Aspirin has been a staple of primary prevention of cardiovascular disease (CVD) in at-risk populations based on recommendations by major organizations including the American Heart Association (AHA) together with the American College of Cardiology (ACC), US Preventive Services Task Force (USPSTF) and others. Accordingly, aspirin became one of the most commonly used medications for primary prevention of CVD, and it is estimated that 40% of US adults over 50 years of age use aspirin for this purpose.¹

The original AHA Prevention Guidelines published in 1997 did not recommend aspirin use for primary prevention, citing the need for additional research.² Major primary prevention studies completed from 1988 to 2001, including the British Doctors Study (BDS),³ US Physicians' Health Study (PHS),⁴ Thrombosis Prevention Trial (TPT),⁵ Hypertension Optimal Treatment (HOT) and low-dose aspirin trial of the Primary Prevention Project (PPP) trials,^6,7 led the USPSTF and AHA to adopt recommendations for aspirin (75-100 mg/day, or 325 mg every other day) for primary prevention in 2002, particularly for high-risk individuals (5-year CVD risk ≥3%).^8-9 Table 1 summarizes the demographic parameters of the major studies of primary prevention using aspirin.

Table 1: Demographic data of the major primary prevention studies of aspirin to date, spanning 1998 to 2018

Study (year, n, % men)	Mean Age, years	Statin use, %	Smokers (current), %	Diabetes, %	MeanBMI, kg/m2	Mean baseline SBP, mmHg	Mean baseline DBP, mmHg
BDS (1988, n = 5139, 100% men)3	61	None	31	2	24.4	136	83
PHS (1989, n = 22071, 100% men)4	53	None	11	2	24.9	126	79
TPT (1998, n = 5085, 100% men)5	61	Low	16	8	28.4	170	105
HOT (1998, n = 18790, 53% men)6	57	Low	41	2	27.4	139	83
PPP (2001, n = 4495, 42% men)7	64	16 ¶	15	17	27.5	145	85
WHS (2005, n = 39876, 0% men)11	54	NR	13	3	26.0	124	77
POPADAD (2008, n = 1276, 46% men)14	60	NR	31	100	29.2	145	79
JPAD (2008, n = 2539, 55% men)15	65	26	21	100	24	135	77
AAA (2010, n = 3350, 29% men)16	62	4 ¶	33	3	NR	148	84
JPPP (2014, n = 14464, 42% men)17	60	NR	13	34	24.2	137	78
ARRIVE (2018, n = 12546, 71% men)20	64	43	29	0	28.4	145	NR
ASCEND (2018, n = 15480, 63% men)21	63	75	8	100	30.7	136	NR
ASPREE (2018, n = 19114, 44% men)22	74*	34	4	11	28.3	139	77

This recommendation was largely driven by the benefit associated with aspirin in the PHS, TPT and HOT studies. In the PHS, healthy male US physicians taking 325 mg of aspirin every other day reduced the rate of first fatal or non-fatal myocardial infarction (MI) by 44% (139 vs. 239 events, 0.25 vs. 0.44% per year) without significantly increasing major GI bleeding (48 vs. 30 events, 0.09 vs. 0.05%/y; RR 1.59 [CI 0.89 – 2.84]).

In TPT, high-risk men were randomized to 75 mg aspirin daily or placebo. Aspirin significantly reduced the rate of non-fatal MI by 30% (96 vs. 137 events, 0.58 vs. 0.83%/y) without a significant increase in major GI bleeding (20 vs. 13, 0.12 vs. 0.08%/y; RR 1.54 [0.63 – 3.77]). The rate of fatal MI was similar between groups.

In HOT, individuals with hypertension on 75 mg daily aspirin had significantly lower rates of major cardiovascular events by 15% (315 vs 368 events, 0.09 vs 0.11%/y) and non-fatal MI by 40% (68 vs 114 events, 0.19 vs. 0.32%/y); however, this was accompanied by a significant increase in major GI bleeds (114 vs. 62 events, 0.32 vs. 0.18%/y, RR = 1.81 [1.22 – 2.66]). Fatal MI rates were also similar between groups.

Table 2 contains the event rates of non-fatal MI, non-fatal stroke and major GI bleed in each of the major primary prevention studies of aspirin. Non-fatal MIs are presented as the only trial to find significant reduction in fatal MI was the PHS (10 vs. 26, 0.02 vs. 0.05%/y; RR 0.34 [0.15 – 0.75]).

