International Polycap Study-3 - TIPS-3

Contribution To Literature:

The TIPS-3 trial showed that a once-daily polypill (fixed-dose combination of simvastatin, atenolol, ramipril, HCTZ) was superior to placebo in reducing systolic BP, LDL-C, and nonfatal CV events at ~5 years among intermediate CV risk patients.


The goal of the trial was to assess the safety and efficacy of a once-daily polypill and aspirin among patients with intermediate cardiovascular (CV) risk.

Study Design

Patients were randomized in a 1:1 fashion to either a once-daily polypill (n = 2,861) or matching placebo (n = 2,852). In a 2x2 fashion, they were also randomized to aspirin 75 mg vs. placebo. Components of polypill: atenolol 100 mg + ramipril 10 mg + hydrochlorothiazide (HCTZ) 25 mg + simvastatin 40 mg.

  • Total number of enrollees: 5,713
  • Duration of follow-up: 4.6 years
  • Mean patient age: 63.9 years
  • Percentage female: 53%
  • Percentage with diabetes: 37%

Inclusion criteria:

  • Target CV disease (CVD) risk: >1.0%/year
  • Men ≥50 years and women ≥55 years with an INTERHEART Risk Score (IHRS) of ≥10, or men and women ≥65 years with an IHRS of ≥5

Exclusion criteria:

  • Vascular disease
  • Specific indication or contraindication for statin, beta-blocker, angiotensin-converting enzyme inhibitor, diuretic, aspirin, clopidogrel, or vitamin D
  • Systolic blood pressure (BP) <120 mm Hg
  • Symptomatic hypotension during run-in
  • Peptic ulcer disease, dyspepsia, bleeding

Other salient features/characteristics:

  • Systolic BP: 144 mm Hg
  • Low-density lipoprotein cholesterol (LDL-C): 120 mg/dl
  • Mean IHRS major bleeding: 16.8

By the end of the study, 43% had discontinued the polypill.

Principal Findings:

Polypill vs. placebo: The primary outcome of CV death, myocardial infarction (MI), stroke, heart failure (HF), cardiac arrest, revascularization, was 4.4% vs. 5.5% (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.63-1.0).

  • CV death: 2.9% vs. 3.5%
  • MI: 0.6% vs. 0.9%
  • Stroke: 0.9% vs. 1.3%
  • Arterial revascularization: 0.4% vs. 0.9% (p < 0.05)

Secondary outcomes for polypill vs. placebo:

  • Mean difference in systolic BP: 5.8 mm Hg (5.1-6.4 mm Hg)
  • Mean difference in LDL-C: 19 mg/dl (17.3-20.8 mg/dl)
  • CVD/MI/stroke: 3.9% vs. 4.9% (p > 0.05)
  • All-cause mortality: 5.2% vs. 5.7%
  • Dizziness or hypotension: 2.7% vs. 1.1%

Aspirin vs. placebo: The primary outcome of CV death, MI, stroke, HF, cardiac arrest, revascularization, was 4.1% vs. 4.7% (HR 0.86, 95% CI 0.67-1.10).

  • CV death: 3.0% vs. 3.5%
  • MI: 0.8% vs. 0.7%
  • Stroke: 0.8% vs. 1.4% (p < 0.05)

Secondary outcomes for aspirin vs. placebo:

  • All-cause mortality: 5.1% vs. 5.9%
  • International Society on Thrombosis and Haemostasis (ISTH) major bleeding: 0.7% vs. 0.7%
  • Gastrointestinal bleed: 0.4% vs. 0.4%

Combination of polypill + aspirin vs. double placebo: The primary outcome was 4.1% vs. 5.8% (HR 0.69, 95% CI 0.50-0.97).

  • CV death/MI/stroke: 3.6% vs. 5.3% (p < 0.05)
  • All-cause mortality: 5.2% vs. 6.5% (p > 0.05)
  • Stroke: 0.7% vs. 1.6% (p < 0.05)


The results of this trial indicate that once-daily polypill (fixed-dose combination of simvastatin, atenolol, ramipril, HCTZ) was superior to placebo in reducing systolic BP, LDL-C, and nonfatal CV events at approximately 5 years among intermediate CV risk patients, mostly in Southeast Asia. Low-dose aspirin use resulted in a lower stroke risk. Adding low-dose aspirin to the polypill showed a greater reduction in nonfatal CV events compared with double placebo. The combination resulted in a higher risk of side effects including hypotension and dizziness.

From a population health standpoint, a polypill strategy is attractive because it seeks to minimize nonadherence, as it provides the major CV drug classes in one pill. It is also likely to be cost-effective, particularly among populations where use of these therapies is low. Downsides include fixed dosing and use of simvastatin and ramipril rather than more potent agents. Also, it may not be usable if a patient has an allergy to any of the drugs in the combination pill. The authors estimate that widespread use of the polypill may avert >3 to 5 million CVD events globally.


Yusuf S, Joseph P, Dans A, et al., on behalf of the International Polycap Study 3 Investigators. Polypill With or Without Aspirin in Persons Without Cardiovascular Disease. N Engl J Med 2020;Nov 13:[Epub ahead of print].

Presented by Dr. Salim Yusuf at the American Heart Association Virtual Scientific Sessions, November 13, 2020.

Presented by Dr. Prem Pais at the American Heart Association Virtual Scientific Sessions, November 13, 2020.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Vascular Medicine

Keywords: AHA20, AHA Annual Scientific Sessions, Aspirin, Atenolol, Blood Pressure, Cholesterol, LDL, Cost-Benefit Analysis, Diuretics, Dizziness, Heart Arrest, Heart Failure, Hemorrhage, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypotension, Myocardial Infarction, Myocardial Revascularization, Primary Prevention, Ramipril, Simvastatin, Stroke

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