Here are the last 20 additions to the PBrain (total entries as of now = 3810)


Association of varicose veins with incident venous thromboembolism and peripheral artery disease (3791)
Chang SL et al JAMA 319:807 02-27-2018

Approximately 25% of U.S. adults have varicose veins, which are thought to be relatively benign. In this retrospective cohort study, researchers in Taiwan explored associations of varicose veins with other vascular diseases, using linked national databases to identify about 212,000 adults (mean age, 55; 69% women) with varicose veins who were propensity matched to the same number of controls without varicose veins.

During follow-up of 7 to 8 years, the incidence of deep venous thrombosis in varicose vein patients was 6.55 per 1000 person-years compared with 1.23 per 1000 person-years in the control group - nearly a fivefold relative increase. The corresponding incidence rates were 0.48 vs. 0.28 for pulmonary embolism and 10.73 and 6.22 for peripheral artery disease.

COMMENT: This retrospective study design cannot be controlled for all confounders, but the DVT association was least likely to reflect confounding, according to additional analysis by the authors. The associations of varicose veins with both arterial disease and thrombotic venous disease suggest that underlying inflammatory and prothrombotic mechanisms might explain these findings. Although the results have no immediate clinical implications, they raise the question of whether varicose veins should be considered a risk factor for deep venous thrombosis.- Thomas L. Schwenk, MD


Association of cigarette, cigar, and pipe use with mortality risk in the US population (3792)
Christensen CH et al JAMA Intern Med 02-19-2018

Cigar and pipe smokers often claim - incorrectly - that their use of tobacco is not harmful, unlike cigarette smoking. In this U.S. national longitudinal mortality study, 26 years of data from nearly 360,000 U.S. adults (age range, 35 to 80) were used to update mortality risk estimates for current and former cigar, pipe, and cigarette smokers. Patients who used smokeless tobacco and those who used multiple products were excluded; participants were assessed every 3 years.

Exclusive cigarette smokers' mortality was roughly twofold higher than that of never-smokers; exclusive cigar smokers' mortality was 20% higher than that of never-smokers. Relatively few deaths occurred for exclusive pipe smokers, and excess mortality was not statistically significant. All three smoking groups had elevated risk for dying from tobacco-related cancers (hazard ratio for cigarettes, 4.1; HR for cigars and pipes, 1.6).

Comment: These results are not surprising but do provide updated evidence with which to counsel patients about risks associated with any combustible tobacco product. - Thomas L. Schwenk, MD


Hemoglobin A1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: A guidance statement update from the American College of Physicians (3793)
Qaseem A et al Ann Intern Med 03-06-2018

Background: Reviewers for the ACP have critically evaluated six recently published guidelines - from the Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE), the American Diabetes Association (ADA), the Institute for Clinical Systems Improvement (ICSI), the National Institute for Health and Care Excellence (NICE), the Scottish Intercollegiate Guidelines Network (SIGN), and the U.S. Department of Veterans Affairs and Department of Defense (VA/DoD). They offer summary guidance in using glycosylated hemoglobin (HbA1c) targets in managing nonpregnant adults with type 2 diabetes.

Key Recommendations:

COMMENT: Five major clinical trials in which intensive versus less-intensive type 2 diabetes control were evaluated have been published during the past 2 decades. The 2008 ACCORD trial was stopped early when its intensive-therapy arm was associated with higher mortality than its conservative-management arm (number needed to harm, 100; NEJM JW Gen Med Jul 1 2008 and N Engl J Med 2008; 358:2545); the ADVANCE trial (NEJM JW Gen Med Jul 1 2008 and N Engl J Med 2008; 358:2460), the two UKPDS trials (NEJM JW Gen Med Nov 1 1998 and Lancet 1998; 352:837), and the VADT trial (NEJM JW Gen Med Jan 15 2009 and N Engl J Med 2009; 360:129) did not demonstrate macrovascular benefits, showed only marginal or surrogate benefits in microvascular outcomes (e.g., less albuminuria, less retinal photocoagulation interventions), and revealed excess morbidity (e.g., severe hypoglycemic episodes). The ACP offers reasonable and conservative guidance on HbA1c targets for managing type 2 diabetes. However, because most study patients were older, a more aggressive approach might be appropriate in younger patients with few comorbid conditions - they might reap microvascular benefits from decades of tighter control. - Daniel D. Dressler, MD, MSc, SFHM, FACP


