Cardiovascular DiseasesPhase 4TNTpost-hocNCT03073863
Evaluation of Statin Mechanism Preventing Cardiovascular Disease by Post-hoc Analysis of Treating to New Targets Study
A Phase 4 study testing Atorvastatin in people with Cardiovascular Diseases, run by Korea University Guro Hospital.
Trial summary
Epidemiological studies have shown that serum cholesterol level is correlated with Cardiovascular Disease (CVD) risk, and that Cardiovascular Disease (CVD) risk increases with increasing LDL cholesterol levels. Read more about this study
- Who is it for?
- Ages 35 to 75 years
- Conditions the study is for
- Cardiovascular Diseases
- What is being tested?
- Atorvastatin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10,001 participants
- Where
- No sites listed yet
- Study dates
- 3 Apr 1998to 1 May 2007
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Men and women 35 to 75 years of age
- Clinically evident Coronary Heart Disease (CHD), defined by one or more of the following:
- previous myocardial infarction,
- previous or current angina with objective evidence of CHD,
- a history of coronary revascularization.
Who cannot join
- hypersensitivity to statins
- active liver disease or hepatic dysfunction defined as alanine aminotransferase or aspartate aminotransferase >1.5 times the upper limit of normal
- women who are pregnant or breastfeeding
- patients with nephrotic syndrome
- uncontrolled diabetes mellitus
- uncontrolled hypothyroidism
Show all 18Show fewer
- uncontrolled hypertension at the screening visit;
- a Myocardial infarction (MI), coronary revascularization procedure or severe/unstable angina within 1 month of screening
- any planned surgical procedure for the treatment of atherosclerosis
- an ejection fraction <30%
- hemodynamically important valvular disease
- gastrointestinal disease limiting drug absorption or partial ileal bypass
- any nonskin malignancy, malignant melanoma or other survival-limiting disease
- unexplained creatine phosphokinase levels >6 times the upper limit of normal
- concurrent therapy with long-term immunosuppressants
- concurrent therapy with lipid-regulating drugs not specified as study treatment in the protocol
- history of alcohol abuse
- participation in another clinical trial concurrently or within 30 days before screening.
About this study
Official title: Statin Intensity, Achieved LDL Cholesterol, and Cardiovascular Outcome in Statin Therapy in Patients With Coronary Artery Disease (Post-hoc Study of TNT Trial)
Epidemiological studies have shown that serum cholesterol level is correlated with Cardiovascular Disease (CVD) risk, and that Cardiovascular Disease (CVD) risk increases with increasing LDL cholesterol levels. Fortunately, it has been confirmed that cholesterol-lowering therapy is effective in preventing Cardiovascular Disease (CVD), and cholesterol lowering with statin therapy is a primary strategy in the prevention of Cardiovascular Disease (CVD). Despite the fact that statins reduce both LDL cholesterol and future cardiovascular outcome, the association of statin intensity and the achieved level of LDL cholesterol with cardiovascular outcome has not been fully elucidated, because statins have pleiotropic effect as well as LDL lowering effect.
The effect of statin on future Cardiovascular (CV) outcome seems to be more associated with statin intensity relating pleiotropic effects rather than with achieved LDL cholesterol level, because LDL-lowering by inhibition of hepatic cholesterol synthesis is linked to reciprocal increment of cholesterol absorption from the intestine.
