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Percutaneous coronary intervention with peripheral artery disease in the contemporary era: Still life or limb?

      Keywords

      In an elegant patient-level pooled analysis from the TWENTE trials, von Clemens and colleagues examined the outcomes of CAD patients receiving PCI with and without PAD using contemporary second-generation drug-eluting stents with clinical trial data largely adjudicated for outcomes and core laboratory analysis of symptomatic PAD [
      • Pinxterhuis T.H.
      • Ploumen E.H.
      • Zocca P.
      • Doggen C.J.M.
      • Schotborgh C.E.
      • Anthonio R.L.
      • et al.
      Outcome after Percutaneous Coronary Intervention with Contemporary Stents in Patients with Concomitant Peripheral Arterial Disease: A Patient-Level Pooled Analysis of Four Randomized Trials.
      ]. The authors report a 7.6% incidence of symptomatic PAD in their study cohort who are at heightened risk compared to PCI patients without PAD. Their analysis is robust and demonstrates PAD as an independent risk for target vessel failure (primary endpoint). Moreover, PAD is associated with an increased risk of target vessel revascularization, death and major adverse cardiovascular events (MACE).
      With the beginnings of a fatty streak, atherosclerotic plaque commonly ensues within the arterial vasculature resulting in heart attacks, strokes and peripheral arterial disease (PAD) [
      • Stary H.C.
      • Chandler A.B.
      • Glagov S.
      • Guyton J.R.
      • Insull W.
      • Rosenfeld M.E.
      • et al.
      A Definition of Initial, Fatty Streak, and Intermediate Lesions of Atherosclerosis. A Report from the Committee on Vascular Lesions of the Council on Arteriosclerosis.
      ]. Despite the recent advancements in pharmacologic management [
      • Sunner S.S.
      • Welsh R.C.
      • Bainey K.R.
      Medical management of peripheral arterial disease: deciphering the intricacies of therapeutic options.
      ], atherosclerosis continues to predominate and remains a burden on healthcare costs [
      • Smolderen K.G.
      • Wang K.
      • De Pouvourville G.
      • Brüggenjürgen B.
      • Röther J.
      • Zeymer U.
      • et al.
      Two-year vascular hospitalisation rates and associated costs in patients at risk of atherothrombosis in France and Germany: highest burden for peripheral arterial disease.
      ,
      • Smolderen K.G.
      • Bell A.
      • Lei Y.
      • Cohen E.A.
      • Steg P.G.
      • Bhatt D.L.
      • et al.
      One-year costs associated with cardiovascular disease in Canada: insights from the REduction of Atherothrombosis for Continued Health (REACH) registry.
      ]. Its pathogenesis starts with impaired lipid metabolism, followed by chronic inflammatory immunomodulation resulting in endothelial dysfunction, impaired smooth muscle response, macrophage cell infiltration, and oxidative stress mediation [
      • Stary H.C.
      • Chandler A.B.
      • Glagov S.
      • Guyton J.R.
      • Insull W.
      • Rosenfeld M.E.
      • et al.
      A Definition of Initial, Fatty Streak, and Intermediate Lesions of Atherosclerosis. A Report from the Committee on Vascular Lesions of the Council on Arteriosclerosis.
      ]. Interaction of genetic, epigenetic, and environmental factors are responsible for the development of atherosclerosis, whose signs are visible early in life leading to vascular injury and altering vascular biology as a chronic systemic disease. As such, atherosclerosis commonly involves more than one vascular bed. Observational data suggest that 15.6% of patients in Canada, 18.2% in France and 27.4% in Germany have established atherosclerotic disease in more than one vascular territory [
      • Smolderen K.G.
      • Wang K.
      • De Pouvourville G.
      • Brüggenjürgen B.
      • Röther J.
      • Zeymer U.
      • et al.
      Two-year vascular hospitalisation rates and associated costs in patients at risk of atherothrombosis in France and Germany: highest burden for peripheral arterial disease.
      ,
      • Smolderen K.G.
      • Bell A.
      • Lei Y.
      • Cohen E.A.
      • Steg P.G.
      • Bhatt D.L.
      • et al.
      One-year costs associated with cardiovascular disease in Canada: insights from the REduction of Atherothrombosis for Continued Health (REACH) registry.
      ]. Moreover, one-third of patients with coronary artery disease (CAD) also have PAD and one-half of patients with PAD have concomitant CAD [
      • Sunner S.S.
      • Welsh R.C.
      • Bainey K.R.
      Medical management of peripheral arterial disease: deciphering the intricacies of therapeutic options.
      ].
