INTRODUCTION — This section highlights specific new recommendations and/or updates that we anticipate may change usual clinical practice. These concepts, reflecting changes to UpToDate over the past year, are presented chronologically, and are discussed in greater detail in the identified topic reviews.
INFECTIOUS DISEASES (MAY 2012)
Initiating treatment for HIV infection — Guidelines from the United States Department of Health and Human Services have been revised to recommend treatment of all patients with HIV infection regardless of CD4 T cell counts. For patients with a CD4 cell count >500/mm3, who are motivated to be treated, we suggest initiation of antiretroviral therapy (Grade 2C).
- The expert panel of the United States Department of Health and Human Services (DHHS) issued a major change in the previously-issued HIV treatment guidelines; antiretroviral therapy (ART) is now recommended in all HIV-infected patients, regardless of CD4 cell counts [1]. Supportive arguments for this significant shift in treatment recommendations include the availability of more potent agents with less toxicity and recognition that untreated HIV infection has been associated with increased morbidity and mortality related to complications including cardiovascular, kidney, and liver disease and malignancy. Additionally, earlier therapy may lead to a more robust immunologic recovery compared with deferred therapy, and suppressive ART decreases the risk of sexual transmission and thereby provides a potential public health benefit.
Previously, we had recommended initiating ART for patients with a CD4 cell count between 350 and 500 cells/mm3, based on clinical trial data supporting a benefit in reducing AIDS- and non-AIDS-related complications and potential mortality-risk reduction. There is less robust evidence for the benefits of treatment at earlier stages of HIV infection, and a clinical trial is in progress. (See "When to initiate antiretroviral therapy in HIV-infected patients".)
ADULT PRIMARY CARE/FAMILY MEDICINE (MAY 2012)
Treatment of acute bacterial rhinosinusitis — We recommend treatment with an antibiotic for patients whose clinical symptoms meet criteria for acute bacterial rhinosinusitis (ABRS) (Grade 1B). In light of increasing microbial resistance to antibiotics, we suggest initial empiric treatment with amoxicillin-clavulanate rather than macrolides (clarithromycin or azithromycin), trimethoprim-sulfamethoxazole, or oral second- or third-generation cephalosporins (Grade 2B).
- Guidelines for the treatment of acute bacterial rhinosinusitis (ABRS) have been released from the Infectious Disease Society of American (IDSA) [2]. Although it is difficult to distinguish viral from bacterial acute rhinosinusitis (ARS), three features suggest the diagnosis of ABRS: 1) persistent symptoms or signs of ARS lasting 10 or more days with no clinical improvement; 2) onset with severe symptoms (fever >39°C or 102°F and purulent nasal discharge or facial pain) lasting at least three consecutive days at the beginning of illness; or 3) onset with worsening symptoms following a viral upper respiratory infection that lasted five to six days and was initially improving. Patients who meet criteria for ABRS should be treated with an antibiotic.
In light of increasing microbial resistance, we no longer recommend treatment with amoxicillin, trimethoprim-sulfamethoxazole or a macrolide as initial therapy for ABRS. We agree with the new guidelines in advising an empiric course of amoxicillin-clavulanate (500 mg/125 mg orally three times daily or 875 mg/125 mg orally twice daily) for five to seven days for most patients; doxycycline is a reasonable alternative. Doxycycline or a respiratory fluoroquinolone may be used in patients with penicillin allergy. Because of high rates of microbial resistance, macrolides (clarithromycin or azithromycin), trimethoprim-sulfamethoxazole, or oral second- or third-generation cephalosporins should not be used for empiric treatment.
Symptomatic therapy for acute rhinosinusitis, whether viral or bacterial, includes mild analgesics, saline nasal irrigation, and intranasal glucocorticoids. (See "Acute sinusitis and rhinosinusitis in adults: Treatment", section on 'Community-acquired acute bacterial rhinosinusitis'.)
ONCOLOGY (APRIL 2012)
Pazopanib for advanced soft tissue sarcoma — For patients with advanced or metastatic soft tissue sarcoma (other than liposarcoma or gastrointestinal stromal tumor [GIST]) who progress after an anthracycline-containing regimen, we recommend pazopanib (Grade 1A).
- Pazopanib is an orally active small molecule inhibitor of several tyrosine kinases, including the vascular endothelial growth factor receptor (VEGFR). The randomized phase III PALETTE trial compared pazopanib (800 mg daily) versus placebo in 369 patients with sarcomas of multiple histologic subtypes (but not including liposarcoma or gastrointestinal stromal tumor [GIST]) whose disease had progressed during or after first-line chemotherapy (including an anthracycline). In a preliminary report, the trial demonstrated significantly improved progression-free survival with pazopanib, with benefit consistent across all histologic subtypes that were studied [3].