Read the detailed description
It is easily extrapolated the relationship between LDL-C level and the incidence of Atherosclerotic Cardiovascular Disease (ASCVD) after statin therapy from the correlation between LDL-C level and the incidence of Atherosclerotic Cardiovascular Disease (ASCVD) in subjects without statin therapy and from the results of most lipid-lowering trials showing that 'the lower achieved LDL-C level, the better clinical outcomes. However, the association of statin intensity and the achieved level of LDL-C with cardiovascular outcome has not been fully elucidated, because the absolute amount of LDL cholesterol reduction is dependent not only on statin intensity, but also on inter-individual variation of statin responsiveness. In studies, the response to therapy with hypolipidemic agents shows considerable individual variation, and the use of the same dose of the same statin in different patients produces LDL-C decrease in a wide range from 8 to 55 %. These differences may be due to the interaction of environmental and genetic factors that affect drug bioavailability, receptor function or ligand structure and candidate gene analyses have found variants in known regulators of cholesterol metabolism such as HMGCR, Apolipoprotein E (APOE), PCSK9, Angiotensin Converting Enzyme (ACE), NPC1L1, and Low-Density Lipoprotein Receptor (LDLR) to be associated with statin response. Therefore, investigator suspects there could be some mistakes in interpreting the result of clinical trials with different intensities of statin. Actually, most of statin trials only compared the mean values of achieved LDL-C to the clinical outcomes in the statin therapy with different intensity, and there were few reports about the relationship between the individual values of achieved LDL-C and clinical outcomes in the statin therapy with same intensity. To accept the role of achieved LDL-C level for the prevention of Cardiovascular (CV) outcomes, it should still have a significant value after adjusting with statin intensity. In PROVE IT-Thrombolysis In Myocardial Infarction (TIMI) 22 study using either 80 mg of atorvastatin or 40 mg of pravastatin in Acute Coronary Syndrome (ACS) patients, IDEAL study with either 80 mg of atorvastatin or 20 mg of simvastatin in Acute Mycardial Infarction (AMI) patients, and TNT study with 80 mg of atorvastatin or 10 mg of atorvastatin in Coronary Artery Disease (CAD) patients, the authors demonstrated the relationships between the levels of achieved LDL-C after statin therapy and those between statin intensity and the risk of recurrent myocardial infarction or death from coronary causes separately. However, they did not report the relation between achieved LDL-C level and primary outcome after adjustment with statin intensity. Therefore, investigator think it may be inaccurate to determine the role of achieved LDL-C level in Atherosclerotic Cardiovascular Disease (ASCVD) prevention in clinical trials when those trials include the subjects with different intensity of statin therapy. Same phenomenon can also occur in meta-analysis of clinical trials with different statin intensity. Therefore, in Cholesterol Treatment Trialists' Collaboration (CTTC) meta-analyses, it should be reconsidered that the absolute amount of LDL-C reduction is dependent not only on statin intensity, but also on inter-individual variation of statin responsiveness.
All analyses will be performed on an intention-to-treat basis. Univariate analysis for each baseline characteristic of the patients, Cox proportional hazard model including age, sex, hypertension, diabetes, cardiovascular disease including coronary artery disease, cerebrovascular disease, peripheral artery disease, Congestive Heart Failure (CHF), achieved LDL cholesterol level, achieved C-Reactive Protein (CRP) level, statin intensity As in other studies using multiple doses of statin, investigator would like to evaluate the linear regression analysis between achieved LDL cholesterol level and CV outcome in total group, and it will show the correlation between them.
However, when investigator evaluates the linear regression analysis between achieved LDL cholesterol level and Cardiovascular (CV) outcome in the group treated with 10 mg of atorvastatin, it will show no relation between them, because of individual variability of LDL-C lowering effects by same statin.
The same result can be expected the relationship between achieved LDL cholesterol level and Cardiovascular (CV) outcome in the group treated with 80 mg of atorvastatin.
With the survival curve using Cox proportional hazard model for total Major Adverse Cardiac Events (MACE) and each component, investigator evaluates the impact of the followings:
- Achieved LDL-C level ( quartiles)
- Statin intensity
- Achieved C-Reactive Protein (CRP) level ( quartiles)
- Absolute mount of LDL-C lowering
- Absolute mount of C-Reactive Protein (CRP) lowering
- Other risk factors such as age, sex, hypertension, diabetes, hyperlipidemia, and etc.
- Conditions
- Cardiovascular Diseases
- Being tested
- Atorvastatin
- Keywords
- LDL Cholesterol, Statin intensity, post hoc analysis, Achieved LDL Cholesterol level
- Medical subject headings
- Cardiovascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AtorvastatinDrug
Analysis
| Study group | Role | What they receive |
|---|---|---|
| Atorvastatin 10mg | Active comparator | 5006 patients received continuous medication with atorvastatin 10mg/day after run-in period. Receives: Drug: Atorvastatin |
| Atorvastatin 80mg | Experimental | 4995 patients received medication with atorvastatin 80mg/day after run-in period. Receives: Drug: Atorvastatin |
What is being measured
The primary outcome is the main question the study is designed to answer.
The Relation between achieved LDL cholesterol level and the occurence of a first major CV event after adjustment of statin intensity
The effect of the achieved LDL cholesterol level on CV outcomes after adjustment of statin intensity.
Definition of a first major cardiovascular event: death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke
Measured: Up to 6 years
Secondary outcomes (2)
The Relation between statin intensity and the occurence of a first major CV event after adjustment of achieved LDL cholesterol level
The effect of the statin intensity on CV outcomes after adjustment of achieved LDL cholesterol level
Measured: Up to 6 years
The Relation between th amount of LDL cholesterol level and the occurence of a first major CV event after adjustment of statin intensity
The effect of LDL cholesterol lowering amount from baseline LDL-cholesterol on future CV outcome in statin therapy.
