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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
4
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
6
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
7
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)
8
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
9
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%
12
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
15
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
19
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
21
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)
26
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
27
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:
28
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:
29
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
30
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
31
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.