      Recognizing the substantial overlap in vascular territory, CAD patients with polyvascular disease have worse clinical outcomes with heightened risk of recurrent cardiovascular (CV) events and earlier mortality [
      • Sunner S.S.
      • Welsh R.C.
      • Bainey K.R.
      Medical management of peripheral arterial disease: deciphering the intricacies of therapeutic options.
      ]. With advancements in second -generation drug eluting stents and more potent antithrombotic therapy, the incidence of stent failure, myocardial infarction and cardiovascular mortality has decreased in CAD patients receiving percutaneous coronary intervention (PCI) [
      • Giacoppo D.
      • Matsuda Y.
      • Fovino L.N.
      • D'Amico G.
      • Gargiulo G.
      • Byrne R.A.
      • et al.
      Short dual antiplatelet therapy followed by P2Y12 inhibitor monotherapy vs. prolonged dual antiplatelet therapy after percutaneous coronary intervention with second-generation drug-eluting stents: a systematic review and meta-analysis of randomized clinical trials.
      ]. Whether this improves clinical outcomes in patients with concomitant PAD remains largely unknown.
      It should be recognized that the investigators captured patients with symptoms of PAD – this cohort would be larger if PAD patients without symptoms were included, albeit adding to the heterogeneity of the comparator population. We suspect the long-term outcomes may be worse in those with PAD irrespective of symptoms. While their primary endpoint of target vessel failure (TVF) was worse in those with PAD, it is still striking that even those without PAD have a 1/10 risk of TVF at 3 years. While the authors consider these events low in the current era with second-generation DES and potent dual antiplatelet therapy (DAPT), one must remember this is a clinical trial population expected to have lower event rates compared to ‘real-world’ clinical practice. The incremental risk in patients with PAD is clinically concerning, even with advancements in PCI technique and pharmacotherapy. We agree with the authors' opinion that patients requiring PCI with simultaneous PAD, have more advanced stages of atherosclerosis. The increased global vascular burden undoubtedly will lead to adverse events [
      • Sunner S.S.
      • Welsh R.C.
      • Bainey K.R.
      Medical management of peripheral arterial disease: deciphering the intricacies of therapeutic options.
      ]. Hence, the presence of PAD in the setting of PCI should prompt the treating clinician to be vigilant with secondary preventative therapies in order to mitigate clinical events and improve overall survival. Both patients and clinicians should be aware of this increased risk and incorporate this factor in their decision-making process before performing non-urgent procedures.
      Accordingly, we believe it is prudent to reflect on current pharmacotherapy, which may (or may not) benefit patients with polyvascular disease. The role of risk reduction by cholesterol lowering therapies in polyvascular management has been definitively proven in multiple studies. In the Heart Protection Study, cardiovascular event rates including first major event, stroke, repeat revascularization in patients with or without known PAD were considerably lower in the statin group [
      Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions.
      ], suggesting reduced cholesterol with statin-based regimes provide benefit for CAD and PAD patients. Reducing LDL cholesterol beyond guideline-recommended targets with PCSK9 inhibition, as shown in the PAD subgroup of the FOURIER trial, reduced the risk of MACE [
      • Bonaca M.P.
      • Nault P.
      • Giugliano R.P.
      • Keech A.C.
      • Pineda A.L.
      • Kanevsky E.
      • et al.
      Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk).
      ]. Interestingly, in the PAD subgroup of the ODESSEY Outcomes trial, alirocumab did not reduce MACE in PAD patients with a recent acute coronary syndrome (ACS) [
      • Jukema J.W.
      • Szarek M.
      • Zijlstra L.E.
      • de Silva H.A.
      • Bhatt D.L.
      • Bittner V.A.
      • et al.
      Alirocumab in patients with polyvascular disease and recent acute coronary syndrome: ODYSSEY OUTCOMES trial.
      ]. The use of SGLT-2 inhibitors has been controversial with diabetes and PAD, however the PAD analysis from the EMPA-REG trial found empagliflozin improved survival in PAD patients with a trend towards decreased MACE [
      • Verma S.
      • Mazer C.D.
      • Al-Omran M.
      • Inzucchi S.E.
      • Fitchett D.
      • Hehnke U.
      • et al.
      Cardiovascular outcomes and safety of empagliflozin in patients with type 2 diabetes mellitus and peripheral artery disease: a subanalysis of EMPA-REG outcome.
      ]. The CANVAS trial found an increased risk of amputation with the use of canagliflozin despite a reduction in MACE in diabetics with or without CAD [
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • de Zeeuw D.
      • Fulcher G.
      • Erondu N.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ]. The PAD subgroup from the DECLARE TIMI 58 trial found no risk of amputation with dapagliflozin but no MACE benefit [
      • Bonaca M.P.
