RESUMEN
BACKGROUND: The incidence of stroke/TIA during annual dual antiplatelet therapy (ADAPT) for acute coronary syndrome (ACS) remains high. Some evidence suggests that shorter than ADAPT may diminish such risk, still providing adequate vascular protection. However, the precise timing of strokes/TIA occurrences during ADAPT is unclear but may be important for determining optimal preventive treatment duration. STUDY QUESTION: The precise timing of secondary cerebrovascular events over ADAPT. STUDY DESIGN: Access was gained to the FDA-issued Platelet Inhibition and Outcomes (PLATO) trial data set on which post hoc analyses of stroke/TIA timing after ticagrelor and clopidogrel on top of aspirin was explored. MEASURES AND OUTCOMES: Events were counted and plotted over time from day 1 till day 365 after the index ACS event. RESULTS: Among 18,624 enrollees, 252 strokes and 49 TIAs were reported. After the exclusion of entries with missing dates, unclear randomization codes, and events beyond 1-year follow-up, 238 strokes and 45 TIAs were analyzed. Overall, most frequent strokes/TIAs occurred within the first day after qualifying ACS, with the gradual declines after day 7 and day 40 reaching background counts thereafter. The strokes/TIAs patterns did not differ much between P 2 Y12 inhibitors except for twice more events at day 1 and excess exclusions after day 365 in the ticagrelor arm. CONCLUSIONS: Most cerebrovascular events emerged very early after ACS despite ADAPT. This large hypothesis-generating evidence may justify shorter than the ADAPT duration after ACS. Twice more events at day 1 and excess late ticagrelor exclusions in PLATO deserve further scrutiny. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00391872.
Asunto(s)
Síndrome Coronario Agudo , Ataque Isquémico Transitorio , Accidente Cerebrovascular , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Ticagrelor/efectos adversos , Ataque Isquémico Transitorio/epidemiología , Ataque Isquémico Transitorio/prevención & control , Resultado del Tratamiento , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/epidemiologíaRESUMEN
BACKGROUND: Excess mortality remains the cornerstone concern despite dual antiplatelet therapy (DAPT) after acute coronary syndrome. Some data suggest that shorter periods than 12 months of DAPT diminish bleeding risks yet still provide adequate vascular protection and improving survival. However, the precise timing of deaths after acute coronary syndrome has not been mapped in many studies. This knowledge may be critical for defining optimal treatment duration. METHODS: Access was gained to the data set for the Platelet Inhibition and Outcomes (PLATO) trial, which was issued by the Food and Drug Administration, in which post hoc analyses of timing of death events during DAPT (with either aspirin/ticagrelor or aspirin/clopidogrel) were performed. All-cause individual deaths were counted and plotted over time from day 1 to day 365 after the index event. RESULTS: Among 18,624 enrollees, 938 total deaths were reported to the Food and Drug Administration in PLATO. After exclusion of deceased patients with missing dates, randomization errors, and deaths beyond 1 year of follow-up, 913 fatalities (509 after clopidogrel and 404 after ticagrelor) were analyzed. The PLATO records did not indicate where exactly deaths occurred making impossible to triage in the hospital versus outpatient fatalities. Most frequent deaths occurred within the Day 1 (n = 41); Day 2 (n = 48); and Day 3 (n = 33) and overall during the first week (n = 202; 22.1%) after the index acute coronary syndrome, with a gradual decline after Day 10 and Day 60, reaching background counts after Day 220. CONCLUSION: Focusing on mortality reduction, this large data set may support a shorter than 12 months' duration of DAPT.
