Current Evidence and Clinical Approaches

Peripheral artery disease (PAD) represents a significant global health burden, affecting >200 million individuals worldwide.¹ Characterized by atherosclerosis and thrombosis in lower limb arteries, PAD affects approximately 6% of adults and leads to substantial morbidity, including exertional leg pain, reduced mobility, tissue damage, and impaired quality of life.² More critically, PAD confers a markedly increased risk of major adverse cardiovascular events (MACE), including myocardial infarction (MI), stroke, cardiovascular (CV) mortality, and limb-related complications such as critical limb ischemia and amputation.²

Hypertension (HTN) emerges as the most prevalent and modifiable CV risk factor in this population, present in 35-55% of patients at the time of PAD diagnosis.^1,3 This frequent coexistence is clinically significant, as HTN not only accelerates PAD progression but also correlates with a progressive decline in ankle-brachial index (ABI), particularly among adults >65 years of age. Epidemiological data consistently demonstrate that the concurrent presence of HTN and PAD leads to worse clinical outcomes, highlighting the importance of optimal blood pressure (BP) management in this high-risk population.³ Current guidelines recommend a target BP <130/80 mm Hg for most patients with PAD, aiming to reduce CV risk while maintaining adequate peripheral perfusion.¹

Evolution of Blood Pressure Management Paradigms

Early clinical concerns suggested that aggressive BP reduction might compromise limb perfusion in patients with established arterial stenosis, potentially exacerbating ischemic symptoms.¹ However, contemporary evidence from large-scale randomized controlled trials (RCTs) has largely alleviated these concerns. The results of the INVEST (International Verapamil-Trandolapril Study), which included 2,699 participants with PAD, revealed a J-curve relationship between systolic blood pressure (SBP) and CV outcomes, emphasizing the need for balanced rather than excessive BP reduction.⁴

Further insights come from the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial data, which demonstrated that, although SBP reductions <125 mm Hg were associated with increased MACE risk (hazard ratio, 1.19; 95% confidence interval, 1.09-1.31), they showed no significant effect on limb-related complications.⁵

Pharmacotherapeutic Strategies

The selection of antihypertensive agents in PAD requires careful consideration of both vascular protection and metabolic effects. Renin-angiotensin system (RAS) inhibitors, including angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), have emerged as cornerstone therapies on the basis of robust RCT evidence. The HOPE (Heart Outcomes Prevention Evaluation) trial results demonstrated that ramipril significantly reduced CV death, MI, and stroke in a cohort in which 43% of participants had PAD. These benefits extended even to patients with normotension, suggesting vascular protective effects beyond BP reduction.

Subsequent findings from the ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) reinforced these observations, showing that the ARB telmisartan was noninferior to ramipril in preventing CV events among 3,468 participants with PAD.⁶ This evidence has led current guidelines, including the 2024 multisociety Guideline for the Management of Lower Extremity PAD, to recommend ACE inhibitors or ARBs for MACE reduction in patients with PAD regardless of HTN status.¹ These benefits are underpinned by direct vascular effects. RAS inhibitors improve endothelial function, reduce vascular inflammation, and inhibit the progression of atherosclerosis within the peripheral arterial bed. These pleiotropic effects contribute to stabilizing plaque and improving overall vascular health in patients with PAD, which is complementary to systemic BP control.⁷

Calcium channel blockers (CCBs), particularly dihydropyridine agents, represent another valuable option.⁶ These agents are particularly advantageous in patients with concomitant carotid artery atherosclerosis, for whom their vasodilatory properties may offer additional benefits.⁶ Beta-blockers (BBs) remain safe; although they have not demonstrated specific benefit for limb-related outcomes, they remain foundational in coronary artery disease (CAD) and heart failure (HF). Consequently, it is advisable to administer BBs to patients with PAD who also present with HF and CAD.⁶ The ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) results further established the role of thiazide diuretics, demonstrating that chlorthalidone was noninferior to amlodipine and lisinopril in patients with HTN at high risk, including those with PAD.⁶

Special Considerations in Comorbid Populations

The management of HTN in PAD becomes particularly nuanced in the presence of diabetes mellitus (DM), which coexists in approximately 30% of cases.³ This metabolic comorbidity necessitates careful drug selection, as certain antihypertensive classes may adversely affect glucose metabolism. Diuretics and BBs, although effective for BP control, may worsen insulin resistance and are generally avoided as first-line agents in patients with PAD and DM.³ Instead, ACE inhibitors or ARBs are preferred due to their neutral or potentially beneficial metabolic effects, with CCBs serving as suitable alternatives in cases of ACE inhibitor intolerance or hyperkalemia.³

The ABCD (Appropriate Blood Pressure Control in Diabetes) trial results provided important insights into this population, showing that intensive BP control (targeting a 10 mm Hg diastolic reduction) with enalapril or nisoldipine significantly reduced CV events compared with moderate control in patients with PAD and DM (ABI <0.9).⁸ These findings underscore the importance of tailored BP targets in high-risk subgroups.