The USPSTF meta-analysis concluded that patients with 5-year CVD risk of 3% and 5% would have 4 to 12 and 6 to 20 fewer CHD events per 1000 person-years, respectively, at the cost of 2-4 major GI bleeding events per 1000 person-years in each group.⁸ (Note: CVD refers only to coronary events, whereas ASCVD includes strokes and coronary events. As stroke risk is similar to cardiovascular event rates in most patients, ASCVD is roughly twice CVD. Consequently, a 10-year CVD risk of 10% is roughly equal to a 10-year ASCVD risk of 20%).

Table 2: Summary of outcomes of the major primary prevention studies of aspirin, including non-fatal myocardial infarctions (MI), non-fatal strokes and major gastrointestinal (GI) bleeds. Fatal MIs were only reduced in the PHS study. Data that are statistically significant are bolded. Table adapted from ATT,¹³ USPSTF (2016),²⁶ and calculations from primary source.^20,21,22

Study (year, n, % men) Primary study population	Events (% per annum), aspirin versus control Rate Ratio [confidence interval]
	Non-fatal MI	Non-fatal Ischemic Stroke	Major GI Bleed
BDS (1988, n = 5139, 100% men) Healthy male physicians	104 (0.54%/y) vs. 90 (0.47%/y) 1.15 [0.73 – 1.79]	61 (0.30%/y) vs. 27 (0.26%/y) 1.13 [0.72 – 1.77]	20 (0.10%/y) vs. 20 (0.10%/y) 1.00 [0.37 – 2.70]
PHS (1989, n = 22071, 100% men) Healthy male physicians	129 (0.24%/y) vs. 213 (0.39%/y) 0.61 [0.46 – 0.81]	110 (0.20%/y) vs. 92 (0.17%/y) 1.20 [0.91 – 1.59]	48 (0.09%/y) vs. 30 (0.05%/y) 1.59 [0.89 – 2.84]
TPT (1998, n = 5085, 100% men) High CV risk males	96 (0.58%/y) vs 137 (0.83%/y) 0.70 (0.50 – 0.98]	18 (0.21%/y) vs. 25 (0.29%/y) 0.64 [0.34 – 1.20]	20 (0.12%/y) vs. 13 (0.08%/y) 1.54 [0.63 – 3.77]
HOT (1998, n = 18790, 53% men) Hypertension	68 (0.19%/y) vs. 114 (0.32%/y) 0.60 (0.41 – 0.88]	146 (0.41%/y) vs. 148 (0.42%/y) 0.98% [0.78 – 1.24] ¶	114 (0.32%/y) vs. 62 (0.18%/y) 1.81 [1.22 – 2.66]
PPP (2001, n = 4495, 42% men) 1 or more CV risk factors	15 (0.18%/y) vs. 21 (0.25%/y) 0.72 [0.31 – 1.71]	15 (0.19%/y) vs. 18 (0.23%/y) 0.84 [0.42 – 1.07]	6 (0.07%/y) vs. 3 (0.04%/y) 1.98 (0.36 – 11.02)
WHS (2005, n = 39876, 0% men) Healthy nurses	184 (0.09%/y) vs. 181 (0.09%/y) 1.02 [0.78 – 1.33]	198 (0.10%/y) vs. 244 (0.12%/y) 0.81 [0.85 – 0.97]	127 (0.06%/y) vs. 91 (0.05%/y) 1.39 [0.98 – 1.97]
POPADAD (2008, n = 1276, 46% men) Diabetics with ABI ≤0.99	55 (1.29%/y) vs. 56 (1.31%/y) 0.98 [0.69 – 1.40]	29 (0.68%/y) vs. 41 (0.96%/y) 0.71 [0.45 – 1.12]	28 (0.66%/y) vs. 31 (0.73%/y) 0.89 [0.53 – 1.50]
JPAD (2008, n = 2539, 55% men) Diabetes	12 (0.22%/y) vs. 9 (0.16%/y) 1.35 [0.57 – 3.19]	27 (0.49%/y) vs. 27 (0.48%/y) 1.01 [0.60 – 1.72]	10 (0.18%/y) vs. 7 (0.13%/y) 1.45 [0.55 – 3.81]
AAA (2010, n = 3350, 29% men) ABI ≤0.95	62 (0.45%/y) vs. 68 (0.50%/y) 0.91 [0.65 – 1.28]	37 (0.27%/y) vs. 38 (0.28%/y) 0.97 [0.62 – 1.52]	9 (0.07%/7) vs. 8 (0.06%/y) 1.13 [0.43 – 2.92]
JPPP (2014, n = 14464, 42% men) 1 or more CV risk factors	20 (0.06%/y) vs. 38 (0.10%/y) 0.53 [0.31 – 0.91]	109 (0.30%/y) vs. 109 (0.30%/y) 1.00 [0.77 – 1.31]	103 (0.28%/y) vs. 31 (0.08%/y) 3.33 [2.22 – 4.98]
ARRIVE (2018, n = 12546, 71% men) Men with 2-4 or women with ≥3 CV risk factors	88 (0.28%/y) vs. 98 (0.31%/y) 0.90 [0.67 – 1.20]	75 (0.24%/y) vs. 67 (0.21%/y) 1.12 [0.80 – 1.55] ¶	61 (0.19%/y) vs. 29 (0.09%/y) 2.11 [1.35 – 3.28]
ASCEND (2018, n = 15480, 63% men) Diabetes	191 (0.33%/y) vs. 195 (0.34%/y) 0.98 [0.80 – 1.19]	227 (0.40%/y) vs. 244 (0.43%/y) 0.93 [0.77 – 1.12] *	137 (0.24%/y) vs. 101 (0.18%/y) 1.36 [1.05 – 1.75]
ASPREE (2018, n = 19114, 44% men) Healthy elderly	171 (0.40%/y) vs. 184 (0.43%/y) 0.93 [0.76 – 1.15] ¶	148 (0.35%/y) vs. 167 (0.39%/y) 0.89 [0.71 – 1.11]	361 (0.86%/y) vs. 265 (0.62%/y) 1.38 [1.18 – 1.62] †

