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


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ACTION A C oronary disease T rial I nvestigating O utcome with N ifedipine GITS (gastrointestinal therapeutic system). presented by Philip A Poole-Wilson on behalf of the ACTION investigators. ACTION: rationale. Nifedipine GITS is widely used to treat angina and hypertension

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

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Action a coronary disease trial investigating outcome with nifedipine gits gastrointestinal therapeutic system

ACTIONACoronary disease Trial Investigating Outcome with Nifedipine GITS(gastrointestinal therapeutic system)

presented by

Philip A Poole-Wilsonon behalf of the ACTION investigators


Action rationale

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


Action features

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


Action primary objective

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)


Action primary endpoints

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


Action patient selection

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


Action exclusions

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)


Action power calculation

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


Action design

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


Action a coronary disease trial investigating outcome with nifedipine gits gastrointestinal therapeutic system

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


Action history and symptoms

ACTION: history and symptoms


Action risk factors

ACTION: risk factors


Action co treatment at entry

ACTION: co-treatment at entry


Action tolerance

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


Heart rate and blood pressure

Heart rate and blood pressure

p<0.0001

p<0.0001

nifedipine

placebo

p<0.0001


Systolic bp 140 diastolic 90 mm hg

Systolic BP140, Diastolic90 mm Hg

nifedipine

placebo


Action outcome

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


Action clinical events

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)


Clinical events rates 100 pyrs

Clinical events (rates / 100 pyrs)

* p<0.05


Cardiovascular procedures

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)


Cv procedures rates 100 pyrs

CV procedures (rates / 100 pyrs)

* p<0.05


Pre defined combined endpoints

Pre-defined combined endpoints

Primary endpoint for safety

Cardiovascular (CV) events

Primary endpoint for efficacy

, any CV event or procedure

Vascular events


Combined endpoints

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)


Comb endp rates 100 pyrs

Comb endp (rates / 100 pyrs)


Event free survival

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


Death any cv event or procedure

Death, any CV event or procedure

First events only

RR=0.89 (95% CI 0.83 – 0.95)


Primary endpoint efficacy subgroups

Primary endpoint efficacy: subgroups

RR, 95% CI

Test for interaction:

Favours nifedipine


Primary endpoint efficacy subgroups1

Primary endpoint efficacy: subgroups

RR, 95% CI

Test for interaction:

Favours nifedipine


Action conclusions

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


Action conclusions1

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


The action research group

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


Action a coronary disease trial investigating outcome with nifedipine gits gastrointestinal therapeutic system

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.


Action a coronary disease trial investigating outcome with nifedipine gits gastrointestinal therapeutic system

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.


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