Abstract
Recommendations for the duration of clopidogrel (Plavix®, Bristol Meyers Squibb, New York, NY) therapy following drug eluting stent (DES) insertion have been subject to recent criticism. Suggested recommendations for the continuation of clopidogrel have been extended to one year following DES insertion. However, patients with a previously inserted DES who now require cardiac surgery are requested to stop clopidogrel perioperatively. The safety of this practice is unclear. We report two cases of elective cardiac surgical intervention after the insertion of DES complicated by perioperative or intraoperative acute coronary ischemia attributed to DES closure.
Clinical Summary
Patient 1
A 65 year-old male presented with an NSTEMI. On cardiac catheterization, he was found to have three-vessel coronary disease Figure 1a,b), a 5 cm ascending aortic aneurysm (Figure 1c), and a normal ejection fraction. Two Cypher® (Johnson and Johnson, New Brunswick, NJ) DES were inserted in the right coronary and left circumflex arteries. The 90% lesion in the left anterior descending (LAD) artery was then determined to be unamenable to percutaneous intervention (Figure 1b). Due to continued intermittent chest pain, the patient was referred by his cardiologist for surgical intervention one month following DES insertion. Clodiprogel was discontinued five days prior to surgery. No other antiplatelet agent was used in the interim.
Preoperative cardiac catheterization of Patient 1 demonstrating
Ascending aortic aneurysm repair and left-internal-mammary-artery (LIMA) to LAD bypass was performed without incident. Aspirin was initiated on postoperative day one. Clopidogrel therapy (75 mg daily) was reinstituted on postoperative day two. On postoperative day three, the patient acutely deteriorated after noting acute chest pain with ST elevation in the lateral leads. Transthoracic echocardiography demonstrated a hypokinetic lateral wall. Prior to reaching the cardiac catheterization laboratory, the patient sustained a cardiopulmonary arrest and expired. The cause of death was from acute infarction of the lateral wall due to presumed DES thrombosis.
Patient 2
A 53-year-old male underwent a bioprosthetic aortic valve replacement two years previously at another institution. He was referred to us with dyspnea and found to have severe aortic stenosis (peak gradient = 70 mmHg, mean gradient = 40 mmHg) secondary to prosthetic valve degeneration. A cardiac catheterization performed seven months previously demonstrated left dominant normal coronary system but was complicated by an acute dissection of the circumflex and ramus arteries (Figure 2a). The coronary artery dissection was treated with the insertion of several Taxus® DES (Boston Scientific, Natick, MA, Figure 2b) with good result.
Preoperative cardiac catherization of patient 2 demonstrating
Seven months after DES insertion, the patient underwent a reoperative aortic valve replacement. Clopidogrel had been initiated after DES insertion but was discontinued four days prior to surgery. At the start of the operation, ST depression was noted by electrocardiography in the lateral leads; transesophageal echocardiography (TEE) at that time did not demonstrate any wall function abnormality.
A mechanical aortic valve replacement was performed with clear visualization of both coronary orifices. After removal of the cross-clamp, the patient developed sustained ventricular tachycardia. Electrocardiography during the brief periods the patient was in a sinus rhythm demonstrated persistent ST depression in the lateral leads with normal ST segments in the anterior leads. TEE documented acutely depressed wall motion abnormality inferiorly and laterally. After arresting the heart again, saphenous vein to the posterior descending and obtuse marginal arteries coronary artery bypass grafting (CABG) was performed. He was weaned off cardiopulmonary bypass in sinus rhythm with an intraaortic balloon pump without difficulty or arrhythmia. The TEE demonstrated remarkably improved lateral and inferior wall function. The balloon pump was removed within 6 hours postoperatively. The patient recovered and was discharged home on postoperative day six with preserved ventricular function.
