Targeting Inflammation Using Salsalate in CardioVascular Disease

OBJECTIVE:

To determine whether targeting inflammation using salsalate compared with placebo reduces
progression of noncalcified coronary artery plaque.

DESIGN, SETTING, AND PARTICIPANTS:

In the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial
participants were randomly assigned to 30 months of salsalate or placebo in addition to
standard, guideline-based therapies. Randomization was computerized and centrally allocated,
with patients, health care professionals, and researchers masked to treatment assignment.
Participants were overweight and obese statin-using patients with established, stable
coronary heart disease.

INTERVENTIONS:

Salsalate (3.5 g/d) or placebo orally over 30 months.

MAIN OUTCOMES AND MEASURES:

The primary outcome was progression of noncalcified coronary artery plaque assessed by
multidetector computed tomographic angiography. Secondary outcomes were other measures of
safety and efficacy.

Inclusion Criteria:

Eligibility will be based upon the presence of established coronary artery disease
including

- previous myocardial infarction (≥6 months ago), or

- previous coronary bypass surgery (> 12 months ago), or

- stable angina, or

- significant non-calcified plaque in at least one coronary artery, or

- abnormal exercise tolerance test or

- an area of reversible ischemia on nuclear imaging study or pharmacologic stress, with
subsequent revascularization, or angioplasty, or

- abnormal exercise treadmill stress test with or without nuclear imaging or
echocardiography with the following exclusions:

Exclusions based on nuclear imaging:

1. Transient cavity dilation

2. More than one vascular territory involved with reversible defect (multiple defects)

3. Reversible defects involving the anterior wall, septum or apex (LAD territory)

Exclusions based on echocardiography imaging:

1. More than one vascular territory involved with inducible wall motion abnormalities
(multiple defects)

2. Inducible wall motion abnormalities involving the anterior wall, septum or apex (LAD
territory)

Subjects should be at list 6 months after a myocardial infarction and/or revascularization
procedure to be eligible.

In addition, subjects must be:

1. aged 21- 75 years inclusive,

2. BMI ≥ 27 kg/m2 and ≤ 35 kg/m2 if female and ≤ 40 kg/m2 if male (a BMI ≥24.5 for
subjects from Asian origin)

3. on a stable dose of an HMG CoA reductase inhibitor (statin) for 1 month at screening
or unable to tolerate a statin,

4. have normal renal function, (note estimated creatinine clearance calculated using
Cockcroft-Gault (CG) equation ≥60 at screening [eCrCLCG (ml/min) = [(140 - age) x
weight (kg)]/[SCr(mg/dl) x 72] x [0.85 if female],

5. have liver function (ALT, AST) < 3 times upper limits of normal),

6. normal thyroid function (on stable dose replacement therapy is acceptable),

7. if women are of child bearing potential they must have a pregnancy test prior to the
CT angio and use contraception for the remainder of the study

8. patients with T2D must have a fasting glucose of ≤ 200 mg/dl at screening and cannot
be treated with thiazolidinedione class agents or insulin or Extendin-4 (Byetta)
therapy.

Subjects must be willing to have at least three visits at the Beth Israel-Deaconess Medical
Center/Joslin Diabetes Center with a baseline and a 30-month follow-up series of imaging
studies including CT angiography of the coronary arteries and imaging of the aorta,
abdominal adiposity and liver, and interim visit at 1 year.

Exclusion Criteria:

1. Unstable angina (increase in frequency or severity of anginal episodes or development
of chest pain at rest)

2. significant obstructive disease (≥ 70%) in left main coronary artery, ostial LAD or
three-vessel disease by MDCTA

3. Significant heart failure (NYHA class III and IV)

4. Current atrial fibrillation or Wolf-Parkinson-White (WPW) syndrome

5. Allergy to beta-blocker in subjects with resting heart rate > 65 bpm

6. Systolic blood pressure > 160 mm Hg

7. Diastolic BP > 100 mm Hg

8. Persons with allergies to contrast material

9. History of asthma if unable to tolerate beta blocker

10. Allergy to iodinated contrast material or shellfish

11. Allergy to nitroglycerin

12. BMI > 35 kg/m2 if female and > 40 kg/m2 if male

13. Body weight > 350 lbs

14. Use of drugs for weight loss [e.g. Xenical (orlistat), Meridia (sibutramine), Acutrim
(phenylpropanolamine) or similar over-the counter medications] within three months of
screening

15. Surgery within 30 days of screening

16. History of acquired immune deficiency syndrome or human immunodeficiency virus (HIV)

17. Poor mental function or history of dementia/ Alzheimer's Disease or on medications
used for treatment of dementia [e.g. Tacrine (Cognex), Rivastigmine (Exelon),
Galantamine (Razadyne, Reminyl), Donepezil (Aricept), Memantine (Namenda)] or any
other reason to expect patient difficulty in complying with the requirements of the
study

18. Medicine for erectile dysfunction within 72 hours prior to MDCTA

19. History of significant chronic rheumatologic or other chronic inflammatory disease
(including foot ulcers)

20. Prior hemorrhagic stroke

21. persons with known aspirin allergy

22. Use of continuous oral corticosteroid treatment (more than 2 weeks), or patients
requiring corticosteroids within 3 months

23. Anti-diabetic medication including thiazolidinedione (pioglitazone or rosiglitazone),
or insulin or Extendin-4 (Byetta)

24. History of peptic ulcer or gastritis within 5 years

25. Positive stool guaiac

26. Hemoglobin 2 standard deviations below normal

27. Low platelet count (2 standard deviations below normal)

28. Known bleeding disorder

29. Coumadin (warfarin compounds)

30. History of type 1 diabetes and/or history of ketoacidosis

31. Daily use of NSAIDS (including salsalate) for arthritis

32. History of malignancy, except subjects who have been disease-free for greater than 5
years, or whose only malignancy has been basal or squamous cell skin carcinoma

33. History of drug or alcohol abuse, or current weekly alcohol consumption >14 units/week
(1 unit = 1 beer, 1 glass of wine, 1 mixed cocktail containing 1 ounce of alcohol)

34. Use of probenecid (Benemid, Probalan), sulfinpyrazone (Anturane) or other uricosuric
agents

35. Chronic tinnitus.