Towards effective and efficient care pathways: thrombolysis in acute ischaemic stroke

Over the past decade, specialist services for stroke patients have been introduced, and evidence suggests that they are both effective and efficient. 1–5 In many European countries, these services consist of stroke units in hospitals, rehabilitation facilities and community care organizations. In such networks, health professionals and organizations must coordinate their work to ensure that patients receive appropriate timely care, in appropriate settings. However, the pathway from stroke onset to hospital treatment is often far from seamless. Many stroke patients are admitted too late for appropriate treatment, or not at all. With the increasing effectiveness of acute stroke unit care and of thrombolysis, it is vital that this situation changes. If patients with an acute ischaemic stroke receive thrombolytic therapy within 3 h, they have an increased chance of recovery with a good outcome. 6 We therefore need to identify and use tools and strategies for creating an effective and efficient continuum of care for acute stroke patients. 7,8 In this paper, we summarize the evidence in favour of a beneficial effect of intravenous thrombolysis, explore the barriers for the delivery of this treatment, suggest ways to overcome these barriers, and discuss an approach to measuring improvements in the organization of stroke care. The NINDS-rtPA trial is the only phase III trial of thrombolysis for acute ischaemic stroke that showed an unequivocal positive result. 9 In this study, patients were treated with intravenous alteplase within 3 h from onset of symptoms. Other trials showed no comparable results, partly because of difficulties with the design and choice of outcome parameters, and perhaps also because of a longer (6 h) time window, and higher doses of thrombolytic agent. 10 Wardlaw and colleagues 10 included all published randomized controlled trials of thrombolysis in a Cochrane review. They concluded that thrombolytic therapy, administered up to 6 h after ischaemic stroke, significantly reduced the proportion of patients who were dead or dependent at the end of follow-up at 3–6 months. However, they noted a substantial heterogeneity of effect. In the subgroup of patients who were treated within 3 h of stroke onset, thrombolytic therapy appeared to be more effective in reducing dependency, with no statistically significant adverse effect on death, and no appreciable heterogeneity in effect. International consensus now exists among stroke researchers and clinicians that thrombolytic treatment with rtPA, administered within 3 h after onset of the symptoms of a stroke, is safe and effective. 11 It can save 1 in 10 stroke patients from death or dependency. 10 Although the overall positive effects of thrombolysis are evident, the effect in the individual patient remains difficult to predict: about 6% of patients suffer symptomatic and often fatal haemorrhage as a consequence of treatment. 6 How prognostic variables such as stroke severity, ischaemic stroke subtype and risk factors for haemorrhagic complications should affect treatment decisions concerning thrombolysis is not entirely clear. In spite of the evidence and the existing consensus on the effectiveness of intravenous thrombolysis for acute ischaemic stroke, only a limited proportion of stroke patients receive thrombolytic treatment in most hospitals. In a survey in Cleveland, Ohio, only 2% of all patients admitted with acute stroke were eventually treated with thrombolysis. 12 A study in 11 hospitals in the Netherlands showed similar results. 13,14 Admission delay may be an important factor, but does not fully explain why the proportion treated with thrombolysis is so low. It has been suggested that >25% of all admitted stroke patients could be candidates for thrombolytic treatment. Nevertheless, in most hospitals, only 1–8% of all stroke patients are thrombolysed. 13,14 These figures suggest that both outside and inside the hospital, there are barriers to quick referral and management of these patients. In a recent survey among neurologists in 12 hospitals, we identified 15 potential problems ( Table 1 ), 14 confirming earlier findings. 13 Top three obstacles ranked by vascular neurologists in 12 centres in the Netherlands, in a baseline survey, 2004 Top three obstacles ranked by vascular neurologists in 12 centres in the Netherlands, in a baseline survey, 2004 Factors that are associated with delayed admittance and delay in in-hospital management are associated with non-delivery of thrombolysis. Several factors play a part, both outside and inside the hospital. These factors will be described chronologically: from onset to needle. First of all, the general public is not always aware of the symptoms of a stroke, and may call too late for professional help. If they do call a general practitioner, neurologists may be consulted too late, or not at all by different GPs. Many GPs still visit their stroke patients to check whether there is an indication for hospital admission. This takes up precious time. Some even wait to see if the symptoms clear up to determine if it was ‘just’ a minor stroke (or TIA). Next, transport may be slow, because personnel in the emergency incident room or paramedics are not able to identify an acute stroke, or are not aware that these patients need to be transported to a hospital with a stroke unit as quickly as possible. They may not know which hospitals in the region have a stroke unit and perform thrombolysis, or a system for efficient allocation of emergency stroke beds may be lacking. In the hospital, ER procedures can be slow and diagnostics may take too much time (lab tests, CT, ECG) when stroke patients have no priority over other patients. Beds may not unavailable, or a CT scan may not be available outside office hours. When patients do arrive in time, and all procedures in the hospital are performed swiftly, some neurologists may be conservative in judging patient's eligibility for thrombolysis. Medical decision-making under conditions of uncertainty with a strict time constraint can be demanding. Anticipation of regret and disappointment are common psychological barriers to rational decision-making. In such cases, doctors may prefer a conservative treatment. 