Trial Of Aspirin Research Articles

Aspirin is First‐Line Treatment for Migraine and Episodic Tension‐Type Headache Regardless of Headache Intensity

(1) To establish whether pre-treatment headache intensity in migraine or episodic tension-type headache (ETTH) predicts success or failure of treatment with aspirin; and (2) to reflect, accordingly, on the place of aspirin in the management of these disorders. Stepped care in migraine management uses symptomatic treatments as first-line, reserving triptans for those in whom this proves ineffective. Stratified care chooses between symptomatic therapy and triptans as first-line on an individual basis according to perceived illness severity. We questioned the 2 assumptions underpinning stratified care in migraine that greater illness severity: (1) reflects greater need; and (2) is a risk factor for failure of symptomatic treatment but not of triptans. With regard to the first assumption, we developed a rhetorical argument that need for treatment is underpinned by expectation of benefit, not by illness severity. To address the second, we reviewed individual patient data from 6 clinical trials of aspirin 1000 mg in migraine (N = 2079; 1165 moderate headache, 914 severe) and one of aspirin 500 and 1000 mg in ETTH (N = 325; 180 moderate, 145 severe), relating outcome to pre-treatment headache intensity. In migraine, for headache relief at 2 hours, a small (4.7%) and non-significant risk difference (RD) in therapeutic gain favored moderate pain; for pain freedom at 2 hours, therapeutic gains were almost identical (RD: -0.2%). In ETTH, for headache relief at 2 hours, RDs for both aspirin 500 mg (-4.2%) and aspirin 1000 mg (-9.7%) favored severe pain, although neither significantly; for pain freedom at 2 hours, RDs (-14.2 and -3.6) again favored severe pain. In neither migraine nor ETTH does pre-treatment headache intensity predict success or failure of aspirin. This is not an arguable basis for stratified care in migraine. In both disorders, aspirin is first-line treatment regardless of headache intensity.

Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: A meta-analysis of randomized trials

The benefit of aspirin to prevent cardiovascular events in subjects without clinical cardiovascular disease relative to the increased risk of bleeding is uncertain. A meta-analysis of randomized trials of aspirin versus placebo/control to assess the effect of aspirin on major cardiovascular events (MCEs) (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), individual components of the MCE, stroke subtype, all-cause mortality, and major bleeding. Nine trials involving 102,621 patients were included: 52,145 allocated to aspirin and 50,476 to placebo/control. Over a mean follow-up of 6.9 years, aspirin was associated with a reduction in MCE (risk ratio [RR] 0.90, 95% CI 0.85-0.96, P < .001). There was no significant reduction for myocardial infarction, stroke, ischemic stroke, or all-cause mortality. Aspirin was associated with hemorrhagic stroke (RR 1.35, 95% CI 1.01-1.81, P = .04) and major bleeding (RR 1.62, 95% CI 1.31-2.00, P < .001). In meta-regression, the benefits and bleeding risks of aspirin were independent of baseline cardiovascular risk, background therapy, age, sex, and aspirin dose. The number needed to treat to prevent 1 MCE over a mean follow-up of 6.9 years was 253 (95% CI 163-568), which was offset by the number needed to harm to cause 1 major bleed of 261 (95% CI 182-476). The current totality of evidence provides only modest support for a benefit of aspirin in patients without clinical cardiovascular disease, which is offset by its risk. For every 1,000 subjects treated with aspirin over a 5-year period, aspirin would prevent 2.9 MCE and cause 2.8 major bleeds.

Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension

Background— Pulmonary arterial hypertension (PAH) is a progressive disease that causes exercise limitation, heart failure, and death. We aimed to determine the safety and efficacy of aspirin and simvastatin in PAH. Methods and Results— We performed a randomized, double-blind, placebo-controlled 2×2 factorial clinical trial of aspirin and simvastatin in patients with PAH receiving background therapy at 4 centers. A total of 92 patients with PAH were to be randomized to aspirin 81 mg or matching placebo and simvastatin 40 mg or matching placebo. The primary outcome was 6-minute walk distance at 6 months. Sixty-five subjects had been randomized when the trial was terminated by the Data Safety and Monitoring Board after an interim analysis showed futility in reaching the primary end point for simvastatin. After adjustment for baseline 6-minute walk distance, there was no significant difference in the 6-minute walk distance at 6 months between aspirin (n=32) and placebo (n=33; placebo-corrected difference −0.5 m, 95% confidence interval −28.4 to 27.4 m; P =0.97) or between simvastatin (n=32) and placebo (n=33; placebo-corrected difference −27.6 m, 95% confidence interval −59.6 to 4.3 m; P =0.09). There tended to be more major bleeding episodes with aspirin than with placebo (4 events versus 1 event, respectively; P =0.17). Conclusions— Neither aspirin nor simvastatin had a significant effect on the 6-minute walk distance, although patients randomized to simvastatin tended to have a lower 6-minute walk distance at 6 months. These results do not support the routine treatment of patients with PAH with these medications. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00384865.

