Atherosclerotic Cardiovascular Disease
Conditions
Keywords
Hyperlipidemia, Secondary Cardiovascular Prevention, Atherosclerotic Cardiovascular Disease (ASCVD), Hypercholesterolemia, Lipid lowering therapies, Inclisiran
Brief summary
The purpose of this study was to assess the effectiveness of an inclisiran first implementation strategy (addition of inclisiran to maximally tolerated statin therapy immediately upon failure to achieve acceptable LDL-C with maximally tolerated statin therapy alone) compared to usual care in an atherosclerotic cardiovascular disease (ASCVD) population.
Detailed description
The study design was a randomized, two-arm, parallel-group, open-label, multicenter, clinical trial comparing an inclisiran first implementation strategy to usual care (1:1 randomization) with established ASCVD and elevated LDL-C (or non-HDL-C) despite treatment with maximally tolerated statin therapy. Eligible patients had established ASCVD and elevated LDL-C levels ≥ 70 mg/dL (or non-HDL-C ≥ 100 mg/dL) despite treatment with maximally tolerated statin therapy. In the inclisiran first implementation strategy group post-randomization, addition of other non-statin LDL-C lowering therapies (e.g., ezetimibe or bempedoic acid, excluding PCSK9 inhibiting monoclonal antibodies) were allowed to reach acceptable LDL-C levels. In the inclisiran first implementation strategy group, inclisiran was administered initially at randomization, 90 days later, and six months, thereafter.
Interventions
DRUGInclisiran
Inclisiran sodium 300 mg/1.5 ml (equivalent to 284 mg inclisiran liquid) in prefilled syringe (PFS).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
randomized, two-arm, parallel-group, open-label, multicenter clinical trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria: 1. Signed informed consent must be obtained prior to participation in the study 2. Males and females ≥18 years of age 3. History of ASCVD, documented by hospital records, claims data and/or prior laboratory/imaging assessments a Coronary heart disease (CHD): * Prior myocardial infarction * Prior coronary revascularization (PCI or CABG) * Angiographic or CT-imaging (e.g., MDCT/CTA) evidence of coronary atherosclerosis (\>70% stenosis in at least one major epicardial coronary artery) b Cerebrovascular disease: * Prior ischemic stroke confirmed by a brain imaging study, CT or MRI; thought not to be caused by atrial fibrillation, valvular heart disease or mural thrombus * Carotid artery stenosis \>70% on prior angiography or ultrasound * History of prior percutaneous or surgical carotid artery revascularization c Peripheral arterial disease (PAD): * Prior documentation of a resting ankle-brachial index ≤0.85 * History of prior percutaneous or surgical revascularization of an iliac, femoral, or popliteal artery or aortic aneurysm * Prior non-traumatic amputation of a lower extremity due to peripheral artery disease 4. Serum LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL 5. Fasting triglyceride \<5.65 mmol/L (\<500 mg/dL) at screening 6. Calculated glomerular filtration rate \>30 mL/min by estimated glomerular filtration rate (eGFR) using standardized local clinical methodology 7. Participants should be on maximally tolerated statin therapy, as determined by the investigator, with no immediate plans to modify lipid lowering therapies. Statin intolerant patients are eligible if they had documented side effects on at least 2 different statins, including one at the lowest standard dose 8. Participants must be willing and able to give informed consent before initiation of any study related procedures and willing to comply with all required study procedures
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study. 1. Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with participation in the clinical study, and/or put the participant at significant risk (according to investigator's \[or delegate\] judgment) if he/she participates in the clinical study 2. An underlying known disease, or surgical, physical, or medical condition that, in the opinion of the investigator (or delegate) might interfere with interpretation of the clinical study results 3. New York Heart Association (NYHA) class III or IV heart failure or last known left ventricular ejection fraction \<30% 4. Significant cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via ablation at the time of screening 5. Major adverse cardiovascular event within 6 months prior to randomization 6. Uncontrolled severe hypertension: systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg prior to randomization despite antihypertensive therapy 7. Severe concomitant non-cardiovascular disease that carries the risk of reducing life expectancy to less than 2 years 8. History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy and/or systemic therapy during the two years prior to randomization 9. