Primecuts – This Week in the Journals

October 23, 2018

By Sean Kelly, MD

Peer Reviewed

Recent news has brought stories of new technology promising to change the way we monitor for atrial fibrillation, one of the world’s most common and most dangerous heart arrhythmias. The newest version of the Apple Watch includes an electrical heart sensor equivalent to a single lead EKG that can detect certain irregular heart beats and wirelessly transmit the data as an alert [1]. While the announcement of the device’s release was initially met with excitement that the technology represents a revolution allowing unprecedented link between patients and doctors as well as a breakthrough in the primary detection of heart problems, more cautionary and measured reviews have popped up in the weeks since. Many physicians cite concern about the rates of both false positives and false negatives. Will patients be overly trusting of a device that is not an official medical device and thus overlook a serious adverse event? Will we see a surge in ER and clinic visits for spurious apple watch alarms for paroxysmal atrial fibrillation? It is too early to say for sure, but an ongoing review of the technology is already underway [2]. Suffice it to say, the new apple watch will certainly make an impact in medicine, for better or for worse.

As we continue with the theme of how to best use machines and medications for primary prevention, this week’s research in the journals calls on us to rethink how we use one of our oldest and most well established medications: aspirin. Here we review evidence to determine if an aspirin a day really does keep the doctor away, as the stories make their own ripples in the press [3].

Effect of Aspirin on Disability-free Survival in the Healthy Elderly (NEJM) [4]

Design and enrollment (for all aspirin studies):

In the first of a series of high impact articles this month in the New England Journal of Medicine, McNeil and colleagues sought to clarify the controversy surrounding the use of aspirin for primary prevention in the elderly, given the recent data suggesting that the risk of major hemorrhage may outweigh the benefit to patients. In the study, 19,114 subjects 70 years and older (65 among blacks and Hispanics) with no active cardiovascular disease, disability, or dementia were enrolled for a period of four years for a randomized, double-blind assignment into two groups: one receiving 100 mg enteric-coated aspirin and one a placebo. This study design was used in each of the subsequent papers reviewed here, with distinct grouping and analyses for three separate questions related to the rate of adverse cardiovascular events and all-cause mortality as indicated below.

In this initial article, the primary endpoint was a composite score of death, dementia and persistent physical disability, with secondary endpoints including individual components of the composite score and the key safety endpoint of clinically significant major hemorrhage. Subjects were enrolled from US and Australia, with evenly split genders, 8.7% of subjects non-white, and 11% with a history of previous aspirin use. Patients with major medical conditions likely to result in death within 5 years or high blood pressure were excluded.

Results and Discussion

Results were reported as hazard ratios (HR) with 95% confidence intervals (CI) except for the safety endpoint of major hemorrhage, which used a p-value of <0.05. The study found that the rate of composite of death, dementia, or persistent physical disability was 21.5 events per 1000 person-years in the aspirin group and 21.2 events per 1000 person-years in the placebo group, with a HR of 1.01 and CI 0.92 – 1.11. Thus there was no significant benefit to patients taking aspirin in terms of disability free survival. Even more concerning were the results for the secondary endpoint, showing a higher rate of hemorrhage in the aspirin group of 3.8% compared to 2.8% in the placebo group. These results were significant, with a CI of 1.18-1.62, suggesting a greater risk to patients taking aspirin during the study period.

Strengths and limitations of the study

Here the authors present a large, well-powered study demonstrating the lack of an independent effect of aspirin for primary prevention in an elderly patient population. The study was appropriately blinded and controlled, demonstrated statistically significant conclusions, and had excellent subject retention with only 1.2% withdrawing and 1.6% lost to follow up. However, there are several important caveats in interpreting these results. First, the authors note that they cannot rule of that aspirin may have a beneficial effect in primary prevention if started at an earlier age or used for a longer period of time, and the study does not address whether patients already taking aspirin for primary prevention should discontinue doing so. Of note only a small proportion of the study sample was non-white, and the screening tools used such as the modified mini-mental exam for dementia or ADL score for disability may be imperfect tools for estimating outcomes. The study also does not address doses of aspirin other than 100 mg, and the results from a relatively short duration of a few years limited the interpretation of the data with regards to more slowly developing chronic conditions such as Alzheimer’s disease and some cancers.

