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By H. Torn. Stephen F. Austin State University.

Outcome measures and study eligibility criteria Outcome Outcome Measures Study Eligibility Criteria • Head-to-head randomized controlled clinical trials or meta-analyses • Response evaluating: • Remission - One second-generation • Speed of response/remission antidepressant compared with Efficacy/ • Relapse another Effectiveness • Quality of life • When sufficient evidence was not • Functional capacity available for head-to-head trials within • Hospitalization a specific diagnostic group discount cialis professional 40mg mastercard, we evaluated: - Placebo-controlled trials • Overall adverse effect reports • Head-to-head randomized controlled • Withdrawals because of adverse effects clinical trials or meta-analyses • Serious adverse event reports evaluating: • Specific adverse events or withdrawals - One second-generation because of specific adverse events buy cialis professional 40mg fast delivery, antidepressant compared with including: another - gastrointestinal symptoms Safety/ Tolerability - hepatoxicity • When sufficient evidence was not - hyponatremia available for head-to-head trials within - loss of libido a specific diagnostic group cheap 20 mg cialis professional with amex, we - seizures evaluated - suicide - Placebo-controlled trials - weight gain - Observational studies, n > 1000 - others Second-generation antidepressants 12 of 190 Final Update 5 Report Drug Effectiveness Review Project METHODS A. Literature Search To identify articles relevant to each key question we searched PubMed, Embase, The Cochrane Library, CINAHL, PsycINFO, and the International Pharmaceutical Abstracts. We used either Medical Subject Headings (MeSH or MH) as search terms when available or key words when appropriate. We combined terms for selected indications (MDD, dysthymia, subsyndromal depression, seasonal affective disorder, general anxiety disorder, PTSD, OCD, panic disorder, social anxiety disorder, PMDD), drug interactions, and adverse events with a list of 12 specific second-generation antidepressants (citalopram, desvenlafaxine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, mirtazapine, duloxetine, venlafaxine, bupropion, and nefazodone). We limited the electronic searches to “human” and “English language. We manually searched reference lists of pertinent and relevant review articles and letters ® to the editor. All citations were imported into an electronic database (Endnote v. Additionally, we handsearched the Center for Drug Evaluation and Research (CDER) database to identify unpublished research submitted to the FDA. Furthermore the Center for Evidence-based Policy at the Oregon Health and Science University (OHSU) contacted pharmaceutical manufacturers and invited them to submit dossiers, including citations, using a protocol issued by the Center for Evidence-based Policy (http://www. We received dossiers from six pharmaceutical companies. Study Selection Two persons independently reviewed abstracts. If both reviewers agreed that the trial did not meet eligibility criteria, we excluded it. We obtained the full text of all remaining articles. Records were considered for exclusion if they did not meet pre-established eligibility criteria with respect to study design or duration, patient population, interventions, outcomes, and comparisons to antidepressant medications outside our scope of interest. For this review, results from well-conducted, valid head-to-head trials provide the strongest evidence to compare drugs with respect to effectiveness, efficacy, and adverse events. RCTs of at least 6 weeks’ duration and an outpatient study population with a sample size greater than 40 participants were eligible for inclusion. We defined head-to-head trials as those comparing one second-generation antidepressant with another. We did not examine placebo-controlled trials in detail if head-to-head trials were available. We viewed FDA approval as evidence for general efficacy; therefore, we did not review placebo-controlled trials for FDA-approved indications except when outcome measures assessed quality of life or other health outcomes that are not generally required for FDA approval. If no head-to-head evidence was published, we reviewed placebo-controlled trials for indications of interest that had not already been approved by the FDA. We reviewed all placebo- controlled trials for indications without FDA approval to provide an overview of efficacy without taking drug equivalency into account. In other words, we did not evaluate the dosage of Second-generation antidepressants 13 of 190 Final Update 5 Report Drug Effectiveness Review Project one drug relative to the dosage of an alternative drug in a different trial. High dosages may yield greater treatment effects compared to placebo than do low or medium dosages. Comparisons of treatment effects across trials must, therefore, be made cautiously. For adverse events we included both experimental and observational studies. For observational studies, we included those with large sample sizes (≥ 100 patients), lasting at least 1 year that reported an included outcome. Initially, we reviewed studies with health outcomes as primary outcome measures. Outcomes for efficacy or effectiveness were response, remission, speed of response, relapse, functional capacity, and hospitalization. If no study measuring health outcomes was available for a particular indication or population subgroup, we included intermediate outcomes (e. Safety outcomes included overall and specific adverse events (e. We included meta-analyses