Joseph P. Carrozza

Stent Thrombosis in the Modern Era

Background—There are limited studies of stent thrombosis in the modern era of second-generation stents, high-pressure deployment, and current antithrombotic regimens. Methods and Results—Six recently completed coronary stent trials and associated nonrandomized registries that enrolled 6186 patients (6219 treated vessels) treated with ≥1 coronary stent followed by antiplatelet therapy with aspirin and ticlopidine were pooled for this analysis. Within 30 days, clinical stent thrombosis developed in 53 patients (0.9%). The variables most significantly associated with the probability of stent thrombosis were persistent dissection NHLBI grade B or higher after stenting (OR, 3.7; 95% CI, 1.9 to 7.7), total stent length (OR, 1.3; 95% CI, 1.2 to 1.5 per 10 mm), and final minimal lumen diameter within the stent (OR, 0.4; 95% CI, 0.2 to 0.7 per 1 mm). Stent thrombosis was documented by angiography in 45 patients (0.7%). Clinical consequences of angiographic stent thrombosis included 64.4% incidence of death or myoc...

Hospital delays in reperfusion for ST-elevation myocardial infarction: implications when selecting a reperfusion strategy.

Background— It has been suggested that the survival benefit associated with primary percutaneous coronary intervention (PPCI) in ST-segment elevation myocardial infarction may be attenuated if door-to-balloon (DB) time is delayed by >1 hour beyond door-to-needle (DN) times for fibrinolytic therapy. Whereas DB times are rapid in randomized trials, they are often prolonged in routine practice. We hypothesized that in clinical practice, longer DB-DN times would be associated with higher mortality rates and reduced PPCI survival advantage. We also hypothesized that in addition to PPCI delays, patient risk factors would significantly modulate the relative survival advantage of PPCI over fibrinolysis. Methods and Results— DB-DN times were calculated by subtracting median DN time from median DB time at a hospital using data from 192 509 patients at 645 National Registry of Myocardial Infarction hospitals. Hierarchical models that adjusted simultaneously for both patient-level risk factors and hospital-level covariates were used to evaluate the relationship between PCI-related delay, patient risk factors, and in-hospital mortality. Longer DB-DN times were associated with increased mortality (P<0.0001). The DB-DN time at which mortality rates with PPCI were no better than that of fibrinolysis varied considerably depending on patient age, symptom duration, and infarct location. Conclusions— As DB-DN times increase, the mortality advantage of PPCI over fibrinolysis declines, and this advantage varies considerably depending on patient characteristics. As indicated in the American College of Cardiology/American Heart Association guidelines, both the hospital-based PPCI-related delay (DB-DN time) and patient characteristics should be considered when a reperfusion strategy is selected.

Clinical restenosis after coronary stenting: perspectives from multicenter clinical trials

OBJECTIVES We sought to evaluate clinical restenosis in a large population of patients who had undergone coronary stent placement. BACKGROUND One-year success after coronary stenting is limited mainly by restenosis of and requirement for repeat revascularization of the treated lesion. We studied 6,186 patients (6,219 lesions) pooled from several recently completed coronary stent trials. Clinical restenosis was defined using three different definitions: target lesion revascularization (TLR) beyond 30 days, target vessel revascularization (TVR) beyond 30 days, and target vessel failure (TVF), defined as TVR, any death, or myocardial infarction (MI) of the target vessel territory after hospital discharge. RESULTS By one year, 638 (12.2%) patients had TLR, 748 (14.3%) had TVR, and 848 (16.0%) had TVF, more than two-thirds higher than the rate of these end points at six months. The severity of angiographic restenosis (> or =50% follow-up diameter stenosis [DS]) in 419 of 1,437 (29%) patients undergoing routine angiographic follow-up correlated directly with the likelihood of TLR (73% vs. 26% for >70% DS compared with <60% DS). Smaller pretreatment minimum lumen diameter (MLD), smaller final MLD, longer stent length, diabetes mellitus, unstable angina, and hypertension were independent predictors of TLR. Prior MI and current smoking were negative predictors. CONCLUSIONS At one year after stenting, most clinical restenosis reflected TLR, which was predicted by the same variables previously associated with an increased risk of angiographic restenosis. The lower absolute rate of clinical restenosis relative to angiographic restenosis was due to infrequent TLR in lesions with less severe (<60% DS) angiographic renarrowing.