Measured: Up to 6 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Mar 2017
- Study start3 Apr 1998
- Primary completion1 May 2007
- Study completion1 May 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Cardiovascular DiseasesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Parallel Assignment
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 10,001 participants (actual)
Sponsor and investigators
- Lead sponsor
- Korea University Guro Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Pfizer
- Responsible party
- Principal investigator, Hong Seog Seo, Korea University Guro Hospital
- Investigators
- Hong Seog Seo, MD, Principal investigator, Korea University Guro Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03073863
- Sponsor's protocol ID
- KUGH16082
- Acronym
- TNTpost-hoc
- Status last verified
- Apr 2017
- First submitted
- 28 Feb 2017
- Last updated
- 1 May 2017
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005 Apr 7;352(14):1425-35. doi: 10.1056/NEJMoa050461. Epub 2005 Mar 8.
PubMed 15755765
Study at a glance
From the registry record, last updated by the sponsor on 1 May 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Statin Intensity, Achieved LDL Cholesterol, and Cardiovascular Outcome in Statin Therapy in Patients With Coronary Artery Disease (Post-hoc Study of TNT Trial)
- ClinicalTrials.gov ID
- NCT03073863
- Acronym / sponsor ID
- TNTpost-hoc / KUGH16082
- Conditions
- Cardiovascular Diseases
- Keywords
- LDL Cholesterol, Statin intensity, post hoc analysis, Achieved LDL Cholesterol level
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10,001 participants (actual)
- Lead sponsor
- Korea University Guro HospitalUniversity, hospital or other
- Collaborators
- Pfizer
- Study start
- 3 Apr 1998 (actual)
- Primary completion
- 1 May 2007 (actual)
- Study completion
- 1 May 2007 (actual)
- First posted
- 8 Mar 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Epidemiological studies have shown that serum cholesterol level is correlated with Cardiovascular Disease (CVD) risk, and that Cardiovascular Disease (CVD) risk increases with increasing LDL cholesterol levels. Fortunately, it has been confirmed that cholesterol-lowering therapy is effective in preventing Cardiovascular Disease (CVD), and cholesterol lowering with statin therapy is a primary strategy in the prevention of Cardiovascular Disease (CVD). Despite the fact that statins reduce both LDL cholesterol and future cardiovascular outcome, the association of statin intensity and the achieved level of LDL cholesterol with cardiovascular outcome has not been fully elucidated, because statins have pleiotropic effect as well as LDL lowering effect.
The effect of statin on future Cardiovascular (CV) outcome seems to be more associated with statin intensity relating pleiotropic effects rather than with achieved LDL cholesterol level, because LDL-lowering by inhibition of hepatic cholesterol synthesis is linked to reciprocal increment of cholesterol absorption from the intestine.
Detailed description
It is easily extrapolated the relationship between LDL-C level and the incidence of Atherosclerotic Cardiovascular Disease (ASCVD) after statin therapy from the correlation between LDL-C level and the incidence of Atherosclerotic Cardiovascular Disease (ASCVD) in subjects without statin therapy and from the results of most lipid-lowering trials showing that 'the lower achieved LDL-C level, the better clinical outcomes. However, the association of statin intensity and the achieved level of LDL-C with cardiovascular outcome has not been fully elucidated, because the absolute amount of LDL cholesterol reduction is dependent not only on statin intensity, but also on inter-individual variation of statin responsiveness. In studies, the response to therapy with hypolipidemic agents shows considerable individual variation, and the use of the same dose of the same statin in different patients produces LDL-C decrease in a wide range from 8 to 55 %. These differences may be due to the interaction of environmental and genetic factors that affect drug bioavailability, receptor function or ligand structure and candidate gene analyses have found variants in known regulators of cholesterol metabolism such as HMGCR, Apolipoprotein E (APOE), PCSK9, Angiotensin Converting Enzyme (ACE), NPC1L1, and Low-Density Lipoprotein Receptor (LDLR) to be associated with statin response. Therefore, investigator suspects there could be some mistakes in interpreting the result of clinical trials with different intensities of statin. Actually, most of statin trials only compared the mean values of achieved LDL-C to the clinical outcomes in the statin therapy with different intensity, and there were few reports about the relationship between the individual values of achieved LDL-C and clinical outcomes in the statin therapy with same intensity. To accept the role of achieved LDL-C level for the prevention of Cardiovascular (CV) outcomes, it should still have a significant value after adjusting with statin intensity. In PROVE IT-Thrombolysis In Myocardial Infarction (TIMI) 22 study using either 80 mg of atorvastatin or 40 mg of pravastatin in Acute Coronary Syndrome (ACS) patients, IDEAL study with either 80 mg of atorvastatin or 20 mg of simvastatin in Acute Mycardial Infarction (AMI) patients, and TNT study with 80 mg of atorvastatin or 10 mg of atorvastatin in Coronary Artery Disease (CAD) patients, the authors demonstrated the relationships between the levels of achieved LDL-C after statin therapy and those between statin intensity and the risk of recurrent myocardial infarction or death from coronary causes separately. However, they did not report the relation between achieved LDL-C level and primary outcome after adjustment with statin intensity. Therefore, investigator think it may be inaccurate to determine the role of achieved LDL-C level in Atherosclerotic Cardiovascular Disease (ASCVD) prevention in clinical trials when those trials include the subjects with different intensity of statin therapy. Same phenomenon can also occur in meta-analysis of clinical trials with different statin intensity. Therefore, in Cholesterol Treatment Trialists' Collaboration (CTTC) meta-analyses, it should be reconsidered that the absolute amount of LDL-C reduction is dependent not only on statin intensity, but also on inter-individual variation of statin responsiveness.
