Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial
Download the PDF here
Download the PDF here
perhaps more interesting is the study in diabetics, coming next. Jules
Full Study article follows below the 2 Commentaries....
from 2nd commentary below " Better management of blood pressure, dyslipidaemia, and other risk factors is likely to lower the risk of developing disease, and these interventions are most aggressively used in patients at higher risk.. ARRIVE reflects a contemporary cardiovascular risk prevention (therapy) study in which widespread statin use is the norm. 43% of ARRIVE participants were taking statins. The exclusion of patients with diabetes could also contribute to lower overall risk.........Aspirin also did not show a significant effect on any of the individual components of the primary endpoint.......But daily aspirin was associated with more gastrointestinal bleeding, although such events were few in the study, at less than 1% in either group. The HR was 2.11 (95% CI, 1.36 - 3.28; P = .0007). Hemorrhagic strokes were also rare, with a rate of 0.13% in the aspirin group and 0.18% among controls.,,,,,In prior studies of primary prevention aspirin, many of which were conducted in the 1980s and 1990s, said Gaziano, "when a patient developed angina or a TIA, it wasn't standard practice to put them on aspirin." By the time ARRIVE was conducted, aspirin had become a much more common therapy.
"We have much better treatments for atherosclerotic disease now than we had in these old aspirin studies," agreed John G.F. Cleland, MD, Imperial College London, United Kingdom, speaking with theheart.org | Medscape Cardiology.....Cleland, who was not involved with ARRIVE but is an outspoken opponent of aspirin for CV primary prevention, isn't surprised at the low-risk status of the trial participants, who enrolled in an era of "good antihypertensive medications" and widespread statin therapy.
"Once you've dealt with the lipids, and once you've dealt with the hypertension, I'm really not sure what's left for aspirin," Cleland said.....One lesson of ARRIVE is that an aspirin recommendation for primary prevention should be based on "a complex calculus involving estimates of cardiovascular risk, potentially cancer risk, and bleeding risk," he said......Even per protocol, aspirin fell short of significance for the composite primary endpoint, at an HR of 0.81 (95% CI, 0.64 - 1.02; P = .076). But there were significant risk reductions for any MI at 0.53 (95% CI, 0.36 - 0.79; P = .0014) and nonfatal of MI 0.55 (95% CI, 0.36 - 0.84; P = .0056)........I'm looking at it for some insights as to why the results are somewhat different from a study we know quite well, the Physicians' Health Study," Gaziano said when interviewed.
That study from the 1980s, which randomly assigned more than 22,000 health professionals to aspirin at 325 mg every other day or placebo, famously saw a 44% reduction in risk acute MI (P < .00001)."
Aspirin for primary prevention of cardiovascular disease
Lancet Aug 26 2018 - *Davide Capodanno, Dominick J Angiolillo
Division of Cardiology, AOU "Policlinico Vittorio Emanuele", PO Rodolico, Catania 95123, Sicily, Italy (DC); and Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA (DJA)
The benefit of aspirin for patients with established cardiovascular disease outweighs the risk of bleeding, but the role of aspirin for individuals with no overt cardiovascular disease is more controversial.12
In a meta-analysis 3, 4 of 118 445 individuals from 11 trials of aspirin for primary cardiovascular disease prevention, aspirin reduced the relative risk of non-fatal myocardial infarction by 22% and death by 6%, at the cost of a 59% increase in gastrointestinal bleeding and a 33% increase in haemorrhagic stroke. This compromise in bleeding complications has called into question the level of baseline cardiovascular disease risk for which use of aspirin in primary prevention is clinically acceptable. Indeed, in patients at low cardiovascular disease risk, the relative benefit of aspirin translates into marginal absolute benefit, making its use largely unjustifiable. To better define the net benefit of aspirin for primary prevention, four more trials were designed to include individuals at higher cardiovascular disease risk: two of patients with diabetes (ASCEND and ACCEPT-D), one of patients of advanced age (ASPREE), and one of patients at moderate cardiovascular disease risk (ARRIVE; appendix).2 J Michael Gaziano and colleagues5now report the results of ARRIVE in The Lancet.