Stent Thrombosis After Successful Sirolimus-Eluting Stent Implantation

Background—Stent thrombosis (ST) is a rare but devastating complication of coronary stent implantation, occurring in 0.5% to 1.9% of patients with bare metal stents. The incidence of ST with drug-eluting stents is less well studied, particularly among patients outside of clinical trials. Methods and Results—The aim of this study was to evaluate the incidence and potential risk factors for ST in patients receiving sirolimus-eluting stents (SES) in the “real world” after commercial release in the United States in April 2003. All 652 patients who underwent SES implantation (776 lesions treated) at our institution between April and October 2003 were followed up prospectively after the procedure (median follow-up 100 days). During that period, 7 patients (1.1%, 95% CI 0.4% to 2.2%) developed ST within a range of 2 to 13 days, and 1 patient had an ST-elevation myocardial infarction on day 39 with evidence of thrombus within the SES at angiography. Patients with an ST had significantly smaller final nominal balloon diameters (2.75 versus 3.00 mm, P =0.04), and in 4 (57%) of the 7 patients with ST versus 1.7% of patients without ST (P <0.001), antiplatelet therapy had been discontinued after the procedure. Among the ST patients, 1 died and 5 had myocardial infarctions. Conclusions—In this single-center experience, the incidence of ST after SES implantation was ≈1%, which is within the expected range of bare metal stents. The discontinuation of antiplatelet therapy was strongly associated with the development of ST in this patient population.

The importance of acute luminal diameter in determining restenosis after coronary atherectomy or stenting.

BackgroundWe evaluated native coronary arteries treated by directional coronary atherectomy or balloon-expandable stent placement in an effort to derive a quantitative geometric model relating the luminal diameter immediately after intervention to that present 6 months later. The minimal luminal diameter of each lesion was measured before and immediately after intervention in 102 single Palmaz-Schatz stents and 134 directional atherectomies, 192 (81%) of which had repeat angiographic measure-ment of minimal luminal diameter 6 months after the intervention. The immediate enlargement in luminal diameter produced by the intervention (acute gain) and the subsequent reduction in luminal diameter from the time of intervention to 6 months of follow-up (late loss) were calculated. Methods and ResultsLuminal diametes increased from 0.69 ± 0.40 mm to 3.11 ± 0.64 mm (acute gain, 2.41 ± 0.64 mm) after intervention, providing an immediate postprocedure residual stenosis of 1 ± 14% relative to a reference diameter of 3.13 ± 0.65 mm. At 6-month follow-up, the late luminal diameter was 1.97 ± 0.92 mm (late loss, 1.13 ± 0.89 mm), yielding a late diameter stenosis of 36 ± 26%. The restenosis rate (according to the traditional definition of diameter stenosis.≥50%) was 30%. Multivariable analysis demonstrated that late luminal diameter (p=0.02), late percent stenosis (p=0.04), and restenosis (according to a≥50% definition, p=0.04) were each strongly associated with the luminal diameter present immediately after the procedure. Whereas late luminal diameter was also influenced by reference artery size and the vessel treated (left anterior descending versus right coronary artery), reference vessel size was rejected by the multivariable models of late percent stenosis and binary restenosis after they were adjusted for the effect of postprocedure luminal diameter. Once adjusted for postprocedure luminal diameter, neither late luminal diameter nor late loss was found to be independently determined by which device was used (atherectomy versus stents). Rather, late loss was determined independently by the immediate postprocedure luminal diameter (p=0.005) and the postprocedure percent stenosis (p=0.02). Although late loss thus increased with acute gain, the net beneficial effect of increased acute gain was maintained: Late loss was only a fraction (0.47) of acute gain, so the ability of a larger postprocedure luminal diameter to reduce the probability of subsequent restenosis was preserved. ConclusionsThis quantitative model demonstrates that the late coronary lumen diameter and the probability of restenosis after Palmaz-Schatz stenting or directional atherectomy are influenced strongly by the lumen diameter present immediately after the procedure rather than by the specific device used. Although the influence of a larger acute result on reduced restenosis appears to be well established in this treatment population, the interplay among the multiple other biological influences on restenosis limits the ability to predict the probability of restenosis for the individual patient based on a large acute result alone. Future studies of restenosis, however, can further refine this multivariable quantitative model by adjusting for the effects of other clinical variables, mechanical interventions, or drug therapies in addition to the clear effect of postprocedure luminal diameter.

Restenosis after arterial injury caused by coronary stenting in patients with diabetes mellitus.

