CONCERN: Naproxen vs celecoxib in patients with recent upper GI bleed with an indication for low-dose ASA

in

Chan FKL, et al. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet [epub ahead of print]

Bottom line:

  • Issues in reporting of this trial preclude a fully-informed interpretation of its results

  • In patients receiving a PPI & ASA, recurrent upper GI bleed occurred in ~6% of patients also receiving daily celecoxib at a dose of 100 mg BID compared to ~12% of those receiving naproxen 500 mg BID over 18 months.

 

Patients (n=514)

  • Included
    • Presenting with upper GI bleed while on NSAID + low-dose ASA
    • Follow-up endoscopy confirming ulcer healing 8 weeks after GI bleed
    • Negative for H pylori or successful H pylori eradication
    • Ongoing indication for low-dose ASA ("cardiothrombotic diseases" or "multiple CV risk factors")
    • Chronic arthritis pain anticipated to require regular NSAID use
  • Key exclusion criteria
    • Erosive esophagitis
    • Gastric outlet obstruction
    • Renal failure (SCr >200 umol/L)
    • Use of anticoagulants
  • Typical study patient
    • Age 72 y (>80 y in 24%)
    • Female 46%
    • Indication for NSAID: OA 70%, RA 3%, other 27%
    • Baseline upper GI bleed
      • Gastric origin 55%
      • Required endoscopic therapy ~30%
      • Required blood transfusions 55%
    • ASA indication: Secondary prevention (67%), primary prevention with 10-year CV risk >10% (33%)

Interventions x18 months

  • I: Celecoxib 100 mg PO BID
  • C: Naproxen 500 mg PO BID
  • ~90% in both groups took at least 70% of their doses; ~18% in each group discontinued the study drug before 18 months
  • Co-interventions:
    • Esomeprazole 20 mg PO once daily in all patients
    • ASA 80 mg/d (discontinued in ~30% of patients during trial in both groups)

Results @ median 18 months

  • Efficacy (not designed or powered to evaluate this)
    • Patient's global assessment of disease activity scale (range 1-5, lower=better):
      • Baseline: 3.0 in both groups
      • Month 18: Celecoxib 2.1 versus naproxen 2.3, p=0.386 for difference between groups
    • Quality of life, pain, use of other analgesics: ?
  • Safety
    • Primary outcome - recurrent upper GI bleed (hematemesis/melena or hemoglobin drop >20 g/L+ endoscopically-confirmed ulcers or bleeding erosions): Celecoxib 5.6%, naproxen 12.3% (NNT 15), hazard ratio (HR) 0.44 (0.23-0.82)
      • Fatal recurrent GI bleed: 0 in both groups
    • Major CV event (vascular death, MI or stroke): Celecoxib 4.4% vs naproxen 5.5%, HR 0.78 (0.36-1.73)
  • Discontinued treatment before 18 months: Celecoxib 18% vs naproxen 19%

Subgroup analysis (reported in supplement of authors' reply to letter to the editor)

  • Primary outcome
    • Continued ASA: Celecoxib 7.2%, naproxen 13.8% (p=.042)
    • Discontinued ASA: 1.4% vs 8.4% (p=.054)
  • CV events: 
    • Continued ASA: Celecoxib 5.5% vs naproxen 6.0% (p=.825)
    • Discontinued ASA: 1.5% vs 4.3% (p=.312)

Internal validity

  • Unclear/high risk of allocation bias
  • Unclear risk of performance/detection bias
    • Proper blinding dependent upon allocation concealment. If sealed opaque envelope method was subverted, then blinding would also be compromised
    • Blinding by "double-dummy" pills not prepared by manufacturer
    • GI & CV outcomes adjudicated by committee blinded to allocated treatment group
  • Attrition bias
    • Premature discontinuation occurred in ~18% of patients in each group
    • Modified intention-to-treat analysis for GI safety outcome only counted outcomes that occurred "during treatment," therefore excluding any outcomes occurring after premature discontinuation

