Sage Journals: Discover world-class research

Abstract

Background:

The well-described morning peak in the onset of acute coronary syndromes has been partly attributed to increased platelet activity upon arising. It has been suggested that stent thrombosis (ST) exhibits a similar pattern. We assessed whether a diurnal variation in ST occurs, and whether more robust antiplatelet therapy with prasugrel (vs clopidogrel) can attenuate a morning excess.

Methods and Materials:

Patients from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial (N = 13 608) with adjudicated ST classified per the Academic Research Consortium definitions of definite (N = 135) and probable (N = 27) were grouped into prespecified 8-hour intervals by time of onset: early (6 am-2 pm), late-day (2 pm-10 pm), and overnight (10 pm-6 am). We compared the rates per 1000 patients of ST across time intervals and stratified by treatment and stent type.

Results:

A diurnal variation in definite/probable ST was observed with rates of 6.5, 3.7, and 2.1 for early, late-day, and overnight intervals, respectively (P < .001), per 1000 patients treated. A sensitivity analysis excluding periprocedural acute-ST (<24 hours after index percutaneous coronary intervention [PCI]) resulted in similar findings (5.2, 2.5, and 1.8 per 1000, P < .001). The circadian variation in ST was observed in patients on clopidogrel (9.7, 4.8, and 3.1 per 1000, P < .001) with the highest rate of ST early in the day. Patients on prasugrel also demonstrated a circadian variation with particularly low rates of overnight ST (3.4, 3.0, and 1.1 per 1000, P = .020).

Conclusions:

In TRITON-TIMI 38 trial, the timing of ST exhibited a significant diurnal variation similar to that seen with onset of other acute coronary syndromes. ST occurred less frequently among patients randomized to prasugrel compared to clopidogrel with the greatest absolute reduction (6.2 per 1000 patients) in events earlier in the day when platelet activity is known to be highest.

Keywords

stent thrombosis circadian variation prasugrel clopidogrel

Introduction

Stent thrombosis (ST) is a feared complication of percutaneous coronary interventions (PCIs) which carries a high risk of mortality and is more common in patients treated with PCI for an acute coronary syndrome (ACS) than with stable coronary artery disease.^1–3 Observational studies have suggested that ST exhibits a diurnal variation with a higher incidence during the morning hours, but these studies required angiographic confirmation of ST that potentially exclude a large number of events due to high mortality prior to angiography.^4,5 If a circadian variation of ST does exist, identification of factors that alter the timing of ST may provide insight into the biological processes responsible for the triggering of these events and lead to more effective therapies. In other forms of ACS, aspirin and β-blockers have been shown to attenuate the morning excess of myocardial infarction (MI) and helped identify platelet activity and adrenergic tone as mediators of a circadian variation.^6–8 Using data from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in MI (TRITON-TIMI 38) trial,^9,10 we sought both to confirm the presence of a circadian variation in ST and to assess the effects of more robust platelet inhibition on the timing of events.

Methods and Materials

The TRITON-TIMI 38 trial was an international double-blind, randomized clinical trial comparing the effectiveness of 2 platelet P2Y₁₂ receptor antagonists in patients with ACS and a planned PCI. The details of this trial have been described previously.^9,10 Briefly, the trial included 13 608 patients with ACS who were randomized to either prasugrel (60 mg loading dose, 10 mg/d maintenance dose) or clopidogrel (300 mg loading dose and 75 mg/d maintenance dose) at the time of PCI in a double-blind manner. The inclusion criteria for patients with unstable angina or non-ST-segment elevation MI were ischemic symptoms lasting ≥10 minutes within 72 hours of randomization, a TIMI risk score of ≥3, and 1 mm ST-segment deviation or cardiac biomarker elevation. Patients with ST-segment elevation MI could be enrolled within 12 hours after the onset of symptoms if primary PCI was planned or within 14 days after receiving medical treatment for ST-segment elevation MI. The major exclusion criteria included high baseline risk of bleeding, anemia, thrombocytopenia, known intracranial pathology, or recent P2Y₁₂ receptor antagonist use. The primary efficacy reported in TRITON-TIMI 38 trial was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke and was reduced with prasugrel versus clopidogrel (9.9% vs 12.1%, hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.73-0.90, P <.001) as was the rate of ST (1.1% vs 2.4%, HR 0.48, 95% CI 0.36-0.64, P < .001).¹⁰

ST was a prespecified end point in TRITON-TIMI 38 trial and was classified by the Academic Research Consortium (ARC) Definition as follows: (1) definite, angiographic, or pathological confirmation of coronary thrombus in the setting of ACS; (2) probable, any unexplained death within 30 days or ACS involving the target vessel territory without confirmation by angiography; and (3) possible, any unexplained death beyond 30 days.¹¹ Adverse events, including ST, other clinical cardiovascular events, and all deaths were adjudicated by an independent clinical end point committee that was blinded to treatment assignment. Event times were also determined by the end point committee as the time of symptom onset or time of sudden death. For patients with more than 1 occurrence of ST, only the first event was considered. Noncompliance with dual antiplatelet therapy was reported if a patient did not adhere to the study medication at any point during the clinical trial, but the timing of nonadherence in relation to the episode of ST was not recorded.

