Jama_LODESTAR

Jihee Han

2023-09-16

Introduction

Introduction

Objective

  • To assess whether a treat-to-target strategy is noninferior to a strategy of high-intensity statins for long-term clinical outcomes in patients with coronary artery disease

Study Design

  • Investigator-initiated, Open-label, Randomized, Multicenter, Noninferiority trial

Participants

  • Patients with clinically diagnosed CAD

Methods

Randomization and Study Procedures

  • 1:1 randomized in treat-to-target strategy or high-intensity strategy group
  • each group 1:1 randomized in rosuvastatin or atorvastatin

Methods

Randomization and Study Procedures

Methods

Randomization and Study Procedures

  • high or moderate intensity according to the guideline for the treatment of blood cholesterol
    • high: 20 mg of rosuvastatin or 40 mg of atrovastatin
    • moderate: 10 mg of rosuvastatin or 20 mg of atrovastatin
  • target LDL-C level
    • treat-to-target group: below 70 mg/dL
uptitration maintenance undertitration
70 mg/dL ~ 50 mg/dL ~ 70 mg/dL ~ 50 mg/dL
  • high-intensity group: maintenance of high-intensity statin therapy was recommended
  • Non-statin add-on therapy was not recommended strongly
  • other medical treatments allowed except for the change in the statin intensity

Methods

  • Primary endpoint: major adverse cardiac and cerebrovascular events defubed as a composite of all-cause death(cardiovascular or not), MI, stroke, and any coronary revascularization at 3 years
  • Secondary endpoint
  1. occurance of new-onset diabetes
  2. hospitalization due to heart failure
  3. deep vein thrombosis or pulmonary thromnoemnolism
  4. endovascular revasculatization for perepheral artery disease
  1. aortic intervention or surgery
  2. end-stage kidney disease
  3. discontinuation of study drugs due to intolerance
  4. cataract operation
  5. composite of laboratory abnormalities

Methods

Sample Size Calculation

  • expected event rate of the primary endpont at 3 years: 12% group
  • NI margin of 3.0 %
  • total 3686 patients was required with 2.5% one-sided alpha error rate and 80% power
  • considering 15% loss => total of 4400 patients was required

Methods

Statistical Analysis

  1. Kaplan-Meier curves for a time-to-event analysis: cumulative incidence of the primary endpoint at 3 years
  2. Test of NI for the primary endpoint using Com-Nougue approach to estimating the z statisticc for the Kaplan-Meier failure rates with the Greenwood formula for estimating the standard error
  • perspecified subgroup analyses: performed for clinically relevant factors - age, sex, BMI, hypertension, diabete, chronic kidney disease, clinical pesentation at radomization, baseline LDL-C levels

Results

Base

Results

Base

  • 98.7% completed the 3-year clinical follow-up

  • in treat-to-target group
    • uptitrated in 17%, downtitrated in 9%m maintained in 73%
    • high-intensity statin at 1 year: 53%, at 2 years: 55%, at 3-years: 56%
  • in high-intensity group
    • high-intensity statin at 1 year: 93%, at 2 years: 91%, at 3-years: 89%

Results

Base

  • Ezetimibe: treat-to-target > high-intensity
    • mostly as a comnimation therapy with high-intensity statin therapy
  • other cardiovascular medications were not statistically different

Results

LDL-C level

  • 6 weeks: LDL-C level was significantly higher in the treat-to-target group than the high-intensity statin therapy group
  • after 6 weeks: no significant difference
  • overall period: no significant difference

Results

LDL-C level

etb7 - proportion of participants with LDL-C level below 70 mg/dL at 6 weeks and 3 months was significantly lower inthe treat-to-target group than the high-intensity group

Results

Primary Endpoint

Results

Primary Endpoint

  • primary endpoint occurred in 8.3% of treat-to-target group and 8.5% of high-intensity group
  • difference upper CI was 1.5%, p <. 001 for NI

Secondary Endpoint

  • no statistical difference
  • post-hoc analysis: (1) new-onset diabetes (2) amino-transferase (3) creatine kinase elevation (4) end-stage kidney disease were significantly lower in the treat-to-target group

Discussion

Limitations

  1. open-label
  2. lower event rates than anticipated
  3. small num of events -> comparison of individual clinical outcomes within the primary endpoint was difficult
  4. recruited exclusively patients with CAD -> other subsets of patients(e.g., prevention)
  5. 60% of treat-to-target group achieved below 70mg/dL -> add-on therapy should be considered
  6. 3 years -> relatively short to reflect longer-term effects of 2 strategies

Discussion

Conclusion

  • treat-to-target LDL-C strategy of 50 to 70 mg/dL as the goal was NI to high-intensity statin therapy for the 3 year composite of death, MI, stroke or coronary revascularization