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Brief Communication: High Incidence of Venous Thrombotic Events Among Patients With Wegener Granulomatosis: The Wegener's Clinical Occurrence of Thrombosis (WeCLOT) Study

Posted on: Saturday, 23 April 2005, 03:00 CDT

Background: Venous thrombotic events (VTEs) have been observed in Wegener granulomatosis, but the incidence rate is not known.

Objective: To measure the incidence of VTEs in patients with Wegener granulomatosis.

Design: Prospective, observational cohort study.

Setting: A multicenter, randomized, double-blind, placebo- controlled treatment trial for Wegener granulomatosis.

Patients: 180 patients with Wegener granulomatosis enrolled during periods of active disease.

Measurements: Venous thrombotic events (deep venous thromboses or pulmonary emboli) were documented and confirmed prospectively. Incidence rates were calculated on the basis of time to first VTE.

Results: Thirteen patients had VTEs before enrollment. During 228 person-years of prospective follow-up, 16 VTEs occurred in 167 patients with no history of VTE. Median time from enrollment to VTE for patients with an event was 2.1 months. The incidence of VTE among patients with Wegener granulomatosis was 7.0 per 100 person- years (95% CI, 4.0 to 11.4).

Limitations: Although prospectively recorded, screening for VTEs did not occur.

Conclusions: The incidence rate of VTEs in Wegener granulomatosis is high when compared with available rates in the general population, patients with lupus, and patients with rheumatoid arthritis. These results have important implications for clinical care of patients with Wegener granulomatosis.

Ann Intern Med. 2005;142:620-626. www.annals.org

Wegener granulomatosis is characterized by inflammation of small- and medium-sized vessels and granulomatous inflammation of various organs (1, 2). The involvement of the venous system in Wegener granulomatosis has received little attention in the past, with only a few reported cases of venous thrombosis (3-5), and textbooks and review articles do not mention an increased risk for venous thrombotic events (VTEs) (1, 6, 7).

Early in the enrollment phase of a multicenter treatment trial for Wegener granulomatosis (8-10), several patients had VTEs, including both deep venous thromboses and pulmonary emboli. This observation led to our investigation of VTE incidence in patients with Wegener granulomatosis.

METHODS

Patients and Visit Schedule

The Wegener's Granulomatosis Etanercept Trial (WGET) is a multicenter, randomized, double-blind, placebo-controlled study of the efficacy of etanercept, 25 mg subcutaneously twice weekly, in addition to conventional immunosuppressive therapy with glucocorticoids and either methotrexate or cyclophosphamide. Details of the trial design and study results have been published (8, 10). All patients fulfilled the modified American College of Rheumatology Classification Criteria for Wegener granulomatosis, had no history of either exposure to inhibitors of tumor necrosis factor-α or a malignant condition, and had no evidence of active infection upon enrollment (8). All patients in WGET were enrolled and randomly assigned to either the active experimental medication or placebo during a period of active vasculitis (flare). Patients were evaluated at study visits every 3 months. Data collection included a full interim medical history with determination of Wegener granulomatosis disease activity, physical examination, laboratory studies, and assessment and review of adverse events.

We measured Wegener granulomatosis disease activity by using the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) (11), which considers all manifestations of active disease present during the 28-day period before the date of assessment. A score of 1 or greater indicates active disease, and a score of 0 indicates remission. Patients were required to have a score of 3 or greater to be enrolled in the trial. Investigators measured cumulative disease damage with the Vasculitis Damage Index (12). "Severe" disease was defined as having a life- or organ-threatening manifestation; other patients were considered to have "limited" disease (8).

The patients who we observed for incidence of VTEs included all 180 patients enrolled in WGET. Details of the baseline demographic and clinical characteristics of this study cohort have been published (9).

Diagnosis and Documentation of VTEs

All VTEs in WGET were considered serious adverse events necessitating a separate written report documenting the event and outcome (8). A patient was considered to have had a VTE if the event was clinically apparent and was confirmed by diagnostic studies. Clinical evidence of VTEs included edematous or painful limbs, dyspnea, hypoxemia, chest pain, hemoptysis, or other features of deep venous thrombosis or pulmonary embolism. Diagnostic confirmation included results of vascular ultrasonography, impedance plethysmography, ventilation-perfusion scanning, computed tomographic angiography, spiral computed tomograpy, venography, or angiography.