A phase IIa clinical biomarker trial of aspirin and dietary arginine restriction in colorectal cancer patients.

TPS132 Background: Colorectal cancer (CRC) patients are at high risk for recurrence and for secondary CRC development. Our preliminary findings provide a rationale for reducing tissue polyamines as tertiary chemoprevention in local and locally-advanced CRC patients. We will attempt to demonstrate rectal tissue putrescine reduction in stage I-III, optimally-treated CRC patients after treatment with dietary arginine restriction + daily oral aspirin in a phase IIa clinical biomarker trial. Methods: 24 participants will be treated with aspirin and an individualized dietary regimen to reduce arginine intake by >30% during the 12-week intervention. Sample size calculations were based on the Binomial test for a single proportion, to yield 80% Power. Six patients will receive psychosocial telephone counseling (PTC). Endoscopy with serial biopsies, phlebotomy, and urine collection will be performed pre- and post-intervention to assess potential biomarkers. The primary endpoint is a > 50% decrease in rectal tissue putrescine levels from baseline, as a measure of polyamine reduction in the target tissue of CRC patients. Secondary aims include: to demonstrate significant alterations in secondary endpoint biomarkers relevant to polyamine metabolism in CRC patients, including rectal mucosa Odc1 and Ssat expression and urinary polyamine metabolites; to determine this intervention’s side-effect profile in a population of optimally-treated CRC patients; to determine the efficacy of accrual to this novel type of clinical trial involving dietary intervention and oral aspirin therapy among a group of potentially cured cancer patients for whom there is currently no recommended further therapy; to assess feasibility of PTC and collect pilot data regarding the influence of PTC on compliance with the dietary prescription and compliance with aspirin, and if PTC further influences healthy exercise, reduced fatigue and improved quality of life when compared to the non-counseled cohort. Hypothesis: Among optimally-treated stage I-III CRC patients, a 12-week intervention of daily aspirin and a low-meat, arginine-restricted diet will favorably alter polyamine-related tissue, serum, and urinary biomarker levels.

Antithrombotic Management for Transient Ischemic Attack and Ischemic Stroke (Other than Atrial Fibrillation)

The new definition and risk stratification for transient ischemic attack (TIA) have clear implications for the urgency of evaluation and treatment. The optimal antithrombotic treatment for TIA is being intensively studied. New guidelines for prevention of non-cardioembolic stroke in patients with stroke or TIA recommend the use of antiplatelet agents rather than oral anticoagulation. New antiplatelet drugs are being used in cardiovascular patients, and their role in cerebrovascular patients is being studied. The impact of genetic CYP2C19 polymorphisms is becoming clarified in cardiovascular patients and it is likely these polymorphisms will affect the management of cerebrovascular patients. The results of trials of clopidogrel plus aspirin in patients with lacunar strokes and acute TIAs are forthcoming. The results of CLOSURE I, a study of a patent foramen ovale device closure trial for cryptogenic stroke or TIA, showed no differences in stroke or TIA at 2 years.

Effect of Aspirin on Mortality in the Primary Prevention of Cardiovascular Disease

