Senior Scientist, Clinical Epidemiology, Ottawa Hospital Research Institute

My most significant contributions have been in the areas of (a) diagnosis of pulmonary embolism (PE) and deep vein thrombosis (DVT), (b) treatment and (c) meta-analysis. With respect to diagnosis, my most important work has been the introduction of clinical assessment in the diagnostic process for patients with suspected DVT or PE. Clinical assessment was felt to be irrelevant and of no use in the diagnostic process until our paper was published in the Lancet in 1995. In this study we were able to demonstrate that patients could be classified as low, moderate or high probability for DVT. This has subsequently led to an improvement in the diagnostic process in terms of safety, convenience and cost. Subsequent studies have demonstrated the utility of the clinical assessment in outpatients, inpatients and patients presenting to the emergency department. My research continues to build on this aspect of investigation. Many investigators now use the clinical model and it is widely quoted. We have carried this diagnostic work into the area of PE and developed a clinical model that has shown similar utility and this has been used in a management strategy. I have presented this work at international meetings and we have also demonstrated the utility of D-dimer testing in this group of patients. Most recently, we showed that we can eliminate diagnostic testing in the many patients with suspected DVT or PE who have a low clinical probability and a negative D-dimer.

We have published the largest randomized trial ever performed in patient with suspected DVT. This was recently published in the New England Journal and definitely demonstrated the utility of adding D-dimer testing to clinical probability in the diagnostic process.

I have also published several meta-analyses that have been important. In 1995, we were able to demonstrate that there is a significant difference in the accuracy of ultrasound for the diagnosis of patients with asymptomatic DVT in post-operative patients. This study started a paradigm change in interpretation of diagnostic tests that sensitivity and specificity of a diagnostic can vary between patient populations and led to a better understanding of the fact that asymptomatic and symptomatic DVT are different diseases. This knowledge has led to an appreciation that DVT developing post-operatively have a very different natural history than symptomatic DVT and has led to another paradigm shift. Symptomatic DVT, not those detected by venography post-op, are the relevant clinical issue. In one of my publications, with this paradigm shift it can be demonstrated that Warfarin is the most cost-effective method to prevent post-op DVT. In work with our collaborative group in a randomized trial, we demonstrated the utility of a Warfarin nomogram. The nomograms we have published have been adopted across the world and also in guidelines, including those recently published in Thorax 2003. (see publication list). Our group has also published the largest series on the use of low molecular weight heparin for acute venous thrombosis in pregnancy and we have been pioneers in the outpatient treatment of pulmonary embolism

In the areas of treatment of DVT and PE, I demonstrated that a wide spectrum of patients can be treated on an outpatient basis. The importance of expanding the eligibility of outpatient treatment is that we now know it is safe to treat the vast majority of patients with DVT or PE on an outpatient basis and this is becoming the norm worldwide. Previous studies had enrolled selected and limited numbers of patients for outpatient therapy. As importantly, in a study performed with my then graduate student, Marc Rodger, we demonstrated that low molecular weight heparin is more cost effective than unfractionated heparin. In the later case, this conclusion holds true even if patients are treated as outpatients with unfractionated heparin. This has eased the transition to low molecular weight heparin in venous thrombosis in institutions across Canada. We have since demonstrated in a large randomized controlled trial that there are no differences between low molecular weight heparin preparations (submitted to Annals of Internal Medicine). More recently, I have looked at trying to predict bleeding risk (Arch Intern Med 2003) and VTE recurrence. More recently, our work is also involving genetic thrombophilias. Through rigorous study design, we have demonstrated that the ACE gene is protective against venous thrombosis. We have also demonstrated by a systematic review, accurate rates of venous thromboembolic events in first degree relatives of patients with a thrombophilia. This is forming the foundation for a larger trial, a study that we are currently performing in a pilot format.