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of investigational drug. Basic contraception methods include: 1. Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception 2. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment 3. Male sterilization (at least 6 m prior to screening). For female participants in the study, the vasectomized male partner should be the sole partner for that participant 4. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) 5. Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking investigational drug. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. 10. Known history of alcohol and/or drug abuse within the last 5 years (occasional casual users of illicit drugs in the opinion of the investigators are not excluded) 11. Treatment with other investigational products or devices within 30 days or five half-lives of the screening visit, whichever is longer 12. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes 13. Planned use of other investigational products or devices during the course of the study 14. Any condition that according to the investigator could interfere with the conduct of the study, such as but not limited to: 1. Participants who are unable to communicate or to cooperate with the investigator 2. Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study (including participants whose cooperation is doubtful due to drug abuse or alcohol dependency) 3. Unlikely to comply with the protocol requirements, instructions, and study-related restrictions (e.g., uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study - including potential participants who indicate that their participation is contingent on receiving inclisiran) 4. Have any medical or surgical condition, which in the opinion of the investigator would put the participant at increased risk from participating in the study 5. Persons directly involved in the conduct of the study 15. Previous or current treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9 or ezetimibe 16. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or alanine aminotransferase (ALT) elevation \>3x ULN, aspartate aminotransferase (AST) elevation \>3x ULN, or total bilirubin elevation \>2x ULN (except patients with Gilbert's syndrome) at screening confirmed by a repeat measurement at least one week apart
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in LDL-C | Baseline, Day 330 | Percent change from baseline in Low-Density Lipoprotein Cholesterol (LDL-C) of an inclisiran first implementation strategy compared to usual care at Day 330. |
| Percentage of Participants Who Discontinued Statin Therapy | Day 330 | Percentage of patients who discontinued statin therapy ≥ 30 days before the end-of-study visit of an inclisiran first implementation strategy compared to usual care, for patients in the FAS excluding those with a medical history of statin intolerance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Absolute Change From Baseline in LDL-C Levels Across Visits | Up to 330 days | Average absolute change in Low-Density Lipoprotein Cholesterol (LDL-C) of an inclisiran first implementation strategy compared to usual care across visits. Calculated by averaging the observed post-baseline values (absolute change) for each participant across analysis visits. |
| Percentage of Participants Achieving ≥ 50% Reduction From Baseline in LDL-C | Baseline, Day 330 | Percentage of patients achieving a ≥ 50% reduction from baseline in Low-Density Lipoprotein Cholesterol (LDL-C) levels of an inclisiran first implementation strategy compared to usual care at Day 330. Missing data is imputed using non-responder (i.e., negative outcome) imputation. |
| Percentage of Participants Achieving LDL-C < 100 mg/dL. | Day 330 | Percentage of participants achieving Low-Density Lipoprotein Cholesterol (LDL-C) \< 100 mg/dL (among the subset of participants with LDL-C \>=100 mg/dL at baseline) of an inclisiran first implementation strategy compared to usual care at Day 330. Missing data is imputed using non-responder (i.e., negative outcome) imputation. |
| Percentage of Participants Achieving LDL-C < 70 mg/dL | Day 330 | Percentage of participants achieving Low-Density Lipoprotein Cholesterol (LDL-C) \< 70 mg/dL of an inclisiran first implementation strategy compared to usual care at Day 330. Missing data is imputed using non-responder (i.e., negative outcome) imputation. |
| Percentage of Participants Achieving LDL-C < 55 mg/dL | Day 330 | Percentage of participants achieving Low-Density Lipoprotein Cholesterol (LDL-C) \< 55 mg/dL of an inclisiran first implementation strategy compared to usual care at Day 330. Missing data is imputed using non-responder (i.e., negative outcome) imputation. |
| Absolute Change From Baseline in LDL-C | Baseline, Day 330 | Absolute change in Low-Density Lipoprotein Cholesterol (LDL-C) of an inclisiran first implementation strategy compared to usual care at Day 330 |
