Part Of Dual Antiplatelet Therapy Research Articles

Use of Cangrelor during Venoarterial Extracorporeal Membrane Oxygenation Following Percutaneous Coronary Intervention

Purpose In patients undergoing percutaneous coronary intervention (PCI) complicated by cardiogenic shock, venoarterial extracorporeal membrane oxygenation (VA-ECMO) is used as a bridge to surgery, ventricular assist device (VAD), or recovery. Bleeding and thrombotic complications afflict patients on VA-ECMO support. Cangrelor is an ideal agent to use as part of dual antiplatelet therapy after PCI due to its short half-life, however there are no data regarding the use of cangrelor in the setting of VA-ECMO. Methods This was a single-center retrospective case series of patients who received cangrelor while on VA-ECMO following PCI from January 1, 2016 through August 31, 2018. The objective of this case series was to describe the complications and outcomes associated with the use of cangrelor during VA-ECMO. Results Thirteen patients were included (median age of 61 years). Past medical history included hyperlipidemia (69%), type 2 diabetes mellitus (62%), and hypertension (46%). Forty-six percent of patients presented with a ST-segment elevation myocardial infarction (STEMI), 31% with a NSTEMI, and 23% were elective PCI. Nearly all patients (92%) received a drug-eluting stent and 48% were placed in the LAD. Eighty-five percent of patients received VA-ECMO combined with an Impella for LV venting. Patients were on VA-ECMO for a median of eight days (IQR 6 - 11) and cangrelor for a median of five days (IQR 3 - 8). The dose of cangrelor in all cases was 0.75 mcg/kg/min. Only one patient experienced a thrombotic event (deep vein thrombosis), however 77% patients had a hemorrhagic complication (Figure) and received a median of three units of PRBCs while on cangrelor and VA-ECMO. Fifty-four percent of patients were bridge to recovery, 38% of patients died, and 8% were bridge to ventricular assist device. Conclusion Hemorrhagic complications were frequent in this case series of patients who received cangrelor while on VA-ECMO following PCI, and no repeat coronary events were observed.

TICAGRELOR-INDUCED TRANSAMINITIS: A RARE AND UNEXPECTED PHENOMENON

Ticagrelor, a new type of P2Y12 receptor antagonist, has been widely used in acute coronary syndrome and become a part of dual anti-platelet therapy after percutaneous coronary intervention (PCI). A 60-year-old man with medical history of hyperlipidemia and coronary artery disease s/p PCI to mid

Genetic Polymorphisms of ABCB1 Gene in Patients Having Resistance to Clopidogrel

Objectives: We sought to study the genetic polymorphisms of ABCB1 gene in post percutaneous coronary intervention (PCI) patients with clopidogrel resistance. Background: Dual antiplatelet therapy (DAPT) is a guideline mandated therapy for patients who undergo PCI. However there exists interindividual variability in drug response to the antiplatelet agents leading to recurrent thrombotic events. Genetic polymorphisms of ABCB1 gene are one among the causes of this interindividual variability. Methods: It is a single center prospective trial and includes221 patients who underwent PCI and were given clopidogrel as a part of DAPT. Platelet reactivity was assessed by grading of platelet activity index (PAI) and considered as high on treatment platelet reactivity (HTPR), i.e., clopidogrel resistance if PAI > 5. Genetic analysis for ABCB1 C-T polymorphism was done by polymerase chain reaction (PCR) and single strand confirmation polymorphism (SSCP) analysis. Results: Amongst 221 patients, 37 (16.7%) patients had ABCB1 C-T polymorphisms. The mean PAI value in these patients was 5.1 ± 3.0, while it was 3.5 ± 2.5 in those patients without ABCB1 C-T polymorphisms (p = 0.004). Compared to patients without HTPR, the occurrence of primary endpoints was not significantly increased in patients with HTPR except for stent thrombosis which was significantly high in patients with HTPR. HTPR was also associated with ABCB1 C-T polymorphisms (p = 0.04), but these polymorphisms did not predict the clinical outcome. Conclusions: There was significant prevalence of ABCB1 C-T polymorphisms in patients with HTPR. However it was not an independent risk factor for clopidogrel resistance and also it did not influence adverse cardiovascular outcomes.

