Drug adherence and multidisciplinary care in patients with multiple sclerosis: Protocol of a prospective, web-based, patient-centred, nation-wide, Dutch cohort study in glatiramer acetate treated patients (CAIR study)

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, for which no definitive treatment is available. Most patients start with a relapsing-remitting course (RRMS). Disease-modifying drugs (DMDs) reduce relapses and disability progression. First line DMDs include glatiramer acetate (GA), interferon-beta (INFb)-1a and INFb-1b, which are all administered via injections. Effectiveness of DMD treatment depends on adequate adherence, meaning year-long continuation of injections with a minimum of missed doses. In real-life practice DMD-treated patients miss 30% of doses. The 6-month discontinuation rate is up to 27% and most patients who discontinue do so in the first 12 months.Treatment adherence is influenced by the socio-economic situation, health care and caregivers, disease, treatment and patient characteristics. Only a few studies have dealt with adherence-related factors in DMD-treated patients. Self-efficacy expectations were found to be related to GA adherence. Patient education and optimal support improve adherence in general. Knowledge of the aspects of care that significantly relate to adherence could lead to adherence-improving measures. Moreover, identification of patients at risk of inadequate adherence could lead to more efficient care.In the near future new drugs will become available for RRMS. Detailed knowledge on factors prognostic of adherence and on care aspects that are associated with adequate adherence will improve the chances of these drugs becoming effective treatments. We investigate in RRMS patients the relationship between drug adherence and multidisciplinary care, as well as factors associated with adherence. Given the differences in the frequency of administration and in the side effects between the DMDs we decided to study patients treated with the same DMD, GA.Methods/design: The Correlative analyses of Adherence In Relapsing remitting MS (CAIR) study is an investigator-initiated, prospective, web-based, patient-centred, nation-wide cohort study in the Netherlands.The primary objective is to investigate whether GA adherence is associated with specific disciplines of care or quantities of specific care. The secondary objective is to investigate whether GA adherence is associated with specific aspects of the socio-economic situation, health care and caregivers, disease, treatment or patient characteristics.All data are acquired on-line via a study website. All RRMS patients in the Netherlands starting GA treatment are eligible. Patients are informed by neurologists, nurses, and websites from national MS patient organisations. All data, except on disability, are obtained by patient self-reports on pre-defined and random time points. The number of missed doses and the number of patients having discontinued GA treatment at 6 and 12 months are measures of adherence. Per care discipline the number of sessions and the total duration of care are measures of received care. The full spectrum of non-experimental care that is available in the Netherlands is assessed. Care includes 'physical' contacts, contacts by telephone or internet, health-promoting activities and community care activities. Care received over the preceding 14 days is assessed by patients at baseline and every other week thereafter up to month 12. Every 3 months neurologists and nurses record care disciplines to which patients have been referred.The Dutch Adherence Questionnaire-90 (DAQ-90) is a 90-item questionnaire based on the World Health Organisation (WHO) 2003 report on adherence and comprehensively assesses five domains of evidence-based determinants of adherence: socio-economic, health care and caregivers, disease, treatment, and patient-related factors. In addition, self-efficacy is assessed by the MS Self-Efficacy Scale (MSSES), and mood and health-related quality of life (HRQoL) by the Multiple Sclerosis Quality of Life-54 questionnaire (MSQoL-54). Relapses and adverse events probably or definitively related to GA are also reported.Discussion: In this study data is mainly acquired by patients' self-reporting via the internet. On-line data acquisition by patients does not require study visits to the hospital and can easily be integrated into daily life. The web-based nature of the study is believed to prevent missing data and study drop-outs. Moreover, the automated process of filling in questionnaires ensures completeness and consistency, thus improving data quality. The combination of patient-reported outcomes, fully web-based data capture and nation-wide information to all eligible patients are distinguishing features of the study and contribute to its scientific potential.Trial registration: Netherlands Trial Register (NTR): NTR2432

Veiligheid en farmacokinetiek van levetiracetam intraveneus add-on bij status epilepticus

