A patient's perspective:the impact of adverse drug reactions on patients and their views on reporting

What is known and objective: Adverse drug reactions to prescribed medication are relatively common events. However, the impact such reactions have on patients and their attitude to reporting such events have only been poorly explored. Previous studies relying on self-reporting patients indicate that altruism is an important factor. In the United Kingdom, patient reporting started in 2005; though, numbers of serious reports remain low. Method: A purposive sample of fifteen patients who had been admitted to an inner city hospital with an adverse drug reaction were interviewed using a semi-structured questionnaire. Patients were asked to relate in their own words their experience of an adverse drug reaction. Patient's reactions to the information leaflet, adherence to treatment and use of other sources of information on medication were assessed. Interviews were recorded, and a thematic analysis of patients'responses was performed. Results and discussion: Analysis of the patient interviews demonstrated the reality of being admitted to hospital is often a frightening process with a significant emotional cost. Anger, isolation, resentment and blame were common factors, particularly when medicines had been prescribed for acute conditions. For patients with chronic conditions, a more phlegmatic approach was seen especially with conditions with a strong support networks. Patients felt that communication and information should have been more readily available from the health care professional who prescribed the medication, although few had read the patient information leaflet. Only a minority of patients linked the medication they had taken to the adverse event, although some had received false reassurance that the drug was not related to their illness creating additional barriers. In contrast to previous studies, many patients felt that adverse drug reporting was not their concern, particularly as they obtained little direct benefit from it. The majority of patients were unaware of the Yellow Card Scheme in the UK for patient reporting. Even when explained, the scheme was felt too cold and impersonal and not a patient's 'job'. What is new and conclusion: Patients having a severe adverse drug reaction following an acute illness felt negative emotions towards their health care provider. Those with a chronic condition rationalized the event and coped better with its impact. Neither group felt that reporting the adverse reaction was their responsibility. Encouraging patients to report remains important but expecting patients to report solely for altruistic purposes may be unrealistic. © 2011 Blackwell Publishing Ltd.

Quality of life after total laparoscopic hysterectomy versus total abdominal hysterectomy for stage I endometrial cancer (LACE) : a randomised trial

Background: The two-stage Total Laparoscopic Hysterectomy (TLH) versus Total Abdominal Hysterectomy (TAH) for stage I endometrial cancer (LACE) randomised controlled trial was initiated in 2005. The primary objective of stage 1 was to assess whether TLH results in equivalent or improved QoL up to 6 months after surgery compared to TAH. The primary objective of stage 2 was to test the hypothesis that disease-free survival at 4.5 years is equivalent for TLH and TAH. Results addressing the primary objective of stage 1 of the LACE trial are presented here. Methods: The first 361 LACE participants (TAH n= 142, TLH n=190) were enrolled in the QoL substudy at 19 centres across Australia, New Zealand and Hong Kong, and 332 completed the QoL analysis. Randomisation was performed centrally and independently from other study procedures via a computer generated, web-based system (providing concealment of the next assigned treatment) using stratified permuted blocks of 3 and 6, and assigned patients with histologically confirmed stage 1 endometrioid endometrial adenocarcinoma and ECOG performance status <2 to TLH or TAH stratified by histological grade and study centre. No blinding of patients or study personnel was attempted. QoL was measured at baseline, 1 and 4 weeks (early), and 3 and 6 months (late) after surgery using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. The primary endpoint was the difference between the groups in QoL change from baseline at early and late time points (a 5% difference was considered clinically significant). Analysis was performed according to the intention-to-treat principle using generalized estimating equations on differences from baseline for the early and late QoL recovery. The LACE trial is registered with clinicaltrials.gov (NCT00096408) and the Australian New Zealand Clinical Trials Registry (CTRN12606000261516). Patients for both stages of the trial have now been recruited and are being followed up for disease-specific outcomes. Findings: The proportion of missing values at the 5%, 10% 15% and 20% differences in the FACT-G scale was 6% (12/190) in the TLH and 14% (20/142) in the TAH group. There were 8/332 conversions (2.4%, 7 of which were from TLH to TAH). In the early phase of recovery, patients undergoing TLH reported significantly greater improvement of QoL from baseline compared to TAH in all subscales except the emotional and social well-being subscales. Improvements in QoL up to 6 months post-surgery continued to favour TLH except for the emotional and social well-being of the FACT and the visual analogue scale of the EuroQoL five dimensions (EuroQoL-VAS). Length of operating time was significantly longer in the TLH group (138±43 mins), than in the TAH group at (109±34 mins; p=0.001). While the proportion of intraoperative adverse events was similar between the treatment groups (TAH 8/142, 5.6%; TLH 14/190, 7.4%; p=0.55), postoperatively, twice as many patients in the TAH group experienced adverse events of CTC grade 3+ than in the TLH group (33/142, 23.2% and 22/190, 11.6%, respectively; p=0.004). Postoperative serious adverse events occurred more frequently in patients who had a TAH (27/142, 19.0%) than a TLH (15/190, 7.9%) (p=0.002). Interpretation: QoL improvements from baseline during early and later phases of recovery, and the adverse event profile significantly favour TLH compared to TAH for patients treated for Stage I endometrial cancer.

