Document Detail

Heart rate and use of beta-blockers in stable outpatients with coronary artery disease.
Jump to Full Text
MedLine Citation:
PMID:  22570699     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Heart rate (HR) is an emerging risk factor in coronary artery disease (CAD). However, there is little contemporary data regarding HR and the use of HR-lowering medications, particularly beta-blockers, among patients with stable CAD in routine clinical practice. The goal of the present analysis was to describe HR in such patients, overall and in relation to beta-blocker use, and to describe the determinants of HR.
METHODS AND FINDINGS: CLARIFY is an international, prospective, observational, longitudinal registry of outpatients with stable CAD, defined as prior myocardial infarction or revascularization procedure, evidence of coronary stenosis of >50%, or chest pain associated with proven myocardial ischemia. A total of 33,438 patients from 45 countries in Europe, the Americas, Africa, Middle East, and Asia/Pacific were enrolled between November 2009 and July 2010. Most of the 33,177 patients included in this analysis were men (77.5%). Mean (SD) age was 64.2 (10.5) years, HR by pulse was 68.3 (10.6) bpm, and by electrocardiogram was 67.2 (11.4) bpm. Overall, 44.0% had HR ≥ 70 bpm. Beta-blockers were used in 75.1% of patients and another 14.4% had intolerance or contraindications to beta-blocker therapy. Among 24,910 patients on beta-blockers, 41.1% had HR ≥ 70 bpm. HR ≥ 70 bpm was independently associated with higher prevalence and severity of angina, more frequent evidence of myocardial ischemia, and lack of use of HR-lowering agents.
CONCLUSIONS: Despite a high rate of use of beta-blockers, stable CAD patients often have resting HR ≥ 70 bpm, which was associated with an overall worse health status, more frequent angina and ischemia. Further HR lowering is possible in many patients with CAD. Whether it will improve symptoms and outcomes is being tested.
Authors:
Ph Gabriel Steg; Roberto Ferrari; Ian Ford; Nicola Greenlaw; Jean-Claude Tardif; Michal Tendera; Hélène Abergel; Kim M Fox;
Related Documents :
25292459 - Associations between n-terminal procollagen type iii, fibrosis and echocardiographic in...
19734999 - Cardiotoxicity induced by tyrosine kinase inhibitors.
14517189 - Levosimendan: implications for clinicians.
14728049 - Role of metabolically active drugs in the management of ischemic heart disease.
17170629 - Atorvastatin therapy associated with improvement in left ventricular remodeling in a ca...
19846039 - Pharmaceutical management of decompensated heart failure syndrome in children: current ...
16779349 - Using outpatient prescription claims to evaluate medication adherence in an acute myoca...
8221759 - Left ventricular energetics: heat production by the human heart.
16159079 - Reversal of locked-in syndrome with anticoagulation, induced hypertension, and intraven...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-05-03
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-05-09     Completed Date:  2013-01-24     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e36284     Citation Subset:  IM    
Affiliation:
INSERM U698, Paris, France. gabriel.steg@bch.ap-hop-paris.fr
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-Antagonists / pharmacology*,  therapeutic use*
Aged
Cohort Studies
Coronary Artery Disease / drug therapy*,  physiopathology*
Depression, Chemical
Factor Analysis, Statistical
Female
Heart Rate / drug effects*
Humans
Male
Middle Aged
Outpatients*
Treatment Outcome
Chemical
Reg. No./Substance:
0/Adrenergic beta-Antagonists
Investigator
Investigator/Affiliation:
P G Steg / ; R Ferrari / ; I Ford / ; K Fox / ; J C Tardif / ; M Tendera / ; Fernando José Sokn / ; Christopher Reid / ; Irene Lang / ; Frank Van den Branden / ; Luis Machado César / ; Marco Antonio Mattos / ; Hj Nazar Luqman / ; Assen Goudev / ; Paul Dorian / ; Dayi Hu / ; Petr Widimsky / ; Christian Hassager / ; Nicolas Danchin / ; Stefan Kääb / ; Panos Vardas / ; Kadhim J Sulaiman / ; Wael Al Mahmeed / ; Jassim Al Suwaidi / ; Ibrahim Al Rashdan / ; Fuad Abdulkader / ; Béla Merkely / ; Upendra Kaul / ; Kieran Daly / ; Luigi Tavazzi / ; Roberto Ferrari / ; Yangsoo Jang / ; Andrejs Erglis / ; Aleksandras Laucevičius / ; Ahmad Nizar Jamaluddin / ; Marco Alcocer Gamba / ; Igor I Tulevski / ; Janina Stępińska / ; Joao Morais / ; Cezar Macarie / ; Rafael Oganov / ; Svetlana Shalnova / ; Muayed Al-Zaibag / ; Mak Koon Hou / ; Gabriel Kamensky / ; Zlatko Fras / ; Vojko Kanič / ; Datshana Prakesh Naidoo / ; José Luis Zamorano / ; Hans Rickli / ; Andres Jaussi / ; Charn Sriratanasathavorn / ; Paul Kalra / ; Mykhailo Lutai / ; Lan Viet Nguyen / ; Ronald Henry / ; A Ahuad Guerrero / ; M Basara / ; F Belcastro / ; J A Bertarini / ; C Cazenave / ; H Dreycopp / ; J Egido / ; J Estrella / ; D Garofalo / ; J Giordano / ; H Lagioia / ; N Lago / ; R La Greca / ; L Lema / ; N Lopez Cabanillas / ; H Luquez / ; C Miller / ; E Prada / ; P Rodenas / ; R G Schena / ; G Suarez / ; A Tomatti / ; D M Colquhoun / ; A Conradie / ; S Cox / ; D Cross / ; R Fathi / ; B Fitzgerald / ; I Hamilton-Craig / ; G Holt / ; S R Jayasinghe / ; N Mai / ; J Moolman / ; R A Motyer / ; K Phillips / ; A Rafter / ; A Rahman / ; A Rainbird / ; G Scalia / ; A Taylor / ; P West / ; K Alford / ; R Amor / ; P Astridge / ; B Bastian / ; F Bates / ; M M Doohan / ; J Du Plooy / ; J C Ford / ; L Kanagaratnam / ; V Khoury / ; R Parkin / ; J Rogers / ; G Sceats / ; A Waldman / ; D Wang / ; S Wright / ; J Ardill / ; P Aylward / ; J F Beltrame / ; J Bradley / ; W Heddle / ; M Joseph / ; S Rajendran / ; S Varughese / ; E Brice / ; B Hockings / ; J Janssen / ; A Kozlowski / ; J O'Shea / ; D A Playford / ; K Woollard / ; A Ajani / ; G Barron / ; N Better / ; B Chan / ; R Chan / ; J Cotroneo / ; J T Counsell / ; D S Eccleston / ; B H R Forge / ; A Hamer / ; M Horrigan / ; V M J Jelinek / ; R Lew / ; D O'Donnell / ; F Panetta / ; M Sebastian / ; A Soward / ; P Srivastava / ; N F Strathmore / ; S Sylivris / ; G Szto / ; V Veth / ; T Yip / ; R Badr-Eslam / ; L Kleemann / ; G Steurer / ; B Mörz-Proszowski / ; F Auhser / ; U Teleky / ; G Sepp / ; A Beinhauer / ; D Kerö / ; C Lavicka / ; T Perger / ; V Hadjiivanov / ; M Feldner-Busztin / ; R Mika / ; W Filip / ; A Mahr / ; J Toplak / ; M G Millauer / ; P Haralambus / ; K Walcher / ; K H Karner / ; E Ziak / ; P Painsipp / ; U Frank / ; A Suntinger / ; W Gritsch / ; G Bode / ; R Herrmann / ; R Raffelsberger / ; H Topf / ; E Moser / ; J Föchterle / ; T Honsig / ; K Mayr / ; H Mayr / ; R Kaserbacher / ; A Dzien / ; E Galehr / ; M Felbermayer / ; R Schwarz / ; R Amini / ; H Appeltants / ; A Ballet / ; J-R Bar / ; J Beckers / ; J-M Bergen / ; G Berkenboom / ; X Bernard / ; T Bouvy / ; R Briki / ; M Claeys / ; Y Dascotte / ; L Davin / ; T De Backer / ; F De Keyser / ; A De Meester / ; S De Ridder / ; P Dendale / ; K Denef / ; E Dhondt / ; M Emonts / ; J T M Geraedts / ; M Goethals / ; J-M Grégoire / ; E Haine / ; T Herbots / ; E Hoffer / ; W H J Hutse / ; A Kassab / ; P Lafontaine / ; P Lancellotti / ; P Lefebvre / ; H Lesseliers / ; A Lozano / ; R Maamar / ; C Martinez / ; J-F Noël / ; G Odent / ; A Pasquet / ; B Peperstraete / ; P Purnode / ; A Rogowsky / ; M Rosseel / ; J-P Salembier / ; P Surmont / ; P Thermol / ; A M F Vandeplas / ; S Van de Walle / ; F Van den Branden / ; P Vandergoten / ; B G Vanhauwaert / ; L Vanneste / ; J Vercammen / ; D Verleyen / ; D Vermander / ; G Vervoort / ; C Weytjens / ; N Yanni / ; A da Costa Pereira / ; A Rocha de Lorenzo / ; A Felice Castro Issa / ; B Mahler Mioto / ; C de Brito Vianna / ; C A W Segre / ; C J Grupi / ; C Okawabata / ; D Favarato / ; E Giusti Rossi / ; F Fernandes / ; F Pitella / ; F J Alvarez Ramires / ; F Henpin Yue Cesena / ; J F Monteiro Ferreira / ; J F Junior / ; L Tonet / ; L Nastari / ; L Machado Cesar / ; L H Gowdak / ; M A Matos / ; M Moretti / ; P C Morgado / ; R Vicente Amato / ; Tadeu Munhoz / ; S R Coimbra / ; H N Luqman / ; S Yakovova / ; M Mantcheva / ; V Mincheva / ; L Baurenski / ; K Karastanev / ; V Yordanova / ; Y Peneva / ; A Bailey / ; P Wong / ; M Fagan / ; G Sabe-Affaki / ; F M Villasenor / ; P Belisle / ; W K Son / ; D E Manyari / ; N Giacomantonio / ; B J Lubelsky / ; D Ezekiel / ; J C S Leong / ; A Grover / ; J Vavougios / ; Y Pesant / ; A M Kushner / ; M M M Yeung / ; G E Vertes / ; F J Nasser-Sharif / ; A H K Abdulla / ; D Spensieri / ; A Roy / ; T T Nguyen / ; M Leclair / ; P Morra / ; C Everton Biglow / ; J F Baril / ; K Lai / ; D S Wong / ; V Martinho / ; G A Antoniadis / ; G R Searles / ; D Rouse / ; G Brisson / ; S King Wong / ; R S Collette / ; M S C Ho / ; C Constance / ; R Gendreau / ; G W Kellam / ; T A Cieza Lara / ; H A Boyrazian / ; M Shamsuzzaman / ; D R Spink / ; A P T Wong / ; R S Grewal / ; C Che / ; J Janes / ; N Hechtenthal / ; M Czarnecka / ; D Saulnier / ; G Levesque / ; P F Clavette / ; D R Kennedy / ; A Kokis / ; T L Orenstein-Lyall / ; A Shekhar Pandey / ; J Robb / ; G Verret / ; W Czarnecki / ; W W H Tsui / ; F Perreault / ; G Chouinard / ; G Lafrance / ; G M Fullerton / ; J P Lavoie / ; P LeBouthillier / ; Q H Tran / ; I Rodriguez Marrero / ; F B Ramadan / ; P Talbot / ; M A Fazil / ; J Yi-Ming Cha / ; S Garg / ; R Chehayeb / ; B Roy / ; Y K Chan / ; H E Harlos / ; H B Matheson / ; R Patel / ; G F Vaz / ; J S Bhatt / ; E Liu / ; T H Ashton / ; H Sullivan / ; L P Quinn / ; K Yared / ; A Gupta / ; B Sullivan / ; J Campbell / ; S Pallie / ; H Kim / ; S Vizel / ; D Savard / ; J M Cherry / ; J Gold / ; S Chiu / ; G Brouillette / ; R R Singh / ; S Varma / ; A Belanger / ; J L Myburgh / ; J Berlingieri / ; W Nisker / ; G Boutros / ; A I Bakbak / ; W Healley / ; F Liu / ; C Tu / ; S Lv / ; X Liu / ; H Gao / ; H Li / ; H Zhao / ; L Cao / ; S Zhao / ; Y Wang / ; D Wu / ; F Gu / ; G Pan / ; P Liu / ; X Wang / ; H Jiang / ; J Li / ; J Wang / ; L Zhang / ; X Wang / ; Y Ke / ; D Li / ; G Chen / ; H Xue / ; Q Jin / ; W Dong / ; Y Chen / ; Z Fu / ; J Wang / ; H Hu / ; Q Liang / ; X Yang / ; Z Zhou / ; Z Xu / ; C Shao / ; H Zhang / ; H Pei / ; L Song / ; M Yu / ; T Guan / ; Y Tang / ; Y Wu / ; M Yang / ; G Ceng / ; X Chen / ; L Lin / ; Y Peng / ; X Yan / ; E Yao / ; X Zheng / ; B Chen / ; H Chen / ; W Chen / ; R Wang / ; Y Zheng / ; H Tan / ; S Zhou / ; Y Zhou / ; Z Liu / ; R Wang / ; Q Lu / ; L Lai / ; J Pan / ; L Wang / ; Q Fu / ; J Peng / ; N Du / ; H Li / ; Y Lv / ; W Miao / ; H Wang / ; Y Pu / ; T Wang / ; M Dong / ; L Gong / ; X Liu / ; J Zhang / ; L Zhang / ; Z Chen / ; Q Jiang / ; F Ma / ; W Xu / ; M Dai / ; Y Wang / ; J Wu / ; X Yu / ; C Chen / ; Y Huo / ; L Sun / ; W Gao / ; X Liu / ; Z Li / ; Y Hu / ; H Li / ; M Chen / ; G Li / ; M Xue / ; Y Yao / ; X Pan / ; Z Sang / ; G Zhao / ; J Pan / ; J Hang / ; L Sun / ; S Ma / ; G Zhang / ; G Zhou / ; W Li / ; Y Wang / ; B Zhu / ; B