Here are the last 20 additions to the PBrain (total entries as of now = 3859)


ESC Guidelines for the diagnosis and management of syncope (3840)
Brignole M et al Eur Heart J 03-19-2018

Background: Syncope is a transient loss of consciousness due to cerebral hypoperfusion, with rapid onset, short duration, and complete spontaneous recovery; lifetime risk for syncope is 50% in the general population. A multidisciplinary task force, including experts in cardiology, emergency medicine, geriatrics, internal medicine, neurology, and nursing, updated the 2009 ESC syncope guidelines (Eur Heart J 2009; 30:2631) with evidence-based recommendations.

Key Recommendations:

  1. Initial Diagnostic Evaluation
  2. Subsequent Diagnostic Investigation
  3. Treatment

Comment: These updated European guidelines complement the 2017 American College of Cardiology guidelines (NEJM JW Emerg Med May 2017 and Circulation 2017; 139:25). Practical explanations of each testing modality are detailed, and rational, evidence-based recommendations are provided. Additional resources are available on the ESC guidelines web page. - Daniel D. Dressler, MD, MSc, SFHM, FACP


Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA (3841)
Johnston SC et al NEJM 05-06-2018

In 2013, the CHANCE study showed that in patients with transient ischemic attack (TIA) or minor stroke, short-term (21-day) dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel (A+C) was associated with a 32% reduction in stroke and no increased bleeding risk compared with antiplatelet monotherapy (NEJM JW Neurol Aug 2013 and N Engl J Med 2013; 369:11). Whether these findings in China, with a high preponderance of intracranial atherosclerosis, apply to other populations was unclear.

To find out, researchers compared A+C versus aspirin alone in 4881 patients (mean age, 65; 45% women; 57% with stroke) from 269 international sites (83% in the U.S.). Most patients (58%) were already taking aspirin at study entry. Patients in the A+C group received a 600 mg loading dose of clopidogrel, followed by 75 mg daily for 90 days. The aspirin dose ranged from 50 to 325 mg per day. All patients had a high-risk transient ischemic attack (TIA; ABCD2 score ≥4) or minor stroke (NIH stroke scale score ≤3) and were randomized within 12 hours after symptom onset. The primary endpoint was stroke, myocardial infarction, or vascular death within 90 days.

The primary endpoint occurred in 5.0% of patients taking A+C and 6.5% of patients taking aspirin alone, a significant difference (hazard ratio, 0.75; 95% confidence interval, 0.59-0.95). Stroke alone was 28% lower with A+C. Major (but not cerebral) hemorrhages were a significant 0.5% more common with A+C than aspirin alone (0.9% vs. 0.4%). In a secondary analysis, the benefit of A+C was greater at 7 days and 30 days than at 90 days.

Comment: These findings reinforce the benefits of short-term DAPT with aspirin plus clopidogrel. For every 1000 patients, 15 strokes would be prevented, at the cost of 5 additional major noncerebral hemorrhages. Most clinicians would likely accept this trade-off and prescribe DAPT, especially for higher-risk patients. A pragmatic strategy to reduce the bleeding risk could be to shorten DAPT duration to 30 days.


Education plus exercise versus corticosteroid injection use versus a wait and see approach on global outcome and pain from gluteal tendinopathy: Prospective, single blinded, randomised clinical trial (3842)
Mellor R et al BMJ 361:k1662 05-02-2018

Lateral hip pain sometimes is called "greater trochanteric bursitis," but the preferred term now is greater trochanteric pain syndrome (because this disorder usually is caused by gluteal tendinopathies, sometimes with adjacent bursitis). Although corticosteroids often are used in patients with greater trochanteric pain syndrome, the best treatment is unknown. In this multicenter trial from Australia, investigators randomized 204 patients (82% women; mean age, 55) with lateral hip pain for >3 months to education plus exercise, to corticosteroid injection, or to no treatment. Education-plus-exercise participants received 14 education sessions during 8 weeks on progressive tendon loading plus a targeted exercise program; injection participants received one ultrasound-guided corticosteroid injection.

At 8 weeks, both the education-plus-exercise and injection groups reported significantly greater overall improvement in their "hip condition" than did the no-treatment group (77% and 58% vs. 29%), as well as significantly lower pain intensity; differences between the education-plus-exercise group and the injection group also were significant. At 52 weeks, education plus exercise was superior to both injection and no treatment for global hip improvement (79% vs. 58% and 52%).

Comment: In this randomized trial, education plus exercise resulted in better hip function and greater pain relief than did corticosteroid injection or no treatment in patients with greater trochanteric pain syndrome, with the benefit for hip function sustained at 52 weeks. Although these results support education plus exercise as the preferred approach, whether routine physical therapy referrals will yield the outcomes achieved in this trial (in which an intensive program was delivered by highly trained therapists) is unclear.


Systematic review and meta-analysis of outcomes of patients with subsegmental pulmonary embolism with and without anticoagulation treatment (3843)
Bariteau A et al Acad Emerg Med 2018 Mar 2 03-02-2018

A systematic review found no evidence for or against anticoagulation in these patients.

Although anticoagulation is typically used to treat patients with central and segmental pulmonary emboli (PE), deep vein thromboses (DVTs), or both, controversy exists around its use in patients with isolated (i.e., no associated DVT) subsegmental PE. In a systematic review and meta-analysis, investigators sought to inform this controversy by searching for evidence regarding the potential risks (bleeding) and benefits (prevention of PE/DVT recurrence or death) of anticoagulation in these patients.

A total of 14 studies involving 15,563 patients were included. The pooled prevalence of subsegmental PE was 4.6%. Of the 715 patients with subsegmental PE, 82% were treated with anticoagulants. The incidence of bleeding was only reported for anticoagulated patients (8.1%). There were no significant differences between anticoagulated patients and nonanticoagulated patients in incidence of recurrent PE/DVT (5.3% and 3.9%, respectively) or death (2.1% and 3.0%).

