Stephen O'Connor

Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial.

BACKGROUND Optimum duration of dual antiplatelet treatment (DAPT) after coronary stenting remains uncertain, with an unknown efficacy to safety ratio of extended treatment leading to discrepancies between international guidelines and clinical practice. We assessed whether DAPT continuation beyond 1 year after coronary stenting is beneficial. METHODS This analysis was a planned extension of the previously published ARCTIC-Monitoring trial, in which we randomly allocated 2440 patients to a strategy of platelet function testing with antiplatelet treatment adjustment or a conventional strategy after coronary stenting with drug-eluting stent (DES). We recruited patients (aged 18 years or older) scheduled for planned DES implantation at 38 centres in France. After 1 year of follow-up, patients without contraindication to interruption of DAPT were eligible for a second randomisation to this second phase of the study (ARCTIC-Interruption). Using a computer-generated randomisation sequence (1:1; stratified by centre), we allocated patients to a strategy of interruption of DAPT where the thienopyridine was interrupted and single aspirin antiplatelet treatment was maintained (interruption group) or a strategy of DAPT continuation for 6-18 months (continuation group). The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularisation, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00827411. FINDINGS Between Jan 4, 2011, and March 3, 2012, 1259 eligible patients were randomly allocated to treatment in ARCTIC-Interruption: 624 to the interruption group and 635 to the continuation group. After a median follow-up of 17 months (IQR 15-18), the primary endpoint occurred in 27 (4%) patients in the interruption group and 24 (4%) patients in the continuation group (hazard ratio [HR] 1·17 [95% CI 0·68-2·03]; p=0·58). STEEPLE major bleeding events occurred more often in the continuation group (seven [1%] patients) compared with the interruption group (one [<0·5%] patient; HR 0·15 [0·02-1·20]; p=0·073). Major or minor bleedings were also more common in the continuation group compared with the interruption group (12 [2%] patients vs three [1%] patients; HR 0·26 [0·07-0·91]; p=0·04). INTERPRETATION Our finding suggests no apparent benefit but instead harm with extension of DAPT beyond 1 year after stenting with DES when no event has occurred within the first year after stenting. No conclusion can be drawn for high-risk patients who could not be randomised. The consistency between findings from all trials of such interruption suggests the need for a reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of treatment. FUNDING Allies in Cardiovascular Trials Initiatives and Organized Networks (ACTION Study Group), Fondation de France, Sanofi-Aventis, Cordis, Medtronic, Boston Scientific, Fondation SGAM.

High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIOR-PLATELET study

AIMS The aim of this study was to compare on-thienopyridine platelet reactivity of elderly patients (≥75 years) vs. younger patients (<75 years). Elderly patients represent a growing and challenging segment of the coronary population for whom the effect of dual antiplatelet therapy on platelet inhibition has not been specifically addressed. METHODS AND RESULTS The SENIOR-PLATELET study included 1331 coronary patients chronically (>14 days) treated with aspirin and a thienopyridine (clopidogrel 75 mg, n= 1027; clopidogrel 150 mg, n= 139; or prasugrel 10 mg, n= 165). Platelet response to clopidogrel and prasugrel was assessed by the VerifyNow assay and light transmission aggregrometry (LTA). Response to treatment, rate of high platelet reactivity (HPR), and inhibition (HPI) were compared in the two age categories. On-treatment platelet reactivity with clopidogrel 75 mg, 150 mg or prasugrel 10 mg was higher in elderly patients (n= 205) than in younger patients (n= 1126) whichever the test used. The difference in P2Y(12) reaction units (PRU) between the two populations was +45 in patients treated with clopidogrel 75 mg (P< 0.0001), +30 in patients treated with clopidogrel 150 mg (P= 0.17), and +20 with prasugrel 10 mg (P= 0.10). Differences in residual platelet aggregation were consistent when measured by LTA. Elderly patients treated with clopidogrel 75 mg were more likely to have HPR than younger patients (38.2 vs. 18.2%, OR: 2.58, 95% CI: 1.76-3.79; P< 0.0001) even after adjustment for potential confounders (adj OR: 1.83, 95% CI: 1.16-2.87; P= 0.009). CONCLUSION Elderly patients present an impaired response to clopidogrel with a high rate of HPR. Clopidogrel 150 mg or prasugrel 10 mg blunt, but do not eliminate the difference in response observed between old and young patients.

