June 2012 FAQs
June 2012 FAQs Heading link
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How should Helicobacter pylori infection be treated in the context of increasing resistance to antibiotics and current shortages of clarithromycin and tetracycline?
How should Helicobacter pylori infection be treated in the context of increasing resistance to antibiotics and current shortages of clarithromycin and tetracycline?
Introduction
Helicobacter pylori (H. pylori) infection is associated with many upper gastrointestinal (GI) diseases such as chronic gastritis, peptic ulcer disease (PUD), and gastric malignancy.1-4H. pylori infection is prevalent in 30% to 40% of the United States (US) population.5 Infection is more common in developing countries and has been correlated with a lower socioeconomic status, including crowded living conditions, poor sanitation, and lower household income.1,2H. pylori infection is most frequently transmitted via gastro-oral or fecal-oral means during early childhood. Many individuals infected with H. pylori may be asymptomatic; however, infection may be associated with dyspepsia or symptoms of PUD. 1 Uncomplicated PUD has been associated with epigastric tenderness upon physical examination, but no physical signs have been specifically determined for indication of H. pylori infection. Therefore, clinical presentation does not provide adequate data for diagnosis of H. pylori infection.
The test-and-treat strategy has been used for diagnosis and management of H. pylori infection.6 However, the American College of Gastroenterology (ACG) only recommends to screen for H. pylori in patients with the following conditions: active PUD; confirmed history of PUD ( H. pylori treatment-naïve); low-grade, gastric mucosa-associated lymphoid tissue (MALT) lymphoma; post-endoscopic resection of early gastric cancer; and, uninvestigated dyspepsia in regions with increased H. pylori prevalence. Currently, a gold standard for testing the presence of H. pylori infection has not been determined. Antibody tests may remain positive for a prolonged period after infection; thus, urea breath tests (UBT) and fecal antigen tests are the recommended methods for testing post-therapy if endoscopy is not indicated. Testing should commence at a length greater than 4 weeks after completion of therapy due to drug effects on test sensitivity. Treatment of H. pylori has radically decreased the incidence in developed countries; however, antibiotic resistance and drug shortages are new challenges to successful eradication. After a brief overview of the current standards of care, these challenges will be addressed.
Treatment Regimens
According to ACG, the greatest potential for eradicating H. pylori is the selection of the first course of therapy, which requires the use of 2 or more antimicrobial agents.6-8 Antimicrobials are given in combination with proton pump inhibitors (PPIs) or histamine (H2) antagonists due to proposed increased effectiveness of antibiotics within a less acidic environment.9,10 The current ACG guidelines list several options for first-line therapy of H. pylori.6 Table 1 outlines these recommendations. Treatment regimens generally include more than 1 antibiotic due to H. pylori resistance.8 The ACG guidelines recommend a 14-day duration of therapy in the US due to <80% eradication rates with shorter durations.6 Nonetheless, a 7-day regimen has been used in Canada and abroad since there is no evidence for therapeutic gain and only marginal clinical significance with treating for >7 days. Historically, clarithromycin-based triple-therapy has been considered the “gold standard” for treatment of H. pylori, but the integrity of this standard is complicated by issues of clarithromycin resistance and shortages. Metronidazole resistance and tetracycline shortages are also issues that complicate drug therapy selection for H. pylori.
Table 1. ACG recommendations for first-line therapy of H. pylori. 6
Regimen Duration (Days) Standard Triple Therapy (STT) a
Standard dose PPI twice a day* +
Clarithromycin 500 mg twice a day +
Amoxicillin 1,000 mg twice a day10 to 14 Alternative Triple Therapy a,b
Standard dose PPI twice a day* +
Clarithromycin 500 mg twice a day +
Metronidazole 500 mg twice a day10 to 14 Quadruple Therapy (BQT) b
Standard dose PPI twice daily* OR ranitidine 150 mg twice a day +
Bismuth subsalicylate 525 mg 4 times a day +
Metronidazole 500 mg 4 times a day +
Tetracycline 500 mg 4 times a day10 to 14 Sequential Therapy c
Standard dose PPI twice a day* +
Amoxicillin 1000 mg twice a day (5 days)
Followed byStandard dose PPI twice a day* +
Clarithromycin 500 mg twice a day
Metronidazole 500 mg twice a day (5 days)10 *Standard dosages for PPIs include: lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg, rabeprazole 20 mg, and esomperazole 40 mg (dosed once a day). Dexlansoprazole was not approved prior to publication of ACG Guidelines.
a Consider in patients who have not previously received a macrolide.
b Consider in penicillin-allergic patients.
c Needs validation in the US.
