Decisions about which men should receive low-dose aspirin for CHD prevention involves trade-offs between aspirin’s adverse effects and its beneficial effects. Some investigators have attempted to estimate the benefit/harm trade-off by determining relative risks of each event through meta-analyses and then informally “weighing up” likely benefits and disadvantages for patient populations with different CHD and gastrointestinal bleed risk profiles.7,11
Such informal processes, however, are difficult to perform because main outcomes of interest (stroke, myocardial infarction, and gastrointestinal bleed) each have different health effects.1
We and others have attempted to rigorously model effects of aspirin and have found aspirin to be cost-saving or cost-effective for men with moderate and greater CHD risk levels.5,19
Recent data, however, have suggested that gastrointestinal bleed risk may be higher than levels observed in clinical trials6
and that patients with elevated CHD risk may be at higher risk for gastrointestinal bleed.7
Some decision makers have advocated using PPI therapy concurrently with aspirin to reduce the risk of bleeding, after considering clinical trial evidence from patients at high risk for gastrointestinal bleed3
and decision-analytic modeling studies suggesting PPI use is beneficial in secondary CHD prevention.4
In this updated analysis, we attempted to address some of these concerns and better estimate the net effect of aspirin with or without PPI for patients at different levels of CHD and gastrointestinal bleed risk. In modeling an age-dependent gastrointestinal bleed risk, we found that aspirin remained cost-saving compared with no treatment across a wide range of CHD and gastrointestinal bleed risk levels for men aged 45 to 65 considering initiation of aspirin. We also found that adding generic PPI therapy to aspirin for all men was not cost-effective in most cases because risk of gastrointestinal bleed was not large enough to warrant routine prophylaxis. However, under favorable assumptions about PPI efficacy and pricing, adding PPI when gastrointestinal bleed risk is 5/1,000 per year for men aged 45 (and slightly higher for older men), had a favorable cost-effectiveness ratio of $22,000 per QALY gained. This represents about a 4-fold increase in baseline bleeding risk. Assuming a branded cost of a PPI at $1,951 per year, a man’s gastrointestinal bleed risk would need to be 6.7/100 per year (over 10 times higher than our base case) in order for the addition of a PPI to be cost-effective in a man with the same CHD risk.
Our analysis highlights that some men who are at increased gastrointestinal bleeding risk may benefit from adding PPI when using low-dose aspirin for CHD risk reduction. Providers should assess the risk of gastrointestinal bleeding by considering the patients age, prior history of gastrointestinal bleeding, and use of other medications that increase bleeding risk ().6,20
For example, a 55-year-old man taking naproxen (a nonsteroidal anti-inflammatory drug) for arthritis and a selective serotonin reuptake inhibitor for depression would have a 4.8 per 1000 annual risk of bleeding and would be a reasonable candidate for PPI if those medications could not be discontinued.20
Estimated Baseline Risk per 1,000 Patient-Years of Gastrointestinal Bleeding in Men With No History of Ulcer
Our findings were robust across a range of CHD risk levels and were not affected by factors such as a reduced relative benefit of aspirin on nonfatal CHD or an increased risk of fatal gastrointestinal bleed. In addition, results were insensitive to changes in aspirin risk of MI and stroke, as obtained from a gender-specific meta-analysis.12
However, if PPI’s actual gastrointestinal bleed risk reduction is much lower than the modeled effect or its pricing is much higher than $200 per year, the benefits of adding PPI to aspirin will be small or negligible, even for those at increased risk.
Other modeling studies have reached similar results when considering the effect of aspirin in men at different CHD risk levels. Specifically, Greving and colleagues developed a Markov model to evaluate the cost-effectiveness of aspirin for primary prevention in the Netherlands.19
They used a 10-year time horizon and drew baseline event probabilities and costs from Dutch data. Relative risk reductions were based on available meta-analyses and were similar to those used in our model. Utility of taking aspirin was assumed to be 0.999, and annual cost of aspirin was €97, to account for pharmacist and practitioner prescribing and dispensing costs. They found aspirin to be cost-effective (incremental cost per QALY < €20,000) for men 55 to 75 years old with 10-year CHD risk over 10%. However, the study found an incremental cost per QALY of greater than €100,000 for men younger than 55 years old with CHD risk of between 5% and 6%. Results were sensitive to aspirin cost assumptions and disutility associated with aspirin use. Lamotte and colleagues developed models of effect of aspirin for primary prevention and reached conclusions similar to our current and previous analyses.21
None of the previous models, however, have examined the cost-effectiveness of adding routine PPI plus aspirin compared with aspirin alone or no treatment for primary prevention. Our study has a number of limitations. Given the lack of trials of PPIs in aspirin users without prior history of ulcer bleeding, we estimated benefit of PPI therapy among aspirin users on the basis of a single, randomized controlled trial among high-risk users.3
This estimate is supported by a large body of observational data that informed the recommendation that PPIs be given to patients with high gastrointestinal bleed risk.2
We used data on upper gastrointestinal bleeding for our analysis; aspirin may increase the risk of lower gastrointestinal bleeding, as well as other extracranial bleeds, but we did not model these directly. However, aspirin remains cost-effective compared with no therapy, even if the annual risk of gastrointestinal bleeding is 5%, so not including other, less common sources of gastrointestinal bleeding is unlikely to change our results.
Although PPI therapy may increase the risk of various adverse clinical outcomes among long-term users, we did not include such effects in our model. Specifically, observational studies have demonstrated a modest but significantly increased risk for community-acquired pneumonia as well as enteric infections, particularly involving Clostridium difficile
In addition, high-dose, twice-daily PPI therapy has been proposed to increase risk of osteoporotic fractures. Existing data on these effects remain controversial, and robust data to model their risk are limited.2,23,24