Determinants of long-term clinical outcomes in patients with angina but without obstructive coronary artery disease: a systematic review and meta-analysis
Running title: Clinical outcomes of angina without obstructive coronary artery disease Francesco Radicoa, MD, Marco Zimarinoa, MD, PhD, Fabio Fulgenzia, MD, Fabrizio Riccib, MD, Marta Di Nicolac, PhD, Lasse Jespersend, MD, PhD, Su Min Change, MD, Karin H Humphriesf, DSc, Mario Marzillig, MD and Raffaele De Caterinaa, MD, PhD a
Institute of Cardiology and Center of Excellence on Aging, “G. d’Annunzio” University, Chieti, Italy
b
Department of Neuroscience, Imaging and Clinical Sciences & Institute for Advanced Biomedical
Technologies, University G. d'Annunzio, Chieti, Italy c
Department of Medical, Oral and Biotechnological Sciences, Laboratory of Biostatistics, University
"G. d'Annunzio" Chieti-Pescara, Chieti, Italy d
Department of Cardiology, Bispebjerg University Hospital, Bispebjerg Bakke, Copenhagen,
Denmark e
Houston Methodist DeBakey Heart and Vascular Center, Houston Methodist Hospital, Houston,
Texas, USA f
BC Centre for Improved Cardiovascular Health, St Paul's Hospital, Vancouver, British Columbia,
Canada g
Department of Cardiology, University of Pisa, Pisa, Italy.
ONLINE SUPPLEMENT (Online Figures 1-4) Address for correspondence: Raffaele De Caterina, MD, PhD, FESC Institute of Cardiology, "G. d'Annunzio" University – Chieti C/o Ospedale SS. Annunziata, Via dei Vestini, 66013 Chieti, Italy Tel. +39-0871-41512; FAX: +39-0871-402817 E-mail:
[email protected]
LEGEND TO ONLINE FIGURES
Online Figure 1. Jackknife sensitivity analysis of the primary endpoint of the study, the combined incidence of all-cause death and myocardial infarction. Pooled estimates for the combined endpoint all-cause mortality and non-fatal myocardial infarction re-calculated, using a random-effects model, by omitting one study at a time. Each line represents a re-analysis of the data with the exclusion of one study at a time to assess the influence of that particular study on the overall result and to evaluate whether the summary estimate of the effect could have been significantly affected by a single study. Acronyms as in Figure 2. Online Figure 2. Subgroup analysis of the primary study outcome (the combined incidence of all-cause death and myocardial infarction (MI) by vasospastic angina. Forest plots for estimated event rates of the primary outcome with 95% confidence interval (CI), dividing the studies in two subgroups (yellow diamonds) according to the presence, among inclusion criteria, of vasospastic angina. Black squares indicate weighted point estimates of the event rate of each single study of the vasospastic angina subgroup (single studies not including vasospastic angina here not showed), with grey horizontal lines indicating 95% CI. The vertical red line indicates the pooled averaged event rate estimate and the blue diamond represents the overall estimated event rate with 95% CI. Graph symbols, acronyms and other abbreviations as in Figure 2. Online Figure 3. Assessment of publication bias for all-cause mortality. Begg’s funnel plot of studies (white dots) according to all-cause mortality (x axis) versus standard error for mortality (y axis). The vertical blue dotted line indicates the pooled averaged incidence estimate and the oblique black lines the pseudo-95% confidence intervals. A lower standard error indicates better precision and larger study size. Online Figure 4. Cardiovascular hospitalization. Forest plot with individual and overall estimated event rates with 95% confidence interval (CI) of cardiovascular hospitalization. Graph symbols, acronyms and other abbreviations as in Figure 2.
