Association of beta blockers with survival on patients presenting with ACS treated with PCI: a propensity score analysis from the Bleemacs registry.
Authors: Fabrizio D´Ascenzo1, Dario Celentani1, Alessandro Brustio1 Sergio Raposeiras-Roubín2, Emad Abu-Assi2,Jose Paulo Simao Henriques3, Jorge Saucedo4, José Ramón González-Juanatey5,Stephen B. Wilton6,Wouter J. Kikkert3, Iván Nuñez-Gil7, Albert Ariza-Sole8, Xiantao Song9, Dimitrios Alexopoulos10, Christoph Liebetrau11,Tetsuma Kawaji12, Zenon Huczek13,Shao-Ping Nie14, Toshiharu Fujii15, Luis Correia16, Masa-aki Kawashiri17, José María García-Acuña2, Danielle Southern6, Emilio Alfonso7, Belén Terol7, Alberto Garay8, Dongfeng Zhang9, Yalei Chen9,Ioanna Xanthopoulou10, Neriman Osman11,Helge Möllmann11, Hiroki Shiomi12, , Michal Kowara13, Krzysztof Filipiak13, Xiao Wang14, Yan Yan14, Jing-Yao Fan14,Yuji Ikari15, Takuya Nakahayshi17, Kenji Sakata17, Masakazu Yamagishi17, Oliver Kalpak18, Sasko Kedev18, Claudio Moretti1, Maurizio D’Amico1, Fiorenzo Gaita1
Affiliation: 1) Dipartimento di Scienze Mediche, Divisione di Cardiologia, Città della Salute e della Scienza, Turin. 2) University Hospital Álvaro Cunqueiro, Vigo, Spain. 3) University Academic Medical Center, Amsterdam. 4) NorthShore University Hospital, Chicago. 5) University Clinical Hospital of Santiago de Compostela, Spain. 6) Libin Cardiovascular Institute of Alberta, Calgary. 7) San Carlos Hospital, Madrid. 8) Bellvitge Hospital, Barcelona. 9) Beijing Anzhen Hospital, Capital Medical University, Beijing. 10) University Patras Hospital, Athens. 11) Kerckhoff Heart and Thorax Center, Frankfurt. 12) University Clinical Hospital, Kyoto; 13) University Clinical Hospital, Warsaw. 14) Institute of Heart, Lung and Blood Vessel Disease, Beijing. 15) Tokai University School of Medicine, Tokyo. 16) Hospital Sao Rafael, Salvador. 17) Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa. 18) University Clinic of Cardiology,
Skopje.
Running title: BBS in ACS patients treated with PCI
Word count: 2432
Corresponding author: Fabrizio D’Ascenzo, MD
Department of Medical Sciences, Division of Cardiology University of Turin
Città della Salute e della Scienza, Turin, Italy Email: [email protected]
ABSTRACT
Purpose: to evaluate prognostic value of Beta blocker (BB) administration in ACS patients in the Percutaneous Coronary Intervention (PCI) era.
Methods and Results: The BleeMACS project is a multicenter observational retrospective registry enrolling patients with ACS worldwide in 15 hospitals. Patients discharged with BB therapy were compared to those discharged without before and after propensity score with matching. Primary endpoint was all cause mortality at one year. Secondary endpoints included in-hospital reinfarction, in-hospital heart failure, 1-year myocardial infarction, 1-year bleeding and 1-year composite of death and recurrent myocardial infarction. After matching, 2935 patients for each group were enrolled: Primary endpoint of 1-year death was significantly lower in the group on BBs therapy (4.5% Vs 7%, p <0.05), while only a trend was noted for re-AMI (4.5% vs. 4.9%, p 0.54). These results were consistent for patients older than 80 years old, for STEMI patients, for those discharged with complete vs. incomplete revascularization but not for NSTEMI/UA ones.
Conclusions: BBS therapy was related to one year lower risk of all cause mortality, independently from completeness of revascularization, admission diagnosis, age and EF . Randomized controlled trials for patients treated with PCI for ACS should be performed.
