Gianluca Campo

Short- Versus Long-Term Duration of Dual-Antiplatelet Therapy After Coronary Stenting A Randomized Multicenter Trial

Background— The optimal duration of dual-antiplatelet therapy and the risk-benefit ratio for long-term dual-antiplatelet therapy after coronary stenting remain poorly defined. We evaluated the impact of up to 6 versus 24 months of dual-antiplatelet therapy in a broad all-comers patient population receiving a balanced proportion of Food and Drug Administration–approved drug-eluting or bare-metal stents. Methods and Results— We randomly assigned 2013 patients to receive bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stent implantation. At 30 days, patients in each stent group were randomly allocated to receive up to 6 or 24 months of clopidogrel therapy in addition to aspirin. The primary end point was a composite of death of any cause, myocardial infarction, or cerebrovascular accident. The cumulative risk of the primary outcome at 2 years was 10.1% with 24-month dual-antiplatelet therapy compared with 10.0% with 6-month dual-antiplatelet therapy (hazard ratio, 0.98; 95% confidence interval, 0.74–1.29; P=0.91). The individual risks of death, myocardial infarction, cerebrovascular accident, or stent thrombosis did not differ between the study groups; however, there was a consistently greater risk of hemorrhage in the 24-month clopidogrel group according to all prespecified bleeding definitions, including the recently proposed Bleeding Academic Research Consortium classification. Conclusions— A regimen of 24 months of clopidogrel therapy in patients who had received a balanced mixture of drug-eluting or bare-metal stents was not significantly more effective than a 6-month clopidogrel regimen in reducing the composite of death due to any cause, myocardial infarction, or cerebrovascular accident. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00611286.

Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome.

OBJECTIVES This study sought to investigate the evolving pattern over time of on-clopidogrel platelet reactivity (PR) and its relationship with genotype and clinical outcomes after percutaneous coronary intervention. BACKGROUND Whether on-clopidogrel PR and role of genotype differ over time is unknown. METHODS On-clopidogrel PR before percutaneous coronary intervention, and 1 and 6 months thereafter via VerifyNow P2Y12 (Accumetrics Inc., San Diego, California), CYP2C19*2, *17, CYP3A5*3, and ABCB1 polymorphisms were evaluated in 300 patients. Death, stroke, myocardial infarction, and bleedings were assessed up to 1 year. RESULTS On-clopidogrel PR varied significantly over time, being higher at baseline than at 1 and 6 months after. From baseline to 1 month, 83 of 300 patients varied their response status. This was mainly due to baseline poor responders becoming full responders (75 of 83). Genotype justifies roughly 18% of this trend. CYP2C19*2 and *17 influence on PR was consistent over time, whereas that of ABCB1 appeared of greater impact at baseline. On-clopidogrel PR at 1 month independently best predicts ischemic and bleeding events. We found a therapeutic window (86 to 238 P2Y₁₂ reactivity units) with a lower incidence of both ischemic and bleeding complications. A risk score was created by combining genotype (ABCB1 and CYP2C19*2), baseline PR, and creatinine clearance to predict 1-month poor responsiveness and 1-year poor prognosis. CONCLUSIONS In patients at steady state for clopidogrel undergoing percutaneous coronary intervention, PR decreases from baseline to 1 month. Genotype influences ≈18% of this trend. On-clopidogrel PR at 1 month is the strongest predictor of adverse outcomes, and this can be predicted by combining genotype to baseline phenotype and clinical variables.

Comparison of Angioplasty With Infusion of Tirofiban or Abciximab and With Implantation of Sirolimus-Eluting or Uncoated Stents for Acute Myocardial Infarction: The MULTISTRATEGY Randomized Trial

