Off-label Drug-eluting Stents Research Articles

Clinical outcome following second-generation drug-eluting stent use for off-label versus on-label indications: insights from the two-year outcome of the TWENTE trial.

Drug-eluting stents (DES) were first used on-label - in simple patients with low clinical risk and easily accessible lesions. Currently, DES are increasingly used off-label - in complex patients undergoing percutaneous coronary interventions (PCI) with historically higher event risk. Therefore, our aim was to investigate whether patients with off-label indications for DES use had similar outcomes compared to patients who were treated for on-label indications only. We analysed two-year follow-up data of 1,387 TWENTE trial patients, treated with second-generation everolimus-eluting XIENCE V or zotarolimus-eluting Resolute stents, and compared off-label vs. on-label DES use with regard to the following clinical endpoints: cardiac death, myocardial infarction (MI), periprocedural MI (≤48 hrs), and target vessel revascularisation (TVR). Patients with off-label DES use (n=1,033; 74.5%) had more diabetes (22.9% vs. 17.5%; p=0.032), previous MI (35.9% vs. 22.3%; p<0.001), type B2/C lesions (84.7% vs. 62.7%; p<0.001), and acute coronary syndromes (57.8% vs. 33.3%; p<0.001). Nevertheless, cardiac death and TVR rates were similar to those of patients with on-label DES use (p>0.8). Following off-label DES use, there was a higher incidence of PMI (5.0% vs. 1.4%; p=0.003), of which only 1.1% reached creatine kinase levels >5x the upper limit of normal (ULN). Despite differences in risk profile, patients with off-label DES use did not differ from patients with on-label DES use in clinical endpoints other than periprocedural MI. These largely positive findings underline the favourable safety profile of second-generation DES.

Clinical impact of off-label use of contemporary drug-eluting stents in the randomized TWENTE trial

Purpose: Drug-eluting stents (DES) were initially used in simple lesions and low-risk patients (on-label indications). Nowadays, DES are mostly implanted off-label, however, there is limited knowledge about potential differences in outcome between indication groups. Methods: We assessed this issue in the 1-year clinical outcome data of the randomised TWENTE trial, which evaluated second-generation DES (Xience V and Resolute) in 1387 patients. Off-label indications included: renal insufficiency; ejection fraction 27 mm; acute myocardial infarction (MI); >1 lesion/vessel or >2 vessels treated; bifurcation, graft, in-stent restenotic, left main, thrombotic, and totally occluded lesions. Primary endpoint was target vessel failure, a composite of cardiac death, target-vessel related MI, or target-vessel revascularization. Periprocedural MI was defined as MI ≤48 hours after PCI. Results: Patients with off-label DES (n=1033; 74.5%) had more diabetes mellitus (22.9% vs. 17.5%; p=0.03), previous MI (35.9% vs. 22.3%; p<0.001), complex lesions (76.1% vs. 60.7%; p<0.001), and acute coronary syndromes (57.8% vs. 33.3%; p<0.001). Outcome was similar except for more target vessel-related MI in off-label DES (5.6% vs. 1.7%; p<0.001), which reflected more periprocedural MI (5.0% vs. 1.4%; p=0.003) that resulted in a higher target vessel failure rate (p=0.004; Fig.). However, logistic regression analysis demonstrated absence of an independent association between off-label DES use and target vessel failure (adjusted HR 1.11, 0.95% CI: 0.62-2.00; p=0.73). ![Figure][1] Conclusion: Despite significant differences in baseline data between patients with off-label and on-label DES use, 1-year clinical outcome was similar except for more periprocedural MI in patients with off-label DES use. [1]: pending:yes

Long-Term Predictors of Clinical Events after Off-Label Use of Drug-Eluting Stent beyond 1 Year