Future Research:

Dr. Wells is Professor of Medicine and Canada Research Chair who has been performing research in venous thromboembolic diseases for over a decade now. He has participated in several large clinical trials which have required collections of bios samples. Through his Canada Research Chair, he established a genetics research lab in conjunction with molecular biologist, Dr. Frederique Tesson. This laboratory has already been involved in the collection of samples and DNA assays in the ACE study which was a case control study of over 300 cases and controls involving idiopathic venous thrombosis. He has also been collecting samples throughout the conduct of the First Degree Relative (FDR) pilot study funded by CIHR. Dr. Nancy Carson, molecular biologist, co-supervises Dr. Wells' laboratory with him and is responsible for quality assurance of assays. Dr. Wells is also the Director of a Program Grant, recently funded by Heart and Stroke Foundation of Ontario, which endeavours to perform research in the area of thrombophilia. This research will carry through all of the four so-called pillars of the CIHR, including gene discovery right through to policy management. This is the mandate of Dr. Wells' research chair and the Program Grant and this grant fits in perfectly with this mandate. So the resources provided to the Program Grant will ensure the smooth running of this proposed application and will, hopefully, enable future projects to evolve out of it.

Major Awards:

Grants Currently Held:

Most Recent Publications (2009 -2010)

1.  Stein PD, Sostman HD, Dalen JE, Bailey DL, Bajc M, Goldhaber SZ, Goodman LR, Gottschalk A, Hull RD, Matta F, Pistolesi M, Tapson VF, Weg JG, Wells PS, Woodard PK for the Consensus Group.  Controversies in Diagnosis of Pulmonary Embolism. In Press. Clin Appl Thrombosis / Hemostasis 2010.

2.  Diamantopoulos A, Lees M, Wells PS, Forster F, Ananthapavan J, McDonald H. Cost-effectiveness of rivaroxaban versus enoxaparin for the prevention of postsurgical venous thromboembolism in Canada. Thromb Haemost 2010; 104(4):760-770. (October)

3.  Erkens P, Gandara E, Wells PS, Shen AY, Bose G, Le Gal G, Rodger M, Prins MH, Carrier M.  Safety of outpatient treatment in acute pulmonary embolism. In Press. JTH 2010.

4.  Rodger MA, Le Gal G, Carrier M, Betancourt MT, Kahn SR, Wells PS, Anderson DA, Lacut K, Chagnon I, Solymoss S,  Crowther M, Perrier A, White R, Vickars L, Ramsay T, Kovacs MJ. Serum Lipoprotein (a) levels in patients with first unprovoked venous thromboembolism is not associated with subsequent risk of recurrent VTE. Thromb Res 2010;126 (3):222-226.

5.  Kovacs MJ, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G, Solymoss S, Crowther M, Perrier A, Ramsay T, Betancourt MT, Rodger MA. Patients with a first symptomatic unprovoked DVT are at higher risk of recurrent VTE than patients with a first unprovoked PE. J Thromb Haemost 2010;8:1926-1932.

6.  Borah BJ, McDonald H, Wells P, Sengupta N, Supina D, Kwong L. Venous thromboprophylaxis duration and outcomes in orthopaedic patients in a US Health-plan. In Press J Managed Care 2010 (November)

7.  Le Gal G, Kovacs MJ, Carrier M, Do K, Khan SR, Wells PS, Anderson DA, Chagnon I, Solymoss S, Crowther M, Righini M, Lacut K, White RH, Vickars L, Rodger M. Risk of recurrent venous thromboembolism after a first oestrogen-associated episode. Data from the REVERSE cohort study. Thromb Haemost 2010;104(3):498-503.

