Dual Antiplatelet Therapy with Prasugrel or Ticagrelor Versus Clopidogrel in Interventional Cardiology

For several years, clopidogrel plus aspirin has been the dual antiplatelet therapy (DAPT) of choice for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation. More recently, prasugrel and ticagrelor have demonstrated greater efficacy than clopidogrel. In TRITON-TIMI 38, the risk of TIMI major bleeding unrelated to coronary artery bypass graft (CABG) surgery was similar for prasugrel and clopidogrel after excluding subgroups with increased bleeding risk (previous stroke or transient ischemic event; age ≥75 years; weight <60 kg). In the PLATO trial, rates of TIMI major bleeding were similar for ticagrelor and clopidogrel, but ticagrelor was associated with a significantly higher rate of non-CABG-related TIMI major bleeding. Current evidence suggests that prasugrel or ticagrelor plus aspirin should be the DAPT of choice in patients with ACS undergoing PCI unless they are at particularly high risk of bleeding. No studies have yet compared prasugrel and ticagrelor in ACS patients, however prasugrel and ticagrelor have different side effect profiles, and the choice of agent should be made either as a default choice and/or on an individual patient basis. Ongoing trials in ACS patients will increase the evidence base for new P2Y₁₂ receptor inhibitors and help to establish the most effective DAPT regimens.     

Gastroprotection in patients on antiplatelet and/or anticoagulant therapy: a position paper of National Association of Hospital Cardiologists (ANMCO) and the Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO)

Aspirin and P2Y₁₂ receptor antagonists are widely used across the spectrum of cardiovascular and cerebrovascular diseases. Gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, concomitant proton pump inhibitor (PPI) treatment is often prescribed. However, potential increased risk of cardiovascular events has been suggested for PPIs, and, in recent years, it has been discussed whether these drugs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Indeed, pharmacodynamic and pharmacokinetic studies suggested an interaction through hepatic CYP2C19 between PPIs and clopidogrel, which could translate into clinical inefficacy, leading to higher rates of cardiovascular events. The FDA and the EMA sent a warning in 2010 discouraging the concomitant use of clopidogrel with omeprazole or esomeprazole. In addition, whether the use of PPIs may affect the clinical efficacy of the new P2Y₁₂ receptor antagonists, ticagrelor and prasugrel, remains less known. According to current guidelines, PPIs in combination with antiplatelet treatment are recommended in patients with risk factors for gastrointestinal bleeding, including advanced age, concurrent use of anticoagulants, steroids or non-steroidal anti-inflammatory drugs, and Helicobacter pylori infection. Like vitamin K antagonists (VKAs), DOACs can determine gastrointestinal bleeding. Results from both randomized clinical trials and observational studies suggest that high-dose dabigatran (150 mg bid), rivaroxaban and high-dose edoxaban (60 mg daily) are associated with a higher risk of GI bleeding as compared with apixaban and warfarin. In patients taking oral anticoagulant with GI risk factor, PPI could be recommended, even if usefulness of PPIs in these patients deserves further data. Helicobacter pylori should always be searched, and treated, in patients with history of peptic ulcer disease (with or without complication). Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition or anticoagulant effect potentially carries a considerable clinical impact. The present joint statement by ANMCO and AIGO summarizes the current knowledge regarding the widespread use of platelet inhibitors, anticoagulants, and PPIs in combination. Moreover, it outlines evidence supporting or opposing drug interactions between these drugs and discusses consequent clinical implications.     

Combination antiplatelet treatment in coronary artery disease patients: A necessary evil or an overzealous practice?

