USPSTF Tightens Up Primary-Prevention Recommendations, Saying Aspirin Should Be Used Only in High-Risk Individuals

The United States Preventive Services Task Force (USPSTF) has finalized its guidelines on the use of aspirin in the primary prevention of cardiovascular disease and colorectal cancer, recommending low-dose aspirin for certain men and women with a high risk of cardiovascular disease.

Importantly, the task force is tightening up the use of low-dose aspirin by limiting its use to high-risk individuals between the ages of 50 to 69 years—as opposed to a much broader patient population in the 2009 recommendations.

Released in draft form last year, the new document caps a decade of protracted debate over the relative benefits and risks of aspirin in healthy adults and the confusion this sows for patients, amid efforts—ultimately unsuccessful—by aspirin-maker Bayer to obtain FDA approval for a primary prevention indication in cardiovascular disease.

Now, in its final version, the USPSTF document recommends low-dose aspirin for adults aged 50 to 59 years of age with a life expectancy of 10 years or more and a 10% or greater 10-year risk of MI or stroke (B recommendation). These adults should be willing to take aspirin daily for at least 10 years and have a low risk of bleeding. According to the task force, starting aspirin in this age group has the largest average net benefit.

Among individuals aged 60 to 69 years with a 10% or greater 10-year risk of cardiovascular disease, those with a life expectancy of a decade or more and a low risk of bleeding can also take low-dose aspirin if they are willing to continue treatment for at least 10 years (C recommendation). The recommendation in these older adults is optional, and therapy is only recommended for those who “place a higher value on the potential benefits than potential harms.” The USPSTF recommends “selectively offering or providing” low-dose aspirin to this age group based on professional judgement and patient preference.

“In the case of aspirin, we have new evidence from two main areas,” USPSTF member Kirsten Bibbins-Domingo, MD (University of California, San Francisco), told TCTMD. “One is that aspirin helps to prevent the development of colorectal cancer and the second area is in the harms of aspirin, which really helps us quantify the bleeding risks associated with aspirin. With this recommendation, we really wanted to try integrate the benefits—preventing heart attacks, preventing strokes, preventing colorectal cancer—with the potential harms.”

Taken together, she said, physicians and patients can make an informed decision about the risks and benefits of therapy. Aspirin is not recommended in adults 70 years of age or older, nor is it recommended in adults younger than 50 years, because the “current evidence is insufficient to assess the balance of harms and benefits” in these populations, according to the task force. In 2009, the task force recommended aspirin for men aged 45 to 79 years and women aged 55 to 79 years, provided the risks outweighed the benefits.

Colin Baigent, BMBCh (University of Oxford, England), one of the principal investigators of the landmark Antithrombotic Trialists’ (ATT) Collaboration, said he doesn’t disagree with the recommendations of the USPSTF, telling TCTMD that it remains a personal choice for individuals deciding upon life-long aspirin therapy for primary prevention. He noted that the USPSTF analysis yielded relative-risk estimates for nonfatal MI, stroke, mortality, and gastrointestinal bleeding that were almost identical to those reported by their group in 2009.

“It’s a pretty fine balance between some small vascular benefit—aspirin basically reduces the risk of nonfatal MI—and an increased risk of bleeding, mainly gastrointestinal bleeding with a very small risk of hemorrhagic stroke,” said Baigent. “When you put those two together, there’s not much between them. There is probably a small benefit overall. A rational person could choose to take it if they felt it was preferable to avoid a nonfatal acute MI even though they might be taking on some risk of bleeding.”

While such an individual decision might be a rational choice for some, it is a different issue when recommending aspirin for primary prevention as public health policy, said Baigent. And while the emergence of aspirin as a potential treatment for the prevention of colorectal cancer does alter the risk-benefit equation, Baigent does not believe it is yet strong enough to make general recommendations. For example, the magnitude of the treatment effect on cancer prevention is unknown as is the varying effect in different populations.

