ACTION A C oronary disease T rial I nvestigating O utcome with N ifedipine GITS (gastrointestinal therapeutic system

1. ACTIONACoronary disease Trial Investigating Outcome with Nifedipine GITS(gastrointestinal therapeutic system) presented by Philip A Poole-Wilsonon behalf of the ACTION investigators

2. ACTION: rationale • Nifedipine GITS is widely used to treat angina and hypertension • Debate circa 1995 on safety based on: • Data from unapproved indications • Observational studies • Meta-analyses (Furberg, 1995) • Short-acting formulations of nifedipine possibly harmful • No evidence from outcome trials in patients with stable angina

3. ACTION: features • First-ever placebo-controlled clinical out-come trial in symptomatic stable angina • Long-acting nifedipine (GITS) • Investigator initiated and designed • Independent Steering Committee and study management (SOCAR Research) • Multi-centre (291 centres, 19 countries) • 7665 patients, mean f-up 4.9 years • Supported by Bayer HealthCare AG

4. ACTION: primary objective Effect of: addition of 60 mg once-daily long-acting nifedipine GITS to the basic regimen ( blockers, nitrates, lipid lowering…) On: cardiovascular event-free survival In: patients with stable symptomatic coro-nary disease (angina pectoris)

5. ACTION: primary endpoints For efficacy: combined rate of • Death (any cause) • MI (acute or procedural) • Refractory angina  angiography • New overt HF  hospitalisation • Disabling stroke • Peripheral revascularisation (cardiovascular event-free survival) For safety: combined rate of • Death, MI, disabling stroke

6. ACTION: patient selection Stable symptomatic angina treated with: •  blockers, nitrates, etc • Lipid / blood pressure as indicated And one of the following: • History of myocardial infarction • Angiographic CAD (known abnormal angiogram, history of PTCA or CABG) • Positive exercise or radionuclide test • No history of myocardial infarction • Coronary angiography never done

7. ACTION: exclusions • Less than 35 years of age • Clinical heart failure (HF) • EF less than 40% (2D-echo) • Valve disease • Abnormal kidney or liver function • On a CCB, digitalis for HF, class I + III anti-arrhythmic (sotalol / amiodarone allowed) • Gastrointestinal problem (absorption / passage of GITS tablet)

8. ACTION: power calculation Sample size estimation: • Based on simvastatin arm of 4S • Assumed rate of primary endpoint for efficacy: 5.6 /100 patient-years • 30,000 patient-years planned: 80% power for 14% of primary endpoint • Exclude 3.1 excess deaths per 1000 patient-years • 37,867 patient-years realised Interim analyses to protect patient safety

9. ACTION: design • Washout of incompatible medication • Baseline assessments • Randomised, double-blind addition of once daily Nifedipine GITS (30  60 mg) or placebo • Follow-up 4½ - 6 years • Patient contacted every three months • Out-patient clinic visit every six months

10. 7 797allocated 5 centres (128 pts) excluded 4 didn’t start 7 665in ITT 3 825nifedipine 3 840placebo 310 died 291 died 181 incomplete 179 incomplete 3 334complete 3 370complete ACTIONtrial profile 97.3% of planned follow-up was actually completed

11. ACTION: history and symptoms

12. ACTION: risk factors

13. ACTION: co-treatment at entry

14. ACTION: tolerance % follow-up time on study medication: • 79% for nifedipine arm • 82% for placebo arm Withdrawal because of adverse event: • 10% nifedipine • 4% peripheral oedema • 1% headache • 4% placebo • 1% peripheral oedema • 0.5% headache

15. Heart rate and blood pressure p<0.0001 p<0.0001 nifedipine placebo p<0.0001

16. Systolic BP140, Diastolic90 mm Hg nifedipine placebo

17. ACTION: outcome All-cause death(p=0.4) Primary endpoint for efficacy(death, MI, RA, HF, CVA, PREV)p=0.5 Primary endpoint for safety (death, MI, CVA, p=0.9) nifedipine placebo RA = refractory angina PREV = peripheral revascularisation

18. ACTION: clinical events n=310 n=291 n=178 n=177 n=132 n=114 n=267 n=257 n=150 n=174 n=86 n=121 n=77 n=99 RR=1.07 (p=0.4) RR=1.01 (p=0.9) nifedipine placebo RR=1.16 (p=0.2) RR=1.04 (p=0.6) RR=0.86 (p=0.2) RR=0.71 (p=0.02) RR=0.78 (p=0.1)

