70 – Should a patient with active lower extremity DVT undergo an orthopaedic procedure?

Michael Meghpara, James Purtill, Paul Tornetta III, Felix Vilchez.

Response/Recommendation: There is limited scientific evidence to support the safety of orthopaedic surgery in a patient with an active deep venous thrombosis (DVT) or pulmonary embolism (PE); its management must be individualized based on the patient history, procedure, extent of the DVT/PE, physiologic parameters, and the risk of bleeding during and after surgery.

Strength of Recommendation: Limited.

Rationale: Acute or active venous thromboembolism (VTE) in the form of DVT or PE may be present in a patient undergoing both elective and emergent orthopaedic procedures. While no formal cutoff exists, studies have often utilized 21 days from the onset of symptoms to define acute VTE1. When VTE occurs prior to surgical intervention, the need for anticoagulation or other intervention to treat the VTE and to avoid further associated morbidity must be incorporated into the perioperative orthopaedic management.

If the surgical intervention is not time-sensitive, then it should be delayed for as long as possible until the DVT/PE is treated and/or resolved. When a patient undergoing elective surgery develops VTE prior to surgery, due to a recurrence rate of nearly 40% within the first 4 weeks, surgery should be delayed at least one month2. The longer surgery can be delayed, the lower the risk for VTE recurrence3–5.

Patients undergoing elective orthopaedic procedures, such as hip or knee arthroplasty are already at high risk for venous thromboembolism6. The American Academy of Orthopaedic Surgeons (AAOS) guidelines report that a history of VTE significantly increases the risk in patients undergoing elective arthroplasty, and several studies cite additional risk factors such as: middle or old age, trauma, body mass index (BMI), cholesterol, high-density lipoprotein, apolipoprotein A, malignancy, prolonged surgery or contraceptive use, hormone therapy and pregnancy in women79. The risk of DVT is also increased in patients undergoing spinal surgery. Zervos, et al., reported that patients with a history of DVT who underwent elective spinal surgery have a higher risk of developing symptomatic DVT postoperatively10.

However, the surgical intervention may be time-sensitive and/or emergent. For example, patients with hip fractures have optimal outcomes and decreased morbidity and mortality when operative intervention is delivered within the first 24-48 hours11–14. Patients with hip fracture are known to have an incidence of DVT ranging from 9 to 13% preoperatively15. It may be necessary to surgically treat the hip fracture in the face of an active/acute DVT/PE. Another group of patients with time-sensitive surgical issues are those with open fractures and orthopaedic infections. Interestingly, fractures and infections both trigger an inflammatory cascade which may make patients prone to developing DVT16,17.

Sixty percent of DVT occur in the proximal venous system and 40% occur distally18. Distal DVT that occur in the gastrocnemius or soleal veins have a low probability of propagating proximally or developing into a PE19,20. The evidence on whether to treat a distal DVT varies21 and the use of anticoagulants for isolated distal DVT in otherwise low-risk patients may not be superior to either a placebo or non-treatment22–24. With no treatment, close observation with ultrasound at two weeks is suggested25. Proximal DVT, however, have a higher association with PE26–28. In addition to the increased risk of developing PE (6% – 32%) as an acute complication or post-thrombotic syndrome (25% – 38%) and venous ulceration (9.8%) as chronic complications29–32; progression may also be associated with increased morbidity with mortality rates up to 40%33–35.

