Search

Background: Continued expansion of indications for sodium-glucose cotransporter-2 inhibitors increases importance of evaluating cardiovascular and kidney efficacy and safety of empagliflozin in patients with type 2 diabetes compared to similar therapies., Methods: The EMPRISE Europe and Asia study is a non-interventional cohort study using data from 2014-2019 in seven European (Denmark, Finland, Germany, Norway, Spain, Sweden, United Kingdom) and four Asian (Israel, Japan, South Korea, Taiwan) countries. Patients with type 2 diabetes initiating empagliflozin were 1:1 propensity score matched to patients initiating dipeptidyl peptidase-4 inhibitors. Primary endpoints included hospitalization for heart failure, all-cause mortality, myocardial infarction and stroke. Other cardiovascular, renal, and safety outcomes were examined., Findings: Among 83,946 matched patient pairs, (0·7 years overall mean follow-up time), initiation of empagliflozin was associated with lower risk of hospitalization for heart failure compared to dipeptidyl peptidase-4 inhibitors (Hazard Ratio 0·70; 95% CI 0.60 to 0.83). Risks of all-cause mortality (0·55; 0·48 to 0·63), stroke (0·82; 0·71 to 0·96), and end-stage renal disease (0·43; 0·30 to 0·63) were lower and risk for myocardial infarction, bone fracture, severe hypoglycemia, and lower-limb amputation were similar between initiators of empagliflozin and dipeptidyl peptidase-4 inhibitors. Initiation of empagliflozin was associated with higher risk for diabetic ketoacidosis (1·97; 1·28 to 3·03) compared to dipeptidyl peptidase-4 inhibitors. Results were consistent across continents and regions., Interpretation: Results from this EMPRISE Europe and Asia study complements previous clinical trials and real-world studies by providing further evidence of the beneficial cardiorenal effects and overall safety of empagliflozin compared to dipeptidyl peptidase-4 inhibitors., Competing Interests: Declaration of Competing Interest Avraham Karasik has received research grants and consulting fees from Boehringer Ingelheim; research grants from Astra Zeneca; research grants, consulting fees, and speaker fees from Novo Nordisk. Daisuke Yabe has received consulting/lecture fees from Eli Lilly Japan K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Company Limited, and grants from Arkray Inc., Novo Nordisk Pharma Ltd., Nippon Boehringer Ingelheim, Ono Pharmaceutical Co. Ltd., Taisho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, and Terumo Corporation. Dae Jung Kim has received grants support from Boehringer Ingelheim, AstraZeneca, Sanofi-Aventis Korea, Jeil Pharmaceutical, and Chong Kun Dang, speaker fees from Boehringer-Ingelheim, Novo Nordisk, Boryung, Hanmi, Novartis, Donga ST, Celltrion, AstraZeneca, and Dong Wha Pharmaceuticals. Wayne HH Sheu has been an advisor and/or speaker for AstraZeneca, Bayer HealthCare, Boehringer Ingelheim Pharmaceuticals, Daiichi-Sankyo, Eli Lilly and Company, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Sanofi-Aventis, Takeda Pharmaceutical Company. Kamlesh Khunti has acted as a consultant, speaker or received consultation/lecture grants for investigator-initiated studies for Astra Zeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, and Merck Sharp & Dohme, Boehringer Ingelheim, Bayer. Francesco Zaccardi has received speaker fees from Boehringer Ingelheim and Napp Pharmaceuticals. Thomas Nyström has received unrestricted grants from AstraZeneca and NovoNordisk and has been a national advisor of Abbot, Amgen, Novo Nordisk, Sanofi-Aventis, Eli Lilly, MSD, and Boehringer Ingelheim. Leo Niskanen has received speaker and consulting fees from Boehringer Ingelheim, MSD, AstraZeneca, and Sanofi, research grant to the institution, consulting fees, and speaker fees from Novo Nordisk. Majken Linnemann Jensen, Fabian Hoti, Riho Klement are employees of IQVIA and contracted by Boehringer Ingelheim to conduct the analyses. Soulmaz Fazeli Farsani, Anouk Déruaz-Luyet are employees of Boehringer Ingelheim International GmbH. Moe H Kyaw was employee of Boehringer Ingelheim. Lisette Koeneman is employee of Eli Lilly & Company and owns stock of Eli Lilly & Company. Dorte Vistisen has received research grants from Bayer A/S, Sanofi, Novo Nordisk A/S, and Boehringer Ingelheim. She holds shares in Novo Nordisk A/S. Sigrun Halvorsen has received speaker fees from Sanofi, Novartis, Boehringer Ingelheim, Bayer, Pfizer, and Bristol-Myers Squibb. Gisle Langslet has received consulting/lecture fees from Amgen, Sanofi, and Boehringer Ingelheim. Elisabetta Patorno has received a research grant from Boehringer Ingelheim. Julio Núñez reports personal fees from AstraZeneca, Novartis, Boehringer-Ingelheim, Eli Lilly, Rovi, Novo Nordisk, and Vifor Pharma (outside the submitted work). Stefanie Lanzinger, Reinhard W Holl, Elise Chia-Hui Tan, Cheli Melzer-Cohen, Kyong Hwa, Bendix Carstensen: None., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Platelet transfusion after acute spontaneous primary intracerebral haemorrhage in people taking antiplatelet therapy might reduce death or dependence by reducing the extent of the haemorrhage. We aimed to investigate whether platelet transfusion with standard care, compared with standard care alone, reduced death or dependence after intracerebral haemorrhage associated with antiplatelet therapy use., Methods: We did this multicentre, open-label, masked-endpoint, randomised trial at 60 hospitals in the Netherlands, UK, and France. We enrolled adults within 6 h of supratentorial intracerebral haemorrhage symptom onset if they had used antiplatelet therapy for at least 7 days beforehand and had a Glasgow Coma Scale score of at least 8. With use of a secure web-based system that concealed allocation and used biased coin randomisation, study collaborators randomly assigned participants (1:1; stratified by hospital and type of antiplatelet therapy) to receive either standard care or standard care with platelet transfusion within 90 min of diagnostic brain imaging. Participants and local investigators giving interventions were not masked to treatment allocation, but allocation was concealed from outcome assessors and investigators analysing data. The primary outcome was shift towards death or dependence rated on the modified Rankin Scale (mRS) at 3 months, and analysed by ordinal logistic regression, adjusted for stratification variables and the Intracerebral Haemorrhage Score. The primary analysis was done in the intention-to-treat population and safety analyses were done in the intention-to-treat and as-treated populations. This trial is registered with the Netherlands Trial Register, number NTR1303, and is now closed., Findings: Between Feb 4, 2009, and Oct 8, 2015, 41 sites enrolled 190 participants. 97 participants were randomly assigned to platelet transfusion and 93 to standard care. The odds of death or dependence at 3 months were higher in the platelet transfusion group than in the standard care group (adjusted common odds ratio 2·05, 95% CI 1·18-3·56; p=0·0114). 40 (42%) participants who received platelet transfusion had a serious adverse event during their hospital stay, as did 28 (29%) who received standard care. 23 (24%) participants assigned to platelet transfusion and 16 (17%) assigned to standard care died during hospital stay., Interpretation: Platelet transfusion seems inferior to standard care for people taking antiplatelet therapy before intracerebral haemorrhage. Platelet transfusion cannot be recommended for this indication in clinical practice., Funding: The Netherlands Organisation for Health Research and Development, Sanquin Blood Supply, Chest Heart and Stroke Scotland, French Ministry of Health., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Stroke prevention is central to the management of patients with atrial fibrillation (AF). As effective stroke prophylaxis essentially requires oral anticoagulants, an understanding of the risks and benefits of oral anticoagulant therapy is needed. Although AF increases stroke risk 5-fold, this risk is not homogeneous. Many stroke risk factors also confer an increased risk of bleeding. Various stroke and bleeding risk-stratification schemes have been developed to help inform clinical decision-making. These scores were derived and validated in different study cohorts, ranging from highly selected clinical-trial cohorts to real-world populations. Thus, their performance and classification accuracy vary depending on their derivation cohort(s). In the present review, we provide an overview of currently available stroke and bleeding risk-stratification schemes. We particularly focus on the CHA2 DS2 -VASc and HAS-BLED schemes, as these are recommended by the latest European guidelines on AF management. Other risk-stratification schemes (eg, CHADS2 , R2 CHADS2 , ATRIA, HEMORR2 HAGES, QStroke) and their place in the decision-making are also considered., (© 2014 Wiley Periodicals, Inc.)

