Joseph Sweeny

Impact of the everolimus-eluting stent on stent thrombosis: a meta-analysis of 13 randomized trials

OBJECTIVES We evaluated the impact of the everolimus-eluting stent (EES) on the frequency of stent thrombosis (ST), target vessel revascularization (TVR), myocardial infarction (MI), and cardiac death in randomized controlled trials comparing the EES to non-everolimus-eluting drug-eluting stents (EE-DES). BACKGROUND Whether or not the unique properties of the EES translate into reductions in ST remains unknown. METHODS We searched MEDLINE, Scopus, the Cochrane Library, and Internet sources for articles comparing outcomes between EES and non-EE-DES without language or date restriction. Randomized controlled trials reporting the frequency of ST were included. Variables relating to patient and study characteristics and clinical endpoints were extracted. RESULTS We identified 13 randomized trials (n = 17,101) with a weighted mean follow-up of 21.7 months. Compared with non-EE-DES, the EES significantly reduced ST (relative risk [RR]: 0.55; 95% confidence interval [CI]: 0.38 to 0.78; p = 0.001), TVR (RR: 0.77; 95% CI: 0.64 to 0.92; p = 0.004), and MI (RR: 0.78; 95% CI: 0.64 to 0.96; p = 0.02). There was no difference in cardiac mortality between the groups (RR: 0.92; 95% CI: 0.74 to 1.16; p = 0.38). The treatment effect was consistent by different follow-up times and duration of clopidogrel use. The treatment effects increased with higher baseline risks of the respective control groups with the strongest correlation observed for ST (R(2) = 0.89, p < 0.001). CONCLUSIONS Intracoronary implantation of the EES is associated with highly significant reductions in ST with concordant reductions in TVR and MI compared to non-EE-DES. Whether these effects apply to different patient subgroups and DES types merits further investigation.

Aspirin A Historical and Contemporary Therapeutic Overview

> Among the many useful discoveries which this age has made, there are very few which better deserve the attention of the public that what I am going to lay before your Lordship. > > —Reverend Edward Stone –Chipping-Norton, Oxfordshire –April 25, 1763 These prophetic words, written by Reverend Edward Stone in a 1763 letter to George Parker, the second Earl of Macclesfield, describe the results of the first clinical trial recorded in medical history.1 Stones report on the rediscovery of the medicinal value of willow bark among subjects suffering from malarial symptoms is considered a significant milestone in the development of aspirin. Although society now takes many of its beneficial effects for granted, aspirin did not suddenly appear for medicinal use after Reverend Stones discovery. Instead, its tumultuous journey was fueled by individual scientific curiosity, accidental discoveries, and intense business rivalry.1 No other drug is used by a greater number of people worldwide than aspirin, the benefits of which span centuries, beginning with the very first uses of willow bark by Egyptian physicians (Figure 1). Aspirin single-handedly transformed a coal-dye company into a pharmaceutical giant and has emerged as a cornerstone in the present-day therapies available for treating cardiovascular disease (CVD), pain, and inflammation. This article discusses the sentinel historical aspects of the discovery and clinical cardiovascular developments of aspirin, as well as its contemporary use in todays medical arena. Figure 1. Timeline of historical events in the development of aspirin. ### Historical Developments of Salicylates On January 20, 1862, Edwin Smith made one of the most historically important purchases of his life. Well-regarded among his peers for his keen scholarship and intricate knowledge of Egyptology, Smith purchased, for £12, 2 worn papyrus scrolls in a local Luxor street market1 that later turned out to be a formative medical textbook unlocking ancient Egyptians practice of medicine. Although authorless, the Ebers Papyrus is 110 pages …

Antiplatelet drug 'resistance'. Part 1: mechanisms and clinical measurements

Antiplatelet drug therapy has become one of the cornerstones of treatment for patients with cardiovascular disease. Large clinical trials have shown that antiplatelet medications have important clinical benefits and prevent adverse outcomes in patients with coronary artery disease. Recurrent adverse cardiovascular events still occur in a substantial proportion of patients on standard dual antiplatelet therapy, however, which has been attributed to nonresponsiveness to this treatment. Both pharmacological and pharmacokinetc mechanisms are involved in variability in responsiveness to antiplatelet agents, and include drug bioavailability, medication noncompliance, drug–drug interactions, cytochrome P450 activity, and genetic polymorphisms. Numerous observational studies have consistently shown an association between antiplatelet drug nonresponsiveness and adverse clinical outcomes. However, these studies are limited by varying antiplatelet drug dosing regimens, heterogeneous laboratory assessments for ex vivo platelet function, and wide interindividual variation in platelet responses. Only within the last 2 years have randomized clinical trials indicated that increased dosing with antiplatelet drugs could reduce adverse clinical outcomes. Nonetheless, large clinical trials with standardized laboratory methods and well-defined protocols are needed that will definitively determine the association between antiplatelet drug nonresponsiveness and clinical events, and establish therapeutic strategies to overcome blunted antiplatelet effects.