CONTEXT Abciximab infusion and uncoated-stent implantation is a complementary treatment strategy to reduce major adverse cardiac events in patients undergoing angioplasty for ST-segment elevation myocardial infarction (STEMI). It is uncertain whether there may be similar benefits in replacing abciximab with high-dose bolus tirofiban. Similarly, the use of drug-eluting stents in this patient population is currently discouraged because of conflicting results on efficacy reported in randomized trials and safety concerns reported by registries. OBJECTIVE To evaluate the effect of high-dose bolus tirofiban and of sirolimus-eluting stents as compared with abciximab infusion and uncoated-stent implantation in patients with STEMI undergoing percutaneous coronary intervention. DESIGN, SETTING, AND PATIENTS An open-label, 2 x 2 factorial trial of 745 patients presenting with STEMI or new left bundle-branch block at 16 referral centers in Italy, Spain, and Argentina between October 2004 and April 2007. INTERVENTIONS High-dose bolus tirofiban vs abciximab infusion and sirolimus-eluting stent vs uncoated stent implantation. MAIN OUTCOME MEASURES For drug comparison, at least 50% ST-segment elevation resolution at 90 minutes postintervention with a prespecified noninferiority margin of 9% difference (relative risk, 0.89); for stent comparison, the rate of major adverse cardiac events, defined as the composite of death from any cause, reinfarction, and clinically driven target-vessel revascularization within 8 months. RESULTS ST-segment resolution occurred in 302 of 361 patients (83.6%) who had received abciximab infusion and 308 of 361 (85.3%) who had received tirofiban infusion (relative risk, 1.020; 97.5% confidence interval, 0.958-1.086; P < .001 for noninferiority). Ischemic and hemorrhagic outcomes were similar in the tirofiban and abciximab groups. At 8 months, major adverse cardiac events occurred in 54 patients (14.5%) with uncoated stents and 29 (7.8%) with sirolimus stents (P = .004), predominantly reflecting a reduction of revascularization rates (10.2% vs 3.2%). The incidence of stent thrombosis was similar in the 2 stent groups. CONCLUSIONS In patients with STEMI undergoing percutaneous coronary intervention, compared with abciximab, tirofiban therapy was associated with noninferior resolution of ST-segment elevation at 90 minutes following coronary intervention, whereas sirolimus-eluting stent implantation was associated with a significantly lower risk of major adverse cardiac events than uncoated stents within 8 months after intervention. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00229515.

Intensifying Platelet Inhibition With Tirofiban in Poor Responders to Aspirin, Clopidogrel, or Both Agents Undergoing Elective Coronary Intervention Results From the Double-Blind, Prospective, Randomized Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel Study

Background— Inhibition of platelet aggregation after aspirin or clopidogrel intake varies greatly among patients, and previous studies have suggested that poor response to oral antiplatelet agents may increase the risk of thrombotic events, especially after coronary angioplasty. Whether this reflects suboptimal platelet inhibition per se, which might benefit from more potent antiplatelet agents such as tirofiban, is unknown. Methods and Results— We screened 1277 patients to enroll 93 aspirin, 147 clopidogrel, and 23 dual poor responders, based on a point-of-care assay, who underwent elective coronary angioplasty at 10 European sites for stable or low-risk unstable coronary artery disease. Patients were randomly assigned in a double-blind manner to receive either tirofiban (n=132) or placebo (n=131) on top of standard aspirin and clopidogrel therapy. The primary end point, consisting of troponin I/T elevation at least 3 times the upper limit of normal, was attained in 20.4% (n=27) in the tirofiban group compared with 35.1% (n=46) in the placebo group (relative risk, 0.58; 95% confidence interval, 0.39 to 0.88; P=0.009). The rate of major adverse cardiovascular events within 30 days in the tirofiban group also was reduced (3.8% versus 10.7%; P=0.031). The overall incidence of bleeding was low, likely explained by a substantial use of the transradial approach, and did not differ between the 2 groups. Conclusions— In low-risk patients according to clinical presentation who had poor responsiveness to standard oral platelet inhibitors via a point-of-care assay, intensified platelet inhibition with tirofiban lowers the incidence of myocardial infarction after elective coronary intervention.

Comparison of an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent for the treatment of coronary artery stenosis (ABSORB II): a 3 year, randomised, controlled, single-blind, multicentre clinical trial