INTRODUCTION
Despite therapeutic advances, Acute Coronary Syndromes (ACS) remain a leading cause of death in Western Countries with a detrimental impact on long term survival, mainly related to extent of coronary artery disease, features of coronary plaque and ejection fraction (1-3). Beta blockers (BBs) represent a cornerstone of pharmacological therapy, offering a reduction in long-term mortality and recurrent acute myocardial infarction (AMI) (4), and are a class I recommendation in American and European guidelines, despite optimal duration of beta blocker therapy is not known.
The evidence supporting their clinical benefit is largely derived from studies in AMI patients in the pre-Percutaneous Coronary Intervention (PCI) era, without drug eluting stents and without anti-thrombotic therapy (4-6).
In the reperfusion era, only reductions in AMI and angina have been observed, while some trials questioned the benefit of Beta-Blockers (BBs) in the acute phase of AMI due to an increase in shock rates (7, 8). and recent analyses found that early BBs administration was of no benefit (9). Actually in the meta-analysis of Al-Reesi et al (9), 6 week mortality was not reduced by use of BB (OR 0.95:0.90-1.01). Furthermore, an observational analysis of the REACH registry in more than 10000 patients found that BB use was not associated with lower incidence of cardiovascular events among patients with a prior history of MI, with an incidence of cardiovascular death, MI and stroke of 16.9% vs. 18.6% after 44 months (p 0.14 ; 9). Finally adherence of BBs is known to be reduced for these patients, with less than 50% of them being compliant after one year (10).
Consequently we conducted a propensity-score matched analysis on the BleeMACS registry (11) to determine the impact of BBs therapy in the spectrum of ACS treated with PCI.
METHODS.
The present is a sub-analysis of the BleeMACS (Bleeding complications in a Multicenter registry of patients discharged with diagnosis of Acute Coronary Syndrome) study. BleeMACS is an international multicenter investigator-initiated retrospective registry, without financial support, including 15,401 consecutive patients from 15 tertiary hospitals in Europe, Asia, North and South America (Germany, Netherlands, Poland, Spain, Italy, Greece, Japan, China, Canada and Brazil). More details may be consulted in previous papers as definitions of included variables (11).
Patients’ selection
All consecutive patients discharged alive after admission for ACS, including ST elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI) and unstable angina (UA) -diagnosis according to ESC guidelines (2), and treated with PCI during the index admission between 2003 and 2014 were eligible for inclusion. To be as possible as consistent with everyday clinical practice, no pre-specified exclusion criteria have been described.
Patients were divided into two cohorts based upon therapy at discharge: - Patients with BB therapy
- Patients without BB therapy
No data about intravenous BB therapy was recorded. Features of the patients.
Baseline clinical features including age, burden of cardiovascular risk factors, presence of malignancy, history of previous bleeding, creatinine (md/dl) and haemoglobin (g/dl) were recorded.
Femoral or radial access for PCI, number and kind of stent (Bare Metal Stents vs. Drug Eluting Stents vs. plain Balloon Only Angioplasty) and thrombolysis were the procedural features described along with complete revascularization (defined as PCI
performed in all coronary vessels with more than 70% of stenosis) and Ejection Fraction (EF) at discharge.
Medications at discharge, including aspirin, choice of second anti-platelet drug (aspirin, clopidogrel, prasugrel or ticagrelor), use of beta-blocker, statin, Angiotensin Converting Enzyme Inhibitors, Angiotensin Receptor Blockers were recorded.
Endpoint
All cause death at one year of follow up was the primary end-point. Secondary endpoints included in hospital reinfarction, in-hospital heart failure, in-hospital bleedings and transfusion, 1-year myocardial infarction and 1-year bleeding and 1-year MACE (the composite of one year death and myocardial infarction). One year bleedings were classified according to TIMI and BARCcriteria (12,13). In-hospital events were defined as those occurring during hospitalization for index PCI.