Генетические маркеры годового исхода инфаркта миокарда с подъемом сегменты ST

Aim: to analyze the prognostic value of gene polymorphisms ACE (D/I), SLCO1B1 (Val174Ala), LIPC (C514T), CYP2C19*2, CYP2C19*3, ADRB1 (Ser49Gly), ADRB1 (Arg389Gly) of patients with ST-segment elevation myocardial infarction (STEMI). Materials and methods: 145 patients with STEMI from 45 to 75 years of age were involved into the study. All patients were prescribed all recommended preparations improving prognosis (statins, angiotensin-converting enzyme inhibitors, beta-blockers, clopidogrel as part of dual antiplatelet therapy) from the first day of hospitalization. To determine gene polimorphismspolimerase chain reactionwas used. Prognosis was assessed by a combined endpoint, including cardiovascular mortality, nonfatal myocardial infarction, unplanned revascularization of coronary arteries and hospitalization for unstable angina, throughout 12 months. Results. The II genotype of the polymorphic gene ACE (I / D) is a predictor of the 12-month STEMI fa-vorable outcome. Allele Ser of the polymorphic gene ADRB1 Ser49Gly is associated with an increased incidence of adverse cardiovascular events within 12 months after STEMI. Gene polymorphisms SLCO1B1 (Val174Ala), CYP2C19*2, CYP2C19*3, ADRB1 (Arg389Gly), LIPC (C514T) does not affect the 12-month forecast after STEMI. Conclusions. Genotyping of ACE (I /D) and ADRB1 Ser49Gly can be used to assess the long-term prog-nosis and effectiveness of pharmacotherapy STEMI by means of personalizing it.

PREDICTORS OF LONG-TERM PROGNOSIS OF MYOCARDIAL INFARCTION: FOCUS ON THE PHARMACOKINETICS

Aim: to analyze the prognostic value of gene polymorphisms ACE (D/I), SLCO1B1 (Val174Ala), LIPC (C514T), CYP2C19*2, CYP2C19*3, ADRB1 (Ser49Gly), ADRB1 (Arg389Gly) of patients with ST-segment elevation myocardial infarction (STEMI). Materials and methods. 155 patients with STEMI from 45 to 75 years of age were involved into the study. All patients were prescribed all recommended preparations improving prognosis (statins, angiotensin-converting enzyme inhibitors, beta-blockers, clopidogrel as part of dual antiplatelet therapy) from the fi rst day of hospitalization. Prognosis was assessed by endpoints: cardiovascular mortality, nonfatal myocardial infarction throughout 12 months. Results. Carriers genotypes *1*2 and *1*3 had in 3,27 times higher risk of recurrent myocardial infarction within 1 year from the STEMI (р=0,03). There was no effect of gene polymorphisms ACE (D/I), SLCO1B1 (Val174Ala), LIPC (C514T), ADRB1 (Ser49Gly), ADRB1 (Arg389Gly) on the probability of recurrent myocardial infarction (p>0,05). Associative links studied polymorphisms with the cardiovascular mortality is not installed (p> 0,05).

Systematic review of the clinical impact of dual antiplatelet therapy discontinuation after acute coronary syndromes.

The aim of this systematic literature review was to assess the consequences of dual antiplatelet therapy discontinuation on clinical outcomes after acute coronary syndromes. A systematic literature search was conducted in PubMed to identify studies reporting data on patients who discontinued dual antiplatelet therapy (planned or unplanned) following acute coronary syndromes and on the clinical impact of dual antiplatelet therapy discontinuation. To be included, more than 50% of the study population had to have had acute coronary syndrome as their index event or, if less than 50%, outcomes data must have been reported separately for the group with acute coronary syndromes. Thirty publications covering 29 studies were identified for inclusion. There was much heterogeneity across studies regarding the included patient populations, treatment durations and outcome definitions and ascertainments. Dual antiplatelet therapy discontinuation was most commonly based on physician decision. Twenty-six studies reported that clopidogrel was prescribed as part of dual antiplatelet therapy. Dual antiplatelet therapy duration was positively associated with a lower risk of all-cause mortality (seven/eight studies), cardiovascular mortality (two/two studies), non-fatal myocardial infarction (two/three studies) and stent thrombosis (five/five studies) in patients and/or patient subgroups in studies without randomised treatment designs, although such associations were not observed in the one study that randomly assigned patients to treatment (i.e. planned discontinuation). Results from our systematic literature review generally support the benefit of longer-term dual antiplatelet therapy after acute coronary syndromes; however, further research is needed to determine the optimal length of dual antiplatelet therapy in patients after acute coronary syndrome, ideally using prospective studies.

