Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). Interpretation: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice

Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Background High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053. Findings Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants’ systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital admission. We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2–5; n=420) in the GTN group versus 3 (2–5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97–1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2–5]; n=544, in the GTN group vs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups. Interpretation Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultraacute prehospital setting. Funding British Heart Foundation

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy.Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388.Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16,

Increasing SARS-Cov2 Cases, Hospitalizations, and Deaths among the Vaccinated Populations during the Omicron (B.1.1.529) Variant Surge in UK

Background: There were increased SARS-CoV2 hospitalizations and deaths noted during Omicron (B.1.1.529) variant surge in the UK despite decreased cases, and the reasons are unclear. Methods: In this retrospective observational study, we analyzed reported SARS-CoV2 cases, hospitalizations, deaths, and variables that affect the outcomes (including ethnicity, deprivation score, vaccination disparities, and pre-existing conditions during the COVID-19 pandemic in the UK. The vaccine effectiveness among those ≥ 18 years of age was also analyzed (August 16, 2021-March 27, 2022).Results: During the latter part of the Omicron variant surge (February 28-May 1, 2022 a significantly increased proportion of cases (23.7% vs 40.31.70 [1.70-1.71]; p\u3c0.001) and hospitalizations (39.3% vs 50.3%; RR 1.28 [1.27- 1.30]; p\u3c0.001) among ≥ 50 years of age, and deaths (67.89% vs 80.07%; RR 1.18 [1.16-1.20]; p\u3c0.001) among ≥ 75 years of age was observed compared to the earlier period (December 6, 2021-February 27, 2022). There was a significant decline in case fatality rate (all ages [0.21% vs 0.39%; RR 0.54 (0.52-0.55); p\u3c0.001], ≥ 18 years of age [0.25% vs 0.58%; RR 0.44 (0.43-0.45); p\u3c0.001], and ≥ 50 years of age [0.72% vs 1.57%; RR 0.46 (0.45-0.47); p\u3c0.001]) and the risk of hospitalizations (all ages [0.62% vs 0.99%; RR 0.63 (0.62-0.64); p\u3c0.001], ≥ 18 years of age [0.67% vs 1.38%; RR 0.484 (0.476-0.492); p\u3c0.001], and ≥ 50 years of age [1.45% vs 2.81%; RR 0.52 (0.51-0.53); p\u3c0.001] during the Omicron variant surge (December 27, 2021-March 20, 2022) compared to the Delta variant surge (August 16-December 5, 2021). Both the unvaccinated (0.41% vs 0.77%; RR 0.54 (0.51-0.57); p\u3c0.001) and vaccinated (0.25% vs 0.59%; RR 0.43 (0.42-0.44); p\u3c0.001) populations of ≥ 18 years of age showed a significant decline in the case fatality rate during the Omicron variant surge versus the Delta variant surge. In summary, a significant decline in the risk of hospitalizations was observed among both the unvaccinated (1.27% vs 2.92%; RR 0.44 (0.42-0.45); p\u3c0.001) and vaccinated (0.65% vs 1.19%; RR 0.54 (0.53-0.55); p\u3c0.001) populations of ≥ 18 years of age during the same period. We observed negative vaccine effectiveness for the third dose since December 20, 2021, with a significantly increased proportion of SARS-CoV2 cases hospitalizations, and deaths among the vaccinated; and a decreased proportion of cases, hospitalizations, and deaths among the unvaccinated. The preexisting conditions were present in 95.6% of all COVID-19 deaths. We also observed various ethnicity, deprivation score, and vaccination rate disparities that can adversely affect hospitalizations and deaths among the compared groups based on the vaccination status. Conclusion: There is no discernable optimal vaccine effectiveness among ≥ 18 years of age and vaccinated third dose population since the beginning (December 20, 2021) of the Omicron variant surge. Other data including preexisting conditions, ethnicity, deprivation score, and vaccination rate disparities need to be adjusted by developing validated models for evaluating vaccine effectiveness against hospitalizations and deaths. Both the vaccinated and unvaccinated populations showed favorable outcomes during the Omicron variant surge. The increased proportion of cases among the vaccinated population with suboptimal vaccine effectiveness was associated with a significantly increased proportion of hospitalizations and deaths during the Omicron variant surge. This underscores the need to prevent infections, especially in the elderly vaccinated population irrespective of vaccination status by employing uniform screening protocols and protective measures