Drug resistance to clarithromycin and metronidazole has prompted investigation of alternative regimens for the treatment of H. pylori infection. Recent data have indicated clarithromycin resistance rates of approximately 20% to 29% in the US and even greater rates of resistance in areas of Europe and Asia, such as Spain and Japan.7,11,12 In most studies, metronidazole resistance rates are approximately 30% to 40%; but this is less of a concern than clarithromycin resistance because metronidazole resistance may be overcome with larger doses.6,12 The ACG recommends quadruple therapy with bismuth subsalicylate (BQT) as first-line therapy in patients located in areas with a high prevalence of clarithromycin-resistant H. pylori, and patients who have previously been treated with macrolide antibiotics or metronidazole (as literature suggests that previous exposure significantly increases the likelihood of H. pylori resistance).6,7
Tackling Antibiotic Resistance
Quadruple Therapy
Studies evaluating the efficacy of quadruple therapy have increased due to rising antibiotic resistance levels, particularly abroad.7 A 2010 meta-analysis evaluated the efficacy of empiric BQT versus standard triple therapy (STT) for treatment of H. pylori.13 Nine randomized controlled trials performed in multiple countries with 1,679 patients were included in the analysis. Quadruple therapy consisted of a PPI twice daily, tetracycline 3 or 4 times daily, a bismuth salt 3 or 4 times daily, and metronidazole 3 or 4 times daily. Triple therapy consisted of a PPI twice daily, amoxicillin twice daily (one trial administered amoxicillin 4 times daily), and clarithromycin twice daily. Treatment duration for the studies was 7, 10, or 14 days. Eradication rates in the intent-to-treat (ITT) population were similar between groups: 78.3% for BQT and 77.0% for STT, with a risk ratio=1.002 (95% confidence interval [CI], 0.936 to 1.073). No treatment differences were observed between groups when data were compared between Eastern and Western hemispheres, as well as between treatment durations. Two studies reported data on resistance, and clarithromycin resistance significantly decreased the eradication rates in the STT groups but metronidazole resistance only modestly decreased eradication rates in the BQT group. Compliance rates were available for 7 of the 9 trials. The overall compliance rate for BQT was 92.6% and 96.9% for STT. Rates of side effects were also similar in the BQT group (35.5%) versus the STT group (35.4%).
Another trial conducted in 2011 evaluated the efficacy of 10 days of BQT in comparison to 7 days of STT.14 This was a phase 3, open-label, non-inferiority trial conducted in multiple countries. The BQT group received a 3-in-1 capsule (140 mg bismuth subcitrate potassium, 125 mg metronidazole, and 125 mg tetracycline hydrochloride), along with omeprazole 20 mg twice daily. The STT group received 1000 mg amoxicillin, 500 mg clarithromycin, and 20 mg omeprazole twice daily. The investigators used a per-protocol (PP) analysis to determine non-inferiority and ITT analysis on imputed data to determine superiority if non-inferiority criteria were met. The results indicated that BQT was non-inferior to STT in the PP population with eradication rates of 93% and 70%, respectively (95% CI, 15.1 to 32.2, p<0.0001). Post-hoc analysis on the ITT population with imputed data revealed superiority of BQT to STT. Baseline sensitivity rates for clarithromycin (77% for BQT and 81% for STT) and metronidazole (71% for BQT and 69% for STT) were similar between groups. Within the STT group, there was only 8% eradication among those with clarithromycin resistance compared to 85% in those without resistance (p=0.001). Dual clarithromycin and metronidazole resistance also resulted in a difference in eradication rates within the STT group, with only 20% eradication achieved in those with dual resistance and 74% eradication in those without dual resistance (p<0.001). Metronidazole resistance had no significant impact on eradication rates in the BQT group.
These studies demonstrate that BQT is at least as effective as STT for empiric eradication of H. pylori, and is more effective than STT in patients with clarithromycin resistance or dual clarithromycin and metronidazole resistance.13,14 However, neither study is without limitations. The meta-analysis had moderate heterogeneity which could not be accounted for statistically.13 Various dosing regimens were also used in the included studies, and inclusion/exclusion criteria varied as well. The trial conducted by Malfertheiner, et al was not blinded and may have been susceptible to investigator and funding bias.14 Also, the ACG guidelines recommend treatment duration of STT for 10 to 14 days, and the meta-analysis included studies of STT arms with shorter duration. Malfertheiner and colleagues also used a shorter duration of 7 days, so these results may not be entirely applicable to current US practice.6,14 While these studies evaluated BQT in patient populations with clarithromycin and metronidazole resistance rates similar to those reported in the US, further investigation is warranted in the US population to determine efficacy in comparison to STT in light of current rates of H. pylori resistance. Other concerns with BQT include the complexity of dosing and compliance; however, the meta-analysis concluded that compliance rates were similar for STT and BQT.13
Sequential Therapy and Concomitant Therapy (Non-bismuth Quadruple Therapy)
Other proposed regimens that have become more utilized include sequential therapy and concomitant therapy.7 Sequential therapy is a 10-day regimen that begins with double therapy and switches to triple therapy: 5 days of a standard-dose PPI and amoxicillin 1000 mg dosed twice daily; then 5 days of a PPI, clarithromycin 500 mg, and metronidazole 500 mg (or tinidazole 500 mg) – all dosed twice daily.7,15 Concomitant therapy, also referred to as non-bismuth quadruple therapy, involves the same 4 medications that are used in sequential therapy, but taken concomitantly, resulting in a less complicated regimen. Concomitant therapy is a standard-dose PPI, amoxicillin 1000 mg, clarithromycin 500 mg, and metronidazole 500 mg, all administered twice daily for 10 days. A recent study conducted in Taiwan investigated these 2 regimens in the treatment of H. pylori within the context of high metronidazole resistance and rising rates of clarithromycin resistance.15 Two hundred and thirty-two H. pylori-infected patients were randomized and enrolled over a 1-year period in this non-inferiority trial. Both the ITT and PP analyses found eradication rates >90% in both groups with no significant differences. Compliance rates between groups were similar as well. H. pylori resistance rates to antibiotics at baseline for 167 patients were as follows: metronidazole (33.5%), clarithromycin (6.6%), and levofloxacin (10.2%). Only clarithromycin resistance had a significant effect on efficacy in the sequential group, decreasing the eradication rate from 96.1% to 57.1% in those patients with clarithromycin resistance (p<0.0001). Eradication rates were also significantly lower in the sequential group in those who had dual resistance to clarithromycin and metronidazole compared to those who did not. The authors concluded that sequential and concomitant therapies are viable options for treatment of H. pylori infection, but that concomitant therapy may be more appropriate in populations with known clarithromycin or dual resistance. These results validate previous study results; however, there are limited clinical data available in the US.7 Cure rates for sequential therapy have been as high as 92% in Europe. Other European and Asian studies have found sequential therapy to be similar, and sometimes more effective, than STT. European and Asian studies on concomitant therapy also found higher eradication rates when compared to STT. Due to a lack of studies performed in North America, these regimens do not have a definite place in therapy for the US population.
