Risk stratification and treatment effect of statins in secondary cardiovascular prevention in old age: additive value of N-terminal pro-B-type natriuretic peptide

Background To date, no validated risk scores exist for prediction of recurrence risk or potential treatment effect for older people with a history of a cardiovascular event. Therefore, we assessed predictive values for recurrent cardiovascular disease of models with age and sex, traditional cardiovascular risk markers, and ‘SMART risk score’, all with and without addition of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Treatment effect of pravastatin was assessed across low and high risk groups identified by the best performing models. Design and methods Post-hoc analysis in 2348 participants (age 70–82 years) with a history of cardiovascular disease within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. Composite endpoint was a recurrent cardiovascular event/cardiovascular mortality. Results The models with age and sex, traditional risk markers and SMART risk score had comparable predictive values (area under the curve (AUC) 0.58, 0.61 and 0.59, respectively). Addition of NT-proBNP to these models improved AUCs with 0.07 (p for difference ((pdiff)) = 0.003), 0.05 (pdiff = 0.009) and 0.06 (pdiff < 0.001), respectively. For the model with age, sex and NT-proBNP, the hazard ratio for the composite endpoint in pravastatin users compared with placebo was 0.67 (95% confidence interval 0.49–0.90) for those in the highest third of predicted risk and 0.91 (0.57–1.46) in the lowest third, number needed to treat 12 and 115 (pdiff = 0.038) respectively. Conclusion In secondary cardiovascular prevention in old age addition of NT-proBNP improves prediction of recurrent cardiovascular disease, cardiovascular mortality and treatment effect of pravastatin. A minimal model including age, sex and NT-proBNP predicts as accurately as complex risk models including NT-proBNP

Study protocol; thyroid hormone replacement for untreated older adults with subclinical hypothyroidism - a randomised placebo controlled trial (TRUST)

Background: Subclinical hypothyroidism (SCH) is a common condition in elderly people, defined as elevated serum thyroid-stimulating hormone (TSH) with normal circulating free thyroxine (fT4). Evidence is lacking about the effect of thyroid hormone treatment. We describe the protocol of a large randomised controlled trial (RCT) of Levothyroxine treatment for SCH. Methods: Participants are community-dwelling subjects aged ≥65 years with SCH, diagnosed by elevated TSH levels (≥4.6 and ≤19.9 mU/L) on a minimum of two measures ≥ three months apart, with fT4 levels within laboratory reference range. The study is a randomised double-blind placebo-controlled parallel group trial, starting with levothyroxine 50 micrograms daily (25 micrograms in subjects <50Kg body weight or known coronary heart disease) with titration of dose in the active treatment group according to TSH level, and a mock titration in the placebo group. The primary outcomes are changes in two domains (hypothyroid symptoms and fatigue / vitality) on the thyroid-related quality of life questionnaire (ThyPRO) at one year. The study has 80% power (at p = 0.025, 2-tailed) to detect a change with levothyroxine treatment of 3.0% on the hypothyroid scale and 4.1% on the fatigue / vitality scale with a total target sample size of 750 patients. Secondary outcomes include general health-related quality of life (EuroQol), fatal and non-fatal cardiovascular events, handgrip strength, executive cognitive function (Letter Digit Coding Test), basic and instrumental activities of daily living, haemoglobin, blood pressure, weight, body mass index and waist circumference. Patients are monitored for specific adverse events of interest including incident atrial fibrillation, heart failure and bone fracture. Discussion: This large multicentre RCT of levothyroxine treatment of subclinical hypothyroidism is powered to detect clinically relevant change in symptoms / quality of life and is likely to be highly influential in guiding treatment of this common condition. Trial registration: Clinicaltrials.gov NCT01660126; registered 8th June 2012

Patient-reported satisfaction with thyroid hormone replacement therapy for subclinical hypothyroidism in older adults: a pooled analysis of individual participant data from two randomized controlled trials

