Polyvascular Disease – An Opportunity for Personalized Medicine
Cardiovascular disease is a leading cause of death in the United States, with more than 900,000 deaths in 2016 and a substantial portion related to ischemic disease. As a result, much research has focused on stratification of patients most at risk for events. One particular subset of patients is those with polyvascular disease (PVD), or patients with disease in more than one vascular territory, typically coronary artery disease (CAD), peripheral arterial disease (PAD), or cerebrovascular disease (CVD). Prior studies have demonstrated an alarmingly high prevalence of PVD and have consistently demonstrated higher mortality and lower quality of life for these patients. Despite this, recent guidelines do not encourage routine screening for PVD. Here, we explore the historical and more recent literature describing PVD and newer evidence concerning the potential benefits of targeted screening and therapy.
Prevalence of PVD
Some of the earliest data on the prevalence of PVD comes from the REACH registry. Briefly, over 45,000 patients aged >45 years with either three or more risk factors for atherosclerosis or established CAD, PAD, or CVD, were longitudinally followed for 4 years, with the aim of categorizing risk of coronary events.1 In this group of stable outpatients, 1 in 6 patients enrolled in the study were found to have PVD. Subsequent studies have largely verified this prevalence of PVD in the population of patients with stable CAD.2-4 Among patients presenting with acute coronary syndrome (ACS), PVD was found in 13% of patients in the CRUSADE and ALLIANCE studies, and as high as 22% in the more recent AMERICA study. A final subpopulation with evidently the highest rates of PVD is patients initially presenting with PAD or another manifestation of peripheral vascular disease. Very recent studies, including the EUCLID trial, have noted that up to 43% of patients presenting with either carotid artery stenosis or PAD have PVD.5,6
Outcomes Associated with PVD
It has been well established in numerous studies that cardiovascular event rates are significantly higher among patients with PVD compared with those with single vascular bed disease or those with only risk factors for atherosclerotic disease. The REACH study, again the earliest of these studies, demonstrated a nearly three-fold cumulative increase of cardiovascular death, myocardial infarction (MI) or stroke in patients with PVD compared with patients with only risk factors for atherothrombosis.1 Demonstrated in Table 1, these findings were true for patients both with and without prior ischemic events.
More recent analyses of randomized trials geared towards secondary prevention in patients with CAD have shown higher rates of major adverse cardiac events (MACE), up to 50%, in patients with PVD, particularly PAD in addition to CAD.7,8 This pattern of increased cardiac event rates in patients with PVD has been further studied in other patient subpopulations. In patients with acute coronary syndrome, for instance, early studies showed not only worse in-hospital mortality for patients with PVD, but a worsening mortality for each additional vascular bed involved.2,9 The more recent IMPROVE-IT trial replicated these initial findings, with ACS patients with PVD at 7 years having greater primary cardiac endpoints compared with those without PVD.10 Surprisingly, even in asymptomatic populations screened for disease, PVD has been shown to be associated with higher mortality. In a recent study, Zhang et al. found asymptomatic patients found to have PVD via ankle-brachial index (ABI) and transcranial doppler screening had higher rates of MACE at 4 years.11
In different subpopulations, PVD has been associated with an even more diverse set of outcomes. Among patients with heart failure with preserved ejection fraction (HFpEF), those with PVD had higher rates of unstable angina and increased coronary revascularizations compared to those without it.12 In patients with chronic stable angina, patients with PVD report more episodes of angina and poorer quality of life measures.4 Finally, and perhaps most significantly, the recent EUCLID trial provided insight on screening patients presenting with symptomatic PAD. In this study of over 16,000 patients, the authors found that rates of lower extremity revascularizations increased with each additional vascular bed involved.6 Primary endpoints of cardiovascular death, MI or stroke were higher in patients with PVD, with the type of event reflecting the additional vascular bed involved (e.g. increased stroke risk in patients with PAD plus CVD). The presence of PVD in these populations seems significant in predicting interventions or exacerbations, suggesting an overall unique subtype of patients with high risks of morbidity and mortality.
