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INTRODUCTION — This section highlights selected specific new recommendations and/or updates that we anticipate may change usual clinical practice. Practice Changing UpDates focus on changes that may have significant and broad impact on practice, and therefore do not represent all updates that affect practice. These Practice Changing UpDates, reflecting important changes to UpToDate over the past year, are presented chronologically, and are discussed in greater detail in the identified topic reviews.
PSYCHIATRY, ADULT PRIMARY CARE (August 2017)
Management of treatment resistant depression in adults
●For patients with mild to moderate treatment resistant major depression, we suggest augmenting the initial antidepressant with a second drug and/or psychotherapy, rather than other strategies such as switching antidepressants or switching from pharmacotherapy to psychotherapy (Grade 2C).
For patients with treatment resistant depression, there has been little comparative evidence to guide the choice between add-on therapy (augmentation) and switching to a different antidepressant drug. In an open label trial, more than 1500 patients with treatment resistant depression were randomly assigned to one of three treatment strategies: augment the current antidepressant with aripiprazole, augment with bupropion sustained release, or switch to bupropion . At 12 weeks, remission was more likely in the augment-aripiprazole group than the switch group, but the clinical difference was small (29 versus 22 percent). Akathisia, somnolence, weight gain, and laboratory abnormalities were more common with aripiprazole, and anxiety occurred more often in the other groups. Based on these results, we now favor augmentation for managing treatment resistant depression; however, switching remains a reasonable alternative, especially for patients who want to avoid medication side effects. (See "Unipolar depression in adults: Treatment of resistant depression", section on 'Efficacy of augmentation compared with switching'.)
INFECTIOUS DISEASES (August 2017)
Glecaprevir-pibrentasvir and sofosbuvir-velpatasvir-voxilaprevir for chronic HCV infection
●For patients with chronic HCV genotype 1 infection who have not been previously treated with sofosbuvir or an NS5A inhibitor, we suggest ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, or glecaprevir-pibrentasvir (Grade 2B).
For patients with chronic HCV genotype 2 or 3 infection who have not been previously treated with a DAA regimen, we suggest sofosbuvir-velpatasvir or glecaprevir-pibrentasvir (Grade 2B).
Treatment options for patients with chronic hepatitis C virus (HCV) continue to grow. Two new combination therapies, glecaprevir-pibrentasvir and sofosbuvir-velpatasvir-voxilaprevir, were recently approved by the Food and Drug Administration in the United States and are expected to be approved in Europe this year. Glecaprevir-pibrentasvir is highly effective for patients with genotypes 1 through 6 infection, offers the possibility of an eight-week regimen for most patients without cirrhosis, and can be used in patients with renal impairment (including those on dialysis) [2-5]. It is now one of our preferred regimens for all genotypes; regimen duration depends on the genotype, the presence of cirrhosis, and the treatment history (algorithm 1 and algorithm 2 and algorithm 3 and algorithm 4). Sofosbuvir-velpatasvir-voxilaprevir is highly effective in patients with genotypes 1 through 6 infection who have failed a prior direct acting antiviral (DAA) regimen and is now the main treatment option for those who have failed an NS5A inhibitor-containing regimen . Like other contemporary DAA regimens, these new combinations are well tolerated, with common but mild side effects. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Selection of treatment regimens' and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Selection of treatment regimen' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults", section on 'Selection of treatment regimens'.)
HEMATOLOGY, ALLERGY AND IMMUNOLOGY (August 2017)
Midostaurin for advanced systemic mastocytosis
Cytoreductive treatment of advanced systemic mastocytosis (SM) can mitigate organ dysfunction, improve quality of life, and limit disease progression until a suitable donor for allogeneic hematopoietic cell transplant is identified. Midostaurin is a multikinase inhibitor that is effective against SM with wild type or mutant KIT (eg, KIT D816V). A recent phase II study found that midostaurin was associated with improved measures of organ damage (eg, cytopenias, liver function studies) in two-thirds of patients with advanced SM, with median overall survival >3 years , confirming similar findings from an earlier trial . The drug was well tolerated, with primarily grade 1 to 2 nausea/vomiting or modest cytopenias. The US Food and Drug Administration approved midostaurin for treatment of advanced SM earlier this year. We now suggest midostaurin for initial systemic therapy of advanced SM. (See "Systemic mastocytosis: Management and prognosis", section on 'Choice of therapy'.)