Objective The lack of a mortality benefit of aspirin in prior meta-analyses of primary prevention trials of cardiovascular disease has contributed to uncertainty about the balance of benefits and risks of aspirin in primary prevention. We performed an updated meta-analysis of randomized controlled trials of aspirin to obtain best estimates of the effect of aspirin on mortality in primary prevention. Methods Eligible articles were identified by searches of electronic databases and reference lists. Outcomes of interest were all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and bleeding. Data were pooled from individual trials using the DerSimonian-Laird random-effects model, and results are presented as relative risk (RR) and 95% confidence intervals (CIs). Results Nine randomized controlled trials enrolling 100,076 participants were included. Aspirin reduced all-cause mortality (RR 0.94; 95% CI, 0.88-1.00), myocardial infarction (RR 0.83; 95% CI, 0.69-1.00), ischemic stroke (RR 0.86; 95% CI, 0.75-0.98), and the composite of myocardial infarction, stroke, or cardiovascular death (RR 0.88; 95% CI, 0.83-0.94), but did not reduce cardiovascular mortality (RR 0.96; 95% CI, 0.84-1.09). Aspirin increased the risk of hemorrhagic stroke (RR 1.36; 95% CI, 1.01-1.82), major bleeding (RR 1.66; 95% CI, 1.41-1.95), and gastrointestinal bleeding (RR 1.37; 95% CI, 1.15-1.62). A lack of availability of patient-level data precluded exploration of benefits and risks of aspirin in key subgroups. Conclusion Aspirin prevents deaths, myocardial infarction, and ischemic stroke, and increases hemorrhagic stroke and major bleeding when used in the primary prevention of cardiovascular disease.

TP receptor antagonists (TXRAs): expensive irrelevance or wonder drugs strangled at birth?

TP receptor antagonists (TXRAs): expensive irrelevance or wonder drugs strangled at birth?

A Randomized Placebo-Controlled Prevention Trial of Aspirin and/or Resistant Starch in Young People with Familial Adenomatous Polyposis

Evidence supporting aspirin and resistant starch (RS) for colorectal cancer prevention comes from epidemiologic and laboratory studies (aspirin and RS) and randomized controlled clinical trials (aspirin). Familial adenomatous polyposis (FAP) strikes young people and, untreated, confers virtually a 100% risk of colorectal cancer and early death. We conducted an international, multicenter, randomized, placebo-controlled trial of aspirin (600 mg/d) and/or RS (30 g/d) for from 1 to 12 years to prevent disease progression in FAP patients from 10 to 21 years of age. In a 2 × 2 factorial design, patients were randomly assigned to the following four study arms: aspirin plus RS placebo; RS plus aspirin placebo; aspirin plus RS; RS placebo plus aspirin placebo; they were followed with standard annual clinical examinations including endoscopy. The primary endpoint was polyp number in the rectum and sigmoid colon (at the end of intervention), and the major secondary endpoint was size of the largest polyp. A total of 206 randomized FAP patients commenced intervention, of whom 133 had at least one follow-up endoscopy and were therefore included in the primary analysis. Neither intervention significantly reduced polyp count in the rectum and sigmoid colon: aspirin relative risk = 0.77 (95% CI, 0.54-1.10; versus nonaspirin arms); RS relative risk = 1.05 (95% CI, 0.73-1.49; versus non-RS arms). There was a trend toward a smaller size of largest polyp in patients treated with aspirin versus nonaspirin--mean 3.8 mm versus 5.5 mm for patients treated 1 or more years (adjusted P = 0.09) and mean 3.0 mm versus 6.0 mm for patients treated more than 1 year (P = 0.02); there were similar weaker trends with RS versus non-RS. Exploratory translational endpoints included crypt length (which was significantly shorter in normal-appearing mucosa in the RS group over time) and laboratory measures of proliferation (including Ki67). This clinical trial is the largest ever conducted in the setting of FAP and found a trend of reduced polyp load (number and size) with 600 mg of aspirin daily. RS had no clinical effect on adenomas.

Aspirin and Familial Adenomatous Polyposis: Coming Full Circle

This perspective discusses the clinical trial reported by Burn and colleagues in this issue of the journal (beginning on page 655), which assessed aspirin and resistant starch for the prevention of colorectal adenomas in patients with familial adenomatous polyposis (FAP). The findings are examined in the context of previous clinical trials of aspirin in patients with sporadic adenomas and of sulindac or celecoxib in patients with FAP. This newly reported work raises important considerations of a role for aspirin in the clinical management of FAP patients and adds to considerations of a role for aspirin in the chemoprevention of colorectal cancer among broader populations.