Switching Acute Coronary Syndrome Patients From Prasugrel to Clopidogrel

OBJECTIVES This study sought to assess the consequences of switching prasugrel to clopidogrel on platelet inhibition and clinical outcomes after an acute coronary syndrome (ACS). BACKGROUND Many ACS patients are switched from prasugrel to clopidogrel within the recommended 1-year duration of treatment. METHODS Platelet reactivity was measured with the VerifyNow P2Y(12) assay (Accumetrics, San Diego, California) in 300 ACS patients treated for 15 days with prasugrel 10 mg. Patients displaying low on-treatment platelet reactivity (LPR) and/or at high risk of bleeding were switched to clopidogrel 75 mg and tested again 15 days later. The rate of patients with high on-treatment platelet reactivity (HPR), P2Y(12) reaction units (PRU) >208, and LPR (PRU <0) were evaluated before and after the switch. Bleeding and ischemic events were also recorded. RESULTS On a regimen of prasugrel 10 mg, the rate of patients with LPR was 45.6% (n = 137), whereas 4.3% (n = 13) had HPR. A group of 31 patients (10.3%) was switched to clopidogrel 75 mg, of whom 29 had LPR (93.5%) on a regimen of prasugrel. On-treatment platelet reactivity (PRU) increased from 14 ± 4 on a regimen of prasugrel to 155 ±15 on a regimen of clopidogrel (p = 0.0001), resulting in a much lower rate of patients with LPR (9.7%). The rate of patients with HPR increased from 0% with prasugrel to 29% (n = 9) with clopidogrel. The rate of minor bleeding decreased after the switch from 32.2% to 9.7%; p = 0.03. CONCLUSIONS An LPR is frequent in patients treated with prasugrel 10 mg. Early switching from prasugrel 10 mg to clopidogrel 75 mg reduces the number of patients with LPR and minor bleeding events but unmasks a group of nonresponders to clopidogrel with unknown consequences on clinical outcomes.

Prasugrel Monitoring and Bleeding in Real World Patients

The aim of this study was to evaluate platelet reactivity and 30-day bleeding events in patients treated with prasugrel 10 mg after acute coronary syndromes. A total of 444 patients with acute coronary syndromes treated with percutaneous coronary intervention and prasugrel 10 mg/day were monitored by measurement of the vasodilator-stimulated phosphoprotein (VASP) index 2 to 4 weeks after hospital discharge. Platelet reactivity was also assessed using the VerifyNow P2Y(12) assay and light transmission aggregometry. Bleeding events (per the Bleeding Academic Research Consortium [BARC] definition) and ischemic events (death, myocardial infarction, and definite stent thrombosis) were collected over 30 days of follow-up. Two thirds of the patients presented with ST-segment elevation myocardial infarctions, 28.8% had diabetes, and 12.4% were aged >75 years. High on-treatment platelet reactivity according to 3 prespecified definitions (VASP index ≥ 50%, platelet reactivity ≥ 235 P2Y(12) reaction units, and residual platelet reactivity ≥ 46.2%) was found in 6.8%, 3.4%, and 3.2% of patients, respectively. Obesity (body mass index >30 kg/m(2)) and multivessel disease were the only independent factors associated with high on-treatment platelet reactivity (p = 0.006 and p = 0.045, respectively). At 30 days, there was no major bleeding complication (BARC grade 3 or 5), and 1.6% of patients had recurrent ischemic events. Nuisance bleeding (BARC grade 1) and minor bleeding (BARC grade 2) occurred in 14.2% (n = 63) and 2.5% (n = 11) of patients, respectively, but were not predicted by VASP index. In conclusion, patients with acute coronary syndromes receiving maintenance doses of prasugrel have low rates of HPR and ischemic events within the first month. Minor or minimal bleeding is frequent, but not major bleeding. VASP was poorly correlated with the risk for minor or minimal bleeding.