In patients with acute VTE, various agents can be utilized to achieve therapeutic anticoagulation to prevent further clot development. Warfarin and newer direct-acting oral anticoagulants (DOAC) have limited utility. Warfarin anticoagulation would need to be bridged with heparin peri-operatively while DOAC have limited anticoagulation reversal options. Treatment with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) may be more useful for patients with acute VTE requiring non-elective surgery36. In the setting of an acute or active DVT or PE, stopping UFH or LMWH treatment for a period of time for a patient to undergo surgery is feasible and carries low risk37,38. To limit undesirable anticoagulant effects intraoperatively, LMWH should be held for 24 hours or reduced by 50% the evening prior to surgery3,36 while UFH should be discontinued 4-6 hours prior to procedure39. All patients should receive mechanical prophylaxis prior to and during surgery which can decrease the risk of VTE by up to 60%4,40. However, mechanical compression should be avoided in a limb with a DVT due to the potential risk of embolizing a clot41. Postoperatively, patients are at increased risk of bleeding, and anticoagulation is often restarted once post-procedural hemostasis is ensured. Data related to the optimal start time of prophylaxis is limited36. Based on the findings of the PROSPECT trial, a multicenter prospective study of 260 patients, restarting enoxaparin 12-24 hours postoperatively resulted in bleeding in 20% of patients undergoing major surgery42. Patients may be bridged with UFH or LMWH to warfarin or DOAC, beginning 24 to 72 hours after major surgery and 18-14 hours after minor surgery36,43–46.

Use of an inferior vena cava (IVC) filter should be considered when a patient has contraindications to anticoagulation or a history of recurrent VTE on prophylaxis4. Although controversial, the utilization of IVC filters has increased over the years, especially with the advent of percutaneous insertion47,48. IVC filters in high risk patients with an acute proximal DVT have been shown to initially prevent acute PE49, and can capture a thrombus in up to 13% of patients postoperatively50. Although rare, complications associated with IVC filters increase after 30 days and include filter migration, fracture, vena cava perforation, and vena cava occlusion51–53.

If immediate intervention is required in an unstable patient with cardiac strain identified by echocardiogram, the benefits associated with more invasive options such as thrombolysis or embolectomy may outweigh the risks to a surgical patient28,56,55,56. Systemic thrombolysis may significantly increase the risk of bleeding, however thrombolysis may prevent further hemodynamic decompensation from VTE57–59. While no specific studies exist about performing thrombolysis in orthopaedic patients, a few studies60–62 show the safety of thrombolysis in post-surgical patients with one report suggesting the use of a thigh tourniquet to prevent surgical site hemorrhage until the thrombolytic agent was no longer active63. Another option in patients with pulmonary embolism is catheter-directed thrombolysis which has demonstrated effectiveness in improving right ventricular strain and pulmonary artery pressure with no risk of major bleeding64–66.

While there is limited high-level evidence to support definitive general recommendations, patients with DVT or PE are not advised to undergo elective surgery due to the high surgical risk associated with increased mortality. However, its management prior to an emergent orthopaedic procedure varies based on individual patient factors with perioperative implications of each clinical scenario.


1.         Watson, L, Broderick, C, Armon, MP: Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev  2016;11:CD002783.

2.         Coon, WW, Willis, PW: Recurrence of venous thromboembolism. Surgery  1973;73:823–827.

3.         O’Donnell, MJ, Kearon, C, Johnson, J, Robinson, M, Zondag, M, Turpie, I, Turpie, AG: Brief Communication: Preoperative Anticoagulant Activity after Bridging Low-Molecular-Weight Heparin for Temporary Interruption of Warfarin. Ann Intern Med  2007;146:184.

4.         Geerts, WH, Bergqvist, D, Pineo, GF, Heit, JA, Samama, CM, Lassen, MR, Colwell, CW: Prevention of Venous Thromboembolism. Chest  2008;133:381S-453S.

5.         Liem, TK, Huynh, TM, Moseley, SE, Minjarez, RC, Landry, GJ, Mitchell, EL, DeLoughery, TG, Moneta, GL: Symptomatic perioperative venous thromboembolism is a frequent complication in patients with a history of deep vein thrombosis. J Vasc Surg  2010;52:651–657.

6.         Jacobs, JJ, Mont, MA, Bozic, KJ, Della Valle, CJ, Goodman, SB, Lewis, CG, Yates, AJ, Boggio, LN, Watters, WC, Turkelson, CM, et al.: American Academy of Orthopaedic Surgeons clinical practice guideline on: Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Bone Jt Surg – Ser A  2012;94:746–747.