HEMATOLOGY (August 2017)
Rituximab in acquired TTP
Acquired thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening condition; standard treatment includes plasma exchange (PEX) and glucocorticoids. The role of additional up-front rituximab in acquired TTP is evolving, as evidence continues to accumulate suggesting that rituximab may reduce the risk of relapse and refractory disease and may hasten initial response. The latest evidence comes from a retrospective study from the United Kingdom TTP Registry, which found low rates of relapse in patients treated with rituximab as part of initial therapy, although patients were only observed for a median of 15 months . Based on this and other studies, we now use rituximab as a component of initial therapy for acquired TTP. Some experts may reasonably omit rituximab due to concerns about toxicity, pending additional data. Other considerations for rituximab use In TTP include the optimal dose, timing relative to PEX, and risk of hepatitis B reactivation. (See "Acquired TTP: Initial treatment", section on 'Rituximab'.)
ONCOLOGY (June 2017)
Management of a positive sentinel lymph node biopsy in patients with cutaneous melanoma
●For patients with cutaneous melanoma and a positive sentinel lymph node biopsy, we suggest clinical observation and ultrasound surveillance of the positive nodal basin rather than immediate completion lymph node dissection (Grade 2B).
Historically, completion dissection of all involved nodal basins was considered the standard treatment approach for patients with cutaneous melanoma and a positive sentinel lymph node biopsy (SLNB). In the phase III Multicenter Selective Lymphadenectomy Trial II (MSLT II), patients with a positive SLNB were randomly assigned to either completion lymph node dissection or observation that included ultrasound evaluation of the appropriate lymph node basins at each follow-up visit . Melanoma-specific survival at three years was the same for both groups, although the incidence of recurrence in regional lymph nodes was higher in patients managed with observation and ultrasound surveillance. The incidence of lymphedema was higher in patients who underwent immediate lymph node dissection. For patients with a positive SLNB, we suggest clinical observation coupled with ultrasound surveillance of the positive nodal basin. Completion lymph node dissection is indicated if, in the absence of distant metastases, there is evidence of regional lymph node recurrence. (See "Evaluation and treatment of regional lymph nodes in melanoma", section on 'Multicenter Selective Lymphadenectomy Trial II'.)
ONCOLOGY (June 2017)
Next-generation ALK-inhibitors in crizotinib-naive ALK-positive NSCLC
●For patients with newly diagnosed ALK-positive NSCLC, we recommend alectinib as first-line treatment (Grade 1B). For those without access to alectinib, appropriate alternatives include crizotinib or ceritinib.
For patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), crizotinib has been administered as frontline therapy. However, newer agents have shown promising efficacy in advanced ALK-positive NSCLC:
●In a global trial of 303 patients randomly assigned to frontline crizotinib versus the next-generation inhibitor alectinib (ALEX), those receiving alectinib experienced a longer progression-free survival (PFS, not reached versus 11.1 months), with fewer toxicities, at a median follow-up of approximately 18 months . These results are consistent with an earlier Japanese trial .
●In a phase III trial of 376 patients comparing ceritinib, another next-generation ALK inhibitor, with pemetrexed and a platinum agent, ceritinib improved progression-free survival (17 versus 8 months) . Ceritinib has not been compared with crizotinib in the frontline setting.