in our evidence report if we found them to be relevant for a 10 key question and of good or fair methodological quality. We did not review individual studies if they were included in a high-quality meta-analysis. We excluded meta-analyses that were not based on a comprehensive systematic literature search or did not maintain the units of the studies in their statistical analyses. We checked our database to guarantee that our literature search had detected trials included in any meta-analyses that we discarded, and we then obtained any missing articles. Data Abstraction We designed and used a structured data abstraction form to ensure consistency of appraisal for each study. Trained reviewers abstracted data from each study and assigned an initial quality rating. A senior reviewer read each abstracted article, evaluated the completeness of the data abstraction, and confirmed the quality rating. We abstracted the following data from included trials: study design, eligibility criteria, intervention (drugs, dose, duration), additional medications allowed, methods of outcome assessment, population characteristics, sample size, loss to follow-up, withdrawals due to adverse events, results, and adverse events reported. We recorded intention-to-treat results if available. Quality Assessment We assessed the internal validity (quality) of trials based on predefined criteria (Appendix B). These criteria are based on those developed by the US Preventive Services Task Force (ratings: 11 12 good-fair-poor) and the National Health Service Centre for Reviews and Dissemination. External validity (generalizability) was assessed and reported but did not influence quality ratings. Two independent reviewers assigned quality ratings; they resolved any disagreements by discussion and consensus or by consulting a third, independent party. Elements of internal validity assessment included, among others, randomization and allocation concealment, similarity of compared groups at baseline, use of intention-to-treat analysis, and overall and differential loss to follow-up. Loss to follow-up was defined as the number of persons randomized who did not reach 13 the endpoint of the study, independent of the reason and the use of intention-to-treat analysis. We adopted a cut-off point of 20 percent loss to follow-up as a limit beyond which bias was Second-generation antidepressants 14 of 190 Final Update 5 Report Drug Effectiveness Review Project likely to be introduced because of missing endpoint assessments. Trials with more than 20 percent but less than 40 percent loss to follow-up were eligible for a quality rating of fair (but not good). Studies with more than 40 percent overall loss to follow-up or more than 15 percentage points differential loss to follow-up between study groups were rated as poor. These cut-off points took into consideration that loss to follow-up appears to be higher in psychiatric populations than in other study populations. Trials that had a fatal flaw in one or more categories were rated poor quality and not included in the analysis of the evidence report (Appendix C) unless the evidence was severely lacking for an indication. Trials that met all criteria were rated good quality.

Antiepileptic drugs Page 106 of 117 Final Report Update 2 Drug Effectiveness Review Project J Clin Psychiatry discount cialis professional 20mg. New data on the use of lithium order 20mg cialis professional, divalproate discount cialis professional 20mg mastercard, and lamotrigine in rapid cycling bipolar disorder. Gabapentin significantly improves analgesia in people receiving opioids for neuropathic cancer pain. Australian and New Zealand clinical practice guidelines for the treatment of depression. Antiepileptic drug use increases rates of bone loss in older women: a prospective study. Polypharmacy treatment approaches to the psychiatric and somatic comorbidities found in patients with chronic pain. American Journal of Physical Medicine and Rehabilitation. Pregabalin: In the treatment of painful diabetic peripheral neuropathy. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. A 6-month, multicenter, open-label evaluation of beaded, extended-release carbamazepine capsule monotherapy in bipolar disorder patients with manic or mixed episodes. Rec #: 2075 Antiepileptic drugs Page 107 of 117 Final Report Update 2 Drug Effectiveness Review Project 22. Pharmacotherapy of bipolar II disorder: A critical review of current evidence. Pharmacological treatment of peripheral neuropathic pain conditions based on shared commonalities despite multiple etiologies. American Journal of Physical Medicine and Rehabilitation. A review of the evidence for carbamazepine and oxcarbazepine in the treatment of bipolar disorder. Divalproex versus valproate in patients with bipolar disorder. Patterns of lamotrigine use in daily clinical practice during the first 5 years after introduction in the Netherlands. Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Are anticonvulsants a satisfactory alternative to opiate analgesia in patients experiencing pain with Guillain-Barre syndrome? A 52-week, open-label continuation study of lamotrigine in the treatment of bipolar depression. Treating bipolar disorder: Evidence-based guidelines for family medicine. Quality of life assessment in patients with bipolar disorder treated with olanzapine added to lithium or valproic acid. Rec #: 2085 Antiepileptic drugs Page 108 of 117 Final Report Update 2 Drug Effectiveness Review Project 34. Postherpetic neuralgia: What do we know and where are we heading? Gabapentin: A pooled analysis of adverse events from 3 clinical trials in patients with postherpetic neuralgia. Systematic overview of the pharmacological management of postherpetic neuralgia: An evaluation of the clinical value of critically selected drug treatments based on efficacy and safety outcomes from randomized controlled studies. Psychotropic medication in chronic spinal disorders. The relationship between polycystic ovary syndrome and antiepileptic drugs: a review of the evidence. Developing the BALANCE trial - The role of the pilot study and start-up phase. Treatment of painful diabetic neuropathy: A review of the most efficacious pharmacological treatments. A mood stabilizer with risperidone or haloperidol for mania. Psychosis in mania: specificity of its role in severity and treatment response. Clinical study of patients with persistent orofacial pain. The effect of carbamazepine and lithium on remission from affective illness. Antiepileptic drugs Page 109 of 117 Final Report Update 2 Drug Effectiveness Review Project 1987 Feb; 150:180-2. Predictors of response to treatment of acute bipolar manic episodes with divalproex sodium or placebo in 2 randomized, controlled, parallel-group trials. Manic-like state after bilateral orbitofrontal and right temporoparietal injury: efficacy of clonidine. Long-term randomized clinical trial on oxcarbazepine vs lithium in bipolar and schizoaffective disorders: Preliminary results. Lamotrigine in spinal cord injury pain: a randomized controlled trial. Baclofen in the treatment of trigeminal neuralgia: Double-blind study and long-term follow-up. The analgesic effect of tocainide in trigeminal neuralgia. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Rec #: 505 Excluded studies Update 2 A total of 87 studies (Head to head trials, Active control trials, Placebo-controlled trials and Observational studies). Reasons for exclusion are: 1=Foreign language, 2=Wrong outcome, 3=Wrong Intervention, 4=Wrong population, 5=Wrong publication type, 6=Wrong study design, 7=Insufficient duration. Excluded studies Codes Altamura A, Russo M, Vismara S, Mundo E. Comparative Evaluation of Olanzapine Efficacy in the Maintenance Treatment of Bipolar Disorder. Antiepileptic drugs Page 110 of 117 Final Report Update 2 Drug Effectiveness Review Project Excluded studies Codes Alvestad S, Lydersen S, Brodtkorb E. Rash from antiepileptic drugs: influence by gender, age, and learning disability. Comparison and predictors of rash associated with 15 antiepileptic drugs. Therapeutic effects of carbamazepine in affective illness: a preliminary report. Carbamazepine in manic-depressive illness: a new 6 treatment. Phenytoin as an augmentation for SSRI failures: A controlled 5 study.

Leukapheresis and low-dose chemotherapy do not reduce early mortality in acute myeloid leukemia 22 order genuine cialis professional on-line. Leukapheresis reduces early hyperleukocytosis: a systematic review and meta-analysis buy cialis professional 20 mg amex. Del Vasto F best purchase for cialis professional, Caldore M, Russo F, Bertuccioli A, Pellegrini F. Thiebaut A, Thomas X, Belhabri A, Anglaret B, Archimbaud E. Porcu P, Danielson CF, Orazi A, Heerema NA, Gabig TG, McCarthy patients with extreme leukocytosis. Therapeutic leukapheresis in hyperleucocytic leukaemias: lack of 2634. The prevalence of chronic health conditions approaches 75% among allogeneic HCT survivors and that for severe or life-threatening conditions exceeds 20%. This chapter describes the burden of morbidity carried by HCT survivors to help healthcare providers and policy makers understand the scope of the problem and the need for life-long follow-up and proactive care for this vulnerable population. These complications are Learning Objectives 7 more common and often occur earlier than would be expected in ● To describe the burden of morbidity experienced by alloge- the general population. These Conditioning with total body irradiation (TBI) is associated with an complications have a direct impact on the morbidity and mortality increased risk of dyslipidemia and diabetes. The burden of morbidity resulting calcineurin inhibitors used to manage GVHD also increase the risk from the cumulative impact of the individual complications occur- of CVRFs. The high burden of morbidity Cardiomyopathy experienced by HCT survivors forms the basis for life-long, Late-occurring ( 1 year post-HCT) clinical heart failure is primar- standardized follow-up of HCT survivors at high risk for post-HCT 13 ily due to pre-HCT exposure to anthracyclines. I also describe the health behaviors and prevention patterns of healthcare utilization by the HCT survivors. Finally, I Patients exposed to anthracyclines before HCT should undergo describe the current recommendations for follow-up and monitoring monitoring for late-onset cardiomyopathy using serial echocardio- with the goal of early detection such that appropriate management grams. The intensity of echocardiographic screening can range from of these complications can result in reduced morbidity. HCT survivors who received radiation involving Allogeneic HCT survivors are at risk for cardiovascular complica- the heart field should also be monitored for early-onset atherosclero- tions, including arterial disease (cerebrovascular disease and coro- sis, especially if they have one or more CVRFs. Lifestyles that Hematology 2014 495 promote good heart health should be recommended to all survivors, tions from chest x-rays show peripheral patchy consolidation, including a regular exercise program, dietary considerations, and ground glass attenuation, and nodular opacities. Definitive diagnosis screening for (and aggressive