By 2009, USPSTF expanded their previous recommendation to include all men aged 45 to 79 (to reduce MI) and women aged 55 to 79 (to reduce strokes), as long as patients' CVD risk outweighed the risk of bleeding.¹⁰ This recommendation was influenced by the 2005 Women's Health Study (WHS) and a 2006 sex-specific meta-analysis.^11,12

In WHS, healthy nurses randomized to 100 mg of aspirin every other day had similar cardiovascular event rates (184 vs. 181 non-fatal MI events, 0.09 vs. 0.09%/y, RR 1.02 [0.78 – 1.33]), but reduced rates of stroke, including non-fatal stroke (198 vs. 244, 0.10%/y vs. 0.12%/y, RR 0.81 [0.85 – 0.97]). In the sex-specific meta-analysis, cardiovascular outcomes were significantly lower in men and women on aspirin, but only men had a significant reduction in MI (OR 0.68 [0.54 – 0.86]). Only women had a significant reduction in ischemic strokes (OR 0.76 [0.63 – 0.93]).

The landmark 2009 Antithrombotic Trialists' (ATT) Collaboration meta-analysis pooled data from these six studies and reported a 12% relative reduction in serious vascular events with aspirin (1671 vs 1883 events per 330,000 person-years, 0.51 vs 0.57%/y) at the cost of 54% higher relative risk of major extracranial bleeds (355 vs 219 events per 330,000 person-years, 0.11 vs 0.07%/y). No significant reduction in vascular mortality was detected.¹³

However, more recent studies did not demonstrate a clear benefit of aspirin, including the Prevention of Progression of Arterial Disease and Diabetes (POPADAD),¹⁴ Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD),¹⁵ Aspirin for Asymptomatic Atherosclerosis (AAA) and Japanese Primary Prevention Project (JPPP).^16,17 In 2016, the USPSTF Guidelines were pared back, recommending aspirin for CVD and colorectal cancer prevention in adults aged 50 to 59 with a 10-year ASCVD risk of at least 10% without increased risk of bleeding and with life expectancy of at least 10 years (Grade B). Aspirin use in adults aged 60 to 69 who have the same risk requires an individualized approach based on a weaker recommendation (Grade C).¹⁸

