Major adverse cardiovascular events in older emergency department patients presenting with non-cardiac medical complaints.

OBJECTIVE: The risk of major adverse cardiovascular events (MACE) for older emergency department (ED) patients presenting with non-cardiac medical complaints is unknown. To apply preventive measures timely, early identification of high-risk patients is incredibly important. We aimed at investigating the incidence of MACE within one year after their ED visit and the predictive value of high-sensitivity cardiac troponin T (hs-cTnT) and N­terminal pro-B-type natriuretic peptide (NT-proBNP) for subsequent MACE. METHODS: This is a substudy of a Dutch prospective cohort study (RISE UP study) in older (≥ 65 years) medical ED patients who presented with non-cardiac complaints. Biomarkers were measured upon ED arrival. Cox-regression analysis was used to determine the predictive value of the biomarkers, when corrected for other possible predictors of MACE, and area under the curves (AUCs) were calculated. RESULTS: Of 431 patients with a median age of 79 years, 86 (20.0%) developed MACE within 1 year. Both hs-cTnT and NT-proBNP were predictive of MACE with an AUC of 0.74 (95% CI 0.68-0.80) for both, and a hazard ratio (HR) of 2.00 (95% CI 1.68-2.39) and 1.82 (95% CI 1.57-2.11) respectively. Multivariate analysis correcting for other possible predictors of MACE revealed NT-proBNP as an independent predictor of MACE. CONCLUSION: Older medical ED patients are at high risk of subsequent MACE within 1 year after their ED visit. While both hs-cTnT and NT-proBNP are predictive, only NT-proBNP is an independent predictor of MACE. It is likely that early identification of those at risk offers a window of opportunity for prevention.

Severe mitral regurgitation caused by eosinophilic endocarditis.

We describe a patient with symptoms of heart failure caused by severe mitral regurgitation. Echocardiography revealed an intracardiac mass embedding the posterior mitral valve leaflet, and cardiac magnetic resonance imaging showed two intracardiac thrombi and endomyocardial fibrosis. Eosinophil count kept rising and a mutation in the gene for platelet-derived growth factor receptor alpha was found. The combination of these findings led to the diagnosis of Loeffler's endocarditis. Treatment with prednisone and a tyrosine kinase inhibitor resulted in complete remission of the hypereosinophilia and mitral valve regurgitation was only mild at 9-month follow-up visit. .

Diagnosing diastolic heart failure.

BACKGROUND: increasing evidence supports the existence of left ventricular diastolic dysfunction as an important cause of congestive heart failure, present in up to 40% of heart failure patients. AIM: to review the pathophysiology of LV diastolic dysfunction and diastolic heart failure and the currently available methods to diagnose these disorders. RESULTS: for diagnosing LV diastolic dysfunction, invasive hemodynamic measurements are the gold standard. Additional exercise testing with assessment of LV volumes and pressures may be of help in detecting exercise-induced elevation of filling pressures because of diastolic dysfunction. However, echocardiography is obtained more easily, and will remain the most often used method for diagnosing diastolic heart failure in the coming years. MRI may provide noninvasive determination of LV three-dimensional motion during diastole, but data on correlation of MRI data with clinical findings are scant, and possibilities for widespread application are limited at this moment. CONCLUSIONS: in the forthcoming years, optimal diagnostic and therapeutic strategies for patients with primary diastolic heart failure have to be developed. Therefore, future heart failure trials should incorporate patients with diastolic heart failure, describing precise details of LV systolic and diastolic function in their study populations.

A comparison of the effects of nabumetone vs meloxicam on serum thromboxane B2 and platelet function in healthy volunteers.