| Absolute Change in Lipids and Other Lipoproteins From Baseline | Baseline, Day 330 | Absolute change in plasma lipids, lipoproteins and triglycerides in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330 |
| Percentage of Participants by Intensity of Lipid Lowering Therapy | Baseline, Day 330 | Percentage of participants with decrease in dose, no change in dose or increase in dose to assess changes in background lipid-lowering therapy in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330 |
| Proportion of Days Covered by Medication | Up to 330 Days | Proportion of days covered refers to the total number of days on either statin, ezetimibe, bempedoic acid or PCSK9 inhibiting monoclonal antibody therapies taken during the study divided by total number of study days, calculated for each participant; If a participant did not take any of the four medications then the total number of days will be assumed to be zero. |
| LDL-C Measures of Variability - Standard Deviation | Day 90, Day 180, Day 270 and Day 330 | Visit-to-visit LDL-C variability from Day 90 until Day 330 of an inclisiran first implementation strategy compared to usual care. It was assessed using two measures of variability: standard deviation and coefficient of variation. |
| LDL-C Measures of Variability - Coefficient of Variation | Day 90, Day 180, Day 270 and Day 330 | Visit-to-visit LDL-C variability from Day 90 until Day 330 of an inclisiran first implementation strategy compared to usual care. It was assessed using two measures of variability: standard deviation and coefficient of variation. |
| Percent Change in Lipids and Other Lipoproteins From Baseline | Baseline, Day 330 | Percent change in plasma lipids, lipoproteins and triglycerides in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330 |
| Average Percent Change From Baseline in LDL-C Levels Across Visits | Up to 330 Days | Average percent change in Low-Density Lipoprotein Cholesterol (LDL-C) of an inclisiran first implementation strategy compared to usual care across visits. Calculated by averaging the observed post-baseline values (percent change) for each participant across analysis visits. |
Countries
United States
Participant flow
Recruitment details
The study was conducted in 43 centers in the United States
Participants by arm
| Arm | Count |
|---|---|
| Inclisiran First Inclisiran sodium 300 mg 1.5 ml (equivalent to 284 mg of inclisiran) + usual care | 225 |
| Usual Care Treating physicians were recommended to treat patients in accordance with the 2018 ACC/AHA guidelines | 225 |
| Total | 450 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Lost to Follow-up | 3 | 11 |
| Overall Study | Subject decision | 6 | 8 |
| Overall Study | Technical problems | 0 | 1 |
| Overall Study | Withdrew consent | 0 | 8 |
Baseline characteristics
| Characteristic | Inclisiran First | Usual Care | Total |
|---|---|---|---|
| Age, Continuous | 66.3 years STANDARD_DEVIATION 9.01 | 66.8 years STANDARD_DEVIATION 9.84 | 66.5 years STANDARD_DEVIATION 9.43 |
| Race/Ethnicity, Customized Asian | 8 Participants | 4 Participants | 12 Participants |
| Race/Ethnicity, Customized Black or African American | 27 Participants | 29 Participants | 56 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 4 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized White | 186 Participants | 187 Participants | 373 Participants |
| Sex: Female, Male Female | 67 Participants | 72 Participants | 139 Participants |
| Sex: Female, Male Male | 158 Participants | 153 Participants | 311 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 234 | 1 / 216 |
| other Total, other adverse events | 64 / 234 | 53 / 216 |
| serious Total, serious adverse events | 27 / 234 | 29 / 216 |
Outcome results
Primary
Percentage of Participants Who Discontinued Statin Therapy
Percentage of patients who discontinued statin therapy ≥ 30 days before the end-of-study visit of an inclisiran first implementation strategy compared to usual care, for patients in the FAS excluding those with a medical history of statin intolerance.
Time frame: Day 330
Population: Full Analysis Set (FAS) comprised of all randomized patients. Participants with Medical History of Statin Intolerance were excluded from this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inclisiran First | Percentage of Participants Who Discontinued Statin Therapy | 6.0 Percentage of participants |
| Usual Care | Percentage of Participants Who Discontinued Statin Therapy | 16.7 Percentage of participants |
97.5% CI: [-18.3, -3]Normal approx. to binomial distribution
Primary
Percent Change From Baseline in LDL-C
Percent change from baseline in Low-Density Lipoprotein Cholesterol (LDL-C) of an inclisiran first implementation strategy compared to usual care at Day 330.