7.         Zhang, H, Mao, P, Wang, C, Chen, D, Xu, Z, Shi, D, Dai, J, Yao, Y, Jiang, Q: Incidence and risk factors of deep vein thrombosis (DVT) after total hip or knee arthroplasty: A retrospective study with routinely applied venography. Blood Coagul Fibrinolysis  2017;28:126–133.

8.         Obalum, DC, Giwa, SO, Adekoya-Cole, TO, Ogo, CN, Enweluzo, GO: Deep vein thrombosis: Risk factors and prevention in surgical patients. West Afr J Med  2009;28:77–82.

9.         Ahmad, J, Lynch, MK, Maltenfort, M: Incidence and Risk Factors of Venous Thromboembolism After Orthopaedic Foot and Ankle Surgery. Foot Ankle Spec  2017;10:449–454.

10.       Zervos, TM, Bazydlo, M, Tundo, K, Macki, M, Rock, J: Risk Factors Associated with Symptomatic Deep Vein Thrombosis Following Elective Spine Surgery: A Case–Control Study. World Neurosurg  2020;144:e460–e465.

11.       Bretherton, CP, Parker, MJ: Early surgery for patients with a fracture of the hip decreases 30-day mortality. Bone Jt J  2015;97-B:104–108.

12.       Mariconda, M, Costa, GG, Cerbasi, S, Recano, P, Aitanti, E, Gambacorta, M, Misasi, M: The determinants of mortality and morbidity during the year following fracture of the hip: a prospective study. Bone Jt J  2015;97-B:383–390.

13.       Elliott, J, Beringer, T, Kee, F, Marsh, D, Willis, C, Stevenson, M: Predicting survival after treatment for fracture of the proximal femur and the effect of delays to surgery. J Clin Epidemiol  2003;56:788–795.

14.       Zuckerman, JD, Skovron, ML, Koval, KJ, Aharonoff, G, Frankel, VH: Postoperative complications and mortality associated with operative delay in older patients who have a fracture of the hip. J Bone Jt Surg Am Vol  1995;77:1551–1556.

15.       Roberts, TS, Nelson, C, Barnes, CL, Ferris, EJ, Holder, JC, Boone, DW: The Preoperative Prevalence and Postoperative Incidence of Thromboembolism in Patients With Hip Fractures Treated With Dextran Prophylaxis: Clin Orthop  1990;NA;198???203.

16.       Liu, D, Zhu, Y, Chen, W, Li, J, Zhao, K, Zhang, J, Meng, H, Zhang, Y: Relationship between the inflammation/immune indexes and deep venous thrombosis (DVT) incidence rate following tibial plateau fractures. J Orthop Surg  2020;15:241.

17.       Beristain-Covarrubias, N, Perez-Toledo, M, Thomas, MR, Henderson, IR, Watson, SP, Cunningham, AF: Understanding Infection-Induced Thrombosis: Lessons Learned From Animal Models. Front Immunol  2019;10:2569.

18.       Galanaud, J-P, Sevestre-Pietri, M-A, Bosson, J-L, Laroche, J-P, Righini, M, Brisot, D, Boge, G, van Kien, AK, Gattolliat, O, Bettarel-Binon, C, et al.: Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study. Thromb Haemost  2009;102:493–500.

19.       Brateanu, A, Patel, K, Chagin, K, Tunsupon, P, Yampikulsakul, P, Shah, GV, Wangsiricharoen, S, Amah, L, Allen, J, Shapiro, A, et al.: Probability of developing proximal deep-vein thrombosis and/or pulmonary embolism after distal deep-vein thrombosis. Thromb Haemost  2016;115:608–614.

20.       Macdonald, PS, Kahn, SR, Miller, N, Obrand, D: Short-term natural history of isolated gastrocnemius and soleal vein thrombosis. J Vasc Surg  2003;37:523–527.