Investigators collected detailed clinical data on VTEs on all patients for all events that occurred before and during WGET. A study physician completed a separate standardized thrombosis event form for each VTE on the basis of information obtained from patients, nonstudy physicians, and medical records review. The form included the date of event, clinical details of event, diagnostic test results, and determination of Wegener granulomatosis dis ease status at the time of event. We excluded thromboses of hemodialysis vascular accesses from these analyses.

For our investigation of VTE incidence, the observation period started with the date of enrollment of the first patient (9 June 2000) and ended 3 months after the final patient was enrolled (31 December 2002).

Statistical Analyses

We evaluated differences among patient characteristics in the Wegener granulomatosis cohort at the start of the observation period with the Wilcoxon rank-sum test for continuous variables and with either chi-square or Fisher exact tests for categorical variables (SAS, version 8.0, SAS Institute, Inc., Cary, North Carolina). We calculated the incidence rate and 95% CIs for VTEs by using Stata, version 8.0 (cii command) (Stata Corp., College Station, Texas). The cumulative incidence curve is based on Kaplan-Meier estimates.

Role of the Funding Sources

The National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, the U.S. Food and Drug Administration Office of Orphan Products, and the Amgen Corporation supported this study. The Amgen Corporation provided the data on the incidence of VTEs among patients with rheumatoid arthritis. The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the paper for publication.

RESULTS

Patients

We included data from all 180 study patients enrolled in WGET in our study. Table 1 outlines key demographic characteristics and clinic data for the entire cohort and the VTE subgroups.

Incidence Rates of VTE in Wegener Granulomatosis and Comparison Groups

At the end of the observation period, 29 of 180 patients (16%) with Wegener granulomatosis had had a VTE at some time: 13 (7.2%) had a history of VTE before WGET enrollment and 16 (8.9%) had first- time VTEs during WGET. The 16 new VTEs among the 167 patients with no history of VTE occurred over 228 person-years of observation, yielding an incidence rate of 7.0 per 100 person-years (95% CI, 4.0 to 11.4). The rates of VTEs did not differ between the etanercept and placebo groups.

Clinical Characteristics of Patients with VTEs

Appendix Table 1 and 2 (available at www.annals.org) outline the clinical details of all VTEs among the Wegener granulomatosis study sample during and before WGET, respectively. The median time from WGET enrollment (active disease) to VTE in patients who experienced an event was 2.07 months (range, 0.07 to 21.13 months). The Figure shows the time to first VTE for the Wegener granulomatosis group. No participant had more than 1 VTE during WGET.

Table 1. Baseline Demographic Characteristics and Clinical Data of Full Study Cohort and Venous Thrombotic Event Subgroups within Wegener Granulomatosis Cohort*

Figure. Time to first venous thrombotic event (VTE) among patients with Wegener granulomatosis.

Ten of 16 patients (63%) had active Wegener granulomatosis at the time of the event during WGET. In addition, 11 of the 16 patients (69%) were found to have active Wegener granulomatosis on the study visit before the event, including 3 of the 7 patients whose Wegener granulomatosis was not active at the time of the event. Visits for these 3 patients occurred 14, 33, and 49 days, respectively, before the event. Thus, for 13 of 16 patients (81%) who had VTEs during WGET, Wegener granulomatosis was active at the time of the event or within 2 months before the event.

Before WGET enrollment, 18 VTEs occurred among 13 patients. Information on Wegener granulomatosis disease status was available for 12 of 13 first VTEs: Wegener granulomatosis was active in 10 of 12 cases (83%) at the time of the event. Seven of the 13 first VTEs occurred within the 3 months before WGET randomization, including 3 VTEs occurring less than 2 weeks before randomization. We excluded these 7 events from prospective ca\lculation of incident VTE.

There were few differences between the 16 patients who had VTE during WGET and the 151 WGET participants who had no history of VTE (Table 1). Compared with participants who did not have an event, those who had a VTE were older at baseline (mean age, 57.5 years vs. 48.6 years; P = 0.039). Aspirin use did not differ between patients with or without VTEs (2 of 16 patients vs. 14 of 151 patients; P > 0.2). Length of hospitalization (4.5 days vs. 6.0 days; P > 0.2) and the proportion of patients hospitalized (50.0% vs. 34.4%, P > 0.2) also did not differ between patients with VTE during WGET and those without a VTE.

DISCUSSION

To our knowledge, our study is the first to investigate the incidence of VTE in Wegener granulomatosis using a large, well- characterized study cohort and to identify deep venous thrombosis as an important clinical feature of Wegener granulomatosis.

Most VTEs in the WGET occurred either during periods of unequivocally active disease or within 2 months of a documented disease flare. Similarly, most VTEs that occurred before the start of the WGET observation period were also associated with active vasculitis. These results suggest that the increased risk for thrombosis bears an important relationship to disease activity in Wegener granulomatosis.

