Pierfrancesco Agostoni

Radial Versus Femoral Randomized Investigation in ST-Segment Elevation Acute Coronary Syndrome The RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) Study

OBJECTIVES The purpose of this study was to assess whether transradial access for ST-segment elevation acute coronary syndrome undergoing early invasive treatment is associated with better outcome compared with conventional transfemoral access. BACKGROUND In patients with acute coronary syndrome, bleeding is a significant predictor of worse outcome. Access site complications represent a significant source of bleeding for those patients undergoing revascularization, especially when femoral access is used. METHODS The RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) was a multicenter, randomized, parallel-group study. Between January 2009 and July 2011, 1,001 acute ST-segment elevation acute coronary syndrome patients undergoing primary/rescue percutaneous coronary intervention were randomized to the radial (500) or femoral (501) approach at 4 high-volume centers. The primary endpoint was the 30-day rate of net adverse clinical events (NACEs), defined as a composite of cardiac death, stroke, myocardial infarction, target lesion revascularization, and bleeding). Individual components of NACEs and length of hospital stay were secondary endpoints. RESULTS The primary endpoint of 30-day NACEs occurred in 68 patients (13.6%) in the radial arm and 105 patients (21.0%) in the femoral arm (p = 0.003). In particular, compared with femoral, radial access was associated with significantly lower rates of cardiac mortality (5.2% vs. 9.2%, p = 0.020), bleeding (7.8% vs. 12.2%, p = 0.026), and shorter hospital stay (5 days first to third quartile range, 4 to 7 days] vs. 6 [range, 5 to 8 days]; p = 0.03). CONCLUSIONS Radial access in patients with ST-segment elevation acute coronary syndrome is associated with significant clinical benefits, in terms of both lower morbidity and cardiac mortality. Thus, it should become the recommended approach in these patients, provided adequate operator and center expertise is present. (Radial Versus Femoral Investigation in ST Elevation Acute Coronary Syndrome [RIFLE-STEACS]; NCT01420614).

Prognostic Value of Fractional Flow Reserve: Linking Physiologic Severity to Clinical Outcomes

BACKGROUND Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear. OBJECTIVES The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization. METHODS Meta-analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold. RESULTS A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief. CONCLUSIONS FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy.

A collaborative systematic review and meta-analysis on 1278 patients undergoing percutaneous drug-eluting stenting for unprotected left main coronary artery disease ☆

BACKGROUND Cardiac surgery is the standard treatment for unprotected left main disease (ULM). Drug-eluting stent (DES) implantation has been recently reported in patients with ULM but with unclear results. We systematically reviewed outcomes of percutaneous DES implantation in ULM. METHODS Several databases were searched for clinical studies reporting on > or = 20 patients and > or = 6-month follow-up. The primary end point was major adverse cardiovascular events (MACEs; ie, death, myocardial infarction, or target vessel revascularization [TVR]) at the longest follow-up. Incidence and adjusted risk estimates were pooled with generic inverse variance random-effect methods (95% CIs). RESULTS From 823 initial citations, 16 studies were included (1278 patients, median follow-up 10 months). Eight were uncontrolled registries, 5 nonrandomized comparisons between DES and bare-metal stents and 3 nonrandomized comparisons between DES and CABG, with no properly randomized trial. Meta-analysis for DES-based PCI showed, at the longest follow-up, rates of 16.5% (11.7%-21.3%) MACE, 5.5% (3.4%-7.7%) death, and 6.5% (3.7%-9.2%) TVR. Comparison of DES versus bare-metal stent disclosed adjusted odds ratios for MACE of 0.34 (0.16-0.71), and DES versus CABG showed adjusted odds ratios for MACE plus stroke of 0.46 (0.24-0.90). Meta-regression showed that disease location predicted MACE (P = .001) and TVR (P = .020), whereas high-risk features predicted death (P = .027). CONCLUSIONS Clinical studies report apparently favorable early and midterm results in selected patients with ULM. However, given their limitations in validity and the inherent risk for DES thrombosis, results from randomized trials are still needed to definitely establish the role of DES implantation instead of the reference treatment, surgery.

Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease

AIMS Stem cell therapy is a treatment strategy for ischaemic heart disease patients. Meta-analysis of randomized human trials showed <5% improvement in left ventricular ejection fraction (LVEF). Meta-analysis of available pre-clinical data of ischaemic heart disease could provide important clues to design human clinical trials. METHODS AND RESULTS Random-effects meta-analysis was performed on pig, dog, or sheep studies investigating the effect of cardiac stem cell therapy in ischaemic cardiomyopathy (52 studies; n = 888 animals). Endpoints were LVEF and death. Ischaemia/reperfusion infarction was performed in 23 studies and chronic occlusion in 29 studies. Pooled analysis showed a LVEF difference of 7.5% at follow-up after cell therapy vs. control (95% confidence interval, 6.2-8.9%; P < 0.001). By exploratory multivariable meta-regression, significant predictors of LVEF improvement were: cell type [bone marrow mononuclear cells (BM-MNC) showed less effect than other cell types, e.g. mesenchymal stem cells; P = 0.040] and type of infarction (left anterior descending artery 8.0 vs. left circumflex artery 5.8%; P = 0.045). Cell therapy was not associated with increased mortality (P = 0.68). Sensitivity analysis showed trends towards more improvement with higher cell number (≥10(7)), chronic occlusion models, and late injections (>1 week). After follow-up of 8 weeks, the effect of cell therapy decreased to 6%. CONCLUSION This meta-analysis showed that large animal models are valid to predict the outcome of clinical trials. Our results showed that cell therapy is safe and leads to a preserved LVEF. Future trials should focus on cell types other than BM-MNC, large infarction, and strategies to obtain sustained effects.