Is Low-Dose Aspirin Use Associated With a Reduced Risk of Colorectal Cancer? A Qresearch Primary Care Database Analysis

Introduction The chemopreventive effect of aspirin for colorectal cancer (CRC) is now well established. However, the dose and duration of aspirin use necessary for this effect is still unclear. Two very large US RCTs using low dose aspirin (325 and 100 mg alt. die) found no reduction in CRC incidence after 10 years follow-up, but a recent meta-analysis of five European aspirin trials suggested that aspirin in a dose of 75–300 mg daily resulted in a 24% reduction in CRC incidence.1 We have therefore examined the relationship between prescribed aspirin and CRC risk in QResearch, the largest primary care database in the United Kingdom. Methods A nested case-control study was conducted using data from 574 UK general practices in the QResearch database. Cases were all patients with >15 years of records and diagnosed with colorectal cancer between 1998 and 2008. Cases were matched to up to five controls. Prescriptions in the year before diagnosis were ignored. Association of aspirin use with risk of cancer was estimated in STATA using conditional logistic regression adjusted for comorbidities, smoking status, socio-economic status and use of non-steroidal anti-inflammatory drugs and statins. Results There were 6643 patients diagnosed with CRC with 15 years of records in the database. Of 24% CRC cases and their controls had been prescribed aspirin at some point, 77% in a dose of 75 mg, 93% as ≤150 mg and 98% as 300 mg or less. Table 1 shows a gradual reduction in CRC risk (odds ratios) with increasing total duration of aspirin use (p for trend = 0.012). In a larger cohort with only 10 years of database records, there were 9534 CRCs and the risk of CRC with 7–9 years of aspirin use was 0.82 (0.73–0.93, p Conclusion Use of low dose aspirin is associated with about a 20% reduction in CRC incidence but this reduction is only evident after over 7 years of use. Although this is a modest reduction aspirin, combined with other agents such as calcium could result in a more substantial effect.

Acetyl-11-Keto-Beta-Boswellic Acid Inhibits Cell Growth, Invasion, and Migration in Colon Cancer Cells by Modulating the Expression of MicroRNA Let-7 and the Mir-200 Family

Introduction: The chemopreventive effect of aspirin for colorectal cancer (CRC) is now well established. However the dose and duration of aspirin use necessary for this effect is still unclear. Two very large US RCTs using low dose aspirin (325mg and 100mg alt.die) found no reduction in CRC incidence after 10 years follow-up but a recent meta-analysis of 5 European aspirin trials suggested that aspirin in a dose of 75-300mg daily resulted in a 24% reduction in CRC incidence.1 We have therefore examined the relationship between prescribed aspirin and CRC risk in QResearch, the largest primary care database in the UK. Methods: A nested case-control study was conducted using data from 574 UK general practices in the Qresearch database. Cases were all patients with >15 years of records and diagnosed with colorectal cancer between 1998 and 2008. Cases were matched to up to 5 controls. Prescriptions in the year before diagnosis were ignored. Association of aspirin use with risk of cancer was estimated in STATA using conditional logistic regression adjusted for co-morbidities, smoking status, socio-economic status and use of non-steroidal antiinflammatory drugs and statins. Results: There were 6643 patients diagnosed with CRC with 15 years of records in the database. 24% of CRC cases and their controls had been prescribed aspirin at some point, 77% in a dose of 75mg, 93% as ≤150mg and 98% as 300mg or less. The Table shows a gradual reduction in CRC risk (odds ratios) with increasing total duration of aspirin use (p for trend=0.012). In a larger cohort with only 10 years of database records there were 9534 CRC's and the risk of CRC with 7-9 years of aspirin use was 0.82 (0.73-0.93, p<0.001) Conclusion: Use of low dose aspirin is associated with about a 20% reduction in CRC incidence but this reduction is only evident after over 7 years of use. Although this is a modest reduction aspirin combined with other agents such as calcium could result in a more substantial effect.

Implementing Home Blood Pressure Into Practice

See related article, pp 1081–1086 The growing worldwide epidemic of high blood pressure in both developed and developing nations is a challenge on many levels.1 The need for better prevention of cardiovascular disease through control of hypertension is clear.2 Public awareness of the need to treat hypertension is partly reflected by the widespread purchases of home blood pressure devices in several of the developed countries. In the United States, Japan, and Finland, the estimates are that 55% to 75% of hypertensive patients already have a home device.3 Research studies have provided a robust epidemiological basis for supporting the greater accuracy of home blood pressure monitoring (HBPM) compared with clinic pressures for prognosis of fatal and nonfatal cardiovascular disease in long-term follow-up surveys and in cross-sectional designs.4 There is a general consensus that HBPM is more convenient, available, and less costly than ambulatory blood pressure monitoring, but the superiority of ambulatory blood pressure monitoring for special clinical problems (ie, detection of nondippers or need for sleep pressures in chronic renal disease, autonomic neuropathies, and sleep apnea) is also clearly recognized.5 Surveys of both physicians6 and patients7 suggest that HBPM is both appreciated and recognized as a valuable strategy. Several experts in the field of hypertension research and care have published appeals to expand the use of HPBM for routine care and to have it supported by health care …

