effect of long term DAPT risks treatment.

Medical Therapy for Secondary Prevention of Atherothrombotic Events in Peripheral Artery Disease

Patients with peripheral artery disease (PAD) are at risk for severe morbidity and mortality, including ischaemic-related events. Furthermore, there is heterogeneity within the PAD population, where the drivers of risk for cardiovascular and limb-specific ischaemic events differ. Patients with PAD with concomitant coronary artery disease are at increased risk for cardiovascular ischaemic events, whereas patients with PAD with a prior history of lower-extremity revascularization are at increased risk for limb-specific ischaemic events. The current therapeutic challenge is identifying these risk factors to tailor therapy optimally for each patient. Additionally, the majority of our current medical therapeutics in patients with PAD have been shown to reduce atherothrombotic events, such as myocardial infarction, stroke and cardiovascular death, with a paucity of medical therapeutics specifically targeting a reduction in limb-specific ischaemic events. Over the past several years, there have been several contemporary clinical trials evaluating antithrombotic agents and their efficacy in reducing limb-specific ischaemic events. Specifically, rivaroxaban, with the addition of aspirin, has emerged as an efficacious therapeutic. In this article, we provide a review of the current clinical burden of PAD, the rationale behind current PAD medical therapeutics and the contemporary trials that have described the benefit of a novel therapeutic in PAD, rivaroxaban.

Cost-effective analysis of clopidogrel versus aspirin for high risk patients with established peripheral arterial disease in China

Objective: To assess the cost-effectiveness of clopidogrel versus aspirin for high risk patients (pre-existing symptomatic atherosclerosis or multi-vascular territory involvement) with established peripheral arterial disease (PAD) for secondary prevention of atherothrombotic events in a Chinese setting.Methods: A Markov model with a lifetime horizon was developed from the perspective of the national healthcare system in China. The primary outputs are quality adjusted life years (QALYs), direct medical costs, and the incremental cost-effectiveness ratios (ICERs). Clinical efficacy data were obtained from the CAPRIE trial. Drug acquisition cost, other direct medical costs, and utilities were from pricing records and the literature. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) were conducted to test the robustness of the model on all parameters.Results: In patients with pre-existing atherosclerosis, 2 years of treatment with clopidogrel and aspirin would yield total QALYs of 8.776 and 8.576 at associated costs of ¥18,777 ($2,838) and ¥12,302 ($1,859), respectively, resulting in an ICER of ¥32,382 ($4,893) per QALY gained. In patients with PVD, secondary prevention with the same drugs would expect to lead to total QALYs of 8.836 and 8.632 at associated costs of ¥18,518 ($2,798) and ¥12,041 ($1,820), respectively, resulting in a corresponding ICER of ¥31,743 ($4,797) per QALY gained. The results were most sensitive to the discount rate for future outcomes and costs. The PSA indicated that the probability of clopidogrel being cost-effective was 100% at the willingness-to-pay threshold of 3-times GDP.Conclusions: Secondary prevention with clopidogrel is an attractive cost-effective option compared with aspirin for high risk patients with established PAD from the perspective of the national healthcare system in Chinese settings.

ACETYLSALICYLIC ACID RESISTANCE: RISK FACTORS, MECHANISMS, DIAGNOSTIC TESTS

Acetylsalicylic acid (aspirin) is one the most widespread drugs in the world. It is used for secondary prevention of atherothrombotic events in patients with cardiovascular disease. Accordingly, the problem of the effectiveness of aspirin treatment is among the crucial issues of cardiology. The issue of personalization of antiplatelet therapy remains relevant, since there is no convincing evidence in favor of using aspirin for primary prevention in the general population. In this review, recent data on aspirin resistance are considered. Potential mechanisms of non-responsiveness to aspirin, the role of genetic factors, standardization of tests and diagnostic criteria for aspirin resistance, and the treatment options are discussed. The data on the clinical and prognostic value of 11-dehydrothromboxane B2 as a promising marker of thromboxane-dependent platelet activation are analyzed.

ASSOCIATION BETWEEN SMOKING AND THE ANTIPLATELET EFFECT OF CLOPIDOGREL

Clopidogrel is the most widely used P2Y12 inhibitor, which is administered for secondary prevention of atherothrombotic events in patients with cardiovascular disease after myocardial infarction and coronary stenting. Given the complexity of the clopidogrel metabolism and variety of potential drug-drug interactions, the issue of individual variability of its antiplatelet effects is of paramount concern. Another issue of clinical relevance is related to so-called “smoker’s paradox”. This phenomenon implies that in some patients smoking is associated with increased antiplatelet potency of clopidogrel. In this review, we analyze recent international data on the features of pharmacokinetics and pharmacodynamics of clopidogrel, plausible mechanisms of the “smoker’s paradox” and its clinical significance in patients with coronary artery disease. Comparative efficacy of available P2Y12 inhibitors and possible implications of smoking are considered. Pharmacogenetic aspects and the issues of personalized antiplatelet therapy are discussed.