BACKGROUND No medium-term data are available on the random comparison between everolimus-eluting bioresorbable vascular scaffolds and everolimus-eluting metallic stents. The study aims to demonstrate two mechanistic properties of the bioresorbable scaffold: increase in luminal dimensions as a result of recovered vasomotion of the scaffolded vessel. METHODS The ABSORB II trial is a prospective, randomised, active-controlled, single-blind, parallel two-group, multicentre clinical trial. We enrolled eligible patients aged 18-85 years with evidence of myocardial ischaemia and one or two de-novo native lesions in different epicardial vessels. We randomly assigned patients (2:1) to receive treatment with an everolimus-eluting bioresorbable scaffold (Absorb; Abbott Vascular, Santa Clara, CA, USA) or treatment with an everolimus-eluting metallic stent (Xience; Abbott Vascular, Santa Clara, CA, USA). Randomisation was stratified by diabetes status and number of planned target lesions. At 3 year follow-up, the primary endpoint was superiority of the Absorb bioresorbable scaffold versus the Xience metallic stent in angiographic vasomotor reactivity after administration of intracoronary nitrate. The co-primary endpoint is the non-inferiority of angiographic late luminal loss. For the endpoint of vasomotion, the comparison was tested using a two-sided t test. For the endpoint of late luminal loss, non-inferiority was tested using a one-sided asymptotic test, against a non-inferiority margin of 0·14 mm. The trial is registered at ClinicalTrials.gov, number NCT01425281. FINDINGS Between Nov 28, 2011, and June 4, 2013, we enrolled 501 patients and randomly assigned them to the Absorb group (335 patients, 364 lesions) or the Xience group (166 patients, 182 lesions). The vasomotor reactivity at 3 years was not statistically different (Absorb group 0·047 mm [SD 0·109] vs Xience group 0·056 mm [0·117]; psuperiority=0·49), whereas the late luminal loss was larger in the Absorb group than in the Xience group (0·37 mm [0·45] vs 0·25 mm [0·25]; pnon-inferiority=0·78). This difference in luminal dimension was confirmed by intravascular ultrasound assessment of the minimum lumen area (4·32 mm2 [SD 1·48] vs 5·38 mm2 [1·51]; p<0·0001). The secondary endpoints of patient-oriented composite endpoint, Seattle Angina Questionnaire score, and exercise testing were not statistically different in both groups. However, a device-oriented composite endpoint was significantly different between the Absorb group and the Xience group (10% vs 5%, hazard ratio 2·17 [95% CI 1·01-4·70]; log-rank test p=0·0425), mainly driven by target vessel myocardial infarction (6% vs 1%; p=0·0108), including peri-procedural myocardial infarction (4% vs 1%; p=0·16). INTERPRETATION The trial did not meet its co-primary endpoints of superior vasomotor reactivity and non-inferior late luminal loss for the Absorb bioresorbable scaffold with respect to the metallic stent, which was found to have significantly lower late luminal loss than the Absorb scaffold. A higher rate of device-oriented composite endpoint due to target vessel myocardial infarction, including peri-procedural myocardial infarction, was observed in the Absorb group. The patient-oriented composite endpoint, anginal status, and exercise testing, were not statistically different between both devices at 3 years. Future studies should investigate the clinical impact of accurate intravascular imaging in sizing the device and in optimising the scaffold implantation. The benefit and need for prolonged dual antiplatelet therapy after bioresorbable scaffold implantation could also become a topic for future clinical research. FUNDING Abbott Vascular.

Prasugrel Versus Tirofiban Bolus With or Without Short Post-Bolus Infusion With or Without Concomitant Prasugrel Administration in Patients With Myocardial Infarction Undergoing Coronary Stenting : The FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) Trial

OBJECTIVES The authors sought to compare the effect on inhibition of platelet aggregation (IPA) of prasugrel therapy versus tirofiban bolus with or without a post-bolus short drug infusion in ST-segment elevation myocardial infarction (STEMI) patients. BACKGROUND The degree and rapidity of IPA after prasugrel alone with or without concomitant glycoprotein IIb/IIIa inhibition in STEMI patients is unknown. METHODS A total of 100 STEMI patients randomly received prasugrel 60 mg versus 25 μg/kg tirofiban bolus with or without post-bolus 2-h infusion of tirofiban, with or without concomitant prasugrel. IPA at light transmission aggregometry was performed throughout 24 h. The primary endpoint was IPA stimulated with 20 μmol/l adenosine diphosphate (ADP) at 30 min. RESULTS At 30 min, patients in the prasugrel group showed a significantly lower IPA to 20 μmol/l ADP stimulation as compared with tirofiban-treated patients (36 ± 35 vs. 87 ± 31, p < 0.0001). Similarly, patients taking prasugrel showed a suboptimal degree of platelet inhibition for at least 2 h compared with tirofiban patients. Post-bolus tirofiban infusion was necessary to maintain a high level of IPA beyond 1 h after bolus administration if concomitant clopidogrel was given, whereas the bolus-only tirofiban and concomitant prasugrel led to the higher and more consistent IPA levels after both ADP and thrombin receptor-activating peptide stimuli than either therapy alone. CONCLUSIONS Our study shows that prasugrel administration leads to a suboptimal IPA for at least 2 h in STEMI patients. Yet, prasugrel, given in association with a bolus only of glycoprotein IIb/IIIa inhibitor, obviates the need of post-bolus infusion and almost completely abolishes residual variability of IPA after treatment. (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse [The FABOLUS PRO trial]; NCT01336348).