Time frame: Baseline, Day 330
Population: Full Analysis Set (FAS) comprised of all randomized patients. Number of participants analyzed corresponds to the number of subjects who had LDL-C values at baseline and Day 330.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran First | Percent Change From Baseline in LDL-C | -60.0 percent change in LDL-C |
| Usual Care | Percent Change From Baseline in LDL-C | -7.0 percent change in LDL-C |
p-value: <0.00197.5% CI: [-60, -46]Mixed Models Analysis
Secondary
Absolute Change From Baseline in LDL-C
Absolute change in Low-Density Lipoprotein Cholesterol (LDL-C) of an inclisiran first implementation strategy compared to usual care at Day 330
Time frame: Baseline, Day 330
Population: Full Analysis Set (FAS) comprised of all randomized patients. Number of participants analyzed corresponds to the number of subjects who had LDL-C values at baseline and Day 330.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran First | Absolute Change From Baseline in LDL-C | -58.0 mg/dL |
| Usual Care | Absolute Change From Baseline in LDL-C | -10.5 mg/dL |
p-value: <0.00195% CI: [-52.8, -42.3]Mixed Models Analysis
Secondary
Absolute Change in Lipids and Other Lipoproteins From Baseline
Absolute change in plasma lipids, lipoproteins and triglycerides in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330
Time frame: Baseline, Day 330
Population: Full Analysis Set (FAS) comprised of all randomized patients. Number of participants analyzed corresponds to the number of subjects who had values at baseline and Day 330
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Inclisiran First | Absolute Change in Lipids and Other Lipoproteins From Baseline | Non-HDL Cholesterol | -63.0 mg/dL |
| Inclisiran First | Absolute Change in Lipids and Other Lipoproteins From Baseline | Triglycerides | -25.4 mg/dL |
| Inclisiran First | Absolute Change in Lipids and Other Lipoproteins From Baseline | HDL Cholesterol | 3.5 mg/dL |
| Inclisiran First | Absolute Change in Lipids and Other Lipoproteins From Baseline | Apolipoprotein B | -43.6 mg/dL |
| Inclisiran First | Absolute Change in Lipids and Other Lipoproteins From Baseline | VLDL Cholesterol | -4.6 mg/dL |
| Inclisiran First | Absolute Change in Lipids and Other Lipoproteins From Baseline | Lipoprotein(a) | -9.8 mg/dL |
| Inclisiran First | Absolute Change in Lipids and Other Lipoproteins From Baseline | Total Cholesterol | -59.6 mg/dL |
| Usual Care | Absolute Change in Lipids and Other Lipoproteins From Baseline | Lipoprotein(a) | -1.0 mg/dL |
| Usual Care | Absolute Change in Lipids and Other Lipoproteins From Baseline | Total Cholesterol | -9.7 mg/dL |
| Usual Care | Absolute Change in Lipids and Other Lipoproteins From Baseline | HDL Cholesterol | 0.3 mg/dL |
| Usual Care | Absolute Change in Lipids and Other Lipoproteins From Baseline | Non-HDL Cholesterol | -10.5 mg/dL |
| Usual Care | Absolute Change in Lipids and Other Lipoproteins From Baseline | VLDL Cholesterol | 0.0 mg/dL |
| Usual Care | Absolute Change in Lipids and Other Lipoproteins From Baseline | Triglycerides | -0.1 mg/dL |
| Usual Care | Absolute Change in Lipids and Other Lipoproteins From Baseline | Apolipoprotein B | -7.3 mg/dL |
Comparison: Total Cholesterolp-value: <0.00195% CI: [-56, -43.9]Mixed Models Analysis
Comparison: HDL Cholesterolp-value: <0.00195% CI: [1.8, 4.4]Mixed Models Analysis
Comparison: Non-HDL Cholesterolp-value: <0.00195% CI: [-58.1, -46.7]Mixed Models Analysis
Comparison: VLDL Cholesterolp-value: <0.00195% CI: [-6.5, -2.8]Mixed Models Analysis
Comparison: Triglyceridesp-value: <0.00195% CI: [-34.8, -15.8]Mixed Models Analysis
Comparison: Apolipoprotein Bp-value: <0.00195% CI: [-39.7, -32.9]Mixed Models Analysis
Comparison: Lipoprotein(a)p-value: <0.00195% CI: [-10.7, -6.8]Mixed Models Analysis
Secondary
Average Absolute Change From Baseline in LDL-C Levels Across Visits
Average absolute change in Low-Density Lipoprotein Cholesterol (LDL-C) of an inclisiran first implementation strategy compared to usual care across visits. Calculated by averaging the observed post-baseline values (absolute change) for each participant across analysis visits.