In April 2012, pazopanib was approved by the US Food and Drug Administration for treatment of advanced soft tissue sarcoma in patients who have received prior anthracycline-containing chemotherapy. (See "Systemic treatment of metastatic soft tissue sarcoma", section on 'Pazopanib'.)
PRIMARY CARE/GYNECOLOGY/GERIATRICS (APRIL 2012)
Screening for cervical cancer — We recommend that women aged 21 to 65 years who have a cervix receive screening for cervical cancer (Grade 1A). We suggest Pap smear screening at intervals of every three years for average-risk women aged 21 through 29 years (Grade 2C). For average-risk women aged 30 to 65 years, we suggest either Pap smear screening every three years, or a combination of Pap smear and HPV testing every five years, if both initial tests are negative (Grade 2C).
- New guidelines for screening for cervical cancer have been issued by the U.S. Preventive Services Task Force (USPSTF) [4] and by a combined group representing the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology (ACS/ASCCP/ASCP) [5]. The two sets of guidelines, developed independently, overlap in their major recommendations (table 1). The American College of Obstetricians and Gynecologists (ACOG) is currently reviewing guidelines they last issued in 2009, and ACOG members were involved in the development of the ACS/ASCCP/ASCP guidelines [6]. The two new guidelines advise initiating cervical cancer screening for average-risk women at age 21 and discontinuing screening at age 65 for women who have had adequate negative prior screening. Average-risk women have no history of cervical cancer, DES in utero exposure, or significant immunocompromise (such as HIV infection). Women aged 21 to 29 should be screened every three years with Pap test (cytology) only, and women aged 30 to 65 should be screened by either cytology alone every three years, or co-testing (HPV test plus cytology) every five years. The ACS/ASCCP/ASCP prefers the co-testing strategy, while the USPSTF suggests co-testing as an alternative for those women who wish to lengthen their screening interval while accepting an increased risk that colposcopy would be needed. All guidelines advise that cervical cancer screening is not indicated for women who have had a hysterectomy, in the absence of a history of cervical cancer or high grade cervical cancer precursor.
There are no randomized trials comparing different screening intervals, and the decision to lengthen the interval for screening is based largely upon modeling studies. These studies indicate that screening with cytology every three years and screening with a combination of cytology and HPV testing every five years are equally effective in identifying cervical cancer in women greater than age 30. Furthermore, the longer screening intervals now suggested, compared with annual or biannual screening, have only a marginal impact on the predicted lifetime cancer risk while greatly decreasing the risk of harms associated with screening, including need for colposcopy. (See "Screening for cervical cancer: Rationale and recommendations", section on 'Recommendations of professional organizations' and "Screening for cervical cancer: Rationale and recommendations", section on 'Screening frequency'.)
GASTROENTEROLOGY/PRIMARY CARE/GERIATRICS (MARCH 2012)
Treatment for constipation — In patients over the age of 70 years being treated with enemas for constipation, we suggest that patients receive warm water enemas rather than sodium phosphate enemas (Grade 2C).
- Constipation is a common complaint in older adults and one commonly used treatment is sodium phosphate enemas. However, there is evidence that the use of sodium phosphate enemas may be associated with serious adverse events. In a retrospective series, the use of sodium phosphate enemas in older adults (mean age 80 years, only one of whom was younger than age 70 years) for the treatment of constipation was associated with complications including hypotension and volume depletion, hyperphosphatemia, hypo- or hyperkalemia, metabolic acidosis, severe hypocalcemia, renal failure, and EKG changes (prolonged QT interval) [7]. Therefore, we suggest alternative management for constipation in adults over 70 years of age.
The preparation for flexible sigmoidoscopy also typically involves sodium phosphate enemas. In patients over the age of 70 years undergoing preparation for flexible sigmoidoscopy, the risks of sodium phosphate enemas must be weighed against the risks of oral preparations (eg, polyethylene glycol lavage or magnesium citrate) for each individual patient before deciding upon an appropriate preparation. (See "Constipation in the older adult", section on 'Stool softeners, suppositories, and enemas' and "Bowel preparation for flexible sigmoidoscopy and colonoscopy", section on 'Preparation for flexible sigmoidoscopy'.)
ENDOCRINOLOGY/PRIMARY CARE/GERIATRICS (MARCH 2012)
Repeat screening for bone mineral density — In women 65 years of age and older with normal or slightly low bone mass (T-score -1.01 to -1.49) at baseline measurement and no risk factors for accelerated bone loss, we suggest follow-up dual-energy x-ray absorptiometry (DXA) in 10 to 15 years (Grade 2C).
- Data regarding the frequency of follow-up bone mineral density (BMD) testing in women who have had an initial screening test are limited. The goal of follow-up testing is to detect low bone density before a major fracture occurs. Whether the rate of BMD loss is an independent risk factor for fracture has been uncertain. In a retrospective cohort study using a database of all clinical BMD results from Manitoba, Canada, 146 women sustained one or more osteoporotic fractures after the second BMD test [8]. The annualized percentage change in BMD did not differ in women who did and did not sustain major osteoporotic fractures.