Lifestyle Modifications and Emerging Adjuncts

Beyond pharmacotherapy, comprehensive PAD management must incorporate lifestyle interventions. The DAPHNE (Doxazosin Atherosclerosis Progression study in Hyper-tensives in the Netherlands) trial results demonstrated that antihypertensive therapy combined with lifestyle modifications could yield structural vascular benefits.³ This 3-year RCT showed significant reductions in carotid and femoral artery intima-media thickness with both doxazosin and hydrochlorothiazide, suggesting that BP control itself may help reverse peripheral atherosclerosis.³

Supervised exercise programs, smoking cessation, and Mediterranean-style diets have all shown benefits in improving functional capacity and CV outcomes in patients with PAD.^1,3 Emerging research also explores potential adjunctive roles for nutraceuticals such as inorganic nitrates (found in beetroot juice) and mitochondrial antioxidants (present in dark chocolate), which may improve endothelial function and walking distance, although these require further investigation before routine clinical adoption.⁹

Conclusion

The management of HTN in PAD represents a critical opportunity to reduce both CV- and limb-related morbidity. Current evidence supports the use of RAS inhibitors as first-line agents, with CCBs and thiazides as valuable alternatives.^1,6 BP targets should be individualized, particularly in older adults and those with DM, to balance CV protection with maintenance of adequate perfusion.^1,3 As the understanding of PAD pathophysiology evolves, integrated approaches combining optimal pharmacotherapy, lifestyle modification, and careful risk factor management will continue to shape best practices in this high-risk population.^1,2,9

References

1. Writing Committee Members, Gornik HL, Aronow HD, et al. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS guideline for the management of lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2024;83(24):2497-2604. doi:10.1016/j.jacc.2024.02.013
2. Golledge J. Update on the pathophysiology and medical treatment of peripheral artery disease. Nat Rev Cardiol. 2022;19(7):456-474. doi:10.1038/s41569-021-00663-9
3. Abraham AT, Mojaddedi S, Loseke IH, Bray C. Hypertension in patients with peripheral artery disease: an updated literature review. Cureus. 2024;16(6):e62246. Published 2024 Jun 12. doi:10.7759/cureus.62246
4. Pastori D, Farcomeni A, Milanese A, et al. Statins and major adverse limb events in patients with peripheral artery disease: a systematic review and meta-analysis. Thromb Haemost. 2020;120(5):866-875. doi:10.1055/s-0040-1709711
5. Fudim M, Hopley CW, Huang Z, et al. Association of hypertension and arterial blood pressure on limb and cardiovascular outcomes in symptomatic peripheral artery disease: the EUCLID trial. Circ Cardiovasc Qual Outcomes. 2020;13(9):e006512. doi:10.1161/CIRCOUTCOMES.120.006512
6. Bevan GH, White Solaru KT. Evidence-based medical management of peripheral artery disease. Arterioscler Thromb Vasc Biol. 2020;40(3):541-553. doi:10.1161/ATVBAHA.119.312142
7. Khan SZ, O'Brien-Irr MS, Rivero M, et al. Improved survival with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in chronic limb-threatening ischemia. J Vasc Surg. 2020;72(6):2130-2138. doi:10.1016/j.jvs.2020.02.041
8. Yang Q, Zheng R, Wang S, et al. Systolic blood pressure control targets to prevent major cardiovascular events and death in patients with type 2 diabetes: a systematic review and network meta-analysis. Hypertension. 2023;80(8):1640-1653. doi:10.1161/HYPERTENSIONAHA.123.20954
9. Rossman MJ, Gioscia-Ryan RA, Santos-Parker JR, et al. Inorganic nitrite supplementation improves endothelial function with aging: translational evidence for suppression of mitochondria-derived oxidative stress. Hypertension. 2021;77(4):1212-1222. doi:10.1161/HYPERTENSIONAHA.120.16175