In seeking to improve care in coronary artery disease patients, further platelet inhibition has been occasionally applied beyond that provided by aspirin and a P2Y₁₂ receptor antagonist. This review aims to offer insights about the rationale, the efficacy and safety of combination antiplatelet therapy, involving three or more agents. Overall, the use of glycoprotein (GP) IIb/IIIa inhibitors did not significantly modify the treatment effect of different antiplatelet strategies, including double vs standard clopidogrel, prasugrel vs clopidogrel, ticagrelor vs clopidogrel, cangrelor vs clopidogrel, and vorapaxar vs placebo. With the caveat that the use of GP IIb/IIIa inhibitor was not randomized, adding such an agent to aspirin and a P2Y₁₂ receptor antagonist appears to carry a significantly increased bleeding potential. Moreover, adding vorapaxar to aspirin- and clopidogrel-treated patients is associated with more bleeding events, while the bleeding potential is further exacerbated in cases of quadruplicate antiplatelet treatment including aspirin, clopidogrel, vorapaxar, and a GP IIb/IIIa inhibitor. In ST-segment elevation, myocardial infarction patients’ administration of an intravenous antiplatelet agent (GP IIb/IIIa inhibitor or cangrelor), in addition to aspirin and a P2Y₁₂ receptor antagonist, efficiently bridges the pharmacodynamic gap of oral agents. Cilostazol on top of aspirin and clopidogrel appears to be safe, although of questionable clinical benefit. In conclusion, combination antiplatelet therapy should be reserved only for selected cases and following thoughtful consideration of the associated risk/benefit ratio.     

Current evidence for monitoring platelet reactivity in acute coronary syndrome: A plea for individualized antiplatelet treatment

Although clopidogrel is more effective in preventing thrombotic complications than aspirin alone in a broad spectrum of patients with ischemic heart disease, many of its limitations were recently brought to light including a delayed onset of action and highly unpredictable P2Y₁₂-receptor inhibition. New-generation ADP-receptor antagonists, such as prasugrel and ticagrelor, were designed and developed to overcome these limitations, providing a more rapid, more reliable and more potent P2Y₁₂-receptor inhibition. These pharmacodynamic benefits of new-generation antiplatelet agents were translated into significant clinical advantage among patients with acute coronary syndrome (ACS), especially in preventing stent thrombosis. However, the downsides of the unselected use of novel P2Y₁₂-receptor antagonists include higher risk of bleeding and increased costs. Platelet reactivity testing might become a useful tool to help balance between bleeding and thrombosis with P2Y₁₂-receptor antagonists; however, its role in clinical practice for patients undergoing percutaneous coronary intervention (PCI) remains uncertain. The aim of this viewpoint article is to summarize the currently available evidence supporting a role of platelet function testing in patients with ACS after PCI.     

Novel antiplatelet agent ticagrelor in the management of acute coronary syndrome

Current clinical guidelines recommend dual antiplatelet agents namely aspirin and clopidogrel for the treatment of patients suffering from acute coronary syndrome (ACS). But the efficacy of clopidogrel is variable as it is a pro-drug, which has to be metabolized to become an active drug thus exhibiting variable platelet inhibition, increases risk of bleeding, stent thrombosis, and ischemia. To overcome this limitation, prasugrel was developed with increased antiplatelet activity thereby reducing the risk of myocardial ischemia and stent thrombosis. This action of prasugrel was associated with an increased risk of major bleeding. Finally, a novel reversible and direct-acting oral adenosine diphosphate (ADP) receptor antagonist, ticagrelor was developed that showed consistent and increased P2Y12 inhibition with similar incidence of bleeding but greater reduction in cardiac events compared to clopidogrel. The focus of this article is to review ticagrelor as a new class of P2Y12 inhibitor.     

Comparing newer oral anti-platelets prasugrel and ticagrelor in reduction of ischemic events-evidence from a network meta-analysis

The two newer antiplatelet drugs, prasugrel and ticagrelor have both been incorporated in various national guidelines and are both under consideration for approval or have already been approved by various drug regulatory authorities. Mortality benefits with clopidogrel were comparable to newer anti-platelets, and prasugrel had great anti-ischemic potency than ticagrelor. We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials’ databases for randomized controlled trials conducted between 1990 and 2012 that assessed clinical outcomes with prasugrel or ticagrelor. The comparator was standard dosage of clopidogrel. Outcomes assessed were the risk of all causes mortality, TIMI non-CABG major bleeding, and a composite of stent thrombosis, recurrent ischemia and serious recurrent ischemia in the intervention groups versus the comparator groups. Event rates were compared using a forest plot of relative risk using a random effects model (Mantel–Haenszel); and Odd’s ratio was calculated in the absence of significant heterogeneity. Prasugrel was indirectly compared with ticagrelor using network meta-analysis. Four studies (total N = 34,126) met the inclusion/exclusion criteria. Both drugs had improved mortality and greater risk of bleeding compared to clopidogrel; but outcomes were comparable for both (p = NS). However a composite of recurrent ischemic events, including rates of stent thrombosis (p = 0.045) was reduced to a modest degree with prasugrel compared with ticagrelor. This systematic review suggests greater clinical efficacy of both prasugrel and ticagrelor compared with clopidogrel and an indirect comparison indicates prasugrel may be more effective than ticagrelor for preventing stent thrombosis and recurrent ischemic events.     

