Making Sense of Composite Endpoints in Clinical Research.

Multiple drugs currently used in clinical practice have been approved by regulatory agencies based on studies that utilize composite endpoints. Composite endpoints are appealing because they reduce sample size requirements, follow-up periods, and costs. However, interpreting composite endpoints can be challenging, and their misuse is not uncommon. Incorrect interpretation of composite outcomes can lead to misleading conclusions that impact patient care. To correctly interpret composite outcomes, several important questions should be considered. Are the individual components of the composite outcome equally important to patients? Did the more and less important endpoints occur with similar frequency? Do the component endpoints exhibit similar relative risk reductions? If these questions receive affirmative answers, the use and interpretation of the composite endpoint would be appropriate. However, if any component of the composite endpoint fails to satisfy the aforementioned criteria, interpretation can become difficult, necessitating additional steps. Regulatory agencies acknowledge these challenges and have specific considerations when approving drugs based on studies employing composite endpoints. In conclusion, composite endpoints are valuable tools for evaluating the efficacy and net clinical benefit of interventions; however, cautious interpretation is advised.

Serious neurological adverse events following immunization against SARS-CoV-2: a narrative review of the literature.

Amid the coronavirus disease 2019 (COVID-19) pandemic, massive immunization campaigns became the most promising public health measure. During clinical trials, certain neurological adverse effects following immunization (AEFIs) were observed; however, acceptable safety profiles lead to emergency authorization for the distribution and use of the vaccines. To contribute to pharmacovigilance and lessen the potential negative impact that vaccine hesitancy would have on immunization programs, we conducted a review of the scientific literature concerning the epidemiological data, clinical presentation, and potential mechanisms of these neurological AEFIs. There is some epidemiological evidence linking COVID-19 vaccines to cerebral venous sinus thrombosis, arterial ischemic stroke, convulsive disorder, Guillain-Barré syndrome, facial nerve palsy, and other neurological conditions. Cerebral venous sinus thrombosis has been associated with a thrombotic thrombocytopenia induced by the vaccine, similar to that induced by heparin, which suggests similar pathogenic mechanisms (likely involving antibodies against platelet factor 4, a chemokine released from activated platelets). Arterial ischemic stroke is another thrombotic condition observed among some COVID-19 vaccine recipients. Vaccine-induced convulsive disorder might be the result of structural abnormalities potentially caused by the vaccine or autoimmune mechanisms. Guillain-Barré syndrome and facial nerve palsy may also be linked to the immunization event, possibly due to immune mechanisms such as uncontrolled cytokine release, autoantibody production, or bystander effect. However, these events are mostly uncommon and the evidence for the association with the vaccine is not conclusive. Furthermore, the potential pathophysiological mechanisms remain largely unknown. Nevertheless, neurological AEFIs can be serious, life-threatening or even fatal. In sum, COVID-19 vaccines are generally safe and the risk of neurological AEFIs does not outweigh the benefits of immunization. However, early diagnosis and treatment of neurological AEFIs are of utmost importance, and both health professionals and the public should be aware of these conditions.

A review of undesired effects involving the nervous system following the administration of COVID-19 vaccines Among the range of complications that can occur after a vaccine, some of them can affect the nervous system and its vasculature. This narrative review aims to evaluate some serious neurological conditions following COVID-19 vaccination. We searched biomedical journal databases where physicians around the globe reported different complications after the administration of different COVID-19 vaccines. Besides reports of cases in individual patients or small groups, we reviewed studies that included bigger groups of patients (e.g. vaccinated versus non-vaccinated) and compared the occurrence of these events between them. We found that after the administration of a certain type of vaccine (e.g. ChAdOx1-S/Oxford, AstraZeneca vaccine), serious neurological complications were rare, with abnormal clot formation involving cerebral blood vessels being one of the most important among them. Nonetheless, other conditions have been observed after the administration of the vaccines; however, it is not certain yet if the vaccines are the actual cause of these complications. There are some hypotheses that could explain why these adverse reactions take place after a vaccine. For instance, an abnormal immune response to the vaccine leads to the production of antibodies (i.e. proteins made by the immune system in response to the presence of a foreign substance). These antibodies trigger a response that could eventually result in clot formation. Besides, the immune response can also produce other adverse effects, including convulsive disorder, Guillain­Barré syndrome, and facial nerve palsy. Scientific evidence suggests that vaccines are safe overall. While mild complications, such as pain at the site of injection or bruising might occur, more serious events remain rare. Furthermore, the complications derived from COVID-19 are far more likely in non-vaccinated individuals than the complications associated with the vaccine. Thus, vaccination continues to be the safest and most effective strategy to control the ongoing pandemic. However, both health professionals and the public should be aware of the possibility of serious neurological adverse reactions occurring after vaccination to allow early diagnosis and treatment.

Genetic and Molecular Aspects of Drug-Induced QT Interval Prolongation.

Long QT syndromes can be either acquired or congenital. Drugs are one of the many etiologies that may induce acquired long QT syndrome. In fact, many drugs frequently used in the clinical setting are a known risk factor for a prolonged QT interval, thus increasing the chances of developing torsade de pointes. The molecular mechanisms involved in the prolongation of the QT interval are common to most medications. However, there is considerable inter-individual variability in drug response, thus making the application of personalized medicine a relevant aspect in long QT syndrome, in order to evaluate the risk of every individual from a pharmacogenetic standpoint.

Pulmonary embolism secondary to inappropriate use of oral contraceptive therapy: a case report

Forty-one year old female admitted to the hospital because of symptoms and signs suggestive of pulmonary thromboembolism which was confirmed by CT angiography. There was no history of prior thromboembolic events, smoking, venous stasis or vascular lesion (negative lupus anticoagulant and anticardiolipins). The only documented hypercoagulability factor was the use of an oral contraceptive containing drospirenone and ethinylestradiol for the last year. The patient was treated with anticoagulants such as enoxaparin and she recovered without sequelae; she is currently under treatment with warfarin as an outpatient. It is known that the use of combined oral contraceptives in patients over 35 years old requires caution, largely due to higher risk of thromboembolic events associated with increased hepatic synthesis of several coagulation factors. Therefore, this case represents a potentially fatal and preventable severe adverse reaction(AU)

Mujer de 41 años que ingresa al hospital por cuadro clínico sugestivo de tromboembolismo pulmonar, el cual fue confirmado por AngioTAC. No había antecedentes de eventos tromboembólicos previos, tabaquismo, estasis venosa ni de lesión vascular (anticoagulante lúpico y anticardiolipinas negativo). Como único factor de hipercoagulabilidad que se documenta es el consumo de un anticonceptivo oral que contenía drospirenona y etinilestradiol desde un año atrás. La paciente fue anticoagulada con enoxaparina y se recuperó sin secuelas y actualmente se encuentra en manejo ambulatorio con warfarina. El uso de anticonceptivos orales en combinación se debe realizar con precaución en pacientes mayores de 35 años, en buena medida por el aumento del riesgo de eventos tromboembólicos asociado al incremento en la síntesis hepática de algunos factores de coagulación. Por lo tanto, éste representa un caso de reacción adversa severa, potencialmente fatal y prevenible(AU)