By S. Marik. Our Lady of Holy Cross College. 2018.
This was followed by the approval of peer-reviewed journals and have been the topic of numerous review articles effective 5mg folvite,2 buy discount folvite 5mg on line,3 including recent ASH education sessions discount 5mg folvite with amex. Rivaroxaban has been approved for thromboprophylaxis after total hip or knee replace- whether NOACs or warfarin should be used as frontline agents for ment and the initial treatment and secondary prevention of venous stroke prevention in atrial ﬁbrillation has been, and continues to be, vigorously debated6,7; therefore, the clinical trials will not be thromboembolism (VTE). In other countries, dabigatran etexilate and apixaban were approved for the prevention of VTE after hip and reviewed here in detail. This chapter primarily focuses on the pros knee replacement. Edoxaban and betrixaban are other oral factor Xa and cons of the NOACs for the various indications that have gained approval in the United States by the middle of 2013, particularly inhibitors in development. Phase 3 trials comparing edoxaban to focusing on real-world concerns related to their effectiveness, warfarin for the prevention of stroke and systemic embolism in safety, and use. Betrixaban is being evaluated in a phase 3 trial versus enoxaparin for the prevention of VTE in medically ill patients Pharmacologic properties of warfarin and NOACs undergoing hospitalization. The pharmacologic properties of warfarin, dabigatran etexilate, rivaroxaban, and apixaban are summarized in Table 1. Its pharmacokinetics thereby facilitating ﬁxed dosing in adults without the need for and pharmacodynamics are inﬂuenced by genetic polymorphisms laboratory monitoring or dose adjustments for body weight. In general, the results for the approved indications have been robust, with NOACs being either noninferior or Dabigatran etexilate is an oral prodrug that is converted to superior to standard treatment regimens. Despite the advantages dabigatran, a competitive direct thrombin inhibitor (Ki 4. Properties of warfarin and oral inhibitors of thrombin and factor Xa inhibitors approved for use in the United States Warfarin Dabigatran etexilate Rivaroxaban Apixaban Target Vitamin K epoxide reductase (VKORC1) Thrombin Factor Xa Factor Xa lowers levels of vitamin K–dependent coagulation factors Prodrug No Yes No No Bioavailability 95% 6. Dabigatran etexilate has relatively low oral bioavailability and not be prescribed to patients with moderate or severe liver disease. The capsules, however, must be ingested intact (ie, they pharmacy programs, but requires that all of their other medications cannot be crushed, broken before administration, or chewed) and be inputted. If there is a strong drug interaction, it is best not to the medication cannot be administered to patients receiving nutri- prescribe the NOAC rather than altering doses as suggested by the tion and oral medications via nasogastric, gastrostomy, or jejunos- label. As yet, there are neither assays available to measure drug tomy tubes. The capsules are hygroscopic and expire 4 months after levels on a routine basis nor evidence-based algorithms for adjust- the seal of the bottle is broken upon opening. Although warfarin has innumerable drug interactions, the has relatively few drug interactions, but p-glycoprotein transporter dose can be adjusted by monitoring the INR more frequently to inhibitors such as amiodarone, verapamil, or quinidine increase account for any concomitant interactions. The use of the drug with rifampin, a p-glycoprotein regarding NOAC absorption in patients who have undergone inducer, should be avoided because it reduces the drug’s anticoagu- gastric-bypass or lap band surgery for obesity or resection of large lant effect. In patients with moderate renal impairment (creatinine portions of the small bowel; NOACs should therefore not be clearance 30-50 mL/min) taking potent p-glycoprotein inhibitors prescribed to such patients until data or algorithms for adjusting (eg, ketoconazole or dronedarone), it is recommended that consider- dose become available. Some of the potential advantages and ation be given to reducing the dose of dabigatran etexilate to 75 mg disadvantages of oral direct thrombin or factor Xa inhibitors twice daily (BID). Efﬁcacy and safety of the NOACs in atrial ﬁbrillation Although both agents have high oral bioavailability, it is necessary The key ﬁndings of the randomized trials comparing dabigatran (RE-LY),11 rivaroxaban (ROCKET-AF),12 and apixaban (ARIS- to take higher doses of rivaroxaban (15 or 20 mg tablets) with food TOTLE)13 with warfarin for stroke prevention in atrial ﬁbrillation were to ensure optimal drug absorption. Rivaroxaban is absorbed best in the stomach, whereas apixaban is absorbed throughout the gastroin- as follows. Rivaroxaban may be crushed and mixed and adminis- tered with food through a gastrostomy tube. Rivaroxaban has a dual NOACs are noninferior to warfarin for the prevention of stroke and mode of elimination; one-third is excreted unchanged by the kidney systemic embolism (see Table 3 for approved doses and schedules). All reduced mortality by 10% per year compared with tors)/inducers (carbamazepine, phenytoin, rifampin, St John’s wort) warfarin. Apixaban is also The rates of major bleeding for dabigatran at the 150 mg BID dose metabolized by the liver (partially by CYP 3A4); 75% is eliminated and rivaroxaban were similar to warfarin. Apixaban demonstrated a in the feces and 25% by the kidneys. All 3 and it is recommended that the dose be reduced to 2. However, both dabigatran and Hematology 2013 465 Table 2. Potential advantages and disadvantages of oral direct thrombin and factor Xa inhibitors compared with vitamin K antagonists Advantages Disadvantages Rapid onset/offset of action eliminates need for initial treatment with Use is contraindicated or dose reduction is required in patients with a parenteral anticoagulant in patients with acute thrombosis; also severe chronic kidney disease; such patients also require longer reduces need for “bridging” patients at high risk of thrombosis periods off therapy prior to procedures with high risk of bleeding. Absence of food interactions, limited hepatic metabolism, and few Limited availability of assays for measuring drug levels and absence strong drug interactions. Wide therapeutic window enables ﬁxed of validated monitoring strategies prevent dose titration or dosing in adults without need for laboratory monitoring. Greater convenience for patients and providers