The promise of effective P2Y12 platelet receptor pretreatment: Not crushed yet

• Pre‐treatment with intact oral clopidogrel and prasugrel tablets in a representative observational study is not associated with altered ischemic or bleeding outcomes in acute coronary syndrome (ACS) patients.
• Limited by cost, cangrelor, a rapidly acting intravenous P2Y₁₂ platelet receptor inhibitor, achieved meaningful reductions in major adverse cardiovascular events (MACE) and stent thrombosis (ST) compared to oral clopidogrel pretreatment.
• Crushed prasugrel and ticagrelor (CP&T) administered orally achieve accepted thresholds of therapeutic platelet inhibition in one hour in approximately 2/3rds of patients compared to 1/3rd with intact oral tablets. A large, simple randomized trial should test whether CP&T pre‐treatment could capture some of the potential outcome benefit of rapid P2Y₁₂ inhibition at no incremental risk and cost.

     

Pl?ttchenaggregationshemmer

Patients with coronary artery disease and a history of recent percutaneous coronary intervention (PCI) with stent implantation depend on an adequate inhibition of blood platelets during and in the months after the intervention. In this respect activation and aggregation of blood platelets plays a central role in the pathogenesis of ischemic events including the occurrence of stent thrombosis. Administration of a dual antiplatelet treatment regimen should minimize such complications. This mode of drug treatment consists of the administration of the cyclooxygenase inhibitor aspirin, which is given over a patient??s lifetime and additional treatment with a P2Y₁₂ receptor inhibitor. With clopidogrel, prasugrel and ticagrelor, various drugs are available to choose from. The choice of treatment depends on the clinical scenario of the patient, on relevant comorbidities and on the side-effects of treatment. Platelet function testing may be useful as well, to choose the right drug for the right patient and the difficulty lies in balancing the risk for ischemic and bleeding events the same time.     

Safety and efficacy of IIb/IIIa inhibitors in combination with highly active oral antiplatelet regimens in acute coronary syndromes: A meta-analysis of pivotal trials

The risk and benefit of GP-IIb/IIIa Inhibition (GPI) in combination with recent antiplatelet regimens in acute coronary syndromes (ACS) remain unassessed. The advent of fast-acting highly active oral P2Y₁₂ inhibitors questions the additional value and risk of their association with GPI. We studied the effect of GPI in combination with prasugrel and ticagrelor, compared to clopidogrel on major bleeding in pivotal randomized controlled trials in the setting of ACS, using a meta-analytic approach. A similar analysis, further including the comparison of a double versus standard dose clopidogrel regimen, was performed for the risk of the primary efficacy endpoint. The combination of GPI and recent P2Y₁₂ inhibitors was associated with a similar risk of bleeding as compared with GPI and the standard clopidogrel regimen (RR 0.92 [0.74; 1.13]). The benefit of recent regimens, including double dose clopidogrel, in reducing the primary ischemic endpoint (RR 0.86 [0.78; 0.94]) persisted in those treated with GPI. Although GPI use was associated with a consistent increase in the risk of bleeding in both recent (RR 1.27 [1.05–1.55]) and standard regimens (RR 2.01 [1.64–2.47]), the relative magnitude of such an increase was lower in association with prasugrel or ticagrelor as compared with clopidogrel. The risk of bleeding using a combination of GPI and oral antiplatelet regimens is mainly related to the use of GPI and not the oral antiplatelet regimen. Considering the absence of increased risk of bleeding and the persistence of the benefit of recent P2Y₁₂ regimens in combination with GPI as compared with the standard clopidogrel regimen, the use of such a combination within the guidelines is supported by our findings.     