“The evidence is getting stronger that it prevents colorectal cancer, but, in my opinion, it is not yet good enough to allow us to say we can predict the benefit will be this big in this type of patient,” he said. “So, I don’t yet feel we’re at the point where we can be making recommendations about taking aspirin for primary prevention of cardiovascular disease and cancer. I think too little is known.”

The USPSTF recommendations, including systematic evidence reviews on the use of aspirin for prevention of cardiovascular disease and cancer, an assessment of bleeding risks, a modelling study on benefits and harms in different subgroups, and an editorial written by Baigent, are an update to the 2009 recommendations that endorsed aspirin for the primary prevention of CVD. The updated recommendations, which consider additional randomized controlled trials not available in the last USPSTF analysis, are published April 11, 2016, in the Annals of Internal Medicine.

What the Data Show

In a review of the evidence led by Janelle Guirguis-Blake, MD (University of Washington, Tacoma), the researchers evaluated 11 eligible randomized controlled trials—two of “good quality” and nine of “fair quality”—testing the benefits of aspirin for the primary prevention of cardiovascular events in 118,445 individuals.

Ten of the studies evaluated the effect of aspirin for the primary prevention of MI. In a meta-analysis of the studies, which included the Physicians’ Health Study and Women’s Health Study, treatment with aspirin reduced the risk of nonfatal MI by 22%. In an analysis of eight studies using low-dose aspirin (less than 100 mg), treatment reduced the risk of nonfatal MI by 17%. Overall, there was no beneficial effect of aspirin on nonfatal stroke, except when investigators analyzed trials using aspirin doses less than 100 mg. In that analysis, which included seven studies, low-dose aspirin reduced the risk of nonfatal stroke by 14%.

Aspirin therapy had no impact on cardiovascular mortality or all-cause mortality, regardless of the dose used.

In a systematic review of the bleeding risks with aspirin use, Evelyn Whitlock, MD (Patient-Centered Outcomes Research Institute, Washington, DC), and colleagues analyzed the data from the same cardiovascular disease primary prevention studies, including seven studies that addressed the risk of major gastrointestinal bleeding. In those trials, the use of aspirin in a range of doses over a period of 4 to 10 years increased the risk of gastrointestinal bleeding by 59%. In five studies where low-dose aspirin was used (less than 100 mg), the risk of major gastrointestinal or extracranial bleeding was increased 58%. These results are in line with data from the ATT Collaboration, according to the researchers.  

In nine studies that evaluated the risk of hemorrhagic stroke, aspirin increased the risk by approximately one-third (OR 1.33; 95% CI 1.03-1.71). The researchers point out that of the nine studies they analyzed, only one trial, a Japanese study that included an older, hypertensive population, showed a statistically significant increased risk of hemorrhagic stroke with aspirin. When used at the low dose, the risk of hemorrhagic stroke was not statistically significant (OR 1.27; 95% CI 0.96-1.68) in the meta-analysis.

Based on their projections, they estimate 1.39 excess major bleeding events and 0.32 excess hemorrhagic strokes per 1,000 person-years of aspirin exposure. These “events could be greater among older persons, men, and those with cardiovascular disease risk factors that also increase bleeding risk,” state Whitlock and colleagues.

Regarding cancer, investigators analyzed 20 randomized controlled trials where cancer outcomes were reported with aspirin use, including ten CVD primary prevention studies. Treatment with aspirin ranged from 3.6 to 10 years, and the analysis included 103,787 participants. Overall, cancer deaths were similar between participants assigned to aspirin and those assigned to a control group (RR 0.96; 95% CI 0.87-1.06). In terms of cancer incidence in six primary prevention studies, there was no difference between those who received aspirin and those who did not (RR 0.98; 95% CI 0.93-1.04).

Regarding colorectal cancer, however, evidence for use was significantly stronger. Pooled data from four primary and secondary CVD prevention studies showed the long-term cumulative risk of death from colorectal cancer was reduced by 33% among individuals who took 75 to 1,200 mg of aspirin per day for at least 1 year compared with controls. In three of these trials, where individuals were treated for at least 5 years, aspirin reduced colorectal cancer mortality 10 to 20 years after randomization (HR 0.51; 95% CI 0.35-0.74). The analysis also showed that aspirin therapy reduced the risk of colorectal cancer incidence by approximately 40% between 10 and 19 years after starting treatment.