For patients with newly diagnosed, ALK-positive NSCLC, we now recommend frontline therapy with alectinib. For those without access to alectinib, appropriate alternatives include crizotinib or ceritinib. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)
PULMONARY AND CRITICAL CARE MEDICINE (June 2017)
Revised follow-up for a solitary pulmonary nodule
●For patients with an asymptomatic solid or subsolid (pure ground glass or part-solid) solitary pulmonary nodule (SPN) <6 mm, no routine follow-up is required. For patients with solid SPNs that have been stable on serial CT over a two year period, or with subsolid SPNs that have been stable over a five year period, we suggest no further diagnostic testing.
Fleischner Society guidelines have been updated to reflect the accumulating data on the malignancy risk of incidental pulmonary nodules and growth rates of lung cancer . Important changes include guidance on identifying benign nodules with minimal follow-up imaging. For patients with a solid or subsolid (ground glass or part-solid) solitary pulmonary nodule measuring <6 mm, follow-up computed tomography (CT) is optional, but no longer required. A solitary pulmonary nodule that is solid and unchanged on serial CT over a two-year period, or subsolid and unchanged over a five-year period, is likely benign and does not need further diagnostic evaluation. Recommendations in UpToDate have been revised to reflect these new guidelines. (See "Diagnostic evaluation and management of the solitary pulmonary nodule", section on 'Management strategy' and "Diagnostic evaluation and management of the solitary pulmonary nodule", section on 'Solid nodules ≤8 mm'.)
OBSTETRICS, GYNECOLOGY AND WOMEN'S HEALTH (May 2017)
Tranexamic acid for management of postpartum hemorrhage
●For women with postpartum hemorrhage diagnosed within three hours of delivery, we recommend administration of tranexamic acid as a component of overall treatment (Grade 1B). When more than three hours have elapsed since delivery, we still suggest tranexamic acid (Grade 2C), but the benefit of treatment is less clear.
Tranexamic acid, an antifibrinolytic drug, reduces bleeding in surgical and trauma patients. In a pragmatic randomized trial involving over 20,000 women with postpartum hemorrhage in over 20 countries (the World Maternal Antifibrinolytic Randomized Trial [WOMAN]), tranexamic acid, compared with placebo, reduced the relative risk of death due to bleeding by 20 to 30 percent, reduced the incidence of laparotomy to control bleeding, and was not associated with an increase in adverse effects . Overall mortality was not reduced. We now recommend administration of tranexamic acid as a component of the treatment for postpartum hemorrhage.
NEUROLOGY (May 2017)
Edaravone for amyotrophic lateral sclerosis
●For patients with ALS who have a disease duration of two years or less, are living independently, and have an FVC ≥80 percent, we suggest treatment with edaravone (Grade 2B). We also suggest edaravone for patients with more advanced ALS (Grade 2C).
Edaravone is a free radical scavenger that is thought to reduce oxidative stress, which has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Edaravone may slow functional deterioration in some patients with ALS. An earlier trial found no benefit for edaravone compared with placebo, but a post-hoc analysis showed a possible treatment effect in a subgroup of individuals with early-stage ALS. A subsequent trial enrolled 137 Japanese patients within two years of ALS diagnosis who were living independently and had a forced vital capacity (FVC) of ≥80 percent . Compared with placebo, functional decline at 24 weeks was smaller in the edaravone group, and the difference was considered clinically meaningful. Edaravone was approved in 2015 for the treatment of ALS in Japan and Korea and has now received regulatory approval to treat patients with ALS in the United States . We now suggest edaravone for patients with early-stage disease as well as for those with more advanced disease, although the data are less compelling for the latter group. (See "Disease modifying treatment of amyotrophic lateral sclerosis", section on 'Edaravone'.)
HEMATOLOGY (May 2017)
Eltrombopag for adults with acquired severe aplastic anemia unable to undergo HCT
●For adults with acquired severe aplastic anemia who are not candidates for allogeneic hematopoietic cell transplantation, we suggest eltrombopag plus standard immunosuppressive therapy (IST) rather than IST alone (Grade 2C).
