The International Polycap Study 3 (TIPS-3)

The randomized 2x2x2 factorial design placebo controlled trial will enroll 5000 participants (women 60 years or older and men 55 years or older) without known heart disease or prior stroke and without a clear indication or contraindication to any of the study medications. Eligible and consenting individuals will be randomized to receive either the active study medications or placebo (dummy pills) and will be monitored for an average of 5 years. The study will include people from at 10 countries, will be conducted by an international group of scientists and physicians and will be coordinated by the Population Health Research Institute at Hamilton Health Sciences.

Sex

All

Minimum age

50 Years

Inclusion Criteria:

* Men aged ≥ 50 years and women aged ≥ 55 years with an INTERHEART risk score ≥ 10 OR men and women aged ≥ 65 years with an INTERHEART risk score of ≥5.
* Provision of informed consent

Exclusion Criteria

* Participants with a clear clinical indication, contraindication, preference for or intolerance to statin, beta blocker (e.g. bradycardia), ACE inhibitor, diuretic, aspirin or clopidogrel in the judgment of the physician.
* Regular use of vitamin D at doses higher than 400 IU per day.
* Hypercalcemia, hyperparathyroidism, osteomalacia or other contraindication or indication for vitamin D therapy.
* Peptic ulcer disease, frequent dyspepsia or bleeding.
* Expected long term use of anticoagulants
* Known vascular disease. (e.g., Stroke, TIA, Angina, MI, ACS, PVD including claudication and amputation).
* Mean systolic BP (using 2 automatic readings) below 120 mm Hg at run-in.
* Symptomatic hypotension (e.g., dizziness with SBP \<110 mm Hg systolic) during the run-in phase.
* Chronic liver disease or abnormal liver function, i.e. ALT or AST \> 3 x ULN.
* Inflammatory muscle disease (such as dermatomyositis or polymyositis) or creatine kinase (CK) \> 3 x ULN.
* Severe renal impairment (serum creatinine \>264 µmol/L).
* History of malignancy affecting any organ system, except basal cell carcinoma of the skin, within the previous 5 years.
* Other serious condition(s) likely to interfere with study participation or with the ability to complete the trial.
* Concurrent use of any experimental pharmacological agent.
* Inability to attend follow-up as required by the protocol for at least 5 years.

• DERIVEDJoseph P, Pais P, Gao P, Teo K, Xavier D, Lopez-Jaramillo P, Yusoff K, Santoso A, Gamra H, Talukder SH, Christou C, Dagenais G, Tyrwhitt J, Bosch J, Dans A, Yusuf S; International Polycap Study (TIPS)-3 Investigators. Vitamin D supplementation and adverse skeletal and non-skeletal outcomes in individuals at increased cardiovascular risk: Results from the International Polycap Study (TIPS)-3 randomized controlled trial. Nutr Metab Cardiovasc Dis. 2023 Feb;33(2):434-440. doi: 10.1016/j.numecd.2022.11.001. Epub 2022 Nov 15. PMID 36604262
• DERIVEDYusuf S, Joseph P, Dans A, Gao P, Teo K, Xavier D, Lopez-Jaramillo P, Yusoff K, Santoso A, Gamra H, Talukder S, Christou C, Girish P, Yeates K, Xavier F, Dagenais G, Rocha C, McCready T, Tyrwhitt J, Bosch J, Pais P; International Polycap Study 3 Investigators. Polypill with or without Aspirin in Persons without Cardiovascular Disease. N Engl J Med. 2021 Jan 21;384(3):216-228. doi: 10.1056/NEJMoa2028220. Epub 2020 Nov 13. PMID 33186492
• DERIVEDJoseph P, Pais P, Dans AL, Bosch J, Xavier D, Lopez-Jaramillo P, Yusoff K, Santoso A, Talukder S, Gamra H, Yeates K, Lopez PC, Tyrwhitt J, Gao P, Teo K, Yusuf S; TIPS-3 Investigators. The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct. Am Heart J. 2018 Dec;206:72-79. doi: 10.1016/j.ahj.2018.07.012. Epub 2018 Aug 2. PMID 30342297