Comparative Effectiveness and Safety of New-Generation Versus Early-Generation Drug-Eluting Stents According to Complexity of Coronary Artery Disease: A Patient-Level Pooled Analysis of 6,081 Patients.

OBJECTIVES The purpose of this study was to compare the 2-year safety and effectiveness of new- versus early-generation drug-eluting stents (DES) according to the severity of coronary artery disease (CAD) as assessed by the SYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score. BACKGROUND New-generation DES are considered the standard-of-care in patients with CAD undergoing percutaneous coronary intervention. However, there are few data investigating the effects of new- over early-generation DES according to the anatomic complexity of CAD. METHODS Patient-level data from 4 contemporary, all-comers trials were pooled. The primary device-oriented clinical endpoint was the composite of cardiac death, myocardial infarction, or ischemia-driven target-lesion revascularization (TLR). The principal effectiveness and safety endpoints were TLR and definite stent thrombosis (ST), respectively. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated at 2 years for overall comparisons, as well as stratified for patients with lower (SYNTAX score ≤11) and higher complexity (SYNTAX score >11). RESULTS A total of 6,081 patients were included in the study. New-generation DES (n = 4,554) compared with early-generation DES (n = 1,527) reduced the primary endpoint (HR: 0.75 [95% CI: 0.63 to 0.89]; p = 0.001) without interaction (p = 0.219) between patients with lower (HR: 0.86 [95% CI: 0.64 to 1.16]; p = 0.322) versus higher CAD complexity (HR: 0.68 [95% CI: 0.54 to 0.85]; p = 0.001). In patients with SYNTAX score >11, new-generation DES significantly reduced TLR (HR: 0.36 [95% CI: 0.26 to 0.51]; p < 0.001) and definite ST (HR: 0.28 [95% CI: 0.15 to 0.55]; p < 0.001) to a greater extent than in the low-complexity group (TLR pint = 0.059; ST pint = 0.013). New-generation DES decreased the risk of cardiac mortality in patients with SYNTAX score >11 (HR: 0.45 [95% CI: 0.27 to 0.76]; p = 0.003) but not in patients with SYNTAX score ≤11 (pint = 0.042). CONCLUSIONS New-generation DES improve clinical outcomes compared with early-generation DES, with a greater safety and effectiveness in patients with SYNTAX score >11.

Effect of Chronic Kidney Disease in Women Undergoing Percutaneous Coronary Intervention With Drug-Eluting Stents: A Patient-Level Pooled Analysis of Randomized Controlled Trials.

OBJECTIVES This study sought to evaluate: 1) the effect of impaired renal function on long-term clinical outcomes in women undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES); and 2) the safety and efficacy of new-generation compared with early-generation DES in women with chronic kidney disease (CKD). BACKGROUND The prevalence and effect of CKD in women undergoing PCI with DES is unclear. METHODS We pooled patient-level data for women enrolled in 26 randomized trials. The study population was categorized by creatinine clearance (CrCl) <45 ml/min, 45 to 59 ml/min, and ≥60 ml/min. The primary endpoint was the 3-year rate of major adverse cardiovascular events (MACE). Participants for whom baseline creatinine was missing were excluded from the analysis. RESULTS Of 4,217 women included in the pooled cohort treated with DES and for whom serum creatinine was available, 603 (14%) had a CrCl <45 ml/min, 811 (19%) had a CrCl 45 to 59 ml/min, and 2,803 (66%) had a CrCl ≥60 ml/min. A significant stepwise gradient in risk for MACE was observed with worsening renal function (26.6% vs. 15.8% vs. 12.9%; p < 0.01). Following multivariable adjustment, CrCl <45 ml/min was independently associated with a higher risk of MACE (adjusted hazard ratio: 1.56; 95% confidence interval: 1.23 to 1.98) and all-cause mortality (adjusted hazard ratio: 2.67; 95% confidence interval: 1.85 to 3.85). Compared with older-generation DES, the use of newer-generation DES was associated with a reduction in the risk of cardiac death, myocardial infarction, or stent thrombosis in women with CKD. The effect of new-generation DES on outcomes was uniform, between women with or without CKD, without evidence of interaction. CONCLUSIONS Among women undergoing PCI with DES, CKD is a common comorbidity associated with a strong and independent risk for MACE that is durable over 3 years. The benefits of newer-generation DES are uniform in women with or without CKD.

