Why are Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) considered first-line therapy for patients with lower extremity Peripheral Artery Disease (PAD) and hypertension?

ACE Inhibitors and ARBs in Lower Extremity PAD with Hypertension

ACE inhibitors and ARBs are considered first-line therapy for patients with lower extremity peripheral artery disease (PAD) and hypertension because they have been shown to reduce the risk for major adverse cardiovascular events (MACE), although an impact on the risk for major adverse limb events (MALE) has not been consistently demonstrated in this patient population. 1

Evidence for Cardiovascular Benefits

The 2024 ACC/AHA/Multisociety guideline for the management of lower extremity PAD specifically recommends ACE inhibitors and ARBs with a Class 1, Level of Evidence B-R recommendation, stating:

• "In patients with PAD and hypertension, the selective use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers is recommended to reduce the risk of MACE." 1

This recommendation is based on evidence from randomized controlled trials showing that these medications effectively reduce cardiovascular events in patients with PAD, including:

• Reduction in myocardial infarction
• Reduction in stroke
• Reduction in heart failure
• Reduction in cardiovascular death

Mechanism of Benefit

ACE inhibitors and ARBs provide cardiovascular protection through:

1. Blood pressure reduction
2. Blockade of the renin-angiotensin-aldosterone system
3. Potential vascular protective effects beyond blood pressure control

Impact on Limb Outcomes

While the primary benefit of ACE inhibitors and ARBs in PAD is cardiovascular protection, the evidence for limb-specific benefits is less robust:

• Some research suggests ACE inhibitors may improve pain-free walking distance by approximately 86 meters in patients with claudication 2
• A study found that ACE inhibitors/ARBs were associated with improved limb salvage in critical limb ischemia patients undergoing infrapopliteal interventions 3
• However, these medications have not consistently demonstrated a significant reduction in major adverse limb events (MALE) in the broader PAD population

Blood Pressure Targets

The 2024 guideline recommends:

• A systolic blood pressure goal of <130 mm Hg
• A diastolic blood pressure target of <80 mm Hg 1

This is more aggressive than previous guidelines, which recommended <140/90 mmHg for non-diabetics and <130/80 mmHg for diabetics and those with chronic renal disease 1.

ACE Inhibitors vs. ARBs

When choosing between ACE inhibitors and ARBs:

• Both classes have similar efficacy for blood pressure control and cardiovascular outcomes 4, 5
• ARBs have fewer side effects, particularly cough, which is common with ACE inhibitors 4
• Some meta-analyses suggest ACE inhibitors may have a slight edge in mortality reduction compared to ARBs 6

Implementation in Clinical Practice

For patients with PAD and hypertension:

1. Start with an ACE inhibitor or ARB as first-line therapy
2. Target blood pressure <130/80 mmHg
3. Switch from ACE inhibitor to ARB if cough develops
4. Consider combination therapy with other antihypertensives if blood pressure targets are not achieved

Potential Pitfalls and Caveats

• Monitor renal function when initiating therapy, especially in patients with possible renal artery stenosis
• Be cautious about orthostatic hypotension, particularly in elderly patients
• Avoid combining ACE inhibitors with ARBs as this increases adverse effects without additional benefit
• Consider potential drug interactions with other medications commonly used in PAD patients

In conclusion, while ACE inhibitors and ARBs have proven cardiovascular benefits in PAD patients with hypertension, their impact on limb-specific outcomes is less well-established. Their first-line recommendation is primarily based on their ability to reduce MACE rather than MALE in this high-risk population.