Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events

doi:10.1016/0140-6736(91)92233-R

The Lancet

Volume 338, Issue 8779, 30 November 1991, Pages 1345-1349

https://doi.org/10.1016/0140-6736(91)92233-R Get rights and content

Abstract

The efficacy of aspirin in daily doses of 300 mg and more as secondary prophylaxis after cerebrovascular events is well established. Since much lower doses of aspirin can inhibit platelet function, and carry a lower risk of adverse effects, the Swedish Aspirin Low-dose Trial (SALT) was set up to study the efficacy of 75 mg aspirin daily in prevention of stroke and death after transient ischaemic attack (TIA) or minor stroke. 1360 patients entered the study 1-4 months after the qualifying event: 676 were randomly assigned to aspirin treatment and 684 to placebo treatment. The median duration of follow-up was 32 months. Compared with the placebo group, the aspirin group showed a reduction of 18% in the risk of primary outcome events (stroke or death; relative risk 0·82, 95% confidence interval 0·67-0·99; log-rank analysis p=0·02), and reductions of 16-20% in the risks of secondary outcome events (stroke; stroke or two or more TIAs within a week of each other necessitating a change of treatment; or myocardial infarction). Adverse drug effects were reported by 147 aspirin-treated and 123 placebo-treated patients Gastrointestinal side-effects were only slightly more common in the aspirin-treated patients, but that group had a significant excess of bleeding episodes (p=0·04). Thus, we have found that a low dose (75 mg/day) of aspirin significantly reduces the risk of stroke or death in patients with cerebrovascular ischaemic events.

References (22)

Jr O'Brien
Effects of salicylates on human platelets
Lancet
(1968)
J. Svensson et al.
Inhibition of platelet function by low dose acetylsalicylic acid in patients with cerebrovascular disease
Thromb Res
(1983)
P. Alessandrini et al.
Physiologic variables affecting thromboxane B2 production in human whole blood
Thromb Res
(1985)
The RISC Group
Risk of myocardial infarction and death during treatment with low-dose aspirin and intravenous heparin in men with unstable coronary artery disease
Lancet
(1990)
Aspirin all round?
Br Med J
(1988)
Secondary prevention of vascular disease by prolonged anti-platelet therapy
Br Med J
(1988)
S. Moncada et al.
Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls
N Engl J Med
(1979)
P. Patrignani et al.
Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects
J Clin Invest
(1982)
Ga FitzGerald et al.
Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man
J Clin Invest
(1983)
Bb Weksler et al.
Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients
N Engl J Med
(1983)

There are more references available in the full text version of this article.

Cited by (698)

