Efficacy and safety analysis of new P2Y12 inhibitors versus clopidogrel in patients with percutaneous coronary intervention: a meta-analysis

Objective:

New P2Y₁₂ inhibitors, classified as oral (prasugrel and ticagrelor) and intravenous (cangrelor and elinogrel) drugs, have shown improved antithrombotic effects compared with clopidogrel in patients with acute coronary syndrome (ACS) or patients undergoing percutaneous coronary intervention (PCI) in landmark trials. The purpose of this study was to perform a meta-analysis of randomized trials that compared new P2Y₁₂ inhibitors with clopidogrel to determine their efficacy and safety in patients undergoing PCI.

Methods:

Randomized controlled trials of at least 4 weeks, comparing new P2Y₁₂ inhibitors with clopidogrel in PCI, were identified using the electronic databases Cochrane Central Register of Controlled Trials, Medline, PubMed, Web of Science, and Google Scholar from January 1, 1980, to July 31, 2014.

Main outcome measures:

The primary efficacy endpoints were all-cause death and major adverse cardiovascular events (MACEs). The primary safety endpoint was thrombolysis in myocardial infarction (TIMI) major bleeding.

Results:

Twelve studies including 71,097 patients met the inclusion criteria. New P2Y₁₂ inhibitors significantly reduced all-cause death (odds ratio [OR]: 0.81; 95% confidence interval [CI] 0.73–0.90, p?p?p?p?=?0.03) and cardiovascular death (OR 0.82; 95% CI 0.73–0.92, p?=?0.001) compared with clopidogrel. There were no significant differences between stroke (OR 0.87; 95% CI 0.72–1.05, p?=?0.14) and major bleeding events (OR 1.22; 95% CI 0.99–1.52, p?=?0.06) between the new P2Y₁₂ inhibitor and clopidogrel groups.

Conclusion:

New P2Y₁₂ inhibitors decreased death in patients undergoing PCI compared with clopidogrel with a considerable safety and tolerability profile; however, the risk/benefit ratio of ischemic and bleeding events should be further investigated.     

Pharmacokinetics and pharmacodynamics of ticagrelor in the treatment of cardiac ischemia

Introduction: After acute coronary syndromes (ACS), the so-called dual antiplatelet therapy (DAPT), which usually consists of low-dose of aspirin in combination with a thienopyridine (clopidogrel, prasugrel) or with a cyclopentyltriazolopyrimidine (ticagrelor), reduces the risk of ischemic events. Ticagrelor, un particular, is an effective drug as it isn’ a prodrug, doesn’t require metabolic activation and demonstrates a rapid onset and faster offset of action.

Areas covered: This article evaluates the pharmacokinetics, efficacy, safety and tolerability of ticagrelor during DAPT after ACS and its potential use beyond the canonical twelve months after PCI. The review discusses studies comparing: ticagrelor and clopidogrel (DISPERSE, DISPERSE-2, PLATO, RESPOND Trial, ONSET/OFFSET Trials), ticagrelor and placebo (PEGASUS TIMI 54 Trial).

Expert opinion: For ACS patients, the PLATO trial showed that ticagrelor was superior to clopidogrel in the reduction of cardiovascular death, myocardial infarction and stroke. PEGASUS TIMI 54 showed that patients in whom ischemic events and cardiovascular death outweigh the risk of life-threatening bleeding, may benefit from prolonged ticagrelor-based dual antiplatelet therapy, over 12 months. This strategy has been recently approved by the ACC/AHA guidelines. Further studies are needed to evaluate and eventually validate the role of the prolonged DAPT in patients treated with new generation stents.     

Safety of bivalirudin in patients with coronary artery disease

Introduction: Various limitations of unfractionated heparin (UFH) have triggered a search for new antithrombotic therapies for patients with coronary artery disease (CAD). Bivalirudin is a direct thrombin inhibitor with several pharmacological advantages over UFH and is currently endorsed by practice guidelines, particularly in patients with acute coronary syndromes undergoing percutaneous coronary intervention (PCI). To maximize effectiveness of an antithrombotic regimen and reduce complications, both ischemic and bleeding risks should be known when an antithrombotic strategy is chosen.

