Japanese Primary Prevention Project - JPPP

Description:

The current trial sought to assess the safety and efficacy of low-dose aspirin in primary prevention of cardiovascular (CV) events in patients with atherosclerotic risk factors.

Contribution to the Literature: The JPPP trial showed that low-dose aspirin is not superior to no aspirin for primary prevention of CV events in patients with atherosclerotic risk factors.

Study Design

  • Placebo Controlled
  • Blinded
  • Randomized
  • Parallel

Patient Populations:

  • Ages 60-85 years
  • Hypertension, dyslipidemia, and/or diabetes mellitus

    Number of enrollees: 14,658
    Duration of follow-up: 5 years
    Mean patient age: 70.5 years
    Percentage female: 58%

Exclusions:

  • History of coronary artery disease or cerebrovascular disease (including transient ischemic attack [TIA])
  • Atherosclerotic disease requiring surgery or intervention
  • Atrial fibrillation (confirmed or suspected)
  • Patients with peptic ulcer or conditions associated with bleeding (e.g., von Willebrand disease) and those with serious blood abnormalities (e.g., clotting factor deficiencies)
  • Patients with aspirin-sensitive asthma or those with a history of hypersensitivity to aspirin or salicylic acid
  • Patients who were receiving antiplatelet agents, anticoagulants, or long-term treatment with nonsteroidal anti-inflammatory drugs

Primary Endpoints:

  • CV death/myocardial infarction (MI)/stroke

Secondary Endpoints:

  • CV death/MI/stroke/TIA/angina/atherosclerotic disease requiring intervention or surgery
  • Serious extracranial hemorrhage requiring transfusion or hospitalization

Drug/Procedures Used:

Patients were randomized 1:1 to receive enteric-coated aspirin 100 mg once daily or no aspirin in addition to ongoing medications to control hypertension, dyslipidemia, and/or diabetes mellitus.

Principal Findings:

The trial was terminated early due to lower than anticipated event rates. At this time, a total of 14,658 patients were randomized, 7,323 to aspirin and 7,335 to no aspirin. Baseline characteristics were fairly similar between the two arms. Nearly 55% of all patients were >70 years of age. Approximately 85% had hypertension, 34% had diabetes, and 72% had dyslipidemia. All three risk factors were present in 20%. Approximately 13% were smokers and 27% had a family history of premature CV disease.

The primary endpoint of CV death/MI/stroke was similar between the aspirin and no aspirin arms (2.8% vs. 3.0%, hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.77-1.15, p = 0.54). CV death (0.86% vs. 0.78%, p = 0.89) and nonfatal cerebrovascular disease (1.65% vs. 1.64%, p = 0.78) were similar, nonfatal MI (0.3% vs. 0.6%, p = 0.019) and TIA (0.26% vs. 0.49%, p = 0.044) were lower in the aspirin arm. Serious extracranial hemorrhage was higher in the aspirin arm (0.86% vs. 0.51%, HR 1.85, 95% CI 1.22-2.81; p = 0.004). Rates of intracranial hemorrhage were similar (0.07% vs. 0.07%). Numerous gastrointestinal (GI) side effects including stomach/abdominal discomfort, heartburn, ulcer, reflux esophagitis, GI hemorrhage, and erosive gastritis were all individually higher in the aspirin arm compared with no aspirin (p < 0.05 for all).

Cumulative risk of cerebrovascular events at 5 years for aspirin vs. no aspirin: fatal or nonfatal stroke, 2.1% vs. 2.3% (HR 0.93; 95% CI 0.74-1.16, p = 0.51), ischemic stroke or TIA (HR 0.78, 95% CI 0.61-1.01; p = 0.06), and intracranial hemorrhage (HR 1.46, 95% CI 0.96-2.24; p = 0.08) were similar.

Interpretation:

The results of this trial indicate that low-dose enteric-coated aspirin is not superior to no aspirin in reducing CV events, including cerebrovascular events, as a primary prevention strategy in elderly Japanese patients. There appeared to be reductions in the risk of nonfatal MI and TIA, but this was a tempered by an increase in extracranial bleeding including GI bleeding and numerous other GI side effects. The results of this trial are more or less in concordance with primary prevention data with aspirin in other populations. There appears to be a modest reduction in MI/ischemic stroke, but with a higher risk of bleeding in most studies. Current guidelines do not endorse routine use of aspirin for primary prevention of CV events.

It is unknown if the use of a risk calculator such as the Framingham Risk Score or similar would have shown a beneficial effect in higher-risk individuals. The role of aspirin in cancer prevention in this study also needs to be assessed.

References:

Uchiyama S, Ishizuka N, Shimada K, et al., on behalf of the JPPP Study Group. Aspirin for Stroke Prevention in Elderly Patients With Vascular Risk Factors: Japanese Primary Prevention Project. Stroke 2016;47:1605-11.

Ikeda Y, Shimada K, Teramoto T, et al. Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Japanese Patients 60 Years or Older With Atherosclerotic Risk Factors: A Randomized Clinical Trial. JAMA 2014;Nov 17:[Epub ahead of print].

Presented by Dr. Kazuyuki Shimada at the American Heart Association Scientific Sessions, Chicago, IL, November 17, 2014.

Clinical Topics: Diabetes and Cardiometabolic Disease, Clinical Topic Collection: Dyslipidemia, Prevention, Vascular Medicine, Hypertension

Keywords: Myocardial Infarction, Stroke, Neoplasms, Follow-Up Studies, Ischemic Attack, Transient, Esophagitis, Peptic, Risk Factors, Aspirin, Gastritis, Dyslipidemias, Intracranial Hemorrhages, Ulcer, Cerebrovascular Disorders, Heartburn, Confidence Intervals, Hypertension, Diabetes Mellitus, Hemorrhage, AHA Annual Scientific Sessions


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