21.       Kirkilesis, G, Kakkos, SK, Bicknell, C, Salim, S, Kakavia, K: Treatment of distal deep vein thrombosis. Cochrane Database Syst Rev  2020;doi:10.1002/14651858.CD013422.pub2.

22.       Horner, D, Hogg, K, Body, R, Nash, MJ, Baglin, T, Mackway-Jones, K: The anticoagulation of calf thrombosis (ACT) project: results from the randomized controlled external pilot trial. Chest  2014;146:1468–1477.

23.       Righini, M, Galanaud, J-P, Guenneguez, H, Brisot, D, Diard, A, Faisse, P, Barrellier, M-T, Hamel-Desnos, C, Jurus, C, Pichot, O, et al.: Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial. Lancet Haematol  2016;3:e556–e562.

24.       Schwarz, T, Buschmann, L, Beyer, J, Halbritter, K, Rastan, A, Schellong, S: Therapy of isolated calf muscle vein thrombosis: a randomized, controlled study. J Vasc Surg  2010;52:1246–1250.

25.       Kearon, C, Akl, EA, Comerota, AJ, Prandoni, P, Bounameaux, H, Goldhaber, SZ, Nelson, ME, Wells, PS, Gould, MK, Dentali, F, et al.: Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest  2012;141:e419S-e496S.

26.       Verlato, F, Zucchetta, P, Prandoni, P, Camporese, G, Marzola, MC, Salmistraro, G, Bui, F, Martini, R, Rosso, F, Andreozzi, GM: An unexpectedly high rate of pulmonary embolism in patients with superficial thrombophlebitis of the thigh. J Vasc Surg  1999;30:1113–1115.

27.       Sover, ER, Brammer, HM, Rowedder, AM: Thrombosis of the proximal greater saphenous vein: ultrasonographic diagnosis and clinical significance. J Ultrasound Med Off J Am Inst Ultrasound Med  1997;16:113–116.

28.       Kearon, C, Akl, EA, Ornelas, J, Blaivas, A, Jimenez, D, Bounameaux, H, Huisman, M, King, CS, Morris, TA, Sood, N, et al.: Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest  2016;149:315–352.

29.       Sachdeva, A, Dalton, M, Lees, T: Graduated compression stockings for prevention of deep vein thrombosis. Cochrane Database Syst Rev  2018;2018:

30.       Kahn, SR: The post-thrombotic syndrome. 2016;413–418.

31.       Wilbur, J, Shian, B: Diagnosis of deep venous thrombosis and pulmonary embolism. Am Fam Physician  2012;86:913–919.

32.       Stubbs, MJ, Mouyis, M, Thomas, M: Deep vein thrombosis. BMJ Online  2018;360:1–6.

33.       LaMori, JC, Shoheiber, O, Mody, SH, Bookhart, BK: Inpatient resource use and cost burden of deep vein thrombosis and pulmonary embolism in the United States. Clin Ther  2015;37:62–70.

34.       Saleh, J, El-Othmani, MM, Saleh, KJ: Deep Vein Thrombosis and Pulmonary Embolism Considerations in Orthopedic Surgery. Orthop Clin North Am  2017;48:127–135.

35.       van der Meer, RW, Pattynama, PMT, van Strijen, MJL, van den Berg-Huijsmans, AA, Hartmann, IJC, Putter, H, de Roos, A, Huisman, MV: Right ventricular dysfunction and pulmonary obstruction index at helical CT: prediction of clinical outcome during 3-month follow-up in patients with acute pulmonary embolism. Radiology  2005;235:798–803.

36.       Douketis, JD: Perioperative Management of Patients Receiving Anticoagulant or Antiplatelet Therapy: A Clinician-Oriented and Practical Approach. Hosp Pract  2011;39:41–53.

37.       McBane, RD, Wysokinski, WE, Daniels, PR, Litin, SC, Slusser, J, Hodge, DO, Dowling, NF, Heit, JA: Periprocedural Anticoagulation Management of Patients With Venous Thromboembolism. Arterioscler Thromb Vasc Biol  2010;30:442–448.

