USPSTF: aspirin for primary CVD prevention?

 The US Preventive Services Task Force (USPSTF) just published their 2022 update on the use of aspirin to prevent cardiovascular disease (CVD), an update of their 2016 recommendation (see aspirin prim prev USPSTF2022 in dropbox, or doi:10.1001/jama.2022.4983 ). For full report and evidence, see aspirin prim prev USPSTF full doc2020 in dropbox, or doi:10.1001/jama.2022.3337

 

2022 recommendations: 

-- the decision to initiate low-dose aspirin for the primary prevention of cardiovascular disease (CVD) in adults aged 40 to 59 who have a 10% or greater 10-year CVD risk should be an individual one. Evidence of benefit is small in this group, and it might benefit those who are not at increased risk of bleeding and are willing to take low-dose aspirin daily (Grade C recommendation: USPSTF recommends selectively offering or providing the service based on professional judgment and patient preferences; there is at least moderate certainty that the net benefit is small) 

    -- they endorse using the ACC/AHA cardiac risk estimator to assess 10-year CVD risk (though this has been found to over-predict CVD events) 

-- USPSTF recommends against initiating low-dose aspirin for the primary prevention of CVD in adults 60 years or older (Grade D recommendation: USPSTF recommends against their service; there is moderate or high certainty that the service has no net benefit or that harms outweigh benefits)  

-- USPSTF also commissioned a microsimulation modeling study to assess the net balance of benefits and harms from aspirin use for primary prevention of CVD and colorectal cancer (CRC), stratified by age, sex, and CVD risk level 

 

2016 recommendations: 

-- the 2022 recommendations above were an update of the the 2016 recommendations because of new data, as below. The prior 2016 recommendations gave a grade B recommendation (a recommended service, with high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial) for initiating low-dose aspirin for the primary prevention of both CVD and colorectal cancer in adults aged 50 to 59 who have a 10% or greater 10 year CVD risk, are not at increased risk of bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years; and a grade C recommendation for those 60 to 69 years old . And there was insufficient evidence to make a recommendation in adults 70 years or older

    --Of note, in surveys in 2017-18, after these recommendations, one third of adults 50 years of or older were taking aspirin for primary CVD prevention

 

So, this 2022 recommendation was a significant downgrading of the 2016 recommendation, and did not find sufficient evidence to include potential benefit for colorectal cancer. Also, they did change the age ranges: the 2016 guidelines focused on those 50 to 59 years old and the current 2022 ones on those 40 to 59, noting too little information on those less than 50 or greater than 70 years old; the new 2022 recommendations suggest it might well confer more harm to take aspirin if older than 59

 

Background for 2022 recommendations: 

-- the basis for the recommendations Is a review of 11 RCTs comprising 134,470 patients comparing low-dose aspirin vs placebo in the prevention of cardiovascular disease (overall 63% women and a mean age of 63yo, ranging from 55yo in the Women's Health Study to 74yo in the ASPREE study)

--Overall, aspirin was associated with a statistically significant decrease in total ischemic stroke, OR 0.82 (0.72-0.92); decrease in non-fatal ischemic stroke, OR 0.88 (0.78-1.00); and an absolute difference between the aspirin vs control groups in the composite and in the individual CVD outcomes, ranging in the individual RCTs from -2.5% to 1.2%

-- no statistically significant association between aspirin use and CVD mortality, OR 0.95 (0.86-1.05); similarly for assessment of all-cause mortality

-- CRC outcomes: four studies measured events that occurred within the timing of the study and found no statistically significant association between low-dose aspirin and CRC incidence at 5 to 10 years of follow-up

    -- The ASPREE study noted below actually found a statistically significant higher total mortality in those on aspirin (5.9% vs 5.2%) as well as cancer mortality (3.1% vs 2.3%) and CRC mortality with OR 1.74 (1.02-2.95)

    -- And, overall it was felt that the number of deaths due to CRC was relatively low and the studies were not powered to assess the effect of aspirin on CRC mortality. In  addition, there was little information about CRC risk factors in the studies (eg, family history) or screening done

--Overall, low-dose aspirin was associated with increases of all bleeding events examined (except for total hemorrhagic stroke, which had overall a very low incidence and wide confidence intervals), with statistically significant OR point estimates ranging from 1.31 to 1.58, and absolute differences of -0.07% to 1.0% in the individual RCTs. 