Areas covered: This review focuses on the safety and tolerability of bivalirudin in patients with CAD in the setting of currently approved indications. Synthesis of evidence has been made from clinical trials, systematic reviews, meta-analyses and registries (1992 – 2011). The reader is provided with an overview of pharmacological properties of bivalirudin and its efficacy, with special emphasis on its safety in patients with CAD.

Expert opinion: Bivalirudin has an impressive safety profile in CAD patients treated with PCI. Bivalirudin is the antithrombotic of choice in suspected or verified heparin-induced thrombocytopenia. For ST elevation myocardial infarction patients undergoing primary PCI, bivalirudin should become the preferred antithrombotic agent together with early institution of antiplatelet therapy.     

Resistance to antiplatelet drugs: what progress has been made?

Introduction: Despite well-documented efficacy, recurrent thrombotic event occurrences, particularly stent thrombosis, have been repeatedly demonstrated in stented patients treated with aspirin and clopidogrel. The latter observation stimulated the close scrutiny of the pharmacodynamic effects of clopidogrel and revealed the ‘wide variability’ and the phenomenon of ‘antiplatelet resistance’. High on-treatment platelet reactivity to ADP (HPR) during clopidogrel therapy is an independent risk factor for ischemic event occurrences in post-percutaneous coronary intervention (post-PCI) patients. Recent observational studies demonstrated a link between low on-treatment platelet reactivity to bleeding. The concept of a ‘therapeutic window’ of P2Y₁₂ receptor reactivity associated with both ischemic event occurrence (upper threshold) and bleeding risk (lower threshold) has been proposed.

Areas covered: An update on and a brief review of the current knowledge on antiplatelet resistance were presented. Evidence available from studies evaluating aspirin resistance and high and low on-treatment platelet reactivity to ADP during P2Y₁₂ receptor blocker therapy was collected from a selective literature search.

Expert opinion: The available evidence indicates that HPR is an independent risk factor for post-PCI ischemic event occurrences. The therapeutic window concept for the P2Y₁₂ receptor blocker therapy may facilitate the balance between reducing ischemic events and avoiding bleeding events, thereby improving net clinical outcome.     

Tobramycin for the treatment of bacterial pneumonia in children

Introduction: Percutaneous coronary intervention (PCI) is a highly effective treatment for obstructive coronary artery disease. Oral platelet P2Y₁₂ receptor antagonists reduce ischemic events in patients treated with PCI. However, there are several limitations to their use, including variable pharmacodynamics, a slow onset and offset, and in those patients who are pretreated but subsequently require cardiac surgery, increased bleeding. Cangrelor is an intravenous agent that provides rapid and intensive inhibition of the P2Y₁₂ receptor that quickly dissipates after discontinuation. A recent, Phase III randomized clinical trial of PCI patients demonstrated that cangrelor bolus and infusion reduced ischemic events compared with conventional clopidogrel therapy without increasing major bleeding.

Areas covered: This review outlines the pharmacodynamics, pharmacokinetics, and the safety and efficacy of cangrelor for the acute treatment of patients undergoing planned PCI.

Expert opinion: Cangrelor is an important addition to the current armamentarium of platelet inhibitors as it significantly reduces periprocedural myocardial infarction and stent thrombosis in a broad spectrum of patients, without increasing major bleeding or the need for transfusion. Cangrelor will have particular benefit in clopidogrel-naïve patients with high anatomical complexity and/or increased clinical risk (where the absolute risk for thrombotic and ischemic complications of PCI is greatest).     

Prasugrel hydrochloride for the treatment of acute coronary syndromes

Introduction: P2Y12 receptor antagonists, by inhibiting platelet activation and subsequent aggregation, are critical to prevent ischemic event recurrence after an acute coronary syndrome (ACS). Prasugrel is a third-generation thienopyridine whose metabolites target the P2Y12 receptor. Compared with clopidogrel, prasugrel has a more potent, faster in onset, and more consistent P2Y12 receptor inhibition.