Time frame: Up to 330 days
Population: Full Analysis Set (FAS) comprised of all randomized patients. Number of participants analyzed corresponds to the number of subjects who had LDL-C average change from baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran First | Average Absolute Change From Baseline in LDL-C Levels Across Visits | -55.0 mg/dL |
| Usual Care | Average Absolute Change From Baseline in LDL-C Levels Across Visits | -6.0 mg/dL |
p-value: <0.00195% CI: [-52.9, -44.9]Regression, Linear
Secondary
Average Percent Change From Baseline in LDL-C Levels Across Visits
Average percent change in Low-Density Lipoprotein Cholesterol (LDL-C) of an inclisiran first implementation strategy compared to usual care across visits. Calculated by averaging the observed post-baseline values (percent change) for each participant across analysis visits.
Time frame: Up to 330 Days
Population: Full Analysis Set (FAS) comprised of all randomized patients. Number of participants analyzed corresponds to the number of subjects who had LDL-C average change from baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inclisiran First | Average Percent Change From Baseline in LDL-C Levels Across Visits | -57.2 Average percent change in LDL-C |
| Usual Care | Average Percent Change From Baseline in LDL-C Levels Across Visits | -2.8 Average percent change in LDL-C |
p-value: <0.00195% CI: [-59, -49.8]Regression, Linear
Secondary
LDL-C Measures of Variability - Coefficient of Variation
Visit-to-visit LDL-C variability from Day 90 until Day 330 of an inclisiran first implementation strategy compared to usual care. It was assessed using two measures of variability: standard deviation and coefficient of variation.
Time frame: Day 90, Day 180, Day 270 and Day 330
Population: Full Analysis Set (FAS) comprised of all randomized patients. Number of participants analyzed corresponds to the number of subjects who had available values at each timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Inclisiran First | LDL-C Measures of Variability - Coefficient of Variation | Day 90 | 63.90 Coefficient of Variation |
| Inclisiran First | LDL-C Measures of Variability - Coefficient of Variation | Day 180 | 69.00 Coefficient of Variation |
| Inclisiran First | LDL-C Measures of Variability - Coefficient of Variation | Day 270 | 67.56 Coefficient of Variation |
| Inclisiran First | LDL-C Measures of Variability - Coefficient of Variation | Day 330 | 65.34 Coefficient of Variation |
| Usual Care | LDL-C Measures of Variability - Coefficient of Variation | Day 330 | 40.89 Coefficient of Variation |
| Usual Care | LDL-C Measures of Variability - Coefficient of Variation | Day 90 | 40.65 Coefficient of Variation |
| Usual Care | LDL-C Measures of Variability - Coefficient of Variation | Day 270 | 36.38 Coefficient of Variation |
| Usual Care | LDL-C Measures of Variability - Coefficient of Variation | Day 180 | 34.67 Coefficient of Variation |
Secondary
LDL-C Measures of Variability - Standard Deviation
Visit-to-visit LDL-C variability from Day 90 until Day 330 of an inclisiran first implementation strategy compared to usual care. It was assessed using two measures of variability: standard deviation and coefficient of variation.
Time frame: Day 90, Day 180, Day 270 and Day 330
Population: Full Analysis Set (FAS) comprised of all randomized patients. Number of participants analyzed corresponds to the number of subjects who had available values at each timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran First | LDL-C Measures of Variability - Standard Deviation | Day 90 | 42.6 mg/dL | Standard Deviation 27.21 |
| Inclisiran First | LDL-C Measures of Variability - Standard Deviation | Day 270 | 46.2 mg/dL | Standard Deviation 31.22 |
| Inclisiran First | LDL-C Measures of Variability - Standard Deviation | Day 180 | 41.1 mg/dL | Standard Deviation 28.39 |
| Inclisiran First | LDL-C Measures of Variability - Standard Deviation | Day 330 | 38.8 mg/dL | Standard Deviation 25.33 |
| Usual Care | LDL-C Measures of Variability - Standard Deviation | Day 180 | 91.2 mg/dL | Standard Deviation 31.61 |
| Usual Care | LDL-C Measures of Variability - Standard Deviation | Day 90 | 94.3 mg/dL | Standard Deviation 38.33 |
| Usual Care | LDL-C Measures of Variability - Standard Deviation | Day 330 | 86.8 mg/dL | Standard Deviation 35.47 |
| Usual Care | LDL-C Measures of Variability - Standard Deviation | Day 270 | 88.4 mg/dL | Standard Deviation 32.16 |
Secondary
Percentage of Participants Achieving ≥ 50% Reduction From Baseline in LDL-C
Percentage of patients achieving a ≥ 50% reduction from baseline in Low-Density Lipoprotein Cholesterol (LDL-C) levels of an inclisiran first implementation strategy compared to usual care at Day 330. Missing data is imputed using non-responder (i.e., negative outcome) imputation.
