Giuseppe Colonna

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.

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.

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.

Atenolol versus amlodipine versus isosorbide-5-mononitrate on anginal symptoms in syndrome X

The effects of a beta blocker (atenolol), a calcium antagonist (amlodipine), and a nitrate (isosorbide-5-mononitrate) on anginal symptoms in 10 patients with syndrome X were assessed in a crossover, double-blind, randomized trial. Only atenolol was found to significantly improve chest pain episodes, suggesting that it should be the preferred drug when starting pharmacologic treatment of patients with syndrome X.

Outcome Comparison of 600- and 300-mg Loading Doses of Clopidogrel in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Results From the ARMYDA-6 MI (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Myocardial Infarction) Randomized Study

OBJECTIVES The purpose of this study was to compare 600- and 300-mg clopidogrel loading doses in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Given the high thrombotic risk of patients with STEMI, greater platelet inhibition may improve outcome in those patients receiving percutaneous coronary intervention (PCI). Although observational data suggest that pretreatment with a 600-mg clopidogrel loading dose may be more effective than the 300-mg regimen in primary PCI, this hypothesis has never been tested in a randomized study. METHODS A total of 201 patients undergoing primary PCI for STEMI randomly received a 600-mg (n = 103) or 300-mg (n = 98) clopidogrel loading dose before the procedure. The primary endpoint was the evaluation of the infarct size, defined as the area under the curve of cardiac markers. RESULTS Infarct size was significantly lower in the high-dose regimen: median creatine kinase-myocardial band 2,070 ng/ml (interquartile range [IQR]: 815 to 2,847 ng/ml) versus 3,049 ng/ml (IQR: 1,050 to 7,031 ng/ml) in the 300-mg group, p = 0.0001; troponin-I 255 ng/ml (IQR: 130 to 461 ng/ml) versus 380 ng/ml (IQR: 134 to 1,406 ng/ml), p < 0.0001. In the 600-mg arm, Thrombolysis In Myocardial Infarction flow grade <3 after PCI was less frequent (5.8% vs. 16.3%, p = 0.031), left ventricular ejection fraction at discharge was improved (52.1 ± 9.5% vs. 48.8 ± 11.3%, p = 0.026), 30-day major adverse cardiovascular events were fewer (5.8% vs. 15%, p = 0.049), and bleeding/entry site complications were not increased (secondary endpoints). CONCLUSIONS In STEMI patients, pre-treatment with a 600-mg clopidogrel loading dose before primary PCI was associated with a reduction of the infarct size compared with a 300-mg loading dose, as well as with improvement of angiographic results, residual cardiac function, and 30-day major adverse cardiovascular events; further studies are warranted to evaluate impact of such strategy on survival.

Transradial access compared with femoral puncture closure devices in percutaneous coronary procedures

BACKGROUND Transradial access (RA) is associated with less complications and is preferred by patients. Vascular closure devices (VCDs) may improve discomfort and may reduce complications associated with transfemoral access. Aim was to evaluate complications and discomfort associated with percutaneous coronary procedures employing RA or VCDs. METHODS We enrolled 1492 consecutive patients who underwent percutaneous coronary procedures with RA (604 procedures), femoral approach with manual compression (MC) (276 procedures), or with either Angioseal (311 procedures) or Starclose (301 procedures) closure device. Discomfort was assessed using procedure-specific questions. Major vascular complications were evaluated during hospitalization. RESULTS RA significantly reduced major complications (0.7%) compared to either the MC (2.9%, p=0.03) or the VCDs (Starclose 2.7%, Angioseal 3.9%, p=0.003). There were no significant differences in major complications between MC and either the Angioseal or the Starclose. At multivariate analysis the RA was predictor of reduced complications (OR 0.26, 95% CI 0.08-0.85, p=0.03 vs MC, and OR 0.19, 95% CI 0.07-0.57, p=0.003 vs VCDs). The RA was associated with a significant reduction in procedural discomfort with 44.2% of patients referring no discomfort (p<0.0001). Starclose and Angioseal were better tolerated than MC (27.8%, 29.3% and 8.9% patients respectively without discomfort, p<0.0001). CONCLUSIONS RA is associated with a significant reduction in major vascular complications compared to femoral approach even if two different VCDs are employed. VCDs are better tolerated than MC but the RA was associated with the lowest discomfort.

Clopidogrel reloading in patients undergoing percutaneous coronary intervention on chronic clopidogrel therapy: results of the ARMYDA-4 RELOAD (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) randomized trial.

AIMS To evaluate safety and effectiveness of clopidogrel reloading in patients on chronic clopidogrel therapy undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS Five hundred and three patients on >10 days clopidogrel therapy (41% with non-ST-segment elevation acute coronary syndrome, ACS) randomly received 600 mg clopidogrel loading 4-8 h before PCI (n = 252) or placebo (n = 251). Primary endpoint was 30-day incidence of major adverse cardiac events (MACE). In the overall population primary endpoint occurred in 6.7% of patients in the reload vs. 8.8% in the placebo arm [odds ratios (OR) 0.75, 95% confidence intervals (CI) 0.37-1.52; P = 0.50]. In stable angina patients, 1-month MACE were not significantly different (7.0 vs. 3.9%; OR 1.84, 0.60-5.88; P = 0.36), whereas ACS patients had significant clinical benefit with reloading (6.4 vs. 16.3%; OR 0.34, 95% CI 0.32-0.90, P = 0.033 at multivariable analysis; interaction test: P = 0.01). There was no excess bleeding in the reload arm (6% in both groups). CONCLUSION ARMYDA-4 RELOAD reveals no overall benefit from reloading patients on chronic clopidogrel therapy prior to PCI; the benefit observed in ACS patients is a hypothesis-generating finding that needs to be confirmed by larger studies.