Objective: To investigate whether there is any association between exposure to atazanavir (ATV), either when boosted or unboosted by ritonavir, and myocardial infarction (MI) or stroke within the D:A:D: Study., Design: Prospective cohort collaboration., Methods: Poisson regression was used to investigate the association between cumulative exposure to ATV and MI/stroke risk after adjusting for known demographic and clinical confounders, as well as cumulative and recent exposure to specific antiretroviral drugs. Follow-up started on enrolment in the study and ended at the earliest of: a new MI/stroke event, death, 6 months after last clinic visit, or 1 February 2011., Results: The incidence of MI varied from 0.28 [95% confidence interval (CI) 0.26-0.30)]/100 person-years of follow-up (PYFU) in those with no exposure to ATV to 0.20 (0.12-0.32)/100 PYFU in those with more than 3 years exposure. There was no evidence of an association between cumulative exposure to ATV and MI risk, either in univariate [relative rate/year 0.96 (95% CI 0.88-1.04)] or multivariable [0.95 (0.87-1.05)] analyses. The incidence of stroke was 0.17 (0.16-0.19)/100 PYFU in those with no exposure to ATV and 0.17 (0.10-0.27)/100 PYFU in those with more than 3 years exposure. As with the MI endpoint, there was no evidence of an association with ATV exposure in either univariate [1.02 (0.98-1.05)] or multivariable [0.95 (0.87-1.05)] analyses., Conclusion: These results argue against a class-wide association between exposure to HIV protease inhibitors and the risk of cardio/cerebrovascular events.