Yu / ; H Wang / ; S Zhu / ; X Chen / ; H Zhang / ; J Mao / ; M Xu / ; Q Liu / ; Q Huang / ; Y Xie / ; L Feng / ; F Chen / ; L Chen / ; Y Liu / ; X Pei / ; A Sun / ; Z Tian / ; W Wang / ; H Yang / ; X Yang / ; A Yu / ; M Zhang / ; C Zhang / ; X Guan / ; X Zhou / ; Y Li / ; Y Xing / ; K Chen / ; L Luo / ; S Dong / ; Y Chen / ; Y Zhou / ; S Zhou / ; Y Zhang / ; F Ai / ; G Chen / ; C Xiong / ; F Yang / ; K Yang / ; Y Zhou / ; J Yan / ; M Zhu / ; A Zhang / ; G Shan / ; J Chen / ; J Guo / ; S Wu / ; Z Li / ; J Chen / ; G Shan / ; Z Li / ; S Wu / ; A Zhang / ; L Li / ; R Liu / ; Y Yang / ; Y Yang / ; H Zhang / ; G Chen / ; X Gao / ; Z Du / ; L Liang / ; Y Wu / ; Y Zhang / ; Y Zhao / ; J Qian / ; L He / ; L Xiong / ; P Chen / ; P Chen / ; L He / ; L Xiong / ; C Peng / ; J Zhu / ; J Liu / ; X Xie / ; F Jiang / ; A Li / ; J Li / ; Q Yang / ; M Chen / ; H Cong / ; Y Guo / ; N Ren / ; J Xiao / ; Y Zhang / ; R Zhao / ; J Jiang / ; X Chen / ; X Deng / ; L Li / ; L Wang / ; S Wang / ; K Wu / ; X Zhang / ; W Du / ; D Shuang / ; J Wei / ; C Yuan / ; F Li / ; X Ou / ; Y Ou / ; G Yu / ; S Zhang / ; J Gao / ; Z Qian / ; G Wu / ; S Zheng / ; D Xu / ; J Xie / ; W Ren / ; X Yao / ; Y Wang / ; Z Chen / ; B Cai / ; L Li / ; J Lv / ; F Li / ; J Dong / ; J Li / ; L Feng / ; Z Deng / ; J Bozkova / ; J Carda / ; S Dedkova / ; A Dufka / ; J Fridrich / ; T Hodac / ; R Jirmar / ; A Kadleckova / ; M Karlicek / ; J Krupicka / ; J Kuchar / ; V Lavicka / ; J Leso / ; Z Lorenc / ; M Micko / ; P Navratil / ; I Petrova / ; P Povolna / ; L Raisova / ; P Raska / ; V Ravlyk / ; S Schlesingerova / ; E Smrckova / ; P Sternthal / ; H Stursova / ; P Vymetal / ; L Zaoral / ; P Wiggers / ; J Markenvard / ; L K Andersen / ; L Frost / ; J Refsgaard / ; S Strange / ; K Egstrup / ; R Sykulski / ; P Hildebrant / ; T Haghfelt / ; M Ege / ; S Cattan / ; M Adam-Blanpain / ; M Adda / ; N Aimouch / ; L Ardouin / ; S Assouline / ; A Aumjaud / ; C Barjhoux / ; R Baroudi / ; C Beaurain / ; M A Bennouna / ; A Bernard / ; C Bernardeau / ; E Blanc / ; I Blum-Decary / ; G Bodur / ; C Boesch / ; J Bonal / ; R Bonhomme / ; J L Bonnet / ; J Bories / ; M L Bourachot / ; F Brumelot / ; M Brunehaut Petaut / ; C Brunschwig / ; P Buffet / ; P Calmettes / ; I Centa / ; B Chartier / ; P Chemin / ; F Chometon / ; J Cohen / ; R Colin / ; Y Cottin / ; F Crespo / ; A Dabboura / ; F David / ; P Dehayes / ; P Dematteo / ; O Dibon / ; P Dodemant / ; V Dormagen / ; X Dreyfus / ; J M Dubois / ; F Duclos / ; M Ducoudre / ; O Duprez / ; P Durand / ; E Durand / ; P Egloff / ; M Escande / ; M C Escourrou Berdou / ; G Esna Ashari / ; I Feldmann / ; J Ferrieres / ; E Foltzer / ; B Fontanet / ; M Garandeau / ; T Garban / ; S Geffroy / ; T Gillet / ; S Godart / ; P Gosse / ; P Gratia / ; O Greiner / ; A Gueusquin / ; E Guiu / ; J M Guy / ; S Haddad / ; V Hennebelle / ; S Honorat / ; A Hourany / ; G Hua / ; P Jacquier / ; S Jean / ; R Jeremiasz / ; P Kohler / ; A Lacroix / ; M Leandri / ; Y Lemiere / ; M Liautard / ; P Loheac / ; J C Louchart / ; P Magnus / ; B Maheu / ; H R Malaterre / ; G Manchet / ; J Mantoux / ; D Manzi / ; M Marachli / ; M Maroun / ; N Meneveau / ; E Messas / ; J L Mougeolle / ; T Mouhat / ; J Muller / ; M Naisseh / ; P Nocon / ; D Onger / ; A Ouguoujil / ; M Ovize / ; E Page / ; K Pareathumby / ; A Pleskof / ; P Poinson / ; G Pons / ; P Pouderou / ; J N Poujois / ; V Probst / ; F Prunier / ; L Prunier / ; V Puel / ; D Rechtman / ; R Rennert / ; B Rijavec / ; Y Riou / ; J Robert / ; C Roche / ; G Roul / ; B Salaun / ; B Saleh / ; A Sandalian / ; M Sander / ; A Schenowitz / ; A Silvestre / ; H Soleille / ; S Tabet / ; M Tardy / ; F Thomas-Richard / ; B Truong / ; J Varaldi / ; H Vial / ; J M Walch / ; M Wazana / ; R Zeitouni / ; H Audibert / ; F Alizon / ; A Amlaiky / ; M Asplanato / ; C Baranes / ; M Bariaud / ; F Bernasconi / ; P Bousquet / ; C Ceraulo / ; G De Geeter / ; J Donetti / ; B Doucet / ; J Doucet / ; T Dutoya / ; D Ennouchi / ; M H Fallacher / ; G Fouquet / ; V Fourchard / ; J Gdalia / ; G Grollier / ; S Guerard / ; P A Jeannerat / ; Y Jobic / ; V Joulie / ; P Jourdain / ; V Jouve / ; R Ketelers / ; G Khaznadar / ; P Kohan / ; B Koujan / ; B Lammens / ; I Landragin / ; E Le Moal / ; D M'Bey / ; F Maes / ; S Maheas Morlet / ; R Massabie / ; D Meddah / ; F X Meriaux / ; C Mestre-Fernandes / ; P Meyssonnier / ; M Migliore / ; J Milewski / ; J F Millet / ; S Mingam / ; P Nazeyrollas / ; F Paganelli / ; F Pellerin / ; F Petitjean / ; A Pinzani / ; A Pladys / ; P Primot / ; A Pucheu / ; A Rahali / ; P Ravoala / ; D Rousson / ; P Samama / ; M Sardon / ; R Silvestri / ; P Soskin / ; X Tabone / ; C Tricot / ; B Vaquette / ; M Vogel / ; M Weingrod / ; V Aboyans / ; R Amoretti / ; J Aubry / ; P Berthezene / ; D Binet / ; X Bonnaud / ; P Bonnet / ; A Bonny / ; T Bouchaya / ; C Boureux / ; J M Bourgeois / ; L Brottier / ; B Cavert / ; S Cleron / ; E Dechoux / ; C Delhomme / ; J P Detienne / ; J P Dubs / ; B Faudon / ; F Fellous / ; R Fressonnet / ; Y Garaud / ; D Garcia / ; M Geneves / ; J L Gleizes / ; C Guyetand / ; B Hermellin / ; D Iovescu / ; J P Kanner / ; P Khanoyan / ; A Leherissier / ; A Maximovitch / ; B Merian / ; P Messali / ; Y Moreau / ; J Moyal / ; L Payot / ; L Petoin Peuch / ; J L Prevot / ; P Raymond / ; D Relange / ; S Reymond / ; J F Robert / ; H Rosenstein / ; J Schneider / ; R Schultz / ; P Tanielian / ; F Thoin / ; L Thomas / ; P Touzet / ; G Steg / ; G Amiel Oster Sauvinet / ; F Baylac Domengetroy / ; K Chamou / ; B Etcheverry / ; J L Farges / ; J Y Fraboulet / ; M Goralski / ; D Janody / ; B Mamez / ; W Manlay / ; F Paillard / ; F Pelier / ; A Petit / ; M Skonieczny / ; R Augarde / ; J B Fournier / ; S Liandrat / ; P Lim / ; A I Noury / ; D Paris / ; M Saade / ; J M Stordeur / ; N Danchin / ; M Pornin / ; L Fauchier / ; M Galinier / ; M A Balice-Pasquinelli / ; P Sosner / ; S Yvorra / ; E Delcoulx / ; F Mouquet / ; J E Poulard / ; A Sudre / ; P Heno / ; F Biausque / ; M Guenoun / ; G Attia / ; S Pouwels / ; L Carpentier / ; E Verbrugge / ; C Ziccarelli / ; M Elkohen / ; J Tricoire / ; P Lang / ; O Huttin / ; B-M Altevogt / ; U Altmann / ; M Baar / ; S Berrisch-Rahmel / ; A Birkenhagen / ; I Bläse / ; R Blindt / ; R Bosch / ; A Brattström / ; H-H Breuer / ; M Castrucci / ; S Cicek-Hartvig / ; R Cierpka / ; M Claus / ; M Deissner / ; M Drexler / ; T Eggeling / ; G Eisele / ; D Enayat / ; S Frickel / ; S Gessner / ; K Giokoglu / ; J Gmehling / ; F Goss / ; P Grooterhorst / ; D B Gysan / ; R Haberl / ; W Haerer / ; N Jun Hassler / ; S Heinemann / ; F Henschel / ; M Hinrichsen / ; W Hofer / ; A Hofmeister / ; G Hoh / ; E Horstkotte / ; F Jäger / ; M Jeserich / ; U Keil / ; H Killat / ; S Kimmel / ; M Kindel / ; P Kindler / ; S Kleta / ; J Könemann / ; K König / ; H Krause-Allmendinger / ; K Kronberg / ; I Kruck / ; V Männl / ; A Meinel / ; G Mentz / ; E Meyer-Michael / ; F Mibach / ; S Möller / ; S Muth / ; E Nelböck-Huber / ; D Ohlmeyer / ; Z Özkan-Rashed / ; P Paulus / ; S Perings / ; J Placke / ; C Raters / ; N Reifart / ; A Rink / ; K Rybak / ; I Salecker / ; K-H Schermaul / ; E Schmidt / ; K-H Schmitz / ; N Schön / ; T Schröder / ; B Sievers / ; M Simon / ; U Spengler / ; M Speth-Nitschke / ; A Stumpp / ; S Szabo / ; J Taggeselle / ; A Tamm / ; A Thelemann / ; C Thelemann / ; H Thümmel / ; G Unger / ; A Utech / ; J Volmar / ; B Wauer / ; G Wehr / ; L Weinrich / ; R Weinrich / ; U Windstetter / ; J H Wirtz / ; N Wittlich / ; P Ziehn / ; P Zündorf / ; Y Al Wahshi / ; P P Singh / ; A Narayan / ; F Al Tamimi / ; J Al Yazeedi / ; M Ayche / ; A Al Lawati / ; M Al Dhanki / ; A Salustri / ; A Al Sousi / ; T Salah / ; M Y Tamimi / ; A Agrawal / ; A Wassef / ; F Baslaib / ; G Al Radaideh / ; A Yusufali / ; N Bazargani / ; M Akbar / ; H Abdel Wahab / ; S Abdel Malak / ; I Ghaly / ; S Al Ghool / ; F Al Kandari / ; M Haiba / ; M Alanbaei / ; A El Menyar / ; M M Gomaa / ; A Khalifa / ; T Garadah / ; C Avgerinos / ; O Gouli / ; D Stergiou / ; I Alexopoulos / ; C Pappas / ; I Petropoulos / ; G Chatzioakim / ; N Pontikakis / ; C Priftis / ; P Mpompoth / ; I Bourazanis / ; A Papathanasioy / ; S Avlonitis / ; C Zakopoulos / ; G Koutsimpanis / ; I Tsamopoulos / ; C Christoforidis / ; V Zachos / ; P Kalaras / ; M Karachaliou / ; C Liatas / ; G Pournaras / ; G Theodorakis / ; I Orestis / ; K Panisois / ; E Chalkiadakis / ; V Arfaras / ; Melainis / ; G Kolios / ; P Boutsikos / ; A Kotsalos / ; D Mitropoulos / ; A Samothrakitis / ; K Svolis / ; E Anastasiou / ; T Gkinis / ; P Dalampyras / ; A Kalampalikis / ; I Leontaridis / ; S Gabriilidis / ; I Konstantinidis / ; V Plastiras / ; P Tarenidis / ; I Marozsán / ; I Édes / ; I Czuriga / ; A Cziráki / ; K Tóth / ; A Dongó / ; P Túri / ; T Forster / ; J Borbola / ; B Bachmann / ; G Masszi / ; M Orbán / ; G Gerges / ; G Balogh / ; E Bajcsi / ; M Sereg / ; A Dézsi / ; I Takács / ; L Nagy / ; B Kisjós / ; A Jánosi / ; A Nagy / ; K Nagy / ; A Büttl / ; J Lippai / ; Zs Sziegl / ; Zs Malkócs / ; A Földi / ; K Fikker / ; E Szabó / ; B Merkely / ; R Gupta / ; S Natarajan / ; J Dalal / ; R K Saran / ; A Mehta / ; M P Samal / ; I A Khan / ; T Ghose / ; J P S Sawhney / ; T Roy / ; S Chandra / ; S Modi / ; M M Singh / ; G Vijayaraghavan / ; L Sreenivasa Murthy / ; S S Ramesh / ; Dayasagar Rao / ; M S Chenniappan / ; A Vadavi / ; K Kunhali / ; K Srinivasa Reddy / ; Su Thillai Vallal / ; P Khera / ; A Dasbiswas / ; K Ganguly / ; S S Chatterjee / ; B Prasad / ; D Shukla / ; A K Trivedi / ; R Ahuja / ; J Deb / ; J Rawal / ; R Karnik / ; M S Hiremath / ; D K Kumbla / ; S R Shetty / ; N S Chonkar / ; Late M Juneja / ; B K Goyal / ; R Sheahan / ; N Mulvihill / ; C Vaughan / ; S Fleming / ; P Shiels / ; P Keelan / ; T Kiernan / ; J Cosgrave / ; B Day / ; K Kelly / ; F MacNamara / ; B Maguire / ; A Clifford / ; A O'Gara / ; G Guardigli / ; G Riccioni / ; R Pedretti / ; S Felis / ; V Pernice / ; A Lillo / ; P Gori / ; F Zacà / ; F Giacomazzi / ; P Terrosu / ; C Cernetti / ; R Antonicelli / ; G Ansalone / ; M Balbi / ; C Tamburino / ; S Tantillo / ; F Proietti / ; V Mallamaci / ; D d'Este / ; F Silvestri / ; F Magliari / ; N Capuano / ; N Marchionni / ; M Turiel / ; P Maxia / ; L Marullo / ; A Vicentini / ; G Pes / ; G Caridi / ; A Grieco / ; B Doronzo / ; A Lacchè / ; F Massari / ; S Orazi / ; G Antonelli / ; M Provvidenza / ; A Nicolino / ; S De Servi / ; G Sinicropi / ; G Maragoni / ; P Azzolini / ; E Brscic / ; A S Bongo / ; G Perna / ; B Perna / ; C La Rosa / ; E Mossuti / ; R Ferrante / ; M E Petrillo / ; M Castellari / ; P Di Pasquale / ; F Saporito / ; F Alitto / ; R Testa / ; S M Kang / ; B K Koo / ; S K Hong / ; W Kim / ; S H Lee / ; H S Seo / ; H C Gwon / ; D H Kang / ; H M Kwon / ; I H Chae / ; S J Oh / ; J H Shin / ; C W Goh / ; D S Kim / ; J H Zo / ; T J Hong / ; T J Cha / ; J K Ryu / ; Y J Kim / ; J Y Hwang / ; S H Hur / ; M H Jeong / ; S K Oh / ; D K Jin / ; K T Jung / ; J Y Rhew / ; S Lee / ; D W Jeon / ; S H Kim / ; I Mintale / ; G Latkovskis / ; S Hansone / ; N Rozkova / ; A Baika / ; I Jasinkevica / ; S Abele / ; I Laizane / ; N Pontaga / ; V Ecina / ; I Mihailova / ; A Kondratovica / ; A Laucevičius / ; R Jurgaitienė / ; R Šlapikas / ; G Barauskienė / ; E Jankauskienė / ; S Revienė / ; T Vaišvila / ; D Zaronskienė / ; O B Šlapikienė / ; N Kupstytė / ; E Rinkūnienė / ; R Steponėnienė / ; J Kojelienė / ; J Badarienė / ; V Dženkevičiūtė / ; E Sadauskienė / ; I Butkuvienė / ; R Stankevičius / ; R Paliulionienė / ; R Snikytė / ; R Mažutavičius / ; A N Jamaluddin / ; A A Abdul Rahim / ; K Mohamed Yusof / ; K H Chee / ; A Sadiq / ; S Ramanaidu / ; K H Sim / ; T K Ong / ; A Y Y Fong / ; B C Chang / ; S K Chua / ; Y L Cham / ; N A Mohd Amin / ; T K Ong / ; S K Tan / ; K Chandran / ; Y W Cheah / ; J Sinnadurai / ; C K Choor / ; K K Sia / ; C C Ang / ; J Singh / ; M Z Abdul Wahab / ; A K Ghapar / ; A Muthu / ; M Kauthaman / ; A H Jaafar / ; K H Ng / ; A R Tahir / ; H Abdul Manap / ; B S K Ch'ng / ; E T Ch'ng / ; O Ismail / ; A S Sahar / ; B B Abdul Kareem / ; S K Ma / ; H B Liew / ; R K M Bhaskaran / ; R P Shah / ; K L Joseph / ; H Noor Hasni / ; W K Ng / ; G H Choo / ; C K Yeo / ; V M Lai / ; Y C Lai / ; M H Tay / ; B A Lim / ; H N Luqman / ; Guillermo Llamas Esperon / ; J de Jeús Zuñiga Sedano y America Alvarez / ; F Azar Manzur / ; C Jerjes Sánchez / ; J Cerda Rojas / ; J Carrillo Calvillo / ; F Petersen Aranguren / ; C Martínez Sánchez / ; G Vieyra / ; S González Romero / ; A Puente Barragán / ; F Redding Escalante / ; J Chávez Paez / ; E Fernandez Valadez / ; E Gaxiola / ; L E Manautou / ; O Henne Otero / ; M Barrera Bustillos / ; J L Leyva Pons / ; E Gómez Alvarez / ; J R Romo Santana / ; J Martínez Redding / ; A Arias Mendoza / ; I Rodríguez Briones / ; J de Jeús Rivera Arellano / ; J L Arenas León / ; M Alcocer Gamba / ; E Alexanderson / ; M E Ruíz Esparza / ; L A Elizondo Sifuentes / ; J L Briseño / ; S Sandoval / ; A Castro / ; R Cue Carpio / ; E Rodríguez / ; G Rojas / ; G Solache / ; R Díaz / ; R Baleón / ; Ferreyra Solorio / ; H Alberto Ramírez Reyes / ; M López Martínez / ; M A Romero Maldonado / ; J Escobedo de la Peña / ; J Hilario Jimenez Orozco / ; F A Reyes Cisneros / ; J Alvarez Gil / ; G Bautista / ; López / ; M Odín de los Ríos Ibarra / ; I I Tulevski / ; G A Somsen / ; J E Wittekoek / ; K Miedema / ; P R W de Sauvage Nolting / ; I Chlewicka / ; P Brodzicki / ; T Stasiuk / ; P Szałkowski / ; W Kulig / ; M Maliszewski / ; K Królicka / ; J Zdrojewska / ; I Nikodemska / ; A Szpak / ; M Wrębiak-Trznadel / ; A Prokop / ; M Szulc / ; A Olszewski / ; W Kępa / ; J Banach / ; M Węglarz / ; A Gałuszka-Bilińska / ; A Królak / ; E Cisowska-Drozd / ; K Orzechowski / ; M Jeżewska / ; K Adamaszek / ; G Glanowska / ; T Pitsch / ; G Matuszewska / ; A Nowowiejska-Wiewióra / ; M Dereń / ; G Walawski / ; M Sołtysiak / ; R Wysocki / ; G Jarosiński / ; A Drzewiecka / ; T Ługowski / ; A Jankowska / ; P Błaszczak / ; J Drozd / ; E Łotocka / ; R Duchowska / ; D Sobczyk / ; P Jarmużek / ; M Sidor / ; D Adamczyk-Kot / ; J Sudnik / ; J Cygler / ; I Skoczylas / ; B Poprawa / ; L Kisiel / ; U Kossowska / ; B Sikorska-Buczkowska / ; K Modzelewska / ; B Demianiuk / ; W Streb / ; T Mularek-Kubzdela / ; P Bogdański / ; E Kaźmierczak / ; R Zimoląg / ; J Lorenc / ; R Furtak / ; A Regulska / ; M Winter / ; M Fic / ; P Turek / ; E Nowicka / ; W Bryl / ; L Lenartowska / ; O Jerzykowska / ; M Maćków / ; W Gadziński / ; R Kacorzyk / ; D Zalewska / ; R Sadłowski / ; J Słaboszewska / ; M Gruchała / ; A Frankiewicz / ; J Walczewska / ; A Adamkiewicz-Piejko / ; R Chyrek / ; L Jankowska / ; A Correia / ; A Girão / ; A Herdade / ; A Sequeira / ; A Tavares E Taveira / ; A Gonzaga / ; A Ribeiro / ; A Albuquerque / ; A Fernandes / ; A Estriga / ; A Rocha De Almeida / ; A Lourenço / ; A Pereira / ; A Faria / ; B Carvalho De Moura / ; C Camossa / ; C Alves / ; C Aguiar / ; C Rodrigues / ; E Wellenkamp / ; E Lins / ; F Fernandes De Sousa / ; F Moreira Pinto / ; F Matias / ; G Silva Alves / ; G Bragança / ; G Proença / ; G Pêgo / ; H Vinhas / ; I Arroja / ; J Rosa Pais / ; J Morais / ; J Silva E Sá / ; J Vasconcelos / ; J Matos / ; J Freitas / ; J Ferreira / ; J Costa / ; J Alcaravela / ; J Mimoso / ; J Antunes / ; J Ferreira Dos Santos / ; J Nobre Dos Santos / ; J Tito Martins / ; J Fernandes / ; J Chambel De Aguiar / ; J Moreira / ; J Carvalho / ; J Forte De Carvalho / ; J Calaça / ; L Simões / ; L Lopes Antunes / ; L Soares / ; L Semedo / ; L Macedo / ; L Sargento / ; L Basto / ; L Carpinteiro / ; L Rebelo / ; L Oliveira / ; M Catarino Carvalho / ; M Alves Costa / ; M C Gamboa / ; M F Ferrão E Vasconcelos / ; M H Custódio / ; M I Mendonça / ; M J Pinto Vaz / ; M Espiga De Macedo / ; M Lazaro / ; M Martins Oliveira / ; N Pelicano / ; N Lousada / ; O Rodrigues / ; P Matos Dias / ; P F Fonseca / ; P Ferreira / ; P E Abreu / ; P Monteiro / ; R Seabra Gomes / ; R Carvalho / ; R Santos / ; R Pires Pereira / ; R Rosado Soares / ; S Baptista / ; S Reis Monteiro / ; V Gil / ; V Sanfins / ; V Martins / ; M Anghel / ; C Arsenescu Georgescu / ; K Babes / ; M Banu / ; R Beyer / ; I Bratu / ; A Bumbu / ; R Capalneanu / ; O D Chioncel / ; T Chiscaneanu / ; R Christodorescu / ; N Cindea Nica / ; M Cinteza / ; S Coman / ; M Constantinescu / ; E Craiu / ; G A Dan / ; D C Dan / ; A Dan / ; C M David / ; M Dorobantu / ; D Farcas / ; V Firastrau / ; C Florescu / ; A Ghicu / ; A Giuca / ; R Grigoriu / ; D A Ionescu / ; D D Ionescu / ; L C Iosipescu / ; M V Ivan / ; D Lighezan / ; S Magheru / ; M Magherusan / ; S M Marinescu / ; A C Motoc / ; R Musetescu / ; M Rau / ; L Rotaru H Rus / ; O Sirbu / ; L Sorodoc / ; C M Spinu / ; G Stanciulescu / ; C Statescu / ; M Toringhibel / ; R Trambitas / ; N Trocan / ; A Tudose / ; D Vinereanu / ; M Zagreanu / ; D Dymova / ; N Semenova / ; A Zherebtsova / ; V Fedoskin / ; N Gurianova / ; N Bolotova / ; V Knyazeva / ; T Spitsina / ; N Sytilina / ; N Atamanchuk / ; M Giorgadze / ; S Zarechnova / ; S Kutuzova / ; Y Sharapova / ; I Stelmakh / ; O Sinyukova / ; S Rostik / ; L Evtukhova / ; L Sukhanova / ; T Makhieva / ; S Tereshko / ; V Kolesnikov / ; E Kochurov / ; B Marchenko / ; S Nurgalieva / ; Z Galeeva / ; E Andreicheva / ; V Zakirova / ; L Baleeva / ; A Minsafina / ; N Borodina / ; Y Arkhipova / ; T Krechunova / ; M Scherbak / ; A Merkhi / ; N Aksyutina / ; O Ratovskaya / ; E Suglobova / ; Y Kozhelenko / ; E Potapova / ; G Poluyanova / ; N Naberezhnova / ; E Daniels / ; K Atueva / ; L Tsaryabina / ; A Kurekhyan / ; N Khishova / ; E Dubinina / ; O Demina / ; P Mochkina / ; E Bukanina / ; S Tolpygina / ; Y Polyanskaya / ; A Malysheva / ; T Kheliya / ; A Serazhim / ; V Voronina / ; Y Lukina / ; R Dubinskaya / ; N Dmitrieva / ; M Kuzyakina / ; N Khartova / ; N Bokuchava / ; E Smirnova / ; A Esenokova / ; Y Pavlova / ; O Smirnova / ; P Astrakhantseva / ; S Bykovskaya / ; O Charikova / ; K Berdnik / ; T Karaseva / ; L Zhabina / ; N Oleinikova / ; O Dzhkha / ; S Grigoryan / ; E Yakovenko / ; T Ivaschenko / ; I Kiseleva / ; T Shokina / ; M Novikova / ; A Khodanov / ; L Popova / ; L Latyntseva / ; O Kilaberiya / ; K Makarenkova / ; N Nosova / ; T Gerasimova / ; L Boikova / ; N Sharapova / ; Y Kulikova / ; N Pasechnaya / ; E Bulakhova / ; S Kurochkina / ; I Bratishko / ; O Likhobabina / ; E Panova / ; N Voronina / ; N Bizyaeva / ; O Gusev / ; N Nevolina / ; T Arsentieva / ; I Budanova / ; E London / ; Melnikova / ; A Khripun / ; L Polyaeva / ; E Osadchuk / ; O Krasnoslobodskaya / ; N Yakimova / ; A Lugin / ; Y Sosnova / ; E Il'ina / ; G Kositsina / ; I Shanina / ; S Kostomarova / ; M Malgina / ; M Omelchenko / ; I Gorlova / ; S Eidelman / ; A Salakhova / ; B Bondarenko / ; R Sopia / ; N Baboshina / ; N Eliseeva / ; F Tumarov / ; N Petrochenko / ; I Khudina / ; N Arabadzhi / ; V Samakhovets / ; L Tkhorzhevskaya / ; T Sinotova / ; E Zherlitsyna / ; S Minkin / ; N Petrova / ; Y Tikhonov / ; N Shmakova / ; V Abduvalieva / ; M Kuzmicheva / ; L Nikolaeva / ; O Varezhnikova / ; T Dmitrieva / ; E Mikhailova / ; Y Yanina / ; L Kapustina / ; Z Vazhdaeva / ; G Golovina / ; N Fedorova / ; I Nikolaeva / ; O Fillipova / ; L Gareeva / ; F Tuktarova / ; N Khmelevskikh / ; V Karnot / ; M Golub / ; I Surovtseva / ; V Kulygina / ; N Shelomova / ; I Kruglova / ; I Pokrovskaya / ; O Rodina / ; L Polkina / ; N Biryukova / ; E Filippova / ; E Kotova / ; T Ignatieva / ; T Alekseeva / ; L Gruznykh / ; E Mozerova / ; E Moksyuta / ; E Kosachek / ; N Srtumilenko / ; O Baranova / ; T Voronova / ; L Bayakhchan / ; I Grudtsina / ; L Gorshkova / ; O Shamsutdinova / ; M Getman / ; I Gorodilova / ; N Karnaukhova / ; V Rotenberger / ; L Isaeva / ; G Lebischak / ; V Ryzhkova / ; E Usoltseva / ; D Mescharekova / ; E Tavlueva / ; E Mineeva / ; M Stikhurova / ; L Kosareva / ; O Grechishkina / ; S Nikishina / ; A Ilyukhina / ; O Gureeva / ; I Soin / ; S Erofeev / ; S Lebedev / ; I Kudryavtsev / ; E Gamzatov / ; N Maximchuk / ; L Grekhova / ; L Kolevatova / ; M Kazakovtseva / ; O Kolesova / ; L Zharikova / ; V Kukaleva / ; N Starostina / ; I Grushetskaya / ; V Kazachkova / ; I Pashentseva / ; S Shimonenko / ; I Sirazov / ; A Chernozemova / ; O Golubeva / ; S Mingalaeva / ; E Zatsarina / ; D Kozlov / ; N Davydova / ; O Larina / ; K Fayez Al-Habib / ; A Al-Hersi / ; H Al-Baker / ; H Al-Faleh / ; A Moberik / ; M Radwan Arafah / ; M Al-Shamiri / ; F El-Shaer / ; M Al Zaibag / ; M Bdeir / ; I Suliman / ; A Mukhtar / ; H Omar / ; A Jamiel / ; A Elkrail / ; M Alanazy / ; M Habab / ; K Ashmak / ; R Nourallah / ; K H Mak / ; B Singh / ; S Baldev / ; T S Chee / ; C C Koo / ; L P Low / ; V P Nair / ; K S Ng / ; S S S Quek / ; E H M Tan / ; A L R Ng / ; H H Chuang / ; G Kamensky / ; G Kaliska / ; J Murin / ; K Hatalova / ; L Gaspar / ; I Simkova / ; J Dubrava / ; J Pjontek / ; D Pella / ; A Banikova / ; M Szentivanyi / ; F Kovar / ; J Benacka / ; I Gonos / ; F Fazekas / ; P Kycina / ; J Poles / ; Z Fras / ; A Pernat / ; A Veternik / ; N Černič-Šuligoj / ; M Kerbev / ; I Krajnc / ; P Zagožen / ; A Alam / ; B Brown / ; B Luke / ; E Variava / ; R Nethononda / ; S Joubert / ; P Matthews / ; L Nkombua / ; V Antia / ; D P Naidoo / ; J Bhayat / ; S K George / ; N Ranjith / ; G H M Vawda / ; S Govender / ; I Soosiwala / ; K Shein / ; M Panajatovic / ; J Flores / ; M S H Khan / ; S Blignaut / ; K Coetzee / ; L Burgess / ; V Freeman / ; H D Theron / ; M A Arnau Vives / ; F J Abardía Oliva / ; V Albero Martínez / ; J M Alegret Colomer / ; E Alegría Ezquerra / ; C A Almeida Fernández / ; N Alvarenga Recalde / ; A AlvarezAuñon / ; P Alvarez García / ; C Amo Fernández / ; C Amoros Galito / ; R Ancín Viguiristi / ; J Antona Makoshi / ; M Aparici Feal / ; A Ardiaca Capell / ; J Arnedillo Pardo / ; G Arquero García / ; V Arrarte Esteban / ; M Baquero Alonso / ; P Barahona Pérez / ; J L Bardají Mayor / ; V Barriales Alvarez / ; A Batalla Celorio / ; D Bierge Valero / ; J Blanco Castiñeiras / ; F Bosa Ojeda / ; C Botana Penas / ; H Brufau Redondo / ; J Bruguera Cortada / ; J Cabau Rubies / ; R Cabrera Solé / ; F Calvo Iglesias / ; S Cantabrana Miguel / ; R Carrillo Cardoso / ; M Casanovas Pié / ; P Casas Giménez / ; E Castillo Lueña / ; J A Castillo Moreno / ; M Castillo Orive / ; A Chirivella González / ; J M Chopo Alcubilla / ; V Climent Payá / ; M A Cobos Gil / ; J L Colomer Martín / ; A Concepción Clemente / ; R Cortés Sánchez / ; D Cremer Luengo / ; S Darnes Soler / ; J de Andrés Novales / ; R De Castro Aritmendiz / ; J L Delgado Prieto / ; J L Díaz Díaz / ; C Escobar Cervantes / ; J Ezcurdia Sasieta / ; L Facila Rubio / ; C Falces Salvador / ; P Federico Zaragoza / ; R Fernández Alvarez / ; F Fernández de la Cigoña / ; L A Fernández Lázaro / ; L C Fernández Léoz / ; R Fernández Mouzo / ; M Fernández-Valls Gómez / ; B Ferreiro Rodríguez / ; C Franco Aranda / ; J Freire Corzo / ; J Fuertes Alonso / ; J Fuertes Beneitez / ; E Galve Basilio / ; C García García / ; M J García González / ; S García Ortego / ; V García Saavedra / ; J García-Moll Marimón / ; R Gascueña Rubia / ; D Gentille Lorente / ; H Gervas Pavón / ; R Gilabert Gómez / ; J J Gómez Barrado / ; J J Gómez Doblas / ; M J Gómez Martinez / ; C González Juanatey / ; V González Toda / ; M Gonzalvez Ortega / ; E Gordillo Higuero / ; J Hernández Afonso / ; D Herrera Fernández / ; E Homs Espinach / ; A Idoate Gastearena / ; M Irurita Latasa / ; R Izquierdo González / ; M Jaquet Herter / ; M Lagares Carballo / ; J A Lastra Galán / ; B Limeres González / ; M A López Aranda / ; L López Barreiro / ; D López Gómez / ; A López Granados / ; V López Mouriño / ; J L López-Sendón / ; L Mainar Latorre / ; E Marín Araez / ; F Marín Ortuño / ; A Martín Santana / ; J Martínez Florez / ; J Martínez González / ; J F Martínez Rivero / ; D Marzal Martín / ; G F Mazzanti Mignaqui / ; A Melero Pita / ; E Molina Laborda / ; Ma A Montero Gaspar / ; J Mora Robles / ; J Morales González / ; J Moreno Arribas / ; Ma T Moreno Casquete / ; J A Moro López / ; C Moya López / ; N Murga Eizagaechevarría / ; F Narro García / ; J Navarro Manchón / ; C Navas Navas / ; E Novo García / ; J A Núñez Gamero / ; A Ordóñez España / ; J A Ortiz de Murua López / ; E Orts Soler / ; E Otero Chulian / ; L Pastor Torres / ; A J Paule Sánchez / ; M A Paz Bermejo / ; G Peña Pérez / ; J A Perea Egido / ; L Pérez de Isla / ; S Pérez Ibiricu / ; Ma A Pérez Martínez / ; M Pérez Paredes / ; E Peris Domingo / ; J Pinar Sopena / ; C Pindado Rodríguez / ; Ma J Pinilla Lozano / ; C Piñero Ramírez / ; Y Porras Ramos / ; F Ramos Ariznabarreta / ; M Rayo Gutiérrez / ; J M Roca Catalán / ; A Rodríguez Almodóvar / ; J Rodríguez Collado / ; A Rodríguez Fernández / ; J A Rodríguez Fernández / ; J A Rodríguez Hernández / ; I Rodríguez Tejero / ; I Romeo Castillejo / ; D Romero Alvira / ; J A Romero Hinojosa / ; C Romero Menor / ; P Rossi Sevillano / ; E C Rueda Calle / ; J Rueda Soriano / ; P Ruiz Pérez / ; T Sagastagoitia Gorostiza / ; I Sainz Hidalgo / ; M Sandin Rollán / ; S Santaolalla Rodríguez / ; E Santas Olmeda / ; J L Santos Iglesias / ; M L Sanz Rodríguez / ; I Segura Laborda / ; S Serrano García / ; B Sevilla Toral / ; L Silva Melchor / ; E Simarro Martín-Ambrioso / ; R Sola Casado / ; C Soriano Navarro / ; Ma I Soto Ruiz / ; P Talavera Calle / ; P L Torres Díaz / ; A Troncoso Gil / ; F Trujillo Berraquero / ; M A Ulecia Martínez / ; J Umaran Sánchez / ; C Vaticón Herreros / ; A Vázquez García / ; J L Vega Barbado / ; E Velasco Espejo-Saavedra / ; T Vicente Vera / ; M Vida Gutiérrez / ; C Villar Mariscal / ; G Vives Bonato / ; L Wu Amen / ; G Yanes Bowden / ; J C Yañez Wonenburger / ; J L Zamorano Gómez / ; J Zarauza Navarro / ; P Monnier / ; A Jaussi / ; A Forclaz / ; M Grobéty / ; L Schlueter / ; C Vuille / ; C A Nacht / ; D Evéquoz / ; S Ciaroni / ; F Dominé / ; J Bérubé / ; H Rickli / ; J Hellermann / ; R Koller / ; G Bourgeois / ; R Engel / ; C Niederberger / ; P Stadler / ; M Gnädinger / ; C Schmied / ; T Wettstein / ; C Badorff / ; P Hilti / ; C A Chételat / ; F Sepulcri / ; H Brunner / ; J Schindler / ; M Kraus / ; W Gmür / ; C Bouranasompop / ; W Jiraroj-ungkun / ; W Lapanun / ; V Vivekaphirat / ; S Panpunnung / ; S Dutsadeevettakul / ; S Tasneeyapant / ; P Ngamjanyaporn / ; S Apitamsuntorn / ; W Tantisiriwat / ; T Suithichaiyakul / ; S Kuanprasert / ; W Wongcharoen / ; A Phrommintikul / ; C Musigchai / ; T Chantrarat / ; P Uerojanaungkul / ; S Apinyasawat / ; T Tangcharoen / ; M Lertnantakul / ; A Wasuwat / ; J Harinasuta / ; O See / ; V Chaithiraphan / ; T Boonyasirinant / ; W Boonyapisit / ; M Kittipovanonth / ; A Buakhamsri / ; D Piyayotai / ; P Hutayanon / ; S Junejo / ; O Aiyegbayo / ; H Ancliff / ; C Bradshaw / ; R Cervenak / ; H Choi / ; E George / ; I Gilmour / ; D Gough / ; A Idrissi-Sbai / ; J Ingham / ; B Al-Khalidi / ; A Liston / ; J Mackrell / ; I Pattison / ; R Ramachandran / ; N Ray / ; G Reddy / ; I Sen / ; K Shetty / ; L Singh / ; M Stanley / ; A Wallace / ; M Weatherhead / ; T Gilbert / ; G McCansh / ; S Higgins / ; C Killeen / ; I Cromarty / ; P Franklin / ; E Pinch / ; A Dhesi / ; C Dernedde / ; M Lawrence / ; H Simper / ; M Noble / ; G Dalton / ; L Stevens / ; P Berry / ; C Hand / ; R Oliver / ; H Jones / ; P Sampson / ; N Taylor / ; R Grogono / ; J Dalrymple / ; A Martin / ; S Thurston / ; K Elsby / ; M Vallis / ; G Morrison / ; C Lang / ; A Watson / ; A Thomson / ; H Dougall / ; B La Hay / ; L Compson / ; A McCracken / ; J Calder / ; F Weber / ; D Richmond / ; R Brownlie / ; G Brown / ; H MacCowan / ; A Heap / ; M Perry / ; L A Holden / ; G Scott / ; N Haldane / ; S Hood / ; I Culllen / ; J Bell / ; P McNaught / ; M Sharif / ; J Dunn / ; D Hay / ; S Ross / ; R Shaw / ; L Hay / ; S Langridge / ; R Burns / ; L Crawford / ; A Kennedy / ; D Logan / ; P McAlavey / ; M Brown / ; P Costello / ; G McLaren / ; A Potter / ; J McPherson / ; M Drijfhout / ; J Finlayson / ; D Troup / ; A Woodall / ; J Pearce / ; S Williams / ; W Parkar / ; A Yusuf / ; I Benett / ; P Bishop / ; H Thomas / ; I Caldwell / ; P Ormiston / ; S Kwok / ; S Wright / ; N Kanumilli / ; P Saul / ; H Milligan / ; I Wilkinson / ; A Vance / ; N Paul / ; C Paul / ; I Shaikh / ; R Ellis / ; N Vites / ; R Steeds / ; D Goodwin / ; A Aftab / ; S Banham / ; N Chauhan / ; M S Grocutt / ; A Gupte / ; R Jordan / ; B S Jheeta / ; K Ladha / ; M Nazir / ; R Pal / ; R P Patel / ; R McManus / ; A Singal / ; P Saunders / ; A B Syed / ; A Bahal / ; H Dau / ; D M Walker / ; R McNeilly / ; A Bolidai / ; N MacCarthy / ; D Lawton / ; M Vardhani / ; G Sengupta / ; D Kinloch / ; F Howie / ; A Serrano-Garcia / ; S E Paget / ; R Till / ; P Seal / ; J Morrell / ; T Maxwell / ; G Singh / ; D Warden / ; R Elias / ; C Dixon / ; R K Pandey / ; V Challenor / ; S Davies / ; M Gibbs / ; A Gillet / ; C Goldie / ; I Jarvis / ; P Johnson / ; M Malden / ; J Moore / ; C Morton / ; K Nehrig / ; P Sheringham / ; G Wilson / ; J Halcox / ; I O'Connor / ; K Ling / ; D Edwards / ; H Charles / ; A Weatherup / ; E Davies / ; N Watkins / ; D Morgan / ; R Davies / ; A Lindsay / ; D Beacock / ; R Balai / ; P Kirmond / ; P Brindle / ; C Bundy / ; T Cahill / ; A Dayani / ; P Eavis / ; S Mohr / ; S Hayne / ; C Krasucki / ; M Micheals / ; I Orpen / ; I Parker / ; R Sewell / ; D Sharp / ; A Smith / ; A Stevens / ; J Upton / ; J Victory / ; C Wernham / ; R Davis / ; C Mays / ; M Andrews / ; J Takhar / ; C Travill / ; P Choudhury / ; W Matta / ; A Ihonor / ; C O'Dong / ; S Rahman / ; P Singer / ; S Gillam / ; P S Bath / ; N Razzaq / ; O O'Toole / ; P Rowe / ; H Williams / ; P Kalra / ; A Allcock / ; A Tucker / ; V Sprott / ; K Kyd / ; G Cunliffe / ; C Arden / ; A Bateman / ; G Kassianos / ; D Sinclair / ; C Turner / ; R Jagathesan / ; F Sattar / ; A Ashford / ; A Chukwu / ; H Taylor / ; R Pradhan / ; T Rundell / ; R Howlett / ; R Bietzk / ; R Patel / ; M Myint / ; M Partington / ; F O'Reilly / ; M Baverstock / ; S Dixon / ; M Tennekoon / ; N Brand / ; P Haimes / ; P Keller / ; S Whetstone / ; R Davis / ; C Mays / ; M Andrews / ; J Takhar / ; O Kovyrshyna / ; V Rogozhyna / ; T Kiver / ; V Vasylenko / ; L Kucheryava / ; S Salimova / ; V Alekseenko / ; O Gukov / ; I Myhailiv / ; L Kardashevskaya / ; O Prikolota / ; O Bashkirtcev / ; E Andreev / ; L Tkachenko / ; M Mospan / ; V Batushkin / ; L Safonova / ; A Ogorodnichuk / ; S Pustovit / ; S Romanov / ; L Burlakova / ; Y Voloshko / ; V Lafarenko / ; S Vlasuk / ; O Leshchuk / ; S Chushak / ; V Koval / ; O Stasuk / ; O Pogrebna / ; S Kornienko / ; S Tikhonova / ; T Fesenko / ; T Kuzmina / ; O Ushakov / ; N Vechtomova / ; L Potapska / ; I Illushechkin / ; E Kryvenkova / ; O Lysunets / ; O Tsygankov / ; L Bardachenko / ; L Voloshyna / ; V Ginzburg / ; L Franskyavichene / ; T Korotich / ; N Vyshnevaya / ; N Bilous / ; S Kulinich / ; V Kulik / ; I Sadykova / ; T Berezhna / ; S Molotyagina / ; L V Nguyen / ; M H Pham / ; H T Pham / ; N H Khong / ; K B Do / ; T B Le / ; P A Do / ; T C Do / ; N Q Nguyen / ; Q H Do / ; K C Vu / ; N H Pham / ; T H T Pham / ; M C Ta / ; D P Phan / ; T T H Nguyen / ; T T N Pham / ; T L To / ; V T Le / ; L Dang / ; L Bui / ; T T H Pham / ; H H Phan / ; T T H Bui / ; T V A Tuong / ; T P Nguyen / ; T H Nguyen / ; B K Nguyen / ; D B Vu / ; N S Pham / ; T K Do / ; T S Pham / ; V D Dang / ; D T Le / ; V C Do / ; T K L Nguyen / ; H L Luong / ; T Q Luu / ; N W Pham / ; T K Huynh / ; N T H Tu / ; K A Ngo / ; T T C Nguyen / ; T T L Ong / ; V B Doan / ; T B Kim / ; T N Vo / ; T T T Tran / ; T A Nguyen / ; V D Tran / ; A K Nguyen / ; A K Tran / ; M H Ngo / ; N H Vu / ; I T Ly / ; N P H Tran / ; L U P Tran / ; T N Nguyen / ; T H Tran / ; P H Truong / ; T L Mai / ; V S Hoang / ; C M A Bui / ; V P Dang / ; Q B Truong / ; M P Vo / ; V T Nguyen / ; N H Chau / ; T T H Ta / ; H N Dinh / ; H Tran / ; H K N Nguyen / ; A Chung / ; E Chung / ; B Martina-Hooi / ; R Angela / ; P Ramoutar / ; R Fillet / ; R Tilluckdharry / ; T Dookie / ; E Foster / ; C Hart / ; F Omardeen / ; S Ramphall / ; C Lalla / ; R Henry / ; J Cheng / ; V Elliott / ; H Falconer / ; L Hurlock-Clarke / ; R Ishmael / ; G Lalljie / ; K Lee / ; A Liqui-Lung / ; R Massay / ; H Mohammed / ; C Brown / ; R Daniel / ; M Didier / ; Z Salas /
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): PLoS One
Journal ID (iso-abbrev): PLoS ONE
Journal ID (publisher-id): plos
Journal ID (pmc): plosone
ISSN: 1932-6203
Publisher: Public Library of Science, San Francisco, USA
Article Information
Download PDF
Steg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received Day: 15 Month: 2 Year: 2012
Accepted Day: 29 Month: 3 Year: 2012
collection publication date: Year: 2012
Electronic publication date: Day: 3 Month: 5 Year: 2012
Volume: 7 Issue: 5
E-location ID: e36284
ID: 3343045
PubMed Id: 22570699
Publisher Id: PONE-D-12-04561
DOI: 10.1371/journal.pone.0036284