with potential for Potential for overuse (eg, long-term treatment of VTE patients at greater use than vitamin K antagonists, particularly in atrial low recurrence risk). May be more cost-effective than vitamin K antagonists (no routine Higher drug acquisition costs. Lower risk of intracranial hemorrhage and lower potential risk of Short half-life leads to rapid decline in anticoagulant/antithrombotic bleeding complications, thereby reducing need for an antidote. No speciﬁc antidote in case of major bleeding; also complicates urgent surgery or interventions. For dabigatran, this appears to be an age-related warfarin places patients at increased risk for adverse events (ie, phenomenon and is most relevant to those older than 85 years. The AVERROES trial compared apixaban with aspirin stroke. Stroke can result from the rapid dissipation of the antithrom- for stroke prevention in atrial ﬁbrillation in such a study popula- botic effect of NOACs if patients do not take their medication as tion. In the phase 3 trials of rivaroxaban and bleeding was surprisingly no different from aspirin. The results of apixaban, there was a clustering of thrombotic events at the end of the AVERROES study suggest that aspirin should not have a role in the double-blind, double-dummy ROCKET-AF and ARISTOTLE the prevention of stroke in atrial ﬁbrillation. Nevertheless, the trials, which was likely due to transitioning of NOAC patients back efﬁcacy and safety of NOACs in patients with atrial ﬁbrillation for to warfarin without “bridging” with low-molecular-weight heparin 15 whom warfarin is not prescribed remains uncertain. In transitioning patients from States, atrial ﬁbrillation treatment rates did not increase in the ﬁrst a NOAC to warfarin, this problem can be overcome by giving the year that dabigatran was available. There are to comply with the requirement for regular visits and follow-up calls many reasons for this, including perceptions of both physicians and and are provided education regarding their disease state and the patients regarding the relative beneﬁts and risks of taking a vitamin importance of medication adherence (monitored with pill counts). Furthermore, only 50% of This will not be the case in practice for some patients who are patients prescribed warfarin are well managed with respect to their prescribed NOACs given the absence of a requirement for regular Table 3. Recommended doses of the dabigatran etexilate, rivaroxaban, and apixaban for approved indications in the United States (2013) Indication Anticoagulant Recommended dose Atrial ﬁbrillation Dabigatran etexilate* Creatinine clearance 30 mL/min: 150 mg BID; creatinine clearance 15-29 mL/min: 75 mg BID Rivaroxaban† Creatinine clearance 50 mL/min: 20 mg QD; creatinine clearance 15-50 mL/min: 15 mg QD Apixaban‡ 5 mg BID; 2. Warfarin’s requirement for INR monitoring effectively also a potential for interactions between various chemotherapeutic allows adherence to be monitored. Standard major orthopedic surgery based on the RECORD trials; 2 were in therapy is also preferred among patients in intensive care units with patients undergoing total hip replacement, with 1 trial having pulmonary emboli and hemodynamic instability or a very extensive different durations of therapy,22,23 and 2 were in total knee DVT (eg, phlegmasia cerulea dolens) in whom thrombolytic therapy replacement using 2 different enoxaparin dosing regimens, 40 mg is being considered.
In our pool of studies purchase folvite 5mg with amex, the rate of patient recruitment was rarely reported order folvite 5mg with visa, but we examined the other factors here to determine if these factors are relevant in our data set buy folvite 5 mg with amex. This may indicate that indirect comparisons may not be accurate. In this review, placebo-controlled trials including the outcome ≥50 % pain reduction from baseline, which were published in the 1980s, had a placebo response rate of 6% compared with those published in the 1990s (23%) or published in the years 2000-2005 (20%) and years 2006 to the present (27%). Duration of the trial also seemed to have affected the placebo response in these studies. Trials of gabapentin, pregabalin, lamotrigine, and tricyclic antidepressants that were 6 weeks or less in duration had a placebo response rate of 15% compared with trials between 7 and 10 weeks duration where the placebo response rate was 21% and trials greater than 10 weeks duration, where the placebo response rate was 27%. Perhaps a better way to examine the effect of trial duration on the placebo response is to compare trials of the same drug using different durations: four 8-week trials of pregabalin with placebo response rates of 19% compared with 5 trials of pregabalin of 12-14 weeks duration with placebo response rates of 25%, which is consistent with Quessy’s finding of a weak tendency for the placebo 57 response to increase as the duration of the trial increases. While the placebo response increased with duration, the treatment effect of pregabalin in these trials decreased from 56% in trials ≤6 weeks duration, 43% in trials 7-10 weeks duration, and 38% in trials ≥11 weeks. Both patterns may simply represent a regression to the mean as trial duration lengthens. With regard to the possible relationship between baseline pain levels and the placebo response in neuropathic pain trials, the baseline pain levels in trials of gabapentin, pregabalin, and lamotrigine were between 6 59 and 7 on an 11-point Likert Scale with the exception of 1 trial with a baseline pain score of 5. Although the specific year of publication of the study, the duration of the study, and the baseline pain levels appear to predict the placebo response, in studies of gabapentin, pregabalin, lamotrigine, and the tricyclic Neuropathic pain 25 of 92 Final Update 1 Report Drug Effectiveness Review Project antidepressants, factors all correlate highly with each other. An important additional factor, not previously mentioned, is study design. All placebo-controlled trials of tricyclics for painful diabetic neuropathy or postherpetic neuralgia in this review are crossover studies. The majority of studies of the other classes of drugs for neuropathic pain are not crossover, making the tricyclic studies different − not only in their placebo response rate, but also in core ways the studies were conducted. The differences in placebo response rate that we observed, based on year and duration of study, imply that the indirect meta-analysis may not be valid. Our own assessment of the response rates (both