Areas covered: This review describes prasugrel chemistry, pharmacokinetics, pharmacodynamics and clinical studies. In a Phase III randomized clopidogrel-controlled trial, prasugrel improved cardiovascular outcome (risk reduction of cardiovascular death, non-fatal heart attack and non-fatal stroke) at the cost of increased major and fatal bleeding complications. Prasugrel, in combination with aspirin, has been approved by European and American regulatory agencies for the prevention of atherothrombotic events in patients with ACS who undergo percutaneous coronary intervention (PCI).

Expert opinion: Prasugrel is effective for managing ACS patients with planned PCI and it offers an alternative with potential benefits over clopidogrel. Prasugrel is currently challenged by ticagrelor, a P2Y12 receptor antagonist with different pharmacokinetic/pharmacodynamic properties. The superiority of one drug to the other cannot be reliably estimated from the current trials. Ongoing randomized and observational studies may help to provide valuable information on the safety and efficacy of these two drugs and their respective places with ACS patients.     

Cost-effectiveness of clopidogrel treatment in percutaneous coronary intervention: a European model based on a meta-analysis of the PCI-CURE,CREDO and PCI-CLARITY trials*

ABSTRACT

Objective: Our objective was to conduct a comprehensive cost-effectiveness analysis of pre-treatment and long-term treatment with clopidogrel in percutaneous coronary intervention (PCI) in three European countries based on a meta-analysis of the PCI-Clopidogrel in Unstable angina to prevent Recurrent Events (CURE), Clopidogrel for the Reduction of Events During Observation (CREDO) and PCI-Clopidogrel as Adjunctive Therapy (CLARITY) trials. This analysis adds to existing knowledge by providing further data on the cost-effectiveness of clopidogrel in PCI across a wide spectrum of patients.

Methods: A combined decision tree and Markov model was created. The relative risks of myocardial infarction, cardiovascular death and of major bleedings with clopidogrel were based on a fixed-effects meta-analysis. The risk of ischaemic events in untreated patients and long-term survival were taken from the Swedish hospital and death registers. A societal perspective was used in Sweden and a payer perspective in Germany and France. Costs are stated in €2006 and effectiveness measured in quality-adjusted life-years (QALYs).

Results: The pooled effects of clopidogrel on the combined endpoint showed a relative risk of 0.711 (p = 0.003) at 30 days and 0.745 (p = 0.002) at end of follow-up (up to 1 year). Pre-treatment with clopidogrel compared with aspirin alone is a dominant strategy. Long-term treatment with clopidogrel compared with 1-month treatment leads to approximately 0.09 QALYs at an incremental cost of €393 in Sweden, €709 in Germany and €494 in France. The corresponding incremental cost-effectiveness ratios range from €4225/QALY to €7871/QALY.

Conclusion: The results of this modelling analysis suggest that pre-treatment and long-term treatment in PCI with clopidogrel for up to 1 year are cost-effective in a range of patient groups and settings given commonly accepted thresholds.     

Prasugrel: a novel platelet ADP P2Y12 receptor antagonist. A review on its mechanism of action and clinical development

Antiplatelet therapy is the cornerstone of treatment for patients who present with acute coronary syndrome (ACS) or undergo percutaneous coronary intervention (PCI). Clopidogrel, in combination with aspirin, is associated with improvement in long-term clinical outcomes in these patients and is currently the antiplatelet therapy of choice. However, a significant number of patients experience recurrent ischemic events, which have been in part attributed to variability in individual response profiles to currently recommended treatment regimens. The presence of variable degrees of responsiveness, thus inadequate platelet inhibition in some patients, underscores the need for novel agents with more potency and less variable platelet inhibitory effects. Prasugrel (CS-747; LY640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet adenosine diphosphate (ADP) P2Y₁₂ receptor. Pre-clinical and early phase clinical studies have shown prasugrel to be characterized by more potent antiplatelet effects, lower interindividual variability in platelet response, and faster onset of activity compared with clopidogrel. Recent findings from large-scale Phase III testing showed prasugrel to be more efficacious in preventing ischemic events in ACS patients undergoing PCI; however, this is achieved at the expense of an increased risk of bleeding. This article reviews the currently available data regarding the efficacy and safety of prasugrel.     