In an analysis of data from the Study of Osteoporotic Fractures (SOF), 4957 women (67 years and older) who did not have osteoporosis at baseline testing were followed for up to 15 years [9]. The interval for 10 percent of participants to make the transition from normal BMD or osteopenia at baseline to osteoporosis (before a hip or clinical vertebral fracture occurred and before initiation of osteoporosis treatment) was estimated. For women with normal (T-score -1.0 or better) or slightly low (T-score -1.01 to -1.49) bone mass at baseline, the interval between baseline testing and the development of osteoporosis was approximately 17 years.
These data suggest that healthy women 65 years of age and older at baseline screening, with normal or slightly low bone mass (T-score -1.01 to -1.49), and with no risk factors for accelerated bone loss, do not require repeat testing for 17 years. These results are not applicable to women with osteoporosis (T-scores below -2.5) at baseline, women already receiving osteoporosis treatment, or women younger than 65 years of age at time of first bone density screening. Women younger than 65 years of age with clinical risk factors for fracture (table 2) may require more frequent monitoring of bone density, depending upon risk factors.
Repeat BMD measurements may be most valuable for individual patients on therapy or to document stability of bone density in untreated patients with underlying clinical factors that might lead to accelerated bone loss. (See "Screening for osteoporosis", section on 'Repeat BMD measurements'.)
PRIMARY CARE/CARDIOVASCULAR MEDICINE (FEBRUARY 2012)
Monitoring liver function tests for statin therapy — We suggest checking baseline aminotransferase levels prior to initiating statin therapy; routine monitoring of these levels is not necessary for patients on statins.
- The US Food and Drug Administration (FDA) had previously recommended liver function testing following the initiation of statins and periodically thereafter. In 2012, the FDA revised its labeling information on statins to only recommend liver function testing prior to initiation of statin therapy and to only repeat such testing for clinical indications [10]. We agree that routine monitoring of liver function tests in patients receiving statin therapy is not necessary. (See "Statins: Actions, side effects, and administration", section on 'Hepatic dysfunction'.)
PEDIATRICS (FEBRUARY 2012)
Ivacaftor for cystic fibrosis — For all patients with cystic fibrosis who carry at least one copy of the G551D mutation and are six years of age or older, we recommend treatment with ivacaftor (Grade 1A).
- Ivacaftor (VX-770) is the first approved cystic fibrosis (CF) therapy that restores the functioning of a mutant CF protein. The drug was specifically developed to overcome the functional defect caused by the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The G551D mutation, which is present in approximately 5 percent of individuals with cystic fibrosis, interferes with activation of the CFTR chloride channel. All individuals with CF should undergo genotyping to determine whether they carry the G551D mutation, if their CFTR genotype is not already known.
The magnitude and breadth of ivacaftor’s beneficial effects significantly exceed those of any other treatment currently available for CF [11]. In a phase 3 multicenter randomized trial of subjects 12 years of age or older with a G551D mutation, ivacaftor for 24 weeks improved mean FEV1 [12]. The beneficial effect was maintained through 48 weeks of ivacaftor treatment. Ivacaftor also decreased sweat chloride values compared with that in the placebo group, bringing the mean value in the ivacaftor group slightly below the cutoff point of 60 mmol/L that is used for diagnosing cystic fibrosis. Finally, treatment with ivacaftor reduced the frequency of pulmonary exacerbations, improved pulmonary symptoms, and resulted in a significant weight gain of 2.7 kg.
Ivacaftor is given at a dose of 150 mg by mouth every 12 hours with fat-containing foods. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'CFTR modulators'.)
INFECTIOUS DISEASE (DECEMBER 2011)
Treatment for latent tuberculosis — For treatment of latent tuberculosis infection (LTBI) in HIV-negative adults we suggest three months of weekly isoniazid and rifapentine (given by direct observation) (table 3) (Grade 2B).
- A three month regimen of weekly isoniazid (INH) and rifapentine (RPT) given as directly observed therapy has been shown to be noninferior to a nine month self-administered regimen of daily isoniazid in a randomized, open label trial [13]. The trial from four countries included 7731 predominantly HIV-negative individuals at high risk for progression from latent tuberculosis infection (LTBI) to active infection with 33 months of followup. The cumulative rate of tuberculosis was 0.19 percent for the combination therapy group compared with 0.43 percent for the INH monotherapy group. Hepatoxicity occurred more frequently in the INH group while hypersensitivity was more frequent in the combination therapy group. The completion rate was higher for the combination therapy group (82 percent compared to 69 percent). This was at least partially attributable to the administration of combination therapy via directly observed therapy (DOT), while isoniazid monotherapy was administered without DOT. Higher completion rates with DOT may also explain some of the difference in efficacy of the two regimens.
