Candesartan for Prevention of Cardiovascular Events After Cypher or Taxus Coronary Stenting (4C) Trial

Study Description

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Brief Summary:

Candesartan is effective in preventing cardiovascular events in patients without restenosis after coronary angioplasty. Therefore, the investigators hypothesized that candesartan after drug-eluting stent (DES) implantation was also effective in preventing cardiovascular events.

The purpose of this study is to investigate whether an angiotensin II receptor blocker, candesartan, is effective in reducing the incidence of cardiovascular events after drug-eluting stent implantation.

Condition or disease	Intervention/treatment	Phase
Hypertension; Coronary Artery Disease	Drug: Candesartan	Phase 4

Detailed Description:

It was reported that low-dose angiotensin II receptor blocker, candesartan, was effective to prevent cardiovascular events in patients with coronary artery disease treated with coronary angioplasty (Am Heart J 146:E20, 2003). In this study, patients without significant coronary stenosis on follow-up angiography 6 months after intervention were randomly assigned into a candesartan group (baseline treatment plus candesartan 4 mg/d) or a control group (baseline treatment alone). It is well known that patients treated with drug-eluting stents (DES) have lower restenosis rate as compared with those with bare metal stents. Therefore, we hypothesized that candesartan started immediately after DES implantation was effective to prevent cardiovascular events.

The primary endpoint is a composite of any cause death and cardiovascular events (nonfatal myocardial infarction, recurrent symptomatic myocardial ischemia, congestive heart failure, and stroke). The secondary endpoints are target lesion revascularization, binary restenosis, newly onset diabetes and newly onset of atrial fibrillation.

Patient population which needs to prove the hypothesis is estimates to be 1,130 cases in total (565 cases in each group). We set the parameters which are needed to calculate the number of study patients as follows; a drop out rate 10%, an event rate of the primary end point for 3 years 20%, a risk reduction rate brought by candesartan 25%, a statistical power 90% and a two-sided significance level 0.05. We assumed the event rate from the study which was conducted to prove the effects of statins after PCI in Japan named MUSASHI-PCI. Also the risk reduction rate from two major RCTs of candesartan conducted in Japan named the Ogaki and HIJ-CREATE studies. In the Ogaki study, the risk reduction rate by candesartan was 52%. However, stents used in the study were only BMS after surviving restenosis. The risk reduction of the present study will be lower because of the higher onset rate of stent thrombosis in regard to DES. Furthermore, the risk reduction rate of candesartan for Japanese was 11% reported in HIJ-CREATE. The ACE-I usage rate was almost 70% in the control subjects of HIJ-CREATE. In the present study, ACE-I will be administered less frequently as low as 30%. Therefore, assumed risk reduction rate by candesartan in the present study could be higher. Considering all the various factors together, a reasonable risk reduction rate could be 25%.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	1119 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	Effects of Candesartan Cilexetil on Cardiovascular Events in Japanese Patients With Hypertension After Sirolimus- or Paclitaxel-Eluting Stents Implantation
Study Start Date :	October 2005
Actual Primary Completion Date :	April 2009
Actual Study Completion Date :	April 2012

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Candesratan	Drug: Candesartan; Candesartan Cilexetil (4-12 mg per day); Other Names: Blopress; 4C
No Intervention: Non-candesartan

Outcome Measures

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Primary Outcome Measures :

1. The primary endpoint is a composite of: 1)any cause mortality and 2)cardiovascular events (non-fatal MI, drug-resistant AP required hospital admission, heart failure required hospital admission and stroke) [ Time Frame: 3 years ]

Secondary Outcome Measures :

1. Target lesion revascularization [ Time Frame: 3 years ]
2. Binary restenosis [ Time Frame: 3 years ]
3. Newly onset diabetes [ Time Frame: 3 years ]
4. Newly onset atrial fibrillation [ Time Frame: 3 yeard ]
5. Each of the primary endpoint events [ Time Frame: 3 years ]
   All cause of death, cardiovascular death, non-fatal myocardial infarction, unstable angina required admission, heart failure required admission and stroke
6. Major adverse cardiac-related events [ Time Frame: 3 years ]
   A composite of cardiovascular death, non-fatal myocardial infarction, unstable angina required admission and heart failure required admission
7. Major cardiac-related events [ Time Frame: 3 years ]
   A composite of non-fatal myocardial infarction, unstable angina required admission and heart failure required admission

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Senior
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• A. Patients with hypertension, systolic blood pressure (SBP) = or > 140 and/or diastolic blood pressure (DBP) = or > 90
• B. Patients with symptomatic heart failure lasting at least for 4 weeks (NYHA class = or > II), or those need continuous use of diuretics
• C. Patients underwent coronary angioplasty with drug-eluting stents

Eligible patients are those who meet (A or B) and C.

Exclusion Criteria:

• Severe renal or hepatic disease
• Candidates for coronary artery bypass grafting (CABG)
• Within 3 months after CABG
• Allergic history to candesartan
• Pregnant women

Contacts and Locations

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Locations

Japan
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
Kumamoto, Japan, 860-8556

Sponsors and Collaborators

Kumamoto University

The 4C trial bureau

Japan Heart Foundation

Investigators

Study Chair:	Hisao Ogawa, MD, PhD	Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Dept of CVM, Kumamoto Univ Hosp 

Publications:

Kondo J, Sone T, Tsuboi H, Mukawa H, Morishima I, Uesugi M, Kono T, Kosaka T, Yoshida T, Numaguchi Y, Matsui H, Murohara T, Okumura K. Effects of low-dose angiotensin II receptor blocker candesartan on cardiovascular events in patients with coronary artery disease. Am Heart J. 2003 Dec;146(6):E20.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Sakamoto T, Ogawa H, Nakao K, Hokimoto S, Tsujita K, Koide S, Yamamoto N, Shimomura H, Matsumura T, Oshima S, Kikuta K, Oka H, Kimura K, Matsui K; 4C (Candesartan for Prevention of Cardiovascular Events after CYPHER™ or TAXUS™ Coronary Stenting) study investigators. Impact of candesartan on cardiovascular events after drug-eluting stent implantation in patients with coronary artery disease: The 4C trial. J Cardiol. 2016 Apr;67(4):371-7. doi: 10.1016/j.jjcc.2015.06.009. Epub 2015 Aug 4.

Responsible Party:	Hisao Ogawa, MD, PhD, Kumamoto University
ClinicalTrials.gov Identifier:	NCT00139386 History of Changes
Other Study ID Numbers:	CVM-RCT-2005-01
First Posted:	August 31, 2005
Last Update Posted:	April 18, 2013
Last Verified:	April 2013

Keywords provided by Hisao Ogawa, Kumamoto University:

Drug-eluting stent; Candesartan; Randomized control study; Coronary Angioplasty

Additional relevant MeSH terms:

Hypertension; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Arteriosclerosis	Arterial Occlusive Diseases; Candesartan; Candesartan cilexetil; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action