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Practice Changing UpDates
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Practice Changing UpDates
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2016. | This topic last updated: Aug 18, 2016.

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.

PEDIATRICS, ADULT PRIMARY CARE, FAMILY MEDICINE, INFECTIOUS DISEASES (August 2016)

Inactivated influenza vaccine for 2016-2017 season in the northern hemisphere

For the 2016-2017 influenza season in the northern hemisphere, we suggest inactivated influenza vaccine (IIV) rather than live attenuated influenza vaccine (LAIV) for the prevention of influenza in both children and adults (Grade 2B).

The effectiveness of seasonal influenza vaccines varies from season to season and is determined by a number of factors, including the match between circulating influenza strains and influenza strains in the vaccine. During the 2015-2016 influenza season, data from the United States Influenza Vaccine Effectiveness Network indicated that inactivated influenza vaccine (IIV) was 63 percent effective in preventing influenza in children, but live attenuated influenza vaccine (LAIV) was not effective [1]. Findings of poor or lower than expected LAIV effectiveness were also noted during the 2013-2014 and 2014-2015 seasons in the United States. These findings are inconsistent with studies sponsored by the manufacturer and studies from other countries that found LAIV was effective (ranging from 46 to 58 percent) during the 2015-2016 season [2-5]; however, LAIV was less effective than IIV in all of these studies [6]. In June 2016, the United States Advisory Committee on Immunization Practices (ACIP) voted to recommend that LAIV not be used during the 2016-2017 influenza season; this recommendation must be approved by the United States Centers for Disease Control and Prevention (CDC) director before it becomes CDC policy [1]. While some countries have elected to continue using LAIV [2], we suggest IIV rather than LAIV for the 2016-2017 influenza season in the northern hemisphere. (See "Seasonal influenza in children: Prevention with vaccines", section on 'IIV versus LAIV' and "Seasonal influenza vaccination in adults", section on 'Choice of vaccine formulation'.)

INFECTIOUS DISEASES, GASTROENTEROLOGY, PRIMARY CARE, FAMILY MEDICINE (July 2016)

Sofosbuvir-velpatasvir for all genotypes of chronic HCV infection

For patients with chronic genotype 1 or 4 hepatitis C virus (HCV) infection, we suggest ledipasvir-sofosbuvir or sofosbuvir-velpatasvir (Grade 2B). For patients with chronic genotype 2 or 3 HCV infection, we suggest sofosbuvir-velpatasvir (Grade 2B). Depending on clinical factors, some patients with genotype 3 infection may also warrant the addition of ribavirin.

All-oral, direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have proliferated over the past two years. Sofosbuvir-velpatasvir, a coformulated combination of an NS5B and an NS5A inhibitor, is the first such regimen that has high, well-established efficacy for all genotypes, even in patients with cirrhosis or prior treatment failure with interferon-based regimens [7-9]. This agent was approved by the US Food and Drug Administration in June 2016 and is now our preferred or one of our preferred regimens for adults with chronic HCV infection of any genotype because of its efficacy, simplicity of administration, and limited drug interactions. Sofosbuvir-velpatasvir is given for 12 weeks for all genotypes. For genotype 3 infection, the addition of ribavirin may be warranted, depending on the presence of cirrhosis, the prior treatment history, and the presence of mutations associated with NS5A resistance. (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'.)

ONCOLOGY, ADULT PRIMARY CARE (July 2016)

Duration of adjuvant endocrine therapy for breast cancer

For postmenopausal women with nonmetastatic hormone receptor-positive breast cancer who have completed a five-year course of an aromatase inhibitor (AI), we suggest continuing the AI for an additional five years (Grade 2A).

For postmenopausal women receiving adjuvant treatment with an aromatase inhibitor (AI) for hormone-positive breast cancer, the standard duration of treatment has been five years. However, data from the MA17R trial demonstrated that a longer course of treatment improves disease-free survival (DFS) [10]. Among approximately 1900 postmenopausal women who had completed four and a half to six years of therapy with an AI, treatment for an additional five years improved five-year DFS relative to those who received placebo (95 versus 91 percent). There was no difference between the groups in regards to overall survival. Bone-related toxic effects were more frequent among those receiving extended treatment. Based on these results, we now offer an additional five years of treatment to those who have completed five years of AI therapy. However, it is reasonable for women with low risk of recurrence who are concerned about the risks and toxicities of extended treatment to omit extended treatment after a risk-benefit discussion. (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer", section on 'Duration of endocrine treatment'.)

