Giuseppe Musumeci

Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: Should we be cautious?

Background—The US Food and Drug Administration recently issued a warning of subacute thrombosis and hypersensitivity reactions to sirolimus-eluting stents (Cypher). The cause and incidence of these events have not been determined. Methods and Results—We present findings of a 58-year-old man who died of late stent thrombosis 18 months after receiving 2 Cypher stents for unstable angina. Although angiographic and intravascular ultrasound results at 8 months demonstrated the absence of neointimal formation, vessel enlargement was present. An autopsy showed aneurysmal dilation of the stented arterial segments with a severe localized hypersensitivity reaction consisting predominantly of T lymphocytes and eosinophils. Conclusions—The known pharmacokinetic elution profile of Cypher stents and the presence of polymer fragments surrounded by giant cells and eosinophils suggest that a reaction to the polymer may have caused late stent thrombosis. Careful long-term follow-up of patients with vessel enlargement after Cypher stent placement is recommended.

Examination of the In Vivo Mechanisms of Late Drug-Eluting Stent Thrombosis: Findings From Optical Coherence Tomography and Intravascular Ultrasound Imaging

OBJECTIVESnThis study investigated the role of uncovered stent struts on late stent thrombosis (LST) after drug-eluting stent (DES) implantation with optical coherence tomography (OCT).nnnBACKGROUNDnAutopsy studies have identified delayed healing and lack of endothelialization of DES struts as the hallmarks of LST. DES strut coverage has not previously been examined in vivo in patients with LST.nnnMETHODSnWe studied 54 patients, including 18 with DES LST (median 615 days after implant) undergoing emergent percutaneous coronary interventions and 36 matched DES control subjects undergoing routine repeat OCT and intravascular ultrasound (IVUS) who did not experience LST for ≥3 years. Thrombus aspiration was performed during emergent percutaneous coronary intervention before OCT and IVUS assessment.nnnRESULTSnBy OCT, patients with LST--compared with control subjects--had a higher percentage of uncovered (median [interquartile range]) (12.27 [5.50 to 23.33] vs. 4.14 [3.00 to 6.22], p < 0.001) and malapposed (4.60 [1.85 to 7.19] vs. 1.81 [0.00 to 2.99], p < 0.001) struts. The mean neointimal thickness was similar in the 2 groups (0.23 ± 0.17 mm vs. 0.17 ± 0.09 mm, p = 0.28). By IVUS, stent expansion was comparable in the 2 groups, although positive remodeling was increased in patients with LST (mean vessel cross-section area 19.4 ± 5.8 mm(2) vs. 15.1 ± 4.6 mm(2), p = 0.003). Thrombus aspiration demonstrated neutrophils and eosinophils in most cases. By multivariable analysis, the length of segment with uncovered stent struts by OCT and the remodeling index by IVUS were independent predictors of LST.nnnCONCLUSIONSnIn this in vivo case-controlled study, the presence of uncovered stent struts as assessed by OCT and positive vessel remodeling as imaged by IVUS were associated with LST after DES.

Optical Coherence Tomography Assessment of In Vivo Vascular Response After Implantation of Overlapping Bare-Metal and Drug-Eluting Stents

OBJECTIVESnWe designed a randomized trial exploiting optical coherence tomography (OCT) to assess coverage and apposition of overlapping bare-metal stents (BMS) and drug-eluting stents (DES) in human coronary arteries.nnnBACKGROUNDnOverlapping DES impair healing in animals. Optical coherence tomography allows accurate in vivo assessment of stent strut coverage and apposition.nnnMETHODSnSeventy-seven patients with long coronary stenoses were randomized to overlapping sirolimus-eluting stents (SES), paclitaxel-eluting stents (PES), zotarolimus-eluting stents (ZES), or BMS. The primary goal of the study was to determine the rate of uncovered/malapposed struts in overlap versus nonoverlap segments, according to stent type, at 6-month follow-up with OCT.nnnRESULTSnA total of 53,047 struts were analyzed. The rate of uncovered/malapposed struts was 1.5 +/- 3.4% and 0.6 +/- 2.7% in overlap versus nonoverlap BMS (p = NS), respectively, and 4.3 +/- 11% and 3.6 +/- 8% in overlap versus nonoverlap DES (p = NS), respectively. There were no differences in the rates of uncovered/malapposed struts between overlapping BMS and DES, likely due to low frequency of uncovered/malapposed struts in ZES (0.1 +/- 0.4%), which offset the higher rates observed in SES (6.7 +/- 9.6%) and PES (6.7 +/- 16.5%, p < 0.05). Overlap segments showed greater neointimal volume obstruction versus nonoverlap segments in all DES (p < 0.05 for all DES types). Strut-level neointimal thickness at overlap and nonoverlap segments were lowest in SES (0.16 +/- 0.1 mm and 0.12 +/- 0.1 mm, respectively) compared with PES (0.27 +/- 0.1 mm and 0.20 +/- 0.1 mm, respectively), ZES (0.40 +/- 0.16 mm and 0.33 +/- 0.13 mm, respectively), and BMS (0.55 +/- 0.31 mm and 0.53 +/- 0.25 mm, respectively, p < 0.05).nnnCONCLUSIONSnAs assessed by OCT the impact of DES on vascular healing was similar at overlapping and nonoverlapping sites. However, strut malapposition, coverage pattern, and neointimal hyperplasia differ significantly according to DES type. (Optical Coherence Tomography for Drug Eluting Stent Safety [ODESSA]; NCT00693030).

