Introduction

It is not uncommon to encounter patients with acute coronary syndromes and coronary artery disease (CAD) who have preexisting peripheral arterial disease (PAD). Data from the AGATHA (A Global Atherothrombosis Assessment) registry reported that one in three patients with CAD had coexistent cerebrovascular disease and one in five had coexistent PAD.¹ The known risk factors for the development of atherosclerosis (ageing, diabetes, smoking, hypertension, obesity, and dyslipidemia) affect disease progression in all of these vascular beds. Atherosclerosis of multiple vascular beds portends worse intermediate and long-term prognoses.^2,3 For example, 4-year data from the REACH (Reduction of Atherothrombosis for Continued Health) registry reported higher mortality in patients with polyvascular atherosclerotic disease versus disease of a single vascular bed (15.4 vs. 10.3% in stable atherosclerosis and 17.7 vs. 12.1% in patients with at least one prior ischemic event).³ In patients with acute coronary syndromes, presence of PAD at baseline is associated with higher in-hospital (7.2 vs. 4.5%) and 6-month mortality (8.8 vs. 3.9%).⁴ The association of underlying polyvascular disease with worse outcomes after acute coronary events has been shown to persist out to 3 years, partially due to lower rates of appropriate coronary revascularization in this population.^5,6

Clinical Trials

Antiplatelet therapy has been shown to reduce major adverse cardiovascular events (MACE) in patients with PAD.⁷ In patients who experienced a recent ischemic event (ischemic stroke, myocardial infarction [MI], or symptomatic PAD), the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial established the slight benefit of long-term clopidogrel over aspirin in reducing the composite of ischemic stroke, MI, or death.⁸ A sub-study of the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, which included patients with prior MI, prior ischemic stroke, or symptomatic PAD, reported a 1.5% absolute risk reduction in the composite of MI, cardiovascular death, and stroke over a 27-month follow-up in patients treated with aspirin and clopidogrel versus aspirin alone.⁹ However, longer duration dual antiplatelet therapy (DAPT) was associated with increased risk of bleeding.¹⁰

Balancing the risks and benefits and duration of DAPT after percutaneous coronary intervention (PCI) is an ongoing debate in the cardiology community. The DAPT Study (The Dual Antiplatelet Therapy Study) and the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) trial evaluated the use of prolonged DAPT (30 months in DAPT and 33 months in PEGASUS-TIMI 54) in patients receiving drug-eluting coronary stents. Both studies showed a reduction in ischemic events but at the cost of increased bleeding.^11,12 Of note, patients with recent bleeding, prior cerebrovascular event, or on oral anticoagulant therapy were excluded from the PEGASUS-TIMI 54 trial.¹² In a post hoc analysis of the PEGASUS-TIMI 54 trial, patients with PAD in the placebo arm had higher rates of MACE (19.3% with PAD vs. 8.4% without PAD). Patients with PAD treated with a prolonged duration of ticagrelor had an absolute risk reduction of MACE by 4.1% (number needed to treat = 25).¹³ A recent meta-analysis of more than 33,000 patients from 6 trials of patients with concomitant MI and PAD reported reduced MACE (6.4 vs. 7.5%; risk ratio 0.78) and cardiovascular death (2.3 vs. 2.6%; risk ratio 0.85) with prolonged DAPT (mean duration of treatment 31 months).¹⁴ These data demonstrate that patients with the highest ischemic burden (involving multiple vascular beds) derive the most benefit from prolonged DAPT.

Recently, Franzone et al. published a subgroup analysis of PRODIGY (Prolonging Dual-Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study).¹⁵ The authors assessed the ischemic and bleeding events in patients with PAD undergoing PCI and the efficacy and safety of 24-month DAPT versus shorter duration DAPT (≤6 months). The primary outcomes reported in the study were two-fold:

1. A composite efficacy endpoint of MI, death, or a cerebrovascular accident at a follow-up of 2 years
2. A composite safety endpoint of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding.

Net adverse clinical events combining both the primary efficacy and safety endpoints were also reported. Out of the PRODIGY population of 1,970 patients, 246 patients had a history of PAD, 118 were randomized to the prolonged DAPT arm, and 128 were randomized to the shorter DAPT arm.

Patients with PAD were older and more likely to have diabetes mellitus, hypertension, prior MI, and prior coronary artery bypass graft surgery compared with patients without PAD. They were also more likely to present with non-ST-elevation MI and have multivessel disease. In the PAD subgroup, those assigned to prolonged DAPT were younger (73.2 vs. 75.5, p = 0.03) and had higher body mass index (27.5 vs. 26.3, p = 0.04) when compared with those assigned to shorter DAPT duration. At 2-year follow-up, patients with PAD were 75% more likely to suffer a primary event (composite of death, MI, and cerebrovascular accidents) compared with patients without PAD (21.9 vs. 8.4%; adjusted hazard ratio [HR] 1.75; 95% confidence interval [CI], 1.26-2.44; p = 0.001). Patients with PAD also had higher mortality (15.8 vs. 5.3%; adjusted HR 1.87; 95% CI, 1.25-2.79; p = 0.002). However, safety endpoint of BARC type 2, 3, or 5 bleeding was similar in patients with and without PAD (6.0 vs. 5.5%, respectively).

