Grand Rounds

TIPS-3 RCT Results: Does a Combined Polypill Plus Aspirin Reduce Cardiovascular Events in Patients at Increased Risk?

BACKGROUND AND PURPOSE:

Yusuf et al. (NEJM, 2020) evaluated the efficacy and safety of the polypill alone (containing lipid-lowering and blood-pressure–lowering medications), aspirin alone, and the combination of polypill plus aspirin for the reduction of cardiovascular events among people at increased risk

Double-blind, randomized, placebo-controlled trial
- TIPS-3 (the International Polycap Study 3)
Participants
- Men ≥50 years of age or older | Women ≥55 years
- No history of CVD
- Elevated INTERHEART Risk Score indicating intermediate or high cardiovascular risk
Interventions
- Polypill: Simvastatin 40 mg | Atenolol 100 mg | Hydrochlorothiazide 25 mg | Ramipril 10 mg |
- Aspirin: 75 mg
Study design
- Patients were assigned to intervention using a 2-by-2-by-2 factorial design
  - Polypill vs placebo
  - Aspirin vs placebo
  - Polypill + aspirin vs double placebo
Primary outcome
- For polypill alone and polypill + aspirin interventions
  - Composite of the following: Major cardiovascular events (including) death from cardiovascular causes, stroke, and myocardial infarction, plus heart failure, resuscitated cardiac arrest, and arterial revascularization
- For aspirin alone
  - Death from cardiovascular causes | Myocardial infarction | Stroke

5713 participants were randomized
- Mean follow-up: 4.6 years
LDL levels and systolic blood pressure were lower with the polypill and the combination therapy vs placebo
- LDL cholesterol level: Lower by 19.0 mg per deciliter (0.50 mmol per liter)
- Systolic blood pressure: Lower by 5.9 mm Hg
There were no significant differences in the primary outcome for the following
- Polypill vs placebo
  - Polypill: 4.4% incidence
  - Placebo: 5.5%
  - Hazard ratio (HR) 0.79 (95% CI, 0.63 to 1.00)
- Aspirin vs placebo
  - Aspirin: 4.1%
  - Placebo: 4.7%
  - HR 0.86 (95% CI, 0.67 to 1.10)
The primary outcome occurred in fewer patients in the combined treatment
- Combined vs double placebo
  - Combined: 4.1%
  - Double-placebo: 5.8%
  - HR 0.69 (95% CI, 0.50 to 0.97)
The incidence of hypotension or dizziness was higher in groups that received the polypill than in their respective placebo groups

Use of combination therapy with polypill (statin plus three blood-pressure–lowering drugs) plus aspirin resulted in a 31% lower relative risk of cardiovascular events in a primary-prevention population at intermediate risk

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