Recurrent Myocardial Infarction Due to One Subacute and Two Very Late Thrombotic Events of Drug-Eluting Stent Associated with Clopidogrel Resistance

ABSTRACT: Although drug-eluting stent (DES) thrombosis is a recognized complication of coronary intervention, recurrent late stent thrombosis is rarely reported. Clopidogrel resistance or low-responsiveness may be associated with recurrent late stent thrombosis after DES implantation. We present a diabetic patient with hypertension, obesity and heavy smoking history, who suffered 3 recurrent attacks of acute anterior ST-segment elevation myocardial infarction over 6 years due to recurrent thromboses of DES despite prolonged and regular triple antiplatelet therapy. Laboratory evaluation of hypercoagulability yielded negative results, but low responsiveness for clopidogrel was revealed by the VerifyNow™ P2Y12 assay.

As the use of drug-eluting stents (DES) becomes widespread, careful long-term follow-up of patients should be considered due to the potential for late stent thromboses.^1,2 Stent thrombosis seems to occur more frequently with DES and occasionally is associated with resistance to antiplatelet therapy.³ We have experienced a diabetic patient with hypertension, obesity and heavy smoking history, who suffered 3 recurrent attacks of acute anterior ST-segment elevation myocardial infarction (STEMI) over 6 years due to repeated thromboses of DES implanted in the left anterior descending (LAD) coronary artery. The recent stent thrombotic event was very late stent thrombosis 50 months after DES implantation despite prolonged and regular triple antiplatelet therapy (aspirin 100 mg, clopidogrel 75 mg, cilostazol 100 mg twice daily). Clopidogrel low-responsiveness was demonstrated with the VerifyNow™ P2Y12 assay.

Case Report. On February 21, 2005, a 42-year-old man with a history of obesity, hypertension, diabetes mellitus and current smoking (20 pack years) visited the Emergency Department (ED) in our hospital due to sudden-onset, anterior chest pain. His electrocardiogram (ECG) revealed 4–5 mm ST-segment elevation in leads aVL, V1–V6 and I with reciprocal ST depression in inferior leads, suggestive of acute anterior STEMI.

He was immediately taken to the cardiac catheterization laboratory and an emergent coronary angiogram showed a thrombotic occlusion in the proximal segment of the LAD (Figure 1A). The left circumflex (LCX) coronary artery and right coronary artery (RCA) had no significant lesion. After angioplasty, the lesion on the LAD was successfully treated with one 3.5 x 24 mm paclitaxel-coated stent (Taxus™, Boston Scientific, Natick, Massachusetts) and an excellent final angiographic result was obtained (Figure 1B).

After administration of a loading dose of aspirin (300 mg) and clopidogrel (450 mg), aspirin (100 mg/day) and clopidogrel (75 mg/day) were given continuously after stent implantation. Four days later, the patient complained of recurrence of chest pain and ECG demonstrated relapse of ST-segment elevation on precordial leads. Emergent coronary angiogram showed total occlusion of the previous stent due to subacute stent thrombosis (Figure 1C). With intravenous administration of abciximab (Reopro™), angioplasty was successfully finished with implantation of another 3.5 x 18 mm sirolimus-eluting stent (Cypher™, Johnson and Johnson, New Brunswick, New Jersey) (Figure 1D). Transthoracic echocardiogram performed during admission showed a reduced left ventricular ejection fraction (LVEF) of 45% with anterior and anteroseptal wall akinesia. He was discharged with warfarin and triple antiplatelet therapy (aspirin 200 mg, clopidogrel 75 mg and cilostazol 200 mg daily).

On August 8, 2005 (6 months after subacute ST), follow-up coronary angiogram demonstrated the patency of the previous stent. At that time, the patient was asymptomatic and cilostazol and warfarin were determined to be withdrawn. Dual antiplatelet therapy (aspirin 100 mg and clopidogrel 75 mg daily) with oral hypoglycemic drug (glimepiride) and antihypertensive drugs (ramipril and carvedilol) were continued. The patient remains asymptomatic and was compliant with the prescribed therapy. On December 4, 2006 (483 days or 14 months after subacute ST), the patient was re-admitted to our ED because of acute anterior STEMI. The LAD where the stent had been implanted was totally occluded and in-stent thrombosis was evident (Figure 2A). With intravenous administration of abciximab (Reopro™), balloon angioplasty was performed and he was successfully treated with another 3.5 x 24 mm paclitaxel-coated stent (TAXUS™, Boston Scientific) (Figure 2B). He was discharged under triple antiplatelet therapy (aspirin 100 mg, clopidogrel 75 mg and cilostazol 200 mg daily). The patient remains asymptomatic and has been compliant with the prescribed therapy. On February 10, 2010 (1,166 days or 50 months after first late stent thrombosis), the patient complained of sudden-onset anterior chest discomfort.