Background: The benefit of levothyroxine treatment of subclinical hypothyroidism (SCH) is subject to debate. This study compared treatment satisfaction between older adults with SCH using levothyroxine or placebo. Methods: We analyzed pooled individual participant data from two randomized, double-blind, placebo-controlled trials investigating the effects of levothyroxine treatment in older adults with SCH. Community-dwelling participants aged ≥65 years, with SCH (persistent thyrotropin levels 4.60–19.99 mIU/L for >3 months and normal free T4 level), were included. Intervention dose titration until thyrotropin levels normalized, with a mock dose adjustment of placebo. Treatment satisfaction was determined during the final study visit using the Treatment Satisfaction Questionnaire for Medication (TSQM), encompassing perceived effectiveness, side effects, convenience, and global satisfaction, along with the participants’ desire to continue study medication after the trial. Results: We included 536 participants. At baseline, the median (interquartile range [IQR]) age was 74.9 (69.7–81.4) years, and 292 (55%) were women. The median (IQR) thyrotropin levels were 5.80 (5.10–7.00) mIU/L at baseline in both groups; at final visit, 4.97 (3.90–6.35) mIU/L in the placebo and 3.24 (2.49–4.41) mIU/L in the levothyroxine group. After treatment, the groups did not differ significantly in global satisfaction (mean difference [CI] −1.1 [−4.5 to 2.1], p = 0.48), nor in any other domain of treatment satisfaction. These results held true regardless of baseline thyrotropin levels or symptom burden. No major differences were found in the numbers of participants who wished to continue medication after the trial (levothyroxine 35% vs. placebo 27%), did not wish to continue (levothyroxine 27% vs. placebo 30%), or did not know (levothyroxine 37% vs. placebo 42%) (p = 0.14). In a subpopulation with high symptom burden from hypothyroid symptoms at baseline, those using levothyroxine more often desired to continue the medication after the trial than those using placebo (mean difference [CI]: −21.1% [−35.6% to −6.5%]). Conclusion: These pooled data from two RCTs showed no major differences in treatment satisfaction between older adults receiving levothyroxine or placebo. This finding has important implications for decision-making regarding initiating levothyroxine treatment for SCH. Our findings generally support refraining from routinely prescribing levothyroxine in older adults with SCH

Biological correlates of blood pressure variability in elderly at high risk of cardiovascular disease

BACKGROUND: Visit-to-visit variability in blood pressure is an independent predictor of cardiovascular disease. This study investigates biological correlates of intra-individual variability in blood pressure in older persons.<p></p> METHODS: Nested observational study within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) among 3,794 male and female participants (range 70–82 years) with a history of, or risk factors for cardiovascular disease. Individual visit-to-visit variability in systolic and diastolic blood pressure and pulse pressure (expressed as 1 SD in mm Hg) was assessed using nine measurements over 2 years. Correlates of higher visit-to-visit variability were examined at baseline, including markers of inflammation, endothelial function, renal function and glucose homeostasis.<p></p> RESULTS: Over the first 2 years, the mean intra-individual variability (1 SD) was 14.4mm Hg for systolic blood pressure, 7.7mm Hg for diastolic blood pressure, and 12.6mm Hg for pulse pressure. After multivariate adjustment a higher level of interleukin-6 at baseline was consistently associated with higher intra-individual variability of blood pressure, including systolic, diastolic, and pulse pressure. Markers of endothelial function (Von Willebrand factor, tissue plasminogen activator), renal function (glomerular filtration rate) and glucose homeostasis (blood glucose, homeostatic model assessment index) were not or to a minor extent associated with blood pressure variability.<p></p> CONCLUSION: In an elderly population at risk of cardiovascular disease, inflammation (as evidenced by higher levels of interleukin-6) is associated with higher intra-individual variability in systolic, diastolic, and pulse pressure.<p></p&gt

N-terminal pro-brain natriuretic peptide and cognitive decline in older adults at high cardiovascular risk

