Summary and Conclusions: Patients with stable atherosclerotic disease derive benefit from secondary prevention with antiplatelet drugs. In this setting, clopidogrel is superior to aspirin. After an ACS event or percutaneous coronary intervention, DAPT with aspirin and a P2Y12 receptor antagonist is the preferred regimen. In many ACS patients at high risk for recurrent cardiovascular events and at low bleeding risk, extending DAPT beyond 12 months may be advantageous. The COMPASS trial has challenged the traditional antiplatelet-only paradigm by demonstrating a considerable ischemic benefit and, importantly, lower rates of cardiovascular mortality and all-cause mortality with very low–dose anticoagulation added to aspirin in patients with stable CAD or PAD. Still, as with any antithrombotic regimen, its use in clinical practice will require careful balancing of the risk of ischemia versus bleeding. Further analyses from the COMPASS trial are likely to identify individuals who will benefit the most from this new therapeutic approach.
Dr. Manan Pareek discloses the following relationships. Advisory Board: AstraZeneca; Other Relationships: AstraZeneca and Medscape. Dr. Deepak L. Bhatt discloses the following relationships. Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute), Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; clinical trial steering committee), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (including for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, PLx Pharma, Takeda.
1. Benjamin EJ, Blaha MJ, Chiuve SE, et alHeart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation. 2017;135:e146–e603.
2. Selvin E, Erlinger TPPrevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation. 2004;110:738–743.
3. GBD 2016 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990 2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1260–344.
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7. Lewis HD Jr, Davis JW, Archibald DG, et alProtective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1983;309:396–403.
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9. Baigent C, Blackwell L, Collins R, et alAntithrombotic Trialists Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373:1849–1860.
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13. Bhatt DL, Marso SP, Hirsch AT, et alAmplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol. 2002;90:625–628.
14. Hiatt WR, Fowkes FG, Heizer G, et alTicagrelor versus clopidogrel in symptomatic peripheral artery disease. N Engl J Med. 2017;376:32–40.
15. Jones WS, Baumgartner I, Hiatt WR, et alTicagrelor compared with clopidogrel in patients with prior lower extremity revascularization for peripheral artery disease. Circulation. 2017;135:241–250.
16. Yusuf S, Zhao F, Mehta SR, et alEffects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502.
17. Mehta SR, Yusuf S, Peters RJ, et alEffects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527–533.
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Improving the Treatment of Peripheral Artery Disease: Providing Individualized, Innovative, and Efficient Care
Manesh R. Patel, MD, Division of Cardiology, Duke University Medical Center, Durham, NC
Introduction: Atherosclerotic peripheral artery disease (PAD) affects more than 200 million adults worldwide1 and an estimated 8 million people in the United States. The prevalence of PAD in patients over 70 or 55 years of age with diabetes is estimated near 30% from the Partners study (Fig. 1).2 Lower extremity PAD is considered a manifestation of systemic atherosclerosis that affects the arteries of the lower limbs. Despite recent advances in diagnosis and treatment, 5%–10% of patients with PAD have recurrent events and millions die from cardiovascular disease each year.3 Many medical strategies are considered important for patients with PAD. These include smoking cessation, diabetes control, blood pressure management, exercise therapy for claudication, and antithrombotic medications. Antithrombotic medications have been proven to reduce cardiovascular morbidity and mortality in a number of scenarios, including acute coronary syndrome, atrial fibrillation, and percutaneous coronary intervention.4–8 Statin therapy is considered a cornerstone treatment to reduce the occurrence of major adverse cardiovascular events in patients with stable atherosclerotic disease.9,10 The evidence base for PAD therapies has evolved recently. The cardiovascular risk of patients with PAD, risk reduction strategies, recent antithrombotic trial data, and opportunities for care improvement moving forward will be reviewed here.
PAD Patient Population and Treatment Opportunities: Most patients with PAD are asymptomatic, and those with symptoms can present with a variety of complaints including atypical leg pain, intermittent claudication (leg pain that occurs with exertion and improves with rest), ischemic rest pain, ulceration, or gangrene.11 The symptom presentation often dictates how patients are identified and brought to clinical specialties. The ankle-brachial index is the guideline recommended and most frequently used diagnostic test to determine the presence of PAD; the degree of hemodynamic abnormality is often used along with symptoms to determine treatment strategies.
Medical treatment of patients with PAD has traditionally involved antiplatelet monotherapy (eg, aspirin or clopidogrel) and moderate- to high-intensity statin medication to reduce cardiovascular risk over time.11 Although PAD is generally considered a coronary artery disease (CAD) risk equivalent, antiplatelet and statin medications are used significantly less frequently in patients with PAD than in patients with CAD. As such, there is significant opportunity to improve treatment rates and compliance with antiplatelet and statin medications in patients with PAD.12,13 In patients with persistent symptoms despite background medical therapy, cilostazol and supervised exercise training for intermittent claudication have been shown to improve walking distance and quality of life.14,15 Until recently, supervised exercise training has been seldom used by eligible patients due to lack of insurance reimbursement and sparse availability around the country. In May 2017, however, the Centers for Medicare and Medicaid Services announced a National Coverage Determination that will reimburse providers for supervised exercise training in patients with intermittent claudication.