Comparison against other groups of patients with VTEs is helpful to appreciate the magnitude of the increased incidence of VTEs in Wegener granulomatosis (Table 2). In a healthy, male, Swedish population, 65 VTEs occurred over 30 years of follow-up, totaling 21 007 observation-years and resulting in an incidence rate of first VTE of 0.31 per 100 person-years (CI, 0.4 to 0.4 per 100 person- years) (13). Comparison with this group is relevant because the age of the sample was similar to that of the WGET cohort; the clinical follow-up rate was 98.2%; and data on VTEs, including both deep venous thromboses and pulmonary emboli, were ascertained prospectively and defined carefully.

Comparing the VTE rate in Wegener granulomatosis with the rate in a cohort of patients with systemic lupus erythematosus is of interest because lupus is also a chronic, recurring, inflammatory, autoimmune disease. Importantly, systemic lupus erythematosus is associated with a significantly increased incidence of VTEs, and a high degree of clinical suspicion of thrombotic disease is now part of routine care. Some clinical authorities even suggest administering prophylaxis against VTEs for subsets of patients with systemic lupus erythematosus. We obtained comparison data from the Hopkins Lupus Cohort study (14), in which carefully documented VTEs of a large, well-characterized cohort were analyzed. Between 1 January 1997 and 31 December 2002, a total of 922 patients had more than 1 visit, 764 of whom had evidence of active disease (lupus activity score ≥ 1 [15, 16]) during at least 1 visit. Twenty- one of these 764 patients had a first VTE during 2094 person-years of observation, for a VTE incidence rate of 1.0 per 100 person- years (CI, 0.6 to 1.5 per 100 person-years).

To facilitate investigating the potential contribution of etanercept to the development of VTEs among patients with Wegener granulomatosis, the Amgen Corporation (Thousand Oaks, California) provided data on VTE incidence on an observational cohort of 1271 patients. These patients were receiving etanercept for rheumatoid arthritis from 1 August 1993 through 31 December 2002 and were followed prospectively as part of long-term safety evaluations of etanercept. This is also another population with chronic inflammatory disease. Among these patients, 12 VTEs occurred during the observation period of 4551 person-years, resulting in a VTE incidence rate of 0.26 per 100 person-years (CI, 0.1 to 0.5).

The final comparison is with patients with histories of VTEs, a population known to have a substantially higher risk for recurrent VTE and for whom treatment with long-term anticoagulation has been advised. A multicenter, randomized, placebo-controlled trial evaluating the efficacy of low-dose warfarin for secondary prevention of VTEs (17) enrolled 508 participants with idiopathic VTEs who had completed full-dose anticoagulant therapy: 253 were randomly assigned to the placebo group and were followed for an average of 2.1 years. In the placebo group, 37 VTEs occurred over 514 person-years for an incidence rate of recurrent VTE of 7.20 per 100 person-years (CI, 5.1 to 9.8) (17).

The comparisons between the rate of first VTE in patients with Wegener granulomatosis and the rate in the groups outlined in Table 2 highlight the large increased risk for VTEs among patients with Wegener granulomatosis. This rate far exceeds the general population rate and the rate for patients with lupus or rheumatoid arthritis, and it is similar to the rate of recurrent thrombosis among patients with recent VTE.

The finding of an increased incidence of venous thrombotic disease in Wegener granulomatosis raises important pathophysiologic questions. Wegener granulomatosis rarely involves medium or large veins, and this finding might indicate that some disruption of venous endothelium in Wegener granulomatosis creates a microenvironment conducive to thrombosis formation but not otherwise clinically apparent. Alternatively, some, as yet unknown, humoral hypercoagulable factors may be produced during active disease, or there could be a genetic link between susceptibility to Wegener granulomatosis and predisposition to thrombosis. Measurements of the incidence of known acquired and genetic risk factors for VTE among our study cohort are the subjects of future investigations. Chronic illness or chronic inflammation is not likely to be a major independent risk factor for thrombosis in Wegener granulomatosis given the much higher relative risk for VTEs in Wegener granulomatosis compared with systemic lupus erythematosus or rheumatoid arthritis. Thus, investigation of the links between Wegener granulomatosis and venous thrombosis may help uncover new insights into the basic biology of Wegener granulomatosis, and such studies are being planned. The absence of a full pathophysiologic understanding of the observed increased VTE incidence in Wegener granulomatosis does not diminish the importance of this observation.