Objective: Elevated levels of N-terminal pro–brain natriuretic peptide (NT-proBNP) are associated with cognitive impairment, which might be explained by cardiovascular diseases or risk factors. The aim of this study was to investigate the association of NT-proBNP with cognitive function and decline in older adults at high risk of cardiovascular disease.<p></p> Methods: We studied 5,205 men and women (mean age = 75 years) who were recruited into the PROspective Study of Pravastatin in the Elderly at Risk. All participants had pre-existing cardiovascular disease or risk factors thereof. Four domains of cognitive function were tested at baseline and repeated during a follow-up period of 3.2 years.<p></p> Results: Participants with higher NT-proBNP (≥450ng/l) had worse baseline cognitive function, including reaction time (mean difference high vs low group = 3.07 seconds, 95% confidence interval [CI] = 0.83 to 5.32), processing speed (−1.02 digits coded, 95% CI = −1.65 to −0.39), and immediate memory (−0.13 pictures remembered, 95% CI = −0.29 to 0.04). There was no significant difference in delayed memory (−0.14, 95% CI = −0.38 to 0.10) between the NT-proBNP groups. Participants with higher NT-proBNP had a steeper cognitive decline, including reaction time (mean annual change high vs low group = 0.60 seconds, 95% CI = 0.14 to 1.07), processing speed (−0.15 digits coded, 95% CI = −0.25 to −0.05), immediate memory (−0.05 pictures remembered, 95% CI = −0.09 to 0.00), and delayed memory (−0.05 pictures remembered, 95% CI = −0.11 to 0.01). Associations were independent of cardiovascular diseases and risks.<p></p> Interpretation: Higher NT-proBNP associates with worse cognitive function and steeper cognitive decline, independent of cardiovascular diseases and risks. Further studies to unravel the underlying mechanisms are warranted

Low blood pressure predicts increased mortality in very old age even without heart failure: the Leiden 85-plus Study

Item does not contain fulltextAIMS: To investigate whether low systolic blood pressure is predictive for increased mortality risk in 90-year-old subjects without heart failure, defined by low levels of NT-proBNP, as well as in 90-year-old subjects with high levels of NT-proBNP. METHODS AND RESULTS: This study was embedded in the Leiden 85-plus Study, an observational population-based prospective study. All 90-year-old participants (n = 267) were included between 2002 and 2004 and followed up for mortality for at least 5 years. Differences in mortality risks were compared between participants with low systolic blood pressure (150 mmHg) within strata of low NT-proBNP (<284 pg/mL for women and <306 pg/mL for men = lowest tertile) vs. high NT-proBNP (middle and highest tertile) at age 90 years. During maximal follow-up of 7.2 years, 212 participants (79%) died. Among participants with low NT-proBNP, low systolic blood pressure gave a two-fold increased risk (hazard ratio 2.0, 95% confidence interval 1.1-3.4) compared with participants with high systolic blood pressure. For participants with high NT-proBNP, low systolic blood pressure provided a 1.7 increased mortality risk (95% confidence interval 1.2-2.3) compared with high systolic blood pressure. CONCLUSION: Low systolic blood pressure is predictive for increased mortality risk in 90-year-old subjects, irrespective of the NT-proBNP level. Therefore, the absence or presence of heart failure as determined by NT-proBNP does not influence the prognostic value of low systolic blood pressure with regard to mortality in the oldest old

Blood pressure trends and mortality: the Leiden 85-plus Study

Item does not contain fulltextOBJECTIVE: To evaluate the independent contributions of both the trend in SBP and the SBP value at age 90 to the prediction of mortality in nonagenarians. METHODS: The trend in SBP between 85 and 90 years and SBP at age 90 years were assessed in a population-based sample of 271 participants (74 men and 197 women) aged 90 years of the Leiden 85-plus Study, an observational population-based prospective follow-up study (started 1997). Primary endpoint, followed up over 5 years (median 3.6 years), was all-cause mortality. RESULTS: A decreasing trend in SBP between 85 and 90 years (decline >/=2.9 mmHg/year) was associated with increased mortality compared to an average SBP trend (hazard ratio 1.45, 95% confidence interval 1.02-2.06), independent of SBP at age 90. The effect was stronger in institutionalized participants compared to those living independently [hazard ratio 1.87 (1.10-3.19) and hazard ratio 1.30 (0.81-2.09)]. After analysis with a fully adjusted model, the estimate approached unity [hazard ratio 1.08 (0.60-1.86)]. Overall, 90-year-old participants with SBP of 150 mmHg or less had a 1.62 times increased mortality risk compared to those with SBP more than 150 mmHg (1.21-2.20), independent of the SBP trend in preceding years. This applied to those with and without antihypertensive drugs and those with and without history of cardiovascular disease or noncardiovascular disease. In the fully adjusted model, the estimate was 1.47 (0.90-2.40). CONCLUSION: In very old age, both decreasing trend in SBP over the previous 5 years and the current SBP value independently contribute to prediction of all-cause mortality. Therefore, in individual patients, all available preceding SBP measurements should be taken into account