Heart Rate and Use of Beta-Blockers in Stable Outpatients with Coronary Artery Disease Alternate Title:Heart Rate and Beta-Blocker Use in CAD
Ph. Gabriel Steg123*
Roberto Ferrari4
Ian Ford5
Nicola Greenlaw5
Jean-Claude Tardif6
Michal Tendera7
Hélène Abergel123
Kim M. Fox8
for the CLARIFY Investigators
Adrian V. Hernandezedit1 Role: Editor
1INSERM U698, Paris, France
2Université Paris Diderot, Paris, France
3AP-HP, Hôpital Bichat, Paris, France
4Department of Cardiology and LTTA Centre, University of Ferrara, Salvatore Maugeri Foundation, IRCCS, Lumezzan, Italy
5University of Glasgow, Glasgow, United Kingdom
6Montreal Heart Institute, Université de Montreal, Montreal, Canada
7Medical University of Silesia, Katowice, Poland
8NHLI Imperial College, ICMS, Royal Brompton Hospital, London, United Kingdom
Lerner Research Institute, Cleveland Clinic, United States of America
Correspondence: * E-mail: gabriel.steg@bch.ap-hop-paris.fr
Contributed by footnote: Conceived and designed the experiments: PGS RF IF KMF J-CT MT. Performed the experiments: HA IF NG. Analyzed the data: IF NG. Wrote the paper: HA RF IF KMF NG J-CT MT. Wrote the first draft of the manuscript: PGS.
[other] ¶ For a full list of the CLARIFY investigators please see Appendix S1.

