Vasculitis
Azathioprine or Methotrexate for Vasculitis?
By Eric Schned, MD
Pagnoux C, Mahr A, Hamidou A, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008;350:2790-2803.
Abstract
Background: Current standard therapy for Wegener’s granulomatosis [WG] and microscopic polyangiitis [MP] combines corticosteroids and cyclophosphamide to induce remission, followed by a less toxic immunosuppressant such as azathioprine [AZA] or methotrexate [MTX] for maintenance therapy. However, AZA and MTX have not been compared with regard to safety and efficacy.
Methods: In this prospective, open-label, multicenter trial, we randomly assigned patients with WG or MP who entered remission with intravenous [IV] cyclophosphamide and corticosteroids to receive oral AZA (at a dose of 2.0 mg per kilogram of body weight per day) or MTX (at a dose of 0.3 mg per kilogram per week, progressively increased to 25 mg per week) for 12 months. The primary end point was an adverse event requiring discontinuation of the study drug or causing death; the sample size was calculated on the basis of the primary hypothesis that MTX would be less toxic than AZA. The secondary end points were severe adverse events and relapse.
Results: Among 159 eligible patients, 126 (79%) had a remission, were randomly assigned to receive a study drug in two groups of 63 patients each, and were followed for a mean (±SD) period of 29±13 months. Adverse events occurred in 29 AZA recipients and 35 MTX recipients (P=0.29); grade 3 or 4 events occurred in 5 patients in the AZA group and 11 patients in the MTX group (P=0.11). The primary end point was reached in 7 patients who received AZA as compared with 12 patients who received MTX (P=0.21), with a corresponding hazard ratio for MTX of 1.65 (95% confidence interval, 0.65 to 4.18; P=0.29). There was one death in the MTX group. Twenty-three patients who received AZA and 21 patients who received MTX had a relapse (P=0.71); 73% of these patients had a relapse after discontinuation of the study drug.
Conclusions: These results do not support the primary hypothesis that MTX is safer than AZA. The two agents appear to be similar alternatives for maintenance therapy in patients with WG and MP after initial remission.
Commentary
Current treatment for most cases of WG and MP continues to be combined corticosteroids and cyclophosphamide, despite the well-recognized risk of serious adverse events (ADE) of both drugs and suboptimal efficacy (relapse rates approach 40% at 30 months).1,2 An advance in treatment of the antineutrophil cytoplasmic antibody–associated vasculitides (AAV) came with the demonstration that a maintenance regimen with a less toxic immunosuppressant, AZA, could prolong the remission of cyclophosphamide.3 Subsequent uncontrolled trials suggested that MTX could provide effective, and probably safer, maintenance therapy for WG than AZA.4
This study was conducted in France and Belgium to evaluate the safety and efficacy of AZA compared with MTX plus prednisone for maintenance therapy after complete remission of AAV with pulse IV cyclophosphamide and corticosteroids. Patients were ill but did not have life-threatening disease: Patients with WG had to have renal disease, two or more organs or systems involved, or one organ system plus constitutional symptoms. Patients with MP had at least one item on a five-factor score indicating a poor prognosis. The induction regimen for all patients was three days of daily IV methylprednisolone, followed by oral prednisone (1 mg/kg/day) tapered to 0 mg at 24 months. Cyclophosphamide was administered in IV pulses (0.6 g/sqm) every two weeks x3, then every three weeks (0.7 g/sqm) until remission, and then three “consolidation” pulses (0.7 g/sqm) at three-week intervals. The dose was adjusted to 0.5 g/sqm in patients with renal impairment and in patients older than 65.
Patients who entered remission after the third consolidation pulse of cyclophosphamide were randomly assigned to receive oral maintenance therapy of AZA (2.0 mg/kg/day) or MTX (0.3 mg/kg/week initially, which was increased weekly by 2.5 mg to 25 mg per week). After 12 months of maintenance therapy, AZA or MTX were withdrawn over three months. There was an option to lower AZA or MTX doses in the event of a non–life threatening ADE before discontinuing the drug.
The primary end point of the study was an ADE requiring discontinuation of therapy or death. Secondary end points were serious ADEs, relapse, relapse- and event-free survival, and quality of life.