management of) dyslipidemia, hyper- necessitates histologic confirmation. In particular, given the increased risk of dyslipidemia among allogeneic HCT recipients, a lower threshold Idiopathic pneumonia syndrome for management of dyslipidemia is recommended than that prac- Idiopathic pneumonia syndrome usually occurs within the first 4 ticed in the general community. Risk factors include exposure to TBI and pre-HCT chemotherapy and presence of GVHD and the risk Delayed pulmonary complications increases with age at HCT. Late-onset interstitial pneumonitis Delayed pulmonary complications after allogeneic HCT include occurs years after HCT, typically in patients with severe chronic the following: bronchiolitis obliterans syndrome (BOS), crypto- GVHD of the sclerodermatous cutaneous variety. A restrictive genic organizing pneumonia (COP) (formerly called bronchioli- defect is found on pulmonary function tests. The cumulative incidence of late- Monitoring for pulmonary dysfunction in HCT survivors should onset pulmonary complications is reported to be 10% at 2 years; include the assessment of symptoms such as chronic cough or the cumulative incidence among those diagnosed with chronic dyspnea. Because of the insidious onset of BOS and late symptom GVHD is significantly higher (15. Although pulmonary occurrence, experts advocate pulmonary function testing every 3 complications of HCT are often initially subtle, they can progress months during the first year after HCT. This strategy should allow and become irreversible in the long term and contribute signifi- the capture of patients during a period of tapering of immunosuppres- cantly to post-HCT morbidity and mortality. Upon entry into long-term BOS follow-up care, patients should be cautioned about the risks of BOS is characterized by a nonspecific inflammatory injury smoking and exposure to secondhand smoke. It is recommended affecting the small airways that results in new fixed airflow that pulmonary function tests and chest x-rays are performed upon obstruction. BOS occurs within the first 2 years after HCT, but entry into long-term follow-up for at-risk patients and should be may develop as late as 4-5 years after transplantation. The repeated as clinically indicated in symptomatic patients and in those prevalence of BOS is 5. Influenza and and 14% among those who develop chronic GVHD. Patients usually present 4 health conditions encountered after HCT ; a brief description of with nonspecific symptoms, including shortness of breath, dry some of them follows. Unfortunately, once these symptoms develop, the degree of airflow obstruction is usually already significant and irreversible. Another common manifesta- Thyroid tion of BOS is the development of air-trapping, which can be Thyroid abnormalities include subclinical and overt hypothyroid- appreciated by high-resolution CT scans (persistent lucency of ism. Conversely, overt hypothyroidism is characterized by image that carries a sensitivity of 74%–91% and a specificity of low T4 levels accompanied with elevated TSH. Criteria used to make a clinical diagnosis of compensated hypothyroidism ranges from 25% to 30%, with a bronchiolitis obliterans include: (1) FEV1/FVC 0. The cumulative incidence of overt 75% of predicted value, (2) evidence of air trapping or small hypothyroidism ranges from 3. Hypothyroidism is related to radiation to the thyroid gland (3) absence of respiratory infection. Use of the airflow obstruction classification may permit study of early intervention Osteopenia/osteoporosis strategies; a recent consensus conference proposes inhaled 20-23 18 HCT recipients are at risk for osteopenia and osteoporosis. The corticosteroids and or inhaled bronchodilators for such cases. Patients with COP are more likely to incidence of osteoporosis approaches 20% at 2 years; the most have GVHD. It significant loss in bone mineral density occurs during the first 6 presents as an interstitial pneumonia and usually occurs within the months after HCT. Bone mineral loss increases the risk of fractures first 12 months after HCT. The clinical presentation in patients is in the HCT population just as it does in the general population; acute, with the sudden onset of a dry cough, dyspnea, and fever. Males with chronic GVHD and those exposed to secretion. The probability of developing gonadal failure increases calcineurin inhibitors are at increased risk of osteonecrosis. Recovery of spermatogenesis seems to occur more frequently in patients receiv- Recommendations for screening, early detection, and ing lower doses of cyclophosphamide (120 mg/kg) than in those prevention treated with higher doses (200 mg/kg). Male survivors have a A careful history and a thorough physical examination are the considerable chance of recovering sperm production even when cornerstone of screening. Early detection could result in the treated with TBI provided that they are 25 years of age at HCT utilization of surgical measures such as cortical decompression, thus and do not develop chronic GVHD. An important and potentially devastating complication of HCT is Although 50% of prepubertal girls exposed to fractionated TBI the occurrence of subsequent malignant neoplasms (SMNs). These include age at HCT, pre-HCT undergoing HCT develop ovarian failure, probably as a result of exposure to chemotherapy and radiation, exposure to TBI as part decreased reserve of primordial follicles. Irreversibility of ovar- of conditioning, infection with oncogenic viruses (EBV, HBV, ian function after HCT in most patients highlights the need for 5,30-32 and HCV), and prolonged immunosuppression after HCT.