--Some risk factors to consider regarding bleeding include older age, male sex, diabetes, liver disease, alcohol disease, peptic ulcer disease, and history of gastrointestinal issues or hospitalizations (for those H Pylori fans amongst us, they do explicitly comment that having H Pylori puts people at higher bleeding risk, with the explicit message that it should be treated!!! See http://gmodestmedblogs.blogspot.com/2022/03/carcinogen-update-now-including-h-pylori.html for a review of the arguments to treat. And, by the way, Jon Pincus commented to me that there are some new easier formulations of H Pylori meds coming out (which may make them unprescribable because of insurance limitations for many people until the drugs are generic): talicia is FDA-approved, contains amoxacillin 250mg, rifabutin 12.5mg, and omeprazole 10mg with directions to take 4 capsules every 8 hours for 14 days, with reputed 84% effectiveness; and vonoprazan 20mg with amoxacillin 750 mg, both bid for 7 days, with reported 85% cure rates, but pending FDA approval (see study at https://gut.bmj.com/content/69/6/1019 ). and, notably, both treatments are clarithromycin- and metronidazole-free regimens.  The talicia capsules do have quite high daily med doses, which raise some concerns: daily intake of amoxicillin 3000mg, rifabutin 150mg, and omeprazole 120mg... and lots of pills, and lots of potential drug interactions with the rifabutin component

 

-- CVD does continue to be the leading cause of mortality in the US, accounting for more than one in four deaths; an estimated 605,000 people have a first myocardial infarction and 610,000 experience a stroke annually 

-- there are significant differences in CVD events related to age, sex and race/ethnicity: 

    -- age is the strongest risk factor for CVD 

    -- men experience CVD events earlier in life than women (and USPSTF feels that it is likely that CVD risk and benefit estimates are driven by sex and not by gender identity, though there does not seem to be any real data on this) 

    -- Black persons have a higher prevalence of CVD, although this is undoubtedly a complex issue and may well reflect stress levels, living conditions, access to medical care/good nutrition/exercise venues, etc:  eg, see stress and cardiovascular disease blog http://gmodestmedblogs.blogspot.com/2022/01/stress-induced-cardiovascular-disease.html . However, the USPSTF does acknowledge that race is a social construct and an imperfect proxy for social determinants of health 

-- they consider appropriate aspirin therapy to be low-dose aspirin (studies have found that <100mg/d is equivalent to higher doses), and that the current US dosage of 81 mg is reasonable 

-- stopping age for those already on aspirin: there is a modestly increased risk of bleeding with advancing age, altering the risk-benefit analysis, suggesting that it might be reasonable to stop aspirin use around 75 years old

    -- the starting and stopping ages are appropriately different: those already on aspirin for 10+ years have already shown tolerance to the bleeding adverse effects that usually manifest themselves much earlier, so are different from a random group considering beginning the aspirin

 

-- the basis for the revision of the recommendations was 3 new studies done in 2018 (after the 2016 recommendations) that were included in the 11 RCTs reviewed. There is argument that these 3 newer studies more truly reflect current conditions, with dramatically decreasing incidence of cardiovascular disease, likely related to using statins (many studies were done prior to the 2001 ATPIII guidelines strongly promoting statin use), and better reduction of other risk factors (less smoking, lower blood pressures).  brief review of these three studies:

 

    -- the ASCEND trial (see aspirin primary prevention ASCEND NEJM2018 in dropbox or DOI: 10.1056/NEJMoa1804988):

         -- 15,480 people at least 40yo with diabetes but no evident cardiovascular disease, randomized to aspirin 100mg daily vs placebo, mean followup 7.4 years. mean age 63, 36% <60yo

         -- primary efficacy outcome: the first serious vascular event (i.e., myocardial infarction, stroke or transient ischemic attack, or death from any vascular cause, excluding any confirmed intracranial hemorrhage)

         -- primary safety outcome was the first major bleeding event (i.e., intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other serious bleeding)

         -- secondary outcomes included gastrointestinal tract cancer

         -- serious vascular events occurred in a significantly lower percentage of participants in the aspirin group than in the placebo group (658 participants [8.5%] vs. 743 [9.6%]; rate ratio, 0.88 (0.79 -0.97), p = 0.01)

         -- major bleeding events occurred in 314 participants (4.1%) in the aspirin group, as compared with 245 (3.2%) in the placebo group, rate ratio 1.29 (1.09-1.52), p = 0.003), with most of the excess being gastrointestinal bleeding and other extracranial bleeding

         -- no significant difference between the aspirin group and the placebo group in the incidence of gastrointestinal tract cancer (157 participants [2.0%] and 158 [2.0%], respectively) or all cancers (897 [11.6%] and 887 [11.5%]); long-term follow-up for these outcomes is planned.