In ARRIVE, 12 546 patients were randomly assigned to receive either low-dose (100 mg) aspirin or placebo tablets once daily, at 501 sites in seven countries. Inclusion criteria included several major cardiovascular disease risk factors, to target a final population at moderate (ie, 20-30%) risk of 10-year cardiovascular disease. Patients with a history of a vascular event or diabetes were excluded. The primary endpoint was a composite outcome of time to first occurrence of cardiovascular death, myocardial infarction, stroke, unstable angina, or transient ischaemic attack, with a median follow-up of 5 years. In the intention-to-treat analysis, there was no significant difference in the primary endpoint, which occurred in 269 (4⋅29%) of patients in the aspirin group and 281 (4⋅48%) of patients in the placebo group (hazard ratio [HR] 0⋅96, 95% CI 0⋅81-1⋅13; p=0⋅6038). There was a lower HR for aspirin in the per-protocol analysis (0⋅81, 0⋅64-1⋅02; p=0⋅0756), paralleled by a significant reduction in fatal or non-fatal myocardial infarction and no effect on mortality. Gastrointestinal bleeding events were mostly mild and approximately two times higher in the aspirin group in the intention-to-treat population (HR 2⋅11, 1⋅36-3⋅28; p=0⋅0007).
Some trial aspects are noteworthy and challenge interpretation of the results. The trial was originally designed under the assumption of a projected 13⋅4% event rate in the placebo group. Because of the lower than anticipated event rate, the investigators expanded the initial primary endpoint to include unstable angina and transient ischaemic attack, modified the study design from event-driven to time-driven, and extended the time of observation. Still, the final number of events was considerably lower than anticipated, based on the calculated risk profile of the intended population (550 vs 1488). The investigators acknowledge that a proportion of events might have been undetected because of ascertainment issues. As such, despite the merits of this relatively large randomised, double-blind, placebo-controlled trial and the attempts to enrich the event rates, it ultimately did not address the role of aspirin in patients with at least moderate cardiovascular disease risk, because the study was primarily done with patients at low risk. Also notable is the high number of participants who prematurely terminated the study (approximately a third in both groups). Because crossovers were not tracked and non-compliance to the study allocation was only patient-reported, the results of both the intention-to-treat and per-protocol analyses should be interpreted with caution, particularly in the context of their diverging results and lower than anticipated statistical power.
The optimal dosing of aspirin has been a subject of debate.6 Notably, another study published this year, in The Lancet, questions the efficacy of fixed low doses of aspirin for primary prevention in patients of different bodyweight categories. 7 With minimum and maximum bodyweights of 43 kg and 177 kg reported in the placebo group of ARRIVE, whether the same neutral results would be replicated by tailoring the dose of aspirin according to bodyweight remains a matter of interest. Weight-stratified analyses of cardiovascular disease events in the ARRIVE trial are planned. Despite also being designed as one-dose-fits-all trials, important lessons can be learned from two ongoing studies of aspirin for secondary prevention, in which twice-daily versus once-daily (ANDAMAN) and high-dose versus low-dose (ADAPTABLE) strategies are being investigated (appendix). Finally, a key question is whether there is a protective effect of aspirin in cancer prevention (not reported in ARRIVE), for which longer-term follow-up than that reported by the ARRIVE investigators (ie, >10 years) is necessary. 8
There are important take-home messages from the ARRIVE trial. First, the overall findings replicate those from previous studies testing the use of aspirin for primary prevention in patients at low cardiovascular disease risk. On the one hand, these study findings reinforce recommendations against the use of aspirin in this setting but, on the other hand, leave unanswered the role of aspirin for primary prevention in patients without diabetes who have at least moderate cardiovascular disease risk. To this extent, the European guidelines do not recommend using antiplatelet therapy in individuals without cardiovascular disease because of the increased risk of major bleeding, 9 whereas the US Preventive Services Task Force advocates initiating aspirin on the basis of age and a 10-year cardiovascular disease risk of at least 10%, as defined by available risk estimators. 10
Second, this study highlights the weakness and over-estimation of current methods to define the 10-year risk of cardiovascular disease, which are still based on historical data, underscoring the need for more reliable and contemporary estimates of cardiovascular risk. Finally, the study provides insight into the challenge of doing pragmatic trials of aspirin in an era characterised by other preventive and therapeutic interventions. Overall, the consistent trend in negative results from trials of aspirin in primary prevention, particularly in patients without diabetes, suggests that new avenues of research are needed for the prevention of cardiovascular events.