Comment: Patients with PE, regardless of size, are typically anticoagulated. However, given that there were no significant differences in outcomes between patients with isolated subsegmental PE who were and were not anticoagulated, the decision whether to anticoagulate should rest with patients and their providers (at least until a randomized trial is conducted). Discuss the risks and benefits with your patients, and know that choosing not to begin anticoagulation treatment - although a complicated and perhaps counterintuitive decision - is a perfectly valid and rational option.


Antithrombotic Therapy for Peripheral Artery Disease in 2018 (3844)
Hess et al JAMA 319:2329 06-12-2018

In summary, patients with PAD without ischemic limb symptoms or clinically manifest coronary or cerebrovascular disease should have cardiovascular risk factors treated, but current evidence does not support antithrombotic therapy. Symptomatic patients with PAD without clinically manifest coronary or cerebrovascular disease should be treated with clopidogrel monotherapy (with ticagrelor as an alternative) to prevent MACE (major adverse cardiac events), although aspirin plus clopidogrel is not more effective than aspirin alone and has not been evaluated for preventing MALE (major adverse limb events). Patients with symptomatic PAD and clinically manifest coronary or cerebrovascular disease should be treated with aspirin or clopidogrel monotherapy. Patients with symptomatic PAD who are at increased risk for ischemic limb events (eg, prior history of acute limb ischemia or ABI<0.60) should be treated with aspirin combined with vorapaxar to reduce MALE, whereas aspirin plus ticagrelor or aspirin plus low-dose rivaroxaban alone reduces MACE and MALE in patients with PAD and clinically manifest coronary artery disease. Adding antithrombotic therapies to aspirin is associated with increased risk of major bleeding, necessitating consideration of the net clinical benefit of combination therapies (number of MACE and MALE events avoided relative to major bleeding events caused). The optimal antithrombotic therapy for patients with critical leg ischemia remains unclear and is currently under investigation for patients undergoing lower extremity revascularization.

Full article


Oxymetazoline Hydrochloride 1% Cream (Rhofade) for Persistent Facial Erythema Associated with Rosacea (3845)
Garcia et al AFP 97:808 06-15-2018

A new cream formulation of oxymetazoline 1% cream can help with redness of rosacea - as a cost of $540 for 30 gm vs $83 for a 45 gm tube of metronidazole 0.75% cream vs $440 for 30 gm of brimonidine gel vs $2 for 1 oz bottle of OTC 0.05% oxymetazoline spray (Afrin). I would suggest trying Afrin spray topically before considering the topical cream or bimonidine.

Full article


Subclinical Hyperthyroidism (3846)
Biondi and Cooper NEJM 378:2411 06-21-2018

Full article


Clinical implications of revised pooled cohort equations for estimating atherosclerotic cardiovascular disease risk (3847)
Yadlowsky S et al Ann Intern Med 06-05-2018

Tools for estimating 10-year cardiovascular disease (CVD) risk were published by the American College of Cardiology and American Heart Association (ACC/AHA) in 2013 (NEJM JW Gen Med Dec 15 2013 and J Am Coll Cardiol 2014; 63:2935). These Pooled Cohort Equations (PCEs) were derived from data from five large population cohorts and were designed to inform guideline-based recommendations for primary-prevention prescribing - including statins, aspirin, and antihypertensives. However, clinician experience and recent publications have suggested that the 2013 PCEs overestimate risk (NEJM JW Gen Med Apr 15 2015 and Ann Intern Med 2015; 162:266).

Investigators used revised statistical methods and only the more modern cohorts to update the PCEs. Among patients who had been classified previously as high-risk (i.e., 10-year risk, ≥7.5%), the new classification system would reclassify many more people correctly than incorrectly, resulting in nearly 12 million Americans reclassified correctly as having lower risk by the new equations. Such reclassification could affect prevention recommendations and reduce prescribing of statins, aspirin, or antihypertensives to patients who are actually at low risk.

Comment: This study validates what some clinicians have observed in practice: Some patients are classified inaccurately as "high risk." Although guidelines that depend on risk calculation would not necessarily need to change if risk calculators are updated, the number of patients who would be affected by guideline recommendations could be lowered dramatically. For example, assume the patient is a 68-year-old white man with the following favorable risk profile: Total cholesterol, 160 mg/dL; HDL cholesterol, 55 mg/dL; blood pressure, 120/70 mm Hg; and no history of diabetes, hypertension, or smoking. His 10-year CVD risk is 12% on the ACC/AHA calculator, but only 6% on this new model's calculator. The latter risk is below the threshold at which most clinicians would recommend statin therapy. - Daniel D. Dressler, MD, MSc, SFHM, FACP at time of publication

Updated CAD risk calculator


Association of hydrochlorothiazide use and risk of malignant melanoma (3848)
Pottegard A et aa JAMA Intern Med 05-29-2018

Hydrochlorothiazide use is associated with excess risk for lip and nonmelanoma skin cancers, especially squamous cell cancers. Investigators in Denmark explored whether hydrochlorothiazide also is associated with risk for melanoma. They identified 19,000 adults with melanoma and compared them with 193,000 age- and sex-matched controls without cancer (except nonmelanoma skin cancer).

High use of hydrochlorothiazide (>50,000 mg total lifetime exposure or ≈6 years of use at standard doses) occurred in significantly more melanoma patients than controls (2.1% vs. 1.8%; odds ratio, 1.22). The researchers noted a nonsignificant trend toward a dose-dependent relation between lifetime hydrochlorothiazide use and diagnosis of melanoma and a significant association between hydrochlorothiazide use and two specific melanoma subtypes (nodular melanoma and lentigo melanoma). No association was found between melanoma and use of other antihypertensives.