ONCOLOGY (June 2016)

Choice of adjuvant chemotherapy for resected pancreatic cancer

Following resection of pancreatic cancer, we suggest six months of combination chemotherapy with gemcitabine plus capecitabine rather than gemcitabine monotherapy for most patients (Grade 2B). However, therapy with gemcitabine alone (or, where available, S-1) is a reasonable option, particularly for patients with a borderline performance status or a comorbidity profile that precludes intensive therapy.

Adjuvant chemotherapy is recommended for all patients with resected pancreatic cancer. The standard approach has been gemcitabine monotherapy or, where available, S-1 alone. The benefit of a two-drug regimen was tested in the ESPAC-4 trial, which randomly assigned 730 patients with resected pancreatic adenocarcinoma to six months of gemcitabine with or without capecitabine [11]. In a preliminary report presented at the 2016 annual meeting of the American Society of Clinical Oncology (ASCO), combination therapy was associated with significantly longer median overall survival (28 versus 25.5 months), and twice as many patients remaining alive at five years (19 versus 9). Severe diarrhea, hand-foot syndrome, and neutropenia were all significantly more common with combined therapy.

For most patients we suggest six months of combination chemotherapy with gemcitabine plus capecitabine rather than gemcitabine monotherapy after resection of pancreatic cancer. However, therapy with gemcitabine or S-1 alone remains a reasonable option, particularly for patients with a borderline performance status or a comorbidity profile that precludes intensive therapy. (See "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Gemcitabine plus capecitabine'.)

ONCOLOGY (May 2016)

No survival benefit from chemoradiotherapy after initial chemotherapy for locally advanced pancreatic cancer

For most patients with locally advanced pancreatic cancer who are not considered candidates for surgical exploration after initial chemotherapy, we suggest continued chemotherapy rather than chemoradiotherapy (Grade 2B). However, for patients in whom resection is being considered, chemoradiotherapy is still advised in an attempt to increase the likelihood of a complete resection.

There is no consensus as to the best approach for patients with locally advanced pancreatic cancer. Given that initial chemoradiotherapy (CRT) has not demonstrated a consistent survival benefit, and that up to one-third of patients develop overt metastases during the initial phase of treatment, it had been hoped that reserving CRT for patients without metastases after initial chemotherapy would improve survival. However, data from the randomized LAP-07 trial suggest no survival benefit from CRT compared with continued systemic chemotherapy alone, at least for patients treated initially with gemcitabine monotherapy [12].

For patients who do not progress following initial chemotherapy, subsequent therapy depends on whether the patient is a candidate for resection. For patients in whom resection is being considered, we continue to suggest combined treatment with external beam radiotherapy plus concomitant low-dose fluorouracil (eg, 200 mg/m2 daily), in an attempt to increase the rate of complete (R0) resection. For most patients with truly unresectable tumors following initial chemotherapy, we now suggest continued chemotherapy rather than CRT. However, CRT may be appropriate for selected patients, such as those with localized disease and a good performance status who cannot tolerate further chemotherapy. (See "Initial chemotherapy and radiation for nonmetastatic locally advanced unresectable and borderline resectable exocrine pancreatic cancer".)

INFECTIOUS DISEASES (May 2016)

Option for shortened MDR-TB regimen in updated WHO guidelines

Consistent with WHO updated guidelines for patients with multidrug-resistant tuberculosis (MDR-TB), we suggest a shortened 9 to 12-month MDR-TB regimen for nonpregnant patients who have no extrapulmonary disease, an isolate known to be susceptible to fluoroquinolones and injectable antituberculous agents, and no prior exposure to second-line agents for more than one month (Grade 2C).