A Role for Screening and Personalized Therapy – Medication Optimization and the Use of Newer Agents?
Given the prevalence of PVD and its well-established relationship to poorer outcomes in a variety of subpopulations, a recent question of interest is if there is a role for screening high-risk individuals for PVD and targeting therapies to this population. The AMERICA study sought to systematically answer this question by evaluating the benefit of screening and aggressive therapy for PVD in high risk coronary patients that either had three-vessel disease or recent ACS.13 At 2-year follow-up in the study, despite a prevalence of PVD of approximately 22%, there was no significant difference in time to death, organ failure or re-hospitalization between the pro-active screening and conservative, standard of care groups. Does this then confirm the lack of benefit of screening for PVD?
Medical Therapy Optimization
Perhaps that most significant criticism of the AMERICA study is that in both arms of the study, the prospective screening and conventional care arms were in large part optimized on medical therapy prior to randomization. Over 87% of patients in the screening arm were on DAPT, beta blockers, and statins prior to randomization. Not only does this diminish the impact of any further aggressive therapy, but as much prior literature suggests, this is in fact contrary to real-world treatment of the subset of patients with PVD. From earlier studies14 to more recent analyses,5 patients with PVD have been found to have higher rates of hyperlipidemia, hypertension, diabetes and current smoking. Moreover, these patients are less likely to receive guideline-directed medical therapy. The ALLIANCE study noted only 41% of patients presenting with ACS found to have PVD received the four guideline-recommended medications.15 Similarly, Brilakis et al. noted that ACS patients with PVD were less likely to receive smoking cessation counseling, ACE-inhibitors, or statins at discharge.. Notably, these medication classes, ACE-inhibitors and statins, are the two in the AMERICA study that paradoxically had higher rates of usage in the pro-active screening arm relative to the controls. Overall, patients with PVD in real-world practice seem to be undertreated despite their higher risk status. Screening for this subpopulation may then be beneficial as it would alert providers to the particular need to aggressive titrate guideline-directed medical therapy (GDMT) and address risk factor modification in this higher risk group.
Patient Populations with PVD
Another important point to note about the AMERICA study is that it was limited to patients with high risk coronary disease or ACS. As has already been noted, PVD has been shown to impact outcomes among a wide range of patient populations, from those with HFpEF12 to those with chronic stable angina.4 This is most striking in the population of those presenting with symptomatic PAD, where prevalence rates of PVD are among the highest described in the literature. PVD in these patients not only seems to be directly predictive of mortality outcomes but also independently predictive of need for lower extremity interventions.6 The benefits of screening for PVD has much room for study. Future research should focus on specific subpopulations to tease out the impact of PVD screening on outcomes for both quality of life and mortality.
The Role of Newer Therapies
Both newer therapies and more aggressive anticoagulation for patients with PVD have been shown to reduce the risk of coronary events associated with this patient population. In a recent prespecified analysis of the ODYSSEY trial involving approximately 19,000 patients with recent ACS and dyslipidemia while on maximal statin therapy, PVD was shown to be associated with higher levels of LDL and increasing MACE at X years, from 10% for one vascular bed involvement to 39.7% for three vascular bed involvement.16 More notable, the gradient of absolute risk reduction with treatment with alirocumab, a PCSK9 inhibitor that lowers lipid levels, paralleled this increase in MACE. In a similar analysis of the IMPROVE-IT trial,10 ezetimibe was shown to have the largest absolute risk reduction on MACE with those patients with PVD, largely due to the higher risk of this subgroup. A growing body of literature has demonstrated the absolute reductions in MACE that accompany more aggressive anti-thrombotic regimens for patients with PVD.7,8,17 The COMPASS trial,3 which indirectly included PVD patients by its inclusion criteria, showed the addition of rivaroxaban 2.5 mg twice daily to aspirin significantly reduced MACE, albeit with a heightened risk of bleeding events. PVD, then, may be an important marker used to personalize anticoagulation regimens to the patients most likely to suffer from thrombotic events.