Clinical characteristics of patients and the mean duration of induction therapy and daily prednisone dose were similar in both groups. At a mean follow up of 29.2 months, the relapse rate for AZA and MTX was similar, 23 and 21 patients respectively. The relapse–survival rates (71.8% for AZA and 74.5% for MTX patients) and event-free survival rates (69.9% for AZA and 60.8% for MTX patients) at 24 months and quality-of-life scores were not significantly different. There was a trend toward more ADEs in MTX recipients than AZA patients. After maintenance therapy was begun, 29 AZA patients and 35 MTX patients had at least one ADE (46 % vs. 56%). There were more discontinuations of drug in MTX recipients (seven AZA patients and 11 MTX patients). Overall, an ADE leading to the primary end point occurred in seven AZA patients and 12 MTX patients; the hazard ratio for MTX compared with AZA was 1.65.
This study showed that the two drugs are similar in maintaining remission after induction in the AAVs. However, perhaps surprisingly, the hypothesis that MTX would be a safer alternative was not proven. Why might this be the case? One possibility is that the target dose of MTX (25 mg per week) was higher than doses commonly used in RA and other inflammatory arthritides. In addition, significant numbers of patients had renal disease. That the presence of renal disease may have influenced the frequency of ADEs is suggested by findings in the NORAN trial (Nonrenal Wegener’s Granulomatosis Treated Alternatively with Methotrexate) in which ADEs led to discontinuation of the drug in only 8% of patients.5 In the present study, there was no association between the frequency and severity of ADEs and renal impairment in the MTX group, but numbers were relatively small.
I see both good and bad news in the outcome of this study. Both AZA and MTX are effective as maintenance medications in patients with AAV achieving remission, so the clinician has options and might tailor maintenance therapy to the individual. However, both agents have a significant failure rate as measured by late relapses and significant ADEs. Clearly, more refined treatment regimens—both induction and maintenance—are required. Based on extensive experience using MTX relatively safely for RA and other arthritic diseases, I think that many clinicians, including myself, may still consider MTX the preferred agent for maintenance in individuals with more limited forms of AAV—for example, in patients with no renal disease or other high-risk disease features and for whom lower doses of MTX might be adequate.
References
- Haubitz M, Schellong S, Gobel U, et al. Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement. Arthritis Rheum. 1998;41:1835-1844.
- Guillerin L, Cordier JF, Lhote F, et al. A prospective, multi-center, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of Wegener’s granulomatosis. Arthritis Rheum. 1997;40:2187-2198.
- Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutophil cytoplasmic antibodies. N Engl J Med. 2003; 349:36-44.
- Langford C, Talar-Williams C, Barron KS, Sneller MC. Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener’s granulomatosis: extended follow-up and rate of relapse. Am J Med. 2003;114:463-469.
- deGroot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005; 52:2461-2469.
Pain Medication
Mortality Risk and NSAIDs
By Michael M. Ward, MD
Gislason GH, Rasmussen JN, Abildstrom SZ, et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med. 2009;169:141-149.
Abstract
Background: Accumulating evidence indicates increased cardiovascular risk associated with nonsteroidal anti-inflammatory drug (NSAID) use, in particular in patients with established cardiovascular disease. We studied the risk of death and hospitalization because of acute myocardial infarction and heart failure (HF) associated with use of NSAIDs in an unselected cohort of patients with HF.
Methods: We identified 107,092 patients surviving their first hospitalization because of HF between January 1, 1995, and December 31, 2004, and their subsequent use of NSAIDs from individual-level linkage of nationwide registries of hospitalization and drug dispensing by pharmacies in Denmark. Data analysis was performed using Cox proportional hazard models adjusted for age, sex, calendar year, comorbidity, medical treatment, and severity of disease; and propensity-based risk-stratified models and case-crossover models.