Introduction

Coronary artery disease (CAD) is the leading cause of death worldwide [1], [2], yet there is a paucity of data regarding the clinical characteristics and management of outpatients with stable CAD. Most of the available data are from patients admitted for acute coronary syndromes or treated with percutaneous coronary intervention (PCI). In addition, data often originate from Europe or North America. The prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease (CLARIFY) registry was initiated to improve our knowledge about patients with stable CAD from a broader geographic perspective [3]. The main objectives of the registry are to define contemporary stable CAD outpatients in terms of their demographic characteristics, clinical profiles, management, and outcomes; identify gaps between evidence-based recommendations and treatment; and investigate long-term prognostic determinants in this population.

Heart rate (HR) is a primary determinant of myocardial ischemia, and has been established as a prognostic factor in patients with CAD [4], [5], [6], [7], [8] and in those with congestive heart failure (CHF) [9]. It has also been correlated with the risk of future coronary events [4], [10]. Accordingly, the clinical benefits of beta-blockers in patients with CAD are well established, particularly the reduction in cardiovascular events in survivors of myocardial infarction [11].

Although beta-blockers have many actions other than simply reducing HR, emerging data show that HR reduction with pure bradycardic agents is also associated with clinical benefits, such as prevention of angina and reduction in myocardial ischemia [12], [13], [14]; and subset analyses from the BEAUTIFUL trial suggest that HR reduction may prevent coronary events [15], [16]. Despite these data indicating the prognostic impact of HR in CAD and the possible benefits of HR reduction, little is known regarding HRs actually achieved in clinical practice, including in patients receiving HR-reducing treatments such as beta-blockers. Likewise, there is a paucity of data on the management of elevated HR in patients with CAD in relation to the use of beta-blockers and other HR-reducing agents.

The goal of the present analysis is to describe, using a large contemporary database stemming from a broad geographic representation, the HR achieved in stable outpatients with CAD overall, and in relation to the use of beta-blockers, and to describe the determinants of HR. An additional goal is to assess the proportion of patients in whom resting HR exceeds some commonly described prognostic and therapeutic thresholds.


Methods
Study Design

CLARIFY is an ongoing international, prospective, observational, longitudinal cohort study in stable CAD outpatients, with 5 years of follow-up. The study rationale and methods have been published previously [3]. Patients were enrolled in 45 countries in Africa, Asia, Australia, Europe, the Middle East, and North, Central and South America. They are being treated according to usual clinical practice at each institution, with no specific tests or therapies defined in the study protocol.

Study Population

Patients eligible for enrolment were outpatients with stable CAD proven by a history of at least one of the following: documented myocardial infarction (>3 months ago); coronary stenosis >50% on coronary angiography; chest pain with myocardial ischemia proven by stress electrocardiogram, stress echocardiography, or myocardial imaging; and history of coronary artery bypass graft surgery or percutaneous coronary intervention (performed >3 months ago).

Patients hospitalized for cardiovascular disease within the previous 3 months (including for revascularization), patients for whom revascularization was planned, and patients with conditions expected to hamper participation or 5-year follow-up (e.g. limited cooperation or legal capacity, serious non-cardiovascular disease, conditions limiting life expectancy, or severe cardiovascular disease [advanced heart failure, severe valve disease, history of valve repair/replacement, etc.]) were excluded from participating in the study.

Site Selection

In order to enroll a population of stable CAD outpatients that mimicked the epidemiological patterns in each country, recruitment was based on a predefined selection of physician types (cardiologists, internists, primary care physicians) and aimed for consecutive enrollment of eligible patients. Physician selection was based on the best available sources, either local or regional, concerning the epidemiology and medical care data, including available market data and epidemiological surveys. A general target of 25 patients per million inhabitants was used (range 12.5–50) to ensure balanced representation of participating countries. Each physician recruited 10–15 outpatients with stable CAD, as defined by the inclusion criteria, over a brief period of time, in order to avoid selection bias.

Baseline Evaluations and Data Management

Information collected at baseline included: demographics; medical history; risk factors and lifestyle; results of physical examination; HR (determined by both pulse palpation and the results of the most recent electrocardiogram [ECG] performed within the previous 6 months); current symptoms; laboratory values (e.g. fasting blood glucose, hemoglobin A1c [HbA1c], cholesterol, triglycerides, serum creatinine, and hemoglobin, if available); and current chronic medical treatments (i.e. those taken regularly by the patient, for ≥7 days before entry in the registry).

Data were collected centrally using an electronic, standardized, international case report form (translated into local languages) and sent electronically to the data management center where checks for completeness, internal consistency, and accuracy were run.

Data quality control is performed onsite in 5% of sites chosen at random in each country with, at each site, monitoring of 100% of case report forms for source documentation and accuracy. The study is being performed in accordance with the principles of the Declaration of Helsinki and was approved by the National Research Ethics Service, Isle of Wight, Portsmouth and Southeast Hampshire Research Ethics Committee, UK. Approval was also obtained in all 45 participating countries, in accordance with local regulations before recruitment of the first participant. All patients gave written informed consent to participate, in accordance with national and local guidelines. The CLARIFY Registry is registered in the ISRCTN registry of clinical trials with the number ISRCTN43070564.

Statistical Analysis

All CLARIFY data are collected and analyzed at an independent academic statistics center at the Robertson Centre for Biostatistics, University of Glasgow, UK, which is responsible for managing the database, performing all analyses, and storing the data according to regulations. Baseline variables are summarized as means, standard deviations (SDs), medians, interquartile ranges (IQRs), and ranges for continuous data; and as counts and percentages for categorical data.

A multivariable analysis of independent correlates of HR≥70 beats per minute (bpm) was performed using a logistic regression model. The cutoff of 70 bpm was selected based on the results of several studies showing that it is an important prognostic threshold across a variety of patient populations [17], [18], [19], [20], [21]. All clinical baseline variables were considered for entry into the model as predictors of HR≥70 bpm and univariate models for each were produced. The use of HR-lowering medications was considered to be the most important treatment variable, and so this was the only treatment predictor entered in the analyses. The multivariable model was then built using a stepwise selection method applied to the remaining significant univariate predictors, with the use of HR-lowering medications being forced into the model.


Results

A total of 33,438 patients were enrolled by 2,898 investigators in 45 countries between November 2009 and July 2010. Of these, 41 patients did not meet the inclusion criteria and 112 did not provide consent. Baseline data were available for 33,285 patients, of whom 33,177 patients had HR data recorded. Patient flow is depicted in Figure 1; and the geographic distribution of the study population is depicted in Figure 2.

The mean (SD) age was 64.2 (10.5) years and 77.5% of the patients were men (Table S1). The median time since the diagnosis of CAD was 5 years (IQR 2–9 years). Overall, 59.7% of the patients had a history of prior myocardial infarction and 58.7% had a history of PCI, while 23.4% had a history of coronary artery bypass grafting (CABG). A total of 22.0% of the patients had anginal symptoms; coronary angiography had been performed in 85.4% of the patients; and 61.9% of the patients had undergone a non-invasive test for ischemia. The mean (SD) pulse HR was 68.3 (10.6) bpm, while the ECG-derived HR was 67.2 (11.4) bpm. HR measured by pulse palpation was highly correlated to HR measured by ECG (correlation 0.81; p<0.0001). The distribution of HR as measured by pulse palpation is depicted in Figure 3.

Patients were divided in three mutually exclusive categories of baseline pulse palpation HR: ≤60 bpm (9,246, 27.9%), 61–69 bpm (9,322, 28.1%), and ≥70 bpm (14,609, 44.0%). The clinical characteristics of these three HR groups are described in Table S1. There were important, significant differences between the HR subgroups: patients with highest HR were younger, less frequently male or of Western descent, had less frequently undergone PCI or CABG, but had a more frequent history of hospitalization for CHF, stroke, history of asthma/chronic obstructive pulmonary disease (COPD), treated hypertension, diabetes, current smoking, and sedentarity (Table S1). They also had more frequent and more severe anginal symptoms and CHF symptoms (even though patients with Class IV New York Heart Association [NYHA] were excluded), and more frequent evidence of myocardial ischemia (Table S1).

The use of medications in the overall population and the three HR groupings is described in Table 1. With respect to HR-lowering medications, 75.1% of the population was treated with beta-blockers (any molecule and any dose), 9.8% received ivabradine, 2.5% digoxin or derivatives, 5.8% verapamil or diltiazem, and 2.9% amiodarone or dronedarone. The median number of HR-lowering agents used was one in the entire population and in each of the HR subgroups. Patients with higher HR less frequently received beta-blockers, but more frequently received ivabradine and digoxin, than patients with lower HR (Table 1). HR was higher as the number of HR-lowering medications increased above 1, from 67.6 (SD 10.3) bpm for patients receiving one agent, to 70.3 (11.8) bpm and 72.5 (12) bpm for patients receiving 2 and 3 HR-lowering agents, respectively (p<0.0001). The most commonly used beta-blockers were bisoprolol (34.1% of the patients), metoprolol tartrate (15.5%), atenolol (15.1%), metoprolol succinate (12.5%), carvedilol (11.6%), and nebivolol (5.6%). All other molecules were used in <2% of the patients receiving beta-blockers.