Oral antiplatelet agents in cardiovascular disease.

Antiplatelet agents significantly reduce mortality and morbidity in ischemic heart disease, cerebrovascular disease and peripheral artery disease (PAD), and are therefore part of guideline-driven daily medical treatment in these patients. Due to its beneficial effects in the secondary prevention of atherothrombotic events, aspirin remains the most frequently prescribed antiplatelet agent in cardiovascular disease. In patients with acute coronary syndromes (ACS) and in those undergoing angioplasty with stent implantation dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) receptor antagonist is indicated. The development of the newer ADP P2Y12 inhibitors prasugrel and ticagrelor has further improved prognosis in ACS patients compared to clopidogrel. Moreover, vorapaxar allows the inhibition of platelet activation by thrombin via protease-activated receptor-1 and has been approved for the use in patients with PAD and in those with a history of myocardial infarction. This review article summarizes the current evidence on oral antiplatelet agents in cardiovascular disease. Keywords: Aspirin, clopidogrel, prasugrel, ticagrelor, vorapaxar, cardiovascular disease.

Efficacy and safety of ticagrelor were similar in patients with past MI, regardless of multivessel coronary disease.

Source Citation Bansilal S, Bonaca MP, Cornel JH, et al. Ticagrelor for secondary prevention of atherothrombotic events in patients with multivessel coronary disease. J Am Coll Cardiol. 2018;71:489...

Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease

BackgroundPatients with prior myocardial infarction (MI) and multivessel coronary disease (MVD) are at high risk for recurrent coronary events. ObjectivesThe authors investigated the efficacy and safety of ticagrelor versus placebo in patients with MVD in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54) trial. MethodsPatients with a history of MI 1 to 3 years before inclusion in the PEGASUS-TIMI 54 trial were stratified in a pre-specified analysis based on the presence of MVD. The effect of ticagrelor (60 mg and 90 mg) on the composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events [MACE]), as well as the composite of coronary death, MI, or stent thrombosis (coronary events), and on TIMI major bleeding, intracranial hemorrhage (ICH), and fatal bleeding were evaluated over a median of 33 months. ResultsA total of 12,558 patients (59.4%) had MVD. In the placebo arm, compared with patients without MVD, those with MVD were at higher risk for MACE (9.37% vs. 8.57%, adjusted hazard ratio [HRadj]: 1.24; p = 0.026) and for coronary events (7.67% vs. 5.34%, HRadj: 1.49; p = 0.0005). In patients with MVD, ticagrelor reduced the risk of MACE (7.94% vs. 9.37%, HR: 0.82; p = 0.004) and coronary events (6.02% vs. 7.67%, HR: 0.76; p < 0.0001), including a 36% reduction in coronary death (HR: 0.64; 95% confidence interval: 0.48 to 0.85; p = 0.002). In this subgroup, ticagrelor increased the risk of TIMI major bleeding (2.52% vs. 1.08%, HR: 2.67; p < 0.0001), but not ICH or fatal bleeds. ConclusionsPatients with prior MI and MVD are at increased risk of MACE and coronary events, and experience substantial relative and absolute risk reductions in both outcomes with long-term ticagrelor treatment relative to those without MVD. Ticagrelor increases the risk of TIMI major bleeding, but not ICH or fatal bleeding. For patients with prior MI and MVD, ticagrelor is an effective option for long-term antiplatelet therapy. (Prevention of Cardiovascular Events [e.g., Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562)

