Late and very late drug-eluting stent thrombosis in the immediate postoperative period after antiplatelet withdrawal: a retrospective study

Abstract

Background:

Late (31–360 days after deployment) and very late (>360 days after deployment) stent thrombosis is a feared complication after drug-eluting stent (DES) deployment. The American College of Cardiology/American Heart Association guidelines recommend dual antiplatelet therapy for 12 months due to the lack of protection beyond this period in randomized trials. The perioperative period is a unique state of generalized hypercoagulability which can predispose people to DES thrombosis when combined with the rebound hypercoagulable effect of antiplatelet withdrawal.

Methods:

A retrospective chart review was performed to detect incidences of late and very late postoperative DES thrombosis after elective noncardiac surgery. Only definite and probable cases of stent thrombosis were included. All cases were analyzed for patient demographics, comorbidities, type of surgery, intervention history, preoperative antiplatelets management, postoperative course and outcome.

Results:

A total of six patients with prior DES deployment (10–42 months earlier, average 30 months) developed DES thrombosis (five very late and one late) in the immediate postoperative period. All patients had stable coronary artery disease and were cleared for surgery (intermediate cardiac risk surgery) by their cardiologist. In all patients, antiplatelets were discontinued 4–7 days (average 5.6 days) prior to surgery to minimize operative bleeding. Five of six patients developed ST-segment elevation myocardial infarction. Half of the patients had simultaneous two-vessel DES thrombosis and two cases had single vessel thrombosis. Three patients developed ventricular fibrillation and cardiac arrest. One-third of the patients died during the index hospitalization. Coronary thrombectomy and angioplasty was successful in the remaining four cases. The incidence of postoperative late and very late DES thrombosis among all patients undergoing noncardiac surgery who were older than 40 years was 0.006%.

Conclusion:

Caution should be exercised when attempting to withdraw antiplatelets preoperatively in patients with DES even when the recommended 12-month period of dual antiplatelet therapy (DAPT) has elapsed. The significant morbidity and mortality of this complication warrants further research to study the ideal perioperative management of antiplatelets in patients with prior DES deployment over 1 year who are still receiving DAPT.

Keywords

stent thrombosis drug-eluting stent antiplatelet withdrawal

Introduction

Despite the success of drug-eluting sent (DES) compared with bare metal stent (BMS) in suppressing neointimal proliferation and reducing in-stent restenosis, concerns have arisen because of the significantly higher risk of late and very late DES thrombosis. This has been more recognized with first-generation DES. Nevertheless, reports emerge that describe this complication with second-generation DES. The risk of stent thrombosis is increased in the perioperative period secondary to catecholamine production, promoting vasospasm, increased platelet activation and decreased fibrinolysis. Additionally, preoperative interruption of antiplatelet therapy to decrease bleeding complications can trigger a rebound increase in platelet activation and platelet aggregation further increasing the risk of stent thrombosis [Collet et al. 2004; Ferrari et al. 2005]. Published reports that illustrate simultaneous two-vessel and three-vessel stent thrombosis suggest that this phenomenon is due to a generalized hypercoagulable state in a setting of a predisposed stent. Cessation of dual antiplatelet therapy (DAPT) was found to be the single most significant predictor of stent thrombosis in prior trials [Park et al. 2006]. The American College of Cardiology (ACC)/American Heart Association (AHA) recommend DAPT for 12 months after DES deployment due to lack of evidence for protection beyond that period in randomized trials [Park et al. 2010]. However, there are no studies to demonstrate the safety of antiplatelet withdrawal in patients with prior DES deployed for longer than 12 months who are anticipating surgery. We were vigorously exposed to this dilemma and have encountered six cases with acute postoperative DES thrombosis due to preoperative antiplatelet withdrawal. We attempted to study the magnitude, prevalence, causes and outcome of this complication at our institution.