Acquired aplastic anemia (AA) has a high morbidity, and allogeneic hematopoietic cell transplantation (HCT) is suggested as therapy for patients healthy enough to tolerate HCT who have a suitable donor. Immunosuppressive therapy (IST) is offered to those for whom HCT is not an option but is often ineffective in improving outcomes over the long term. A prospective cohort study in adults with acquired severe AA evaluated the effectiveness of IST plus eltrombopag, a thrombopoietin receptor agonist that acts on platelet precursors and hematopoietic stem cells . Eltrombopag plus IST produced higher rates of overall hematologic response at six months compared with responses in a historical cohort (80 to 94 percent versus 66 percent for the historical group). Based on these findings, we now suggest administration of eltrombopag plus IST for individuals with acquired severe AA who are not candidates for allogeneic HCT. (See "Treatment of aplastic anemia in adults", section on 'Evidence for efficacy'.)
NEUROLOGY (April 2017)
Ocrelizumab for primary progressive multiple sclerosis
Ocrelizumab is the first drug to reduce the risk of disability progression among patients with primary progressive multiple sclerosis (PPMS), as shown by the multicenter ORATORIO randomized trial . Compared with placebo, ocrelizumab modestly reduced the proportion of patients with disability progression at 24 weeks (30 versus 36 percent). In addition, ocrelizumab slowed deterioration from baseline to week 120 on the timed 25-foot walk and led to improvements on other endpoints. While the long-term risks of infection and neoplasm with ocrelizumab are uncertain, there are no other disease-modifying therapies for PPMS. Therefore, we suggest treatment with ocrelizumab for most patients with PPMS. Ocrelizumab has also been approved by the US Food and Drug Administration for use in relapsing-remitting MS (RRMS), although its role in the early treatment of this form of the disease remains to be determined. (See "Treatment of progressive multiple sclerosis in adults", section on 'Ocrelizumab'.)
ONCOLOGY (March 2017)
Scalp hypothermia to prevent chemotherapy-induced alopecia
●For women with breast cancer who are receiving chemotherapy that is expected to result in significant alopecia, and who place a high value on avoiding chemotherapy-induced alopecia, we suggest the use of a scalp cooling device (Grade 2A). Scalp hypothermia could also be discussed as a potential option for patients with other solid tumors who are receiving chemotherapy that is expected to result in significant alopecia, although the evidence base is less robust.
Two prospective studies have evaluated the efficacy of two different automated scalp cooling devices in women with early stage breast cancer [20,21]:
●In an interim analysis of a randomized trial comparing the Paxman Scalp Cooling device and no scalp hypothermia for women with breast cancer receiving adjuvant chemotherapy (one-third anthracycline-based, the remainder taxane-based), one-half of the hypothermia group had limited hair loss (to less than 50 percent, not requiring a wig) compared with none in the control group . Adverse events were all grade 1 and 2, including primarily headache and feeling cold. The success rate was higher with taxane-containing regimens.
●In a multicenter prospective cohort study, 101 patients receiving non-anthracycline taxane-based chemotherapy and who used the DigniCap Scalp Cooling device were compared with 16 concurrently treated controls who did not use the device . Two-thirds of the intervention group, compared with none of the control group, had limited hair loss (to less than 50 percent) one month after the end of chemotherapy. At a median follow-up of 2.5 years, no patient developed scalp metastases.
These results confirm prior studies on the efficacy and safety of scalp hypothermia to reduce chemotherapy-related hair loss. The FDA approved one device (DigniCap) for patients with breast cancer in December 2015 and expanded the approval to cover all solid tumors in July 2017. (See "Chemotherapy-induced alopecia", section on 'Efficacy and safety'.)
ALLERGY AND IMMUNOLOGY (February 2017)
Immunotherapy for stinging insect hypersensitivity in adults
●We suggest not giving venom immunotherapy (VIT) to patients with reactions to stinging insects limited to cutaneous systemic symptoms and not involving other organ systems (Grade 2C). However, VIT is effective in reducing the severity of future reactions and may still be offered in selected situations.