Ticagrelor for Secondary Prevention of Atherothrombotic Events After Myocardial Infarction: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited AstraZeneca, the manufacturer of ticagrelor (Brilique®), to submit evidence on the clinical and cost effectiveness of ticagrelor 60 mg twice daily (BID) in combination with low-dose aspirin [acetylsalicylic acid (ASA)] compared with ASA only for secondary prevention of atherothrombotic events in patients with a history of myocardial infarction (MI) and who are at increased risk of atherothrombotic events. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Centre+, was commissioned as the evidence review group (ERG). This paper summarises the company submission (CS), the ERG report and the NICE guidance produced by the appraisal committee (AC) for the use of ticagrelor in England and Wales. The ERG critically reviewed the clinical- and cost-effectiveness evidence in the CS. The systematic review conducted as part of the CS identified one randomised controlled trial (RCT), PEGASUS-TIMI 54. This trial reported the time to first occurrence of any event from the composite of cardiovascular death, MI and stroke as the primary outcome (hazard ratio 0.84 ticagrelor 60 mg BID vs. placebo, 95% confidence interval 0.74–0.95). The population addressed in the CS was a subgroup of the PEGASUS-TIMI 54 trial population, i.e. the ‘base-case’ population, which comprised patients who had experienced an MI between 1 and 2 years ago, whereas the full trial population included patients who had experienced an MI between 1 and 3 years ago. While the ERG believed the findings of this RCT to be robust, doubts concerning the applicability of the trial to UK patients were raised. The company submitted an individual patient simulation model to estimate the cost-effectiveness of ticagrelor 60 mg BID + ASA versus ASA only. Parametric time-to-event models were used to estimate the time to first and subsequent (cardiovascular) events, time to treatment discontinuation and time to adverse events. The company’s base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of £20,098 per quality-adjusted life-year (QALY) gained. The main issues surrounding the cost effectiveness of ticagrelor 60 mg BID + ASA were the use of parametric time-to-event models estimated based on the full trial population instead of being fitted to the ‘label’ population (the ‘label’ population comprised the ‘base-case’ population and patients who started ticagrelor 60 mg BID within 1 year of previous adenosine diphosphate inhibitor treatment), the incorrect implementation of the probabilistic sensitivity analysis (PSA) of the individual patient simulation, and simplifications of the model structure that may have biased the health benefits and costs estimations of the intervention and comparator. The ERG believed the use of the full trial population to inform the parametric time-to-event models was not appropriate because the ‘label’ population was the main focus of the scope and CS. The ERG could not investigate the magnitude of the bias introduced by this assumption. The PSA of the individual patient simulation provided unreliable probabilistic results and underestimated the uncertainty surrounding the results because it was based on a single patient. The ERG used the cohort simulation presented in the cost-effectiveness model to perform its base-case and additional analyses and to obtain probabilistic results. The ERG amended the company cost-effectiveness model, which resulted in an ERG base-case ICER of £24,711 per QALY gained. In its final guidance, the AC recommended treatment with ticagrelor 60 mg BID + low-dose ASA for secondary prevention of atherothrombotic events in adults who have had an MI and are at increased risk of atherothrombotic events.

Ticagrelor: A Review in Long Term Secondary Prevention of Cardiovascular Events.

Ticagrelor (Brilique®) is an orally administered P2Y12 inhibitor. A long-term (maintenance) regimen of ticagrelor 60mg twice daily is indicated in the EU for coadministration with low-dose aspirin 75-150mg/day for the secondary prevention of atherothrombotic events in high-risk patients with a history of myocardial infarction (MI) of at least 1year. Approval is based on the results of the PEGASUS-TIMI 54 trial that compared ticagrelor with placebo (in conjunction with low-dose aspirin) in stable patients who had had a spontaneous MI 1-3years prior to enrolment and were at high risk of atherothrombotic events. At 3years, the composite primary efficacy endpoint of cardiovascular (CV) death, MI or stroke occurred in significantly fewer ticagrelor 60mg twice daily than placebo recipients. Long-term ticagrelor had a manageable tolerability and safety profile. The risk of TIMI major bleeding (primary safety endpoint) was significantly increased in ticagrelor 60mg twice daily versus placebo recipients; however, the risk appeared to decline after the first year of therapy. Landmark analyses have demonstrated that patients with a history of MI remain at a persistent high risk of the composite primary endpoint up to 5years after the event. Furthermore, these analyses demonstrated that the efficacy of ticagrelor 60mg twice daily was maintained over time, with less excess in bleeding after the first year. Thus, long-term dual antiplatelet therapy with ticagrelor 60mg twice daily and low-dose aspirin is a valuable new option for the secondary prevention of atherothrombotic events in stable, high-risk patients with a history of MI of at least 1year.