AIMS: To compare the effects of nabumetone and meloxicam, two cyclo-oxygenase-2 (COX-2) preferential nonsteroidal anti-inflammatory drugs (NSAIDs), on platelet COX-1 activity and platelet function. METHODS: Twelve healthy volunteers (3 male, 9 female, median age 22 years) participated in an open, randomized, cross-over trial of nabumetone 1000 mg twice daily vs meloxicam 7.5 mg twice daily during 1 week with 2 weeks wash-out. After a second 2 week wash-out period, one dose of indomethacin 50 mg was given as a positive control to check for NSAID induced inhibition of platelet function. COX-1 inhibition was measured as percentage inhibition of serum TXB2 generation in clotting whole blood, and as closure time with use of the platelet function analyser PFA-100. Data are reported as median with range. Paired variables were analysed using Wilcoxons signed rank test. RESULTS: TXB2 levels decreased significantly after all three medications, but percentage inhibition after nabumetone and indomethacin (88% and 97%, respectively) was significantly higher than after meloxicam (63%) (P<0.05). Closure times increased significantly after administration of all three medications (P<0.05). Increases in closure time after administration did not differ between nabumetone and meloxicam (24% and 14%, respectively), but were significantly larger after indomethacin administration (63%) (P<0.01). CONCLUSIONS: In the maximum registered dosage, nabumetone inhibits thromboxane production much more than meloxicam, signifying less COX-2 selectivity of the former. However, both nabumetone and meloxicam cause only minor impairment in platelet function in comparison with indomethacin and the difference between them is not significant.

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.

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.

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.

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.

Prescription patterns of diuretics in Dutch community-dwelling elderly patients.

AIMS: To describe age- and gender-related prescription patterns of diuretics in community-dwelling elderly, and to compare diuretics to other cardiovascular (CV) medications. METHODS: Cross-sectional study of patient-specific prescription data derived from a panel of 10 Dutch community pharmacies. Determination of proportional prescription rates and prescribed daily dose (PDD) of diuretics, cardiac glycosides, nitrates, angiotensin converting enzyme (ACE) inhibitors, beta-adrenoceptor blockers, and calcium channel blockers in all 5326 patients aged 65 years or older dispensed CV medications between August 1st, 1995 and February 1st, 1996. RESULTS: Diuretics were prescribed to 2677 of 5326 patients (50.3%), 1325 patients (24.9%) using thiazides and 1198 patients (22.5%) using loop diuretics. Prescription rates of loop diuretics increased from 15.1% in patients aged 65-74 years to 37.2% in patients aged 85 years or older. Rates also increased for digoxin and nitrates. Rates for thiazide diuretics remained unchanged with age; rates for beta-adrenoceptor blockers, ACE inhibitors and calcium channel blockers declined with age. Thiazides were prescribed to 30.1% of women compared with 16% of men (P < 0.001). Average PDD was 135 +/- 117% of defined daily dose (DDD) for loop diuretics, and highest for bumetanide (245 +/- 2.01% of DDD, equivalent to 2.5 +/- 2.0 mg). Average PDD was 74 +/- 40% of DDD for thiazides, and highest for chlorthalidone (100 +/- 49% of DDD, equivalent to 25 +/- 12 mg). CONCLUSIONS: Important characteristics of diuretic usage patterns in this elderly population were a steep increase in loop diuretic use in the oldest old, a large gender difference for thiazide use, and high prescribed doses for thiazides.

Loop diuretics in patients aged 75 years or older: general practitioners' assessment of indications and possibilities for withdrawal.

OBJECTIVE: To examine the indications for prescription and possibilities for withdrawal of loop diuretics in community-dwelling patients aged 75 years or older, as reported by their general practitioners (GPs). METHODS: Analysis of dispensary data to identify patients aged 75 years or older using loop diuretics on 1 February 1996. Questionnaires were sent to the GPs of these patients to inquire about the indications for loop diuretic prescription and the necessity for continuation. We subsequently determined loop diuretic prescription rates in the survey population over the next 9 months. SETTING: A panel of nine Dutch community pharmacies. RESULTS: Questionnaires were returned for 338 out of 667 patients (50.7%) using loop diuretics on 1 February 1996. Reported indications for loop diuretic use were heart failure in 223 patients (66.0%), hypertension in 35 patients (10.4%), and a combination of both in 23 patients (6.8%). Loop diuretics were used for ankle edema in 27 patients (8.0%) and for unknown reasons in another 27 patients (8.0%). Continuation of treatment was considered unnecessary by GPs in 66 out of 338 patients (19.5%). However, prescription rates for these 66 patients in the following months were no different from rates for the remaining 272 patients. Loop diuretics were still prescribed to 47 of 66 patients (71.2%) after 12 weeks, and to 26 patients (39.4%) after 36 weeks. CONCLUSIONS: GPs reported substantial opportunities for withdrawal of loop diuretics in patients over 75 years of age, but this did not influence actual prescription rates in these patients. Future studies should explore means of facilitating withdrawal of these medications in this population.