Daily Aspirin Fails to Lower CV Risk in Long-term, Primary Prevention ARRIVE Trial
MUNICH - Aspirin at a daily dose of 100 mg was not seen to reduce the long-term risk for cardiovascular (CV) or cerebrovascular events in a trial that randomly assigned more than 12,000 nondiabetic adults with multiple CV risk factors but no history of CV events. Nor was the risk for stroke reduced.
In the study's primary intention-to-treat (ITT) analysis, 4.29% of persons assigned to aspirin and 4.48% of those in the placebo group experienced the primary endpoint of CV death, myocardial infarction (MI), unstable angina, stroke, or transient ischemic attack (TIA) over a mean of 5 years. The adjusted hazard ratio (HR) for aspirin vs placebo was 0.96 (95% confidence interval [CI], 0.81 - 1.13; P = .604).
Aspirin also did not show a significant effect on any of the individual components of the primary endpoint.
But daily aspirin was associated with more gastrointestinal bleeding, although such events were few in the study, at less than 1% in either group. The HR was 2.11 (95% CI, 1.36 - 3.28; P = .0007). Hemorrhagic strokes were also rare, with a rate of 0.13% in the aspirin group and 0.18% among controls.
The Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) trial, initiated a decade ago, sought to answer long-standing questions about whether aspirin is cardioprotective in a primary prevention setting, in this case in patients thought to be at moderate CV risk.
As described by J. Michael Gaziano, MD, Brigham and Women's Hospital, Boston, Massachusetts, the lack of aspirin effect likely stems from the trial having entered what turned out to be a lower-risk population than its design anticipated.
The trial had aimed to enroll a moderate-risk cohort, and the risk calculators applied to persons who entered the study put their estimated 10-year CV risk at 17.3%. Yet the mean observed 10-year rate of events was less than 9%, Gaziano observed.
Moreover, any outcomes difference that might have emerged between the two groups was likely diluted by the dynamic, evolving backdrop of CV therapies throughout the trial, Gaziano told theheart.org | Medscape Cardiology.
In prior studies of primary prevention aspirin, many of which were conducted in the 1980s and 1990s, said Gaziano, "when a patient developed angina or a TIA, it wasn't standard practice to put them on aspirin." By the time ARRIVE was conducted, aspirin had become a much more common therapy.
"We have much better treatments for atherosclerotic disease now than we had in these old aspirin studies," agreed John G.F. Cleland, MD, Imperial College London, United Kingdom, speaking with theheart.org | Medscape Cardiology.
Cleland, who was not involved with ARRIVE but is an outspoken opponent of aspirin for CV primary prevention, isn't surprised at the low-risk status of the trial participants, who enrolled in an era of "good antihypertensive medications" and widespread statin therapy.
"Once you've dealt with the lipids, and once you've dealt with the hypertension, I'm really not sure what's left for aspirin," Cleland said.