19. Clinical events (rates / 100 pyrs) * p<0.05

20. Cardiovascular procedures n=895 n=1068 n=385 n=417 n=294 n=371 nifedipine placebo n=146 RR=1.25 (p=0.07) n=118 RR=0.82p<0.0001 RR=0.92 (p=0.3) RR=0.79 (p=0.002)

21. CV procedures (rates / 100 pyrs) * p<0.05

22. Pre-defined combined endpoints Primary endpoint for safety Cardiovascular (CV) events Primary endpoint for efficacy , any CV event or procedure Vascular events

23. Combined endpoints n=804 n=828 n=562 n=558 n=694 n=736 n=1439 n=1583 n=1026 n=1121 1st endpoint efficacy(death, MI, RA, HF,CVA, PREV) nifedipine placebo RR=0.97(p=0.5) 1st endpoint safety(death, MI, CVA) RR=1.01 (p=0.9) CV events(CV death, MI, RA, HF,CVA, PREV) RR=0.94 (p=0.3) RR=0.89(p=0.001) Death, CV event or proc.(death, MI, RA, HF, CVA, PREV, CAG, PCI, CABG) Vascular events(CV death, MI, RA, CVA, PREV, PCI, CABG) RR=0.91 (p=0.03)

24. Comb endp (rates / 100 pyrs)

25. Event-free survival All-cause death (p=0.4) Death, MI, CVA(p=0.9) Death, MI, RA, HF, CVA, PREV (p=0.5) Death, CV event or proc.(death, MI, RA, HF, CVA, PREV, CAG, PCI, CABG)p=0.001 RA = refractory angina PREV = peripheral revascularisation CAG = coronary angiography PCI = percutaneous coronary interv. CABG = coronary artery bypass graft nifedipine placebo

26. Death, any CV event or procedure First events only RR=0.89 (95% CI 0.83 – 0.95)

27. Primary endpoint efficacy: subgroups RR, 95% CI Test for interaction: Favours nifedipine

28. Primary endpoint efficacy: subgroups RR, 95% CI Test for interaction: Favours nifedipine

29. ACTION: conclusions In pts with stable angina, nifedipine GITS: • overall did not prolong major cardiovascular event-free survival • is safe • prolongs cardiovascular event and procedure free survival • reduces the incidence of heart failure • prolongs major cardiovascular event-free survival in patients with angina and elevated blood pressure Manuscript is available on the Lancet Web site

30. ACTION: conclusions In pts with stable angina, nifedipine GITS: • overall did not prolong major cardiovascular event-free survival • is safe • prolongs cardiovascular event and procedure free survival • reduces the incidence of heart failure • prolongs major cardiovascular event-free survival in patients with angina and elevated blood pressure Manuscript is available on the Lancet Web site

31. The ACTION Research Group Steering Committee: PA Poole-Wilson (chair), H Just, M. Motro, JD Parker, MG Bourassa, AM Dart, J-M Detry(), KAA Fox, P Hildebrandt, Å Hjalmarson, JA Kragten, GP Molhoek, JE Otterstad, P Rizzon, R Seabra-Gomes, J Soler-Soler, S Weber Critical Events Committee: N Danchin (chair), A Battler, A Bayes de Luna, P Dunselman, S Glasser, P Koudstaal, G Sutton Data Monitoring / Ethical Review Committee: SJ Pocock (chair), J-P Boissel, WW Parmley, W Rutishauser, L Wilhelmsen Management: B-A Kirwan (project director), P Jonkers, J Lubsen, T Pauchard, J van Rossum, AB Parker, D Sekarski, FJ van Dalen (SOCAR Research SA) Bayer HealthCare AG: G Wagener

