Cost-effectiveness of ticagrelor plus aspirin versus aspirin in acute ischaemic stroke or transient ischaemic attack: an economic evaluation of the THALES trial.

Objective: THALES demonstrated that ticagrelor plus aspirin reduced the risk of stroke or death but increased bleeding versus aspirin during the 30 days following a mild-to-moderate acute non-cardioembolic ischaemic stroke (AIS) or high-risk transient ischaemic attack (TIA). There are no cost-effectiveness analyses supporting this combination in Europe. To address this, a cost-effectiveness analysis was performed. Methods: Cost-effectiveness was evaluated using a decision tree and Markov model with a short-term and long-term (30-year) horizon. Stroke, mortality, bleeding and EuroQol-5 Dimension (EQ-5D) data from THALES were used to estimate short-term outcomes. Model transitions were based on stroke severity (disabling stroke was defined as modified Rankin Scale >2). Healthcare resource utilisation and EQ-5D data beyond 30 days were based on SOCRATES, another trial in AIS/TIA that compared ticagrelor with aspirin. Long-term costs, survival and disutilities were based on published literature. Unit costs were derived from national databases and discounted at 3% annually from a Swedish healthcare perspective. Results: One-month treatment with ticagrelor plus aspirin resulted in 12 fewer strokes, 4 additional major bleeds and cost savings of €95 000 per 1000 patients versus aspirin from a Swedish healthcare perspective. This translated into increased quality-adjusted life-years (0.04) and reduced societal costs (-€1358) per patient over a lifetime horizon. Key drivers of cost-effectiveness were number of patients experiencing subsequent disabling stroke and degree of disability. Findings were robust over a range of input assumptions. Conclusion: One month of treatment with ticagrelor plus aspirin is likely to improve outcomes and reduce costs versus aspirin in mild-to-moderate AIS or high-risk TIA. Trial registration number: NCT03354429.

Methodologies for pragmatic and efficient assessment of benefits and harms: Application to the SOCRATES trial.

BACKGROUND/AIMS: Standard approaches to trial design and analyses can be inefficient and non-pragmatic. Failure to consider a range of outcomes impedes evidence-based interpretation and reduces power. Traditional approaches synthesizing information obtained from separate analysis of each outcome fail to incorporate associations between outcomes and recognize the cumulative nature of outcomes in individual patients, suffer from competing risk complexities during interpretation, and since efficacy and safety analyses are often conducted on different populations, generalizability is unclear. Pragmatic and efficient approaches to trial design and analyses are needed. METHODS: Approaches providing a pragmatic assessment of benefits and harms of interventions, summarizing outcomes experienced by patients, and providing sample size efficiencies are described. Ordinal outcomes recognize finer gradations of patient responses. Desirability of outcome ranking is an ordinal outcome combining benefits and harms within patients. Analysis of desirability of outcome ranking can be based on rank-based methodologies including the desirability of outcome ranking probability, the win ratio, and the proportion in favor of treatment. Partial credit analyses, involving grading the levels of the desirability of outcome ranking outcome similar to an academic test, provides an alternative approach. The methodologies are demonstrated using the acute stroke or transient ischemic attack treated with aspirin or ticagrelor and patient outcomes study (SOCRATES; NCT01994720), a randomized clinical trial. RESULTS: Two 5-level ordinal outcomes were developed for SOCRATES. The first was based on a modified Rankin scale. The odds ratio is 0.86 (95% confidence interval = 0.75, 0.99; p = 0.04) indicating that the odds of worse stroke categorization for a trial participant assigned to ticagrelor is 0.86 times that of a trial participant assigned to aspirin. The 5-level desirability of outcome ranking outcome incorporated and prioritized survival; the number of strokes, myocardial infarction, and major bleeding events; and whether a stroke event was disabling. The desirability of outcome ranking probability and win ratio are 0.504 (95% confidence interval = 0.499, 0.508; p = 0.10) and 1.11 (95% confidence interval = 0.98, 1.26; p = 0.10), respectively, implying that the probability of a more desirable result with ticagrelor is 50.4% and that a more desirable result occurs 1.11 times more frequently on ticagrelor versus aspirin. CONCLUSION: Ordinal outcomes can improve efficiency through required pre-specification, careful construction, and analyses. Greater pragmatism can be obtained by composing outcomes within patients. Desirability of outcome ranking provides a global assessment of the benefits and harms that more closely reflect the experience of patients. The desirability of outcome ranking probability, the proportion in favor of treatment, the win ratio, and partial credit can more optimally inform patient treatment, enhance the understanding of the totality of intervention effects on patients, and potentially provide efficiencies over standard analyses. The methods provide the infrastructure for incorporating patient values and estimating personalized effects.