Salvage regimens
Some patients have failed all of the above regimens, leaving limited treatment options.16 It can be assumed that those patients have resistance to both clarithromycin and metronidazole (having received and failed regimens containing these), and retreatment with any previously used antibiotics is not recommended.6 Levofloxacin-based triple therapy (with a PPI and amoxicillin) is a possible regimen to try next, as it has shown H. pylori eradication rates between 63% and 94% in Asian and European populations.7 However, the optimal duration and dosing have not yet been determined, with studies using 7 or 10 days and levofloxacin doses of 250 mg twice daily, 500 mg once daily, and 500 mg twice daily. Also, some experts only recommend use of levofloxacin if susceptibility is confirmed. Rifabutin has also been used as an alternative to clarithromycin in a standard therapy regimen, but its use is discouraged due to associated adverse effects and concern for increased resistance of mycobacteria.
Drug Shortages
Drug shortages are another obstacle facing clinicians in the current treatment of H. pylori infection, specifically the availability of clarithromycin immediate-release tablets and tetracycline capsules.17 According to ASHP (March 14, 2012), Ranbaxy has an import ban on their clarithromycin products, and while the ban on Apotex clarithromycin products has been lifted, production has not resumed. Meanwhile, other manufacturers have not provided reasons for the shortage of clarithromycin and release dates for products on backorder remain unclear. Likewise, there is also a shortage of tetracycline capsules. According to ASHP (March 20, 2012), Teva states that capsules are unavailable due to a raw materials shortage, while Watson has not provided a reason for the shortage of tetracycline.
Although shortages of clarithromycin and tetracycline products exist, combination packs containing these medications for the purpose of treating H. pylori remain available in brand form.7 These products include: Prevpac, a 10 to 14-day, twice-daily-dosed combination regimen of lansoprazole 30 mg, clarithromycin 500 mg, and amoxicillin 1000 mg (2 capsules); Helidac, a regimen containing bismuth subsalicylate 525 mg (2 tablets), metronidazole 250 mg, and tetracycline 500 mg dosed 4 times daily for 14 days and FDA-approved in combination with an H2 antagonist; and, Pylera, a regimen containing bismuth subcitrate 140 mg, metronidazole 125 mg, and tetracycline 125 mg, dosed as 3 capsules 4 times daily for 10 days, given in combination with omeprazole 20 mg twice daily.10 Additional metronidazole (approximately 500 mg for a total daily dose of 1500 mg) is recommended with use of Helidac in order to overcome potential metronidazole resistance.7 The greatest concern in using Prevpac, Helidac, or Pylera is the increase in cost to the patient.
Conclusion
The combination of increasing antibiotic resistance and shortages of clarithromycin and tetracycline makes selection of an appropriate H. pylori treatment regimen difficult. Evidence suggests efficacy of BQT as an appropriate regimen, particularly when used in patients who live in areas of high rates of clarithromycin-resistant H. pylori.6 However, with the current shortage of tetracycline, only brand-name products are available (Pylera and Helidac), but at a greater cost to patients.7 The alternatives of sequential and concomitant therapies would also be affected by the shortage of clarithromycin immediate-release tablets. Concomitant therapy could be an option with use of Prevpac, but metronidazole 500 mg twice daily would also need to be added. Expert opinion currently does not recommend substitution of macrolides or doxycycline for unavailable clarithromycin and tetracycline. Instead, it is recommended to delay antibiotic treatment until appropriate drugs become available, and administer a PPI if warranted for treatment of ulcers. In sum, clinicians should consider treatment history, local susceptibilities, drug availabilities, and cost when selecting a regimen for patients infected with H. pylori.
References
1. Dynamed. Helicobacter pylori infection. Updated February 27, 2012. Available at: http://web.ebscohost.com.proxy.cc.uic.edu/dynamed. Accessed March 1, 2012.
