Luis Gruberg, MD, FACC   

Introduction

Drug-eluting stents (DES) have been extremely successful in reducing restenosis and the need for repeat revascularization procedures in patients who undergo percutaneous coronary artery intervention (PCI). However, recently, there has been an increased concern regarding the overall safety of these stents, particularly as it relates to the incidence of late-stent thrombosis.

At the European Society of Cardiology 2006 World Congress (WCC) in Barcelona, Spain, the results of 2 large meta-analyses called the long-term safety of DES into question. Eduardo Camenzind, MD (University Hospital Geneva, Switzerland)^[1] and Alain J Nordmann, MD (University Hospital Basel, Switzerland)^[2] presented their findings of their study, which incorporated data from all randomized controlled trials involving the Cypher (Cordis Corporation, Miami Lakes, Florida) sirolimus-eluting stent and data from the Taxus (Boston Scientific, Natick, Massachusetts) paclitaxel-eluting stent TAXUS trial program).

In brief, the results of the meta-analyses demonstrated that patients treated with DES had higher rates of Q-wave myocardial infarction (MI), which was attributed to a higher rate of late stent thrombosis. The incidence of Q-wave MI in patients treated with either the sirolimus- or the paclitaxel-eluting stents was of borderline statistical significance when compared with patients who had been randomized to the bare-metal stent arm of these studies. When the data for all available randomized trials were analyzed, it was noted that, the incidence of serious adverse events (death/MI) was significantly higher with the sirolimus-eluting stent vs the bare-metal stent group or vs the paclitaxel-eluting stent group. The increased relative risk of death/MI was 38% among patients treated with the sirolimus-eluting stent and 16% in patients treated with the paclitaxel-eluting stent. Similar trends were seen in the Basel Stent Kosten Effectivitats Trial (BASKET), which compared sirolimus- and paclitaxel-eluting stents with bare-metal stents in patients undergoing PCI for any indication.^[3]

Furthermore, recent published reports have shown that the rate of stent thrombosis in "real-world" DES-treated patients is substantially higher than the rates reported in clinical trials and has dire consequences, including high rates of MI and mortality.^[4] The increased incidence of late-stent thrombosis prompted clinicians to prolong the use of dual antiplatelet therapy, particularly for high-risk patients.

The long-term DES safety was a main topic of debate at the recent Transcatheter Cardiovascular Therapeutics (TCT) 2006 meeting in Washington, DC. One session entirely dedicated to this topic fueled the fire of uncertainty by presenting new data from the same pivotal DES trials that challenged the results Drs. Camenzind and Nordmann presented 1 month earlier. Of note, whereas the WCC meta-analyses included data obtained from published and presented studies or in a restricted fashion from the stent manufacturers, the 2 meta-analyses, presented at TCT by Martin B. Leon, MD^[5] and Gregg W. Stone, MD^[6] from Columbia University Medical Center (New York, NY), consisted of "raw" data collected directly from the manufacturers.

New Data on DES Safety

Taxus Trials. Dr. Leon presented the results of a meta-analysis that included 3506 patients enrolled in 5 major randomized controlled trials with the Taxus stent (TAXUS I, II, IV, V, and VI).^[5] At 4-year follow-up, the overall rate of stent thrombosis trended higher in the Taxus group than in the bare-metal stent group, but the difference was not significant (1.3% vs 0.9%, respectively; P = .29). However, the rate of late-stent thrombosis (occurring between 1 and 4 years) was significantly higher in patients treated with the Taxus vs bare metal stents (Figure 1).

Figure 1. Taxus meta-analysis: rate of stent thrombosis.

Hard clinical endpoints such as death, cardiac death, MI, and Q-wave MI rates were similar in both arms of the meta-analysis (Figure 2). As expected, DES was associated with a significant reduction in the rates of target lesion and target vessel revascularization (Figure 3).

Figure 2. Taxus meta-analysis: clinical outcomes.

Figure 3. Taxus meta-analysis: target lesion revascularization (TLR) and target vessel revascularization (TVR) rates.