Background and ObjectivesWe evaluated the long-term outcomes and predictors of clinical events after off-label use of drug-eluting stents (DES) beyond 1 year after procedure.Subjects and MethodsA total of 518 patients who underwent DES implantation for off-label indications and did not have any major adverse cardiac events (MACE) during the first year were analyzed. The occurrence of MACE, including cardiac death, myocardial infarction (MI), stent thrombosis and target vessel revascularization, were evaluated for a median 1179 days (interquartile range 769-1541) after the first year.ResultsMajor adverse cardiac events occurred in 43 patients (8.3%) including 8 cases (1.5%) of cardiac death, 9 cases (1.7%) of MI, 24 cases (4.6%) of target vessel revascularization, and 11 cases (2.1%) of stent thrombosis. Patients with MACE had a higher serum creatinine level, higher incidence of in-stent restenosis lesion, more overlapping stents, a greater number of stents, and longer stents than did patients without MACE. Multivariate analysis revealed that serum creatinine level >1.5 mg/dL {hazard ratio (HR) 2.3, p=0.019}, stent length >33 mm (HR 2.4, p=0.035), and in-stent restenosis lesions (HR 2.4, p=0.040) were independent risk factors for MACE. Patients with DES length >33 mm had a higher incidence of MACE than those with DES length ≤33 mm (HR 2.7, log rank p=0.002).ConclusionThe risk of stent thrombosis and target vessel revascularization persisted in patients undergoing off-label DES implantation beyond 1-year follow-up. A total DES length >33 mm was a significant procedural predictor associated with the incidence of MACE.

Beneficial Impact of Prolonged Dual Antiplatelet Therapy after Drug‐Eluting Stent Implantation

Twelve-month dual antiplatelet therapy (DAT) with aspirin and clopidogrel after drug-eluting stent (DES) implantation is routinely recommended. It is unclear if prolonged (>12-month) DAT is also favorable. We compared the outcome of patients discontinuing DAT 12 months after off-label DES implantation versus those with DAT for >12 months. Baseline, treatment, and outcome data of patients undergoing off-label DES implantation and free from events 11.5 months after index procedure were retrospectively retrieved. Those discontinuing DAT between 11.5 and 12.5 months (12-month DAT group) were compared to those discontinuing DAT after 12.5 months (>12-month DAT group). The primary end-point was the long-term (>24-month) rate of major adverse cerebro-cardiovascular events (MACCE). Two hundred seventy-two patients met study inclusion criteria: 133 (48.9%) in the 12-month DAT group and 139 (51.1%) in the >12-month DAT group (who were on DAT for an average of 24 months). After an average of 36 months after DES implantation, 14 patients (5.1%) developed MACCE, with 6 (3.5%) cardiac deaths, 7 (2.2%) myocardial infarctions, no stroke, and 5 (1.8%) repeat revascularizations. The >12-month DAT group had a significantly lower risk of MACCE (1 [0.7%] vs. 13 [9.8%] in the 12-month DAT group, P < 0.001) and myocardial infarction (0 vs. 7 [5.3%], P = 0.006), with such differences confirmed at multivariable propensity-adjusted analyses. No significant differences in terms of minor or major bleedings occurred. In this retrospective registry, patients with off-label DES implantation receiving prolonged (>12 months) DAT presented with lower rates of MACCE and myocardial infarction.

Drug-eluting stents for off-label indications in real clinical world: Evidence based or ‘intuition’ based clinical practice?

BackgroundThe use of drug-eluting stents (DES) is an example of the disparity between recommendations given by regulatory agencies and the real clinical world. Such disparity might lead cardiologists to adopt different routines in the use of DES. We aimed to assess variability of off-label DES use between hospitals and to what extent it can be explained by differences in patient or hospital characteristics. MethodsCharacteristics of consecutive patients receiving DES in 29 hospitals were recorded. Individual and hospital determinants of receiving DES for off-label indications were assessed by multilevel logistic regression. Results1903 patients were recruited and 1188 (62.4%) received DES for off-label indications. Individual variables associated with off-label use were age (OR 1.01 (1–1.02)), previous percutaneous (OR 2.24 (1.68–2.97)) or surgical (2.41 (1.52–3.84)) revascularization, repeated procedure at the same admission (OR 4.66 (2.7–8.05)), receiving two (OR 4.17 (3.24–5.37)) or three or more DES (OR 14.12 (9.08–21.96)) vs one. Adjusting for individual variables, the Odds of receiving DES for off-label indication was higher in public funding hospitals with surgery availability vs private hospitals: 1.49 (0.86–2.6), and in public hospitals without surgery vs public with surgery availability: OR 1.76 (1.02–3.03). Interhospital variability reminded significant after adjustment for individual and contextual variables. ConclusionOff-label DES use is highly variable between centers. Although this variability is partially determined by hospital type of funding and cardiac surgery availability, the substantial interhospital variability after multilevel adjustment suggests heterogeneity in the process of care.