Meta-Analysis of Multiple Primary Prevention Trials of Cardiovascular Events Using Aspirin

Several meta-analyses have focused on determination of the effectiveness of aspirin (acetylsalicylic acid) in primary prevention of cardiovascular (CV) events. Despite these data, the role of aspirin in primary prevention continues to be investigated. Nine randomized trials have evaluated the benefits of aspirin for the primary prevention of CV events: the British Doctors' Trial (BMD), the Physicians' Health Study (PHS), the Thrombosis Prevention Trial (TPT), the Hypertension Optimal Treatment (HOT) study, the Primary Prevention Project (PPP), the Women's Health Study (WHS), the Aspirin for Asymptomatic Atherosclerosis Trial (AAAT), the Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial, and the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial. The combined sample consists of about 90,000 subjects divided approximately evenly between those taking aspirin and subjects not taking aspirin or taking placebo. A meta-analysis of these 9 trials assessed 6 CV end points: total coronary heart disease, nonfatal myocardial infarction (MI), total CV events, stroke, CV mortality, and all-cause mortality. No covariate adjustment was performed, and appropriate tests for treatment effect, heterogeneity, and study size bias were applied. The meta-analysis suggested superiority of aspirin for total CV events and nonfatal MI, (p <0.05 for each), with nonsignificant results for decreased risk for stroke, CV mortality, and all-cause mortality. There was no evidence of a statistical bias (p >0.05). In conclusion, aspirin decreased the risk for CV events and nonfatal MI in this large sample. Thus, primary prevention with aspirin decreased the risk for total CV events and nonfatal MI, but there were no significant differences in the incidences of stroke, CV mortality, all-cause mortality and total coronary heart disease.

Update on Atacas: A Randomised Trial of Aspirin and Tranexamic Acid in Coronary Artery Surgery

Update on Atacas: A Randomised Trial of Aspirin and Tranexamic Acid in Coronary Artery Surgery

Is low-dose aspirin use associated with a reduced risk of colorectal cancer? A QResearch primary care database analysis

<h3>Introduction</h3> The chemopreventive effect of aspirin for colorectal cancer (CRC) is now well established. However, the dose and duration of aspirin use necessary for this effect is still unclear. Two very large US RCTs using low dose aspirin (325 and 100 mg alt. die) found no reduction in CRC incidence after 10 years follow-up, but a recent meta-analysis of five European aspirin trials suggested that aspirin in a dose of 75–300 mg daily resulted in a 24% reduction in CRC incidence.1 We have therefore examined the relationship between prescribed aspirin and CRC risk in QResearch, the largest primary care database in the United Kingdom. <h3>Methods</h3> A nested case-control study was conducted using data from 574 UK general practices in the QResearch database. Cases were all patients with &gt;15 years of records and diagnosed with colorectal cancer between 1998 and 2008. Cases were matched to up to five controls. Prescriptions in the year before diagnosis were ignored. Association of aspirin use with risk of cancer was estimated in STATA using conditional logistic regression adjusted for comorbidities, smoking status, socio-economic status and use of non-steroidal anti-inflammatory drugs and statins. <h3>Results</h3> There were 6643 patients diagnosed with CRC with 15 years of records in the database. Of 24% CRC cases and their controls had been prescribed aspirin at some point, 77% in a dose of 75 mg, 93% as ≤150 mg and 98% as 300 mg or less. Table 1 shows a gradual reduction in CRC risk (odds ratios) with increasing total duration of aspirin use (p for trend = 0.012). In a larger cohort with only 10 years of database records, there were 9534 CRCs and the risk of CRC with 7–9 years of aspirin use was 0.82 (0.73–0.93, p &lt; 0.001). <h3>Conclusion</h3> Use of low dose aspirin is associated with about a 20% reduction in CRC incidence but this reduction is only evident after over 7 years of use. Although this is a modest reduction aspirin, combined with other agents such as calcium could result in a more substantial effect.