Table 2. Venous Thrombotic Event Incidence Rates for Wegener Granulomatosis Cohort and Comparison Groups*

Table 2. Venous Thrombotic Event Incidence Rates for Wegener Granulomatosis Cohort and Comparison Groups*

Our study has several notable strengths. For purposes of incidence calculations, we performed our prospective cohort study at 8 expert vasculitis centers with rigorous data quality controls. We collected all data with standardized data forms, and no data on VTE events during the parent study were missing. We designed the data analysis to prevent overestimating VTE incidence by taking the more conservative approach of excluding VTEs present at study entry, patients with VTEs before randomization, and vascular access thromboses.

Our study also has a few limitations. The WGET did not include a prospective screening protocol for deep venous thromboses. Consequently, investigators counted only clinically apparent VTEs for incidence estimates. However, the clinically apparent events are of primary importance, and the study design, conducted in concert with a rigorously performed clinical trial, made the likelihood of missing any VTEs low. In addition, counting subclinical VTEs would have inflated the incidence rate that we observed. Thus, the results reported in our study are conservative estimates. The generalizability of these data to all patients with Wegener granulomatosis may be questioned. However, the clinical features of the cohort (9, 10) are similar to the clinical features of cohorts in other previously published studies from the United States and Europe (6, 7). Furthermore, while we excluded some potential study patients with Wegener granulomatosis because they had comorbid conditions that might influence their risk for VTE, including malignant conditions and pregnancy, these conditions probably would have increased the VTE incidence. Therefore, these data are generalizable to a large percentage of patients with Wegener granulomatosis whose vasculitis is active.

Our study demonstrates that patients with Wegener granulomatosis are at increased risk for VTEs. Our results may have several clinical implications for the care of patients with Wegener granulomatosis and suggest a future research agenda. At a minimum, clinicians caring for patients with Wegener granulomatosis should now maintain a heightened awareness of the risks for VTE and a lower threshold for evaluating patients for possible deep venous thrombosis or pulmonary embolism. Although pulmonary embolism has always been a consideration for patients presenting with dyspnea or hemoptysis, VTE has not been considered "high on the differential" for patients with established Wegener granulomatosis who present with such clinical findings. Hemoptysis in a patient with Wegener granulomatosis is almost always considered to be caused by alveolar hemorrhage or bleeding from pulmonary nodules, and these manifestations are often recurrent. Previous disease and subsequent scarring may further add to the challenge of establishing a diagnosis for new clinical findings. A similar heightened awareness of the risks for VTEs, as well as the discovery of other "hypercoagulable" clinical states (for example, malignant conditions) and mutations affecting the coagulation system, has led to changes in clinical practice in the care of patients with systemic lupus erythematosus and other conditions. In addition, these data suggest that future prospective trials should be conducted to examine the roles of screening, prophylaxis, and treatment strategies for VTE in Wegener granulomatosis.

Permission to reproduce material from Annals of Int\ernal Medicine: To purchase a single copy of Annals, contact the American College of Physicians Customer Service Department at 800-523-1546. For permissions information, contact Stacey Gallo, Permissions Coordinator, at 800-523-1546, extension 2678. For bulk reprint information, contact Tracy Taylor, Reprints Coordinator, at 973-808- 1329.

Context

Are patients with Wegener granulomatosis at increased risk for venous thrombotic events (VTEs)?

Contribution

This prospective observational study found 16 VTEs in 167 patients with Wegener granulomatosis who had no history of VTE. The incidence of VTE was 7 per 100 person-years of follow-up.

Implications

Patients with Wegener granulomatosis probably have an increased risk for VTE compared with healthy populations who have less than 1 VTE per 100 person-years of follow-up.

-The Editors

* For a list of members of The Wegener's Granulomatosis Etanercept Trial Research Group, see the Appendix (available at www.annals.org).

References

1. Huffman GS, Gross WL. Wegner's granulomatosis: clinical aspects. In: Hoffman GS, Weyand CM, eds. Inflammatory Diseases of Blood Vessels. New York: Marcel Dekker; 2001:381-97.

2. Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum. 1990;33: 1101-7. [PMID: 2202308]

3. Mickle JP, McLennan JE, Lidden CW. Cortical vein thrombosis in Wegener's granulomatosis. Case report. J Neurosurg. 1977;46:248-51. [PMID: 833643]

4. Hansen KE, Moore KD, Ortel TL, Allen NB. Antiphospholipid antibodies in patients with Wegener's granulomatosis and polyaneritis nodosa. Arthritis Rheum. 1999;42:2250-2. [PMID: 10524702]

5. von Scheven E, Lu TT, Emery HM, Elder ME, Wara DW. Thrombosis and pediatric Wegener's granulomatosis: acquired and genetic risk factors for hypercoagulability. Arthritis Rheum. 2003;49:862-5. [PMID: 14673976]

6. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488-98. [PMID: 1739240]

7. Reinhold-Keller E, Beuge N, Latza U, de Groot K, Rudert H, N lle B, et al. An interdisciplinary approach to the care of patients with Wegener's granulomatosis: long-term outcome in 155 patients. Arthritis Rheum. 2000;43:1021-32. [PMID: 10817555]

8. Design of the Wegener's Granulomatosis Etanercept Trial (WGET). Control Clin Trials. 2002;23:450-68. [PMID: 12161090]

9. Limited versus severe Wegener's granulomatosis: baseline data on patients in the Wegener's granulomatosis etanercept trial. Arthritis Rheum. 2003;48:2299-309. [PMID: 12905485]

10. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. 2005;352:351-61. [PMID: 15673801]

11. Stone JH, Hoffman GS, Merkel PA, Min YI, Uhlfelder ML, Hellmann DB, et al. A disease-specific activity index for Wegener's granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS). Arthritis Rheum. 2001;44:912-20. [PMID: 11318006]

12. Exley AR, Bacon PA, Luqmani RA, Kitas GD, Gordon C, Savage CO, et al. Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis Rheum. 1997;40:371-80. [PMID: 9041949]

13. Hansson PO, Welin L, Tibblin G, Eriksson H. Deep vein thrombosis and pulmonary embolism in the general population. 'The Study of Men Born in 1913'. Arch Intern Med. 1997;157:1665-70. [PMID: 92502271

14. Petri M. Hopkins Lupus Cohort. 1999 update. Rheum Dis Clin North Am. 2000;26:199-213, v. [PMID: 10768209]

15. Petri M, Genovese M, Engle E, Hochberg M. Definition, incidence, and clinical description of flare in systemic lupus erythematosus. A prospective cohort study. Arthritis Rheum. 1991;34:937-44. [PMID: 1859487]

16. Petri M, Hellmann D, Hochberg M. Validity and reliability of lupus activity measures in the routine clinic setting. J Rheumatol. 1992;19:53-9. [PMID: 1556700]

17. Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348:1425-34. [PMID: 12601075]

Peter A. Merkel, MD, MPH; Grace H. Lo, MD; Janet T. Holbrook, PhD, MPH; Andrea K. Tibbs, BS; Nancy B. Allen, MD; John C. Davis Jr., MD, MPH; Gary S. Hoffman, MD; W. Joseph McCune, MD; E. William St. Clair, MD; Ulrich Specks, MD; Robert Spiera, MD; Michelle Petri, MD, MPH; and John H. Stone, MD, MPH, for The Wegener's Granulomatosis Etanercept Trial Research Group*

From Boston University, Boston, Massachusetts; Johns Hopkins University, Baltimore, Maryland; Duke University, Durham, North Carolina; University of California, San Francisco, San Francisco, California; Cleveland Clinic Foundation, Cleveland, Ohio; University of Michigan, Ann Arbor, Michigan; Mayo Clinic, Rochester, Minnesota; and Beth Israel Medical Center, New York, New York.

Grant Support: By the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (contract no. N01-AR-9-2240 and center grant AR47785); U.S. Food and Drug Administration, Office of Orphan Products (grant no. FD-R- 001652-01); General Clinical Research Center grants M01-RRO-00533 (Boston University), M01-RRO-0042 (The University of Michigan), M01- RR-30 (Duke University), and M01-RRO-2719 (Johns Hopkins University School of Medicine), from the National Center for Research Resources, National Institutes of Health (NIAMS-NIH AR2224); and Amgen Corporation, Thousand Oaks, California. Drs. Merkel, St. Clair, and Stone are partly supported by a Mid-Career Development Awards in Clinical Investigation (NIH-NIAMS K24 AR2224-01A1, K24 AR049185-01, and K24 AR049185-01).

Potential Financial Conflicts of Interest: Grants received: E.W. St. Clair (Amgen Corp.).

Requests for Single Reprints: Peter A. Merkel, MD, MPH, Boston University School of Medicine, Vasculitis Center, E-5, 715 Albany Street, Boston, MA 02118; e-mail, pmerkel@bu.edu.

Current author addresses and author contributions are available at www .annals.org

Copyright American College of Physicians Apr 19, 2005

Source: Annals of Internal Medicine

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