Clinical impact of early clopidogrel discontinuation following acute myocardial infarction hospitalization or stent implantation: analysis in a nationally representative managed-care population

ABSTRACT

Objectives: To evaluate the association between discontinuation of clopidogrel therapy and risk of acute myocardial infarction (AMI) hospitalization or cardiac revascularization in a nationally-representative patient population following hospitalization for an AMI or coronary stent insertion.

Research design and methods: This observational cohort study was performed using data on patients from the PharMetrics Anonymous Patient-Centric Database who were hospitalized for an AMI or coronary stent insertion and subsequently treated with clopidogrel. Cox proportional hazard modeling was used to evaluate the association between clopidogrel discontinuation prior to 1 year post-initial AMI hospitalization and the primary endpoint of repeat AMI hospitalization or coronary intervention defined as percutaneous coronary intervention (PCI) with or without stent, or coronary artery bypass graft (CABG).

Main outcome measures: The main outcome for this study was AMI hospitalization or coronary intervention defined as PCI with or without stent placement or CABG.

Results: A total of 31?835 patients were included in the analyses. Patients were predominantly male and the average patient age was approximately 60 years. After controlling for baseline patient characteristics and follow-up time, discontinuation of clopidogrel was associated with a significantly higher rate of hospitalization for AMI or coronary intervention (HR 1.34, 95% CI 1.22–1.44).

Conclusion: Within a population of ACS patients drawn from a database of 85 US health plans, clopidogrel discontinuation within 1 year following hospitalization for AMI or stent placement is associated with an increased risk of AMI hospitalization or coronary intervention. The results of this study should be interpreted within the context of observational research, which does not address cause and effect relationships.     

Cardiovascular events associated with nicorandil administration prior to primary percutaneous coronary intervention in patients with acute ST-segment elevated myocardial infarction: a systematic review and meta-analysis

Introduction: Nicorandil may exert cardioprotective effects in ischemic heart disease. However, its efficacy in combination with early reperfusion is uncertain. The authors performed a meta-analysis of the short- and long-term clinical outcomes of nicorandil administration at the time of primary percutaneous coronary intervention (PCI) in patients with ST-elevated myocardial infarction (STEMI).

Methods: PubMed, MEDLINE, Embase, and the Cochrane Library databases were systematically searched for eligible randomized controlled studies. The primary endpoint was major adverse cardiovascular events (MACE), both in-hospital and post-discharge. The secondary endpoint was the incidence of no-reflow phenomenon.

Results: Ten studies were included (n = 1105). Mean patient age was 63.0 ± 10.0 years; 76.6% of patients were male. Compared with controls who received primary PCI, combined nicorandil/primary PCI significantly reduced in-hospital MACE (pooled odds ratio [OR] 0.16; 95% confidence interval [CI] 0.09–0.27), follow-up MACE (pooled OR 0.53; 95% CI 0.37–0.75), and total MACE (pooled OR 0.27; 95% CI 0.15–0.49). The combined treatment also reduced the incidence of no-reflow phenomenon (pooled OR 0.34; 95% CI 0.23–0.50).

Conclusion: Nicorandil administration at the time of primary PCI is associated with reduced MACE (both short- and long-term) and no-reflow phenomenon in patients with STEMI.     

Developments in antiplatelet therapy for acute coronary syndromes and considerations for long-term management

ABSTRACT

Objective: This article reviews the currently available antiplatelet therapies and emerging investigational drugs in the treatment of acutecoronary syndrome (ACS), and considerations for primary and secondary prevention in the long-term management of ACS patients undergoing percutaneous coronary intervention (PCI).

Research design and methods: Primary studies and reviews in the peer-reviewed, English-language literature were identified through searches of MEDLINE (1966–2008) using the terms ‘acute coronary syndrome’, ‘antiplatelet’, ‘aspirin’, ‘long-term management’, ‘P2Y₁₂ receptor’, and ‘thienopyridine’. Additional references were obtained by searching the reference lists of the identified articles. Articles were included if they were recently published and pertinent, patient-focused, and authors were recognized as leaders in the field. Current review is limited by literature search on single database.