Use of diuretics and opportunities for withdrawal in a Dutch nursing home population.

BACKGROUND: Diuretics are frequently used by elderly patients and overprescription has been suggested. However, the present withdrawal patterns of these medications in clinical practice elderly patients are unclear. METHODS: Retrospective medical record analysis of all 584 patients aged 75 years or older admitted to a 240-bed nursing home facility in the years 1990-1994. One-year follow-up by record review and collection of updated information from nursing home physicians. RESULTS: Two hundred and twenty patients (37.7%) used diuretics, and use increased with age (p < 0.05). Reported indications for prescription were heart failure (n = 77), hypertension (n = 38), ankle edema without heart failure (n = 21), or not reported (n = 84). Diuretics were withdrawn in 82 of 220 patients (37.3%), but a doubtful actual indication for diuretic use was found in 72 of the remaining 138 patients (52.2%). After withdrawal, the probability of remaining free from diuretics for at least one year was 0.47. There were no reports of life-threatening or fatal incidents after withdrawal. Mortality rates for the patients whose diuretics were withdrawn did not differ from patients continuing on diuretics. CONCLUSIONS: Withdrawal of diuretics was frequently performed and often successful. In addition, doubtful indications for diuretics were found in half of the patients continuing on these medications, suggesting additional opportunities for diuretic withdrawal.

Use of the Valsalva manoeuvre to identify haemodialysis patients at risk of congestive heart failure.

BACKGROUND: In the presence of elevated cardiac filling pressures, the decline of blood pressure (BP) during the straining phase of a Valsalva manoeuvre is blunted or absent. We compared the use of non-invasively measured BP response to a Valsalva manoeuvre with clinical assessment and bioimpedance measurements to identify haemodialysis patients at risk of acute congestive heart failure (CHF). METHODS: Continuous BP response (Finapres) to a Valsalva manoeuvre, clinical assessment by nephrologists, and bioimpedance estimations of extracellular fluid volume were determined before and after haemodialysis, once every week during a 5-week period. Acute CHF was defined according to preset clinical and radiological criteria. RESULTS: Participants (age 60+/-19 years, six females, nine males) had an average predialysis weight of 66.8+/-11.8 kg. Patients were dialysed for 3.8+/-0.8 h with a mean ultrafiltration of 2.4+/-1.1 litres. Valsalva systolic BP ratios (phase 2 to 1) decreased significantly during dialysis from 0.81+/-0.11 to 0.73+/-0.10 (P<0.05). Five patients experienced an episode of acute CHF. The Valsalva BP ratios for these patients before and after dialysis (0.89+/-0.05 and 0.78+/-0.05 respectively) were higher than for the remaining ten patients (0.77+/-0.10 and 0.70+/-0.11, respectively) (P<0.05). A cutoff Valsalva BP ratio of 0.82 resulted in positive and negative predictive values for CHF of 62 and 100% respectively. No differences in clinical assessment or bioimpedance parameters were found, with the exception of postdialysis diastolic BP and predialysis ankle oedema. After treatment of CHF, Valsalva BP ratios decreased significantly without changes in the other hydration parameters. CONCLUSIONS: Non-invasive assessment of the BP response to a Valsalva manoeuvre appears to be a potential tool for identifying patients at risk of acute CHF during maintenance haemodialysis.

[Recruitment and selection of test subjects for scientific research in geriatrics: literature review and experiences of the Nijmegen NESTOR study]. / Werving en selectie van proefpersonen voor wetenschappelijk onderzoek in de geriatrie: literatuurgegevens en ervaringen uit het Nijmeegse NESTOR-onderzoek.

The conduct of research in geriatric medicine differs from that in other medical specialties in a number of ways. In geriatric research it is almost impossible to study a large, homogeneous group of subjects, suffering solely from the problem to be studied. Moreover, measurements and questionnaires should be short, simple and not very troublesome. These differences are due to the heterogeneity of geriatric patients and the high prevalence of multimorbidity, often resulting in impaired physical, psychological and social performance. In this article a number of issues which are important for successful recruitment and selection of subjects for geriatric research are discussed. First, a review of relevant literature is given, and subsequently, experiences concerning recruitment and selection appreciated in the Nijmegen geriatric research programme' are described. This programme was part of the governmental Netherlands Programme for Research on Ageing (NESTOR). According to the literature the efficacy of recruitment may be improved by: personal contact between researcher and subject in view, introduction of the selection criteria already at the time of subjects' recruitment, a balance between research burden and profit, sufficient rewards for participation, both financially and non-financially, maximal effort in the subjects' transport, and also piloting of the recruitment procedure. In the NESTOR-studies the average number of subjects who were recruited and who completed the studies was low (23%), because a lot of the recruited subjects did not meet the selection criteria or considered participation as too troublesome. Subjects who agreed to participate showed high research compliance.