Japanese Versus Non-Japanese Patients with Transient Ischemic Attack or Minor Stroke: Subanalysis of TIA registry.org.

BACKGROUND: TIAregistry.org is an international cohort of patients with transient ischemic attack (TIA) or minor stroke within 7 days before enrollment in the registry. Main analyses of 1-year follow-up data have been reported.5 We conducted subanalysis on the baseline and 1-year follow-up data of Japanese patients. METHODS: The patients were classified into 2 groups based on Japanese ethnicity, Japanese (345) and non-Japanese (3238), and their baseline data and 1-year event rates were compared. We also determined risk factors and predictors of 1-year stroke. RESULTS: Current smoking, regular alcohol drinking, intracranial arterial stenosis, and small vessel occlusion; and hypertension, dyslipidemia, coronary artery disease, and extracranial arterial stenosis were more and less common among Japanese patients, respectively. Stroke risk was higher and TIA risk was lower at 1-year follow-up among Japanese patients. The baseline risk factors for recurrent stroke were diabetes, alcohol drinking, and large artery atherosclerosis. Independent predictors of 1-year stroke risk were prior congestive heart failure and alcohol consumption. CONCLUSIONS: The two populations of patients featured differences in risk factors, stroke subtypes, and outcome events. Predictors of recurrent stroke among Japanese patients included congestive heart failure and regular alcohol drinking. Strategies to attenuate residual risk of stroke aside from adherence to current guidelines should take our Japanese-patient specific findings into account.

Patient and caregiver productivity loss and indirect costs associated with cardiovascular events in Europe.

AIMS: The aim of this study was to estimate patient and caregiver productivity loss and indirect costs following an acute coronary syndrome (ACS) or a stroke in Europe. METHODS: A cross-sectional study was conducted in seven European countries. A validated questionnaire was used during a cardiologist/neurologist visit 3-12 months post event. We included patients who returned to work ( ≥ 4 weeks prior to recruitment), given specific interest in presenteeism. Patient absenteeism, presenteeism and caregiver loss in the past four weeks were pro-rated to one year and combined with time-off due to initial hospitalisation/sick-leave. Hours lost were valued according to country labour cost (2018 euros). RESULTS: The analysis included 196 ACS (86% myocardial infarction) and 198 stroke (99% ischaemic, 77% modified Rankin Scale 0-1) patients. Mean age in ACS and stroke patients was 53 years, 86% and 78% respectively were men, 28% and 25% had previous cardiovascular event or established cardiovascular disease. Mean (country range) total productivity time loss was 70 (47-91) workdays for ACS and 68 (45-88) workdays for stroke (25% of annual workdays). Particularly, ACS patient lost 59 (37-79) workdays, and caregivers lost 11 (0-16) workdays, with total mean indirect cost per case €13,953 (€6641-23,160). After stroke, 56 (42-70) workdays were lost by patient plus 12 (3-20) days by caregiver, amounting to €13,773 (€10,469-20,215). Patients with previous events or established cardiovascular disease lost 80 (ACS) and 73 (stroke) workdays, costing €16,061 and €14,942 respectively. CONCLUSIONS: Our results suggest that lost productive time and indirect costs following ACS/stroke are substantial, with indirect costs comparable to direct costs.

close: Closure of patent foramen ovale, oral anticoagulants or antiplatelet therapy to prevent stroke recurrence: Study design.