The conventional treatment regimen for multidrug-resistant tuberculosis (MDR-TB) consists of a fluoroquinolone, an injectable agent, and at least two other core second-line agents for a total duration of 20 to 26 months. Updated World Health Organization (WHO) guidelines present the option of a shortened regimen for nonpregnant patients with MDR-TB who have no extrapulmonary disease, an isolate known to be susceptible to fluoroquinolones and injectable antituberculous agents, and no prior exposure to second-line agents for more than one month [13]. The shortened regimen consists of an intensive phase (four to six months of high-dose isoniazid, ethambutol, pyrazinamide, gatifloxacin [or moxifloxacin], kanamycin, prothionamide, and clofazimine) followed by a continuation phase (five months of ethambutol, pyrazinamide, gatifloxacin [or moxifloxacin], and clofazimine). Support for this regimen comes in part from a large study from Bangladesh that reported high rates of favorable bacteriologic outcomes with a similar 9 to 12-month regimen [14]. The new WHO guidance also indicates that patients with rifampin monoresistance should be treated as for MDR-TB. Patients with known or suspected MDR-TB who do not meet criteria for the shortened MDR-TB regimen should be treated with the conventional regimen. (See "Diagnosis, treatment, and prevention of drug-resistant tuberculosis", section on 'General principles'.)

CARDIOVASCULAR MEDICINE (April 2016)

Surgical revascularization in patients with coronary disease and left ventricular systolic dysfunction

For patients with ischemic cardiomyopathy (LVEF 35 percent or less) and coronary artery disease that is amenable to surgical revascularization, we suggest the combination of surgical revascularization and medical therapy rather than medical therapy alone (Grade 2B). Medical therapy alone is a reasonable option for patients who prioritize concerns about early CABG-associated morbidity and a small risk of early mortality over an overall decrease in longer-term mortality.

Most observational studies suggest that surgical revascularization in patients with ischemic cardiomyopathy (left ventricular ejection fraction [LVEF] of 35 percent or less) improves survival compared with medical therapy. Previously reported five-year outcomes of the randomized Surgical Treatment for Ischemic Heart Failure (STICH) trial comparing surgical revascularization with medical therapy alone showed a trend toward reduced mortality following surgical revascularization, but this primary outcome did not achieve statistical significance. An updated report, the STICH Extension Study (STICHES), extended the follow-up to a median of 9.8 years and found a significant 7 percent absolute reduction in total mortality for patients who underwent surgical revascularization [15]. On the basis of this new evidence, we have revised our previous suggestion for initial management with medical therapy alone for most patients with LVEF 35 percent or less and coronary artery disease amenable to coronary artery bypass graft (CABG) surgery. For such patients, we now suggest the combination of surgical revascularization and medical therapy rather than medical therapy alone. This suggestion is based primarily on the long-term absolute reduction in mortality over the 10 years following CABG surgery. Based on the small but nontrivial early mortality risk associated with CABG surgery as well as other post-CABG morbidities, patients may also reasonably choose medical therapy as the initial treatment option. (See "Diagnosis and management of ischemic cardiomyopathy", section on 'Randomized trials'.)

CARDIOVASCULAR MEDICINE (April 2016)

Transcatheter versus surgical aortic valve replacement in intermediate risk patients with aortic stenosis

For patients with severe aortic stenosis and intermediate surgical risk, new studies suggest that transcatheter aortic valve replacement (TAVR) is an alternative to surgical AVR; the choice between these therapies is based on patient-specific factors.

Transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) result in similar survival rates in high-risk patients with severe aortic stenosis, but the comparative outcomes in lower risk patients had not been previously evaluated until publication of a recent randomized trial and an observational study (see "Transcatheter aortic valve replacement: Indications"):

The randomized, controlled PARTNER 2A Trial, which enrolled over 2000 intermediate-risk patients, found that TAVR (Sapien XT valve) was noninferior to SAVR for the primary composite end point of death or disabling stroke at two years [16]. For patients included in the transfemoral-access cohort of this trial (76 percent of the trial population), TAVR resulted in a lower event rate than SAVR. Additionally, TAVR resulted in lower rates of acute kidney injury, severe bleeding, and new onset atrial fibrillation, while SAVR resulted in lower rates of paravalvular regurgitation and major vascular complications.

The Sapien 3 observational study included 1000 intermediate-risk patients undergoing TAVR (Sapien 3 valve, 88 percent via the transfemoral route) who were compared with propensity score-matched patients from the SAVR arm of the PARTNER 2A trial [17]. TAVR was superior to SAVR for the composite end point (death from any cause, stroke, and incidence of moderate or severe aortic regurgitation) as well as for the individual outcomes of death and stroke. SAVR was associated with less frequent moderate or severe aortic regurgitation.