Irbesartan in Patients with Atrial Fibrillation

The risk of cardiovascular events among patients with atrial fibrillation is high. We evaluated whether irbesartan, an angiotensin-receptor blocker, would reduce this risk. We randomly assigned patients with a history of risk factors for stroke and a systolic blood pressure of at least 110 mm Hg to receive either irbesartan at a target dose of 300 mg once daily or double-blind placebo. These patients were already enrolled in one of two trials (of clopidogrel plus aspirin versus aspirin alone or versus oral anticoagulants). The first coprimary outcome was stroke, myocardial infarction, or death from vascular causes; the second was this composite outcome plus hospitalization for heart failure. A total of 9016 patients were enrolled and followed for a mean of 4.1 years. The mean reduction in systolic blood pressure was 2.9 mm Hg greater in the irbesartan group than in the placebo group, and the mean reduction in diastolic blood pressure was 1.9 mm Hg greater. The first coprimary outcome occurred at a rate of 5.4% per 100 person-years in both groups (hazard ratio with irbesartan, 0.99; 95% confidence interval [CI], 0.91 to 1.08; P=0.85). The second coprimary outcome occurred at a rate of 7.3% per 100 person-years among patients receiving irbesartan and 7.7% per 100 person-years among patients receiving placebo (hazard ratio, 0.94; 95% CI, 0.87 to 1.02; P=0.12). The rates of first hospitalization for heart failure (a prespecified secondary outcome) were 2.7% per 100 person-years among patients receiving irbesartan and 3.2% per 100 person-years among patients receiving placebo (hazard ratio, 0.86; 95% CI, 0.76 to 0.98). Among patients who were in sinus rhythm at baseline, there was no benefit of irbesartan in preventing hospitalization for atrial fibrillation or atrial fibrillation recorded on 12-lead electrocardiography, nor was there a benefit in a subgroup that underwent transtelephonic monitoring. More patients in the irbesartan group than in the placebo group had symptomatic hypotension (127 vs. 64) and renal dysfunction (43 vs. 24). Irbesartan did not reduce cardiovascular events in patients with atrial fibrillation. (Funded by Bristol-Myers Squibb and Sanofi-Aventis; ClinicalTrials.gov number, NCT00249795.).

Aspirin

> Among the many useful discoveries which this age has made, there are very few which better deserve the attention of the public that what I am going to lay before your Lordship. > > —Reverend Edward Stone –Chipping-Norton, Oxfordshire –April 25, 1763 These prophetic words, written by Reverend Edward Stone in a 1763 letter to George Parker, the second Earl of Macclesfield, describe the results of the first clinical trial recorded in medical history.1 Stone's report on the rediscovery of the medicinal value of willow bark among subjects suffering from malarial symptoms is considered a significant milestone in the development of aspirin. Although society now takes many of its beneficial effects for granted, aspirin did not suddenly appear for medicinal use after Reverend Stone's discovery. Instead, its tumultuous journey was fueled by individual scientific curiosity, accidental discoveries, and intense business rivalry.1 No other drug is used by a greater number of people worldwide than aspirin, the benefits of which span centuries, beginning with the very first uses of willow bark by Egyptian physicians (Figure 1). Aspirin single-handedly transformed a coal-dye company into a pharmaceutical giant and has emerged as a cornerstone in the present-day therapies available for treating cardiovascular disease (CVD), pain, and inflammation. This article discusses the sentinel historical aspects of the discovery and clinical cardiovascular developments of aspirin, as well as its contemporary use in today's medical arena. Figure 1. Timeline of historical events in the development of aspirin. ### Historical Developments of Salicylates On January 20, 1862, Edwin Smith made one of the most historically important purchases of his life. Well-regarded among his peers for his keen scholarship and intricate knowledge of Egyptology, Smith purchased, for £12, 2 worn papyrus scrolls in a local Luxor street market1 that later turned out to be a formative medical textbook unlocking ancient Egyptian's practice of medicine. Although authorless, the Ebers Papyrus is 110 pages …

Opinion & HypothesisCould early aspirin prophylaxis prevent against preterm birth?

