Cardiovascular Disease, Hypertension, Hyperlipidemia, Heart Disease
Conditions
Keywords
Cardiovascular disease, primary prevention, Polypill, efficacy, safety, ADR, Diabetes, Adherence, Compliance
Brief summary
Cardiovascular is a major cause of mortality in Iran, accounting for 45.7% of deaths. In Golestan (North Eastern Iran) preliminary findings from follow-up of the Golestan Cohort are consistent with national figures: with 45% (at least 22 of 48 deaths) of all deaths attributed to cardiovascular events. Cardiovascular diseases will become an increasing problem as the Iranian population ages. In 2003 Law and Wald proposed prevention of cardiovascular disease using fixed-dose combination therapy combining antihypertensive, lipid lowering and antiplatelet drugs in a single preparation. They proposed that this treatment should be offered to all persons at high risk of cardiovascular disease whether or not they have elevated blood pressure or elevated serum lipid concentrations. This pilot study aims to investigate the safety and efficacy of fixed-dose combination therapy with two antihypertensive drugs, aspirin and atorvastatin in a population who would not currently be considered eligible for antihypertensive treatment or for lipid lowering treatment. Methods: This is a double-blind randomized controlled trial. The intervention group will be assigned to take a tablet consisting of a single daily tablet comprising Aspirin 81mg, Hydrochlorothiazide 12.5mg, Enalapril 2.5mg and Atorvastatin 20mg. The control group will be assigned to an identical placebo. The population studied includes men aged 50 to 80 (inclusive) and women aged 55 to 80 (inclusive) who are currently not eligible for or taking antihypertensive or lipid lowering therapy. Persons who are found at baseline to have blood pressure \>160/100 mm Hg, total cholesterol \>240mg/dL, existing cardiovascular disease or to be taking antihypertensive ore lipid lowering therapy are excluded. It is intended to randomize and follow up 500 subjects for 12 months. The primary outcome for the purpose of sample size calculation is change in systolic blood pressure. Additional outcomes include change in diastolic blood pressure, change in LDL cholesterol and occurrence of adverse events.
Interventions
DRUGPolypill
Fixed dose combination therapy - aspirin 81mg, hydrochlorothiazide 12.5mg, enalapril 2.5mg and atorvastatin 20mg Once daily
DRUGPlacebo drug
Inactive tablet Once a day Identical in appearance to intervention drug
Sponsors
University of Birmingham
Tehran University of Medical Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
All men over 50 to 80 and all women 55 to 80 who are resident in Kalaleh, Golestan, for at least one year.
Exclusion criteria
* Existing cardiovascular disease (stroke, transient ischaemic attack, myocardial infarction or angina) * Already taking antihypertensive drugs, aspirin or statins * Already have clinical indications for treatment with antihypertensive drugs, aspirin or statins. * Blood pressure \>160/100 mm Hg * Total Cholesterol \> 240 mg/dL (or LDL \>190 mg/dL) * Probable diabetes: HbA1c \>6.0 Contraindication to a component of the Polypill Contraindications to aspirin * Previous history of allergy to aspirin * History of peptic ulcer bleeding in whole life or endoscopic evidence of peptic ulcer within the past 3 months Contraindications to statins * Liver failure Contraindications to further blood pressure lowering * Systolic blood pressure ≤90 mm Hg or diastolic blood pressure ≤70 mm Hg * Symptomatic postural hypotension * Difference between mean seated BP and standing BP greater than 20 mm Hg Contraindications to thiazide * Uric acid \>8 for men and uric acid \>6 for women / gout (\ 10%) * Creatinine \>1.2 mg/dl Other predominant medical problem that may limit compliance with study treatment including: * History of alcohol abuse: more than 60cc for women and more than 80cc for men * History of drug abuse: IV drug abuser or eating or smoking more than 4 times a week * Limiting psychiatric illness (eg: mania, schizophrenia, severe depression, psychosis or dementia) * Limiting physical disability sufficient to prevent subject from walking * Other life-threatening condition such as cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Systolic Blood Pressure | One year | Systolic blood pressure. Mean of two seated measurements. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Diastolic Blood Pressure | One year | Mean of two seated diastolic blood pressures |
| LDL Cholesterol | One year | Serum LDL cholesterol |
Countries
Iran
Participant flow
Recruitment details
Between July 2006 and January 2007, 1,733 subjects attended the Kalaleh heart clinic. Of those assessed 872 were included in the run-in phase of the study. Of these 475 were randomized.