Asunto(s)
Síndrome Coronario Agudo , Intervención Coronaria Percutánea , Humanos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Clopidogrel/uso terapéutico , Ticagrelor/uso terapéutico , Ticlopidina/uso terapéutico , Hemorragia/inducido químicamente , Hemorragia/tratamiento farmacológico , Quimioterapia Combinada , Resultado del Tratamiento , Aspirina/uso terapéuticoRESUMEN
PURPOSE: The FDA-issued PLATO trial dataset revealed that some primary death causes (PDCs) were inaccurately reported favouring ticagrelor. However, the PLATO Investigators operated the shorter death list of uncertain quality. We compared if PDC match when trial fatalities were reported to the FDA and by the PLATO Investigators. METHOD: The FDA list contains precisely detailed 938 PLATO deaths, while shorter investigators dataset consists of 905 deaths. We matched four vascular (sudden, post-MI, heart failure and stroke), and three non-vascular (cancer, sepsis and suicide) PDC between death lists. RESULTS: There were more sudden deaths in the shorter list than in the FDA dataset (161 vs 138; P < .03) and post-AMI (373 vs 178; P < .001) but fewer heart failure deaths (73 vs 109; P = .02). Stroke numbers match well (39 vs 37; P = NS) with only two ticagrelor cases removed. Cancer matched well (32 vs 31; P = NS), and sepsis cases were identical (30 vs 30; P = NS). However, two extra clopidogrel suicides in the shorter list are impossible to comprehend. CONCLUSIONS: The PLATO trial PDCs were mismatched between FDA and investigators sets. We are kindly asking the ticagrelor sponsor or/and concerned PLATO Investigators to clarify the PDC dataset match.
Asunto(s)
Síndrome Coronario Agudo , Suicidio , Humanos , Adenosina , Inhibidores de Agregación Plaquetaria , Antagonistas del Receptor Purinérgico P2Y , Ticlopidina , Resultado del TratamientoRESUMEN
BACKGROUND: Ivabradine, a heart rate-slowing drug used to treat heart failure and (in Europe) angina, had varying impacts upon cardiovascular events in its 3 large outcome trials. Food and Drug Administration (FDA) analyses may explain the reasons for the variability. METHODS: An FDA reviewer analyzed the raw data from the 3 trials using logistic regressions to assess interactions between ivabradine and other drugs and forest plots to display dose responses. RESULTS: Ivabradine in its SHIFT heart failure trial shows a significant interaction with loop diuretics with a beneficial impact upon cardiovascular deaths (odds ratio 0.61; 95% confidence interval, 0.42-0.87, P = .007). This favorable effect is supported by similar interactions in the other 2 trials (BEAUTIFUL, SIGNIFY) and by a dose response for loop diuretics interacting with ivabradine in the SHIFT and BEAUTIFUL trials. The interaction is not related to heart failure severity. CONCLUSION: Ivabradine used concomitantly with a loop diuretic has a beneficial impact upon cardiovascular death.
Asunto(s)
Fármacos Cardiovasculares/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Ivabradina/uso terapéutico , Insuficiencia Cardíaca/mortalidad , Humanos , Modelos Logísticos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Tegaserod, a serotonin (5-HT4) agonist initially approved for constipation but withdrawn from use in 2007 because of concerns about cardiovascular adverse effects, was resubmitted to the Food and Drug Administration (FDA) in 2018 for use in a restricted population. AREAS OF UNCERTAINTY: Despite an 18-year regulatory history, there remain pharmacology and clinical trial concerns that have not been addressed but are critical for proper assessment of the drug safety and efficacy profile. SOURCES: Original FDA reviews, FDA and developer advisory committee briefing documents, and published literature. RESULTS: The major pharmacology concern is that the fate and effects of half of the molecule, the pentylaminoguanidine moiety, are unknown. There is evidence that pentylaminoguanidine may contribute to both efficacy and safety. There are other metabolites that are poorly characterized, and potential receptor interactions that suggest cardiovascular effects are possible. The major clinical trial concern is that, while the trial data support a low but definite cardiovascular risk, both subject follow-up and cardiovascular event descriptions were incomplete such that an accurate estimate of cardiovascular risk is not possible. CONCLUSIONS: The uncertainties and lack of reliable evidence regarding tegaserod metabolism and cardiovascular risk estimates may discourage clinical use. Signals for cardiovascular toxicity in typical drug development programs are subtle and must be pursued aggressively, with complete case follow-up and cardiovascular event capture in the clinical trials.