The Centers for Disease Control and Prevention (CDC) recommends either the three month regimen of isoniazid and rifapentine (directly observed therapy) or the nine month regimen of isoniazid as equal alternatives for treatment of LTBI in otherwise healthy patients aged ≥12 years with risk for TB reactivation [14]. We favor the three month regimen of INH-RPT for treatment of LTBI in adults when directly observed therapy is feasible, given its noninferiority to INH and the higher treatment completion rate (table 3).
Rifapentine is a rifamycin derivative with a long half-life and greater potency against M. tuberculosis than rifampin. Important drug interactions with rifamycins, including with warfarin, oral contraceptives, methadone, and the protease-inhibitor class of antiretroviral drugs, should be taken into account when selecting a regimen. (See "Treatment of latent tuberculosis infection in HIV-negative adults", section on 'Treatment regimens' and "Treatment of latent tuberculosis infection in HIV-negative adults", section on 'Selecting a regimen'.)
PEDIATRICS (OCTOBER 2011)
Voiding cystourethrogram following febrile urinary tract infection — In contrast to earlier suggestions for evaluation after an initial episode, we now suggest voiding cystourethrogram (VCUG) to evaluate possible vesicoureteral reflux (VUR) for children of any age with ≥2 febrile urinary tract infections (UTIs) or a first febrile UTI and any of the following: a family history of renal or urologic disease; poor growth; hypertension; or a non-E. coli organism.
- The utility of the routine voiding cystourethrogram (VCUG) in the evaluation of children with UTI has been questioned due to changes in the view of the role of vesicoureteral reflux (VUR) in the development of progressive kidney disease and uncertainty of the effectiveness of medical or surgical management of VUR in reducing the risk of renal scarring.
In contrast to the 1999 guidelines, the 2011 American Academy of Pediatrics (AAP) clinical practice guideline no longer recommends routine VCUG for infants and young children 2 to 24 months of age after the first febrile UTI [15]. According to the guideline, the benefit of avoiding radiation exposure and discomfort in the majority of patients outweighs delayed detection of a small number of cases of high-grade reflux or surgically correctible abnormalities. However, the guideline acknowledges that parent preferences may play a role in the decision to perform VCUG.
Pending results of an ongoing randomized trial comparing trimethoprim-sulfamethoxazole prophylaxis and placebo in children two months to six years with grade I to IV VUR following UTI, we suggest VCUG to evaluate possible VUR for:
- Children of any age with two or more febrile UTIs
- Children of any age with a first febrile UTI who have a family history of renal or urologic disease; poor growth; hypertension; or non-E. coli organism. Urinary tract anomalies are more frequent among children with UTI caused by pathogens other than E. coli.
(See "Acute management, imaging, and prognosis of urinary tract infections in infants and children older than one month", section on 'Voiding cystourethrogram'.)
PEDIATRICS/INFECTIOUS DISEASE (OCTOBER 2011)
Acyclovir suppression for neonatal herpes simplex virus — We suggest oral acyclovir suppressive therapy for six months immediately following parenteral acyclovir for neonatal herpes simplex virus (HSV) disease, including skin, eye, and mouth disease; central nervous system disease; and disseminated HSV disease (Grade 2B).
- Neurodevelopmental problems and cutaneous recurrence are common among survivors of neonatal herpes simplex virus (HSV) infection. Approximately 30 percent of survivors of neonatal central nervous system (CNS) HSV have normal neurologic development, and 50 percent of infants who survive neonatal HSV disease have cutaneous recurrence. A multicenter randomized trial demonstrated improved neurodevelopmental outcomes and/or delayed cutaneous recurrence among infants who received six months of oral acyclovir suppression after completion of parenteral acyclovir therapy for neonatal HSV [16].
We suggest oral acyclovir suppression therapy (300 mg/m2 per dose three times per day for six months) for infants with neonatal HSV, whether it is disseminated, involves the CNS, or is localized to the skin, eyes, and mouth. Adverse effects of oral acyclovir suppression may include dose-dependent reversible neutropenia (in one-half to two-thirds of infants in previous studies) and emergence of HSV mutants that are acyclovir resistant. (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Suppressive therapy'.)
CARDIOVASCULAR MEDICINE (OCTOBER 2011)
Antithrombotic therapy for patients with atrial fibrillation — In patients with atrial fibrillation for whom anticoagulant therapy is chosen, we recommend an oral direct thrombin inhibitor or a factor Xa inhibitor rather than warfarin (Grade 1B).
