AHA 2008: JPAD: No Effect of Aspirin Primary-CV-Event Prevention in Diabetics

November 09, 2008

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November 9, 2008 (New Orleans, Louisiana) — Daily low-dose aspirin taken for more than four years by diabetics initially without a cardiovascular-disease history failed to show a significant effect on a broad composite vascular-disease end point in a prospective, randomized trial published online in the Journal of the American Medical Association and presented here today at the American Heart Association 2008 Scientific Sessions [1].

Among a range of secondary end points, only CV mortality seemed to decline significantly among the patients taking aspirin, although it did seem to benefit those age >65 with respect to overall cardiovascular events.

In addition, there were nonsignificant signs that chronic aspirin therapy in the trial's overall population may have promoted excess bleeding, particularly gastrointestinal bleeding.

The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD), scheduled for the November 12, 2008 issue of the journal, was statistically underpowered for its primary end point of "atherosclerotic events" due to an unexpectedly low rate of clinical events and so can't say much definitive about daily aspirin for primary CV prevention in diabetics.

Dr Hisao Ogawa

But the trial's principal investigator, Dr Hisao Ogawa (Kumamoto University, Kumamoto City, Japan), and several independent experts at the meeting pointed out that the aspirin vs no-aspirin hazard ratios for the primary end point at least trended downward.

Dr Paul M Ridker (Brigham and Women's Hospital, Boston, MA), who wasn't associated with JPAD, at a press briefing on the trial considered a range of studies looking at aspirin for primary prevention in various populations and said, "I think at the end of the day, what we're seeing again [in JPAD] is evidence of modest benefits. I think in the large studies we also see some evidence of modest hazard--aspirin does come with a risk/benefit profile."

Dr J Michael Gaziano

Commenting on JPAD for heartwire , Dr J Michael Gaziano (Brigham and Women's Hospital), said, "What we have is a trend in the direction that we would have expected, a trend for benefit." Did the findings fail to reach significance, he asked, because the trial was underpowered or because aspirin really doesn't reduce risk? Further trials are the only way to know, he said. But for now, he said, "It would be a mistake to take [JPAD] as evidence that aspirin doesn't work in diabetics."

JPAD randomized 2539 patients aged 85 or younger with type 2 diabetes and no history of atherosclerotic disease, including structural or arrhythmic CV disease, stroke or other cerebrovascular disease, or other peripheral vascular disease to receive or not receive aspirin at either 81 mg/day or 100 mg/day on an open-label basis. Patients on antiplatelet or other antithrombotic therapy were excluded.

Patients in the aspirin and nonaspirin groups had been diabetic for 7.3and 6.7 years, respectively, and their diabetes was well controlled, according to Ogawa, as was their blood pressure.

Over a median follow-up of 4.4 years, the 1262 patients on aspirin experienced 68 atherosclerotic events as compared with 86 among the 1277 in the nonaspirin group (5.4% vs 6.7%), a nonsignificant difference. Atherosclerotic events included sudden death; death from coronary, cerebrovascular, or aortic causes; nonfatal MI, unstable angina, new exertional angina; nonfatal ischemic or hemorrhagic stroke; transient ischemic attack; or nonfatal aortic or peripheral vascular disease.

The risk of fatal coronary or cerebrovascular events was significantly decreased in the aspirin group; no other secondary end point, including death from any cause, showed a benefit from aspirin.

In a subgroup analysis, the 1363 patients aged >65 years showed a significant aspirin-related decrease in risk of atherosclerotic events; younger patients showed no such difference.

Hazard Ratio (95% CI) for Primary and Secondary End Points and in Age Subgroup Analysis, Aspirin vs Nonaspirin

Clinical outcomes HR (95% CI) p
Primary end point* 0.80 (0.58–1.10) 0.16
Fatal coronary or cerebrovascular events 0.10 (0.01–0.79) 0.0037
All-cause mortality 0.90 (0.57–1.14) 0.67
Atherosclerotic events* (among age >65 y) 0.68 (0.46–0.99) 0.047

*Composite of sudden death; death from coronary, cerebrovascular, or aortic causes; nonfatal MI, unstable angina, new exertional angina; nonfatal ischemic or hemorrhagic stroke; transient ischemic attack; or nonfatal aortic or peripheral vascular disease

As the discussant following Ogawa's presentation, Dr Marian Limacher (University of Florida, Gainesville) observed that current guidelines recommend daily aspirin for diabetics to reduce cardiovascular risk. "Yet we lack firm evidence for such recommendations, and we may need to rethink the guidelines. JPAD did show that low-dose aspirin is not effective in preventing atherosclerotic events in diabetic patients. Importantly, it demonstrated no increased risk in hemorrhagic stroke, although aspirin did result in a higher gastrointestinal symptom rate and some GI bleeding."

There were 12 gastrointestinal hemorrhagic events in the aspirin group and four in the nonaspirin group; among aspirin recipients they included four cases of severe GI bleeding requiring surgery, Ogawa had reported.

Also, in the aspirin and nonaspirin groups, respectively, there were 22 and 24 nonfatal ischemic strokes, five and three nonfatal hemorrhagic strokes, and five and eight transient ischemic attacks, with none of the differences reaching significance.

Ogawa and others noted that JPAD may allay some concerns about the safety of daily aspirin in an Asian population--in particular, when it's given at the dosages used in the trial. "Historically, the Asian population has higher rates of hemorrhagic stroke," Gaziano observed. "I think this trial helps us in this regard, in that this high-risk population with diabetes did not seem to have a dramatic increase in hemorrhagic strokes when placed on aspirin. It was a very small number of events, but there wasn't a signal that it was a problem."

Limacher posed the question, "Will [JPAD] change clinical practice? Maybe. In the group under age 65, perhaps we'll be rethinking whether everyone should be on aspirin. Will it change guidelines? I think this is something that should be reviewed and will depend on studies in the works."

In an accompanying editorial [2], Dr Antonio Nicolucci (Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy) describes several such trials looking at aspirin therapy in diabetics. One is A Study of Cardiovascular Events in Diabetes (ASCEND) and another is Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D), which together "are expected to enroll more than 15 000 patients overall and will help clarify the role of aspirin for primary prevention of cardiovascular disease."

In addition, he notes, the recently published Prevention of Progression of Arterial Disease and Diabetes (POPADAD) study [3], as reported by heartwire , "found no evidence of benefit of aspirin on cardiovascular events and mortality."

Meanwhile, Nicolucci writes, "The decision to prescribe aspirin should be made on an individual patient basis after careful evaluation of the balance between the expected benefits and the risk of major bleeding."

Disclosure information for Ogawa and his colleagues appears in the paper. Limacher reports receiving research support from Orexigen Therapeutics. Nicolucci reports being the principal investigator of the ACCEPT-D trial, "a nonprofit trial supported by the Italian Drug Agency." He also reports having received research grants from Bayer.

  1. Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008; 300:2180-2181.

  2. Nicolucci A. Aspirin for primary prevention of cardiovascular events in diabetes. Still an open question. JAMA 2008; 300:2134-2141.

  3. Belch J, MacCuish A, Campbell I, et al. The prevention and progression of arterial disease and diabetes (POPADAD) trial: factorial randomized placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008; DOI:10.1136/bmj.a1840. Available at: http://www.bmj.com. Abstract

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.


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