The patient population was also divided according to the use of beta-blockers. Baseline characteristics of patients receiving and not receiving any dose of beta-blockers are depicted in Table S2. Overall, 75.1% of the population received beta-blockers, but this proportion varied largely with co-morbidities: e.g. among patients with asthma, 50.9% were on beta-blockers. Patients receiving beta-blockers were significantly younger, more frequently diabetic, hypertensive, or dyslipidemic, and had a more frequent history of myocardial infarction, PCI or CABG, hospitalization for CHF, less frequent asthma/COPD, and more frequent anginal and CHF symptoms (Table S2). Systolic blood pressure was similar among patients with and without beta-blockers. The distribution of HR in patients treated or not with beta-blockers is depicted in Figure 4. Mean (SD) pulse HR was 67.6 (10.4) and 70.3 (11.2) bpm for patients with and without beta-blockers, respectively. The proportion of patients with HR≥70 bpm was 41.1% and 52.9% for patients with and without beta-blockers, respectively (p<0.001). Among 7,301 patients with anginal symptoms, 1611 patients (22.1%) had HR≤60 bpm.

A multivariable analysis was performed to identify the independent correlates of HR (Table 2). Among the most important predictors of elevated HR≥70 bpm were Asian ethnicity, asthma/COPD, diabetes, lack of use of HR-lowering drugs, increased diastolic blood pressure, angina class, hospitalization for CHF, and evidence of myocardial ischemia. Conversely, increasing physical activity was associated with decreased risk of elevated HR≥70 bpm.


Discussion

This analysis provides a description of HR among stable outpatients with CAD. In this population, the mean (SD) pulse HR was 68.3 (10.6) bpm. Despite the fact that three quarters of the CAD population received treatment with beta-blockers, nearly half of the population had HR≥70 bpm, an emerging prognostic threshold in CAD patients with angina [6], [8], [15], [16], [21], and only 27.9% of all patients with CAD had HR≤60 bpm. Even among patients on beta-blockers, the proportion with HR≥70 bpm was 41.1%. Also, among patients with anginal symptoms, only 22.1% achieved a HR≤60 bpm, despite the fact that stable angina guidelines recommend a target HR of 55–60 bpm in patients with angina on beta-blockers [22]. This is consistent with observations from the EuroHeart Survey on angina [23], in which 19% of patients had HR≤62 bpm. By multivariable analysis, there were many independent predictors of HR≥70 bpm, a large proportion of which are markers of a poor health status, such as higher blood pressure, presence of diabetes, dyslipidemia, increased alcohol intake, history of chronic heart failure, increased body mass and lack of physical exercise. Among other independent predictors of HR≥70 bpm, angina class and evidence of myocardial ischemia were also important and strong correlates of elevated HR, as was the lack of use of HR-lowering agents.

These findings have important clinical implications: HR remains elevated in a substantial proportion of patients. Elevated HR has been associated with worse clinical outcomes in prior studies [4], [5], [6], [7], [8], [10]; and in the present study, was independently associated with more frequent evidence of myocardial ischemia and a worse anginal status. Elevated HR was, as expected, also more frequent among patients who did not receive HR-lowering agents. Thus, further HR reduction can be achieved and may yield substantial clinical benefit in these patients. Indeed, HR lowering with beta-blockers has been shown to have potent anti-ischemic and anti-anginal effects in patients with CAD [24] and yields improved clinical outcomes after myocardial infarction [11], but the effects of beta-blockers on HR are difficult to separate from their other major pharmacodynamic properties. Extrapolating from the evidence of prognostic benefit of beta-blockers in patients with angina who have a history of prior myocardial infarction (most of which antedate the advent of modern reperfusion therapy) or heart failure, both European and American guidelines for the management of stable angina suggest that beta-blockers be the first-line antianginal therapy in patients without contraindications [24], [25]. Yet, in the present analysis, poorly controlled HR was independently associated with diabetes mellitus, more severe angina class, higher blood pressure, evidence of myocardial ischemia, and physical inactivity, factors that point to patient populations most likely to benefit from beta-blockers. Because low blood pressure may be a limiting factor for using beta-blockers, it is noteworthy that patients not on beta-blockers did not actually have lower blood pressure. In fact, there was an association between increasing HR and higher mean systolic and diastolic blood pressures, which suggests that in this cohort, low blood pressure was not a major barrier to using beta-blockers and achieving HR control. In contradistinction to heart failure [26], there is no recommended target dose or beta-blocker molecule recommended in treating angina, and thus a wide variety of agents and doses are commonly used. Titration is usually based on resting HR achieved and therefore it is conceivable that increasing beta-blocker dosage might achieve superior HR control.

There are multiple potential barriers to more widespread use of beta-blockers at appropriate doses to achieve adequate HR control, such as inadequate knowledge of evidence or treatment goals by clinicians [27], access to care and reimbursement, co-morbidities that represent contraindications or decrease tolerance to beta-blockers, side effects of beta-blockers, and marketing efforts for other agents. Interestingly, in the present cohort, the proportion of patients fully reimbursed for drugs was actually greater among patients not receiving than among patients receiving beta-blockers, suggesting that lack of full reimbursement is not a major barrier to the prescription of beta-blockers. Likewise, it is striking that two thirds of patients not receiving beta-blockers had no apparent symptoms or conditions that would potentially contraindicate their use. Therefore, it is likely that it is possible to improve HR control by increasing the use of beta-blockers (and possibly their dose).

Whether other antianginal agents that lower HR might provide similar benefits as those of beta-blockers (i.e. beyond symptom control) is still debated. The rates of cardiac death and myocardial infarction are not different when comparing beta-blockers and calcium antagonists [28]. Pure HR-reducing agents such as ivabradine have been shown to be potent anti-anginal agents, alone and in combination with beta-blockers [12], [14]. In the BEAUTIFUL randomized trial in patients with stable CAD and left ventricular dysfunction [15], ivabradine did not improve clinical outcomes overall, but in a prespecified analysis, it reduced the incidence of coronary outcomes in the subset of patients with HR≥70 bpm [8]. These effects were more marked in a post-hoc analysis of patients with limiting anginal symptoms at baseline [16]. Whether pure HR reduction improves clinical outcomes in patients with CAD and without heart failure is currently being explored in the ongoing SIGNIFY randomized trial (http://www.controlled-trials.com/ISRCTN61576291). Also, because increased heart rate was correlated to an overall poor health status and lifestyle (e.g. with less physical activity, increased alcohol intake and higher prevalence of risk factors), lifestyle changes and correction of risk factors may be safe and effective ways to address the risk associated with increased heart rate.

The CLARIFY registry also provides a useful description of clinical characteristics, demographics, risk factors, drug treatment, and management of patients with CAD in stable outpatients from a broad geographic perspective. It provides a useful reference, which differs from the highly selected patient populations often enrolled in randomized trials [29], [30], and stems from a more diverse geographic representation, as trials are often skewed towards predominant representation of Europe and North America, and with diverse ethnicity.

Finally, while HR is emerging as a potentially important prognostic determinant in patients with CAD [4], [5], [6], [7], [8], [10] and heart failure [9], the determinants of HR are not well known. The present study allowed a detailed univariate and multivariable analysis of the correlates of elevated HR, which highlighted important and previously unrecognized factors in determining HR in this population. Apart from the previously mentioned greater burden of risk factors and markers of a poorer health status, such as increased alcohol intake, increased body mass index and lower level of physical activity, the presence of asthma/COPD, for instance, was one of the strongest predictors of an elevated HR (≥70 bpm) (odds ratio 1.63; 95% confidence interval 1.50–1.78, p<0.0001), which is consistent with the fact that use of beta-blockers is far less frequent in this population, who may in fact often receive beta agonists. In CLARIFY, 75.1% of the overall population received beta-blocker therapy (regardless of the dose) whereas this proportion was only 50.9% among patients with asthma/COPD. Likewise, increasing physical activity was associated with decreasing risks of elevated HR, a finding consistent with the well-documented effects of regular exercise on lowering HR [31].

While the CLARIFY registry is a large, international initiative taking place in 45 countries in four continents, it is subject to limitations. The study population may not fully reflect regional differences in clinical characteristics and patterns of care of stable CAD patients, and results may not therefore be representative of practice elsewhere. For example, no patients from the United States participated in CLARIFY. In addition, despite attempts to optimize the representativeness of the registry, it was not population-based. Finally, pending the availability of outcomes, the cross-sectional nature of the analysis limits the ability to draw causal inferences from the observations made which are susceptible to confounding.

In conclusion, despite the use of beta-blockers in three quarters of patients, nearly half of stable outpatients with CAD had a resting HR≥70 bpm. Even among patients on beta-blockers, 41% had HR≥70 bpm. An increasing HR was an independent correlate, among many other factors suggestive of an overall poorer health status, of higher prevalence and severity of angina, and higher prevalence of myocardial ischemia. These findings suggest that further HR lowering is possible in patients with stable CAD. Whether it will impact symptoms, ischemia, and risk of cardiovascular events is being tested.


Supporting Information Table S1

Baseline characteristics of the study population classified according to resting HR by palpation.

(DOCX)


Click here for additional data file (pone.0036284.s001.docx)

Table S2

Characteristics of study population classified according to beta-blocker usage.

(DOCX)


Click here for additional data file (pone.0036284.s002.docx)

Appendix S1

CLARIFY Registry Investigators.

(DOC)


Click here for additional data file (pone.0036284.s003.doc)


Notes

Competing Interests: The authors have read the journal's policy and have the following conflicts: This study was supported by research grants from Servier, France. PGS: has received research grants from Servier; consultancy fees/honoraria from Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo/Eli Lilly alliance, Eisai, GlaxoSmithKline, Medtronic, Merck Sharpe and Dohme, Pfizer, Roche, sanofi-aventis, Servier, and The Medicines Company; and has equity ownership in Aterovax. RF: Speaker's bureau: Servier, Roche and Boehringer Ingelheim; Research Grant: Servier, Boehringer Ingelheim and Roche; Advisory Board: Servier, Bayer, Roche and Boehringer Ingelheim. IF: Research grants, honoraria for committee membership, and support for conference attendance from Servier. NG: none. J-CT: Research grants and honoraria from Servier. MT: Fees, honoraria, and research grants from Amgen, Bayer, Menarini, Servier and TIMI Group. HA: none. KMF: Fees, honoraria, and research grants from Servier. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Funding: This study was supported by research grants from Servier, France (http://www.clarify-registry.com). The study was designed and conducted by the investigators and funded via grants from Servier, including a grant to the academic statistical center. The sponsor provided assistance for study set-up and management in each country, and funded editorial assistance in the preparation of the manuscript, tables, and figures by Sophie Rushton-Smith. The sponsor was sent the manuscript before submission. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The preliminary results of this study were presented at the European Society of Cardiology Paris, August 29, 2011. Sophie Rushton-Smith, PhD, provided editorial assistance in the preparation of the manuscript, tables, and figures and was funded by the sponsor.


