Prevention of Cardiovascular Disease in Middle-aged and Elderly Iranians Using a Single PolyPill (PolyIran)

• Time to first major cardiovascular event (long-term) [ Time Frame: 5 years ] [ Designated as safety issue: No ]

  Major cardiovascular events are defined as:

  1. Major coronary events include: sudden cardiac death, myocardial infarction, a diagnosis of angina, revascularization procedure
  2. Cerebrovascular accidents (CVA) including TIA, stroke C) hospitalization because of cardiovascular disease
• Cardiovascular-specific mortality (long-term) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Rate of cardiovascular disease caused mortality
• Time to first major cardiovascular event (short-term) [ Time Frame: 2 years ] [ Designated as safety issue: No ]

  Major cardiovascular events are defined as:

  1. Major coronary events include: sudden cardiac death, myocardial infarction, a diagnosis of angina, revascularization procedure
  2. Cerebrovascular accidents (CVA) including TIA, stroke C) hospitalization because of cardiovascular disease
• Cardiovascular-specific mortality (short-term) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Rate of cardiovascular disease caused mortality

• Blood pressure [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Changes in blood pressure after 5 years
• Fasting blood sugar, total cholesterol, HDL-C and LDL-C [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Changes in fasting blood sugar and lipid profile after 5 years
• Adverse Events [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
  Number of participants who experience adverse effects to the PolyPill tablet,
• Compliance [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Compliance is measured by pill-count in participants of the intervention arm
• Rate of major cardiovascular events [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  Number of major cardiovascular events (as described above) during 5 years

• Blood pressure (long-term) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
• LDL, HDL and cholesterol (long-term) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  lipid profile defined as LDL (low density lipoprotein), HDL (low density lipoprotein)and cholesterol
• blood glucose level (long-term) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
• Number of Participants with Adverse Events (long-term) [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
  Number of Participants with adverse effects of drugs used in POLYIRAN as a Measure of Safety and Tolerability
• compliance (long-term) [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  compliance is assessed for subjects in the intervention group who receive POLYIRAN. It is measured by pill-count (percentage of pill intake)
• Blood pressure (short-term) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• LDL, HDL and cholesterol (short-term) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  lipid profile defined as LDL (low density lipoprotein), HDL (low density lipoprotein)and cholesterol
• blood glucose level (short-term) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Number of Participants with adverse effects (short-term) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  Number of Participants with adverse effects of drugs used in POLYIRAN as a Measure of Safety and Tolerability
• compliance (short-term) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  compliance is assessed for subjects in the intervention group who receive POLYIRAN. It is measured by pill-count (percentage of pill intake).

The purpose of this study is to determine the effects of PolyPill tablet (a fixed dose combination of two anti-hypertensive medications, atorvastatin and aspirin) on primary and secondary prevention of cardiovascular disease in Iranian adults older than 50.

Cardiovascular diseases (myocardial infarction and stroke) are the most common cause of death and disability in Iran and account for nearly half of all-cause mortality in Iranians. Therefore, prevention of cardiovascular diseases is a top priority in countries with limited health system budgets such as Iran.

Eighty seven to hundred percent of patients dying from Coronary Heart Disease (CHD) have at least one risk factor for cardiovascular diseases. Therefore, risk factor modification in middle-aged and old individuals might prevent death and is a main priority. Combination drug therapy has been proposed as a cost-effective measure to reduce modifiable risk factors for cardiovascular disease in aged people. It has been showed that combination drug therapy can potentially decrease ischemic heart events and strokes by 88 and 80 percent, respectively.

The purpose of this study is to determine the effects of PolyPill tablet (a fixed dose combination of two anti-hypertensive medications, atorvastatin and aspirin) on primary and secondary prevention of cardiovascular disease in Iranian adults older than 50.

This is a study on subjects older than 50 enrolled in the Golestan Cohort Study. The study is designed as a cmRCT. The study comprises three arms as follows:

1. 3500 randomly selected participants receive PolyPill tablets once daily and Minimal care (which consists of direct education and pamphlet on cardiovascular risk reduction, biannual follow-ups and BP measurements).
2. 3500 randomly selected participants receive only Minimal care as described above.
3. 24000 participants receive usual care (the basic primary health care provided by the local physicians and Community Health Workers for the whole participants of Golestan Cohort study consistent with the current Iranian Health Care System guidelines).

Arms #1 and #2 are compared via a 2-armed open-labeled cluster Randomized Controlled Trial. The comparisons between arm #3 and the other 2 arms are performed by means of a cohort multiple Randomized Controlled Trial (cmRCT) design.

Endpoints include major cardiovascular events (death and hospitalization)

• Drug: PolyPill
  A combination tablet containing Aspirin 81 mg, enalapril 5 mg (or valsartan 40 mg), atorvastatin 20 mg and hydrochlorothiazide 12.5 mg taken once daily
• Other: Minimal care
  Health education pamphlet on reducing cardiovascular risk factors, direct education on reducing cardiovascular risk factors provided by the study physician and the Community Health Worker, biannual follow-up and BP measurement

• Active Comparator: PolyPill
  PolyPill once daily and Minimal Care
  Interventions:

  • Drug: PolyPill
  • Other: Minimal care
• Active Comparator: Minimal care
  Minimal care.
  Intervention: Other: Minimal care
• No Intervention: Usual care
  Basic primary health care provided by the local physicians and Community Health Workers consistent with the current Iranian Health Care System guidelines.

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Inclusion Criteria:

• 50-79 years old
• Enrollment in the Golestan Cohort Study

Exclusion Criteria:

1. Hypersensitivity to any of PolyPill components:

   1. Hypersensitivity to Non-steroidal anti-inflammatory agents
   2. Hypersensitivity to statins
   3. Hypersensitivity to hydrochlorothiazide or sulfonamides
   4. Hypersensitivity to enalapril and valsartan
2. Past medical history of angioedema
3. Medical history of GI bleeding or peptic ulcer in the last 3 months
4. Pregnancy or lactation
5. Bleeding disorders such as hemophilia
6. Receiving anticoagulation therapy
7. Alcohol consumption greater than 40gr/week
8. Advanced liver disease
9. Uncontrolled seizures

10. Asthma with any of the following criteria present:

    1. Daily symptoms
    2. Asthmatic attacks waking the patient from sleep more than once a week
    3. History of nasal polyps
    4. Aspirin sensitive asthma
    5. Presence of rhinitis symptoms not due to infection
11. Past medical history of gout
12. Serum creatinine values above 2 mg/dL or a Glomerular Filtration Rate (GFR) below 30 mL/min
13. Hemoglobin concentrations below 11 g/dL for males and 10 g/dL for females
14. BP < 90/60
15. Debilitating medical/mental disorders affecting medication compliance (including psychosis, disabilities, and blindness)
16. Past medical history of stroke

• Golestan University of Medical Science
• University of Birmingham