- The randomized RE-LY trial, published in 2009, demonstrated that dabigatran 150 mg twice daily was more effective for stroke prevention than adjusted-dose warfarin in patients with atrial fibrillation [17]. In the fall of 2010, the US Food and Drug Administration (FDA) and Health Canada approved the use of dabigatran for patients with atrial fibrillation who are at risk for stroke. Apixaban and rivaroxaban are two newer oral anticoagulants that also do not require laboratory monitoring. In two randomized trials (ARISTOTLE and ROCKET-AF), apixaban and rivaroxaban separately met the criteria for non-inferiority to warfarin for the lowering of the risk of stroke and systemic embolization [18,19]. Based upon these three trials, we recommend a direct thrombin inhibitor or a factor Xa inhibitor rather than warfarin in patients with atrial fibrillation who require anticoagulation.
Although these three randomized trials with the newer anticoagulants (dabigatran, rivaroxaban, or apixaban) have found similar or superior efficacy compared with warfarin, we currently prefer dabigatran (compared with either rivaroxaban or apixaban) based upon uncertainties around reimbursement and pending review of further data by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
Warfarin is a reasonable choice for patients who are already taking it and whose international normalized ratio (INR) is relatively easy to keep within the therapeutic range, for those who are not likely to comply with the twice daily dosing of dabigatran or apixaban and for whom rivaroxaban is not available, for those for whom the cost of medication is an important consideration, and for patients with a creatinine clearance less than 30 mL/min. (See "Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation", section on 'Direct thrombin and factor Xa inhibitors'.)
ALLERGY AND IMMUNOLOGY/INFECTIOUS DISEASE/PEDIATRICS/PRIMARY CARE (OCTOBER 2011)
Influenza vaccination in patients with egg allergy — For the patient who is six months of age or older and has known egg allergy of any severity, we suggest administration of an age-appropriate, approved trivalent inactivated influenza vaccine (TIV) in a single dose followed by a 30-minute observation period in a facility prepared to recognize and treat anaphylaxis (Grade 2C).
- Many patients with egg allergy are at increased risk of influenza complications, including young children and those with a history of asthma or wheezing, and therefore would benefit from vaccination. Data suggest that the trivalent inactivated influenza vaccine (TIV) is safe in individuals with egg allergy [20-22]. Thus, the American Academy of Pediatrics (AAP), the United States Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP), and the National Institute of Allergy and Infectious Diseases (NIAID) in the United States have removed the relative contraindication to administration of the inactivated influenza vaccine in patients with egg allergy [23-25]. Beginning with the 2011-2012 influenza season, these organizations specifically recommend that patients with egg allergy receive TIV with some precautions. The vaccine package inserts, which were approved prior to these changes, still contain the contraindication, although some list only severe egg allergy as a contraindication to receiving the influenza vaccine. The live-attenuated influenza vaccine (LAIV) is not recommended in patients with egg allergy because its safety in such patients has not been evaluated.
Skin testing with influenza vaccine prior to administration and two-step graded challenges are no longer recommended for patients with egg allergy. Individuals with a history of a reaction no more severe than hives after egg ingestion can receive TIV at their primary care provider’s office. Individuals with a history of more severe reactions suggesting anaphylaxis (including angioedema or cardiovascular, respiratory, or gastrointestinal symptoms) after egg ingestion should be referred to an allergy specialist to receive TIV. Any provider who administers TIV to an individual with egg allergy must have the personnel, medications, and resuscitative equipment available to treat potential anaphylaxis. In addition, the patient must be observed for 30 minutes after the vaccination to monitor for signs or symptoms of such a reaction. (See "Influenza vaccination in individuals with egg allergy", section on 'Administration protocols'.)
ONCOLOGY (SEPTEMBER 2011)
Immunotherapy and molecularly targeted therapy for metastatic melanoma — For patients with metastatic melanoma whose tumor does not contain the V600 mutation in BRAF and who will not be treated with interleukin-2, we recommend treatment with ipilimumab rather than cytotoxic chemotherapy (Grade 1A). For patients with metastatic melanoma that contains an activating mutation at the V600 site in BRAF, we suggest treatment with vemurafenib rather than ipilimumab in those cases where a prompt response to treatment is desirable due to symptoms or the presence of bulky disease, or when there is a contraindication to ipilimumab therapy (Grade 2C).
- Ipilimumab is a monoclonal antibody directed at the CTLA-4 receptor, and vemurafenib is a potent inhibitor of the tyrosine kinase domain of the mutated BRAF oncogene, which is a component of the mitogen-activated protein (MAP) kinase pathway. Activating mutations in BRAF are present in 40 to 60 percent of metastatic cutaneous melanomas.
