A Comparative Effectiveness & Long Term Health Study in Wisconsin Smokers

The proposed study will recruit and treat a large sample of contemporary smokers and former
smokers at an age of increasing health risk, to achieve the following over-arching aims that
are important to the NHLBI mission:

- Specific Aim 1: Produce important new data on how to treat smoking optimally by
conducting an open label comparative effectiveness trial (CET) that for the first time
directly contrasts the two smoking cessation pharmacotherapies with the strongest extant
evidence of efficacy: combination NRT and varenicline.

- Specific Aim 2: Determine the impact of smoking cessation on biomarkers and health risk
factors, especially those relevant to CVD, in today's smokers, which will elucidate the
mechanisms via which cessation benefits health.

- Specific Aim 3: Identify which individuals are at greatest risk for exacerbation of
biomarkers or risk factor status due to continued smoking, and who will benefit most
from cessation. This will help identify individuals who are most in need of cessation
intervention. While all smokers need to quit, this evidence could ultimately be used to
help focus treatment and motivate smokers and clinicians to intervene more intensively
with patients at greatest risk.

Two secondary aims are to use the results of Primary Aim 1 to develop a treatment assignment
algorithm for the optimal treatment of today's smokers and to use the results from Primary
Aim 2 to determine the relation of health biomarkers to clinically meaningful disease
outcomes such as CVD events.

We will re-recruit as many smoking and non smoking participants from our past longitudinal
cohort study("Wisconsin Smokers' Health study"; NCT01122238) in 2004. We will then recruit
additional smokers to participate in the comparative effectiveness trial and join the
longitudinal cohort..

All participants who enroll will complete questionnaires about their demographics, smoking
history, withdrawal symptoms, affect, alcohol use, stressors, medication usage and diet. They
will also complete a structured clinical interview to assess mental health. They will provide
blood samples for testing of various markers of cardiovascular disease and risk as well as
for genetics testing. They will all have carotid ultrasounds, pulmonary function tests,
arterial tonometry assessments, and 12-lead ECGs. Participants in Madison will also have a
treadmill stress test. Participants will wear a pedometer for 1 week and record the daily
number of steps. Participants will provide permission for staff to review their medical
charts to assess smoking-relevant diagnoses and treatment. These assessments will occur at
baseline and again 3 years later. A smaller subset of these assessments will also be
conducted 1 year after enrollment. Participants will also complete brief phone assessments at
6-month intervals up to the 3-year visit.

Interested and eligible smoking participants from the original cohort study and all newly
recruited participants will enroll in a new smoking cessation intervention study.
Participants in the cessation treatment study will be randomly assigned to receive the
nicotine patch, nicotine patch + nicotine lozenge or varenicline. If the participant from the
original cohort study is not eligible to use all study medications but is otherwise eligible
for cessation treatment, s/he will be assigned to a non-randomized treatment arm and will
receive nicotine patch (if appropriate). All cessation participants will receive 6 individual
counseling sessions.

We are only recruiting by invitation only (to members of our past cohort). We will open up
enrollment to the public in the Madison, WI and Milwaukee WI areas at the end of 2012.

Inclusion Criteria:

a. To be eligible for the Comparative effectiveness trial, participants must:

- smoke 5 or more cigarettes per day,

- desire to quit smoking but not be currently engaged in cessation treatment,

- be medically eligible to use either combination NRT or varenicline,

- have reliable phone access,

- if female, must not be pregnant and must be willing to use an acceptable birth control
method.

Exclusion Criteria:

1. There are no exclusion criteria for participating in the main health outcomes study,
other than being unwilling to complete study assessments.

2. All smoking participants from new and original cohorts will be excluded from the
cessation trial for the following reasons:

- end-stage renal disease with hemodialysis;

- prior suicide attempts within the last 5 years or current suicidal ideation;

- diagnosis of and/or treatment for schizophrenia;

- other psychotic disorders or bipolar disorder within the last 10 years;

- current PHQ-9 score indicative of moderately severe depression;

- severe untreated hypertension >200/100 mmHg;

- currently taking Wellbutrin, Zyban or bupropion;

- hospitalized for a stroke, heart attack, congestive heart failure or diabetes
within the last year;

- used pipe tobacco, cigars, snuff or chew more than twice in the past week.

It should be noted that if any incidental findings appear in any of the cardiology tests
(e.g., ultrasound, tonometry, ECG, or exercise stress test; see forms in Supplemental
Information section of application), the study cardiologist (Dr. Stein or his designee)
will be assign the participant to the non-randomized treatment arm and they will be given
the nicotine patch and the same counseling intervention as CET participants. They will not
be included in the CET analyses. This will be done to properly address the cardiovascular
risk warning from the FDA regarding varenicline (Chantix).