Six Months Efficacy and Safety of Aliskiren Therapy on Top of Standard Therapy, on Morbidity and Mortality in Patients With Acute Decompensated Heart Failure

Congestive Heart Failure Clinical Trial

— ASTRONAUT  

Official title:

A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Study to Evaluate the 6 Months Efficacy and Safety of Aliskiren Therapy on Top of Standard Therapy, on Morbidity and Mortality When Initiated Early After Hospitalization for Acute Decompensated Heart Failure

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00894387
• Other study ID #: CSPP100A2368
• Secondary ID: 2009-010236-18
• Status: Completed
• Phase: Phase 3
• First received: May 5, 2009
• Last updated: October 15, 2013
• Start date: May 2009
• Est. completion date: August 2012

Study information

• Verified date: October 2013
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study evaluated the effect of early initiation of aliskiren therapy, compared to standard therapy, in the reduction of cardiovascular death and heart failure re-hospitalization events within 6 months, in congestive heart failure (CHF) patients hospitalized for an episode of acute decompensated heart failure.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1639
• Est. completion date: August 2012
• Est. primary completion date: August 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Patient hospitalized with a primary diagnosis of worsening heart failure = 18 years of age, male or female.

• Patients with a diagnosis of acute heart failure expressed by symptoms (dyspnea or fatigability - NYHA Class III-IV) and signs of fluid overload (i.e., jugular venous distension, edema or positive rales auscultation or pulmonary congestion on chest x-ray) at the time of hospitalization.

• LVEF < 40% (measured within the last 6 months).

• Hospitalization for ADHF and remain "stabilized" for at least 6 hours (defined as SBP = 110 mm Hg after acute decompensated episode) and did not receive IV vasodilators (other than nitrates) and/or IV inotropic drugs at anytime from ADHF presentation to time of randomization.

• Elevated BNP at Visit 1 or at randomization (BNP = 400 pg/ml).

• Patients with a history of chronic heart failure on standard therapy defined as requiring HF treatment for at least 30 days before the current hospitalization (NYHA Class II - IV).

Exclusion Criteria:

• Patients that required any use of IV vasodilators (except nitrates), and/or any IV inotropic therapy from the time of presentation for worsening HF to randomization.

• Concomitant use of ACEI and ARB at randomization.

• Right heart failure due to pulmonary disease.

• Diagnosis of postpartum cardiomyopathy.

• Myocardial infarction or cardiac surgery, including percutaneous transluminal coronary angioplasty (PTCA), within past 3 months.

• Patients with a history of heart transplant or who are on a transplant list.

• Unstable angina or coronary artery disease likely to require coronary artery bypass graft (CABG) or PTCA before randomization.

Other protocol-defined inclusion/exclusion criteria applied.

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Decompensated Heart Failure
• Congestive Heart Failure
• Heart Failure