There are few proven medical therapies for patients with critical limb ischemia, the most severe form of PAD. In patients with limb-threatening ischemia, noninvasive and invasive imaging is recommended to define the burden and severity of obstructive disease and revascularization is frequently recommended to preserve limb function and mobility. Typically, only 30% of patients who undergone a limb amputation have an arterial diagnostic study of any kind performed before the amputation. The heterogeneity that exists in the application of these diagnostic and interventional strategies is also geographically variable across the country.16,17 Finally, in Medicare patients, the mortality rate of patients with critical limb ischemia at 1 year is nearly 50%, signaling the need for therapies aimed at this population.18
Dual Antiplatelet Therapy: When compared with patients with other forms of atherosclerotic disease, including CAD, patients with PAD have a higher risk of cardiovascular death, myocardial infarction (MI), and stroke. In the Reduction of Atherothrombosis for Continued Health (REACH) registry, PAD patients had a 21.1% annual risk of cardiovascular death, MI, stroke, or hospitalization for an atherothrombotic cause.19 Also, the risk of major adverse limb events, typically defined as major amputation or surgical intervention, varies from 2% to 10% annually depending on age, symptom classification, concomitant medical therapy, and prior revascularization procedures.
Importantly, major amputation of the lower extremities due to PAD has decreased significantly in the United States, but it remains an important public health concern because mortality rates are nearly 50% at 1 year and 70% at 3 years after major amputation in Medicare patients.20 Lower extremity peripheral vascular interventions have increased significantly over the last 2 decades (Fig. 2).
Risk Reduction From Antithrombotic Agents: Antiplatelet therapies have been the center of treatment for patients with atherosclerotic vascular disease; the American College of Cardiology/American Heart Association (ACC/AHA) guidelines place a Class Ia recommendation for antiplatelet monotherapy with aspirin (75–325 mg daily) or clopidogrel (75 mg daily) to reduce the incidence of MI, stroke, and vascular death in patients with symptomatic PAD.11 Because the data for antiplatelet therapy in asymptomatic patients with PAD are derived from small studies and are more heterogeneous, the ACC/AHA guidelines place a Class IIa recommendation for antiplatelet therapy in these patients. There remains uncertainty about the long-term safety and efficacy of dual antiplatelet therapy in patients with PAD based on a single subgroup analysis from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study, thus prolonged dual antiplatelet therapy for all patients with PAD remains a Class IIb recommendation.
There are multiple antithrombotic targets to reduce the risk of atherothrombosis in stable patients with PAD (Fig. 3). Therapies have targeted platelet activity and receptors and include aspirin, clopidogrel, ticagrelor, and vorapaxar (targeting thromboxane, P2Y12, and protease-activated receptor-1, respectively). Aspirin has been the dominant therapy used by vascular physicians because of its low cost, availability, and safety; however, patients remain at high risk for life-threatening events such as MI and stroke despite aspirin therapy.21 With the introduction of ticlopidine22 and clopidogrel, multiple studies were performed in high-risk patients, including those with PAD. The use of ticlopidine was truncated due to an excess risk of thrombotic thrombocytopenic purpura, and although clopidogrel was found to reduce the risk of vascular death, MI, or stroke by 23.8% in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial,23 the substitution of clopidogrel for aspirin did not routinely occur in clinical practice due to cost. More recently, the use of oral anticoagulants has been studied in patients with atherosclerotic disease including PAD.
Recent Antithrombotic Clinical Trial Data: Vorapaxar is a protease-activated receptor-1 inhibitor that binds to platelets and has been studied in the setting of acute coronary syndrome and stable atherosclerotic disease (prior MI or PAD) as an addition to baseline antiplatelet therapy. In the pivotal Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50 (TRA 2°P-TIMI 50) study, 26,449 patients (3787 with PAD) were randomized to vorapaxar or placebo.24 Eighty-eight percent of these patients were receiving aspirin therapy, 37% were taking a thienopyridine, and 28% were receiving dual antiplatelet therapy on study entry. In the overall cohort, vorapaxar reduced the incidence of the composite endpoint (cardiovascular death, MI, or stroke) by 1.2%. In the PAD cohort, the risk reduction for the primary composite endpoint was not statistically significant [11.3% vs. 11.9%; hazard ratio, 0.94; 95% confidence interval (CI), 0.78–1.14; P = 0.53]. Vorapaxar did reduce the risk of hospitalization for acute limb ischemia and peripheral revascularization, but the hazard of Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) moderate and severe bleeding and intracranial hemorrhage was statistically significantly higher with vorapaxar. In 2014, the US Food and Drug Administration approved the use of vorapaxar in patients with prior MI or PAD albeit with a warning for bleeding on the label.
