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 4.29% 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.
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. Fausto, 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.
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