38.       Kim, HC, Park, J-H, Song, J-M, Hwang, J-J, Hong, S-B, Oh, Y-M, Lee, S-D, Lee, JS: Safety of early orthopedic surgery in patients with intermediate/low- or low-risk pulmonary embolism. J Thorac Dis  2020;12:232–239.

39.       Kearon, C, Hirsh, J: Management of Anticoagulation before and after Elective Surgery. N Engl J Med  1997;336:1506–1511.

40.       Urbankova, J, Quiroz, R, Kucher, N, Goldhaber, SZ: Intermittent pneumatic compression and deep vein thrombosis prevention: A meta-analysis in postoperative patients. Thromb Haemost  2005;94:1181–1185.

41.       Siddiqui, AU: Pulmonary Embolism as a Consequence of Applying Sequential Compression Device on Legs in a Patient Asymptomatic of Deep Vein Thrombosis. CASE Rep  2000;92:3.

42.       Dunn, AS, Spyropoulos, AC, Turpie, AGG: Bridging therapy in patients on long-term oral anticoagulants who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT). J Thromb Haemost  2007;5:2211–2218.

43.       Schulman, S, Kearon, C, Kakkar, AK, Mismetti, P, Schellong, S, Eriksson, H, Baanstra, D, Schnee, J, Goldhaber, SZ, RE-COVER Study Group: Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med  2009;361:2342–2352.

44.       Agnelli, G, Buller, HR, Cohen, A, Gallus, AS, Lee, TC, Pak, R, Raskob, GE, Weitz, JI, Yamabe, T: Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost JTH  2015;13:2187–2191.

45.       EINSTEIN Investigators, Bauersachs, R, Berkowitz, SD, Brenner, B, Buller, HR, Decousus, H, Gallus, AS, Lensing, AW, Misselwitz, F, Prins, MH, et al.: Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med  2010;363:2499–2510.

46.       EINSTEIN–PE Investigators, Büller, HR, Prins, MH, Lensin, AWA, Decousus, H, Jacobson, BF, Minar, E, Chlumsky, J, Verhamme, P, Wells, P, et al.: Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med  2012;366:1287–1297.

47.       Deguchi, J, Nagayoshi, M, Miyahara, T, Nishikage, S, Kimura, H, Shigematsu, K, Miyata, T: Do inferior vena cava filters reduce the risk of acute pulmonary embolism in preoperative patients with venous thromboembolism? Surg Today  2010;40:533–537.

48.       Athanasoulis, CA, Kaufman, JA, Halpern, EF, Waltman, AC, Geller, SC, Fan, C-M: Inferior Vena Caval Filters: Review of a 26-year Single-Center Clinical Experience. Radiology  2000;216:54–66.

49.       Decousus, H, Leizorovicz, A, Parent, F, Page, Y, Tardy, B, Girard, P, Laporte, S, Faivre, R, Charbonnier, B, Barral, F-G, et al.: A Clinical Trial of Vena Caval Filters in the Prevention of Pulmonary Embolism in Patients with Proximal Deep-Vein Thrombosis. N Engl J Med  1998;338:409–416.

50.       Kim, H, Han, Y, Ko, G-Y, Jeong, M-J, Choi, K, Cho, Y-P, Kwon, T-W: Clinical Outcomes of a Preoperative Inferior Vena Cava Filter in Acute Venous Thromboembolism Patients Undergoing Abdominal-Pelvic Cancer or Orthopedic Surgery. Vasc Spec Int  2018;34:103–108.

51.       Angel, LF, Tapson, V, Galgon, RE, Restrepo, MI, Kaufman, J: Systematic review of the use of retrievable inferior vena cava filters. J Vasc Interv Radiol JVIR  2011;22:1522-1530.e3.