Based on these studies, TAVR is now a reasonable option for patients with intermediate surgical risk. For symptomatic patients with severe aortic stenosis, we recommend AVR rather than medical therapy; both SAVR and TAVR are effective treatments, and the choice between them is made by a Heart Valve Team with consideration of patient-specific factors (including the feasibility of transfemoral TAVR) and patient values and preferences. (See "Transcatheter aortic valve replacement: Indications", section on 'Choice of therapy'.)

INFECTIOUS DISEASES, ADULT PRIMARY CARE, FAMILY MEDICINE, EMERGENCY MEDICINE, HOSPITAL MEDICINE (March 2016)

Indications for antibiotics in the management of skin abscess

We suggest antibiotic therapy as adjunctive therapy to incision and drainage for patients with a skin abscess that is ≥2 cm (Grade 2B).

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has raised uncertainty regarding the role of antimicrobial therapy for treatment of skin abscess following incision and drainage. In a randomized trial including 1220 patients >12 years of age (median 35 years) with drained skin abscess (≥2 cm in diameter) comparing trimethoprim sulfamethoxazole (TMP-SMX, 320 mg/1600 mg twice daily) with placebo, the cure rate 7 to 14 days after treatment was higher in the TMP-SMX group (80.5 versus 73.6 percent); wound cultures were positive for MRSA in 45 percent of cases [18]. Based on these findings, abscess size ≥2 cm in diameter is a useful threshold for guiding decisions regarding use of antibiotic therapy for adjunctive treatment of skin abscess.

Additional factors for which we recommend antibiotic therapy include the presence of multiple lesions, extensive surrounding cellulitis, associated comorbidities or immunosuppression, signs of systemic infection, or inadequate clinical response to incision and drainage alone; we suggest antibiotic therapy for patients with an indwelling device or high risk for transmission of S. aureus to others. For otherwise healthy patients with none of these factors, we suggest not administering antimicrobial therapy. (See "Skin abscesses, furuncles, and carbuncles", section on 'Role of antibiotics'.)

HEMATOLOGY (March 2016, Modified March 2016)

Ibrutinib in older adults with newly diagnosed CLL

For older adults with symptomatic CLL, we suggest single agent ibrutinib as initial treatment, rather than chlorambucil plus a novel anti-CD20 monoclonal antibody (obinutuzumab or ofatumumab) (Grade 2B).

Ibrutinib is commonly used for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and for the initial treatment of patients with CLL who carry a deletion in chromosome 17. Until now, there was little data regarding its use in other patients with previously untreated disease. In a phase III trial (RESONATE-2), 269 older adults with previously untreated CLL were randomly assigned to initial therapy with ibrutinib or chlorambucil [19]. Ibrutinib was better tolerated and resulted in higher response rates and superior rates of progression-free and overall survival at two years. These results led to the approval of ibrutinib by the US Food and Drug Administration for the initial treatment of CLL [20]. Ibrutinib is now our preferred therapy for previously untreated older adults with CLL. We continue to use fludarabine-based therapies for younger patients. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia", section on 'Ibrutinib'.)

PULMONOLOGY AND CRITICAL CARE, HEMATOLOGY, ADULT PRIMARY CARE, FAMILY MEDICINE, EMERGENCY MEDICINE, HOSPITAL MEDICINE (March 2016)

Agent selection for anticoagulation in venous thromboembolism

For long-term anticoagulation for venous thromboembolism in most nonpregnant patients who do not have severe renal insufficiency or active cancer, we suggest a direct oral anticoagulant (ie, apixaban, edoxaban, rivaroxaban, or dabigatran) rather than other agents (Grade 2B).