Patient education to prevent falls among older hospital inpatients : a randomized controlled trial

Background Falls are a common adverse event during hospitalization of older adults, and few interventions have been shown to prevent then. Methods This study was a 3-group randomized trial to evaluate the efficacy of 2 forms of multimedia patient education compared with usual care for the prevention of in-hospital falls. Older hospital patients (n = 1206) admitted to a mixture of acute (orthopedic, respiratory, and medical) and subacute (geriatric and neurorehabilitation) hospital wards at 2 Australian hospitals were recruited between January 2008 and April 2009. The interventions were a multimedia patient education program based on the health-belief model combined with trained health professional follow-up (complete program), multi-media patient education materials alone (materials only), and usual care (control). Falls data were collected by blinded research assistants by reviewing hospital incident reports, hand searching medical records, and conducting weekly patient interviews. Results Rates of falls per 1000 patient-days did not differ significantly between groups (control, 9.27; materials only, 8.61; and complete program, 7.63). However, there was a significant interaction between the intervention and presence of cognitive impairment. Falls were less frequent among cognitively intact patients in the complete program group (4.01 per 1000 patient-days) than among cognitively intact patients in the materials-only group (8.18 per 1000 patient-days) (adjusted hazard ratio, 0.51; 95% confidence interval, 0.28-0.93]) and control group (8.72 per 1000 patient-days) (adjusted hazard ratio, 0.43; 95% confidence interval, 0.24-0.78). Conclusion Multimedia patient education with trained health professional follow-up reduced falls among patients with intact cognitive function admitted to a range of hospital wards.

Under the carpet : the politics and trauma of patient harm

Few studies have investigated iatrogenic outcomes from the viewpoint of patient experience. To address this anomaly, the broad aim of this research is to explore the lived experience of patient harm. Patient harm is defined as major harm to the patient, either psychosocial or physical in nature, resulting from any aspect of health care. Utilising the method of Consensual Qualitative Research (CQR), in-depth interviews are conducted with twenty-four volunteer research participants who self-report having been severely harmed by an invasive medical procedure. A standardised measure of emotional distress, the Impact of Event Scale (IES), is additionally employed for purposes of triangulation. Thematic analysis of transcript data indicate numerous findings including: (i) difficulties regarding patients‘ prior understanding of risks involved with their medical procedure; (ii) the problematic response of the health system post-procedure; (iii) multiple adverse effects upon life functioning; (iv) limited recourse options for patients; and (v) the approach desired in terms of how patient harm should be systemically handled. In addition, IES results indicate a clinically significant level of distress in the sample as a whole. To discuss findings, a cross-disciplinary approach is adopted that draws upon sociology, medicine, medical anthropology, psychology, philosophy, history, ethics, law, and political theory. Furthermore, an overall explanatory framework is proposed in terms of the master themes of power and trauma. In terms of the theme of power, a postmodernist analysis explores the politics of patient harm, particularly the dynamics surrounding the politics of knowledge (e.g., notions of subjective versus objective knowledge, informed consent, and open disclosure). This analysis suggests that patient care is not the prime function of the health system, which appears more focussed upon serving the interests of those in the upper levels of its hierarchy. In terms of the master theme of trauma, current understandings of posttraumatic stress disorder (PTSD) are critiqued, and based on data from this research as well as the international literature, a new model of trauma is proposed. This model is based upon the principle of homeostasis observed in biology, whereby within every cell or organism a state of equilibrium is sought and maintained. The proposed model identifies several bio-psychosocial markers of trauma across its three main phases. These trauma markers include: (i) a profound sense of loss; (ii) a lack of perceived control; (iii) passive trauma processing responses; (iv) an identity crisis; (v) a quest to fully understand the trauma event; (vi) a need for social validation of the traumatic experience; and (vii) posttraumatic adaption with the possibility of positive change. To further explore the master themes of power and trauma, a natural group interview is carried out at a meeting of a patient support group for arachnoiditis. Observations at this meeting and members‘ stories in general support the homeostatic model of trauma, particularly the quest to find answers in the face of distressing experience, as well as the need for social recognition of that experience. In addition, the sociopolitical response to arachnoiditis highlights how public domains of knowledge are largely constructed and controlled by vested interests. Implications of the data overall are discussed in terms of a cultural revolution being needed in health care to position core values around a prime focus upon patients as human beings.

Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX) : an open-label randomised phase III trial

Background: Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer. Methods: In a multinational, multicentre, open-label, phase III trial, chemotherapy-naive patients (≥18 years) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy. Chemotherapy was cisplatin 80 mg/m 2 intravenous infusion on day 1, and vinorelbine 25 mg/m 2 intravenous infusion on days 1 and 8 of every 3-week cycle) for up to six cycles. Cetuximab-at a starting dose of 400 mg/m 2 intravenous infusion over 2 h on day 1, and from day 8 onwards at 250 mg/m 2 over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred. The primary endpoint was overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Between October, 2004, and January, 2006, 1125 patients were randomly assigned to chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11·3 months vs 10·1 months; hazard ratio for death 0·871 [95% CI 0·762-0·996]; p=0·044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3). Interpretation: Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer. Funding: Merck KGaA. © 2009 Elsevier Ltd. All rights reserved.

Reversibility of liver failure secondary to metastatic breast cancer by vinorelbine and cisplatin chemotherapy

Purpose: The development of liver metastases from breast cancer is associated with a very poor prognosis, estimated at 4 months median survival. Since treatment with many chemotherapeutic agents is relatively contraindicated, we assessed the safety, tolerability and potential efficacy of combination chemotherapy with vinorelbine and cisplatin (ViP). Method: Pilot study in 11 patients with histologically confirmed breast carcinoma, radiological evidence of liver metastases and serum bilirubin greater than 1.5 times the upper limit of normal. Patients received up to six cycles of cisplatin (75 mg/m 2) every 21 days and vinorelbine (20 mg/m 2) on days 1 and 8 of every 21-day cycle. Measurement of liver lesions was performed on CT scan every 8 weeks into treatment. Results: The most frequently reported adverse event was myelosuppression. Other adverse effects included nausea, vomiting and mild neurotoxicity. Two patients died after one treatment with ViP, one of whom suffered an intracerebral haemorrhage that was possibly treatment-related. Improvement in liver function tests was observed in 10 patients, and mean time to normalization of bilirubin levels was 36 days. Partial responses were documented radiologically in 7 out of 11 patients treated. Median overall survival from trial entry was 6.5 months (range 11-364 days), with one patient alive 13 months from trial entry. Conclusion: Normalization of liver function is possible with ViP treatment of metastatic breast cancer, offering the potential to prolong survival. Phase II clinical trials of this regimen in this patient group should include measurement of quality of life in order to assess risk versus benefit.

A stepped-wedge cluster randomised controlled trial for evaluating rates of falls among inpatients in aged care rehabilitation units receiving tailored multimedia education in addition to usual care : a trial protocol

Introduction Falls are the most frequent adverse event reported in hospitals. Approximately 30% of in-hospital falls lead to an injury and up to 2% result in a fracture. A large randomised trial found that a trained health professional providing individualised falls prevention education to older inpatients reduced falls in a cognitively intact subgroup. This study aims to investigate whether this efficacious intervention can reduce falls and be clinically useful and cost-effective when delivered in the real-life clinical environment. Methods A stepped-wedge cluster randomised trial will be used across eight subacute units (clusters) which will be randomised to one of four dates to start the intervention. Usual care on these units includes patient's screening, assessment and implementation of individualised falls prevention strategies, ongoing staff training and environmental strategies. Patients with better levels of cognition (Mini-Mental State Examination >23/30) will receive the individualised education from a trained health professional in addition to usual care while patient's feedback received during education sessions will be provided to unit staff. Unit staff will receive training to assist in intervention delivery and to enhance uptake of strategies by patients. Falls data will be collected by two methods: case note audit by research assistants and the hospital falls reporting system. Cluster-level data including patient's admissions, length of stay and diagnosis will be collected from hospital systems. Data will be analysed allowing for correlation of outcomes (clustering) within units. An economic analysis will be undertaken which includes an incremental cost-effectiveness analysis. Ethics and dissemination The study was approved by The University of Notre Dame Australia Human Research Ethics Committee and local hospital ethics committees. Results The results will be disseminated through local site networks, and future funding and delivery of falls prevention programmes within WA Health will be informed. Results will also be disseminated through peer-reviewed publications and medical conferences.