8.  Gretarsdottir S, Baas AF, Thorleifsson G, Holm H, den Heijer M, de Vries J-P, Kranendonk SE, Zeebregts CJ, van Sterkenburg SM, Geelkerken RH, van Rij AM, Williams MJA, Boll APM, Kostic JP, Jonasdottir Ad, Jonasdottir As, Walters GB, Masson G, Sulem P, Saemundsdottir J, Mouy M, Magnusson KP, Tromp G, Elmore JR, Sakalihasan N, Limet R, Defraigne J-O, Ferrell RE, Ronkainen A, Ruigrok YM, Wijmenga C, Groggee DE, Shah SH, Granger CB, Quyyumi AA, VaccarinoV, Patel RS, Zafari AM, Levey AI, Austin H, Girelli D, Pignatti PF, Martinelli N, Malerba G, Trabetti E, Becker LC, Becker DM, Reilly MP, Rader DJ, Mueller T, Dieplinger B, Haltmayer M, Urbonavicius S, Lindblad B, Gottsater A, Gaetani E, Pola  R, Wells PS, Rodger M, Forgie M, Langlois N, Corral J, Vicente V, Fontcuberta J, Espana F, Grarup N,, Jorgensen T, Witte DR, Hansen T, Pedersen O, Aben KK, de Graaf J, Holewijn S, Folkersen L, Franco-Cereceda V, Eriksson P, Collier DA, Stefansson H, Steinthorsdottir V, Rafnar T, Valdimarsson EM, Magnadottir HB, Sveinbjornsdottir S, Olafsson I, Magnusson MK, Palmason R, Haraldsdottir V, Andesen K, Onundarson PT, Thorgeirsson G, Kiemeney LA, Powell JT, Carey DJ, Kuivaniemi H, Lindholt JS, Jones GT, Kong A, Blankensteijn JD, Matthiasson SE, Thorsteinsdottir U, Stefansson K.  Genome-side association study identifies a sequence variant with the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm. Nature Genetics 2010; 42(8):692-697. (July)

9.  Carrier M, Righini M, Wells PS, Perrier A, Anderson DR, Rodger MA, Pleasance S, Le Gal G. Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies. J Thromb Haemost 2010; 8(8): 1716-22, (June)

10.  Carrier M, Le Gal G, Rodger M, Wells PS, Tao H, Danovitch KE, Levac-Mbanga A. Should we screen patients with unprovoked venous thromboembolism for occult cancers? A pilot study. Blood Coag Fibrinolysis 2010; 21(7):709-710.

11.  Gandara E, Wells PS. Will there be a role for genotyping in warfarin therapy? Current Opinion in Hematology 2010; 17(5):439-443.

12.  Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: Case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010;152(9):578-589.

13.  Kahn S, Shrier I, Shapiro S, Houweling A, Hirsch A, Kearon C, Rodger M, Kovacs MJ, Wells PS, Anderson DR, Reid R. Six month exercise training program to treat the post-thrombotic syndrome: A randomized, controlled two-center trial. In Press. CMAJ 2010.

14.  Wells PS, Majeed H, Kassem S, Fleming S, Langlois N, Gin B, Clermont J, Taljaard M. A regression model to predict warfarin dose from clinical variables and polymorphisms in CYP2C9, CYP4F2, and VKORC1: Derivation in a population with predominantly venous thromboembolism. Thromb Res 2010; 125:e259-e264.

15.  Boodhwani W, Hamilton A, de Varennes B, Mesana T, Williams K, Wells G, Nathan H, Dupuis J, Babaev A, Wells P, Rubens FD.  A multi-centre randomized controlled trial to assess the feasibility of testing modified ultrafiltration as a blood conservation technology in cardiac surgery. J Thorac Cardiovasc Surg 2010; 139(3):701-706.

16.  Shen AY, Le Gal G, Dennie C, Wells PS, Carrier M. Incidence and clinical outcomes of occult cancers detected by computed tomographic pulmonary angiography in patients with acute pulmonary embolism. J Thromb Haemost 2010; 8(5):1128-29.