      • Wiviott S.D.
      • Zelniker T.A.
      • Mosenzon O.
      • Bhatt D.L.
      • Leiter L.A.
      • et al.
      Dapagliflozin and cardiac, kidney, and limb outcomes in patients with and without peripheral artery disease in DECLARE-TIMI 58.
      ]. As for the GLP-1 receptor agonists, the PAD subgroup from the HARMONY Outcomes trial found no significant reduction in MACE with albiglutide [
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • D'Agostino R.B.
      • Granger C.B.
      • Jones N.P.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      ]. Similarly the PAD subgroup from the EXCEL trial found no reduction in clinical events with exenatide [
      • Badjatiya A.
      • Merrill P.
      • Buse J.B.
      • Goodman S.G.
      • Katona B.
      • Iqbal N.
      • et al.
      Clinical outcomes in patients with type 2 diabetes mellitus and peripheral artery disease: results from the EXSCEL trial.
      ]. In a combined analysis from the LEADER and SUSTAIN-6 trials, both liraglutide and semaglutide reduced MACE with consistent CV efficacy irrespective of PAD [
      • Verma S.
      • Al‐Omran M.
      • Leiter L.A.
      • Mazer C.D.
      • Rasmussen S.
      • Saevereid H.A.
      • et al.
      Cardiovascular efficacy of liraglutide and semaglutide in individuals with diabetes and peripheral artery disease.
      ]. As for the role of DAPT, in a subgroup analysis of 3096 PAD patients from the CHARISMA trial, no difference in MACE was noted with clopidogrel-based DAPT but rates of MI and CV hospitalization rates were lowered [
      • Cacoub P.P.
      • Bhatt D.L.
      • Steg P.G.
      • Topol E.J.
      • Creager M.A.
      Patients with peripheral arterial disease in the CHARISMA trial.
      ]. In an analysis of PEGASUS-TIMI 54 PAD patients, MACE was reduced with ticagrelor-based DAPT with a 35% reduction in major adverse limb events (MALE) [
      • Bonaca M.P.
      • Bhatt D.L.
      • Storey R.F.
      • Steg P.G.
      • Cohen M.
      • Kuder J.
      • et al.
      Ticagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease.
      ]. While DAPT should be considered in these patients, the most compelling data for antithrombotic management in stable CAD and PAD comes from the COMPASS trial. In over 27,000 participants with stable CAD and/or PAD, the combination of low dose rivaroxaban (2.5mg twice daily) and low-dose aspirin significantly reduced MACE and mortality alone compared to aspirin [
      • Eikelboom J.W.
      • Connolly S.J.
      • Bosch J.
      • Dagenais G.R.
      • Hart R.G.
      • Shestakovska O.
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      ]. These results were even more pronounced in those with prior PCI [
      • Bainey K.R.
      • Welsh R.C.
      • Connolly S.J.
      • Marsden T.
      • Bosch J.
      • Fox K.A.A.
      • et al.
      Rivaroxaban plus aspirin versus aspirin alone in patients with prior percutaneous coronary intervention (COMPASS-PCI).
      ]. In a prespecified analysis of over 5000 PAD participants, dual pathway inhibition lowered MACE and showed a near 50% reduction in MALE, without any difference in fatal, intracranial hemorrhage or critical organ bleeding events [
      • Anand S.S.
      • Bosch J.
      • Eikelboom J.W.
      • Connolly S.J.
      • Diaz R.
      • Widimsky P.
      • et al.
      Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial.
      ]. The recent VOYAGER PAD trial evaluating over 6500 patients with PAD and recent limb revascularization found that low-dose rivaroxaban and aspirin compared to aspirin alone reduced the composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes without increasing bleeding risk [
      • Bonaca M.P.
      • Bauersachs R.M.
      • Anand S.S.
      • Debus E.S.
      • Nehler M.R.
      • Patel M.R.
      • et al.
      Rivaroxaban in peripheral artery disease after revascularization.
      ]. Given the results of COMPASS and VOYAGER PAD, we believe low-doses of rivaroxaban and aspirin should be the default antithrombotic choice for patients with chronic CAD and PAD.
      PAD constitutes an independent risk for adverse outcome in patients undergoing PCI. Further studies are needed to ascertain which therapies may mitigate this risk. With the advances in recent pharmacotherapy for CAD and PAD, we provide detailed recommendations (Fig. 1) congruent with recent clinical trials, which we believe will help in reducing residual risk in these complex polyvascular patients.
      Fig. 1
      Fig. 1Chronic pharmacologic management of CAD and PAD based on contemporary studies.

      Declaration of competing interests

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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