52.       Al-Hakim, R, Kee, ST, Olinger, K, Lee, EW, Moriarty, JM, McWilliams, JP: Inferior vena cava filter retrieval: effectiveness and complications of routine and advanced techniques. J Vasc Interv Radiol JVIR  2014;25:933–939; quiz 940.

53.       Nicholson, W, Nicholson, WJ, Tolerico, P, Taylor, B, Solomon, S, Schryver, T, McCullum, K, Goldberg, H, Mills, J, Schuler, B, et al.: Prevalence of fracture and fragment embolization of Bard retrievable vena cava filters and clinical implications including cardiac perforation and tamponade. Arch Intern Med  2010;170:1827–1831.

54.       Jaff, MR, McMurtry, MS, Archer, SL, Cushman, M, Goldenberg, N, Goldhaber, SZ, Jenkins, JS, Kline, JA, Michaels, AD, Thistlethwaite, P, et al.: Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation  2011;123:1788–1830.

55.       Wan, S, Quinlan, DJ, Agnelli, G, Eikelboom, JW: Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation  2004;110:744–749.

56.       Samoukovic, G, Malas, T, de Varennes, B: The role of pulmonary embolectomy in the treatment of acute pulmonary embolism: a literature review from 1968 to 2008☆. Interact Cardiovasc Thorac Surg  2010;11:265–270.

57.       Chatterjee, S, Chakraborty, A, Weinberg, I, Kadakia, M, Wilensky, RL, Sardar, P, Kumbhani, DJ, Mukherjee, D, Jaff, MR, Giri, J: Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA  2014;311:2414–2421.

58.       Kline, JA, Nordenholz, KE, Courtney, DM, Kabrhel, C, Jones, AE, Rondina, MT, Diercks, DB, Klinger, JR, Hernandez, J: Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost JTH  2014;12:459–468.

59.       Goldhaber, SZ, Haire, WD, Feldstein, ML, Miller, M, Toltzis, R, Smith, JL, Taveira da Silva, AM, Come, PC, Lee, RT, Parker, JA: Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet Lond Engl  1993;341:507–511.

60.       Zhang, K, Zeng, X, Zhu, C, Xu, L, Fu, X, Jiang, H, Wang, J, Lu, W: Successful thrombolysis in postoperative patients with acute massive pulmonary embolism. Heart Lung Circ  2013;22:100–103.

61.       Mardinger, C, Boiteau, PJE, Kortbeek, JB: Thrombolysis of Postoperative Acute Pulmonary Embolism with a Thrombus in Transit. Case Rep Med  2020;2020:7561986.

62.       Chalela, JA, Katzan, I, Liebeskind, DS, Rasmussen, P, Zaidat, O, Suarez, JI, Chiu, D, Klucznick, RP, Jauch, E, Cucchiara, BL, et al.: Safety of intra-arterial thrombolysis in the postoperative period. Stroke  2001;32:1365–1369.

63.       Wright, HJM, Campbell, R, Ellis, S, Batley, M: Thrombolysis for postoperative pulmonary embolism: limiting the risk of haemorrhage. Thorax  2011;66:452.

64.       Kuo, WT, Banerjee, A, Kim, PS, DeMarco, FJ, Levy, JR, Facchini, FR, Unver, K, Bertini, MJ, Sista, AK, Hall, MJ, et al.: Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): Initial Results From a Prospective Multicenter Registry. Chest  2015;148:667–673.

65.       Engelberger, RP, Moschovitis, A, Fahrni, J, Willenberg, T, Baumann, F, Diehm, N, Do, D-D, Baumgartner, I, Kucher, N: Fixed low-dose ultrasound-assisted catheter-directed thrombolysis for intermediate and high-risk pulmonary embolism. Eur Heart J  2015;36:597–604.

66.       Kucher, N, Boekstegers, P, Müller, OJ, Kupatt, C, Beyer-Westendorf, J, Heitzer, T, Tebbe, U, Horstkotte, J, Müller, R, Blessing, E, et al.: Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation  2014;129:479–486.