Another antiplatelet agent, ticagrelor, has been tested extensively in patients with PAD. The 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 (PEGASUS-TIMI 54) trial enrolled 21,162 patients with a history of MI, of which 1143 had PAD.25 Patients were randomized in a 1:1:1 fashion to ticagrelor 90 mg twice daily versus ticagrelor 60 mg twice daily versus placebo on a background of aspirin. PAD patients in the ticagrelor 60 mg arm had a statistically significant reduction in cardiovascular death, MI, or stroke, but the reduction with the ticagrelor 90 mg dose was not statistically significant. Hospitalization for acute limb ischemia or peripheral revascularization was significantly reduced in the ticagrelor 90 mg arm, but the reduction in the 60 mg arm was not statistically significant.25 The Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial randomized 13,885 symptomatic patients with PAD in a 1:1 fashion to ticagrelor or clopidogrel monotherapy.26 Patients were followed for approximately 30 months, and there was no difference between the 2 groups in terms of the primary composite endpoint of cardiovascular death, MI, or stroke (10.8% vs. 10.6%; hazard ratio, 1.02; 95% CI, 0.92–1.13; P = 0.65). Both major bleeding (1.6% vs. 1.6%; hazard ratio, 1.10; 95% CI, 0.84–1.43; P = 0.49) and hospitalization for acute limb ischemia (1.7% vs. 1.7%; hazard ratio, 1.03; 95% CI, 0.79–1.33; P = 0.85) were also similar between treatment groups.
In the recently published Cardiovascular Outcomes for People Us ing Anticoagulation Strategies (COMPASS) trial, a total of 27,395 patients with stable atherosclerotic vascular disease (CAD, PAD, or both) were randomized to 3 arms (aspirin 100 mg daily vs. rivaroxaban 5 mg twice daily vs. aspirin 100 mg daily plus rivaroxaban 2.5 mg twice daily) at 602 centers worldwide.27 The study was terminated earlier than expected due to overwhelming efficacy in the aspirin and low-dose rivaroxaban arm. Over approximately 2 years of follow-up, patients randomized to aspirin plus rivaroxaban 2.5 mg twice daily had a significantly lower rate of the primary composite endpoint (MI, ischemic stroke, cardiovascular death) when compared with aspirin alone (4.1% vs. 5.4%; hazard ratio, 0.76; 95% CI, 0.66–0.86; P < 0.001). There was a significantly higher rate of major bleeding in the aspirin plus rivaroxaban group when compared with aspirin alone (3.1% vs. 1.9%; hazard ratio, 1.70; 95% CI, 1.40–2.15; P < 0.001). Nevertheless, there was an 18% risk reduction in all-cause mortality in favor of aspirin and low-dose rivaroxaban (3.4% vs. 4.1%; hazard ratio, 0.82; 95% CI, 0.71–0.96; P < 0.001).
In a simultaneous report, rivaroxaban was shown to have similar efficacy in the PAD cohort from the COMPASS trial. In 7470 patients who met inclusion criteria based on a history of PAD, 55.2% had symptomatic limbs, 25.7% had carotid disease, and 19.1% had a low ankle-brachial index. The rate of the primary composite endpoint was reduced with aspirin plus rivaroxaban 2.5 mg twice daily when compared with aspirin alone (5.1% vs. 6.9%; hazard ratio, 0.72; 95% CI, 0.57–0.90; P < 0.001). The risk of major bleeding was also very similar to the main trial results, with aspirin plus rivaroxaban 2.5 mg twice daily being associated with a significantly higher rate of major bleeding when compared with aspirin alone (3.1% vs. 1.9%; hazard ratio, 1.61; 95% CI, 1.12–2.31; P < 0.001). However, this finding is also significant in that PAD patients did not have an elevated risk of major bleeding when compared with patients without PAD.
In aggregate, these recent trial results provide some insight into the potential pathobiology of cardiovascular and limb events in patients with PAD. These recent data demonstrated no improvement in cardiovascular outcomes with more potent mono antiplatelet therapy (EUCLID). Subgroups of studies with dual therapy versus mono antiplatelet therapy show some benefit (PEGASUS and CHARISMA). Finally, there is now evidence that dual pathway therapy with antiplatelet and antithrombotic therapy (COMPASS PAD) may provide the most significant cardiovascular and limb protection for PAD patients. Table 1 summarizes clinical trials of antithrombotic agents in patients with stable peripheral arterial disease and patients undergoing peripheral revascularization.
Ongoing Clinical Trial: The Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects with Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremity (VOYAGER PAD) study is a 1:1 randomized, placebo-controlled trial of rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily after peripheral surgical and/or endovascular revascularization. VOYAGER will enroll over 6500 patients and should be reported in early 2019.
Conclusions: In conclusion, PAD is a systemic manifestation of atherosclerosis that affects over 200 million people worldwide. Proven therapies such as blood pressure reduction, statin therapy, and smoking cessation are variable and used less in patients with PAD compared to patients with CAD. Antithrombotic therapy for patients with PAD has recently evolved, and monotherapy with clopidogrel has been shown to be similar to ticagrelor. Rivaroxaban 2.5 mg twice daily in addition to aspirin was shown to reduce cardiovascular events and limb events when compared with aspirin alone. Clinicians and patients will need to have personalized discussions on how to reduce their cardiovascular and limb risk for clinical events.
Dr. Manesh R. Patel discloses the following relationships: Grants/Research Support Recipient: AstraZeneca, Bayer and Janssen; Advisor or Review Panel Member: AstraZeneca, Bayer, and Janssen.
