1

ACTIONACTIONAA CCoronary disease TTrial

IInvestigating OOutcome with NNifedipine GITS

(gastrointestinal therapeutic system)

presented by

Philip A Poole-Wilsonon behalf of the ACTION investigators

2

ACTION: rationaleACTION: 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: featuresACTION: 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

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ACTION: primary objectiveACTION: 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)

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ACTION: primary endpointsACTION: 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

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ACTION: patient selectionACTION: patient selection

Stable symptomatic angina treated with: blockers, nitrates, etc Lipid / blood pressure as indicatedAnd one of the following:1. History of myocardial infarction2. Angiographic CAD (known abnormal

angiogram, history of PTCA or CABG)3. Positive exercise or radionuclide test

• No history of myocardial infarction • Coronary angiography never done

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ACTION: exclusionsACTION: 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)

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ACTION: power calculationACTION: 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 realisedInterim analyses to protect patient safety

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ACTION: designACTION: 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

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7 797allocated

7 665in ITT

5 centres (128 pts) excluded

4 didn’t start

3 825nifedipine

3 840placebo

3 334complete

3 370complete

179 incomplete181 incomplete

291 died310 died

ACTIONACTIONtrial profiletrial profile

97.3% of planned follow-up was actually completed

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ACTION: history and symptomsACTION: history and symptomsNifedipine(n=3 825)

Placebo(n=3 840)

Mean (SD) age (years) 63.5 (9.3) 63.4 (9.3)

Male / Caucasian 80% / 98% 79% / 98%

1. History of MI 52% 50%

+ Coronary revascularisation 25% 25%

2. Angiographic CAD, no MI 32% 33%

+ Coronary revascularisation 20% 20%

3. Pos X or radionuclide test only 16% 17%

Significant angiographic lesions 69% 69%

Angiography not done 30% 30%

Current NYHA class II 46% 46%

No anginal symptoms 7% 8%

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ACTION: risk factorsACTION: risk factorsNifedipine(n=3 825)

Placebo(n=3 840)

Peripheral CV disease 13% 13%

Diabetes 15% 14%

Treated with insulin 2% 3%

Current smoker 18% 17%

Total cholesterol 5 mmol/l 62% 63%

Body mass index 30 kg/m2 22% 23%

Blood pres. 140/90 mm Hg 52% 52%

Any of these 86% 88%

Mean (SD) heart rate (bpm) 64.3 (10.3) 64.4 (10.3)

Mean (SD) EF (%) 48.3 (6.4) 48.2 (6.4)

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ACTION: co-treatment at entryACTION: co-treatment at entryNifedipine(n=3 825)

Placebo(n=3 840)

Prior CCB (washed-out) 22% 21%

Any one anti-anginal / 2 99% / 64% 99% / 65%

blocker 79% 80%

Nitrate as required / cont. 56% / 38% 57% / 37%

Any lipid lowering 68% 67%

Statin 63% 62%

Any BP lowering 30% 30%

Diuretic 11% 12%

ACE-inhibitor / AR blocker 20% / 2% 21% / 2%

Aspirin / vitamin K antagonist 86% / 4% 86% / 4%

Digoxin / anti-arrhythmic 1% / 4% 1% / 4%

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ACTION: toleranceACTION: tolerance

% follow-up time on study medication: 79% for nifedipine arm 82% for placebo armWithdrawal because of adverse event: 10% nifedipine

• 4% peripheral oedema• 1% headache

4% placebo• 1% peripheral oedema• 0.5% headache

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646668Heart

rate(bpm)

74

80

0 1 2 3 4 5 6years

Diastolicblood pr.(mm Hg)

125

130

135

140Systolicblood pr.(mm Hg)

Heart rate and blood pressureHeart rate and blood pressure

nifedipineplacebo

p<0.0001

p<0.0001

p<0.0001

16

0

10

20

30

40

50

60

BL 1 2 3 4 5 6years

% of patients

Systolic BPSystolic BP140, Diastolic140, Diastolic90 mm Hg90 mm Hg

nifedipineplacebo

17

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6

years

Proportion event-free

ACTION: outcomeACTION: outcome

nifedipineplacebo

All-cause death (p=0.4)

RA = refractory anginaPREV = peripheral revascularisation

Primary endpoint for efficacy(death, MI, RA, HF, CVA, PREV)p=0.5 Primary endpoint

for safety (death, MI, CVA, p=0.9)

180.0 0.5 1.0 1.5 2.0

Disabling stroke

New overt HF

Refractory angina

Myocardial Inf.

Non-CV death

CV death

All-cause death

rate/100 patient-yrs

ACTION: clinical eventsACTION: clinical eventsRR=1.07 (p=0.4)

n=310n=291

n=267n=257

n=178n=177

n=132n=114

n=150n=174

n=86n=121

n=77n=99

RR=1.01 (p=0.9)

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)

nifedipineplacebo

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Clinical events (rates / 100 pyrs)Clinical events (rates / 100 pyrs)Nifedipine(n=3 825)

Placebo(n=3 840)

RR (95% CI)

All death 310 (1.64) 291 (1.53) 1.07 (0.91 – 1.25)

CV death 178 (0.94) 177 (0.93) 1.01 (0.82 – 1.24)

Non-CV 132 (0.70) 114 (0.60) 1.16 (0.90 – 1.49)

Myocardial infarction

267 (1.46) 257 (1.39) 1.04 (0.88 – 1.24)

Refractory angina

150 (0.81) 174 (0.94) 0.86 (0.69 – 1.07)

New overt HF 86 (0.46) 121 (0.65) 0.71 (0.54 – 0.94)*

Debilitating stroke

77 (0.41) 99 (0.53) 0.78 (0.58 – 1.05)

* p<0.05

200 1 2 3 4 5 6 7

CABG

Percutaneouscoronary int.

