[Contraindications to DOACs in atrial fibrillation]. / Contra-indicaties voor DOAC's bij atriumfibrilleren.

Sometimes there is doubt as to whether or not anticoagulants should be initiated, and if so which ones, in patients with atrial fibrillation and advanced age, increased frailty, or fall risk, kidney, or liver impairment, alcohol abuse, uncontrolled hypertension, or a history of major bleeding. These subgroups have increased risk of haemorrhage as well as thromboembolism. Treatment with anticoagulants is indicated in the vital elderly, preferably with direct oral anticoagulants as demonstrated by robust data. The available study results for the other subgroups may not be (fully) generalisable to clinical practice. In such patients, a comprehensive risk assessment is therefore advised; as is discussing the pros and cons of (not) using anticoagulants and of both type of anticoagulants. Only in exceptional cases is it justified not to use anticoagulants.

CSF neurofilament proteins in the differential diagnosis of dementia.

BACKGROUND: Neurofilament (NF) proteins are major cytoskeletal constituents of neurons. Increased CSF NF levels may reflect neuronal degeneration. OBJECTIVE: To investigate the diagnostic value of CSF NF analysis to discriminate in relatively young dementia patients between frontotemporal lobe degeneration (FTLD) and early onset Alzheimer's disease (EAD; onset < or = 65 years of age), and in elderly dementia patients between dementia with Lewy bodies (DLB) and late onset AD (LAD; onset > 65 years of age). METHODS: In CSF of 28 FTLD, 37 EAD, 18 DLB and 33 LAD patients, and 26 control subjects, we analysed NF light chain (NFL), phosphorylated NF heavy chain (pNFH), amyloid beta42 protein (Abeta42), total tau and tau phosphorylated at threonine 181 (p-tau181). RESULTS: CSF NFL levels were higher in FTLD patients compared with EAD patients (p<0.001), and diagnostic accuracy of p-tau181 and Abeta42 analysis improved with addition of NFL analysis (sensitivity 86%, specificity 100%). CSF pNFH levels were elevated in DLB, LAD and FTLD compared with controls (p<0.05) but no significant differences were found between the dementia groups. CONCLUSIONS: In the diagnostic workup of relatively young dementia patients, CSF NFL levels may play a role in the discrimination between FTLD and EAD, especially in combination with Abeta42 and p-tau181 analysis.

[Elderly heart failure patients and the role of beta-blocker therapy]. / De oudere patiënt met hartfalen en de rol van bètablokkers bij de behandeling.

In this article different aspects of chronic heart failure in old age are described. We mainly focus on the place of beta-blocker therapy in chronic heart failure. Beta-blockers are recommended for the treatment of stable chronic heart failure with left ventricular systolic dysfunction. There is additional information from recent studies that there is proven efficacy for beta-blocker therapy in patients with heart failure up to the age of 80 years. For patients with heart failure aged 80 and over the evidence to prescribe beta-blockers is limited. However, it is known that also in very elderly patients beta-blocker therapy is well tolerated. In patients with heart failure with preserved systolic ventricular function there is still no evidence that there is a beneficial effect of beta-blockers. It is still not clear if there are differences between beta-blocking agents. Of all beta-blockers, only bisoprolol, carvedilol, nebivolol and metoprolol CR are proven effective in stable chronic heart failure with impaired left ventricular systolic function and can be recommended in elderly patients on standard treatment with diuretics and ACE inhibition.

Reproducibility of cerebral blood volume measurements by near infrared spectroscopy in 16 healthy elderly subjects.

Near infrared spectroscopy (NIRS) is a non-invasive method to monitor cerebral haemodynamics. Used either alone or in combination with other non-invasive methods such as transcranial Doppler sonography, this technique is well suited for use in cerebrovascular research in ageing. Reproducibility of NIRS, however, has only been determined in neonates and adults. We applied controlled desaturation (the O(2)-method) to measure the cerebral blood volume (CBV) with NIRS in 16 healthy subjects aged 65 to 88. This method uses deoxygenated haemoglobin (the concentration of which is manipulated by desaturation) as an intravascular tracer for NIRS. We determined repeatability (between tests interval: 2 min), short-term reproducibility (intervals of 20 and 40 min) and long-term reproducibility (interval > 2 weeks). We found a coefficient of variation (CV) of 12.5% for repeatability and a CV of 11.7% for short-term reproducibility. The CV for long-term reproducibility was 15%. We conclude that NIRS can reproducibly measure CBV in subjects aged 65 and older, using the O(2)-method. In this group of healthy subjects, this method was well tolerated.

