Giuseppe Patti

Randomized Trial of High Loading Dose of Clopidogrel for Reduction of Periprocedural Myocardial Infarction in Patients Undergoing Coronary Intervention Results From the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) Study

Background—Aggressive platelet inhibition is crucial to reduce myocardial injury and early cardiac events after coronary intervention. Although observational data have suggested that pretreatment with a high loading dose of clopidogrel may be more effective than a conventional dose, this hypothesis has never been tested in a randomized trial. Methods and Results—A total of 255 patients scheduled to undergo percutaneous coronary intervention were randomized to a 600-mg (n=126) or 300-mg (n=129) loading regimen of clopidogrel given 4 to 8 hours before the procedure. Creatine kinase MB, troponin I, and myoglobin levels were measured at baseline and at 8 and 24 hours after intervention. The primary end point was the 30-day occurrence of death, myocardial infarction (MI), or target vessel revascularization. The primary end point occurred in 4% of patients in the high loading dose versus 12% of those in the conventional loading dose group (P=0.041) and was due entirely to periprocedural MI. Peak values of all markers were significantly lower in patients treated with the 600-mg regimen (P≤0.038). Safety end points were similar in the 2 arms. At multivariable analysis, the high loading regimen was associated with a 50% risk reduction of MI (OR 0.48, 95% CI 0.15 to 0.97, P=0.044). An incremental benefit was observed in patients randomized to the 600-mg dose who were receiving statins, with an 80% risk reduction. Conclusions—Pretreatment with a 600-mg loading dose of clopidogrel 4 to 8 hours before the procedure is safe and, as compared with the conventional 300-mg dose, significantly reduced periprocedural MI in patients undergoing percutaneous coronary intervention. These results may influence practice patterns with regard to antiplatelet therapy before percutaneous revascularization.

Randomized Trial of Atorvastatin for Reduction of Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery Results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery) Study

Background— Atrial fibrillation (AF) after cardiac surgery is associated with increased risk of complications, length of stay, and cost of care. Observational evidence suggests that patients who have undergone previous statin therapy have a lower incidence of postoperative AF. We tested this observation in a randomized, controlled trial. Methods and Results— Two hundred patients undergoing elective cardiac surgery with cardiopulmonary bypass, without previous statin treatment or history of AF, were enrolled. Patients were randomized to atorvastatin (40 mg/d, n=101) or placebo (n=99) starting 7 days before operation. The primary end point was incidence of postoperative AF; secondary end points were length of stay, 30-day major adverse cardiac and cerebrovascular events, and postoperative C-reactive protein (CRP) variations. Atorvastatin significantly reduced the incidence of AF versus placebo (35% versus 57%, P=0.003). Accordingly, length of stay was longer in the placebo versus atorvastatin arm (6.9±1.4 versus 6.3±1.2 days, P=0.001). Peak CRP levels were lower in patients without AF (P=0.01), irrespective of randomization assignment. Multivariable analysis showed that atorvastatin treatment conferred a 61% reduction in risk of AF (odds ratio 0.39, 95% confidence interval 0.18 to 0.85, P=0.017), whereas high postoperative CRP levels were associated with increased risk (odds ratio 2.0, 95% confidence interval 1.2 to 7.0, P=0.01). The incidence of major adverse cardiac and cerebrovascular events at 30 days was similar in the 2 arms. Conclusions— Treatment with atorvastatin 40 mg/d, initiated 7 days before surgery, significantly reduces the incidence of postoperative AF after elective cardiac surgery with cardiopulmonary bypass and shortens hospital stay. These results may influence practice patterns with regard to adjuvant pharmacological therapy before cardiac surgery.

Randomized Trial of Atorvastatin for Reduction of Myocardial Damage During Coronary Intervention Results From the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) Study

Background—Small myocardial infarctions after percutaneous coronary intervention have been associated with higher risk of cardiac events during follow-up. Observational studies have suggested that statins may lower the risk of procedural myocardial injury. The aim of our study was to confirm this hypothesis in a randomized study. Methods and Results—One hundred fifty-three patients with chronic stable angina without previous statin treatment were enrolled in the study. Patients scheduled for elective coronary intervention were randomized to atorvastatin (40 mg/d, n=76) or placebo (n=77) 7 days before the procedure. Creatine kinase-MB, troponin I, and myoglobin levels were measured at baseline and at 8 and 24 hours after the procedure. Detection of markers of myocardial injury above the upper normal limit was significantly lower in the statin group versus the placebo group: 12% versus 35% for creatine kinase-MB (P=0.001), 20% versus 48% for troponin I (P=0.0004), and 22% versus 51% for myoglobin (P=0.0005). Myocardial infarction by creatine kinase-MB determination was detected after coronary intervention in 5% of patients in the statin group and in 18% of those in the placebo group (P=0.025). Postprocedural peak levels of creatine kinase-MB (2.9±3 versus 7.5±18 ng/mL, P=0.007), troponin I (0.09±0.2 versus 0.47±1.3 ng/mL, P=0.0008), and myoglobin (58±36 versus 81±49 ng/mL, P=0.0002) were also significantly lower in the statin than in the placebo group. Conclusions—Pretreatment with atorvastatin 40 mg/d for 7 days significantly reduces procedural myocardial injury in elective coronary intervention. These results may influence practice patterns with regard to adjuvant pharmacological therapy before percutaneous revascularization.

