医療薬学 Vol. 30, No. 12 (2004)

789 Jpn. ノ

Aspirin

Therapy

for the Primary

Cardiovascular A Meta-analysis Yuichi Ohwaki*1,2, Choichiro Tamio

Mitsuhiro

Prevention

ト

Health

Care

Sci.

30(12)789-793 (2004)

of

Disease

of Randomized

Miyazaki2,

Inohira2, Tetsuya

J. Pharm. ー

Kosuke

Hamada2,

Trials

Yamagata2,

Mihoko

Wadal and Kenichiro

Tsutomu

Tahara2,

N. Nakashima1,

Nakashima1

Department of Clinical Pharmacy, Course of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University1 Health Care Pharmacy Corporation2 Received

July 28, 2004

Accepted

October

11, 2004

Although the daily use of aspirin reduces the risks of myocardial infarction, stroke and vascular death in patients at high risk of developing vascular disease, the use of preventative aspirin therapy in patients with no history of cardiovascular disease is controversial. For this reason, we studied the benefits and risks of aspirin therapy in the primary prevention of cardiovascular disease, in particular for aspirin at low doses. On performing a meta-analysis of 4 randomized trials with low-dose aspirin therapy for primary prevention, the low-dose aspirin was found to significantly reduce the risk of myocardial infarction (summary odds ratio (OR), 0.64 ; 95 % confidence interval (CI), 0.56 to 0.74). Though the all-cause mortality (summary OR, 0.94 ; 95 % CI, 0.84 to 1.04) was not significantly affected by aspirin therapy, it significantly increased the risk of gastrointestinal bleeding (summary OR , 2.03 ; 95 % CI, 1.55 to 2.65). These results suggest that low-dose aspirin therapy is beneficial in the primary prevention increases the risk of gastrointestinal bleeding. Key words

aspirin, primary prevention,

cardiovascular

disease, meta-analysis,

of myocardial

gastrointestinal

without a history of cardiovascular

The benefitof aspirin therapy in patientswith a historyof cardiovasculardiseasehas been well established1,2). An influential meta-analysisof over 100 randomized clinical trials showedthat the aspirin therapy reduced the risk of non-fatal myocardial infarctionby 34%, and in the setting of secondary prevention reduces non-fatal strokes by 31%, cardiovascular events by 27% , and cardiovasculardeaths by 18%, respectively2). On the other hand, two early randomizedtrials of aspirin in healthy men, the British Male Doctors' Trial3) and the U.S. Physicians' Health Stud?), had contradictive results regarding whether aspirin could reduce the risk for myocardial infarction. Neither trial had sufficient power to precisely estimate major harms such as gastrointestinal bleeding and hemorrhagic stroke3,4).Recently, three additional large primary preventiontrials for aspirin were published5,7). However, a benefit of aspirin therapy for patients 1 

長 崎 市 文 教 町 1-14

; 1-14,

Bunkyo-machi,

長 崎 市 上 野 町 1-2

; 1-2,

Ueno-machi,

but it

bleeding

disease has not been still

clarified. Further, aspirin doses used in these trials were too

Introduction

2 

infarction,

Nagasaki-shi, Nagasaki-shi,

852-8521 852-8113

high for Japanese. The aim of this study is to estimate the benefits of lowdose aspirin therapy in primary prevention disease. Moreover,

we especially

of cardiovascular

attempted

to evaluate

the

harms of the low-dose aspirin therapy.

Materials

and

We searched the MEDLINE

Methods data base from 1966 to 2002

to identify studies on aspirin's ability to prevent cardiovascular events and its likelihood of causing adverse effects. In addition, the reference

lists of published

trials of aspirin therapy3-7) and previous

primary prevention reviews8-11) were re-

searched. Our search was limited to articles published in English-language. The criteria as the trials in the metaanalysis

were as follows : (1) randomized

than 1 year follow-up

Japan Japan

period that examined

trials with more aspirin therapy

医療薬学 Vol. 30, No. 12 (2004)

790

in patients without a history of cardiovascular disease, (2) aspirin doses were less than 324 mg per day, (3) data on myocardial infarction, stroke, all-cause mortality and bleeding complications were available. Four randomized trials were identified such as the Physicians' Health Study (PHS), the Thrombosis Prevention Trial (TPT), the Hypertension Optimal Treatment Trial (HOT) and the Primary Prevention Project (PPP)4-7).Two large trials that examined the effect of aspirin in patients with diabetes or with stable angina were excluded due to more than 10% of the participants had defined or suspected vascular disease12,13). The British Male Doctors' (BMD) Trial was also excluded because of high dose of aspirin (500 mg per day)3). Results of these randomized clinical trials were combined using a Peto method, and the odds ratio (OR) and 95 % confidence intervals (95 % CI)14)were estimated. Homogeneity was evaluated by a X2 statistic method, in which the weighted difference of each individual estimate from the pooled one was summed up.