References
1. Murray CJ,Lopez AD. Year: 1997Mortality by cause for eight regions of the world: Global Burden of Disease Study.Lancet349126912769142060
2. Anderson GF,Chu E. Year: 2007Expanding priorities–confronting chronic disease in countries with low income.N Engl J Med35620921117229946
3. Steg PG. Year: 2009Heart rate management in coronary artery disease: the CLARIFY registry.Eur Heart J11suppl DD13D18
4. Diaz A,Bourassa MG,Guertin MC,Tardif JC. Year: 2005Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease.Eur Heart J2696797415774493
5. Hjalmarson A,Gilpin EA,Kjekshus J,Schieman G,Nicod P,et al. Year: 1990Influence of heart rate on mortality after acute myocardial infarction.Am J Cardiol655475531968702
6. Kolloch R,Legler UF,Champion A,Cooper-Dehoff RM,Handberg E,et al. Year: 2008Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST).Eur Heart J291327133418375982
7. Fox K,Borer JS,Camm AJ,Danchin N,Ferrari R,et al. Year: 2007Resting heart rate in cardiovascular disease.J Am Coll Cardiol5082383017719466
8. Fox K,Ford I,Steg PG,Tendera M,Robertson M,et al. Year: 2008Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial.Lancet37281782118757091
9. Bohm M,Swedberg K,Komajda M,Borer JS,Ford I,et al. Year: 2010Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial.Lancet37688689420801495
10. Hsia J,Larson JC,Ockene JK,Sarto GE,Allison MA,et al. Year: 2009Resting heart rate as a low tech predictor of coronary events in women: prospective cohort study.BMJ338b21919193613
11. Freemantle N,Cleland J,Young P,Mason J,Harrison J. Year: 1999beta Blockade after myocardial infarction: systematic review and meta regression analysis.BMJ3181730173710381708
12. Tardif JC,Ponikowski P,Kahan T. ASSOCIATE Study InvestigatorsYear: 2009Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial.Eur Heart J3054054819136486
13. Borer JS,Fox K,Jaillon P,Lerebours G. Ivabradine Investigators GroupYear: 2003Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial.Circulation10781782312591750
14. Tardif JC,Ford I,Tendera M,Bourassa MG,Fox K,et al. Year: 2005Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina.Eur Heart J262529253616214830
15. Fox K,Ford I,Steg PG,Tendera M,Ferrari R,et al. Year: 2008Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial.Lancet37280781618757088
16. Fox K,Ford I,Steg PG,Tendera M,Robertson M,et al. Year: 2009Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial.Eur Heart J302337234519720635
17. Fox K,Ford I,Steg PG,Tendera M,Ferrari R. Year: 2008Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial.Lancet37280781618757088
18. Antoni ML,Boden H,Delgado V,Boersma E,Fox K,et al. Year: 2012Relationship between discharge heart rate and mortality in patients after acute myocardial infarction treated with primary percutaneous coronary intervention.Eur Heart J339610221862462
19. Rambihar S,Gao P,Teo K,Bohm M,Yusuf S,et al. Year: 2010Heart rate is associated with increased risk of major cardiovascular events, cardiovascular and all-cause death in patients with stable chronic cardiovascular disease: an analysis of ONTARGET/TRANSCEND.Circulation122A12667
20. Waters DD,Ho J,Demicco DA,Breazna A,Pedersen TR. Year: 2010Heart rate as a predictor of cardiovascular risk in coronary heart disease patients with diabetes.Eur Heart J31Abstract Suppl801
21. Ho JE,Bittner V,Demicco DA,Breazna A,Deedwania PC,et al. Year: 2010Usefulness of heart rate at rest as a predictor of mortality, hospitalization for heart failure, myocardial infarction, and stroke in patients with stable coronary heart disease (Data from the Treating to New Targets [TNT] trial).Am J Cardiol10590591120346304
22. Gibbons RJ,Chatterjee K,Daley J,Douglas JS,Fihn SD,et al. Year: 1999ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Chronic Stable Angina).J Am Coll Cardiol332092219710362225
23. Daly CA,Clemens F,Sendon JL,Tavazzi L,Boersma E,et al. Year: 2010Inadequate control of heart rate in patients with stable angina: results from the European heart survey.Postgrad Med J8621221720354044
24. Fox K,Garcia MA,Ardissino D,Buszman P,Camici PG,et al. Year: 2006Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology.Eur Heart J271341138116735367
25. Fraker TD Jr,Fihn SD,Gibbons RJ,Abrams J,Chatterjee K,et al. Year: 20072007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina.J Am Coll Cardiol502264227418061078
26. Dickstein K,Cohen-Solal A,Filippatos G,McMurray JJ,Ponikowski P,et al. Year: 2008ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM).Eur J Heart Fail1093398918826876
27. Bagnall AJ,Yan AT,Yan RT,Lee CH,Tan M,et al. Year: 2010Optimal medical therapy for non-ST-segment-elevation acute coronary syndromes: exploring why physicians do not prescribe evidence-based treatment and why patients discontinue medications after discharge.Circulation Cardiovascular quality and outcomes353053720716715
28. Heidenreich PA,McDonald KM,Hastie T,Fadel B,Hagan V,et al. Year: 1999Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina.JAMA2811927193610349897
29. Steg PG,Lopez-Sendon J,Lopez de Sa E,Goodman SG,Gore JM,et al. Year: 2007External validity of clinical trials in acute myocardial infarction.Arch Intern Med167687317210880
30. Rothwell PM. Year: 2005External validity of randomised controlled trials: “to whom do the results of this trial apply?”.Lancet365829315639683
31. Clausen JP. Year: 1976Circulatory adjustments to dynamic exercise and effect of physical training in normal subjects and in patients with coronary artery disease.Prog Cardiovasc Dis184594956992

Figures

[Figure ID: pone-0036284-g001]
doi: 10.1371/journal.pone.0036284.g001.
Figure 1  Patient flow chart.

[Figure ID: pone-0036284-g002]
doi: 10.1371/journal.pone.0036284.g002.
Figure 2  Geographical distribution of patients with baseline HR on palpation (n = 33,177).

[Figure ID: pone-0036284-g003]
doi: 10.1371/journal.pone.0036284.g003.
Figure 3  HR distribution in stable CAD patients.

[Figure ID: pone-0036284-g004]
doi: 10.1371/journal.pone.0036284.g004.
Figure 4  Distribution of HR for patients with versus without beta-blocker use.

The vertical lines represent the minimum and maximum values. The box represents the lower (25th percentile) and upper (75th percentile) quartiles. Within the box, the vertical line is the median and the diamond the mean. Values>1.5 times the interquartile range were considered outliers and are shown as individual circles.



Tables
[TableWrap ID: pone-0036284-t001] doi: 10.1371/journal.pone.0036284.t001.
Table 1  Medications of the study population classified according to resting HR by palpation.
Population According to Palpation HR
Variable Patients with Data Total Population (n = 33,177) ≤60 bpm (n = 9,246) 61–69 bpm (n = 9,322) ≥70 bpm (n = 14,609) p-Value
Aspirin, n (%) 33,157 29,068 (87.7) 8,071 (87.3) 8,257 (88.6) 12,740 (87.3) 0.0037
Thienopyridine, n (%) 33,111 8,959 (27.1) 2,561 (27.8) 2,493 (26.8) 3,905 (26.8) 0.21
Other antiplatelets, n (%) 33,108 3,069 (9.3) 742 (8.0) 875 (9.4) 1,452 (10.0) <0.0001
Oral anticoagulants, n (%) 33,134 2,738 (8.3) 673 (7.3) 685 (7.4) 1,380 (9.5) <0.0001
Beta-blockers, n (%) 33,161 24,910 (75.1) 7,390 (80.0) 7,281 (78.1) 10,239 (70.1) <0.0001
Symptoms indicative of intolerance or contraindication to beta-blockers, n (%) 33,149 4,783 (14.4) 1,451 (15.7) 1,202 (12.9) 2,130 (14.6) <0.0001
Ivabradine, n (%) 33,160 3,259 (9.8) 677 (7.3) 757 (8.1) 1,825 (12.5) <0.0001
Calcium antagonists, n (%) 33,155 9,038 (27.3) 2,344 (25.4) 2,525 (27.1) 4,169 (28.6) <0.0001
Verapamil or diltiazem, n (%) 33,155 1,931 (5.8) 421 (4.6) 491 (5.3) 1,019 (7.0) <0.0001
ACE inhibitors, n (%) 33,160 17,044 (51.4) 4,792 (51.8) 4,835 (51.9) 7,417 (50.8) 0.15
Angiotensin II receptor blockers, n (%) 33,156 8,800 (26.5) 2,354 (25.5) 2,430 (26.1) 4,016 (27.5) 0.0012
Lipid-lowering drugs, n (%) 33,163 30,606 (92.3) 8,710 (94.2) 8,634 (92.7) 13,262 (90.8) <0.0001
Long-acting nitrates, n (%) 33,156 7,329 (22.1) 1,761 (19.1) 1,999 (21.5) 3,569 (24.5) <0.0001
Other antianginal agents, n (%) 33,151 4,618 (13.9) 999 (10.8) 1,284 (13.8) 2,335 (16.0) <0.0001
Diuretics, n (%) 33,156 9,695 (29.2) 2,478 (26.8) 2,600 (27.9) 4,617 (31.6) <0.0001
Other antihypertensive agents, n (%) 33,156 2,277 (6.9) 602 (6.5) 604 (6.5) 1,071 (7.3) 0.011
Digoxin and derivatives, n (%) 33,158 837 (2.5) 149 (1.6) 169 (1.8) 519 (3.6) <0.0001
Amiodarone/dronedarone, n (%) 33,151 966 (2.9) 344 (3.7) 234 (2.5) 388 (2.7) <0.0001
Other antiarrhythmics, n (%) 33,151 305 (0.9) 99 (1.1) 78 (0.8) 128 (0.9) 0.20
Antidiabetic agents, n (%) 33,160 8,153 (24.6) 1,698 (18.4) 2,186 (23.5) 4,269 (29.2) <0.0001
Thyroid HRT, n (%) 33,157 1,422 (4.3) 427 (4.6) 393 (4.2) 602 (4.1) 0.17
Number of antianginals, median (IQR) 33,177 1 (1–2) 1 (1–2) 1 (1–2) 1 (1–2) <0.0001
Number of HR-lowering agents, median (IQR) 33,177 1 (1–1) 1 (1–1) 1 (1–1) 1 (1–1) 0.0119
Number of antianginals or HR-lowering agents, median (IQR) 33,177 1 (1–2) 1 (1–2) 1 (1–2) 1 (1–2) <0.0001

ACE, angiotensin-converting enzyme; HR, heart rate; HRT, hormone replacement therapy; IQR, interquartile range.


[TableWrap ID: pone-0036284-t002] doi: 10.1371/journal.pone.0036284.t002.
Table 2  Factors associated with HR≥70 bpm.
Variable OR (95% CI) Pr>Chi-Square
Female sex 1.21 (1.14–1.28) <0.0001
Age (per 10-year increase) 0.89 (0.87–0.92) <0.0001
Ethnicity <0.0001
Japanese/Korean 1.63 (1.41–1.88)
South Asian 1.92 (1.76–2.11)
Chinese 1.51 (1.38–1.67)
Hispanic 1.43 (1.28–1.59)
Black/African 0.88 (0.71–1.10)
Unknown 0.80 (0.74–0.87)
Angina CCS Class 0.018
I 1.07 (0.97–1.18)
II 1.10 (1.02–1.19)
III 1.18 (1.04–1.34)
IV 0.97 (0.61–1.54)
Asthma/COPD 1.63 (1.50–1.78) <0.0001
Atrial fibrillation/flutter 1.35 (1.23–1.48) <0.0001
BMI (per 2-unit increase) 1.03 (1.02–1.04) <0.0001
Current smoker 1.37 (1.27–1.47) <0.0001
Diabetes 1.54 (1.47–1.63) <0.0001
Dyslipidemia 0.93 (0.88–0.98) 0.0101
Family history of premature CAD 0.94 (0.90–0.99) 0.026
Diastolic blood pressure (per 10-mmHg increase) 1.31 (1.28–1.34) <0.0001
Current evidence of myocardial ischemia 1.19 (1.11–1.27) <0.0001
Prior hospitalization for CHF 1.19 (1.06–1.32) 0.0023
Coronary artery bypass graft 0.93 (0.87–0.99) 0.025
Percutaneous coronary intervention 0.89 (0.84–0.95) 0.0001
Alcohol intake (units/week) 0.0005
>40 1.02 (0.69–1.51)
20–40 1.10 (0.97–1.26)
>0 and <20 0.91 (0.87–0.96)
Physical activity level <0.0001
Light physical activity most weeks 0.88 (0.82–0.94)
≥20 min vigorous physical activity 1–2 times a week 0.75 (0.69–0.81)
≥20 min vigorous activity ≥3 times a week 0.64 (0.59–0.70)
Non-invasive test performed 0.80 (0.76–0.85) <0.0001
Coronary territories with stenosis >50%; coronary angiography not done 1.13 (1.04–1.22) 0.0036
Coronary territories with stenosis >50%; right coronary artery 0.94 (0.89–0.99) 0.014
Not taking HR-lowering drugs 1.52 (1.42–1.61) <0.0001
Reimbursement of cardiovascular agents 0.026
None 1.02 (0.96–1.09)
Full 0.94 (0.89–0.995)

BMI, body mass index; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; CHF, congestive heart failure; CI, confidence interval; COPD, chronic obstructive pulmonary disease; HR, heart rate; OR, odds.



Article Categories:
  • Research Article
Article Categories:
  • Medicine
    • Cardiovascular
      • Angina
      • Cardiovascular Pharmacology
      • Coronary Artery Disease
      • Hemodynamics
      • Myocardial Infarction
    • Clinical Research Design
      • Cohort Studies
    • Drugs and Devices
      • Drug Research and Development
    • Epidemiology
      • Cardiovascular Disease Epidemiology


Previous Document:  Selective blockade of trypanosomatid protein synthesis by a recombinant antibody anti-Trypanosoma cr...
Next Document:  First international external quality assessment study on molecular and serological methods for yello...