Objective: To evaluate safety of intravenous levetiracetam added to the standard therapeutic regimen in adults with status epilepticus. and to assess a population pharmacokinetic model for intravenous levetiracetam in patients with status epilepticus. Design: Prospective, single-centre, single-arm, open-label study. Methods: In 12 adults presenting with status epilepticus, levetiracetam 2500 mg intravenous was added as soon as possible to standardized protocol. During 24 hours of follow-up, patients were observed for any clinically relevant side effects. A population pharmacokinetic model was developed by iterative two-stage Bayesian analysis and compared to pharmacokinetic data of healthy volunteers. Results: 11 patients with a median age of 60 years were included in the per protocol analysis. 5 were diagnosed as having generalised-convulsive status epilepticus, 5 as partial-convulsive status epilepticus and 1 as a non-convulsive status epilepticus. Blood samples for pharmacokinetic analysis were available for 10 patients. No serious side effects could be directly related to the intravenous administration of levetiracetam. A two-compartment population pharmacokinetic model gave the best description of intravenous levetiracetam pharmacokinetics. Mean (SD) population parameters included volume of distribution of central compartment: 0.45 (0.084) l/kg, and total body clearance: 0.048 (0.0147) l·h-1·kg-1. Mean maximum plasma concentration was 85 (19) mg/l. No large deviations from the known pharmacokinetic of intravenous levetiracetam in healthy volunteers were observed. Conclusion: The addition of intravenous levetiracetam to the standard regimen for controlling status epilepticus seems feasible and safe. Pharmacokinetic data of intravenous levetiracetam in patients with status epilepticus correspond to earlier values derived from healthy volunteers, confirming a two-compartment population model

Safety and pharmacokinetics of intravenous add-on levetiracetam in status epilepticus

Objective: To evaluate safety of intravenous levetiracetam added to the standard therapeutic regimen in adults with status epilepticus. and to assess a population pharmacokinetic model for intravenous levetiracetam in patients with status epilepticus. Design: Prospective, single-centre, single-arm, open-label study. Methods: In 12 adults presenting with status epilepticus, levetiracetam 2500 mg intravenous was added as soon as possible to standardized protocol. During 24 hours of follow-up, patients were observed for any clinically relevant side effects. A population pharmacokinetic model was developed by iterative two-stage Bayesian analysis and compared to pharmacokinetic data of healthy volunteers. Results: 11 patients with a median age of 60 years were included in the per protocol analysis. 5 were diagnosed as having generalised-convulsive status epilepticus, 5 as partial-convulsive status epilepticus and 1 as a non-convulsive status epilepticus. Blood samples for pharmacokinetic analysis were available for 10 patients. No serious side effects could be directly related to the intravenous administration of levetiracetam. A two-compartment population pharmacokinetic model gave the best description of intravenous levetiracetam pharmacokinetics. Mean (SD) population parameters included volume of distribution of central compartment: 0.45 (0.084) l/kg, and total body clearance: 0.048 (0.0147) l·h-1·kg-1. Mean maximum plasma concentration was 85 (19) mg/l. No large deviations from the known pharmacokinetic of intravenous levetiracetam in healthy volunteers were observed. Conclusion: The addition of intravenous levetiracetam to the standard regimen for controlling status epilepticus seems feasible and safe. Pharmacokinetic data of intravenous levetiracetam in patients with status epilepticus correspond to earlier values derived from healthy volunteers, confirming a two-compartment population model

Safety and pharmacokinetics of intravenous levetiracetam infusion as add-on in status epilepticus

PURPOSE: To evaluate the feasibility and safety of intravenous (iv) levetiracetam (LEV) added to the standard therapeutic regimen in adults with status epilepticus (SE), and as secondary objective to assess a population pharmacokinetic (PK) model for ivLEV in patients with SE. METHODS: In 12 adults presenting with SE, 2,500 mg ivLEV was added as soon as possible to standardized protocol, consisting of iv clonazepam and/or rectal diazepam, as needed followed by phenytoin or valproic acid. ivLEV was administered over approximately 5 min, in general after administration of clonazepam, regardless the need for further treatment. During 24-h follow-up, patients were observed for any clinically relevant side-effects. Blood samples for PK analysis were available in 10 patients. A population PK model was developed by iterative two-stage Bayesian analysis and compared to PK data of healthy volunteers. RESULTS: Eleven patients with a median age of 60 years were included in the per protocol analysis. Five were diagnosed as generalized-convulsive SE, five as partial-convulsive SE, and one as a nonconvulsive SE. The median time from hospital admission to ivLEV was 36 min. No serious side effects could be related directly to the administration of ivLEV. During PK analysis, four patients showed a clear distribution phase, lacking in the others. The PK of the population was best described by a two-compartment population model. Mean (standard deviation, SD) population parameters included volume of distribution of central compartment: 0.45 (0.084) L/kg; total body clearance: 0.0476 (0.0147) L/h/kg; distribution rate constants, central to peripheral compartment (k(12)): 0.24 (0.12)/h, and peripheral to central (k(21)): 0.70 (0.22)/h. Mean maximal plasma concentration was 85 (19) mg/L. DISCUSSION: The addition of ivLEV to the standard regimen for controlling SE seems feasible and safe. PK data of ivLEV in patients with SE correspond to earlier values derived from healthy volunteers, confirming a two-compartment population model

Patient reported postoperative pain with a smartphone application: A proof of concept

Postoperative pain management and pain assessment are still lacking the perspective of the patient. We have developed and studied a prototype smartphone application for patients to self-record postoperative pain. The main objective was to collect patient and stakeholder critique of improvements on the usability in order to develop a definitive version. The secondary objective was to investigate if patient self-recording compared to nurse-led assessment is a suitable method for postoperative pain management. Fifty patients and a stakeholder group consisting of ten healthcare- and ICT professionals and two members of the patient council participated in this study. Main outcome Thirty patients (60%) found it satisfying or very satisfying to communicate their pain with the app. Pain experienced after surgery was scored by patients as ‘no’: 3 (6%), ‘little’: 5 (10%), ‘bearable’: 25 (50%), ‘considerable’: 13 (26%) and ‘severe’: 1 (2%). Forty-five patients (90%) were positive about the ease of recording. Forty-five patients (90%) could correctly record their pain with the app. Thirty-eight patients (76%) agreed that in-app notifications to record pain were useful. Two patients (4%) were too ill to use the application. Based on usability feedback, we will redesign the pain intensity wheel and the in-app pain chart to improve clarity for patients to understand the course of their pain. Secondary outcomes The median patient recorded pain app score 4.0 (range 0 to 10) and nurse recorded numerical rating scale (NRS) for pain NRS 4.0 (range 0 to 9) were not statistically different (p = 0.06). Forty-two percent from a total of 307 patient pain app scores were ≥ 5 (on a scale from 0 no pain at all to 10 worst imaginable pain). Of these, 83% were recorded as ‘bearable’ while only in 18% of the recordings patients asked for additional analgesia. The results suggest that self-recording the severity of postoperative pain by patients with a smartphone application could be useful for postoperative pain management. The application was perceived as user-friendly and had high satisfaction rates from both patients and stakeholders. Further research is needed to validate the 11-point numeric and faces pain scale with the current gold standards visual analogue scale (VAS) and NRS for pain

Drug adherence and multidisciplinary care in patients with multiple sclerosis: Protocol of a prospective, web-based, patient-centred, nation-wide, Dutch cohort study in glatiramer acetate treated patients (CAIR study)

Abstract Background Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, for which no definitive treatment is available. Most patients start with a relapsing-remitting course (RRMS). Disease-modifying drugs (DMDs) reduce relapses and disability progression. First line DMDs include glatiramer acetate (GA), interferon-beta (INFb)-1a and INFb-1b, which are all administered via injections. Effectiveness of DMD treatment depends on adequate adherence, meaning year-long continuation of injections with a minimum of missed doses. In real-life practice DMD-treated patients miss 30% of doses. The 6-month discontinuation rate is up to 27% and most patients who discontinue do so in the first 12 months. Treatment adherence is influenced by the socio-economic situation, health care and caregivers, disease, treatment and patient characteristics. Only a few studies have dealt with adherence-related factors in DMD-treated patients. Self-efficacy expectations were found to be related to GA adherence. Patient education and optimal support improve adherence in general. Knowledge of the aspects of care that significantly relate to adherence could lead to adherence-improving measures. Moreover, identification of patients at risk of inadequate adherence could lead to more efficient care. In the near future new drugs will become available for RRMS. Detailed knowledge on factors prognostic of adherence and on care aspects that are associated with adequate adherence will improve the chances of these drugs becoming effective treatments. We investigate in RRMS patients the relationship between drug adherence and multidisciplinary care, as well as factors associated with adherence. Given the differences in the frequency of administration and in the side effects between the DMDs we decided to study patients treated with the same DMD, GA. Methods/design The Correlative analyses of Adherence In Relapsing remitting MS (CAIR) study is an investigator-initiated, prospective, web-based, patient-centred, nation-wide cohort study in the Netherlands. The primary objective is to investigate whether GA adherence is associated with specific disciplines of care or quantities of specific care. The secondary objective is to investigate whether GA adherence is associated with specific aspects of the socio-economic situation, health care and caregivers, disease, treatment or patient characteristics. All data are acquired on-line via a study website. All RRMS patients in the Netherlands starting GA treatment are eligible. Patients are informed by neurologists, nurses, and websites from national MS patient organisations. All data, except on disability, are obtained by patient self-reports on pre-defined and random time points. The number of missed doses and the number of patients having discontinued GA treatment at 6 and 12 months are measures of adherence. Per care discipline the number of sessions and the total duration of care are measures of received care. The full spectrum of non-experimental care that is available in the Netherlands is assessed. Care includes 'physical' contacts, contacts by telephone or internet, health-promoting activities and community care activities. Care received over the preceding 14 days is assessed by patients at baseline and every other week thereafter up to month 12. Every 3 months neurologists and nurses record care disciplines to which patients have been referred. The Dutch Adherence Questionnaire-90 (DAQ-90) is a 90-item questionnaire based on the World Health Organisation (WHO) 2003 report on adherence and comprehensively assesses five domains of evidence-based determinants of adherence: socio-economic, health care and caregivers, disease, treatment, and patient-related factors. In addition, self-efficacy is assessed by the MS Self-Efficacy Scale (MSSES), and mood and health-related quality of life (HRQoL) by the Multiple Sclerosis Quality of Life-54 questionnaire (MSQoL-54). Relapses and adverse events probably or definitively related to GA are also reported. Discussion In this study data is mainly acquired by patients' self-reporting via the internet. On-line data acquisition by patients does not require study visits to the hospital and can easily be integrated into daily life. The web-based nature of the study is believed to prevent missing data and study drop-outs. Moreover, the automated process of filling in questionnaires ensures completeness and consistency, thus improving data quality. The combination of patient-reported outcomes, fully web-based data capture and nation-wide information to all eligible patients are distinguishing features of the study and contribute to its scientific potential. Trial registration Netherlands Trial Register (NTR): NTR2432</p