All analyses will be performed on an intention-to-treat basis. Univariate analysis for each baseline characteristic of the patients, Cox proportional hazard model including age, sex, hypertension, diabetes, cardiovascular disease including coronary artery disease, cerebrovascular disease, peripheral artery disease, Congestive Heart Failure (CHF), achieved LDL cholesterol level, achieved C-Reactive Protein (CRP) level, statin intensity As in other studies using multiple doses of statin, investigator would like to evaluate the linear regression analysis between achieved LDL cholesterol level and CV outcome in total group, and it will show the correlation between them.
However, when investigator evaluates the linear regression analysis between achieved LDL cholesterol level and Cardiovascular (CV) outcome in the group treated with 10 mg of atorvastatin, it will show no relation between them, because of individual variability of LDL-C lowering effects by same statin.
The same result can be expected the relationship between achieved LDL cholesterol level and Cardiovascular (CV) outcome in the group treated with 80 mg of atorvastatin.
With the survival curve using Cox proportional hazard model for total Major Adverse Cardiac Events (MACE) and each component, investigator evaluates the impact of the followings:
- Achieved LDL-C level ( quartiles)
- Statin intensity
- Achieved C-Reactive Protein (CRP) level ( quartiles)
- Absolute mount of LDL-C lowering
- Absolute mount of C-Reactive Protein (CRP) lowering
- Other risk factors such as age, sex, hypertension, diabetes, hyperlipidemia, and etc.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- Model description
- Parallel Assignment
| Arm | Type | Receives |
|---|---|---|
| Atorvastatin 10mg | Active comparator | Drug: Atorvastatin5006 patients received continuous medication with atorvastatin 10mg/day after run-in period. |
| Atorvastatin 80mg | Experimental | Drug: Atorvastatin4995 patients received medication with atorvastatin 80mg/day after run-in period. |
Who may qualify
- Ages
- 35 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Men and women 35 to 75 years of age
- Clinically evident Coronary Heart Disease (CHD), defined by one or more of the following:
Key exclusion criteria (18 listed)
- hypersensitivity to statins
- active liver disease or hepatic dysfunction defined as alanine aminotransferase or aspartate aminotransferase >1.5 times the upper limit of normal
- women who are pregnant or breastfeeding
- patients with nephrotic syndrome
- uncontrolled diabetes mellitus
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AtorvastatinAnalysis | Drug | Atorvastatin 10mg, Atorvastatin 80mg |
Primary outcome
The Relation between achieved LDL cholesterol level and the occurence of a first major CV event after adjustment of statin intensity
Time frame: Up to 6 years
The effect of the achieved LDL cholesterol level on CV outcomes after adjustment of statin intensity. Definition of a first major cardiovascular event: death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke
2 secondary outcomes
The Relation between statin intensity and the occurence of a first major CV event after adjustment of achieved LDL cholesterol level
Time frame: Up to 6 years
The Relation between th amount of LDL cholesterol level and the occurence of a first major CV event after adjustment of statin intensity
Time frame: Up to 6 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 May 2017.
- Background: PubMed 15755765LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005 Apr 7;352(14):1425-35. doi: 10.1056/NEJMoa050461. Epub 2005 Mar 8.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hong Seog Seo, MD principal investigator
Korea University Guro Hospital
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Atorvastatin in people with Cardiovascular Diseases, run by Korea University Guro Hospital.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 May 2017. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The Relation between achieved LDL cholesterol level and the occurence of a first major CV event after adjustment of statin intensity (time frame: Up to 6 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03073863, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 May 2017.