Strut coverage and late malapposition with paclitaxel-eluting stents compared with bare metal stents in acute myocardial infarction: optical coherence tomography substudy of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial.

Background— The safety of drug-eluting stents in ST-segment elevation myocardial infarction (STEMI) continues to be debated. Pathological studies have demonstrated an association between uncovered struts and subsequent stent thrombosis. Optical coherence tomography can detect stent strut coverage in vivo on a micron-scale level. We therefore used optical coherence tomography to examine strut coverage in patients with STEMI treated with paclitaxel-eluting stents (PES) and bare metal stents (BMS). Methods and Results— In the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, patients with STEMI were randomized 3:1 to PES or BMS implantation. In a formal substudy, optical coherence tomography at 13 months was performed in 118 consecutive randomized patients (89 PES, 29 BMS) in whom 188 stents were assessed (146 PES and 42 BMS). A total of 44 139 stent struts were analyzed by an independent core laboratory blinded to stent assignment. The primary prespecified end point, the percentage of uncovered stent struts per lesion at follow-up, was 1.1±2.5% in BMS lesions versus 5.7±7.0% in PES lesions (P<0.0001). Malapposed struts were observed in 0.1±0.2% of BMS lesions versus 0.9±2.1% of PES lesions (P=0.0003). Percentage net volume obstruction was 36.0±15.4% with BMS and 19.2±11.3% with PES (P<0.0001). Conclusions— In patients with STEMI undergoing primary percutaneous coronary intervention, implantation of PES as compared with BMS significantly reduces neointimal hyperplasia but results in higher rates of uncovered and malapposed stent struts as assessed by optical coherence tomography at 13-month follow-up. Further studies are required to determine the clinical significance of these findings. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966.

Strut Coverage and Late Malapposition With Paclitaxel-Eluting Stents Compared With Bare Metal Stents in Acute Myocardial Infarction

Background— The safety of drug-eluting stents in ST-segment elevation myocardial infarction (STEMI) continues to be debated. Pathological studies have demonstrated an association between uncovered struts and subsequent stent thrombosis. Optical coherence tomography can detect stent strut coverage in vivo on a micron-scale level. We therefore used optical coherence tomography to examine strut coverage in patients with STEMI treated with paclitaxel-eluting stents (PES) and bare metal stents (BMS). Methods and Results— In the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, patients with STEMI were randomized 3:1 to PES or BMS implantation. In a formal substudy, optical coherence tomography at 13 months was performed in 118 consecutive randomized patients (89 PES, 29 BMS) in whom 188 stents were assessed (146 PES and 42 BMS). A total of 44 139 stent struts were analyzed by an independent core laboratory blinded to stent assignment. The primary prespecified end point, the percentage of uncovered stent struts per lesion at follow-up, was 1.1±2.5% in BMS lesions versus 5.7±7.0% in PES lesions (P<0.0001). Malapposed struts were observed in 0.1±0.2% of BMS lesions versus 0.9±2.1% of PES lesions (P=0.0003). Percentage net volume obstruction was 36.0±15.4% with BMS and 19.2±11.3% with PES (P<0.0001). Conclusions— In patients with STEMI undergoing primary percutaneous coronary intervention, implantation of PES as compared with BMS significantly reduces neointimal hyperplasia but results in higher rates of uncovered and malapposed stent struts as assessed by optical coherence tomography at 13-month follow-up. Further studies are required to determine the clinical significance of these findings. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966.