Q uality assessm entoflong term uncontrolled interventionstudies ofsafety and adverse events A scertainm ent N on-biased and A dverse events tech niques adequate Statisticalanalysis A uth or N on-biased L ow overallloss pre-specified and adequately ascertainm ent ofpotential O veralladverse event Y ear selection? The purpose of this report is to make available information regarding the comparative effectiveness and safety profiles of different drugs within pharmaceutical classes buy cialis professional online. Reports are not usage guidelines buy cheap cialis professional 20 mg online, nor should they be read as an endorsement of buy cialis professional 40 mg on line, 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 Susan Carson, MPH Sujata Thakurta, MPA:HA Drug Effectiveness Review Project Marian McDonagh, PharmD, Principal Investigator Oregon Evidence-based Practice Center Mark Helfand, MD, MPH, Director Oregon Health & Science University Copyright © 2009 by Oregon Health & Science University Portland, Oregon 97239. Final Report Update 5 Drug Effectiveness Review Project TABLE OF CONTENTS INTRODUCTION.......................................................................................................................... What is the comparative efficacy of different proton pump inhibitors in patients with symptoms of gastroesophageal reflux disease? What is the comparative effectiveness of different proton pump inhibitors in treating patients with peptic ulcer and nonsteroidal anti-inflammatory drug-induced ulcer?............................... What is the comparative effectiveness of different proton pump inhibitors in preventing ulcer in patients taking a nonsteroidal anti-inflammatory drug? What is the comparative effectiveness of different proton pump inhibitors in eradicating Helicobacter pylori infection?............................................................................................... Is there evidence that a particular treatment strategy is more effective or safer than another for longer-term treatment (more than 8 weeks) in patients with gastroesophageal reflux disease?.................................................................................................................................................. What is the comparative safety of different proton pump inhibitors in patients being treated for symptoms of gastroesophageal reflux disease, peptic ulcer, and nonsteroidal anti- inflammatory drug-induced ulcer? Are there subgroups of patients based on demographics, other medications, or comorbidities for which a particular medication or preparation is more effective or associated with fewer adverse effects? Proton pump inhibitors and their US Food and Drug Administration-approved indications...... Symptom resolution in head-to-head trials in patients with erosive gastroesophageal reflux disease................................................................................................................................................... Symptom resolution at 4 weeks in trials of esomeprazole compared with another proton pump inhibitor in erosive gastroesophageal reflux disease............................................................................. Time to symptom relief in trials comparing esomeprazole with omeprazole in erosive gastroesophageal reflux disease........................................................................................................... Pooled estimates of healing rates for esophagitis in head-to-head trials of proton pump inhibitors................................................................................................................................................. Risk differences in healing of esophagitis in trials of omeprazole 20 mg compared with another proton pump inhibitor................................................................................................................ Risk differences in healing of esophagitis in head-to-head trials of esomeprazole 40 mg compared with lansoprazole 30 mg....................................................................................................... Risk differences in healing of esophagitis in trials of esomeprazole 40 mg compared with another proton pump inhibitor................................................................................................................ Estimated healing rates in patients with moderate to severe esophagitis at baseline............ Percent patients with resolution of heartburn at 4 weeks from Cochrane review............... Proton pump inhibitors and treatment durations in longer-term studies of gastroesophageal reflux disease: Comparisons of standard doses with lower doses........................................................ Remission of gastroesophageal reflux disease erosions and symptoms in longer-term studies of proton pump inhibitors: Comparisons of standard doses with lower doses.......................... Proton pump inhibitors and treatment durations in longer-term studies of gastroesophageal reflux disease: Comparisons of daily treatment with intermittent or on-demand treatment.................. Remission of gastroesophageal reflux disease erosions and symptoms in longer-term studies of proton pump inhibitors: Comparisons of daily treatment with intermittent or on-demand treatment................................................................................................................................................ Risk of adverse events for proton pump inhibitors compared with other ulcer drugs 252 (Salgueiro 2006)................................................................................................................................ Resolution of symptoms at 4 weeks in head-to-head trials of proton pump inhibitors........... Esophagitis healing at 4 weeks in head-to-head trials of proton pump inhibitors.................. Esophagitis healing at 8 weeks in head-to-head trials of proton pump inhibitors.................. Healing of moderate to severe esophagitis at 4 weeks in head-to-head trials of proton pump inhibitors................................................................................................................................................. Healing of moderate to severe esophagitis at 8 weeks in head-to-head trials of proton pump inhibitors................................................................................................................................................. Esophagitis healing at 8 weeks in 22 randomized controlled trials comparing proton pump inhibitor with H2 receptor antagonist..................................................................................................... Duodenal ulcer healing at 4 weeks in trials comparing proton pump inhibitors..................... Duodenal ulcer healing at 4 weeks in comparisons of proton pump inhibitor with H2 receptor antagonist.............................................................................................................................................. Gastric ulcer healing at 4 weeks in comparisons of proton pump inhibitor with H2 receptor antagonist.............................................................................................................................................. Quality assessment methods for drug class reviews for the Drug Effectiveness Review Project.................................................................................................................................................. Esophagitis grading scales used in randomized controlled trials.................................... Prior versions of this report can be accessed at the DERP website. Acknowledgments We thank Leah Williams, our publications editor, for putting this report into its present form for you to read. We also thank Arkady Mak, PhD, MD, for editorial suggestions, Miranda Walker, MA, for assistance with data abstraction and quality assessment of studies, and Theresa Nguyen for retrieval of articles and assistance with editing and formatting. Suggested citation for this report McDonagh MS, Carson S, Thakurta S. Funding The Drug Effectiveness Review Project, composed of 15 organizations including 14 state Medicaid agencies and the Canadian Agency for Drugs and Technology in Health commissioned and provided funding for this report. These organizations selected the topic of the report and had input into its Key Questions. The content and conclusions of the report were entirely determined by the Evidence-based Practice Center researchers. The authors of this report have no financial interest in any company that makes or distributes the products reviewed in this report. Proton pump inhibitors Page 5 of 121 Final Report Update 5 Drug Effectiveness Review Project INTRODUCTION Proton pump inhibitors decrease secretion of gastric acid. They act by blocking the last enzyme in the system that actively transports acid from gastric parietal cells into the gastrointestinal lumen, hydrogen–potassium adenosine triphosphatase, also known as the proton pump.