Dr. Leon concluded that overall there was "no significant increase in stent thrombosis in patients treated with the Taxus stent, but there was a small but significant increase in late-stent thrombosis (between years 1 and 4) of 0.5% (roughly 0.15% per year)."

Cypher Trials. Dr. Stone presented similar data collected from 1748 patients enrolled in 4 pivotal trials that assessed the Cypher stent (RAVEL, SIRIUS, E-SIRIUS and C-SIRIUS). As with the TAXUS findings, at 4-year follow-up, the rate of stent thrombosis was higher in the Cypher group than in the bare-metal group, but the difference was not significant (1.2% vs 0.6%, respectively; P = .20). There was also no significant difference in the rate of subacute stent thrombosis (< 30 days) between the Cypher and bare-metal stent groups (4 vs 1, P = .18). However, there were 5 cases of late-stent thrombosis (> 1 year) in the Cypher stent arm vs 0 in the bare-metal stent group (P = .025) (Figure 4).

Figure 4. Cypher trials: rate of stent thrombosis.

Clinical outcomes were similar in both arms of the study (Figure 5) with the exception of repeat revascularization procedures, which were performed at a significantly higher rate in the bare-metal stent arm (Figure 6).

Figure 5. Cypher trials: clinical outcomes.

Figure 6. Cypher trials: target lesion revascularization (TLR) and target vessel revascularization (TVR) rates.

Dr. Stone concluded that these findings demonstrate: "there was no significant increase in stent thrombosis, death or myocardial infarction but there was a small but significant increase in late stent thrombus (between 1 and 4 years) of 0.6% (roughly 0.2% per year)."

DES and Mortality. Researchers from the Basel Institute in Switzerland presented data from a meta-analysis of 17 trials performed at their institution.^[7] All of these trials had at least 1-year follow-up; 12 trials had 2-year follow-up; 9 trials had 3-year follow-up; and 2 trials had 4-year follow-up. The presenters reported that the use of a DES was not associated with an increase in long-term all-cause mortality (odds ratio [OR] 1.46, 95% confidence interval [CI] 0.92-2.31; P = .5) or in cardiac mortality (OR 1.24, 95% CI 0.64-2.4; P = .2). However, there was a trend for higher rates of noncardiac mortality in DES-treated patients (OR 1.65, 95% CI 0.88-3.1; P = .08), the most frequently causes being cancer, stroke, and lung disease. Therefore, the authors concluded that DES do not reduce mortality when compared with bare-metal stents, and that preliminary evidence suggests the use of the Cypher stent may actually lead to an increase in noncardiac death.

ESTROFA. Jose M. de la Torre Hernandez, MD, PhD (University Hospital Marques de Valdecilla, Santander, Spain)^[8] was the main investigator of the ESTROFA study, which tracked the incidence of stent thrombosis in patients treated at 17 hospitals in Spain between 2002 and 2006. DES are used at these centers at the discretion of the operator, and their use has steadily increased, jumping from 5% in 2002 to 52% in 2005. Clinical follow-up data were obtained from hospital registries and medical clinical records.

Preliminary clinical follow-up out to 4 years (median 18 months) was available at the time of the presentation. Between 2002 and 2006, a total of 13,500 patients were treated with either a Cypher stent (40%) or a Taxus stent (60%). Baseline clinical characteristics of these patients were standard; mean age was 63 years and 29% of patients had diabetes. Dr. de la Torre Hernandez reported that there were 162 cases of stent thrombosis (1.2%), including 1.35% in patients treated with the sirolimus-eluting stent and 1.1% in those treated with the paclitaxel-eluting stent. The majority of cases (0.56%) were subacute (occurring between > 24 hours and < 30 days) (Table 1). The rate of very late stent thrombosis (> 6 months) was 0.37% (the median was 11.4 months; range, 6-46 months).

