Anna S. Ghini

Immunosuppressive therapy for the prevention of restenosis after coronary artery stent implantation (IMPRESS study)

OBJECTIVES This study tested the effect of oral prednisone on clinical and angiographic restenosis rate after successful stent implantation in patients with persistent elevation of systemic markers of inflammation after the procedure. BACKGROUND Experimental studies have shown that corticosteroids have the potential to reduce the inflammatory response associated with stent implantation. METHODS Eighty-three patients undergoing successful stenting with C-reactive protein (CRP) levels >0.5 mg/dl 72 h after the procedure were randomized to receive oral prednisone or placebo for 45 days. The primary clinical end point was 12-month event-free survival rate (defined as freedom from death, from myocardial infarction, and from recurrence of symptoms requiring additional revascularization). The angiographic end points were restenosis rate and late loss at six months. RESULTS Twelve-month event-free survival rates were 93% and 65% in patients treated with prednisone and placebo, respectively (relative risk [RR] 0.18, 95% confidence intervals [CI], 0.05 to 0.61, p = 0.0063). Six-month restenosis rate and late loss were lower in prednisone-treated than in placebo-treated patients (7% vs. 33%, p = 0.001, and 0.39 +/- 0.6 mm vs. 0.85 +/- 0.6 mm, p = 0.001, respectively). CONCLUSIONS In patients with persistently high CRP levels after successful coronary artery stent implantation, oral immunosuppressive therapy with prednisone results in a striking reduction of clinical events and angiographic restenosis rate.

Effects of Naloxone on Myocardial Ischemic Preconditioning in Humans

OBJECTIVES We attempted to establish whether naloxone, an opioid receptor antagonist, abolishes the adaptation to ischemia observed in humans during coronary angioplasty after repeated balloon inflations. BACKGROUND Experimental studies indicate that myocardial opioid receptors are involved in ischemic preconditioning. METHODS Twenty patients undergoing angioplasty for an isolated stenosis of a major epicardial coronary artery were randomized to receive intravenous infusion of naloxone or placebo during the procedure. Intracoronary electrocardiogram and cardiac pain (using a 100-mm visual analog scale) were determined at the end of the first two balloon inflations. Average peak velocity in the contralateral coronary artery during balloon occlusion, an index of collateral recruitment, was also assessed by using a Doppler guide wire in the six patients of each group with a stenosis on the left anterior descending coronary artery. RESULTS In naloxone-treated patients, ST-segment changes and cardiac pain severity during the second inflation were similar to those observed during the first inflation (12+/-6 vs. 11+/-7 mm, p = 0.3, and 58+/-13 vs. 56+/-12 mm, p = 0.3, respectively), whereas in placebo-treated patients, they were significantly less (6+/-3 vs. 13+/-6 mm, p = 0.002 and 31+/-21 vs. 55+/-22 mm, p = 0.008, respectively). In both naloxone- and placebo-treated patients, average peak velocity significantly increased from baseline to the end of the first inflation (p = 0.04 and p = 0.02, respectively), but it did not show any further increase during the second inflation. CONCLUSIONS The adaptation to ischemia observed in humans after two sequential coronary balloon inflations is abolished by naloxone and is independent of collateral recruitment. Thus, it is due to ischemic preconditioning and is, at least partially, mediated by opioid receptors, suggesting their presence in the human heart.

Coronary artery stent placement in patients with variant angina refractory to medical treatment

We performed a prospective study to establish the efficacy of coronary stent placement in a highly selected group of patients with focal coronary artery spasm in whom anginal attacks could not be prevented by full medical therapy. The results of this study indicate that intracoronary stent placement may represent an alternative and feasible treatment for patients with vasospastic angina refractory to aggressive medical therapy.

Phentolamine Prevents Adaptation to Ischemia During Coronary Angioplasty Role of α-Adrenergic Receptors in Ischemic Preconditioning

BACKGROUND Experimental studies indicate that alpha-adrenergic receptors are involved in ischemic preconditioning. Their role in humans is unknown. METHODS AND RESULTS Eighteen patients undergoing angioplasty for an isolated stenosis of the left anterior descending coronary artery were randomized to receive intravenous infusion of phentolamine or placebo during the procedure. Intracoronary ECG and cardiac pain were determined at the end of the first two balloon inflations. Average peak velocity in the contralateral coronary artery during balloon occlusion, an index of collateral recruitment, was also assessed by using a Doppler guide wire. In both phentolamine- and placebo-treated patients, average peak velocity significantly increased from baseline to the end of the first inflation (P<.01), but it did not show any further increase during the second inflation. In phentolamine-treated patients, ST-segment changes and cardiac pain severity during the second inflation were similar to those observed during the first inflation (13+/-9 versus 12+/-8 mm, P=NS, and 51+/-34 versus 54+/-32 mm, P=NS, respectively), whereas in placebo-treated patients, they were significantly less (6+/-4 versus 13+/-7 mm, P<.01, and 26+/-20 versus 49+/-22 mm, P<.05, respectively). CONCLUSIONS The adaptation to ischemia observed in humans after two sequential coronary balloon inflations is abolished by phentolamine and is independent of collateral recruitment. Thus, it occurs due to ischemic preconditioning and is, at least in part, mediated by alpha-adrenergic receptors.

