Joaquim Oristrell

The Persistent Exclusion of Older Patients From Ongoing Clinical Trials Regarding Heart Failure

BACKGROUND Much clinical research of relevance to elderly patients examines individuals who are younger than those who have the disease in question. A good example is heart failure. Therefore, we investigated the extent of exclusion of older individuals in ongoing clinical trials regarding heart failure. METHODS In the context of the Increasing the PaRticipation of the ElDerly in Clinical Trials (PREDICT) study, data from ongoing clinical trials regarding heart failure were extracted from the World Health Organization Clinical Trials Registry Platform on December 1, 2008. Main outcome measures were the proportion of trials excluding patients by an arbitrary upper age limit or by other exclusion criteria that might indirectly cause limited recruitment of older individuals. We classified exclusion criteria into 2 categories: justified or poorly justified. RESULTS Among 251 trials investigating treatments for heart failure, 64 (25.5%) excluded patients by an arbitrary upper age limit. Such exclusion was significantly more common in trials conducted in the European Union than in the United States (31/96 [32.3%] vs 17/105 [16.2%]; P = .007) and in drug trials sponsored by public institutions vs those by private entities (21/59 [35.6%] vs 5/36 [13.9%]; P = .02). Overall, 109 trials (43.4%) on heart failure had 1 or more poorly justified exclusion criteria that could limit the inclusion of older individuals. A similar proportion of clinical trials with poorly justified exclusion criteria was found in pharmacologic and nonpharmacologic trials. CONCLUSION Despite the recommendations of national and international regulatory agencies, exclusion of older individuals from ongoing trials regarding heart failure continues to be widespread.

Exclusion of older people from clinical trials: professional views from nine European countries participating in the PREDICT study.

AbstractBackground: There has been concern about under-representation of older people in clinical trials. The PREDICT study reported that older people and those with co-morbidity continue to be excluded unjustifiably from clinical trials. However, there is no information about differences of opinion on these issues between EU countries. The results of a survey of health-related professionals from nine EU countries that participated in the PREDICT study are presented in this study. Objective: The aim of the study was to identify and examine any differences of opinion between EU countries on the inclusion of older patients in clinical trials. Methods: A questionnaire using a Likert scale and free text was completed by 521 general practitioners, geriatricians, clinical researchers, ethicists, nurses and industry pharmacologists/pharmacists. The questions explored the impact of the present situation, possible reasons for under-representation and potential methods of improving participation. Countries participating were the Czech Republic, Israel, Italy, Lithuania, the Netherlands, Poland, Romania, Spain and the UK. Results: There was agreement that exclusion from clinical trials on age grounds alone was unjustified (87%) and that under-representation of older people in trials caused difficulties for prescribers (79%) and patients (73%). There were national differences between professionals. All but the Lithuanians believed that older people were disadvantaged because of under-representation. The Czech, Lithuanian and Romanian professionals felt that it was justified to have age limits based on co-morbidity (61–83%) and polypharmacy (63–85%). Romanians also thought that having age limits on trial participation was justified because of reduced life expectancy (62%) and physical disability (58%) in older people. All but the Romanian professionals felt that the present arrangements for clinical trials were satisfactory (62%). All but the Israelis (56%) and Lithuanians (70%) agreed that regulation of clinical trials needed alteration. Conclusions: Although respondent selection bias cannot be excluded, the differences that emerged between countries may be the result of the political and healthcare-system differences between older and newer members of the EU. These differences may influence decision making about clinical trial regulations and practice in older people.

The PREDICT (increasing the participation of the elderly in clinical trials) study: the charter and beyond

There is general agreement that the growth of the numbers of older people throughout the world has significant implications for both health and social care and for the prevention and treatment of disease and disability. The optimum use of pharmaceuticals and possibly nutraceuticals is, and will to a greater extent, therefore be of crucial importance. A snapshot of the current status of older people in relation to the issues discussed in this review is provided in an informative report published by Age UK.

Off-label use of rituximab for systemic lupus erythematosus in Europe.