We included the 162 patients with ARC definite or probable ST in our analyses. Based on our prior work in patients with ST-segment elevation MI, we anticipated a late morning peak in events would occur and that 6 am to 2 pm would be the 8-hour cohort of highest incidence.^12,13 We divided the 24 hours into 3 prespecified groups, early (6 am to 2 pm), late day (2 pm to 10 pm), and overnight (10 pm to 6 am). Patients in these 3 cohorts were stratified by their random assignment to either clopidogrel or prasugrel. A sensitivity analysis was performed using alternate 6-hour time intervals to validate the arbitrary selection of the initial cohorts. Timing relative to index PCI was defined as acute (<24 hours), subacute (24 hours-30 days), late (30 days-1 year), and very late (>1 year). We also analyzed patients stratified by use of at least 1 drug-eluting stent (DES) or only bare metal stents (BMSs). Significance was determined by a 3-way chi-square test compared to a uniform distribution.

Results

The baseline characteristics for the 162 patients (135 definite, 27 probable ST) with event times are reported in Table 1. The 44 cases of ST without a reported time of onset were excluded from this analysis. There were 40 cases of acute ST, 79 cases of subacute ST, 34 cases of late ST, and 9 cases of very late ST.

Table 1.

Baseline Characteristics of Patients With Definite or Probable Stent Thrombosis.

Variable	Definite or Probable Stent Thrombosis (N = 162)
Mean age (years)	62.7 ± 12.0
Male sex (%)	123 (76)
White race (%)	150 (93)
Hypertension (%)	101 (62)
Hyperlipidemia (%)	93 (57)
Diabetes mellitus (%)	60 (37)
Active smoking (%)	48 (30)
Prior myocardial infarction (%)	35 (22)
Prior coronary artery bypass surgery (%)	18 (11)
Bare metal stent only (%)	90 (56)
Any drug-eluting stent (%)	72 (44)
Creatinine clearance <60 mL/min (%)	23 (15)
Any medication noncompliance	14 (9)
Qualifying event
Unstable angina (%)	26 (16)
Non-ST segment elevation myocardial infarction (%)	82 (51)
ST-segment elevation myocardial infarction (%)	54 (33)

A circadian variation in definite/probable ST was observed with the highest incidence in the early cohort compared to late day and overnight (Figure 1). Patients who received either of the 2 P2Y₁₂ inhibitors exhibited a significant circadian variation when compared to the null hypothesis of a uniform distribution. There was a particularly pronounced peak in early events with those randomized to clopidogrel and a low number of overnight events with prasugrel (Figure 2). No significant difference was observed in the circadian distribution of patients on clopidogrel versus prasugrel (P = .51), but there were statistically significant decreases in ST from 6 am to 2 pm and 10 pm to 6 am with the largest absolute reduction observed earlier in the day (Figure 2). A sensitivity analysis performed with alternate 6-hour time intervals revealed similar findings (Figure 3).

Figure 1.

Definite or probable stent thrombosis (ST) by time of event. Academic Research Consortium defined definite (N = 135) and probable (N = 27) ST were significantly more common from 6 am to 2 pm.

Figure 2.

Stent thrombosis (ST) by assigned P2Y₁₂ receptor antagonist. In Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 trial, fewer ST events were observed in patients randomized to prasugrel compared to clopidogrel with a circadian variation observed in both the groups. The greatest absolute reduction in events (6.2 per 1000 patient randomized) was observed when platelet activity is highest in the earlier part of the day (P < .001). The circadian distribution with clopidogrel versus prasugrel did not reach statistical significance (P = .51).

Figure 3.

Stent thrombosis by assigned P2Y₁₂ receptor antagonist, alternate time intervals. A sensitivity analysis was performed using alternate 6-hour time intervals to validate the arbitrary selection of the initial 8-hour cohorts. Similar findings were observed regardless of the chosen time intervals.