placebo and drug) in the older, tricyclic antidepressant studies compared to any newer study also indicated differences that were concerning. Therefore, although the indirect comparisons of gabapentin, pregabalin, and lamotrigine with tricyclic antidepressants significantly favor the tricyclics for providing ≥50% pain relief, we do not feel that these indirect comparisons are valid. Indirect analysis of other comparisons 59-65 40, 66-80 Based on 6 placebo-controlled trials of gabapentin, 15 trials of pregabalin, 3 trials of 81-83 84 85-88 89, 90 duloxetine, 1 trial of venlafaxine, 4 trials of lacosamide, 2 trials of oxcarbazepine, 91,92 and 2 studies representing 4 trials of topiramate, we conducted adjusted indirect comparisons. The primary outcome for comparison was ≥ 50% reduction in pain from baseline pain scores. Duloxetine, pregabalin, and gabapentin were superior to lamotrigine and lacosamide when measuring ≥50% pain relief. Neuropathic pain 26 of 92 Final Update 1 Report Drug Effectiveness Review Project Table 5. Indirect comparison of pain measured as ≥50% pain reduction Drug Total N Relative risk (95% confidence interval) Compared with placebo Duloxetine 681 1. The difference of the difference indicates that a drug reduces pain scores from baseline, better than another drug, after the reductions due to placebo have been taken into account. Pregabalin was, again, superior to lamotrigine using the McGill Pain Questionnaire. Pregabalin was also superior to lacosamide on the 11-point scale and the 0-100 visual analogue scale. Gabapentin was, again, superior to lamotrigine on both the 11-point scale and the McGill Pain Questionnaire. In addition, gabapentin was superior to lacosamide on the 11-point Likert scale. No other comparisons were significant using these scales. Neuropathic pain 27 of 92 Final Update 1 Report Drug Effectiveness Review Project Table 6. Significant indirect comparisons of pain reduction on 3 different scales Mean difference Difference of difference (95% confidence (95% confidence Drug interval) Indirect comparison interval) 11-point Likert Scale Duloxetine ‒1. Additionally, there were several diabetic neuropathy and postherpetic 93-100 101 trials not incorporated into this review due to poor quality, no longer of an included drug, 102 103 did not report result statistics, substituted drugs based on tolerability, or based drug dosages 104 on sparteine phenotype. As a group divalproex, lacosamide, lamotrigine, oxcarbazepine, and topiramate were superior to placebo in achieving response, defined as at least a 50% reduction in pain (relative risk, 1. See Table 7 for a summary of these anticonvulsant trials. The 105 91 individual anticonvulsant drugs with significant results included divalproex and topiramate. Neuropathic pain 28 of 92 Final Update 1 Report Drug Effectiveness Review Project Table 7. Anticonvulsant trials measuring 50% response rate in pain reduction Relative risk Study, year N Duration (95% confidence interval) Divalproex Kochar, 2005 40 8 weeks 4. All 3 trials of divalproex were 105, 107, 108 107, 108 small (N≤60). Two studies focused on painful diabetic neuropathy, while the third 105 trial was of postherpetic neuralgia patients. All 3 demonstrated significant pain reduction on 107 108 1200 mg daily (P<0. Of 3 trials of oxcarbazepine, 1 was rated poor quality, in part due to 41% attrition in the oxcarbazepine group compared with 24% in the placebo group and lack of clarity regarding 94 which subjects were analyzed. The remaining 2 were fair-quality, 16-week, parallel group 89, 90 trials. In 1 of the studies, patients experienced a larger decrease in pain as recorded on a visual analogue scale with oxcarbazepine compared to placebo (P=0. In the second study, there was no difference using the visual analogue scale between oxcarbazepine at doses of 600 mg daily, 1200 mg daily, and 1800 mg daily compared with placebo, although there was a trend toward significance with the latter 2 doses (P=0. One noted difference between the eligibility criteria of the 2 studies was that the first study required an average pain score of 50 on the visual analogue scale over 4 of the last 7 days prior to randomization and the second study required an average visual analogue scale pain rating of 40 during the prerandomization phase. This difference of baseline pain scores may have contributed to the different findings in the 2 fair-quality trials. Neuropathic pain 29 of 92 Final Update 1 Report Drug Effectiveness Review Project 91, 92 The results from 2 publications representing 4 trials of topiramate were mixed. In a 91 12-week trial demonstrating significant pain reduction, the mean baseline pain score on a 0-100 visual analogue scale was 68. Additionally, the differences in trial duration may have contributed to the mixed results. A single, fair-quality trial of venlafaxine was a parallel study of 6 weeks duration where 150-225 mg daily of extended release venlafaxine showed benefit on a 0-100 visual analogue 52, 84 scale compared to placebo (P<0.
Yeo et al conducted a containing chemotherapy without antiviral prophylaxis has been Hematology 2014 579 reported to be 59%–80% generic 5 mg folvite with mastercard. Of the HBsAg-positive patients buy discount folvite 5 mg online, most HBV reactivation occurs during and after chemotherapy generic 5 mg folvite, but patients with high HBV DNA levels at baseline potentially suffer HBV reactivation at an early stage of chemotherapy. Which drug is recommended in an antiviral prophylaxis setting to prevent HBV reactivation? Lamivudine is a ﬁrst-generation nucleo- side analog that can suppress HBV replication and improve hepatitis B. Some prospective studies have demonstrated the efﬁcacy and safety of lamivudine for preventing HBV reactivation in HBsAg- positive patients who received immunosuppressive therapy. Lamivudine resistance was reported as 24% at 1 year and 50% at 5 years in patients with chronic hepatitis B. Kim et al recently reported that no HBV reactiva- tion was observed in 31 HBsAg-positive patients who received entecavir, whereas 30 of 96 (31%) who received lamivudine developed HBV reactivation after R-CHOP-like regimens. There is no consensus regarding the optimal duration of antiviral prophylaxis for HBsAg-positive patients. To establish when to discontinue the antiviral prophylaxis safely, we propose the following criteria as being essential: (1) planned immunosuppres- sive therapy completed, (2) undetectable HBV DNA levels by real-time PCR assay, and (3) both conditions 1 and 2 maintained at