The David Y. Graham lecture: use of nonsteroidal antiinflammatory drugs in a COX-2 restricted environment

Recent evidence suggests that both cyclooxygenase-2 (COX-2) inhibitors and nonselective NSAIDs, with the possible exception of naproxen, increase cardiovascular (CV) hazard. Clinicians should assess not only patients' GI risk but also their CV risk before prescribing these drugs. Patients with low CV risk can be managed according to their GI risk—low-risk patients (without risk factors) receive nonselective NSAIDs, medium risk patients (1–2 risk factors) receive COX-2 inhibitors or nonselective NSAIDs plus a proton pump inhibitor (PPI) or misoprostol, whereas high-risk patients (multiple risk factors, previous ulcer complications, or concomitant anticoagulants) receive a COX-2 inhibitor plus a PPI or misoprostol. Among patients with high CV risk ( e.g. , prior cardiothrombotic events) who require NSAIDs, naproxen is preferred. These patients should receive a prophylactic PPI or misoprostol because the risk of ulcer bleeding is substantially increased with concomitant use of naproxen and low-dose aspirin. Substitution of clopidogrel for aspirin is not recommended in patients at risk for upper GI bleeding who require antiplatelet therapy. Patients with high GI and high CV risk should avoid NSAIDs and COX-2 inhibitors. If antiinflammatory analgesics are required, the choice of therapy depends on the relative importance of GI and CV risks of individual patients. Combination of naproxen, low-dose aspirin, and a PPI or misoprostol is recommended if CV risk is the major concern ( e.g. , recent myocardial infarction). In contrast, combination of low-dose COX-2 inhibitor, low-dose aspirin, and a PPI or misoprostol is preferred if GI risk outweighs CV risk ( e.g. , recent ulcer bleeding and stable CV disease).     

Cangrelor inhibits the binding of the active metabolites of clopidogrel and prasugrel to P2Y12 receptors in vitro

Cangrelor is a rapid-acting, direct-binding, and reversible P2Y₁₂ antagonist which has been studied for use during percutaneous coronary intervention (PCI) in patients with or without pretreatment with an oral P2Y₁₂ antagonist. As cangrelor is administered intravenously, it is necessary to switch to an oral P2Y₁₂ antagonist following PCI, such as the thienopyridines clopidogrel, and prasugrel or the non-pyridine ticagrelor. Previous studies have suggested a negative pharmacodynamic interaction between cangrelor and thienopyridines. This in vitro study evaluated the receptor-level interaction between cangrelor and the active metabolite (AM) of clopidogrel or prasugrel by assessing functional P2Y₁₂ receptor number using a ³³P-2MeSADP binding assay. All P2Y₁₂ antagonists studied resulted in strong P2Y₁₂ receptor blockade (cangrelor: 93.6%; clopidogrel AM: 93.0%; prasugrel AM: 97.9%). Adding a thienopyridine AM in the presence of cangrelor strongly reduces P2Y₁₂ receptor blockade by the AM (clopidogrel AM: 7%, prasugrel AM: 3.2%). The thienopyridine AMs had limited ability to compete with cangrelor for binding to P2Y₁₂ (% P2Y₁₂ receptor blockade after co-incubation with cangrelor 1000?nmol/L: 11.7% for clopidogrel AM 3?µmol/L; 34.1% for prasugrel AM 3?µmol/L). In conclusion, in vitro cangrelor strongly inhibits the binding of clopidogrel and prasugrel AMs to the P2Y₁₂ receptor, consistent with the previous observation of a negative pharmacodynamic interaction. Care may need to be taken to not overlap exposure to thienopyridine AMs and cangrelor in order to reduce the risk of thrombotic complications following PCI.     

Comparison of P2Y12 inhibitors for mortality and stent thrombosis in patients with acute coronary syndromes: Single center study of 10 793 consecutive ‘real-world’ patients

Three oral platelet P2Y₁₂ inhibitors, clopidogrel, prasugrel, and ticagrelor, are available for reducing the risk of cardiovascular death and stent thrombosis in patients with acute coronary syndromes (ACS). We sought to compare the efficacy of these antiplatelet drugs in contemporary practice.

Data were collected for 10 793 consecutive ACS patients undergoing coronary angiography at Sheffield, UK (2009–2015). Since prasugrel use was mostly restricted to the STEMI subgroup, clopidogrel and ticagrelor were compared for all ACS patients, and all three agents were compared in the STEMI subgroup. Differences in outcomes were evaluated at 12 months by KM curves and log-rank test after adjustment for independent risk factors.