Novel sequential methods in dose-finding designs : extensions of the continual reassessment method

Dose-finding trials are a form of clinical data collection process in which the primary objective is to estimate an optimum dose of an investigational new drug when given to a patient. This thesis develops and explores three novel dose-finding design methodologies. All design methodologies presented in this thesis are pragmatic. They use statistical models, incorporate clinicians' prior knowledge efficiently, and prematurely stop a trial for safety or futility reasons. Designing actual dose-finding trials using these methodologies will minimize practical difficulties, improve efficiency of dose estimation, be flexible to stop early and reduce possible patient discomfort or harm.

Preventing infections following caesarean section

Surgical site infections following caesarean section are a serious and costly adverse event for Australian hospitals. In the United Kingdom, 9% of women are diagnosed with a surgical site infection following caesarean section either in hospital or post-discharge (Wloch et al 2012, Ward et al 2008). Additional staff time, pharmaceuticals and health supplies, and increased length of stay or readmission to hospital are often required (Henman et al 2012). Part of my PhD investigated the economics of preventing post-caesarean infection. This paper summarises a review of relevant infection prevention strategies. Administering antibiotic prophylaxis 15 to 60 minutes pre-incision, rather than post cordclamping, is probably the most important infection prevention strategy for caesarean section (Smaill and Gyte2010, Liu et al 2013, Dahlke et al 2013). However the timing of antibiotic administration is reportedly inconsistent in Australian hospitals. Clinicians may be taking advice from the influential, but out-dated RANZCOG and United States Centers for Disease Control and Prevention guidelines (Royal Australian and New Zealand College of Obstetricians and Gynaecologists 2011, Mangram et al 1999). A number of other important international clinical guidelines, including Australia's NHMRC guidelines, recommend universal prophylactic antibiotics pre-incision for caesarean section (National Health and Medical Research Council 2010, National Collaborating Centre for Women's and Children's Health 2008, Anderson et al 2008, National Collaborating Centre for Women's and Children's Health 2011, Bratzler et al 2013, American College of Obstetricians and Gynecologists 2011a, Antibiotic Expert Group 2010). We need to ensure women receive preincision antibiotic prophylaxis, particularly as nurses and midwives play a significant role in managing an infection that may result from sub-optimal practice. It is acknowledged more explicitly now that nurses and midwives can influence prescribing and administration of antibiotics through informal approaches (Edwards et al 2011). Methods such as surgical safety checklists are a more formal way for nurses and midwives to ensure that antibiotics are administered pre-incision (American College of Obstetricians and Gynecologists 2011 b). Nurses and midwives can also be directly responsible for other infection prevention strategies such as instructing women to not remove pubic hair in the month before the expected date of delivery and wound management education (Ng et al 2013). Potentially more costly but effective strategies include using a Chlorhexidine-gluconate (CHG) sponge preoperatively (in addition to the usual operating room skin preparation) and vaginal cleansing with a povidone-iodine solution (Riley et al 2012, Rauk 2010, Haas, Morgan, and Contreras 2013).

Building a "brain attack" team to administer thrombolytic therapy for acute ischemic stroke

Before tissue plasminogen activator (tPA) was licensed for use in Canada, in February 1999, the Calgary Regional Stroke Program spearheaded the development and organization of local resources to use thrombolytic therapy in patients who had experienced acute ischemic stroke. In 1996 special permission was obtained from the Calgary Regional Health Authority to use intravenously administered tPA for acute ischemic stroke, and ethical and scientific review boards approved the protocols. After 3 years our efforts have resulted in improved patient outcomes, shorter times from symptom onset to treatment and acceptable adverse event rates. Areas for continued improvement include the door-to-needle time and broader education of the public about the symptoms of acute ischemic stroke.