Subacute ST was the most common form of ST (48.8%, N = 79) and displayed a circadian variation (per 1000 patients randomized, early 7.3 [N = 47], late-day 2.5 [N = 16], and overnight 2.5 [N = 16], P < .001). Acute ST was less frequent overnight (per 1000 patients randomized, early 1.3 [N = 17], late-day 1.5 [N = 19], overnight 0.3 [N = 4], P = .007). No significant circadian variation was observed with late ST (early 2.2 [N = 14], late-day 2.0 [N = 13], overnight 1.1 [N = 7] per 1000 patients randomized, P = .28). Exclusion of the periprocedural acute events into nonacute (all ST >24 hours after index PCI) revealed a predominance of events early in the day (early 5.2 [N = 67], late-day 2.5 [N = 32], and overnight 1.8 [N = 23], per 1000 patients randomized, P < .001).

A circadian variation persisted regardless of stent type (any DES: early 6.3 [N = 40], late-day 3.3 [N = 21], and overnight 1.7 [N = 11] per 1000 patients randomized, P < .001; only BMS: early 6.9 (N = 44), late-day 4.7 (N = 30), and overnight 2.5 (N = 16) per 1000 patients randomized, P = .001).

Discussion

Our analysis demonstrates a diurnal variation in the incidence of ST in the TRITON-TIMI 38 trial with a peak from 6 am to 2 pm and a nadir overnight. The ST occurred less frequently among patients randomized to prasugrel compared to clopidogrel, especially in the early hours of the day when the rates of ST were highest.

When analyzing the circadian variation of an ACS related to coronary stent implantation, it is critical to consider the impact of logistical issues that may alter the time of events. It is well established that the majority of PCI for non-ST elevation MI or unstable angina occur during routine working hours¹⁴ which may affect the time of onset of an acute ST, since ST occurring <24 hours after the index procedure is more likely due to procedural complications such as stent underexpansion.¹⁵ After excluding these 40 periprocedural events in the TRITON-TIMI 38 trial, a prominent circadian rhythm remained with an approximately 3-fold increase in the incidence of ST from 6 am to 2 pm compared to overnight. Previous studies have required the diagnosis of ST to be confirmed by angiography, but with estimated mortality as high as 45% this potentially excludes a large number of individuals who died prior to angiography.^4,5,16,17 Our analysis from the TRITON-TIMI 38 trial has the advantage of including secondary events related to ST, which ensured that MIs and deaths were adjudicated for ST as defined by the ARC.

ST has been attributed to a number of factors, including noncompliance with dual antiplatelet therapy, stent underexpansion, delayed neointimal strut coverage, positive remodeling leading to acquired strut exposure, and an augmented underlying inflammatory response.¹⁸ Platelet activity has been implicated as an important trigger for converting a subclinical arterial abnormality into a ST.¹⁹ The biological plausibility of a circadian variation is suggested by the observation that platelets are more active upon arising and assuming an upright position.^20,21 In addition, the highest number of new active platelets appear in the blood stream shortly after waking.²² Since the time to maximum platelet inhibition for clopidogrel is 2 to 4 hours and the active metabolite has a half-life of only 0.5 hours,^23,24 we hypothesize that fresh platelets may be circulating for some of the day before being exposed to irreversible P2Y₁₂ inhibition, even if clopidogrel is dosed in the morning. In contrast, prasugrel reaches peak platelet inhibition after 1 hour, and the active metabolite has a half-life of 3.7 hours,^23,24 theoretically making it less susceptible to this effect. Although this offers some biological plausibility, we also acknowledge that the circadian effects of daily dosing may be rendered insignificant by the irreversible inhibition of the P2Y₁₂ receptor with both the drugs, and the overall more robust platelet inhibition with prasugrel may be primarily responsible for our findings.

We acknowledge a number of limitations associated with this analysis. The timing of a ST relies on subjective findings such as symptom onset and can be limited by its susceptibility to recall bias. There were 44 (21%) events without a reported time of ST; however, had all these events occurred overnight, there still would have been an excess of morning ST. We acknowledge that some of the subgroup analyses have small numbers of events, and therefore cannot rule out type II error. We were also unable to fully quantify medication noncompliance at the time of ST; however, it was unlikely to be substantial given the low rates of overall noncompliance (<10%) reported in patients with ST during the clinical trial. Technical details of the index PCI were not available and may alter the risk of subsequent ST. We also cannot comment on the timing of ST after PCI is performed for stable disease, as the TRITON-TIMI 38 trial included only patients with acute coronary syndromes.

Summary

The incidence of ST in the TRITON-TIMI 38 trial exhibited a circadian variation with the highest number of events in the early day, between 6 am and 2 pm. More robust platelet inhibition with prasugrel reduced the overall incidence of ST with the highest absolute reduction in events early in the day when platelet activity is known to be the highest.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following conflicts of interest with respect to the research, authorship, and/or publication of this article: The TIMI Study Group (of which Dr. Mogabgab is a research fellow and remaining authors are current members) received research grant support for the TRITON-TIMI 38 trial from Daiichi-Sankyo and Lilly. Dr. Giugliano has received honorarium from Daiichi-Sankyo for consulting and CME lectures. Drs. Braunwald (CME lectures) and Sabatine (consulting and CME lectures) have received honoraria from Daiichi-Sankyo and Lilly.