Comment: These findings might be related to one of hydrochlorothiazide's known side effects, photosensitivity, although the authors note that nodular melanoma is not clearly linked to sun exposure. Excess risk for melanoma is modest and probably would not be a major factor in deciding to use hydrochlorothiazide; however, clinicians should advise patients who use hydrochlorothiazide to minimize sun exposure. - Thomas L. Schwenk, MD


Treating Patients When Asthma Symptoms Worsen (3849)
Amarol JW 38:112 07-15-2018

From March through May 2018, the New England Journal of Medicine published results of four industry-sponsored, randomized trials in which researchers examined novel ways to use inhaled corticosteroids (ICS) to treat patients whose asthma symptoms worsen, with the goal of preventing major exacerbations. Because these regimens probably are unfamiliar to most primary care clinicians, I will briefly outline the findings and suggest how they might be incorporated into current practice.

Quadruple-Dose Inhaled Steroids for Worsening Symptoms: Despite little evidence of efficacy, some asthma guidelines and asthma action plans recommend quadrupling the dose of ICS to prevent exacerbations in patients with early worsening asthma symptoms. In two randomized trials, researchers examined such regimens, started at the earliest sign of worsening symptoms, in patients with mild-to-moderate asthma who were treated with daily ICS. The results were disappointing: Quadruple-dose or quintuple-dose ICS was ineffective in children and only marginally effective at preventing exacerbations in adults, despite exposing patients to a systemic steroid level similar to that of an oral corticosteroid burst (NEJM JW Gen Med Apr 15 2018 and N Engl J Med 2018; 378:891 and 902). Based on these studies, I no longer use short-term quadruple doses of ICS to prevent asthma exacerbations. Instead, I usually supply patients with 5-day courses of oral corticosteroids, to be started for exacerbations according to an asthma action plan.

As-Needed Inhaled Corticosteroids Without Daily Maintenance Therapy: For many years, a cornerstone of asthma therapy has been managing persistent asthma with daily ICS to reduce inflammation and improve symptoms, prevent exacerbations, and perhaps prevent loss of lung function. But two additional new studies - which involved about 8000 patients with mild persistent asthma - call this conventional wisdom into question. As-needed use of inhalers that combine an ICS (i.e., budesonide) plus a long-acting β-agonist (LABA) with quick onset of action (i.e., formoterol) - without daily ICS maintenance therapy - was compared with a conventional maintenance regimen (daily ICS plus as-needed short-acting β-agonist as rescue therapy). Although the regimen with only as-needed ICS/LABA was not as effective as daily-maintenance therapy for day-to-day asthma control, it was just as effective in preventing exacerbations, and total annual ICS exposure was dramatically lower (NEJM JW Gen Med Jul 1 2018 and N Engl J Med 2018; 378:1877 and 1865).

These studies were done with Symbicort Turbohaler dry powder (200 μg of budesonide plus 6 μg of formoterol), which is not available in the U.S. The budesonide/formoterol combination in the U.S. (Symbicort) is available in metered-dose inhalers that are not FDA-approved for as-needed rescue treatment. Nevertheless, I have started using as-needed budesonide/formoterol in selected patients with mild persistent asthma who do not want to take daily ICS and who are not bothered by mild increases in day-to-day symptoms. In a real-world setting, many patients with mild persistent asthma do not use daily ICS consistently anyway.

Single Maintenance and Reliever Therapy ("SMART"): So-called SMART (Single Maintenance and Reliever Therapy) also is worth mentioning. SMART refers to use of combination inhalers (low-dose ICS plus long-acting bronchodilator with quick onset) for both daily maintenance and as-needed rescue therapy, without use of an as-needed short-acting β-agonist, such as albuterol. In an April 2018 meta-analysis, SMART lowered the incidence of asthma exacerbations, although it didn't improve day-to-day symptoms (NEJM JW Gen Med Jun 1 2018 and JAMA 2018; 319:1473). SMART should be reserved for patients with moderate-to-severe asthma who require daily therapy (in contrast, the two studies discussed above involved as-needed ICS without daily maintenance therapy for patients with mild asthma). Although SMART is not FDA approved in the U.S., I have used it in patients with moderate-to-severe asthma who have symptoms and exacerbations despite daily ICS/LABA therapy and in whom tiotropium (Spiriva) was not helpful and biologics were not an option.

Wrap-Up: In summary, the 2018 studies provide little support for quadrupling ICS doses in patients whose symptoms worsen while they are using daily ICS therapy. But the studies do support use of as-needed ICS/LABA in selected patients. Keep in mind that these currently are off-label uses in the U.S., and clinicians should make that clear in discussions with patients. Although European asthma guidelines currently recommend using SMART for patients with moderate-to-severe asthma, whether the next National Asthma Education and Prevention Program guidelines will endorse these as-needed regimens as treatment options remains to be seen. - David J. Amrol, MD


Anticholinergic drugs and risk of dementia: Case-control study (3850)
Richardson K et al BMJ 361:k1315 04-25-2018

Guidelines suggest that anticholinergic drugs be avoided in older people, and evidence suggests that they are associated with cognitive decline. In this case-control study, investigators evaluated associations between exposure to anticholinergic drugs and risk for dementia among 41,000 elders (age range, 65-99; median age, 83) newly diagnosed with dementia and 284,000 controls without dementia who were matched to cases by sex, age, and residence.

The median drug-exposure period was 7 years. After adjustment for multiple covariates, prescription of any anticholinergic drug was associated with a significant 10% higher risk for dementia. By class, prescriptions for antidepressants, anti-Parkinson drugs, and urologic drugs with scores ≥3 on an anticholinergic-burden calculator - but not antispasmodics, antipsychotics, and antihistamines - were associated with excess risk for dementia. Exposures to drugs with high anticholinergic activity were associated with a 15% higher risks for dementia.

Comment: In this study, anticholinergic drug use was associated with excess risk for dementia in elders. Given the study design, residual confounding is possible. Nonetheless, the authors appropriately recommend that clinicians should "be vigilant with respect to the use of anticholinergic drugs" and consider the short- and long-term cognitive risks associated with them.