Of 10 793 patients with ACS (36% STEMI), 43% (4653) received clopidogrel, 11% (1223) prasugrel and 46% (4917) ticagrelor, with aspirin for all. In the overall group, ticagrelor was associated with lower all-cause mortality compared with clopidogrel (adjusted hazard ratio (adjHR) 0.82, 95% confidence intervals (CI) 0.71–0.96, p = 0.01). In the STEMI subgroup, both prasugrel and ticagrelor were associated with a lower mortality compared with clopidogrel (prasugrel vs. clopidogrel: adjHR 0.65, CI 0.48–0.89, p = 0.007; ticagrelor vs. clopidogrel: adjHR 0.70, CI 0.61–0.99, p = 0.05). Of the 7595 patients who underwent PCI, 78 (1.0%) had definite stent thrombosis by 12 months. Patients treated with ticagrelor had a lower incidence of definite stent thrombosis compared with clopidogrel (0.6% vs. 1.1%; adjHR 0.51, CI 0.29–0.89, p = 0.03). In the STEMI subgroup, there was no significant difference between the three groups (ticagrelor 1.0%, clopidogrel = 1.5%, prasugrel = 1.6%; p = 0.29).

In conclusion, ticagrelor was superior to clopidogrel for reduction in both mortality and stent thrombosis in unselected invasively managed ACS patients. In STEMI patients, both ticagrelor and prasugrel were associated with lower mortality compared with clopidogrel, but there was no significant difference in the incidence of stent thrombosis.     

Evolving pattern of platelet P2Y12 inhibition in patients with acute coronary syndromes

Abstract

Dual antiplatelet therapy consisting of clopidogrel in addition to aspirin has previously been the standard of care for patients with acute coronary syndromes (ACS) but international guidelines have been evolving over the last 4 years with the introduction of prasugrel and ticagrelor. In October 2009, prasugrel was approved in the UK by the National Institute of Health and Clinical Excellence (NICE) for use in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), diabetic patients with non-ST-elevation (NSTE) ACS undergoing PCI and patients with stent thrombosis while other ACS patients were to continue receiving clopidogrel. Ticagrelor was approved in October 2011 by NICE for use in patients with moderate-to-high risk NSTE ACS and STEMI undergoing primary PCI and was recommended in preference to clopidogrel in European guidelines. These recommendations were adopted in our region, constituting a population of 1.8 million. We studied the effect of changing patterns of P2Y₁₂ inhibitor usage on levels of platelet inhibition during maintenance therapy. Patients admitted to Northern General Hospital, Sheffield, with NSTE ACS or STEMI managed with primary PCI were enrolled over two periods of time: May 2010 to November 2011 (T1); and October 2012 to February 2013 (T2). Venous blood samples were obtained at 1 month after the onset of ACS. Light transmittance aggregometry (LTA) was performed and maximum aggregation response to ADP 20?μM was determined. A total of 116 patients were enrolled in T1 of whom 82 were receiving clopidogrel and 34 were receiving prasugrel. Twenty-nine patients were enrolled in T2, all of whom were receiving ticagrelor. Mean LTA results according to treatment with clopidogrel, prasugrel and ticagrelor were 57?±?18%, 41?±?20%, and 31?±?12%, respectively. Prasugrel was associated with significantly lower platelet aggregation responses than clopidogrel (p?<?0.001) and ticagrelor was associated with significantly lower platelet aggregation responses than both prasugrel (p?=?0.015) and clopidogrel (p?<?0.001). We conclude that international guidelines and NICE approval have led to increasing levels of P2Y₁₂ inhibition in ACS patients in this UK centre between May 2010 and February 2013. Ticagrelor was associated with significantly greater P2Y₁₂ inhibition than both clopidogrel and prasugrel during maintenance therapy.     