Diuretic usage and withdrawal patterns in a Dutch geriatric patient population.

OBJECTIVES: To describe diuretic usage and withdrawal patterns in a population of very old geriatric patients and to evaluate the long-term probability of remaining free from diuretic therapy after withdrawal. DESIGN: Retrospective analysis of medical records and 1-year follow-up study. SETTING: University Hospital Nijmegen and Rijnstate Hospital Arnhem, a non-academic teaching hospital, The Netherlands. PARTICIPANTS: All 1547 patients, aged 75 years or older, visiting geriatric medicine departments in the two hospitals for the first time in the years 1990 through 1993. MEASUREMENTS: Data on medical history, physical examinations, and medication use were obtained from medical records. Diuretic withdrawal and motivation was recorded as reported. Record review indicating diuretic withdrawal prompted a 1-year follow-up investigation and collection of additional updated information from family care and/or nursing-home physicians. RESULTS: A total of 593 three patients (38.3%) were using diuretics. Use of diuretics increased with age from 33.6% in patients aged 75 to 79 years to 47.4% in patients aged 90 years or older (P < .05). Diuretics were withdrawn in 218 patients (36.8%), in 101 patients because of doubts about the initial or persistent indication for diuretic use and in 91 patients because of adverse effects. No reasons for withdrawal were reported in 26 patients. Withdrawal of diuretics was attempted more often in cases of diuretic prescriptions for unknown reasons (51.2%) or ankle edema without heart failure (45.0%) than when prescriptions were for heart failure (28.5%) or hypertension (35.4%). The overall probability of remaining free of diuretic therapy for 1 year was 0.41. Success of diuretic withdrawal was significantly less when congestive heart failure was the initial indication for prescription (probability 0.24). We did not find other clinical parameters related to the success of withdrawal. CONCLUSIONS: Our study demonstrates that diuretic therapy can be withdrawn for at least a 1-year period in a substantial number of very old geriatric patients receiving these medications, regardless of the initial indications for prescription. However, withdrawal is performed without application of uniform criteria. Future prospective studies should be directed at developing clear guidelines for diuretic withdrawal in order to facilitate identification of eligible patients and to further improve the success of withdrawal attempts.

Drug use and adverse drug reactions in 105 elderly patients admitted to a general medical ward.

OBJECTIVE: To examine the influence of admission to hospital on the number of drugs used by the elderly and to study the occurrence of adverse drug reactions (ADRs), their contribution to the need for hospitalization and the relation to hospital stay. PATIENTS AND METHODS: Drug use and its sequelae were studied by one observer in 105 patients aged 65 years and older, successively admitted to a general medical ward. Naranjo's algorithm was used to estimate the probability of an ADR. Multiple regression analysis was used to measure interrelationships between variables. RESULTS: There was a slight but significant increase in drug use per patient (4.9 prescriptions on admission, 5.3 at discharge); 120 ADRs occurred, 57 on admission, 63 during stay. Two ADRs were potentially fatal. Drugs most often involved were diuretics, ADRs occurring mainly on admission. During stay in hospital antimicrobials were mainly responsible. There was a strong correlation of both ADRs on admission and ADRs during stay with duration of hospital stay. ADRs did not correlate with the number of drugs in use on admission or with the number of diagnoses. A direct correlation between the occurrence of ADRs and age could not be confirmed, when corrected for possible confounding factors. Fourteen of 105 admissions were definitely or probably drug-induced; diuretics were incriminated 6 times. CONCLUSIONS: Drug use per patient corresponded with that in the literature. Thirty-seven per cent of patients experienced a definite or probable ADR. The percentage of drug-induced admissions (14.7%) agrees with the literature, although the drugs involved (mainly diuretics in our study) were markedly different. The occurrence of ADRs, both on admission and during stay is correlated with the duration of hospital stay, but not with drugs in use or with the number of diagnoses.