Diabetes, Dyslipidemia, Hypertension
Conditions
Keywords
Hypertension, Dyslipidemia, Diabetes, Polypill, Cardiovascular disease risk, Cardiovascular Diseases, Cognitive function, Randomized controlled trial
Brief summary
The Polypill Approach for Multiple Cardiovascular Risk Factors (PACIF) trial is a multicenter randomized controlled trial that will test the effectiveness and safety of a fixed-dose combination strategy for the integrated management of hypertension, dyslipidemia, and type 2 diabetes among adults aged 50 to 75 years without prior cardiovascular disease in China. The trial will evaluate whether a fixed-dose combination strategy improves the 10-year cardiovascular disease risk estimated using the PREVENT equations at Phase 1. Participants will be further followed to determine whether the fixed-dose combination strategy reduces major cardiovascular events and improves cognitive outcomes compared with usual care at Phase 2.
Detailed description
The overall objective of the PACIF Trial is to test a fixed-dose combination strategy for the integrated management of hypertension, dyslipidemia, and diabetes. This multicenter randomized controlled trial will evaluate whether a polypill-based approach, compared with usual care, improves cardiovascular risk factor control and reduces cardiovascular disease events among adults with multiple cardiovascular risk factors but without prior cardiovascular disease. The trial will recruit an estimated 8,252 participants aged 50 to \<75 years who have hypertension, dyslipidemia, and type 2 diabetes. Participants will be randomly assigned to receive either a fixed-dose combination strategy or usual care. In the intervention group, the study medication regimen will consist of eight prespecified fixed-dose formulations combining blood pressure-lowering, lipid-lowering, and glucose-lowering therapies. These formulations include olmesartan medoxomil/amlodipine, rosuvastatin, ezetimibe, and dapagliflozin, with indapamide included in selected formulations. Treatment will be adjusted among the prespecified fixed-dose formulations according to participants' blood pressure levels, treatment targets, tolerability, and safety. Additional open-label medications may be used according to guideline recommendations and clinical judgment if the prespecified treatment targets are not achieved with the fixed-dose combination strategy. Treatment targets are defined as blood pressure \<130/80 mmHg, LDL cholesterol \<1.8 mmol/L, and HbA1c \<7.0%. The primary outcome at Phase 1 is the ACC/AHA 10-year cardiovascular disease risk estimated by the PREVENT equations. In addition, changes in PREVENT-estimated 10-year ASCVD and heart failure risk, the proportions of participants achieving the prespecified blood pressure, lipid, and glycemic targets, and changes in individual cardiovascular risk factors will also be evaluated. The primary outcome at Phase 2 is a composite cardiovascular disease outcome including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, heart failure requiring hospitalization or treatment, and coronary revascularization. Cognitive outcomes will also be assessed, with incident all-cause dementia prespecified as a major secondary outcome.
Interventions
DRUGFixed-Dose Combination Strategy
Participants assigned to the intervention group will receive a fixed-dose combination strategy for the integrated control of blood pressure, lipid, and glucose. Eight prespecified fixed-dose formulations will be used, differing in antihypertensive intensity and rosuvastatin dose. All formulations will include olmesartan medoxomil/amlodipine, rosuvastatin, ezetimibe 10 mg, and dapagliflozin 10 mg, with indapamide 2.5 mg included in selected formulations. The olmesartan medoxomil/amlodipine dose will range from 5/1.25 mg to 20/5 mg, and the rosuvastatin dose will be either 5 mg or 10 mg. Treatment will be selected and adjusted among the prespecified fixed-dose formulations according to participants' blood pressure levels, treatment targets, tolerability, and safety. If the prespecified blood pressure, lipid, or glycemic targets are not achieved despite the highest fixed-dose regimen, additional open-label medications may be prescribed according to guideline recommendations.
Sponsors
China Medical University, China
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Outcome Assessment Committee members will be blinded to outcome assignment.