Asunto(s)
Enfermedades Cardiovasculares/inducido químicamente , Indoles/administración & dosificación , Síndrome del Colon Irritable/tratamiento farmacológico , Agonistas del Receptor de Serotonina 5-HT4/administración & dosificación , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/prevención & control , Ensayos Clínicos como Asunto , Aprobación de Drogas/legislación & jurisprudencia , Electrocardiografía/efectos de los fármacos , Humanos , Indoles/efectos adversos , Agonistas del Receptor de Serotonina 5-HT4/efectos adversos , Estados Unidos , United States Food and Drug Administration/legislación & jurisprudenciaRESUMEN
BACKGROUND: Ranolazine is an anti-angina agent with many metabolites creating the potential for off-target effects. The U.S. Food and Drug Administration (FDA) reviews sometimes contain clinically relevant data not found in other sources. METHODS: We reanalyzed data in an FDA review of the placebo-controlled MERLIN trial of ranolazine to display differences in adverse event rates graphically. RESULTS: Rates of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)-related adverse events (eg, angioedema, dry cough, renal impairment, hypotension, anemia, and serum potassium > 5.5 mmol/L) were higher in patients receiving ranolazine and an ACEI or ARB. Rates of adverse events that should be decreased by ACEI/ARBs (eg, hypokalemia, hypertension, and serum potassium < 3.5 mmol/L) were lower in patients receiving ranolazine and an ACEI or ARB compared to rates in patients receiving placebo and an ACEI or ARB. CONCLUSIONS: Ranolazine potentiates the effects of ACEIs and ARBs. Clinicians should monitor for this potentiation when initiating treatment with ranolazine and an ACEI or ARB.
Asunto(s)
Angina de Pecho/tratamiento farmacológico , Antagonistas de Receptores de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Ranolazina/efectos adversos , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/mortalidad , Angina de Pecho/diagnóstico , Angina de Pecho/mortalidad , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/mortalidad , Ranolazina/uso terapéutico , Medición de Riesgo , Tasa de Supervivencia , Resultado del Tratamiento , Estados Unidos , United States Food and Drug AdministrationAsunto(s)
Fármacos Cardiovasculares/uso terapéutico , Aprobación de Drogas/legislación & jurisprudencia , Medicina Basada en la Evidencia/legislación & jurisprudencia , Regulación Gubernamental , Disparidades en Atención de Salud/legislación & jurisprudencia , Insuficiencia Cardíaca/tratamiento farmacológico , Ivabradina/uso terapéutico , United States Food and Drug Administration/legislación & jurisprudencia , Europa (Continente) , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Humanos , Ivabradina/efectos adversos , Seguridad del Paciente , Formulación de Políticas , Medición de Riesgo , Factores de Riesgo , Estados UnidosRESUMEN
AIMS: Clopidogrel is commonly used even after expiring patents. The brand clopidogrel (BC) was dealt by single company, while numerous manufacturers produce generic clopidogrel (GC). There are no convincing data to compare the safety of different formulations. Therefore, the data yielded from international, uniform, government-mandated registries may be useful. METHODS AND RESULTS: We assessed primary causative adverse events (PCAE) after BC and GC in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The outcomes were divided into death, cardiac, thrombotic/embolic, haemorrhagic, and rash/dermal complications. These primary endpoints were then examined by proportional reporting ratios (PRR) and chi-square (χ2). Among total FAERS (n = 9 466 679) reports, overall BC (n = 88 863) cases were more common than after GC (n = 36 559). When triaged by PCAE role, BC (n = 18 328) was also more abundant than GC (n = 3987). The reported death rates were more than doubled after BC [18.4% vs. 7.0%; PRR = 0.38; 95% confidence interval (95% CI) 0.32-0.43; χ2=369.7; P<0.0001] for total FAERS, and consistent for late 2010-2017 (17.6% vs. 7.0% PRR = 0.40; 95% CI 0.37-0.45; χ2=286.2; P<0.004) PCAE cases. In contrast, GC trended to co-report more cardiac (14.6% vs. 13.3%; PRR = 1.12; 95% CI 1.0-1.25; χ2=3.5; P<0.06). The haemorrhagic (40.9% vs. 32.3%; PRR = 1.45; 95% CI 1.33-1.57; χ2=75.8; P<0.0001), and rash/dermal (5.4% vs. 4.6%; PRR = 1.20; 95% CI 1.0-1.44; χ2=3.75; P<0.05) events were also more common for GC. Thrombotic/embolic events were reported equally (at 7.0%) after each formulation. CONCLUSION: The PCAE profiles differ with BC and GC in FAERS. While deaths reports were higher, the rates of cardiac, haemorrhagic, and skin complications were less common for BC. Despite expected reporting bias, this may indicate that the manufacturers of GC are reluctant to report deaths to the FDA. However, the overall adverse event profile suggests potentially better safety of BC over GC formulations.