Effects of acetylsalicylic acid alone or with omega-3 in patients with chronic coronary artery disease
2023, REC: CardioClinics
Antiplatelet agents such as acetylsalicylic acid (ASA) play a prominent role in preventing atherothrombosis. However, low-responsive patients who will not benefit from an increased dosage of this drug, which can cause bleeding and gastrointestinal irritation, need to be identified. Drugs such as omega-3 fatty acids, which enhance the vasodilating condition and diminish platelet aggregation, can potentiate the anti-aggregating effects of ASA, avoiding its side effects. Thus, we assessed the alternative use of 200 mg/day of ASA and 100 mg/day of this drug combined with 1 g of omega-3 in 152 patients with chronic coronary artery disease.
Our analysis included platelet function (ASPItest), TBX2 concentrations (ELISA), and SNPs polymorphisms in the rs3842787 and rs3842798 regions of the PTGS1 gene of the COX-1 enzyme and the rs5918 region of the ITGB3 gene of the fibrinogen's receptor subunit glycoprotein IIIa.
ASPItest detected 38 non-responders. The reduction of ASPItest values was more significant in this group than in responders and fell to levels of responders in non-responders of the 200 mg/day treatment. A rare allele of rs3842787 is associated with a worse ASPItest response, and the rare allele of the rs5918 polymorphism with a worse response related to TBX2 concentration. Both treatments showed no statistically significant difference in hematuria or bleeding, constituting safe treatment alternatives, and omega-3 treatment reduced monocyte levels.
Our results underscore the usefulness of pharmacogenetics for personalized treatments, avoiding gastrointestinal effects and undesirable bleeding.
El ácido acetilsalicílico (AAS) es ampliamente utilizado para prevenir la trombosis arterial. Sin embargo, deben identificarse pacientes refractarios para los cuales dosis altas de AAS son ineficaces y pueden causar irritación gastrointestinal y hemorragia. El fármaco omega-3 puede aumentar los efectos anticoagulantes del AAS y evitar sus efectos colaterales. Por ese motivo evaluamos el uso de 200 mg/día de AAS o 100 mg/día de AAS combinado con 1 g de omega-3 en 152 pacientes con enfermedad coronaria crónica.
Se analizaron la función plaquetaria (ASPItest), las concentraciones de TBX2 (ELISA) y polimorfismos de SNP en las regiones rs3842787 y rs3842798 del gen PTGS1 de la enzima COX1y la región rs5918 del gen ITGB3 de la subunidad glicoproteína IIIa del receptor de fibrinógeno.
El ASPItest detectó 38 pacientes refractarios. La reducción de la función plaquetaria fue más significativa en este grupo que en los respondedores, cayendo a niveles de respondedores en los refractarios al tratamiento con 200 mg/día. Un alelo raro de rs3842787 está asociado a una peor respuesta al ASPItest, y un alelo raro del polimorfismo rs5918, a una peor respuesta en el análisis de la concentración de TBX2. Los tratamientos analizados no mostraron evidencia estadísticamente significativa de hematuria o de sangrado, y el tratamiento con omega-3 mostró reducción en los niveles de monocitos.
La farmacogenética es una herramienta indispensable para una medicina personalizada con tratamientos que eviten efectos gastrointestinales y hemorragias, como los descritos en este estudio.
A mechanistic model to study the kinetics and toxicity of salicylic acid in the kidney of four virtual individuals
2021, Computational Toxicology
In comparison to liver toxicology, little is known about mechanisms of adverse effects in the kidney and only limited computational models exist to investigate nephrotoxicity. However, the kidney is a major target for toxicity by pharmaceuticals and environmental pollutants. Accumulation is known to play an important role in certain nephrotoxicity pathways. Therefore, physiologically-based kinetic (PBK) and mechanistic models are considered to offer valuable insights into mechanisms of nephrotoxicity. This study addresses the growing attention given to exposure-based and toxicokinetics-driven toxicity which has resulted in increasing recent application of PBK modelling. This research presents the development of a novel mechanistic kidney model embedded in a PBK model parameterised for aspirin and salicylic acid. It is set up to study a combination of young/healthy individuals as well as the elderly, with three exposure scenarios simulating real renal exposure. Key challenges in this endeavour revolve around limited data available in the public literature and uncertainties related to scaling in vitro data to an in vivo setting. Results show that at a low, chronic therapeutic dose the predicted proximal tubular cell concentrations in all considered population groups are below the hypothesised toxicity threshold of 0.09 mM. Sensitivity analyses indicate that at both higher dose scenarios, active transporter activity has the most impact on predicted proximal tubular cell concentrations and therefore individual transporter expression may be key indicators of cellular toxicity. In addition, the fraction unbound of salicylic acid in plasma, the glomerular filtration rate and a decreased urinary pH have a high impact on predicted proximal tubular cell concentrations which largely exceed the toxicity threshold for all individuals at both higher dose scenarios.
Antiplatelet Therapy for Secondary Prevention of Stroke
2021, Stroke: Pathophysiology, Diagnosis, and Management
Antplatelet agents are the gold standard for secondary prevention of non-cardioembolic stroke. Aspirin, aspirin plus dipyridamole, or clopidogrel, ticagrelor, and possibly cilostazol are acceptable therapeutic alternatives. The combination of aspirin plus clopidogrel should not be used for long-term secondary stroke prevention. For prevention of early stroke recurrence after minor stroke or high-risk TIA, the combination of aspirin and clopidogrel or aspirin and ticagrelor are superior to monotherapy. Such dual antiplatelet therapy produces excessive bleeding if given for more than 21 days.
Repurposing antipsychotics of the diphenylbutylpiperidine class for cancer therapy
2021, Seminars in Cancer Biology