Clopidogrel and the Reduced-Function CYP2C19 Genetic Variant: A Limited Piece of the Overall Therapeutic Puzzle

FFECTIVE PLATELET INHIBITION HAS BECOME A CORnerstone in the management of patients with acute coronary syndrome (ACS). The addition of clopidogrel to aspirin has provided significant reductions in major cardiovascular events in patients with ACS in general, and particularly among those treated invasively by percutaneous coronary intervention (PCI). 1 Yet studies have demonstrated that the therapeutic response of clopidogrel is variable among patients, 2 and low or incomplete platelet inhibition has been associated with increased risk

Coronary Bifurcation Lesions: A Current Update

Coronary bifurcations are prone to develop atherosclerotic plaque because of turbulent blood flow and high shear stress. When compared with nonbifurcation coronary interventions, bifurcation interventions have historically reported a lower rate of procedural success, higher procedural costs, longer hospitalization, and higher clinical and angiographic restenosis. Treating bifurcation lesions is challenging, but a simple algorithm based on the side branch size, stenosis, and angulation can be used. The ongoing development of novel drug-eluting stent devices designed specifically for coronary bifurcations and the large randomized clinical trials being conducted to address their utility will add to the already present literature regarding treatment of coronary bifurcation lesions.

The relationship among extent of lipid-rich plaque, lesion characteristics, and plaque progression/regression in patients with coronary artery disease: a serial near-infrared spectroscopy and intravascular ultrasound study.

AIMS To evaluate the relationship between lipid content and plaque morphometry as well as the process of lesion progression and regression in patients with significant coronary artery disease. METHODS AND RESULTS The present study, using data from the YELLOW trial, was conducted in patients having significant coronary lesions (fractional flow reserve <0.8) who underwent serial intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) at baseline and after 7 weeks. For each coronary plaque (≥50% plaque burden that was ≥5 mm in length), we evaluated plaque characteristics and the extent of lipid-rich plaque [LRP, defined as the 4 mm long segment with the maximum lipid-core burden index (maxLCBI4 mm)] on NIRS. Among 66 patients (age 63.0 ± 10.1 years; 82% statin use at baseline), 94 plaques were identified. The extent of LRP at baseline was positively correlated with IVUS plaque burden (r = 0.317, P = 0.002). A large LRP (maxLCBI4 mm ≥500) was present only in plaques with a large plaque burden (≥70%). Multivariate analysis demonstrated that plaque burden was the best predictor of the extent of LRP (P < 0.001). In lesions with a large plaque burden and a large amount of LRP at baseline, a reduction in LRP was seen in all lesions in patients receiving intensive statin therapy (P = 0.004) without a significant change in plaque burden. CONCLUSIONS Coronary lesions containing a large amount of LRP also had a large plaque burden. Short-term regression of LRP (without a change in plaque burden) was observed mainly in plaques with a large plaque burden and a large amount of LRP at baseline. CLINICAL TRIAL REGISTRATION http://www.clinicaltrials.gov. Unique identifier: NCT01567826.

Clustering of acute and subacute stent thrombosis related to the introduction of generic clopidogrel.

Introduction: Generic clopidogrel recently became available in the United States and was rapidly adopted as a cost-effective alternative to the brand name formulation. However, unlike other medications, subtle differences in clopidogrel bioavailability may lead to acute consequences including stent thrombosis (ST). Materials and Methods: We studied the incidence of acute and subacute ST during the initial period of generic clopidogrel use (June 18, 2012-September 6, 2012 [80 days]) at a single percutaneous coronary intervention (PCI) center. There were 4 definite ST cases within 30 days of successful PCI in patients receiving generic clopidogrel, which were compared to historic control ST cases from 80 days prior to generic clopidogrel use and for 3 years from June 18, 2009 to June 17, 2012. Results: During generic clopidogrel administration, 1054 PCIs were performed, giving a definite 30-day ST incidence of 0.38% (4 of 1054) among these patients. By comparison, there were 2 episodes of definite 30-day ST during the 80 days immediately preceding generic clopidogrel use (2 of 1114), while 3-year historic data indicated a definite 30-day ST incidence of 0.14% (20 of 14 432), representing a 2.7-fold increase in definite 30-day ST with generic clopidogrel use (P = .076). Exclusion of 3 historic controls with a defined reason for ST (noncompliance, marked thrombocytosis) gave a 3.2-fold increase in 30-day ST with generic clopidogrel (P = .050). An ST-predictive algorithm revealed no difference in the likelihood of ST between patients receiving generic clopidogrel and historic controls. Conclusions: We observed an unexpected >2-fold increase in ST coincident with generic clopidogrel use. Although we cannot ascribe causality, this observation warrants increased vigilance and close monitoring of patients receiving generic clopidogrel.

