Intravenous thrombolytic treatment after acute stroke and secondary antithrombotic prevention treatment (antiplatelet and anticoagulant treatment) after stroke
Health technology assessment
|Updated
Stroke is the third most common cause of death, a major cause of severe disability and accounts for considerable consumption of healthcare resources. Which medication should be chosen for the treatment of stroke depends on several factors, including efficiency and price?
Key message
Background
Stroke is the third most common cause of death, a major cause of severe disability and accounts for considerable consumption of healthcare resources. Which medication should be chosen for the treatment of stroke depends on several factors, including efficiency and price.
Task requirement
The Norwegian Directorate of Health’s development groups for the preparation of national clinical guideline for stroke have commissioned the Norwegian Knowledge Centre for the Health Services to conduct economic evaluations of some central recommendations in the stroke guideline. We evaluated the clinical efficacy and conducted health economic evaluation of:
1. Intravenous thrombolytic treatment of patients with acute stroke (within 3 hours and between 3 to 5 hours after symptom onset) in addition to standard treatment compared to treatment without thrombolysis
2. Pharmacological secondary prevention of stroke
- Antiplatelet therapy: acetylsalicylic acid (ASA) combined with slow-release dipyridamole compared with ASA monotherapy
- Antiplatelet therapy: ASA combined with slow-release dipyridamole compared with clopidogrel monotherapy
- Anticoagulation therapy with warfarin compared with ASA for prophylaxis of stroke in patients with atrial fibrillation
Main Results
- Thrombolytic treatment within 3 hours after stoke reduces lifetime costs and adds quality-adjusted life years (QALYs) compared with standard treatment without thrombolysis for selected stroke patients.
- Thrombolysis given between 3 and 5 hours after stroke is cost-effective compared to no thrombolytic treatment. However, the choice of thrombolysis in this time interval should also be carefully considered from an ethical perspective, because it leads to shorter life expectancy relative to no thrombolytic treatment.
- The combination of ASA and extended-release dipyridamole increases QALYs and reduces lifetime costs compared with ASA monotherapy in secondary prevention of stroke.
- The use of ASA combined with slow-release dipyridamole for patients of 70 years reduces lifetime costs and adds QALYs compared to clopidogrel for secondary prevention of stroke.
- Anticoagulation therapy with warfarin has lower expected costs and higher expected QALYs compared with ASA therapy for stroke patients with atrial fibrillation.
Summary
Background
Stroke is the third most common cause of death, a major cause of severe disability and accounts for considerable consumption of healthcare resources. Approximately 15,000 persons each year have a stroke in Norway; about 25 % of these strokes are recurrences.
Stroke is defined as a sudden local or global disturbance in brain functions of vascular cause that persists for more than 24 hours or cause death. Stroke can be caused by either ischemia (a lack of blood supply to the brain) or bleeding in the brain (haemorrhagic cerebral stroke).
Intravenous thrombolytic treatment for patients with acute stoke
Thrombolytic therapy, when predefined criteria are met, is one of the most promising treatments for acute cerebral ischemia and should be started quickly after the onset of stroke. Thrombolytic therapy can significantly reduce disability; however it can also cause serious bleeding in the brain. The national clinical guideline for treatment and rehabilitation of stroke has recommended that intravenous thrombolytic treatment should be offered at every hospital that accepts patients with acute stroke.
Pharmacological secondary prevention of stroke
The risk of suffering a recurrent stroke is between 5 and 15 % during the first year after the initial stroke if preventive treatment is not used. For patients surviving an acute stroke, there is a 2-3 times increased risk of other vascular events. Therefore, effective secondary prevention may reduce the incidence of recurrent strokes and other cardiovascular events.
The Norwegian national guideline for stroke has recommended that due to a large potential gain from secondary prophylaxis, all patients with cerebral stroke should be offered a secondary preventive treatment. Expected benefit, life expectancy and comorbidity are important factors in choosing between different secondary prevention strategies.
The objective of this report is to evaluate the clinical efficacy and conduct health economic analyses of the pharmacological strategies of acute treatment or secondary prevention of stroke for the following comparisons which are recommended in the national guideline for stroke:
1. Intravenous thrombolytic treatment of patients with acute stroke (within 3 hours and between 3 to 5 hours after symptom onset) in addition to standard treatment compared to treatment without thrombolysis
2. Pharmacological secondary prevention of stroke
- Antiplatelet therapy: acetylsalicylic acid (ASA) combined with slow-release dipyridamole compared with ASA monotherapy
- Antiplatelet therapy: ASA combined with slow-release dipyridamole compared with clopidogrel monotherapy
- Anticoagulation therapy with warfarin compared with ASA for prophy-laxis of stroke in patients with atrial fibrillation
We emphasize that this is only an excerpt of the issues in the stroke guidelines, and these comparisons therefore do not represent a complete picture of all the interventions and comparisons that are relevant in stroke treatment. The objectives in this report were chosen by the commissioner in the Directorate of Health and are intended to represent the most central points in the guidelines.
Methods
This report was conducted as a health technology assessment. For each objective, we checked the documentation basis in the national guideline. Subsequently, we searched for the latest systematic reviews and randomized controlled trials in relevant bibliographic databases. Two persons have gone through all the titles and abstracts and selected the articles independently. We have ordered relevant systematic reviews and primary articles in full text, and assessed the quality using checklists and graded the overall quality of evidence.
Health economic evaluations were done using NorCaD (developed by Norwegian Knowledge Centre for the Health Services and University of Oslo), a Markov-model based on Norwegian incidence data and treatment costs. The model calculated quality-adjusted life years (QALYs) and life years gained with different strategies and life time costs related to stroke. The model was run on 70-year-old men with average risk for further cardiovascular diseases. We also analysed males at 50 years of age and females at both 50 and 70 years of age. The patients were followed until death or 100 years of age.
