Expansion of Rotation 2 week 4 PICO

Clinical Question: As in the past, please briefly outline the scenario and state your clinical question as concisely and specifically as possible

A 72 year old female with PMH of COPD presents to the ED with fever, chills, cough, and body aches. RT-PCR test is positive Influenza. There are two options for treating this patients influenza peramivir or oseltamivir.

PICO Question:

Identify the PICO elements – this should be a revision of whichever PICO you have already begun in a previous week

In the ED is peramivir a comparative option to oseltamivir in treating adults with Influenza?

PICO search terms:

P	I	C	O
Influenza	Peramivir	Oseltamivir	Improvement of symptoms
Influenza A and B	Rapivab	Tamiflu	Complications
Adult influenza			Adverse effects
High risk adult influenza			Clinical outcome
Adult			Influenza clinical outcome

Search Strategy:

Outline the terms used, databases or other tools used, how many articles returned, and how you selected the final articles to base your CAT on.  This will likewise be a revision and refinement of what you have already done.

Google scholar: peramivir vs oseltamivir influenza.

Filters: The date range between 2011 and 2021. I obtained 4,330 results. I narrowed down by title looking for randomized control studies, meta analysis and systematic reviews.

Pubmed: oseltamivir vs peramivir influenza.

Filters:  Date range between 2011 and 2021. I obtained 7 results. I limited to meta analysis and found none. I then put in RCTs and obtained one result.

Cochrane: oseltamivir vs peramivir influenza

                Filters: results by years 2011 to 2021. Filtered by reviews obtained 0 results. When filtered by trials obtained 7 randomized control trial studies.

Wiley online library: peramivir vs oseltamivir influenza

                Filters: 2011-2021. Looked for journals and not books. I obtained 87 results. I looked for RCTs, systematic reviews and meta analysis. Most of the results were RCTs. Only one systematic review was found.

Science journals: oseltamivir vs peramivir.

                Filters: full text articles and peer reviewed articles. I obtained 26 results. I looked then at the titles to further narrow my search, I looked for titles discussing treatment of humans using these two drugs. I obtained one result from the Lancet but I chose not to include it because it was not a research article but instead a discussion article and it did not discuss the outcomes I was looking for.

I wanted to select articles that were high levels of evidence, systematic reviews or meta analysis. However after a long search I was only able to find one systematic review. There were no additional articles I could find on this level of evidence. Therefore I went to the next level of evidence in this case, which is randomized control trials (RCTs). I also wanted data that was recent so I only included articles from 2011-2021. There were several articles of RCTs comparing the two drugs so my next step was to look at the outcomes they were oomparing.

I looked for articles comparing negative outcomes, positive outcomes, complications and time to symptom relief, those were the metrics I thought were appropriate for comparing the efficacy of these two drugs in the treatment of influenza A and B. Some articles I chose were of value as well because they discussed high risk patients with influenza which was relevant to my patient because of her history of COPD.

Many of the databases returned the same articles including PubMed, Cochrane and google scholar. In the end I chose the systematic review that I found and three RCTs that compared the two drugs for the treatment of influenza. I chose one article that was different from my other three in that it looked at high risk patients with either 1 dose peramivir, 2 doses of peramivir vs oseltamivir. I chose to include this one because it answered my questions about peramivir vs oseltamivir and it included the high risk respiratory disease, even though it was also comparing doses which was not my question, because it did compare oseltamivir vs peramivir in the study. I chose a small RCT in spite of its sample size because it was the final article I could find that answered my question and was a high enough level of evidence worth including. Even though its small sample size limits its clinical importance, I needed four articles. There were no additional articles of higher levels of evidence that I could find that were looking at the outcomes I was researching.

Articles Chosen (4 or more) for Inclusion (please copy and paste the abstract with link):

Please pay attention to whether the articles actually address your question and whether they are the highest level of evidence available.  If you cannot find high quality articles, be prepared to explain the extensiveness of your search and why there aren’t any better sources available.
Please note that if the evidence is not in the abstract, you must clearly summarize the evidence in your posting. 