least for 1 year. More importantly, regular monitoring of HBV DNA for at least 6 months after discontinuation of antiviral prophylaxis is desirable to prevent HBV reactivation because reemergence of HBV was observed within 6 months after withdrawal of antiviral prophylaxis according to data collected by the Zenyaku Kogyo Company and the Chugai Pharmaceutical Company. Strategy to prevent HBV reactivation in patients with resolved HBV infection (anti-HBc-positive and/or anti-HBs-positive in HBsAg-negative patients, Risk Group 3) Although there is no consensus on a strategy to prevent HBV reactivation in patients with resolved HBV infection, regular HBV DNA-monitoring-guided preemptive antiviral therapy is a reason- 580 American Society of Hematology Table 2. Comparison of large-scale prospective studies on HBV DNA-monitoring-guided preemptive antiviral therapy in lymphoma patients with resolved HBV infection after rituximab-containing chemotherapy (preliminary results) ID no. NCT00931229 UMIN000001299 Locations Taiwan Japan Study design Prospective Prospective observational HBV DNA-monitoring-guided preemptive HBV DNA-monitoring-guided preemptive antiviral therapy antiviral therapy No. Conversely, although antiviral prophylaxis is an 2 study designs: preemptive antiviral therapy and antiviral alternative approach to preventing HBV reactivation in patients prophylaxis. We hypothesized that by measuring serum HBV markers including HBsAg, anti-HBc, and monthly HBV DNA-monitoring-guided preemptive antiviral therapy anti-HBs to identify groups at risk of HBV reactivation. To prevent can prevent hepatitis due to HBV reactivation7 and conducted a hepatitis due to HBV reactivation after anti-B-cell therapy, antiviral multicenter prospective study in Japan (Study UMIN000001299, prophylaxis is recommended for HBsAg-positive patients and/or Table 1). These studies demonstrated that Acknowledgments monthly monitoring of HBV DNA could prevent HBV-related 38,39 Financial Support was partly provided by the Ministry of Health, death. However, in the Taiwanese study, 10 of 150 (7%) Labour and Welfare of Japan (Grant-in-Aid H24-kanen-004-MM). HBV-resolved patients who received R-CHOP developed hepatitis due to HBV reactivation and 7 of 150 (5%) developed severe This study was also supported in part by the National Cancer Center hepatitis deﬁned as alanine aminotransferase 10-fold the upper Research and Development Fund (Grant 26-S-4). Patients with HBV reactivation were more likely to Yasuhito Tanaka (Department of Virology and Liver Unit, Nagoya have a poorer prognosis. Ryuzo Ueda (Department of Tumor Immunology, Aichi tive HBV clones such as precore mutants. Chugai Pharmaceutical Company for providing clinical data on 211 These 2 studies also showed that most HBV reactivation was patients developing serious hepatitis B after rituximab-containing observed within 1 year after completion of rituximab-containing chemotherapy. Frequency of hepatitis B virus Conﬂict-of-interest disclosures: K. Mortality secondary to Kensei Tobinai, MD, PhD, Department of Hematology, National fulminant hepatic failure in patients with prior resolution of hepatitis B Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, virus infection in Japan. Phone: 81-3-3542-2511; Fax: 81-3-3542-3815; e-mail: 20. Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving 21. Reverse seroconversion of preemptive lamivudine therapy for hepatitis B patients undergoing hepatitis B after allogeneic bone marrow transplantation: a retrospective chemotherapy. Hepatitis B virus reactivation in B-cell N Engl J Med. Hepatitis B virus reactivation in immunosuppressive therapy: evaluation of both HBsAg-positive and lymphoma patients with prior resolved hepatitis B undergoing antican- HBsAg-negative cohorts. B virus following systemic chemotherapy for malignant lymphoma. Rituximab-associated hepatitis hepatitis B virus infection. B virus (HBV) reactivation in lymphoproliferative diseases: meta- 28. Prevention of hepatitis B virus analysis and examination of FDA safety reports. FDA: Increased HBV reactivation risk with ofatumumab or 29. Management of patients with hepatitis B who rituximab. EASL clinical practice targeted therapy with rituximab in patients with rheumatoid arthritis. A revisit of prophylactic lamivudine for granulomatosis with polyangiitis (Wegener’s granulomatosis): compari- chemotherapy-associated hepatitis B reactivation in non-Hodgkin’s son of efﬁcacy in granulomatous versus vasculitic manifestations. Clinical and virological mide for ANCA-associated vasculitis. A comparison of entecavir and CD20 immunotherapy in ﬂudarabine-refractory chronic lymphocytic lamivudine for HBeAg-positive chronic hepatitis B. Tenofovir disoproxil fumarate patients with CLL and coexisting conditions. Efﬁcacy of entecavir treatment virus persists for decades after patients’ recovery from acute viral for lamivudine-resistant hepatitis B over 3 years: histological improve- hepatitis despite active maintenance of a cytotoxic T-lymphocyte ment or entecavir resistance? Retrospective and prospective therapy: results of interim analysis [abstract]. Blood (ASH Annual studies of hepatitis B virus reactivation in malignant lymphoma with Meeting Abstracts). Chemotherapy-induced hepatitis B entecavir prophylaxis for rituximab-associated hepatitis B virus reactiva- reactivation in lymphoma patients with resolved HBV infection: a tion in patients with lymphoma and resolved hepatitis B. Is Antiviral Prophylaxis observational study of hepatitis B virus (HBV) DNA monitoring and Necessary to Prevent Hepatitis B Virus (HBV) Reactivation in Patients preemptive antiviral therapy for HBV reactivation in patients with With HBV-Resolved Infection Receiving Rituximab-Containing Chemo- B-cell non-Hodgkin lymphoma following rituximab containing chemo- therapy? Grupp1,3 1Division of Oncology and 3Department of Pathology, The Children’s Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; and 2University of Texas M. Anderson Cancer Center, Houston, TX Relapsed and refractory leukemias pose substantial challenges in both children and adults, with very little progress being made in more than a decade. Targeted immunotherapy using chimeric antigen receptor (CAR)-modiﬁed T cells has emerged as a potent therapy with an innovative mechanism. Dramatic clinical responses with complete remission rates as high as 90% have been reported using CAR-modiﬁed T cells directed against the B-cell-speciﬁc antigen CD19 in patients with relapsed/refractory acute lymphoblastic leukemia.