Three-year efficacy and safety of new- versus early-generation drug-eluting stents for unprotected left main coronary artery disease insights from the ISAR-LEFT MAIN and ISAR-LEFT MAIN 2 trials.

BACKGROUND In percutaneous coronary intervention (PCI) patients new-generation drug-eluting stent (DES) has reduced adverse events in comparison to early-generation DES. The aim of the current study was to investigate the long-term clinical efficacy and safety of new-generation DES versus early-generation DES for PCI of unprotected left main coronary artery (uLMCA) disease. METHODS The patient-level data from the ISAR-LEFT MAIN and ISAR-LEFT MAIN 2 randomized trials were pooled. The clinical outcomes of PCI patients assigned to new-generation DES (everolimus- or zotarolimus-eluting stent) versus early-generation DES (paclitaxel- or sirolimus-eluting stent) were studied. The primary endpoint was the composite of death, myocardial infarction (MI), target lesion revascularization and stroke (MACCE, major adverse cardiac and cerebrovascular event). RESULTS In total, 1257 patients were available. At 3 years, the risk of MACCE was comparable between patients assigned to new-generation DES or early-generation DES (28.2 versus 27.5 %, hazard ratio-HR 1.03, 95 % confidence intervals-CI 0.83-1.26; P = 0.86). Definite/probable stent thrombosis was low and comparable between new-generation DES and early-generation DES (0.8 versus 1.6 %, HR 0.52, 95 % CI 0.18-1.57; P = 0.25); in patients treated with new-generation DES no cases occurred beyond 30 days. Diabetes increased the risk of MACCE in patients treated with new-generation DES but not with early-generation DES (P interaction = 0.004). CONCLUSIONS At 3-year follow-up, a PCI with new-generation DES for uLMCA disease shows comparable efficacy to early-generation DES. Rates of stent thrombosis were low in both groups. Diabetes significantly impacts the risk of MACCE at 3 years in patients treated with new-generation DES for uLMCA disease. ClinicalTrials.gov Identifiers: NCT00133237; NCT00598637.

Impact of Diabetic Status on Outcomes After Revascularization With Drug-Eluting Stents in Relation to Coronary Artery Disease Complexity: Patient-Level Pooled Analysis of 6081 Patients.

BACKGROUND Diabetes mellitus and angiographic coronary artery disease complexity are intertwined and unfavorably affect prognosis after percutaneous coronary interventions, but their relative impact on long-term outcomes after percutaneous coronary intervention with drug-eluting stents remains controversial. This study determined drug-eluting stents outcomes in relation to diabetic status and coronary artery disease complexity as assessed by the Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) score. METHODS AND RESULTS In a patient-level pooled analysis from 4 all-comers trials, 6081 patients were stratified according to diabetic status and according to the median SYNTAX score ≤11 or >11. The primary end point was major adverse cardiac events, a composite of cardiac death, myocardial infarction, and clinically indicated target lesion revascularization within 2 years. Diabetes mellitus was present in 1310 patients (22%), and new-generation drug-eluting stents were used in 4554 patients (75%). Major adverse cardiac events occurred in 173 diabetics (14.5%) and 436 nondiabetic patients (9.9%; P<0.001). In adjusted Cox regression analyses, SYNTAX score and diabetes mellitus were both associated with the primary end point (P<0.001 and P=0.028, respectively; P for interaction, 0.07). In multivariable analyses, diabetic versus nondiabetic patients had higher risks of major adverse cardiac events (hazard ratio, 1.25; 95% confidence interval, 1.03-1.53; P=0.026) and target lesion revascularization (hazard ratio, 1.54; 95% confidence interval, 1.18-2.01; P=0.002) but similar risks of cardiac death (hazard ratio, 1.41; 95% confidence interval, 0.96-2.07; P=0.08) and myocardial infarction (hazard ratio, 0.89; 95% confidence interval, 0.64-1.22; P=0.45), without significant interaction with SYNTAX score ≤11 or >11 for any of the end points. CONCLUSIONS In this population treated with predominantly new-generation drug-eluting stents, diabetic patients were at increased risk for repeat target-lesion revascularization consistently across the spectrum of disease complexity. The SYNTAX score was an independent predictor of 2-year outcomes but did not modify the respective effect of diabetes mellitus. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00297661, NCT00389220, NCT00617084, and NCT01443104.