Should it become necessary to consult a urologist cheap cialis professional 20 mg visa, the risks involved in using contrast medium must be clarified cialis professional 40mg with mastercard. Elevation of creatinine with long-term indinavir therapy was often seen in the late 1990s (Fellay 2001 buy 20 mg cialis professional mastercard, Boubaker 2001). Typical signs of indinavir nephropathy include sterile leukocyturia with loss of renal function (Gagnon 2000, Dielemann 2003) and an echogenic transformation of the renal parenchyma in otherwise normal kidneys. Discontinuing indinavir leads to normal function in most cases. Tuberculosis in the urinary tract with sterile leukocyturia should be considered. HIV and Renal Function 579 Hypophosphatemia, tubulotoxic damage, Fanconi’s syndrome Alongside glomerular filtration of substances such as creatinine, an alternative form of secretion via transporters in the tubulus is possible. In the proximal tubulus, the transporter OCT2 leads to an intake of creatinine from the the blood in the tubular cell, which in turn is secreted into the urine via MATE 1. The integrase inhibitor dolutegravir inhibits OCT2, whereas the pharmacoenhancer cobicistat inhibits MATE 1. Thus, both substances block the alternative secretion route via the tubular cells, which leads to a slight increase in creatinine (0. Of course, this does not change the true GFR and therefore has no effect on the glomerulus or the renal function. Tivicay can thus also be used in patients with limited kidney function. However, care must be taken regarding the combination with TDF, as it may be difficult to identify a true impairment of renal function, and TDF must be reduced in cases of a GFR of less than 60 ml. The fixed- dose combination Stribild should thus only be used in patients with an eGFR >90 ml and should be avoided below 70 ml. Tenofovir itself is absorbed into the tubular cell not only via glomerular filtration but also via the transporter OAT 1 and is then secreted actively (dependent on ATP) via MRP 2 and 4 into the urine of the proximal tubulus. Should true filtration in the glomerulus decline (for example, in cases of acute kidney failure), attempts are made to eliminate more TDF via the tubular cell (increased activity of OAT 1). This results in an increased concentration of TDF in the tubular cell, which in turn leads via a disruption of the mitochondrial polymerase gamma to a decline in energy-depen- dent MRP 2 and 4 transport capacity and can thus end in tubular damage (Perazella 2010). Indeed, concentration-dependent damage caused by TDF to the tubular cell can be demonstrated: patients with low body weight are more vulnerable (Nishijirna 2012). When the agents filtered from the glomerulus in primary urine exceed the transport capacity of the reabsorbing tubular cells they are excreted with the urine. The most prominent example is the glucose threshold of the kidneys (180 mg/dl). However, a transport dysfunction in the tubular system can also be caused by drugs such as cidofovir, tenofovir and adefovir. This is known as secondary (drug-induced) Fanconi’s syndrome and is distinguished by a malfunction of the tubular system without there necessarily being any impairment of the GFR. There is an increased amount of phosphate, amino acids and glucose in the urine, whereas phosphate in the blood is reduced. The loss of amino acids, phosphate, glucose, bicarbonate and other organic and inorganic substances, as well as water, can become clinically manifest in the form of increased urination, thirst, tiredness, bone pain or weakness, and lead to secondary changes in the bone metabolism. Special caution is required when dealing with fixed-dose combinations (FDCs) such as Stribild. This also includes determination of blood sugar, potassium in the blood and glucose concentration in the urine. In patients whose creatinine clear- ance is confirmed to drop to <50 ml/min or whose serum phosphate level drops to 1. Hypophosphatemia also occurs under the influence of alcohol, with diabetes, cachexia, diarrhea or a disorder of vitamin D metabolism or hyperparathyroidism. About 10% of cases are found in untreated HIV+ patients, 23% in people on ART and up to 31% in those taking tenofovir. The reasons are many and varied, includ- 580 Interdisciplinary Medicine ing a low phosphate absorption (normal: 1200 mg/day). The determination of intact parathormone, vitamin D or an anamnesis with diuretics, vomiting or a tumor may indicate other causes of hypophosphatemia. The secretion ratio of phosphate to creatinine can be a sign of tubular damage if, despite hypophosphatemia, more that 10% of the filtrated phos- phate is secreted (Jamison 1982). Secretion ratio: (urine phosphate, mg/dl) x (serum creatinine, mg/dl) (serum phosphate, mg/dl) x (urine creatinine, mg/dl) In case reports, renal failure has above all been described in patients with other reasons for renal insufficiency, mostly in ART combinations that include boosted PI regimens and tenofovir as well as secondary disorders and cirrhosis of the liver or hepatitis. Nephrologists advise caution in selecting antiretroviral therapy for patients with proteinuria, nephritic syndrome, cirrhosis of the liver, and/or dyslipoproteine- mia. Potentially nephrotoxic agents such as