Pre-assignment details
872 subjects entered the run in phase, 258 were excluded. Most exclusions were due to laboratory test results. 614 completed the run-in phase of the study, 65 were excluded. Most were excluded because they did not attend the clinic. Of 549 subjects remaining, 74 were not randomized. 475 subjects who were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Polypill Polypill (Atorvastatin 20 mg, Asprin 81 mg, Enalapril 2.5 mg, Hydrochlorothiazide 12.5 mg) | 241 |
| Control Identical placebo tablet | 234 |
| Total | 475 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Cardiovascular event | 0 | 1 |
| Overall Study | Did not attend study clinic | 39 | 30 |
| Overall Study | Lost to Follow-up | 8 | 4 |
| Overall Study | Patient discontinued study drug | 22 | 15 |
| Overall Study | Refused blood test | 5 | 1 |
Baseline characteristics
| Characteristic | Control | Polypill | Total |
|---|---|---|---|
| Age Continuous | 59.1 Years STANDARD_DEVIATION 7.3 | 59.0 Years STANDARD_DEVIATION 6.5 | 59.0 Years STANDARD_DEVIATION 6.9 |
| Diastolic Blood Pressure | 81.2 mm Hg STANDARD_DEVIATION 9.7 | 78.4 mm Hg STANDARD_DEVIATION 10.4 | 79.8 mm Hg STANDARD_DEVIATION 10.1 |
| LDL cholesterol | 116.6 mg/dL STANDARD_DEVIATION 24.8 | 116.7 mg/dL STANDARD_DEVIATION 25.8 | 116.6 mg/dL STANDARD_DEVIATION 25.2 |
| Region of Enrollment Iran, Islamic Republic of | 234 participants | 241 participants | 475 participants |
| Sex: Female, Male Female | 67 Participants | 91 Participants | 158 Participants |
| Sex: Female, Male Male | 167 Participants | 150 Participants | 317 Participants |
| Systolic Blood Pressure | 130.3 mm Hg STANDARD_DEVIATION 17.4 | 124.8 mm Hg STANDARD_DEVIATION 17.3 | 127.5 mm Hg STANDARD_DEVIATION 17.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / — | 0 / — |
| serious Total, serious adverse events | 0 / — | 1 / — |
Outcome results
Primary
Systolic Blood Pressure
Systolic blood pressure. Mean of two seated measurements.
Time frame: One year
Population: Intention to treat Results shown here are based on 12 month observation. Analysis for final paper will be last observation carried forward
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Polypill | Systolic Blood Pressure | 121.7 mm Hg | Standard Deviation 16.8 |
| Control | Systolic Blood Pressure | 129.7 mm Hg | Standard Deviation 18.3 |
Secondary
Diastolic Blood Pressure
Mean of two seated diastolic blood pressures
Time frame: One year
Population: Analysis by intention to treat. Results shown here are based on 12 month observation. Analysis for final paper will be last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Polypill | Diastolic Blood Pressure | 77.6 mm Hg | Standard Deviation 10.6 |
| Control | Diastolic Blood Pressure | 81.3 mm Hg | Standard Deviation 11.1 |
Secondary
LDL Cholesterol
Serum LDL cholesterol
Time frame: One year
Population: Intention to treat Results shown here are based on 12 month observation. Analysis for final paper will be last observation carried forward
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Polypill | LDL Cholesterol | 87.8 mg/dL | Standard Deviation 26.7 |
| Control | LDL Cholesterol | 112.0 mg/dL | Standard Deviation 26.8 |