Methods

The Institutional Review Board at Tampa General Hospital approved the study and waived the need for patient consent. A retrospective chart review was performed for patients admitted to Tampa General Hospital for elective surgical procedures between January 2005 and August 2012 who suffered late and very late DES thrombosis in the immediate postoperative period. Stent thrombosis is deﬁned on the basis of the Academic Research Consortium deﬁnitions [Cutlip et al. 2007]. According to the timing of presentation, stent thrombosis is considered late when it occurs 31–360 days after deployment, or very late when it occurs after 360 days. According to the level of certainty, stent thrombosis can be definite, probable or possible. Definite is classified in the presence of acute coronary syndrome and either angiographic or pathological (autopsy) conﬁrmation of stent thrombosis. Probable is classified in case of an acute myocardial infarction involving the target-vessel territory without angiographic conﬁrmation of thrombosis or other identiﬁed culprit lesion and/or any unexplained death within 30 days. Possible is defined in the case of any unexplained death after 30 days [Cutlip et al. 2007]. Only definite and probable cases were classified as stent thrombosis in this study. Cases with possible stent thrombosis were excluded. Myocardial infarction was classified as ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) according to the third universal definition of myocardial infarction [Thygesen et al. 2012]. The collected cases were analyzed for patient demographics, comorbidities, type of surgery, DES type, time of coronary stenting, type of antiplatelet medication the patient received and onset of withdrawal, intraoperative hemodynamic and telemetric events, postoperative course and final outcome. We also investigated the patients’ baseline degree of severity of coronary artery disease based on historical data (according to a preoperative interview with primary cardiologist) or noninvasive cardiac stress testing. Our main objective was to study the magnitude, causes, presentation and outcome of late and very late DES thrombosis in the perioperative period. We also attempted to calculate the incidence of postoperative late and very late DES thrombosis among all surgical cases. Continuous data were presented as mean (±standard deviation) and dichotomous data were expressed as numbers and percentages.

Results

Study population

A total of six patients developed DES thrombosis in the immediate postoperative period during the study timeframe. They were five men and one woman, with a mean age of 59 years (range 54–69) and a mean body mass index of 35 kg/m² (range 25–45). One third of the patients had diabetes mellitus. Other comorbidities are listed in Table 1. The patients had DES deployed 10–42 months prior to surgery with a mean of 30 months. In patients with simultaneous DES thrombosis, the date of the last deployed DES was used as ‘onset of stenting’ if DES were placed on separate occasions. Five cases had first-generation DES (Taxus or Cypher) and one case had second-generation DES (Endeavor). All patients were referred to their primary cardiologist for preoperative cardiac evaluation and risk stratification. No patient had unstable coronary artery disease prior to surgery. Stability was based on patients’ symptomatology and a prior noninvasive cardiac stress test. Antiplatelet therapy was discontinued 4–7 days prior to surgery with a mean of 5.6 days. Discontinuation of antiplatelets by the cardiologist was decided after a risk/benefit assessment favored their interruption to decrease operative bleeding in five cases who had stable coronary artery disease and in whom DES deployment had been for longer than 1 year. In one case, clopidogrel was stopped to avoid the need for blood transfusion in a Jehovah’s Witness (case no. 1). Throughout the study period, there were approximately 100,000 noncardiac surgeries that were performed in patients older than 40 years. The incidence of postoperative late and very late DES thrombosis among all noncardiac surgeries was therefore 0.006 %. We did not calculate the incidence of postoperative DES thrombosis among the surgical cases who had prior DES placement due to unavailability of data in a large percentage of patients.

Table 1.

Compilation of patient’s demographics, comorbidities and clinical course.

N	Age	Sex	BMI	DM	Other comorbidities	Surgery	Duration of surgery (min)*	EBL (ml)	LVEF preop%	LVEF postop%	Peak troponin	OR events^$	LOS
1 ‡	54	Male	34	No	AFib, HTN, hypertriglyceridemia, sleep apnea, bilateral knee osteoarthritis	Bilateral knee replacement	233	400	68	20	600	Occasional SB during surgery (no ST shifts)	14
2 ‡	69	Male	25	No	HTN, hyperlipidemia, colon cancer, jaundice due to biliary obstruction	Roux en- Y hepaticojejunostomy	286	200			<0.01^§	None (no ST shifts)	1
3	55	Male	27	No	HTN, CHF, PVD, hyperlipidemia, GERD, cervical spondylitic myelopathy	Spondylosis	215	< 50	40	20–25	90	Occasional SB (no ST shifts)	3
4	56	Male	45	No	HTN, hyperlipidemia, depression, GERD,	Gastric banding	180	50		55–60	100	None (no ST shifts)	16
5	64	Male	32	Yes	HTN, CABG, PVD, hyperlipidemia, GERD, DJD, COPD, sleep apnea	Hip replacement	170	350			0.7^§	None (no ST shifts)	5
6	55	Female	45	Yes	HTN, DVT, DJD, incisional hernia, GERD	Hernia repair	217	50	50–55	35	125	None (no ST shifts)	1

Duration of surgery is calculated from anesthesia start to anesthesia stop.