Results Four randomized cluded 47,896

trials, i.e. PHS, TPT, HOT and PPP, in-

patients,

of whom 23,930

3.6 to 6.8 years.

Aspirin

doses were remarkably

different

from 75 to 162.5 mg daily. The HOT and PPP studies included women, and all participants trolled hypertension. Meta-analysis all myocardial

in HOT had well con-

of the 4 trials for the combined infarction

produced

a summary

outcome of OR of 0.64

(95 % CI, 0.56 to 0.74) (Fig. 1). The summary OR and CIs showed significant decrease overall in myocardial infarction. There was no heterogeneity myocardial

in odds ratios between trials for

infarction.

The summary ORs (95 % CIs) for the combined

outcome

of all stroke and all-cause mortality produced by 4 trials were 1.01 (0.86 to 1.19) and 0.94 (0.84 to 1.04), respectively. Significant observed

differences

in each outcome.

in OR and CIs could not be These results

Table 1. Outlines of 4 Randomized Trials of Low-dose Aspirin Therapy in Primary Prevention of Cardiovascular Disease. PHS U.S.= Physicians' Health Study ; TPT = Thrombosis Prevention Trial ; HOT =Hypertension Optimal Treatment Trial ; PPP= Primary Prevention Project. †mean

were treated with

aspirin. The outlines of these trials are summarized in Table 1. The follow-up periods of these trials were ranging from

age

Fig. 1. Effect of Low-dose Aspirin Therapy on the Incidence of all Myocardial Infarction in 4 Randomized Trials of Primary Prevention. PPP = Primary Prevention Project ; HOT = Hypertension Optimal Treatment Trial ; TPT = Thrombosis Prevention Trial ; PHS U.S.= Physicians'Health Study ; OR= odds ratio ; 95 % CI = 95 % confidence interval.

were summarized

医療 薬学 Vol. 30, No. 12(2004)

791

in Fig. 2 and 3. Meta-analysis of the 3 trials (except for PPP) for the combined outcome of hemorrhagic rhage produced

the summary

stroke or intracranial

hemor-

OR of 1.38 (95 % CI, 0.86 to

aspirin therapy

for the prevention

of cardiovascular

nese. Thus, we tried meta-analysis

of aspirin therapy which

2.21) (Fig. 4). We can' t use the PPP trial because of no

used the recommended

data on hemorrhagic stroke or intracranial hemorrhage in it. The summary ORs and CIs of these 3 trials showed no sig-

than 324 mg per day. To our best knowledge,

nificant increase. As shown in Fig. 5, meta-analysis of the 3 trials (except for PHS) for the combined outcome of whole gastrointestinal bleeding

produced

the summary

OR of 2.03 (95 % CI,

events.

However due to the high aspirin doses, the findings from these studies could not provide useful information for Japadaily doses in Japan, which one less this is the first

meta-analysis for the harms of low-dose aspirin therapy. Our results suggest that low-dose aspirin therapy for patients without

a history

of cardiovascular

disease

signifi-

cantly reduces the risk of myocardial infarction, though it has no association with all-cause mortality. However, the re-

1.55 to 2.65). We can' t use the PHS trial because of no data

sults also suggest that it significantly

on gastrointestinal

gastrointestinal bleeding. It is difficult to interpret the overall effect of aspirin on

bleeding

in it. Significant

increasing

in

gastrointestinal bleeding could be detected in the ORs and CIs. There was no heterogeneity in all ORs between trials.

In many foreign countries,

there are numerous

the risk of

stroke due to its subtypes. Data from secondary prevention trials suggest that aspirin not only prevents ischemic strokes but also cause hemorrhagic

Discussion

increases

stroke. The effect of aspirin on

the total incidence of stroke depends on the patient's potentistudies on

ality for risk of each stroke subtype2).