A Potentially Fatal Immune Reaction to Lamotrigine (3851)
Med Ltr Med Ltr 60:105 06-18-2018

The FDA has warned that the antiepileptic and mood-stabilizing drug lamotrigine (Lamictal, and generics) can rarely cause hemophagocytic lymphohistiocytosis (HLH), a serious and potentially fatal immune-related reaction.1

HLH, which can be familial, occurs most often in infants, but can occur at any age. Often induced by Epstein-Barr Virus infection (HIV infection and non-Hodgkin's lymphoma are other common triggers), HLH is characterized by an unremitting activation of CD8+ T cells and macrophages.2 If untreated, it causes organ damage, particularly in the liver, bone marrow, and CNS; organ failure and death occur within months after onset.3 Clinical features can include fever and rash, splenomegaly, hepatitis, cytopenias, elevated triglyceride levels or low fibrinogen levels, hyperferritinemia, hemophagocytosis, decreased or absent natural killer cell activity, and elevated blood CD25 levels.4

The optimal treatment for drug-induced HLH is unclear. Treatment of HLH generally involves use of corticosteroids and blood products, sometimes augmented by aggressive immunosuppression with the cytotoxic drug etoposide (Toposar, and generics). The anti-CD52 antibody alemtuzumab (Lemtrada) can be added in refractory HLH cases,5 and allogeneic hematopoietic cell transplantation has been used in genetic cases.

Since lamotrigine first became available in 1994, five confirmed and three suspected cases of HLH associated with its use have been reported. All of these cases occurred within 24 days of starting treatment and required hospitalization. One death was reported; in the other cases, improvement occurred after discontinuation of lamotrigine and treatment of HLH. Because initial signs and symptoms of HLH are nonspecific, the condition can be confused with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), another potentially fatal, multiorgan, immune-related adverse reaction associated with lamotrigine use.1,6

Patients being treated successfully with lamotrigine should continue taking it. Clinicians should monitor patients taking lamotrigine for signs and symptoms of HLH, especially during the first few weeks after starting the drug.


Vertebroplasty versus sham procedure for painful acute osteoporotic vertebral compression fractures (VERTOS IV): Randomised sham controlled clinical trial (3852)
Firanescu CE et al BMJ 361:k1551. 05-09-2018

In previous trials, vertebroplasty for pain relief has not outperformed sham procedures in patients with acute osteoporotic compression fractures (e.g., NEJM JW Gen Med Sep 1 2009 and N Engl J Med 2009; 361:569 and 557). To address some methodological limitations in these trials, investigators conducted a randomized, double-blind, sham-controlled trial using stricter inclusion and exclusion criteria, longer follow-up, and no crossovers.

The study cohort involved 180 participants (age, ≥50) with one to three acute vertebral compression fractures, T5-L5 focal back pain at the level of fracture for as long as 6 weeks, pain scores of ≥5 (on a 10-point scale), and osteoporosis. Both vertebroplasty and sham groups received local anesthetic infiltration at each pedicle. Cement injections were given to the vertebroplasty group and were simulated in the sham group.

In both groups, mean reductions in pain scores were clinically significant (i.e., mean decrease of ≥1.5 points) at all follow-up times, ranging from 1 day to 1 year. However, no statistically significant differences in pain scores were found between the vertebroplasty and sham groups at any follow-up time. Likewise, investigators found no differences between groups for quality-of-life and disability outcomes.

Comment: These negative results are unsurprising, as pain often subsides naturally within a few weeks, and placebo effects of invasive procedures can be substantial. However, an editorialist notes that we still don't know whether improving or preventing progression of kyphosis with vertebroplasty is associated with improved quality of life and disability. Finally, these results do not apply to patients with multiple myeloma or vertebral metastases.


Screening for cardiovascular disease risk with electrocardiography: US Preventive Services Task Force recommendation statement (3853)
Curry SJ et al JAMA 319:2308 06-12-2018

Background: In 2012, the USPSTF recommended against use of resting or exercise electrocardiography (ECG) for cardiovascular (CV) screening in low-risk, asymptomatic adults (Ann Intern Med 2012; 157:512); evidence was insufficient to make a recommendation for adults with intermediate or high risk for CV disease. The Task Force now has examined several new cohort studies of resting or exercise screening ECG in reclassifying or refining risk status for asymptomatic patients. It found no new studies that reported actual clinical outcomes.

Key Points:

Comment: This recommendation against use of resting or exercise ECG in low-risk, asymptomatic patients is consistent with the recommendations of many professional organizations, yet studies continue to show high rates of use in low-risk patients. Some people argue that routine ECGs serve as a useful baseline for patients who present later with nonspecific symptoms. However, baseline ECGs usually are not available when needed, and their clinical value has not been established. ECG use can be influenced by special circumstances, such as screening airplane pilots or others in high-risk occupations and patients with strong family histories of premature CV disease (although the value of ECGs is uncertain, even in those groups). Some evidence suggests that resting ECG screening in athletes has value, and its use for this purpose is increasing. - Thomas L. Schwenk, MD


Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: A randomised clinical trial (3854)
Park JK et al Ann Rheum Dis 77:898 06-01-2018

Rheumatoid arthritis (RA) patients who are receiving immunosuppressive therapy with methotrexate (MTX) require regular vaccination against preventable diseases; however, such patients have attenuated responses to influenza and pneumococcal vaccines. Although suspending MTX improves vaccine immunogenicity, a study in South Korea showed that cessation of MTX for 4 weeks also was associated with slightly higher incidence of RA flares (Ann Rheum Dis 2017; 76:1559). Now, to determine if a 2-week interruption of MTX could improve vaccine immunogenicity without raising risk for RA flares, the same investigators randomized 320 RA patients on MTX therapy to influenza vaccination followed by MTX continuation versus cessation for 2 weeks.

Likelihood of achieving a satisfactory vaccine response (≥4-fold increase in antibody titer 4 weeks after vaccination) was significantly greater with MTX cessation than MTX continuation (76% vs. 55%). Overall average disease activity remained similar in both groups. Incidences of RA flares were slightly higher in the MTX-cessation group (11% vs. 5%, P=0.07), but disease activity returned to baseline when MTX was resumed. The study was not powered to detect a difference in rates of influenza infection.

