Role of CYP2C19 genotype testing in clinical use of clopidogrel: is it really useful?

Introduction: P2Y12 inhibitors, including clopidogrel have become an integral part of treatment for patients receiving coronary stent placement as a result of stable coronary artery disease or acute coronary syndromes (ACS) and also for medically managed ACS patients.

Areas covered: Clopidogrel efficacy can be significantly modified by polymorphism of CYP2C19 genotype (more than 25 allelic variants) involved in its metabolism that can adversely affect its anti-platelet activity. As a result, a substantial number of patients (20–30%) with ACS show an inadequate response to clopidogrel despite a standardized dosing regimen.

Experts commentary: Currently, there is conflicting evidence in regards to the use of CYP2C19 genotyping to identify poor responders to clopidogrel in clinical practice. ACC/AHA guidelines do not recommend routine use of CYP2C19 in clinical practice, whereas Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend its use to identify poor/intermediate metabolizers of Clopidogrel and suggest alternative P2Y12 inhibitors among ACS patients undergoing percutaneous coronary intervention. This review article will look at the literature evidence for the use of CYP2C19 genotyping in clinical practice.     

Prasugrel hydrochloride for the treatment of acute coronary syndrome patients

Introduction: Dual antiplatelet therapy (DAPT) with aspirin combined with either a thienopyridine (clopidogrel or prasugrel) or acyclopentyl-triazolo-pyrimidine (ticagrelor) plays a vital role in the management of acute coronary syndrome (ACS) especially in those undergoing percutaneous coronary intervention (PCI) but even those being managed medically. Observational studies and some formal studies have shown patients on the standard dual antiplatelet regimen (clopidogrel and aspirin) continue to have further ischemic events and can suffer stent thrombosis. It has been demonstrated that clopidogrel is associated with a delayed onset of action with a considerable inter-individual variation to treatment thus making it difficult to achieve an optimal level of platelet inhibition.

Areas covered: This article will review the current evidence that is available regarding the effectiveness and safety of prasugrel in ACS patients undergoing percutaneous coronary intervention (PCI).

Expert commentary: Prasugrel is an oral third-generation inhibitor of platelet activation and aggregation. Laboratory studies and early phase clinical trials show prasugrel has a faster onset of action, is more potent and has reduced inter-patient response variability compared to clopidogrel. The published studies so far demonstrated that prasugrel when compared to clopidogrel also shows a higher degree of effectiveness in the prevention of platelet-initiated thrombotic events in patients with ACS undergoing PCI, however these benefits are offset somewhat by an increased bleeding risk.     

Current controversies in the use of aspirin and ticagrelor for the treatment of thrombotic events

Introduction: A P2Y₁₂ inhibitor plus aspirin is the most widely used antiplatelet strategy to prevent adverse outcomes in the setting of atherothrombotic vascular disease.

Areas covered: A paucity of robust evidence for an optimal dose, gastrointestinal toxicity, ineffectiveness in high-risk patients and interactions with other antiplatelet agents, are major controversies associated with aspirin therapy. Ticagrelor is a reversibly binding oral P2Y₁₂ receptor blocker that mediates potent inhibition of adenosine diphosphate-induced platelet function. It is more effective than clopidogrel in preventing thrombotic events in acute coronary syndrome patients. The absence of a beneficial effect for ticagrelor versus clopidogrel in ACS observed in the North American subgroup of the PLATelet inhibition and patient Outcomes (PLATO) trial has been attributed to a higher concomitant aspirin dose.

Expert commentary: Ongoing studies are now investigating the plausibility of removing aspirin therapy in the setting of potent P2Y₁₂ receptor blockade via ticagrelor monotherapy or replacing aspirin with an oral anticoagulant.     

Current and novel approaches to treat patients presenting with ST elevation myocardial infarction

Introduction: Primary percutaneous coronary intervention (PCI) represents the gold-standard treatment for patients presenting with an ST-elevation myocardial infarction (STEMI). Acute myocardial infarction is a complex clinical scenario, and an appropriate therapeutic approach could be represented by a balanced integration between healthcare system and medical competence.

Areas covered: In this review we discuss how a primary PCI network, and the new therapeutic options could be coupled in order to obtain improved clinical outcomes. The present report will focus on three main issues related to STEMI patients, namely, out of hospital management, primary PCI and pharmacological treatment.