Phenytoin as an augmentation for SSRI failures: a small controlled study order folvite 5mg. Safety of divalproex sodium in migraine prophylaxis: an open-label buy folvite 5mg with mastercard, long-term study 5 mg folvite fast delivery. Long-term Safety of Depakote in 2 Headache Prophylaxis Study Group. Efficacy of gabapentin in treating chronic phantom limb and residual limb pain. Effectiveness of gabapentin in the treatment of chronic post-thoracotomy pain. European journal of cardio- 4 thoracic surgery : official journal of the European Association for Cardio- thoracic Surgery. Safety of newer generation anti-epileptic drugs in non-accidental overdose: an Irish population study. Thomas SV, Sukumaran S, Lukose N, George A, Sarma PS. Intellectual and language functions in children of mothers with epilepsy. Olanzapine versus divalproex for the treatment of acute mania. Paper presented at: Stanley Foundation 3 Conference on Bipolar Disorder; September 21-22, 2000; Amsterdam. Antiepileptic drugs Page 116 of 117 Final Report Update 2 Drug Effectiveness Review Project Excluded studies Codes Tohen M, Baker RW, Altshuler LL, et al. Olanzapine versus divalproex in the treatment of acute mania. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week 3 study. Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry. Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer 3 discontinuation. Safety and efficacy of intravenous sodium valproate in the treatment of acute migraine. Lower effectiveness of divalproex versus valproic acid in a prospective, quasi-experimental clinical trial 4 involving 9,260 psychiatric admissions. The efficiency of gabapentin therapy in 4 patients with lumbar spinal stenosis. Newer anticonvulsants in the treatment of bipolar disorder. Zajecka JM, Weisler R, Sachs G, Swann AC, Wozniak P, Sommerville KW. A comparison of the efficacy, safety, and tolerability of divalproex sodium and 3 olanzapine in the treatment of bipolar disorder. Service utilization and costs of olanzapine versus divalproex treatment for acute mania: results from a randomized, 47- 3 week clinical trial. Reports are not usage guidelines, nor should they be read as an endorsement of, or recommendation for, any particular drug, use, or approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports. McDonagh, PharmD Dana Selover, MD, MPH John Santa, MD Sujata Thakurta, MPA:HA Oregon Evidence-based Practice Center Oregon Health & Science University Mark Helfand, MD, MPH, Director Copyright © 2009 by Oregon Health & Science University Portland, Oregon 97239. Final Report Update 4 Drug Effectiveness Review Project TABLE OF CONTENTS INTRODUCTION.......................................................................................................................... For adult patients with urinary urge incontinence/overactive bladder, do anticholinergic drugs differ in effectiveness?.................................................................................................................. Is there a difference in effectiveness between long-acting and short-acting formulations?......... For adult patients with urinary urge incontinence/overactive bladder, do anticholinergic incontinence drugs differ in safety or adverse events? Is there a difference in adverse events between long-acting and short-acting formulations? Are there subgroups of patients based on demographics (age, racial groups, gender), other medications, or comorbidities for which one anticholinergic incontinence drug is more effective or is associated with fewer adverse effects? Overactive bladder Page 3 of 73 Final Report Update 4 Drug Effectiveness Review Project Note: The medical literature relating to this topic is scanned periodically. Prior versions of this report can be accessed at the DERP website. Suggested citation for this report: McDonagh M, Selover D, Santa J, Thakurta S. Sarah Lopez, MS, Trish Thieda, MA, and Miranda Walker, MA, assisted with data abstraction and quality assessment of studies. Theresa Nguyen assisted through article retrieval and assistance with formatting. Funding: The Drug Effectiveness Review Project, made up of 15 organizations including 14 state Medicaid agencies, commissioned and funded this report. These organizations selected the topic of the report and had input into its Key Questions. Content and conclusions of the report were determined entirely by researchers at the Evidence-based Practice Center. The authors of this report have no financial interest in any company that makes or distributes the products reviewed in the report. Overactive bladder Page 4 of 73 Final Report Update 4 Drug Effectiveness Review Project INTRODUCTION Overactive bladder is defined by the International Continence Society as a syndrome of urinary frequency and urgency, with or without urge incontinence, appearing in the absence of local 1 1 pathological factors. Urinary continence relies heavily upon control and coordination of the smooth muscle found in the wall of the bladder. The effective storage of urine relies on detrusor muscle relaxation, and contraction of internal and external sphincters found within the neck of the bladder while voiding is controlled through the contraction of the bladder’s detrusor muscle and relaxation of its internal and external 2 sphincters. Bladder contraction is mediated via cholinergic muscarinic receptors in bladder smooth muscle. The most common cause of overactive bladder syndrome is detrusor overactivity. Detrusor overactivity may be either idiopathic or neurogenic in origin. A subset of patients with an overactive bladder may complain of urge urinary incontinence, involuntary 3, 4 leakage accompanied by or immediately preceded by urgency. Overactive bladder has been estimated to affect 20% of community-dwelling senior citizens and 2, 5 around 50% of institutionalized elderly persons. Independent risk factors for the development of overactive bladder include neurologic impairment, immobility, female gender, and history of hysterectomy.
Over time quality folvite 5 mg, recombi- nation could break down the associations between advantageous alleles and the VR combinations discount folvite 5mg without prescription,butoverafew years such associations can be strong buy 5mg folvite free shipping. Are diﬀerent antigenic combinations structured into nonoverlapping sets? The pattern by itself is important for the design of vaccines and the study of epidemiological distributions. If discrete antigenic strains occur, are they associated with other com- ponents of the genome that code for attributes such as virulence? Hast- 166 CHAPTER 10 ings and Wedgwood-Oppenheim (1997) provide a good introduction to the processes that potentially link antigenic type to other characters. What processes can potentially structure populations into discrete, nonoverlapping antigenic combinations? Immune selection is one pos- sibility, but any process that reduces gene ﬂow relative to the scale of sampling tends to create nonrandom associations between loci. How can one diﬀerentiate between the various processes that lead to similar patterns? A clear understanding of the processes that reduce gene ﬂow and their consequences (Hastings and Wedgwood-Oppenheim 1997) can help. Direct observations of immune selection disfavoring “recombinant” antigenic types would be useful, but perhaps diﬃcult to obtain. Each host forms an island colonized by parasites from one or more sources. The population of parasites within the host undergoes selection that depends