Point-of-Care Measurement of Clopidogrel Responsiveness Predicts Clinical Outcome in Patients Undergoing Percutaneous Coronary Intervention : Results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) Study

OBJECTIVES The aim of this study was to evaluate the correlation of point-of-care measurement of platelet inhibition with clinical outcome in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND Individual variability of clopidogrel response might influence results of PCI. METHODS A total of 160 patients receiving clopidogrel before PCI were prospectively enrolled. Platelet reactivity was measured by the VerifyNow P2Y12 assay (Accumetrics Inc., San Diego, California). Primary end point was 30-day occurrence of major adverse cardiac events (MACE) according to quartile distribution of P2Y12 reaction units (PRU). RESULTS Primary end point occurred more frequently in patients with pre-procedural PRU levels in the fourth quartile versus those in the lowest quartile (20% vs. 3%; p=0.034), and it was entirely due to periprocedural myocardial infarction (MI). Mean PRU absolute levels were higher in patients with periprocedural MI (258+/-53 vs. 219+/-69 in patients without; p=0.030). On multivariable analysis pre-PCI PRU levels in the fourth quartile were associated with 6-fold increased risk of 30-day MACE (odds ratio: 6.1; 95% confidence interval: 1.1 to 18.3, p=0.033). By receiver-operating characteristic curve analysis, the optimal cut-off for the primary end point was a pre-PCI PRU value>or=240 (area under the curve: 0.69; 95% confidence interval: 0.56 to 0.81, p=0.016). CONCLUSIONS This study indicates that high pre-PCI platelet reactivity might predict 30-day events. Use of a rapid point-of-care assay for monitoring residual platelet reactivity after clopidogrel administration might help identify patients in whom individualized antiplatelet strategies might be indicated with coronary intervention.

Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data.

OBJECTIVES The purpose of the study was to systematically evaluate the significance of platelet reactivity on clopidogrel treatment on adverse cardiovascular events using a collaborative meta-analysis using patient-level data for the VerifyNow P2Y12 assay (Accumetrics, San Diego, California). BACKGROUND Clinical evidence has been controversial regarding the influence of clopidogrel on treatment platelet reactivity and ischemic outcomes. METHODS MEDLINE, Scopus, and the Cochrane library databases were searched through January 2010. A database containing individual patient-level time-to-event data was generated from identified studies. The primary outcome of interest was a composite of death, myocardial infarction (MI), or stent thrombosis. Secondary outcomes included the incidence of: 1) death; 2) MI; and 3) stent thrombosis. RESULTS A total of 6 studies with 3,059 patients was included. In each study, clopidogrel responsiveness was assessed using the same point-of-care assay after percutaneous coronary intervention. The primary endpoint occurred more frequently in higher quartiles of P2Y(12) reaction unit (PRU) values: quartile I, 5.8%; quartile II, 6.9%; quartile III, 10.9%; quartile IV, 15.8% (p < 0.001). Taking quartile I as referent, the hazard ratios (HRs) for the primary endpoint were as follows: quartile II, HR: 1.13 (95% confidence interval [CI]: 0.72 to 1.78; p = 0.60); quartile III, HR: 1.82 (95% CI: 1.20 to 2.75; p = 0.005); quartile IV, HR: 2.62 (95% CI: 1.78 to 3.87; p < 0.001). On a continuous scale, every 10-U increase in PRU was associated with a significantly higher rate of the primary endpoint (HR: 1.04; 95% CI: 1.03 to 1.06; p < 0.0001). According to receiver-operating characteristic curve analysis, a PRU value of 230 appeared to best predict death, MI, or stent thrombosis (p < 0.001). A PRU value ≥230 was associated with a higher rate of the composite primary endpoint (HR: 2.10; 95% CI: 1.62 to 2.73; p < 0.0001), as well as the individual endpoints of death (HR: 1.66; 95% CI: 1.04 to 2.68; p = 0.04), MI (HR: 2.04; 95% CI: 1.51 to 2.76; p < 0.001), and stent thrombosis (HR: 3.11; 95% CI: 1.50 to 6.46; p = 0.002). CONCLUSIONS In this collaborative meta-analysis, the level of on-treatment platelet reactivity according to the P2Y(12) assay is associated with long-term cardiovascular events after percutaneous coronary intervention, including death, MI, and stent thrombosis.