Bottom line: As with many medications in the elderly patient populations, less may be more when it comes to aspirin use for primary prevention, as this study shows no statistical benefit for survival and a higher rate of undesirable major bleeding events that may impact a patient’s quality of life.

Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly [5]

This was a second study from McNeil and colleagues based on the data from the above article, looking to specifically dissect the rates of cardiovascular events and bleeding in an elderly patient population. As such the design and enrollment for the study were the same as above, with the additional key exclusion of patients on anticoagulants or antiplatelet agents other than aspirin, with no active cardiovascular disease such as atrial fibrillation or hypertension. In this case a post-hoc analysis was completed to determine several cardiovascular outcomes including fatal or non-fatal MI,) fatal or nonfatal stroke, and the development of heart failure. The study showed that after a median 4.7 years of follow up, the overall 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 CI 0.83-1.08), suggesting a non-significant risk reduction. In fact, even in the pre-specified subgroups of cardiovascular disease no differential effect was seen. Similar to the initial study, there was a notably increased risk of hemorrhagic events in the aspirin group, half of which were gastrointestinal bleed. Alarmingly, the risk of intracranial bleeding was also higher in the aspirin group (HR 1.5, CI 1.11 – 2.02), although this result is difficult to interpret as it cannot be contributed directly to aspirin and a hemorrhagic stroke could be considered both a cardiovascular and a hemorrhagic event. Additionally, the study noted a lower than expected rate of cardiovascular events overall, possibly related to the demographics of the enrolled population.

Bottom line: The study concludes that the potential modest protective effect of aspirin does not outweigh the increased risk of hemorrhagic stroke or gastrointestinal bleed associated with taking the medication. 

Effect of Aspirin on All-Cause Mortality in the Healthy Elderly [6]

Finally a third article in the series evaluated the effect of aspirin on all cause mortality, with endpoints related to both the immediate cause of death and the proximal cause that may have lead to death in the same population of patients taking aspirin or placebo. The study found that the risk of death from any cause was 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group (HR 1.14; CI 1.01 to 1.29), a significant increase. Interestingly, analysis showed that cancer accounted for the higher mortality in the aspirin group, with 3.1% of the participants in the aspirin group experiencing cancer-related deaths versus 2.3% of those in the placebo group (HR 1.31, CI 1.10 to 1.56). This was notable because previous studies not only did not show this effect, but some have suggested a protective affect of aspirin against the development of some cancers, particularly the development of sporadic colorectal cancers [7,8]. Of note, these results should be interpreted with caution, as it is possible the results related to cancer may be underpowered with about 500 total subjects. Moreover, the results may have been influenced by the algorithms used by adjucators who assigned causes of death in the study.

Bottom line: Higher all-cause mortality noted among otherwise healthy older adults receiving daily aspirin compared to those who received placebo, possibly attributable to increased cancer-related death. In the context of previous studies, this result was unexpected and requires further research for validation.

Overall impact for utilization of aspirin in the elderly

In conclusion, this series of studies from McNeil and colleagues challenges a previously accepted framework for using aspirin for primary prevention, an issue that applies to millions of patients daily and is likely to influence the decision making of countless primary care providers making recommendations to them. The studies found that the benefit of taking aspirin in healthy patients over 65 years of age in most cases does not outweigh the risks, whether considered in terms of overall disability, reduction in cardiovascular events, or even all-cause mortality. Considered collectively, the studies suggest that aspirin is not as harmless as previously thought and may actually increase both morbidity and mortality over a relatively short period of time, with a measurable negative impact on a patient’s quality of life as well if major hemorrhagic events do occur.

Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events [9]

In a new study, Willeit and colleagues revisit the question of whether lipoprotein(a), a once promising biomarker for predicting risk of cardiovascular events, may have merit as a screening tool in select patient populations. Lipoprotein(a) is known to mediate the development of atherosclerosis via its effect on LDL cholesterol deposition and the pro-inflammatory response it creates, so it has become a popular target to be tracked in cases of hyperlipidemia-related heart disease. However, many previous studies have been unable to conclude whether lipoprotein(a) levels truly correlates with the trajectory of cardiovascular disease, and further whether measuring them has any clinical utility. To address this question, the authors completed a data review of seven randomized placebo-controlled statin outcome trials including data from 29069 patients with a mean age 62 and 28% women. In these studies, lipoprotein(a) levels were measured at baseline and after a period of statin or placebo treatment, before subsequently calculating hazard ratios for fatal and nonfatal coronary events, coronary revascularization, or stroke. Compared to prior studies, a more rigorous approach was taken to control confounding variables by using a multivariable adjusted model to help account for changes in many factors such as age, sex, body mass index, glomerular filtration rate, prior cardiovascular disease, diabetes, smoking, and high blood pressure.

The overall conclusion of the study was that the rate of cardiovascular events was correlated linearly with increased lipoprotein(a) levels. This was demonstrated by hazard ratios suggesting an increased rate of adverse cardiovascular events in patients with higher levels of lipoprotein(a). This effect became particularly significant once lipoprotein(a) levels were > 50 mg/dL, and was further found to be true regardless of adjustments using the composite multivariate adjustment mentioned above. In such cases, when lipoprotein(a) were > 50 mg/dL, patients were found to have the highest risk for cardiovascular events despite statin treatment, with a hazard ratio of 1.48 (CI 1.23-1.78). However, patients on placebo instead of statins also had a significantly increased risk based on lipoprotein(a) level > 50 mg/dL, with HR of 1.23 (CI 1.04-1.45). Therefore, the effect of statins could not be reliably tracked with the measurement of lipoprotein(a).

Bottom line: This study suggests that completing a baseline and follow up measurement of lipoprotein(a) level is reliable in predicting risk of cardiovascular events, but may not be useful in monitoring the effect of statins.

Dr. Sean Kelly is a first year internal medicine resident at NYU Langone Health

Peer reviewed by David Kudlowitz, MD, Associate Editor, Clinical Correlations

Image courtesy of CNET


  1. McNeil, J.J., Woods, R.L., Nelson, M.R., Reid, C.M., Kirpach, B., Wolfe, R., Storey, E., Shah, R.C., Lockery, J.E., Tonkin, A.M., et al. (2018b). Effect of Aspirin on Disability-free Survival in the Healthy Elderly. N. Engl. J. Med. 379, 1499–1508.
  2. McNeil, J.J., Wolfe, R., Woods, R.L., Tonkin, A.M., Donnan, G.A., Nelson, M.R., Reid, C.M., Lockery, J.E., Kirpach, B., Storey, E., et al. (2018c). Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly. N. Engl. J. Med. 379, 1509–1518.
  3. McNeil, J.J., Nelson, M.R., Woods, R.L., Lockery, J.E., Wolfe, R., Reid, C.M., Kirpach, B., Shah, R.C., Ives, D.G., Storey, E., et al. (2018a). Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. N. Engl. J. Med. 379, 1519–1528.
  4. Rothwell, P.M., Fowkes, F.G.R., Belch, J.F.F., Ogawa, H., Warlow, C.P., and Meade, T.W. (2011). Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet Lond. Engl. 377, 31–41.
  5. Rothwell, P.M. (2013). Aspirin in prevention of sporadic colorectal cancer: current clinical evidence and overall balance of risks and benefits. Recent Results Cancer Res. Fortschritte Krebsforsch. Progres Dans Rech. Sur Cancer 191, 121–142.
  6. Willeit, P., Ridker, P.M., Nestel, P.J., Simes, J., Tonkin, A.M., Pedersen, T.R., Schwartz, G.G., Olsson, A.G., Colhoun, H.M., Kronenberg, F., et al. (2018). Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. The Lancet 392, 1311–1320.