Guidelines for the treatment of acute venous thromboembolism (VTE) were issued by The American College of Chest Physicians (ACCP) [21]. Compared with earlier versions of the guidelines, the direct oral anticoagulants (DOACs) apixaban, edoxaban, rivaroxaban, or dabigatran are now the preferred agents for long-term anticoagulation in patients who are not pregnant and do not have active cancer or severe renal insufficiency. This preference was based upon randomized trials that consistently reported similar efficacy, a lower bleeding risk, and improved convenience when compared with warfarin. We agree with this preference for DOACs in patients with acute VTE, understanding that choosing among anticoagulants frequently depends upon availability and cost as well as patient comorbidities and preferences. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Selection of agent'.)

HEMATOLOGY, NEUROLOGY, PEDIATRICS (March 2016)

Stroke prevention in sickle cell disease

For children with sickle cell disease and increased risk for a first ischemic stroke based on transcranial Doppler measurements, who have received chronic transfusion therapy for at least two years and who meet criteria for hydroxyurea therapy based on the TWiTCH trial, we suggest transition to hydroxyurea (Grade 2C).

Individuals with sickle cell disease (SCD) are at risk for ischemic and hemorrhagic stroke. Transcranial Doppler (TCD) measures blood flow rate in intracranial arteries and is used to assess stroke risk in children with SCD. Children with increased TCD velocities are treated with chronic prophylactic transfusions to reduce the risk of ischemic stroke. The recently published TWiTCH trial (TCD With Transfusions Changing to Hydroxyurea) randomly assigned 121 children who had completed a period of chronic transfusions and who met study criteria (related to hemoglobin S levels with transfusion, TCD velocities, magnetic resonance angiographic findings, ability to comply with treatment and monitoring, and response to hydroxyurea) to transition to hydroxyurea therapy or to continue transfusions [22]. After approximately two years of follow-up, TCD velocities were similar in both groups and there were no strokes in either group. For children who would have met criteria for the TWiTCH trial, we suggest transitioning to hydroxyurea after two or more years of chronic transfusion, with transfusions tapered and hydroxyurea dosing gradually increased during the transition, as done in the trial. We continue to recommend chronic transfusions for all patients with SCD who have had an ischemic stroke (ie, for secondary prevention). (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Chronic transfusion followed by transition to hydroxyurea'.)

OBSTETRICS, GYNECOLOGY AND WOMEN'S HEALTH, FAMILY MEDICINE (February 2016)

Antenatal steroids at 34 to 37 weeks for pregnancies at high risk of preterm birth

For pregnant women who will deliver at 340/7ths to 366/7ths weeks of gestation by scheduled cesarean, we suggest administration of a first course of antenatal corticosteroids (Grade 2C).

Antenatal corticosteroid therapy at 23 to 34 weeks of gestation for women at risk for preterm delivery reduces the incidence and severity of respiratory distress syndrome in offspring delivered within seven days of administration. Steroids have not been administered after 34 weeks because studies have not demonstrated a benefit, although data have been sparse. Recently, the Antenatal Late Preterm Steroids (ALPS) Trial randomly assigned women at 340/7ths to 365/7ths weeks of gestation at high risk for late preterm birth to receive a first course of antenatal betamethasone or placebo and found that the frequency of a composite outcome of neonatal respiratory problems was reduced in the betamethasone group [23]. Based on these data, we believe offering a first course of antenatal corticosteroids to patients scheduled for cesarean delivery at 340/7ths to 366/7ths weeks is reasonable. We would not administer a first course of steroids to women at 340/7ths to 366/7ths weeks planning vaginal delivery as transient tachypnea of the newborn is less common after labor and vaginal birth. For women in whom delivery at 340/7ths to 366/7ths is uncertain (eg, threatened preterm labor), we would not administer a course of steroids because of the potential for long-term harm with no benefit if the patient does not deliver preterm. For women at 340/7ths to 366/7ths weeks who received a course of antenatal corticosteroids earlier in pregnancy, we would not administer a second course as the benefits and risks have not been studied in this population. This approach limits late preterm in utero steroid exposure to pregnancies certain to deliver preterm and with neonates at most risk for experiencing serious respiratory problems from transient tachypnea of the newborn. We do not administer steroids to women undergoing scheduled cesarean delivery at ≥37 weeks: the overall risk of respiratory illness at this gestational age is low and rarely serious. (See "Antenatal corticosteroid therapy for reduction of neonatal morbidity and mortality from preterm delivery", section on 'After 34 weeks'.)