32. ACTION Principal Investigators Australia – J Amerena, AM Dart, LG Howes, JA Karrasch, RW Watts.Austria - W Klein, W Lin. Belgium – C Brohet, O Gurné, G Heyndrickx, S Pourbaix, W van Mieghem, M Vrolix.Canada – P Auger, M Baird, J Bedard, G Bloomberg, M Bourassa, YK Chan, M-T Cheung, H Conter, M-A Cote, W Czarnecki, C Fortin, P Gervais, D Gossard, WKK Hui, R Iwanochko, P Klinke, WJ Kostuk, S Kouz, C Lai, A Lalani, J Lenis, S Lepage, JF Lopez, GC MacCallum, D Marr, J-P Mayer, AL Morris, M Myers, D Mymin, S Nawaz, AA Panju, JD Parker, JO Parker, P Patel, Y Pesant, SW Rabkin, M Richmond, MH Sami, M Senaratne, N Sharma, JA Stone, JH Swan, P Talbot, T Talibi, KW Tan, RM Vexler, A Walling, LCH Yao.Denmark– M Asklund, H Bjerregaard-Andersen, M Brons, F Davidsen, K Egstrup, P Eliasen, B Engby, DA Hansen, KN Hansen, P Hildebrandt, G Jensen, KK Klarlund, J Larsen, O Lederballe, H Nielsen, I Nielsen, T Nielsen, J Petersen, J Rokkedal, M Scheibel, H Sejersen, K Skagen, TV Stjernebjerg, C Torp-Pedersen. Finland – J Lilleberg, O Luurila, A Palomäki, K Peuhkurinen.France - G Amat, C Bauters, J-P Bousser, J Boutarin, P Dambrine, PP Deloy, P Gosse, P Guenoun, J-L Hirsch, E Page, C Prost, P Voiriot, S Weber. Germany – J Beermann, A Bittersohl, M Camerer, H Dill, M Frey, H-G Fritz, J Gadow, G Garanin, J Grötz, C-J Heydenreich, R Häge, J Iserloh, M Keck, HJ Kleiner, M Klutmann, S Kääb, E Lohr, G Mahla, W Motz, B Rappert, F Richard, S Schönstedt, W Sehnert, W Spitzer, B Winkelmann, J Wunderlich, U Zeymer. Greece – D Alexopoulos, N Exadaktylos, S Foussas, K Nikolaidis, P Toutouzas. Israel – EG Abinader, S Braun, A Caspi, D David, M Eldar, R Elia, M Gottsman, A Keren, Y Kishon, J Klein, BS Lewis, A Marmor, M Motro, L Reisin, T Rosenfeld, Z Schlesinger, A Weiss, I Zahavi.

33. ACTION Principal Investigators Italy – F Arrigo, F Barillà, F Battista, L Bolognese, A Branzi, C Brunelli, C Burelli, C Chieffo, C Corona, F Crea, L Dei Cas, F Fedele, PM Fioretti, G Gensini, G Giuffrida, A Grieco, U Guiducci, P Maiolino, M Mariani, G Mattioli, F Mauri, L Meloni, P Rizzon, PJ Schwartz, D Scrutinio, P Tanzi, F Tartagni, C Vassanelli, P Zardini.New Zealand – C Ellis, H Ikram, H White. Norway – A Brandt-Rantzau, T Gundersen, HO Hoivik, H Istad, KE Langaker, S Njalla, BK Oie, TM Omland, JE Otterstad, PK Ronnevik, A Saeterhaug, PA Sirnes, SM Toft, D Torvik, K Valnes, PJ Vanberg. Portugal – V Da Gama Ribeiro, G Ferreira Da Silva, L Providencia, J Quininha, J Sa, R Seabra-Gomes, J Sieuve Afonso. Spain – J Azpitarte, JR Berrazueta, A Castro-Beiras, J-M Cruz-Fernandez, E De Los Arcos, A Fuertes, E Galve, E Gonzalez-Torrecilla, A Llamas, F Malpartida, A Martinez-Rubio, C Pagola, C Piñero, A Perez De Prado, JA Ruipérez, JR Reguero, F Sogorb, JA Velasco, JL Zamorano.Sweden – J Alvang, B Atmer, C Dahlén, G Dahlen, J Herlitz, C Höglund, S Jensen, L Karlberg, R Larsson, L Lundkvist, B Nordenhäll, P Nyman, U Ohlsson, I Timberg, J Wiberg.Switzerland – L Kappenberger, T Moccetti, B Vetter.The Netherlands – RJJ Claessens, PHJM Dunselman, BJB Hamer, DP Hertzberger, NJ Holwerda, M Kofflard, JA Kragten, GJ Laarman, CM Leenders, AH Liem, HR Michels, P Nierop, PE Polak, JL Posma, CLA Reichert, MG Scheffer, AJ Six, LC Slegers, FCW Tietge, DJ van Doorn, LHJ van Kempen, PMJ Verhorst, AJTM Vet, J Visser, FN Wempe, PHM Westendorp, AJAM Withagen.UK – PJ Allan, DI Dawson, S Dubrey, AR Fuller, RG Hardman, I Hudson, EA Leon, DP Lipkin, MB Maltz, JR Oldham, A Rozkovec, E Southall, LB Tan.