Nonagenarian Siblings and Their Offspring Display Lower Risk of Mortality and Morbidity than Sporadic Nonagenarians: The Leiden Longevity Study

OBJECTIVES: To compare the risk of mortality of nonagenarian siblings with that of sporadic nonagenarians (not selected on having a nonagenarian sibling) and to compare the prevalence of morbidity in their offspring with that of the offsprings' partners.
DESIGN: Longitudinal (mortality risk) and cross-sectional (disease prevalence).
SETTING: Nationwide sample.
PARTICIPANTS: The Leiden Longevity Study consists of 991 nonagenarian siblings derived from 420 Caucasian families, 1,365 of their offspring, and 621 of the offsprings' partners. In the Leiden 85-plus Study, 599 subjects aged 85 were included, of whom 275 attained the age of 90 (sporadic nonagenarians).
MEASUREMENTS: All nonagenarian siblings and sporadic nonagenarians were followed for mortality (with a mean±standard deviation follow-up time of 2.7±1.4 years and 3.0±1.5 years, respectively). Information on medical history and medication use was collected for offspring and their partners.
RESULTS: Nonagenarian siblings had a 41% lower risk of mortality ( P <.001) than sporadic nonagenarians. The offspring of nonagenarian siblings had a lower prevalence of myocardial infarction (2.4% vs 4.1%, P =.03), hypertension (23.0% vs 27.5%, P =.01), diabetes mellitus (4.4% vs 7.6%, P =.004), and use of cardiovascular medication (23.0% vs 28.9%, P =.003) than their partners.
CONCLUSION: The lower mortality rate of nonagenarian siblings and lower prevalence of morbidity in their middle-aged offspring reinforce the notion that resilience against disease and death have similar underlying biology that is determined by genetic or familial factors.     

A Randomized,Placebo-Controlled Study to Investigate the Safety,Tolerability, and Pharmacokinetics of 3 Weeks of Orally Administered Gefapixant in Healthy Younger and Older Adults

Purpose

Patients with chronic cough are typically female and have a mean age of?~?60 years. However, initial pharmacokinetic (PK) characterization of the P2X3-receptor antagonist gefapixant, developed to treat refractory or unexplained chronic cough, was performed in healthy participants who were predominantly younger adult males. The objective of this Phase 1 study was to assess the safety, tolerability, and PK of gefapixant in younger (18–55 years) and older (65–80 years) males and females.

Methods

A randomized, double-blind, placebo-controlled study was conducted. Healthy adult participants were stratified into 4 cohorts by age and sex (younger males/females and older males/females) and randomized 4:1 (younger adults) or 3:1 (older adults) to receive gefapixant 300 mg twice daily (BID) for 1 week, followed by gefapixant 600 mg BID for 2 weeks or placebo. Safety, tolerability, and PK were assessed.

Results

Of 36 randomized and treated participants, 28 (100%) receiving gefapixant and 6 (75%) receiving placebo reported?≥?1 adverse event (AE). The most common treatment-related AEs in the gefapixant group were taste related. Predefined renal/urologic AEs were reported by 7 (25%) participants receiving gefapixant (all mild to moderate in severity). Gefapixant exposure was generally lower in younger males compared with younger females and older adults; however, differences may have been due to estimated glomerular filtration rate.

Conclusion

The safety profile of gefapixant 300–600 mg BID was generally consistent with previous studies. Additional characterization of gefapixant PK as a function of age and sex using population PK modeling is warranted.

     

The role of vagal afferent nerves in chronic obstructive pulmonary disease

Circumstantial evidence supports the hypothesis that the vagal nervous system is dysregulated in chronic obstructive pulmonary disease. This dysregulation can lead to an increased sensitivity of the cough reflex such that the coughing becomes, at times, "nonproductive" or inappropriate. Vagal dysregulation can also lead to an increase in the activity of the parasympathetic reflex control of the airways, which contributes to greater mucus secretion and bronchial smooth muscle contraction. Indirect evidence indicates that lung disease is accompanied by substantive changes to the entire reflex pathways, including enhanced activity of the primary afferent nerves, increases in synaptic efficacy at secondary nerves in the central nervous system, and changes in the autonomic nerve pathways. Drugs aimed at normalizing neuronal activity may, therefore, be beneficial in chronic obstructive pulmonary disease.     