Long-Term Clinical Outcome Based on Aspirin and Clopidogrel Responsiveness Status After Elective Percutaneous Coronary Intervention A 3T/2R (Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel) Trial Substudy

OBJECTIVES The purpose of this study was to investigate the long-term outcome after elective percutaneous coronary intervention in low-risk patients screened for aspirin and/or clopidogrel responsiveness in the 3T/2R (Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel) trial. BACKGROUND The impact of aspirin and/or clopidogrel poor response on long-term outcome is debated. METHODS Aspirin and clopidogrel response was measured with the VerifyNow system aspirin and P2Y12 assays. After percutaneous coronary intervention (PCI), death, stroke, and myocardial infarction were assessed up to 1 year. RESULTS Overall, 1,277 patients were screened, and 826 (65%) were treated with PCI. In all, 124 patients were found to be aspirin poor responders, and there were 179 clopidogrel poor responders (totally, 278 poor responders). The 1-year end point was significantly higher in poor responders as compared to full responders (15.8% vs. 8.6%, p=0.002), which is principally due to more myocardial infarction occurrence. At multivariable analysis, clopidogrel poor response emerged as an independent predictor (hazard ratio: 1.15, 95% confidence interval: 1.03 to 1.28). Receiver-operator characteristic analysis identifies≤23 of percentage of platelet inhibition and ≥208 of P2Y12 reactivity units as optimal cut offs to predict 1-year end point. Excluding periprocedural events, also peri-PCI myocardial infarction, which is strongly related to aspirin/clopidogrel poor response, was an independent predictor (hazard ratio: 1.25, 95% confidence interval: 1.14 to 1.37). Glycoprotein IIb/IIIa inhibitor administration reduces this risk in poor responders (21.2% vs. 34.7%, p=0.02), but not in full responders (6.3% vs. 6.5%, p=0.8). CONCLUSIONS Poor response to clopidogrel is an independent predictor of periprocedural myocardial infarction and worse 1-year outcome in low-risk patients undergoing PCI, whereas poor response to aspirin failed to predict a worse outcome. Contrary to what was observed in poor responders, glycoprotein IIb/IIa inhibitor therapy failed to provide a benefit in aspirin and/or clopidogrel full responders.

Tirofiban as adjunctive therapy for acute coronary syndromes and percutaneous coronary intervention: a meta-analysis of randomized trials

AIMS To perform a thorough and updated systematic review of randomized clinical trials comparing tirofiban vs. placebo or vs. abciximab. METHODS AND RESULTS We searched for randomized trials comparing tirofiban vs. placebo or any active control. Odds ratios (OR) were computed from individual studies and pooled with random-effect methods. Thirty-one studies were identified involving 20,006 patients (12 874 comparing tirofiban vs. heparin plus placebo or bivalirudin alone, and 7132 vs. abciximab). When compared with placebo, tirofiban was associated at 30 days with a significant reduction in mortality [OR = 0.68 (0.54-0.86); P = 0.001] and death or myocardial infarction (MI) [OR = 0.69 (0.58-0.81); P < 0.001]. The treatment benefit persisted at follow-up but came at an increased risk of minor bleedings [OR = 1.42 (1.13, 1.79), P = 0.002] or thrombocytopenia. When compared with abciximab, mortality at 30 days did not differ [OR = 0.90 (0.53, 1.54); P = 0.70], but in the overall group tirofiban trended to increase the composite of death or MI [OR = 1.18 (0.96, 1.45); P = 0.11]. No such trend persisted at medium-term follow-up or when appraising studies testing tirofiban at 25 microg/kg bolus regimen. CONCLUSION Tirofiban administration reduces mortality, the composite of death or MI and increases minor bleedings when compared with placebo. An early ischaemic hazard disfavouring tirofiban was noted when compared with abciximab in studies based on 10 but not 25 microg/kg tirofiban bolus regimen.

