Case Report and Brief Review

Very Late Stent Thrombosis and Antineoplastic Therapy

Michael Ghalchi, MD, Thomas Chengot, DO, Kevin Marzo, MD

Michael Ghalchi, MD, Thomas Chengot, DO, Kevin Marzo, MD

ABSTRACT: Percutaneous coronary intervention (PCI) is now a part of the treatment strategy of patients with both unstable syndromes and chronic angina. As our patients age and live longer with coronary artery disease, many having had PCI, they are more likely to develop potentially life-threatening comorbid conditions, including neoplastic disorders. In the United States, for example, an estimated 41% of the population will develop some form of malignancy.1 As such, they become subject to a multitude of interactions between their cardiac and oncologic diseases, and the therapies used to treat each. This is especially the case when patients have had PCI with drug-eluting stents (DES), as a careful balance between thrombosis and bleeding must be maintained, and is particularly vulnerable to the interactions described above. The following cases and accompanying review will highlight potential risks of very late stent thrombosis with acquired prothrombotic states, following coronary intervention with implantation of both 1st and second-generation DES.
J INVASIVE CARDIOL 2010;22:E216–E219
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Percutaneous coronary intervention (PCI) is now a part of the treatment strategy of patients with both unstable syndromes and chronic angina. As our patients age and live longer with coronary artery disease, many having had PCI, they are more likely to develop potentially life-threatening comorbid conditions, including neoplastic disorders. In the United States, for example, an estimated 41% of the population will develop some form of malignancy.1 As such, they become subject to a multitude of interactions between their cardiac and oncologic diseases, and the therapies used to treat each. This is especially the case when patients have had PCI with drug-eluting stents (DES), as a careful balance between thrombosis and bleeding must be maintained, and is particularly vulnerable to the interactions described above. The following cases and accompanying review will highlight potential risks of very late stent thrombosis (VLST) with acquired pro-thrombotic states, following coronary intervention with implantation of both 1st and 2nd generation DES.

Case Reports

Patient #1. We present the case of a 70-year-old female with remote history of breast cancer treated with lumpectomy, remote lung cancer treated with lobectomy and chemotherapy, hypertension, and coronary artery disease with sirolimus-eluting stent placement in the left anterior descending coronary artery (LAD) for an acute coronary syndrome. She was treated with aspirin and clopidogrel for 12 months after stent placement, and maintained on aspirin 81 mg thereafter. Five years later, she remained asymptomatic from a cardiac perspective. She was, however, diagnosed with myelodysplastic syndrome (MDS) with deletion of chromosome 5q and treatment with lenalidomide was initiated. One week later, she developed resting substernal chest pressure and dyspnea, and presented to the emergency room approximately eight hours after developing symptoms. Initial electrocardiogram (ECG) demonstrated 5 mm ST elevations and Q waves in the anterior precordial leads. Emergent cardiac catheterization was performed and showed thrombosis of the LAD stent. PCI was successfully performed and TIMI III flow re-established. Initial labwork, however, was notable for creatine phosphokinase (CPK) > 2000 IU/L and troponin-I > 50 ng/mL, and an echocardiogram showed severe left ventricular dysfunction with anterior wall dyskinesia. She developed pulmonary edema and deterioration of mentation and urine output, and an intra-aortic balloon pump was inserted. She died several days later from multi-organ system failure related to cardiogenic shock. Patient #2. The second patient we present is a 54-year-old man with history of hypertension, dyslipidemia, and coronary artery disease with several prior myocardial infarctions, and zotarolimus-eluding stent placement in the right coronary artery (RCA) 18 months prior, as well as in the LAD artery 6 months prior to presentation. Three months prior to the reviewed case of VLST, he was diagnosed with adenocarcinoma of the lung with metastases to the pericardium and diaphragm, and was started on carboplatin and paclitaxel. At the same time, he was diagnosed with a left upper extremity deep vein thrombosis; subcutaneous dalteparin was started and aspirin discontinued. His cardiac regimen also included clopidogrel, an angiotensin-converting enzyme inhibitor, beta-blocker, and statin therapy. Three weeks prior to presentation with VLST, his antineoplastic regimen was changed to an experimental protocol with docetaxel and ASA404 or placebo due to progression of disease.
On the day of presentation, he developed substernal chest pressure at rest. An ECG revealed inferior ST elevations and Q waves. Emergent cardiac catheterization showed inferior wall hypokinesia and RCA stent thrombosis. A bare-metal stent was successfully placed. The patient was given aspirin, clopidogrel was replaced with prasugrel, and dalteparin was continued. His chemotherapy was also continued, and he was discharged home in stable condition 5 days later.

