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Effect of Aspirin on Vascular
and Nonvascular Outcomes
Meta-analysis of Randomized Controlled Trials
Sreenivasa Rao Kondapally Seshasai, MD, MPhil; Shanelle Wijesuriya, MA, MBBChir;
Rupa Sivakumaran, MA, MBBChir; Sarah Nethercott, MA, MBBChir;
Sebhat Erqou, MD, PhD; Naveed Sattar, MD, PhD; Kausik K. Ray, MD
Background: The net benefit of aspirin in prevention of 0.96; number needed to treat, 120), driven primarily by
CVD and nonvascular events remains unclear. Our objec- reduction in nonfatal MI (OR, 0.80; 95% CI, 0.67-0.96; num-
tive was to assess the impact (and safety) of aspirin on vas- ber needed to treat, 162). There was no significant reduc-
cular and nonvascular outcomes in primary prevention. tion in CVD death (OR, 0.99; 95% CI, 0.85-1.15) or can-
cer mortality (OR, 0.93; 95% CI, 0.84-1.03), and there was
Data Sources: MEDLINE, Cochrane Library of Clini- increased risk of nontrivial bleeding events (OR, 1.31; 95%
cal Trials (up to June 2011) and unpublished trial data CI, 1.14-1.50; number needed to harm, 73). Significant
from investigators. heterogeneity was observed for coronary heart disease and
bleeding outcomes, which could not be accounted for by
Study Selection: Nine randomized placebo- major demographic or participant characteristics.
controlled trials with at least 1000 participants each, re-
porting on cardiovascular disease (CVD), nonvascular out- Conclusions: Despite important reductions in nonfatal
comes, or death were included. MI, aspirin prophylaxis in people without prior CVD does
not lead to reductions in either cardiovascular death or can-
Data Extraction: Three authors abstracted data. Study- cer mortality. Because the benefits are further offset by clini-
specific odds ratios (ORs) were combined using random- cally important bleeding events, routine use of aspirin for
effectsmeta-analysis.Risksvsbenefitswereevaluatedbycom- primary prevention is not warranted and treatment deci-
paring CVD risk reductions with increases in bleeding. sions need to be considered on a case-by-case basis.
Results: During a mean (SD) follow-up of 6.0 (2.1) years Arch Intern Med. 2012;172(3):209-216.
involving over 100 000 participants, aspirin treatment re- Published online January 9, 2012.
duced total CVD events by 10% (OR, 0.90; 95% CI, 0.85- doi:10.1001/archinternmed.2011.628
W
HILE META - ANALY - guidelines for use of aspirin in primary
Author Affiliations: Cardiac
and Vascular Sciences Research ses to date1,2 have prevention of CVD are based on informa-
Centre, St George’s University shown modest ben- tion from trials published up to 2005,5,6
of London, London, England efits of aspirin for since when at least 3 additional studies
(Drs Seshasai and Ray); the primary preven-
Department of Geriatrics, tion of cardiovascular disease (CVD), it re-
Addenbrooke’s Hospital, mains unclear to what extent these ben- See Invited Commentary
Cambridge, England efits are offset by clinically important at end of article
(Dr Wijesuriya); Department of
Paediatrics, Chelsea and
Westminster Hospital, London CME available online at have been reported.7-9 In this meta-analy-
(Dr Sivakumaran); Department www.jamaarchivescme.com sis we therefore aimed to provide an up-
of Paediatrics, Broomfield and questions on page 208 dated synthesis of evidence regarding the
Hospital, Chelmsford, England wider role of aspirin in primary preven-
(Dr Nethercott); Department of bleeding episodes. Emerging data from pri- tion, including its effect on hitherto un-
Internal Medicine, University of mary and secondary prevention trials also derinvestigated outcomes such as non-
Pittsburgh Medical Center, suggest significant reductions in cancer
Pittsburgh, Pennsylvania vascular disorders (especially cancer),
(Dr Erqou); and Glasgow
mortality in people receiving aspirin pro- and to assess whether the risks vs ben-
Cardiovascular Research phylaxis,3 stimulating discussions for efits of aspirin treatment vary impor-
Centre, University of Glasgow, more widespread use of this agent tantly according to key demographic or
