Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes - JPAD

Nov 09, 2008
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Trial Sponsor:
Ministry of Health, Labor, and Welfare of Japan
Date Presented:
01/01/2008
Date Published:
01/01/2008
Date Updated:
11/09/2008
Original Posted Date:
11/09/2008
References

Description:

Although aspirin is routinely used in patients with diabetes and increased cardiovascular risk, there are limited data from clinical trials on this issue. Accordingly, the JPAD trial sought to evaluate the effect of low-dose aspirin on cardiovascular outcomes in patients with type 2 diabetes mellitus.

Hypothesis:

Aspirin would be associated with a reduction in cardiovascular events in patients with type 2 diabetes, and without evidence of prior coronary artery disease.

Study Design

Study Design:

Patients Screened: 2,567
Patients Enrolled: 2,539
Mean Follow Up: 4.37 years
Mean Patient Age: 65 years
Female: 45

Patient Populations:

  • Type 2 diabetes mellitus
  • Ages 30-85 years

Exclusions:

  • Electrocardiographic changes consisting of ischemic ST-segment depression, ST-segment elevation, or pathologic Q waves
  • History of coronary artery disease, confirmed by coronary angiography
  • History of cerebrovascular accident, consisting of cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, and TIA
  • History of arteriosclerotic disease necessitating medical treatment
  • Atrial fibrillation
  • Pregnancy
  • Use of antiplatelet or antithrombotic medications
  • History of severe gastric or duodenal ulcer
  • Severe liver dysfunction
  • Severe renal dysfunction
  • Allergy to aspirin

Primary Endpoints:

  • Composite of sudden death
  • Death from coronary, cerebrovascular, and aortic causes
  • Nonfatal acute MI
  • Unstable angina
  • Newly developed exertional angina
  • Nonfatal ischemic and hemorrhagic stroke
  • TIA
  • Nonfatal aortic and peripheral vascular disease

Secondary Endpoints:

  • Sudden death
  • Death from coronary, cerebrovascular, and aortic causes
  • Nonfatal acute MI
  • Unstable angina
  • Newly developed exertional angina
  • Nonfatal ischemic and hemorrhagic stroke
  • TIA
  • Nonfatal aortic and peripheral vascular disease
  • GI bleeding
  • Any hemorrhagic event other than hemorrhagic stroke

Drug/Procedures Used:

This was an open-label study. Patients in the aspirin arm received aspirin 81 or 100 mg daily. Patients in the nonaspirin arm were also allowed to use antiplatelet/antithrombotic therapy, including aspirin, if needed, and vice versa.

Concomitant Medications:

Statins (26%), angiotensin-converting enzyme inhibitors (15%), angiotensin-receptor blockers (21%), and beta-blockers (7%)

Principal Findings:

A total of 2,539 patients were randomized, 1,262 to aspirin and 1,277 to nonaspirin. Baseline characteristics were fairly similar between the three groups. About 58% had a history of hypertension, 54% had dyslipidemia, and 12% had a family history of coronary artery disease. The median duration of diabetes was 7.3 years, with a baseline glycated hemoglobin of 7.1%. About 13% of the patients were on insulin, and 5% were on thiazolidines; the majority of the patients (57%) were on sulphonylureas. Fasting blood glucose, triglycerides, and high-density lipoprotein (HDL) were 147, 135, and 55 mg/dl, respectively.

By the end of the trial, 10% of the patients in the aspirin arm had stopped taking aspirin, and 0.7% of the patients in the nonaspirin arm has started taking aspirin or other antithrombotic medications. There was no difference between the aspirin and nonaspirin arms in the incidence of the primary endpoint (5.4% vs. 6.7%, hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.58-1.10, p = 0.16).

There was a significant reduction in the combined incidence of fatal coronary and cerebrovascular events (0.08% vs. 0.8%, p = 0.0037), but no differences in the incidence of nonfatal myocardial infarction (MI) (1.0% vs. 0.7%, p = 0.5), unstable angina (0.3% vs. 0.8%, p = 0.13), stable angina (1.0% vs. 0.9%, p = 0.82), nonfatal ischemic strokes (1.7% vs. 1.9%, p = 0.80), nonfatal hemorrhagic strokes (0.4% vs. 0.2%, p = 0.48), transient ischemic attack (TIA) (0.4% vs. 0.6%, p = 0.42), or all-cause mortality (2.7% vs. 3.0%, p = 0.67).

On subgroup analysis, aspirin was associated with a significant reduction in the incidence of the primary endpoint in patients older than 65 years of age (6.3% vs. 9.2%, p = 0.047), although a formal test of interaction with age was non-significant. There were no other subgroup differences, including for gender, smoking status, history of hypertension, or dyslipidemia.

There were 12 episodes of gastrointestinal (GI) bleeding in the aspirin group, compared with four in the nonaspirin group that were severe enough to require blood transfusion. Other bleeding, such as retinal bleeding, nose-bleeding, and hematuria were also more common with aspirin.

Interpretation:

The results of the JPAD trial indicate that aspirin 81 or 100 mg daily is not associated with a significant reduction in total atherosclerotic events, including coronary, cardiovascular, and peripheral vascular events, in patients with type 2 diabetes. Although the Antithrombotic Trialists’ Collaboration demonstrated a significant reduction in cardiovascular outcomes with aspirin, they did not note a significant reduction for the subgroup of patients with diabetes. JPAD is the first prospectively designed trial to evaluate the use of aspirin in the primary prevention of cardiovascular events in patients with type 2 diabetes, and did not show a significant cardiovascular benefit with low-dose aspirin for primary prevention either.

Limitations of this trial include the open-label assignment to aspirin, such that only the endpoint assessors were blinded to medication allocation, as well as the low event rate, which was a third of the expected incidence, and could thus have resulted in a type II error. The findings of the JPAD trial, including a potential benefit in patients older than 65 years of age, will need to be validated by further prospective studies, given the public health significance of this topic.

References:

Presented by Dr. Hisao Ogawa at the American Heart Association Annual Scientific Sessions, New Orleans, November 2008.

Ogawa H, Nakayama M, Morimoto T, et al., on behalf of the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008;300:2134-41.

Keywords: Coronary Artery Disease, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Angina, Stable, Diabetes Mellitus, Type 2, Risk Factors, Fibrinolytic Agents, Primary Prevention, Glycated Hemoglobin A, Blood Transfusion, Dyslipidemias, Public Health, Hematuria, Confidence Intervals, Thiazolidines, Myocardial Infarction, Stroke, Insulins, Smoking, Blood Glucose, Triglycerides, Lipoproteins, HDL, Fasting


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