Informing the Dialog
In recent years, CV guidelines have emphasized patient predicted risk when recommending medical therapies, such as statins or blood pressure-lowering drugs, Gaziano pointed out. One lesson of ARRIVE is that an aspirin recommendation for primary prevention should be based on "a complex calculus involving estimates of cardiovascular risk, potentially cancer risk, and bleeding risk," he said.
"I do believe that there are patients whose risk calculus is sufficient to warrant aspirin as part of the armamentarium," Gaziano said. "The use of aspirin remains a decision that should involve a thoughtful discussion between the patient and clinician."
But given a plethora studies looking at aspirin therapy for CV disease and CV prevention, going back decades, after ARRIVE "I don't think the overall dialog between doctor and patient should change dramatically."
Gaziano presented ARRIVE here at the European Society of Cardiology (ESC) 2018 Congress and is lead author on its corresponding publication in the Lancet.
The trial reinforces that the decision whether to go on preventive aspirin "should be between the patient and the doctor based on the risk profile of the patient. So it's an individualized decision," agreed Fausto J. Pinto, MD. Pinto, from Lisbon University Medical School, Portugal, who was not involved in the study, made his comment at a briefing on the trial for the media.
At the media briefing, Stephan Achenbach, MD, Friedrich-Alexander University, Erlangen-Nuremberg, Germany, agreed that ARRIVE is an endorsement of the individualized approach to considering aspirin in primary prevention.
There may be a perception among "informed cardiologists and preventionists" that aspirin has been used "too liberally" in the past, he said. ARRIVE may suggest it's time to view aspirin "in a more individualized fashion, and maybe swing back to being a little more positive about aspirin in primary prevention - if it's done right."
Questions Left Unanswered
The large randomized trial "ultimately did not address the role of aspirin in patients with at least moderate cardiovascular disease risk, because the study was primarily done with patients at low risk," write Davide Capodanno, MD, Policlinico Vittorio Emanuele, Catania, Sicily, Italy, and Dominick J. Angiolillo, MD, University of Florida College of Medicine, Jacksonville, in an accompanying editorial.
Still, "There are important take-home messages from the ARRIVE trial. First, the overall findings replicate those from previous studies testing the use of aspirin for primary prevention in patients at low cardiovascular disease risk," they write.
"On the one hand, these study findings reinforce recommendations against the use of aspirin in this setting but, on the other hand, leave unanswered the role of aspirin for primary prevention in patients without diabetes who have at least moderate cardiovascular disease risk."
ARRIVE entered 12,546 women at least 60 years old and men at least 55 years old from primary care offices in Germany, Italy, Ireland, Poland, Spain, the United Kingdom, and the United States from July 2007 to November 2016.
They were required to have two to four CV risk factors, including dyslipidemia, current smoking, high blood pressure, or a family history of CV disease, regardless of what therapies they might be taking for them. People at high risk of bleeding or with diabetes were excluded.
Per Protocol vs ITT
Although the ITT analysis represents the trial's primary message, Gaziano said, he and his colleagues made much of a prespecified per protocol analysis conducted on all patients who were at least 60% adherent to their treatment assignment, whether aspirin (n = 3790) or placebo (n = 3912).
Even per protocol, aspirin fell short of significance for the composite primary endpoint, at an HR of 0.81 (95% CI, 0.64 - 1.02; P = .076). But there were significant risk reductions for any MI at 0.53 (95% CI, 0.36 - 0.79; P = .0014) and nonfatal of MI 0.55 (95% CI, 0.36 - 0.84; P = .0056).
"I'm not relying on the per protocol analysis as a definitive answer. I'm looking at it for some insights as to why the results are somewhat different from a study we know quite well, the Physicians' Health Study," Gaziano said when interviewed.
That study from the 1980s, which randomly assigned more than 22,000 health professionals to aspirin at 325 mg every other day or placebo, famously saw a 44% reduction in risk acute MI (P < .00001).