2. Gratton, MC. Peptic ulcer disease and gastritis. In: Tintinalli JE, Stapczynski JS, Cline DM, Ma OJ, Cydulka RK, and Meckler GD, eds. Tintinalli's Emergency Medicine: A Comprehensive Study Guide. 7th ed. New York, NY: McGraw-Hill; 2011. Available at: http://www.accessmedicine.com.proxy.cc.uic.edu. Accessed March 4, 2012.
3. McColl KL. Clinical practice. Helicobacter pylori infection. N Eng J of Med. 2010;362(17):1597-1604.
4. American Gastroenterological Association. American Gastroenterological Association (AGA) medical position statement: Evaluation of dyspepsia. Gastroenterology. 2005;129(5):1753-1755.
5. Berardi RR and Fugit RV. Peptic ulcer disease. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, Schwinghammer T, eds.Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill; 2011. Available at: http://www.accesspharmacy.com.proxy. cc.uic.edu. Accessed March 4, 2012.
6. Chey WD, Wong BC and the Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102(2):1808-1825.
7. PL Detail-Document. H. pylori treatment: An update. Pharmacist's Letter/Prescriber's Letter. February 2012.
8. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Thomson Reuters (Healthcare), Inc; 2012. http://www.thomsonhc.com/hcs/librarian. Accessed March 5, 2012.
9. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2012. http://clinicalpharmacology-ip.com/default.aspx. Accessed March 5, 2012.
10. Wickersham RM, ed. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health; 2012. http://online.factsandcomparisons.com. Accessed March 5, 2012.
11. Chuah SK, Tsay FW, Hsu PI, Wu DC. A new look at anti-Helicobacter pylori therapy. World J Gastroenterol. 2011;17(35):3971-3975.
12. Selgrad M and Malfertheiner P. Treatment of Helicobacter pylori. Curr Opin Gastroenterol. 2011;27(6);565-570.
13. Luther J, Higgins PD, Schoenfeld PS, Moayyedi P, Vakil N, Chey WD. Empiric quadruple vs. triple therapy for primary treatment of Helicobacter pylori infection: Systematic review and meta-analysis of efficacy and tolerability. Am J Gastroenterol. 2010;105(1):65-73.
14. Malfertheiner P, Bazzoli F, Delchier J, et al. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial. Lancet. 2011;377(9769):905-913.
15. Wu DC, Hsu PI, Wu JY, Opekun AR, Kuo CH, Wu IC, et al. Sequential and concomitant therapy with 4 drugs are equally effective for eradication of H. pylori infection. Clin Gastroenterol H. 2010;8(1):36-41.
16. Gisbert JP. Rescue therapy for Helicobacter pylori infection 2012. Gastroenterol Res Pract. 2012;2012:974594. Epub 2012 Feb 28.
17. American Society of Heath System Pharmacists. Drug shortages: current drugs. Available at: http://www.ashp.org/DrugShortages/Current/. Accessed May 17, 2012.
Written by: Merrideth Gilley, 2012 PharmD Candidate
Edited by: Lara K. Ellinger, PharmD, BCPS
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What do the new guidelines for use of intravenous immunoglobulin (IVIG) in the treatment of neuromuscular disorders recommend?
What do the new guidelines for use of intravenous immunoglobulin (IVIG) in the treatment of neuromuscular disorders recommend?
Introduction
Although intravenous immunoglobulin (IVIG) has a limited number of Food and Drug Administration (FDA) labeled indications, it is common practice to use IVIG off-label in the treatment of a wide variety of diseases.1 This practice is controversial and raises the question of whether there is evidence to support the use of IVIG for various disease states.In March 2012, the American Academy of Neurology (AAN) published an evidence-based guideline on the use of IVIG in the treatment of neuromuscular disorders.2 These new recommendations will be reviewed in this article.
Guideline Recommendations
The AAN classified the literature as class I, II, III, or IV and graded their therapeutic recommendations as level A, B, C, or U according to the quality of available evidence.2 A summary of these criteria are presented in the table.
Literature Classification Therapeutic Recommendations Class I: Randomized controlled trial (RCT) including an appropriately selected patient population with similar baseline characteristics, well-defined outcomes, exclusion and inclusion criteria, and blinded treatment assignment, with at least 80% completion rates Level A: Treatments recognized as either effective/useful, ineffective/not useful, or harmful; available data included at least 2 class I studies Class II: RCTs missing one of the class I criteria or prospective cohort studies meeting the class I criteria Level B: Treatments recognized as either probably effective/useful, ineffective/not useful, or harmful; available data included at least 1 class I study or 2 class II studies Class III: All other controlled trials in relevant populations Level C: Treatments recognized as either possibly effective/useful, ineffective/not useful, or harmful; available data included at least 1 class II or 2 class III studies Class IV: Expert opinion, consensus, or studies not qualifying as class I, II, or III Level U: Unproven treatments in which data are conflicting or insufficient Level A Recommendations
IVIG is an effective long-term treatment option for CIDP
The level A recommendation for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) is based on 2 class I and 2 class II studies in which IVIG was compared to placebo.2 The first class I study was a trial in 53 treatment-naive patients randomized to receive either 1 g/kg IVIG on days 1, 2, and 21 or placebo. This study found a significant difference in its primary outcome of change in average muscle score (an expanded 10-point version of the Medical Research Council [MRC] scale) from baseline with an increase of 0.63 and a decrease of 0.1 in the IVIG and placebo groups, respectively (p=0.006). The other class I study that this recommendation was based on was a crossover study in 117 patients receiving either albumin as placebo or a 2 g/kg loading dose of IVIG followed by 1 g/kg IVIG every 3 weeks. Significantly more patients in the IVIG group (54%) compared to placebo (21%) had improvement in their Inflammatory Neuropathy Cause and Treatment (INCAT) score (p=0.0002), but with a higher rate of adverse effects (55% and 17%, respectively). The effects of IVIG seen in the 2 class II studies were similar to the results found in the class I studies. In addition, the AAN deemed evidence evaluating the comparative efficacy of IVIG to prednisolone in the treatment of CIDP to be insufficient.