Results: Platelets play a major role in atherogenesis and the formation of thrombi, the main events in the pathogenesis of ACS. Although aspirin is an effective antiplatelet agent, efficacy and safety data from a number of randomized clinical trials on atherothrombotic disease support the use of dual antiplatelet therapies such as aspirin and thienopyridines over single antiplatelet therapy for ACS and up to 1?year following ACS. Antiplatelet agents reduce, but do not eliminate, ischemic events after ACS due, in part, to variable individual response (or resistance) in antiplatelet agents, non-compliance, progression of atherosclerosis, modest inhibition of platelet aggregation (IPA) levels and other factors. Several antiplatelet agents, including novel P2Y₁₂-receptor antagonists and thrombin-receptor antagonists, are currently under investigation for ACS and primary and secondary prevention in the long-term management of patients undergoing PCI.

Conclusions: Current antiplatelet therapies have clinical benefits such as reducing immediate and long-term cardiovascular risk, but substantial residual risk remains indicating a need for new therapeutic agents. Additional large randomized trials are necessary to determine the most appropriate treatment regimens for ACS patients.     

Incidence of death and recurring acute coronary syndrome after stopping clopidogrel therapy in a large commercially-insured population in the US

Abstract

Background/objective:

Guidelines support clopidogrel therapy in medically-treated or percutaneous coronary intervention (PCI) patients after hospitalization for acute coronary syndrome (ACS). However, clopidogrel discontinuation has been associated with increased short-term risks. This study evaluated the risk of adverse outcomes (AOs), defined as death or recurrent ACS, after clopidogrel discontinuation in a managed-care population.     

Cangrelor for the treatment of patients with Arterial Thrombosis

Introduction: All oral P2Y₁₂ receptor blockers are associated with some degree of delayed onset and offset of pharmacodynamic (PD) effects in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). Although intravenous glycoprotein IIb/IIIa inhibitors are associated with rapid onset of action, they are also associated with delayed offset and other limitations such as elevated bleeding risk and thrombocytopenia.

Areas covered: In this review, the authors focus on cangrelor, an intravenous, reversible P2Y₁₂ receptor blocker with fast onset and offset of effects. The authors also describe the pharmacologic effects of cangrelor and its pharmacologic interaction with other P2Y₁₂ receptor inhibitors. Finally, the authors discuss the large-scale clinical trials that compared the efficacy and safety of cangrelor with clopidogrel.

Expert opinion: In ACS patients undergoing PCI, cangrelor is most desirable to effectively prevent periprocedural ischemic events and to avoid excessive bleeding. Indeed, any high-risk patient with ST-segment elevation myocardial infraction or patient who is unable to take oral medications is a potential candidate for intravenous cangrelor therapy. Furthermore, stable patients with coronary artery disease, who are considered for ad hoc PCI following coronary angiography, may be considered for treatment with cangrelor to reduce post-PCI thrombotic events.     

Comparison of antiplatelet effect and safety of clopidogrel napadisilate with clopidogrel bisulfate in stroke patients: multicenter,randomized, open-label,phase 4, non-inferiority clinical trial

Objective:

Clopidogrel napadisilate has better chemical stability than clopidogrel bisulfate. Our trial’s objective was to compare the efficacy and safety of clopidogrel napadisilate with clopidogrel bisulfate in participants with ischemic stroke.

Research design and methods:

The study was a phase 4, 4 week, randomized, parallel-group, non-inferiority trial. Patients with ischemic stroke were randomized to receive either clopidogrel napadisilate 75?mg or clopidogrel bisulfate 75?mg. The primary study endpoint was change from baseline in P2Y12 percentage inhibition at week 4. The primary analysis was conducted in the per-protocol population. Non-inferiority was confirmed if the lower limit of the 95% confidence interval (CI) of the treatment difference was greater than or equal to ?9.0% points.