In vitro detection of cytotoxic T and NK cells in peripheral blood of patients with various drug-induced skin diseases

BACKGROUND: Cytotoxic cells are involved in most forms of drug-induced skin diseases. Till now, no in vitro test addressed this aspect of drug-allergic responses. Our report evaluates whether drug-induced cytotoxic cells can be detected in peripheral blood of nonacute patients with different forms of drug hypersensitivity, and also whether in vitro detection of these cells could be helpful in drug-allergy diagnosis. METHODS: GranzymeB enzyme-linked immunosorbent spot-forming (ELISPOT) and cell surface expression of the degranulation marker CD107a were evaluated on peripheral blood mononuclear cells from 12 drug-allergic patients in remission state and 16 drug-exposed healthy controls. RESULTS: In 10/12 allergic patients culprit but not irrelevant drug elicited granzymeB release after 48-72 h stimulation. It was clearly positive in patients with high proliferative response to the drug, measured in lymphocyte transformation tests. In patients, who showed moderate or low proliferation and low drug-response in granzymeB ELISPOT, overnight preincubation with interleukin (IL)-7/IL-15 enhanced drug-specific granzymeB release and allowed to clearly identify the offending agent. CD107a staining was positive on CD4+/CD3+, CD8+/CD3+ T cells as well as CD56+/CD3- natural killer cells. None of the drug-exposed healthy donors reacted to the tested drugs and allergic patients reacted only to the offending, but not to tolerated drugs. CONCLUSION: GranzymeB ELISPOT is a highly specific in vitro method to detect drug-reacting cytotoxic cells in peripheral blood of drug-allergic patients even several years after disease manifestation. Together with IL-7/IL-15 preincubation, it may be helpful in indentifying the offending drug even in some patients with weak proliferative drug-response.

Gender inequity in the provision of care for hip disease: population-based cross-sectional study

Objectives To examine gender differences along the care pathway to total hip replacement. Methods We conducted a population-based cross-sectional study of 26,046 individuals aged 35 years and over in Avon and Somerset. Participants completed a questionnaire asking about care provision at five milestones on the pathway to total hip replacement. Those reporting hip disease were invited to a clinical examination. We estimated odds ratios (ORs) [95% confidence intervals (CI)] for provision of care to women compared with men. Results 3169 people reported hip pain, 2018 were invited for clinical examination, and 1405 attended (69.6%). After adjustment for age and disease severity, women were less likely than men to have consulted their general practitioner (OR 0.78, 95%-CI 0.61–1.00), as likely as men to have received drug therapy for hip pain in the previous year (OR 0.96, 95%-CI 0.74–1.24), but less likely to have been referred to specialist care (OR 0.53, 95%-CI 0.40–0.70), to have consulted an orthopaedic surgeon (OR 0.50, 95%-CI 0.32–0.78), or to be on a waiting list for total hip replacement (OR 0.41, 95%-CI 0.20–0.87). Differences remained in the 746 people who had sought care from their general practitioner, and after adjustment for willingness and fitness for surgery. Conclusions There are gender inequalities in provision of care for hip disease in England, which are not fully accounted for by gender differences in care seeking and treatment preferences. Differences in referral to specialist care by general practitioners might unwittingly contribute to this inequity. Accurate information about availability, benefits and risks of hip replacement for providers and patients, and continuing education to ensure that clinicians interpret and correct patients' assumptions could help reduce inequalities.

The status of olfactory function and the striatal dopaminergic system in drug-induced parkinsonism

Olfactory impairment has been reported in drug-induced parkinsonism (DIP), but the relationship between dopaminergic dysfunction and smell deficits in DIP patients has not been characterized. To this end, we studied 16 DIP patients and 13 patients affected by Parkinson's disease (PD) using the "Sniffin' Sticks" test and [(123)I] FP-CIT SPECT (single-photon emission computed tomography). DIP patients were divided based on normal (n = 9) and abnormal (n = 7) putamen dopamine transporter binding. Nineteen healthy age- and sex-matched subjects served as controls of smell function. Patients with DIP and pathological putamen uptake had abnormal olfactory function. In this group of patients, olfactory TDI scores (odor threshold, discrimination and identification) correlated significantly with putamen uptake values, as observed in PD patients. By contrast, DIP patients with normal putamen uptake showed odor functions-with the exception of the threshold subtest-similar to control subjects. In this group of patients, no significant correlation was observed between olfactory TDI scores and putamen uptake values. The results of our study suggest that the presence of smell deficits in DIP patients might be more associated with dopaminergic loss rather than with a drug-mediated dopamine receptor blockade. These preliminary results might have prognostic and therapeutic implications, as abnormalities in these individuals may be suggestive of an underlying PD-like neurodegenerative process.