IVIG is recommended for GBS in adults
The use of plasmapheresis in the treatment of Guillain-Barre syndrome (GBS) is well established.2 Two class I studies were used to evaluate if IVIG is as effective as plasmapheresis in the treatment of adults with GBS. In one of the class I studies, 150 patients were randomized to 0.4 g/kg/day of IVIG or 5 volumes of plasma exchange in 5 days within 14 days of onset of symptoms. For the primary outcome of a change in 1 point on a 7-point disability scale, 53% of IVIG patients compared to 34% of plasmapheresis patients achieved a significant improvement (p=0.024) at week 4 and did so in a shorter amount of time (27 days for IVIG and 41 days for plasmapheresis; p=0.05). In another class I single-blind trial in which 379 patients were randomized to plasmapheresis, plasmapheresis prior to IVIG, or IVIG alone, no significant difference in change in disability score was found between the 3 groups. Three class III studies that were also evaluated did not alter the recommendation. In addition, it was found that there was insufficient data to recommend an optimal IVIG dose in the treatment of GBS.
Level B Recommendations
Combination of IVIG with plasmapheresis should not be used in the treatment of GBS
The AAN concluded that combination treatment is probably not more effective than either agent given as monotherapy based on the single-blind class I trial in 379 patients mentioned above.2
IVIG is probably effective and therefore should be considered in the treatment of MG
One class I study evaluating improvement in the Quantitative Myasthenia Gravis (QMG) score in 24 patients with myasthenia gravis (MG) treated with IVIG 2 g/kg and 27 patients receiving placebo found a significant improvement in QMG scores at 14 days with a decrease of 2.54 in IVIG-treated patients compared with a decrease of 0.89 in placebo-treated patients (p=0.047).2 However, this difference was only present in patients with moderate or severe MG and not in patients with mild MG; therefore, it is recommended to cautiously evaluate the risk-benefit ratio when using IVIG in patients with mild MG. In addition, AAN noted that there is not enough quality evidence available to compare IVIG to plasmapheresis in the treatment of MG.
Consider IVIG in the treatment of multifocal motor neuropathy; it is probably effective
This recommendation is based on data from 3 class II studies.2 In one class II crossover study 16 patients were treated with either IVIG 0.4 g/kg for 5 days or placebo and a significant difference in scores on a modified neurologic disability scale was found at 28 days with an improvement in score of 6.7 ± 3.3 in IVIG-treated patients and a decline of 2.1 ± 3.0 in placebo-treated patients (p=0.038). In another randomized class II study in 19 patients treated with IVIG 0.5 g/kg/day for 5 days or monthly placebo for 3 months, 7 of 9 patients treated with IVIG showed improvement in MRC scores versus 2 of 9 patients who received placebo (p=0.03). In both studies adverse effects were mild. Another small crossover class II study in 5 patients receiving IVIG 0.4 g/kg/day or placebo for 5 days found a significant improvement in muscle strength 28 days after IVIG treatment (p<0.05).
Level C Recommendations
IVIG is possibly effective and can be considered in the treatment of nonresponsive dermatomyositis
In one small class II crossover trial in 15 patients, patients treated with IVIG had significant improvement in activities of daily living scores and muscle inflammation, neuromuscular symptom scores improved by 7.3 points on a 60-point scale (p<0.035), and MRC scores improved by 8 points on a 90-point scale (p<0.018).2
In the treatment of LEMS, IVIG is possibly effective and can be considered
This recommendation is based on one small class II crossover study in which IVIG demonstrated some improvement in limb strength, drinking time, antibody titer, and vital capacity as compared to placebo.2
Level U Recommendations
For the treatment of GBS, there is insufficient evidence to recommend the use of IVIG in children or as combination therapy with a steroid
The use of IVIG for treatment of GBS in children was evaluated in one class II and one class III trial.2 A class II study involving 21 children who received IVIG 1 g/kg for 2 days or no treatment found significant improvement for IVIG-treated patients in the secondary endpoints of disability duration (p<0.05) and time to improvement (p<0.001). In one class III study 18 children with GBS received IVIG 1 g/kg/day for 2 days or no treatment. The no treatment group had a significantly longer hospitalization length and time to weakness improvement (p<0.05 for all). Although there are no RCTs evaluating the use of IVIG in children with GBS, most experts believe that the use of IVIG in children would be effective based on adult data.