Expert commentary: A possible correct approach to a patient presenting a STEMI could be considered as a stepwise process, given by 5 steps: reducing the time to reperfusion; dual antiplatelet administration; radial access; new generation drug eluting stent implantation; long term management.     

The evolution of dual antiplatelet therapy in the setting of acute coronary syndrome: ticagrelor versus clopidogrel

Review of: Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Eng J Med 2009; 361(11): 1045–1057.

For acute coronary syndrome (ACS), a dual antiplatelet regimen comprised of treatment with aspirin and either P2Y12 adenosine diphosphate receptor antagonists, clopidogrel, prasugrel or ticagrelor is usually employed. This article compares clopidogrel with ticagrelor for the prevention of vascular events and death in broad population of ACS patients ranging from UA, NSTEMI to STEMI, utilizing planned strategies of medical or invasive treatment strategy.     

Optimal duration of dual antiplatelet therapy after PCI: integrating procedural complexity,bleeding risk and the acuteness of clinical presentation

Introduction: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor constitutes the standard of care to prevent major adverse cardiac events in patients who undergo percutaneous coronary intervention (PCI) with drug-eluting stents (DES). However, the anti-ischemic benefits of DAPT are counterbalanced by an increased risk of hemorrhagic complications, which are known to be associated with increased morbidity and mortality. While the efficacy of DAPT in patients presenting with acute coronary syndrome (ACS) has been well established, the risk-benefit balance of DAPT in other subsets of patients remain controversial. As a result, multiple risk scores to inform optimal duration of DAPT have been developed recently for individuals with various degrees of coronary artery disease.

Areas covered: Authors summarize the current evidence and guideline recommendations on the optimal duration and intensity of DAPT across the spectrum of coronary artery disease including those who undergo complex PCI and recapitulated the recently developed risk scores to inform clinical decision on the optimal duration of DAPT.

Expert commentary: Clinical decision-making for upfront duration of DAPT after PCI with DES should consider the individual bleeding risk profile, the initial clinical presentation and the complexity of coronary stenting.     

Role of proprotein convertase subtilisin/kexin type 9 inhibitors in patients with coronary artery disease undergoing percutaneous coronary intervention

Introduction: Although novel therapies have improved outcomes in PCI patients, a sizeable number of patients still remain at high cardiovascular risk for recurrent event. There is therefore an unmet need for novel therapies that can improve clinical outcomes, with an associated satisfactory safety profile. Proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme is a novel lipid-lowering target with a potential to impact high-cardiovascular risk populations including patients with coronary artery disease (CAD), undergoing the percutaneous coronary intervention (PCI). A number of canonical and non-canonical pathways of PCSK9 action, including inflammation and platelet activation, as well as their inhibition, are undergoing intense investigation.

Areas covered: This review will discuss the currently available evidence on PCSK9 inhibitors, pathways of PCSK9 enzyme action and results or its inhibition, the potential role of PCSK9 inhibitors in specific populations undergoing PCI, and completed and ongoing studies in patients with CAD.

Expert commentary: PCSK9 inhibitors clinical outcomes in high risk cardiovascular disease patients and have the potential to function as powerful adjunctive therapy in patients undergoing PCI by a twofold mechanism on both lipid lowering and platelet/inflammation pathways.     

A double-blind placebo-controlled clinical investigation into pain reduction effect of placing the pain spot outside the intersection area of the two currents of interferential therapy compared to traditional method

Background: Interferential therapy (IFT) is applied to intersect in the painful area but no confirmed effect with this method. Experimentally, the highest voltage of IFT is induced outside the intersection of the two currents. Placing the painful area outside the intersection point (external application) would reveal a better effect.

Objectives: To examine the effect of external application in pain compared to traditional method.

Design: A double-blind placebo-controlled clinical investigation.

Setting: A public hospital.

Participants: 168 LBP subjects.

Interventions: Assignment: (1) external IFT, (2) placebo external IFT, (3) traditional IFT and (4) placebo traditional IFT. Groups 1 and 3 received 20 min of IFT at 100 Hz and groups 2 and 4 received sham IFT.

Main outcome measures: Before and after IFT session, pain severity (VAS), pressure threshold (PPT), pain distribution and ROM were assessed.