Statistical Analysis
Continuous variables were expressed as mean ± standard deviation (SD), categorical variables were expressed as number and percentages (%). Correlations between parameters and study groups were tested in cross tabulation tables by means of Pearson Chi Square test or Fisher exact test for categorical variables and by One-Way Analysis of Variance (ANOVA) for continuous variables.
Categorical variables were compared with the Fisher’s exact test. Parametric distribution of continuous variables was tested graphically and with Kolmorogov Smirnov, and the appropriate analyses were used in accordance with the results. For propensity score, first logistic regression analysis was done for all baseline features that differed between groups with BB and not at univariate analysis and for those relevant from a clinical point of view. Matching was computed after division into quintiles and methods of nearest neighbor on the estimated propensity score (14). Calibration was tested with Hosmer-Lermeshow, and accuracy was assessed with Area Under the Curve.
Standardized differences were evaluated before and after matching to evaluate performance of the model. Survival analysis was performed with Kaplan Meier and compared with log rank on patients after propensity score with matching. For all patients, Cox multivariate analysis was performed to indentify independent predictors of one year all cause death and MI. All statistical analyses were performed with SPSS 21 and differences were considered significant at α=0.05.
RESULTS.
From the 15401 patients, 15210 were those with data on BB at discharge (98%).In the study population 12275 patients were on BBs therapy, while 2935 patients were not. At a first comparison, patients on BBs were significantly older, had higher prevalence of male sex, carried a lower burden of comorbidities such as diabetes, hypertension, history of cardiovascular disease, and had a higher STEMI-presentation rate compared to patients not on BBs (for further details see Supplementary tables 1-3).
Variables with a significant difference at univariate analysis (see Supplementary tables 1-2) were inserted into the logistic regression model to built propensity score.
Outcomes before propensity score matching
At one year follow up, one year rates of death were lower for patients discharged with BBs (2.9% vs 7.0%, p<0.05), as those of myocardial infarctions (3.8% vs. 4.9%, p<0.05) and of in hospital heart failure (4.1% vs. 5.2%, p<0.05) (see Supplementary table 3 and figure 1). By means of propensity score matching, based on clinical presentation, risk factors and procedural features, we selected patients in the on BBs therapy group in order to create two comparable groups (n=2.935; see Figure number 1, and tables 1 and 2)
Outcomes after propensity score matching
Primary endpoint of 1-year death was significantly lower in the group on BBs therapy (4.5% Vs 7%, p , confirmed also at Kaplan Meier Analysis (see Figure number 2, p log rank <0.001). One-year re-AMI was 4.9% in the off-BBs group and 4.5% in the on BBs group (p 0.54), while it was significantly reduced for BBS at Kaplan Meier analysis (p 0.007). (see Figure number 1 and Supplementary table 4) These results were confirmed at Cox multivariate analysis, where BB therapy was protective for one year death and MI (HR 0.349:0.286-0.426 and HR 0.737:0.582-0.932 all p <0.005). In-hospital
bleeding and in hospital transfusion did not differ (respectively 6.9% in the group off-BBs therapy and 8.1% in the group on BBs therapy, p 0.08 and 4.8% vs. 3.9% in the on BBs group, p 0.11) while in hospital- re-AMI and heart failure were respectively 1.4% vs. 1.5% (p 0.82 ) and 5.2% vs. 56% (p 0.51).
Sensitivity analysis for clinical features.
After propensity score, in patients older than 80 years old, one-year death was 16.1% in the off-BBs group and 7% in the on BBs group (p 0.045) and one-year re-AMI was 7.7% in the off-BBs group and 5.8 in the on BBs group (p 0.56). (see Figure number 2).
The beneficial association with the use of beta blockers were also confirmed in female patients, with rates of death at follow up of 6.2% vs. and 4.1% (p 0.04; see supplementary figure number 2).
Sensitivity analysis according to clinical presentation.
In STEMI patients, Beta blockers were associated with a reduction of one year death of more than double (8.6% vs. 4.1%, p <0.001), while in UA/NSTEMI patients a trend towards reduction was observed, although not being significant (5.7% vs. 5.3%, p 087; see Figures number 3 and supplementary figure number 3).