cidofovir, adefovir, tenofovir or fixed- dose combinations should be avoided in these patients. In principle, it is possible to administer NRTIs (e. Renal insufficiency and ART In advanced cases (with appropriate resistance testing), NRTI-sparing combinations of a PI/r plus raltegravir, two boosted PIs, a combination of an NNRTI plus a PI or combinations of dolutegravir or maraviroc can be considered as kidney-neutral solu- tions. Careful monitoring of serum creatinine, proteinuria, erythrocyturia and serum phosphate is recommended. Tenofovir and the kidney In view of the broad use of tenofovir, more attention must be devoted to long-term renal toxicity in the future. The increased renal risk observed in early cohort studies was less explicit in more recent analyses – possibly because TDF is now being used more carefully by the treating physicians. Studies verified an increased tubular risk with TDF (Dauchy 2011) higher than that with ABC+3TC (Moyle 2010). Although a meta-analysis of 17 studies showed only a slight reduction of GFR on TDF (-3. In the large D:A:D cohort (n=22,603), a decline in GFR of more that 20 ml to less than 70 ml/min correlated with the use of TDF, boosted atazanavir and lopinavir (Derek 2013). This was also seen in the EuroSIDA cohort, in which renal failure inci- dence amounted to 1. Again, there was a correlation between the use of TDF, atazanavir/r and lopinavir/r. In contrast to the D:A:D group, patients with renal insufficiency were not excluded in EuroSIDA study (Derek 2013). The inci- dence of renal events in the manufacturer’s database since drug approval amounts to 29. In two prospective studies (GS903E and GS934) on patients with good renal health, a creatinine increase to >1. However, patients suffer- ing from renal insufficiency were excluded from these studies (Gallant 2008). The leading renal event during TDF treatment is Fanconi’s syndrome (22. It occurs 7-10 months after starting therapy and disappears 4-6 weeks after discontinuation (Izzedine 2004). HIV and Renal Function 581 An isolated hypophosphatemia without glucosuria in HIV+ patients can also be due to malnutrition, vitamin D deficiency, diuretics or alcohol, and doesn’t necessarily require TDF discontinuation.

However purchase cialis professional pills in toronto, two recent rando- prothrombin gene mutations) order 40 mg cialis professional visa, but individual mized controlled trials (RCTs) did not prove this assessment will be guided by the type of thrombo- empirical treatment as neither of these options im- philia and the presence of other thrombotic risk proved the live birth rate73 cheap cialis professional 40 mg with visa,74 and such practice factors. There is no evidence to justify routine should be discouraged. The common practice of using D&C to clear the womb will not lead to improved pregnancy CERVICAL CERCLAGE outcomes. Indeed, vigorous D&C causes intra- Incidence of mid-trimester loss has commonly uterine scarring and adhesions and further compro- been quoted as ~2%. Many cases are multifactorial mises the chance of successful pregnancy. How- Cervical cerclage has been performed in women ever, the couple should be reassured that the prog- considered to be at high risk of mid-trimester loss nosis for a successful future pregnancy with 11,17 and spontaneous preterm birth with cervical ‘in- supportive care alone is in the region of 75%. Insertion of cerclage may reduce the risk of cated staff during early pregnancy has been shown 11,17,42 further late pregnancy loss by providing a degree of to be beneficial. Close monitoring of these preg- causes before planning a cerclage because the treat- nancies is required to optimize the outcome. Dur- ment is invasive and carries a significant risk of an ing the third trimester, close monitoring of fetal size adverse outcome. There is no specific and accurate method to diag- It has been shown from a RCT that when com- nose cervical incompetence and there is insufficient pared with expectant management, cervical cerc- evidence to recommend the use of pre-pregnancy lage significantly reduced pre-viable birth <24 diagnostic techniques, e. However, it did not prevent birth at Diagnosis is mainly based on the history of mid- >35 weeks of gestation unless the cervical length trimester loss following painless cervical dilatation 77 was <15mm. Risk factors include It is recommended that women with a history of previous major cervical surgery (e. Other causes of preterm ultrasound-indicated cerclage before 24 weeks of delivery such as uterine anomaly, fibroids or infec- gestation if the cervix is ≤25mm. Indications History-indicated cerclage Types of cerclage Insertion of cerclage may be based on the risk fac- McDonald suture (transvaginal)This is the commonest tors in a woman’s obstetric or gynecological history technique used. It involves the placement of a simple which increase the risk of spontaneous second- purse-string suture around the cervico-vaginal junc- trimester loss or preterm delivery. It is performed as tion just below the reflection of the vaginal skin onto a prophylactic measure in asymptomatic women the cervix without bladder mobilization78. Mersilene and should be inserted at 12–14 weeks of gestation tape or nylon can be used and a knot is tied anteri- as an