The treatment of metastatic melanoma depends upon multiple factors including the overall condition of the patient (eg, age and comorbidity), a molecular analysis for the presence of a V600 mutation in the BRAF gene, and the extent of metastatic disease. There are no randomized trials that compare approaches with immunotherapy and molecularly targeted therapy, and there are no data on the appropriate sequencing of these therapies. A phase III trial of 675 patients with the mutated BRAF oncogene and advanced melanoma demonstrated increased six-month survival for patients assigned to vemurafenib compared with dacarbazine [26]. In a phase III trial of 676 patients with metastatic melanoma treated with ipilimumab, immune-related adverse events occurred in approximately 60 percent of patients treated with ipilimumab; these typically did not occur until several weeks into therapy. Overall, severe or life-threatening (grade 3 or 4) toxicity was seen in 10 to 15 percent of ipilimumab-treated patients [27,28]. (See "Anti-CTLA-4 immunotherapy in advanced melanoma" and "Molecularly targeted therapy for metastatic melanoma", section on 'Vemurafenib'.)
Immunotherapy with high-dose interleukin-2 (IL-2) is associated with prolonged survival in a minority of carefully selected patients and may result in cure, but is associated with severe multiorgan toxicity. Treatment with high-dose IL-2 treatment is limited to patients with excellent organ function who are treated by experienced clinicians in specialized programs capable of providing the necessary intensive care.
Ipilimumab was approved by the US Food and Drug Administration on March 26, 2011 for use in patients with metastatic or unresectable melanoma. Vemurafenib was approved by the US Food and Drug Administration in August 2011 for use in patients whose tumors contain the V600E mutation in BRAF [29]. (See "Molecularly targeted therapy for metastatic melanoma", section on 'Choice of therapy for disseminated disease'.)
CARDIOVASCULAR MEDICINE (SEPTEMBER 2011)
Limited indications for nesiritide in acute heart failure — For most patients hospitalized with acute heart failure (HF), we recommend not treating with nesiritide (Grade 1A).
- Multiple modalities are used in the treatment of acute decompensated heart failure (HF), including oxygen, diuretics, vasodilators, and, in selected patients, inotropic agents. Nesiritide (recombinant human brain natriuretic peptide, BNP 1-32) is a vasodilator that has undergone clinical trials in patients with acute HF.
While earlier trails found that nesiritide acutely reduced pulmonary capillary wedge pressure and dyspnea in patients with acute HF, the largest randomized trial, ASCEND-HF, found that nesiritide increased rates of hypotension, did not alter rates of death or rehospitalization at 30 days, and showed a borderline significant trend toward reducing dyspnea [30]. There was no change in risk of worsening renal function.
For most patients hospitalized with acute heart failure (HF), we recommend not treating with nesiritide. In carefully selected patients with appropriate hemodynamics (without hypotension or cardiogenic shock) who remain symptomatic despite routine therapy, a trial of nesiritide may be helpful as an alternative to other vasodilator therapy (nitroglycerin or nitroprusside). Nesiritide has a longer effective half-life than nitroglycerin or nitroprusside, so side effects such as hypotension may persist longer. (See "Treatment of acute decompensated heart failure: Components of therapy", section on 'Nesiritide'.)
ONCOLOGY (SEPTEMBER 2011)
Crizotinib for ALK fusion oncogene positive non-small cell lung cancer — For patients with advanced or metastatic non-small cell lung cancer whose tumors contain a characteristic ALK fusion oncogene, we recommend treatment with crizotinib (Grade 1B).
- The presence of an ALK fusion oncogene defines a molecular subset of non-small cell lung cancer (NSCLC) with distinct clinical and pathologic features. The patients most likely to harbor ALK rearrangement are relatively young, never or light smokers with adenocarcinoma. Screening for this fusion gene in NSCLC is important because "ALK-positive" tumors are highly sensitive to therapy with crizotinib, an inhibitor of the ALK fusion gene.
Two single arm studies of crizotinib administered to patients with NSCLC and the ALK fusion gene demonstrated a response rate of 55 percent and a median duration of response of about 45 weeks [31]. Retrospective analysis also found that crizotinib was associated with a significant prolongation in survival [32]. Crizotinib (Xalkori®) was approved by the US Food and Drug Administration in August 2011 for patients whose tumors contain the ALK fusion oncogene. (See "Anaplastic lymphoma kinase (ALK) fusion gene positive advanced non-small cell lung cancer", section on 'Crizotinib'.)
PRIMARY CARE/PSYCHIATRY (SEPTEMBER 2011, MODIFIED APRIL 2012)
Maximum dosing for citalopram — Clinicians should not prescribe citalopram at doses that exceed 40 mg per day because of dose-dependent QT interval prolongation. The dose should not exceed 20 mg per day in patients with risk factors for increased serum concentrations of citalopram, including hepatic impairment, age >60 years, CYP2C19 variants that slowly metabolize citalopram, and concomitant medications that inhibit CYP2C19.