Comparison between on-label versus off-label use of drug-eluting coronary stents in clinical practice: results from the German DES.DE-Registry

Observational studies from the USA have demonstrated that off-label use of drug-eluting stents (DES) is common. Data on off-label use in Western Europe are limited. We analyzed the data of consecutive patients receiving DES prospectively enrolled in the multicenter German DES.DE registry (Deutsches Drug-Eluting Stent Register) between October 2005 and October 2006. Off-label use was defined in the presence of one of the following criteria: ST-elevation myocardial infarction, in-stent stenosis, chronic total occlusion, lesions in a bypass graft, in bifurcation or left main stem, stent length per lesion≥32mm, and vessel diameter<2.5 or>3.5mm. Overall, 4,295 patients were included in this analysis and divided into two groups: 2,366 (55.1%) received DES for off-label and 1,929 (44.9%) for on-label indications. There were substantial differences in the rates of off-label use at the participating hospitals. Patients with off-label DES more often presented with high-risk features such as acute coronary syndrome, cardiogenic shock, congestive heart failure, and more complex coronary anatomy. Among hospital survivors, the incidence of the composite endpoint of death, myocardial infarction and stroke (MACCE) (9.2 vs. 7.4%, p<0.05), and target vessel revascularization (TVR) (11.3 vs. 9.1%, p<0.05) was increased in the off-label group at the 1-year follow-up. However, in the multivariate analysis off-label use was not linked with an elevated risk for MACCE (hazard ratio 0.86, 95% confidence interval 0.62-1.18) and TVR (hazard ratio 1.05, 95% confidence interval 0.78-1.42). In clinical practice, DES was very frequently used off-label. After adjustment for confounding variables, off-label use was not associated with an increase of adverse events.

Outcome of Drug-Eluting Versus Bare-Metal Stenting Used According to On- and Off-Label Criteria

The aim of this study was to investigate the outcome of bare-metal stents (BMS) versus drug-eluting stents (DES) after on-label as well as off-label use. DES lower restenosis rates while not influencing the risk for death and myocardial infarction when used in Federal Food and Drug Administration (FDA)-approved indications. It is debated whether the clinical results of this so-called on-label use might be extrapolated to off-label situations. The SCAAR (Swedish Coronary Angiography and Angioplasty Registry) was used to investigate the outcomes in 17,198 patients who underwent stenting with an on-label indication (10,431 BMS and 6,767 DES patients) and 16,355 patients in the context of an off-label indication (9,907 BMS and 6,448 DES patients). The patients were included from 2003 to 2005 with a minimum follow-up of 1 year and a maximum of 4 years. The analysis was adjusted for differences in baseline characteristics. There were not significant differences between on-label DES and BMS (adjusted hazard ratio: 1.02; 95% confidence interval: 0.92 to 1.13) or between off-label DES and BMS (adjusted hazard ratio: 0.95; 95% confidence interval: 0.87 to 1.04) use with regard to the incidence of myocardial infarction and death. Off-label use of DES did not lead to significant differences in the combined risk of death and myocardial infarction compared with BMS throughout the whole spectrum of clinical indications. In contemporary Swedish practice, neither on- nor off-label use of DES is associated with worse outcome than use of BMS.

Drug-Eluting Stents Versus Bare-Metal Stents for Off-Label Indications

Background— The US Food and Drug Administration recently concluded that data on off-label drug-eluting stent (DES) safety are limited. However, in actual clinical practice, DES are often used for off-label indications, and observational studies demonstrate that complications are higher when compared with on-label use. We aimed to determine whether clinical outcomes differ after DES and bare-metal stent implantation in a patient cohort defined by DES off-label indications. Methods and Results— We used the national revascularization registry in Scotland to identify patients who underwent coronary stenting for an off-label indication between January 2003 and September 2005. Individual-level linkage to comprehensive national admission and death databases was used to ascertain the end points of death, myocardial infarction, and target-vessel revascularization. We calculated propensity scores on the basis of clinical, demographic, and angiographic variables and matched DES to bare-metal stents on a 1:1 basis. The final study population consisted of 1642 patients, well matched for important covariables at baseline. Event-free survival was calculated over 24 months with the Kaplan-Meier method. All-cause death was more common after bare-metal stent implantation during follow-up (7.7% versus 6.6%; hazard ratio 0.63; 95% confidence interval, 0.40 to 0.99; P =0.04). No difference in the rates of myocardial infarction were noted (7.3% versus 7.5%; hazard ratio 1.02; 95% confidence interval, 0.69 to 1.54; P =0.92). Target-vessel revascularization was reduced in patients treated with DES (13.9% versus 10.7%; hazard ratio 0.67; 95% confidence interval, 0.49 to 0.93; P =0.02). Conclusions— At 24 months, patients treated with DES for off-label indications had lower rates of death and target-vessel revascularization and similar rates of myocardial infarction, as compared with patients treated with bare-metal stents.