Exclusion of venous thromboembolism: evaluation of D-Dimer PLUS for the quantitative determination of D-dimer.

The objective of this study was to evaluate if D-Dimer PLUS (Dade Behring, USA), a rapid fully automated assay, could be used as an initial screening test in the diagnosis of venous thromboembolism (VTE). Samples from 274 consecutive symptomatic patients with suspected pulmonary embolism (n=229; 79% outpatients, 21% inpatients), deep venous thrombosis (n=37; 84% outpatients, 16% inpatients) or suspected for both complications (n=8) were tested with this D-dimer assay with a Sysmex CA-1500 Coagulation Analyzer. Clinical probability for pulmonary embolism (PE) or deep venous thrombosis (DVT) was staged according to a pretest risk score proposed by Wells. Final diagnosis of PE and/or DVT was established by spiral-computed tomography of the pulmonary arteries or compression ultrasonography, respectively. PE was diagnosed in 13.5% of the patients, whereas DVT was confirmed in 17.7% of the patients. The optimal cut-off value for exclusion of venous thromboembolism was 130 mug/l, and sensitivity, specificity and negative predictive value (NPV) were 95.0% (95% CI: 92.4-97.6), 30.4% (95% CI: 25.0-35.8) and 97.2% (95% CI: 95.2-99.2), respectively. In fact, two patient with PE were missed using D-Dimer PLUS; both cases were outpatients. In conclusion, this assay appears to be safe when implemented in an algorithm based on clinical assessment, D-dimer concentration, and radiological diagnostic techniques to stratify the risk for PE or DVT. However, higher sensitivities and negative predictive values were claimed in the scarce published reports for the D-Dimer PLUS assay than found in this study.

Lower body positive pressure by anti-G garment inflation: a suitable method to increase pulmonary capillary wedge pressure in healthy elderly subjects.

In a study on non-invasive assessment of pulmonary capillary wedge pressure (PCWP), we sought a method to increase PCWP non-invasively. We hypothesized that inflation of an anti-G garment was suitable to increase PCWP non-invasively in healthy elderly subjects. In 20 subjects, aged 70 +/- 4 years (mean +/- SD), before, immediately after, and 4 min after anti-G garment inflation to 52 mmHg, PCWP and mean pulmonary artery pressure (MPAP) were measured with a Swan-Ganz catheter, and mean arterial blood pressure (MAP) with Finapres, in supine and semi-recumbent position. Supine, PCWP (mmHg, mean +/- SD) increased from 9.9 +/- 2.1 to 15.5 +/- 3.9** immediately after inflation and 13.4 +/- 3.7** at 4 min; semi-recumbent from 8.9 +/- 2.0 to 17.5 +/- 3.3** and 14.7 +/- 2.9** (*P<0.05, **P< 0.001 versus before inflation). MPAP (mmHg) increased after inflation: supine 16.9 +/- 2.3 to 22.3 +/- 4.6** and 20.6 +/- 3.9** and semi-recumbent 15.7 +/- 2.8 to 24.3 +/- 5.1** and 22.5 +/- 3.5**, suggesting that increased preload was the primary effect of anti-G garment inflation. Supine MAP (mmHg) increased from 96.0 +/- 11.3 to 101.4 +/- 13.4** and 100.5 +/- 12.7* and semi-recumbent from 102.0 +/- 8.9 to 108.3 +/- 11.4** and 106.0 +/- 11.3*, suggesting an effect of increased afterload as well. The latter was supported by an increase in total peripheral resistance (d s cm(-5)) from 1346 +/- 299 to 1441 +/- 384 after 4 min (P = 0.057) and from 1461 +/- 341 to 1532 +/- 406 (P = 0.054), supine and semi-recumbent respectively, while cardiac output remained unchanged. Complications did not occur. We conclude that in healthy elderly subjects, anti-G garment inflation is a safe, non-invasive, method to induce a significant increase in PCWP. Our findings justify its application in future studies in which non-invasive temporary increase in PCWP is required.