1. Fowkes FG, Rudan D, Rudan I, et alComparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382:1329–1340.
2. Roth GA, Dwyer-Lindgren LBertozzi-Villa, et al. Trends and patterns of geographic variation in cardiovascular mortality among US counties, 1980–2014. JAMA. 2010;317:1976–1992.
3. Bhatt DL, Eagle KA, Ohman EM, et alComparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304:1350–1357.
4. Wiviott SD, Braunwald E, McCabe CH, et alPrasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–2015.
5. Wallentin L, Becker RC, Budaj A, et alTicagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
6. Patel MR, Mahaffey KW, Garg J, et alRivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891.
7. Granger CB, Alexander JH, McMurray JJ, et alApixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–992.
8. Mauri L, Kereiakes DJ, Yeh RW, et alTwelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371:2155–2166.
9. Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.
10. LaRosa JC, Grundy SM, Waters DD, et alIntensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–1435.
11. Gerhard-Herman MD, Gornik HL, Barrett C, et al2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2017;69:1465–1508.
12. Subherwal S, Patel MR, Chiswell K, et alClinical trials in peripheral vascular disease: pipeline and trial designs: an evaluation of the ClinicalTrials.gov database. Circulation. 2014;130:1812–1819.
13. Armstrong EJ, Chen DC, Westin GG, et alAdherence to guideline-recommended therapy is associated with decreased major adverse cardiovascular events and major adverse limb events among patients with peripheral arterial disease. J Am Heart Assoc. 2014;3:e000697.
Jones WS, Schmit KM, Vemulapalli S, et alTreatment Strategies for Patients With Peripheral Artery Disease. 2013.Rockville, MD;
15. Vemulapalli S, Dolor RJ, Hasselblad V, et alSupervised vs unsupervised exercise for intermittent claudication: a systematic review and meta-analysis. Am Heart J. 2015;169:924–937 e3.
16. Vemulapalli S, Greiner MA, Jones WS, et alPeripheral arterial testing before lower extremity amputation among Medicare beneficiaries, 2000 to 2010. Circ Cardiovasc Qual Outcomes. 2014;7:142–150.
17. Soden PA, Zettervall SL, Curran T, et alRegional variation in patient selection and treatment for lower extremity vascular disease in the vascular quality initiative. J Vasc Surg. 2017;65:108–118.
18. Iida O, Takahara M, Soga Y, et alPrognostic impact of revascularization in poor-risk patients with critical limb ischemia: the PRIORITY Registry (Poor-Risk Patients With and Without Revascularization Therapy for Critical Limb Ischemia). JACC Cardiovasc Interv. 2017;10:1147–1157.
19. Steg PG, Bhatt DL, Wilson PW, et alOne-year cardiovascular event rates in outpatients with atherothrombosis. JAMA. 2007;297:1197–1206.
20. Jones WS, Patel MR, Dai D, et alTemporal trends and geographic variation of lower-extremity amputation in patients with peripheral artery disease: results from U.S. Medicare 2000 2008. J Am Coll Cardiol. 2012;60:2230–2236.
21. Jones WS, Patel MR, Dai D, et alHigh mortality risks after major lower extremity amputation in Medicare patients with peripheral artery disease. Am Heart J. 2013;165:809–815.
22. Jones WS, Mi X, Qualls LG, et alTrends in settings for peripheral vascular intervention and the effect of changes in the outpatient prospective payment system. J Am Coll Cardiol. 2015;65:920–927.
23. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71–86.
24. Janzon LThe STIMS trial: the ticlopidine experience and its clinical applications. Swedish Ticlopidine Multicenter Study. Vasc Med. 1996;1:141–143.
25. Bonaca MP, Bhatt DL, Storey RF, et alTicagrelor for prevention of ischemic events after myocardial infarction in patients with peripheral artery disease. J Am Coll Cardiol. 2016;67:2719–2728.
26. Hiatt WR, Fowkes FG, Heizer G, et alTicagrelor versus clopidogrel in symptomatic peripheral artery disease. N Engl J Med. 2017;376:32–40.
27. Eikelboom JW, Connolly SJ, Bosch J, et alCOMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377:1319–1330.
Factor Xa Mechanism of Action: Impact on Clotting Cascade, Inflammation, and Platelet Activation
Richard C. Becker, MD, FAHA, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, OH
Introduction: A contemporary view of thrombosis emphasizes the importance of cellular surface biochemistry and the integrated contribution of platelets, leukocytes, nucleic acids, histones, and perturbed endothelial cells. Initiation of coagulation occurs on tissue factor (TF)–bearing cells, whereas amplification (or priming) requires activation of platelets and coagulation proteases. The final phase, propagation, is determined by thrombin generation on platelet surfaces (Fig. 1).1
The cell-based model of thrombosis highlights specific phases or biochemical stages rather than a traditional view of independent coagulation pathways or cascades. Accordingly, TF is considered the key element for initiation of thrombosis, wherein its ability to complex with factor VIIa (fVIIa) and activate factor X (fXa) ultimately causes thrombin generation. Although thrombin is a pivotal enzyme in thrombosis, the importance of fXa and its diverse effects on thrombin generation, inflammatory processes, smooth muscle cell proliferation, and endothelial cell activation represents a point of convergence for each component part.