Correlates of late and very late thrombosis of drug eluting stents

Late and very late thrombosis of coronary drug-eluting stents (DES) has received much attention but essentially remains unpredictable. We sought to identify correlates of stent thrombosis (ST) developing >30 days after DES implantation. We analyzed data from our single-center registry on 5,342 consecutive patients, who underwent a first DES implant between May 2003 and December 2006. The Academic Research Consortium definitions were applied to classify definite, probable, and possible ST. Cox regression analysis was performed to identify predictors of ST. Follow-up information was obtained at 6 months and at 1, 2, and 3 years after DES implantation in 97.2%, 95.2%, 92.4%, and 89.8% of patients, respectively. We identified 34 patients who developed definite and 5 with probable ST >30 days after the index stent procedure. The 3-year cumulative incidence of definite and definite + probable ST >30 days was 1.33% and 1.50%, respectively. By Cox multiple variable regression, predictors of definite + probable ST were age (hazard ratio [HR] 0.95, 95% CI 0.92-0.98, P < .001), current smoking (HR 2.55, 95% CI 1.29-5.07, P = .007), prior percutaneous coronary intervention (HR 2.68, 95% CI 1.42-5.05, P = .002), "off-label" DES indication (HR 3.10, 95% CI 1.10-8.75, P = .032), bifurcation stenting (HR 2.37, 95% CI 1.40-3.99, P = .001), and stenting an occluded vessel (HR 3.02, 95% CI 1.59-5.74, P < .001). We identified several baseline characteristics, which, when combined, may identify patients at risk for late-occurring ST, particularly after off-label DES placement.

Long-Term Follow-Up of Drug-Eluting Stents When Inserted for On- and Off-Label Indications

This study reports long-term follow-up of the on- and off-label implantation of drug-eluting stents (DESs) in a retrospective study of 1,044 patients. Off-label implantation of DESs was performed for left main coronary artery lesions, bifurcation lesions, bare metal stent restenosis, ostial disease, chronic total occlusions, saphenous vein graft lesions, internal mammary artery graft lesions, left ventricular ejection fraction <30%, and acute myocardial infarction. End points examined were procedural complications, in-hospital myocardial infarction, and acute stent thrombosis; end points examined at follow-up were subacute stent thrombosis, late stent thrombosis, target vessel revascularization, myocardial infarction, death, and major adverse clinical events (MACEs; a composite of death, myocardial infarction, and target vessel revascularization). The study included 364 patients who received a DES on an on-label basis and 680 patients who received a DES on an off-label basis. Patient characteristics were not significantly different between the 2 groups, and there was no difference in procedural complications or acute stent thrombosis (on-label, 0%; off-label, 0.3%; p=0.55). There were no significant differences in subacute stent thrombosis (0% vs 0.6%, p=0.3), late stent thrombosis (1.4% vs 1.2%, p=0.78), death at follow-up (4.9% vs 4.1%, p=0.53), or myocardial infarction (1.9% vs 2.4%, p=0.83). Off-label DES implantation was associated with higher rates of target vessel revascularization (13.2% vs 24.1%, p=0.0001) and MACEs (17.6% vs 28.2%, p=0.0001). Multivariate analysis showed associations between target vessel revascularization and MACEs (respective p values) with bare metal stent restenosis (p=0.001 and p=0.001), diabetes mellitus (p=0.002 and p=0.001), and previous coronary artery bypass grafting (p=0.04 and p=0.01), but not off-label DES implantation (p=1.36 and p=1.16). In conclusion, DES use in the off-label situations studied was safe and was not associated with increased stent thrombosis, myocardial infarction, or death. Multivariate analysis showed that off-label DES implantation was not a risk factor for target vessel revascularization or MACEs.