In patients with PAD, prolonged DAPT was associated with lower primary events of a composite of death, MI, and cerebrovascular accidents (HR 0.54; 95% CI, 0.31-0.95; p = 0.03) and lower stent thrombosis (HR 0.07; 95% CI, 0-1.21; p = 0.01). Interestingly, BARC type 2, 3, or 5 bleeding was not increased with prolonged DAPT in this population (5.2% in the prolonged DAPT PAD group vs. 6.9% in the shorter DAPT PAD group). The authors offer a few explanations for this unusual result: smaller sample size and inadequate power, assessment of bleeding events 30 days after PCI, and a higher mortality in the PAD group. The PAD subgroup was also not a pre-specified analysis. Despite these limitations, this study provides important data to guide post-PCI care for the ever-growing population of patients with PAD.

Conclusion

When considered in totality, this study and prior data are reassuring and help guide antiplatelet therapy in patients who are at a higher ischemic burden (i.e., patients with atherosclerosis of multiple vascular beds). Overall ischemic burden (polyvascular atherosclerosis), clinical risk factors for disease progression, DAPT tolerance in the first year, and bleeding risk affect the risk-benefit ratio of prolonged DAPT in patients with MI and PAD.¹⁶ All patients at high ischemic burden should be individually evaluated for the risks and benefits of prolonged DAPT. Given the data available, it is our opinion that prolonged (>12 month) DAPT after PCI should be strongly considered in patients with PAD in the absence of excessive bleeding risk.

References

1. Fowkes FG, Low LP, Tuta S, Kozak J. Ankle-brachial index and extent of atherothrombosis in 8891 patients with or at risk of vascular disease: results of the international AGATHA study. Eur Heart J 2006;27:1861-7.
2. Steg PG, Bhatt DL, Wilson PW, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297:1197-206.
3. Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010;304:1350-7.
4. Mukherjee D, Eagle KA, Kline-Rogers E, et al. Impact of prior peripheral arterial disease and stroke on outcomes of acute coronary syndromes and effect of evidence-based therapies (from the Global Registry of Acute Coronary Events). Am J Cardiol 2007;100:1-6.
5. Subherwal S, Bhatt DL, Li S, et al. Polyvascular disease and long-term cardiovascular outcomes in older patients with non-ST-segment-elevation myocardial infarction. Circ Cardiovasc Qual Outcomes 2012;5:541-9.
6. Cotter G, Cannon CP, McCabe CH, et al. Prior peripheral arterial disease and cerebrovascular disease are independent predictors of adverse outcome in patients with acute coronary syndromes: are we doing enough? Results from the Orbofiban in Patients with Unstable Coronary Syndromes-Thrombolysis In Myocardial Infarction (OPUS-TIMI) 16 study. Am Heart J 2003;145:622-7.
7. Kullo IJ, Rooke TW. CLINICAL PRACTICE. Peripheral Artery Disease. N Engl J Med 2016; 374:861-71.
8. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39.
9. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49:1982-8.
10. Berger PB, Bhatt DL, Fuster V, et al. Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease: results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Circulation 2010;121:2575-83.
11. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66.
12. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791-800.
13. Bonaca MP, Bhatt DL, Storey RF, et al. Ticagrelor for Prevention of Ischemic Events After Myocardial Infarction in Patients With Peripheral Artery Disease. J Am Coll Cardiol 2016;67:2719-28.
14. Udell JA, Bonaca MP, Collet J, et al. Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur Heart J 2016;37:390-9.
15. Franzone A, Piccolo R, Gargiulo G, et al. Prolonged vs Short Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With or Without Peripheral Arterial Disease: A Subgroup Analysis of the PRODIGY Randomized Clinical Trial. JAMA Cardiol 2016;1:795-803.
16. Bonaca MP, Sabatine MS. Antiplatelet Therapy for Long-term Secondary Prevention After Myocardial Infarction. JAMA Cardiol 2016;1:627-8.

Keywords: Acute Coronary Syndrome, Adenosine, Anticoagulants, Body Mass Index, Cerebrovascular Disorders, Coronary Artery Bypass, Coronary Artery Disease, Diabetes Mellitus, Dyslipidemias, Hyperplasia, Hypertension, Myocardial Infarction, Percutaneous Coronary Intervention, Peripheral Arterial Disease, Registries, Risk Assessment, Risk Factors, Smoking, Stents, Stroke, Thrombosis, Ticlopidine, Angina, Stable

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