1. Hsieh YH, Dugas AF, LoVecchio F, McBryde B, Ricketts EP, Saliba-Shaw K, Rothman RE. Intravenous peramivir vs oral oseltamivir in high-risk emergency department patients with influenza: Results from a pilot randomized controlled study. Influenza Other Respir Viruses. 2021 Jan;15(1):121-131. doi: 10.1111/irv.12794. Epub 2020 Oct 2. PMID: 33006445; PMCID: PMC7767951.

Abstract:

Background: Peramivir offers a single-dose intravenous (IV) treatment option for influenza (vs 5-day oral dosing for oseltamivir). We sought to compare outcomes of emergency department (ED) patients at high risk for influenza complications treated with IV peramivir vs oral oseltamivir.

Methods: During the 2015-16 and 2016-17 influenza seasons, adult patients in two US EDs were randomized to either oral oseltamivir or IV peramivir treatment group. Eligibility included positive molecular influenza test; met CDC criteria for antiviral treatment; able to provide informed consent and agree to follow-up assessment. Outcomes were measured by clinical end-point indicators, including FLU-PRO Score, Ordinal Scale, Patient Global Impression on Severity Score, and Karnofsky Performance Scale for 14 days. Non-inferior t test was performed to assess comparative outcomes between the two groups.

Results: Five hundred and seventy-five (68%) of 847 influenza-positive patients were approached. Two hundred and eighty-four met enrollment criteria and 179 were enrolled; of these 95 (53%) were randomized to peramivir, and 84 to oseltamivir. Average FLU-PRO score at baseline was similar (peramivir: 2.67 vs oseltamivir: 2.52); the score decreased over time for both groups (day 5: peramivir: 1.71 vs oseltamivir: 1.62; day 10: peramivir: 1.48 vs oseltamivir: 1.37; day 14: peramivir: 1.40 vs oseltamivir: 1.33; all P < .05 for significantly non-inferior). Influenza-related complications were similar between two groups (All: peramivir: 31% vs oseltamivir: 21%, P > .05; pneumonia: peramivir: 11% vs oseltamivir: 14%, P > .05).

Conclusions: Clinical outcomes of influenza-infected patients treated with single-dose IV peramivir were comparable to those treated with oral oseltamivir, suggesting potential utility of peramivir for influenza-infected patients in the ED.

• Lee J, Park JH, Jwa H, Kim YH. Comparison of Efficacy of Intravenous Peramivir and Oral Oseltamivir for the Treatment of Influenza: Systematic Review and Meta-Analysis. Yonsei Med J. 2017 Jul;58(4):778-785. doi: 10.3349/ymj.2017.58.4.778. PMID: 28540991; PMCID: PMC5447109.

Abstract:

Purpose: Peramivir is the first intravenously administered neuramidase inhibitor for immediate delivery of an effective single-dose treatment in patients with influenza. However, limited data are available on intravenous (IV) peramivir treatment compared to oral oseltamivir for these patients.

Materials and Methods: With a systematic review and meta-analysis, we compared the efficacy of IV peramivir with oral oseltamivir for treatment of patients with seasonal influenza. MEDLINE, EMBASE, and Cochrane Central Register were searched for relevant clinical trials.

Results: A total of seven trials [two randomized controlled trials (RCTs) and five non-randomized observational trials] involving 1676 patients were finally analyzed. The total number of peramivir- and oseltamivir-treated patients was 956 and 720, respectively. Overall, the time to alleviation of fever was lower in the peramivir-treated group compared with the oseltamivir-treated group [mean difference (MD), -7.17 hours; 95% confidence interval (CI) -11.00 to -3.34]. Especially, pooled analysis of observational studies (n=4) and studies of outpatients (n=4) demonstrated the superiority of the peramivir-treated group (MD, -7.83 hours; 95% CI -11.81 to -3.84 and MD, -7.71 hours; 95% CI -11.61 to -3.80, respectively). Mortality, length of hospital stay, change in virus titer 48 hours after admission, and the incidence of adverse events in these patients were not significantly different between the two groups. Conclusion: IV peramivir therapy might reduce the time to alleviation of fever in comparison with oral oseltamivir therapy in patients with influenza; however, we could not draw clear conclusions from a meta-analysis because of the few RCTs available and methodological limitations.