Studies Overall (no omissions)
Incidence % (95% CI) 0.98 (0.77; 1.19)
Omitting Addison D 2014 Omitting Bigi R 2002 Omitting Bugiardini R 2004 Omitting Chaikriangkrai K 2015 Omitting Chauhan A 1993 Omitting Cortigiani L 2014 Omitting Dedic A 2011 Omitting Delcour KS 2009 Omitting Di Monaco A 2010 Omitting Egashira K 1987 Omitting Foussas SG 1998 Omitting Fragasso G 2009 Omitting Fragasso G (2) 2014 Omitting Gimelli A 2008 Omitting Gulati M (WISE) 2009 Omitting Halcox PJ 2002 Omitting Hirota Y 1994 Omitting Humphries KH 2008 Omitting Isner JM 1981 Omitting Jespersen L 2012 Omitting Kaski JC 1995 Omitting Lamendola G 2010 Omitting Leu H 2006 Omitting Li L 2012 Omitting Lichtlen P 1995 Omitting Lim AY 2016 Omitting Masumoto A 2011 Omitting Nitenberg A 2004 Omitting Nitenberg A (2) 2005 Omitting Pasternak RC 1980 Omitting Proudfit WL 1980 Omitting Rubinshtein R 2009 Omitting Rubinshtein R (2) 2013 Omitting Sakata K 2005 Omitting Sánchez-Recalde A 2009 Omitting Schindler TH 2003 Omitting Scholl JM 1988 Omitting Sedlak TL 2013 Omitting Shin DI (VA Korea Registry) 2015 Omitting Shintani S 2003 Omitting Sicari R 2005 Omitting Sicari R (2) 2009 Omitting Sullivan AK 1994 Omitting Sun SS 2001 Omitting Suwaidi J 2000 Omitting Suzuki H 2002 Omitting Takatsu F 2011 Omitting Villines TC (CONFIRM) 2011 Omitting Voelker V 1991
Online Figure 1
0.97 (0.76; 0.96 (0.75; 1.00 (0.78; 0.93 (0.73; 1.00 (0.78; 0.95 (0.75; 0.99 (0.78; 0.95 (0.75; 0.99 (0.79; 0.98 (0.77; 0.98 (0.77; 0.98 (0.77; 0.96 (0.75; 0.99 (0.78; 0.97 (0.75; 0.96 (0.75; 0.99 (0.78; 0.96 (0.74; 0.97 (0.76; 0.90 (0.73; 1.00 (0.79; 1.00 (0.79; 0.99 (0.78; 0.99 (0.78; 0.97 (0.76; 0.98 (0.77; 0.99 (0.78; 0.97 (0.76; 1.00 (0.78; 1.00 (0.78; 1.00 (0.78; 0.99 (0.77; 0.98 (0.76; 0.98 (0.77; 0.99 (0.78; 0.97 (0.76; 0.97 (0.76; 0.98 (0.76; 0.97 (0.76; 0.99 (0.78; 0.96 (0.74; 0.96 (0.74; 0.97 (0.76; 0.99 (0.78; 0.98 (0.77; 1.00 (0.79; 0.98 (0.76; 1.00 (0.78; 0.99 (0.78;
1.19) 1.17) 1.21) 1.14) 1.21) 1.16) 1.21) 1.16) 1.21) 1.19) 1.19) 1.19) 1.17) 1.20) 1.18) 1.17) 1.21) 1.16) 1.18) 1.07) 1.21) 1.21) 1.20) 1.20) 1.18) 1.20) 1.20) 1.18) 1.21) 1.21) 1.21) 1.20) 1.19) 1.19) 1.20) 1.18) 1.18) 1.19) 1.18) 1.20) 1.16) 1.16) 1.18) 1.20) 1.19) 1.21) 1.20) 1.23) 1.20)
0.8
0.9
1.0
1.1
1.2
Combined incidence of all-cause death and myocardial infarction (n. events / 100 person-years)
Incidence % (95% CI)
Studies including vasospastic angina Egashira K 1987
0.83 (0.00; 1.77)
Leu H 2006
0.27 (0.00; 1.01)
Lim AY 2016
0.86 (0.05; 1.17)
Masumoto A 2011
0.44 (0.00; 1.32)
Sakata K 2005
0.81 (0.00; 1.60)
Scholl JM 1988
2.12 (0.06; 4.19)
Shin DI (VA Korea Registry) 2015
1.39 (0.60; 2.16)
Takatsu F 2011
1.16 (0.98; 1.33)
Overall (I2 38.3%, P=0.12)
0.94 (0.69; 1.12)
Studies not including vasospastic angina Overall (I2 92.0%, P