Factor X: Factor X (fX) is a vitamin K–dependent glycoprotein synthesized in the liver and subsequently secreted into the plasma as a precursor to an active serine protease fXa. The human protein is composed of a light chain and a heavy chain linked by a single disulfide bond. The catalytic domain of fXa is contained within the heavy chain.
Factor X is activated by excision of a small peptide from its heavy chain. The cleavage of an alanine–isoleucine peptide bond by either TF-fVIIa or fVIIIa-fIXa complex liberates the 52 amino acid peptide, providing a potentially measureable marker of fX activation. Under optimal conditions (high concentrations of TF), the TF-fVIIa complex can activate fX and, in essence, bypass the contribution of fVIII–fIX.
Prothrombinase Assembly on Platelet Surfaces: Platelets play a critical role in localizing and controlling the burst of thrombin generation leading to fibrin formation. Procoagulant phospholipids (microparticles), particularly phosphatidylserine, stimulate prothrombinase assembly by several orders of magnitude. Factor X activation requires a phospholipid surface; however, recent work suggests that thrombin-stimulated platelets also expose nonlipid-binding sites for fVIIIa, fIXa, and fXa. The platelet receptor for fXa may include membrane bound fVa, effector protease receptor-1, and an anion-exposed binding site in complex with glycoprotein Ib.2–4
Emerging Paradigms in Thrombosis: A traditional perspective of thrombosis begins with vessel wall injury and exposure of subendothelial proteins, including collagen and TF, to circulating cellular and noncellular components. Adhesion and activation of platelets, mediated by their interaction with von Willebrand protein and collagen, respectively, coupled with TF-mediated activation of coagulation proteins results in thrombin generation and fibrin formation. The events as they take place on cell surfaces are summarized above. Although this time-honored paradigm remains firm and soundly based, emerging evidence suggests that thrombosis is much more complex and dynamic than originally believed. Several novel triggers, templates, and facilitators, such as cell-free nucleic acids (cfNAs), histones, DNA-histone complexes, polyphosphates, and microvesicles, have recently been identified and require inclusion in the expanding universe of thrombosis as a dominant phenotype of human conditions, disorders, and diseases.
Neutrophil extracellular traps (NETs) are platforms of intact chromatin fibers with antimicrobial proteins that are produced by neutrophils to “trap and disarm” microbes in the extracellular milieu. These NETs have been shown to interact with the vascular endothelium, platelets, red blood cells, and coagulation factors, each of which is known to participate actively in thrombus formation. Specifically, NETs have been shown to induce endothelial cell death via interactions with NET-associated proteases or cationic proteins, including histones. Histones, in turn, can induce pore formation and influx of ions into cells by binding to their cellular membranes. These interactions promote increased intracellular calcium levels, endothelial activation, and Weibel-Palade content release of von Willebrand factor and other prothrombotic constituent proteins.5–7
Beyond their ability to bind endothelial cells and cause activation, NETs directly activate platelets. NETs have been shown in flow systems to bind platelets and facilitate aggregation. These properties are believed to be the result of both direct and indirect effects, as platelets are known to bind with histones through phospholipids, carbohydrates, and toll-like receptors (TLRs). In addition, platelets can bind double- and single-stranded DNA in vitro, representing an alternative mechanism for NET-induced platelet activation.
Also, NETs may provoke thrombus formation through direct stimulation of both the contact and TF-mediated coagulation pathways (Fig. 2).8 In vitro, NETs have been shown to stimulate fibrin formation and deposition and to colocalize with fibrin in blood clots. The NETs contain neutrophil elastase, which can effectively cleave TF pathway inhibitor and augment fXa activation. By binding to TF pathway inhibitor, NETs also attenuate the endothelium’s primary means to regulate TF. Last, NETs can stimulate thrombin generation and fibrin formation through fXII-mediated contact activation. Similar to cfNAs, DNA-histone complexes have prothrombotic properties. The responsible mechanisms, however, are likely the product of inflammatory states and cellular damage rather than functional pathways.
DNA-Histone Complexes: Histones are cationic proteins that are normally found bound to DNA within the nucleus of a cell, specifically within nucleosomes. Similar to cfNAs, histones and DNA-histone complexes can be released into the circulation from dying or damaged cells. Although release of both DNA-histone complexes and NETs is hypothesized to serve primarily anti-inflammatory and pathogen restricting or constraining roles, recent studies have identified functions for these complexes in thrombosis.