Sensitivity analysis according to completeness of revascularization
The association between beta blockers use and reduction of one year death was persistent both for patients treated with complete and non-complete revascularization, being more evident for those discharged with critical stenosis not treated during index hospitalization (respectively 3.9% vs. 6.9% and 6.0% vs. 12.5%; p 0.04 and p 0.03 see Figures number 4 and supplementary figure number 4).
Sensitivity analysis according to EF.
Similarly, the use of beta blockers was associated with a decrease of one year death independently from EF, being more relevant in those discharged with a
systolic function less than 40% (6.5% vs. 2.3%, p 0.04 for those with EF more than 40% and 17.67% vs. 7.0% for those with reduced, all p<0.001, see Figures number 5 and supplementary figure number 5) as those with a Killip class of 2 or more at admission (see supplementary figure number 6)..
DISCUSSION
The main finding of this study is that BBs therapy is associated with better clinical outcome even in the PCI era and together with all other medical options including novel antiplatelet drugs. This association with clinical benefit persisted in STEMI patients and was greater in patients with uncomplete revascularization, independently of EF, while we found no changes in NSTEMI patients. The importance of the present study lies in sub-populations of ACS patients, in which evidence is lacking.
In ACS patients, there is evidence that BBs reduce mortality, but most of the trials were performed in the 1980s in selected patients. This may limit translation of those benefits for patients treated with PCI or antiaggregant like clopidogrel, prasugrel and ticagrelor which have shown a reduction in recurrent ischemic events (15-18). Moreover indication for PCI has been nowadays expanded to patients with more comorbidities, like renal insufficiency, malignancy or pulmonary disease, potentially limiting impact of BBs on survival (9, 20).
In our study we found that BBs’ association with better outcome persists in STEMI patients but not in NSTE-ACS. Possible reasons of this difference may be related not particularly to the different pathophysiology (related to a erythrocyte-rich red thrombus in STEMI vs. a white, fibrin-rich, thrombus in NSTEMI,21) but especially to different clinical characteristics (21). Actually while data from the GRACE registry has shown the potential benefit on 6 months outcomes of BBs therapy (22), the long term prognosis remains mainly driven by burdened of comorbidities, potentially offsetting the benefit of BBs.
Beneficial role associated with BBs persisted also in patients older than 80 years old. They represent an important number of those admitted for ACS in our registry (about 15%) and their number will increase, but these is uncertainty in literature about their optimal treatment. Actually for one side, the use if often limited by large number of medications already assumed, and by side effects which increase with age, as symptomatic bradycardia, symptomatic hypotension and orthostatic hypotension (23). Our registry showed, even at one year follow up, the persistence of the benefit of beta blocker therapy also for these patients.
Beneficial effect associated with BBs was relevant both for patients discharged with complete and not complete revascularization, but was more evident for the latter population which is at higher risk of subsequent events (24). Actually the absolute risk reduction was of 3% in the first group and of more than 6% for those discharged with significant stenosis not treated with PCI. These data represent a step forward when compared to those of Chen et al (25), derived from the Cooperative Cardiovascular Project showing the increase of benefit of beta blocker in non revascularized patients vs. those treated with percutaneous or surgical revascularization. Moreover similarly the paper of Kernis et al demonstrated the protective role of BBs in patients discharged with STEMI and multivessel disease (26). In the present registry, we showed that the use of BBs was associated with a clinical benefit more evident in those patients discharged with stenosis potentially triggering acute ischemic events, due to the limiting effect on adrenergic activation and ischemic cascade.
Similarly, as expected, BBs were associated with a protective effect on patients with reduced ejection fraction, but also in those with preserved EF. Some experimental data demonstrated an absence of benefit of BBs on left ventricle remodeling in patients with preserved EF, our results, accordingly to those of Konishi et al and Rubin et al (27,28) confirmed, on a larger sample size, their protective role.