Interobserver agreement and predictive value for outcome of two rating scales for the amount of extravasated blood after aneurysmal subarachnoid haemorrhage.

Item does not contain fulltextBACKGROUND: In patients with SAH the amount of extravasated blood on the initial CT scan is related with delayed cerebral ischemia and clinical outcome. We investigated the interobserver variation of the Hijdra and Fisher scales for the amount of extravasated blood and the predictive values of these scales for delayed cerebral ischemia and outcome. METHODS: For 132 patients admitted within 48 hours after SAH three observers assessed the amount of blood on the initial CT scan by means of the Hijdra and Fisher scale. We analyzed interobserver agreement with kappa statistics and used multivariate logistic regression for the association with delayed cerebral ischemia and clinical outcome. RESULTS: The interobserver agreement of all three pairs of observers was good for the Hijdra scale (kappas for total sum scores ranging from 0.67 to 0.75) and mild to moderate for the Fisher scale (kappas ranging from 0.37 to 0.55). For the Hijdra scale the risk of DCI was higher for intermediate (OR 4.2; 95% CI 1.1-16.3) and large (OR 3.6; 95% CI 0.8-16.4) amounts of blood with small amount as reference. Fisher grade III (OR 1.0; 95% CI 0.2-5.2) and IV (OR 0.3; 95% CI 0.02-4.0) were not related with DCI. For the Hijdra scale and clinical outcome we found an increasing risk for poor outcome with intermediate (OR 3.9; 95% CI 1.0-15.9) and large (OR 10.7; 95% CI 2.3-50.1) amounts of blood. Such a relation was not found for Fisher grade III (OR 1.2; 95% CI 0.2-7.0) and IV (OR 0.2; 95% CI 0.01-3.4). CONCLUSIONS: For the Hijdra scale we found a distinct better interobserver agreement than for the Fisher score. Moreover, the Hijdra scale was an independent prognosticator for DCI and clinical outcome, which was not the case for the Fisher score

Foley catheter versus vaginal prostaglandin E2 gel for induction of labour at term (PROBAAT trial): an open-label, randomised controlled trial

Induction of labour is a common obstetric procedure. Both mechanical (eg, Foley catheters) and pharmacological methods (eg, prostaglandins) are used for induction of labour in women with an unfavourable cervix. We aimed to compare the effectiveness and safety of induction of labour with a Foley catheter with induction with vaginal prostaglandin E2 gel. We did an open-label, randomised controlled trial in 12 hospitals in the Netherlands between Feb 10, 2009, and May 17, 2010. We enrolled women with a term singleton pregnancy in cephalic presentation, intact membranes, an unfavourable cervix, an indication for induction of labour, and no prior caesarean section. Participants were randomly allocated by an online randomisation system to induction of labour with a 30 mL Foley catheter or vaginal prostaglandin E2 gel (1:1 ratio). Because of the nature of the intervention this study was not blinded. The primary outcome was caesarean section rate. Secondary outcomes were maternal and neonatal morbidity and time from intervention to birth. All analyses were done on an intention-to-treat basis. We also did a meta-analysis that included our trial. The trial was registered with the Dutch trial registry, number NTR 1646. 824 women were allocated to induction of labour with a Foley catheter (n=412) or vaginal prostaglandin E2 gel (n=412). Caesarean section rates were much the same between the two groups (23%vs 20%, risk ratio [RR] 1·13, 95% CI 0·87-1·47). A meta-analysis including our trial data confirmed that a Foley catheter did not reduce caesarean section rates. We recorded two serious maternal adverse events, both in the prostaglandin group: one uterine perforation and one uterine rupture. In women with an unfavourable cervix at term, induction of labour with a Foley catheter is similar to induction of labour with prostaglandin E2 gel, with fewer maternal and neonatal side-effects. Non