Quality of life after early enteral feeding versus standard care for proven or suspected advanced epithelial ovarian cancer: Results from a randomised trial

Background Malnutrition is common in patients with advanced epithelial ovarian cancer (EOC), and is associated with impaired quality of life (QoL), longer hospital stay and higher risk of treatment-related adverse events. This phase III multi-centre randomised clinical trial tested early enteral feeding versus standard care on postoperative QoL. Methods From 2009 to 2013, 109 patients requiring surgery for suspected advanced EOC, moderately to severely malnourished were enrolled at five sites across Queensland and randomised to intervention (n = 53) or control (n = 56) groups. Intervention involved intraoperative nasojejunal tube placement and enteral feeding until adequate oral intake could be maintained. Despite being randomised to intervention, 20 patients did not receive feeds (13 did not receive the feeding tube; 7 had it removed early). Control involved postoperative diet as tolerated. QoL was measured at baseline, 6 weeks postoperatively and 30 days after the third cycle of chemotherapy. The primary outcome measure was the difference in QoL between the intervention and the control group. Secondary endpoints included treatment-related adverse event occurrence, length of stay, postoperative services use, and nutritional status. Results Baseline characteristics were comparable between treatment groups. No significant difference in QoL was found between the groups at any time point. There was a trend towards better nutritional status in patients who received the intervention but the differences did not reach statistical significance except for the intention-to-treat analysis at 7 days postoperatively (11.8 intervention vs. 13.8 control, p 0.04). Conclusion Early enteral feeding did not significantly improve patients' QoL compared to standard of care but may improve nutritional status.

Educators’ perspectives about how older hospital patients can engage in a falls prevention education programme: A qualitative process evaluation

- Objectives Falls are the most frequent adverse event reported in hospitals. Patient and staff education delivered by trained educators significantly reduced falls and injurious falls in an older rehabilitation population. The purpose of the study was to explore the educators’ perspectives of delivering the education and to conceptualise how the programme worked to prevent falls among older patients who received the education. - Design A qualitative exploratory study. - Methods Data were gathered from three sources: conducting a focus group and an interview (n=10 educators), written educator notes and reflective researcher field notes based on interactions with the educators during the primary study. The educators delivered the programme on eight rehabilitation wards for periods of between 10 and 40 weeks. They provided older patients with individualised education to engage in falls prevention and provided staff with education to support patient actions. Data were thematically analysed and presented using a conceptual framework. - Results Falls prevention education led to mutual understanding between staff and patients which assisted patients to engage in falls prevention behaviours. Mutual understanding was derived from the following observations: the educators perceived that they could facilitate an effective three-way interaction between staff actions, patient actions and the ward environment which led to behaviour change on the wards. This included engaging with staff and patients, and assisting them to reconcile differing perspectives about falls prevention behaviours. - Conclusions Individualised falls prevention education effectively provides patients who receive it with the capability and motivation to develop and undertake behavioural strategies that reduce their falls, if supported by staff and the ward environment.

Reducing falls in hospital through education to change patient and staff behaviour: A stepped wedge cluster randomised controlled effectiveness trial

Background: Falls remain the most frequent adverse event reported in hospitals, particularly geriatric rehabilitation wards. Randomised trials reducing fall injuries in hospitals have been elusive. Our previous randomised trial (n = 1206) demonstrated that multimedia education with physiotherapist falls educator support reduced falls among patients with higher cognition levels, but this benefit was offset by a potential increase in falls rates among patients with poor cognition. In the previous trial, hospital staff were blinded to the allocation of individual patients, and only delivered usual care.

Health-Related Quality of Life, Costs and Treatment of Inflammatory Rheumatic Diseases in Routine Practice : With special emphasis on biological drugs