Venom immunotherapy (VIT) for the treatment of patients with anaphylactic reactions to stings of Hymenoptera insects (eg, bees, yellow jackets, wasps, hornets, and fire ants) is highly effective in preventing future anaphylactic reactions. However, in an updated practice parameter from the American Joint Task Force, VIT is no longer suggested for adults with systemic reactions limited to the skin (ie, generalized erythema, pruritus, urticaria, or angioedema) as studies suggest these patients are at low risk for serious future systemic reactions . This change brings the American approach into closer alignment with guidelines of other countries and is similar to the existing recommendation for children. Despite this revision, VIT may be appropriate for certain adults with cutaneous systemic reactions (eg, those with underlying medical conditions or medications that could affect the outcome of a systemic reaction, frequent unavoidable exposure to Hymenoptera, or impaired quality of life due to fear of future stings). (See "Hymenoptera venom immunotherapy: Efficacy, indications, and mechanism of action", section on 'Patients with past cutaneous systemic reactions'.)
INFECTIOUS DISEASES (December 2016)
Tenofovir alafenamide for the treatment of chronic hepatitis B virus infection
●For most patients with chronic HBV infection who initiate therapy with tenofovir, we recommend tenofovir alafenamide rather than tenofovir disoproxil fumarate (tenofovir DF) (Grade 1B). We also suggest that those initially started on tenofovir DF switch to tenofovir alafenamide (Grade 2B).
Tenofovir disoproxil fumarate is a first-line therapy for chronic hepatitis B virus (HBV) infection. A newer formulation of tenofovir, tenofovir alafenamide, was approved by the US Food and Drug Administration in November 2016 for the treatment of chronic HBV in patients with compensated liver disease . In two large randomized noninferiority trials among patients with chronic HBV infection (both treatment-naive and experienced, and including patients positive or negative for HBV e antigen), tenofovir alafenamide resulted in similar rates of HBV suppression and fewer adverse effects on renal function and bone density at 48 weeks compared with tenofovir disoproxil fumarate [24,25]. Given these findings, tenofovir alafenamide is our preferred formulation for patients with chronic HBV who initiate therapy with tenofovir. We also favor switching those initially started on tenofovir disoproxil fumarate to tenofovir alafenamide. Given limited available safety data, we do not currently use tenofovir alafenamide in pregnant women. (See "Hepatitis B virus: Overview of management", section on 'Nucleos(t)ide analogues'.)
INFECTIOUS DISEASES, PEDIATRICS, ADULT PRIMARY CARE, FAMILY MEDICINE (November 2016)
Meningococcal conjugate vaccination for HIV-infected patients
●For all HIV-infected individuals older than two months, we suggest meningococcal conjugate vaccination (Menactra or Menveo) (Grade 2C).
Growing evidence has suggested that HIV-infected individuals have a disproportionate incidence of invasive meningococcal disease, with an estimated risk 5 to 13 times that of the general population. Because of this, the Centers for Disease Control and Prevention in the United States now recommends meningococcal conjugate vaccination (with MenACWY-CRM [Menveo] or MenACWY-D [Menactra]) for all HIV-infected individuals older than two months . This includes a primary vaccine series for those who have not previously received it and interval booster doses every several years; the precise schedule depends on the age of the patient (table 1). Individuals may also have separate indications for serogroup B meningococcal vaccination. Evidence of vaccine efficacy in HIV-infected patients is limited to immunologic outcomes. (See "Meningococcal vaccines".)
INFECTIOUS DISEASES (November 2016)
HPV vaccine dosing for individuals younger than 15 years
●For individuals younger than 15 years, we advise administration of human papillomavirus (HPV) vaccine in two doses separated by six months. Those 15 years and older should continue to receive a three-dose vaccine series.
For individuals younger than 15 years receiving human papillomavirus (HPV) vaccination, two vaccine doses administered at least six months apart are now recommended by the Centers for Disease Control and Prevention in the United States . This new vaccine schedule is similar to schedules used in other countries and is supported by data demonstrating that two vaccine doses in young females have similar immunogenicity to three doses. However, the efficacy of fewer than three doses for prevention of cervical neoplastic disease has not been directly established. Three doses are still recommended for individuals older than 15 years because they have lower immunologic responses to HPV vaccination.