Intervention

Drug:
• Aliskiren
Aliskiren 150 mg and Aliskiren 300 mg
• Placebo
Placebo

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Corrientes
Argentina	Novartis Investigative Site	Corrientes
Argentina	Novartis Investigative Site	Corrientes
Argentina	Novartis Investigative Site	Posadas	Misiones
Argentina	Novartis Investigative Site	Quilmes
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	San Miguel de Tucuman	Tucuman
Argentina	Novartis Investigative Site	San Nicolas	Buenos Aires
Argentina	Novartis Investigative Site	Santa Fe
Argentina	Novartis Investigative Site	Santa Fe
Argentina	Novartis Investigative Site	Tucuman
Belgium	Novartis Investigative Site	Antwerpen
Belgium	Novartis Investigative Site	Brasschaat
Belgium	Novartis Investigative Site	Genk
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Hasselt
Belgium	Novartis Investigative Site	Huy
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Mechelen
Belgium	Novartis Investigative Site	Mol
Belgium	Novartis Investigative Site	Namur
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Campinas	SP
Brazil	Novartis Investigative Site	Londrina	PR
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Sao Jose do Rio Preto	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Canada	Novartis Investigative Site	Halifax	Nova Scotia
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	St. John's	Newfoundland and Labrador
Canada	Novartis Investigative Site	Toronto	Ontario
Colombia	Novartis Investigative Site	Barranquilla	Atlantico
Colombia	Novartis Investigative Site	Barranquilla
Colombia	Novartis Investigative Site	Bogotá
Colombia	Novartis Investigative Site	Bogotá
Colombia	Novartis Investigative Site	Bogotá	Cundinamarca
Colombia	Novartis Investigative Site	Cali
Colombia	Novartis Investigative Site	Florida Blanca
Czech Republic	Novartis Investigative Site	Brno
Czech Republic	Novartis Investigative Site	Brno - Bohunice
Czech Republic	Novartis Investigative Site	Hradec Kralove	CZE
Czech Republic	Novartis Investigative Site	Olomouc
Czech Republic	Novartis Investigative Site	Prague 4
Czech Republic	Novartis Investigative Site	Prague 5
Czech Republic	Novartis Investigative Site	Praha 10
Czech Republic	Novartis Investigative Site	Praha 2
Czech Republic	Novartis Investigative Site	Slany
Czech Republic	Novartis Investigative Site	Teplice
Czech Republic	Novartis Investigative Site	Znojmo
Finland	Novartis Investigative Site	Jyvaskyla
Finland	Novartis Investigative Site	Turku
France	Novartis Investigative Site	Bordeaux Cedex
France	Novartis Investigative Site	Grenoble
France	Novartis Investigative Site	Le Chesnay
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Pessac Cedex
France	Novartis Investigative Site	Pontoise
France	Novartis Investigative Site	Toulouse Cedex
Germany	Novartis Investigative Site	Augsburg
Germany	Novartis Investigative Site	Bad Bevensen
Germany	Novartis Investigative Site	Bad Nauheim
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bischofswerda
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Bremen
Germany	Novartis Investigative Site	Cloppenburg
Germany	Novartis Investigative Site	Cottbus
Germany	Novartis Investigative Site	Dessau
Germany	Novartis Investigative Site	Detmold
Germany	Novartis Investigative Site	Dortmund
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Greifswald
Germany	Novartis Investigative Site	Halle/'Saale
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Herne
Germany	Novartis Investigative Site	Herrsching
Germany	Novartis Investigative Site	Jena
Germany	Novartis Investigative Site	Köln
Germany	Novartis Investigative Site	Konstanz
Germany	Novartis Investigative Site	Langen
Germany	Novartis Investigative Site	Ludwigslust
Germany	Novartis Investigative Site	Magdeburg
Germany	Novartis Investigative Site	Merseburg
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Nordhorn
Germany	Novartis Investigative Site	Paderborn
Germany	Novartis Investigative Site	Quedlinburg
Germany	Novartis Investigative Site	Regensburg
Germany	Novartis Investigative Site	Rostock
Germany	Novartis Investigative Site	Sömmerda
Germany	Novartis Investigative Site	Weiden
Hungary	Novartis Investigative Site	Balatonfured
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Hodmezovasarhely
Hungary	Novartis Investigative Site	Nagykanizsa
Hungary	Novartis Investigative Site	Pecs	Baranya
Hungary	Novartis Investigative Site	Szolnok
Hungary	Novartis Investigative Site	Zalaegerszeg
India	Novartis Investigative Site	Bangalore	Karnataka
India	Novartis Investigative Site	Bangalore	Karnataka
India	Novartis Investigative Site	Bangalore
India	Novartis Investigative Site	Coimbatore	Tamil Nadu
India	Novartis Investigative Site	Coimbatore	Tamil Nadu
India	Novartis Investigative Site	Hyderabad
India	Novartis Investigative Site	Indore	M.p.
India	Novartis Investigative Site	Kochi	Kerala
India	Novartis Investigative Site	Mangalore	Karnataka
India	Novartis Investigative Site	Mumbai	Maharashtra
India	Novartis Investigative Site	Nagpur	Maharashtra
India	Novartis Investigative Site	Nagpur	Maharashtra
India	Novartis Investigative Site	New Delhi
India	Novartis Investigative Site	Pune	Maharashtra
India	Novartis Investigative Site	Pune	Maharashtra
India	Novartis Investigative Site	Pune	Maharashtra