Antiplatelet efficacy of P2Y<Subscript>12</Subscript> inhibitors (prasugrel,ticagrelor, clopidogrel) in patients treated with mild therapeutic hypothermia after cardiac arrest due to acute myocardial infarction

Survivors after cardiac arrest (CA) due to AMI undergo PCI and then receive dual antiplatelet therapy. Mild therapeutic hypothermia (MTH) is recommended for unconscious patients after CA to improve neurological outcomes. MTH can attenuate the effectiveness of P2Y₁₂ inhibitors by reducing gastrointestinal absorption and metabolic activation. The combined effect of these conditions on the efficacy of P2Y₁₂ inhibitors is unknown. We compared the antiplatelet efficacies of new P2Y₁₂ inhibitors in AMI patients after CA treated with MTH. Forty patients after CA for AMI treated with MTH and received one P2Y₁₂ inhibitor (clopidogrel, prasugrel or ticagrelor) were enrolled in a prospective observational single-center study. Platelet inhibition was measured by VASP (PRI) on days 1, 2, and 3 after drug administration. In-hospital clinical data and 1-year survival data were obtained. The proportion of patients with ineffective platelet inhibition (PRI > 50 %, high on-treatment platelet reactivity) for clopidogrel, prasugrel, and ticagrelor was 77 vs. 19 vs. 1 % on day 1; 77 vs. 17 vs. 0 % on day 2; and 85 vs. 6 vs. 0 % on day 3 (P < 0.001). The platelet inhibition was significantly worse in clopidogrel group than in prasugrel or ticagrelor group. Prasugrel and ticagrelor are very effective for platelet inhibition in patients treated with MTH after CA due to AMI, but clopidogrel is not. Using prasugrel or ticagrelor seems to be a more suitable option in this high-risk group of acute patients.     

Platelet adenosine diphosphate receptor antagonists: ticlopidine to ticagrelor-a long continuing journey

Platelet aggregation plays a central role in the pathogenesis of atherothrombosis. Platelet adenosine diphosphate (ADP) receptor antagonists (ticlopidine, clopidogrel, prasugrel, and ticagrelor) are a major advance in the treatment of atherothrombotic diseases, especially acute coronary syndromes (ACS). Ticlopidine was the first thienopyridine introduced into clinical practice, but its potentially serious haematological side-effects limited its use and it was quickly eclipsed by clopidogrel. Clinical trials established aspirin plus clopidogrel as the standard dual anti-platelet therapy in patients with ACS and patients undergoing percutaneous coronary intervention (PCI) with stenting. Clopidogrel was found to have pharmacokinetic and pharmacodynamic limitations. Prasugrel is the next approved thienopyridine that has shown superior efficacy in ACS patients undergoing PCI in comparison to clopidogrel, although at the cost of a higher bleeding risk. Ticagrelor is the latest non-thienopyridine ADP receptor blocker that is potent, effective, reversible, and relatively safer as compared to clopidogrel. Both prasugrel and ticagrelor are more potent than clopidogrel. The data so far suggests that ticagrelor has a wider applicability in usage in patients with ACS as compared to prasugrel. Prasugrel however seems to be better tolerated. Search is on for newer more potent but safer anti-platelet agents.     

A study on the impact of CYP2C19 genotype and platelet reactivity assay on patients undergoing PCI

Background

A thorough understanding of the patient''s genotype and their functional response to a medication is necessary for improving event free survival. Several outcome studies support this view particularly if the patient is to be started on clopidogrel due to the prevalence of clopidogrel resistance. Such guided therapy has reduced the incidence of Major Adverse Cardiac Events (MACE) after stent implantation.

Methods

Between August 2013 and August 2014, 200 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) were prescribed any one of the anti-platelet medications such as clopidogrel, prasugrel or ticagrelor and offered testing to detect CYP2C19 gene mutations along with a platelet reactivity assay (PRA). Intended outcome was modification of anti-platelet therapy defined as either dose escalation of clopidogrel or replacement of clopidogrel with prasugrel or ticagrelor for the patients in clopidogrel arm, and replacement of ticagrelor or prasugrel with clopidogrel if those patients were non-carrier of mutant genes and also if they demonstrated bleeding tendencies in the ticagrelor and prasugrel arms.

Conclusion

Clopidogrel resistance was observed to be 16.5% in our study population. PRA was useful in monitoring the efficacy of thienopyridines. By having this test, one can be safely maintained on clopidogrel in non-carriers, or with increased dose of clopidogrel in intermediate metabolizers or with newer drugs such as ticagrelor or prasugrel in poor metabolizers. Patients on ticagrelor and prasugrel identified as non-carriers of gene mutations for clopidogrel metabolism could be offered clopidogrel resulting in economic benefits to the patients. Patients at high risk of bleeding were also identified by the PRA.     