- The US Food and Drug Administration issued a safety communication in August 2011 that the antidepressant citalopram should no longer be used at doses exceeding 40 mg per day because higher doses have been associated with an increased risk for potentially fatal cardiac rhythm disturbances, including Torsade de Pointes [33]. In a randomized trial, the maximum mean corrected QT interval prolongation was greater in patients assigned to receive citalopram 60 mg per day compared with 20 mg per day. A subsequent warning, issued in March 2012, advises that the dose of citalopram be limited to 20 mg in patients at risk for increased serum concentrations of citalopram [34]. Risk factors include hepatic impairment, age >60 years, CYP2C19 variants that slowly metabolize citalopram, and concomitant medications that inhibit CYP2C19.
It is not known if escitalopram, the single isomer formulation of citalopram, causes dose-dependent QT prolongation. Other SSRIs have been associated with QT prolongation, but appear to be unlikely to cause serious arrhythmia when used in usual recommended doses and in patients without other risk factors. (See "Unipolar depression in adults and selective serotonin reuptake inhibitors (SSRIs): Pharmacology, administration, and side effects", section on 'Cardiac'.)
INFECTIOUS DISEASES/PEDIATRICS (JULY 2011)
Meningococcal vaccine in 9 to 23 month olds — For children from 9 to 23 months of age in the United States who are at high risk for meningococcal disease, we recommend meningococcal vaccination with Menactra®.
- In June 2011, the United States Advisory Committee on Immunization Practices (ACIP) voted to recommend the use of Menactra® in children from 9 to 23 months of age who are at high risk for meningococcal disease, including those with complement component deficiencies (involving properdin, Factor D, Factor H, and late complement components [C5 through C9]), those in a defined risk group for a community or institutional outbreak, and those traveling to an area where meningococcal disease is epidemic or endemic (table 4) [35].
When administered concurrently with a pneumococcal conjugate vaccine (such as PCV7 or PC13), Menactra® may interfere with the pneumococcal antibody response. Because of the lack of data on the clinical significance of this finding, and because children with sickle cell disease or anatomic asplenia are at greater risk for pneumococcal than meningococcal disease, the ACIP is not recommending Menactra® for children between 9 and 23 months of age who have either sickle cell disease or anatomic asplenia. Such children should continue to receive Menactra® at two years of age. (See "Meningococcal vaccines", section on 'In infants and children from 9 to 23 months'.)
CARDIOVASCULAR MEDICINE (JUNE 2011)
Medical therapy versus surgical revascularization for coronary disease with reduced left ventricular function — For most patients with LVEF of 35 percent or less and coronary artery disease amenable to CABG surgery, we suggest an initial course of optimal medical therapy alone rather than medical therapy plus CABG surgery (Grade 2B).
- Up to 50 percent of patients with left ventricular (LV) systolic dysfunction due to coronary heart disease (CHD) have a significant amount of viable (eg, hibernating) myocardium. Most observational studies have reported that, when compared with medical therapy, surgical revascularization of hibernating myocardium improves both survival and LV function.
The Surgical Treatment for Ischemic Heart Failure (STICH) trial was the first randomized trial to compare the combination of optimal medical therapy and surgical revascularization with optimal medical therapy alone in patients with stable CHD, LV ejection fraction of 35 percent or less, and coronary artery disease amenable to coronary artery bypass graft (CABG) surgery [36]. Compared with optimal medical therapy alone, optimal medical therapy plus CABG surgery resulted in no significant improvement in the primary outcome of all-cause mortality at a median follow-up of 56 months (36 versus 41 percent with medical therapy alone). However, crossover between assigned treatment groups may have led to a diminished benefit for surgery. Analysis of data based upon patients who received their assigned treatment found a reduction in all-cause mortality for patients who underwent CABG surgery; however, caution should be used in interpreting these results given the introduction of bias due to the exclusion of patients who did not receive their randomly assigned treatment.
As such, for most patients with LVEF of 35 percent or less and coronary artery disease amenable to CABG surgery, we suggest an initial course of optimal medical therapy alone rather than optimal medical therapy plus CABG surgery. This is based upon the significant morbidity associated with CABG surgery. CABG surgery, however, may be preferred by patients who are willing to accept the increased risk of morbidity related to surgery in exchange for a potential mortality benefit versus optimal medical therapy alone. Additionally, CABG surgery should be considered for patients with ongoing anginal symptoms despite optimal medical therapy. (See "Diagnosis and management of ischemic cardiomyopathy", section on 'Revascularization'.)
GASTROENTEROLOGY (JUNE 2011)
Protease inhibitors for chronic hepatitis C — For patients with chronic HCV genotype 1 who are candidates for therapy, we recommend triple therapy with peginterferon, weight-based ribavirin, and a protease inhibitor (telaprevir or boceprevir), rather than dual therapy with peginterferon and weight-based ribavirin (Grade 1A).