Efficacy of Atorvastatin Reload in Patients on Chronic Statin Therapy Undergoing Percutaneous Coronary Intervention: Results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) Randomized Trial

OBJECTIVES This study was designed to investigate whether an acute atorvastatin reload before percutaneous coronary intervention (PCI) protects patients receiving chronic statin therapy from periprocedural myocardial damage. BACKGROUND Previous ARMYDA (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) studies demonstrated that short-term pre-treatment with atorvastatin reduces myocardial infarction during PCI in statin-naïve patients with both stable angina and acute coronary syndromes. METHODS A total of 383 patients (age 66 +/- 10 years, 305 men) with stable angina (53%) or non-ST-segment elevation acute coronary syndromes (47%) and chronic statin therapy (55% atorvastatin) undergoing PCI were randomized to atorvastatin reload (80 mg 12 h before intervention, with a further 40-mg pre-procedural dose [n = 192]) or placebo (n = 191). All patients received long-term atorvastatin treatment thereafter (40 mg/day). The primary end point was 30-day incidence of major adverse cardiac events (cardiac death, myocardial infarction, or unplanned revascularization). RESULTS The primary end point occurred in 3.7% of patients treated with atorvastatin reload and in 9.4% in the placebo arm (p = 0.037); this difference was mostly driven by reduction in periprocedural myocardial infarction. There was lower incidence of post-procedural creatine kinase-myocardial band and troponin-I elevation greater than the upper limit of normal in the atorvastatin arm (13% vs. 24%, p = 0.017, and 37% vs. 49%, p = 0.021, respectively). Multivariable analysis identified atorvastatin reload as a predictor of decreased risk of 30-day incidence of major adverse cardiac events (odds ratio: 0.50, 95% confidence interval: 0.20 to 0.80; p = 0.039), mainly in patients with acute coronary syndromes (82% relative risk reduction; p = 0.027). CONCLUSIONS The ARMYDA-RECAPTURE trial suggests that reloading with high-dose atorvastatin improves the clinical outcome of patients on chronic statin therapy undergoing PCI. These findings may support a strategy of routine reload with high-dose atorvastatin early before intervention even in the background of chronic therapy.

Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery.

Objectives:Systemic inflammatory response occurs frequently after coronary artery bypass surgery, and it is strongly correlated with the risk of postoperative morbidity and mortality. Recent studies demonstrate that treatment with statin is associated with a significant and marked decrease in inflammation-associated variables such as the C-reactive protein, cytokines, and adhesion molecules. Therefore, we investigated the effects of preoperative atorvastatin treatment on systemic inflammatory response and perioperative morbidity after cardiopulmonary bypass. Design:Double-blinded, placebo-controlled, randomized study. Setting:University hospital. Patients:Forty patients were randomized to treatment with atorvastatin (20 mg/day, group A, n = 20) or placebo (group B, n = 20) 3 wks before surgery. Interventions:Three-week treatment by atorvastatin 20 mg/day. Measurement and Main Results:Postoperative serum levels of both interleukin-6 and interleukin-8 increased significantly over baseline, but the peak levels observed 4 hrs postoperatively were significantly lower in the atorvastatin group. In the same fashion, CD11b expression on neutrophils was significantly lower in the statin group at 4 and 24 hrs postoperatively. Finally, neutrophil-endothelial adhesion was significantly reduced in the statin patients compared with controls. The operation time, blood loss, need for inotropic support, intubation time, and length of intensive care unit or hospital stay did not differ significantly between the two groups. The systemic inflammatory response syndrome score on postoperative days 1 and 2 was comparable in both groups. Conclusions:Pretreatment with atorvastatin significantly reduces cytokine release and neutrophil adhesion to the venous endothelium in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.