PVD has been shown in numerous studies to have a markedly high prevalence in a variety of patient populations. Almost uniformly, such patients have been shown to higher mortality or lower quality of life. While the AMERICA study seemed to argue against the benefit of proactively screening for PVD, there remain significant opportunities for assessing the role of screening, particularly in patients presenting with symptomatic PAD. Optimizing medical therapy of such patients in the real world as well as using newer therapies, such as PCSK9 inhibitors, are ways in which therapy can be more personalized for this higher risk subgroup.
- 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.
- Bhatt DL, Peterson ED, Harrington RA, et al. Prior polyvascular disease: risk factor for adverse ischaemic outcomes in acute coronary syndromes. Eur Heart J 2009;30:1195–1202.
- Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319–30.
- Wilson WRW, Fitridge RA, Weekes AJ, Morgan C, Tavella R, Beltrame JF. Quality of life of patients with peripheral arterial disease and chronic stable angina. Angiology 2012;63:223–8.
- Vlajinac HD, Marinkovic JM, Maksimovic MZ, Radak DJ, Arsic RB, Jorga JB. The prevalence of polyvascular disease in patients with carotid artery disease and peripheral artery disease. Kardiol Pol 2019;77:926–34.
- Gutierrez JA, Mulder H, Schuyler Jones W, et al. Polyvascular disease and risk of major adverse cardiovascular events in peripheral artery disease: a secondary analysis of the EUCLID Trial. JAMA Netw Open 2018;1:e185239.
- 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.
- 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.
- Brilakis ES, Hernandez AF, Dai D, et al. Quality of care for acute coronary syndrome patients with known atherosclerotic disease. Circulation 2009;120:560-7.
- Bonaca MP, Antonio Gutierrez J, Cannon C, et al. Polyvascular disease, type 2 diabetes, and long-term vascular risk: a secondary analysis of the IMPROVE-IT trial. Lancet Diabetes Endocrinol 2018;6:934–43.
- Zhang Q, Wang A, Zhang S, et al. Asymptomatic polyvascular disease and the risks of cardiovascular events and all-cause death. Atherosclerosis 2017;262;1–7.
- Fujisue K, Tokitsu T, Yamamoto E, et al. Prognostic significance of polyvascular disease in heart failure with preserved left ventricular ejection fraction. Medicine 2019;98:e15959.
- Collet JP, Cayla G, Ennezat PV, et al. Systematic detection of polyvascular disease combined with aggressive secondary prevention in patients presenting with severe coronary artery disease: the randomized AMERICA Study. Int J Cardiol 2018;254:36–42.
- Suárez C, Zeymer U, Limbourg T, et al. Influence of polyvascular disease on cardiovascular event rates. Insights from the REACH Registry. Vasc Med 2010;15;259–65.
- Meizels A, Messika Zeitoun D, Bataille V, et al. Impact of polyvascular disease on baseline characteristics, management and mortality in acute myocardial infarction. The Alliance project. Arch Cardiovasc Dis 2010;103:207–14.
- Wouter Jukema J, Szarek M, Zijlstra LE, et al. Alirocumab in patients with polyvascular disease and recent acute coronary syndrome: ODYSSEY OUTCOMES Trial. J Am Coll Cardiol 2019;74:1167–76.
- Bonaca MP. Polyvascular disease and risk: when two is not better than one. Vasc Med 2018;23:531–53.
Clinical Topics: Acute Coronary Syndromes, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Stable Ischemic Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure, Chronic Angina
Keywords: Aneurysm, Ankle Brachial Index, Angina, Stable, Acute Coronary Syndrome, Prevalence, Hospital Mortality, Coronary Artery Disease, Heart Failure, Secondary Prevention, Peripheral Arterial Disease, Carotid Stenosis, Risk Factors, Cardiovascular Diseases, Outpatients, Cause of Death, Quality of Life, Hyperlipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Angiotensin-Converting Enzyme Inhibitors, Platelet Aggregation Inhibitors, Proprotein Convertase 9, Proprotein Convertase 9, PCSK9 protein, human, Numbers Needed To Treat, Smoking Cessation, Aspirin
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