Generalizability

  • Study conducted in single centre in Hong Kong, with enrolment taking ~10 years (2005-2015)
    • Many changes to GI bleed management (e.g. reduced transfusion threshold) & CV disease management (including ASA prescribing patterns in primary prevention). No reporting or comments on such trends in this publication, which complicates application of these trial results.
  • Many aspects of this trial remain unreported, which further complicates application of these results
    • CV risk & indication for ASA?
      • This is the key reporting issue in this trial. The authors do not clearly describe the indication for ASA beyond "cardiothrombotic diseases or multiple coronary risk factors", and do not describe these in their 'baseline characteristics' table. Notably, the authors report that ~30% of patients discontinued ASA during the trial, suggesting that some of these patients had no clear indication for ASA
      • Addendum: The authors reported in a response to letter to the editor that 67% received ASA for secondary prevention, with the remaining 33% receiving ASA for primary prevention in the context of a calculated 10-year risk of a CV event >10%. The benefit of ASA for primary prevention is minimal, & the harms of continuing ASA (especially in these patients who already developed a GI bleed on ASA) likely outweighed any benefit. Furthermore, reported subgroup analyses showed that those who discontinued ASA had a lower risk of CV events, suggesting that mostly the lower-risk primary CV prevention patients discontinued ASA during the trial. 
      • Use of dual antiplatelet therapy (DAPT) was not specifically prohibited during this trial, though its use was not reported
    • Time from initial upper GI bleed to initiating of study NSAID?
      • Addendum: The authors later reported that endoscopy was routinely performed to confirm ulcer healing 8 weeks after the GI bleed, at which point patients were enrolled into this trial.
    • Previous history of NSAID use and efficacy (i.e. previous treatment failures with either study NSAID)?
  • Effect of giving no NSAID or NSAID PRN?
    • The majority of patients with OA who use oral NSAIDs in practice do so on a PRN basis. The GI risk related to this kind of usage pattern is likely lower, and may be a reasonable alternative
    • In a previous trial by the same authors of patients with ASA-related upper GI bleed, recurrence using the same definition was <1% over 1 year in patients receiving ASA+PPI
  • Clinical importance of primary outcome?
    • The primary outcome of this trial was recurrent endoscopically-confirmed upper GI bleed that presented as either hematemesis/melena or a >20 g/L hemoglobin drop. None of the recurrent GI bleeds in this trial resulted in patient death, and most would be classified as "minor bleeds" under most commonly-used bleeding definitions. As such, impact of these recurrent events on quality of life would be a key domain to measure (but it wasn't).
    • If we accept that this is a clinically-important outcome, the risk remains far too high even with celecoxib, particularly given that only 90% took at least 70% of their doses and that 30% discontinued ASA during the trial.

PRECISION - Comparison of different NSAIDs in patients with arthritis and an increased CV risk

in

Nissen SE, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med 2016;online

Bottom line: For patients with arthritis and a ~1%/year risk of CVD and low risk of GI bleeds, no NSAID (between celecoxib, ibuprofen or naproxen) is clearly safer. Consider a strategy of using the cheapest NSAID, PRN if possible, and optimizing other strategies to decrease the CV risk of NSAIDs (smoking cessation, statins, BP control, ASA for secondary prevention, etc). NSAIDs should be discontinued in patients who do not receive a noticeable improvement in pain & function from these agents.

 

Issues with internal validity?

  • Unclear risk of allocation, performance and detection bias  (likely low risk, but inadequate description in protocol and published report)
  • High risk of attrition and contamination bias
    • 68.8% stopped taking the study drug, though no differences in rates or timing between intervention groups
    • 27.4% discontinued follow-up, and 7.2% were outright lost-to-follow-up
    • The above decrease the study's power to find a difference between groups, especially in the ITT analysis, biasing the conclusions towards non-inferiority. With that said, estimates from ITT and on-treatment populations were almost identical

Special considerations: Non-inferiority trial

  • This study was designed as a non-inferiority safety study to determine that celecoxib was "not much more dangerous" from a CV perspective vs naproxen
  • Criteria to be met to achieve this study's non-inferiority conclusion:
    • Hazard ratio (HR) point estimate <1.12 for the primary outcome
    • Upper limit of HR 97.5% confidence interval <1.33
    • The above had to be met in both intention-to-treat (all patients randomized) and on-treatment populations (events occurring while patient taking study drug + extra 30 days after they discontinued it) to conclude non-inferiority
  • When developing these non-inferiority criteria, assumed would require 762 primary outcome events, and that these would occur at a rate of 2%/year (actual ~1%) & that 40% of patients would discontinue treatment (actual 68%)
    • Actual primary outcome event n=607

Patients (n=24,081)

  • Included
    • Age 18+ y
    • Need for daily NSAID for arthritis pain
    • Increased risk for/established atherosclerotic cardiovascular disease (ASCVD), defined as any of the following:
      • CAD
      • Cerebrovascular disease
      • Symptomatic peripheral vascular disease
      • Arterial surgery/angioplasty for any ASCVD >3 months prior to randomization
      • Diabetes (extra eligibility criterion for women: on insulin)
      • 3+ ASCVD risk factors from the following: Age >55 y, family history of CVD/stroke, current smoker >15 cigarettes/day, HTN, LVH on EKG, dyslipidemia, microalbuminuria or urine protein:creatinine ratio >2, ABI <0.9, waist:hip ratio 0.90 or greater)
  • Excluded
    • ACS, stroke/TIA or CABG within 3 months
    • HF with NYHA class III-IV symptoms or LVEF 35% or less
    • Planned revascularization procedure
    • Uncontrolled arrhythmia within 3 months
    • BP >140/90 mm Hg
    • Malignancy within 5 years
    • Any significant GI, hepatic, renal or coagulation disorders
    • Concomitant meds: Warfarin, prednisone equivalent >20 mg/d, lithium
  • Screened 31,857 -> randomized 24,222 -> analyzed 24,081
  • "Average" patient
    • Age 63 y
    • Female 64%
    • White 75%
    • Arthritis: OA (90%), RA (10%)
      • HAQ disability score 1.1 (0= no disability, 3= complete disability)
      • Pain visual analog score 54 mm (/100)
    • CV risk category: Primary prevention (77%), secondary prevention (23%)
    • PMHx
      • Current smoker 21%
      • HTN 78%
      • Diabetes 35%
      • Dyslipidemia 63%
    • BP 125/75 mm Hg
    • SCr 80 umol/L
    • Meds
      • ASA 46%
      • Statin 54%
      • DMARD 7%

Generalizability: Who does this apply to?