Antiplatelet Agents in Cardiology: A Report on Aspirin, Clopidogrel, Prasugrel, and Ticagrelor.

Antiplatelet drugs are the cornerstone of therapy in many cardiovascular conditions. With the current success and increased use of transcatheter aortic valve implantation (TAVI), the use of antiplatelet therapy is considered part of the medical therapy for these patients. Clinicians caring for these patients need to have a thorough understanding of the pharmacology, pharmacokinetics, pharmacodynamic, and clinical efficacy and safety of commonly used antiplatelet therapy. While aspirin therapy is widely used, dual antiplatelet therapy with clopidogrel has become part of standard of care. Despite the extensive experience with clopidogrel, there are limitations such as drug interactions, metabolism genetic polymorphisms, and variability in the antiplatelet response. More predictable and more potent antiplatelet agents, prasugrel and ticagrelor, have demonstrated superior reductions in ischemic endpoints as part of dual antiplatelet therapy compared to clopidogrel, but at the cost of more major bleeding in patients with an acute coronary syndrome. Significant research needs to be conducted in the setting of TAVI to help define the optimal antiplatelet regimen.

Cost-effectiveness of clopidogrel, prasugrel and ticagrelor for dual antiplatelet therapy after acute coronary syndrome: a decision-analytic model.

The use of prasugrel or ticagrelor as part of dual antiplatelet therapy with acetylsalicylic acid after acute coronary syndrome (ACS) improves clinical outcomes relative to clopidogrel. The relative cost-effectiveness of these agents are unknown. We conducted an economic analysis evaluating 12 months of treatment with clopidogrel, prasugrel or ticagrelor after ACS. We developed a fully probabilistic Markov cohort decision-analytic model using a lifetime horizon, from the perspective of the Ontario Ministry of Health and Long-Term Care. The model incorporated risks of death, recurrent ACS, heart failure, major bleeding and other adverse effects of treatment. Data on probabilities and utilities were obtained from the published literature where available. The primary outcome was quality-adjusted life-years (QALYs). Treatment with clopidogrel was associated with the lowest effectiveness (7.41 QALYs, 95% confidence interval [CI] 1.05-14.79) and the lowest cost ($39 601, 95% CI $8434-$111 186). Ticagrelor treatment had an effectiveness of 7.50 QALYs (95% CI 1.13-14.84) at a cost of $40 649 (95% CI $9327-$111 881). The incremental cost-effectiveness ratio (ICER) for ticagrelor relative to clopidogrel was $12 205 per QALY gained. Prasugrel had an ICER of $57 630 per QALY gained relative to clopidogrel. Ticagrelor was the preferred option in 90% of simulations at a willingness-to-pay threshold of $50 000 per QALY gained. Ticagrelor was the most cost-effective agent when used as part of dual antiplatelet therapy after ACS. This conclusion was robust to wide variations in model parameters.

Clopidogrel, prasugrel, ticagrelor or vorapaxar in patients with renal impairment: do we have a winner?