Trimethoprim use for urinary tract infection and risk of adverse outcomes in older patients: Cohort study (3794)
Crellin E et al BMJ 360:k341 02-09-2018

Trimethoprim/sulfamethoxazole (TMP/SMX) use is associated with excess risk for hyperkalemia and related adverse events in patients who take angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers (NEJM JW Gen Med Sep 1 2010 and JAMA Intern Med 2010; 170:1045; NEJM JW Gen Med Dec 15 2014 and BMJ 2014; 349:6196), or spironolactone (NEJM JW Gen Med Nov 1 2011 and BMJ 2011; 343:5228). However, whether TMP confers risk for hyperkalemia when it is used without SMX and in the absence of renin-angiotensin system blockers is unknown. In the U.K., TMP often is prescribed without SMX, giving researchers an opportunity to clarify this issue in a cohort of 180,000 patients (age, ≥65) who experienced at least one urinary tract infection (UTI) and received antibiotics.

After adjustment for numerous potential confounders (including use of renin-angiotensin system blockers and potassium-sparing antibiotics), odds of acute kidney injury during the 14 days following antibiotic initiation were 72% higher with TMP and 48% higher with ciprofloxacin than with amoxicillin. Odds of hyperkalemia occurrence during the 14 days following antibiotic initiation were 127% higher with TMP than with amoxicillin. TMP, compared with amoxicillin, was not associated with increased odds of death. Trimethoprim was associated with 1 to 2 additional cases of hyperkalemia and 2 admissions for acute kidney injury per 1000 treated patients; for people taking renin-angiotensin system blockers and spironolactone, 18 additional cases of hyperkalemia and 11 additional admissions for acute kidney injury occurred.

Comment: TMP use alone was associated with excess risk for hyperkalemia and acute kidney injury, but not death, compared with amoxicillin use for primary care treatment of UTIs among elders. This hyperkalemia finding is unsurprising, as TMP reduces potassium excretion in the distal renal tubule. Although TMP can raise serum creatinine concentration (by reducing tubular secretion of creatinine), which could result in overestimation of "true" kidney injury, the authors provide several reasons to believe that kidney injury in their study was real - a novel observation for TMP. Antibiotics other than those that contain TMP should be used in patients at risk for hyperkalemia and acute kidney injury. - Paul S. Mueller, MD, MPH, FACP


Arthroscopic partial meniscectomy versus placebo surgery for a degenerative meniscus tear: A 2-year follow-up of the randomised controlled trial (3795)
Sihvonen R et al Ann Rheum Dis 77:188 02-01-2018

Researchers reported in 2014 that, in a randomized trial of 146 patients (age range, 35-65) with knee pain and nontraumatic meniscal tears without osteoarthritis, those who underwent arthroscopic partial meniscectomies showed no benefit after 1 year compared with those who underwent sham procedures. Both groups showed marked improvement in knee pain-related scores, and no significant differences were observed between groups in secondary outcomes (NEJM JW Gen Med Feb 15 2014 and N Engl J Med 2013; 369:2515). Now, the same investigators report a 2-year follow-up.

After 2 years of follow-up, no differences between groups were noted in any of the standardized knee pain scores. In addition, all secondary outcome scores were similar, including in subgroups of patients with mechanical symptoms and certain meniscus tear characteristics.

Comment: This paper extends the conclusion reported earlier: No significant difference in outcomes was found between meniscectomy and a sham procedure among patients with knee pain and meniscal tears without osteoarthritis. Time and physical therapy should remain the initial treatments for patients like these. - Jonathan S. Coblyn, MD


Tinnitus Summary (3796)
Many Many 04-01-2018

The American Tinnitus Association can be found at www.ata.org.

Tinnitus from NEJM, 3/29/18 (Bauer) - provides a nice review of causes and treatments (or lack thereof).

Clinical Practice Guideline: Tinnitus from Otolaryngology: Head Neck Surg 151:S1, 2014.