The recent development of high throughput compound screening has allowed drug repurposing to emerge as an effective avenue for discovering novel treatments for cancer. FDA-approved antipsychotic drugs fluspirilene, penfluridol, and pimozide are clinically used for the treatment of psychotic disorders, primarily schizophrenia. These compounds, belong to diphenylbutylpiperidine class of antipsychotic drugs, are the potent inhibitors of dopamine D2 receptor and calcium channel. A correlation has been found that patients treated for schizophrenia have lower incidences of certain types of cancer, such as respiratory, prostate, and bladder cancers. These compounds have also been shown to inhibit cancer proliferation in a variety of cancer cells, including melanoma, lung carcinoma, breast cancer, pancreatic cancer, glioma, and prostate cancer, among others. Antipsychotic drugs induce apoptosis and suppress metastasis in in vitro and in vivo models through mechanisms involving p53, STAT3, STAT5, protein phosphatase 2A, cholesterol homeostasis, integrins, autophagy, USP1, wnt/β-catenin signaling, and DNA repair. Additionally, pre-clinical evidence suggests that penfluridol and pimozide act synergistically with existing chemotherapeutic agents, such as dasatinib, temozolomide, and cisplatin. Some studies have also reported that the cytotoxic activity of the antipsychotics is selective for dividing cells. Based on this growing body of evidence and the availability and previous FDA-approval of the drugs, the compounds appear to be promising anti-cancer agents.
Adherence to study drug in a stroke prevention trial”?>
2020, Journal of Stroke and Cerebrovascular Diseases
Standards for reporting and analyzing adherence to medical therapy have recently improved due to international consensus efforts. If applied to clinical trial research in patients with stroke, these improvements have the potential to identify when in the sequence of trial operations participants are at risk for non-adherence and opportunities to safeguard adherence.
We analyzed three phases of adherence according to the European Society for Patient Adherence, COMpliance, and Persistence (ESPACOMP) Medication Adherence Reporting Guideline (EMERGE) taxonomy in the Insulin Resistance Intervention after Stroke (IRIS) trial: initiation (did patient start drug), implementation (did patient take a drug holiday, defined as temporary cessation lasting ≥14 days), and persistence (did patient prematurely and permanently discontinue drug). IRIS was a randomized, placebo controlled, double-blind trial testing pioglitazone to prevent stroke or myocardial infarction in patients with a recent ischemic stroke or transient ischemic attack. Adherence was classified by self-report. Researchers used coaching algorithms to seek adherence recovery if participants went off drug.
During 2005-2013, 3876 participants were enrolled from 179 sites in seven countries and followed for a mean of 4.8 years. Less than 1% of participants in each group did not initiate study drug. 20% of patients assigned to pioglitazone and 17% assigned to placebo took at least one drug holiday. 36% and 30%, respectively, discontinued the study drug prematurely with or without a prior holiday. The risk for stopping the study drug (temporarily or permanently) in the first year after randomization was twice the risk in each of the subsequent four years. This was true both for patients assigned to active therapy and placebo. More participants assigned to pioglitazone, compared to placebo, took a drug holiday or permanently stopped study drug, but the difference in rates of discontinuation was only evident in year one. In years two through five, rates of discontinuation were similar in the two treatment groups. The difference in rates during year one was the result of adverse effects related to the active study drug, pioglitazone. During the remainder of the trial, the attribution of discontinuations to adverse effects potentially related to pioglitazone was reduced but still higher in those assigned to active drug. Other reasons for discontinuation were similar between treatment groups and were largely unrelated to pharmacodynamic effects of the study drug. Rates of discontinuation varied widely among research sites.
Patients in a drug trial for stroke prevention are at greatest risk for premature drug discontinuation early after randomization. Reasons for discontinuation change over time. Variable discontinuation rates among sites suggests that adherence can be improved by using best practices from high-performing sites.
Bleeding risk assessment for stroke patients on antithrombotic therapy
2019, Clinica e Investigacion en Arteriosclerosis
Tras un evento cerebrovascular isquémico el riesgo de recurrencias es elevado, por lo que se hace necesario el uso de terapia antitrombótica para disminuir nuevos eventos.
A pesar de su beneficio, estas terapias aumentan el riesgo de sangrado. Por tanto, determinar qué pacientes presentan mayor riesgo de hemorragia es fundamental. Existen diferentes modelos predictores de hemorragia y, en particular, de hemorragia intracraneal, asociados al uso de antiagregantes en pacientes con ictus isquémico o AIT, como las escalas CCSC, Intracranial-B2LEED3S score o la S2TOP-BLEED. No obstante, mientras que las principales guías internacionales recomiendan el uso de escalas, como HAS-BLED, para evaluar el riesgo de sangrado en pacientes anticoagulados, no existe una recomendación específica en el caso del uso de antiagregantes.
En esta revisión se presentan los principales modelos disponibles en la actualidad para la predicción de sangrado de la terapia antitrombótica en pacientes con ictus o AIT.
After an ischemic cerebrovascular event the risk of new ischemic events is high, therefore antithrombotic therapy are indicated to prevent stroke recurrence.
Despite its clear benefit, these therapies increase the risk of bleeding. Therefore, it is essential to identify high hemorrhagic risk patients.
There are different predictive models of hemorrhage, in particular of intracranial hemorrhage, associated with the use of antiaggregants in patients who have presented an ischemic stroke or TIA, such as the CCSC, intracranial scales -B2LEED3S score or S2TOP-BLEED. However, though main international guidelines recommend the use of scales, in particular, the HAS-BLED score, to assess the risk of bleeding in anticoagulated patients, there is no specific recommendation in the case of the use of antiplatelet drugs.
In this review we present the main models currently available for the prediction of bleeding of antithrombotic therapy in patients who have had a stroke or TIA.