Discussion

VLST, which is defined as thrombotic occlusion of a stent more than 1 year after deployment, was recognized as a distinct clinical entity complicating the use of both first and second generation DES. Mechanisms suggested delayed healing, incomplete endothelialization, and vessel remodeling due to chronic inflammation.2–5 It has been suggested that the slightly increased risk of VLST associated with DES is compensated by adverse events caused by the treatment of more frequent recurrences with bare-metal stents. Patient #1, who received a first-generation stent implantation 5 years prior had VLST one week after starting treatment with lenalidomide, an immunomodulator known to induce a pro-thrombotic state. Patient #2, who underwent 2nd-generation DES implantation had VLST 18 months later while receiving platinum-based therapy, also known to increase thrombotic risk. Cancers can increase the risk of thrombosis, primarily through activation of the coagulation cascade. Most cancer-related thrombosis is associated with malignancies of the breast, colon and lung, because of their high prevalence. Cancers of the pancreas, ovaries, and brain, however, have the highest rates of inducing thrombosis.6 Besides cancer type and stage, patient characteristics such as age, immobility, surgery, thrombocytosis, anemia and other comorbid conditions affect thrombosis risk.7 Not only is cancer itself associated with increased thromboses, but so are many of the antineoplastic therapies commonly used (Table 1). Many of the data regarding multiple classes of chemotherapy and risk for thromboembolic disease involve the venous system; in most cases, however, rates of arterial thrombosis are increased as well. There are also reported cases, such as ours, of stent thrombosis occurring soon after initiation of chemotherapy.8 In this context, we will review the likelihood and mechanism of thrombosis associated with individual anti-neoplastic agents. Lenalidomide, a thalidomide analog, is approved in the United States for treatment of multiple myeloma and MDS with deletion of chromosome 5q, as in the case of Patient #1. Although its exact mechanism of action is not understood, it is known to affect both the humoral and cellular immune systems and have anti-angiogenic properties. There is evidence that it modulates immune activity by altering cytokine production, regulating T-cell costimulation, and augmenting natural killer cell cytotoxicity.9 Angiogenesis is thought to be inhibited by reduced expression of VEGF and interleukin-6.10 Lenalidomide has been shown to delay progression of disease in myeloma and reduce transfusion rates in MDS. Thalidomide and its derivatives are also known to increase the risk of thromboembolic disease, particularly of the venous system. Studies indicate the risk of thrombosis is not significantly increased when these medications are used alone;11 the incidence is significantly higher, however, when combined with another anti-neoplastic agent (e.g., doxorubicin), high-dose dexamethasone or erythropoietin. Additionally, thrombosis is more likely to occur when the underlying condition is myeloma. Prospective trials have shown rates of venous thromboembolism ranging from 3–75%.12,13 The mechanism of thrombosis, although not clearly established, has been theorized to involve alterations in protease-activated receptors or thrombomodulin, resistance to activated protein C, or direct endothelial damage.14–16 Although clinical trials have not suggested an increased risk of arterial thrombosis, there are multiple published case series of myocardial infarctions, cerebrovascular accidents and peripheral arterial thromboses occurring soon after initiation of therapy.17,18 Patient #2 was receiving a number of chemotherapies that may affect thrombotic risk. Cisplatin, and its daughter compound carboplatin, are platinum-based alkylating agents that are used to treat carcinomas, sarcomas, germ cell tumors and lymphomas. They are believed to induce thrombosis primarily through platelet activation and aggregation.19 Additionally, these medications alter endothelial cell integrity, elevate von Willebrand factor levels, cause vasospasm and have anti-angiogenic activity.20 In a retrospective review of 271 patients with transitional cell carcinoma receiving cisplatin-based therapy, 12.9% developed thromboembolic events, 20% of which were arterial.21 There are also case reports of patients developing multiple arterial thromboses on cisplatin and carboplatin.22–25 Paclitaxel and docetaxel are taxoid drugs that affect microtubule function and thereby interfere with mitosis. Paclitaxel-coated stents have been routinely used to reduce intimal hyperplasia and have been shown to reduce restenosis rates. When paclitaxel is used systemically, major toxicities include hypersensitivity reactions (usually type I) and an increased propensity for myocardial ischemia and infarction.26 A direct systemic pro-thrombotic effect of these medications is not described in the literature. Chemotherapy regimens may include experimental agents, sometimes with unknown or novel mechanisms of action. Patient #2 was receiving ASA404, an experimental vascular disrupting agent that causes collapse of existing tumor blood vessels. It is being investigated for use in solid tumor cancers, such as those of the