Outcome in Elderly Patients Undergoing Primary Coronary Intervention for Acute Myocardial Infarction Results From the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial

Background—Biological age is a strong determinant of prognosis in patients with acute myocardial infarction (AMI). We sought to examine the impact of age after primary percutaneous coronary intervention in AMI and to determine whether routine coronary stent implantation and/or platelet glycoprotein IIb/IIIa inhibitors improve clinical outcomes in elderly patients after primary angioplasty. Methods and Results—In the CADILLAC trial, 2082 patients with AMI were randomized to balloon angioplasty, angioplasty plus abciximab, stenting alone, or stenting plus abciximab. No patient was excluded on the basis of advanced age; patients ranging from 21 to 95 years of age were enrolled. One-year mortality increased for each decile of age, exponentially after 65 years of age (1.6% for patients <55 years, 2.1% for 55 to 65 years, 7.1% for 65 to 75 years, 11.1% for patients >75 years; P<0.0001). Elderly patients also had increased rates of stroke and major bleeding compared with their younger counterparts. Among elderly patients (≥65 years), 1-year rates of ischemic target revascularization (7.0% versus 17.6%; P<0.0001) and subacute or late thrombosis (0% versus 2.2%; P=0.005) were reduced with stenting compared with balloon angioplasty. Routine abciximab administration, although safe, was not of definite benefit in elderly patients. Rates of mortality, reinfarction, disabling stroke, and major bleeding in the elderly were independent of reperfusion modality. Conclusions—Despite contemporary mechanical reperfusion strategies, mortality, major bleeding, and stroke rates remain high in elderly patients undergoing primary percutaneous coronary intervention, outcomes that are not affected by stents or glycoprotein IIb/IIIa inhibitors. By reducing restenosis, however, stent implantation improves clinical outcomes in elderly patients with AMI.

Sirolimus-Eluting Stent Implanted in Human Coronary Artery for 16 Months Pathological Findings

A 71-year-old woman, enrolled in the RAndomized study with the sirolimus (SRL)–eluting Bx VELocity balloon-expandable stent (RAVEL) Trial (December 5, 2000), received a single SRL-eluting Bx Velocity stent (Cordis) to treat an 80% proximal left anterior descending (LAD) coronary artery stenosis (Figure 1A). Intravascular ultrasound and angiography at 6 months showed 0% stenosis with no in-stent neointimal proliferation (Figure 1, B and D). The patient remained asymptomatic until presenting with unstable angina on May 3, 2002. Angiography demonstrated subtotal occlusion of the left obtuse marginal. The LAD SRL-eluting stent (deployed 16 months previously) showed 0% stenosis (Figure 1C). The left obtuse marginal lesion was successfully stented, but the patient suffered a fatal stroke 24 hours after coronary intervention. nnnnFigure 1. Angiogram of the …

Strut Coverage and Vessel Wall Response to Zotarolimus-Eluting and Bare-Metal Stents Implanted in Patients With ST-Segment Elevation Myocardial Infarction The OCTAMI (Optical Coherence Tomography in Acute Myocardial Infarction) Study

OBJECTIVESnUsing optical coherence tomography, we assessed the proportion of uncovered struts at 6-month follow-up in zotarolimus-eluting stents (ZES), specifically Endeavor (Medtronic CardioVascular, Santa Rosa, California) stents, and identical bare-metal stents (BMS) implanted in patients with ST-segment elevation myocardial infarction (STEMI).nnnBACKGROUNDnSirolimus- and paclitaxel-eluting stents implanted in STEMI have been associated with delayed healing and incomplete strut coverage. ZES are associated with a more complete and uniform strut coverage in stable patients, but whether this holds true also after STEMI is unknown.nnnMETHODSnForty-four patients with STEMI who underwent primary PCI were randomized to ZES or BMS (3:1 randomization). Angiographic, intravascular ultrasound, and optical coherence tomography follow-up was conducted at 6 months and clinical follow-up at 1 year. All images were analyzed by an independent core laboratory that was blind to stent assignments.nnnRESULTSnThere were no differences between ZES and BMS in percentage of uncovered struts (median: 0.00% [interquartile range (IQR): 0.00% to 1.78%] vs. 1.98% [IQR: 0.21% to 7.33%], p = 0.13), maximum length of uncovered segments (0.00 [IQR: 0.00 to 1.19] mm vs. 1.38 [IQR: 0.65 to 3.30] mm, p = 0.10), percentage of malapposed struts (0.00% [IQR: 0.00% to 0.23%] vs. 0.15% [IQR: 0.00% to 5.81%], p = 0.16), and maximum length of malapposed segments (0.00 [IQR: 0.00 to 0.67] mm vs. 0.33 [IQR: 0.00 to 2.55] mm, p = 0.20). Neointimal response was similar between ZES and BMS (332 [IQR: 240 to 429] microm vs. 186 [IQR: 136 to 348] microm, p = 0.99) and evenly distributed. No late acquired malapposition was observed in both groups. There were no deaths, myocardial infarction, or stent thromboses at 1 year.nnnCONCLUSIONSnThis optical coherence tomography study found no difference in strut coverage and similar vessel response to ZES, when compared with identical BMS, implanted during primary percutaneous coronary intervention in STEMI patients. (Six-Month Coverage and Vessel Wall Response of the Zotarolimus Drug-Eluting Stent Implanted in AMI Assessed by Optical Coherence Tomography [OCTAMI]; NCT00704561).