DOES AGGRESSIVE STATIN THERAPY REDUCE CORONARY ATHEROSCLEROTIC PLAQUE LIPID CONTENT? RESULTS FROM: REDUCTION IN YELLOW PLAQUE BY AGGRESSIVE LIPID LOWERING THERAPY (YELLOW) TRIAL

Although statin therapy reduces coronary atherosclerotic burden, the extent to which statins modulate lipid content and coronary flow physiology is not known. We evaluated the short-term impact of aggressive statin therapy on changes in coronary plaque composition, lipid content, and coronary flow

Impact of diabetes mellitus on the pharmacodynamic effects of ticagrelor versus clopidogrel in troponin-negative acute coronary syndrome patients undergoing Ad Hoc percutaneous coronary intervention

Background Diabetes mellitus (DM) is associated with enhanced platelet reactivity and impaired response to oral antiplatelet therapy, including clopidogrel. This post hoc analysis investigated the pharmacodynamic effects of ticagrelor versus clopidogrel loading dose (LD) in troponin‐negative acute coronary syndrome patients with or without DM undergoing percutaneous coronary intervention in the Ad Hoc PCI study. Methods and Results Patients randomized (1:1) to receive ticagrelor 180 mg LD or clopidogrel 600 mg LD were assessed by diabetic status. Platelet reactivity (P2Y12 reaction units [PRU] on VerifyNow® assay) was measured pre‐LD, at 0.5, 2, and 8 hours post‐LD, and at the end of the percutaneous coronary intervention. The primary endpoint was PRU levels 2 hours post‐LD; secondary endpoints included rates of high on‐treatment platelet reactivity (PRU≥208). Of 100 randomized patients, 51 received ticagrelor (DM, n=20; non‐DM, n=31) and 49 clopidogrel (DM, n=16; non‐DM, n=33). At 2 hours post‐LD, mean (SD) PRU levels in DM patients were 130.1 (111.7) with ticagrelor versus 287.6 (71.9) with clopidogrel (mean [95%CI] difference −157.5 [−225.3, −89.8]; P<0.001); in non‐DM patients, they were 75.3 (75.7) versus 243.0 (72.4) (mean difference −167.7 [−207.1, −128.3]; P<0.001). High on‐treatment platelet reactivity rates at 2 hours post‐LD were also significantly (P<0.001) reduced with ticagrelor versus clopidogrel in DM and non‐DM patients. Between‐treatment differences for PRU and high on‐treatment platelet reactivity were not significant at earlier time points but were at 8 hours post‐LD (P<0.001). Conclusions Compared with clopidogrel, ticagrelor achieved faster, enhanced platelet inhibition and reduced high on‐treatment platelet reactivity rates, in DM and non‐DM patients. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603082.

Three Dimensional Volumetric Assessment of Coronary Artery Calcification in Patients with stable Coronary Artery Disease by OCT.

AIMS There is a lack of a reliable technique to quantify coronary artery calcification (CAC). Hence, we used optical coherence tomography (OCT) to quantitate three-dimensional CAC volume to examine its association with plaque characteristics. METHODS AND RESULTS A total of 250 patients with stable angina undergoing OCT imaging before PCI were included. CAC volume was calculated from every frame of the culprit lesion and divided into tertiles (low, intermediate and high). Quantitative calcium characteristics were assessed in 107 patients who underwent both OCT and IVUS. Increase in CAC volume was associated with reduced lipid volume index, lipid length and number of lipid plaques. Diabetes and LDL cholesterol predicted less coronary calcification whereas age and prior MI predicted increased CAC after adjusting for all clinical factors. Lipid volume index (ρ=-0.001 [-0.003 to -0.00003]; p=0.04) and mean calcium depth (ρ=-0.02 [-0.02 to -0.01]; p=0.000) were inversely related to CAC volume after adjusting for all OCT characteristics, whereas cap thickness increased with increase in CAC volume (ρ=0.01 [0.002-0.03]; p=0.02) only in unadjusted analysis. Regression analysis demonstrated a significant correlation between calcium length (ρ=0.83; p<0.001) and calcium arc (ρ=0.86; p<0.001) measured by IVUS and OCT. CONCLUSIONS Target lesions with high CAC volume are characterised by reduced plaque lipid content and calcium closer to the luminal border. Fibrous cap thickness increased with increase in calcium volume.