A growing body of evidence suggests that defective placentation may play a major role in the genesis of preterm birth, indicating that preeclampsia, intra-uterine growth restriction (IUGR), and spontaneous preterm birth can share a similar mechanism of disease. A recent meta-analysis of low-dose aspirin trials for the prevention of preeclampsia and IUGR in high-risk women demonstrated that, when started early in gestation, aspirin could prevent more than half of preeclampsia and IUGR cases but was also linked with a significant decrease of preterm births (relative risk 0.22, 95% confidence interval: 0.10–0.49). Unfortunately, most studies did not report specific data on the cause of preterm deliveries and, therefore, we could not estimate the proportion of this effect that could be related to spontaneous preterm births. Therefore, we hypothesize that low-dose aspirin could become an additional weapon in the prevention of preterm births and we suggest that further studies should be performed in this area of research.

Rationale and design of a phase II clinical trial of aspirin and simvastatin for the treatment of pulmonary arterial hypertension: ASA-STAT

Background Pulmonary arterial hypertension (PAH) is a progressive disease which causes exercise limitation, heart failure, and death. Aspirin and simvastatin are highly effective and safe therapies for other cardiovascular diseases characterized by platelet activation and endothelial dysfunction, but have not been formally studied in PAH. Methods ASA-STAT is a phase II, randomized, double-blind, placebo-controlled 2 × 2 factorial clinical trial of aspirin and simvastatin in patients with PAH. A total of 92 subjects were to be randomized to aspirin or aspirin placebo and simvastatin or simvastatin placebo. The primary outcome is the distance walked in 6 min at 6 months after randomization. Secondary measures include brachial artery flow-mediated dilation, circulating biomarkers of platelet and endothelial function, functional class, quality-of-life, and time to clinical end points. The incidence of adverse events will be compared between treatment groups. Screening and enrollment We screened a total of 712 individuals with PAH. Sixty-five subjects were enrolled when the trial was terminated for futility in reaching the primary end point for simvastatin. Conclusions This study aims to determine whether aspirin or simvastatin have beneficial biologic or clinical effects in patients with PAH. The safety and side effects of these commonly prescribed cardiovascular drugs will also be assessed.

Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials

Treatment with daily aspirin for 5 years or longer reduces subsequent risk of colorectal cancer. Several lines of evidence suggest that aspirin might also reduce risk of other cancers, particularly of the gastrointestinal tract, but proof in man is lacking. We studied deaths due to cancer during and after randomised trials of daily aspirin versus control done originally for prevention of vascular events. We used individual patient data from all randomised trials of daily aspirin versus no aspirin with mean duration of scheduled trial treatment of 4 years or longer to determine the effect of allocation to aspirin on risk of cancer death in relation to scheduled duration of trial treatment for gastrointestinal and non-gastrointestinal cancers. In three large UK trials, long-term post-trial follow-up of individual patients was obtained from death certificates and cancer registries. In eight eligible trials (25 570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer (pooled odds ratio [OR] 0·79, 95% CI 0·68-0·92, p=0·003). On analysis of individual patient data, which were available from seven trials (23 535 patients, 657 cancer deaths), benefit was apparent only after 5 years' follow-up (all cancers, hazard ratio [HR] 0·66, 0·50-0·87; gastrointestinal cancers, 0·46, 0·27-0·77; both p=0·003). The 20-year risk of cancer death (1634 deaths in 12 659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0·80, 0·72-0·88, p<0·0001; gastrointestinal cancers, 0·65, 0·54-0·78, p<0·0001), and benefit increased (interaction p=0·01) with scheduled duration of trial treatment (≥7·5 years: all solid cancers, 0·69, 0·54-0·88, p=0·003; gastrointestinal cancers, 0·41, 0·26-0·66, p=0·0001). The latent period before an effect on deaths was about 5 years for oesophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and oesophageal cancer, benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer death was greatest for adenocarcinomas (HR 0·66, 0·56-0·77, p<0·0001). Benefit was unrelated to aspirin dose (75 mg upwards), sex, or smoking, but increased with age-the absolute reduction in 20-year risk of cancer death reaching 7·08% (2·42-11·74) at age 65 years and older. Daily aspirin reduced deaths due to several common cancers during and after the trials. Benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of aspirin and for understanding of carcinogenesis and its susceptibility to drug intervention. None.