• Shigeki Nakamura, Taiga Miyazaki, Koichi Izumikawa, Hiroshi Kakeya, Yutaka Saisho, Katsunori Yanagihara, Yoshitsugu Miyazaki, Hiroshi Mukae, Shigeru Kohno, Efficacy and Safety of Intravenous Peramivir Compared With Oseltamivir in High-Risk Patients Infected With Influenza A and B Viruses: A Multicenter Randomized Controlled Study, Open Forum Infectious Diseases, Volume 4, Issue 3, Summer 2017, ofx129, https://doi.org/10.1093/ofid/ofx129  

Abstract:

 Background

Clinical studies comparing the different neuraminidase inhibitors for treatment of at-risk patients with influenza have not been performed. To optimize such treatments, we assessed the efficacy and safety of intravenous peramivir compared with oral oseltamivir in treating seasonal influenza A or B virus infection.

Methods

A multicenter, randomized, controlled clinical trial was conducted from December 2012 to May 2014 in high-risk patients infected with seasonal influenza. A total of 92 adult inpatients and outpatients with high risk factors (HRFs) were treated by either a single intravenous infusion of peramivir (600 mg) or oral administration of oseltamivir (75 mg, twice per day for 5 days).

Results

The median times to clinical stability (time to reach <37°C) were 40.0 hours (95% confidence interval [CI] = 23.3–64.5) and 37.8 hours (95% CI = 26.3–45.3) in the peramivir and oseltamivir groups, respectively; these values did not reveal a significant difference. The virus titer and change of mean total symptom scores decreased similarly with both treatments. Results of step-wise regression suggested that virus type was a significantly effective prognostic factor with respect to illness resolution. Adverse events (AEs) with peramivir and oseltamivir occurred in 2.2% (n = 1/46) and 13.0% (n = 6/46) of patients, respectively. The severity of AEs was mild in all cases except 2 patients who showed pneumonia or COPD aggravation; both were in the oseltamivir group.

Conclusions

Intravenous peramivir was effective based on the result of direct comparison with oral oseltamivir. Thus our data show that peramivir is a useful option for the treatment of influenza-infected patients with HRFs.

• Kato M, Saisho Y, Tanaka H, Bando T. Effect of peramivir on respiratory symptom improvement in patients with influenza virus infection and pre-existing chronic respiratory disease: Findings of a randomized, open-label study. Influenza Other Respir Viruses. 2021 Jan;15(1):132-141. doi: 10.1111/irv.12788. Epub 2020 Jul 17. PMID: 32677375; PMCID: PMC7767948.

Abstract

Background: The efficacy of neuraminidase inhibitors on improvement of respiratory symptoms triggered by influenza in patients with pre-existing chronic respiratory diseases is unknown.

Methods: This 2-week, randomized, open-label study evaluated intravenous peramivir 600 mg on two consecutive days (peramivir-repeat), peramivir 300 mg single dose (peramivir-single), and oral oseltamivir 75 mg twice daily for 5 days in patients with confirmed influenza and chronic respiratory diseases. Patients recorded symptom scores daily. The primary endpoint of cumulative area of time vs symptoms (CATVS) was expressed as an index value of area under the curve vs time of the total score of cough, sore throat, and nasal congestion from baseline to 2 weeks.