15 On the other hand, contra-indications to thrombolysis may themselves be too strict, and may be used as an excuse not to give thrombolytic treatment to a patient, because it is not convenient at that moment. Finally, when patients are judged to be eligible for treatment, trained staff are not always available for intensive neurological monitoring on the stroke unit, or there may be no financial coverage for this expensive treatment. Because of the involvement of many health professionals and the priority use of many resources, thrombolytic treatment is difficult to organize in an appropriate way. Neurologists or stroke specialists have to start doing things they have never done before on such a large scale. They have to convince professionals and managers of the effectiveness of thrombolysis, and the need to change procedures and resource allocation. Regional collaboration between hospitals may also be required. In-hospital logistics have to be adapted, and this involves many departments and individuals. Improving thrombolytic therapy is therefore not just a medical issue, but also an organizational issue. We know that thrombolytic treatment is safe, effective and efficient for some patients: now we have to determine the best way to organize a thrombolysis service on a regional, institutional and inter-professional level. To improve the number of treated patients, the EUSI executive committee argues that several measures should be taken. 11,16 First of all, a broad campaign aimed both at the general public and at health professionals should be launched ( Table 2 ). The committee stated: ‘Teaching the public about symptoms and signs of stroke is one of the highest priorities of public medical education’. 16 Health professionals need to learn that they are ‘important and competent partners in the team providing acute stroke care’. 16 Second, protocols and other agreements have to be put into place to make sure stroke patients get priority treatment, and all relevant steps are taken. Thirdly, the infrastructure must be available, namely staff, financing and medical resources ( Table 2 ). The Cochrane review on obstacles in implementation 17 showed that contra-indications may be limited, and need to be defined better. Organizational factors in producing a continuum of care for thrombolysis in acute ischaemic stroke Organizational factors in producing a continuum of care for thrombolysis in acute ischaemic stroke In the medical debate, not much is said about how to implement these changes in an effective and efficient way. We know from a substantial body of literature 8,18 that organizational factors are important contributors to successful improvement of the quality of medical care and the functioning of stroke units, 1,4 and hence in the improvement of the impact of thrombolysis. Such factors should therefore now be an important part of the stroke research agenda. In an ongoing Dutch study, we are trying to incorporate all these factors. We randomly allocated 12 Dutch hospitals to an experimental or a control group. The purpose is: (i) to enhance the implementation of thrombolysis in Dutch general hospitals; (ii) to identify success factors and obstacles in the implementation of thrombolysis; (iii) to evaluate the effect of a high-intensity implementation strategy in the experimental group vs. normal implementation in the other group; (iv) to assess the cost-effectiveness of thrombolysis in routine daily Dutch neurological care settings, taking into account the costs of implementation. For this study, a toolbox of improvement actions has been developed, to be used by vascular neurologists from the experimental regions, who will function as change agents. An implementation strategy has been selected to assist these change agents. The toolbox consists of materials for educating GPs and ambulance personnel, materials on which to base local protocols, and materials for educating health professionals to deal swiftly with contra-indicators and indicators for thrombolysis. Because contra-indications may themselves be too strict, they will be adjusted by a 30-member Delphi panel of international experts. The indications and contra-indications for thrombolysis in the Dutch guideline for acute stroke care are similar to the exclusion and inclusion criteria for the NINDS-rTPA study. 9 These exclusion criteria have not been tested prospectively, and are probably too restrictive. Advise for revision of local protocols will be made available early to the six experimental regions and later, along regular channels, to the six control regions. The experimental regions will be asked to discuss the new protocol and reconsider their local protocol. Evidence about implementation strategies shows that when changing the behaviour of professionals, educational material alone will not suffice. Combined and multifaceted interventions seem to be more effective in improving physician behaviour and the quality of medical care. 18 Implementation must include discussions of evidence, local consensus, feedback on performance (by peers), reminders and making personal and group learning plans. 8 These aspects are part of an implementation strategy we chose for our study, which is based on the Breakthrough Series (BTS) developed by the Boston Institute for Healthcare Improvement. 19 The Breakthrough model is a multifaceted implementation strategy, with emphasis on mutual learning among peer groups, educational meetings, measurement and feedback of results. Other elements, such as the use of opinion leaders, reminders and educational outreach visits, are also incorporated to increase effects. The focus of the strategy is implementation (spread and adaptation) of evidence-based medicine and good practices in health care organizations. At the start of the implementation phase, each centre will be asked to form a team consisting of a leading vascular neurologist and a nurse from the neurology department. Their first task is to define the top three bottlenecks in implementing thrombolysis in their region. For each bottleneck, they are asked to set up an improvement plan for change. 