on the amount of ge- netic variation between parasites within the host. The host transmits mi- grant parasites to colonize new hosts (islands). Each population within ahostexpireswhen the host dies or clears the infection. GENERAL ASPECTS OF TRANSMISSION AND SELECTION The number of genotypes colonizing a host may often be small. For example, only a few parasites may colonize a host, or all of the para- sites may have come from a single donor that itself had little genetic variation among its parasites. If initial genetic variability is low, then selection within the host depends primarily on de novo mutations that arise during the population expansion ofthe parasites. By contrast, high initial genetic variability within hosts causes intense selection between coinfecting genotypes. Theisland structure of parasite populations resembles the genetic structure of multicellular organisms when taking account of selection within individuals. Each new organism begins asasinglecell or, in some clonal organisms, as a small number of progenitor cells. The individual develops as a population of cells, with the potential for selection be- STRUCTURE OF PARASITE POPULATIONS 167 tween cellular lineages thatvarygenetically. Genetic variation may arise from the small number of progenitor cells or from de novo mutations. The individual transmits some of its cells to form new bodies (islands). Thereissome general theory on the population genetics of mutation and selection within individuals (Slatkin 1984; Buss 1987; Orive 1995; Michod 1997; Otto and Hastings 1998). Levin and Bull (1994) discussed how selection within and between hosts can shape patterns of parasite life history (reviewed by Frank 1996). But there has been little work on the consequences of island population structure for antigenic variation. Hastings and Wedgwood-Oppenheim (1997) illustrated how a quanti- tative theory of island-model genetics can be used to understand the buildup or decay of linkage disequilibrium. Ifound one study that develops the theory of island population struc- ture for parasites. GENETIC VARIATION OF HIV WITHIN INDIVIDUAL HOSTS Rouzine and Coﬃn (1999) sought to explain the high genetic diver- sity of HIV within hosts. They developed the theory of island population structure for parasites to compare therelativestrengths of natural se- lection and stochastic processes that can cause genetic variability. Rouzine and Coﬃn (1999) focused on the pro gene, which encodes aproteasethatprocesses other HIV gene products. Analysis of nucle- otide sequences for this particular gene suggested that natural selec- tion acts primarily in a purifying way to remove deleterious mutations. Consequently, their model describes the accumulation of nucleotide di- versity shaped by two opposing forces. On the one hand, stochastic eﬀects occur because only a small number of viruses invade each host— the founders of that island. Stochastic drift during colonization allows deleterious mutations to rise in frequency. On the other hand, purify- ing selection within hosts removes deleterious mutations. How do the opposing forces of mutation and selection in parasites play out in the island structure of hosts? If each new host is colonized by viruses from a single donor host, then the founding population tends tohavelimited genetic diversity. Low diversity causes natural selection to be weak because there is not much opportunity for competition between genetic variants. Only new 168 CHAPTER 10 mutations that arise within the hostprovide an opportunity to replace deleterious mutations by genetic variants that restore full ﬁtness. With colonization from a single donor host, the viruses in each host share a lineage of descent that is isolated from the viruses in other hosts. Isolated lineages and bottlenecks in viral numbers that occur during transmission allow the accumulation of deleterious genetic variation by drift. Coinfection from diﬀerent donor hosts mixes lineages, increases ge- netic variation within hosts, and greatly enhances the power of natural selection to remove deleterious variants. Rouzine and Coﬃn (1999) es- timate that a coinfection frequency higher than 1% provides suﬃciently strong selection within hosts to reduce the level of genetic variation rel- ative to the amount of variation that accumulates by drift in isolated lineages. If coinfection occurs more commonly than 1%, as Rouzine and Coﬃn (1999) believe to be likely, then some other process must explain the high levels of genetic variability observed. Rouzine and Coﬃn (1999) discuss an interesting type of selection that puriﬁes within hosts but diversiﬁes between hosts. According to their model, purifying selection within hosts removes T cell epitopes to avoid host immunity. MHC type varies between hosts, causing diﬀerent T cell epitopes to be recognized by diﬀerent hosts. Thus, diversifying selection acts between hosts to establish reduced recognition by MHC. Purifying selection within hosts and diversifying selection between hosts may account for the apparently paradoxical observations: nucleotide substitutions leave the signature of purifying selection, yet the viral population maintains signiﬁcant ge- netic diversity. Very few studies have considered howthe island population structure of parasites inﬂuences the distribution of genetic diversity. As more sequences accumulate, there will be greater opportunity to match the observed patterns to the combined stochastic and selective processes that shape parasite diversity.
The asone (40 mg/dose/d 4 days) alone or in combination with B cells in turn produce autoantibodies with speciﬁcity for glycoproteins rituximab (375 mg/m2/wk for 4 weeks) cheap folvite 5mg fast delivery. Adapted with permission from Wei patients who received combination therapy with dexamethasone and and Jackson purchase folvite 5 mg free shipping. Th17 cells produce cytokines such as tional study has explored the use of low-dose rituximab (100 IL-17 that may further drive the imbalance between Th1 and Th2 mg/dose 4 doses) in combination with dexamethasone with a 12 6-month sustained remission rate of 76 purchase folvite 5 mg visa. Lastly, T-regulatory cells (Tregs) are reduced and impaired in ITP. In this randomized pilot trial, there was no difference in treatment failures (deﬁned by the composite end point of any platelet count 50 109/L, signiﬁcant bleeding, and As outlined above, the pathophysiology of ITP is complex and many interactions remain undetermined. Increased knowledge re- need for rescue therapy) between the placebo (21 of 26, 80. Further studies are therefore necessary to understand how Initial management of ITP is dependent upon factors such as platelet rituximab should be incorporated in clinical practice and if escala- count, patient age, bleeding symptoms, health-related quality of life tion of initial therapy with more aggressive immunotherapy is (HRQoL), need for upcoming procedures, and side effects associ- warranted. Traditional ﬁrst-line agents include corticoste- roids, IVIg, and anti-D immunoglobulin (anti-D). Table 2 outlines the dose, anticipated response rate, and side effects of ﬁrst-line Special considerations for children agents. The majority of children with newly diagnosed ITP and minimal bleeding can be treated with observation alone regardless of platelet Table 1. New insights into the pathogenesis of ITP count because severe bleeding events are thought be rare. If a rapid increase in platelet count is desired, then IVIg and anti-D are preferred