HEMATOLOGY/PEDIATRICS (JUNE 2011)
Hydroxyurea in young children with sickle cell disease — We suggest that all very young children (ie, 9 to 18 months of age) with sickle cell disease, independent of disease severity, be treated with hydroxyurea (dose: 20 mg/kg per day) (Grade 2A). Compounding pharmacy support is required until a liquid formulation becomes commercially available.
- Hydroxyurea (HU) is currently the only drug in widespread use for stimulating hemoglobin F production in patients with sickle cell disease (SCD). It has been used in the treatment of patients with significant symptoms related to SCD: frequent painful episodes, acute chest syndrome, severe vasoocclusive events, or symptomatic anemia.
The randomized BABY HUG trial was conducted to evaluate whether treating young children (ages 9 to 18 months at entry) with HbSS or HbS-beta(0) thalassemia with hydroxyurea would decrease kidney or splenic organ damage [38]. Although organ protection was not observed, treatment with HU compared with placebo significantly decreased the number of pain events and dactylitis, with some evidence for a decreased incidence of acute chest syndrome, hospital admissions and requirement for transfusions. Toxicity was limited to mild-to-moderate neutropenia. There is no information as yet on the efficacy of this treatment in children younger than nine months of age.
Based upon these findings, we now suggest initiation of HU in all young children (9 to 18 months of age), independent of disease severity. Until a liquid formulation of hydroxyurea becomes commercially available, an oral solution that is stable at room temperature for several months can be prepared from commercially available capsules [39]. (See "Specific therapies for sickle cell disease", section on 'Hydroxyurea'.)
INFECTIOUS DISEASE (JUNE 2011)
Hepatitis B vaccination in the HIV-infected adult — In HIV-infected patients with a CD4 count of >200 cells/mm3, we recommend immunization with a double dose of HBV vaccine (eg, 40 mcg intramuscularly) administered at baseline, one month, two months, and six months rather than standard dosing (Grade 1B).
- Compared with HIV-seronegative persons, HIV-infected patients have lower rates of seroconversion, lower titers of protective antibody, and faster rates of antibody declines after immunization with standard vaccination schedules for hepatitis B (ie, three doses intramuscularly). Some studies in dialysis patients have suggested that a double-dose of vaccine may be more immunogenic than a standard dose. A clinical trial in 437 HIV-infected patients with CD4 counts >200 cells/mm3 compared the immunogenicity of a standard hepatitis B vaccine schedule to either four double doses of vaccine given intramuscularly or four low-doses administered intradermally [40]. The percentage of responders (assessed with protective antibody titers at week 28) was significantly higher among the patients assigned to either the high-dose intramuscular or low-dose intradermal groups compared with those patients in the standard dosing group (82 percent and 77 percent versus 65 percent). Patients in the high dose intramuscular vaccination group, compared with those in the intradermal and standard dosing arms, had earlier seroconversion and achieved higher levels of antibody titers.
HIV-infected patients who are immunocompromised (eg, CD4 cell count <200 cells/mm3) with poorly controlled HIV viremia usually have poor immunization responses to HBV vaccine. Efforts should be made to engage the patient into medical care and address issues that may be interfering with adherence to retroviral therapy. Vaccination should not be deferred in the HBV-seronegative patient who is engaging in high risk behaviors since some patients with advanced immunosuppression may still respond. (See "Prevention of hepatitis B virus infection in the HIV-infected adult", section on 'Studies of alternative vaccine schedules'.)
ONCOLOGY (JUNE 2011, REVISED MARCH 2012)
Longer duration of adjuvant imatinib for resected high-risk GIST — We recommend adjuvant treatment with a tyrosine kinase inhibitor (imatinib 400 mg daily) for a minimum of three years rather than one year in patients who have a completely resected primary high-risk GIST (Grade 1A).
- The molecular hallmark of gastrointestinal stromal tumors (GIST) is the presence of one of two proto-oncogenes, KIT or PDGFRA. Tyrosine kinase inhibitors, such as imatinib, block signaling via KIT and PDGFRA and inhibit tumor proliferation.
The placebo-controlled ACOSOG Z9001 trial established treatment with at least 12 months of adjuvant imatinib as a standard approach for resected high-risk gastrointestinal stromal tumor (GIST) [41]. The benefit of longer duration therapy was addressed in the Scandinavian Sarcoma Group (SSG) XVIII trial, which compared 36 versus 12 months of imatinib (400 mg daily) in 400 patients with high-risk resected GIST [42]. At a median follow-up of 54 months, prolonged treatment was associated with a significant 54 percent improvement in relapse-free survival and a significant 55 percent improvement in overall survival. Most adverse effects were mild.
These data establish at least 36 months of adjuvant imatinib as a new standard for patients with high-risk resected GIST, but questions remain as to whether patients with high-risk tumors should continue treatment for longer than three years. (See "Adjuvant and neoadjuvant imatinib for gastrointestinal stromal tumors", section on 'SSG XVIII trial'.)
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