Strut Coverage and Vessel Wall Response to a New-Generation Paclitaxel-Eluting Stent With an Ultrathin Biodegradable Abluminal Polymer Optical Coherence Tomography Drug-Eluting Stent Investigation (OCTDESI)

Background—Polymer-coated drug-eluting stents are effective in preventing restenosis but have been associated with delayed healing and incomplete strut coverage. It is unknown whether paclitaxel-eluting stents (PES) with minimal biodegradable abluminal coating enhances strut coverage while preventing neointimal hyperplasia. Using optical coherence tomography (OCT) as a primary imaging modality, we assessed the proportion of uncovered struts at 6-month follow-up in PES coated with durable versus ultrathin (<1 &mgr;m) biodegradable abluminal polymers. Methods and Results—In this pilot trial, 60 patients with de novo lesions (⩽25 mm) in native coronary vessels were randomly assigned to receive either TAXUS Liberté PES or JACTAX PES, a Liberté stent with polymer deposited abluminally as microdots (JACTAX HD: 9.2 &mgr;g each of polymer and paclitaxel per 16-mm stent; JACTAX LD: 5 &mgr;g each). OCT follow-up occurred at 6 months with clinical follow-up through 1 year. The primary end point was percent uncovered struts by OCT. An independent core laboratory blinded to stent assignment analyzed images. The 6-month rate of uncovered struts per patient was 5.3±14.7% for TAXUS Liberté, 7.0±12.2% for JACTAX HD, and 4.6±7.3% for JACTAX LD (P=0.81); percent malapposed struts was 1.4±4.4%, 0.8±1.9%, and 1.1±2.8%, respectively (P=0.86). Strut-level intimal thickness was 0.20±0.10, 0.22±0.15, and 0.24±0.15 mm (P=0.64); percent volume obstruction by OCT was 22.2±12.8, 22.5±16.2, and 25.8±15.2 (P=0.69). There were no deaths, Q-wave myocardial infarctions, or stent thromboses through 1 year. Conclusions—JACTAX PES with an ultrathin microdot biodegradable abluminal polymer did not result in improved strut coverage at 6 months compared with TAXUS Liberté. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00776204.

Strut Coverage and Vessel Wall Response to a New-Generation Paclitaxel-Eluting Stent With an Ultrathin Biodegradable Abluminal Polymer

Background—Polymer-coated drug-eluting stents are effective in preventing restenosis but have been associated with delayed healing and incomplete strut coverage. It is unknown whether paclitaxel-eluting stents (PES) with minimal biodegradable abluminal coating enhances strut coverage while preventing neointimal hyperplasia. Using optical coherence tomography (OCT) as a primary imaging modality, we assessed the proportion of uncovered struts at 6-month follow-up in PES coated with durable versus ultrathin (<1 &mgr;m) biodegradable abluminal polymers. Methods and Results—In this pilot trial, 60 patients with de novo lesions (⩽25 mm) in native coronary vessels were randomly assigned to receive either TAXUS Liberté PES or JACTAX PES, a Liberté stent with polymer deposited abluminally as microdots (JACTAX HD: 9.2 &mgr;g each of polymer and paclitaxel per 16-mm stent; JACTAX LD: 5 &mgr;g each). OCT follow-up occurred at 6 months with clinical follow-up through 1 year. The primary end point was percent uncovered struts by OCT. An independent core laboratory blinded to stent assignment analyzed images. The 6-month rate of uncovered struts per patient was 5.3±14.7% for TAXUS Liberté, 7.0±12.2% for JACTAX HD, and 4.6±7.3% for JACTAX LD (P=0.81); percent malapposed struts was 1.4±4.4%, 0.8±1.9%, and 1.1±2.8%, respectively (P=0.86). Strut-level intimal thickness was 0.20±0.10, 0.22±0.15, and 0.24±0.15 mm (P=0.64); percent volume obstruction by OCT was 22.2±12.8, 22.5±16.2, and 25.8±15.2 (P=0.69). There were no deaths, Q-wave myocardial infarctions, or stent thromboses through 1 year. Conclusions—JACTAX PES with an ultrathin microdot biodegradable abluminal polymer did not result in improved strut coverage at 6 months compared with TAXUS Liberté. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00776204.