Table 1. ESTROFA: Incidence of Stent Thrombosis

Stent Thrombosis	Incidence (N = 162)
Acute (%)	0.15
Subacute (%)	0.56
Late (%)	0.15
Very late (%)	0.37

The large majority of patients with stent thrombosis presented with ST-segment elevation MI (STEMI, 82%), with an in-hospital mortality of 8.6%. During the follow-up period, 7 patients died (Figure 7). There was no difference in mortality rates based on the timing of the event. Rethrombosis rates were frequent, 5.2% in the acute/subacute group and 3% among patients who had a late event.

Figure 7. ESTROFA: mortality.

Univariate predictors of all stent thrombosis were older age, presentation as an acute coronary syndrome (ACS), left anterior descending coronary artery lesion, total occlusion at presentation, and stent length. Of interest, renal insufficiency, an important predictor of stent thrombosis in previous analyses, was associated in this study with only acute and subacute stent thrombosis and not with late thrombosis (0 cases).

In addition to renal insufficiency, independent predictors of acute and subacute stent thrombosis by multivariate analysis included: STEMI, lesion in the left anterior descending coronary artery, ACS, small vessel, and female gender. Independent predictors of stent thrombosis are shown in Table 2.

Table 2. ESTROFA: Independent Predictors of Stent Thrombosis

All*	Acute/Subacute	Late	Very Late
Older age ACS LAD Total occlusion at presentation Stent length	Renal insufficiency STEMI LAD ACS Small vessel female gender	STEMI LAD Stent length	STEMI LAD

*By univariate analysis; all others assessed by multivariate analysis
ACS = acute coronary syndrome; LAD = left anterior descending artery (target vessel); STEMI = ST-segment elevation myocardial infarction

The combination of left anterior descending artery and STEMI was associated with a 5.6% incidence of stent thrombosis compared with 0.9% in the rest of patients/lesions. In addition, early discontinuation of dual antiplatelet therapy was associated with 31% of cases before 6 months and 10% of cases after 6 months. Discontinuation of antiplatelet monotherapy was associated with 18% of cases after 6 months. Therefore, the incidence of documented stent thrombosis was 1.2%, with similar rates to those observed with bare-metal stents in the acute, subacute, and late periods. However, in the very late period, the incidence was 0.4%, which is higher than that observed with bare-metal stents.

Conclusion

These data provide us with a more accurate picture than what we had before, where speculation regarding stent thrombosis with DES reigned. But are we the wiser? Can we be certain that patients are not an increased risk when treated with a DES? Are we ready to trade restenosis for thrombosis, as questioned by Miriam Shuchman, MD (University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York) in an editorial recently published in The New England Journal of Medicine?^[9]

Although the conclusive remarks made by Drs. Leon and Stone -- undoubtedly the 2 foremost eminences in this field -- seem appeasing, there is still a 0.4% to 0.6% increased risk of late stent thrombosis associated with the use of DES. This is not a small number, especially when we bear in mind that 1 million of these stents are deployed each year in the United States alone with a market penetration of 91% (3rd quarter 2005). Notably, there has been a 5.4% decrease in the use of DES in the past 8 months and a 2.2% decline since the 2006 WCC presentations by Drs. Camenzind and Nordmann.

But should we ban the use of these stents? I don't believe so. The data presented during the TCT meeting provide important information, serving as a reminder that patients are, in fact, at an increased risk and that we should exercise caution when considering the use of DES in all patients.

In addition, the data emphasize the importance of adequate use of prolonged dual antiplatelet therapy. However, while the premise that we should put all these patients on dual antiplatelet therapy for life sounds relatively easy, it is an unrealistic goal. We have to take into account the increase in bleeding complications that prolonged antiplatelet therapy may cause, as well as the cost burden that it would impose on patients and on the healthcare system.

Initially, we need to assess the risk profile of each patient/artery/lesion for restenosis and long-term dual antiplatelet use, and certainly lower our threshold for the use of bare-metal stents. We definitely need more data to fully understand the implications of these data and at the same time continue intense research on a new generation of DES and new, safer, and more potent antiplatelet drugs. Until then, at this time, it is strongly recommended to avoid off-label use of the stents and ensure that DES-treated patients are on adequate antiplatelet therapy.