India	Novartis Investigative Site	Secunderabad	Andhra Pradesh
India	Novartis Investigative Site	Vadodara	Gujrat
Israel	Novartis Investigative Site	Ashkelon
Israel	Novartis Investigative Site	Hadera
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Nazareth
Israel	Novartis Investigative Site	Safed
Israel	Novartis Investigative Site	Tel-Aviv
Italy	Novartis Investigative Site	Albano Laziale	RM
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Brescia	BS
Italy	Novartis Investigative Site	Casarano	LE
Italy	Novartis Investigative Site	Catania	CT
Italy	Novartis Investigative Site	Cremona	CR
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Foggia	FG
Italy	Novartis Investigative Site	Grosseto	GR
Italy	Novartis Investigative Site	Lagosanto	FE
Italy	Novartis Investigative Site	Lecce	LE
Italy	Novartis Investigative Site	Legnago	VR
Italy	Novartis Investigative Site	Legnano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Monza	MB
Italy	Novartis Investigative Site	Palermo	PA
Italy	Novartis Investigative Site	Parma	PR
Italy	Novartis Investigative Site	Pavia	(pv)
Italy	Novartis Investigative Site	Perugia	PG
Italy	Novartis Investigative Site	Pozzilli	IS
Italy	Novartis Investigative Site	Rimini	RN
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Scorrano	LE
Italy	Novartis Investigative Site	Siena	SI
Italy	Novartis Investigative Site	Verona	(vr)
Philippines	Novartis Investigative Site	Manila
Philippines	Novartis Investigative Site	Quezon City
Philippines	Novartis Investigative Site	Quezon City	Metro Manila
Poland	Novartis Investigative Site	Grodzisk Wielkopolski
Poland	Novartis Investigative Site	Klodzko
Poland	Novartis Investigative Site	Kraków
Poland	Novartis Investigative Site	Lódz
Poland	Novartis Investigative Site	Lublin
Poland	Novartis Investigative Site	Ruda Slaska
Poland	Novartis Investigative Site	Swidnica
Poland	Novartis Investigative Site	Szczecin
Poland	Novartis Investigative Site	Walbrzych
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Wroclaw
Poland	Novartis Investigative Site	Wroclaw
Poland	Novartis Investigative Site	Zabrze
Poland	Novartis Investigative Site	Zamosc
Romania	Novartis Investigative Site	Bucharest
Romania	Novartis Investigative Site	Bucharest
Romania	Novartis Investigative Site	Bucuresti	District 1
Romania	Novartis Investigative Site	Craiova
Romania	Novartis Investigative Site	Timisoara
Romania	Novartis Investigative Site	Tirgoviste
Russian Federation	Novartis Investigative Site	Lubertsi
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Nizhnii Novgorod
Russian Federation	Novartis Investigative Site	S.-Petersburg
Russian Federation	Novartis Investigative Site	S.-Petersburg
Russian Federation	Novartis Investigative Site	S.-Petersburg
Russian Federation	Novartis Investigative Site	S.-Petersburg
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	Saint-Petersburg
Russian Federation	Novartis Investigative Site	Saint-Petersburg
Russian Federation	Novartis Investigative Site	Saint-Petersburg
Russian Federation	Novartis Investigative Site	Sankt-Peterburg
Russian Federation	Novartis Investigative Site	Saratov
Russian Federation	Novartis Investigative Site	Saratov
Russian Federation	Novartis Investigative Site	St.Petersburg
Russian Federation	Novartis Investigative Site	Yaroslavl
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Komarno
Slovakia	Novartis Investigative Site	Kosice
Slovakia	Novartis Investigative Site	Kosice-Saca
Slovakia	Novartis Investigative Site	Levice
Slovakia	Novartis Investigative Site	Liptovsky Mikulas	Slovak Republic
Slovakia	Novartis Investigative Site	Lucenec
Slovakia	Novartis Investigative Site	Martin
Slovakia	Novartis Investigative Site	Nitra
Slovakia	Novartis Investigative Site	Presov	Slovak Republic
Slovakia	Novartis Investigative Site	Trnava
Spain	Novartis Investigative Site	Barcelona	Cataluña
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Majadanonda	Madrid
Spain	Novartis Investigative Site	Palma de Mallorca	Baleares
Spain	Novartis Investigative Site	Pozuelo de Alarcón	Madrid
Spain	Novartis Investigative Site	Sanlúcar de Barrameda	Andalucia
Spain	Novartis Investigative Site	Santiago de Compostela	Galicia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Villamartin	Andalucia
Sweden	Novartis Investigative Site	Göteborg
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Stockholm
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	Keelung City
Taiwan	Novartis Investigative Site	Lin-Ko
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Atakum / Samsun
Turkey	Novartis Investigative Site	Etlik / Ankara
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Kirikkale
Turkey	Novartis Investigative Site	Kocaeli
Turkey	Novartis Investigative Site	Sivas
Turkey	Novartis Investigative Site	Talas / Kayseri
United States	Novartis Investigative Site	Bronx	New York
United States	Novartis Investigative Site	Brownsville	Texas
United States	Novartis Investigative Site	Buffalo	New York
United States	Novartis Investigative Site	Buffalo	New York
United States	Novartis Investigative Site	Chapel Hill	North Carolina
United States	Novartis Investigative Site	Charleston	South Carolina
United States	Novartis Investigative Site	Charlottesville	Virginia