based B cells Production of antiplatelet antibodies (targeting primary on the ability of these agents to increase the platelet count within platelet glycoproteins) 24-48 hours in the majority of children. Production of cross-reactive antiplatelet antibodies produced in response to infection Impaired expression of inhibitory Fc receptors Special considerations for adults T cells Altered apoptosis Treatment in adults with prednisone is reserved for patients with Dysregulation of regulatory T cells signiﬁcant thrombocytopenia (platelet count 30 109/L). First-line agents for the management of primary ITP5,6,9,22 Agent and dose Response Toxicities Corticosteroids Adults: prednisone 1-2 mg/kg/d for Initial rates: adults: 70%-80%, children: Hypertension, psychological, GI distress and ulcers, cataracts, 4 wk; children: no standard regimen 80%-90%; time: 1 wk; durability: hyperglycemia, osteoporosis, avascular necrosis, exists, but shorter courses are 10%-30% of adults have a durable immunosuppression/infections, adrenal insufﬁciency preferred remission IVIg 0. A systematic review representing The most widely studied treatment modalities include splenectomy, 1223 laparoscopic splenectomies showed an immediate response rate rituximab, and the thrombopoietin-receptor agonists (TPO-RAs). Similar rates are seen in children, with 80% demonstrating a durable remission at 4 years. Therefore, splenectomy removes the mechanism of Table 3. ASH recommendations for the use of second-line therapy in children and adults with ITP Children Adults Splenectomy Recommended for children with signiﬁcant or Recommended for adults who have failed persistent bleeding and lack of response or corticosteroid therapy, with similar efﬁcacy with intolerance of other therapies such as open or laparoscopic procedures. Rituximab May be considered for children with ITP who have May be considered for adults at risk of bleeding who signiﬁcant ongoing bleeding and/or have a need have failed one line of therapy such as for improved HRQoL despite conventional corticosteroids, IVIg, or splenectomy. May also be considered as an alternative to splenectomy in children with chronic ITP or as therapy in those who have failed splenectomy. Thrombopoietin receptor agonists Studies are ongoing and no recommendations Recommended for adults at risk of bleeding who were made regarding the use of these agents in relapse after splenectomy or who have a children. These agents may also be considered for adults at risk of bleeding who have failed one line of therapy such as corticosteroids or IVIg and who have not undergone splenectomy. Given that these are not primary immunomodulatory agents, reduced with appropriate presplenectomy vaccinations and postsple- they are not considered “curative” and patients may experience nectomy prophylactic antibiotic practices. Two growing over the possible vascular complications after splenec- agents, romiplostim and eltrombopag, are currently Food and Drug tomy, including the incidence of pulmonary hypertension and Administration (FDA) approved for adults with chronic ITP and venous and arterial thromboembolism. Recent case reports suggest that there is no cross-resistance between Rituximab the two agents. Recog- Two randomized trials with romiplostim enrolling a total of 125 nition that rituximab caused rapid depletion of CD-20 positive patients, 63 splenectomized and 62 nonsplenectomized, with a B cells responsible for antibody production led to its application in platelet count 30 [times 109/L43 were published collectively. Two systematic reviews mized patients given romiplostim. These results were striking given of the adult literature have been published with pooled overall that only one patient in the placebo group achieved the primary end response rates, deﬁned as a platelet count 50 109/L, of 57% point. Predictors of response to rituximab include demonstrating that 59% to 81% of patients receiving the drug ( 75 shorter duration of ITP, secondary ITP, and previous response to mg/d) achieved a platelet count of 50 109/L on day 43 corticosteroids; however, these have not been consistently identiﬁed compared with 11% to 16% of the placebo group. In addition, long-term rates of sustained immune Long-term ﬁgures on both agents suggest that the response in tolerance remain low. It remains unclear what accounts for such vast platelet count can be maintained. Data on 200 patients receiving interpatient variability in response. Of particular interest is the long-term romiplostim therapy (mean duration: 110 weeks) re- ﬁnding that rituximab response is associated with changes to the vealed that patients were able to maintain a platelet count of T-cell compartment, such as restoring the Th1/Th2 ratio36 and 50 109/L for the majority of the study visits (median: 92% of increasing the number and function of Tregs37 in responders, study visits). In addition, in nonresponders, of patients had a platelet count 50 109/L without new or antiplatelet-speciﬁc plasma cells have been found to persist in the increased ITP treatments in 50% of the visits. Pooled data from adult Only one randomized clinical trial examining the efﬁcacy of studies showed that 22% of patients experienced a mild or TPO-RAs in children has been conducted. In this phase 1/2 trial, moderate adverse event, with the majority (83%) being related to pediatric patients with ITP for 6 months were treated with the infusion. Of the 17 patients who were randomized to developed severe or life-threatening events and 9 (2. No pediatric deaths with rituximab have been subjects taking romiplostim. Additional serious adverse events included infection (N 3), serum sickness (N 7), hypersensitivity reaction (N 2), A subset of adult patients receiving TPO-RAs experienced sus- and the development of common variable immunodeﬁciency in one tained remission after the use of these agents. Hepatitis B39 reactivation after rituximab commonly by improving Treg function,55 either as a direct effect of the drug or occurs and JC virus leading to progressive multifocal leukoencepha- an indirect effect secondary to increased platelet number inducing lopathy has been reported rarely. Ultimately, knowledge of BM reticulin formation and thrombosis. During the EXTEND of disease biology coupled with information regarding response study, annual BMs were performed on enrolled patients (N 135) rates, patients’ desires, medication side effects, and relevant patient- and none experienced grade 3 reticulin formation, symptoms related related outcomes will provide for individualized treatment plans. Prospective studies are ongoing to ﬁnancial interests. Thromboembolic events have been reported with both agents with Correspondence long-term data, suggesting an event rate of 3. First, the majority of patients who experience an event have at least one additional risk factor for the development of thromboembolic References events, such as hypertension, smoking, or diabetes. Standardization of the true baseline incidence of thrombosis associated with ITP and terminology, deﬁnitions and outcome criteria in immune throm- the role of antiphospholipid antibodies remains unknown. Lastly, bocytopenic purpura of adults and children: report from an thrombosis does not appear to be dependent upon drug-induced international working group. Severe hemorrhage in children with newly diagnosed immune thrombocytopenic Unique to eltrombopag is the black box warning for hepatotoxicity. In the EXTEND study, 10% of patients met FDA criteria for 3.