The optimal utilization of antiplatelet therapy in patients with renal impairment (RI) following acute coronary syndromes (ACS) represents an urgent, unmet and yet unsolved need with regards to the choice of agents, duration of treatment and potential dose/regimen adjustment. The lack of any large randomized trials designed and powered specifically in such high-risk patients, absence of the uniformed efficacy and safety data reporting policy to the FDA and endless overoptimistic publications based on post hoc analyses of primary trials sometimes exaggerating benefits and hiding risks, clouds reality. In addition, triaging RI patients is problematic due to ongoing kidney deterioration and the fact that such patients are prone to both vascular occlusions and bleeding. The authors summarize available FDA-confirmed evidence from the latest trials with approved antiplatelet agents, namely clopidogrel (CAPRIE, CURE, CREDO, CLARITY, CHARISMA); prasugrel (TRITON, TRILOGY); ticagrelor (PLATO, and PEGASUS); and vorapaxar (TRACER and TRA2P) in RI patient cohorts on top of aspirin as part of dual antiplatelet therapy (DAPT). We deliberately avoided any results unless they were verified by the FDA, with the exception of the recent PEGASUS, since Agency reviews are not yet available. Despite differences among the trials and DAPT choices, RI patients universally experience much higher (HR = 1.3–3.1) rates of primary endpoint events, and bleeding risks (HR = 1.7–3.6). However, only ticagrelor increases creatinine and uric acid levels above that of clopidogrel; has the worst incidence of serious adverse events, more adverse events, and inferior outcomes in patients with severe (eGFR <30 ml/min), especially in the lowest (eGFR <15 ml/min) RI subsets. Clopidogrel, prasugrel and vorapaxar appear safer. Moreover, less aggressive half dose (5 mg/daily) prasugrel and strict DAPT, are well justified in RI, but not predominantly triple strategies with vorapaxar as tested in TRA2P and especially in TRACER. In conclusion, data from clinical trials, their sub-studies and affiliated FDA reviews indicate that RI cause more vascular occlusions and bleeding in ACS patients treated with DAPT. Among the novel antiplatelet agents, prasugrel and vorapaxar, but probably not ticagrelor, offer advantage in RI patients.

FACTORS ASSOCIATED WITH USE OF NEWER ANTIPLATELET AGENTS IN PATIENTS UNDERGOING DRUG ELUTING STENT PLACEMENT: ANALYSIS FROM THE PINNACLE® REGISTRY

Prasugrel and ticagrelor are newer thienopyridines for use as part of dual antiplatelet therapy (DAPT) in patients undergoing drug-eluting stent (DES) placement for CAD. To understand reasons for their use over clopidogrel, we evaluated the factors associated with prescription of these agents.

Young coronary artery disease in patients undergoing percutaneous coronary intervention

BACKGROUND AND OBJECTIVESUnderstanding the nature and pattern of young coronary artery disease (CAD) is important due to the tremendous impact on these patients’ socio-economic and physical aspect. Data on young CAD in the southeast Asian region is rather patchy and limited. Hence we utilized our National Cardiovascular Disease Database (NCVD)—Percutaneous Coronary Intervention (PCI) Registry to analyze young patients who underwent PCI in the year 2007 to 2009.DESIGN AND SETTINGSThis is a retrospective study of all patients who had undergone coronary angioplasty from 2007 to 2009 in 11 hospitals across Malaysia.METHODSData were obtained from the NCVD—PCI Registry, 2007 to 2009. Patients were categorized into 2 groups—young and old, where young was defined as less than 45 years for men and less than 55 years for women and old was defined as more than or equals to 45 years for men and more than or equals to 55 years for women. Patients’ baseline characteristics, risk factor profile, extent of coronary disease and outcome on discharge, and 30-day and 1-year follow-up were compared between the 2 groups.RESULTSWe analyzed 10 268 patients, and the prevalence of young CAD was 16% (1595 patients). There was a significantly low prevalence of Chinese patients compared to other major ethnic groups. Active smoking (30.2% vs 17.7%) and obesity (20.9% vs 17.3%) were the 2 risk factors more associated with young CAD. There is a preponderance toward single vessel disease in the young CAD group, and they had a favorable clinical outcome in terms of all-cause mortality at discharge (RR 0.49 [CI 0.26–0.94]) and 1-year follow-up (RR 0.47 [CI 0.19–1.15]).CONCLUSIONWe observed distinctive features of young CAD that would serve as a framework in the primary and secondary prevention of the early onset CAD.

Discontinuation of preoperative clopidogrel is unnecessary in peripheral arterial surgery