There was 1 trial available evaluating combination therapy of IVIG and a steroid in the treatment of GBS. In an underpowered class I study in which 233 adults were randomized to treatment with IVIG 0.4 g/kg/day daily for 5 days in combination with either placebo or methylprednisolone (MP), no significant difference was found in disability improvement with 68% of IVIG and MP patients improved compared to 56% of placebo patients (odds ratio 1.68, 95% confidence interval [CI] 0.97 to 2.88, p=0.06).
There is insufficient evidence to recommend treatment of postpolio syndrome with IVIG
The recommendation regarding IVIG as a treatment option is based on 2 class I studies.2 The first study was a randomized double-blind trial in 142 patients in which there was no significant improvement in quality of life and there was a statistically significant, but not clinically significant, improvement in muscle strength. The second class I study was an underpowered, randomized, double-blind, pilot study in 20 patients treated with IVIG that found a significant improvement in pain scores after 3 months of treatment but no improvement in fatigue or muscle strength.
There is insufficient evidence recommending for or against IVIG use for IBM
Available evidence from 2 class I trials and 1 class II trial evaluating the use of IVIG for inclusion body myositis (IBM) failed to show a clinical benefit.2 In a class I crossover trial, 37 patients on tapering doses of prednisone were randomized to treatment with IVIG and continued prednisone or placebo with continued prednisone. There was no difference in the primary outcome measure of MRC score; however, for the IVIG and prednisone group there was a significant improvement in the number of endomysial inflammation foci (p<0.005) and number of necrotic muscle fibers (p<0.01). Another class I study, in which 19 patients were randomized to IVIG or placebo found no significant difference in the primary outcome of MRC score or the secondary outcome of quantitative strength, but did show a significant improvement in duration of swallowing (p<0.05; not corrected for multiple comparisons). One class II trial involving 22 patients who received IVIG or placebo for 6 months and then were crossed over to the other treatment group for the following 6 months found no difference in MRC scores but did find an improvement in neuromuscular symptom score in favor of IVIG.
There is insufficient evidence showing benefit of treatment with IVIG for IgM paraprotein-associated neuropathy
Two small studies, a class I study in 22 patients and a class II study in 11 patients, failed to show improvement in primary outcome measures of INCAT or MRC scores, respectively, for patients treated with IVIG versus placebo.2
There is no quality evidence evaluating the use of IVIG in the treatment of other neuromuscular disorders such as Miller Fisher syndrome, polymyositis, or diabetic polyradiculoplexoneuropathy.2
Adverse Effects of IVIG
There are previous reports of rare adverse effects associated with IVIG such as thrombotic events and stroke.2 Therefore, it is recommended to screen for vascular risk factors prior to initiating treatment as well as monitor during and following infusion. The adverse effect information in the AAN guideline is based on data from 632 patients from 18 IVIG studies in which minor and serious adverse effects were monitored. Common adverse effects included dizziness, nausea, chills, malaise, mild hypertension, fever, and headache. Rare, but serious, adverse effects included renal failure, heart failure, myocardial infarction, urticaria, and aseptic meningitis. Most adverse effects were manageable or short-lived, and overall IVIG appeared to be well-tolerated.
Summary
The new AAN guidelines are beneficial in that clinicians can use this document in determining the appropriateness of IVIG therapy for a variety of neuromuscular conditions. Given the costs associated with IVIG administration and the potential for serious adverse effects to occur with this therapy, a careful review of the available evidence and patient-specific factors is warranted.
References
1. Intravenous immunoglobulin (IVIG). MedLett Drugs Ther. 2006;48(1249/1250):101-103.
2. Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2012;78(13):1009-1015.
Written by: Caitlin E. Ash, PharmD Candidate 2012
Edited by: Maria G. Tanzi, PharmD
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What medications are included in the most recent Beer’s criteria?
What medications are included in the most recent Beer’s criteria?
Medication-related adverse events and hospitalization remain a major source of patient morbidity and mortality in addition to contributing to increased healthcare costs.1-3 This especially a concern in elderly patients who may be at increased risk of adverse drug events due to altered pharmacokinetics, increased exposure to multiple concomitant medications, and co-morbid conditions. Beers and colleagues originally published their criteria listing “potentially inappropriate medications” (PIMs) in geriatric patients in 1991.4 The Beers criteria, as it came to be known, were updated in 1997 and 2003 but have always been limited by a paucity of literature regarding drug dosing in the elderly and exclusion of elderly patients from clinical trials.5,6 It has, therefore, been heavily reliant on expert opinion for recommendations regarding PIMs. Despite these limitations, the Beers criteria have been adopted by the Centers for Medicare and Medicaid Services, the National Committee for Quality Assurance, the Pharmacy Quality Alliance, and others as a criterion for assessing healthcare quality in US institutions.7
The most recent update of the Beers criteria was published in the Journal of the American Geriatric Society in February 2012 and includes not only an update on the recommendations themselves, but an updated method of arriving at these recommendations and an additional grouping of medications.7 Initially targeted at medication use in nursing homes, the Beers criteria have been expanded to include all geriatric patients with the exception of patients in the hospice or palliative care setting. The recommendations were determined by a modified Delphi method of repeated survey and discussion by a panel of experts that included 6 physicians, 7 pharmacists, and 2 nurses who specialized in geriatric care. A total of 2,169 references were reviewed and recommendations graded based on the American College of Physicians’ Guideline Grading System (Table 1). The authors caution, however, that due to a continued lack of primary literature regarding drug safety in the geriatric population, the final recommendations regarding medication use may have been influenced by panel opinion regarding the magnitude of potential harm weighed against perceived benefit of drug therapy and availability of safer alternative therapy.7 This may have led to a bias towards patient safety over drug efficacy in the recommendations.