Also, after hundreds of aspirin trials, no single additional one will change practice radically, he said; the per protocol analysis will help compare ARRIVE to other studies. "All trials must be interpreted in context with their background, and in this case we have about four decades worth of previous information that we have to integrate."
Alex C. Spyropoulos, MD, from Lenox Hill Hospital, New York City, pointed out that a per protocol analysis can make more sense for an aspirin trial than a trial of an unapproved drug. An ITT analysis is the appropriate high standard for testing an agent that is still investigational, but for one that is widely available like aspirin, a per protocol analysis can provide useful insights.
"If it's an investigational drug versus one that's readily available, then I think there are different expectations of per protocol vs intention-to-treat," Spyropoulos, who was not involved with ARRIVE, said to theheart.org | Medscape Cardiology.
Cleland doesn't seem to buy into the alleged value of a per protocol analysis and sees it as emblematic of a more widespread problem. "The presentation of aspirin data is always biased," he said.
"I think it's fine for them to show the per protocol analysis, but ultimately, their conclusions are correct, that there isn't a benefit of aspirin." Or, Cleland added, "that such benefits, if they exist, are so small that, why don't we move on to something more useful."
ARRIVE was supported by Bayer. "All voting members of the ARRIVE Executive Committee," which included Gaziano, received fees from Bayer during the study. Disclosures for the other authors are in the report. Capodanno reports receiving speaker's and consulting honoraria from AstraZeneca and Bayer. Angiolillo reports consulting fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Janssen, Merck, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; payment for participating in review activities from CeloNova and St Jude Medical; and institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, Osprey Medical, and Renal Guard Solutions
European Society of Cardiology (ESC) Congress 2018. Lancet. August 26, 2018. Abstract, Editorial
Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial
In the ARRIVE study, we aimed to address the role of aspirin in primary prevention of cardiovascular disease in patients at moderate risk of a first cardiovascular event, in a pragmatic, primary care-based randomised trial. The findings add important information to the body of evidence and are generally consistent with previous primary prevention studies. This study also showed the challenges of doing long-term primary prevention studies in an era of aggressive management of risk factors among higher-risk individuals.
In ARRIVE, aspirin treatment did not lower risk of major cardiovascular events in the enrolled patients, despite the presence of multiple cardiovascular risk factors. Stroke incidence did not differ by treatment group. Similar to other published low-risk primary prevention studies, the risk of myocardial infarction was lower among patients taking aspirin than placebo, but this was not significant; however, this difference was significant in the per-protocol analysis. Of note, none of the p values or secondary endpoints were significant.
When determining whether low-dose aspirin is appropriate for an individual patient, the cardiovascular benefit must be weighed against the potential risk for clinical events such as gastrointestinal bleeding (or other bleeds) that can be associated with aspirin use. ARRIVE contributes meaningful clinical information about the risk of bleeding in middle-aged and older patients. The increased risk of gastrointestinal bleeding was in line with what would be expected, because the events were predominantly mild in severity and there was no difference in fatal bleeding rates, consistent with previous primary prevention studies.
ARRIVE provides valuable lessons about the challenges of carrying out large-scale primary prevention studies when there are multiple widely available preventive and therapeutic interventions, resulting in lower observed cardiovascular risk than expected. Although the targeted estimated risk for enrolment in ARRIVE was achieved, the observed event rate was considerably less than anticipated. The estimated baseline risk of cardiovascular disease over 10 years, calculated with the American College of Cardiology/American Heart Association risk calculator, was modestly lower than intended, at 17⋅3%. However, the actual rate of cardiovascular disease events, defined by the number of events confirmed in the study (550 vs 1488), was much lower than estimated, at less than 10% over 10 years.