The optimal management of preoperative clopidogrel remains controversial, as vascular surgeons are increasingly encountering patients treated with clopidogrel as part of dual antiplatelet therapy. Current practice differs considerably, from cessation of the medication at least 5 days before surgery to proceeding with surgery without delay. The purpose of this prospective, nonrandomized, comparative study was to determine the effect of preoperative exposure to clopidogrel and aspirin on perioperative bleeding complications in patients undergoing open arterial surgery. Data were collected prospectively on 647 consecutive major arterial procedures from 2005 through mid-2012. Patients were classified into two groups: the clopidogrel group consisted of 305 procedures performed in 269 patients who were maintained, after obtaining informed consent, on dual clopidogrel and aspirin up to the time of surgery and the no-clopidogrel group consisted of 342 procedures completed in 298 patients who were taking neither medication together or were taking aspirin alone. The primary composite end point was reoperation for bleeding and bleeding-related death. Secondary end points included blood transfusion requirements, hematoma formation, the procedure duration, as well as hospital and intensive care unit length of stay. The patients taking clopidogrel had a higher cardiovascular risk profile and a higher prevalence of prior peripheral and coronary stents (P< .0001). Clopidogrel use was common across all operation categories: 59% of carotid endarterectomy patients (104 of 177), 43% of lower extremity bypass patients (147 of 344), and 43% of abdominal aortic bypass patients (54 of 126). The difference in the primary end point between the clopidogrel and no-clopidogrel groups was not statistically significant (0.65% and 0.3%, respectively; P =.55). No bleeding-related deaths were observed. Further analysis revealed a similar incidence of stable hematomas. Blood transfusions were mainly required by patients undergoing aortic surgery, at similar rates and volumes in the clopidogrel and no-clopidogrel groups: abdominal aortic bypass cohort (a mean of 1.6 units packed red blood cells needed in 72% vs a mean of 1.6 units in 69%, respectively; P=.76); lower extremity bypass cohort (a mean of 1.5 units needed in 15% vs 1.3 units needed in 11%; P<.004). Themean operative time and intensive care unit and hospital lengths of stay were not longer in clopidogrel recipients. Combined therapy with clopidogrel and aspirin up to the day of surgery is not associated with increased bleeding complications or transfusion requirements. Data from this study do not validate the perceived higher risk of perioperative bleeding in clopidogrel patients and do support the strategy of continued clopidogrel use in patients undergoing peripheral arterial surgery.

Review of ticagrelor in the management of acute coronary syndromes

Introduction: Ticagrelor, an oral P2Y12 receptor antagonist used as part of dual antiplatelet therapy in the treatment of acute coronary syndromes (ACS), has many favorable characteristics when compared with the more frequently used P2Y12 receptor antagonist clopidogrel. Ticagrelor binds reversibly, with a rapid onset and offset of action, and produces high levels of platelet inhibition without variation secondary to genetic polymorphism. Ticagrelor produces increased platelet inhibition and an overall reduction in adverse cardiac events compared with clopidogrel. Clinically relevant side effects include an increase in non-CABG-related bleeding events as well as off-target adverse effects including ventricular pauses and dyspnea.Areas covered: This article details ticagrelor's pharmacokinetic and pharmacodynamic characteristics, development and chemical properties. The authors review relevant clinical trials looking at the efficiency and safety of ticagrelor focusing predominantly on the management of patients with ACS. Finally, the review article concludes with discussion of ticagrelor's current role and future integration into clinical practice.Expert opinion: Ticagrelor is a promising P2Y12 receptor antagonist with characteristics that offer advantages for patients beyond those currently demonstrated by other P2Y12 receptor antagonists. The challenge for prescribers is to identify those most likely to benefit from ticagrelor treatment while minimizing unnecessary bleeding events for ‘real-world' ACS patients.

Clopidogrel is not associated with major bleeding complications during peripheral arterial surgery