Table 1. Summary of literature grading system used in the updated Beers Criteria adapted from the American College of Physicians' Guideline Grading System.7
Quality of evidence regarding health outcomes in an appropriate population High Consistent results from ≥ 2 randomized controlled trials or multiple, consistent observational trials Moderate Sufficient evidence from ≥ 1 high quality trial with > 100 participants, ≥ 2 high quality trials with some inconsistency, ≥ 2 lower quality trials with consistent results, or multiple consistent observational trials with flawed methodology Low Insufficient evidence based on small or inadequately powered studies, inconsistent results from large trials, or trials with significant methodological flaws Strength of recommendations Strong Risks plainly outweighs benefits or vice versa Weak Risks and benefits are balanced Insufficient Lack of sufficient evidence to establish benefits or risks The increased emphasis on the balance between efficacy and safety contributed to development of 3 (as opposed to 2) categories or classifications of recommendations. The first is the traditional “potentially inappropriate medications for use in older adults” where recommendations were based on the risk of adverse effects and availability of alternative therapy (Table 2). The panel also revised recommendations regarding “potentially inappropriate medications due to drug-disease or drug-syndrome interactions” (Table 3). The newest set of recommendations was intended to address the fact that patient care is highly individual and alternative therapy may not be ideal in all patient cases. The panel developed a third classification of “potentially inappropriate medications that should be used with caution in older adults” (Table 4).7 Though not offered in its entirety, a summary of the revised Beers criteria is presented in Tables 2 to 4.
Table 2. Summary of recommendations regarding potentially inappropriate medications in older adults: drugs to avoid. 7
Drug or class Quality of Evidence Strength of recommendation Recommendation: AVOID First-generation antihistamines (e.g., diphenhydramine, cyproheptadine) High and moderate Strong Benztropine and trihexyphenidyl Moderate Strong Dipyridamole, short-acting Moderate Strong Ticlopidine Moderate Strong Disopyramide Low Strong Digoxin > 0.125 mg per day Moderate Strong Nifedipine, immediate-release High Strong Tertiary tricyclic antidepressants (e.g., amitriptyline imipramine) High Strong Thioridazine or mesoridazine Moderate Strong Barbiturates (e.g., pentobarbital, phenobarbital) High Strong Chloral hydrate Low Strong Meprobamate Moderate Strong Ergot mesylates or isoxsuprine High Strong Desiccated thyroid Low Strong Estrogens (with or without progestin), oral or transdermal patch High Strong Insulin, sliding scale Moderate Strong Megestrol Moderate Strong Glyburide or chlorpropamide (long-acting sulfonylureas) High Strong Mineral oil, oral Moderate Strong Trimethobenzamide Moderate Strong Meperidine High Strong Indomethacin Moderate Strong Ketorolac (including parenteral) High Strong Pentazocine Low Strong Skeletal muscle relaxants (e.g., carisprodol, cyclobenzaprine, methocarbamol) Moderate Strong Recommendation: AVOID with exceptions
Antispasmodics, except in palliative care Moderate Strong Nitrofurantoin for long-term suppression or with CrCl < 60 mL/min Moderate Strong Alpha1 blockers as an antihypertensive (e.g. Doxazosin, prazosin) Low Strong Alpha agonists, centrally-acting as routine or first-line antihypertensive (e.g. clonidine, guanabenz, methyldopa) Low Strong Antiarrhythmic drugs (Class Ia, Ic, III) as first-line treatment for atrial fibrillation High Strong Dronaderone in patients with permanent atrial fibrillation or heart failure Moderate Strong Spironolactone in patients with heart failure or CrCl < 30 mL/min Moderate Strong Antipsychotics, atypical or conventional for behavioral control (unless in the presence of harm to self or others or where other treatments have failed) Moderate Strong Benzodiazepines for treatment of insomnia, agitation, or delirium (e.g., alprazolam, lorazepam, diazepam) High Strong Nonbenzodiazepine hypnotics for > 90 days (e.g., zolpidem, eszopiclone) Moderate Strong Methyltestosterone or testosterone unless indicated for hypogonadism Moderate Weak Estrogens (with or without progestin), topical vaginal cream unless at low doses for dyspareunia, UTI, or vaginal symptoms Moderate Weak Growth hormone except after pituitary gland removal High Strong Metoclopramide except for treatment of gastroparesis Moderate Strong Non-COX-2 selective NSAIDs for chronic use unless after failure of alternative agents and a gastroprotective agent is used Moderate Strong Abbreviations: CrCl, creatinine clearance; NSAIDs, nonsteroidal anti-inflammatory drugs; UTI, urinary tract infection.
Table 3. Summary of recommendations regarding potentially inappropriate medications that should be avoided in older adults under most circumstances because of increased risk of disease or syndrome exacerbation7.