Time frame: Baseline, Day 330
Population: Full Analysis Set (FAS) comprised of all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inclisiran First | Percentage of Participants Achieving ≥ 50% Reduction From Baseline in LDL-C | 69.8 Percentage of participants |
| Usual Care | Percentage of Participants Achieving ≥ 50% Reduction From Baseline in LDL-C | 5.3 Percentage of participants |
p-value: <0.00195% CI: [22.07, 81.16]Regression, Logistic
Secondary
Percentage of Participants Achieving LDL-C < 100 mg/dL.
Percentage of participants achieving Low-Density Lipoprotein Cholesterol (LDL-C) \< 100 mg/dL (among the subset of participants with LDL-C \>=100 mg/dL at baseline) of an inclisiran first implementation strategy compared to usual care at Day 330. Missing data is imputed using non-responder (i.e., negative outcome) imputation.
Time frame: Day 330
Population: Full Analysis Set (FAS) comprised of all randomized patients. Only a subset of participants with LDL-C \>=100 mg/dL at baseline were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inclisiran First | Percentage of Participants Achieving LDL-C < 100 mg/dL. | 80.5 Percentage of participants |
| Usual Care | Percentage of Participants Achieving LDL-C < 100 mg/dL. | 32.1 Percentage of participants |
p-value: <0.00195% CI: [6.72, 44.66]Regression, Logistic
Secondary
Percentage of Participants Achieving LDL-C < 55 mg/dL
Percentage of participants achieving Low-Density Lipoprotein Cholesterol (LDL-C) \< 55 mg/dL of an inclisiran first implementation strategy compared to usual care at Day 330. Missing data is imputed using non-responder (i.e., negative outcome) imputation.
Time frame: Day 330
Population: Full Analysis Set (FAS) comprised of all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inclisiran First | Percentage of Participants Achieving LDL-C < 55 mg/dL | 71.6 Percentage of participants |
| Usual Care | Percentage of Participants Achieving LDL-C < 55 mg/dL | 8.9 Percentage of participants |
p-value: <0.00195% CI: [19.51, 63.24]Regression, Logistic
Secondary
Percentage of Participants Achieving LDL-C < 70 mg/dL
Percentage of participants achieving Low-Density Lipoprotein Cholesterol (LDL-C) \< 70 mg/dL of an inclisiran first implementation strategy compared to usual care at Day 330. Missing data is imputed using non-responder (i.e., negative outcome) imputation.
Time frame: Day 330
Population: Full Analysis Set (FAS) comprised of all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inclisiran First | Percentage of Participants Achieving LDL-C < 70 mg/dL | 81.8 Percentage of participants |
| Usual Care | Percentage of Participants Achieving LDL-C < 70 mg/dL | 22.2 Percentage of participants |
p-value: <0.00195% CI: [14.18, 42.19]Regression, Logistic
Secondary
Percentage of Participants by Intensity of Lipid Lowering Therapy
Percentage of participants with decrease in dose, no change in dose or increase in dose to assess changes in background lipid-lowering therapy in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330
Time frame: Baseline, Day 330
Population: Full Analysis Set (FAS) comprised of all randomized patients. Number of participants analyzed corresponds to the number of subjects who had values at baseline and Day 330.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Inclisiran First | Percentage of Participants by Intensity of Lipid Lowering Therapy | Decrease in statin intensity | 2.3 Percentage of participants |
| Inclisiran First | Percentage of Participants by Intensity of Lipid Lowering Therapy | No change in statin intensity | 97.2 Percentage of participants |
| Inclisiran First | Percentage of Participants by Intensity of Lipid Lowering Therapy | Increase in statin intensity | 0.5 Percentage of participants |
| Usual Care | Percentage of Participants by Intensity of Lipid Lowering Therapy | Decrease in statin intensity | 4.5 Percentage of participants |
| Usual Care | Percentage of Participants by Intensity of Lipid Lowering Therapy | No change in statin intensity | 93.0 Percentage of participants |
