Clinical trial NCT06541691: Coated or Chewable Aspirin and a Hybrid Strategy to Mitigate Adverse Effects of Air Pollution in Stable Atherosclerotic Disease
Official title: Coated or Chewable Aspirin in Patients with Established Atherosclerotic Disease and a Hybrid Strategy to Mitigate the Adverse Effects of Air Pollution: the COATED-AIR Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Atherosclerotic Cardiovascular Disease
Coronary Artery Disease
Ischemic Heart Disease
Ischemic Stroke
Peripheral Arterial Disease
Carotid Artery Stenosis
Carotid Atherosclerosis
Keywords: atherosclerosis
atherosclerotic cardiovascular disease
atherosclerotic arterial disease
atherosclerotic plaque
coronay artery disease
ischemic heart disease
atherosclerotic disease
ischemic stroke
peripheral arterial disease
carotid artery stenosis
carotid atherosclerosis
myocardial infarction
acute limb ischemia
bleeding
major bleeding
gastrointestinal bleeding
gastrointestinal ulcer
peptic ulcer disease
gastric ulcer
duodenal ulcer
dyspepsia
intracerebral hemorrhage
aspirin
acetylsalicylic acid
antithrombotic therapy
antithrombotic agents
antiplatelet agents
air pollution
cerebral hemorrhage
hemorrhage
Lead sponsor: Rajaie Cardiovascular Medical and Research Center
Sponsor class: OTHER
Collaborators: name: Brigham and Women's Hospital
First posted: 2024-08-07
Enrollment: 3000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: 2×2 full factorial design
Primary purpose: PREVENTION

Brief summary: Although both enteric-coated and plain formulations of aspirin are being used commonly, there are no high-quality comparisons between these formulations with respect to clinical efficacy outcomes in patients with atherosclerotic cardiovascular diseases (ASCVD). Air pollution is also a major contributor to the excess risk of cardiovascular events in many regions of the world. However, little is known about the effect of individual-level mitigation strategies against air pollution in reducing cardiovascular outcomes. The purpose of the first randomization is to compare the efficacy and safety of enteric-coated versus plain low-dose (81 mg) aspirin formulations in a double-blind fashion. The second randomization compares a multifaceted intervention including one-page educational flashcard, cell phone text messages alerting participants on polluted days, recommending them to stay indoors or wear KN-95 facemasks provided by the study team in case of necessary outdoor activity, and recommendation to consume citrus fruits on polluted days versus usual care. Both randomization are powered for clinical outcomes and the results will inform practice.

Detailed description: - Background: Aspirin is a key treatment option of patients with atherosclerotic cardiovascular disease (ASCVD). The enteric coating has emerged as a potential solution to minimize the exposure of the gastric mucosa to the medication. However, change in the medication main site of absorption might negatively impact the pharmacokinetics/pharmacodynamics of aspirin and alter its antithrombotic properties, leading to diminished efficacy of the medication. A sufficiently large randomized controlled trial with a long-term follow-up to compare the effectiveness of enteric-coated versus plain aspirin in reducing adverse cardiovascular events and mitigating the adverse effects of the medication in patients with ASCVD is lacking.

Ambient air pollution is a prominent cause of mortality, being associated with 6.7 million deaths worldwide every year, half of which are attributable to cardiovascular causes. Near the half of these deaths is attributable to cardiovascular causes. Several patient-level interventions have been proposed to counteract with the adverse effects of the air pollution, including alerting patients via text message, staying at home, using face masks, or consuming citrus fruits (as a source of vitamin C) during the days with air pollution. However, the effect of implementing these strategies, individually and especially as a group, in mitigating the adverse effects of the air pollution has not yet been studied in a randomized controlled trial powered for clinical outcomes.

The purpose of the current randomized clinical trial is to compare the efficacy and safety of enteric-coated versus plain low-dose (81 mg) aspirin formulations in a double-blind fashion, and an open-label comparison of a multifaceted intervention including a one-page informational flashcard, cell phone message alerting on days with poor air quality to encourage patients not to spend time outdoors or to wear KN-95 facemasks outdoors in those days, and encouraging patients to consume citrus fruits on highly polluted days (hereafter referred to as hybrid strategy), versus usual care, in a multicenter randomized controlled trial (RCT) with a 2x2 factorial design.

- Design and Randomization method: Multicenter randomized controlled trial with a 2x2 full factorial design with double-blind randomization with a 1:1 allocation ratio to low-dose enteric-coated vs plain aspirin, and open-label randomization with 1:1 allocation ratio to hybrid strategy to reduce the cardiovascular effects of air pollution vs usual care. Permuted block randomization with block sizes of 8, 12 and 16 chosen randomly via an electronic web-based system will be used for the study. The allocation sequence will be concealed. All outcomes will be adjudicated by a Clinical Events Committee blinded to the assigned treatments.

- Setting: Teaching hospitals in Tehran province, Iran will be involved.