[The possible suppression of Alzheimer's disease by nonsteroidal anti-inflammatory drugs]. / Het mogelijk remmende effect van niet-steroïde anti-inflammatoire geneesmiddelen op de ziekte van Alzheimer.

Ever since inflammatory mediators were detected in and around amyloid plaques in the brain of patients with Alzheimer's disease, there has been great interest in the inflammatory hypothesis and the possibility of treating Alzheimer's disease with anti-inflammatory drugs. Various epidemiological studies have now demonstrated that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is indeed associated with a reduced risk of developing Alzheimer's disease. The effect of NSAIDs in Alzheimer's disease is probably mediated by activation of the peroxisome proliferator-activated receptor-gamma. Administration of NSAIDs in a mouse model of Alzheimer's disease appears to suppress amyloid plaque formation and inflammatory mediators. These findings suggest that NSAIDs may also be able to slow down Alzheimer's disease progression. So far, only one small clinical trial has shown that treatment with NSAIDs significantly delayed cognitive decline in Alzheimer's disease patients. Large randomized double-blind placebo-controlled trials are needed to provide definitive evidence that NSAIDs have a therapeutic effect on Alzheimer's disease.

The influence of low-, normal-, and high-carbohydrate meals on blood pressure in elderly patients with postprandial hypotension.

BACKGROUND: Postprandial hypotension (PPH) is a common and serious disorder of blood pressure (BP) regulation in elderly people. It has been suggested that primarily the carbohydrate (CH) content of a meal induces the BP decrease. Therefore, we examined the relationship between the CH content of meals and postprandial BP responses in elderly patients diagnosed with PPH. METHODS: Twelve geriatric patients (aged 75 to 91 years; 6 men) who were previously diagnosed with PPH received standardized liquid meals with low- (25 g), normal- (65 g), and high- (125 g) CH content in random order on three separate days. Systolic BP (SBP), diastolic BP, and heart rate were measured every 5 minutes from 20 minutes before until 75 minutes after each meal. Postprandial symptoms were recorded every 15 minutes. RESULTS: The maximum decrease in SBP was significantly smaller after the low-CH meal (-28 +/- 5 mm Hg) than after the normal- (-39 +/- 7 mm Hg) and high-CH meals (-40 +/- 5 mm Hg) (p <.050 between groups). In addition, the duration of PPH was significantly shorter (p <.010), and postprandial symptoms were less frequent and less severe after the low-CH meal. CONCLUSIONS: Reducing the CH amount in meals induces significantly smaller decreases in SBP, shorter duration of PPH, and reduction of PPH-related symptoms. Therefore, limiting the CH content of an elderly patient's meal can be a clinically effective nonpharmacological treatment for PPH in elderly patients and can reduce the risk of developing symptomatic PPH.

Effect of levodopa on orthostatic and postprandial hypotension in elderly Parkinsonian patients.

BACKGROUND: This study describes orthostatic and postprandial hypotension in elderly Parkinsonian patients and evaluates the effect of levodopa therapy on orthostatic and postprandial hypotension in these patients. METHODS: Seventeen elderly patients with a clinical diagnosis of Parkinson's disease or Parkinsonism based on the U.K. Parkinson's Disease Society Brain Bank criteria (age range, 66-84 years) participated in the study. Blood pressure was continuously monitored during standardized standing and meal tests, after starting 125-mg b.i.d. doses of levodopa/benserazide (Madopar) or placebo, in a double-blind, randomized, cross-over design. Seventeen age- and sex-matched healthy subjects served as controls. RESULTS: Orthostatic hypotension was infrequently found in Parkinsonian patients (13%) and healthy subjects (6%; p =.58, between groups), whereas postprandial hypotension was more frequent in Parkinsonian patients (82%) than in healthy subjects (41%; p <.05, between groups). Doses of levodopa/benserazide, administered 2 times per day, did not result in significantly larger blood pressure decreases after standing or eating, or in higher frequencies of orthostatic or postprandial hypotension in the Parkinsonian group. Postprandial hypotension was related to disease severity (r = -.56, p <.05). CONCLUSIONS: Postprandial hypotension, but not orthostatic hypotension, was more common in elderly Parkinsonian patients than in healthy subjects. Therapy with 125-mg b.i.d. doses of levodopa/benserazide did not significantly aggravate orthostatic or postprandial hypotension.