Head-to-Head Comparison of Sirolimus-and Paclitaxel-Eluting Stent in the Same Diabetic Patient With Multiple Coronary Artery Lesions : A prospective, randomized, multicenter study

OBJECTIVE—It is still controversial whether sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES) are equally effective in patients with diabetes. In these patients, multiple individual variables may be responsible for neointimal hyperplasia, thus making difficult the comparison of the two drug-eluting stents (DES). RESEARCH DESIGN AND METHODS—We designed a prospective, randomized study to compare the efficacy in prevention of restenosis of SES and PES, both implanted in the same diabetic patient with multiple de novo coronary artery lesions undergoing elective percutaneous coronary intervention. We enrolled 60 patients with diabetes with at least two significant de novo angiographic stenoses in different coronary segments. The primary end point was in-stent late luminal loss (LLL) at 8-month angiographic follow-up. RESULTS—A total of 120 lesions were successfully treated with the randomly assigned DES (SES, n = 60; PES, n = 60). In-stent LLL was lower in the SES than in the PES group (0.26 ± 0.4 vs. 0.50 ± 0.6 mm; P = 0.01). Coronary lesions treated with SES presented a reduced in-stent LLL in 40 (68%) patients, while PES resulted in a lower in-stent LLL in 19 (32%) patients (P = 0.0002). At multivariable analysis, the type of DES implanted was the only independent predictor of in-stent LLL (odds ratio 2.3 [95% CI 1.1–5.0]; P = 0.03). CONCLUSIONS—SES directly compared with PES in the same diabetic patient is associated with a decrease in the extent of in-stent LLL at 8 months, suggesting a reduced risk of restenosis.

Exercise-induced myocardial ischemia triggers the early phase of preconditioning but not the late phase

The aim of the present study was to establish whether exercise-induced ischemia triggers the second window of protection in 15 patients with coronary artery disease undergoing 2 consecutive treadmill exercise tests and a third test 24 hours later. Our findings confirm that a first exercise-induced ischemic challenge induces the early phase of preconditioning but not the late phase, thus suggesting that either a late protective effect of preconditioning does not exist in the setting of demand ischemia or, if it exists, it must be weaker than the early protective effect.

Randomized Comparison of XiEnce-V and Multi-link VisioN Coronary Stents in the sAme muLtivessel Patient with Chronic kiDnEy diSease (RENAL-DES) Study

Background— Percutaneous coronary interventions in patients with chronic kidney disease have shown suboptimal results. Drug-eluting stents (DES) might reduce the rate of target vessel revascularization in comparison with bare-metal stents (BMS) in patients with chronic kidney disease. However, given the multiple concomitant individual variables present in such patients, the comparison of neointimal growth after percutaneous coronary intervention is complex and difficult to assess. Methods and Results— Randomized Comparison of Xience V and Multi-Link Vision Coronary Stents in the Same Multivessel Patient with Chronic Kidney Disease (RENAL-DES) was a prospective, randomized, multicenter study to directly compare the efficacy in the prevention of clinical restenosis of everolimus-eluting stent (Xience V) and BMS with an identical design (Multi-Link Vision), both implanted in the same patient with multivessel coronary artery disease and chronic kidney disease (estimated glomerular filtration rate <60 mL/min). The primary end point of the study was the ischemia-driven target vessel revascularization as detected with myocardial scintigraphy at 12 months. In 215 patients, 512 coronary vessels were successfully treated with the randomly assigned DES (n=257) or BMS (n=255). At 1 year, the rate of ischemia-driven target vessel revascularization for DES and BMS groups was 2.7% (95% confidence interval, 1.1%–5.6%) and 11.4% (95% confidence interval, 7.8% to 16%), respectively, P<0.001. For the multivariate analysis, independent predictors of the ischemia-driven target vessel revascularization were BMS implantation (odds ratio, 4.95; 95% confidence interval, 2.1–11.6; P<0.001) and vessel size (odds ratio, 0.32; 95% confidence interval, 0.1–0.7; P=0.006). Conclusions— This is the first randomized trial showing a reduction of clinical restenosis with a new-generation DES in comparison with a BMS of equal design, in patients who have chronic kidney disease with multivessel coronary artery disease. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT00818792.