United States	Novartis Investigative Site	Cherry Hill	New Jersey
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Novartis Investigative Site	Cleveland	Ohio
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Hartford	Connecticut
United States	Novartis Investigative Site	Iowa City	Iowa
United States	Novartis Investigative Site	Jacksonville	Florida
United States	Novartis Investigative Site	Kalamazoo	Michigan
United States	Novartis Investigative Site	Lafayette	Louisiana
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Macon	Georgia
United States	Novartis Investigative Site	Mobile	Alabama
United States	Novartis Investigative Site	Newark	New Jersey
United States	Novartis Investigative Site	Oakbrook Terrace	Illinois
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Novartis Investigative Site	Pittsburgh	Pennsylvania
United States	Novartis Investigative Site	Rapid City	South Dakota
United States	Novartis Investigative Site	Richmond	Virginia
United States	Novartis Investigative Site	Richmond	Virginia
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	Saratoga Springs	New York
United States	Novartis Investigative Site	Springfield	Tennessee
United States	Novartis Investigative Site	St. Louis	Missouri
United States	Novartis Investigative Site	Sylmar	California
United States	Novartis Investigative Site	Torrance	California
United States	Novartis Investigative Site	Tucson	Arizona
United States	Novartis Investigative Site	Washington	District of Columbia
United States	Novartis Investigative Site	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Canada,  Colombia,  Czech Republic,  Finland,  France,  Germany,  Hungary,  India,  Israel,  Italy,  Philippines,  Poland,  Romania,  Russian Federation,  Singapore,  Slovakia,  Spain,  Sweden,  Taiwan,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Event Analysis: Number of Patients Experienced the First Confirmed Occurrence of Either Cardiovascular Death or Heart Failure (HF) Re-hospitalization Within 6 Months	Time to first confirmed occurrence of either cardiovascular death or heart failure re-hospitalization within 6 months of randomization was the primary efficacy variable. For the primary efficacy analysis, an event will be considered for the analysis if it occurs on or before Day 190 (189 days from randomization). The primary composite endpoint is the the composite of cardiovascular death or heart faliure re-hospitalization within 6 months.	6 months	No
Secondary	Time to Event Analysis: Number of Patients Experienced the First Confirmed Occurrence of Either Cardiovascular Death or Heart Failure (HF) Re-hospitalization Within 12 Months	Time to first confirmed occurrence of either cardiovascular death or heart failure re-hospitalization within 12 months of randomization was the key secondary efficacy variable. For the primary efficacy analysis, an event will be considered for the analysis if it occurs on or before Day 395 (394 days from randomization). The secondary composite endpoint is the the composite of cardiovascular death or heart faliure re-hospitalization within 12 months.	12 months	No
Secondary	Change From Baseline in the Clinical Summary Score to 1 Month, 6 Months and 12 Months	Symptom reduction and reduction in physical limitations was assessed using the clinical summary score of the Kansas City Cardiomyopathy Questionnaire (KCCQ). The KCCQ is a self-administered questionnaire and contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Health-Related Quality of Life (QoL), including limitations, frequency, bother, change in condition, understanding, levels of enjoyment and satisfaction. Each scale score was calculated as the mean of its item scores and transformed to a 0-100 scale, with higher score indicating higher level of functioning. A score of 100 represents perfect health whereas a score of 0 represents death. A positive change in score from baseline indicates an improvement.	Baseline, 1 months, 6 months and 12 months	No
Secondary	Time to Event Analysis: Number of Patients With First Cardiovascular (CV) Event Hospitalized for an Acute Heart Faliure (AHF) Event Within 6 Months	A cardiovascular event defined as CV death, heart faliure re-hospitalization, non-fatal myocardial infarction (MI), nonfatal stroke, sudden death with resuscitation.	6 months	No
Secondary	Time to Event Analysis: Number of Patients With All-cause Mortality Hospitalized for an AHF Event Within 12 Months		12 months	No
Secondary	Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Level at 1 Month, 6 Months, and 12 Months	The reported Least square means, and Confidential Interval were from a repeated measures model on log transformed NT-proBNP data containing treatment, visit, and region as factors, log baseline NT-proBNP as a continuous covariate and treatment by visit and visit by log baseline NT-proBNP as interaction terms.	Baseline, 1 month, 6 months and 12 months	No
Secondary	Time to Event Analysis: Number of Patients With First Cardiovascular (CV) Event Hospitalized for an Acute Heart Faliure (AHF) Event Within 12 Months	A cardiovascular event defined as CV death, heart faliure re-hospitalization, non-fatal myocardial infarction (MI), nonfatal stroke, sudden death with resuscitation.	12 months	No