Comment: These results are encouraging, in that they show a 2-week cessation of MTX after influenza vaccine improves immunogenicity with only minimal excess risk for RA flares. We'll need more data before we can assume this will be true for other vaccines. However, with this information in hand, I will withhold MTX for 2 weeks after administering influenza vaccines this year.


Infective endocarditis in patients with bicuspid aortic valve or mitral valve prolapse (3855)
Zegri-Reiriz I et al J Am Coll Cardiol 71:2731 06-19-2018

Current guidelines recommend antibiotic prophylaxis for patients who have high-risk heart conditions and who are undergoing procedures associated with bacteremia (e.g., NEJM JW Infect Dis Dec 2015 and Circulation 2015; 132:1435); however, bicuspid aortic valve (BAV) or mitral valve prolapse (MVP) is considered to be an intermediate-risk condition by most guidelines. Spanish investigators analyzed a large registry of patients with infective endocarditis to investigate the clinical features that are associated with BAV and MVP. Of 3208 consecutive patients, 1226 were at high risk and 1982 were at low or intermediate risk, including 54 with BAV and 89 with MVP.

Patients with BAV or MVP were significantly younger and had a significantly higher incidence of viridans Streptococci infection (35% and 39%, respectively) than did high-risk patients or other low/intermediate-risk patients (≈14%). BAV and MVP patients and high-risk patients had similar rates of intracardiac complications, such as abscess, fistula, or valve perforation (≈45%); other low/intermediate-risk patients had lower rates of these complications (31%).

Comment: In this analysis, patients with infective endocarditis and underlying BAV and MVP had high rates of viridans infection (presumably often of oral origin) and intracardiac complication rates similar to those in high-risk patients. The authors call for reconsidering antibiotic prophylaxis for these patients, whereas an editorialist suggests narrowing the focus to BAV and MVP patients with moderate or worse regurgitation and taking into consideration other important predictors of infective endocarditis risk, such as age, sex, and type of procedure.


ESR and CRP (3856)
UTD UTD 08-12-2018

ESR values increase markedly with age and are slightly higher among women than men. As a result, any single set of normal values will not be valid for the population at large. One can roughly correct ESR for age by using the following formulas: the upper limit of the reference range equals (age in years)/2 for men and (age in years + 10)/2 for women. Anemia, obesity, and kidney disease also elevated ESR.

The level of CRP that is truly normal or clinically innocuous is not known. Data from a study conducted by the National Health and Nutrition Evaluation Survey of over 21,000 people in the United States revealed that CRP levels vary with age, sex, and race, with slightly higher levels seen with increased age, with female sex, and in African Americans. A rough correction of the CRP for age can be made by using the following formulas: the upper limit of the reference range (mg/dL) equals (age in years)/50 for men and (age in years/50) + 0.6 for women.


Association of initiation of basal insulin analogs vs neutral protamine Hagedorn insulin with hypoglycemia-related emergency department visits or hospital admissions and with glycemic control in patients with type 2 diabetes (3857)
Lipska KJ et al JAMA 320:53 07-03-2018

The marked rise in cost of insulin analogs prompted this retrospective study of specific hypoglycemia-related events and glycemic control in patients taking insulin analogs (glargine [Lantus] or detemir [Levemir]) compared with those taking neutral protamine Hagedorn (NPH) insulin. Using data from Kaiser Permanente of Northern California (an integrated healthcare system), researchers identified more than 25,000 patients (mean age, 60) with type 2 diabetes who initiated basal insulin between 2006 and 2014. Because NPH has been the first-line basal insulin for type 2 diabetes in this healthcare system (in contrast to preferential prescribing of insulin analogs in most of the U.S.), 92% of patients in this cohort used NPH insulin and only 8% used analogs.

During an average follow-up of 1.7 years, patients taking insulin analogs had more hypoglycemia-related hospital admissions and emergency department visits than patients taking NPH (12 and 9 events per 1000 person-years, respectively); the difference was not statistically significant but tended to favor NPH even after adjustment for baseline differences between the two groups. The researchers also compared about 2000 analog users with a similar number of propensity-matched NPH users; again, no statistically significant difference in serious hypoglycemic events was found. Mean glycosylated hemoglobin levels fell by 1.3% and 1.5% in the analog and NPH groups, respectively.

Comment: This observational study could not be controlled for all the factors that might influence why a patient received a particular type of basal insulin. But the results suggest that the higher cost of basal insulin analogs (about 10 times more than NPH insulin) might not be justified. In resisting the national switch to expensive newer insulins, this healthcare system seems to have made a cost-effective choice.


Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: Analysis of individual patient data from randomised trials (3858)
Rothwell PM et al Lancet 07-12-2018

Although aspirin almost completely inhibits thromboxane production in platelets, its overall effectiveness in lowering long-term risk for adverse cardiovascular (CV) events is relatively modest. Might this disparity be due, in part, to a failure to adjust aspirin dosing by body weight? To address this question, researchers analyzed individual patient data from 10 randomized trials of aspirin for primary prevention of adverse CV events in more than 100,000 patients; patients were stratified by weight to determine whether body size affected the efficacy of aspirin. In several studies, researchers also examined the incidence of colorectal cancer.

Compared with no aspirin, low-dose aspirin (75 to 100 mg daily) significantly lowered initial adverse CV events in patients who weighed <70 kg (hazard ratio, 0.77) but not in those who weighed ≥70 kg (HR, 0.95). Efficacy differed by weight similarly regardless of age, sex, or diabetes status. Higher-dose aspirin was effective in heavier patients: 325 mg significantly lowered initial adverse CV events in patients who weighed ≥70 kg, and 500 mg was effective in patients who weighed ≥90 kg. Low-dose aspirin significantly lowered 20-year colorectal cancer risk in patients who weighed <70 kg, but not in those who weighed ≥70 kg, whereas doses ≥325 mg were effective in patients who weighed as much as 80 kg.