References

1. Camenzind E, Steg PG, Wijns W. A meta-analysis of first generation drug eluting stent programs. Program and Abstracts from the World Congress of Cardiology 2006, Barcelona, September 2-5, 2006. Hotline Session I.
2. Nordmann AJ, Briel M, Bucher HC. Safety of drug-eluting stents: insights from a meta-analysis. Program and Abstracts from the World Congress of Cardiology 2006, Barcelona, September 2-5, 2006. Hotline Session I.
3. Kaiser C, Brunner-La Rocca HP, Pfisterer M, on behalf of the BASKET Investigators. Targeted stent use in clinical practice based on evidence from BASKET (Basel Stent 4. Kosten-Effektivitäts Trial). Program and abstracts from the European Society of Cardiology 2006 World Congress; September 2-6, 2006; Barcelona, Spain.
4. 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.
5. Leon BM. Independent physician-led patient-level analysis: TAXUS randomized trials. Program and abstracts from the Transcatheter Cardiovascular Therapeutics 18th Annual Scientific Symposium; October 22-27, 2006; Washington, DC.
6. Stone GW. Independent physician-led patient-level analysis: CYPHER randomized trials. Program and abstracts from the Transcatheter Cardiovascular Therapeutics 18th Annual Scientific Symposium; October 22-27, 2006; Washington, DC.
7. Nordmann AJ, Briel M, Bucher HC. Safety of drug-eluting stents: analysis from a physician-directed clinical trial meta-analysis. Program and abstracts from the Transcatheter Cardiovascular Therapeutics 18th Annual Scientific Symposium; October 22-27, 2006; Washington, DC.
8. de la Torre Hernandez JM. Real-world data on stent thrombosis: the Spanish ESTROFA registry. Program and abstracts from the Transcatheter Cardiovascular Therapeutics 18th Annual Scientific Symposium; October 22-27, 2006; Washington, DC.
9. Shuchman M. Trading restenosis for thrombosis? New questions about drug-eluting stents. N Engl J Med. 2006;355:1949-1952.

Daniel J. McCormick, DO   

Introduction

Atrial septal defect (ASD) and patent foramen ovale (PFO) represent congenital heart defects that involve the atrial septum. Knowledge of the embryologic development of the atrial septum provides the basis for understanding the pathophysiology, anatomy, and clinical manifestations of ASDs and PFO.

During the early stage of embryologic development, the right and left atria comprise a common chamber. At the fourth and fifth weeks of gestation, the division of the atria begins with the formation of the septum primum, which is a crest of tissue that grows from the superior-posterior wall of the developing atrium toward the endocardial cushions. The free margin of the septum primum creates a temporary communication between the 2 atria, called the ostium primum.

Before complete fusion between the ostium primum and the endocardial cushions, numerous perforations appear in the superior aspect of the septum primum. The coalescence of these perforations results in the formation of the ostium secundum. A second semilunar-shaped crest of tissue also begins to develop to the right of the septum primum, named the septum secundum. It overlaps the ostium primum, creating the foramen ovale.

During fetal life, the foramen ovale allows oxygenated blood flow to be diverted to the systemic circulation. At birth, the expansion of the lungs and increased pulmonary blood flow raises the left atrial pressure, resulting in functional and subsequently anatomic closure of the foramen ovale. However, in approximately 25% of the normal population, incomplete closure occurs, leaving a valve-like opening in the atrial septum, known as PFO.

Atrial Septal Defect

ASDs account for 5% to 10% of all coronary heart disease , and for about 30% of the congenital heart defects diagnosed in adults. ASDs are twice as common in females as in males. Most ASDs occur sporadically as a result of spontaneous genetic mutations; however, hereditary forms have been reported. Associated extra-cardiac congenital defects are present in 25% of infants, and about one third have a hereditary syndrome (eg, Down syndrome, Alagille syndrome, Holt-Oram syndrome, Ellis Van Creveld syndrome, or Noonan syndrome).