Results:

Sixty-one participants were randomly assigned clopidogrel napadisilate and 60 were randomly assigned clopidogrel bisulfate. Thirty-nine participants in the clopidogrel napadisilate group and 39 in the clopidogrel bisulfate group were analyzed for the primary endpoint. At 4 weeks, mean P2Y12 percentage inhibition had increased in both treatment groups. The estimated mean change from baseline was 22.3% with clopidogrel napadisilate and 21.4% with clopidogrel bisulfate; the estimated treatment difference of 0.9% (95% CI, ?8.6 to 10.4) confirmed the non-inferiority of clopidogrel napadisilate to clopidogrel bisulfate.

Conclusions:

Clopidogrel napadisilate was non-inferior to clopidogrel bisulfate as assessed by change in P2Y12 percentage inhibition. Rates of adverse events were similar between the two groups. Therefore, clopidogrel napadisilate is a useful alternative option for the dosing of ischemic stroke patient populations.     

Optimizing the treatment of hypertension and stable coronary artery disease: clinical evidence for fixed-combination perindopril/amlodipine

ABSTRACT

Background: Optimized management of hypertension and coronary artery disease (CAD) improves cardiovascular risk and outcomes, and prevents complications. This article reviews evidence for the fixed combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril and the calcium channel blocker amlodipine.

Methods: A literature search was performed in PubMed/MEDLINE to identify articles published in English between 1988 and March 2008 describing clinical trials, particularly outcome trials, or mechanisms of therapeutic action relevant to the use of combination therapy in patients with hypertension or stable coronary artery disease with an ACE inhibitor (perindopril) and a calcium channel blocker (amlodipine).

Findings: Clinical trials indicate that this combination may have a positive impact on cardiovascular mortality and morbidity in hypertensive individuals. The two complementary mechanisms of action appear to work in synergy, leading to more efficient blood pressure lowering, improved fibrinolytic function, and reduction of secondary effects. This also represents a simplified management strategy for stable CAD. Perindopril has proven efficacy in the prevention of cardiovascular events and mortality in CAD patients, while amlodipine is widely used in the symptomatic management of CAD. Both aspects of guideline-recommended management of CAD are therefore addressed in a single tablet.

Conclusions: The clinical evidence for fixed-combination perindopril/amlodipine indicates it as a credible option for the optimization of the management of hypertension and CAD.     

Ticagrelor for the treatment of arterial thrombosis

Importance of the field: High platelet reactivity has been linked to recurrent ischemic events in patients treated with conventional dual antiplatelet therapy, in patients with arterial diseases and particularly in patients treated with coronary artery stenting. The limitations of clopidogrel have served as a major rationale for the development of new P2Y₁₂ blockers that have superior pharmacodynamic profiles uninfluenced by concomitant therapies or specific genotypes. Ticagrelor is the first direct-acting reversibly binding oral P2Y₁₂ receptor antagonist. Extensive Phase II investigations have addressed the pharmacokinetic, pharmacodynamic and safety-related properties of ticagrelor compared with clopidogrel. The recently completed PLATO trial demonstrated promise for ticagrelor as a major treatment strategy for a wide spectrum of patients with acute coronary syndromes. Ticagrelor is now being reviewed by the FDA as a P2Y₁₂ receptor blocker to treat patients with coronary artery disease and, once accepted, will be in widespread use as an antiplatelet agent. Thus, it is both appropriate and timely to review available data and provide a comprehensive review of ticagrelor.

Areas covered in this review: We discuss the rationale for the development of ticagrelor, a reversible and potent P2Y₁₂ receptor blocker. The data regarding ticagrelor based on preclinical and clinical studies are examined. We researched articles about ‘AZD6140’ and ‘ticagrelor’ in PubMed from 2006 to 2010 and also reviewed data presented at recent cardiology meetings.

What the reader will gain: This is an updated and comprehensive review of ticagrelor. The advantages and disadvantages of ticagrelor and available P2Y₁₂ receptor blockers such as clopidogrel and prasugrel are discussed, thus providing a clear picture to readers.