The quest for safer antithrombotic treatment regimens in patients with coronary artery disease: new strategies and paradigm shifts

ABSTRACTIntroduction: Despite the undeniable benefits on reducing ischemic adverse events, antiplatelet regimens including dual antiplatelet therapy (DAPT) with aspirin and P2Y12 receptor inhibitors are associated with an increased risk of bleeding. The awareness of the unfavorable prognostic implications associated with bleeding complications have somewhat hampered the enthusiasm towards the use of more potent antiplatelet treatment regimens or prolonged use of DAPT. This awareness also has prompted a series of investigations geared towards the identification of antithrombotic treatment regimens which are efficacious at reducing ischemic recurrences while also safe in terms of bleeding risk profile.Areas covered: The present manuscript focuses on new approaches for improving the safety profile of antithrombotic treatment regimens, including most recent updates from clinical trials, as well as future perspectives in the field.Expert commentary: Results of ongoing trials testing new antithrombotic treatment regimens, including new drugs, new combinations, which may be used for different duration of time according to the individual’s risk of thrombotic and bleeding complications, may lead to paradigm shifts in secondary prevention of atherothrombotic events in patients with coronary artery disease.

Tailoring naringenin conjugates with amplified and triple antiplatelet activity profile: Rational design, synthesis, human plasma stability and in vitro evaluation

BackgroundThe current standard-of-care antiplatelet therapy in cardiovascular disease patients is consisted of cyclooxygenase-1 (COX-1) inhibitor aspirin, along with a platelet receptor P2Y12 antagonist. Recently, the triple antiplatelet therapy with aspirin, a P2Y12 receptor antagonist and a protease activated receptor-1 (PAR-1) antagonist, has been suggested for the secondary prevention of atherothrombotic events, however presented an increased risk of bleeding. Therefore, the quest for novel antiplatelet agents simultaneously targeting the three pathways with improved efficacy/safety profile is of immense importance. Flavonoids as pre-validated ligands for numerous targets could serve as scaffolds targeting the three platelet activation pathways. MethodsComputational methods, Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS) plasma stability and in vitro platelet aggregation experiments were used to establish the antiplatelet activity of the flavonoid naringenin and its conjugates. ResultsIn silico studies indicated that naringenin could bear a potent triple antiplatelet activity by inhibiting different platelet aggregation mechanisms. However, we found that in human platelets naringenin has diminished activity. We rationally designed and synthesized different naringenin conjugates aiming to amplify the antiplatelet activity of the parent compound. UHPLC-MS/MS revealed a slow degradation rate for a docosahexaenoic acid (DHA) – naringenin conjugate in human plasma. The antiplatelet profile of the new analogues was evaluated against in vitro platelet aggregation induced by several platelet agonists. ConclusionsThe DHA – naringenin hybrid presented triple antiplatelet activity simultaneously targeting PAR-1, P2Y12 and COX-1 platelet activation pathways. General significanceNatural products could offer a rich source for novel bioactives as a powerful alternative to the current combinatorial use of three different antiplatelet drugs.

Role for Thrombin Receptor Antagonism With Vorapaxar in Secondary Prevention of Atherothrombotic Events: From Bench to Bedside.

In spite of treatment with the current standard of care antiplatelet regimens including dual antiplatelet therapy, recurrence rates of ischemic events remain elevated for high-risk patients with atherosclerotic disease. This may be in part attributed to the fact that other key platelet activation pathways remain uninhibited and can thus continue to trigger platelet activation and lead to thrombotic complications. Thrombin is a powerful inducer of platelet activation and mediates its effects directly on platelets through protease activator receptors (PARs), particularly the PAR-1 subtype, making PAR-1 inhibition an attractive approach for reducing atherothrombotic events. These observations have led to the development of several PAR-1 antagonists. Vorapaxar is a direct inhibitor of PAR-1 and the only agent of this class approved for the prevention of recurrent ischemic events in patients with prior myocardial infarction or peripheral artery disease. In the present manuscript, we present a review of the pathophysiologic role of thrombin on thrombotic complications, the impact of vorapaxar on outcomes, including the most recent updates deriving from clinical trials, as well as future perspectives in the field.

Vorapaxar in the long-term secondary prevention of atherothrombotic events: a profile of its use in the USA

Vorapaxar (Zontivity®), is a first-in-class protease-activated receptor-1 antagonist, is approved for use with standard care antiplatelet therapy for the secondary prevention of cardiovascular thrombotic events in patients with a history of myocardial infarction or with peripheral artery disease. In the TRA 2°P-TIMI 50 trial, oral vorapaxar 2.08 mg once daily + standard antiplatelet therapy significantly reduced the risk of major cardiovascular events in stable patients with established atherosclerosis; however, this treatment benefit was accompanied by an increased risk of bleeding. The net clinical benefit of treatment appears to be greatest in patients with increased atherothrombotic risk, such as those with diabetes.