View all citing articles on Scopus

¹: Coordinating centre: Division of Clinical Pharmacology, Danderyd Hospital (C-E. Elwin, B. Peterson). Steering committee: C. Blomstrand, J-E. Olsson, B Nilsson, M. von Arbin, M. Britton, C-E. Elwin, C Helmers, B. Norrving, A. Rosén, K. Samuelsson, K. Strandberg, N. G. Wahlgren Adjudication committees: Stroke: K. Samuelsson, C. Blomstrand, A. Gårde, B. Norrving, J-E. Olsson, Death: M. Britton; Myocardial infarction: M. von Arbin, A. Carlsson, C. Helmers, Compliance: C Blomstrand, C-E. Elwin, A. Rosén, J. Svensson; Adverse effects: N. G. Wahlgren Safety monitoring committee: B. Huitfeldt, P. O. Lundberg, L. Wilhelmsen. Statisticians: H. Melander, I. Selinus. Correspondence to Dr Bo Norrving, Department of Neurology, University Hospital, S-221 85 Lund, Sweden.

View full text

ORIGINAL ARTICLESSwedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events

Abstract

Lancet

Thromb Res

Thromb Res

Lancet

Aspirin all round?

Br Med J

Secondary prevention of vascular disease by prolonged anti-platelet therapy

Br Med J

Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls

N Engl J Med

Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects

J Clin Invest

Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man

J Clin Invest

Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients

N Engl J Med

ORIGINAL ARTICLES
Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events