Reproducibility of orthostatic changes in cerebral oxygenation in healthy subjects aged 70 years or older.

In the elderly, standing can frequently be accompanied by blood pressure (BP) changes and cerebral symptoms such as dizziness, fall, or even syncope, but this may vary from day-to-day. Therefore, we aimed to investigate the reproducibility of orthostatic responses of cerebral cortical oxygenation and systemic haemodynamics in elderly subjects. In 27 healthy elderly subjects (age 70-84 years), changes in systolic BP (SBP), diastolic BP (DBP), heart rate (HR) and stroke volume (SV) were continuously monitored by Finapres (Finger Arterial Pressure), and changes in oxyhaemoglobin ([O2Hb]) and deoxyhaemoglobin ([HHb]) concentrations were continuously measured over the right frontal cortex by near infrared spectroscopy (NIRS) during supine rest and 10 min of active standing on two separate occasions. SBP and DBP increased by 6.7 +/- 15.4 mmHg (P<0.05, mean +/- SD) and 8.2 +/- 6.4 mmHg (P<0.01), respectively, whereas HR increased by 9.5 +/- 5.0 bpm (P<0.01) and SV decreased by -8.3 +/- 7.4 ml (P<0.01) during standing on the first occasion. [O2Hb] decreased by -3.9 +/- 2.9 micromol l-1 (P<0.01), while [HHb] increased by 1.8 +/- 2.2 micromol l-1 (P<0.01). Group-averaged orthostatic changes in cortical oxygenation and systemic haemodynamics were very similar on the two occasions, although an intraindividual variation was found. Cortical oxygenation changes were not accompanied by severe cerebral symptoms. Active standing induced reproducible group-averaged frontal cortical oxygenation declines in healthy elderly subjects, although an intraindividual day-to-day variability was present, possibly related to the variability of orthostatic BP responses. These findings indicate that cerebral autoregulation fails to compensate completely for postural changes in elderly subjects, which might predispose elderly subjects to ischaemic cerebral symptoms.

Achieving haemodynamic baseline values with Finapres in elderly subjects during supine rest.

BACKGROUND: Clear guidelines for the resting time necessary to achieve stable blood pressure (BP) levels are scant in gerontology research. Therefore, we aimed to determine the minimum period required for obtaining haemodynamic baseline values in elderly subjects during supine rest. In addition, we evaluated the effect of cardiovascular morbidity, such as diastolic heart failure, and the effect of complex comorbidity of geriatric patients, on haemodynamic changes during supine rest. METHODS: A total of 17 healthy subjects, 18 heart failure patients with normal systolic function and 24 geriatric patients, aged 70 years and more, participated. After an overnight fast, changes in systolic BP (SBP), diastolic BP (DBP), heart rate (HR), and stroke volume (SV) were determined by Finapres beat-to-beat non-invasive BP monitoring during a 20-min supine rest. The procedure was repeated in the healthy subjects and geriatric patients on a second day. RESULTS: Complete BP stabilization was reached in each group within 5 min of supine rest, as SBP remained essentially unchanged and DBP did not change significantly anymore after the fourth minute. In the heart failure patients, HR decreased and SV increased until the twelfth minute of rest. The SBP, DBP, HR, and SV changes during supine rest showed good reproducibility. CONCLUSIONS: A span of 5 min of supine rest ensured achievement of reliable and reproducible baseline BP values by Finapres in elderly subjects. However, we recommend at least 12 min of rest to obtain full haemodynamic stability in elderly patients with diminished cardiac compliance and diastolic function.