Circulating histones and DNA-histone complexes have been observed in several acute and chronic inflammatory conditions. In addition, extracellular histones function as late mediators of cell damage and organ dysfunction in sepsis. Histones may provoke thrombin generation by activating platelets through stimulation of TLR2 and TLR4. In addition, histone-DNA complexes augment thrombin generation more than histones alone. Considered collectively, these data support the existence of an integrated and complex interface of inflammation, host defenses, and coagulation.9
Factor Xa: Inflammatory and Proliferative Effects: Factor Xa binds to human umbilical vein endothelial cells via a single class of binding sites with a dissociation constant value of 6.6 ± 0.8 nM and density of 57,460 ± 5200 sites per cell. The binding kinetics are considered “pseudo” first order with association and dissociation constants of 0.15 × 10−6 5−1 m−1·s−1 and 4.0 × 10−4 s−1, respectively. FXa binding to vascular endothelial cells is not influenced by thrombin, fVa, antithrombin, or TF pathway inhibitor but is blocked by antibodies specific for effector protease receptor-1, supporting its role in fXa–endothelial cell interactions. The binding of fXa is associated with the following events: (1) increased intracellular calcium; (2) increased phosphoinositide turnover; (3) TF expression; (4) tissue plasminogen activator release; (5) plasminogen activator inhibitor release; (6) interleukin-6 and interleukin-8 release; (7) cellular proliferation; (8) expression of E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1; and (9) nitric oxide release. The ability of indirect and direct antagonists to inhibit fXa-mediated cellular effects, without impacting its surface-binding capacity, suggests strongly that catalytic activity is the determining feature (Fig. 3).7 Macrophages localized within atheromatous plaques can synthesize fX. An ability of fXa to promote smooth muscle cell proliferation suggests that local prothrombotic responses may also influence arterial remodeling after injury. The mitogenic response to fXa probably involves proteinase-activated receptor-2. Functional proteinase-activated receptor-2, an auto-activating–tethered ligand, is widely distributed in human vascular endothelial cells and smooth muscle cells. FXa also exerts mitogenic effects through platelet-derived growth factor. Leukocyte proliferation has been observed after fX activation. In turn, proinflammatory cytokines that activate fX (fXa) are released. FXa also promotes recruitment of mast cells and their secretion of vasoactive mediators including histamine and serotonin.
Translating the Anticoagulant and Anti-Inflammatory Effects of Factor Xa Inhibition to Patient Care: Systemic inflammation has been implicated in coronary artery disease and common phenotypes including acute coronary syndrome. Investigation of plaques points to inflammatory mechanisms as key regulators of fibrous cap fragility and the overall thrombogenic capacity of necrotic lipid core constituents. Activated macrophages, neutrophils, and monocytes elaborate enzymes that degrade extracellular matrix proteins that, in turn, pave the way for plaque instability and rupture.10–12
Clinical trials performed over the past decade suggest strongly that attenuating inflammation exerts a beneficial effect among patients at risk for coronary artery disease-related events. In addition, the recently completed, presented, and published Canakinumab Antiinflammatory Thrombosis Outcomes Study trial, in which over 10,000 patients with prior myocardial infarction and elevated high-sensitivity C-reactive protein level received a monoclonal antibody targeting interleukin-1β or placebo in addition to evidence-based therapy, supports the inflammatory hypothesis of coronary artery disease and its natural history.13
The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial was a randomized, double-blind study of 27,395 patients with stable atherosclerotic vascular disease who received either rivaroxaban, a direct inhibitor of the pluripotent coagulation protease fXa, at a dose of 2.5 mg twice daily plus aspirin 100 mg daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg daily. The primary outcome measure was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban plus aspirin group after a mean follow-up of 23 months.14
Summary: Factor Xa is a coagulation protease that has procoagulant, proinflammatory, and proliferative effects. Its importance in atherosclerotic vascular disease is based on these properties that are known to underlie the pathobiology of atherosclerotic plaque development, rupture, and thrombosis as the causal underpinnings for the transition from stable to unstable disease and resulting clinical events. The findings from COMPASS support the importance of factor Xa and its inhibition as a viable, readily available, and safe therapeutic strategy for patients with atherosclerotic vascular disease at risk for cardiovascular death, stroke, and myocardial infarction.
Dr. Richard C. Becker discloses the following relationships: Advisor or Review Panel Member: Ionis and Portola.
1. Hoffman M, Monroe DMA cell-based model of hemostasis. Thromb Hemost. 2001;85:958–965.
2. Muller MP, Wang Y, Morrissey JH, et alLipid specificity of the membrane binding domain of coagulation factor X. J Thromb Haemost. 2017;15:2005–2016.
3. Koklic T, Chattopadhyay R, Majumder R, et alFactor Xa dimerization competes with prothrombinase complex formation on platelet-like membrane surfaces. Biochem J. 2015;467:37–46.
4. Kovalenko TA, Panteleev MA, Sveshnikova ANSubstrate delivery mechanism and the role of membrane curvature in factor X activation by extrinsic tenase. J Theor Biol. 2017;435:125–133.
5. Helseth R, Solheim S, Arnesen H, et alThe time course of markers of neutrophil extracellular traps in patients undergoing revascularisation for acute myocardial infarction or stable angina pectoris. Mediators Inflamm. 2016;2016:2182358.
6. Wisler JW, Becker RCAntithrombotic therapy: new areas to understand efficacy and bleeding. Expert Opin Ther Targets. 2014;18:1427–1434.
7. Foley JH, Conway EMCross talk pathways between coagulation and inflammation. Circ Res. 2016;118:1392–1408.
8. Becker RCAspirin and the prevention of venous thromboembolism. N Engl J Med. 2012;366:21.
9. Granger V, Faille D, Marani V, et alHuman blood monocytes are able to form extracellular traps. J Leukoc Biol. 2017;102:775–781.