Immunosuppressive therapy with oral prednisone to prevent restenosis after PCI. A multicenter randomized trial

BACKGROUND Prednisone at immunosuppressive doses after stenting has shown remarkable efficacy in reducing ischemic recurrences in nondiabetic patients with high post-procedural levels of C-reactive protein; the study aim was to compare the clinical outcome obtained in a control group of patients treated with bare metal stents versus 2 other study groups--bare metal stent plus oral prednisone or drug eluting stents--assuming similar optimal adjunctive medical treatment. METHODS Five tertiary Italian hospitals enrolled 375 nondiabetic patients with coronary artery disease and no contraindications to dual antiplatelet treatment or corticosteroid therapy in a randomized, controlled study performed between 2007 and 2009. Patients were allocated into 3 study groups: bare metal stents (controls), bare metal stents followed by a 40-day prednisone treatment, or drug-eluting stents. The primary endpoint was the event-free survival of cardiovascular death, myocardial infarction, and recurrence of ischemia needing repeated target vessel revascularization at 1 year as adjudicated by an independent clinical events committee. RESULTS One-year follow-up was obtained in all patients. Patients receiving bare metal stents alone as compared to those treated with prednisone or drug-eluting stents had lower event-free survival; the primary endpoint was 80.8% in controls compared to 88.0% in the prednisone and 88.8% in the drug-eluting stent groups, respectively (P=.04 and .006). CONCLUSION Compared with bare metal stents alone, prednisone treatment after bare metal stents or drug-eluting stent implantation result in a better event-free survival at 1 year.

Twenty year follow-up after successful percutaneous balloon mitral valvuloplasty in a large contemporary series of patients with mitral stenosis

BACKGROUND Percutaneous balloon mitral valvuloplasty (PMV) is currently considered the standard of care for suitable patients with rheumatic mitral stenosis. We sought to assess very long-term outcome after PMV. METHODS Between 1991 and 2010, 482 consecutive patients underwent successful PMV in a single center. Procedural success was defined as post-procedural valve area ≥ 1.5 cm(2) and regurgitation moderate or less, without in-hospital major adverse cardiac and cerebro-vascular events. The primary endpoint was 20-year incidence of major adverse cardiac events (MACE), including cardiovascular death and need for mitral surgery or repeat PMV. RESULTS Long-term follow-up (mean 11.6 ± 4.9 years; range 0.5 to 20) was completed in 441 (91.5%) patients. The incidence of the primary endpoint was 41.9% (95% confidence interval [CI]: 37.3 to 46.7%). The rate of cardiovascular death, need for mitral surgery or repeat PMV was 9.1% (95% CI: 6.6 to 12.1), 27% (95% CI: 22.9 to 31.4), and 5.9% (95% CI: 3.9 to 8.5), respectively. Cumulative MACE-free survival at 20 years was 35.9 ± 4.7%. At multivariate analysis, male gender (hazard ratio [HR]: 1.99; 95% CI: 1.4-2.8, p < 0.001), echocardiographic score > 8 (HR: 2.19; 95% CI: 1.6-2.9, p < 0.001), atrial fibrillation (HR: 1.54; 95% CI: 1.2-2.1, p = 0.003) and valve area ≤ 1.75 cm(2) after PMV (HR: 3.1; 95% CI: 2.3-4.2, p < 0.001) were identified as independent predictors of the primary endpoint. CONCLUSIONS Up to 20 years after successful PMV, a sizeable proportion of patients still exhibit a good clinical result.

Long-term clinical follow-up of the multicentre, randomized study to test immunosuppressive therapy with oral prednisone for the prevention of restenosis after percutaneous coronary interventions: Cortisone plus BMS or DES veRsus BMS alone to EliminAte Restenosis (CEREA-DES)

AIMS To analyse the clinical outcome at 4 years in patients with coronary artery disease treated with bare metal stents (BMS) vs. BMS and oral prednisone, or drug-eluting stents (DES), all assuming similar adjunctive medical treatment. METHODS AND RESULTS Five Italian hospitals enrolled 375 non-diabetic, ischaemic patients without contraindications to dual anti-platelet treatment or corticosteroid therapy in a randomized controlled study. The primary endpoint was the event-free survival of cardiovascular death, myocardial infarction, and recurrence of ischaemia needing repeated target vessel revascularization at 1 year, and this was significantly lower in the BMS group (80.8%) compared with the prednisone (88.0%) and DES group (88.8%, P = 0.04 and 0.006, respectively). The long-term analysis of the primary endpoint was a pre-specified aim of the trial, and was performed at 1447 days (median, IQ range = 1210-1641). Patients receiving BMS alone had significantly lower event-free survival (75.3%) compared with 84.1% in the prednisone group (HR: 0.447; 95% CI: 0.25-0.80, P = 0.007) and 80.6% in DES patients (HR: 0.519; 95% CI: 0.29-0.93, P = 0.03). Prednisone-treated patients did not develop new treatment-related clinical problems. Drug-eluting stents patients suffered more very late stent thrombosis as a cause of spontaneous myocardial infarction. The need for target vessel revascularization remained lower in the prednisone and DES groups (13.6 and 15.2%, respectively), compared with BMS (23.2%). CONCLUSIONS The clinical benefits of prednisone compared with BMS only persisted almost unchanged at 4 years. Drug-eluting stents performed better than BMS at long-term, although the advantages observed at 1 year were in part attenuated because of the occurrence of very late stent thrombosis and late revascularizations. Clinical Trial NCT 00369356.