Fig. 2. Meta-analysis of the Effect of Low-dose Aspirin Therapy on all Stroke Events in the 4 Randomized Trials of Primary Prevention. PPP = Primary Prevention Project ; HOT = Hypertension Optimal Treatment Trial ; TPT= Thrombosis Prevention Trial ; PHS U.S.= Physicians'Health Study ; OR= odds ratio ; 95 % CI= 95 % confidence interval.

Fig. 3. Meta-analysis of the Effect of Low-dose Aspirin Therapy on All-cause Mortality in the 4 Randomized Trials of Primary Prevention. PPP = Primary Prevention Project ; HOT = Hypertension Optimal Treatment Trial ; TPT= Thrombosis Prevention Trial ; PHS U.S.= Physicians'Health Study ; OR = odds ratio ; 95 % CI= 95 % confidence interval.

医療薬学 Vol. 30, No. 12(2004)

792 Point estimates

in PPP and TPT suggested

modest

de-

creases in total strokes in spite of the wide CIs5,7). In HOT,

trointestinal

bleeding

with aspirin use15-18).Derry and Loke15)

no effect of low-dose aspirin on overall rates of stroke was

performed a meta-analysis of trials published up to 1999 that examined the risk for gastrointestinal hemorrhage with long-

shown6). In PHS, tendency

term (>1 year) aspirin use. Twenty

to increase the risk of stroke in

low-dose aspirin-treated patients was observed, but did not achieve statistical significance. Hart and colleagues11) combined data obtained concluded

the 4 primary

prevention

trials')

that aspirin has no effect on ischemic

the- middle-aged, relatively low-risk 1.03 ; 95% CI, 0.87 to 1.21).

patients

strokes in

(relative

Although the event rates of low-dose aspirin-exposed ticipants for hemorrhagic

strokes including

and

intracranial

with a total of 66,000 participants

four randomized

trials

and an average follow-up

period of 28 months were identified. Aspirin use increased the OR of gastrointestinal hemorrhage (summary OR, 1.68 ; 95 % CI, 1.51 to 1.88). Stalnikowicz-Darvasi

performed

a

risk,

meta-analysis of 9 trials of low-dose aspirin therapy that had lasted for more than 3 months16) ; the summary OR for all

par-

gastrointestinal 1.75).

hem-

orrhage were higher than those of controls in PHS and TPT,

bleeding

For the primary

events were 1.52 (95 % CI, 1.32 to

prevention

of vascular

disease

such as

these differences did not show statistical significance in any trial4,5). In HOT and PPP, the risk of hemorrhagic strokes

myocardial infarction, we clarified that the low-dose aspirin therapy contributed to significant beneficial effects. These

was

effects were clinically

almost

equal

between

intervention

and

control

important.

The association

between

groups6,7). Hart and colleagues11) pooled the results of the 4

all-cause mortality or overall stroke and the low-dose aspirin

primary prevention studies and estimated that the relative risk for hemorrhagic stroke due to long-term aspirin use was 1.36 (95% CI, 0.88 to 2.1).

therapy

Several systematic

reviews have examined the risk of gas-

can not be elucidated

because

of insufficient

bers of events in the primary prevention trials. more data on hemorrhagic stroke are needed. In conclusion,

our meta-analysis

Fig. 4. Hemorrhagic Stroke or Intracranial Hemorrhage in the 3 Randomized Trials of Low-dose Aspirin Therapy in the Primary Prevention. HOT= Hypertension Optimal Treatment Trial ; TPT = Thrombosis Prevention Trial ; PHS =U.S. Physicians' Health Study ; OR = odds ratio ; 95 % CI= 95 % confidence interval.

Fig. 5. Gastrointestinal Bleeding in the 3 Randomized Trials of Low-dose Aspirin Therapy in the Primary Prevention. PPP = Primary Prevention Project ; HOT = Hypertension Optimal Treatment Trial ; TPT -=Thrombosis Prevention Trial ; OR = odds ratio ; 95 % CI= 95 % confidence interval.

suggests

num-

Especially

that the low-

医療 薬学 Vol. 30, No. 12 (2004) dose aspirin therapy for primary prevention appears to reduce the risk of myocardial infarction, while it increases the risk of gastrointestinal bleeding. In the case of aspirin therapy, even if low-dose aspirin, we should make our effort to avoid the gastrointestinal bleeding.