Results: IFT changed all outcomes similarly. VAS and ROM improved statistically, P < 0.03. A trend of better VAS reduced with active IFTs.

Conclusions: No therapeutic difference between the two methods.     

Candida auris: a worrisome,globally emerging pathogen

Introduction: Candida auris is a recently discovered, rapidly emerging fungal pathogen. Infections due to C. auris are hospital-acquired, multidrug resistant and associated with high mortality.

Areas covered: This review highlights epidemiology, pathogenesis, microbiological characteristics, clinical presentation, diagnostic challenges and treatment options of C. auris infections. Infection prevention measures to prevent spread of C. auris and special measures during an outbreak situation have also been reviewed.

Expert commentary: Rapid emergence of hospital onset C. auris is worrisome. Early diagnosis of C. auris is essential for better outcomes and the implementation of infection prevention measures. Lack of widespread awareness, absence of general availability of diagnostic testing methods, and limited options for treatment of C. auris infections make it a difficult-to-treat pathogen. Further studies are needed for better understanding of this emerging pathogen.     

Individualizing dual antiplatelet therapy duration after percutaneous coronary intervention: from randomized control trials to personalized medicine

Introduction: Improved stent technologies have lead to reduced minimum durations of dual antiplatelet therapy (DAPT) to prevent stent thrombosis. However, the anti-ischemic benefits seen in extended DAPT in both stent and non-stent related lesions have called into question the optimum duration of DAPT after stent placement.

Areas covered: We review the evidence for varying durations of DAPT after drug eluting stent placement including for patients on oral anticoagulation; decision tools available for clinicians to optimize patient selection for extended therapy and insight into application of these risk assessment tools in clinical practice.

Expert commentary: The use of risk assessment tools in optimizing DAPT duration after stent placement provides an opportunity for improved outcomes by means of a personalized approach to care while allowing clinicians to engage with patients in shared-decision making.     

A systematic review to determine the optimal type and dosage of land-based exercises for treating knee osteoarthritis

Background: Exercise has been acknowledged as an effective non-pharmacological intervention for osteoarthritis. Consensus regarding the type of exercise i.e., aerobic or resistance, weight bearing or non-weight bearing, and dosage i.e., frequency, loading, duration, or intensity, is yet to be reached.

Objective: The purpose of this review was to address two questions: (1) is there a difference in clinical outcomes between different exercise programmes; and (2) what is the optimal dosage of exercises for people with knee osteoarthritis.

Methods: A systematic review was conducted. A study of published (AMED, CINAHL, MEDLINE, EMBASE, PubMed, and the Cochrane Library) and unpublished literature (WHO International Clinical Trials Registry Platform, current controlled trials and the United States National Institute of Health Trials Registry, and Open Grey) was undertaken in January 2013. Studies assessing the clinical outcomes of different types and dosages of exercise for people with osteoarthritis of the knee were included. Methodological quality was assessed using the critical appraisal skills programme (CASP) randomized controlled trial (RCT) appraisal tool.

Results: Ten studies assessing 958 knees from 916 participants were included. Exercise significantly improved pain and function for people with knee osteoarthritis. There was no significant difference in outcomes for different types of exercise i.e., aerobic versus resistance, weight bearing versus non-weight bearing. There was no significant difference in respect to the intensity of exercise i.e., high- versus lower-intensity resistance or aerobic exercises. The quality of the literature was moderate to high.

Conclusions: While exercise appears to improve symptoms and optimize function for people with knee osteoarthritis, the optimal form and dosage of exercise remains unknown.

Funding: None.

PROSPERO Registration Number: CRD42012002811.     

Burden of antimicrobial resistance in an era of decreasing susceptibility

Introduction: Antimicrobial resistance has become a global problem. Many pathogens are becoming multidrug-resistant with the attendant increased risk of failure of standard therapies and the under-recognised outcomes such as increased morbidity, mortality, length of hospitalization and costs of treatment.

Areas covered: We undertook a review of the literature using standard search engines including PubMed, Google Scholar, Scopus and internet sources. Key search terms included antimicrobial resistance, antibiotic resistance, bacterial resistance, clinical outcomes, economic consequences, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae and Staphylococcus aureus.

