Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients.

BACKGROUND: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y12 inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically. METHODS: Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding). RESULTS: A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77-1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66-1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62-1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively. CONCLUSION: In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and patients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in patients using clopidogrel.

Ticagrelor Versus Clopidogrel in Older Patients with NSTE-ACS Using Oral Anticoagulation: A Sub-Analysis of the POPular Age Trial.

There are no randomised data on which antiplatelet agent to use in elderly patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) and an indication for oral anticoagulation (OAC). The randomised POPular Age trial, in patients of 70 years or older with NSTE-ACS, showed a reduction in bleeding without increasing thrombotic events in patients using clopidogrel as compared to ticagrelor. In this sub-analysis of the POPular AGE trial, we compare clopidogrel with ticagrelor in patients with a need for oral anticoagulation. The follow-up duration was one year. The primary bleeding outcome was Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding. The primary thrombotic outcome consisted of cardiovascular death, myocardial infarction and stroke. The primary net clinical benefit outcome was a composite of all-cause death, myocardial infarction, stroke, and PLATO major and minor bleeding. A total of 184/1011 (18.2%) patients on OAC were included in this subanalysis; 83 were randomized to clopidogrel and 101 to ticagrelor. The primary bleeding outcome was lower in the clopidogrel group (17/83, 20.9%) compared to the ticagrelor group (33/101, 33.5%; p = 0.051), as was the thrombotic outcome (7/83, 8.4% vs. 19/101, 19.2%; p = 0.035) and the primary net clinical benefit outcome (23/83, 27.7% vs. 49/101, 48.5%; p = 0.003). In this subgroup of patients using OAC, clopidogrel reduced PLATO major and minor bleeding compared to ticagrelor without increasing thrombotic risk. This analysis therefore suggests that, in line with the POPular Age trial, clopidogrel is a better option than ticagrelor in NSTE-ACS patients ≥70 years using OAC.

Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome (POPular AGE): the randomised, open-label, non-inferiority trial.

BACKGROUND: Current guidelines recommend potent platelet inhibition with ticagrelor or prasugrel in patients after an acute coronary syndrome. However, data about optimal platelet inhibition in older patients are scarce. We aimed to investigate the safety and efficacy of clopidogrel compared with ticagrelor or prasugrel in older patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS: We did the open-label, randomised controlled POPular AGE trial in 12 sites (ten hospitals and two university hospitals) in the Netherlands. Patients aged 70 years or older with NSTE-ACS were enrolled and randomly assigned in a 1:1 ratio using an internet-based randomisation procedure with block sizes of six to receive a loading dose of clopidogrel 300 mg or 600 mg, or ticagrelor 180 mg or prasugrel 60 mg, and then a maintenance dose for the duration of 12 months (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily, or prasugrel 10 mg once daily) on top of standard care. Patient and treating physicians were aware of the allocated treatment strategy, but the outcome assessors were masked to treatment allocation. Primary bleeding outcome consisted of PLATelet inhibition and patient Outcomes (PLATO; major or minor bleeding [superiority hypothesis]). Co-primary net clinical benefit outcome consisted of all-cause death, myocardial infarction, stroke, PLATO major and minor bleeding (non-inferiority hypothesis, margin of 2%). Follow-up duration was 12 months. Analyses were done on intention-to-treat basis. This trial is registered with the Netherlands Trial Register (NL3804), ClinicalTrials.gov (NCT02317198), and EudraCT (2013-001403-37). FINDINGS: Between June 10, 2013, and Oct 17, 2018, 1002 patients were randomly assigned to clopidogrel (n=500) or ticagrelor or prasugrel (n=502). Because 475 (95%) patients received ticagrelor in the ticagrelor or prasugrel group, we will refer to this group as the ticagrelor group. Premature discontinuation of the study drug occurred in 238 (47%) of 502 ticagrelor group patients randomly assigned to ticagrelor, and in 112 (22%) of 500 patients randomly assigned to clopidogrel. Primary bleeding outcome was significantly lower in the clopidogrel group (88 [18%] of 500 patients) than in the ticagrelor group (118 [24%] of 502; hazard ratio 0·71, 95% CI 0·54 to 0·94; p=0·02 for superiority). Co-primary net clinical benefit outcome was non-inferior for the use of clopidogrel (139 [28%]) versus ticagrelor (161 [32%]; absolute risk difference -4%, 95% CI -10·0 to 1·4; p=0·03 for non-inferiority). The most important reasons for discontinuation were occurrence of bleeding (n=38), dyspnoea (n=40), and the need for treatment with oral anticoagulation (n=35). INTERPRETATION: In patients aged 70 years or older presenting with NSTE-ACS, clopidogrel is a favourable alternative to ticagrelor, because it leads to fewer bleeding events without an increase in the combined endpoint of all-cause death, myocardial infarction, stroke, and bleeding. Clopidogrel could be an alternative P2Y12 inhibitor especially for elderly patients with a higher bleeding risk. FUNDING: ZonMw.

Causes for the declining proportion of ventricular fibrillation in out-of-hospital cardiac arrest.