There are several possible explanations for this lower actual risk in the ARRIVE population. First, risk calculators developed with older data might overestimate risk in current practice. Second, as a large pragmatic study based in the primary care setting, the ability to obtain records for vascular events was a challenge for some providers that were often remote from the acute care setting. Additionally, patients were only seen for study follow-up once a year after the first year, potentially giving rise to a failure to reliably report temporally distant events. Both of these factors could have led to an undercounting of possible vascular events. Third, cardiovascular risk in a population is not a static feature, and this has been seen in other studies. Patients are being treated for their risk factors to lower the risk of the development of disease. Better management of blood pressure, dyslipidaemia, and other risk factors is likely to lower the risk of developing disease, and these interventions are most aggressively used in patients at higher risk. ARRIVE reflects a contemporary cardiovascular risk prevention (therapy) study in which widespread statin use is the norm. 43% of ARRIVE participants were taking statins. The exclusion of patients with diabetes could also contribute to lower overall risk.
Finally, better management of cardiovascular disease when it is manifested by non-acute symptoms can reduce the risk of major acute events. If a patient develops stable angina and receives more intense management including non-study aspirin and close follow-up, the chance of developing a myocardial infarction or other cardiovascular disease event is lessened. This finding is suggested by the difference between the intention-to-treat and per-protocol analyses, particularly for myocardial infarction. It is also supported by the suggestion of a bigger effect early in the study, compared with later in the study.
ARRIVE sought to further assess the effects of aspirin on cancer outcomes during the study. However, the ARRIVE study duration was probably not sufficient to investigate cancer outcomes and to rule out the possibility of benefits of aspirin on long-term cancer outcomes; hence the ARRIVE study could not add information in this regard. Results about incidence of all cancers will be reported elsewhere.
Although the absolute event rates in ARRIVE were lower than expected, the relative effects on specific outcomes were generally similar to those in previous studies in primary prevention of vascular events. Meta-analyses of previous studies showed that aspirin reduces risk of non-fatal myocardial infarction and all myocardial infarction, but does not reduce total stroke or all-cause vascular death.22
The results of ARRIVE, which suggested a stronger effect of aspirin early in the study, compared with later in the study, are also consistent with previous analyses of the time-course of effects of daily aspirin on risk of major vascular events in randomised studies. Whether this atrophy of benefit would be seen in routine practice, when patients know that they are taking active drug rather than placebo, is unknown but it could be argued that in studies with high rates of discontinuation of study treatment, the effects of aspirin during the first 3 years of follow-up provide the best estimate of the probable effects in routine practice in patients who take the drug.
A strength of the ARRIVE study was the inclusion of a large number of older individuals and women with risk of cardiovascular disease. The study was a pragmatic study done in the primary care setting. As such, it was challenging to identify a population at true moderate risk throughout the long treatment period, given the preventive and therapeutic care participants were receiving, thereby reducing the overall power of the study to detect an effect on the primary outcome. Furthermore, it was challenging to capture all efficacy and safety events in this setting.
Compliance represents another major challenge in contemporaneous studies given the ongoing discussions about aspirin among providers, patients, and the public. By contrast with the null finding for the intention-to-treat analysis, the significant treatment differences observed in the per-protocol analysis (ie, approximately 60% of the study population; n=7702) suggests that compliance played a role. During the study, it appears that there was an impact of discussions about the use of aspirin in clinical practice in UK. In the UK subset, results seemed to be different from the rest of the study population, possibly reflecting coverage in the UK medical and general news media after 2009, regarding uncertainty about the effectiveness of aspirin in primary prevention.2
High rates of discontinuation of study treatment in the UK subset of the study are consistent with this possibility.
Another related compliance issue was the potential use of aspirin by patients who became higher risk during the study. For example, if a patient developed chest pain or had a transient ischaemic event, they might well have been withdrawn from the study and started taking aspirin. To address this issue, the Executive Committee amended the protocol to add transient ischaemic events and unstable angina to the primary endpoint, given that these are two conditions biologically related to the primary composite endpoint, and for which clinicians would probably have selectively withdrawn the affected patient from the study. Redefinition of the primary composite endpoint is a strategy that has been used in other contemporary studies to link biologically related primary endpoints, compensate for selective withdrawals, and increase the number of primary endpoints. However, the results of the redefined primary endpoint were not different from those of the original primary endpoint.