Objectives Rituximab (RTX) is a biological treatment used off-label in patients with systemic lupus erythematosus (SLE). This survey aimed to investigate the off-label use of RTX in Europe and compare the characteristics of patients receiving RTX with those receiving conventional therapy. Methods Data on patients with SLE receiving RTX were taken from the International Registry for Biologics in SLE retrospective registry and complemented with data on patients with SLE treated with conventional therapy. For nationwide estimates of RTX use in patients with SLE, investigators were asked to provide data through case report forms (CRFs). Countries for which no data were submitted through CRFs, published literature and/or personal communication were used, and for European countries where no data were available, estimates were made on the assumption of similarities with neighbouring countries. Results The estimated off-label use of RTX in Europe was 0.5%–1.5% of all patients with SLE. In comparison with patients with SLE on conventional therapy, patients treated with RTX had longer disease duration, higher disease activity and were more often treated with immunosuppressives. The most frequent organ manifestations for which either RTX or conventional therapy was initiated were lupus nephritis followed by musculoskeletal and haematological. The reason for treatment was, besides disease control, corticosteroid-sparing for patients treated with conventional therapy. Conclusions RTX use for SLE in Europe is restrictive and appears to be used as a last resort in patients for whom other reasonable options have been exhausted.

Clinical characteristics and outcome of Spanish patients with ANCA-associated vasculitides Impact of the vasculitis type, ANCA specificity, and treatment on mortality and morbidity

Abstract The aim of this study was to describe the clinical characteristics of ANCA-associated vasculitides (AAV) at presentation, in a wide cohort of Spanish patients, and to analyze the impact of the vasculitis type, ANCA specificity, prognostic factors, and treatments administered at diagnosis, in the outcome. A total of 450 patients diagnosed between January 1990 and January 2014 in 20 Hospitals from Spain were included. Altogether, 40.9% had granulomatosis with polyangiitis (GPA), 37.1% microscopic polyangiitis (MPA), and 22% eosinophilic granulomatosis with polyangiitis (EGPA). The mean age at diagnosis was 55.6 ± 17.3 years, patients with MPA being significantly older (P < 0.001). Fever, arthralgia, weight loss, respiratory, and ear–nose–throat (ENT) symptoms, were the most common at disease onset. ANCAs tested positive in 86.4% of cases: 36.2% C-ANCA-PR3 and 50.2% P-ANCA-MPO. P-ANCA-MPO was significantly associated with an increased risk for renal disease (OR 2.6, P < 0.001) and alveolar hemorrhage (OR 2, P = 0.010), while C-ANCA-PR3 was significantly associated with an increased risk for ENT (OR 3.4, P < 0.001) and ocular involvement (OR 2.3, P = 0.002). All patients received corticosteroids (CS) and 74.9% cyclophosphamide (CYC). The median follow-up was 82 months (IQR 100.4). Over this period 39.9% of patients suffered bacterial infections and 14.6% opportunistic infections, both being most prevalent in patients with high-cumulated doses of CYC and CS (P < 0.001). Relapses were recorded in 36.4% of cases with a mean rate of 2.5 ± 2.3, and were more frequent in patients with C-ANCA-PR3 (P = 0.012). The initial disease severity was significantly associated with mortality but not with the occurrence of relapses. One hundred twenty-nine (28.7%) patients (74 MPA, 41 GPA, 14 EGPA) died. The mean survival was 58 months (IQR 105) and was significantly lower for patients with MPA (P < 0.001). Factors independently related to death were renal involvement (P = 0.010), cardiac failure (P = 0.029) and age over 65 years old (P < 0.001) at disease onset, and bacterial infections (P < 0.001). An improved outcome with significant decrease in mortality and treatment-related morbidity was observed in patients diagnosed after 2000, and was related to the implementation of less toxic regimens adapted to the disease activity and stage, and a drastic reduction in the cumulated CYC and CS dose.