Rheumatoid arthritis (RA) and other chronic inflammatory joint diseases already begin to affect patients health-related quality of life (HRQoL) in the earliest phases of these diseases. In treatment of inflammatory joint diseases, the last two decades have seen new strategies and treatment options introduced. Treatment is started at an earlier phase; combinations of disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroids are used; and in refractory cases new drugs such as tumour necrosis factor (TNF) inhibitors or other biologicals can be started. In patients with new referrals to the Department of Rheumatology of the Helsinki University Central Hospital, we evaluated the 15D and the Stanford Health Assessment Questionnaire (HAQ) results at baseline and approximately 8 months after their first visit. Altogether the analysis included 295 patients with various rheumatic diseases. The mean baseline 15D score (0.822, SD 0.114) was significantly lower than for the age-matched general population (0.903, SD 0.098). Patients with osteoarthritis (OA) and spondyloarthropathies (SPA) reported the poorest HRQoL. In patients with RA and reactive arthritis (ReA) the HRQoL improved in a statistically significant manner during the 8-month follow-up. In addition, a clinically important change appeared in patients with systemic rheumatic diseases. HAQ score improved significantly in patients with RA, arthralgia and fibromyalgia, and ReA. In a study of 97 RA patients treated either with etanercept or adalimumab, we assessed their HRQoL with the RAND 36-Item Health Survey 1.0 (RAND-36) questionnaire. We also analysed changes in clinical parameters and the HAQ. With etanercept and adalimumab, the values of all domains in the RAND-36 questionnaire increased during the first 3 months. The efficacy of each in improving HRQoL was statistically significant, and the drug effects were comparable. Compared to Finnish age- and sex-matched general population values, the HRQoL of the RA patients was significantly lower at baseline and, despite the improvement, remained lower also at follow-up. Our RA patients had long-standing and severe disease that can explain the low HRQoL also at follow-up. In a pharmacoeconomic study of patients treated with infliximab we evaluated medical and work disability costs for patients with chronic inflammatory joint disease during one year before and one year after institution of infliximab treatment. Clinical and economic data for 96 patients with different arthritis diagnoses showed, in all patients, significantly improved clinical and laboratory variables. However, the medical costs increased significantly during the second period by 12 015 (95% confidence interval, 6 496 to 18 076). Only a minimal decrease in work disability costs occurred mean decrease 130 (-1 268 to 1 072). In a study involving a switch from infliximab to etanercept, we investigated the clinical outcome in 49 patients with RA. Reasons for switching were in 42% failure to respond by American College of Rheumatology (ACR) 50% criteria; in 12% adverse event; and in 46% non-medical reasons although the patients had responded to infliximab. The Disease Activity Score with 28 joints examined (DAS28) allowed us to measure patients disease activity and compare outcome between groups based on the reason for switching. In the patients in whom infliximab was switched to etanercept for nonmedical reasons, etanercept continued to suppress disease activity effectively, and 1-year drug survival for etanercept was 77% (95% CI, 62 to 97). In patients in the infliximab failure and adverse event groups, DAS28 values improved significantly during etanercept therapy. However, the 1-year drug survival of etanercept was only 43% (95% CI, 26 to 70) and 50% (95% CI, 33 to 100), respectively. Although the HRQoL of patients with inflammatory joint diseases is significantly lower than that of the general population, use of early and aggressive treatment strategies including TNF-inhibitors can improve patients HRQoL effectively. Further research is needed in finding new treatment strategies for those patients who fail to respond or lose their response to TNF-inhibitors.

Levosimendan in patients with ischaemic heart disease

Levosimendan is a drug developed for the treatment of heart failure. Its mechanism of action includes calcium sensitization of contractile proteins and the opening of ATP-sensitive potassium channels. The combination of positive inotropy with possible anti-ischaemic effects via potassium channel opening may offer benefits in comparison with currently available intravenous inotropes, which are contraindicated in patients with ongoing myocardial ischaemia. The active levosimendan metabolite OR-1896 significantly prolongs the duration of the haemodynamic effects of levosimendan. The aims of the present study were to investigate: 1) the clinical effects and safety of intravenous and oral levosimendan and 2) the pharmacodynamics and pharmacokinetics of intravenous and oral levosimendan and its metabolites in patients with ischaemic heart disease. Levosimendan was administered intravenously or orally in four studies to 557 patients with ischaemic heart disease with or without concomitant heart failure. One study included patients with acute myocardial infarction, while the other three studies included stable ischaemic patients. Non-invasive haemodynamic measurements were used in all studies, and blood samples for pharmacokinetics were drawn in three studies. Safety was followed by ECG recordings, adverse event inquiries and laboratory assessments. Intravenous levosimendan, administered as a 6-hour infusion did not cause clinically significant hypotension or ischaemia in comparison with placebo and reduced worsening heart failure and short- and long-term mortality. Increase in incidence of hypotension and ischaemia was seen only with the highest dose (0.4 µg/kg/min). Both intravenous and oral levosimendan possessed a moderate positive inotropic effect. Vasodilatory effect was more pronounced with intravenous levosimendan. A chronotropic effect was seen in all studies; however, it was not accompanied by any increase in arrhythmic events. The formation of levosimendan metabolites after oral dosing increased linearly with the daily dose of the parent drug, leading to increased inotropic and chronotropic response. Levosimendan was well tolerated in all studies. In conclusion, levosimendan was safe and effective in the treatment of patients with acute or chronic ischaemia. The risk-benefit ratio of intravenous levosimendan is favourable up to the dose of 0.2 µg/kg/min. The daily dose of oral levosimendan in patients with ischaemic heart failure should not exceed 4 mg due to an increase in chronotropic response.