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Clopidogrel/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Medicamentos Genéricos/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , United States Food and Drug Administration , Anciano , Causas de Muerte , Minería de Datos , Bases de Datos Factuales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/mortalidad , Femenino , Humanos , Masculino , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Estados UnidosAsunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Ticagrelor/efectos adversos , United States Food and Drug Administration/estadística & datos numéricos , Salud Global , Humanos , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Tasa de Supervivencia/tendencias , Estados UnidosAsunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Enfermedades Cardiovasculares/tratamiento farmacológico , Clopidogrel/efectos adversos , Clorhidrato de Prasugrel/efectos adversos , Ticagrelor/efectos adversos , United States Food and Drug Administration , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Estados UnidosRESUMEN
BACKGROUND: The US Food and Drug Administration Adverse Event Reporting System (FAERS) is a global passive surveillance database that relies on voluntary reporting by health care professionals and consumers as well as required mandatory reporting by pharmaceutical manufacturers. However, the initial filers and comparative patterns for oral P2Y12 platelet inhibitor reporting are unknown. We assessed who generated original FAERS reports for clopidogrel, prasugrel, and ticagrelor in 2015. METHODS: From the FAERS database we extracted and examined adverse event cases coreported with oral P2Y12 platelet inhibitors. All adverse event filing originating sources were dichotomized into consumers, lawyers, pharmacists, physicians, other health care professionals, and unknown. RESULTS: Overall, 2015 annual adverse events were more commonly coreported with clopidogrel (n = 13,234) with known source filers (n = 12,818, or 96.9%) than with prasugrel (2,896; 98.9% out of 2,927 cases) or ticagrelor (2,163, or 82.3%, out of 2,627 cases, respectively). Overall, most adverse events were filed by consumers (8,336, or 44.4%), followed by physicians (5,290, or 28.2%), other health care professionals (2,997, or 16.0%), pharmacists (1,125, or 6.0%), and finally by lawyers (129, or 0.7%). The origin of 811 (4.7%) initial reports remains unknown. The adverse event filing sources differ among drugs. While adverse events coreported with clopidogrel and prasugrel were commonly originated by patients (40.4 and 84.3%, respectively), most frequently ticagrelor reports (42.5%) were filed by physicians. CONCLUSION: The reporting quality and initial sources differ among oral P2Y12 platelet inhibitors in FAERS. The ticagrelor surveillance in 2015 was inadequate when compared to clopidogrel and prasugrel. Patients filed most adverse events for clopidogrel and prasugrel, while physicians originated most ticagrelor complaints. These differences justify stricter compliance control for ticagrelor manufacturers and may be attributed to the confusion of treating physicians with unexpected fatal, cardiac, and thrombotic adverse events linked to ticagrelor.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Bases de Datos Factuales/estadística & datos numéricos , Archivo/estadística & datos numéricos , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Adenosina/efectos adversos , Adenosina/análogos & derivados , Clopidogrel , Humanos , Seguridad del Paciente , Clorhidrato de Prasugrel/efectos adversos , Ticagrelor , Ticlopidina/efectos adversos , Ticlopidina/análogos & derivados , Estados Unidos , United States Food and Drug AdministrationAsunto(s)
Control de Medicamentos y Narcóticos/organización & administración , Industria Farmacéutica/estadística & datos numéricos , Control de Medicamentos y Narcóticos/estadística & datos numéricos , Europa (Continente) , Humanos , Factores de Tiempo , Estados Unidos , United States Food and Drug Administration/organización & administraciónAsunto(s)