17.  Crowther M, Garcia D,  Ageno W, Wang L, Witt DM, Clark NP, Blostein MD, Kahn SR, Schulman S, Kovacs MJ, Rodger MA, Wells PS, Anderson DR, Ginsberg J, Selby R, Siragusa S, Silingardi M, Dowd MB, Kearon C. Oral vitamin K effectively treats INR values in excess of 10.0: Results of a prospective cohort study. Thromb Haemost 2010; 104(1):118-121

18.  Schulman S, Anderson DR, Bungard TJ, Jaeger T, Kahn S, Wells PS, Wilson J-A. Direct and indirect costs of management of long-term warfarin therapy in Canada. J Thromb Haemost 2010;8(10):2192-2200.

19.  Le Gal G, Carrier M, Tierney S, Majeed H, Rodger M, Wells PS. Prediction of the warfarin maintenance dose after completion of the 10 mg initiation nomogram – do we really need genotyping? J Thromb Haemost 2010 8(1):90-94.

20.  Scarvelis D, Anderson JL, Davis L, Forgie M, Lee J, Petersson L, Ramsay T, Wells PS. Hospital mortality due to pulmonary embolism and an evaluation of the usefulness of preventative interventions.  Thromb Res 2010; 125:166-170.

21.  Couturaud F, Leroyer C, Julian JA, Kahn SR, Ginsberg JS, Wells PS, Douketis JD, Mottier D, Kearon C. Factors that predict risk of thrombosis in relatives of patients with unprovoked venous thromboembolism. Chest 2009; 136(6):1537-45. (December)

22.  Wells PS, Le Gal G, Tierney S, Carrier M. Practical application of the 10-mg warfarin initiation nomogram. Blood Coag Fibrinolysis 2009; 20:403-408.

23.  Le Gal G, Kovacs MJ, Carrier M, Do K, Kahn SR, Wells PS, Anderson DR, Chagnon I, Solymoss S, Crowther M, Righini M, Perrier A, White RH, Vickars L, Rodger M.  Validation of a diagnostic approach to exclude recurrent venous thromboembolism. J Thromb Haemost 2009;7(5):752-59.(May)

24.  Wells PS, Louzada ML, Talijaard M, Anderson DR, Kahn SR, Langlois NJ, Rutberg J, Kovacs MJ, Rodger MA. A pilot study to assess the feasibility of a multicenter cluster randomized trial for the management of asymptomatic persons with a thrombophilia. J Genet Counsel 2009;18(5):475-482

25.  Crowther MA, Ageno W, Garcia D, Wang L, Witt DM, Clark NP, Blostein MD, Kahn SR, Vesely SK, Schulman S, Kovacs MJ, Rodger MA, Wells PS, Anderson DR, Ginsberg J, Selby R, Siragusa S, Silingardi M, Dowd MB, Kearon C. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin. A randomized trial. Ann Intern Med  2009 ;150:293-300. (March)

26.  Carrier M, Righini M, Karami Djurabi R, Huisman MV, Perrier A, Wells PS, Rodger M, Wuillemin WA, Le Gal G. VIDAS© D-dimer in combination with clinical pre-test probability to rule out pulmonary embolism. A systematic review of management outcome studies. Thromb Haemost 2009; 101(5):886-892. (May)

27.  Douma RA, Gibson NS, Gerdes VEA, Perrier A, Buller HR, Wells PS, Perrier A, Le Gal G. Validity and clinical utility of the simplified Wells rule for assessing clinical probability for the exclusion of  pulmonary embolism. Thromb Haemost 2009;101:197-200.

28.  Louzada ML, Majeed H, Wells PS. Efficacy of low-molecular-weight heparin versus Vitamin K antagonists for long term treatment of cancer-associated venous thromboembolism in adults: a systematic review of randomized controlled trials. Thromb Res 2009;123:837-844. (April)

29.  Lazo-Langner A, Rodger MA, Wells PS. Lessons learned from Ximelagatran: Issues for future studies evaluating new oral direct thrombin inhibitors for venous thromboembolism prophylaxis in orthopedic surgery. Clin Appl Thrombosis / Haemostasis 2009; 15(3):316-26. (May-June)

Note: This is not a complete list of publications. More publications may be available in The Ottawa Hospital Library database and Pubmed (search by last name and initials).