Aspirin for an Extended Amount of Time

Speaking with TCTMD, Bibbins-Domingo said the ‘B’ recommendation for aspirin therapy for men and women aged 50 to 59 years of age is based on the greater likelihood of benefit in younger individuals, particularly those able to take aspirin for a longer period of time.

“The risk of bleeding rises with age, so people who are in their 60s are more likely to bleed, on average, than people in their 50s,” she said. “Secondly, people in their 60s may not have the life expectancy that would allow them to benefit, particularly from colorectal cancer prevention. You need to be able to take aspirin for 5 to 10 years to see those benefits. While people in their 60s have a higher risk of heart disease, they also have other factors we have to balance.”

Bibbins-Domingo said that while aspirin is widely available over the counter, patients need to have a conversation with their physician about starting treatment. In the primary-prevention setting, given the risk of bleeding, there had been concerns too many patients might be taking aspirin needlessly. For this reason, the USPSTF recommendations are designed for patients at increased cardiovascular risk but with an average risk bleeding. “Regardless of when we’re talking about the decision to initiate aspirin, the decision should be made in discussion with a doctor,” she said. “For people in their 60s, I think it’s even more critical to have this conversation.”

She stressed the current guidelines are for the primary prevention of cardiovascular disease, noting there are decades of research supporting aspirin therapy in patients with existing cardiovascular disease.

Stephen Kopecky, MD (Mayo Clinic, Rochester, MN), who commented on the recommendations for TCTMD, said physicians at his center do ask their high-risk patients to take low-dose aspirin for primary prevention, with the recommendation stronger for those at higher risk. He cautioned, however, that balancing the risks and benefits of aspirin can be tricky, particularly as patients get older. For example, the risk of MI and stroke increases with age, as does the risk of bleeding on aspirin, but the risks do not increase at the same rate.

“In actuality, the risk of bleeding on the aspirin goes up faster than the risk of heart attack and stroke,” he said. “It’s just one of those phenomena that as we go through life we have less of the ability to withstand aspirin’s effect on our GI tract.”

Kopecky said the one-size-fits-all approach to clinical care is problematic, noting that in a room full of 55-year-olds, the ability to tolerate aspirin will vary. He added that the 81-mg dose of aspirin is all that patients would need to take to harness the drug’s cardioprotective effects. Even in the Women’s Health Study, the benefit of aspirin occurred in women taking a 100-mg dose every other day, Kopecky reported. 

As for Baigent, he expects more data in the next few years and these clinical trials should be able to address some of the current unknowns. For example, the ongoing Nonvascular Outcomes on Aspirin (NoVA) collaboration will include updated analyses with longer-term follow-up of several aspirin trials, including the Physicians’ Health Study and the Women’s Health Study. Other trials, including Aspirin in Reducing Events in the Elderly (ASPREE), Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D), A Study of Cardiovascular Events in Diabetes (ASCEND), and Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE), a trial of individuals at high cardiovascular risk, are also ongoing.

Given the importance of the question and the implications for population health, Baigent would have preferred a wait-and-see approach when it comes to recommending aspirin in primary prevention. The level of “granularity” when it comes data about the risk and benefits of aspirin—in contrast with statins, for example—is not there, he noted.

“When we have this information, we’re going to be able to at least predict reliably who will gain benefit, and how big that benefit will be,” said Baigent. “As a person who is, thankfully, in the situation of being primary prevention at this point in time, if I’m going to take an aspirin every day, which is not an entirely benign drug, I want to know pretty precisely what the likely benefits and hazards are going to be. While we can do that for vascular disease and bleeding, I don’t believe we can do that very accurately for cancer at this point. We can’t do it for colorectal cancer, and we certainly can’t do it for other types of cancer.”

Related Stories:

• USPSTF Issues Preliminary Recommendations on Statin Use in Primary Prevention
• Aspirin’s GI Bleeding Risk Increased by Concomitant Use of Gastrotoxic Drugs