Aspirin for Primary Prevention of Cardiovascular Disease and Renal Disease Progression in Chronic Kidney Disease Patients: a Multicenter Randomized Clinical Trial (AASER Study)

Background

Patients with chronic kidney disease (CKD) are at high risk for developing cardiovascular events. However, limited evidence is available regarding the use of aspirin in CKD patients to decrease cardiovascular risk and to slow renal disease progression.

Study Design

Prospective, multicenter, open-label randomized controlled trial.

Setting and Participants

One hundred eleven patients with estimated glomerular filtration rate (eGFR) 15–60 ml/min/1.73 m² without previous cardiovascular events.

Intervention

Aspirin treatment (100 mg/day) (n?=?50) or usual therapy (n?=?61). Mean follow-up time was 64.8?±?16.4 months.

Outcomes

The primary endpoint was composed of cardiovascular death, acute coronary syndrome (nonfatal MI, coronary revascularization, or unstable angina pectoris), cerebrovascular disease, heart failure, or nonfatal peripheral arterial disease. Secondary endpoints were fatal and nonfatal coronary events, renal events (defined as doubling of serum creatinine, ≥?50% decrease in eGFR, or renal replacement therapy), and bleeding episodes.

Results

During follow-up, 17 and 5 participants suffered from a primary endpoint in the control and aspirin groups, respectively. Aspirin did not significantly reduce primary composite endpoint (HR, 0.396 (0.146–1.076), p?=?0.069. Eight patients suffered from a fatal or nonfatal coronary event in the control group compared to no patients in the aspirin group. Aspirin significantly reduced the risk of coronary events (log-rank, 5.997; p?=?0.014). Seventeen patients in the control group reached the renal outcome in comparison with 3 patients in the aspirin group. Aspirin treatment decreased renal disease progression in a model adjusted for age, baseline kidney function, and diabetes mellitus (HR, 0.272; 95% CI, 0.077–0.955; p?=?0.043) but did not when adjusted for albuminuria. No differences were found in minor bleeding episodes between groups and no major bleeding was registered.

Limitations

Small sample size and open-label trial.

Conclusions

Long-term treatment with low-dose aspirin did not reduce the composite primary endpoint; however, there were reductions in secondary endpoints with fewer coronary events and renal outcomes. ClinicalTrials.gov Identifier: NCT01709994.

     

In hospital observation of patients with acute coronary syndrome without ST elevation and multivessels coronary artery disease treated with early invasive strategy. Comparison of results of percutaneous coronary intervention and coronary artery by-pass grafting

Acute coronary syndromes (ACS) without persistent ST-segment elevation are the main cause of hospitalization, morbidity and mortality. The objective of this study was to compare clinical and angiographic parameters as well as in-hospital results of treating 307 consecutive patients with ACS without persistent ST-segment elevation with either PCI or CABG. Inclusion criteria were: rest angina within the last 24 hours, ST-segment depression (> 0.5 mm), T-wave inversion (> 1 mm) in at least two leads, positive serum cardiac markers. PCI was performed in 75.9% of patients and 24.1% of patients underwent CABG. Both groups did not differ as to age, sex, history of diabetes, arterial hypertension, heart failure, smoking and ejection fraction. Positive troponin was significantly more frequent in the PCI group. 51% of PCI patients and 80% of CABG patients had complete revascularization (p = 0.00001). Independent predictors of in-hospital death in the CABG group were: inability to determine culprit vessel during coronary angiography due to lesions' severity (OR 13.65; 95% CI 9.40-15.20; p = 0.007) and heart failure (OR 15.58; 95% CI 12.29-18.01; p = 0.003). In the PCI group these independent predictors were: Braunwald's IIIC unstable angina (OR 5.48; 95% CI 3.10-7.17; p = 0.04) and diabetes (OR 2.22; 95% CI 1.07-3.90; p = 0.003). In-hospital mortality rate was significantly higher in the CABG group (8.1% vs 1.7% p < 0.01). Patients with multivessel coronary artery disease and ACS without ST-segment elevation treated with PCI have better in-hospital outcome than patients assigned to CABG, but the rate of complete revascularization is lower.