Table 1.
Summary of retained RCTs of ASA in primary prevention
| Study author (y) | Design | Sample size, n | Average follow-up, y | Mean age, y | Proportion of women, % | Proportion with diabetes, % | ASA dose studied, mg | Primary outcome | Secondary outcomes | Primary safety outcome |
|---|---|---|---|---|---|---|---|---|---|---|
| Fowkes et al.15 (2010) | Double-blind RCT | 3350 | 8.2 | 62 | 72 | 3 | 100 | Initial fatal or nonfatal coronary event, stroke, or revascularization | 1. All initial vascular events defined as a composite of the primary endpoint event or angina, intermittent claudication, or TIA 2. All-cause mortality |
None specified |
| Gaziano et al.9 (2018) | Double-blind RCT | 12,546 | 5 | 64 | 30 | 0 | 100 | CV death, MI, unstable angina, stroke, or TIA | MI and stroke | GI bleeding |
| Bowman et al.7 (2018) | Double-blind RCT | 15,480 | 7.4 | 63 | 37 | 100 | 100 | Vascular death, MI, or stroke/TIA | Nonfatal MI, intracranial hemorrhage, GI hemorrhage, GI cancer | Any major bleed, defined as any confirmed intracranial hemorrhage, sight-threatening eye bleeding, or any other serious bleeding episode (ie, requiring hospitalization or transfusion, or fatal or disabling) |
| McNeil et al.16 (2018) | Double-blind RCT | 19,114 | 4.7 | 74 | 56 | 11 | 100 | Disability-free survival composite (all-cause death, dementia, or physical disability) |
Major hemorrhage, any intracranial bleeding, upper GI bleeding, CV disease (fatal CV disease, MI, stroke, or hospitalization for heart failure), all-cause mortality, cancer mortality | None specified |
| Peto et al. 17 (1988) | Open-label RCT |
5139 | 6 | 60 | 0 | 2 | 500 | Nonfatal MI, nonfatal stroke, or TIA | Noncerebral bleed, hypertension, arrhythmia, acute thrombotic event (pulmonary, venous, or other), peptic ulcer, nonfatal malignant neoplasms, respiratory: acute infections, chronic bronchitis, emphysema, asthma, cataract, migraine, musculoskeletal disorders for which medical advice sought | None specified |
| Hansson et al.18 (1998) | Double-blind RCT | 18,790 | 3.8 | 61.5 | 47 | 8 | 75 | Nonfatal MI, nonfatal stroke, and CV death | Fatal bleeds (GI, cerebral, other), nonfatal major bleeds (GI, cerebral, nasal, other), minor bleeds (GI, nasal, purpura, other) | |
| Ogawa et al.19 (2008) | Open-label RCT | 2539 | 4.37 | 65.0 | 45 | 100 | 81 or 100 | Fatal or nonfatal IHD, fatal or nonfatal stroke, and PAD | Included each primary endpoint and combinations of primary endpoints as well as death from any cause | GI bleeding events and any hemorrhagic events other than hemorrhagic stroke |
| Ikeda et al.20 (2014) | Open-label RCT | 14,658 | 5.02 | 70.5 | 57.7 | 33.9 | 100 | Death from CV causes, nonfatal stroke, nonfatal MI | Composite including primary outcomes, plus TIA, angina pectoris, and arteriosclerotic disease requiring surgery or intervention; death from CV disease, death from non-CV causes, nonfatal stroke (ischemic or hemorrhagic), nonfatal MI, TIA, angina pectoris, arteriosclerotic disease requiring surgery or intervention, and serious extracranial hemorrhage requiring transfusion or hospitalization | Serious extracranial hemorrhage requiring transfusion or hospitalization; GI hemorrhage; gastroduodenal ulcer, reflux oesophagitis; erosive gastritis; stomach or abdominal discomfort, pain or pressure; heartburn; nausea |
| Physicians’ Health Study21 (1989) | Double-blind RCT | 22,071 | 5 | ∗ | 0 | 2.4 | 325 | Death with confirmed cause, nonfatal MI, or nonfatal stroke | Ischemic strokes, hemorrhagic strokes | GI discomfort, upper GI ulcers, other noninfectious disorders of the digestive tract, miscellaneous symptoms of the digestive tract, Bleeding (easy bruising, hematemesis, melena, nonspecific GI bleeding, epistaxis, other), bleeding requiring transfusions, death from GI bleed |