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Men or women * Age ≥50 years and \<75 years * Systolic blood pressure ≥130 mmHg * LDL-C ≥1.8 mmol/L (70 mg/dL) * Type 2 diabetes with HbA1c ≥6.5% and \<12% * Willing to participate and able to sign informed consent
Exclusion criteria
* Known secondary cause of hypertension * Type 1 diabetes * Pancreatic insufficiency or diabetes secondary to pancreatitis * Triglycerides ≥5.65 mmol/L (500 mg/dL) * History of myocardial infarction, stroke, or heart failure * History of coronary, cerebrovascular, or peripheral arterial revascularization * Abnormal kidney function, defined as estimated glomerular filtration rate \<30 mL/min/1.73 m² or dialysis * Abnormal liver function, defined as alanine aminotransferase or aspartate aminotransferase \>3 times the upper limit of normal * Abnormal serum potassium, defined as serum potassium \>5.5 mmol/L or \<3.5 mmol/L * Contraindication to any of the components of the polypill * Currently living with another PACIF participant * Pregnancy, currently trying to become pregnant, or of child-bearing potential and not using birth control * Clinical diagnosis of dementia or treatment with medications for dementia * History of malignancy * Life expectancy \<3 years * Currently participating in another intervention study * Any factors judged by the clinic team to be likely to limit adherence to interventions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 10-year CVD risk | 12 months | Changes in 10-year CVD risk estimated by the PREVENT equations |
| Composite cardiovascular disease outcome | 36 months | Record the occurrence of the composite cardiovascular disease outcome, including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, heart failure requiring hospitalization or treatment, and coronary revascularization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major secondary endpoint: All-cause dementia | 36 months | Record the occurrence of all-cause dementia |
| Hierarchical composite of all-cause mortality, nonfatal cardiovascular events, and improvement in 10-year cardiovascular disease risk estimated by the PREVENT equations | 12 months | Hierarchical composite of all-cause mortality, nonfatal cardiovascular events, and improvement in 10-year cardiovascular disease risk estimated by the PREVENT equations |
| 10-year ASCVD risk | 12 months | Changes in 10-year ASCVD risk estimated by the PREVENT equations |
| 10-year HF risk | 12 months | Changes in 10-year HF risk estimated by the PREVENT equations |
| The proportions of participants achieving the prespecified blood pressure, LDL-C, and HbA1c targets, individually and jointly | 12 months | The proportions of participants achieving the prespecified targets for blood pressure (systolic blood pressure \<130 mmHg and diastolic blood pressure \<80 mmHg), LDL-C (\<1.8 mmol/L), and HbA1c (\<7.0%), individually and jointly |
| Blood pressure, LDL-C, and HbA1c | 12 months | Changes in systolic and diastolic blood pressure, LDL-C, and HbA1c |
| Medication adherence | 12 months | Medication adherence assessed by participant self-report, pill count, or other prespecified adherence measures |
| Cost-effectiveness | 12 months | Data on the costs of CVD risk assessment and management will be collected for both study groups. The cost-effectiveness analysis will estimate the incremental cost per unit reduction in estimated 10-year CVD risk in the intervention group compared with the control group. |
| Composite outcome of composite cardiovascular disease outcome or deaths | 36 months | Record the occurrence of composite outcome of composite cardiovascular disease outcome or deaths |
| Macrovascular outcome | 36 months | Record the occurrence of any of the following: stroke, myocardial infarction, heart failure requiring hospitalization or treatment, aortic dissection, any cardiovascular revascularization procedures, or cardiovascular death |
| Major coronary artery diseases | 36 months | Record the occurrence of any of the following: myocardial infarction, revascularization of coronary arteries, or deaths due to coronary artery diseases |
| Myocardial infarction | 36 months | Record the occurrence of myocardial infarction |
| Stroke | 36 months | Record the occurrence of stroke |
| Ischemic stroke | 36 months | Record the occurrence of ischemic stroke |
| Hemorrhagic stoke | 36 months | Record the occurrence of hemorrhagic stroke |
| Heart failure requiring hospitalization or treatment | 36 months | Record the occurrence of heart failure requiring hospitalization or treatment |
| Coronary revascularization | 36 months | Record the occurrence of coronary revascularization |
| Cardiovascular disease death | 36 months | Record the occurrence of cardiovascular disease death |
| All-cause death | 36 months | Record the occurrence of all-cause death |
| Microvascular outcomes | 36 months | Record the occurrence of microvascular complications (e.g., diabetic kidney disease and diabetic peripheral neuropathy) |
| New-onset chronic kidney disease or progression of chronic kidney disease | 36 months | Record the occurrence of new-onset chronic kidney disease or progression of chronic kidney disease |
| Mild cognitive impairment | 36 months | Record the occurrence of mild cognitive impairment |
| Composite outcome of dementia and mild cognitive impairment | 36 months | Record the occurrence of the composite outcome of dementia and mild cognitive impairment |
| Composite outcome of dementia and all-cause death | 36 months | Record the occurrence of the composite outcome of dementia and all-cause death |
| Health related quality of life | 36 months | Health-related quality of life will be assessed by the Five-Level Version of the EQ-5D (EQ-5D-5L). In this questionnaire, 5 dimensions are measured in 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. A 5-point Likert scale ranging from "no problems" to "extreme problems" is used for every dimension, with higher scores reflecting more problems in a dimension. A VAS ranging from 0 to 100 (0 = "The best health you can imagine" to 100 = "The worst health you can imagine") is applied as well, with higher scores indicating a better health state as perceived by the patient. |
Countries
China
Outcome results
None listed