The effects of etidronate on brain calcifications in Fahr's disease or syndrome: rationale and design of the randomised, placebo-controlled, double-blind CALCIFADE trial.

BACKGROUND: Fahr's disease and syndrome are rare disorders leading to calcification of the small arteries in the basal ganglia of the brain, resulting in a wide range of symptoms comprising cognitive decline, movement disorders and neuropsychiatric symptoms. No disease-modifying therapies are available. Studies have shown the potential of treatment of ectopic vascular calcifications with bisphosphonates. This paper describes the rationale and design of the CALCIFADE trial which evaluates the effects of etidronate in patients with Fahr's disease or syndrome. METHODS: The CALCIFADE trial is a randomised, placebo-controlled, double-blind trial which evaluates the effects of etidronate 20 mg/kg during 12 months follow-up in patients aged ≥ 18 years with Fahr's disease or syndrome. Etidronate and placebo will be administered in capsules daily for two weeks on followed by ten weeks off. The study will be conducted at the outpatient clinic of the University Medical Center Utrecht, the Netherlands. The primary endpoint is the change in cognitive functioning after 12 months of treatment. Secondary endpoints are the change in mobility, neuropsychiatric symptoms, volume of brain calcifications, dependence in activities of daily living, and quality of life. RESULTS: Patient recruitment started in April 2023. Results are expected in 2026 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences. CONCLUSIONS: Fahr's disease and syndrome are slowly progressive disorders with a negative impact on a variety of health outcomes. Etidronate might be a new promising treatment for patients with Fahr's disease or syndrome. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05662111. Registered 22 December 2022, https://clinicaltrials.gov/ct2/show/NCT01585402 .

Treatment of hypercholesterolaemia in older adults calls for a patient-centred approach.

Due to an increasing number of older adults with (risk factors for) cardiovascular disease (CVD), the sum of older adults eligible for lipid-lowering drugs will increase. This has risen questions about benefits and harms of lipid-lowering therapy in older adults with a varying number of (cardiovascular) comorbidities and functional status. The heterogeneity in physical and functional health increases with age, leading to a much wider variety in cardiovascular risk and life expectancy than in younger adults. We suggest treatment decisions on hypercholesterolaemia in adults aged ≥75 years should shift from a strictly 10-year cardiovascular risk-driven approach to a patient-centred and lifetime benefit-based approach. With this, estimated 10-year risk of CVD should be placed into the perspective of life expectancy. Moreover, frailty and safety concerns must be taken into account for a risk-benefit discussion between clinician and patient. Based on the Dutch addendum 'Cardiovascular Risk Management in (frail) older adults', our approach offers more detailed information on when not to initiate or deprescribe therapy than standard guidelines. Instead of using traditional risk estimating tools which tend to overestimate risk of CVD in older adults, use a competing risk adjusted, older adults-specific risk score (available at https://u-prevent.com). By filling in a patient's (cardiovascular) health profile (eg, cholesterol, renal function), the tool estimates risk of CVD and models the effect of medication in terms of absolute risk reduction for an individual patient. Using this tool can guide doctors and patients in making shared decisions on initiating, continuing or deprescribing lipid-lowering therapy.

Frailty in Older Adults with Cardiovascular Disease: Cause, Effect or Both?

Cardiovascular disease (CVD) has been associated with an increased risk of frailty, but the direction of the association remains unclear. This study set out to examine the bidirectional longitudinal association between CVD and frailty over an extended period of time. Data are from 1432 older adults (aged 65-88yrs) of the Longitudinal Aging Study Amsterdam (LASA), who were followed for 17 years. At baseline and follow-up, CVD was assessed through self-report, medication use and medical records, and classified as angina pectoris, myocardial infarction, heart failure (HF), stroke, and peripheral artery disease. Throughout the study, frailty was assessed using Fried's frailty criteria. Cox regression models showed that patients with HF had an increased frailty risk (HR 2.7; 95%CI: 1.5-5.1) after a median follow-up of 8.4 yrs. This finding was independent of potential confounders (age, sex, several comorbidities). Examinations of the reverse association revealed that frail older adults were not at risk of incident CVD. Of all older adults with CVD, those with HF have an increased risk of frailty and frail older adults do not have an increased risk of CVD. Our findings emphasize the need for cardiac rehabilitation programs evaluating the effect of physical exercise programs in order to prevent frailty and therewith improve quality of life and independence of care in CVD patients.