Results: Of 214 randomized patients, 209 (56% female, 77% aged <65 years, 94% outpatients, 91% bronchial asthma, 62% influenza A) received ≥1 dose of study drug. Mean (standard deviation) CATVS was similar for peramivir-repeat (782.78 [487.17]) vs peramivir-single (717.35 [347.55]; P = .4371), and for peramivir-repeat vs oseltamivir (856.34 [404.99]; P = 1.00). However, CATVS was significantly shorter for peramivir-single vs oseltamivir, with an estimated treatment difference (TD) of -145.07 (95% confidence interval: -284.57, -5.56; P = .0416). In subgroup analyses, CATVS was significantly shorter for peramivir-single vs oseltamivir among patients with influenza A (TD: -206.31 [-383.86, -28.76]; P = .0231), bronchial asthma (TD: -156.57 [-300.22, -12.92]; P = .0328), baseline respiratory severity score <5 (TD: -265.32 [-470.42, -60.21]; P = .0120), and age <65 (TD: -184.30 [-345.08, -23.52]; P = .0249).

Conclusions: In patients with chronic respiratory diseases, peramivir-single was not significantly different from peramivir-repeat and was more effective than oseltamivir at alleviating respiratory symptoms.

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Hsieh YH, Dugas AF, LoVecchio F, McBryde B, Ricketts EP, Saliba-Shaw K, Rothman RE. (2021)	RCT	2015-2016 and 2016-2017 influenza seasons Adult patients in the US who presented to the ED Eligibility for the study positive molecular influenza test, met CDC requirement for antiviral treatment, able to provide informed consent, agreed for follow-up assessment 170 patients were enrolled 95 were randomized to peramivir and 84 to oseltamivir	Clinical end-point indicators: FLU-PRO score, Ordinal scale, Patient Global Impression on Severity Score, Karnofsky Performance scale Measured over 14 days	FLU-PRO score at baseline was similar (2.67 with peramivir and 2.52 with oseltamivir) and the score decreased overtime with both groups (1.71 on day 5 with peramivir, 1.62 day 5 with oseltamivir). Overall influenza related complications were similar. Overall complication were 31% with peramivir and 21% with oseltamivir. Those treated with peramivir had a complication with pneumonia 11% and oseltamivir 14%.	Limitations: This is a small sample size. The study was not to determine the overall efficacy of peramivir but to determine the feasibility of future trials in the ED. There was no further subtyping/characterization of influenza done in this study and that can affect the outcome of treatment because outcomes can be influenced by virulence and antiviral resistance. All the data collected here was self-reported, which can be inaccurate due to information bias. Finally duration and amount of antipyretic use was not collected for this trial, which is a variable that can affect outcomes of antiviral treatment. There are some possible biases from the patient daily diary reports due to missing data.
Lee J, Park JH, Jwa H, Kim YH. (2017)	Systematic review and Meta analysis	MEDLINE, EMBASE, and Cochrane central register were searched. Seven trials were included: 2 RCTs and 5 non-randomized observational trials The total number of patients analyzed was 1676. 956 were treated with peramivir and 720 were treated with oseltamivir.	The outcomes they looked at were time to alleviation of symptoms, total mortality, length of hospital stay, change in influenza virus titer for 48 hours after admission, and adverse events.	The reduction in fever was 7.17 hours shorter in those treated with peramivir compared to oseltamivir. The peramivir group overall, had significantly shorter time to alleviation of symptoms compared to the oseltamivir treated group. There were no significant differences between the two treatment groups in: mortality, hospital length of stay, changes in virus titer 48 hours after admission and incidence of adverse effects.	Limitations: They only had two RCTs included and the rest were not randomized observation studies, and overall this is a small number of trials. Potential publication bias could not be estimated due to the small number of trials. Additionally the dosing and duration of IV peramivir treatment varied among the trials.
Shigeki Nakamura et al (2017)	RCT	Trial was conducted from December 2012-May 2014. Criteria for inclusion was high risk patients infected with influenza. A total of 92 patients were included either with IV peramivir or oral oseltamivir randomly in equal sized groups. High risk patients included: age >65, heart disease, chronic respiratory illness, CKD, chronic liver disease, DM, neurological disorder, hematological disorder and immunosuppression.	The primary efficacy endpoint they looked at was fever alleviation time. Secondary outcomes they looked at were: duration of influenza illness, the virus titer and subtype, gene mutation, exacerbation of underlying conditions. They also evaluated safety of the drugs by comparing adverse drug events.	They measured clinical stability by time to reach temperature <37 C. for the peramivir group that was 40 hours, for the oseltamivir group that 37.8 hours. There was no significant difference in this. The viral titer and symptom score decrease was similar between both groups. Adverse effects were similar and mild. . For both groups, the median duration of illness was 5 days, which is consistent with previous studies on oseltamivir to treat influenza.	The limitations of this study include that it is a small sample size. They chose not to extend the study to a third influenza season due to variation in influenza strains.
Kato M, Saisho Y, Tanaka H, Bando T. (2020)	RCT	The study spanned October 2017-February 2019, which was two influenza seasons. Criteria for inclusion: confirmed influenza cases with chronic respiratory disease. Patients were either given 600 mg Peramivir IV repeat dose, 300 mg IV peramivir single dose, or oral oseltamivir 75mg twice a day. Patients were randomized 1:1:1. 214 patients were included.	Outcomes measured included: daily diary of influenza symptom scores and temperature. The COPD assessment test (CAT) along with oxygen saturation and respiratory function testing. The primary efficacy endpoint was cumulative area of time vs symptoms (cough, sore throat, nasal congestion), also known as CATVS.	The mean CATVS was similar for peramivir repeat vs oseltamivir as well as for peramivir repeat vs peramivir single dose. However peramivir single dose vs oseltamivir the CATVS was shorter for peramivir single dose, especially in influenza A patients.	Limitations and biases: this was an open label study there is the potential for selection bias due to the inability to conceal treatment allocation. There was also no control group to compare outcomes in patients with and without chronic respiratory disease. Detection bias may have occurred because the outcome assessment was of patients subjective self reporting of respiratory symptoms.

Conclusion(s):
– Briefly summarize the conclusions of each article

– Then provide an overarching conclusion.

1. Hsieh et al concluded that clinical outcomes of influenza infected patients with single dose IV peramivir were comparable to those treated with oral oseltamivir, peramivir can be used in the ED to treat patients with Influenza.
2. Lee et al concluded that IV peramivir may shorten the duration of fever, compared to oseltamivir but otherwise they are similar. They did not have a recommendation regarding the superiority of IV peramivir to oral oseltamivir due to the limitations of the meta-analysis. Additional large-scale RCTs are needed to establish a criteria for optimal antiviral treatment for influenza
3. Nakamura et al concluded that a single dose of peramivir 600 mg IV has no significant difference in efficacy to 75 mg of oral oseltamivir for 5 days twice a day which was the previously standard treatment. They suggest that peramivir is a useful alternative to oseltamivir in treating high risk patients with influenza in the ED.
4. Kato et al concluded that in patients with Influenza and chronic respiratory disease, peramivir single dose is not significantly different from peramivir repeat dose, but was more effective than oseltamivir in alleviating respiratory symptoms. These findings suggest that peramivir 300 mg single dose is effective and a well-tolerated option in patients with chronic respiratory disease and is able to reduce influenza symptoms compared to oseltamivir.

My overall conclusion based on these studies is that single dose of IV peramivir is as efficacious and maybe even more so than 5 day treatment regimen with oseltamivir. All four studies found similar results in time to alleviation of symptoms was comparable or quicker in patients treated with peramivir. The studies also found that the rate of adverse effects was similar. Finally two of the studies I included looked at high risk patients including those with chronic respiratory disease which my patient has, and found that IV peramivir is effective in this population as well.