20 Also, a specific aim must be chosen, formulated in terms of an ambitious and achievable percentage of thrombolysis. During the project period of 2 years, three meetings are organized in which all six hospitals participate. Between these meetings, participating neurologists and nurses implement changes according to their step-by-step plan. An expert panel will give feedback on these plans. Then the centres implement the changes, while monitoring the results, measured as the percentage of thrombolysis. During joint meetings, neurologists and staff nurses discuss and exchange information about the progress of the implementation process, and try to find solutions for obstacles. Implementation specialists and experts form best practices will support these meetings. During the entire project, the participants are in contact with each other and with the members of the expert panel. These contacts are supported by an interactive website with access to the toolbox. The paradigm of intervention research is a randomized controlled clinical trial with a single well-described intervention. But because the implementation to expand thrombolysis is aimed at organizational changes, many variables play a part. Allocation of the intervention is at the institutional level, and randomization only guarantees an even distribution of potentially confounding factors between experimental and control regions if a large sample of institutions are involved. This makes the study expensive and difficult to run. A second problem is that the intervention itself often remains a black box. Organizational interventions are difficult to standardize because they are part of a complex social setting. For example, many clinical trials have demonstrated the effectiveness of stroke units or stroke services compared to usual stroke care. But it remains difficult to determine which part of a stroke service actually helps to improve performance, because no two stroke services are the same. Replication of these interventions is also difficult, because different countries have different systems and therefore different organizational characteristics. To overcome these problems and to determine how to improve thrombolytic treatment, we use a cluster-randomized controlled trial design with other qualitative and quantitative research methods. 21 The traditional cluster-design is used to select the participants in the trial. Randomization takes place at the hospital level, with pair-wise stratification for prior thrombolysis rate. The primary outcome is the delivery of thrombolysis (or not), at patient level. At hospital level, it is the proportion of patients who received thrombolytic treatment, as a fraction of all admitted stroke patients. Next, we identified the organizational characteristics that are expected to have a direct effect on the primary outcome: delivery of thrombolysis or not. These characteristics are quantified and measured before and after the implementation phase of the trial, and tested in the final multiple logistic regression model, which includes patient characteristics and independent predictors of the delivery of thrombolysis, and an indicator variable to cover regional characteristics: the ‘situation score’. For this purpose, all regions receive a ‘baseline score’ at the beginning and at the end of the project. To assess the relative contribution of some of the implementation actions, (changes in) (subsets of) the situation score can be related to the outcomes, i.e. thrombolysis rate. Table 2 shows the organizational characteristics we used to determine the ‘situation score’ in our trial. Variables were categorized first by distinguishing between intramural (within the hospital) and extramural (outside the hospital) variables. These were then subdivided into three categories. The first category contains all agreements or protocols about procedures involving stroke patients. The second category includes all forms of information or training, so relevant actors (public, caregivers, paramedical workers and others) know how what to do. Both the first and the second category involve all actors who play a role in the pathway from ‘onset to needle’. The third category is the infrastructure, which contains the service characteristics of the region. Extramural infrastructure includes the average time it takes an ambulance in the region to reach a hospital, and the number of ambulance services and hospitals in the region (complexity of the region). Intramural infrastructure includes the number of neurologists that work in the hospital (complexity of the hospital) and how many hours a week all provisions are available in the hospital to perform thrombolysis (trained personal, material, finance). Because not all relevant organizational characteristics and aspects of the intervention can be quantified, qualitative research methods must be used to interpret the results of the quantitative analyses. We ask our participants to keep a diary of the interventions that they make. We also take part in their meetings. Based on the data from the diary and the meetings, topics will be identified that are used to interview participants both in the experimental and control regions. The results will be used to make profiles of the characteristics of, and the developments in our regions during the implementation phase. Based on these profiles, differences and similarities between our regions can be identified that can be used to interpret the results of the quantitative analyses. 22 It has been known for several years that thrombolytic treatment can be effective and efficient (at least within 3 hours from onset of stroke), and that it needs a functioning integrated pathway to increase its application. In our country, we are identifying effective and efficient tools to enhance implementation. We would now like to invite researchers and health professionals from other countries to shift research focus from clinical trials to implementation trials, to evaluate available tools and implementation strategies for supporting the further development of a modern, effective and efficient continuum of care in acute stroke.