 

    -- the ASPREE trial (see aspirin primary prevention ASPREE trial NEJM2018 in dropbox, or DOI: 10.1056/NEJMoa1805819):

        -- 19,114 community-dwelling men and women in Australia and the US who were 70 years of age or older (or ≥65 years of age among Black and Hispanic people in the United States) and did not have cardiovascular disease, dementia, or disability, randomized to enteric-coated aspirin 100mg or placebo. 50% were at least 74yo

        -- median followup 4.7 years

        -- primary end point: composite of death, dementia, or persistent physical disability (reported in another study in NEJM)

        -- secondary end points included major hemorrhage and cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure)

        -- rate of cardiovascular disease was 10.7 events per 1000 person-years in the aspirin group and 11.3 events per 1000 person-years in the placebo group, HR 0.95 (0.83-1.08), nonsignificant

        -- rate of major hemorrhage: 8.6 events per 1000 person-years and 6.2 events per 1000 person-years, respectively, HR 1.38 (1.18-1.62), p<0.001

 

    -- the ARRIVE trial (see aspirin primary prevention ARRIVE lancet2018 in dropbox, or doi.org/10.1016/ S0140-6736(18)31924-X):

         -- 12,546 patients from 501 study sites in 7 countries who were at least 55yo (men) or 60yo (women) and had average cardiovascular risk based on numbers of risk factors, assigned to enteric-coated aspirin 100mg/d vs placebo, median followup 60 months. Mean age 64

         -- primary endpoint: composite of time to first occurrence of cardiovascular death, MI, unstable angina, stroke of TIA

         -- safety endpoints: hemorrhagic events and incidence of other adverse events

         -- primary endpoint was found in 269 (4.29%) patients in the aspirin group versus 281 (4.48%) patients in the placebo group, HR 0.96; (0.81–1.13), p=0.60), not statistically significant

         -- safety endpoints:

             -- gastrointestinal bleeding events (mostly mild): 61 (0.97%) patients in the aspirin group versus 29 (0.46%) in the placebo group, HR 2.11 (1.36-3.28), p=0.0007

             --incidence rate of serious adverse events was similar in both treatment groups (n=1266 [20.19%] in the aspirin group vs n=1311 [20.89%] in the placebo group. The overall incidence of adverse events was similar in both treatment groups (n=5142 [82.01%] vs n=5129 [81.72%] in the placebo group). The overall incidence of treatment-related adverse events: on aspirin (n=1050 [16.75%] vs n=850 [13.54%] in the placebo group

-- bottom line from these 3 studies: lots of people randomized (47,140), some with diabetes but no prior cardiovascular events (though probably lots having significant atherosclerotic disease), some older (>65yo), some younger (>40yo); and these studies found no or small cardiovascular benefit but significant increases in bleeding. These findings led to lowering the age for discussion of potential aspirin benefit to age 40 (the ASCEND trial), and decreasing the oldest age to 59 (the ASPREE and ARRIVE trials; the latter found increased all-cause mortality in those on aspirin). And of note there was no evident benefit in colorectal cancer In the ASCENT study

 

Limitations: 

-- these 2022 recommendations included people with predicted cardiovascular risk >10%. But it is clear that people at higher risk of CVD events, e.g. >15% or >20%, are at higher risk than those simply >10%, and the potential benefits in these higher risk groups might alter the risk-benefit analysis 

    -- the 10-year cardiovascular risk calculators do overstate cardiovascular risk

-- when dealing with younger people who may have an appreciable life expectancy, the 5-7 year follow-up in the three 2018 trials does not fully predict long-term benefits (and even the 10-year risk calculators may not mean so much in people with a 40-year life expectancy). However, many of the individual RCTs did suggest benefit within the first two years of the studies

--Though the data are less clear for CRC prevention with aspirin, longer-term follow-up might yield different results, as noted in an unpublished communication from the Women's Health Study. However, this study formally stopped after 10 years, though data was collected subsequently, but many women in both groups actually took aspirin after the 10 years). Overall it would take more than a 10-year study to document any potential CRC benefit. as noted above, there were very few CRC deaths in the short follow-up periods

-- as with all systematic reviews and meta-analyses, combining data from different studies is fraught: different inclusion and exclusion criteria, age groups, comorbidities, specificity of outcomes measured, etc.

-- the baseline data used in the studies regarding comorbidities, smoking history, etc are one-time assessments at baseline and many may well change over time, and could affect the validity of the results (eg those who subsequently stopped or started smoking, had improved blood pressure control, lost weight, improved or worsened diet...)

 

So,

-- the 2020 recommendations suggest an important change in clinical practice, de-escalating the use of aspirin in primary prevention of cardiovascular disease and eliminating the inclusion of colorectal cancer benefit

-- for those 40-59yo who are at higher risk of heart disease (>10% per the AHA risk calculator), they do suggest shared decision-making, understanding that different people might place different values to the potential risks versus harms of aspirin therapy . One key point is that the benefits of aspirin tend to accrue over time, whereas bleeding outcomes appear to occur immediately or at about one year of aspirin use (ie, bad things can happen soon but the potential benefits require long-term aspirin)

 

geoff

 

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