Expert commentary: Antimicrobial resistance among the five-species presented demonstrates a major, and increasing, deleterious impact seen in each of the key outcomes measured. These negative changes, at a personal, health system and Societal levels, further emphasise the growing problem of increasing antimicrobial resistance at a global level and the vital need for new antimicrobials.     

Hikers poisoned: Veratrum steroidal alkaloid toxicity following ingestion of foraged Veratrum parviflorum

Introduction: Steroidal alkaloids are found in plants of the genus Veratrum. Their toxicity manifests as gastrointestinal symptoms followed by a Bezold–Jarisch reflex: hypopnea, hypotension, and bradycardia. Some Veratrum steroidal alkaloids are also teratogens interfering with the hedgehog-2 signaling pathway, which causes cyclopsia and holoprosencephaly. We present a case of accidental poisoning from Veratrum parviflorum mistaken for the edible Allium tricoccum (ramps, wild leek).

Case history: A 27-year-old man and his 25-year-old wife presented to the emergency department with nausea, vomiting, hypotension, and bradycardia after foraging and ingesting plants that they believed to be a local native species of wild leek.

Methods: We collected and analyzed the implicated fresh plant material and both patients’ serum/plasma. We used liquid chromatography–mass spectroscopy and high-resolution electrospray ionization time of flight tandem mass spectrometry to extract and characterize steroidal alkaloids from the foraged plant and patients’ serum.

Results: Our V. parviflorum samples contained verazine, veratramine, veratridine, and cyclopamine.

Discussion: Steroidal alkaloids have been previously isolated from Veratrum viride and Veratrum album and toxicity has been reported mainly from V. album species.

Conclusion: V. parviflorum toxicity manifests with gastrointestinal and cardiac symptoms. Treatment is symptomatic and supportive as with previous case reports of toxicity with other Veratrum species.     

Infective Endocarditis in Children in Italy from 2000 to 2015

Objective: The Italian Society for Pediatric Infectious Diseases created a registry on children with infective endocarditis (IE) hospitalized in Italy.

Methods: A cross-sectional survey was conducted on patients hospitalized due to IE in Italian paediatric wards between January 1, 2000, and June 30, 2015.

Results: Over the 15-year study period, 47 IE episodes were observed (19 males; age range, 2-17 years). Viridans Streptococci were the most common pathogens among patients with predisposing cardiac conditions and Staphylococcus aureus among those without (37.9% vs. 5.5%, p = 0.018, and 6.9% vs. 27.8%, p = 0.089, respectively). Six of the 7 (85.7%) S. aureus strains were methicillin-resistant. The majority of patients with and without predisposing cardiac conditions recovered without any complications.

Conclusion: In Italy, paediatric IE develops without any previous predisposing factors in a number of children, methicillin-resistant S. aureus has emerged as a common causative agent and the therapeutic approach is extremely variable.     

Pesticide-related poison center exposures in children and adolescents aged ≤19 years in Texas, 2000–2013

Context: Although national poison center data show that pesticides were the 8th most commonly reported substance category (3.27%) for children aged ≤5 years in 2014, there is limited information on childhood and adolescent pesticide exposures.

Objective: This study assessed pesticide-related poison center exposures in children and adolescents aged ≤19 years from 2000–2013 in Texas to characterize the potential burden of pesticides.

Materials and methods: Pesticide-related poison center exposures among children and adolescents aged ≤19 years reported to Texas poison centers were identified. The distribution of exposures was estimated by gender, age category, medical outcome, management site, exposure route, and pesticide category.

Results: From 2000 to 2013, there were 61,147 pesticide-related poison center exposures in children and adolescents aged ≤19 years. The prevalence was highest among males at 864.24 per 100,000 population. The prevalence of unintentional exposures was highest among children aged ≤5 years at 2310.69 per 100,000 population, whereas the prevalence of intentional exposures was highest among adolescents aged 13–19 years at 13.82 per 100,000 population. A majority of medical outcomes reported were classified as having no effect (30.24%) and not followed, but minimal clinical effects possible (42.74%). Of all the exposures, 81.24% were managed on site. However, 57% of intentional exposures were referred to or treated at a health-care facility. The most common routes of exposure were ingestion (80.83%) and dermal (17.21%). The most common pesticide categories included rodenticides (30.02%), pyrethrins/pyrethroids (20.69%), and other and unspecified insecticides (18.14%).