AIMS: The reported proportion of ventricular fibrillation (VF) in out-of-hospital cardiac arrest (OHCA) has declined worldwide. VF decline may be caused by less VF at collapse and/or faster dissolution of VF into asystole. We aimed to determine the causes of VF decline by comparing VF proportions in relation to delay from emergency medical services (EMS) call to initial ECG (call-to-ECG delay), and VF dissolution rates between two study periods. METHODS: Data from the AmsteRdam REsuscitation STudies (ARREST), an ongoing OHCA registry in the Netherlands, were used. We studied cardiac OHCA in the study periods 1995-1997 (n=917) and 2006-2012 (n=5695). Cases with available ECG and information on call-to-ECG delay were included. We tested whether initial VF proportion and VF dissolution rates differed between both study periods using logistic regression. RESULTS: Despite a 15% VF decline between the periods, VF proportion around EMS call remained high in 2006-2012 (64%). The odds ratio (OR) for VF proportion in 2006-2012 vs. 1995-1997 was 0.52 (95%-CI 0.45-0.60, P<0.001), with similar rates of VF dissolution in both periods (P=0.83). VF decline was higher for unwitnessed collapse (OR 0.41, 95%-CI 0.28-0.58) and collapse at home (OR 0.50, 95%-CI 0.42-0.59), but not for categories of bystander CPR, age or sex. CONCLUSION: VF proportion early after collapse remains high. VF decline is explained by the occurrence of less initial VF, rather than faster dissolving VF. An increase in unwitnessed OHCA and collapse at home contributes to the observed VF decline.

Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome associated with mutations in the cardiac ryanodine receptor gene (Ryr2) in the majority of patients. Previous studies of CPVT patients mainly involved probands, so current insight into disease penetrance, expression, genotype-phenotype correlations, and arrhythmic event rates in relatives carrying the Ryr2 mutation is limited. METHODS AND RESULTS: One-hundred sixteen relatives carrying the Ryr2 mutation from 15 families who were identified by cascade screening of the Ryr2 mutation causing CPVT in the proband were clinically characterized, including 61 relatives from 1 family. Fifty-four of 108 antiarrhythmic drug-free relatives (50%) had a CPVT phenotype at the first cardiological examination, including 27 (25%) with nonsustained ventricular tachycardia. Relatives carrying a Ryr2 mutation in the C-terminal channel-forming domain showed an increased odds of nonsustained ventricular tachycardia (odds ratio, 4.1; 95% CI, 1.5-11.5; P=0.007, compared with N-terminal domain) compared with N-terminal domain. Sinus bradycardia was observed in 19% of relatives, whereas other supraventricular dysrhythmias were present in 16%. Ninety-eight (most actively treated) relatives (84%) were followed up for a median of 4.7 years (range, 0.3-19.0 years). During follow-up, 2 asymptomatic relatives experienced exercise-induced syncope. One relative was not being treated, whereas the other was noncompliant. None of the 116 relatives died of CPVT during a 6.7-year follow-up (range, 1.4-20.9 years). CONCLUSIONS: Relatives carrying an Ryr2 mutation show a marked phenotypic diversity. The vast majority do not have signs of supraventricular disease manifestations. Mutation location may be associated with severity of the phenotype. The arrhythmic event rate during follow-up was low.

Assessment of quality of life and cognitive function after out-of-hospital cardiac arrest with successful resuscitation.

This prospective cohort study evaluated the impact of the time-related elements of the "chain of survival" on the quality of life of patients, taking their characteristics into account. Between 1995 and 2002, consecutive, out-of-hospital cardiac arrest patients from Amsterdam and the surrounding areas were included in this study. A total of 227 patients (12%) survived to hospital discharge and 174 were definitive survivors who were available for assessment at 6 months. Quality of life was measured with the 136-item Sickness Impact Profile (SIP); cognitive functioning was assessed through the Mini Mental State Examination. SIP profiles were compared with profiles of an open Dutch population of the elderly and patients who experienced a stroke. Time intervals of the chain of survival were calculated from the estimated moment of collapse and related to outcome using regression analysis. The SIP profile of survivors was a little above the reference profile, indicating a slightly poorer quality of life, and below the profile of patients after stroke, indicating a better quality of life. Impaired cognitive function was associated with delay in the start of cardiopulmonary resuscitation (odds ratio 4.3, 95% confidence interval 1.0 to 19). Absence of the need for advanced cardiopulmonary life support was associated with better cognitive functioning (odds ratio 0.3, 95% confidence interval 0.1 to 0.9). Female gender and older age were associated with impaired physical functioning. Trends were found for better outcomes after early access, immediate resuscitation, early defibrillation, and early advanced care.

Prevention of deterioration of ventricular fibrillation by basic life support during out-of-hospital cardiac arrest.

Survival of cardiac arrest is improved by basic life support (BLS). This study investigated the relationship between ventricular fibrillation (VF) characteristics and survival. In a 2-year prospective study out-of-hospital witnessed non-traumatic cardiac arrests were observed. The probabilities of recording VF, asystole or other rhythms in relation to BLS and the time to the rhythm recording were analyzed with logistic regression. Amplitude and baseline crossings of VF were related to survival, using linear regression analysis. In 873 patients, the probability to record VF decreased per minute (OR 0.92, 95%CI 0.89-0.95) and of asystole increased (OR 1.13, 95%CI 1.09-1.18) as time from collapse elapsed. BLS reduced these trends significantly for VF (OR 0.97, 95%CI 0.94-0.99) and asystole (OR 1.09, 95%CI 1.05-1.13). This effect was not observed for other rhythms. The amplitude of VF decreased in time; significantly less for patients who received BLS than for those who did not (p=0.009). Survival significantly decreased with lower amplitude of VF (OR 0.23 per mV, 95%CI 0.07-0.79) and with less baseline crossings (OR 0.80 per baseline crossings per second, 95%CI 0.71-0.91). Our study demonstrated that BLS and VF as initial rhythm, considered being "baseline" predictors in survival models, were proved not independent of each other. The decrease of VF amplitude and increase in prevalence of asystole is slowed significantly by BLS. Predicting survival from VF amplitude and baseline crossings alone is limited.