Coronaryangiography

Peripheralrevasc.

rate/100patient-yrs

Cardiovascular proceduresCardiovascular procedures

n=146

n=118

RR=1.25 (p=0.07)

RR=0.82p<0.0001

RR=0.79 (p=0.002)

RR=0.92 (p=0.3)

n=895

n=1068

n=385

n=417

n=294

n=371

nifedipineplacebo

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CV procedures (rates / 100 pyrs)CV procedures (rates / 100 pyrs)Nifedipine(n=3 825)

Placebo(n=3 840)

RR (95% CI)

Peripheral revas- cularisation

146 (0.79) 118 (0.63) 1.25 (0.98 – 1.59)

Coronary angio-graphy

895 (5.46) 1 068 (6.69) 0.82 (0.75 – 0.90)*

Percutaneous coronary inter-vention

385 (2.15) 417 (2.34) 0.92 (0.80 – 1.06)

CABG 294 (1.62) 371 (2.06) 0.79 (0.68 – 0.92)*

* p<0.05

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Pre-defined combined endpointsPre-defined combined endpointsNon-CV death X X X

CV death X X X X X

Myocardial inf. X X X X X

Refractory angina X X X X

New overt HF X X X

Debilitating stroke X X X X X

Peripheral revasc. X X X X

Coronary angio X

Perc. cor. interv. X X

CABG X X

Prim

ary

endp

oint

for

effic

acy

Prim

ary

endp

oint

for

safe

ty

Car

diov

ascu

lar

(CV

) ev

ents

, a

ny C

V e

vent

or

proc

edur

e

Vas

cula

r ev

ents

230 1 2 3 4 5 6 7 8 9 10 11rate/100 patient-yrs

Combined endpointsCombined endpoints1st endpoint efficacy(death, MI, RA, HF,

CVA, PREV)

1st endpoint safety(death, MI, CVA)

CV events(CV death, MI, RA, HF,

CVA, PREV)

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=0.89(p=0.001)

RR=0.91 (p=0.03)

RR=0.94 (p=0.3)

n=804n=828

n=562n=558

n=694n=736

n=1439n=1583

n=1026n=1121

RR=0.97(p=0.5)

RR=1.01 (p=0.9)

nifedipineplacebo

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Comb endp (rates / 100 pyrs)Comb endp (rates / 100 pyrs)* p<0.05 Nifedipine Placebo RR (95% CI)

Primary endpoint for efficacy, MI, RA, HF, CVA, PREV 804 (4.60) 828 (4.75) 0.97 (0.88 – 1.07)

Primary endpoint for safety, MI, CVA 562 (3.08) 558 (3.05) 1.01 (0.90 – 1.14)Cardiovascular (CV) eventsCV, MI, RA, HF, CVA, PREV 694 (3.97) 736 (4.22) 0.94 (0.85 – 1.05)

Death, any CV event or procedure, MI, RA, HF, CVA, PREV, CAG, PCI, CABG

1 439 (9.32) 1 583 (10.50) 0.89 (0.83 – 0.95)*

Vascular eventsCV, MI, RA, CVA, PREV, PCI, CABG 1 026 (6.22) 1 121 (6.85) 0.91 (0.83 – 0.99)*

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0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6

years

Proportion event-free

Event-free survivalEvent-free survival

RA = refractory anginaPREV = peripheral revascularisationCAG = coronary angiographyPCI = percutaneous coronary interv. CABG = coronary artery bypass graft

nifedipineplacebo

Death, CV event or proc. (death, MI, RA, HF, CVA, PREV, CAG, PCI, CABG)

p=0.001

All-cause death (p=0.4)

Death, MI, CVA(p=0.9)

Death, MI, RA, HF, CVA, PREV (p=0.5)

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Death, any CV event or procedureDeath, any CV event or procedureNifedipine Placebo Difference

Mean survival (days) 1 805 1 805 0Mean event-free days: 1 475 1 434 +41

Death (any cause) 175 153 +22Myocardial inf. 190 186 +4Refractory angina 113 125 -12New overt HF 44 60 -16Debilitating stroke 58 72 -14Peripheral revasc. 109 77 +32Coronary angiogr. 629 779 -150Perc. cor. interv. 116 127 -11CABG 5 4 +1

Any event 1 439 1 583 - 144RR=0.89 (95% CI 0.83 – 0.95)

Fir

st e

ven

ts o

nly

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Primary endpoint efficacy: subgroupsPrimary endpoint efficacy: subgroups

All patients

Age<65 yrs (54%)

65 yrs (46%) p=0.4

GenderMale (79%)

Female (21%) p=0.07

History of MI

No (49%)

Yes (51%) p=0.2

DiabetesNo (86%)

Yes (14%) p=0.6

Past useof CCBs

No (78%)

Yes (22%) p=0.8

Favours nifedipine

RR, 95% CI

Test for interaction:

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Primary endpoint efficacy: subgroupsPrimary endpoint efficacy: subgroups

All patients

blockerat entry

No (20%)

Yes (80%) p=0.5

lipidat entry

No (32%)

Yes (68%) p=0.5

ACE-i ARB at entry

No (77%)

Yes (23%) p=0.2

Ejectionfr. at entry

<45% (28%)

45% (78%) p=0.5

Blood pr.at entry

<140/90 (48%)

140/90 (52%) p=0.02

Favours nifedipine

RR, 95% CI

Test for interaction:

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ACTION: conclusionsACTION: conclusionsIn 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

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ACTION: conclusionsACTION: conclusionsIn 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

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The ACTION Research GroupThe ACTION Research GroupSteering 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

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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.

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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.