Evaluation of the learning curve for transcatheter aortic valve implantation via the transfemoral approach

BACKGROUND The aim of this study was to evaluate the learning curve in performing transfemoral TAVI (TF-TAVI). METHODS Between October 2006 and October 2013, 312 consecutive TF-TAVI cases performed by 6 interventional cardiologists, using the Edwards Sapien valve and 104 using the CoreValve, were included in the present analysis. Cumulative sum (CUSUM) failure analysis of combined 30-day safety endpoint was used to evaluate learning curves. RESULTS The CUSUM analysis revealed a learning curve regarding the occurrence of 30-day adverse events with an improvement after the initial 86 cases using the Edwards valve and 40 cases using the CoreValve. We divided the Edwards valve cases into two groups (early experience: Cases 1 to 86; late experience: Cases 87 to 312). The rate of 30-day mortality and 1-year mortality significantly decreased in the late experience group (17% to 7%, p=0.019; 34% to 21%, p=0.035, respectively). We divided the CoreValve cases into two groups (early experience: Cases 1 to 40; late experience: Cases 41 to 104). The rate of 30-day mortality and 1-year mortality significantly decreased in the late experience group (20% to 6%, p=0.033; 38% to 15%, p=0.040, respectively). The groups including both valves were also analyzed after propensity-matching (early [n=52] vs late [n=52]). This model also showed that 30-day and 1-year mortality rates were significantly lower in the late experience group (13% to 1%, p=0.028; 34% to 20%, p=0.042, respectively). CONCLUSIONS An appropriate level of experience is needed to reduce the complication rate and mortality in TF-TAVI.

Impact of pre- and post-procedural anemia on the incidence of acute kidney injury and 1-year mortality in patients undergoing transcatheter aortic valve implantation (from the French Aortic National CoreValve and Edwards 2 [FRANCE 2] Registry)

The relationship between anemia, renal insufficiency, and the outcomes of TAVI patients has not been thoroughly studied. We aimed to evaluate the influence of pre‐ and post‐procedural anemia on the incidence of renal insufficiency, especially AKI, and on the outcomes of TAVI.

Ectopic Focus in an Accessory Left Atrial Appendage Radiofrequency Ablation of Refractory Atrial Fibrillation

A 65-year-old man with symptomatic atrial fibrillation refractory to medical therapy was referred for repeat pulmonary vein (PV) isolation. Clinical symptoms included paroxysmal palpitations once to twice per week with associated light-headedness and chest pain. Initial PV isolation had been performed 6 months earlier without cessation of atrial fibrillation despite combined medical therapy with oral flecainide and bisoprolol. His past medical history was significant for hypertension, and in his family history, 1 brother had experienced a stroke at the age of 57 years. Physical examination, ECG, chest radiography, and coronary angiography were normal. Holter 24-hour ECG recordings revealed occasional atrial premature beats and paroxysmal atrial tachycardia. A magnetic resonance imaging study of the patient’s PVs and left atrium (LA) was performed before the repeat radiofrequency ablation. Images were acquired with a 1.5-T whole-body magnetic resonance system (Siemens Avanti, Siemens Medical Solutions, Forcheim, Germany) with an 8-element cardiac synergy coil for radiofrequency signal reception. First-pass breath-hold 3-dimensional contrast-enhanced magnetic resonance angiography of the PV was obtained after pump injection (3 mL/s) of 15 mmol of …