Cerebral oxygenation declines in healthy elderly subjects in response to assuming the upright position.

BACKGROUND AND PURPOSE: With increasing age, assuming the upright position is more often accompanied by symptoms such as dizziness and lightheadedness, possibly as a result of a diminished oxygen supply to the brain due to impaired cerebral autoregulation. We aimed to quantify postural changes in cerebral oxygenation and systemic hemodynamics in healthy elderly and young subjects. METHODS: In 18 healthy elderly subjects (aged 70 to 83 years) and 10 healthy young subjects (aged 22 to 45 years), frontal cortical oxygenation and hemodynamic responses were continuously monitored by near infrared spectroscopy and Finapres, respectively, before and during 10 minutes of active standing. RESULTS: -Cortical oxyhemoglobin concentration [O(2)Hb] decreased by -4.6+/-2.2 micromol/L (P<0.001) and cortical deoxyhemoglobin concentration increased by 1.5+/-2.4 micromol/L (P<0.05) in the elderly subjects after posture change, whereas these variables did not change significantly in the young subjects. The postural hemodynamic changes tended to be attenuated in the elderly subjects, except for the increases in systolic blood pressure (BP). Smaller postural increases in diastolic BP were related to larger [O(2)Hb] decreases (r=0.53, P<0.01, corrected for the age effect). CONCLUSIONS: Assuming the upright position evokes an asymptomatic decrease in frontal cortical oxygenation in healthy elderly subjects but not in healthy young subjects. Cortical [O(2)Hb] changes are affected by diastolic BP changes. These findings may indicate that regulation of cerebral oxygenation alters with increasing age.

Furosemide withdrawal in elderly heart failure patients with preserved left ventricular systolic function.

To explore the possibilities of furosemide withdrawal in elderly heart failure (HF) patients with intact left ventricular (LV) systolic function and assess its effects on functional status and orthostatic blood pressure homeostasis, we performed a placebo-controlled pilot trial of furosemide withdrawal with 3 months of follow-up in 32 HF patients (aged 75.1 +/- 0.7 years [mean +/- SEM]) with a LV ejection fraction of 60 +/- 2% and without overt congestion. Investigations included repeated clinical assessment, spirometry, standardized 6-minute walking test, and chest x-rays. Measurements of blood pressure response on active standing and Doppler echocardiography were performed before and 3 months after furosemide withdrawal. Recurrent congestive HF occurred in 2 of 21 patients (10%) who discontinued furosemide use, and in 1 of 11 patients (9%) who continued furosemide (p = NS). Three patients restarted furosemide for ankle edema and 1 for blood pressure levels >180/100 mm Hg. After 3 months, there were no differences regarding HF symptom scores, blood pressure, heart rate, spirometric results, 6-minute walking distance, or quality of life scores between patients who discontinued use and patients who continued the therapy. In patients successfully withdrawn, Doppler E/A ratio increased from 0.68 +/- 0.05 to 0.79 +/- 0.06 after withdrawal (p <0.01), and maximum blood pressure decrease on active standing changed from -8 +/- 5 mm Hg to +5 +/- 3 mm Hg systolic (p <0.05). Thus, in this pilot investigation of furosemide withdrawal in elderly HF patients without overt congestion and with a normal LV systolic function, withdrawal was successful in almost all patients and was associated with improvement of LV diastolic filling and blood pressure homeostasis on active standing.

Diuretic therapy in elderly heart failure patients with and without left ventricular systolic dysfunction.