Impaired Flow-Mediated Dilation and Risk of Restenosis in Patients Undergoing Coronary Stent Implantation

Background—Impaired endothelial function is a key event in the atherosclerosis process and predicts future cardiovascular events in subjects with and without coronary artery disease (CAD). We performed the first prospective study evaluating whether early measurement of brachial artery endothelium-dependent dilation (flow-mediated dilation [FMD]) after coronary stenting could predict occurrence of in-stent-restenosis. Methods and Results—The study population included 136 patients with single-vessel CAD undergoing percutaneous coronary intervention (PCI) with stenting and at least 6 months of follow-up. All patients underwent ultrasound detection of brachial artery reactivity 30 days after PCI; FMD was investigated before and after 5 minutes of occlusion of the brachial artery, and nitroglycerin-mediated dilation was investigated before and after administration of sublingual nitrates. Clinical in-stent restenosis was demonstrated in 20 patients (15%), whereas 116 patients (85%) remained free of signs or symptoms of recurrent ischemia. FMD was significantly impaired in patients with restenosis versus those without restenosis (percent diameter variation 4.6±5.8% versus 9.5±6.6%, P=0.002); moreover, 4% of patients with FMD ≥7% (median value) developed in-stent restenosis versus 28% of those with FMD <7% (P=0.0001). On multivariate analysis, FMD was the strongest predictor of restenosis (OR 4.5, 95% CI 2.4 to 12.0); conversely, nitroglycerin-mediated dilation did not independently predict the risk of restenosis (OR 2.4, 95% CI 0.8 to 6.3). Conclusions—This is the first prospective study indicating that impaired FMD independently predicts occurrence of in-stent restenosis in patients undergoing PCI. Early evaluation of endothelial function after stenting may represent a useful screening tool to stratify patients according to future risk of restenosis.

Short-term, high-dose Atorvastatin pretreatment to prevent contrast-induced nephropathy in patients with acute coronary syndromes undergoing percutaneous coronary intervention (from the ARMYDA-CIN [atorvastatin for reduction of myocardial damage during angioplasty--contrast-induced nephropathy] trial.

Contrast-induced nephropathy (CIN) impairs clinical outcome in patients undergoing angiographic procedures. The aim of this study was to investigate whether short-term high-dose atorvastatin load decreases the incidence of CIN after percutaneous coronary intervention (PCI). Statin-naive patients with acute coronary syndrome undergoing PCI (n = 241) randomly received atorvastatin (80 mg 12 hours before intervention with another 40-mg preprocedure dose, n = 120) or placebo (n = 121). All patients had long-term atorvastatin treatment thereafter (40 mg/day). Primary end point was incidence of CIN defined as postintervention increase in serum creatinine ≥0.5 mg/dl or >25% from baseline. Five percent of patients in the atorvastatin arm developed CIN versus 13.2% of those in the placebo arm (p = 0.046). In the atorvastatin group, postprocedure serum creatinine was significantly lower (1.06 ± 0.35 vs 1.12 ± 0.27 mg/dl in placebo, p = 0.01), creatinine clearance was decreased (80.1 ± 32.2 vs 72.0 ± 26.6 ml/min, p = 0.034), and C-reactive protein peak levels after intervention were decreased (8.4 ± 10.5 vs 13.1 ± 20.8 mg/l, p = 0.01). Multivariable analysis showed that atorvastatin pretreatment was independently associated with a decreased risk of CIN (odds ratios 0.34, 95% confidence interval 0.12 to 0.97, p = 0.043). Prevention of CIN with atorvastatin was paralleled by a shorter hospital stay (p = 0.007). In conclusion, short-term pretreatment with high-dose atorvastatin load prevents CIN and shortens hospital stay in patients with acute coronary syndrome undergoing PCI; anti-inflammatory effects may be involved in this renal protection. These results lend further support to early use of high-dose statins as adjuvant pharmacologic therapy before percutaneous coronary revascularization.

Combining Antiplatelet and Anticoagulant Therapies

Antiplatelet therapy is the cornerstone for both primary and secondary prevention therapies for ischemic events resulting from coronary atherosclerotic disease. Dual antiplatelet therapy (aspirin plus a thienopyridine, usually clopidogrel) has assumed a central role in the treatment of acute coronary syndromes and after coronary stent deployment. In addition to antiplatelet therapy, anticoagulant therapy might be indicated for stroke prevention in a variety of conditions that include atrial fibrillation, profound left ventricular dysfunction, and after mechanical prosthetic heart valve replacement. For this reason, the use of triple antithrombotic therapy (a dual antiplatelet regimen plus warfarin) is expected to become more prominent, given an aging patient population. But although triple therapy can prevent both thromboembolism and stent thrombosis, it is also associated with significant bleeding hazards. Furthermore, when bleeding events do occur, the challenge of balancing the risk of stent thrombosis or stroke and the need for hemostasis requires considerable expertise. It is both prudent and timely to review treatment strategies that employ combinations of antiplatelet and anticoagulant therapies as well as strategies aimed at reducing bleeding risk in patients treated with these therapies.