Evaluation of Statin Mechanism Preventing Cardiovascular Disease by Post-hoc Analysis of Treating to New Targets Study
Condition: Cardiovascular Diseases
MeSH terms: Cardiovascular Diseases
Study type: Interventional
Phase: Phase 4

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. 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:

        1. Achieved LDL-C level ( quartiles)

        2. Statin intensity

        3. Achieved C-Reactive Protein (CRP) level ( quartiles)

        4. Absolute mount of LDL-C lowering

        5. Absolute mount of C-Reactive Protein (CRP) lowering

        6. Other risk factors such as age, sex, hypertension, diabetes, hyperlipidemia, and etc.
    

Intervention name(s): Atorvastatin
Intervention type(s): Drug
Intervention description(s): Analysis
Intervention MeSH terms: Atorvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: LDL Cholesterol; Statin intensity; post hoc analysis; Achieved LDL Cholesterol level