In addition, we performed sensitivity analyses to get an impression on uncertainty surrounding our analyses.
Results
The overall documentation of efficacy was based on four systematic reviews (with 14 different RCT’s) of high and moderate quality and a randomized controlled trial with low risk of bias. The results showed that:
Thrombolytic treatment given within 3 hours after acute ischemic stroke appeared more effective in reducing disability compared with standard treatment without thrombolysis; RR 0.75, 95 % CI (confidence interval) 0.64-0.89 (the quality of evidence was moderate). There is not sufficient evidence to conclude regarding whether there is any difference in mortality between these strategies; RR 1.03, 95 % CI 0.70-1.53 (the quality of evidence was low). Thrombolytic therapy increased the risk of symptomatic intracranial haemorrhage; RR 3.63, 95 % CI 1.55-8.52 (the quality of evidence was low).
We found no evidence that thrombolysis given between 3-5 hours after stroke onset reduced mortality compare with standard treatment without thrombolysis; RR 1.20, 95 % CI 0.77-1.87 (the quality of evidence was moderate). There is no clear difference in reducing disability between these strategies; RR 0.90, 95 % CI 0.77-1.05 (the quality of evidence was high). Thrombolytic therapy (in the range between 3-5 hours) increased the risk of symptomatic intracranial haemorrhage; RR 5.25, 95 % CI 2.12-12.97 (the quality of evidence was moderate).
The combination of ASA and slow-release dipyridamole reduced the risk of recurrent stroke compared with ASA alone in the secondary prevention of stroke; RR 1.20, 95 % CI 0.77-1.87 (the quality of evidence was moderate). When we compared the effects of ASA plus slow-release dipyridamole with ASA alone, there was little or no difference on death from vascular causes (RR 0.94, 95 % CI 0.79-1.13) and heart attacks; RR 0.94, 95 % CI 0.69-1.27 (the quality of evidence was high or moderate). For bleeding events, the quality of evidence was too low to determine that there is difference between these two strategies; RR 1.07, 95%CI 0.65-1.79 (the quality of evidence was low).
There was little or no difference in the rate of recurrent stroke (RR 1.01, 95 % CI 0.92-1.11), heart attacks (RR 0.90, 95 % CI 0.73-1.10), death from vascular causes (RR 0.94, 95 % CI 0.82-1.07) and hemorrhagic event (RR 1.08, 95% CI 0.96-1.22) between the recipients of ASA plus slow-release dipyridamole and the recipients of clopidogrel. The quality of evidence for these outcomes was moderate and none of the analyses were statistically significant.
Warfarin reduced the risk of recurrent stroke in patients with atrial fibrillation and recent ischaemic stroke compared with ASA (RR 0.37, 95 % CI 0.18-0.75). On the other hand, patients treated with warfarin suffered bleeding events more often than patients treated with ASA (RR 2.80, 95 % CI 1.70-4.80). The quality of evidence for the results of these comparisons was moderate.
Results from our health economic model showed that thrombolytic treatment within 3 hours after stoke was the dominant strategy (provided 0.05 additional QALYs and reduced lifetime costs by NOK 195,000 per patient) compared with standard treatment.
Thrombolysis given between 3 and 5 hours resulted in a loss in QALYs of 0.24 compared to no thrombolytic treatment. Thrombolysis also reduced costs, resulting in a cost-effectiveness ratio of NOK 665,000 per QALY gained.
The combination of ASA and slow-release dipyridamole was the dominant strategy (providing a gain of 0.13 QALYs and reduced lifetime cost NOK 46,000) compared with ASA monotherapy in secondary prevention of stroke.
The use of ASA combined with slow-release dipyridamole for patients of 70 years resulted in a QALY gain of 0.09 and reduced lifetime costs (NOK -33,000) compared to clopidogrel in secondary prevention of stroke.
Anticoagulation therapy with warfarin improved effectiveness by 0.03 QALYs and reduced cost by NOK 79,000 (dominant strategy) compared with ASA therapy for stroke patients with atrial fibrillation.
Probabilistic sensitivity analysis showed the cost per QALY gained was dependent on the health effect estimate and drug costs. The results also showed little sensitivity with gender variation but some of the conclusions may change with age variation.
We also calculated the cost per life year gained, and found that the main results changed only in a small degree.
Discussion
The quality of the evidence varied from high to low. In cases where quality is assessed as low or very low it means that we are uncertain what the effects of intervention really is. This entails that there is possibility that future research will affect our confidence in the estimate of effect and that future estimates may be different.
The limitations of our analysis comprise the fact that the transition probabilities in the model are based on sources from different countries and of different information sources. There is variation in which and how many outcomes we have found estimates of effect for. Average follow-up of the included trials of thrombolytic therapy was only 3 months, which increases the uncertainty in the assessment of data for long-term survival.
Conclusion
Intravenous thrombolysis given within 3 hours resulted in better quality of life of the patients and lower cost (dominant strategy) compared with no thrombolytic treatment. Thrombolytic therapy given between 3 and 5 hours is more likely to have negative than positive total effects on health. Treatment in this time interval was less expensive than traditional therapy in a life time perspective, however the choice of such treatment should also be considered based on other criteria, such as expected benefit of treatment and an ethical perspective.
Antiplatelet therapy with a combination of ASA and slow-release dipyridamole was a dominant strategy (more effective and lower cost) compared with only ASA and clopidogrel in secondary prophylaxis after stroke. Anticoagulation therapy with warfarin was a dominant strategy (more effective and lower cost) relative to ASA for stroke patients with atrial fibrillation.