The cardiology literature has suggested for decades that β-blockade protects patients with ischaemic heart disease. Extending this concept to perioperative patients initially produced promising results, with reductions in perioperative myocardial ischaemia and longer-term cardiovascular complications observed in several small randomized trials. However, subsequent larger trials have either shown no benefit or greater morbidity (especially stroke), despite reductions in cardiovascular events. Retrospective database analyses have confirmed or disputed these findings. Speciality societies, most importantly, the American Heart Association/American College of Cardiology Foundation, have promulgated guidelines for perioperative β-blockade, which have been revised, as the evidence has changed. While the European guidelines continue to emphasize perioperative β-blockade in high-risk patients, the American guidelines have reduced the strength and breadth of recommendations, focusing on haemodynamic titration. Future work will need to focus on identifying populations most likely to benefit or to be harmed, including pharmacogenetic analyses and distinctions between individual β-blockers.

Objective: Although systemic heparinisation is routine during CEA, reversal with protamine is controversial with 3 studies suggesting increased peri-operative stroke rates and 3 no effect. None included independent peer-review., Design: Non-randomised observational study of data derived from a randomised controlled study of anaesthetic technique for CEA., Methods: Data on heparin and protamine use and risk factors potentially influencing CEA outcome were collected prospectively. Stroke, death, MI, wound haematoma and re-operation rates were recorded following independent peer-review., Results: 1513/2107 patients received heparin alone (H) and 594/2107 had heparin reversed with protamine (H+P). Risk factors for outcome were similar in both groups. The frequency of outcome events (H v H+P) were: stroke: 67/1513 (4.4%) v 17/594 (2.9%), p=0.098; non stroke or MI death: 10/1513 (0.7%) v 5/594 (0.8%), p=0.657; MI: 6/1513 (0.4%) v 3/594 (0.5%), p=0.718; haematoma: 157/1513 (10.4%) v 44/594 (7.4%), p=0.037; re-operation: 51/1380 (3.7%) v 18/565 (3.2%), p=0.581., Conclusions: These results show a non-significant increase in stroke rate in patients receiving heparin alone refuting suggestions that protamine is harmful. Conversely post-operative haematoma was more frequent when protamine was withheld but re-operation rates were no different. Thus protamine use appears safe and should remain a matter for individual surgeon preference.

Background: Selective cyclooxygenase-2 (Cox-2) inhibitors, developed to reduce the risk of NSAID-related gastrointestinal (GI) complications, have been associated with an increased risk of cardiovascular events. Our objective was to determine the balance of potential harm and benefit related to Cox-2 inhibitors' exposure., Methods: The study population included patients aged 40+ years who received a prescription for Cox-2 inhibitors and were included in the General Practice Research Database. The incidence of upper GI events, myocardial infarction (MI) and stroke was estimated in this cohort. It was assumed that patients had experienced the upper GI and cardiovascular effects, as observed in clinical trials [relative rate (RR) of 0.49 for upper GI and 1.86 for MI]. Simulation methodology was used to estimate attributable risks, i.e. the difference between exposed and unexposed event probabilities., Results: The study population included 155,439 Cox-2 users. The number of upper GI events prevented by Cox-2 inhibitors was 179, while the number of excess MI cases was 83 per 10,000 patients treated for 4 years. A strong association was found between extent of GI benefit and cardiovascular harm. There was a large difference in the frequency of benefit over harm in only 6% of the patients (difference of 1% or more); 23% of the patients had more harm than benefit, including those with a history of ischaemic heart disease., Conclusions: The benefit of Cox-2 inhibitors in reducing the frequency of upper GI events may be offset by their cardiovascular harm, particularly in patients with risk factors for cardiovascular disease.