  • Middle-aged to elderly adults with arthritis (mainly OA) with a low-intermediate risk of CV events (~10% over 10 years), and minimal non-CV comorbidity
    • Despite enrolling patients with CV risk factors, actual CV event rates were closer to low-intermediate risk (~1%/year), likely resulting from concomitant treatments to lower CV disease & enrolment of a sample of patients generally healthier than the underlying population.

Interventions

  • Celecoxib
    • Initial dose 100 mg PO BID
    • (RA only) dose could be increased to 200 mg PO BID
    • Mean treatment duration: 20.8 months
  • Ibuprofen
    • Initial dose 600 mg PO TID
    • Dose could be increased to 800 mg PO TID
    • Note: In practice, most clinicians will recommend a lower dose than what was used in this trial (usually ~200-400 mg PO TID-QID)
    • Mean treatment duration: 19.6 months
  • Naproxen
    • Initial dose 375 mg PO BID
    • Dose could be increased to 500 mg PO BID
    • Mean treatment duration: 20.5 months
  • Co-intervention for all: Gastroprotection with daily PPI (esomeprazole 20-40 mg)

Results (reported in the following order: celecoxib, ibuprofen, naproxen)

ITT analyses (mean follow-up 2.8 years)

  • Death: 1.6% vs 1.8% vs 2.0%
    • Celecoxib vs naproxen: HR 0.80 (0.63-1.00)
  • CV
    • Primary outcome (CV death, non-fatal MI, non-fatal stroke): 2.3% vs 2.7% vs 2.5%
      • Celecoxib vs naproxen: HR 0.93 (0.75-1.13)
      • Ibuprofen vs naproxen: HR 1.08 (0.90-1.31)
    • Major adverse cardiovascular event (primary outcome, coronary revascularization, hospitalization for unstable angina, or TIA): 4.2% vs 4.8% vs 4.3%
      • Ibuprofen vs naproxen: HR 1.11 (0.96-1.29)
    • HF hospitalization: 0.6% in all groups
    • Hospitalization for HTN: 0.3% vs 0.5% vs 0.4%
  • GI - Clinically significant events (GI hemorrhage, obstruction, perforation, or symptomatic gastric/duodenal ulcer): 0.7% vs 0.9% vs 0.7%
    • Celecoxib vs naproxen: HR 0.97 (0.67-1.40)
  • Renal (creatinine increase to >177 umol/L, hospitalization for AKI, or initiation of dialysis): 0.7% vs 1.1% vs 0.9%
    • Celecoxib vs naproxen: HR 0.79 (0.56-1.12)
  • Change in pain visual analogue score from baseline (/100 mm): -9.3 vs -9.5 vs -10.2

On-treatment analyses (mean follow-up 1.8 y [mean treatment duration + 1 month])

  • Primary outcome: 1.7% vs 1.9% vs 1.8%
    • Celecoxib vs naproxen: HR 0.90 (0.71-1.15)
    • Ibuprofen vs naproxen: HR 1.12 (0.89-1.40)

Interpretation

  • Caveats to consider
    • The authors performed over 100 analyses including subgroup analyses in addition to the primary non-inferiority analysis, so chance is a plausible explanation for any differences (or lack of differences) in secondary & tertiary outcomes
    • The upper limit of the non-inferiority margin of 1.33 (a 33% relative risk increase) conceptually accepts that NSAIDs could offset the effect of 1-2 interventions to reduce CV events (i.e. CV risk reduction for smoking cessation, ASA, statins, BP & diabetes control are all in the ballpark of a 15-35% relative reduction)
    • Event rates were lower than predicted based on enrolment criteria, likely due to concomitant treatments to reduce CV events
    • Patients discontinued study treatment at a mean 1.7 years, limiting long-term follow-up and assessment of long-term risk
    • No comparison group that received placebo/no NSAID
  • In the context of the above caveats, this study provides some evidence that
    • Celecoxib, ibuprofen and naproxen have similar CV and renal safety profiles at the doses and duration used in this trial, but cannot absolutely refute other studies demonstrating a greater risk with celecoxib;
    • GI event rates between NSAIDs & celecoxib differed only when iron-deficiency anemia of presumed GI origin was added to the predefined outcome of clinically-significant GI events. The difference was not different when considering only serious events. This weakens the rationale for using celecoxib over a non-selective NSAID;
    • Ibuprofen used at doses higher than routinely prescribed may pose a greater risk of CV and non-serious GI events than celecoxib or naproxen. The implications of this for lower doses are unclear;
  • None of the drugs in this study achieved a minimally clinically important change in the pain score (13.7/100). It's likely that a subset achieved a demonstrable reduction in pain, but for the majority of the trial participants, the benefits were non-existent and therefore risks outweighed the benefits.