BBS reduced MI at KM analysis, but not when comparing crude rate of events. As demonstrated in figure number 1, the benefit increased after the first month. This is the period in which platelet aggregation and thrombosis risk are more relevant, and these mechanisms are reduced by platelet antiaggregation rather than BBs (29-31). After this period, role of BBs in reducing MI may become more relevant.
The present paper, demonstrating the benefit of BBs in a large contemporary cohort of ACS patients treated with PCI differ from that of Bangalore et al (9) showing on a similar number of patients absence of benefit in patients with prior MI. This difference may not be related to the shorter follow up of our cohort, potentially focusing on a more acute phase, because Kaplan Meier curves did not show any differences in the previously quoted paper even at short term (9). Moreover we showed the consistent association of BBs with better clinical outcome across different ages, for those with complete and non-complete revascularization and preserved or reduced EF. The present results, finally, were different from those of the paper of Motivala et al. (20) which enrolled prevalently patients with stable angina without a history of MI and with preserved EF and this may explain the lack of benefit of survival.
The present paper has some limitations. First these data are retrospective, with potential adjudication and attribution bias. Despite this, it is not an institutional database, as many of those evaluating effectiveness of BBs in these patients (9,20) but it is based and evaluated on medical records by physicians, improving accuracy of the data. Second, we did not have data on different types of BBs, on possible use of by ultra short-acting beta blocker and when BB therapy was started or discontinued. Despite this, apart from patient with heart failure (32), guidelines do not recommend a particular drug, while the only randomized trial on this topic, the CAMIS (Carvedilol Acute Myocardial Infarction Study) did not show difference between carvedilol and atenolol (33). However, as reported in a recent review, in patients with CAD selective BB without intrinsic
sympathomimetic activity should be preferred (34). Moreover, cause of death has not been appraised, although usefulness of Beta Blockers to reduce sudden death and cardiac mortality in patients with reduced EF has been largely demonstrated (28). Rates of in hospital cardiogenic shock were not recorded, although BB did not increase rate of in hospital HF irrespectively of EF at discharge. The present results did not derive from randomized controlled trials, but from observational data based on propensity score, with all potential limitations, despite a good accuracy (area under the curve of 0.78 [0.76-0.81]) and discrimination (not significant test of Hosmer–Lemeshow) and with an overall good performance when evaluating standardized difference (see supplementary tables number 5 and 6). Finally propensity score adjustement was performed for overall population and not for subgroups analysis which were performed only for clinical reasons without inferential aims.
REFERENCES.
1. Iannaccone M, Quadri G, Taha S, D'Ascenzo F, Montefusco A, Omede' P, Jang IK, Niccoli G, Souteyrand G, Yundai C, Toutouzas K, Benedetto S, Barbero U, Annone U, Lonni E, Imori Y, Biondi-Zoccai G, Templin C, Moretti C, Luscher TF, Gaita F - Prevalence and predictors of culprit plaque rupture at OCT in patients with coronary artery disease: a meta- analysis. Eur Heart J Cardiovasc Imaging. 2015 Oct 27.
2. Task Force Members - 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery
(EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014 Oct 1;35(37):2541-619.
3. Naito R, Miyauchi K, Konishi H, Tsuboi S, Ogita M, Dohi T, Kasai T, Tamura H, Okazaki S, Isoda K, Daida H - Gender difference in long-term clinical outcomes following percutaneous coronary intervention during 1984-2008. Atherosclerosis. 2016 Apr;247:105-10.
4. Moretti C, D’Ascenzo F, Omedè P, Sciuto F, Presutti DG, Di Cuia M, Colaci C, Giusto F, Ballocca F, Cerrato E, Colombo F, Gonella A, Giordana F, Longo G, Vilardi I, Bertaina M, Orlando A, Andrini R, Ferrando A, DiNicolantonio JJ, Zoccai GB, Sheiban I, Gaita F - Thirty-day readmission rates after PCI in a metropolitan center in Europe: incidence and impact on prognosis. J Cardiovasc Med (Hagerstown). 2015 Mar;16(3):238-45.