Comment: Optimizing the effect of aspirin for primary cardiovascular risk reduction could have substantial public health effects, although one has to balance potential benefit versus bleeding risk in individual patients. No randomized trials have compared different aspirin doses directly for people in each weight category, but these results are sufficiently compelling that I will consider recommending doses higher than 81 mg to patients who weigh ≥70 kg.


Association of coffee drinking with mortality by genetic variation in caffeine metabolism: Findings from the UK biobank (3859)
Loftfield E et al JAMA Intern Med 2018 Jul 2 07-02-2018

Most studies have shown an inverse relation between coffee consumption and mortality (e.g., NEJM JW Gen Med Jan 15 2018 and BMJ 2017; 359:j5024). However, some variations in this relation could be related to genetic polymorphisms. In this U.K. study, researchers used a population-based set of genetic, behavioral, and clinical data in about 500,000 participants who were followed to assess coffee intake and all-cause and cause-specific mortality. Analyses were adjusted for a wide range of clinical and demographic variables, including smoking and alcohol intake.

During median follow-up of 7 years, about 14,000 people died. The relative reduction in all-cause mortality among the 78% of participants who were coffee drinkers varied from 6% to 16% for various levels of daily intake, from <1 to ≥8 cups. Similar relative reductions were found for mortality due to cardiovascular disease and cancer. There was no relationship between mortality and various combinations of polymorphisms in four genetic loci that influenced caffeine metabolism.

Comment: Clinicians can be reasonably reassuring to patients about the benefits of coffee drinking across a wide range of intake and regardless of potential genetic differences in caffeine metabolism. This study exemplifies the value of large population-based databases that integrate genetic and clinical information.


Here are the last 10 additions to the PBrain by date


ESR and CRP (3856)
UTD UTD 08-12-2018

ESR values increase markedly with age and are slightly higher among women than men. As a result, any single set of normal values will not be valid for the population at large. One can roughly correct ESR for age by using the following formulas: the upper limit of the reference range equals (age in years)/2 for men and (age in years + 10)/2 for women. Anemia, obesity, and kidney disease also elevated ESR.

The level of CRP that is truly normal or clinically innocuous is not known. Data from a study conducted by the National Health and Nutrition Evaluation Survey of over 21,000 people in the United States revealed that CRP levels vary with age, sex, and race, with slightly higher levels seen with increased age, with female sex, and in African Americans. A rough correction of the CRP for age can be made by using the following formulas: the upper limit of the reference range (mg/dL) equals (age in years)/50 for men and (age in years/50) + 0.6 for women.


Treating Patients When Asthma Symptoms Worsen (3849)
Amarol JW 38:112 07-15-2018

From March through May 2018, the New England Journal of Medicine published results of four industry-sponsored, randomized trials in which researchers examined novel ways to use inhaled corticosteroids (ICS) to treat patients whose asthma symptoms worsen, with the goal of preventing major exacerbations. Because these regimens probably are unfamiliar to most primary care clinicians, I will briefly outline the findings and suggest how they might be incorporated into current practice.

Quadruple-Dose Inhaled Steroids for Worsening Symptoms: Despite little evidence of efficacy, some asthma guidelines and asthma action plans recommend quadrupling the dose of ICS to prevent exacerbations in patients with early worsening asthma symptoms. In two randomized trials, researchers examined such regimens, started at the earliest sign of worsening symptoms, in patients with mild-to-moderate asthma who were treated with daily ICS. The results were disappointing: Quadruple-dose or quintuple-dose ICS was ineffective in children and only marginally effective at preventing exacerbations in adults, despite exposing patients to a systemic steroid level similar to that of an oral corticosteroid burst (NEJM JW Gen Med Apr 15 2018 and N Engl J Med 2018; 378:891 and 902). Based on these studies, I no longer use short-term quadruple doses of ICS to prevent asthma exacerbations. Instead, I usually supply patients with 5-day courses of oral corticosteroids, to be started for exacerbations according to an asthma action plan.

As-Needed Inhaled Corticosteroids Without Daily Maintenance Therapy: For many years, a cornerstone of asthma therapy has been managing persistent asthma with daily ICS to reduce inflammation and improve symptoms, prevent exacerbations, and perhaps prevent loss of lung function. But two additional new studies - which involved about 8000 patients with mild persistent asthma - call this conventional wisdom into question. As-needed use of inhalers that combine an ICS (i.e., budesonide) plus a long-acting β-agonist (LABA) with quick onset of action (i.e., formoterol) - without daily ICS maintenance therapy - was compared with a conventional maintenance regimen (daily ICS plus as-needed short-acting β-agonist as rescue therapy). Although the regimen with only as-needed ICS/LABA was not as effective as daily-maintenance therapy for day-to-day asthma control, it was just as effective in preventing exacerbations, and total annual ICS exposure was dramatically lower (NEJM JW Gen Med Jul 1 2018 and N Engl J Med 2018; 378:1877 and 1865).

These studies were done with Symbicort Turbohaler dry powder (200 μg of budesonide plus 6 μg of formoterol), which is not available in the U.S. The budesonide/formoterol combination in the U.S. (Symbicort) is available in metered-dose inhalers that are not FDA-approved for as-needed rescue treatment. Nevertheless, I have started using as-needed budesonide/formoterol in selected patients with mild persistent asthma who do not want to take daily ICS and who are not bothered by mild increases in day-to-day symptoms. In a real-world setting, many patients with mild persistent asthma do not use daily ICS consistently anyway.

