Aspirin Use by Elderly Patients After Vascular Events Linked to More Bleeding, Especially GI Bleeds

While the researchers recommend upping the use of PPIs for gastroprotection, two experts put the brakes on that idea.

Aspirin Use by Elderly Patients After Vascular Events Linked to More Bleeding, Especially GI Bleeds

Older patients receiving aspirin-based antiplatelet therapy following an ischemic vascular event are at a significantly increased risk of bleeding, particularly when it comes to disabling or fatal upper gastrointestinal bleeding, according to the results of a new study.

Overall, the risk of nonmajor bleeding was unrelated to age, but the risk of major bleeding with aspirin “increased steeply” among patients 75 years and older, with these older patients being more than five times more likely to have a fatal bleeding event compared with younger patients.

Led by Peter Rothwell, MD (University of Oxford, England), the Oxford Vascular Study researchers state in their paper that the risks of bleeding with aspirin in elderly patients are “higher and more sustained than in the younger age groups including in previous trials” and recommend increased use of proton pump inhibitors (PPIs) to combat the risk.

Given that half of the major bleeds in patients aged 75 years or older were upper gastrointestinal, the estimated numbers needed to treat for routine PPI use to prevent major upper gastrointestinal bleed are low, and [use of PPIs] should be considered in future secondary prevention guidelines,” they conclude.

In an editorial, Hans-Christoph Diener, MD (University of Duisberg-Essen, Germany), points out that most upper gastrointestinal bleeds were disabling or fatal in the older cohort, outnumbering disabling or fatal intracerebral hemorrhages. Like the study investigators, Diener recommends PPIs to reduce the risk of upper GI bleeding in patients 75 years and older.

We can’t [say] we should give PPIs to all elderly people on aspirin, because that’s not really supported by the data. Paul Gurbel

For Paul Gurbel, MD (Inova Health System, Falls Church, VA), though, recommending routine use of PPIs in older patients treated with aspirin is a stretch given the available research. “We don’t have the data on the efficacy of PPIs in the elderly,” he told TCTMD. “I don’t know of any large-scale, randomized data. We don’t have a lot of randomized data on drug efficacy in the elderly either.”

The results, he said, support the conclusion that age is a risk factor for bleeding, as is the use of aspirin. “A lot of what we see here concludes previous observations, but we can’t really make a statement that we should give PPIs to all elderly people on aspirin because that’s not really supported by the data,” said Gurbel. “It’s logical, but it’s not a scientifically robust conclusion.” 

Large Percentage of Bleeds in Upper GI Tract

Published June 13, 2017, in the Lancet, the study included 3,166 patients with a first transient ischemic attack, ischemic stroke, or MI treated with aspirin without routine use of PPIs between 2002 and 2012. Of these individuals, 35% presented with an MI and the remaining with a cerebrovascular event. Half of patients were 75 years or older, and 18% were older than 85 years.

The 10-year risk of major nonfatal and fatal bleeding was significantly higher among patients ≥ 75 years compared with younger individuals, with the risk of fatal bleeding more than five times higher in this older cohort (HR 5.53; P < 0.0001). In patients who survived the major bleeding event, there was a significantly higher risk the bleed would be disabling in patients 75 years and older (HR 7.60; P < 0.0001).

Major nonfatal and fatal upper gastrointestinal bleeding was also significantly increased in the older cohort compared with those younger than 75 years, with the risk of death resulting from the bleed more than 7 times higher (HR 6.67; P < 0.003). Again, for those who survived the bleed, there was a greater likelihood the event would be disabling in the 75-plus cohort (HR 13.72; P < 0.0001). 

Of the bleeding events requiring medical attention, 40% were upper gastrointestinal bleeds. The researchers point out that the use of PPIs as a gastric protection strategy has been shown to reduce upper GI bleeding by as much as 70% to 90% in patients receiving long-term antiplatelet therapy.

“However, consistent with other UK or European studies, PPI use in patients receiving long-term antiplatelet treatment in our study was only about 30%,” state the Oxford researchers. “We did not routinely co-prescribe PPIs, partly because clinical guidelines on secondary prevention of vascular events make no specific recommendations on PPI use, and partly because no accepted definition exists of patients at high risk of upper gastrointestinal bleeding.”