RATIONALE: Currently available data do not provide definitive evidence on the comparative benefits of closure of patent foramen ovale, oral anticoagulants and antiplatelet therapy in patients with patent foramen ovale-associated cryptogenic stroke AIM: To assess whether transcatheter patent foramen ovale closure plus antiplatelet therapy is superior to antiplatelet therapy alone and whether oral anticoagulant therapy is superior to antiplatelet therapy, for secondary stroke prevention in patients aged 16 to 60 years with a large patent foramen ovale or a patent foramen ovale associated with an atrial septal aneurysm, and an otherwise unexplained ischaemic stroke or retinal ischaemia. SAMPLE SIZE: Six hundred and sixty-four patients were included in the study. METHODS AND DESIGN: CLOSE is an academic-driven, multicentre, randomized, open-label, three-group, superiority trial with blinded adjudication of outcome events. The trial has been registered with Clinical Trials Register (Clinicaltrials.gov, NCT00562289). Patient recruitment started in December 2007. Patient follow-up will continue until December 2016. Expected mean follow-up = 5.6 years. STUDY OUTCOMES: The primary efficacy outcome is the occurrence of fatal or nonfatal stroke. Safety outcomes include fatal, life-threatening or major procedure- or device-related complications and fatal, life-threatening or major haemorrhagic complications. DISCUSSION: CLOSE is the first specifically designed trial to assess the superiority of patent foramen ovale closure over antiplatelet therapy alone and the superiority of oral anticoagulants over antiplatelet therapy to prevent stroke recurrence in patients with patent foramen ovale-associated cryptogenic stroke.

Impact of living and socioeconomic characteristics on cardiovascular risk in ischemic stroke patients.

OBJECTIVE: We aimed to stratify the risk of vascular event recurrence in patients with cerebral infarction according to living and socioeconomic characteristics and geographic region. METHOD: The Outcomes in Patients with TIA and Cerebrovascular Disease (OPTIC) study is an international prospective study of patients aged 45 years or older who required secondary prevention of stroke [following either an acute transient ischemic attack, minor ischemic strokes, or recent (less than six-months previous), stable, first-ever, nondisabling ischemic stroke]. A total 3635 patients from 245 centers in 17 countries in four regions (Latin America, Middle East, North Africa, South Africa) were enrolled between 2007 and 2008. The outcome measure was the two-year rate of a composite of major vascular events (vascular death, myocardial infarction and stroke). RESULTS: During the two-year follow-up period, 516 patients experienced at least one major cardiovascular event, resulting in an event rate of 15·6% (95% confidence interval 14·4-16·9%). Event rates varied across geographical region (P < 0·001), ranging from 13·0% in Latin America to 20·7% in North Africa. Unemployment status, living in a rural area, not living in fully serviced accommodation (i.e., house or apartment with its own electricity, toilet and water supply), no health insurance coverage, and low educational level (less than two-years of schooling) were predictors of major vascular events. Major vascular event rates steeply increased with the number of low-quality living/socioeconomic conditions (from 13·4% to 47·9%, adjusted P value for trend <0·001). CONCLUSION: Vascular risk in stroke patients in low- and middle-income countries varies not only with the number of arterial beds involved but also with socioeconomic variables.

Demographics, socio-economic characteristics, and risk factor prevalence in patients with non-cardioembolic ischaemic stroke in low- and middle-income countries: the OPTIC registry.

BACKGROUND: There is a paucity of data on patients with stroke/transient ischaemic attack in low- and middle-income countries. We sought to describe the characteristics and management of patients with an ischaemic stroke and recent transient ischaemic attack or minor ischaemic strokes in low- or middle-income countries. METHODS: The Outcomes in Patients with TIA and Cerebrovascular disease registry is an international, prospective study. Patients ≥ 45 years who required secondary prevention of stroke (either following an acute transient ischaemic attack or minor ischaemic strokes (National Institutes of Health Stroke Scale <4) of <24 h duration, or recent (<6 months), stable, first-ever, non-disabling ischaemic stroke) were enrolled in 17 countries in Latin America, the Middle East, and Africa. The main measures of interest were risk factors, comorbidities, and socio-economic variables. RESULTS: Between January 2007 and December 2008, 3635 patients were enrolled in Latin America (n = 1543), the Middle East (n = 1041), North Africa (n = 834), and South Africa (n = 217). Of these, 63% had a stable, first-ever ischaemic stroke (median delay from symptom onset to inclusion, 25 days interquartile range, 7-77); 37% had an acute transient ischaemic attack or minor ischaemic stroke (median delay, two-days; interquartile range, 0-6). Prevalence of diabetes was 46% in the Middle East, 29% in Latin America, 35% in South Africa, and 38% in North Africa; 72% had abdominal obesity (range, 65-78%; adjusted P < 0.001); prevalence of metabolic syndrome was 78% (range, 72-84%, P < 0.001). Abnormal ankle brachial index (<0.9) was present in 22%, peripheral artery disease in 7.6%, and coronary artery disease in 13%. Overall, 24% of patients had no health insurance and 27% had a low educational level. INTERPRETATION: In this study, patients in low- and middle-income countries had a high burden of modifiable risk factors. High rates of low educational level and lack of health insurance in certain regions are potential obstacles to risk factor control. FUNDING: The Outcomes in Patients with TIA and Cerebrovascular disease registry is supported by Sanofi-Aventis, Paris, France.