Evaluation and Treatment of Male Hypogonadism (3797)
Sargis et al JAMA 319:1375 04-03-2018

Full guideline


Relationship between clinic and ambulatory blood-pressure measurements and mortality (3798)
Banegas JR et al NEJM 378:1509 04-19-2018

Some research suggests that 24-hour ambulatory blood pressure (BP) predicts cardiovascular (CV) outcomes more accurately than does clinic BP. Now, Spanish researchers provide additional insights drawn from a national primary care-based registry. The study included 64,000 adults (mean age, 58) who had guideline-specified indications for 24-hour ambulatory BP monitoring and who were followed for a mean 5 years. Patients were categorized as having sustained hypertension (elevated clinic and ambulatory readings), white-coat hypertension (elevated clinic but not ambulatory readings), masked hypertension (elevated ambulatory but not clinic readings), or normotension.

During follow-up, all-cause and CV-related mortality were 6% and 2%, respectively. Both clinic and ambulatory BP measurements (systolic and diastolic) were associated, in graded fashion, with excess all-cause and CV-related mortality. However, in models in which clinic BP was adjusted for ambulatory BP (and vice versa), ambulatory BP predicted mortality more strongly. Interestingly, masked hypertension predicted CV mortality as strongly as did sustained hypertension (whether or not patients were receiving treatment at the time of BP measurement). White-coat hypertension in untreated patients was associated with excess mortality, whereas the white-coat pattern in treated patients was not.

Comment: This study validates the utility of 24-hour ambulatory BP measurement as a stronger prognostic tool than clinic measurement. Limitations include the fact that only baseline BP measurement and baseline drug-treatment status were used to predict outcomes; thus, the study didn't tell us how subsequent drug treatment of patients with the various hypertensive phenotypes (sustained, white-coat, and masked) affects outcomes. Moreover, many clinicians base treatment decisions on readings from patient-owned home BP units. Self-monitoring appears to be valuable (NEJM JW Gen Med Apr 12 2018; [e-pub] and Lancet 2018; 391:949), but additional research on how those readings compare with 24-hour ambulatory readings would be useful.


Cessation of ureteral colic does not necessarily mean that a ureteral stone has been expelled (3799)
Hernandez N et al J Urol 199:1011 04-01-2018

We know that a painful ureteral stone has passed if the patient brings it to us. But what about patients whose pain resolves but who don't retrieve their stones? In this single-center retrospective study, researchers identified 52 patients who met the following criteria: acute ureteral colic, stone confirmed by imaging, follow-up within several weeks, and no pain during the 72 hours prior to the follow-up visit.

At the follow-up encounters (which occurred an average of 35 days after the acute presentations), 26% of these pain-free patients still had ureteral stones (seen on plain film, ultrasound, computed tomography, or ureteroscopy). Most of these patients did not have microscopic hematuria. Imaging confirmed passage of stones in the remaining 74% of patients.

Comment: In this study of patients whose acute ureteral colic resolved but who didn't retrieve their stones, the ureteral stone persisted in about one quarter of patients at 1 month. The authors argue for repeat imaging in such patients, so that those with ongoing obstruction and hydronephrosis can be identified and treated. Among patients who don't pass their stones, it's unclear why pain resolves in some but persists in others.


Atrial fibrillation detected after stroke is related to a low risk of ischemic stroke recurrence (3800)
Sposato LA et al Neurology 90:e924 03-13-2018

Atrial fibrillation (AF) is widely recognized as the leading cause of cardioembolic stroke. Identification of AF is important because patients with AF derive greater benefit from oral anticoagulant (OAC) medications than from antiplatelet agents.

Owing to the importance of identifying AF, cardiac monitoring is frequently performed after a stroke or transient ischemic attack. These authors evaluated recurrent stroke risk in patients at multiple centers participating in the Ontario Stroke Registry. Patients were divided into three groups: (1) known AF prior to the stroke; (2) AF diagnosed after the stroke (AFDAS); or (3) sinus rhythm. The authors compared comorbidities in the three groups and the subsequent rate of stroke at 1 year, determined using administrative data.