Switching antiplatelet regimens: Alternatives to clopidogrel in patients with acute coronary syndrome undergoing PCI: A review of the literature and practical considerations for the interventional cardiologist

Dual antiplatelet therapy with aspirin plus a P2Y₁₂ receptor inhibitor is the cornerstone of treatment for patients with acute coronary syndrome and in those undergoing percutaneous coronary intervention. Clopidogrel is the most widely used P2Y₁₂ receptor inhibitor. Despite the clinical benefits associated with adjunctive clopidogrel therapy, a considerable number of patients continue to experience recurrent cardiovascular events. Importantly, the interindividual response to clopidogrel is variable and is affected by multiple factors, including genetic polymorphisms and drugs that interfere with the conversion of clopidogrel to its active metabolite. The individual variability to clopidogrel‐induced antiplatelet effects has significant clinical implications that can result in an increased risk of atherothrombotic recurrences, including stent thrombosis. The introduction of novel P2Y₁₂ receptor inhibitors, such as prasugrel or ticagrelor, characterized by more potent and consistent platelet inhibitory effects, represents an opportunity for clinicians to consider these alternative therapies to overcome the limitations of clopidogrel. Understanding the strategies and implications of switching antiplatelet treatment regimens is, therefore, key in the clinical setting. This article provides an overview of the literature on switching antiplatelet treatment strategies and practical considerations for the interventional cardiologist. © 2012 Wiley Periodicals, Inc.     

Clinical relevance of clopidogrel-proton pump inhibitors interaction

Clopidogrel is a widely used antiplatelet agent for the secondary prevention of cardiovascular events in patients with stable coronary heart disease, acute coronary syndromes and ischemic stroke. Even though clopidogrel is safer than aspirin in terms of risk for gastrointestinal(GI) bleeding, the elderly, and patients with a history of prior GI bleeding, with Helicobacter pylori infection or those who are also treated with aspirin, anticoagulants, corticosteroids or nonsteroidal antiinflammatory drugs are at high risk for GI complications when treated with clopidogrel. Accordingly, proton pump inhibitors are frequently administered in combination with clopidogrel to reduce the risk for GI bleeding. Nevertheless, pharmacodynamic studies suggest that omeprazole might attenuate the antiplatelet effect of clopidogrel. However, in observational studies, this interaction does not appear to translate into increased cardiovascular risk in patients treated with this combination. Moreover, in the only randomized, double-blind study that assessed the cardiovascular implications of combining clopidogrel and omeprazole, patients treated with clopidogrel/omeprazole combination had reduced risk for GI events and similar risk for cardiovascular events than patients treated with clopidogrel and placebo. However, the premature interruption of the study and the lack of power analysis in terms of the cardiovascular endpoint do not allow definite conclusions regarding the cardiovascular safety of clopidogrel/omeprazole combination. Other proton pump inhibitors do not appear to interact with clopidogrel. Nevertheless, given the limitations of existing observational and interventional studies, the decision to administer proton pump inhibitors to patients treated with clopidogrel should be individualized based on the patient’s bleeding and cardiovascular risk.     

Anithrombotische Therapie und Vorhofflimmern

Current guidelines recommend dual antiplatelet therapy preferably with prasugrel or ticagrelor for 12 months in patients after acute coronary syndrome with stent implantation. Problems occur in patients with a need for oral anticoagulation, such as patients with atrial fibrillation. In these patients a combination of oral anticoagulation and platelet inhibitors is necessary. Antithrombotic combination therapy is known to increase bleeding complications. In a small randomized trial the combination of a vitamin K antagonist (VKA) and clopidogrel decreased bleeding compared to triple therapy with VKA, clopidogrel and aspirin. The new oral anticoagulants have consistently been shown to decrease bleeding complications compared to VKAs regardless of additional antiplatelet therapy. Because of the lack of randomized trials the individual decision about the intensity and duration of antithrombotic combination therapy should be based on the bleeding and ischemic risk in the individual patient. However, in most patients in addition to oral anticoagulation, antiplatelet monotherapy preferably with clopidogrel seems necessary only for 3–6 months.