Background: The rate of stroke in atrial fibrillation (AF) depends on the presence of comorbid conditions and the use of antithrombotic therapy. Although adjusted-dose warfarin is superior to aspirin for reducing stroke in AF, the absolute risk reduction of warfarin depends on the stroke rate with aspirin. This prospective cohort study tested the predictive accuracy of 5 stroke risk stratification schemes., Methods and Results: The study pooled individual data from 2580 participants with nonvalvular AF who were prescribed aspirin in a multicenter trial (Atrial Fibrillation, Aspirin, Anticoagulation I study [AFASAK-1], AFASAK-2, European Atrial Fibrillation Trial, Primary Prevention of Arterial Thromboembolism in patients with nonrheumatic Atrial Fibrillation in primary care study, and Stroke Prevention and Atrial Fibrillation [SPAF]-III high risk or SPAF-III low risk). There were 207 ischemic strokes during 4887 patient-years of aspirin therapy. All schemes predicted stroke better than chance, but the number of patients categorized as low and high risk varied substantially. AF patients with prior cerebral ischemia were classified as high risk by all 5 schemes and had 10.8 strokes per 100 patient-years. The CHADS(2) scheme (an acronym for Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack) successfully identified primary prevention patients who were at high risk of stroke (5.3 strokes per 100 patient-years). In contrast, patients identified as high risk by other schemes had 3.0 to 4.2 strokes per 100 patient-years. Low-risk patients identified by all schemes had 0.5 to 1.4 strokes per 100 patient-years of therapy., Conclusions: Patients with AF who have high and low rates of stroke when given aspirin can be reliably identified, allowing selection of antithrombotic prophylaxis to be individualized.

(1) The results of a randomised placebo-controlled double-blind trial in 16 000 women (the WHI trial), published in 2002, showed that post-menopausal hormone replacement therapy based on sulphoconjugated equine oestrogen and medroxyprogesterone led to an excess risk of serious adverse events (pulmonary embolism, coronary events, stroke, and invasive breast cancer). (2) Further analysis showed that invasive breast cancer diagnosed in women treated with the hormone combination had a similar histology and grade to cancers diagnosed in the placebo group, but that they were larger and more advanced. (3) The excess risk of stroke was mainly due to ischaemic events. In the group treated with the hormone combination, the only identifiable risk factor was lengthy use of hormone replacement therapy before enrollment in the trial. (4) No subgroup of women at risk of coronary events was found apart from women with elevated LDL-cholesterol at enrollment. (5) In the WHIMS subtrial in women aged 65 years or more, the risk of dementia was twice as high in women receiving hormone therapy as in those receiving placebo. (6) In the British ESPRIT placebo-controlled trial, oral estradiol valerate, at a dose of 2 mg/day, was ineffective as secondary prevention of myocardial infarction. (7) Follow-up of a very large British cohort (the Million Women Study) showed a significantly increased risk of breast cancer with all types of hormone replacement therapy, including oestrogen-progestin combinations (relative risk 2.00; 95% confidence interval 1.88-2.12), oestrogen monotherapy (RR 1.30; 95% CI 1.21-1.40) and tibolone (RR 1.45; 95% CI 1.25-1.68). There was no significant difference between oestradiol and equine oestrogen, between medroxyprogesterone acetate and progestins derived from nortestosterone, between oral, transdermal and implanted oestrogen preparations, or between sequential and continuous regimens. (8) A Swedish cohort study and an American case-control study also showed a higher risk of breast cancer linked to progestin use. (9) In a small French epidemiological case-control study, the risk of thromboembolism was higher among women taking oral rather than transdermal estradiol as part of their hormone replacement therapy. (10) In practice, the risk-benefit ratios of the hormone replacement therapies most commonly used in France are poorly characterised. It is therefore logical to use the drugs with which we have most experience (in clinical trials or during lengthy follow-up). The benefits and drawbacks should be regularly discussed with women using hormone replacement therapy, and they should be closely monitored for signs of breast cancer or cardiovascular disease.