A randomised determination of the effect of fluvastatin and atorvastatin on top of dual antiplatelet treatment on platelet aggregation after implantation of coronary drug-eluting stents. The EFA-Trial

Drug-drug interaction between statins metabolised by cytochrome P450 3A4 and clopidogrel have been claimed to attenuate the inhibitory effect of clopidogrel. However, published data regarding this drug-drug interaction are controversial. We aimed to determine the effect of fluvastatin and atorvastatin on the inhibitory effect of dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel. One hundred one patients with symptomatic stable coronary artery disease undergoing percutaneous coronary intervention and drug-eluting stent implantation were enrolled in this prospective randomised study. After an interval of two weeks under dual antiplatelet therapy with ASA and clopidogrel, without any lipid-lowering drug, 87 patients were randomised to receive a treatment with either fluvastatin 80 mg daily or atorvastatin 40 mg daily in addition to the dual antiplatelet therapy for one month. Platelet aggregation was assessed using light transmission aggregometry and whole blood impedance platelet aggregometry prior to randomisation and after one month of receiving assigned statin and dual antiplatelet treatment. Platelet function assessment after one month of statin and dual antiplatelet therapy did not show a significant change in platelet aggregation from 1st to 2nd assessment for either statin group. There was also no difference between atorvastatin and fluvastatin treatment arms. In conclusion, neither atorvastatin 40 mg daily nor fluvastatin 80 mg daily administered in combination with standard dual antiplatelet therapy following coronary drug-eluting stent implantation significantly interfere with the antiaggregatory effect of ASA and clopidogrel.

Long-term clinical outcomes of biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting stents in patients with coronary artery disease (LEADERS): 4 year follow-up of a randomised non-inferiority trial

Background The effectiveness of durable polymer drug-eluting stents comes at the expense of delayed arterial healing and subsequent late adverse events such as stent thrombosis (ST). We report the 4 year follow-up of an assessment of biodegradable polymer-based drug-eluting stents, which aim to improve safety by avoiding the persistent inflammatory stimulus of durable polymers. Methods We did a multicentre, assessor-masked, non-inferiority trial. Between Nov 27, 2006, and May 18, 2007, patients aged 18 years or older with coronary artery disease were randomly allocated with a computer-generated sequence to receive either biodegradable polymer biolimus-eluting stents (BES) or durable polymer sirolimus-eluting stents (SES; 1:1 ratio). The primary endpoint was a composite of cardiac death, myocardial infarction, or clinically-indicated target vessel revascularisation (TVR); patients were followed-up for 4 years. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389220. Findings 1707 patients with 2472 lesions were randomly allocated to receive either biodegradable polymer BES (857 patients, 1257 lesions) or durable polymer SES (850 patients, 1215 lesions). At 4 years, biodegradable polymer BES were non-inferior to durable polymer SES for the primary endpoint: 160 (18·7%) patients versus 192 (22·6%) patients (rate ratios [RR] 0·81, 95% CI 0·66–1·00, p for non-inferiority <0·0001, p for superiority=0·050). The RR of definite ST was 0·62 (0·35–1·08, p=0·09), which was largely attributable to a lower risk of very late definite ST between years 1 and 4 in the BES group than in the SES group (RR 0·20, 95% CI 0·06–0·67, p=0·004). Conversely, the RR of definite ST during the first year was 0·99 (0·51–1·95; p=0·98) and the test for interaction between RR of definite ST and time was positive (pinteraction=0·017). We recorded an interaction with time for events associated with ST but not for other events. For primary endpoint events associated with ST, the RR was 0·86 (0·41–1·80) during the first year and 0·17 (0·04–0·78) during subsequent years (pinteraction=0·049). Interpretation Biodegradable polymer BES are non-inferior to durable polymer SES and, by reducing the risk of cardiac events associated with very late ST, might improve long-term clinical outcomes for up to 4 years compared with durable polymer SES. Funding Biosensors Europe SA, Switzerland.

Spot drug-eluting stenting for long coronary stenoses: long-term results of a randomized clinical study

Preliminary results of a randomized trial have suggested that total lesion coverage with drug-eluting stents (DES) is not necessary in the presence of diffuse disease of nonuniform severity. In the present study, we report long-term results of this trial.

