Aspirin Resistance

Gurbel, Paul A., MD
Director, Sinai Center for Thrombosis Research
Sinai Hospital of Baltimore
Associate Professor of Medicine
Johns Hopkins University School of Medicine
Baltimore, Maryland
Also by this Author 

Identifying Risk To Guide Patient Management

Daily intake of low-dose aspirin (acetylsalicylic acid) has been established as the standard of care in managing cardiovascular disease in the United States.1 While aspirin plays an important role in helping prevent cardiovascular events, a proportion of patients do not respond as expected to aspirin therapy, a phenomenon commonly called “aspirin resistance.”

Dr. Paul Gurbel, Director of the Sinai Center for Thrombosis Research at the Sinai Hospital of Baltimore, discusses aspirin resistance, and how a better understanding of the effect of aspirin can guide the management of high-risk patients.

Definition and Prevalence

The effect of aspirin in the secondary prevention of cardiovascular events is mostly attributed to the permanent inactivation of cyclooxygenase-1 (COX-1), which leads to decreased production of the platelet activator, thromboxane A2 and its stable metabolite, 11-dehydro-thromboxane B2.2

“The Working Group on Aspirin Resistance stated that aspirin resistance is best defined biochemically, as evidence of persistent activity of cyclooxygenase in the presence of aspirin,” notes Dr. Gurbel, who was a member of that group.3 “We very rarely see platelet aspirin resistance, but if you look in vivo, there is evidence of persistent thromboxane generation in the presence of aspirin therapy. This thromboxane comes from thromboxane synthase in the platelet and is derived from prostaglandins produced up-stream by cyclooxygenase-2 (COX-2) activity.”

Aspirin Resistance - A Marker of Risk

Dr. Gurbel explains how identifying the presence of COX-2 activity may help to identify risk. “COX-2 is present in areas of the vascular wall where there’s inflammation, and it’s present in leucocytes and other cells that are involved in atherosclerosis, so it’s likely a barometer of atherosclerosis activity. In that way, it’s a marker of risk.”

“In fact, if you look at urinary 11-dehydro -thromboxane B2 levels, using a validated assay, you see a relation between the level of the compound excreted and the level of cardiovascular risk. This has been demonstrated in clinical trials.4 It may be a marker of the extent of atherosclerosis or it could be a marker of disease activity. An assessment of disease activity may further assist in the management of the patient with known atherosclerosis or the at-risk patient.”

Managing At-Risk Patients

Once a patient is identified as having high urinary 11-dehydro -thromboxane B2 levels, Dr. Gurbel believes that intensification of their current  medical regimen may be considered. “We believe that these selected patients are at increased risk for  ischemic event occurrence and that this should be taken into consideration by the treating physician in deciding subsequent therapies. We’re not saying that aspirin is not blocking platelet COX-1, we’re just saying there’s a lot of thromboxane being generated even though the COX-1 in the platelet is blocked.”

Other steps to consider are optimizing imaging to define the extent of atherosclerosis and possibly performing a functional test to determine whether there is physiologically significant stenosis in their coronary arteries.

Dr. Gurbel would consider assessing levels of urinary 11-Dehydro Thromboxane B2, in patients who are at increased risk for cardiovascular disease, for example diabetic patients treated with aspirin. “We know that many of these people have extensive atherosclerosis, they’re just not symptomatic yet,” he says. “If they had high thromboxane generation, you may think about whether you’re optimally addressing their risk profile “

Preventing Cardiac Events

“Once a patient needs a stent their disease is in a  well advanced stage– they have uncontrolled atherosclerosis. The optimal goal is to intervene much earlier. so they never come to the cath lab. Once patients are there, they are in trouble - and they’re at the far end of the bell-shaped curve. The goal of diagnostic testing is to facilitate treatment when the patient is far up on the other side of the bell-shaped curve.”

Role of 11-Dehydro Thromboxane B2 Testing

Dr. Gurbel believes that 11-Dehydro Thromboxane B2 testing may enhance the identification of risk. Unfortunately multi-center prospective studies have not yet been conducted to provide the basis for such a change in practice.

Dr. Gurbel is concerned about the lack of data. “The most important drugs we give to someone with heart disease are the drugs that directly combat thrombosis, because that’s what really kills the patient. We know now that the people treated with stents who leave the hospital with high platelet reactivity are at a higher risk of having a thrombotic event. Yet today we give the same dose of the same drug to the majority of patients.

Dr. Gurbel’s hope is that studies will be conducted to change physicians’ understanding of the issue and to change practice. “Studies also need to be conducted in the primary prevention area where we treat many high risk patients, particularly those with diabetes or with an early family history of coronary artery disease.  We should undertake prospective studies in this population, to determine whether intensification of therapy in patients with high levels of COX activity actually improves outcomes. We don’t have those data yet and we need to do the studies.”

References

  1. Aspirin for the Prevention of Cardiovascular Disease; Recommendation Statement Date: March 2009; Agency for Healthcare Research and Quality (AHRQ), U.S. Preventive Services Task Force.
    http://www.ahrq.gov/clinic/USpstf/uspsasmi.htm

  2. Tantry US, Mahla E, Gurbel PA. Aspirin resistance. Prog Cardiovasc Dis. 2009;52:141-52.

  3. Michelson AD, Cattaneo M, Eikelboom JW, et al; Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis; Working Group on Aspirin Resistance. J Thromb Haemost. 2005;3:1309-1311.

  4. Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation. 2002;105:1650-1655.