Discussion
In-stent thrombosis of DES has become a topic of several recent major reports.(Kastrati et al. 2007; Lagerqvist et al. 2007; Maisel, 2007) This rare complication, with significant mortality, has been linked to the discontinuation of clopidogrel. Initial recommendations of 3-6 months of clopidogrel therapy have been under question as many have suggested a minimum of one year and perhaps even life long treatment with this antiplatelet agent is necessary. (Eisenstein et al. 2007)
Patients receiving clopidogrel who require cardiac surgery are often asked to stop the drug 5-7 days preoperatively to decrease the risk of bleeding. Furthermore, the use of aprotinin (Bayer Pharmaceutical, West Haven, CT) has been linked to adverse outcomes in cardiac surgery, despite decreasing the need for blood transfusion requirements. (Mangano et al. 2006) Current practice patterns including the avoidance of aprotinin supports the need to stop clopidogrel preoperatively to minimize the risk of bleeding. Thus, the dilemma of perioperative use of clopidogrel becomes more vexing.
We report two cases of significant adverse outcomes following the insertion of DES and cessation of clopidogrel perioperatively. As these two cases do not have documented angiographic or pathologic confirmation of stent thrombosis, these cases are considered probable stent thrombosis, as defined by the Academic Research Consortium, with acute ischemia in the territory of an implanted stent without evidence of other cause. (Cutlip et al. 2007) The first case required surgical intervention one month following DES insertion due to a significant LAD lesion and recurrent chest pain. The patient was referred to us from the outside physician only after the decision had been made to attempt to percutaneously treat the coronary disease. Unfortunately, the LAD was felt to be unamenable to percutaneous intervention after DES insertion in the other vessels. Stenting of triple vessel disease is not typical in our practice especially given the presence of an ascending aortic aneurysm. The second case resulted in intraoperative coronary ischemia in the distribution of dissected coronary vessels treated with numerous DES. This occurred following a seven month course of clopidogrel treatment and was treated successfully with CABG.
The timing of elective cardiac surgery following the insertion of DES is unclear. In patients who must be operated on soon after DES insertion, the benefits of clopidogrel cessation must be weighed against the risks. The clopidogrel in unstable angina to prevent recurrent ischemic events (CURE) trial suggested the initiation of clopidogrel in addition to aspirin prior to CABG may decrease the risk of cardiovascular death, myocardial infarction, or stroke by 20%, although this was not a significantly different than aspirin alone. (Fox et al. 2004) The CLARITY TIMI 28 trial also documented a trend toward less ischemic events with the administration of clopidogrel prior to CABG. (Mclean et al. 2007) A recent meta-analysis of 11 studies suggested that perioperative complication rate including bleeding, prolonged ventilation, and length of stay are significantly increased in patients receiving clopidogrel prior to CABG. (Purkayastha et al. 2006) Maintenance of clopidogrel therapy for patients with DES should be considered accepting these additional risks. Alternatively, planned CABG of any stented vessels with a DES should be considered despite the possibility of graft occlusion due to competitive flow.
Our current practice is to continue clopidogrel until the day of surgery in cases where the anti-platelet agent cannot be discontinued (patients with DES) and treat intraoperative and postoperative bleeding with platelet transfusion. Clopidogrel (75 mg) is routinely restarted on postoperative day one along with aspirin (81 mg). Clopidogrel (75 mg) alone after CABG may not inhibit platelet function as well as aspirin even by five days after initiation. (Lim et al. 2004) Alternative loading dose of clopidogrel (300 mg) on postoperative day one is unlikely to increase bleeding but may provide sufficient platelet inhibition.
It has been suggested that off-pump CABG (OPCAB) in patients receiving clopidogrel may result in less bleeding than traditional on-pump CABG and may be the preferred approach in patients receiving this antiplatelet agent. (Shim et al. 2007) Other data, however, document a 5-fold increase in reexploration for bleeding and a 2.5-fold increase in platelet administration in OPCAB patients receiving clopidogrel prior to surgery. (Kapetanakis et al. 2006) Nevertheless, OPCAB was not an option in our patients since concomitant on-pump surgery was required.
Bleeding complications are expected to become more frequent as operations on patients with drug eluting stents become increasingly common. Early diagnosis of probably stent thrombosis will be critical to ensuring a good outcome. Team awareness of the possibility of acute coronary ischemia from DES thrombosis perioperatively in patients who have ceased clopidogrel should be heightened. Strong consideration for the perioperative maintenance of clopidogrel for these patients should be considered.