Adjusted indirect comparison meta-analysis of prasugrel versus ticagrelor for patients with acute coronary syndromes

BACKGROUND Clopidogrel is beneficial after ACS. Recent data suggest the superiority of prasugrel or ticagrelor compared with clopidogrel. However, there is no comparison of prasugrel vs. ticagrelor. We performed an adjusted indirect meta-analysis comparing prasugrel vs. ticagrelor for acute coronary syndromes (ACSs). METHODS Randomized trials were searched in PubMed. The primary end-point was the composite of death, myocardial infarction (MI) or stroke. Odds ratios (OR) were computed (95% confidence intervals). RESULTS Three trial (32,893) patients were included. Overall, either prasugrel or ticagrelor appeared significantly superior to clopidogrel for the 12-month risk of death, MI or stroke (OR=0.83 [0.77-0.89], p<0.001), death (OR=0.83 [0.74-0.93], p=0.001), MI (OR=0.79 [0.73-0.86], p<0.001), and stent thrombosis (OR=0.61 [0.51-0.74], p<0.001), without any significant difference in stroke or major bleeding (both p>0.05), despite more frequent drug discontinuation (OR=1.12 [1.05-1.19], p<0.001). Head-to-head comparison of prasugrel vs. ticagrelor showed no significant differences in overall death, MI, stroke, or their composite (all p>0.05). Prasugrel was associated with a significantly lower risk of stent thrombosis (OR=0.64 [0.43-0.93], p=0.020). Ticagrelor was associated with a significantly lower risk of any major bleeding (OR=1.43 [1.10-1.85], p=0.007), and major bleeding associated with bypass grafting (OR=4.30 [1.73-10.6], p=0.002). However, the more clinically relevant risk of major bleeding not related to bypass surgery was similar with either prasugrel or ticagrelor (OR=1.06 [0.77-1.45], p=0.34). CONCLUSIONS Prasugrel and ticagrelor are superior to clopidogrel for ACS. Head-to-head comparison suggests similar efficacy and safety of prasugrel and ticagrelor, but prasugrel appears more protective from stent thrombosis, while causing more bleedings.

Are propensity scores really superior to standard multivariable analysis

Clinicians often face difficult decisions despite the lack of evidence from randomized trials. Thus, clinical evidence is often shaped by non-randomized studies exploiting multivariable approaches to limit the extent of confounding. Since their introduction, propensity scores have been used more and more frequently to estimate relevant clinical effects adjusting for established confounders, especially in small datasets. However, debate persists on their real usefulness in comparison to standard multivariable approaches such as logistic regression and Cox proportional hazard analysis. This holds even truer in light of key quantitative developments such as bootstrap and Bayesian methods. This qualitative review aims to provide a concise and practical guide to choose between propensity scores and standard multivariable analysis, emphasizing strengths and weaknesses of both approaches.

Treatment of bifurcation lesions with two stents: one year angiographic and clinical follow up of crush versus T stenting

Objectives: To compare long term outcomes of the crush versus the T technique in bifurcation lesions. Design: 182 consecutive patients were identified who underwent percutaneous coronary interventions for bifurcation lesions with drug eluting stents between April 2002 and January 2004. Two techniques were used according to the operator’s discretion: crush (group C, n  =  121) or T (group T, n  =  61). Results: In-hospital outcome differed significantly between the two groups. Angiographic follow up was available for 142 (78%) patients. Groups C and T did not differ significantly regarding late loss (0.42 (0.39) mm v 0.34 (0.35) mm, p  =  0.52) and rate of restenosis (16.2% v 13.0%, p  =  0.80) in both the main and the side branch without final kissing balloon post-dilatation. However, when final kissing balloon post-dilatation was performed, group C had significantly lower late lumen loss (0.23 (0.21) mm v 0.37 (0.33) mm, p  =  0.02) and restenosis rate (8.6% v 26.5%, p  =  0.04) in the side branch. At one year’s clinical follow up, group C compared with group T had lower rates of target lesion revascularisation (14.0% v 31.1%, p  =  0.01) and target vessel revascularisation (16.5% v 32.8%, p  =  0.02). Conclusions: In non-selected bifurcation lesions treated with drug eluting stents, the restenosis rate remains relatively high in the side branch. Compared with the T stenting technique, crush stenting with kissing balloon post-dilatation is associated with a reduced rate of restenosis in the side branch.