Glasgow, Scotland (Dr Sattar). among healthy individuals.4 Current participant characteristics.10-12
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SBP,
No. of Age, Mean Mean (SD),
Source Location Year Participants (SD), y Male, % Diabetes, % Smokers, % mm Hg
BDS 24 England 1988 5139 63.6 100 2 31 135.8
PHS 15 US 1989 22 071 53.8 100 2 11 128.5
HOT 14 Multiple 1998 18 790 61.5 53 8 16 170
TPT 25 UK 1998 5085 57.5 100 NS 41 139
PPP 26 Italy 2001 4495 64.4 42 17 15 145.1
WHS 13 US 2005 39 876 54.6 0 3 13 127.3
POPADAD 7 Scotland 2008 1276 60.3 44 100 31 145
JPAD 8 Japan 2008 2539 64.5 55 100 21 135
AAA 9 Scotland 2010 3350 61.6 28 3 32 147.5
Total or 102 621 57.3 a (4.1) 46 8 16 138 a (17)
Mean (SD)
Abbreviations: AAA, Aspirin for Asymptomatic Atherosclerosis Trial 9; BDS, British Doctors Study 24; HOT, Hypertension Optimal Treatment Trial 14; JPAD, Japanese
Primary Prevention of Atherosclerosis With Aspirin for Diabetes Trial 8; NS, not stated; PHS, Physicians’ Health Study 15; POPADAD, Prevention of Progression of Arterial
Disease and Diabetes Trial 7; PPP, Primary Prevention Project 26; SBP, systolic blood pressure; TPT, Thrombosis Prevention Trial 25; WHS, Women’s Health Study. 13
Conventional unit conversion factor: To convert cholesterol to milligrams per deciliter, divide by 0.0259.
a Represents weighted mean (SD).
b Concomitant treatments include agents other than anti-platelet drugs (eg, blood pressure-lowering medication), as in factorial trials.
c Follow-up duration shown for POPADAD and JPAD represents median follow-up, not mean. Also, total cholesterol values for POPADAD are median, not mean. Data
on cholesterol measurements at baseline were missing in approximately 0.6% of all participants in the AAA study.
d Follow-up duration shown in person-years according to treatment arm was obtained directly from study reports for BDS and TPT, and was calculated based on
numbers per group multiplied by mean (or median) follow-up time for other studies. In PHS, the reported duration of follow-up differed for various outcomes, and the
numbers shown correspond to those for MI (including nonfatal and fatal MI).
ports,28 we did not find any signifi- Aspirin for Asymptomatic Athero- events increased proportionately with
cant sex differences in treatment effect sclerosis Trial [AAA]9), or health care background event rates for these out-
for total CVD events (eFigure 7). professionals (British Doctors Study comes, although the benefit ap-
Lastly, no significant heterogeneity [BDS],8 PHS,15 and WHS13) were ex- peared to be more modest for CVD
between studies was observed for cluded (eTable 4). Results were also than nonfatal MI (Figure 4). Such
nonvascular, cancer, and all-cause similar when fixed-effect meta- benefits were offset by increased rates
mortality (P⬎.10; Figure 2). analysis was used instead of random- of nontrivial bleeding, even though for
effects models. There was no evi- nonfatal MI there was a suggestion
SENSITIVITY ANALYSES dence of publication bias (Egger test that at high baseline event rates there
The effect of aspirin on nonfatal MI P value ⬎.05 for all major out- may be net benefit in favor of aspirin
or total CVD events was unrelated to comes; eFigure 8). prophylaxis. The NNT to avoid 1
its average daily dose and was more nonfatal MI event over 6 years was
pronounced in trials published be- COMPARATIVE MERITS 162 (NNT was 120 to avert 1 CVD
fore 2000 (compared with more re- OF ASPIRIN event over the same period). By com-
cent studies; Figure 3). Findings were parison, the NNT for nonvascular
comparable when studies con- The net benefit due to aspirin treat- death was 292 (247 for cancer death),
ducted exclusively in non-Western ment (expressed as a difference be- and at least 1 nontrivial bleeding event
populations (JPAD8), or people with tween absolute event rates in the pla- was caused for every 73 persons
diabetes (JPAD8 and POPADAD7) or cebo and aspirin treatment arms) for treated with aspirin for approxi-
asymptomatic PAD (POPADAD7 and both nonfatal MI and total CVD mately 6 years.