Single Maintenance and Reliever Therapy ("SMART"): So-called SMART (Single Maintenance and Reliever Therapy) also is worth mentioning. SMART refers to use of combination inhalers (low-dose ICS plus long-acting bronchodilator with quick onset) for both daily maintenance and as-needed rescue therapy, without use of an as-needed short-acting β-agonist, such as albuterol. In an April 2018 meta-analysis, SMART lowered the incidence of asthma exacerbations, although it didn't improve day-to-day symptoms (NEJM JW Gen Med Jun 1 2018 and JAMA 2018; 319:1473). SMART should be reserved for patients with moderate-to-severe asthma who require daily therapy (in contrast, the two studies discussed above involved as-needed ICS without daily maintenance therapy for patients with mild asthma). Although SMART is not FDA approved in the U.S., I have used it in patients with moderate-to-severe asthma who have symptoms and exacerbations despite daily ICS/LABA therapy and in whom tiotropium (Spiriva) was not helpful and biologics were not an option.

Wrap-Up: In summary, the 2018 studies provide little support for quadrupling ICS doses in patients whose symptoms worsen while they are using daily ICS therapy. But the studies do support use of as-needed ICS/LABA in selected patients. Keep in mind that these currently are off-label uses in the U.S., and clinicians should make that clear in discussions with patients. Although European asthma guidelines currently recommend using SMART for patients with moderate-to-severe asthma, whether the next National Asthma Education and Prevention Program guidelines will endorse these as-needed regimens as treatment options remains to be seen. - David J. Amrol, MD


Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: Analysis of individual patient data from randomised trials (3858)
Rothwell PM et al Lancet 07-12-2018

Although aspirin almost completely inhibits thromboxane production in platelets, its overall effectiveness in lowering long-term risk for adverse cardiovascular (CV) events is relatively modest. Might this disparity be due, in part, to a failure to adjust aspirin dosing by body weight? To address this question, researchers analyzed individual patient data from 10 randomized trials of aspirin for primary prevention of adverse CV events in more than 100,000 patients; patients were stratified by weight to determine whether body size affected the efficacy of aspirin. In several studies, researchers also examined the incidence of colorectal cancer.

Compared with no aspirin, low-dose aspirin (75 to 100 mg daily) significantly lowered initial adverse CV events in patients who weighed <70 kg (hazard ratio, 0.77) but not in those who weighed ≥70 kg (HR, 0.95). Efficacy differed by weight similarly regardless of age, sex, or diabetes status. Higher-dose aspirin was effective in heavier patients: 325 mg significantly lowered initial adverse CV events in patients who weighed ≥70 kg, and 500 mg was effective in patients who weighed ≥90 kg. Low-dose aspirin significantly lowered 20-year colorectal cancer risk in patients who weighed <70 kg, but not in those who weighed ≥70 kg, whereas doses ≥325 mg were effective in patients who weighed as much as 80 kg.

Comment: Optimizing the effect of aspirin for primary cardiovascular risk reduction could have substantial public health effects, although one has to balance potential benefit versus bleeding risk in individual patients. No randomized trials have compared different aspirin doses directly for people in each weight category, but these results are sufficiently compelling that I will consider recommending doses higher than 81 mg to patients who weigh ≥70 kg.


Association of initiation of basal insulin analogs vs neutral protamine Hagedorn insulin with hypoglycemia-related emergency department visits or hospital admissions and with glycemic control in patients with type 2 diabetes (3857)
Lipska KJ et al JAMA 320:53 07-03-2018

The marked rise in cost of insulin analogs prompted this retrospective study of specific hypoglycemia-related events and glycemic control in patients taking insulin analogs (glargine [Lantus] or detemir [Levemir]) compared with those taking neutral protamine Hagedorn (NPH) insulin. Using data from Kaiser Permanente of Northern California (an integrated healthcare system), researchers identified more than 25,000 patients (mean age, 60) with type 2 diabetes who initiated basal insulin between 2006 and 2014. Because NPH has been the first-line basal insulin for type 2 diabetes in this healthcare system (in contrast to preferential prescribing of insulin analogs in most of the U.S.), 92% of patients in this cohort used NPH insulin and only 8% used analogs.

During an average follow-up of 1.7 years, patients taking insulin analogs had more hypoglycemia-related hospital admissions and emergency department visits than patients taking NPH (12 and 9 events per 1000 person-years, respectively); the difference was not statistically significant but tended to favor NPH even after adjustment for baseline differences between the two groups. The researchers also compared about 2000 analog users with a similar number of propensity-matched NPH users; again, no statistically significant difference in serious hypoglycemic events was found. Mean glycosylated hemoglobin levels fell by 1.3% and 1.5% in the analog and NPH groups, respectively.

Comment: This observational study could not be controlled for all the factors that might influence why a patient received a particular type of basal insulin. But the results suggest that the higher cost of basal insulin analogs (about 10 times more than NPH insulin) might not be justified. In resisting the national switch to expensive newer insulins, this healthcare system seems to have made a cost-effective choice.


Association of coffee drinking with mortality by genetic variation in caffeine metabolism: Findings from the UK biobank (3859)
Loftfield E et al JAMA Intern Med 2018 Jul 2 07-02-2018

Most studies have shown an inverse relation between coffee consumption and mortality (e.g., NEJM JW Gen Med Jan 15 2018 and BMJ 2017; 359:j5024). However, some variations in this relation could be related to genetic polymorphisms. In this U.K. study, researchers used a population-based set of genetic, behavioral, and clinical data in about 500,000 participants who were followed to assess coffee intake and all-cause and cause-specific mortality. Analyses were adjusted for a wide range of clinical and demographic variables, including smoking and alcohol intake.

During median follow-up of 7 years, about 14,000 people died. The relative reduction in all-cause mortality among the 78% of participants who were coffee drinkers varied from 6% to 16% for various levels of daily intake, from <1 to ≥8 cups. Similar relative reductions were found for mortality due to cardiovascular disease and cancer. There was no relationship between mortality and various combinations of polymorphisms in four genetic loci that influenced caffeine metabolism.

Comment: Clinicians can be reasonably reassuring to patients about the benefits of coffee drinking across a wide range of intake and regardless of potential genetic differences in caffeine metabolism. This study exemplifies the value of large population-based databases that integrate genetic and clinical information.