Adenosina/análogos & derivados , Sistemas de Registro de Reacción Adversa a Medicamentos , Enfermedades Cardiovasculares/mortalidad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/mortalidad , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Adenosina/efectos adversos , Adenosina/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Ensayos Clínicos como Asunto , Humanos , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Ticagrelor , Estados Unidos/epidemiología , United States Food and Drug AdministrationRESUMEN
Background The U.S. Food and Drug Administration (FDA) Adverse Event (AE) Reporting System (FAERS) is a global passive surveillance repository requiring mandatory updates by pharmaceutical manufacturers. Oral antiplatelet agents (OAAs) including aspirin (acetylsalicylic acid [ASA]) are broadly used to prevent thrombosis, at the expense of extra bleeding risks. However, the OAA filing quality and their comparative patterns in FAERS are unknown. We assessed completeness of original annual FAERS reports for OAA with special attention on ASA. Methods We extracted AE cases co-reported with OAA including ASA, clopidogrel, prasugrel, ticagrelor, vorapaxar, or their combination. The 2015 FAERS cases were examined based on OAA distribution, suspected causative role, missing gender or age, and most common AEs after ASA. Results A total of 1,187,729 reports qualified the inclusion criteria. The majority ( n = 1,121,989) of the reports contain no reference of OAA, while 65,730 reports contain reference of at least one OAA, including 47,900 ASA cases. Therapy with ASA was heavily (>50%) underreported when used with prasugrel or ticagrelor, but still dominant (72.8%) among OAAs, followed by clopidogrel (18.7%), prasugrel (4.1%), ticagrelor (3.6%), and anecdotal vorapaxar (0.05%). Despite current recommendations, some (0.73%) reports contain multi-OAAs. The primary role of ASA in AE reporting was seldom (<1%), followed by clopidogrel (2.9%), prasugrel (3.7%), and highest for ticagrelor (9.3%). Missing gender after OAA was not common (<10%), but age was missing in approximately 25% of reports. Bleeding was the most frequent AE associated with ASA. Conclusion The quality of reporting for OAA in general and ASA in particular can be improved by stricter FDA rules, better surveillance, and enforcements. Heavy ASA underreporting during dual antiplatelet therapy and missed demographic variables challenge outcome research capacities for establishing drug interactions in FAERS.
RESUMEN
Despite advanced techniques and improved clinical outcomes, the optimal antiplatelet strategy following coronary artery bypass grafting (CABG) is an unsolved mystery. Vorapaxar, a novel platelet thrombin receptor (PAR-1/4) blocker, is currently approved for post-myocardial infarction and peripheral artery disease indications on top of clopidogrel or/and aspirin. We here summarize the outcomes in patients after CABG for justification of a future vorapaxar trial. We comprehended the CABG outcomes after vorapaxar yielded from TRACER, TRA2P trials, and affiliated FDA reviews. The verified evidence suggests that composite of death, myocardial infarction and stroke occurred in 2.2% of vorapaxar vs. 8.1% placebo in TRA2P. These data were similar to the endpoint differences (5.9% after vorapaxar vs. 8.3% for placebo) in TRACER. The mortality reduction also consistently suggests vorapaxar advantage (1.7% vs. 2.5% in TRA2P, and 1.7% vs. 3.9% in TRACER). Notably, the post-CABG bleeding risks after vorapaxar were only slightly, but not significantly higher. Moreover, the bleeding disadvantage in the experimental arm was most likely related to overtreatment since majority of patients in both TRACER and TRA2P received triple antiplatelet therapy with aspirin, clopidogrel on top of vorapaxar. Overall, the FDA-confirmed evidence advocate for the future vorapaxar post-CABG outcome-driven trial. The head-to-head trial testing dual therapy with continued over CABG vorapaxar versus withdrawed clopidogrel, both on top of low dose aspirin is warranted. We conclude that the primary outcomes including mortality were consistently better for heart surgery patients after vorapaxar, while the excess of bleeding was mild. Continuing vorapaxar during CABG may be superior to currently recommended withdrawal antiplatelet strategies, and should be tested in an adequately powered randomized outcome-driven trial.