Take home message: Ticagrelor has an important role as an antiplatelet agent in the settings of acute coronary syndrome and percutaneous coronary intervention and once accepted will be in widespread use.     

Proton pump inhibitors and clopidogrel: is it a significant drug interaction?

Importance of the field: Clopidogrel is indicated as part of a dual antiplatelet therapy (DAT) with aspirin for the prevention of cardiac related events in acute coronary syndromes particularly in patients undergoing percutaneous coronary intervention. Recently, there have been reports of a clinically significant drug interaction between clopidogrel and proton pump inhibitors (PPI), which are frequently co-prescribed to prevent DAT associated gastrointestinal (GI) bleeding.

Areas covered in this review: This review evaluates the risk of GI bleeding associated with DAT and the rationale for the use of PPI. This review also describes the pharmacokinetic and pharmacodynamic basis for the interaction and evaluates its significance on clinical outcomes. An extensive literature search on PubMed from January 1980 to August 2009 was performed. Additionally, abstracts and presentations from key cardiology meetings and press releases were reviewed for relevant studies related to the interaction.

What the reader will gain: At the end of the review, readers should have a complete understanding of the interaction and steps that can be taken to limit the interaction.

Take home message: There is a mechanistic basis and pharmacodynamic data supporting an interaction between PPIs, particularly omeprazole and clopidogrel. The clinical significance of this interaction is, however, still a subject of intense debate and ongoing research.     

Safety of bivalirudin in patients with coronary artery disease

INTRODUCTION: Various limitations of unfractionated heparin (UFH) have triggered a search for new antithrombotic therapies for patients with coronary artery disease (CAD). Bivalirudin is a direct thrombin inhibitor with several pharmacological advantages over UFH and is currently endorsed by practice guidelines, particularly in patients with acute coronary syndromes undergoing percutaneous coronary intervention (PCI). To maximize effectiveness of an antithrombotic regimen and reduce complications, both ischemic and bleeding risks should be known when an antithrombotic strategy is chosen. AREAS COVERED: This review focuses on the safety and tolerability of bivalirudin in patients with CAD in the setting of currently approved indications. Synthesis of evidence has been made from clinical trials, systematic reviews, meta-analyses and registries (1992 - 2011). The reader is provided with an overview of pharmacological properties of bivalirudin and its efficacy, with special emphasis on its safety in patients with CAD. EXPERT OPINION: Bivalirudin has an impressive safety profile in CAD patients treated with PCI. Bivalirudin is the antithrombotic of choice in suspected or verified heparin-induced thrombocytopenia. For ST elevation myocardial infarction patients undergoing primary PCI, bivalirudin should become the preferred antithrombotic agent together with early institution of antiplatelet therapy.     

Effect of clopidogrel besylate on platelet reactivity in patients with acute coronary syndromes. Comparison with clopidogrel hydrogen sulfate

Objective: The efficacy of clopidogrel therapy in patients with an acute coronary syndrome (ACS) has been established using the clopidogrel hydrogen sulfate (CHS) formulation. In this study we compared the antiplatelet effectiveness of a generic clopidogrel salt, clopidogrel besylate (CB), with the original CHS in patients with an ACS.

Research design and methods: Ninety-six ACS patients were randomized to receive a 600-mg loading dose of either CHS (n = 45) or CB (n = 51), followed by 75 mg/day. Sixty-eight patients underwent a percutaneous coronary intervention (PCI), whereas 28 were treated conservatively. Platelet aggregatory response, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, P-selectin expression and platelet–leucocyte conjugates were determined before clopidogrel loading (baseline), as well as at 5 days and at 1 month afterwards.

Results: No difference in the clopidogrel response variability was observed between patients receiving CHS or CB either at 5 days or at 1 month of follow-up. Similarly, no difference in the inhibition of platelet aggregation, P-selectin expression or in the platelet–leucocyte conjugates was observed between CHS and CB group during the follow-up.

Conclusions: There is no overall significant difference in the antiplatelet efficacy between CB and CHS during their administration in ACS patients for up to 1 month after the episode.