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Three Part Question

In [healthy adults with influenza A or an influenza-like illness presenting in the emergency department] are the [m2 ion channel blockers more effective than the neuraminidase inhibitors] at [relieving symptoms and reducing duration of illness]?

Clinical Scenario

A 30 year old man attends the emergency department who has suspected Influenza A(H1N1). You know that the m2 ion channel blocking antiviral drugs amantadine and rimantadine are cheaper than the neuraminidase inhibitors. You want to know if they have similar or greater efficacy and need to take into account possible adverse effects. The intention is for treatment and not for prophylaxis.

Search Strategy

MEDLINE (1950 to June week 2 2009) and EMBASE, via OVID interface

{[exp Influenza, Human/] OR [exp Influenza A Virus, H1N1 Subtype/] OR [swine flu.mp.]} AND {[exp Amantadine/] OR [exp Rimantadine/] OR [exp Antiviral Agents] OR [m2 ion channel blockers.mp.] OR [exp Oseltamivir/] OR [tamiflu.mp.] OR [exp Zanamivir/] OR [relenza.mp] OR [neuraminidase inhibitor.mp.]} LIMIT to [English language AND humans]
he search of MEDLINE returned 2346 papers. These papers were refined further by accepting systematic reviews and any RCTs published since then. 91 evidence based medicine reviews were found. Of these 91 papers, 84 were either irrelevant to the question or of a lower quality of evidence. Of the seven remaining papers, three were older versions of a subsequently updated Cochrane systematic review, and were therefore excluded. The most up to date Cochrane systematic review was included, which covered both sets of antiviral drugs. The one RCT published since the latest systematic review was discounted as it focused mainly on influenza B, which is not the focus of this guideline. EMBASE returned no new papers.

Search Outcome

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Jefferson, T. et al 2006 Italy	Healthy adults aged 16 to 65 years old	Systematic review	Time to alleviation of symptoms	Hazard ratio for neuraminidase inhibitors vs placebo; 1.22 (95% CI ,1.14 to 1.31) [p<0.05]	Too few datasets to analyse adverse effects of both drug groups Outcomes for both drug sets not directly comparable Various statistical presentation of results make comparison difficult
			Time to return to normal activit	Hazard ratio for neuraminidase inhibitors vs placebo; 1.26 (95% CI, 1.14 to 1.40) [p<0.05]
			Complications [all types]	Odds ratio for neuraminidase inhibitors vs placebo; 0.43 (95% CI, 0.33 to 0.56) [p<0.05]
			Mean nasal titre at 24 hours (concentration)	Weighted mean difference for neuraminidase inhibitors vs placebo; -0.62 (95% CI, -0.82 to -0.41) [p<0.05]
			Duration of fever (hours)	Weighted mean difference for amantadine vs placebo; -0.99 (95% CI, -1.26 to -0.71) [p<0.05] , Weighted mean difference for rimantadine vs placebo; -1.24 (95% CI, -1.71 to -0.76) [p<0.05]
			Reduction in cases with fever at 48 hours	Amantadine vs placebo; Efficacy 79% (95% CI, 34 to 93) [p<0.05], Rimantadine vs placebo; Efficacy 84% (95% CI, 47 to 95) [p<0.05]
			Viral shedding at 5 daysRR* 0.96 (0.72 to 1.27), RR	Risk ratio for amantadine vs placebo; 0.96 (95% CI, 0.72 to 1.27), Risk ratio for rimantadine vs placebo; 0.67 (95% CI, 0.22 to 2.07)

Comment(s)

The results show that the neuraminidase inhibitors decrease the time to alleviation of symptoms and the time to return to normal activity by 22% and 26% respectively. Mean nasal titres of excreted viruses were also significantly decreased with these drugs. Treatment did not, however, suppress viral excretion, regardless of dose. Furthermore, neuraminidase inhibitors may also have a role in reducing the incidence of complications such as pneumonia and bronchitis. The m2 ion channel blockers are both similarly effective at reducing fever at 48 hours (79%, 84%, p<0.05). There was no effect with either drug on nasal shedding or persistence of virus in upper airways after up to 5 days of treatment [10]. There were not enough trials available to study the adverse effects of the antiviral drugs with any statistical significance. Some adverse effects are also difficult to differentiate from the symptoms of the virus. One study showed that 10 to 27% patients prescribed amantadine developed and secreted an antiviral resistant virus within four to five days of starting treatment.

Clinical Bottom Line

The results show that the neuraminidase inhibitors decrease the time to alleviation of symptoms and the time to return to normal activity by 22% and 26% respectively. Mean nasal titres of excreted viruses were also significantly decreased with these drugs. Treatment did not, however, suppress viral excretion, regardless of dose. Furthermore, neuraminidase inhibitors may also have a role in reducing the incidence of complications such as pneumonia and bronchitis. The m2 ion channel blockers are both similarly effective at reducing fever at 48 hours (79%, 84%, p<0.05). There was no effect with either drug on nasal shedding or persistence of virus in upper airways after up to 5 days of treatment [10]. There were not enough trials available to study the adverse effects of the antiviral drugs with any statistical significance. Some adverse effects are also difficult to differentiate from the symptoms of the virus. One study showed that 10 to 27% patients prescribed amantadine developed and secreted an antiviral resistant virus within four to five days of starting treatment.

References

1. Jefferson, T. et al Antivirals for influenza in healthy adults: systematic review Lancet 2006 Jan 28; 303 - 313