elective procedure. The largest randomized trial which was co- Shirodkar suture (high transvaginal) This is usually ordinated by the Medical Research Council performed in women with a short cervix, which (MRC)/RCOG comparing history-indicated cer- makes insertion of a McDonald suture difficult. A purse- However, similar benefit has not been proven in a string suture is placed above the level of cardinal meta-analysis of four randomized trials which in- 79 ligaments. Subgroup analysis showed only women with a history of three or Transabdominal cerclage This is indicated when there more pregnancies ending before 37 weeks of gesta- has been a previous failed vaginal suture, traumatic tion would be likely to benefit. Based on the current or surgical damage making a vaginal approach available data, history-indicated cerclage should difficult, or severe scarring or chronic cervicitis or only be offered to women with three or more pre- the presence of a cervico-vaginal fistula. This type vious preterm births and/or second-trimester losses. Cervical assessment by ultrasound is usually performed at 14 and 24 weeks of gestation and a Cerclage is potentially a dangerous treatment as it short cervix of <25mm is the best independent needs to be removed before labor starts (in cases of 142 Recurrent Miscarriage including Cervical Incompetence vaginal cerclage) or the woman needs a primary salbutamol or nifedipine) in women undergoing cesarean section (in cases of abdominal cerclage). In cases of pres- • Doubt about patient compliance for early ad- ence of positive culture from a genital swab, a com- mission (see above). Bed rest Bed rest after insertion of cerclage is not • Ongoing vaginal bleeding. Serial sonographic surveillance of cervical length Routine • Lethal fetal defect. Potential risks with cervical cerclage Removal of cerclage • Intraoperative bladder damage, cervical trauma, Transvaginal cerclage membrane rupture or bleeding, miscarriage. Transvaginal cerclage (McDonald suture or • Cervical laceration/trauma/uterine rupture Shirodkar suture) should be removed before labor, if there is spontaneous labor with suture in usually between 36 and 37 weeks of gestation un- place. In Cervical cerclage has not been shown to be asso- women presenting with established preterm labor, ciated with an increased risk of PPROM, chorio- the cerclage should be removed to avoid potential amnionitis, induction of labor or cesarean section, trauma to the cervix with progressive dilatation. Shirodkar suture as the technique involves the burial of the suture and manipulation of the cervix Preoperative management is required during removal. Patients should be properly counseled on the potential benefits and risks of the procedure and Transabdominal cerclage written information should be given. It is recom- All women with transabdominal cerclage require mended that an ultrasound scan is performed be- delivery by cesarean section and the abdominal fore insertion of cerclage to confirm the viability suture may be left in place following delivery. There are no published data on the long-term out- In cases of clinical vaginal infection, a wet mount come comparing removing the abdominal cerclage and culture should be done and cervical cerclage or leaving it in place after delivery. In women should be performed after treating with broad- planning for further pregnancies, it is reasonable to spectrum antibiotics. Routine maternal white cell count to detect subclinical chorioamnionitis is not necessary and should not be the reason to delay clinically indi- SUMMARY cated rescue cerclage. Recurrent miscarriage is a devastating event and affects 1% of couples. The healthcare of couples Perioperative care should ideally be managed by someone with a Tocolysis There is no evidence to support the special interest in the area in a sensitive and system- routine use of perioperative tocolysis (e. Mid- competence, APS and APCR are established causes trimester loss: appraisal of screening protocol. Hum Reprod 1998;13:1975–80 of recurrent miscarriage. Lancet 2006; should be targeted and include a pelvic scan (prefer- 368:601–11 ably transvaginal) to screen for uterine abnormali- 7. The importance of careful history taking reproductive performance on risk of spontaneous should not be overlooked, especially in establishing abortion. Prognosis of the diagnosis of cervical incompetence. Eur J Obstet Gynecol Reprod Biol 1991;39:31–6 therapy for women with APS and are associated 9. Mater- with a live birth rate of over 70%, and low-dose nal age and fetal loss: population based register linkage heparin may be beneficial for women with recur- study. Risk rent miscarriage associated with factor V Leiden and factors for spontaneous abortion and its recurrence. Am APCR but is not readily available in many low-re- J Epidemiol 1988;128:420–30 source settings. A longitudinal fer benefits for women with one or more study of pregnancy outcome following idiopathic recur- mid-trimester losses as a result of cervical incompet- rent miscarriage. Cervical length ultrasound screening during women with recurrent spontaneous abortions and pregnancy may be useful in equivocal cases, but in- women with favorable reproductive histories.

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