ADULT PRIMARY CARE, FAMILY MEDICINE, GERIATRICS, CARDIOVASCULAR MEDICINE, ENDOCRINOLOGY AND DIABETES (January 2016)

Screening for diabetes mellitus

For adults with hypertension or hyperlipidemia, as well as for those aged 40 to 70 years with BMI ≥25 kg/m2, we suggest screening for type 2 diabetes as part of cardiovascular risk assessment (Grade 2C).

Although it has not been firmly established that screening for type 2 diabetes improves long-term outcomes, well-established treatments for diabetes can reduce progression to microvascular disease and early identification of diabetes allows interventions to prevent or limit cardiovascular disease. The US Preventive Services Task Force (USPSTF) has issued new recommendations for diabetes screening. Previously, the USPSTF only recommended screening for diabetes in adults with hypertension, but the new guideline recommends screening for diabetes as part of cardiovascular risk assessment in adults aged 40 to 70 years with body mass index (BMI) ≥25 kg/m2 [24]. The USPSTF suggests screening every three years based on limited evidence. We agree with the new USPSTF guideline and also suggest diabetes screening for adults with hypertension or hyperlipidemia. A fasting plasma glucose (FPG) and/or a glycated hemoglobin (A1C) are the preferred screening tests. (See "Screening for type 2 diabetes mellitus", section on 'A suggested approach'.)

EMERGENCY MEDICINE (ADULT AND PEDIATRIC) (January 2016)

Epinephrine for the treatment of fluid-refractory, cold septic shock in infants and children

We suggest that infants and children with fluid-refractory cold shock receive epinephrine infusions (initial starting dose 0.05 to 0.1 mcg/kg/minute, titrate to response up to 1.5 mcg/kg/minute) rather than dopamine (Grade 2C).

The 2009 American College of Critical Care Medicine (ACCM) pediatric sepsis guidelines recommended dopamine as the first-line agent for the treatment of fluid-refractory septic shock in patients with signs of vasoconstriction or "cold" shock (eg, cold extremities and diminished peripheral pulses). However, in a single-center randomized trial of 120 infants and children (1 month to 15 years of age) undergoing treatment for fluid-refractory septic shock in a pediatric intensive care unit (88 percent with cold shock), patients who received infusions of dopamine rather than epinephrine had significantly higher mortality (21 versus 7 percent) and more healthcare-associated infections (29 versus 2 percent) [25]. Based on these findings, we now suggest that infants and children with fluid-refractory, hypotensive, cold septic shock receive infusions of epinephrine rather than dopamine. Epinephrine infusions are initiated at a dose of 0.05 to 0.1 mcg/kg/minute and titrated to response up to 1.5 mcg/kg/minute. The 2009 ACCM pediatric sepsis guidelines are undergoing review. (See "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Cold shock'.)

NEPHROLOGY AND HYPERTENSION, ADULT PRIMARY CARE, CARDIOVASCULAR MEDICINE, FAMILY MEDICINE, GERIATRICS (November 2015, Modified December 2015)

SPRINT trial on goal blood pressure

In hypertensive patients with characteristics similar to those enrolled in the SPRINT trial (age 50 years or older with systolic blood pressure 130 to 180 mmHg and an additional risk factor for cardiovascular disease other than diabetes, proteinuric chronic kidney disease, or stroke), as well as for hypertensive patients with diabetes, we now recommend the same lower goal blood pressure, although the strength of recommendation and the quality of evidence varies depending on patient group and the method used to measure blood pressure:

● If blood pressure is measured using an automated oscillometric device that averages multiple readings with the patient resting alone in a room, we recommend targeting a blood pressure of 120-125/<90 mmHg rather than <140/<90 mmHg (Grade 1A). For diabetic patients, we suggest targeting this same goal blood pressure (Grade 2B).

● If other methods of blood pressure measurement are used, we recommend targeting a blood pressure of 125-130/<90 mmHg rather than <140/<90 mmHg (Grade 1B). For diabetic patients, we suggest targeting this same goal blood pressure (Grade 2B).