Results: A total of 36,354 patients (33.9%) claimed at least one prescription of an NSAID after discharge; 60,974 (56.9%) died, and 8,970 (8.4%) and 39,984 (37.5%) were hospitalized with myocardial infarction or HF, respectively. The hazard ratio (95% confidence interval) for death was 1.70 (1.58–1.82), 1.75 (1.63–1.88), 1.31 (1.25–1.37), 2.08 (1.95–2.21), 1.22 (1.07–1.39), and 1.28 (1.21–1.35) for rofecoxib, celecoxib, ibuprofen, diclofenac, naproxen, and other NSAIDs, respectively. Furthermore, there was a dose-dependent increase in risk of death and increased risk of hospitalization because of myocardial infarction and HF. Propensity-based risk-stratified analysis and case-crossover models yielded similar results.
Conclusions: NSAIDs are frequently used in patients with HF and are associated with increased risk of death and cardiovascular morbidity. Inasmuch as even commonly used NSAIDs exerted increased risk, the balance between risk and benefit requires careful consideration when any NSAID is given to patients with HF.
Commentary
Among their serious complications, NSAIDs can cause exacerbations of congestive heart failure (CHF). This effect has been attributed to the ability of NSAIDs to cause systemic vasoconstriction, hypertension, reduced renal blood flow, and fluid retention, all leading to an increase in cardiac afterload. This study documented an increased risk of hospitalization for treatment of CHF among patients using NSAIDs but also—and most importantly—found an increased risk of mortality among users of NSAIDs.
This nationwide population-based study examined all patients discharged alive from hospitals in Denmark from 1995 to 2004 who had a diagnosis of congestive HF. Data on NSAID use were obtained by linking the patients’ records with a national prescription registry, which in the Danish universal health care system captures all NSAID prescriptions except those for low-dose ibuprofen (which can be obtained without prescription). The outcomes of these patients were tracked using national hospitalization and mortality registries, which allowed the investigators to know the timing of death or subsequent hospitalizations for CHF or myocardial infarction. Patients were elderly, with a mean age 74.8 years, and 33.9% received a prescription for an NSAID after their hospital discharge for CHF. NSAID use was generally short-term, with median durations of treatment ranging from 40 to 97 days among different medications.
Compared with patients who were not prescribed an NSAID, the risk of mortality was twice as high among those prescribed diclofenac, 75% higher among those prescribed celecoxib, 70% higher among those prescribed rofecoxib, 31% higher among those prescribed ibuprofen, 22% higher among those prescribed naproxen, and 28% higher among those prescribed other NSAIDs. The number needed to treat to cause one additional death was 9 for rofecoxib, 11 for diclofenac, 14 for celecoxib, 51 for naproxen, and 53 for ibuprofen, indicating that naproxen and ibuprofen were safer than rofecoxib, celecoxib, and diclofenac. Risks were dose dependent, but even low doses of diclofenac, rofecoxib, and celecoxib were associated with an increased risk of mortality. Ibuprofen at a dose of 1200 mg/d or less and naproxen at a dose of 500 mg/d or less were not associated with an increased risk of death. The risk of death associated with NSAID use was comparable in subgroups that at baseline were predicted to have a high or low risk of death. A similar pattern of risk was found for hospitalizations for CHF and myocardial infarction.
This study is important because it extends the range of complications of NSAID use among patients with CHF to include not only more frequent exacerbations of HF, but also an increased risk of death. The large population-based sample, validated coding of discharge diagnoses, and near-complete data on medication use enhance the validity of the findings. The investigators did not have information on the clinical indications for which NSAIDs were prescribed, raising the question of whether the underlying condition was the true risk factor, rather than the medication itself, or whether the indications for treatment differed among users of different NSAIDs. Only 1.7% of patients had connective tissue disease included among their hospital discharge diagnoses, suggesting that the most common indication for the use of an NSAID was for mechanical musculoskeletal pain. The study did not include a comparison group that received prescriptions for analgesics, which would have helped isolate the associations with mortality and morbidity better to the medications, rather than the condition being treated. The source group of patients had all been hospitalized and had a discharge diagnosis of CHF. We do not know how severe their HF was, how heterogeneous these patients were with respect to their HF, or whether the NSAID-associated risks extend to those with milder HF.
Despite these questions, this study highlights the need to review medication choices for patients with CHF. Although low-dose naproxen or ibuprofen may be safer than other NSAIDs, this study cautions us to consider alternatives to NSAIDs for this group of patients.