OR events include any documented intraoperative hemodynamics or ECG monitoring problems.

‡

Cases no. 1 and 2 were previously reported by our team [Omar et al. 2012, 2014].

These two cases expired after the episode of stent thrombosis and the reported troponin level represents the first set of cardiac enzyme.

AFib, atrial fibrillation; BMI, body mass index; CABG, coronary artery bypass graft; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; DJD, degenerative joint disease; EBL, estimated blood loss; GERD, gastroesophageal reflux disease; HTN, hypertension; LVEF, left ventricular ejection fraction; LOS, length of hospital stay; OR, operating room; PVD, peripheral vascular disease; SB, sinus bradycardia.

Operative details

All six patients were operated upon by different surgeons. All surgeries (three abdominal surgeries, one hip replacement, one knee replacement and one spine surgery) are classified as elective noncardiac surgeries that are intermediate risk surgeries according to the ACC/AHA guidelines [Fleisher et al. 2008]. The mean duration of surgery was 217 min (range 170–286). Estimated blood loss during surgery was 178 ml (range 50–400). All patients had stable intraoperative electrocardiographic monitoring which showed no evidence of ST-segment shift. In two cases there were transient episodes of sinus bradycardia without any consequent hypotension. No episodes of cardiac arrest occurred during surgery.

Postoperative course and outcome

One case developed late DES thrombosis and five cases developed very late DES thrombosis. There were five cases of definite and one case of probable stent thrombosis according to the aforementioned definitions. Five cases had a STEMI in the respective territory of thrombosed DES and one case had an NSTEMI. Fifty percent of the patients experienced cardiac arrest due to ventricular fibrillation. Coronary angiography was performed in five patients and revealed evidence of acute stent thrombosis. In one case, coronary angiography was not performed as the patient developed a fatal ventricular tachycardia due to anterior STEMI. Three out of six cases developed simultaneous two-vessel DES thrombosis and two cases developed single vessel stent thrombosis. Thrombectomy and angioplasty was successful in four cases and was associated with a TIMI-3 flow. Two cases died during the index hospitalization due to recurrent ventricular fibrillation resistant to resuscitative efforts. The mean value of peak troponin I level was 152 μg/liter (range 0.01–600). Three patients had significant postoperative drop in their ejection fraction. The mean hospital stay was 6.8 days (range 1–40). Tables 1 and 2 represent the patient demographics, comorbidities, intervention history, preoperative antiplatelets management, postoperative course and outcome. Figure 1 illustrates the electrocardiogram of the six cases with postoperative stent thrombosis and Figure 2 shows the angiographic findings.

Table 2.

Intervention history, preoperative antiplatelets management, postoperative course and outcome.

N	Stent type	Onset of stenting (months)	Onset of stopping antiplatelets	Postoperative event	Procedure	Outcome
1*	Taxus (PES) and Cypher (SES)	42	Clopidogrel stopped 4 days before surgery	Low lateral STEMI, cardiogenic shock and V-fib arrest due to LAD and LCX stent thrombosis	AngioJet thrombectomy of LAD and LCX with stenting of both vessels	Survived
2*	DES	54	Aspirin stopped 1 week before surgery	Inferior STEMI and Vfib arrest due to simultaneous LAD and RCA stent thrombosis	V-fib arrest and death prior to intervention	Death
3	Taxus (PES)	36	Aspirin and clopidogrel stopped 1 week before surgery	NSTEMI. In-stent thrombosis of the LCX and 2nd diagonal branch	Suction thrombectomy and balloon angioplasty of the LCX, 1st and 2nd diagonal and stent of 1st diagonal	Survived
4	Taxus (PES)	19	Clopidogrel stopped 1 week before surgery	High lateral STEMI. V-fib cardiac arrest due to totally occluded ramus intermedius	PTCA of the ramus intermedius	Survived
5	Taxus (PES)	18	Aspirin and clopidogrel stopped 5 days before surgery	Anterior STEMI	None due to V-tach cardiac arrest	Death
6	Endeavor (ZES)	10	Aspirin and Effient (Eli Lilly and Company, Indianapolis) stopped 4 days prior to surgery	High lateral STEMI due to total LAD occlusion	Thrombectomy and PTCA for total LAD occlusion	Survived

Cases no. 1 and 2 were previously reported by our team [Omar et al. 2012, 2014].