Resting ECG revealed ST elevation on precordial leads. Emergent coronary angiogram revealed stent thrombosis beginning at the proximal edge of the stent (Figure 2C). With abciximab (ReoPro™) infusion, the lesion was successfully treated with balloon angioplasty and implantation of another 3.5 x 20 mm Evolimus-eluting stent (Promus™, Boston Scientific) (Figure 2D). The intravascular ultrasound (IVUS) performed after implantation of the stent demonstrated good expansion of the stent with in-stent restenosis and in-stent thrombus. Considering the tendency of recurrent stent thrombosis, laboratory tests were carried out to assess whether the patient had an hypercoagulable state or resistance for aspirin and clopidogrel (P2Y12). Lupus anticoagulant and anti-cardiolipin antibody were negative and the patient was not deficient in antithrombin III, proteins C and S. On Verifynow P2Y12 assay (Accumetrics, San Diego, California), low responsiveness for clopidogrel was found. The patient refused anticoagulation and was discharged with triple antiplatelet therapy consisting of aspirin 200 mg/day, clopidogrel 150 mg/day and cilstazol 200 mg/day.

Discussion. Our patient experienced recurrent STEMI due to subacute ST and 2 recurrent very late stent thromboses with the events occurring 14 months after subacute stent thrombosis and 1,166 days after first very late stent thrombosis. To the best of our knowledge, this is the first case of recurrent very late stent thrombosis associated with clopidogrel low responsiveness.

Multiple predictors of late thrombosis of DES have been identified.^4,5 In our case, stent implantation in STEMI, culprit lesion at the LAD, overlapped stents (4 DES), history of diabetes mellitus and a lower level of LVEF are known to increase risk of late stent thrombosis. Abnormal platelet aggregation (clopidogrel resistance) also played a role in late stent thrombosis in our case.³ The patient began aspirin and clopidogrel therapy indefinitely after the first thrombotic event and adhered to medical therapy, but this failed to prevent stent thrombosis; this finding highly suggests antiplatelet (aspirin or clopidogrel) resistance. Although there are no evidence-based guidelines regarding the management of patients with clopidogrel resistance and myocardial infarction due to stent thrombosis as in our case, increasing the maintenance (150 mg/day) dose of clopidogrel or addition of warfarin therapy might be an appropriate treatment strategy in our case.⁶

Also, to correct the clinical factors known to affect platelet reactivity (diabetes in our patient) may be of value and strict control of glucose levels may reduce platelet reactivity and risk of stent thrombosis.⁷ New P2Y12 receptor antagonists, such as prasugrel, exhibit more potent platelet inhibition compared to clopidogrel and are associated with significantly reduced rate of stent thrombosis.⁸

Although DES are associated with better clinical outcomes (low risk of restenosis and target vessel revascularization) when compared with bare-metal stents (BMS), VLST is unusual with the use of BMS due to rapid endothelialization.^9,10 Therefore, considering our patient’s history of recurrent VLST, the use of BMS rather than DES would be the preferred strategy.

In conclusion, our case highlights that the antiplatelet resistance or low responsiveness should be borne in mind in patients with recurrent stent thrombotic events and aggressive antiplatelet therapy or addition of anticoagulation should be considered.

References

1. Jeremias A, Sylvia B, Bridges J, et al. Stent thrombosis after successful sirolimus eluting stent implantation. Circulation 2004;109:1930–1932.

2. Schulz S, Schuster T, Mehilli J, et al. Stent thrombosis after drug-eluting stent implantation: Incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period. Eur Heart J 2009;30:2714–2721.

3. Wenaweser P, Dörffler-Melly J, Imboden K, et al. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol 2005;45:1748–1752.

4. Uren NG, Schwarzacher SP, Metz JA, et al. Predictors and outcomes of stent thrombosis. Eur Heart J 2002;23:124–132.

5. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126–2130.

6. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines; ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention) Circulation 2006;113:E166–E286.

7. Machecourt J, Danchin N, Lablanche JM, et al. Risk factors for stent thrombosis after implantation of sirolimus-eluting stents in diabetic and nondiabetic patients: The EVASTENT Matched-Cohort Registry. J Am Coll Cardiol 2007;50:501–508.

8. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–2015.

9. Manjappa N, Agarwal A, Cavusoglu E. Very late bare-metal stent thrombosis. A case report and review of the literature. J Invasive Cardiol 2006;18:E203–E206.

10. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: Delayed healing and late thrombotic risk. N Engl J Med 2001;344:250–256.

From the Cardiovascular Center, Department of Internal Medicine, Inje University Seoul Paik Hospital, Inje University, and *Cardiovascular Center, Department of Internal Medicine, National Medical Center, Seoul, South Korea. The authors report no conflicts of interest regarding the content herein. Manuscript submitted April 21, 2010, provisional acceptance given May 7, 2010, final version accepted June 23, 2010. Address for correspondence: Jung-Ju Sir, MD, Cardiovascular Center, Department of Internal Medicine, National Medical Center, 18-79 Euljiro 6-ga, Jung-gu, Seoul, 100-799, South Korea. E-mail: seo0515@medimail.co.kr