Long term prescription of diuretics for heart failure is very prevalent among elderly patients, although the rationale for such a treatment strategy is often unclear, as diuretics are not indicated if volume overload is absent. The concept of diastolic heart failure in the elderly might particularly change the role of diuretic therapy, since diuretics may have additional adverse effects in these patients. This paper reviews the effects of diuretic therapy in elderly patients with heart failure, emphasising the differences between patients with normal and decreased left ventricular systolic function. Studies on diuretic withdrawal in elderly patients with heart failure are discussed, with emphasis on issues involved in decision making such as diuretic dose reduction and withdrawal in elderly patients and factors that have been established to predict successful withdrawal. Existing guidelines on the prescription of diuretics in elderly patients with heart failure with normal and decreased left ventricular systolic function and in those with diastolic heart failure are also discussed. By reducing intravascular volume, diuretics may further impair ventricular diastolic filling in patients with diastolic heart failure and thus reduce stroke volume. Indeed, preliminary studies demonstrate that diuretics may provoke or aggravate hypotension on standing and after meals in these patients. Therefore, it is suggested that elderly patients with heart failure with intact left ventricular systolic function should not receive long term diuretic therapy, unless proven necessary to treat or prevent congestive heart failure. This implies that physicians should carefully evaluate the opportunities for diuretic dose tapering or withdrawal in all of these patients, and that a cautiously guided intermittent diuretic treatment modality may be critical in the care for older patients with heart failure with intact left ventricular systolic function.

Monitoring hypovolemia in healthy elderly subjects by measuring blood pressure response to Valsalva's maneuver.

Quantification of hypovolemia by physical examination has limited validity. We explored the use of non-invasive measurement of blood pressure (BP) response to Valsalva's maneuver in monitoring hypovolemia in nine healthy elderly volunteers, recruited from participants of the Nijmegen Annual Four-Days Marches. Heart rate (HR), systolic and diastolic BP, and mean arterial pressure (MAP) response (Finapres) to a Valsalva's maneuver as well as clinical and laboratory assessment of fluid balance were determined 5 minutes before, and 3, 5, and 48 hours after administration of 40 mg furosemide orally. Subjects' (4 males aged 74.2 +/- 3.0 years) weight was 66.1 +/- 9.7 kg, mean BP was 139 +/- 21 over 76 +/- 12 mm Hg. A maximum weight loss of -2.8 +/- 0.9% occurred 5 hours after furosemide administration. Systolic and diastolic BP, HR, clinical assessment scores, and serum creatinine and urea nitrogen did not change during the total study period. Significant changes occurred in Valsalva phase I to phase II systolic BP response (difference +14.2 +/- 11.3 mm Hg, ratio difference -0.09 +/- 0.07 after 5 hours, P < 0.01). Changes after 48 hours did not differ from baseline values. Finapres measurement of Valsalva BP response may be useful in monitoring hypovolemia in the elderly.

Furosemide withdrawal improves postprandial hypotension in elderly patients with heart failure and preserved left ventricular systolic function.

OBJECTIVE: To assess the effects of furosemide withdrawal on postprandial blood pressure (BP) in elderly patients with heart failure and preserved left ventricular systolic function. METHODS: Noninvasive measurement of blood pressure (BP) and heart rate, computation of stroke volume and cardiac output (after a 1247-kJ (297-kcal) meal, and Doppler echocardiography before and 3 months after placebo-controlled withdrawal of furosemide therapy. RESULTS: Of 20 patients with heart failure (mean+/-SEM age, 75+/-1 years; left ventricular ejection fraction, 61%+/-3%), 13 were successfully able to discontinue furosemide therapy. At baseline, 11 (55%) of the 20 patients (had maximum postprandial systolic BP declines of 20 mm Hg or more. In the withdrawal group, the maximum systolic BP decline lessened from -25+/-4 to -11+/-2 mm Hg (P<.001) and the maximum diastolic BP from -18+/-3 to -9+/-1 mm Hg (P= .01), compared with no changes in the continuation group. In the withdrawal group, maximum postprandial declines in stroke volume and cardiac output decreased from -9+/-1 to -4+/-2 mL (P =.01) and from -0.6+/-0.2 to -0.2+/-0.1 L/min) (P = .04), respectively. The baseline maximum postprandial systolic BP decrease was correlated with the ratio of early to late flow (n = 20; Spearman rank correlation coefficient, 0.58; P = .007). For patients in the withdrawal group, the changes in postprandial systolic BP response were independently related to changes in peak velocity of early flow (n = 13; r2= 0.61; P = .003). CONCLUSIONS: Postprandial hypotension is common in elderly patients with heart failure and preserved left ventricular systolic function. The withdrawal of furosemide therapy ameliorates postprandial BP homeostasis in these patients, possibly by improving left ventricular diastolic filling.