SMART

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Nelson HS, et al. "The salmeterol multicenter asthma research trial". Chest. 2006. 129(1):15-26.
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Clinical Question

In asthmatics, does the addition of the long-acting ß-agonist salmeterol to asthma therapy increase respiratory-related adverse events and mortality?

Bottom Line

Salmeterol increases the risk of respiratory-related deaths, particularly among African American patients and those not using an inhaled corticosteroid.

Major Points

Long-acting beta-agonists (LABAs) such as salmeterol have since the 1990s been mainstays of therapy for persistent asthma. This trial was designed after observational studies suggested an increase in asthma-related mortality despite optimal medical therapy, raising the question that perhaps some deaths were related to complications of therapy.

The Salmeterol Multicenter Asthma Research Trial (SMART) randomized over 26,000 adolescent and adult patients with asthma to salmeterol or placebo in addition to standard asthma therapy. There was no difference in the composite primary outcome of respiratory-related deaths or life-threatening events with salmeterol. However, salmeterol was associated with significant increases in secondary outcomes such as asthma-related deaths or life-threatening events, deaths from asthma, and respiratory-related deaths. Subgroup analyses revealed that this increased morbidity and mortality was most pronounced among African Americans and those not taking an inhaled corticosteroid (ICS).

In large part due to the results of SMART, the 2007 NHLBI ECS 3 guidelines recommend adding a LABA to ICS therapy as step 3 of treatment for persistent asthma (level of evidence A). In addition, the FDA provides a black box warning on LABA preparations because of their association with asthma-related deaths.

Design

  • Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
  • N=26,355 asthmatics
    • Salmeterol (n=13,176)
    • Placebo (n=13,179)
  • Setting: 6,163 sites
  • Enrollment: 1996-2003
  • Follow-up: 28 weeks (median)
  • Analysis: Intention-to-treat

Population

Inclusion Criteria

  • Age ≥12 years
  • Diagnosis of asthma
  • Receiving ≥1 prescription asthma medication

Exclusion Criteria

  • Prior use of LABA
  • Use of ß-blockers
  • Pregnancy or lactation
  • Significant systemic disease

Baseline Characteristics

  • Mean age: 39.2 years
  • Female: 64%
  • Race/ethnicity:
    • Caucasian: 71%
    • African-American: 18%
    • Hispanic: 8%
    • Asian: 1%
    • Other: 2%
  • PEF: 355 L/min (82% predicted)
  • Duration of asthma: 16.3 years
  • Emergency visits in prior year: 26%
  • Hospitalizations in prior year: 8%
  • Nocturnal symptoms: 61%
  • Inhaled corticosteroid use: 47%

Interventions

  • Randomized to salmeterol xinafoate MDI 42µg BID vs. placebo MDI BID for 28 wks
  • Initial office visit for screening and randomization; subsequent follow-up via telephone every 4 wks
  • All patients were also given a supply of albuterol

Outcomes

Comparisons are salmeterol vs. placebo. P values weren't provided by the authors.

Primary Outcome

Respiratory-related deaths or life-threatening events
50 (<1%) vs. 36 (<1%), RR 1.39 (95% CI 0.91 to 2.14)
African-Americans: 20 (<1%) vs. 5 (<1%), RR 4.10 (95% CI 1.54 to 10.90)
Caucasians: 29 (<1%) vs. 28 (<1%), RR 1.05 (95% CI 0.62 to 1.76)

Secondary Outcomes

All-cause mortality
42 (<1%) vs. 36 (<1%), RR 1.30 (95% CI 0.82 to 2.06)
African-Americans: 12 (<1%) vs. 7 (<1%), RR 1.69 (95% CI 0.67 to 4.28)
Caucasians: 29 (<1%) vs. 22 (<1%), RR 1.32 (95% CI 0.76 to 2.30)
Asthma-related deaths or life-threatening events
37 (<1%) vs. 22 (<1%), RR 1.71 (95% CI 1.01 to 2.89)
African-Americans: 19 (<1%) vs. 4 (<1%), RR 4.92 (95% CI 1.68 to 14.45)
Caucasians: 17 (<1%) vs. 16 (<1%), RR 1.08 (95% CI 0.55 to 2.14)
Deaths from asthma
13 (<1%) vs. 3 (<1%), RR 4.37 (95% CI 1.25 to 15.34)
African-Americans: 7 (<1%) vs. 1 (<1%), RR 7.26 (95% CI 0.89 to 58.94)
Caucasians: 6 (<1%) vs. 1 (<1%), RR 5.82 (95% CI 0.70 to 48.37)
Respiratory-related deaths
24 (<1%) vs. 11 (<1%), RR 2.16 (95% CI 1.06 to 4.41)
African-Americans: 8 (<1%) vs. 2 (<1%), RR 3.89 (95% CI 0.82 to 18.26)
Caucasians: 16 (<1%) vs. 7 (<1%), RR 2.29 (95% CI 0.94 to 5.56)
Combination of death or life threatening experiences
70 (<1%) vs. 59 (<1%), RR 1.19 (95% CI 0.84 to 1.68)
African-Americans: 24 (1%) vs. 11 (<1%), RR 2.17 (95% CI 1.06 to 4.41)
Caucasians: 44 (<1%) 44 vs. (<1%), RR 1.01 (95% CI 0.67 to 1.53)
Hospitalizations
469 (4%) vs. 420 (3%), RR 1.11 (95% CI 0.97 to 1.26)
African-Americans: 102 (4%) vs. 77 (3%), RR 1.29 (95% CI 0.96 to 1.72)
Caucasians: 323 (3%) vs. 317 (3%), RR 1.02 (95% CI 0.88 to 1.19)

Subgroup Analysis

For the primary outcome.

ICS at baseline
Yes: 23 (<1%) 19 (<1%), RR 1.21 (95% CI 0.66 to 2.23)
No: 27 (<1%) 17 (<1%), RR 1.60 (95% CI 0.87 to 2.93)

Adverse Events

Frequency of serious adverse events
4% in each group
Time to first serious event causing discontinuation, in survival rate
95.6% vs. 96.2% (P=0.02)

Criticisms

Unable to tell if differences in African American group is from imbalances between baseline factors (e.g. use of controller medications, socioeconomics)

Funding

Multiple authors with connections to GlaxoSmithKline, the makers of Serevent.