Use of Entresto Sacubitril/Valsartan for the Treatment of Peripheral Arterial Disease

Current approaches for the treatment of peripheral arterial disease (PAD) lack the success
observed in the treatment of other forms of vascular diseases. A potential reason for this
may be that available treatments do not target the pathological mechanisms implicated in the
development of PAD. These mechanisms include obstruction of aortic-iliac arteries and its
branches due to the formation of atherosclerotic plaques and mitochondrial and microvascular
dysfunction. Although blood flow improves following surgical revascularization, pain free and
maximal walking duration does not improve to the same degree. This suggests that in addition
to blood flow obstruction, mitochondrial and microvascular dysfunction are significant
factors implicated in the development of PAD.

Therefore, any treatment designed for patients with PAD should be aimed at improving
mitochondrial and microvascular function. In this regard, natriuretic peptides (NP) have been
shown to increase mitochondrial and microvascular density and these two findings have been
associated with increases in oxygen consumption and perfusion of skeletal muscles.

The Investigator proposes that an increase in endogenous natriuretic peptides by inhibiting
the enzyme that degrades it in blood will increase mitochondrial and microvascular function
and this will be associated with an increase in maximal and pain free walking duration. To
test this hypothesis the investigators have designed a double blind randomized controlled
clinical trial providing sacubitril/valsartan for 12 weeks trial period.The improvements in
mitochondrial and microvascular function will be measured using magnetic resonance (MR)
spectroscopy and functional MR imaging and an exercise stress test will be used to assess
maximal and pain free walking duration. This trial will provide patients with PAD with a
non-surgical, cause-specific treatment option.

Inclusion Criteria:

1. Subject with symptoms of intermittent claudication, such as exercise-induced pain,
cramps, fatigue, or other equivalent discomfort, involving large muscle groups of the
leg(s) (calf, thigh, buttocks), relieved by rest.

2. Ankle-brachial index ≤ 0.90 acquired according to the American Heart Association
guidelines.

3. Highest ankle pressure reduced by at least 25 mm Hg after exercise compared to resting
pressure (or loss of previously present Doppler signal for both the posterior tibial
and anterior tibial arteries immediately after exercise if arteries were
incompressible).

4. Patients on medical treatment for PAD without significant improvement in intermittent
claudication within the last 6 months.

Exclusion Criteria:

1. Age < 18 and > 80 years.

2. Patients with physician diagnosed chronic kidney disease or heart failure stage II or
IV or unstable angina.

3. Echocardiographic evidence of cardiomyopathies and pulmonary hypertension.

4. Patients that have received cancer treatment within the last year (except skin
cancer).

5. Severe limitations in mobility due to osteomuscular disorders present at time of
interview.

6. Dementia or other mental disorders that prevent patients from following a research
protocol present at time of interview

7. Patients engaged in an exercise rehabilitation program within the past 6 months.

8. Patients schedule to undergo an arterial revascularization procedure during the study
or have undergone one within the past 6 months.

9. Inconsistent maximal walking distance on the treadmill test.