The longest study (over 5 years) compared omeprazole with rabeprazole generic folvite 5 mg with mastercard. Symptom relief in patients with nonerosive gastroesophageal reflux disease or presumptively treated symptoms of gastroesophageal reflux disease • Three head-to-head trials in patients with gastroesophageal reflux disease but without erosive esophagitis on endoscopy found no difference between esomeprazole 20 mg and omeprazole 20 mg order folvite 5 mg mastercard, pantoprazole 20 mg generic folvite 5mg amex, or rabeprazole 10 mg. Evidence in children • There were no direct comparisons of proton pump inhibitors for reflux esophagitis in children. A fair-quality placebo-controlled trial in infants did not find omeprazole to be superior to placebo in controlling symptoms or acid-exposure time. Detailed Assessment Erosive esophagitis We identified 31 randomized controlled trials comparing 2 or more proton pump inhibitors in patients with gastroesophageal reflux disease with endoscopically-proven erosive esophagitis 4-6, 10-38 (Evidence Table 1). Two publications are supplemented with additional data provided by 4, 5 the manufacturer. No study of omeprazole in combination with sodium bicarbonate met inclusion criteria. The scales used to grade esophagitis in these studies are described in Appendix E. In most studies of proton pump inhibitors, patients who have esophagitis before treatment undergo another endoscopy for assessment of healing 4 or 8 weeks after starting treatment. There is no evidence that rate of esophageal healing after 4 or 8 weeks of treatment is associated with risk of stricture or esophageal cancer in the long run. As distinct from symptom relief, the benefit of quicker esophageal healing is also uncertain. The clinical importance of small differences in healing rates at 4 or 8 weeks is not known. In addition, patients who have clinically significant improvements but who are not completely healed (for example, patients whose esophagitis improves from LA classification scale grade D to grade B) are considered unhealed. Studies do not report the esophagitis grade for patients “not healed” at follow-up. Resolution of symptoms Proton pump inhibitors Page 17 of 121 Final Report Update 5 Drug Effectiveness Review Project Five head-to-head comparisons of proton pump inhibitors measured symptom relief as a primary 10, 11, 13, 16, 37 4, 5, 12, 14, 15, 17, 21-26, 30, 32, outcome, and 14 reported symptoms as a secondary outcome. Sixteen head-to-head trials reported the proportion of patients with resolution of 4, 5, 10, 12-14, 16, 17, 20, 23, 24, 26, 27, 29, 33, 36 symptoms at 4 weeks. We performed a random-effects meta- analysis of data from these studies to determine an estimate of the proportion who were symptom-free at 4 weeks for each drug. Proportions ranged from 65% to 77%, and 95% confidence intervals overlapped, indicating the drugs are similarly efficacious for resolution of symptoms at 4 weeks. A systematic review of most of these trials, with search dates through 2004, evaluated the 39 proton pump inhibitors as a group and compared to one another. This meta-analysis found omeprazole 20 mg daily to be inferior to esomeprazole 40 mg or lansoprazole 30 mg daily in heartburn relief at day 1, with relative risks of 0. Lansoprazole and esomeprazole were not found statistically different (relative risk 1. Our analysis includes more recently published trials. Symptom resolution in head-to-head trials in patients with erosive gastroesophageal reflux disease Proton pump inhibitor Resolution of symptoms at 4 Reference number and daily dose weeks (95% CI) 4, 5, 10, 12, 16, 20, 29 Esomeprazole 40 mg 73% (65 to 82) 4, 13-15, 23, 29 Lansoprazole 30 mg 70% (61 to 80) 5, 12, 13, 16, 24, 26, 27 Omeprazole 20 mg 65% (54 to 76) 14, 17 Omeprazole 40 mg 76% (65 to 87) 27 Pantoprazole 20 mg 77% (70 to 84) 10, 13, 17, 20, 23, 26 Pantoprazole 40 mg 72% (62 to 83) 24 Rabeprazole 20 mg 69% (52 to 86) 4, Figure 2 shows risk differences in rates of symptom resolution at 4 weeks in these trials. The pooled data on the comparison of esomeprazole 40 mg with omeprazole 20 mg significantly favored esomeprazole; for every 13 persons treated with esomeprazole 40 mg instead of omeprazole 20 mg, 1 additional patient would be symptom-free at 4 weeks in the esomeprazole group. The pooled data for comparison of esomeprazole 40 mg with either lansoprazole 30 mg or pantoprazole 40 mg did not indicate a significant difference between drugs. Proton pump inhibitors Page 18 of 121 Final Report Update 5 Drug Effectiveness Review Project Figure 2. Resolution of symptoms at 4 weeks in head-to-head trials of proton pump inhibitors Review: PPIs update #5 Comparison: 01 Complete resolution of symptoms at 4 weeks Outcome: 01 Complete resolution of symptoms at 4 weeks Study Drug A Drug B RD (random) Risk difference (random) Number symptom-free/TotalN Number symptom-free/Total N 95% CI 95% CI 01 Esomeprazole 20 mg vs omeprazole 20 mg Kahrilas 2000 382/626 357/624 0. Symptom resolution at 4 weeks in trials of esomeprazole compared with another proton pump inhibitor in erosive gastroesophageal reflux disease Portion of group with resolution of Risk difference Study symptoms at 4 weeks (95% CI) Pooled estimate Esomeprazole 40 mg compared with omeprazole 20 mg 5 Kahrilas 2000 65% vs. A head-to-head trial of pantoprazole 40 mg compared with esomeprazole 40 mg used the 35 ReQuest Score to assess symptoms. ReQuest is a validated self-assessment scale used to measure symptoms in erosive and nonerosive gastroesophageal reflux disease. Measured on the last 3 days of a 4-week treatment period, the median ReQuest-GI score in patients taking pantoprazole was found to be non-inferior to the median score in patients taking esomeprazole. Time to relief of symptoms Fourteen studies reported the time to resolution of symptoms (no heartburn). This outcome usually was reported as the percentage of patients with symptom resolution by a given time point, such as 1 day or 7 days), the median number of days to resolution, or both. One study reported this outcome as the number of days needed for 50% and 75% of patients to achieve 10 resolution of symptoms. Another measure was the time to sustained resolution of heartburn, defined as the first of 7 consecutive days without heartburn. This outcome was used only in studies funded by the maker of esomeprazole, so it is not possible to compare this outcome with studies funded by others. Proton pump inhibitors Page 20 of 121 Final Report Update 5 Drug Effectiveness Review Project Esomeprazole compared with omeprazole. In 4 studies that compared esomeprazole 40 mg with omeprazole 20 mg, the median number of days to the first resolution of symptoms was similar; however, the median number of days to sustained resolution of symptoms favored esomeprazole 5, 12, 16 in the 2 studies reporting this measure (Table 4). More patients taking esomeprazole 40 mg reached first of resolution of symptoms by day 1 and day 7 in absolute proportions than patients 12 taking omeprazole 20 mg. These findings were statistically significant in 1 study, 16, 31 5 nonsignificant in 2 others, and not assessed in the fourth. The time to sustained resolution of heartburn was statistically superior with esomeprazole 40 mg compared to omeprazole 20 mg at 12, 16 day 14 in 2 studies. The differences at other time points were mixed or not statistically assessed. One of these studies used a tablet formulation of esomeprazole that is not available in 31 the US or Canada. The median number of days to sustained resolution was similar. This pattern was also seen in the time to first resolution of symptoms. Time to symptom relief in trials comparing esomeprazole with omeprazole in erosive gastroesophageal reflux disease Proportion with first resolution of Proportion that has begun sustained resolution Study heartburn of heartburn (7 consecutive days) Esomeprazole 20 mg compared with omeprazole 20 mg Day 1: Kahrilas Day 7: Day 1: Day 28: 38% vs. In 3 studies comparing esomeprazole 40 mg with lansoprazole 30 mg, results were mixed and outcomes were reported differently (Table 4). Overall, results did not favor one drug over another.
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