DES, drug-eluting stents; LAD, left anterior descending; LCX, left circumflex; NSTEMI, non-ST-segment elevation myocardial infarction; PES, paclitaxel-eluting stent; PTCA, percutaneous transluminal coronary angioplasty; RCA, right coronary artery; SES, sirolimus-eluting stent; STEMI, ST-segment elevation myocardial infarction; V-fib, ventricular fibrillation; V-tach, ventricular tachycardia; ZES, zotarolimus-eluting stent.

Figure 1.

Electrocardiogram (ECG) of six cases with postoperative stent thrombosis. ECG of case no. 1 shows low lateral STEMI (ST elevation in V5, V6 with reciprocal depression in V1–V3. ECG of case no. 2 shows inferior STEMI (the fact the ST elevation in lead III > lead II and ST depression in aVL > lead I suggests that the RCA is the culprit vessel). ECG of case no. 3 shows no ST elevation. ECG of case no. 4 shows high take off coved ST segments in leads I and aVL with reciprocal ST depression in V1–V3, suggesting high lateral STEMI. ECG of case no. 5 shows anterior STEMI with RBBB, suggesting a very proximal LAD lesion. ECG of case no. 6 shows high lateral STEMI (ST-segment elevation in leads I and aVL with reciprocal depression in the inferior leads). RBBB; right bundle branch block; LAD, left anterior descending coronary artery; RCA, right coronary artery; STEMI, ST-segment elevation myocardial infarction. Panels for patients 1 and 2 are adapted with permission and modification from Elsevier Science [Omar et al. 2012, 2014].

Figure 2.

Coronary angiography (CA) of case no. 1 reveals mid LCX and proximal LAD drug-eluting stent thrombosis with sparing of a mid-LAD bare metal stent that shows in-stent restenosis (a). CA of case no. 2 reveals subtotal proximal LAD occlusion with an evident thrombus (b) and total mid RCA occlusion (c). CA of case no. 3 shows in-stent thrombosis and total occlusion of the LCX and diagonal branch (d). CA of case no. 4 shows total occlusion of the ramus intermedius branch (e). CA of case no. 6 shows in-stent thrombosis and total LAD occlusion (f). Panels (a–c) are adapted with permission from Elsevier Science [Omar et al. 2012, 2014].

Discussion

In this retrospective study, we found a total of six cases of postoperative late and very late DES thrombosis in patients with stable coronary artery disease. None of the surgical procedures were high-risk surgeries with expected higher perioperative mortality, and five out of six patients had already completed over 1 year of DAPT. After a risk/benefit assessment, the patients’ cardiologists discontinued antiplatelets preoperatively to minimize operative blood loss, which might have triggered stent thrombosis. Three out of six cases had two-vessel DES thrombosis (cases no. 1, 2, 3), suggesting that a generalized thrombotic state is created causing thrombosis at multiple sites. The significant morbidity (evident in five out of six cases who developed STEMI) and mortality (two out of six cases) of this complication warrants further research for its prevention. The literature has several case reports of one-vessel, two-vessel and triple-vessel very late DES thrombosis. This report represents the first case series of this complication in the postoperative period.

