Susan Jeffrey

November 18, 2014

CHICAGO — A new trial shows no benefit of low-dose, once-daily aspirin in the primary prevention of cardiovascular events in patients with multiple risk factors, including hypertension, diabetes, and dyslipidemia.

No benefit was seen for the composite endpoint of nonfatal myocardial infarction (MI), nonfatal stroke, or death from cardiovascular causes. There were significant reductions in MI and in transient ischemic attack (TIA), but a significant increase in serious extracranial hemorrhage meant the net benefit was questionable.

The overall rate of events was much lower than anticipated in this study, and it did not reach statistical significance, said study coauthor Kazuyuki Shimada, MD, Department of Cardiology, Shin-Oyama City Hospital, Tochigi, Japan. "Therefore, the possibility that aspirin does have a beneficial effect in this population cannot be excluded."

Still, the clinical importance of aspirin for primary prevention was "less than originally anticipated in this population," he concluded, and further analyses are planned to see whether they can identify patients who may benefit most from aspirin.

"Lastly, it will be interesting to see if the ongoing studies ARRIVE, ASCEND, ASPREE and ACCEPT-D, which are assessing primary prevention in predominantly Western populations, have different outcomes to our study in Japanese patients," Dr Shimada said.

The results of the Japanese Primary Prevention Project (JPPP) were published online November 17 in JAMA to coincide with presentation here at the American Heart Association 2014 Scientific Sessions.

Primary Prevention

Dr Kazuyuki Shimada

For the last several years, the benefits and risks of aspirin for primary prevention of cardiovascular events for those at moderately increased risk have been "hotly debated," Dr Shimada said. "Recently the FDA [Food and Drug Administration] cautioned against the general use of aspirin for the primary prevention of heart attacks and strokes," he noted. An FDA release on May 5 concluded that after a review of the literature, the evidence does not support the use of aspirin for primary prevention.

"In order to inform our decision-making in Japan and to develop country-specific recommendations, we conducted the Japanese Primary Prevention Project study, which prospectively evaluated daily, low-dose aspirin in the primary prevention of CV [cardiovascular] events in elderly Japanese patients with cardiovascular risk factors," Dr Shimada said.

The Japanese Primary Prevention Project (JPPP) was a multicenter, open-label, randomized, parallel-group trial. Using a Prospective Randomized Open Blinded Endpoint (PROBE) study design, patients with hypertension, dyslipidemia, and/or diabetes mellitus without a history of cardiovascular disease were enrolled during routine visits to their primary care provider at one of 1007 clinics in Japan between March 2005 and June 2007.

A total of 14,658 patients were randomly assigned to receive 100 mg of enteric-coated aspirin per day or no aspirin, along with continuous management of their other risk factors. Patients were to be followed for up to 6.5 years, with last follow-up in May 2012. Study outcomes were adjudicated by an expert panel blinded to treatment assignments.

"At the time of the second interim analysis in May 2011, the independent data monitoring committee recommended that the study was to be discontinued at the next annual study assessment due to futility and to avoid unnecessary risk of adverse events," he said. At the time of study discontinuation, patients had been followed up for a median of 5.02 years (interquartile range, 4.55 to 5.33 years).

The primary outcome was a composite of death from cardiovascular causes (MI, stroke, and other cardiovascular causes), nonfatal stroke (ischemic or hemorrhagic, including undefined cerebrovascular events), and nonfatal MI. Secondary outcomes included those events plus TIA, angina pectoris, and atherosclerotic disease requiring surgery or intervention, as well as each individual outcome.

A total of 56 fatal events occurred in each group. Nonfatal stroke occurred in 114 patients in the aspirin group and 108 in the no-aspirin group. Nonfatal MI was seen in 20 patients taking aspirin vs 38 in the no-aspirin group, and undefined cerebrovascular events occurred in three patients receiving aspirin vs five patients not receiving aspirin.

"There was no statistically significant difference between the two groups in time to the primary endpoint," Dr Shimada reported. "The hazard ratio indicates that there was an insignificant 6% reduction in the risk of a primary endpoint event in the aspirin group vs the no aspirin group."

Table. JPPP: Main Outcomes

Endpoint Aspirin No Aspirin Hazard Ratio (95% Confidence Interval) P Value
5-year cumulative event rate (%) 2.77 (2.40- 3.20) 2.96 (2.58 - 3.40) 0.94 (0.77 - 1.15) .54
Nonfatal MI 0.30 (0.19 – 0.47) 0.58 (0.42 – 0.81) 0.53 (0.31 – 0.91) .02
TIA 0.26 (0.16 – 0.42) 0.49 (0.35 – 0.69) 0.57 (0.32 – 0.99) .04
Extracranial hemorrhage requiring transfusion or hospitalization 0.86 (0.67 – 1.11) 0.51 (0.37 – 0.72) 1.85 (1.22 – 2.81) .004

 

The risk of a primary endpoint event did not differ significantly for aspirin vs no aspirin in any of the disease risk factor subgroups assessed, including hypertension vs no hypertension, dyslipidemia vs no dyslipidemia, diabetes vs no diabetes, and family history vs no family history, or by demographic factors such as age and sex.

For most secondary endpoints, there was no significant difference between the treatment groups. However, nonfatal MI was significantly reduced by 47% with aspirin vs no aspirin, and TIA was reduced by a significant 43%, Dr Shimada said.

"Conversely, there was a significant increase in serious extracranial hemorrhage in the aspirin group — the hazard ratio indicates an 85% increase in such events," he said. "Therefore, any benefits of aspirin in terms of the reduced risk of nonfatal MI and TIA must be counterbalanced with consideration of the significantly increased risk of serious extracranial hemorrhage."

Finally, there was a prespecified analysis of gastrointestinal (GI) adverse events in the randomized population. "The results clearly indicate that aspirin is associated with an increased incidence of these GI events, the known side-effect profile of aspirin, although the study was unblinded and these were not primary or secondary analyses," he said.

Less Power, Increasing Challenge

In an accompanying editorial, J. Michael Gaziano, MD, MPH, Veterans Affairs Boston Healthcare System, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, and associate editor, JAMA, and Philip Greenland, MD, Departments of Preventive Medicine and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, and senior editor, JAMA, point to the lower than expected event rate in this study, "leading to a study with less power to detect differences in the primary outcome than anticipated."

Aspirin primary prevention trials have "become increasingly challenging to conduct," they write. "There is wider use of a number of prevention medications such as antihypertensive agents and lipid-lowering drugs, as well as other preventive measures that collectively result in fewer events than expected, as seen in JPPP."

The findings add to the "body of evidence that helps refine the answer to the question of when aspirin should be used to prevent vascular events," they say. "Decision making involves an assessment of individual risk-to-benefit that should be discussed between clinician and patient."

In some situations the benefit of aspirin is clear, such as those at high short-term risk after an acute vascular event, or those undergoing certain vascular procedures, they add. "On the other hand, patients at very low risk of vascular events should not take aspirin for prevention of vascular events, even at low dose."

In the middle are those without overt vascular disease but risk levels approaching those with cardiovascular disease. "It remains likely that there is some level of risk of CVD [cardiovascular disease] events that would result in a positive trade-off of benefit and risk for the use of aspirin, but the precise level of risk is uncertain. This is in part because most populations studied have been at very low risk."

The editorialists also point to the ongoing ASCEND, ARRIVE, and ASPREE studies to help refine guidelines in higher-risk patients.

"Findings from these studies, with additional data about risks and other potential long-term benefits, such as reducing the risk of colorectal and other cancers, will prove helpful for clinical decision making involving the role of aspirin for primary prevention," Dr Gaziano and Dr Greenland conclude.

End of the Road?

At the meeting here, Dorairaj Prabhakaran, DM, vice president and professor of epidemiology, Public Health Foundation of India, and professor of epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom, was the invited discussant for this trial. He considered the question of whether these findings spell the "end of the road for aspirin in primary prevention."

Among the reasons the trial was negative were the lack of power due to early termination, he said, and the fact that aspirin on a background of widespread statin use may make it difficult to show a benefit.

"Benefit is very unlikely in low-risk populations such as those with less than 1% events per year," Dr Prabhakaran said. "There could be a role in special groups, particularly younger populations that are not being evaluated well from low-/middle-income countries like India, where the risk of coronary artery disease is extremely high."

Risk scores are needed for these countries to identify high-risk people, he added, and "we also await the results of other studies in primary prevention," such as the TIPS-2 trial in India that combines a "polypill" with aspirin, he noted.

If risk is less than 10%, benefit is unlikely, but there is a "gray area" between 10% and 20% where benefit may yet be seen with aspirin for primary prevention, he said (J Am Coll Cardiol. 2014;64:319-327).

He quoted Sir Richard Doll, who once said, "Death is inevitable, but premature death is not."

"In reducing premature death, aspirin is the most inexpensive option and we should pursue with vigor in identifying individuals and populations who may benefit," Dr Prabhakaran concluded.

During a discussion after the presentation, Christopher Cannon, MD, Harvard Medical School, pointed out that in his practice, many patients arrive having already started aspirin therapy on their own, "whereas we're seeing there's an active decision of benefit and risk that needs to be taken.

"It's a serious decision whether to start aspirin, so this is a terrific reminder that we really need to calculate based on risk and see could this be of benefit, or would there be more harm?" he added.

The JPPP was sponsored by the Japanese Ministry of Health, Labor, and Welfare and the Waksman Foundation of Japan. Enteric coated 100-mg aspirin tablets were provided free of charge by Bayer Yakuhin. Dr Ikeda reports receiving fees for medical advice from AstraZeneca, Bayer, Daiichi Sankyo, GlaxoSmithKline, and sanofi-aventis. Disclosures for coauthors appear in the publication.

JAMA. Published online November 17, 2014. Abstract Editorial

American Heart Association (AHA) 2014 Scientific Sessions. Presented November 17, 2014.

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