Discussion: The study found differences in the frequency of exposures by intent for sex and age categories, and identified the most common medical outcomes, management site, exposure route, and pesticide category.

Conclusion: Through characterizing pesticide-related poison center exposures, future interventions can be designed to address groups with higher prevalence of exposure.     

Optical coherence tomography to guide percutaneous treatment of coronary bifurcation disease

Introduction: Cardiovascular disease remains the most common cause of death worldwide. Enormous progress in the technology and applicability of percutaneous techniques to treat obstructive coronary heart disease has been made, and the number of percutaneous coronary interventions (PCI) is increasing. Coronary bifurcations are involved in a substantial number of PCIs and despite recent advances, bifurcation PCI remains a challenge in terms of immediate success and long-term outcome. Angiography has a limited capacity for showing important features of the 3 dimensional coronary vessel anatomy, position of stent struts and exact wire positions and is therefore suboptimal for guiding bifurcation PCI. Intracoronary optical coherence tomography (OCT) provides high resolution and the information gained during PCI is unprecedented compared with angiography guidance and intravascular ultrasound.

Areas covered: This review will provide an overview of the use of OCT to guide bifurcation-PCI.

Expert commentary: OCT is a promising guide for bifurcation-PCI at each individual step: from planning the strategy (provisional versus two-stent strategy), to guidance during PCI, and finally checking the interventional result. Until dedicated randomized trails are complete, we recommend OCT guidance for interventions in complex coronary bifurcation disease and for imaging when unexpected procedural events occur.     

Robotics in percutaneous cardiovascular interventions

Introduction: The fundamental technique of performing percutaneous cardiovascular (CV) interventions has remained unchanged and requires operators to wear heavy lead aprons to minimize exposure to ionizing radiation. Robotic technology is now being utilized in interventional cardiology partially as a direct result of the increasing appreciation of the long-term occupational hazards of the field. This review was undertaken to report the clinical outcomes of percutaneous robotic coronary and peripheral vascular interventions.

Areas covered: A systematic literature review of percutaneous robotic CV interventions was undertaken. The safety and feasibility of percutaneous robotically-assisted CV interventions has been validated in simple to complex coronary disease, and iliofemoral disease. Studies have shown that robotically-assisted PCI significantly reduces operator exposure to harmful ionizing radiation without compromising procedural success or clinical efficacy. In addition to the operator benefits, robotically-assisted intervention has the potential for patient advantages by allowing more accurate lesion length measurement, precise stent placement and lower patient radiation exposure. However, further investigation is required to fully elucidate these potential benefits.

Expert commentary: Incremental improvement in robotic technology and telecommunications would enable treatment of an even broader patient population, and potentially provide remote robotic PCI.     

Pain pattern classification and directional preference for patients with neck pain

Objectives:

Pain Pattern Classification (PPC) and Directional Preference (DP) have been shown to be predictive of health care outcomes and serve to guide orthopedic clinical decision making. We conducted a prospective, observational cohort study to verify the association between PPC, DP, and clinical outcomes.

Methods:

Clinical outcome measures including pain intensity and disability were completed at first examination and follow-up by 335 patients. A Pearson’s chi-squared test was used to determine differences in prevalence rates for the categorical variables, and two-sample t-tests were used to determine differences in rates for the continuous variables. A Tukey’s range test was used to determine differences in follow-up pain intensity and disability for neck pain dual-classification schemes.

Results:

The prevalence of DP was 82.4%. The prevalence of CEN, Non-CEN, and Non-Classifiable (NC) was 15.2%, 42.1%, and 25.1%, respectively. The prevalence of DP was lowest for patients with sub-acute symptoms and who were <45 years old. Patients classified as DP CEN had, on average 2.62 NDI units less than patients classified as Non-DP. Patients classified as DP CEN had, on average, 0.90 pain intensity units less than patients classified as Non-DP at follow-up. Patients who demonstrated DP CEN did not have clinically significant lower pain intensity or disability at follow-up than patients who demonstrated Non-DP.

Discussion:

The results of this investigation need to be interpreted with caution with respect to the study design and it’s subsequent strengths and limitations.

Level of Evidence:

1b.