- Statistical consideration and sample size calculation: An event-driven approach was considered for the calculation of sample size. Considering a relative hazard reduction of 23% in the first (aspirin formulation) randomization and 25% in the second (air pollution mitigation strategy) randomization, to provide a two-sided alpha of 0.05 and a statistical power of 80%, a total number of 460 primary efficacy outcomes for the first randomization and 380 primary efficacy outcomes for the second randomization would be needed. An event-rate of 18.5% for the incidence of primary efficacy outcome in the control arm of the first randomization, and 19.2% for the incidence of primary efficacy outcome in the control arm of the second randomization was assumed per a median follow-up of 2-year. Ultimately, Considering 4% dropout rate per each randomization, a total number of 2920 and 2732 patients would be needed for the first and second randomizations, respectively.

Eligibility criteria: Inclusion Criteria:

* Adult patients (≥18 years) with documented ASCVD defined as at least one of the following:

  * Coronary artery disease (CAD):

    1. Previous or recent documented type I myocardial infarction \*(if not specified, will be assumed as type I)
    2. History of coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft surgery)
    3. History of obstructive CAD (\>50% stenosis) documented by coronary computed tomography (CT) or conventional angiography
  * Peripheral arterial disease (PAD):

    1. Previous or recent acute ischemic limb event (\>7 days prior)
    2. History of previous endovascular/surgical lower or upper extremities revascularization for an atherosclerotic cause
    3. History of ulcer or lower extremities amputation due to ASCVD.
  * Carotid arterial diseases:

    1. History of previous endovascular/surgical carotid artery revascularization for atherosclerotic causes
    2. History of \> 50% carotid artery stenosis based on documented imaging tests (Duplex US, CT angiography, magnetic resonance angiography, or conventional angiography)
  * Ischemic stroke:

    1. History of recent or previous documented ischemic stroke not due to atrial fibrillation, endocarditis, or systemic hypoperfusion/hypotension, being treated with low-dose aspirin
* Inhabitant of Tehran province
* Willing to participate and able to provide written informed consent

Exclusion Criteria:

* Being within 72 days of acute/unstable atherosclerotic cardiovascular events (acute myocardial infarction, acute limb event, and acute ischemic stroke), or within 72 hours of revascularization.
* Patients receiving triple antithrombotic therapy
* History of upper gastrointestinal bleeding within the past 30 days
* History of intracranial hemorrhage within the past 30 days
* End-stage kidney disease with estimated creatinine clearance \< 15 mL/min, or undergoing hemodialysis or peritoneal dialysis
* Known comorbidities associated with poor prognosis (e.g., metastatic cancer) in conjunction with an estimated life expectancy of less than one year according to the treating clinician
* Any other conditions that make the participants unsuitable for recruitment or follow-up (e.g., illiteracy)
* Not having aspirin as part of the planned durable treatment regimen
* Inability to receive/read text messages/phone calls by personal mobile phone (or that of a caregiver who lives with the patient and is willing to relay messages)

  * The full list of exclusion criteria is provided in the study protocol

Primary outcomes:
measure: Composite of fatal or nonfatal ischemic stroke (not deemed to be related to systemic hypotension), type I myocardial infarction, and acute limb events
timeFrame: within maximum of 30-month follow-up
measure: Composite of non-fatal ischemic stroke (not deemed to be related to systolic hypotension), type I myocardial infarction, acute limb events, or cardiovascular death
timeFrame: within maximum of 30-month follow-up
Secondary outcomes:
measure: Type I myocardial infarction
timeFrame: within maximum of 30-month follow-up
measure: Ischemic stroke (not deemed to be related to systemic hypotension)
timeFrame: within maximum of 30-month follow-up
measure: Acute limb event
timeFrame: within maximum of 30-month follow-up
measure: All-cause death
timeFrame: within maximum of 30-month follow-up
measure: Cardiovascular death
timeFrame: within maximum of 30-month follow-up
measure: Unplanned vascular hospitalization
timeFrame: within maximum of 30-month follow-up
measure: Composite of International Society on Thrombosis and Haemostasis (ISTH) major or clinically-relevant non-major gastrointestinal (GI) bleeding that bleeding and new symptomatic diagnosed gastroduodenal ulcer
timeFrame: within maximum of 30-month follow-up
measure: Upper GI bleeding
timeFrame: within maximum of 30-month follow-up
measure: Clinically relevant non-major GI bleeding
timeFrame: within maximum of 30-month follow-up
measure: Any Major bleeding
timeFrame: within maximum of 30-month follow-up
measure: Intracranial hemorrhage
timeFrame: within maximum of 30-month follow-up
measure: Any clinically relevant non-major bleeding
timeFrame: within maximum of 30-month follow-up
measure: New symptomatic diagnosed gastroduodenal ulcer
timeFrame: within maximum of 30-month follow-up
Other outcomes:
Locations:
city: Tehran
country: Iran, Islamic Republic of
facility: Rajaie Cardiovascular Medical and Research Center
Study officials:
affiliation: Rajaie Cardiovascular Medical and Research Center
name: Parham Sadeghipour, M.D
role: PRINCIPAL_INVESTIGATOR
References: