Were Some Studies Overlooked In Nausea and Vomiting Paper?

With regard to the article in the May, 2012 issue entitled “Reviewing the Evidence for Using Continuous Subcutaneous Metoclopramide and Ondansetron to Treat Nausea & Vomiting During Pregnancy [1]” (Reichmann 2012), the report, as presented, contains inaccuracies and omissions which prevent the reader from obtaining a balanced assessment of effective therapies for this diagnosis.

The authors begin by stating “All of the published, peer-reviewed articles on the subject were assembled…” and “All identified articles are included in this review; none were excluded.” However, while Buttino’s report was included (Buttino 1998), two larger, more contemporaneous reports examining distinct outcomes parameters are notably absent (Barton 2003, McCauley 2002). The evidence presented in Table 1 is particularly concerning:

1. The authors dismiss the validity of Buttino’s 2000 publication as “…compromised by the fact that 82.1% of the patients were previously reported…” (Buttino 2000). However, they inexplicably: a) fail to clarify that the publication differentiates treatment outcomes in distinct groups of patients during different treatment times; b) omit the “resolution of hyperemesis gravidarum” symptom rate data (54.7% and 75.0%; Groups I and II); c) omit the “failed therapy” rate data (14.3% and 6.9%; Groups I and II); and d) omit side effects rate data (54.5% and 49.9%; Groups I and II) of which the “overwhelming majority were characterized as ‘mild.’”
2. The authors incorrectly characterize Lombardi’s (2004) case series outcomes as “indiscernible.” In actuality, the Methods section of this report clearly identifies metoclopramide therapy as the treatment intervention, and the study outcomes are reported based solely upon therapy with this agent. In the study population, 10.7% of patients failed metoclopramide therapy and transitioned to ondansetron. After failing metoclopramide therapy, descriptive statistics characterizing time of treatment at failure, duration of ondansetron therapy, pretreatment standardized nausea scores, gestational age when starting metoclopramide, and intravenous hydration requirements are clearly described.
3. The report by Klauser (2011) is incorrectly described as a “matched cohort” study. Rather, the distinct differences in the clinical characteristics of the two patient populations and the profiles of patients treated with the two therapies are clearly outlined in the methods section. Klauser identifies transition rates between the medication therapies as the primary outcome measure, and quantifies therapy responses individually to standardized nausea scores, weight gain, ketonuria, and ability to tolerate a regular diet.

Guidelines and treatment algorithms for nausea and vomiting in pregnancy are well established and reported by specialty-trained clinicians expert in the management of this diagnosis (Badell 2006, ACOG 2004). All guidelines and treatment algorithms include use of both parenteral metoclopramide and ondansetron for patients who fail more conservative therapies (Badell 2006, ACOG 2004, Arssenult 2002, Levichek 2002, Niebyl 2010). Home-based subcutaneous antiemetic therapy is effective, safe, and economical (Arssenult 2002). The authors failed to discuss these recognized treatment protocols.

Sincerely,

F. Miguel Fernandez, DO

Senior medical director, Alere Health

References

• ACOG (American College of Obstetrics and Gynecology) Practice Bulletin: nausea and vomiting of pregnancy. Obstet Gynecol Apr 2004;103(4):803–14.
• Arssenult M, Lane C. The management of nausea and vomiting of pregnancy clinical practice guidelines no. 120. J Obstet Gynaecol Can 2002;24(10):817–23.
• Badell JL., Ramin DM, Smith JA. Treatment options for nausea and vomiting during pregnancy, Pharmacotherapy Sep 2006:26(9):1273–87.
• Barton J, O’Brien J, Lombardi D, et al. Subcutaneous metoclopramide therapy for the treatment of nausea and vomiting of pregnancy. Obstet Gynecol 2003;101(4):84S.
• Buttino L, Gambon C, Coleman S. Home subcutaneous metoclopramide therapy for hyperemesis gravidarum. In: Koren G, Bishai R, editors. Nausea and vomiting of pregnancy: state of the art, 2000, Vol 1. Toronto: Motherisk; 2000. P. 84–9.
• Buttino L, Gambon C. Home subcutaneous metoclopramide therapy for hyperemesis gravidarum. Primary Care Update for Ob/Gyns 1998 Jul 1;5(4):189.
• Klauser CK, Fox NS, Istwan N, et al. Treatment of severe nausea and vomiting of pregnancy with subcutaneous medications. Am J Perinatol 2011 Oct;28(9):715–21.
• Levichek Z, Atanackovic G, Oepkes D, et al. Nausea and vomiting of pregnancy. Evidence-based treatment algorithm. Can Fam Physician 2002 Feb;48:267–68, 277.
• Lombardi DG, Istwan NB, Rhea DJ, O’Brien JM, Barton JR. Measuring outpatient outcomes of emesis and nausea management in pregnant women. Manag Care 2004 Nov;13(11):48–52.
• McCauley L, Coleman S, Jacques D, Palmer B, Stanziano G. Safety and efficacy of ondansetron therapy for nausea and vomiting of pregnancy. Obstet Gynecol 2002;99(4):S24.
• Naef RW, 3rd, Chauhan SP, Roach H, Roberts WE, Travis KH, Morrison JC. Treatment for hyperemesis gravidarum in the home: an alternative to hospitalization. J Perinatol 1995 Jul-Aug;15(4):289–92.
• Niebyl JR. Clinical practice. Nausea and vomiting in pregnancy. New England J Med 2010 Oct 14;363(16):1544–50.
• Reichmann JP, Kirkbride MS. Nausea and vomiting of pregnancy: cost effective pharmacologic treatments. Manag Care 2008 Dec;17(12):41–5.
• Reichmann JP, Kirkbride MS. Reviewing the evidence for using continuous subcutaneous metoclopramide and ondansetron to treat nausea & vomiting during pregnancy. Manag Care 2012 May;21(5):44–7.