5. Yusuf S1, Wittes J, Friedman L - Overview of results of randomized clinical trials in heart disease. I. Treatments following myocardial infarction. JAMA. 1988 Oct 14;260(14):2088-93
6. Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group.Lancet 1986;2:57-66
7. Metoprolol in acute myocardial infarction (MIAMI). A randomised placebo-controlled international trial. The MIAMI Trial Research Group.Lancet 2005;366:1622-3Eur Heart J. 1985 Mar;6(3):199-226
8. Kontos MC, Diercks DB, Ho PM, Wang TY, Chen AY, Roe MT. Treatment and outcomes in patients with myocardial infarction treated with acute β-blocker therapy: results from the American College of Cardiology's NCDR(®). Am Heart J. 2011 May;161(5):864-70.
9. Bangalore S - β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA. 2012 Oct 3;308(13):1340-9.
10.Al-Reesi A, Al-Zadjali N, Perry J, Fergusson D, Al-Shamsi M, Al-Thagafi M, Stiell I. Do beta-blockers reduce short-term mortality following acute myocardial infarction? A systematic review and meta-analysis. CJEM. 2008 May;10(3):215-23.
11.D'Ascenzo F, Abu-Assi E, Raposeiras-Roubín S, Simao Henriques JP, Saucedo J, González-Juanatey JR, Wilton SB, Kikkert WJ, Nuñez-Gil I, Ariza-Sole A, Song X, Alexopoulos D, Liebetrau C, Kawaji T, Moretti C, Huczek Z, Nie SP, Fujii T, Correia LC, Kawashiri MA, García-Acuña JM, Southern D, Alfonso E, Terol B, Garay A, Zhang D, Chen Y, Xanthopoulou I, Osman N, Möllmann H, Shiomi H, Giordana F, Scarano S, Gaita F, Kowara M, Filipiak KJ, Wang X, Yan Y, Fan JY, Ikari Y, Nakahayshi T, Sakata K, Yamagishi M, Kalpak O, Kedev S. BleeMACS: rationale and design of the study. J Cardiovasc Med (Hagerstown). 2016 Jan 27. [Epub ahead of print]), in the BleeMACS webpage (http://bleemacs.wix.com/registry), or in clinicaltrials.gov (Identifier: NCT02466854).
12.Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT,Francis CK, Hillis D, Ludbrook P, Markis JE, Mueller H, Passamani ER, Powers ER,Rao A Robertson T, Ross A, Ryan TJ, Sobel BE, Willerson J, Williams DO, Zaret BL,Braunwald - Thrombolysis in Myocardial Infarction (TIMI) Trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous
streptokinase: clinical findings through hospital discharge. Circulation.1987;76:142– 154
13.Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. - Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47.
14.D'Ascenzo F , Cavallero E, Biondi-Zoccai G, Moretti C, Omedè P, Bollati M, Castagno D, Modena MG, Gaita F, Sheiban I - Use and misuse of multivariable approaches in interventional cardiology studies on drug-eluting stents: a systematic review. J Interv Cardiol. 2012 Dec;25(6):611-21.
15.Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, Cornel JH, Bhatt DL, Clemmensen P, Martinez F, Ardissino D, Nicolau JC, Boden WE, Gurbel PA, Ruzyllo W, Dalby AJ, McGuire DK, Leiva-Pons JL, Parkhomenko A, Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR, Oto A, Tseng CD, Merkely B, Gasparovic V, Corbalan R, Cinteză M, McLendon RC, Winters KJ, Brown EB, Lokhnygina Y, Aylward PE, Huber K, Hochman JS, Ohman EM; TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012 Oct 4;367(14):1297-309. D
16.Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Oude Ophuis T, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E, Sabatine MS; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction.N Engl J Med. 2015 May 7;372(19):1791-800.