Subclinical Hyperthyroidism (3846)
Biondi and Cooper NEJM 378:2411 06-21-2018

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Infective endocarditis in patients with bicuspid aortic valve or mitral valve prolapse (3855)
Zegri-Reiriz I et al J Am Coll Cardiol 71:2731 06-19-2018

Current guidelines recommend antibiotic prophylaxis for patients who have high-risk heart conditions and who are undergoing procedures associated with bacteremia (e.g., NEJM JW Infect Dis Dec 2015 and Circulation 2015; 132:1435); however, bicuspid aortic valve (BAV) or mitral valve prolapse (MVP) is considered to be an intermediate-risk condition by most guidelines. Spanish investigators analyzed a large registry of patients with infective endocarditis to investigate the clinical features that are associated with BAV and MVP. Of 3208 consecutive patients, 1226 were at high risk and 1982 were at low or intermediate risk, including 54 with BAV and 89 with MVP.

Patients with BAV or MVP were significantly younger and had a significantly higher incidence of viridans Streptococci infection (35% and 39%, respectively) than did high-risk patients or other low/intermediate-risk patients (≈14%). BAV and MVP patients and high-risk patients had similar rates of intracardiac complications, such as abscess, fistula, or valve perforation (≈45%); other low/intermediate-risk patients had lower rates of these complications (31%).

Comment: In this analysis, patients with infective endocarditis and underlying BAV and MVP had high rates of viridans infection (presumably often of oral origin) and intracardiac complication rates similar to those in high-risk patients. The authors call for reconsidering antibiotic prophylaxis for these patients, whereas an editorialist suggests narrowing the focus to BAV and MVP patients with moderate or worse regurgitation and taking into consideration other important predictors of infective endocarditis risk, such as age, sex, and type of procedure.


A Potentially Fatal Immune Reaction to Lamotrigine (3851)
Med Ltr Med Ltr 60:105 06-18-2018

The FDA has warned that the antiepileptic and mood-stabilizing drug lamotrigine (Lamictal, and generics) can rarely cause hemophagocytic lymphohistiocytosis (HLH), a serious and potentially fatal immune-related reaction.1

HLH, which can be familial, occurs most often in infants, but can occur at any age. Often induced by Epstein-Barr Virus infection (HIV infection and non-Hodgkin's lymphoma are other common triggers), HLH is characterized by an unremitting activation of CD8+ T cells and macrophages.2 If untreated, it causes organ damage, particularly in the liver, bone marrow, and CNS; organ failure and death occur within months after onset.3 Clinical features can include fever and rash, splenomegaly, hepatitis, cytopenias, elevated triglyceride levels or low fibrinogen levels, hyperferritinemia, hemophagocytosis, decreased or absent natural killer cell activity, and elevated blood CD25 levels.4

The optimal treatment for drug-induced HLH is unclear. Treatment of HLH generally involves use of corticosteroids and blood products, sometimes augmented by aggressive immunosuppression with the cytotoxic drug etoposide (Toposar, and generics). The anti-CD52 antibody alemtuzumab (Lemtrada) can be added in refractory HLH cases,5 and allogeneic hematopoietic cell transplantation has been used in genetic cases.

Since lamotrigine first became available in 1994, five confirmed and three suspected cases of HLH associated with its use have been reported. All of these cases occurred within 24 days of starting treatment and required hospitalization. One death was reported; in the other cases, improvement occurred after discontinuation of lamotrigine and treatment of HLH. Because initial signs and symptoms of HLH are nonspecific, the condition can be confused with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), another potentially fatal, multiorgan, immune-related adverse reaction associated with lamotrigine use.1,6

Patients being treated successfully with lamotrigine should continue taking it. Clinicians should monitor patients taking lamotrigine for signs and symptoms of HLH, especially during the first few weeks after starting the drug.


Oxymetazoline Hydrochloride 1% Cream (Rhofade) for Persistent Facial Erythema Associated with Rosacea (3845)
Garcia et al AFP 97:808 06-15-2018

A new cream formulation of oxymetazoline 1% cream can help with redness of rosacea - as a cost of $540 for 30 gm vs $83 for a 45 gm tube of metronidazole 0.75% cream vs $440 for 30 gm of brimonidine gel vs $2 for 1 oz bottle of OTC 0.05% oxymetazoline spray (Afrin). I would suggest trying Afrin spray topically before considering the topical cream or bimonidine.

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Antithrombotic Therapy for Peripheral Artery Disease in 2018 (3844)
Hess et al JAMA 319:2329 06-12-2018

In summary, patients with PAD without ischemic limb symptoms or clinically manifest coronary or cerebrovascular disease should have cardiovascular risk factors treated, but current evidence does not support antithrombotic therapy. Symptomatic patients with PAD without clinically manifest coronary or cerebrovascular disease should be treated with clopidogrel monotherapy (with ticagrelor as an alternative) to prevent MACE (major adverse cardiac events), although aspirin plus clopidogrel is not more effective than aspirin alone and has not been evaluated for preventing MALE (major adverse limb events). Patients with symptomatic PAD and clinically manifest coronary or cerebrovascular disease should be treated with aspirin or clopidogrel monotherapy. Patients with symptomatic PAD who are at increased risk for ischemic limb events (eg, prior history of acute limb ischemia or ABI<0.60) should be treated with aspirin combined with vorapaxar to reduce MALE, whereas aspirin plus ticagrelor or aspirin plus low-dose rivaroxaban alone reduces MACE and MALE in patients with PAD and clinically manifest coronary artery disease. Adding antithrombotic therapies to aspirin is associated with increased risk of major bleeding, necessitating consideration of the net clinical benefit of combination therapies (number of MACE and MALE events avoided relative to major bleeding events caused). The optimal antithrombotic therapy for patients with critical leg ischemia remains unclear and is currently under investigation for patients undergoing lower extremity revascularization.

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