| Belch et al.22 (2008) | Double-blind RCT | 1276 | 6.7 | 60.2 | 55.8 | 100 | 100 | Death from coronary heart disease or stroke, non-fatal MI or stroke, or amputation above the ankle for critical limb ischemia† | All-cause mortality, nonfatal MI, other vascular events including stroke, TIA, coronary or peripheral arterial bypass surgery, coronary or peripheral arterial angioplasty, angina, claudication or critical limb ischemia | Adverse events: Malignancy, GI bleeding, GI symptoms including dyspepsia, arrhythmia, allergy including skin rash |
| Roncaglioni25 PPP (2001) | Open-label RCT | 4495 | 3.6 | 64.4 | 57.5 | 17 | 100 | CV death, nonfatal MI, and nonfatal stroke | CV deaths, total deaths, total CV events (CV death, nonfatal MI, nonfatal stroke, angina pectoris, TIA, PAD, and revascularization procedures | Cancer, bleeding (GI, intracranial not parenchymal, ocular, epistaxis, other), GI disease (except bleeding), other events |
| Thrombosis prevention trial23 (1998) | Double-blind RCT | 2540 | 6.8 | 57 | 0 | ∗ | 75 | Coronary death and fatal and nonfatal MI | Stroke | Bleeding episodes: Major episodes; confirmed cerebral haemorrhages and fatal or life-threatening haemorrhages at other sites that required transfusion and/or surgery Intermediate episodes; include macroscopic hematuria, larger bruises, and prolonged nose bleeds Minor episodes; ie, bruising, nose bleeds, rectal bleeding, and pink or red urine |
| Ridker et al.24 (2005) | Double-blind RCT | 39,876 | 10.1 | 54.6 | 100 | 2.6 | 100 every other day | Combination of major CV events, including nonfatal MI, nonfatal stroke, and death from CV causes | Fatal or nonfatal MI, fatal or nonfatal stroke, ischemic stroke, hemorrhagic stroke, and death from CV causes Additional analyses included the incidence of death from any cause, TIA, and the need for coronary revascularization |
Fatal GI hemorrhages, GI bleeding requiring transfusion; self-reported hematuria, easy bruising and epistaxis, symptoms suggestive of gastric upset †The presence of gastrointestinal bleeding or peptic ulcer was confirmed by a specific follow-up questionnaire. |
| Yusuf et al.6 (2021) | Double-blind RCT | 5713 | 4.6 | 63.9 | 52.9 | 36.7 | 75 | Death from CV causes, MI, stroke (ASA vs placebo comparison only) |
Major CV events and the composite of the primary outcome plus angina with evidence of ischemia / death from any cause, first and recurrent CV events, cancer | Major bleeding, minor bleeding, GI bleeding Major bleeding based on ISTH criteria‡ |
Follow-up is mean or median, as reported in each study.
ASA, acetylsalicylic acid (aspirin); CV, cardiovascular, GI, gastrointestinal; IHD, ischemic heart disease; ISTH, International Society on Thrombosis and Hemostasis; MI, myocardial infarction; PAD, peripheral artery disease; PPP, Primary Prevention Project; RCT, randomized controlled trials; TIA, transient ischemic attack.
∗
Not reported.
†
This study included 2 hierarchical composite primary outcomes. The most comprehensive composite is described.
‡
The ISTH criteria are defined as follows: (i) fatal bleeding; (ii) bleeding in a critical site or area (retroperitoneal, cardiac tamponade, hemoptysis, intraocular, intracranial, definite hemorrhagic stroke or subarachnoid hemorrhage); or (iii) bleeding causing a fall in hemoglobin level of 20 g/L or more or leading to transfusion of 2 or more units of blood.34