There are 4 types of ASDs:

1. The ostium secundum defect, located in the area of the fossa ovalis, is the most common type of ASD, accounting for 75% of all cases. Although it usually consists of a single defect, fenestrated defects have also been reported. Secundum ASDs can be associated with partial anomalous pulmonary venous return (< 10%) and mitral valve prolapse.
   
   
2. The ostium primum defect accounts for 15% of ASDs, and is located in the lower part of the interatrial septum. It can be associated with a "cleft" anterior mitral valve leaflet, resulting in mitral regurgitation.
   
   
3. The sinus venosus defect, which accounts for 10% of ASDs, usually involves the junction of the superior vena cava. Anomalous pulmonary venous return is a common manifestation. Sinus venous-inferior vena cava defects are rare.
   
   
4. Coronary sinus ASDs are also rare and result from direct communication of the coronary sinus and the left atrium. Persistent left superior vena cava is commonly associated with this condition.

ASD: Pathophysiology

Small ASDs result in trivial shunting and have no hemodynamic consequences. Larger defects are associated with substantial shunting, which may lead to volume overload of the right atrium, right ventricle, and pulmonary arteries. The magnitude of left-to-right shunting depends on the size of the ASD, the relative compliance of the 2 ventricles, and the pulmonary and systemic vascular resistance. If left untreated, this may result in pulmonary hypertension, right ventricular failure, decreased right ventricular compliance, and potentially right-to-left shunting. However, Eisenmenger's syndrome secondary to ASDs is rare in the adult population (5%).

ASD: Symptoms

Patients are usually asymptomatic in the first and second decades of life. The most common manifestations of this condition are development of fatigue, dyspnea on exertion, and exercise intolerance. Occasionally patients may present with paradoxical embolization, palpitations secondary to supraventricular arrhythmias, or recurrent respiratory infections. If left untreated, patients with hemodynamically significant ASDs will develop symptoms of right-sided heart failure.

ASD: Cardiac Examination

The cardiac examination is consistent with right heart overload. A right ventricular or pulmonary artery impulse can be appreciated by palpation. The first heart sound is normal. There is fixed splitting of the second heart sound. Cardiac auscultation reveals a systolic outflow murmur as a result of the increased flow through the pulmonic valve. Shunting across the ASD does not produce a murmur. In patients with ostium primum ASD and a cleft anterior mitral valve leaflet, a mitral regurgitation murmur can be appreciated at the apex. The development of pulmonary hypertension results in narrowing of the splitting of the second heart sound and accentuation of the pulmonary closure component. Furthermore, the pulmonic systolic murmur decreases in intensity, and a diastolic pulmonic regurgitation murmur may appear. The development of shunt reversal (Eisenmenger's syndrome) results in cyanosis and clubbing.

ASD: Diagnostic Testing

Electrocardiogram. In patients with ostium secundum ASD, the electrocardiogram reveals right axis deviation and incomplete right bundle branch block. Ostium primum defects are accompanied by left axis deviation and atrioventricular nodal conduction delay. The presence of an ectopic atrial pacemaker is suggestive of a sinus venosus ASD. With the development of pulmonary hypertension, right ventricular hypertrophy becomes evident. Atrial arrhythmias such as atrial fibrillation and supraventricular tachycardia may appear in patients in the third or fourth decades of life.

Chest Roentgenogram. Prominent pulmonary vascular markings, right atrial and ventricular enlargement, and dilation of the pulmonary artery are typical findings in patients with hemodynamically significant shunting.

Imaging. Echocardiographic findings include right chamber enlargement and evidence of right ventricular volume overload. Transthoracic echocardiography (TTE) is the imaging study of choice for ostium primum and secundum ASDs. Identification of sinus venosus defects usually requires transesophageal echocardiography (TEE). Evaluation of the location, size, and direction of shunt can be facilitated by use of color flow Doppler and echocardiographic contrast agents. Important information such as estimated pulmonary artery pressure and presence of additional cardiac abnormalities can also be obtained.

TEE is an essential tool in the selection of patients who are candidates for percutaneous closure of secundum ASDs. Although still not widely used, magnetic resonance imaging and computed tomography are emerging imaging modalities for the evaluation of patients with congenital heart disease.