The impact of anemia on long-term clinical outcome in patients undergoing revascularization with the unrestricted use of drug-eluting stents

Anemia is frequent among patients with cardiovascular disease and adversely affects prognosis. The objective of this analysis was to assess the impact of anemia on long-term clinical outcomes among patients undergoing percutaneous coronary intervention (PCI) with the unrestricted use of drug-eluting stents (DES).

Associations of Reactive Hyperemia Index and Intravascular Ultrasound-Assessed Coronary Plaque Morphology in Patients With Coronary Artery Disease

Although reactive hyperemia index (RHI) predicts future coronary events, associations with intravascular ultrasound (IVUS)-assessed coronary plaque structure have not been reported. This study therefore investigated associations between RHI and IVUS-assessed coronary plaques. In 362 patients RHI was measured by noninvasive peripheral arterial tonometry and coronary plaque components (fibrous, fibrofatty, necrotic core, and dense calcium) were identified by IVUS in 594 vessel segments of the left anterior descending, circumflex, and/or right coronary arteries. RHI values <1.67 were considered abnormal. Analysis of variance was used to detect independent associations between RHI and plaque composition. Patients with an abnormal RHI had greater plaque burden (41% vs 39% in patients with normal RHI, p = 0.047). Compared to patients with normal RHI, plaque of patients with abnormal RHI had more necrotic core (21% vs 17%, p <0.001) and dense calcium (19% vs 15%, p <0.001) and less fibrous (49% vs 54%, p <0.001) and fibrofatty (11% vs 14%, p = 0.002) tissue. After adjustment for age, gender, cardiovascular risk factors, and drug therapy, abnormal RHI remained significantly associated with fibrous (F ratio 14.79, p <0.001), fibrofatty (F ratio 5.66, p = 0.018), necrotic core (F ratio 14.47, p <0.001), and dense calcium (F ratio 10.80, p = 0.001) volumes. In conclusion, coronary artery plaques of patients with abnormal RHI had a larger proportion of necrotic core and dense calcium. The association of an abnormal RHI with a plaque structure that is more prone to rupture may explain why these patients exhibit a greater risk of coronary events.

Owner assessment in judging the efficacy of airway disease treatment

REASONS FOR PERFORMING STUDY: Efficacy of medications for recurrent airway obstruction is typically tested using clinical, cytological and lung function examinations of severely affected animals. These trials are technically challenging and may not adequately reflect the spectrum of disease and owner complaints encountered in clinical practice. OBJECTIVE: To determine if owners of horses with chronic airway disease are better able to detect drug efficacy than a veterinarian who clinically examines horses infrequently. METHOD: In a double-blinded randomised controlled trial, owners and a veterinarian compared the efficacy of dexamethasone (0.1 mg/kg bwt per os, q. 24 h, for 3 weeks; n = 9) to placebo (n = 8) in horses with chronic airway disease. Before and after treatment, owners scored performance, breathing effort, coughing and nasal discharge using a visual analogue scale (VAS). The clinician recorded vital parameters, respiratory distress, auscultation findings, cough and nasal discharge, airway mucus score, bronchoalveolar lavage fluid (BALF) cytology and arterial blood gases. RESULTS: The VAS score improved significantly in dexamethasone- but not placebo-treated horses. In contrast, the clinician failed to differentiate between dexamethasone- and placebo-treated animals based on clinical observations, BALF cytology or endoscopic mucus score. Respiratory rate (RR) and arterial oxygen pressure (PaO(2)) improved with dexamethasone but not placebo. CONCLUSIONS AND CLINICAL RELEVANCE: In the design of clinical trials of airway disease treatments, more emphasis should be placed on owner-assessed VAS than on clinical, cytological and endoscopic observations made during brief examinations by a veterinarian. Quantifiable indicators reflecting lung function such as RR and PaO(2) provide a good assessment of drug efficacy.

[Drug-independent blood pressure control through the autonomous nervous system]

Arterial hypertension is a chronic disease with a therapeutical challenge for the patient and the physician involved. Patient-independent techniques with good efficacy and tolerability are wanted. The autonomous nervous system insufficiently therapeutically exploited to date, is now approachable by two types of intervention: renal nerve ablation, an endovascular approach without remaining foreign body, and BAT, baroreflex activating therapy using an implantable device stimulating the carotid sinus. The blood pressure lowering potency of BAT appears more than with renal nerve ablation and also clinical study data are more prevalent. With both treatment options the patients having the most profit are insufficiently defined. Given this knowledge, any form of secondary hypertension needs to be excluded beforehand.