The incidence of late DES thrombosis is around 0.4–0.6% per year [Daemen et al. 2007; Siddiqi and Faxon, 2012]. Most studies with long-term DES outcomes analyzed first-generation sirolimus (SES) and paclitaxel (PES) eluting stents. Outcomes from a registry of first-generation SES (Cypher, Cordis Corporation, Bridgewater, New Jersey) implantation revealed a cumulative incidence of late stent thrombosis of 0.6% and of very late stent thrombosis of 1.6% at 5-year follow up without evidence of plateau at 5 years [Kimura et al. 2012]. In a meta-analysis by Bavry and colleagues, the incidence of very late thrombosis was 3.6 events per 1000 with SES versus 5.9 events per 1000 with PES [Bavry et al. 2006]. The median time of late SES thrombosis was 15.5 months versus 18 months with PES [Bavry et al. 2006]. Second-generation DES are associated with a significantly lower risk of stent thrombosis compared with first-generation DES. Smits and colleagues compared the Xience (Abbott Vascular, Santa Clara, California) everolimus-eluting stent (EES) with the Taxus Liberté (Boston Scientific Corporation, Natick, Massachusetts) PES at 2-year follow up and concluded a significantly lower rate of stent thrombosis (0.9% versus 3.9% respectively; relative risk 0.23; 95% confidence interval 0.11–0.49) [Smits et al. 2011]. Stone and colleagues concluded a lower incidence of stent thrombosis with EES versus PES (0.4% versus 1.2%, p = 0.008) [Stone et al. 2011b]. Similarly, EES [Räber et al. 2011] and zotarolimus-eluting stent [Yeung et al. 2011] were associated with lower rates of very late DES thrombosis compared with SES. Therefore, these second-generation stents have superior long-term safety compared with first-generation stents. This was clear in our series in which five of six cases had first-generation DES (mainly Taxus) and one case had second-generation DES (Endeavor, Medtronic CardioVascular, Santa Rosa, California).

There are various proposed mechanisms of very late DES thrombosis, including delayed endothelialization and neoinitimal coverage, intra-stent hypersensitivity reaction to polymers, late stent malapposition and stent fracture. Antiplatelet agents are mandatory in prevention of stent thrombosis, which is a platelet-mediated process. Adding thienopyridines to aspirin (DAPT) exerts a synergistic antiplatelet action and is recommended by the ACC/AHA for 12 months after DES implantation. There are limited data in the literature regarding DES thrombosis in the immediate postoperative period and are mostly related to antiplatelet withdrawal.

It should be noted that the main evidence of increased postoperative bleeding from DAPT is mainly related to cardiac surgery. Data regarding the risk of operative bleeding after noncardiac surgery are limited and controversial. A meta-analysis by Burger and colleagues found that continuation of aspirin led to an increased rate of bleeding by a factor of 1.5, however it did not lead to a higher level of the severity of bleeding complications, with the exception of intracranial surgery, and possibly transurethral prostatectomy [Burger et al. 2005]. Stone and colleagues found no difference in incidence of transfusion and reoperation for bleeding in 10,406 patients who underwent vascular surgery and were randomized to either aspirin alone, clopidogrel alone, aspirin and clopidogrel, or neither [Stone et al. 2011a]. Perioperative antiplatelet management remains controversial and usually represents a debate between cardiologists and surgeons. This has provoked some countries to develop national societal guidelines with partnership between cardiologists and surgeons for ideal perioperative antiplatelet management. For example, the national society of interventional cardiology in Italy recommended that DAPT should not be withdrawn before low bleeding risk surgeries, whereas at least aspirin should be continued in the majority of surgeries [Rossini et al. 2012].

We do agree that there is no evidence from randomized trials to support continuing DAPT for longer than 1 year after DES deployment. Withdrawing antiplatelets immediately before surgery carries more risk than elective withdrawal due to the rebound increase in platelet function in the hypercoagulable perioperative state. We are occasionally met with a patient who is still prescribed DAPT indefinitely and is coming for our advice before a noncardiac surgery to decide on antiplatelet withdrawal. This decision is variable among cardiologists due to the absence of societal guidelines in this specific instance. A question to be answered is whether discontinuing antiplatelet therapy after 12 months can be generalized to all patients with DES. In our opinion, patients with DES who are still on DAPT and are anticipating surgery should be approached more cautiously with proper risk/benefit assessment, even if the recommended 1-year period of DAPT has elapsed. In cases in whom operative risk of bleeding is minimal, we propose continuing DAPT if the patient is on it. When operative bleeding is a concern, then continuing a single antiplatelet agent with aspirin might be a reasonable alternative. We aim to draw attention to this serious complication and warn of the consequences of preoperative discontinuation of DAPT in patients with DES. Future randomized trials are mandatory in this specific group of patients to test the risks and benefits associated with implementing either approach.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare no conflicts of interest in preparing this article.

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