Diabetes mellitus is a well-known risk factor for the development of atherosclerotic coronary artery disease [1, 2]. Findings in several studies suggest that diabetic patients are also at increased risk for restenosis after percutaneous transluminal coronary angioplasty [3-6]. Because restenosis is a complex biologic process, involving vessel recoil, vasospasm, thrombosis, and intimal smooth muscle cell hyperplasia [7-9], we did a study to determine whether the exacerbation of one or more of these processes accounts for the increased rate of restenosis in diabetic patients. Such an analysis has previously been frustrated by the lack of a suitable model to separate the contribution of smooth muscle hyperplasia to restenosis from the contributions of acute geometric factors. Coronary artery stenting [10, 11] provides a rigid endovascular lattice that prevents both elastic recoil and vasospasm at the treated site. Restenosis within a stent results almost exclusively from intimal hyperplasia; thus, a study in patients with stents provides a potent model for evaluating the role of smooth muscle cell hyperplasia in restenosis independent of any contribution from elastic recoil or vasospasm. The effects of metabolic disorders, such as diabetes, on intimal hyperplasia and the contribution of intimal hyperplasia to restenosis can be examined directly. Further complicating the study of the relation between metabolic disorders and restenosis has been the reliance on traditional concepts of restenosis as a dichotomous event [12, 13]. However, using a continuous geometric model in which restenosis is separated into its constituent parts (acute gain and late loss of minimum lumen diameter [14]), one can examine the effect of disease states such as diabetes on specific components of restenosis. Methods Patient Sample Between June 1988 and July 1991, 250 Palmaz-Schatz stents (Johnson & Johnson, Interventional Systems, Warren, New Jersey) were placed in 220 patients as part of a multicenter study of this investigational device. Patients were selected for stenting based on morphologic features of the lesion that suggested an increased risk for a suboptimal result or restenosis after conventional balloon angioplasty. The protocol was approved by the Committee on Clinical Investigation, Beth Israel Hospital, Boston, Massachusetts, and all patients gave informed consent. The inclusion and exclusion criteria have been described previously [15]. Briefly, all patients had objective evidence of myocardial ischemia, as well as stenosis of 70% or more in either native vessels or saphenous vein grafts, with a lesion length of less than 15 mm and a reference artery diameter of 3 mm or more. Medical Therapy All patients were pretreated with aspirin, 325 mg/d; dipyridamole, 200 mg/d; and dextran, 200 mL. Intravenous heparin, 10 000 units, was administered before balloon dilatation with additional heparin given to maintain an activated clotting time of more than 300 seconds. Therapeutic heparinization (activated partial thromboplastin time 2 to 2.5 times the control value) was continued until warfarin therapy prolonged the prothrombin time to 16 to 18 seconds; warfarin therapy was continued for 8 weeks to prevent subacute stent thrombosis. Aspirin and dipyridamole were continued indefinitely. Coronary Stents The Palmaz-Schatz stent is a 15-mm, articulated, slotted, stainless steel tube mounted on a conventional angioplasty balloon. By November 1991, more than 1500 Palmaz-Schatz stents had been placed in coronary arteries and saphenous vein grafts as part of this multicenter study. The procedure for stent deployment [11, 15] entails predilation with a conventional angioplasty balloon, following which the stent (mounted on an angioplasty balloon) is positioned across the lesion. The balloon is inflated to expand the stent, permanently deploying it against the vessel wall. The stent was dilated further with a larger balloon to match the stent diameter to that of the adjacent reference artery. Angiographic Follow-up Follow-up angiograms were obtained in 189 (82%) of 230 eligible lesions. Lesions became eligible for follow-up study 4 months after successful stent placement. Angiographic Analysis and the Geometric Model Baseline angiograms were obtained in multiple projections before intervention. Identical angiographic views were repeated immediately after stent placement and at the follow-up study. Each lesion and its proximal and distal reference segments were measured before and after stent placement, as well as at follow-up, using digital calipers (Fowler Ultra-Cal II, Sylvac, Zurich, Switzerland) from an optically magnified image. Absolute lumen diameters were obtained by comparing measured values with known absolute values from the calipered guiding catheter. Percent stenosis was calculated by subtracting the ratio of the minimum lumen diameter (MLD) to the reference artery diameter from unity (1 ;MLDMLD/reference artery). Minimum lumen diameter (mm), reference artery diameter (mm), and percent stenosis were obtained for all lesions before and after stenting and at follow-up. Angiographic restenosis was analyzed per lesion according to a continuous geometric model first described by Kuntz [14]: Acute gain = MLD (post-procedure) MLD (pre-procedure) Late loss = MLD (post-procedure) MLD (at follow-up) Loss index = late loss acute gain or MLD (post-procedure) MLD (at follow-up) MLD (post-procedure) MLD (pre-procedure) Statistical Analysis Data are expressed as mean SD. Categorical variables were compared using the chi-square test, and continuous variables were compared using the Student t-test. A P value of 0.05 or less was considered statistically significant. Results Patient Characteristics Two hundred fifty stents were successfully placed in 216 of 220 patients, 37 (17%) of whom had diabetes mellitus. Thirty-five of 37 patients (94%) were classified as having type II diabetes. At the time of stent placement, 15 of 37 patients (41%) were receiving oral hypoglycemic agents, 11 of 37 (30%) were receiving insulin, and 11 of 37 (30%) were receiving dietary management alone. Follow-up angiograms were obtained for 189 of 230 stents (82%): 29 of 40 stents (73%) in diabetic patients and 160 of 190 stents (84%) in nondiabetic patients. Based on our analysis of lesions eligible for follow-up, diabetic and nondiabetic patients did not differ significantly with regard to age, sex, history of cigarette smoking, hypertension, hypercholesterolemia, family history of coronary artery disease, or previous coronary intervention (Table 1). The incidence of clinical events that might preclude repeated angiographic study did not differ between diabetic patients (two deaths and one bypass surgery) and nondiabetic patients (three deaths, one subacute thrombosis, and one bypass surgery). Because the end point of our analysis was angiographic restenosis, a lesion-based analysis was done. In studies of clinical restenosis, patient-based analysis is more appropriate. Table 1. Demographic and Clinical Characteristics* Baseline Angiography The distribution of vessels in which stents were placed was similar for diabetic and nondiabetic patients (Table 2). Vessels in patients with diabetes mellitus did not differ from those in nondiabetic patients regarding size (reference artery diameter, 3.31 0.65 mm compared with 3.39 0.65; P > 0.2) Table 3 or percent stenosis before treatment. After stent placement, the mean residual percent stenosis and minimum lumen diameter were similar in both groups. Thus, the acute gain did not differ significantly between stents placed in diabetic and nondiabetic patients (Figure 1). Table 2. Stent Placement by Vessel Location Table 3. Quantitative Angiography* Figure 1. Restenosis in diabetic and nondiabetic patients according to the terms of the geometric model. Follow-up Angiography The time to angiographic follow-up did not differ for stents placed in diabetic and nondiabetic patients (176 49 days compared with 175 49 days; P > 0.2). At follow-up, however, the minimum lumen diameter of stents placed in diabetic patients was significantly smaller than that of stents placed in nondiabetic patients (1.66 1.18 mm compared with 2.24 0.93 mm; P = 0.004), with greater corresponding percent stenosis (see Table 3). Therefore, late loss in stents placed in diabetic patients was significantly greater than in those placed in nondiabetic patients (1.66 1.28 mm compared with 1.23 0.97 mm; P = 0.04) (see Table 3), explaining the smaller late lumen diameter seen in stents placed in diabetic patients. Because the amount of late loss is known to depend on the amount of acute gain, late loss can be normalized for acute gain. The resulting loss index was significantly greater in stents placed in diabetic patients (Figure 2). This increase in the loss index seen in stents in diabetic patients accounts for the significantly higher incidence of restenosis (55% compared with 20%; P = 0.001) among stents placed in diabetic patients when restenosis is expressed as a traditional dichotomous outcome: stenosis of 50% or more at follow-up (Figure 3). Although a greater number of stents was placed in saphenous vein grafts in diabetic patients, the restenosis rate did not differ statistically between native vessels and vein grafts (27% compared with 21%; P = 0.30). Figure 2. Loss index in diabetic and nondiabetic patients. Figure 3. Cumulative distribution of percent stenosis in stents at follow-up for diabetic and nondiabetic patients. Discussion Diabetes mellitus often results in angiopathy of both large and small vessels [1, 16, 17]. Patients with diabetes also exhibit abnormal wound healing [18, 19], which involves three phasesinflammation, granulation, and extracellular matrix formation [20, 21]that bear a superficial similarity to the healing process in a vessel after coronary angioplasty. The anatomic derangements that follow balloon dilatation have been further cha