Prediction of 1-year clinical outcomes using the SYNTAX score in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

OBJECTIVES This study sought to evaluate the impact of SYNTAX score (SXscore), and compare its performance in isolation and combination with the PAMI (The Primary Angioplasty in Myocardial Infarction Study) score, for the prediction of 1-year clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. BACKGROUND Patients with STEMI were excluded from the original SYNTAX score (SXscore) algorithm. Therefore, the utility of using the SXscore in this patient group remains undefined. METHODS SXscore was calculated retrospectively in 807 patients with STEMI enrolled in the randomized STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) clinical trials. Clinical outcomes of all-cause death, reinfarction, and clinically driven target vessel revascularization were subsequently stratified according to SXscore tertiles: SX(LOW) ≤ 9 (n = 311), 9 < SX(MID) ≤ 16 (n = 234), SX(HIGH) >16 (n = 262). RESULTS At 1-year follow-up, all clinical outcomes including mortality, mortality/reinfarction, major adverse cardiac events (MACE) (a composite of all-cause death, reinfarction and target vessel revascularization), and definite, definite/probable, and any stent thrombosis were all significantly higher in patients in the highest SXscore tertile. SXscore was identified as an independent predictor of mortality, MACE, and stent thrombosis out to 1-year follow-up. The combination SYNTAX-PAMI score led to a net reclassification improvement of 15.7% and 4.6% for mortality and MACE, respectively. The C-statistics for the SXscore, PAMI score, and the combined SYNTAX-PAMI score were 0.65, 0.81, and 0.73 for 1-year mortality, and 0.68, 0.64, and 0.69 for 1-year MACE, respectively. CONCLUSIONS SXscore does have a role in the risk stratification of patients with STEMI having primary percutaneous coronary intervention; however, this ability can be improved through a combination with clinical variables. (Multicentre 2×2 Factorial Randomised Study Comparing Tirofiban Versus Abciximab and SES Versus BMS in AMI; NCT00229515).

Randomized comparison of 6- versus 24-month clopidogrel therapy after balancing anti-intimal hyperplasia stent potency in all-comer patients undergoing percutaneous coronary intervention: Design and rationale for the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia study (PRODIGY)

BACKGROUND The optimal duration of clopidogrel therapy after coronary stenting is debated because of the scarcity of randomized controlled trials and inconsistencies arising from registry data. Although prolonged clopidogrel therapy after bare metal stenting is regarded as an effective secondary prevention measure, the safety profile of drug-eluting stents itself has been questioned in patients not receiving ≥ 12 months of dual-antiplatelet therapy. HYPOTHESIS Twenty-four months of clopidogrel therapy after coronary stenting reduces the composite of death, myocardial infarction, or stroke compared with 6 months of treatment. STUDY DESIGN PRODIGY is an unblinded, multicenter, 4-by-2 randomized trial. All-comer patients with indication to coronary stenting are randomly treated-balancing randomization-with bare metal stent (no active late loss inhibition), Endeavor Sprint zotarolimus-eluting stent (Medtronic, Santa Rosa, CA) (mild late loss inhibition), Taxus paclitaxel-eluting stent (Boston Scientific, Natick, MA) (moderate late loss inhibition), or Xience V everolimus-eluting stent (Abbott Vascular, Santa Clara, CA) (high late loss inhibition). At 30 days, patients in each stent group are randomly allocated to receive 24 or up to 6 months of clopidogrel therapy-primary end point randomization. With 1,700 individuals, this study will have >80% power to detect a 40% difference in the primary end point after sample size augmentation of 5% and a background event rate of 8%. SUMMARY The PRODIGY trial aims to assess whether 24 months of clopidogrel therapy improves cardiovascular outcomes after coronary intervention in a broad all-comer patient population receiving a balanced mixture of stents with various anti-intimal hyperplasia potency.