lung, ovarian, breast and prostate. Preliminary phase II studies in patients with advanced non-small cell lung cancer have not demonstrated an increased propensity for thrombosis, but further investigation is ongoing.27 Bevacizumab is another anti-angiogenic agent that works by binding to and neutralizing vascular endothelial growth factor, thereby reducing tumor vascularization. It has been shown to increase the risk of thrombosis. A meta-analysis examined 15 trials and included 7,956 patients with varying types and stages of cancer, and showed the risk of thrombosis on bevacizumab to be 11.9%, a 33% higher relative risk compared with controls.28 Another meta-analysis showed a 5% risk of arterial thrombosis; the risk was highest in elderly patients and those with a history of arterial thromboembolic disease.29 The exact mechanism is not understood. Vorinostat is a histone deacetylase inhibitor, currently used to treat cutaneous T-cell lymphoma, although it has preliminarily shown effectiveness against other malignancies as well. Two phase II trials found the risk of thromboembolic disease to be between 5–8%.30,31 L-Asparaginase is used to treat acute lymphoblastic leukemia (ALL), and works by depleting plasma asparagine, thereby inhibiting protein synthesis. As such, concentrations of albumin and proteins involved in both pro- and anticoagulation are reduced. In a retrospective study of 548 patients with ALL treated with L-Asparaginase, 44 (8%) developed thromboembolic disease.32 There is some suggestion that treatment with antithrombin III reduces the likelihood of thrombosis.33 Several of the common chemotherapy regimens used to treat breast cancer have been associated with a modest elevation of the risk of thrombosis. Tamoxifen and raloxifene are selective estrogen receptor modulators used to prevent recurrence of breast cancer and primary prevention in those at high risk for developing a first breast cancer. They have been shown to promote thrombogenesis, conceivably through their weak estrogenic effects. A Danish study of 16,289 women prescribed tamoxifen for secondary prevention showed a 5-year risk of thromboembolic disease of 1.2%, compared to 0.50% in those not on tamoxifen. The highest risk of an event was in the first 2 years of treatment.34 There is some evidence that tamoxifen may also increase the risk of ischemic stroke, but reduce the risk of myocardial infarction. Diethylstilbestrol (DES) is a synthetic estrogen compound being investigated for use in patients with advanced prostate cancer. It is believed to cause hypercoagulability by inducing production of factors II, VII, IX and C. In a phase II trial, 21% of patients treated with DES and docetaxel developed deep vein thromboses, despite receiving prophylaxis with warfarin and full-dose aspirin.35 Retrospective trials have demonstrated that prophylactic anticoagulation or anti-platelet therapy in patients receiving thalidomide or lenalidomide reduces the incidence of thromboembolism; concurrent aspirin, low-molecular weight heparin or warfarin is generally prescribed based on the patient’s medication regimen and underlying risk for thrombosis.36 The American Society of Clinical Oncology does not recommend routine prophylactic anticoagulation for patients receiving other chemotherapy regimens.37 The treatment strategy, however, for patients at higher risk for thrombosis, particularly those with coronary stents, may need to be individualized. These patients often have an increased hemorrhagic risk as well, making decisions regarding anti-platelet and/or anticoagulant therapy challenging. A careful assessment of hemorrhagic and thrombotic risk must be made for each individual patient, and therapies prescribed accordingly. We present these cases in order to highlight the issue of medical interactions in cardiac patients, particularly those receiving treatment for oncologic disease. As our patients with prior PCI survive longer, they will undoubtedly develop comorbid conditions including cancer, and undergo treatments that can affect their stent and overall cardiac health. As such, it is important to constantly reassess treatment to maintain the delicate balance between bleeding and thrombosis. For example, in Patient #1, it may have been reasonable to restart dual-antiplatelet therapy when lenalidomide was initiated. Additionally, we must continue to reinforce with the patient with prior PCI undergoing antineoplastic therapy the need for prompt evaluation of concerning symptoms. Seeking emergent evaluation for symptoms of myocardial infarction could be lifesaving. Finally, in patients with stable coronary artery disease and malignancy, coronary intervention and the late consequences of prothrombotic states need to be considered prior to and following revascularization, if performed.

References

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From the Department of Cardiology, Winthrop University Hospital, Mineola, New York. The authors report no conflicts of interest regarding the content herein. Manuscript submitted February 19, 2010, provisional acceptance given March 24, 2010, final version accepted April 8, 2010. Address for correspondence: Michael Ghalchi, MD, Winthrop University Hospital, Department of Cardiology, 120 Mineola Ave. Suite 500, Mineola, NY 11501. E-mail: mghalchi@yahoo.com