The European Society of Cardiology (ESC) gave aspirin in primary prevention a Class III recommendation, stating that antiplatelet therapy is not recommended due to increased risk of major bleeding.¹⁹ Given conflicting results of prior studies, the recently published Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE),²⁰ A Study of Cardiovascular Events in Diabetes (ASCEND) and Aspirin in Reducing Events in the Elderly (ASPREE) trials were designed to further clarify aspirin recommendations for primary prevention.^21,22

In ARRIVE, aspirin administered at 100 mg daily in an intermediate-risk population did not reduce the combined outcome of first MI, stroke, CV death, unstable angina or transient ischemic attack (269 vs. 281 events, 0.84 vs. 0.88%/y, HR 0.96 [0.81–1.13]). GI bleeding events were more than twice as likely (61 vs. 29 events, 0.46 vs. 0.19%/y, HR 2.11 [1.35 – 3.28]). Only 61% of participants (60% in aspirin and 62% in placebo arms) adhered to their randomization. This led investigators to complete a per-protocol analysis, which demonstrated a reduction in fatal and non-fatal MI by 47% (37 vs. 72 events, 0.19 vs. 0.36%/y, HR 0.53 [0.36 – 0.79]). Per-protocol bleeding events were not reported.

In ASCEND, persons with diabetes given 100 mg daily of aspirin had a 12% relative reduction in non-fatal MI, stroke, transient ischemic attack or vascular death excluding intracerebral hemorrhage (658 vs. 743 events, 1.15 vs. 1.30%/y, RR 0.88 [0.79 – 0.97]). Major bleeds, including GI, cerebral hemorrhage or sight-threatening eye bleed, were 29% more likely with aspirin (314 vs. 245 events; 0.55%/y vs. 0.43%/y, RR 1.29 [1.09 – 1.52]). The number needed to treat (NNT) was 91 to prevent one serious vascular event, while the number needed to harm (NNH) was 112 to cause one major bleed.

In ASPREE, healthy individuals at least 70 years old (≥65 among blacks and Hispanics) were given 100 mg aspirin daily. After a median of 4.7 years, there was no difference in the composite primary endpoint of death, dementia or persistent physical disability. Pre-specified secondary outcomes including CVD events were similar (448 vs 474 events, 1.07 vs 1.13%/y, HR 0.95 [0.83 – 1.08]), and aspirin did not reduce MI or ischemic strokes when separate outcomes were evaluated. However, there was a substantial increase in major hemorrhage (361 vs. 265, 0.86 vs. 0.62%/y, HR 1.38 [1.18 – 1.62]). Surprisingly, there was also an increase in all-cause death in the aspirin group by 14% (558 vs. 494 events, 1.27 vs 1.11%/y; HR 1.14 [1.01 – 1.29]), mainly due to increased cancer deaths, in particular colorectal cancer. Only 49% of participants randomized to aspirin were adherent by the end of the study.

The role of aspirin in primary prevention is called into question in this era of modern medicine that emphasizes stricter blood pressure control, smoking cessation and cholesterol reduction. The primary prevention studies that showed a significant reduction in cardiovascular events were completed prior to the rise of these modern prevention efforts. As shown in Table 2, the PHS, TPT and HOT trials reduced first non-fatal MI by 39%, 30% and 40%, respectively, though only PHS showed a significant reduction in fatal MI. Seven of the eight primary prevention studies published since 2005 are collectively less convincing (notably, JPPP was stopped early for futility despite a significant reduction in non-fatal MI).

Impact of Recent Aspirin Trials

So what is the role of aspirin in primary prevention of cardiovascular disease in the modern era? To answer this, we rely more heavily on the recent ARRIVE, ASCEND and ASPREE studies, which reflect the effect of aspirin in the setting of modern preventive practices. In interpreting the results of ARRIVE, we recognize that intention-to-treat (ITT) analysis is preferred in that it preserves randomization. However, per-protocol analysis is important to consider in studies of relatively healthy populations with low event rates and a prolonged study duration with low adherence. In per-protocol analysis, there is a reduction in non-fatal MI in individuals following recommended therapy.

In ASCEND, we see a modest net-benefit with aspirin use in patients with diabetes. In ASPREE, healthy patients at least 70 years old are harmed by aspirin initiation as bleeding events increase without a reduction in cardiovascular events. While there was an increase in cancer deaths, this effect was not consistent with prior studies. In fact, some prior studies suggested colorectal protection, but most recently no significant difference was observed in cancer incidence in ASCEND.