References 1) J. He, P.K. Whelton, B. Vu, M.J. Klag, Aspirin and risk of hemorrhagic stroke : a meta-analysis of randomized controlled trials, JAMA, 280, 1930-1935 (1998). 2) Antiplatelet Trialists' Collaboration, Collaborative overview of randomized trials of antiplatelet therapy-I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients, Br. Med. J., 308, 81-106 (1994). 3) R. Peto, R. Gray, R. Collins, K. Wheatley, C. Hennekens, K. Jamrozik, C. Warlow, B. Hafner, E. Thompson, S. Norton, J. Gilliland, R. Doll, Randomized trial of prophylactic daily aspirin in British male doctors, Br. Med.J., 296, 313-316 (1988). 4) Steering Committee of the Physicians' Health Study Research Group, Final report on the aspirin component of the ongoing Physicians' Health Study, N. Engl. J. Med., 321, 129-135 (1989). 5) The Medical Research Council's General Practice Research Framework, Thrombosis prevention trial : randomized trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischemic heart disease in men at increased risk, Lancet, 351, 233-241 (1998). 6) L. Hansson, A. Zanchetti, S.G. Carruthers, B. Dahla, D. Elmfeldt, S. Julius, J. Menard, K.H. Rahn, H. Wedel, Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension : principal results of the Hypertension Optimal Treatment (HOT) randomized trial, Lancet, 351, 1755-1762 (1998). 7) Collaborative Group of the Primary Prevention Project (PPP), Low-dose aspirin and vitamin E in people at cardiovascular risk : a randomized trial in general practice, Lancet, 357, 89-95 (2001). 8) M. Hayden, M. Pignone, C. Phillips, C. Mulrow, Aspi-

793

rin for primary prevention of cardiovascular events : a summary of the evidence for the U.S. preventive services task force, Ann. Intern. Med., 136, 161-172 (2002). 9) P.S. Sanmuganathan, P. Ghahramani, P.R. Jackson, E.J. Wallis, L.E. Ramsay, Aspirin for primary prevention of coronary heart disease : safety and absolute benefit related to coronary risk derived from meta-analysis of randomized trials, Heart, 85, 265-271 (2001). 10) P.R. Hebert, C.H. Hennekens, An overview of the 4 randomized trials of aspirin therapy in the primary prevention of vascular disease, Arch. Intern. Med., 160, 3123-3127 (2000). 11) R.G. Hart, J.L. Halperin, R. McBride, 0. Benavente, M. Man-Son-Hing, R.A. Kronmal, Aspirin for the primary prevention of stroke and other major vascular events : meta-analysis and hypotheses, Arch. Neurol., 57, 326-332 (2000). 12) ETDRS Investigators, Aspirin effects on mortality and morbidity in patients with diabetes mellitus : Early Treatment Diabetic Retinopathy Study report 14, JAMA, 268, 1292-300 (1992). 13) S. Juul-Moller, N. Edvardsson, B. Jahnmatz, A. Rosen, S. Sorensen, R. Omblus, Double-blind trial of aspirin in

14)

15)

16)

17) 18)

primary prevention of myocardial infarction in patients with stable chronic angina pectoris, Lancet, 340, 14211425 (1992). S. Yusuf, R. Peto, J. Lewis, R. Collins, P. Sleight, Beta blockade during and after myocardial infarction, Prog. Cardiovasc. Dis. 27, 335-371 (1985). S. Derry, Y.K. Loke, Risk of gastrointestinal haemorrhage with long term use of aspirin : meta-analysis, Br. Med.J., 321, 1183-1187 (2000). R. Stalnikowicz-Darvasi, Gastrointestinal bleeding during low-dose aspirin administration for prevention of arterial occlusive events : A critical analysis, J. Clin. Gastroenterol., 21, 13-16 (1995). J.P. Dickinson, C.R. Prentice, Aspirin : benefit and risk in thromboprophylaxis, QJM , 91, 523-538 (1998). P.J. Roderick, H.C. Wilkes, T.W. Meade, The gastrointestinal toxicity of aspirin : an overview of randomized controlled trials, Br. J. Clin. Pharmacol., 35, 219-226 (1993).