While ARRIVE attempted to add relevant information about the cardiovascular benefits and bleeding risks of aspirin in patients at moderate cardiovascular risk, it showed some of the challenges in doing long-term prevention studies in the current era. ARRIVE is generally consistent with many other studies that show aspirin's ability to lower the risk of first non-fatal myocardial infarction without affecting risk of total stroke. With respect to safety, as expected, rates of gastrointestinal bleeding events and some other minor bleeding events were higher in the aspirin treatment group, but there was no significant difference in the incidence of fatal events.
The use of aspirin remains a decision that should involve a thoughtful discussion between a clinician and a patient, given the need to weigh cardiovascular and possible cancer prevention benefits against the bleeding risks, patient preferences, cost, and other factors. The ARRIVE data must be interpreted and used in the context of other studies, which have tended to show a reduction primarily in myocardial infarction, with less of an effect on total stroke (including both ischaemic and haemorrhagic stroke). The overall decision to use aspirin for cardiovascular effects should be done with the help a clinician, given the complex calculus needed to balance all potential benefits and risks.
The use of aspirin in the primary prevention of cardiovascular events remains controversial. We aimed to assess the efficacy and safety of aspirin versus placebo in patients with a moderate estimated risk of a first cardiovascular event.
ARRIVE is a randomised, double-blind, placebo-controlled, multicentre study done in seven countries. Eligible patients were aged 55 years (men) or 60 years (women) and older and had an average cardiovascular risk, deemed to be moderate on the basis of the number of specific risk factors. We excluded patients at high risk of gastrointestinal bleeding or other bleeding, or diabetes. Patients were randomly assigned (1:1) with a computer-generated randomisation code to receive enteric-coated aspirin tablets (100 mg) or placebo tablets, once daily. Patients, investigators, and others involved in treatment or data analysis were masked to treatment allocation. The primary efficacy endpoint was a composite outcome of time to first occurrence of cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischaemic attack. Safety endpoints were haemorrhagic events and incidence of other adverse events, and were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00501059.
Between July 5, 2007, and Nov 15, 2016, 12 546 patients were enrolled and randomly assigned to receive aspirin (n=6270) or placebo (n=6276) at 501 study sites. Median follow-up was 60 months. In the intention-to-treat analysis, the primary endpoint occurred in 269 (4⋅29%) patients in the aspirin group versus 281 (4⋅48%) patients in the placebo group (hazard ratio [HR] 0⋅96; 95% CI 0⋅81-1⋅13; p=0⋅6038). Gastrointestinal bleeding events (mostly mild) occurred in 61 (0⋅97%) patients in the aspirin group versus 29 (0⋅46%) in the placebo group (HR 2⋅11; 95% CI 1⋅36-3⋅28; p=0⋅0007). The overall incidence rate of serious adverse events was similar in both treatment groups (n=1266 [20⋅19%] in the aspirin group vsn=1311 [20⋅89%] in the placebo group. The overall incidence of adverse events was similar in both treatment groups (n=5142 [82⋅01%] vs n=5129 [81⋅72%] in the placebo group). The overall incidence of treatment-related adverse events was low (n=1050 [16⋅75%] vs n=850 [13⋅54%] in the placebo group; p<0⋅0001). There were 321 documented deaths in the intention-to-treat population (n=160 [2⋅55%] vs n=161 [2⋅57%] of 6276 patients in the placebo group).
The event rate was much lower than expected, which is probably reflective of contemporary risk management strategies, making the study more representative of a low-risk population. The role of aspirin in primary prevention among patients at moderate risk could therefore not be addressed. Nonetheless, the findings with respect to aspirin's effects are consistent with those observed in the previously published low-risk primary prevention studies.