Safety and effectiveness of outpatient parenteral antimicrobial therapy in older people

OBJECTIVES We analyse the safety and effectiveness of self-outpatient parenteral antimicrobial therapy (s-OPAT) in older patients. METHODS We prospectively evaluated all adults admitted to our home hospitalization unit (HHU) for s-OPAT in the period 2008-12 in whom the bacteria responsible for the infection were identified. We divided patients into three age groups: <65, 65-79 and ≥80 years. s-OPAT was administered by patients or their caregivers using elastomeric infusion devices. Effectiveness was assessed by analysing readmissions to hospital for inadequate control of underlying infection. Safety was assessed by analysing adverse events, catheter-related complications and readmission to hospital for causes unrelated to inadequate control of underlying infection. RESULTS During the study period, 420 episodes of s-OPAT were registered in 351 patients: 139 (33.1%) in patients aged <65 years, 182 (43.3%) in those aged 65-79 years and 99 (23.6%) in those aged ≥80 years. Patients aged ≥80 years had a significantly lower Barthel index. The length of stay for s-OPAT and the complete HHU stay were similar in the three groups. Older people had similar changes in antibiotic treatment and hospital readmission rates due to poor control of underlying infection but higher readmission rates due to worsening of underlying diseases than younger adults. Adverse events and catheter-related complications were similar in the three age groups. CONCLUSIONS s-OPAT administered by patients or their caregivers using elastomeric devices was safe and effective in the treatment of infections in older people.

FRI0388 Ussefulnes of Bvas and Ffs at Diagnosis To Predict Survival in Anca Associated Vasculitis (AAV)

Background The Birmingham Vasculitis Activity Score (BVAS), and the Five Factor Score (FFS) at the time of diagnosis have been shown useful to asses prognosis in AAV (1,2), but few studies have been done comparing these tools to predict survival Objectives To compare the usefulness of BVAS vs 3, 1996 FFS and 2009 FFS at the time of diagnosis, to predict survival in a large cohort of patients with AAV from Spain Methods multicenter retrospective-longitudinal study that included patients diagnosed with AAV between Jan1995 and Nov13 in 20 Hospitals from Spain (REVAS Study). Patient survival was assessed by life-table analysis using the Kaplan-Meier method. Statistical analysis was done using SPSS vs21 Results 455 patients were included: 188 (41.3%) GPA, 167 (36.7%) MPA and 100 (22%) EGPA; 50.8% were men. Mean age at diagnosis was 55.7±17.2 y. ANCA were positive in 86.8% of cases: 35.8% C-ANCA and 51% P-ANCA. Median time to diagnosis was 4 weeks (IQR 10). Median follow-up time was 80 months (IQR 105) for global population. Renal involvement was present in 61.5% of cases, lung involvement in 54.7%, pulmonary-renal syndrome in 16.9%, neurological involvement in 34.5%, and cardiac involvement in 12.7%. ENT was observed in 44.8% of cases and eye involvement in 18.9%. Mean BVAS at diagnosis was 17.7±7.7; 1996FFS was ≤1 in 390 (85.8%) patients, and 2009FFS was ≤2 in 361 (79.4%). All patients received oral corticoids, 342 (75.1%) cyclophosphamide (49.7% IV and 50.3% oral), and 6.6% biological therapy. Dialysis was required in 16.4% of cases. During the follow-up, 39.1% of patients suffered bacterial infections, 9.2% sepsis,12.7% opportunistic infections and 5.3% neoplasms. One hundred thirty (28.6%) died:74 (44.3%) with PAM, 42 (22.3%) with GPA and 14 (14%) with EGPA (p<0.001). Univariate analysis showed that BVAS, 1996FFS and 2009FFS at diagnosis were significantly related to death (p<0.001). A multifactorial Cox regression analysis including the three activity scores confirmed that all of them were statistically related to survival rate but the stronger predictor of poor prognosis was the 2009FFS with a HR 2.7. This result was confirmed by curve ROC: 2009FFS showed the greater area under the curve (75%), in front of 1996FFS (66%) and BVAS (62%) Conclusions BVAS and FFS at diagnosis are signifivantly related to survival in AAV, but the stronger predictor of survival is the 2009 FFS. References Merkel P, Cuthbertson D, et al. Comparison of disease activity measures for ANCA-associated vasculitis. ARD 2009;68:103–6 Guillevin L, Seror R, et al. The Five-Factor Score Revisited Assessment of Prognoses of Systemic Necrotizing Vasculitides. Medicine 2011;90:19–27 Disclosure of Interest None declared