The authors respond

Senior medical director F. Miguel Fernandez, DO, may not be aware that the citations for Barton (Obstet Gynecol 2003; 101(4):84S) and McCauley (Obstet Gynecol 2002; 99(4):S24) both contain an “S” indicating inclusion in a supplement of Obstetrics & Gynecology. Both are merely meeting abstracts and sadly never were published, rendering them unusable for evidence review. So while Dr. Fernandez declares there were omissions and misinterpretations in the article, no published evidence was omitted from this review (Reichmann 2012). Neither abstract was footnoted in subsequent published studies which were actually written in part by Alere employees (Lombardi 2004, Klauser 2011). Regarding the suggestions on Table 1:

1. Buttino 2000b, a book chapter, data were not included in the table because the authors were unable to identify the 18.9% of the patients that were unique and not included in the initial report. “Double counting” would have occurred for the majority of patients and would as a result distort the review. Redundancy of publication prevented inclusion but we felt the mention of the chapter was necessary so readers would understand all evidence was reviewed and none was arbitrarily left out. (Buttino 2000b).
2. Lombardi 2004 did not report meaningful pregnancy outcomes for the 46 women that failed metoclopramide and were switched to ondansetron. The outcomes for the reported population, namely metoclopramide, are included in the table. We wish to thank Dr. Fernandez for pointing this minor unintentional oversight that is not material to the review (Lombardi 2004).
3. The Klauser study is in fact a “matched cohort” study, although the patients were initially selected on the basis of being diagnosed by their physician with severe NVP and having a PUQUE score of >12 at initiation of therapy. The matching, which appears to have taken place after patient selection, is presented in table 1, entitled “Comparison of Maternal Characteristics for Metoclopramide versus Ondansetron Groups.” We graded this study as a level II matched cohort; however, it could be downgraded to a level III observational descriptive trial, in light of the fact that the matching was done after patient selection. Either way, as we acknowledged in the original review, this study shows continuous subcutaneous ondansetron is better tolerated than metoclopramide when administered similarly (Klauser 2011).

The guidelines and treatment algorithms mentioned discuss short term IV metoclopramide and ondansetron, usually administered in the hospital setting. They are routinely given after more conservative measures are exhausted and in agreement with the conclusions of this review. It is important to point out that Dr. Fernandez inadvertently used a sentence out of context when paraphrasing one of the guidelines. The guideline states, “No RCTs have been published to support the effectiveness of metoclopramide in the treatment of NVP. An observational study using home subcutaneous therapy for HG suggested that metoclopramide is effective, safe, and economical” (Arssenult 2002). This is based on the book chapter written in part by Alere employees (Buttino 2000b).

In summary, no published clinical trials were omitted from the article, clinical guidelines do not recommend these therapies, and the data in this review are neither misrepresented nor incomplete.

Sincerely,

James P. Reichmann, MBA

Michael S. Kirkbride, PharmD

References

• Barton J, O’Brien J, Lombardi D, et al. Subcutaneous metoclopramide therapy for the treatment of nausea and vomiting of pregnancy. Obstet Gynecol 2003;101(4):84S.
• Buttino L, Gambon C. Home subcutaneous metoclopromide therapy for hyperemesis gravidarum. Prim Care Update Ob Gyns 1998; 5(4):189.
• Buttino L Jr., Coleman SK, Bergauer NK, Gambon C, Stanziano GJ. Home subcutaneous metoclopromide therapy for hyperemisis gravidarum. J Perinatol 2000; 20(6):359–62.
• Buttino L Jr., Gambon C, Coleman S. Home subcutaneous metoclopromide therapy for hyperemesis gravidarum . In: Koren G, Bishai R, editors. Nausea and vomiting of pregnancy: state of the art 2000. First International Conference of Nausea and Vomiting of Pregnancy. Toronto: Motherisk; 2000 P 84–9.
• Klauser CK, Fox NS, Istwan N, Rhea D, Rebarber A, Desch C, Palmer B, Saltzman D. Treatment of severe nausea and vomiting of pregnancy with subcutaneous medications. Am J Perinatol. 2011 Oct; 28(9):715–22.
• Lombardi DG, Istwan NB, Rhea DJ, O’Brien JM. Measuring outpatient outcomes of emesis and nausea management in pregnant women. Manag Care 2004; 13(11):48–51.
• McCauley L, Coleman S, Jacques D, Palmer B, Stanziano G. Safety and efficacy of ondansetron therapy for the nausea and vomiting of pregnancy. Obstet Gynecol 2002;99(4):S24.
• Neaf RW 3rd, Chauhan SP, Roach H, Roberts WE, Travis KH, Morrison JC. Treatment for hyperemesis gravidarum in the home: an alternative to hospitalization. J Perinatol 1995;15(4):289–92.
• Reichmann JP, Kirkbride MS. Nausea and vomiting of pregnancy-cost effective pharmacologic treatments. Manag Care. 2008 Dec; 17(12):41–45.
• Reichmann JP, Kirkbride MS. Reviewing the evidence for using continuous subcutaneous metoclopramide and ondansetron to treat nausea & vomiting during pregnancy. Manag Care 2012 May;21(5):44–7.