Cost-Effectiveness of Sirolimus-Eluting Stents for Treatment of Complex Coronary Stenoses Results From the Sirolimus-Eluting Balloon Expandable Stent in the Treatment of Patients With De Novo Native Coronary Artery Lesions (SIRIUS) Trial

Background—Recently, sirolimus-eluting stents (SESs) have been shown to dramatically reduce the risk of angiographic and clinical restenosis compared with bare metal stent (BMS) implantation. However, the overall cost-effectiveness of this strategy is unknown. Methods and Results—Between February and August 2001, 1058 patients with complex coronary stenoses were enrolled in the SIRIUS trial and randomized to percutaneous coronary revascularization with either a SES or BMS. Clinical outcomes, resource use, and costs were assessed prospectively for all patients over a 1-year follow-up period. Initial hospital costs were increased by

Mechanisms of restenosis and redilation within coronary stents—Quantitative angiographic assessment

2881 per patient with SESs. Over the 1-year follow-up period, use of SESs led to substantial reductions in the need for repeat revascularization, including repeat percutaneous coronary intervention and bypass surgery. Although follow-up costs were reduced by

VEGF administration in chronic myocardial ischemia in pigs

2571 per patient with SESs, aggregate 1-year costs remained

Decreased myofilament responsiveness in myocardial stunning follows transient calcium overload during ischemia and reperfusion.

309 per patient higher. The incremental cost-effectiveness ratio for SES was