Clinical Bottom Line:

Please include an assessment of the following:

– Weight of the evidence – summarize the weaknesses/strengths of the articles and explain how they factored into your clinical bottom line (this may recap what you discussed in the criteria for choosing the articles)

I weighed the results of Lee et al the strongest because it was a meta-analysis and systematic review which is a high level of evidence. I liked this study because they did not draw a clear conclusion because the evidence was not there. They did not try to force a conclusion or recommendation. They did acknowledge that it might result in time to alleviation of fever compared to oseltamivir but did not recommend that it be used instead. I think they did a good job discussing the studies they included, and acknowledging the possible limitations and biases.

The next one I weighed was the Hsieh et al study, because it was a study done in the US and was published most recently in 2021. It was a RCT which is a high level of evidence. I also liked that they used many clinical outcome scorings. I also liked how did they suggested their outcome based on their study which is that IV peramivir has the potential to be used in the ED. I liked how they mentioned that because most patients in the ED receive IV lines anyway administering the IV peramivir is unlikely to burden the ED staff or have a negative effect on ED patient flow. I think that this is important because the trade off of having 1 dose vs 5 days of treatment is better patient compliance but you do not want to end up causing inefficiency elsewhere in the healthcare system. Some limitations to this study were the small sample size and the fact that they did not control for all variables that can affect the outcomes such as antipyretic use.

I weighed the Kato et al. study next because it was the more recent of my final two RCTs. I liked that this study particularly looked at patients with COPD, because that is part of my patients history and it is important to take into consideration when utilizing treatment. I liked that they had a clear outcome measurement and that they looked at baseline symptoms and symptoms at two weeks. There are some limitations to this study including that all outcomes were self reported which can lead to a bias, the sample size was small and that there was no control group.

Finally I weighed Nakamura et al. I liked this study because it is a randomized control study looking at a comparison of IV peramivir vs oral oseltamivir to treat influenza in high risk patients. My patient is high risk, which is why I chose this study, in addition to a RCT being a good choice for this question. This study looked at viral titers, adverse effects, symptom scores, and clinical stability, which are all good parameters for evaluating the effectiveness of a drug in treating the disease. It was also a relatively recent article from 2017. Some limitations to this study were the small sample size, and the fact that it was done in a different country.

– Magnitude of any effects

It is hard to conclude the magnitude of any effects with the current data available. All four studies came to a similar conclusion that IV peramivir is just as effective and possibly even more effective than Oseltamivir in treating influenza and lessening the symptoms.

– Clinical significance (not just statistical significance)

Based off the articles here I think more studies are required for clinical significance. I think that the data is promising that a single dose of IV peramivir may be more effective than 5 days of treatment with PO oseltamivir. However, I do not think that the level of evidence is high enough to make that conclusion. The possible clinical benefits of IV peramivir are a single one time dose will improve patient compliance with medication. I think it is difficult to draw clinical conclusions with such small sample sizes.

– Any other considerations important in weighing this evidence to guide practice  – If the evidence you retrieved was not enough to conclude an answer to the question, discuss what aspects still need to be explored and what the next studies will have to answer/provide (e.g. larger number, higher level of evidence, answer which sub-group benefits, etc)

I think that studies of higher levels of evidence are still needed in order to draw a conclusion whether IV peramivir can be utilized instead of PO oseltamivir in the ED. There is only one meta analysis that I can find and that is lacking in RCTs. We need also more large scale RCTs as all the RCTs I was able to find had small sample sizes. For the future I will be keeping an eye out for RCTs with larger sample sizes and meta analysis or systematic reviews that include more large scale RCTs as those articles are not currently available.

I think more studies on particular risk factors, need to be done as well, right now only two of the studies discussed high risk groups (eg chronic respiratory diseases) and both were small RCTs.

Additionally studies comparing treatment of IV peramivir vs PO oseltamivir in influenza flu typing is needed. All these studies looked at confirmed influenza, but most of them did not look specifically at Influenza A vs. B and more data is needed in that area.

Additionally, the use of this medication may have limitations in other areas of practice, since not all outpatient offices have the capability of giving medicine via IV, however, I do think it is important to compare the two for patients in the ED and for patients admitted with Influenza.