Goal blood pressure in most hypertensive patients had been <140/90 mmHg, or <150/90 mmHg in older adults. The potential benefit of lowering the systolic blood pressure goal in nondiabetic older adults with risk factors for cardiovascular disease or with chronic kidney disease was evaluated in the Systolic Blood Pressure Intervention Trial (SPRINT), a multicenter, randomized, open-label trial performed in 9361 hypertensive patients in the United States [26]. Patients were randomly assigned to a standard treatment group (target systolic pressure <140 mmHg) or an intensive treatment group (target systolic pressure <120 mmHg); the diastolic goal in both groups was <90 mmHg. Blood pressure during the trial was measured using automated oscillometric blood pressure (AOBP) and not using manual (ausculatory) blood pressure (perhaps more commonly used in routine practice), typically yielding readings 5 to 10 mm lower than with manual measurement. In the SPRINT trial, consecutive automated blood pressure readings were taken with the patient at rest and averaged. After a median of 3.26 years, intensive as compared with standard treatment reduced the rate of the primary end point, a composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death (5.2 versus 6.8 percent), and also reduced mortality (3.3 versus 4.5 percent). Intensive treatment increased the rates of acute kidney injury, syncope, and hyponatremia, but not orthostatic hypotension or falls resulting in hospitalization.

As a result of the SPRINT trial, UpToDate now recommends lower systolic pressure goals (depending on the method of measurement) for nondiabetic adults 50 years and older at high risk for cardiovascular events, and suggests such goals for patients with diabetes. Goals for other groups, including those with proteinuric chronic kidney disease, have not changed based upon the SPRINT data. A trial examining goal blood pressure for patients with diabetes is likely to report findings for this population in 2016. (See "What is goal blood pressure in the treatment of hypertension?", section on 'Benefit according to overall cardiovascular risk' and "Goal blood pressure in patients with cardiovascular disease or at high risk".)

HEMATOLOGY (October 2015)

Dabigatran reversal agent approved

For patients anticoagulated with dabigatran who are at an imminent risk of death from bleeding, in addition to treatment with an antifibrinolytic agent and drug removal with oral charcoal and/or hemodialysis, we suggest administering idarucizumab (Grade 2C). For those for whom idarucizumab is not available, we suggest using an activated prothrombin complex concentrate (aPCC; eg, factor eight inhibitor bypassing agent [FEIBA]) (Grade 2C).

The lack of a specific reversal agent for the direct thrombin inhibitor dabigatran has been a persistent concern in its use for patients with atrial fibrillation or venous thromboembolism. Idarucizumab (Praxbind) is a reversal agent for dabigatran that was approved by the US Food and Drug Administration in October 2015 to reverse dabigatran effect in the setting of life-threatening or uncontrolled bleeding or emergency surgery [27,28]. Approval was based on studies in healthy volunteers and an interim analysis of the RE-VERSE AD trial, which included a cohort of 90 older adult patients who had clinically significant bleeding or the need for an urgent invasive procedure while taking dabigatran for atrial fibrillation [29]. Idarucizumab produced rapid normalization of clotting times and/or surgical hemostasis; there were five thrombotic events and 18 deaths. Without a control group it is unclear how these outcomes would compare with similar patients who did not receive idarucizumab. For patients with life-threatening bleeding, we would use idarucizumab, if available, along with other measures to decrease bleeding risk, but we would not combine idarucizumab with procoagulant products such as an activated prothrombin complex concentrate (aPCC). Idarucizumab is an antibody-based therapy and does not have known activity against direct factor Xa inhibitors or other anticoagulants. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal'.)

ADULT PRIMARY CARE, FAMILY MEDICINE, CARDIOVASCULAR MEDICINE, GERIATRICS, HOSPITAL MEDICINE, ENDOCRINOLOGY AND DIABETES, NEUROLOGY (September 2015)

PCSK9 antibodies for cardiovascular risk reduction

In patients with stable cardiovascular disease (CVD) at very high risk for CVD events (expected 10-year event rate of greater than 25 percent), such as those in the proposed NCEP guidelines, we suggest high-intensity statin therapy plus a PCSK9-ab rather than targeting a goal LDL-C (Grade 2B). Other experts, including other authors for UpToDate, would make decisions about adding medications to statin therapy based on goal LDL-cholesterol.

In very high-risk patients who do not tolerate any statin regimen, we recommend treatment with a PCSK9-ab (Grade 1B). In higher-risk patients who do not tolerate any statin regimen, we suggest treatment with a PCSK9-ab (Grade 2B).