An evidence-based review of current anti-platelet options for STEMI patients

Drug-eluting stents are the default treatment for acute coronary syndromes, unless concerns or contraindications preclude dual antiplatelet therapy (DAPT). Platelet microemboli and mediators from activated platelets can undermine the restoration of perfusion. Therefore, ST-segment elevation MI (STEMI) patients should receive antiplatelet treatments regardless of reperfusion strategy. This review offers an evidence-based comparison of the P2Y12 antagonists that have been evaluated in STEMI. While several studies support clopidogrel in STEMI, the benefits emerge several hours after administration and vary considerably reflecting genetic, cellular and clinical inter-individual differences. Although higher clopidogrel loading doses may improve outcomes, ticagrelor and prasugrel are more potent, produce less inter-individual variability, and show a faster onset of action. Ticagrelor and prasugrel improve outcomes compared to clopidogrel, with manageable bleeding risks, although further studies with a longer follow up are needed. Studies directly comparing ticagrelor and prasugrel are now needed. In the meantime, most current guidelines focus on clopidogrel and, therefore, need revision. While several polymorphisms influence platelet activity, CYP2C19 variants are the most consistently linked to clopidogrel responsiveness. Consensus groups should consider the studies needed to allow routine pharmacogenomic testing. The evidence-based use of P2Y12 antagonists in DAPT should further reduce the morbidity and mortality associated with STEMI.

Pharmacogenetics of Clopidogrel

Clopidogrel used in conjunction with aspirin has a central role in the treatment of patients with an acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI). The pharmacokinetic and pharmacodynamic responses to this drug are highly variable leaving up to one third of patients with inadequate platelet inhibition or high on-treatment platelet reactivity (HPR), and subsequent increased ischemic cardiovascular events. Genetic variability in drug absorption and metabolism is a key factor responsible for the inefficient generation of the active drug metabolite. The two-step hepatic cytochrome P450 (CYP)-dependant oxidative metabolism of the prodrug appears to be of particular importance. Pharmacogenomic analyses have identified loss-of-function variant alleles of CYP 2C19 and specifically the 2C19*2 allele, to be the predominant genetic mediators of the antiplatelet effect of clopidogrel. Carriers were have been shown to have lower active metabolite levels of clopidogrel, higher platelet reactivity and associated poorer outcomes. Rapid and accurate point-of-care genetic tests to identify these alleles are currently in development but several questions about the role of such testing remain such as patient selection and whether personalized treatment based on genotype has a positive impact on clinical outcome. At present, genetic testing cannot be recommended in routine clinical practice due to insufficient prospective data. However, the significant body of research published to date suggests a likely role when used in combination with platelet function analysis in ACS patients undergoing stenting who have other known risk factors for recurrent ischemic events.

Optimal time for catheterization in NSTE-ACS patients with impaired renal function: insights from the ABOARD Study.

BACKGROUND To assess the impact of impaired renal function (IRF) and timing of catheterization (immediate versus delayed intervention) on outcomes in intermediate/high risk NSTE-ACS patients. METHODS We performed a post-hoc analysis of the randomized ABOARD population to compare 1) patients with vs. without IRF and 2) the two intervention strategies in patients with IRF. A creatinine clearance <60 mL/min defined IRF. The primary endpoint was the in-hospital peak troponin I value; the secondary endpoints were a) the composite of death, myocardial infarction, urgent revascularization or recurrent ischemia (death/MI/UR/RI) and b) STEEPLE major bleeding (MB) at 1-month follow-up. RESULTS Among the 345 patients, 75 (21.7%) had IRF. Patients with IRF were older, had more comorbidities and were at higher cardiovascular risk. Radial catheterization was predominant (84%). Among IRF patients, 37 (49%) and 38 (51%) patients were randomized to an immediate and delayed strategy, respectively. The primary and secondary endpoints rates were not different for the two comparisons. IRF was associated with more death (5.3% vs. 1.1%, p=0.043) and non-CABG MB (9.3% vs. 2.2%, p=0.001). In patients with IRF, a delayed strategy was associated with more recurrent ischemia (28.9% vs. 8.1%, p=0.021). Absence of clopidogrel pretreatment, insulin therapy and left main culprit lesion were independently associated with death/MI/UR/RI, while age and CABG surgery were related with MB. CONCLUSION IRF is associated with worse outcomes in NSTE-ACS patients. The primary results of the ABOARD study apply also to patients with IRF in which the timing of catheterization does not impact hard outcomes.