Early Morning Circadian Rhythms Linked to Stent Thrombosis

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Coronary stent thrombosis may be more common in the early morning due to patient circadian rhythms, according to a new study published in the February 2011 issue of JACC: Cardiovascular Interventions.

To investigate the potential effects of circadian variation, as well as weekly and seasonal changes, on stent thrombosis, David R. Holmes Jr, MD, and colleagues at the Mayo Clinic (Rochester, MN) conducted a retrospective analysis of 124 patients who presented to their center with definite stent thrombosis between February 1995 and August 2009. All subsequently underwent repeat PCI in the previously stented coronary artery segment. Stent thrombosis was confirmed by angiographic review and its timing was derived from medical records. Patients with sudden death were excluded.

The investigators observed an association between the onset of stent thrombosis and time of day, with the lowest incidence at 8 p.m. and the highest at 7 a.m. (P = 0.006). Looking separately at early (0-30 days), late (31-360 days), and very late (> 360 days) stent thrombosis, only early cases continued to show a significant link to time of day (P = 0.030). Although no variation was found among different days of the week, stent thrombosis was most common during the summer, peaking at the end of July and beginning of August (P = 0.036).

Multiple Potential Triggers Investigated

Potential triggers of stent thrombosis, including medication use and patient activity level, also were explored. Overall, 96% were taking aspirin at the time of occurrence. In the early stent thrombosis group, 89% were on clopidogrel or ticlopidine, but fewer than half of patients with late or very late stent thrombosis had remained on dual antiplatelet therapy.

Among the 62 patients whose activity levels were documented in their medical records, 33.9% were sleeping prior to the event, 25.8% were lying or sitting, 29.0% were engaged in light-to-moderate physical exertion, and 11.3% were engaged in heavy physical activity. However, the link between physical exertion and coronary stent thrombosis was only circumstantial, the authors conclude.

Other possible triggers found in the full study population were medication noncompliance (5.6%) and hospital admission for:

  • Surgery/invasive diagnostics 4.0%
  • Pneumonia 3.2%
  • Factor V Leiden 2.4%
  • Current chemotherapy/radiotherapy 1.6%
  • Urinary tract infection            0.8%
  • Pulmonary embolism 0.8%
  • Stroke 0.8%
  • Onset during hemodialysis 0.8%
  • Onset during adenosine sestamibi 0.8%
  • History of chest radiation 0.8%

A number of mechanisms may explain why coronary stent thrombosis risk is elevated in the early morning, the researchers note. For example, elevated blood pressure and heart rate could cause shear stress leading to thrombosis. Higher blood viscosity and coagulation in the morning may also be problematic, as may coronary spasm. Finally, levels of antithrombotic medication tend to be lower in the patient’s system at this time of day.

Unlike prior data demonstrating that acute MI is more likely to occur on Mondays, it appears from the current study that mental stress does not play an integral role in stent thrombosis. Increased risk in the summer could be due to a higher activity level during warm weather, the researchers point out.

Circadian Rhythm Can Inform Care

In a telephone interview with TCTMD, Dr. Holmes put the study into the broad context of circadian rhythms. “It is clear that circadian rhythms are critical to a variety of physiologic processes, some of which occur when people first get up in the morning and others that occur when people are tired or go to bed at night,” he said.

Some circadian rhythms have important signature characteristics, such as fatal heart rhythms in the middle of the night or, as is the case with this study, coronary stent thrombosis in the early morning, he explained. Identifying such characteristics and studying their pathophysiology allows physicians to then develop strategies and systems of care, added Dr. Holmes.

Based on this study, practitioners might consider giving antiplatelet therapy in the evening, rather than in the morning, so that drug levels are high enough during critical times, Dr. Holmes advised. Moreover, “once-a-day use of antiplatelet treatment may not be enough,” he said. “Maybe aspirin in the morning and [clopidogrel] at night may be more appropriate to cover all the bases.”

Speculative for Now

The pathophysiological reasons for coronary stent thrombosis are mainly hypotheses about which “we can only speculate at this point, although all seem relatively plausible,” cautioned Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY).

Generally, MI occurs more frequently in the morning, so it is not unreasonable for coronary stent thrombosis to be associated with similar circadian rhythms, Dr. Kirtane told TCTMD in a telephone interview. But while the authors mentioned exertion as having a circumstantial link to early morning coronary stent thrombosis, “you wouldn’t expect people to be exerting themselves at this time of day,” he noted. Consequently, this hypothesis needs further evaluation, as does the heightened risk during summer, Dr. Kirtane said.

“It’s tough to say how a study like this might influence practice,” he added. “One could argue that if you had a short-acting antiplatelet agent, you might take it at night.” But these drugs can also have longer half-lives, making the issue less relevant, he pointed out.

Overall, the literature has indicated that the majority of coronary stent thrombosis occurs early after stent placement. While the same held true in the current paper, the median time to thrombosis was 97 days after stent placement, prompting Dr. Kirtane to express his wish for the results to be replicated. That being said, “the present study was based on a well-known database and an established group of investigators,” he concluded.

Study Details

At baseline, patients with stent thrombosis tended to have high rates of diabetes (33%), peripheral vascular disease (19%), malignancy (15%), and dissection of the coronary artery segment in which thrombosis would later occur (16%), which prior research has shown to be independent risk factors for coronary stent thrombosis.

Mahmoud KD, Lennon RJ, Ting HH, Rihal CS, Holmes DR. Circadian variation in coronary stent thrombosis. J Am Coll Cardiol Intv. 2011;4(2):183-190.



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  • Drs. Holmes and Kirtane report no relevant conflicts of interest.

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