Monoclonal antibodies that inhibit proprotein convertase subtilisin kexin 9 (PCSK9-abs) reduce LDL-cholesterol levels by as much as 70 percent. Randomized trials with small numbers of events and limited follow-up suggest that at least two of these agents, alirocumab and evolocumab, substantially reduce cardiovascular events and mortality when used for secondary prevention, both as monotherapy and in combination with statin therapy [30,31]. (See "Lipid lowering with drugs other than statins and fibrates", section on 'PCSK9 inhibitors'.)

PCSK9-abs are becoming available for clinical use. The agents require subcutaneous injection every two to four weeks and are very expensive. While awaiting greater experience with these agents, we would use them in situations where the expected reductions in cardiovascular events are likely to outweigh any as yet unknown adverse events from a new therapy. These include using them in combination with statin therapy in very high-risk patients with stable cardiovascular disease, such as those in the proposed NCEP guidelines , and as monotherapy in very high-risk and higher-risk patients who are intolerant of statin therapy. Other experts, including other authors for UpToDate, would make decisions about adding medications to statin therapy based on goal LDL-cholesterol. (See "Intensity of lipid lowering therapy in secondary prevention of cardiovascular disease", section on 'Stable CVD' and "Treatment of lipids (including hypercholesterolemia) in secondary prevention", section on 'Summary and recommendations'.)

PULMONARY AND CRITICAL CARE MEDICINE, CARDIOVASCULAR MEDICINE (September 2015)

Combination therapy with ambrisentan and tadalafil for pulmonary arterial hypertension

For most patients with group 1 pulmonary arterial hypertension who have class II or III symptoms, we suggest ambrisentan and tadalafil rather than other combinations or single agent therapy (Grade 2B).

Typically, patients with group 1 pulmonary arterial hypertension (PAH) who have World Health Organization (WHO) class II or III symptoms are treated with single agent advanced therapy. In a randomized trial, the combination of ambrisentan (a selective endothelin receptor A antagonist) and tadalafil (a cyclic GMP phosphodiesterase type 5 [PDE5] inhibitor) was associated with a significant reduction in the rate of clinical failure when compared with either agent alone [32]. The improved clinical outcome was driven primarily by reduction in the rate of hospitalizations for progressive PAH, a factor that portends poor prognosis, rather than by improved survival or WHO functional class. We now suggest this combination as first-line therapy for newly diagnosed patients with group 1 PAH and functional class II or III symptoms, who have either a negative vasoreactivity test or who are vasoreactive but fail to respond to calcium channel blocker therapy. (See "Treatment of pulmonary hypertension in adults", section on 'Combination therapy'.)

GASTROENTEROLOGY AND HEPATOLOGY (September 2015)

Mechanical bowel preparation and oral antibiotics prior to elective colon surgery

For patients undergoing elective colon resection, we suggest mechanical bowel preparation combined with oral antibiotics rather than mechanical bowel preparation alone or no preparation (Grade 2C).

Traditionally, mechanical bowel preparation was used with oral antibiotics to prepare for all elective colon surgeries. After several randomized trials reported no benefit from mechanical bowel preparation (MBP) without antibiotics, colon resection without preoperative bowel preparation and without oral antibiotics became widespread. A retrospective study of data from over 8000 patients undergoing colorectal resection found that MBP combined with oral antibiotics, compared with MBP alone, was associated with lower rates of anastomotic leak, and that MBP, with or without antibiotics, was associated with lower rates of surgical site infection and postoperative ileus compared with no preparation prior to surgery [33]. A subsequent meta-analysis of seven randomized trials reached a similar conclusion [34]. One drawback is a potential increase in the rate of Clostridium difficile infection for patients treated with oral antibiotics.

Thus, for patients undergoing elective colon surgeries, we suggest mechanical bowel preparation combined with oral antibiotics. Mechanical bowel preparation is usually accomplished with polyethylene glycol solution and is followed by oral antibiotics such as neomycin and erythromycin base. Administering oral antibiotics in the absence of mechanical bowel preparation is of unproven benefit and is not advised. (See "Overview of colon resection", section on 'Bowel preparation'.)

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