In his editorial, Diener notes that underpowered, observational studies linking PPIs to an increased risk of dementia may have caused unnecessary angst over the drug class. Other studies have raised the potential of cardiovascular risk. He added that cardiologists and neurologists are influenced more by what they see in practice than what they read in the data, meaning these specialists may not fully realize the risks of aspirin.

“Cardiologists will rarely see intracranial bleeds, and neurologists and cardiologists will rarely see major gastrointestinal bleeds,” writes Diener. “Therefore, they might underestimate the real risk in patients on antithrombotic therapy.” He recommends physicians reassess the benefit/risk trade-off of antiplatelet therapy in patients 75 years and older every 3 to 5 years.

More Data Needed Before PPIs Routinely Used, Says One Expert

Shamir Mehta, MD (McMaster University, Hamilton, Canada), who was not involved in the study, also took issue with the broad recommendation for PPI use in elderly patients. Mehta told TCTMD there is “good, randomized evidence” supporting the concomitant use of the drugs in patients who have had a prior history of upper gastrointestinal bleeding, as well as for use in patients treated with dual antiplatelet therapy at high risk for bleeding.

“But in patients who are solely on aspirin, the data is not as strong for a prophylactic  effect of a proton pump inhibitor,” he said. “It’s an encouraging analysis and there might be something here, but I think we need a randomized trial to really determine what the treatment effect really is, what patient groups benefit, and who we should be considering for use.”

We need a randomized trial to really determine what the treatment effect really is, what patient groups benefit, and who we should be considering for use. Shamir Mehta

To TCTMD, Gurbel noted that the estimated number needed to treat (NNT) to prevent one upper gastrointestinal bleeding event at 5 years was 23 for patients aged 75 to 84 years and 21 for patients 85 years and older. However, the NNT was calculated from a published meta-analysis of PPIs versus placebo in patients taking predominantly aspirin, one that showed upper gastrointestinal bleeding was reduced by 74%, instead of from a randomized trial dedicated specifically to elderly patients.

More randomized trial data should be available soon with the COMPASS study. That trial, a phase III study testing rivaroxaban (Xarelto, Janssen) for the prevention of major adverse cardiovascular events in CAD and PAD patients, is using a partial factorial design and includes PPI-naive patients randomized to pantoprazole 40 mg once daily or placebo. The trial is designed to help inform decisions about the protective effects of PPIs in patients with cardiovascular disease who require longer and more intensive antithrombotic therapy.

“In general, if the patient who has had a prior gastrointestinal bleed, or if they have other risk factors for bleeding, yes, then we should consider putting them on a proton-pump inhibitor,” said Mehta. “But we’re not going to be putting everyone on them. We’re just not there yet. If there’s a benefit shown in randomized trials, then maybe we will but not yet.”  

In the COGENT trial, which was halted early due to loss of funding, the addition of a PPI to clopidogrel reduced the risk of gastrointestinal clinical events, including upper GI bleeding, compared with placebo for CAD patients taking dual antiplatelet therapy.  

Disclosures
  • Rothwell reports receiving personal fees from Bayer outside the completed study.
  • Diener reports receiving honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from AstraZeneca, Bayer Vital, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Sanofi Aventis, Servier, Abbott, Allergan, CoAxia, Corimmun, Covidien, D-Pharm, Fresenius, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, Medtronic, Merck, Sharp, & Dohme, MindFrame, Neurobiological Technologies, Novartis, Novo Nordisk, Paion, Parke-Davis, Pfizer, Schering-Plough, Solvay, St Jude, Syngis, Talecris, Thrombogenics, WebMD Global, Wyeth, and Yamanouchi. He reports financial support for research projects from AstraZeneca, Boehringer Ingelheim, GSK, Janssen-Cilag, Lundbeck, Novartis, Sanofi Aventis, Syngis, and Talecris. He chairs the Treatment Guidelines Committee of the German Society of Neurology and has contributed to the European Heart Rhythm Association and European Society of Cardiology guidelines for the treatment of atrial fibrillation.
  • Gurbel reports having received consulting honoraria from AstraZeneca, Boehringer Ingelheim, Haemonetics, Merck, Janssen, and Bayer; having received research grants from Haemonetics, the Duke Clinical Research Institute, Merck, National Institutes of Health, Bayer, Medimmune, and Coramed; and having patents on platelet function testing.

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