Cardiac Catheterization. Invasive evaluation becomes necessary when the results of the noninvasive studies are inconclusive. It allows estimation of the magnitude of the shunt (pulmonary to systemic flow ratio, Qp:Qs), and measurement of the pulmonary artery pressure. Coronary angiography is recommended in patients with suspected coronary artery disease and in those over the age of 40 years.

ASD: Treatment

ASD repair is indicated in patients with hemodynamically significant ASD (Qp:Qs > 1.5:1), in the absence of severe and irreversible pulmonary hypertension. Consideration for ASD repair may be given in patients with paradoxical embolism. Surgical repair is the treatment modality of choice. Percutaneous closure is the preferred treatment in patients with ostium secundum ASD and suitable anatomy, in the absence of other cardiac conditions requiring surgical repair.

The operative mortality is < 1% in the absence of significant pulmonary hypertension. Surgical repair in young adults (< 25 years) results in long-term survival rates similar to those of matched controls. Repair in patients older than 40 years does not eliminate the risk of atrial arrhythmias and cerebrovascular accidents. Long-term surveillance is recommended in these patients.

Related Reading

• Bolger AP, Sharma R, Li W, et al. Neurohormonal activation and the chronic heart failure syndrome in adults with congenital heart disease. Circulation. 2002;106:92-99.
• Costache V, Chavanon O, Thony F, Blin D. Aortic arch embolization of an Amplatzer occluder after an atrial septal defect closure: hybrid operative approach without circulatory arrest. Eur J Cardiothorac Surg. 2005;28:340-342.
• Du ZD, Hijazi ZM, Kleinman CS, Silverman NH, Larntz K. Comparison between transcatheter and surgical closure of secundum atrial septal defect in children and adults: results of a multicenter nonrandomized trial. J Am Coll Cardiol. 2002;39:1836-1844.
• Heller J, Hagege AA, Besse B, Desnos M, Marie FN, Guerot C. "Crochetage" (notch) on R wave in inferior limb leads: a new independent electrocardiographic sign of atrial septal defect. J Am Coll Cardiol. 1996;27:877-882.
• John Sutton MG, Tajik AJ, McGoon DC. Atrial septal defect in patients ages 60 years or older: operative results and long-term postoperative follow-up. Circulation. 1981;64:402-409.
• Mullen MJ, Dias BF, Walker F, Siu SC, Benson LN, McLaughlin PR. Intracardiac echocardiography guided device closure of atrial septal defects. J Am Coll Cardiol. 2003;41:285-292.
• Murphy JG, Gersh BJ, McGoon MD, et al. Long-term outcome after surgical repair of isolated atrial septal defect: follow-up at 27 to 32 years. N Engl J Med. 1990;323:1645-1650.
• Prasad SK, Soukias N, Hornung T, et al. Role of magnetic resonance angiography in the diagnosis of major aortopulmonary collateral arteries and partial anomalous pulmonary venous drainage. Circulation. 2004;109:207-214.
• Ruge H, Wildhirt SM, Libera P, Vogt M, Holper K, Lange R. Images in cardiovascular medicine: left atrial thrombus on atrial septal defect closure device as a source of cerebral emboli 3 years after implantation. Circulation. 2005;112:e130-e131.
• Srivastava D, Olson EN. A genetic blueprint for cardiac development. Nature. 2000;407:221-226.
• Therrien J, Warnes C, Daliento L, et al. Canadian Cardiovascular Society Consensus Conference 2001 update: recommendations for the management of adults with congenital heart disease part III. Can J Cardiol. 2001;17:1135-1158.
• Webb G, Gatzoulis MA. Atrial septal defects in the adult: recent progress and overview. Circulation. 2006;114:1645-1653.
• Zufelt K, Rosenberg HC, Li MD, Joubert GI. The electrocardiogram and the secundum atrial septal defect: a reexamination in the era of echocardiography. Can J Cardiol. 1998;14:227-232.

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