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J Am Coll Cardiol, 2006; 47:182-183, doi:10.1016/j.jacc.2005.09.045
(Published online 21 November 2005). © 2006 by the American College of Cardiology Foundation |
David Geffen School of Medicine at UCLA, Los Angeles, California
* Reprint requests and correspondence: Dr. Jesse W. Currier, Division of Cardiology, David Geffen School of Medicine at UCLA, CHS 47-123, Box 951679, 10833 Le Conte Avenue, Los Angeles, California 90095. (Email: jcurrier{at}mednet.ucla.edu).
Data for the study were obtained from the Food and Drug Administration’s (FDA) Manufacturer and User Device Experience Center (MAUDE) (7), but the authors also utilized data obtained from a review of electronic databases and their own clinical practice. A total of 262 cases of hypersensitivity reactions associated with DES implantation were evaluated to assess the etiology as well as the severity.
On the basis of available information, 17 of 262 cases (14 CYPHER [Cordis Corp., Miami Lakes, Florida] and 3 TAXUS [Boston Scientific Corp., Natick, Massachusetts]) were classified as probably or certainly caused by the stent implantation. Four autopsies in patients who died of coronary thrombosis confirmed intrastent eosinophilic inflammation, thrombosis, and lack of intimal healing; 13 cases were classified as "probably" having a hypersensitivity reaction to DES (8). Clinical manifestations were primarily cutaneous, usually beginning within 10 days of stent implantation. Symptom duration was >4 weeks in 11 of 17 patients.
Based on the findings of the autopsy studies, one can conclude that hypersensitivity to DES is a real entity. The authors have shown that when present, hypersensitivity reactions after DES can result in serious clinical sequelae, including need for hospitalization (18%), emergent interventions such as intravenous steroids or repeat catheterization (34%), or death (2%). However, determination of the incidence and overall clinical significance of hypersensitivity reactions after DES implantation is more problematic.
There are several important limitations of this study, including those pertaining to the use of the FDA’s MAUDE center. First, the true incidence of the event cannot be reliably estimated. These events are primarily self-reported either by the manufacturer or health care personnel. While adverse post-marketing events are generally underreported to the FDA (9), the magnitude of underreporting is unknown for any given device or medication. Adverse event reports require only the suspicion of a relationship to the device or medication and do not imply causality. The clinical information may be incomplete in many instances. In the study, concomitant medications were not reported 40% of the time, and the de-challenge response to medications was not reported in 81% of cases. Although the authors made an attempt to ascertain the cause of the hypersensitivity reaction, an unequivocal cause and effect could be proven in only four cases.
Finally, the denominator is unknown. Although the number of stents implanted is available, the exact number of patients who have undergone DES implantation is unknown. However, even assuming two DES are placed per patient, the incidence would still be extremely low (0.002%).
Nevertheless, post-marketing analysis of adverse events has many advantages. Pre-marketing clinical trials typical enroll <5,000 patients and are not powered to detect rare adverse events (10); post-marketing analysis can detect these rare events (11). Also, after marketing, many medications and devices are used in a broader, higher-risk population that was not included in the pre-marketing studies. Post-marketing adverse event reporting has contributed to the withdrawal of several medications (12).
In patients with documented hypersensitivity reactions after DES implantation, the reaction could be due either to medical therapy associated with stent implantation or to the DES itself. Several components of the DES could be responsible for the hypersensitivity reaction. These include the polymer coating, the drug (rapamycin for CYPHER and paclitaxel for TAXUS), or the stent itself. The use of bare-metal stents has not been associated with hypersensitivity reactions. A series of >400 autopsies revealed no evidence of hypersensitivity reactions to the bare-metal stent (13). Drug reactions to rapamycin are extremely uncommon (14). Paclitaxel has been associated with hypersensitivity reactions, but many of these reactions have been attributed to the castor oil vehicle (15). Thus, the most likely etiology of the hypersensitivity reaction is the polymer coating of the DES. Related synthetic polymers, when applied to bare-metal stents, have demonstrated both local and systemic hypersensitivity responses after implantation in one animal study (16).
Patients with known coronary artery disease who have undergone implantation of DES typically require multiple medications. Determining the cause of a hypersensitivity reaction is often confounded by the potential for hypersensitivity to concomitant medications. Of particular importance for the clinician is the hypersensitivity reaction to the commonly prescribed thienopyridine antiplatelet agent clopidogrel, which occurs in 5% of patients (14). The most common presentation is rash; more serious hypersensitivity reactions requiring treatment with corticosteroids are rare (17). Clopidogrel desensitization has been accomplished successfully in one case report and is an option in patients with prior reactions (18). Alternatively, one could utilize ticlopidine. However, use of ticlopidine is associated with higher rates of adverse reactions, including thrombotic thrombocytopenic purpura and neutropenia.
It is important to not terminate thienopyridine therapy early after stent implantation in patients with a suspected hypersensitivity reaction as this has been associated with stent thrombosis (19,20). In a recent study, stent thrombosis occurred in 29% of patients in whom antiplatelet therapy was prematurely discontinued (20). On the other hand, continuation of the offending agent in the presence of a serious allergic reaction can also be dangerous.
In summary, hypersensitivity to DES is a real entity and can result in serious clinical sequelae including stent thrombosis and death. While the exact incidence is unknown, it appears to be extremely low based on available data. Clinicians should be familiar with the clinical presentation of these hypersensitivity reactions, and any suspected patient with a potential hypersensitivity reaction after DES implantation should be evaluated thoroughly and monitored closely; failure to do so can result in serious clinical consequences. Continued surveillance of hypersensitivity reactions after DES implantation is an important process and should further enhance our current understanding of this entity.
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