17.D'Ascenzo F, Moretti C, Bianco M, Bernardi A, Taha S, Cerrato E, Omedè P, Montefusco A, Frangieh AH, Lee CW, Campo G, Chieffo A, Quadri G, Pavani , Zoccai GB, Gaita F, Park SJ, Colombo A, Templin C, Lüscher TF, Stone GW. Meta-Analysis of the Duration of Dual Antiplatelet Therapy in Patients Treated With Second-Generation Drug-Eluting Stents Am J Cardiol. 2016 Jun 1;117(11):1714-23.
18.Eisen A, Giugliano RP, Braunwald E. Updates on Acute Coronary Syndrome: A Review.JAMA Cardiol. 2016 Jul 20.
19.Olivari Z, Chinaglia A, Gonzini L, Falsini G, Pilleri A, Valente S, Gregori G, Rollo R, My L, Scrimieri P, Lanzillo T, Corrado L, Chiti M, Picardi E; BLITZ 4 Investigators. Invasive strategy in non-ST-segment elevation acute coronary syndrome: What should be the benchmark target in the real world patients? Insights from BLITZ-4 Quality Campaign. Int J Cardiol. 2016 Jun 23;220:761-767.
20.Motivala AA, Parikh V, Roe M, Dai D, Abbott JD, Prasad A, Mukherjee D. Predictors, Trends, and Outcomes (Among Older Patients ≥65 Years of Age) Associated With Beta-Blocker Use in Patients With Stable Angina Undergoing Elective Percutaneous Coronary Intervention: Insights From the NCDR Registry. JACC Cardiovasc Interv. 2016 Aug 22;9(16):1639-48.
21.Gili S, D'Ascenzo F, Lococo MF, Moretti C, Gaita F, Raposeiras-Roubín S, Abu-Assi E, Henriques JP, Saucedo J, González-Juanatey JR, Wilton SB, Kikkert WJ, Nuñez-Gil I, Ariza-Sole A, Song X1, Alexopoulos D, Liebetrau C, Kawaji T, Huczek Z, Nie SP,
Fujii T, Correia L, Kawashiri MA, García-Acuña JM, Southern D, Alfonso E, Terol B, Garay A, Zhang D, Chen Y, Xanthopoulou I, Osman N, Möllmann H, Shiomi H, Scarano S, Kowara M, Filipiak K, Wang X, Yan , Fan JY, Ikari Y, Nakahashi T, Sakata K, Yamagishi M, Kalpak O, Kedev S. Impact of blood transfusion on in-hospital myocardial infarctions according to patterns of acute coronary syndrome: Insights from the BleeMACS registry Int J Cardiol. 2016 on press
22.Emery M, López-Sendón J, Steg PG, Anderson FA Jr, Dabbous OH, Scheuble A, Eagle KA; GRACE Investigators. Am Heart J. 2006 Dec;152(6):1015-2
23.Hiitola P, Enlund H, Kettunen R, et al. Postural changes in blood pressure and the prevalence of orthostatic hypotension among home-dwelling elderly aged 75 years or older. J Hum Hypertens. 2009;23:33
24.Quadri G, D'Ascenzo F, Moretti C, D'Amico M, Raposeiras-Roubín S, Abu-Assi E, Henriques JPS, Saucedo J, González-Juanatey JR, Wilton SB, Kikkert WJ, Nuñez-Gil I, Ariza-Sole A, Song X, Alexopoulos D, Liebetrau C, Kawaji T, Huczek Z, Nie SP, Fujii T, Correia L, Kawashiri MA, García-Acuña JM, Southern D, Alfonso E, Terol B, Garay A, Zhang D, Chen Y, Xanthopoulou I, Osman N, Möllmann H, Shiomi H, Omedè P, Montefusco A, Giordana F, Scarano S, Kowara M, Filipiak K, Wang X, Yan Y, Fan JY, Ikari Y, Nakahashi T, Sakata K, Yamagishi M, Kalpak O, Kedev S, Varbella F, Gaita F Complete or incomplete coronary revascularisation in patients with myocardial infarction and multivessel disease: a propensity score analysis from the "real-life" BleeMACS (Bleeding complications in a Multicenter registry of patients discharged with diagnosis of Acute Coronary Syndrome) registry. EuroIntervention. 2017 Jul 20;13(4):407-414
25.Chen J, Radford MJ, Wang Y, Marciniak TA, Krumholz HM. Are beta-blockers effective in elderly patients who undergo coronary revascularization after acute myocardial infarction? Arch Intern Med. 2000 Apr 10;160(7):947-5
26.Kernis SJ, Harjai KJ, Stone GW, Grines LL, Boura JA, O'Neill WW, Grines CL. Does beta-blocker therapy improve clinical outcomes of acute myocardial infarction after successful primary angioplasty? J Am Coll Cardiol. 2004 May 19;43(10):1773-9.