Ischemic-like ST-Segment Changes During Holter Monitoring in Patients With Angina Pectoris and Normal Coronary Arteries But Negative Exercise Testing

To evaluate whether Holter electrocardiographic monitoring may improve the detection of ST-segment depression in patients with anginal chest pain and normal coronary arteries, we performed symptom-limited exercise testing and 24-hour Holter monitoring in a group of 38 such patients (27 women, age 54 +/- 8 years). Patients were divided into 2 groups:group X1 included 28 patients with and group X2 10 patients without significant ST-segment depression during exercise testing. There were no significant differences between the 2 groups in age, gender, characteristics of chest pain, exercise duration, heart rate (HR), and blood pressure at peak exercise, but anginal pain during exercise testing was reported by 10 patients of group X1 (36%) and 9 of group X2 (90%) (p <0.01). Episodes of ST-segment depression on Holter monitoring were found in 17 patients of group X1 (61%) and in 5 patients of group X2 (50%) (p = NS). There were no differences between the 2 groups in daily number of ST episodes (3.6 +/- 4 vs 2.8 +/- 5 episodes per patient), symptomatic episodes (8% vs 18%), and duration of the episodes. On average, HR increased significantly, in a similar way, from 15 minutes before ST-segment depression to 1-mm ST in both groups, and its value at the onset of ischemia was similar in the 2 groups (102 +/- 22 vs 109 +/- 18 beats/min, p = NS). Finally, HR at 1-mm ST during Holter monitoring was significantly lower than that observed at 1-mm ST during exercise testing (127 +/- 16 beats/min, p < or = 0.01) in group X1, and it was also lower than that observed at peak exercise (136 +/- 22 beats/min, p < or = 0.01) in group X2. In conclusion, Holter monitoring can significantly increase the detection of ST-segment depression in patients with anginal pain and normal coronary arteries, indicating a cardiac, although not necessarily ischemic, origin of the pain. Indeed, 50% of our patients with negative symptom-limited exercise testing showed spontaneous ST changes, compatible with transient myocardial ischemia, during daily activities. Differences in the response of coronary microvascular tone to exercise testing and to stimuli operating during daily life are likely to play a significant role in determining these findings.

Cardiac Autonomic Function and Sensitivity to Pain in Postmenopausal Women With Angina and Normal Coronary Arteries

An increased sensitivity to painful stimuli and an abnormal cardiac autonomic function have previously been reported in patients with angina and angiographically normal coronary arteries, a syndrome that mainly affects postmenopausal women. In this study we compared both general sensitivity to pain, by evaluating time to forearm ischemic pain (FIP) provoked by sphygmomanometer cuff inflation, and cardiac autonomic function, by measuring heart rate variability (HRV), and QT and QT(c) intervals on 24-hour Holter recordings, in 25 postmenopausal women with angina and normal coronary arteries and in 22 healthy postmenopausal women. Compared with controls, patients had a reproducible strikingly lower time to FIP (149 +/- 121 vs 295 +/- 158 seconds, p <0.001), whereas there were no differences between the 2 groups in HRV variables and mean 24-hour QT and QT(c) intervals. HRV indexes, and QT and QT(c) intervals also showed similar circadian patterns. Thus, our data show that postmenopausal women with angina and normal coronary arteries have an enhanced sensitivity to systemic painful stimuli, but no detectable impairment in cardiac autonomic function compared with a well-matched control group of postmenopausal healthy women.

Circadian variation of ischemic threshold in syndrome X

To evaluate whether the ischemic threshold has a circadian rhythm in patients with syndrome X, we analyzed 90 episodes of ST depression detected on 24-hour Holter recordings of 12 such patients. Ischemic threshold was considered as heart rate (HR) at 1 mm ST depression. To correct for differences in basal HR among patients, however, the ischemic threshold was also calculated as a normalized index of HR at 1 mm ST depression: [(HR at 1 mm ST-24-hour modal HR)/24-hour modal HR]-100. Mean hourly values of both absolute and normalized HRs at 1 mm ST depression were obtained by grouping and averaging respective values of all episodes detected in every hour of the day in all patients. Chronobiologic analysis was performed by single cosinor method. A significant circadian rhythm was found for HR (mesor 76 beats/min, amplitude 10 beats/min, acrophase at 2:16 P.M., p < 0.001), number of episodes of ST depression (mesor 3.75, amplitude 2.9, acrophase at 2:45 P.M., p < 0.001) and cumulative time of ischemia, with a high correlation of distributions. Episodes of ST depression showed a double peak initially in the morning, and again in the afternoon. Both raw and normalized values of HR at 1 mm ST depression also had a significant circadian variation in ischemic threshold, which was lower in the night and early morning hours, progressively increased until the first afternoon hours, and subsequently decreased in the evening.(ABSTRACT TRUNCATED AT 250 WORDS)