Nehaj F, Sokol J, Ivankova J, et alFirst evidence: TRAP-induced platelet aggregation is reduced in PATIENTS receiving Xabans. Clin Appl Thromb Hemost. October 2017;1–6.
11. Wisler JW, Becker RCOral factor Xa inhibitors for the long-term management of ACS. Nat Rev Cardiol. 2012;9:392–401.
12. Qi H, Yang S, Zhang LNeutrophil extracellular traps and endothelial dysfunction in atherosclerosis and thrombosis. Front Immunol. 2017;8:928.
13. Ridker PM, Everett BM, Thuren T, et alfor the CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–1131.
14. Eikelboom JW, Connolly SJ, Bosch J, et alRivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377:1319–1330.
Clinical and Economic Value of Rivaroxaban in Coronary Artery Disease
Christopher B. Granger, MD, Department of Medicine, Duke Clinical Research Institute, Durham, NC; and Division of Cardiology, Duke University Medical Center, Durham, NC
Introduction: Coronary heart disease is the number one cause of death and disability in the world and is projected to continue to be so for the foreseeable future.1 An estimated 16.5 million Americans have coronary heart disease based on current data from the National Health and Nutrition Examination Survey (NHANES).2
The combination of control of risk factors and use of effective medical treatments cut the death rate from coronary heart disease in half over 20 years from 1980 to 2000.3 Patients with peripheral artery disease have fewer available options that improve outcomes. Thus, there remains a major need for more effective treatments for patients with peripheral vascular disease.
Oral Anticoagulation Prevents Vascular Events and Causes Bleeding: Although antiplatelet therapy has been the mainstay of antithrombotic therapy for patients with stable vascular disease, there is strong evidence that oral anticoagulation with warfarin provides protection against myocardial infarction (MI). This benefit is counterbalanced by increased bleeding, and the net effect, including the effect on mortality, is neutral (Fig. 1).4 A similar pattern has been seen in chronic heart failure without atrial fibrillation where warfarin reduces stroke but causes bleeding, resulting in a net neutral effect on mortality.5 Therefore, oral anticoagulation has been shown to reduce arterial vascular events, but at a cost in bleeding that counterbalances the benefits. Because of this reduction in net clinical benefit, warfarin is not used for these patients.
In recent years, non-vitamin K antagonist oral anticoagulants (NOACs), which have the advantage of less life-threatening bleeding than warfarin, have been tested for treatment of vascular disease. The Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2) trial found reduced rates of MI and stent thrombosis with apixaban in addition to dual antiplatelet therapy after acute coronary syndromes (ACSs). This reduction in events was accompanied by more bleeding, including intracranial hemorrhage.6 The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome (ATLAS-2) investigators used a different strategy, testing low-dose rivaroxaban in addition to dual antiplatelet therapy in 93% of patients without a history of stroke. They showed benefit that exceeded risk, with a reduction in mortality using the lower dose of rivaroxaban (2.5 mg twice daily) added to antiplatelet therapy.7 There was also a reduction in stent thrombosis with rivaroxaban added to antiplatelet therapy. This trial showed that oral Xa inhibitor therapy can provide overall benefit in patients with ACS. Benefit from oral factor IIa (thrombin) inhibition for patients with ACS is less clear. There is a modestly higher rate of MI with dabigatran than with warfarin across the randomized trials of atrial fibrillation and venous thromboembolic disease.8 Phase II trials have suggested that targeting thrombin may provide some benefit after ACS, although these trials have not progressed to phase III.
Rivaroxaban or Dabigatran With Clopidogrel—Safer Than Warfarin Triple Therapy: Two completed trials have tested oral anticoagulation with warfarin versus NOACs, rivaroxaban in the Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention (PIONEER) trial9 (Fig. 2 and Table 1) and dabigatran in the Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (RE-DUAL) trial,10 for stroke prevention in patients with atrial fibrillation who underwent stent placement and were also treated with P2Y12 inhibitor therapy. These trials found that NOACs with P2Y12 inhibitors (without aspirin) are safer than the combination of warfarin, aspirin, and P2Y12 inhibitors.
Rivaroxaban 15 mg daily without aspirin or 2.5 twice daily with aspirin and dabigatran 110 mg or 150 mg twice daily appeared to be nearly equally effective at preventing thrombotic events, although the number of thrombotic events was too small to have high confidence in those findings. The 110 mg twice daily dose of dabigatran without aspirin had numerically more MIs and stent thromboses than warfarin with aspirin, although the differences were not statistically significant. The use of rivaroxaban 15 mg daily or dabigatran 150 mg twice daily with a P2Y12 inhibitor, but without aspirin beyond the first few days after coronary stenting, appears to result in comparable rates of stent thrombosis compared to “triple therapy” with warfarin, clopidogrel, and aspirin. The observation that aspirin may not be required to prevent stent thrombosis in the presence of a NOAC, and P2Y12 inhibitor was also seen in the Study to Compare the Safety of Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome (GEMINI) trial11 in which low-dose rivaroxaban and clopidogrel had comparable rates of stent thrombosis as aspirin and clopidogrel. An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention (AUGUSTUS) trial will test, in a full factorial design, the impact of aspirin versus placebo combined with either warfarin or apixaban12 in patients with atrial fibrillation and coronary stenting and/or ACS.