Persistent variation in practice surrounds preoperative clopidogrel management at the time of vascular surgery. While some surgeons preferentially discontinue clopidogrel citing a perceived risk of perioperative bleeding, others will proceed with surgery in patients taking clopidogrel for an appropriate indication. The purpose of this study was to determine whether preoperative clopidogrel use was associated with significant bleeding complications during peripheral arterial surgery. We reviewed a prospective regional vascular surgery registry recorded by 66 surgeons from 15 centers in New England from 2003 to 2009. Preoperative clopidogrel use within 48 hours of surgery was analyzed among patients undergoing carotid endarterectomy (CEA), lower extremity bypass (LEB), endovascular abdominal aortic aneurysm repair (EVAR), and open abdominal aortic aneurysm repair (oAAA). Ruptured AAAs were excluded. Endpoints included postoperative bleeding requiring reoperation, as well as the incidence and volume of blood transfusion. Statistical analysis was performed using analysis of variance, Fisher exact, χ(2), and Wilcoxon rank-sum tests. Over the study interval, a total of 10,406 patients underwent surgery, including 5264 CEA, 2883 LEB, 1125 EVAR, and 1134 oAAA repair. Antiplatelet use among all patients varied, with 19% (n = 2010) taking no antiplatelet agents, 69% (n = 7132) taking aspirin (ASA) alone, 2.2% (n = 229) taking clopidogrel alone, and 9.7% (n = 1017) taking both ASA and clopidogrel. Clopidogrel alone or as dual antiplatelet therapy was most frequently used prior to CEA and least frequently prior to oAAA group (CEA 16.1%, LEB 9.0%, EVAR 6.5%, oAAA 5%). Reoperation for bleeding was not significantly different among patients based on antiplatelet regimen (none 1.5%, ASA 1.3%, clopidogrel 0.9%, ASA/clopidogrel 1.5%, P = .74). When analyzed by operation type, no difference in reoperation for bleeding was seen across antiplatelet regimens. There was also no difference in the incidence of transfusion among antiplatelet treatment groups (none 18%, ASA 17%, clopidogrel 0%, ASA/clopidogrel 24%, P = .1) and none when analyzed by individual operation type. Among patients who did require transfusion, there was no significant difference in the mean number of units of packed red blood cells required (none 0.7 units, ASA 0.5 units, clopidogrel 0 units, ASA/clopidogrel 0.6 units, P = .1) or when stratified by operation type. Patients undergoing peripheral arterial surgery in whom clopidogrel was continued either alone or as part of dual antiplatelet therapy did not have significant bleeding complications compared with patients taking no antiplatelet therapy or ASA alone at the time of surgery. These data suggest that clopidogrel can safely be continued preoperatively in patients with appropriate indications for its use, such as symptomatic carotid disease or recent drug-eluting coronary stents.

Impact of concomitant treatment with proton pump inhibitors and clopidogrel on clinical outcome in patients after coronary stent implantation

The aim of the study was to evaluate the effect of the concomitant treatment with proton-pump inhibitors (PPIs) and clopidogrel on the incidence of stent thrombosis, acute coronary syndrome (ACS) and death in patients who underwent percutaneous coronary intervention (PCI) and stent implantation. In total, 1,210 patients under dual antiplatelet therapy, who underwent PCI and stent implantation, were included in a prospective registry from January 2003 until December 2006. The patients were divided retrospectively into those with or without long-term PPI treatment (for the duration of dual antiplatelet therapy). All-cause mortality, cardiovascular death, re-hospitalisation for re-ACS, stent thrombosis, as well as the combined endpoint all-cause death, re-ACS or stent thrombosis were evaluated over a mean follow-up period of 7.8 (± 3.63) months (range 1-12 months). Propensity score analysis was performed to reduce potential selection bias and exhibited no significant difference between the two study groups with respect to all-cause mortality, cardiovascular death, re-ACS, stent thrombosis and the combined endpoint. In pre-specified subgroup analyses performed in patients presenting with ACS and referred for acute PCI or for stable patients referred for elective PCI, receiving drug-eluting stents or bare metal stents, in diabetics or non-diabetics, in males or females, and in patients older than 75 years or ≤75 years of age use of PPIs had no significant impact on clinical outcome. Our data suggest that a combined use of clopidogrel as part of dual antiplatelet therapy (DAPT) after coronary stenting and PPIs does not significantly influence the clinical outcome.

Dual antiplatelet therapy in the drug-eluting stent era

Data continue to accumulate showing that implantation of coronary stents, particularly drug-eluting stents (DES), is associated with persistent, long-term risk of thrombotic events. Dual antiplatelet therapy with aspirin and clopidogrel has reduced the risk of early and late thrombosis. However, early risk persists due to implantation, stent-related factors, and suboptimal response to clopidogrel, whereas late risk persists due not only to these factors, but to the limited duration of dual antiplatelet therapy as well. Third-generation oral P2Y12 antagonists that exhibit faster onset of action and greater and more consistent inhibition of platelet aggregation than clopidogrel include the new thienopyridine prasugrel and the reversible P2Y12 inhibitor AZD6140. Prospective, randomized, long-term trials are warranted to investigate the benefits and risks of more effective P2Y12 antagonists as part of dual antiplatelet therapy after both bare-metal stent and DES implantation.