Funding

The author(s) received no financial support for the research,authorship, and/or publication of this article.

References

Biondi-Zoccai

Sangiorgi

Chieffo

. Validation of predictors of intraprocedural stent thrombosis in the drug-eluting stent era. Am J Cardiol. 2005;95(12):1466–1468.

Lagerqvist

Carlsson

Frobert

. Stent thrombosis in Sweden: a report from the Swedish Coronary Angiography and Angioplasty Registry. Circ Cardiovasc Interv. 2009;2(5):401–408.

Lasala

Cox

Dobies

. Drug-eluting stent thrombosis in routine clinical practice: two-year outcomes and predictors from the TAXUS ARRIVE registries. Circ Cardiovasc Interv. 2009;2(4):285–293.

Tamura

Watanabe

Nagase

. Circadian variation in symptomatic subacute stent thrombosis after bare metal coronary stent implantation. Am J Cardiol. 2006;97(2):195–197.

Mahmoud

Lennon

Ting

Rihal

Holmes

Jr . Circadian variation in coronary stent thrombosis. JACC Cardiovasc Interv. 2011;4(2):183–190.

Muller

Stone

Turi

. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985;313(21):1315–1322.

Willich

Linderer

Wegscheider

Leizorovicz

Alamercery

Schroder

. Increased morning incidence of myocardial infarction in the ISAM Study: absence with prior beta-adrenergic blockade. ISAM Study Group. Circulation. 1989;80(4):853–858.

Ridker

Manson

Buring

Muller

Hennekens

. Circadian variation of acute myocardial infarction and the effect of low-dose aspirin in a randomized trial of physicians. Circulation. 1990;82(3):897–902.

Wiviott

Antman

Gibson

. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J. 2006;152(4):627–635.

10.

Wiviott

Braunwald

McCabe

. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–2015.

11.

Cutlip

Windecker

Mehran

. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344–2351.

12.

Mogabgab

Giugliano

Sabatine

. Circadian variation in patient characteristics and outcomes in ST-segment elevation myocardial infarction. Chronobiol Int. 2012;29(10):1390–1396.

13.

Mogabgab

Wiviott

Antman

. Relation between time of symptom onset of ST-segment elevation myocardial infarction and patient baseline characteristics: from the National Cardiovascular Data Registry. Clin Cardiol. 2013;36(4):222–227.

14.

Pollack

Jr Hollander

Chen

. Non-ST-elevation myocardial infarction patients who present during off hours have higher risk profiles and are treated less aggressively, but their outcomes are not worse: a report from Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines CRUSADE initiative. Crit Pathw Cardiol. 2009;8(1):29–33.

15.

Alfonso

Suarez

Angiolillo

. Findings of intravascular ultrasound during acute stent thrombosis. Heart. 2004;90(12):1455–1459.

16.

Doyle

Rihal

O'Sullivan

. Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents. Circulation. 2007;116(21):2391–2398.

17.

Iakovou

Schmidt

Bonizzoni

. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293(17):2126–2130.

18.

Holmes

Jr Kereiakes

Garg

. Stent thrombosis. J Am Coll Cardiol. 2010;56(17):1357–1365.

19.

Lemesle

Torguson

Bonello

. Relation between clopidogrel discontinuation and early cardiovascular events after percutaneous coronary intervention with drug-eluting stents. EuroIntervention. 2011;6(9):1053–1059.

20.

Brezinski

Tofler

Muller

. Morning increase in platelet aggregability. Association with assumption of the upright posture. Circulation. 1988;78(1):35–40.

21.

Winther

Hillegass

Tofler

. Effects on platelet aggregation and fibrinolytic activity during upright posture and exercise in healthy men. Am J Cardiol. 1992;70(11):1051–1055.

22.

Behnke

Forer

. From megakaryocytes to platelets: platelet morphogenesis takes place in the bloodstream. Eur J Haematol Suppl. 1998;61:3–23.

23.

Brandt

Payne

Wiviott

. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. 2007;153(1):66 e9–66 e16.

24.

Floyd

Passacquale

Ferro

. Comparative pharmacokinetics and pharmacodynamics of platelet adenosine diphosphate receptor antagonists and their clinical implications. Clin Pharmacokinet. 2012;51(7):429–442.

Circadian Variation of Stent Thrombosis and the Effect of More Robust Platelet Inhibition

Abstract

Background:

Methods and Materials:

Results:

Conclusions:

Keywords

Introduction

Methods and Materials

Results

Discussion

Summary

Footnotes

Declaration of Conflicting Interests

Funding

References