Oral Anticoagulation and Coronary Disease Events in Patients With Atrial Fibrillation: A substantial portion of the populations in the clinical trials of NOACs versus warfarin for atrial fibrillation also had coronary artery disease. In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial, 17% of the population had prior MI.12 Not surprisingly, these patients were at higher risk for ischemic events and for bleeding, and they were more likely to be on concomitant aspirin. Overall, the rates of ischemic events tended to be lower with rivaroxaban than with warfarin, with a 14% reduction in hazard with rivaroxaban, P = 0.05. The hazard ratio of MI with rivaroxaban versus warfarin was 0.81 (95% confidence interval, 0.63–1.06). These findings, and similar findings with apixaban and edoxaban, suggest that factor Xa inhibitors are at least as effective as warfarin at preventing coronary events with lower risk of life-threatening bleeding.
Rivaroxaban in Patients With Stable Coronary Disease: Whether patients with coronary disease without atrial fibrillation may benefit from low-dose rivaroxaban with or without aspirin, compared to aspirin alone, was tested in the Cardiovascular Outcomes for People Using Anti coagulation Strategies (COMPASS) trial. Overall, 91% of the trial population had coronary artery disease; 20% of these were women. Half of those with prior MI had their infarction within 5 years of enrollment, and only 5% within 1 year. Importantly, the patients were on good background medical therapy to reduce vascular events, with 92% on lipid lowering drugs and 72% on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.
The 26% relative risk reduction in the primary outcome of cardiovascular death, MI, or stroke with low-dose rivaroxaban plus aspirin versus aspirin alone in the coronary disease subgroup (P < 0.0001) was similar to the effect in the overall trial (Fig. 3). The hazard ratio for major bleeding was 1.66 (P < 0.0001) with rivaroxaban plus aspirin versus aspirin. In the coronary disease population, the 1.3% absolute reduction in cardiovascular death, MI, and stroke was counterbalanced by a 1.2% absolute increase in major bleeding. The overall impact on mortality becomes key to understanding the net effect. There was a 23% relative risk reduction in all-cause mortality in the coronary disease population (P = 0.001),14 providing strong evidence of an overall benefit.
With respect to ischemic heart disease outcomes in the coronary disease population, MI was not significantly reduced (hazard ratio, 0.86; 95% confidence interval, 0.70–1.05) perhaps related to small numbers, but the hazard of a broader ischemic heart disease composite (MI, coronary heart disease death, sudden death, resuscitated cardiac arrest, or unstable angina) was reduced by 17% (P = 0.03) (Table 2).14 The 46% relative risk reduction (P < 0.0001) in stroke in this population, similar to in the overall trial, was the most striking effect on major clinical outcomes.
Cost Implications of Rivaroxaban for Patients With Stable Coronary Disease: The overall effects of rivaroxaban plus aspirin versus aspirin alone compare favorably to other commonly used treatments to improve outcome for patients with vascular disease, such as antiplatelet therapy, lipid lowering agents, and blood pressure lowering agents. Preliminary data regarding the cost impact of rivaroxaban in the COMPASS trial have been presented.16 Examining direct costs of care, not including costs of the drug, rivaroxaban plus aspirin resulted in substantially lower health care costs than aspirin alone, driven largely by lower costs related to the reduction in stroke. There were larger differences favoring rivaroxaban in patients with peripheral artery or polyvascular arterial disease. Formal cost-effectiveness analyses are ongoing.
Summary: Coronary heart disease continues to be the most important cause of death and disability in the United States and around the world. There is now another treatment proven to prevent vascular events in patients with stable coronary disease—low-dose rivaroxaban added to aspirin—with an even larger absolute benefit for patients who have both coronary disease and concomitant peripheral or cerebrovascular disease. The net benefit of low-dose rivaroxaban with aspirin, compared to aspirin alone, is underscored by the 23% relative risk reduction in all-cause mortality.
Dr. Christopher B. Granger discloses the following relationships: Grants/Research Support Recipient: Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Duke Clinical Research Institute, FDA, Glaxo SmithKline, Janssen Pharmaceuticals, Medtronic Foundation, Novartis, and Pfizer; Consultant: Abbvie, Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Gilead, Glaxo SmithKline, Janssen, Medscape, Medtronic, Merck, NIH, Novartis, Pfizer, Sirtex, and Verseon.
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14. Eikelboom JW, Connolly SJ, Bosch J, et alRivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377:1319–1330.
15. Connolly SJ, Eikelboom JW, Bosch J, et alRivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;391:179–280.
Lamy ACost Impact of Rivaroxaban Plus Aspirin Versus Aspirin in the COMPASS Trial. November 13, 2017. Anaheim, CA: American Heart Association Scientific Sessions; Available at: http://professional.heart.org/professional/EducationMeetings/MeetingsLiveCME/Scienti.cSessions/UCM_497351_SS17-Late-Breaking-Clinical-Trials.jsp#compass.Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved