JPPPタイトル画像

JPPP
Japanese Primary Prevention Project with Aspirin in the elderly with one or more risk factors of vascular events

Background
Cerebro/cardiovascular (CV) death accounts for approximately 30% of total deaths in Japan and therefore it is important to establish a preventive treatment for CV events from the point of public health. Efficacy of aspirin for the secondary prevention of CV events has already been established [1]. Efficacy of aspirin for the primary prevention has also investigated widely [2-7]. The guidelines proposed by a joint study group centering on the Japanese Circulation Society recommend administration of aspirin to patients with multiple risk factors for primary prevention of arteriosclerotic diseases [8]. In addition, the 2002 AHA guidelines recommend use of aspirin in patients with a 10% or higher 10-year risk of CV events [9]. However, these guidelines are based on the data mainly among Caucasian, and benefits of aspirin for primary prevention among Asian such as Japanese, in whom incidence of stroke is higher than myocardial infarction (MI), remains uncertain.

Study design
JPPP is a multicenter, open-label, centrally randomized, controlled trial. In total, 10,000 elderly patients with one or more CV risk factors (age 60-85 years combined with hypertension, hyperlipidemia, and/or diabetes) will be assigned to enteric-coated aspirin (100mg/day) or control.
Protocol has been registered on ClinicalTrials.gov (NCT00225849), and has been submitted to Lancet.

Criteria
Inclusion criteria:

  • Elderly patients not previously diagnosed to have any arteriosclerotic disease, including coronary artery disease or cerebrovascular disease, but meeting any one or more of the following criteria (or on medication for any one or more of the following conditions).
    • Hypertension: SBP ≥ 140 mmHg or DBP ≥ 90 mmHg
    • Hyperlipidemia: Hypercholesterolemia (total cholesterol ≥ 220 mg/dL or LDL cholesterol ≥ 140 mg/dL) or Hypertriglyceridemia (Triglycerides ≥ 150 mg/dL) or Low-HDL cholesterolemia (HDL cholesterol < 40 mg/dL)
    • Diabetes: Fasting blood glucose ≥ 126 mg/dL or casual blood glucose ≥ 200 mg/dL or blood glucose at 2 hrs in the 75-g glucose tolerance test ≥ 200 mg/dL, or HbA1c ≥ 6.5%
  • Age: 60 to 85 years
  • Patients who can give written consent for participation in the study

Exclusion criteria:

  • Patients with a history of coronary artery disease or cerebrovascular disease (including transient ischemic attack)
  • Patients with arteriosclerotic disease requiring surgery or intervention
  • Patients who have or may have atrial fibrillation
  • Patients being treated with aspirin, other antiplatelet agents or anticoagulants
  • Patients using NSAIDs chronically
  • Patients with a history of hypersensitivity to aspirin or salicylic acid
  • Patients with peptic ulcers
  • Patients with a bleeding tendency
  • Patients with serious blood abnormalities
  • Patients with aspirin-sensitive asthma or a history of the same
  • Patients who are otherwise judged by the investigator to be unsuitable for enrollment in the study.

Endpoints
Primary endpoints:

  • Composite of CV death, nonfatal cerebral stroke (of any cause) and nonfatal MI

Secondary endpoints:

  • Individual events or various combinations of the following events:
    • CV death
    • Non-CV death
    • Nonfatal cerebral stroke
    • Nonfatal MI
    • Angina pectoris
    • TIA
    • Arteriosclerotic disease requiring surgery or intervention
    • Extracranial bleeding requiring transfusion or hospital admission
  • Severe side effects that lead to interruption of the study medication.

Assessment of endpoints will be blinded (PROBE).

Rationale for sample size
The annual incidence of CV death, nonfatal stroke (ischemic or hemorrhagic) or nonfatal MI was estimated to be about 1.5-2% for no-aspirin patients, based on the results of domestic epidemiological and interventional studies. Relative risk (RR) in the aspirin group was estimated to be about 0.8 (RR reduction 20%), based on the results of RCTs for primary prevention. To test these hypothesis using long-rank test with 2a = 0.05 and a detection power of 80%, about 10,000 patients (5,000 patients in each group) will be needed if the enrolment period is 1.5 years and the follow-up period is 4 years.

Study period
Study start: March 2005
Expected completion: December 2011

Conclusion
If the benefit of aspirin is demonstrated, that will accelerate dissemination of the primary prevention rationale and contribute to public health not only in Japan but also in other Asian countries.

Principal investigator
Yasuo Ikeda, MD, Keio University School of Medicine, Tokyo, Japan
+81-3-3353-1211 Ext. 62421 yikeda@sc.itc.keio.ac.jp

References
1. Antithrombotic Trialists' Collaoration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. British Medical Journal 2002; 324: 71-86.
2. Steering Committee of the Physicians' Health Study Research Group. Final Report on the Aspirin Component of the Ongoing Physicians' Health Study. New England Journal of Medicine 1989; 321: 129-135.
3. Peto R, Gray R, Collins R. et al. Ramdomised trial of prophylactic daily aspirin in British male doctors. British Medical Journal 1988; 296: 313-316.
4. The Medical Research Council's General Practice Research Framework. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233-241.
5. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351: 1755-1762.
6. Collaborative Group of the Primary Prevention Project (PPP). Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet 2001; 357: 89-95.
7. Ridker PM, et al.: A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. New England Journal of Medicine 2005; 352: 1293-1304.
8. The Joint Study Group 1999-2000. Guidelines for Primary Prevention of Ischemic Heart Disease. Japanese Circulation Journal 2001; 65 (Suppl V): 999-1065. (in Japanese)
9. Pearson TA, Blair SN, Daniels SR, et al. AHA Scientific Statement. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update. Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. Circulation 2002; 106: 388-391.