Moderate Alcohol and Cardiovascular Health Trial

• Alcohol (Other), also known as ethanol, beer, wine, spirits: \~15 gm daily of beer, wine, or spirits for \~6 years

Primary outcomes

• Cardiovascular Disease or Death [Every 3 months for up to 90 months or close out, or until date of death]: Time from baseline to a composite endpoint comprised of the first occurrence of a non-fatal myocardial infarction, non-fatal ischemic stroke, hospitalization for angina, coronary/carotid revascularization, or all-cause mortality.

Secondary outcomes

• Cardiovascular Disease [Every 3 months for up to 90 months or close out, or until date of death]: Time from baseline to a composite endpoint comprised of the first occurrence of a non-fatal myocardial infarction, non-fatal ischemic stroke, hospitalization for angina, coronary/carotid revascularization, or cardiovascular mortality.
• Diabetes [Every 12 months for 90 months or close out, or until date of first documented occurence]: Progression among normoglycemic and pre-diabetes individuals to American Diabetes Association (ADA)-defined diabetes.

Other outcomes

• Hard Cardiovascular Disease or Death [Every 3 months for 90 month or close out, or until date of death]: Time from baseline to a composite endpoint comprised of the first occurrence of a non-fatal myocardial infarction, non-fatal ischemic stroke, or cardiovascular death.
• Components of Primary Composite Endpoint [Every 3 months for up to 90 months or close out, or until date of death]: Time from baseline to the first occurrence of each of the components of primary outcome (5 outcomes).
• Cardiovascular Death [Every 3 months for 90 months or closeout, or date of death]: Time from baseline to cardiovascular mortality.
• Pre-Diabetes [Every 12 months for 90 months or closeout]: Progression among normoglycemic individuals to ADA-defined pre-diabetes.

Sex: All, ages: 50 Years to any

Inclusion Criteria:

* Age ≥50 years at screening
* Postmenopausal, defined as 12 consecutive months without menstruation
* Not alcohol naïve, defined by having consumed at least one drink of alcohol in the past five years
* High risk for the occurrence of a new cardiovascular disease event, defined as having any one of the following:

  1. American Heart Association (AHA)/American College of Cardiology (ACC) Risk Score ≥15% within the past 24 months (among those without clinical or subclinical cardiovascular disease \[CVD\])
  2. Clinical CVD (more than 6 months prior to randomization), defined by:

     1. Previous myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), carotid endarterectomy (CE), carotid stenting;
     2. Peripheral artery disease (PAD) with revascularization;
     3. Acute coronary syndrome with or without resting electrocardiogram (ECG) change, ECG changes on a graded exercise test (GXT), or positive cardiac imaging study;
     4. Prior stroke documented on brain imaging or with a persistent deficit.
  3. Subclinical CVD, confirmed in available medical records:

     1. At least a 50% diameter stenosis of a coronary, carotid, or lower extremity artery;
     2. Coronary artery calcium score ≥400 Agatston units;
     3. Ankle brachial index (ABI) ≤0.90;
     4. Left ventricular hypertrophy (LVH) by ECG (based on computer reading), echocardiogram report, or other cardiac imaging procedure report;
     5. Abdominal aortic aneurysm (AAA) ≥5 cm with or without repair.

Exclusion Criteria:

* High alcohol consumption, defined by any one of the following:

  1. Alcohol Use Disorders Identification Test (AUDIT) score >5 at screening
  2. Drinking, on average, >7 alcoholic beverages/week during the past 6 months
  3. Drinking 6 or more alcoholic beverages on one occasion during the past 6 months
* Yale-Brown Obsessive Compulsive Scale-heavy drinking (Y-BOCS-hd) total score of ≥6 on questions 7, 8, and 10
* Cardiovascular disease event (MI, revascularization procedure, or stroke) within the 6 months prior to randomization
* AHA Class III-IV heart failure
* History of alcohol or substance abuse (medical record confirmed or self-reported history)
* Other intolerance or allergy to alcohol
* Dual antiplatelet therapy
* History of gastric bypass surgery
* Any serious chronic liver disease (e.g., active hepatitis B and C infections) or liver tests (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\] and gamma-glutamyl transpeptidase \[GGT\]) >2 times the upper limit of the normal range using local standards
* Personal history of any colon or liver cancer
* Any other cancer with a life expectancy of less than 3 years
* Diagnosed with breast cancer that required either surgery or removal of breast tissue or chemotherapy
* Mother or sister ever diagnosed with breast cancer that required either surgery or removal of breast tissue or chemotherapy
* Estimated glomerular filtration rate (eGFR) <30 ml/min /1.73m2 or end-stage renal disease (ESRD)
* Ongoing use of any medication for which alcohol consumption is contraindicated
* A Patient Health Questionnaire (PHQ-9) ≥15 at screening
* History of any organ transplant
* Unintentional weight loss >10% in last 6 months
* Currently participating in another clinical trial (intervention trial) with CVD outcomes. Note: Participant must wait until the completion of his/her activities or the completion of the other trial before being screened for MACH15. Local restrictions for entry by participants can be more conservative if mandated.
* Not willing or able to provide a name and contact information for at least one additional contact person other than self
* Investigator discretion regarding appropriateness of participation or concern about intervention adherence, including:

  1. moderate - severe psychiatric illness
  2. behavioral concerns regarding likelihood of low adherence to trial protocol
  3. a medical condition likely to limit survival to less than 3 years
  4. advanced chronic disease, such as dementia, that requires 24-hour care
* Not willing or able to provide a signed and dated informed consent form
* Not willing or able to comply with all trial procedures.

Participant flow

Outcome results

• Cardiovascular Disease or Death (Primary)
• Cardiovascular Disease (Secondary)
• Diabetes (Secondary)
• Hard Cardiovascular Disease or Death (Other pre specified)
• Components of Primary Composite Endpoint (Other pre specified)
• Cardiovascular Death (Other pre specified)
• Pre-Diabetes (Other pre specified)

Adverse events

Time frame: 5 months; from first enrolled subject until study termination.

• Mukamal KJ, Clowry CM, Murray MM, Hendriks HF, Rimm EB, Sink KM, Adebamowo CA, Dragsted LO, Lapinski PS, Lazo M, Krystal JH. Moderate Alcohol Consumption and Chronic Disease: The Case for a Long-Term Trial. Alcohol Clin Exp Res. 2016 Nov;40(11):2283-2291. doi: 10.1111/acer.13231. Epub 2016 Sep 30. PMID 27688006

• Study Protocol and Statistical Analysis Plan (PDF, 2018-04-06)
• Informed Consent Form (PDF, 2018-04-06)

• Kenneth J Mukamal, MD, Principal investigator, Beth Israel Deaconess Medical Center

NIH grants: U10AA025286