Disease or syndrome Drug or class Quality of Evidence Strength of recommendation Heart failure NSAIDs or COX-2 inhibitors Moderate Strong Diltiazem or verapamil (systolic heart failure only) Pioglitazone or rosiglitazone High Cilostazol Low Dronaderone Moderate Syncope Acetylcholinesterase inhibitors Moderate Strong Tertiary tricyclic antidepressants Alpha1 blockers High Weak Chlorpromazine Moderate Thioridazine Olanzapine Chronic seizure or epilepsy Bupropion Moderate Strong Chlorpromazine Clozapine Maprotiline Olanzapine Thioridazine Thiothixene Tramadol Delirium Tricyclic antidepressants Moderate Strong Anticholinergics Benzodiazepines Chlorpromazine Corticosteroids Histamine (H2)-receptor antagonists Meperidine Sedative hypnotics Throridazine Dementia and cognitive impairment Anticholinergics High Strong Benzodiazepines Histamine (H2)-receptor antagonists Zolpidem Antipsychotics for all uses History of fractures or falls Anticonvulsants High Strong Antipsychotics Benzodiazepines Non-benzodiazepine hypnotics Tricyclic antidepressants Selective serotonin reuptake inhibitors Insomnia Pseudoephedrine or phenylephrine Moderate Strong Stimulants (e.g., amphetamine, methylphenidate) Theophylline or caffeine Parkinson’s disease Antipsychotics (except quetiapine and clozapine) Moderate Strong Metoclopramide Prochlorperazine Promethazine Chronic constipation Antimuscarinics for urinary incontinence (e.g., oxybutynin, tolterodine) High Weak Diltiazem or verapamil Moderate to low First-generation antihistamines Anticholinergics Antispasmodics History of gastric or duodenal ulcers Aspirin > 325mg per day Moderate Strong Non-COX-2 selective NSAIDs CKD ≥ Stage IV NSAIDs Moderate Strong Triamterene Low Weak Urinary incontinence (women only) Estrogen, oral and transdermal patch High Strong Benign prostatic hyperplasia or lower urinary tract symptoms (men only) Inhaled anticholinergic agents (e.g., tiotropium, ipratropium) Moderate Strong Strongly anticholinergic drugs (excluding antimuscarinics used for urinary incontinence) Moderate Weak Stress or mixed urinary incontinence Alpha1 blockers Moderate Strong Abbreviations: CKD, chronic kidney disease; COX-2, cyclooygenase-2; NSAIDs, nonsteroidal anti-inflammatory drugs.
Table 4. Summary of recommendations regarding potentially inappropriate medications to be used with caution in older adults.7
Drug or class Quality of Evidence Strength of recommendation Aspirin for primary prevention of cardiac events in patients ≥ 80 years Low Weak Dabigatran in patients ≥ 75 years or with CrCl ≤ 30 mL/min Moderate Weak Prasugrel in patients ≥ 75 years Moderate Weak Agents that may exacerbate syndrome of inappropriate antidiuretic hormone secretion or hyponatremia (antipsychotics, carbamazepine, mirtazapine, SNRIs, SSRIs, TCAs, carboplatin, cisplatin, vincristine) Moderate Strong Vasodilators in patients with history of syncope Moderate Weak Abbreviations: CrCl, creatinine clearance; SNRIs, serotonin norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.
Several medications or medication indications were removed from the Beers criteria in this update. The majority of the drugs removed from the criteria have been withdrawn from the US market.
- Cimetidine (replaced with histamine [H2]-receptor antagonists as a drug class)
- Cyclandelate
- Daily fluoxetine
- Ferrous sulfate > 325mg per day
- Guanadrel
- Guanethidine
- Halazepam
- Long-term use of stimulant laxatives
- Mesoridazine
- Propoxyphene and combination products
- Tripelennamine
Summary
The Beers criteria provide a guideline for safer use of medications in geriatric patients. The updated guidelines have removed drugs withdrawn from the US market and, for the first time, used a validated literature evaluation tool to support recommendations. While still limited by the scarcity of literature directly assessing drug safety in patients ≥ 65 years, the update represents a step forward in the evaluation of drug safety in older patients and an important tool for healthcare providers who care for this population. A free full-text of the updated guidelines can be accessed at:
References
1. Gurwitz JH, Field TS, Harrold LR, et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA. 2003;289(9):1107-1116.
2. Fu AZ, Jiang JZ, Reeves JH, et al. Potentially inappropriate medication use and healthcare expenditures in the US community-dwelling elderly. Med Care. 2007;45(5):472-476.
3. Tache SV, Sonnichsen A, Ashcroft DM. Prevalence of adverse drug events in ambulatory care: a systematic review. Ann Pharmacother. 2011;45(7-8):977-989.
4. Beers MH, Ouslander JG, Rollingher I, et al. Explicit criteria for determining inappropriate medication use in nursing home residents. Arch Intern Med. 1991;151(9):1825-1832.
5. Beers MH. Explicit criteria for determining inappropriate medication use in nursing home residents. An update. Arch Intern Med. 1997;157(14):1531-1536.
6. Fick DM, Cooper JW, Wade WE, Waller JL, Maclean R, Beers MH. Updating the Beers criteria for potentially inappropriate medication use in older adults. Arch Intern Med. 2003;163(22):2716-2724.
7. The American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60(4):616-631.
Written by: Stephanie Bennett, PharmD
UIC PGY1 Resident