27.Konishi H, Miyauchi K, Kasai T, Tsuboi S, Ogita M, Naito R, Nishizaki Y, Okai I, Tamura H, Okazaki S, Isoda K, Daida H. Long-term effect of β-blocker in ST-segment elevation myocardial infarction in patients with preserved left ventricular systolic function: a propensity analysis. Heart Vessels. 2016 Apr;31(4):441-8.
28.Raposeiras-Roubín S, Abu-Assi E, Redondo-Diéguez A, González-Ferreiro R, López-López A, Bouzas-Cruz N, Castiñeira-Busto M, Peña Gil C, García-Acuña JM, González-Juanatey JR. Prognostic Benefit of Beta-blockers After Acute Coronary Syndrome With Preserved Systolic Function. Still Relevant Today? Rev Esp Cardiol (Engl Ed). 2015 Jul;68(7):585-91.
29.Giustino G1, Mehran R1, Dangas GD1, Kirtane AJ2, Redfors B3, Généreux P4, Brener SJ5, Prats J6, Pocock SJ7, Deliargyris EN8, Stone GW9. Characterization of the Average Daily Ischemic and Bleeding Risk After Primary PCI for STEMI. J Am Coll Cardiol. 2017 Oct 10;70(15):1846-1857.
30.D'Ascenzo F, Moretti C, Bianco M, Bernardi A, Taha S, Cerrato E, Omedè P, Montefusco A, Frangieh AH, Lee CW, Campo G, Chieffo A, Quadri G, Pavani M, Zoccai GB, Gaita F, Park SJ, Colombo A, Templin C, Lüscher TF, Stone
GW.Meta-Analysis of the Duration of Dual Antiplatelet Therapy in Patients Treated With Second-Generation Drug-Eluting Stents. Am J Cardiol. 2016 Jun 1;117(11):1714-23
31.D'Ascenzo F, Iannaccone M, Saint-Hilary G, Bertaina M, Schulz-Schüpke S, Wahn Lee C, Chieffo A, Helft G, Gili S, Barbero U, Biondi Zoccai G, Moretti C, Ugo F, D'Amico M, Garbo R, Stone G, Rettegno S, Omedè P, Conrotto F, Templin C, Colombo A, Park SJ, Kastrati A, Hildick-Smith D, Gasparini M, Gaita F. Impact of design of coronary stents and length of dual antiplatelet therapies on ischaemic and bleeding events: a network meta-analysis of 64 randomized controlled trials and 102 735 patients. Eur Heart J. 2017 Nov 7;38(42):3160-3172.
32.Chatterjee S, Biondi-Zoccai G, Abbate A, D'Ascenzo F, Castagno D, Van Tassell B, Mukherjee D, Lichstein E. Benefits of β blockers in patients with heart failure and reduced ejection fraction: network meta-analysis. BMJ. 2013 Jan 16;346:f55. doi: 10.1136/bmj.f55.
33. Jonsson G, Abdelnoor M, Mu¨ ller C, Kjeldsen SE, Os I, Westheim A. A comparison of the two betablockers carvedilol and atenolol on left ventricular ejection fraction and clinical endpoints after myocardial infarction: a single-centre, randomized study of 232 patients. Cardiology. 2005;103(3):148-155
34.Dézsi CA, Szentes V. The Real Role of β-Blockers in Daily Cardiovascular Therapy. Am J Cardiovasc Drugs. 2017 Oct;17(5):361-373.