Afterload reduction: a comparison of captopril and nifedipine in dilated cardiomyopathy.

Nifedipine and captopril are potent vasodilators and may be expected to help left ventricular failure by reducing afterload. Nifedipine (20 mg three times a day) and captopril (50 mg three times a day) were added to an optimal regimen of digitalis and diuretics in a double blind crossover trial in 18 cases of dilated cardiomyopathy. New York Heart Association functional class rating symptoms and exercise tolerance times improved on captopril but not on nifedipine. The reduction in pulmonary capillary wedge pressure and the increase of cardiac output on captopril indicated that the augmented functional capacity may have resulted in part from an improved performance of the left ventricle. Although there were comparable decreases in systemic vascular resistance and presumably in impedence to ejection by the left ventricle on both drugs, the dimensions of the ventricular cavity were found to be reduced by captopril and augmented by nifedipine, and only captopril reduced the afterload (wall stress). In addition, the force-length relation (between left ventricular end systolic stress and end systolic diameter) was shifted to the left of baseline by captopril and to the right by nifedipine, suggesting that muscle contractility was reduced by nifedipine and not by captopril. These results suggest that nifedipine and captopril have different effects on afterload and contractility and these may account for the different effects of these drugs on the performance of the heart and clinical responses.

Infragenicular stent implantation for below-the-knee atherosclerotic disease: clinical evidence from an international collaborative meta-analysis on 640 patients.

Purpose: To report a systematic review of the literature published on the outcomes of stenting for below-the-knee disease in patients with critical limb ischemia (CLI). Methods: Potentially relevant studies of stent implantation in the infragenicular arteries in ≥5 patients with ≥1-month follow-up were systematically sought in BioMedCentral, ClinicalTrials.gov, The Cochrane Collaboration Register of Controlled Trials (CENTRAL), Google Scholar, and PubMed. Data were abstracted and pooled with a random-effect model to generate risk estimates with 95% confidence intervals (CI). Interaction tests were performed to compare different stent types. A risk of bias assessment was conducted separately, as were appraisals for small study bias, statistical heterogeneity, and inconsistency. Results: Eighteen nonrandomized studies were retrieved comprising 640 patients. After a median follow-up of 12 months, binary in-stent restenosis occurred in 25.7% (95% CI 11.6% to 40.0%), primary patency in 78.9% (95% CI 71.8% to 86.0%), improvement in Rutherford class in 91.3% (95% CI 85.5% to 97.1%), target vessel revascularization in 10.1% (95% CI 6.2% to 13.9%), and limb salvage in 96.4% (95% CI 94.7% to 98.1%). Head-to-head comparisons showed that sirolimus-eluting stents were superior to balloon-expandable bare metal stents in preventing restenosis and increasing primary patency (both p<0.001); sirolimus-eluting stents were also better than paclitaxel-eluting stents in terms of primary patency (p<0.001) and repeat revascularizations (p=0.014). Conclusion: Percutaneous infragenicular stent implantation after failed or unsuccessful balloon angioplasty is associated with favorable clinical results in patients with CLI. Notwithstanding limitations of primary studies, sirolimus-eluting stents appear superior to bare metal and paclitaxel-eluting stents in terms of angiographic and/or clinical outcomes.

Systematic review and meta-analysis of randomized clinical trials appraising the impact of cilostazol after percutaneous coronary intervention

BACKGROUND Drug-eluting stents reduce the risk of restenosis after percutaneous coronary intervention (PCI) but may pose a risk of thrombosis. Cilostazol, an oral antiplatelet agent with pleiotropic effects including inhibition of neointimal hyperplasia, could hold the promise of preventing both restenosis and thrombosis. We systematically reviewed randomized clinical trials (RCTs) on the angiographic and clinical impact of cilostazol after PCI. METHODS We searched RCT in BioMedCentral, CENTRAL, clinicaltrials.gov, EMBASE, and PubMed (November 2007). Coprimary end points were binary angiographic restenosis and repeat revascularization, abstracted and pooled by means of random-effect relative risks (RRs). Small study/publication bias was appraised with multiple methods. RESULTS A total of 23 RCTs were included (5428 patients), with median follow-up of 6 months. Pooled analysis showed that cilostazol was associated with statistically significant reductions in binary angiographic restenosis (RR = 0.60 [0.49-0.73], P < .001) and repeat revascularization (RR = 0.69 [0.55-0.86], P = .001). Cilostazol appeared also safe, with no significant increase in the risk of stent thrombosis (RR = 1.35 [0.71-2.57], P = .36) or bleeding (RR = 0.71 [0.43-1.16], P = .17). However, small study bias was evident for both binary restenosis (P < .001) and repeat revascularization (P < .001), suggesting that at least part of the apparent benefits of cilostazol could be due to this type of confounding effect. CONCLUSIONS Cilostazol appears effective and safe in reducing the risk of restenosis and repeat revascularization after PCI, but available evidence is limited by small study effects. Awaiting larger RCTs, this inexpensive treatment can be envisaged in selected patients in which drug-eluting stents are contraindicated or when there is a need for neointimal hyperplasia inhibition.