Costs of stroke care according to handicap levels and stroke subtypes.

BACKGROUND: If new advances in stroke management are to be put into practice, crucial information about their costs needs to be considered in relation to clinically pertinent variables (e.g. handicap level and stroke subtypes). Details of costs throughout the entire period of stroke care are essential in the political decision-making process, in order to avoid other budget-balancing approaches, which are not always satisfactory. Our aim was to perform an in-depth evaluation of the direct medical cost of stroke care in a large cohort. METHODS: We included 435 consecutive patients with brain infarction in 12 primary-care and referral neurology departments. Information on acute care was prospectively collected. Information on postacute care was collected by research nurses' visits to the patient's or a relative's home 18-40 months after the stroke onset. We thus collected detailed information on handicap levels, stroke subtypes, acute hospitalization costs, rehabilitation, nursing care and ambulatory costs. This enabled us to calculate costs over an 18-month period after the initial acute hospital discharge. RESULTS: By the 12th month after discharge, the costs amounted to 17,799 euros (16,440-19,158) per patient; the initial hospitalization accounted for 42% of this cost, rehabilitation for 29% and ambulatory care for 8%. These costs were mostly concentrated within the first 3- to 6-month period. After 46 months without recurrence, the cost of ambulatory care outweighed the cost of the first 6 months. Handicap levels explained 43% of the variance of costs (p < 0.0001) and, according to the Rankin scale divided into 3 classes (0-2, 3 and 4-5), cumulative costs over time differed considerably. Stroke subtypes were not discriminating variables except for lacunar strokes, which were significantly less costly than the other groups. CONCLUSIONS: By providing a fairly comprehensive figure for the details of direct costs of stroke care over time, our study gives some clues about the economic burden of stroke care which is mostly driven by a high handicap level. This suggests that any early intervention aimed at reducing the handicap level will probably dramatically reduce this burden.

Socioeconomic aspects of postacute care for patients with brain infarction in France.

BACKGROUND: In France, the socioeconomic aspects of stroke have never been addressed. Such analyses are essential for health authorities to justify the establishment of new stroke units when resources are low, provided it can be shown that stroke units are effective in reducing both the morbidity and mortality of stroke. Only 6 dedicated stroke services exist for 60 million inhabitants in France. Our aim was to study acute and postacute pathways and to determine the factors that influence destination after discharge, handicap evolution and costs. METHODS: In a cohort of 494 consecutive patients with brain infarction, we collected information on medical and socioeconomic variables, handicap and its evolution using the modified Rankin scale and Mini-Mental Status score at the 10th day, 6th month and 18th-40th month. These data were recorded during the initial hospital stay, at the follow-up clinic visit and in a home interview done 18-40 months after discharge by research nurses. We used multiple logistic regression for analyses. RESULTS: The most important factor for not returning home was having a Rankin score greater than 3 with an odds ratio of 41.7 (95% confidence interval 19.2-90.0; p = 0.001). Multivariate analysis showed that when the Rankin score was 0, 1 or 2, the main factors for not returning home were socioeconomic variables and serious medical disorders. When the Rankin score was 4 or 5, the main reason for not being sent for rehabilitation was medical status. After adjustment for the Rankin score, patients who returned home or were transferred to rehabilitation were quite similar regarding socioeconomic and medical variables. Other patients transferred to a geriatric ward, nursing home or new housing were more frequently living alone, 60 years of age or older, had less than 2 children, low level of education, dementia or cancer. Overall, the mean cost was 19,513 Euros over an 18-month period and was mainly driven by the level of the Rankin score (e.g. 10,530 vs. 34,809 Euros for Rankin scores of 0-1 and 4-5, respectively). CONCLUSION: These data showed that not only handicap level but also socioeconomic variables are important in determining the destination of stroke patients after discharge. They may help health authorities to make decisions to establish new approaches to treat stroke. This study can also serve as a basis for future cost-effectiveness studies of new drugs being evaluated in therapeutic trials or of new management strategies of stroke patients.