| Usual Care | Percentage of Participants by Intensity of Lipid Lowering Therapy | Increase in statin intensity | 2.5 Percentage of participants |
p-value: 0.89995% CI: [0.43, 2.61]proportional odds model
Secondary
Percent Change in Lipids and Other Lipoproteins From Baseline
Percent change in plasma lipids, lipoproteins and triglycerides in participants receiving an inclisiran first implementation strategy compared to usual care at Day 330
Time frame: Baseline, Day 330
Population: Full Analysis Set (FAS) comprised of all randomized patients. Number of participants analyzed corresponds to the number of subjects who had values at baseline and Day 330.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Inclisiran First | Percent Change in Lipids and Other Lipoproteins From Baseline | Non-HDL Cholesterol | -49.3 Percent change |
| Inclisiran First | Percent Change in Lipids and Other Lipoproteins From Baseline | Triglycerides | -10.6 Percent change |
| Inclisiran First | Percent Change in Lipids and Other Lipoproteins From Baseline | HDL Cholesterol | 8.5 Percent change |
| Inclisiran First | Percent Change in Lipids and Other Lipoproteins From Baseline | Apolipoprotein B | -46.4 Percent change |
| Inclisiran First | Percent Change in Lipids and Other Lipoproteins From Baseline | VLDL Cholesterol | -10.1 Percent change |
| Inclisiran First | Percent Change in Lipids and Other Lipoproteins From Baseline | Lipoprotein(a) | -19.6 Percent change |
| Inclisiran First | Percent Change in Lipids and Other Lipoproteins From Baseline | Total Cholesterol | -34.1 Percent change |
| Usual Care | Percent Change in Lipids and Other Lipoproteins From Baseline | Lipoprotein(a) | 2.3 Percent change |
| Usual Care | Percent Change in Lipids and Other Lipoproteins From Baseline | Total Cholesterol | -4.1 Percent change |
| Usual Care | Percent Change in Lipids and Other Lipoproteins From Baseline | HDL Cholesterol | 2.0 Percent change |
| Usual Care | Percent Change in Lipids and Other Lipoproteins From Baseline | Non-HDL Cholesterol | -5.1 Percent change |
| Usual Care | Percent Change in Lipids and Other Lipoproteins From Baseline | VLDL Cholesterol | 6.8 Percent change |
| Usual Care | Percent Change in Lipids and Other Lipoproteins From Baseline | Triglycerides | 7.2 Percent change |
| Usual Care | Percent Change in Lipids and Other Lipoproteins From Baseline | Apolipoprotein B | -3.8 Percent change |
Comparison: Total Cholesterolp-value: <0.00195% CI: [-33.8, -26.3]Mixed Models Analysis
Comparison: HDL Cholesterolp-value: <0.00195% CI: [3.6, 9.5]Mixed Models Analysis
Comparison: Non-HDL Cholesterolp-value: <0.00195% CI: [-49.1, -39.3]Mixed Models Analysis
Comparison: VLDL Cholesterolp-value: <0.00195% CI: [-23.8, -10]Mixed Models Analysis
Comparison: Triglyceridesp-value: <0.00195% CI: [-24.7, -10.9]Mixed Models Analysis
Comparison: Apolipoprotein Bp-value: <0.00195% CI: [-47.5, -37.8]Mixed Models Analysis
Comparison: Lipoprotein(a)p-value: <0.00195% CI: [-25.8, -18]Mixed Models Analysis
Secondary
Proportion of Days Covered by Medication
Proportion of days covered refers to the total number of days on either statin, ezetimibe, bempedoic acid or PCSK9 inhibiting monoclonal antibody therapies taken during the study divided by total number of study days, calculated for each participant; If a participant did not take any of the four medications then the total number of days will be assumed to be zero.
Time frame: Up to 330 Days
Population: Full Analysis Set (FAS) comprised of all randomized patients. Participants with missing baseline LDL-C are excluded from the regression analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Inclisiran First | Proportion of Days Covered by Medication | 0.894 proportion of days covered | Standard Error 0.0169 |
| Usual Care | Proportion of Days Covered by Medication | 0.902 proportion of days covered | Standard Error 0.0169 |
p-value: 0.72795% CI: [-0.055, 0.039]Regression, Linear