Taken collectively, aspirin is likely effective in reducing cardiovascular events in high-risk patients, but less so than in the decades preceding modern preventive practices. Aspirin should not be initiated in individuals 70 years or older, but it remains unclear whether it should be continued in patients already on aspirin who turn 70 years old.

Accurately estimating ASCVD risk has been less reliable when applying estimates derived from older cohorts in the era of modern medicine. The mean estimated baseline 10-year ASCVD risk in ARRIVE was 17.4%, but the actual observed event rate was 8.6% (550 observed vs. 1488 expected events), suggesting that preventive measures proved successful in mitigating ASCVD risk. This is further supported by a recently published analysis of the revised Pooled Cohort Equation (PCE), which was derived from six studies (ARIC [1987], CHS [1989 to 1999], CARDIA [1983 to 2006], FHS offspring cohort [1971 to 2014], JHS [2000 to 2012] and MESA [2000 to 2012]).1,23 This study suggested the ASCVD risk calculator overestimates true ASCVD risk by 20% or higher in all age groups, particularly in black adults. A separate study using the MESA cohort suggested that the ASCVD PCE could overestimate risk by 25 to 115%.²⁴ This risk estimation is subject to the same improved preventive measures compared to the aspirin trials.

Prudent Recommendations

We recommend continued use of low-dose aspirin (75-100 mg) daily in patients 40 to 70 years old without diabetes at high-risk for cardiovascular events (10-year ASCVD ≥20% by PCE) who do not have a high risk of bleeding. For adults with diabetes 40 to 70 years old, we recommend use of low-dose aspirin daily in patients at intermediate- to high-risk for cardiovascular events (ASCVD ≥10% by PCE) who do not have a high-risk of bleeding. It is reasonable to continue aspirin in patients already on therapy when they turn 70 years old after re-evaluation of their bleeding risk, but this requires further study. These recommendations differ from prior AHA guidelines recommending that aspirin is considered for patients with ASCVD ≥10%.

Assessing bleeding risk remains a challenge. We agree with the USPSTF recommendation that providers qualitatively evaluate bleeding risk and withhold aspirin in patients with increased risk, including those with prior GI bleeding or ulceration, prior complications from aspirin use, or known bleeding diathesis.²⁵

Remaining Questions About Aspirin

Many questions remain regarding aspirin use in primary prevention, several of which we highlight now after recent publications. First, do statins blunt the cardioprotective effect of aspirin? Statin use has risen in the modern era (shown in Table 1), but use was similar in ASCEND between study groups and presumably in ACCORD based on randomization (though between-group use was not reported). Analysis of statin use in these trials with regard to outcomes would be informative. Additionally, outcomes of the upcoming ACCEPT-D trial (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes)l, in which individuals at least 50 years of age with diabetes on simvastatin were randomized to low-dose aspirin versus placebo, will help further probe this question.

Second, can a lower dose of aspirin maintain CVD risk reduction while reducing the bleeding risk? The WHS used the lowest absolute dose (100 mg every other day), but even lower doses may be effective in reducing CVD risk while minimizing bleeding events. Third, does aspirin have a higher margin of benefit in specific higher-risk comorbid conditions such as in chronic kidney disease and HIV? Lastly, with the improved bleeding data in recent studies, can a predictive calculator be created to estimate bleeding risk? Better estimation of future bleeding risk will better inform shared decision making with our patients and allow selective targeting of therapies to avoid use in those at high risk of adverse event.

In summary, the recent contribution of the ARRIVE, ASCEND and ASPREE trials provides useful insight into the role of aspirin use for primary prevention in the modern era. We recommend narrowing its use to the highest-risk populations, including individuals aged 40 to 70 years old without diabetes with 10-year ASCVD ≥20% or patients with diabetes with ASCVD ≥10%, provided they are not at high-risk of bleeding. When patients already on aspirin turn 70 years old, it remains unclear whether therapy should be continued. Further analysis of these recent studies, as well as upcoming results from on-going studies, will continue further clarify the role of aspirin in primary prevention.

References

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18. Bibbins-Domingo K, US Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2016;164:836-45.
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Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Nonstatins, Novel Agents, Statins

Keywords: Dyslipidemias, Aspirin, Hydroxymethylglutaryl-CoA Reductase Inhibitors

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