A new wave of COVID-19 cases caused by the highly transmissible delta variant is exacerbating the worldwide public health crisis, and has led to consideration of the potential need for, and optimal ...timing of, booster doses for vaccinated populations.1 Although the idea of further reducing the number of COVID-19 cases by enhancing immunity in vaccinated people is appealing, any decision to do so should be evidence-based and consider the benefits and risks for individuals and society. If unnecessary boosting causes significant adverse reactions, there could be implications for vaccine acceptance that go beyond COVID-19 vaccines. ...widespread boosting should be undertaken only if there is clear evidence that it is appropriate. Among vaccinated people, more of the severe disease could be in immunocompromised individuals, who are plausibly more likely to be offered and seek vaccination even though its efficacy is lower than it is in other people.2 Test-negative designs, which compare vaccination status of people who tested positive and those who tested negative, can sometimes reduce confounding,8 but do not prevent distortion of results due to the so-called collider bias.9 The probability that individuals with asymptomatic or mild COVID-19 infection will seek testing might be influenced by whether they are vaccinated. Mean follow-up was, however, only about 7 person-days (less than expected based on the apparent study design); perhaps more importantly, a very short-term protective effect would not necessarily imply worthwhile long-term benefit.12 In the USA, large numbers of adults are fully vaccinated, large numbers are unvaccinated, and systematic comparisons between them are ongoing.
Objective
To assess the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with tocilizumab compared to those treated with the tumor necrosis factor ...inhibitor etanercept.
Methods
This randomized, open‐label, parallel‐group trial enrolled patients with active seropositive RA (n = 3,080) who had an inadequate response to conventional synthetic disease‐modifying antirheumatic drugs and who had at least 1 cardiovascular (CV) risk factor. Patients were randomly assigned 1:1 to receive open‐label tocilizumab at 8 mg/kg/month or etanercept at 50 mg/week. All patients were followed up for a mean of 3.2 years. The primary end point was comparison of time to first occurrence of MACE. The trial was powered to exclude a relative hazard ratio for MACE of 1.8 or higher in the tocilizumab group compared to the etanercept group.
Results
By week 4 of treatment, the serum low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, and triglyceride levels were a median 11.1%, 5.7%, and 13.6% higher, respectively, in patients receiving tocilizumab compared to those receiving etanercept (each P < 0.001). During follow‐up, 83 MACE occurred in the tocilizumab group compared to 78 MACE in the etanercept group. The estimated hazard ratio for occurrence of MACE in the tocilizumab group relative to the etanercept group was 1.05 (95% confidence interval 0.77–1.43). Results were similar in sensitivity analyses and in the on‐treatment population analysis. Adverse events occurred more frequently in the tocilizumab group, including serious infection and gastrointestinal perforation.
Conclusion
The results of this trial, which provide insights into the CV safety of tocilizumab as compared to etanercept, ruled out a risk for occurrence of MACE of 1.43 or higher in patients treated with tocilizumab. This result should be interpreted in the context of the clinical efficacy and non‐CV safety of tocilizumab.
The reliability and interpretability of results from clinical trials can be substantially reduced by missing data. Frequently used approaches to address these concerns, such as upward adjustments in ...sample sizes or simplistic methods for handling missing data, including last-observation-carried-forward, complete-case, or worst-case analyses, are usually inadequate. Although rational imputation methods may be useful to treat missingness after it has occurred, these methods depend on untestable assumptions. Thus, the preferred and often only satisfactory approach to addressing missing data is to prevent it. Procedures should be in place to maximize the likelihood that outcome data will be obtained at scheduled times of evaluation for all surviving patients who have not withdrawn consent. To meaningfully reduce missing data, it is important to recognize and address many factors that commonly lead to higher levels of missingness.
Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint-that is, an endpoint that directly measures how a patient feels ...(symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or functional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints.
Pediatric Pulmonary Hypertension Ivy, D. Dunbar, MD; Abman, Steven H., MD; Barst, Robyn J., MD ...
Journal of the American College of Cardiology,
12/2013, Letnik:
62, Številka:
25
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Pulmonary hypertension (PH) is a rare disease in newborns, infants, and children that is associated with significant morbidity and mortality. In the majority of pediatric patients, PH is idiopathic ...or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. Incidence data from the Netherlands has revealed an annual incidence and point prevalence of 0.7 and 4.4 for idiopathic pulmonary arterial hypertension and 2.2 and 15.6 for pulmonary arterial hypertension, respectively, associated with congenital heart disease (CHD) cases per million children. The updated Nice classification for PH has been enhanced to include a greater depth of CHD and emphasizes persistent PH of the newborn and developmental lung diseases, such as bronchopulmonary dysplasia and congenital diaphragmatic hernia. The management of pediatric PH remains challenging because treatment decisions continue to depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts.
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