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Figure 2. Effect of aspirin on vascular and nonvascular outcomes or death. CHD indicates coronary heart disease; CVD, cardiovascular disease; and
MI, myocardial infarction.
Concomitant treatment
Yes 0.78 (0.61-1.00) .39 0.90 (0.84-0.98) .88 1.33 (1.05-1.69) .08
No 0.83 (0.60-1.15) 0.90 (0.79-1.03) 1.26 (1.14-1.39)
0.25 0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0
Odds Ratio Odds Ratio Odds Ratio
Favors aspirin Favors placebo Favors aspirin Favors placebo Favors aspirin Favors placebo
Figure 3. Effect of aspirin on nonfatal myocardial infarction (MI), total cardiovascular disease (CVD) events, and nontrivial bleeding events according to various
study-level characteristics. For nonfatal MI, the number of events per study were categorized as 100 and above or below 100. For total CVD events and nontrivial
bleeding, the corresponding categories were 500 and above or below 500. P values are shown for the overall test of heterogeneity between subgroups.
COMMENT Available data also suggest that the ceiving daily (vs alternate day) as-
principal cardiovascular effect of as- pirin treatment, with a particularly
This meta-analysis provides the larg- pirin in primary prevention is on unfavorable risk to benefit ratio for
est evidence to date regarding the nonfatal MI with no real benefit with individuals at lower baseline CVD
wider effects of aspirin treatment in regard to fatal MI, stroke, or CVD risk. Since it may be argued that
primary prevention and contextu- death. Even these benefits are con- events such as MI are potentially
alizes the relevance of aspirin pro- siderably offset by an elevated risk more serious compared with bleed-
phylaxis by comparing CVD risk of bleeding (NNT for nonfatal MI of ing, both patients and physicians
reduction against concomitant el- 162 vs NNH for nontrivial bleed of should carefully consider the rela-
evation in risk of bleeding. Unlike 73). Although our data failed to con- tive merits of daily aspirin treat-
previous studies,3 the findings re- clusively identify subgroups of ment in primary prevention.
ported herein do not suggest a participants likely to benefit from as- However, modest, nonsignifi-
protective role for aspirin against pirin treatment, the results never- cant reductions in nonvascular death
cancer mortality in people at low- theless suggest an increased risk of and all-cause mortality were ob-
to-moderate risk for CVD events. nontrivial bleeding in individuals re- served, with questionable benefits
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213
TPT
different for participants with pre-
4 existing CVD, and since concomi-
PHS TPT
tant lifestyle or treatment decisions
PPP
JPAD may alter risks associated with these
JPAD
2 HOT
PHS WHS outcomes, assessments of risk based
PPP PHS HOT on primary prevention trials is likely
HOT
AAA PPP
WHS AAA POPADAD to be more informative. It has also
POPADAD BDS
0
BDS WHS BDS been argued that the frequency of as-
AAA
JPAD
POPADAD
pirin administration is an impor-
tant determinant of cancer out-
–2
comes, with more sustained benefits
0 10 20 30
Absolute Event Rate in Placebo Group per 1000 Person-years
with daily compared with alternate-
B day treatment.3 However, we were
6 TPT unable to confirm these observa-
tions because cancer mortality failed
Absolute No. of Nontrivial Bleeding Events
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