PULMONARY AND CRITICAL CARE MEDICINE (October 2016)
Mycophenolate mofetil for scleroderma lung disease
●For patients with systemic sclerosis who have respiratory symptoms, abnormal and/or declining pulmonary function, imaging evidence of interstitial lung disease, and no active infection, we suggest initiating treatment with mycophenolate mofetil (MMF) (Grade 2B).
Cyclophosphamide has been the suggested treatment for moderate-to-severe interstitial lung disease complicating systemic sclerosis (SSc-ILD) but has well-known toxicity. A recent randomized trial compared mycophenolate mofetil (MMF) with oral cyclophosphamide in 142 patients with SSc-ILD, exertional dyspnea, and features of progressive disease . Pulmonary function and dyspnea improved in both groups, without a significant difference between groups. MMF was better tolerated than cyclophosphamide based on a longer time to patient withdrawal and lower incidence of leukopenia and thrombocytopenia. We now suggest initiating treatment for symptomatic progressive SSc-ILD with mycophenolate, rather than cyclophosphamide, due to comparable efficacy, better safety profile, and the option for longer-term therapy. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Choice of an agent'.)
ONCOLOGY (October 2016)
Pembrolizumab in treatment-naïve advanced non-small cell lung cancer
●For patients with treatment-naïve advanced non-small cell lung cancer that lacks EGFR or ALK genetic aberrations and expresses PD-L1 in at least 50 percent of tumor cells, we recommend pembrolizumab for initial therapy (Grade 1B).
Immunotherapy for patients with advanced non-small cell lung cancer (NSCLC) that lacks a driver mutation has shown promising results in the frontline setting:
●In a phase III trial enrolling over 300 such patients whose tumors expressed programmed death ligand 1 (PD-L1) on at least 50 percent of tumor cells, pembrolizumab monotherapy improved progression-free survival, overall survival, and objective response rate compared with standard platinum-doublet chemotherapy . It was also associated with lower treatment-related adverse effects.
●In a randomized phase II trial of 123 patients with PD-L1 unselected advanced nonsquamous NSCLC, the addition of pembrolizumab to carboplatin and pemetrexed improved objective response rate (55 versus 29 percent, respectively) and progression-free survival (13 versus 6 months, respectively) relative to chemotherapy alone .
These data have led to approval by the US Food and Drug Administration (FDA) of pembrolizumab in the frontline setting for patients with advanced NSCLC lacking a driver mutation as monotherapy if PD-L1 is expressed on at least 50 percent of cells. More recently it has been approved in nonsquamous advanced NSCLC, in combination with carboplatin and pemetrexed, irrespective of PD-L1 levels. This regimen has not been compared, however, with platinum-based combinations incorporating concurrent and maintenance bevacizumab, which remains another option for such patients. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'First-line setting'.)
HEMATOLOGY (October 2016, Modified October 2016)
Daratumumab-based regimens in relapsed multiple myeloma
●Subject to availability, we recommend a daratumumab-based regimen for the treatment of first relapse in myeloma (Grade 1B).
Two recent multicenter randomized trials including over 1000 patients have demonstrated large improvements in progression-free survival (PFS) when the anti-CD38 monoclonal antibody daratumumab is added to standard regimens in relapsed multiple myeloma. The addition of daratumumab to either lenalidomide plus dexamethasone (POLLUX trial) or to bortezomib plus dexamethasone (CASTOR trial) resulted in substantially improved response rates and PFS with a mild to moderate increase in toxicity [31,32]. Mostly mild infusion reactions were common with the first infusion, but rarely resulted in drug discontinuation. Overall survival data are not yet mature. Based on these results we now recommend a daratumumab-based regimen for the treatment of first relapse in myeloma. (See "Treatment of relapsed or refractory multiple myeloma", section on 'Daratumumab'.)
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