Overall, 23,376 patients were evaluated in the registry; 6904 patients (29.5%) had known AF. Of the remaining patients, 5793 underwent at least 24 hours of cardiac monitoring and 587 (10.1%) of these had AFDAS. Compared with patients who had known AF, patients with AFDAS had lower frequencies of hypertension (70% vs. 77%), diabetes (18% vs. 26%), and dyslipidemia (36% vs. 44%) and lower histories of myocardial infarction (12% vs. 21%), congestive heart failure (6% vs. 17%), and coronary artery disease (18% vs. 35%). The 1-year risk for recurrent stroke was highest in the known AF group (9.6%), versus 8.0% with sinus rhythm and 6.6% with AFDAS. After adjustment for key variables such as age and sex, known AF, but not AFDAS, was associated with a higher risk for stroke compared with sinus rhythm.

Comment: This intriguing study suggests heterogeneity among AF patients with a recent stroke. The authors comment that many patients with AF detected after stroke may have a neurogenic mechanism for the AF, perhaps owing to autonomic imbalance. AFDAS patients differ in key ways from patients with known AF, including a lower frequency of vascular risk factors and fewer cardiac comorbidities. These findings should be replicated in other cohorts before the treatment paradigm of OAC medication for poststroke AF is altered.


Spironolactone versus clonidine as a fourth-drug therapy for resistant hypertension: The ReHOT randomized study (Resistant Hypertension Optimal Treatment) (3801)
Krieger EM et al Hypertension 71:681 04-01-2018

Resistant hypertension is an infrequent but difficult-to-manage clinical problem. After prescription of the common frontline drugs (diuretic, angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker, and calcium-channel blocker), the most suitable drug to add is uncertain. In the ReHOT study (Resistant Hypertension Optimal Treatment), researchers in Brazil compared spironolactone and clonidine as a fourth drug in patients with resistant hypertension.

In the two-phase study, 1597 hypertensive patients were treated with ≤3 drugs for 12 weeks, and 187 patients (11.7%) were identified as having resistant hypertension. Compared with the other patients, those with true resistant hypertension had higher incidences of stroke and diabetes and lower glomerular filtration rates. Of this group, 162 were randomized to spironolactone or clonidine; mean daily doses were 40 mg and 0.35 mg, respectively.

The primary combined endpoint of blood pressure (BP) control during office measurement (less than 140/90 mm Hg) and 24-hour ambulatory BP monitoring was not different between the two groups. Only 21% of patients achieved normal BP levels. On secondary endpoints, spironolactone was associated with greater decreases than clonidine in 24-hour systolic and diastolic BP and diastolic daytime ambulatory BP. Analyses limited to patients with greater than 80% adherence to drugs showed similar trends on the primary outcome. The rates of adverse effects were low for both drugs.

Comment - Cardiology - Joel M. Gore, MD: In this multicenter trial, more than 1 of 10 hypertension patients had resistant hypertension. Clonidine was not superior to spironolactone as a fourth-drug therapy. As the authors note, because spironolactone is taken once daily, it should be considered the better choice for patients with resistant hypertension who require a fourth drug.

Comment - General Medicine - Allan S. Brett, MD: Here's another reason to avoid clonidine. In some patients considered to have resistant hypertension, the "resistance" actually reflects poor adherence to their medication regimens, sometimes for understandable reasons (e.g., financial constraints in uninsured, impoverished populations). Adding clonidine can be risky, given the severe rebound hypertension that can occur in such patients when clonidine is started or stopped abruptly and unpredictably.


Early time course of major bleeding on antiplatelet therapy after TIA or ischemic stroke (3802)
Hilkens NA et al Neurology 90:e683 02-20-2018

Antiplatelet therapy is one of the most commonly used therapies for prevention of recurrent events in patients with ischemic stroke or transient ischemic attack (TIA). Prevention of recurrent ischemic events is intended to offset a potential increase in bleeding. To examine how this bleeding risk changes over time, researchers combined data from six large secondary prevention trials that evaluated either single or dual antiplatelet therapy. The authors evaluated major bleeds, gastrointestinal bleeding events, and intracranial hemorrhage during several time periods after study enrollment: ≤0 days, 31 to 90 days (reference period), 91 to 180 days, 181 to 365 days, and >365 days. Major bleeds were defined as events that were fatal, intracranial, or significantly disabling or that necessitated hospital admission. Median time from the stroke or TIA to study entry ranged from 15 to 126 days.

Of 45,195 patients analyzed (mean age, 65.5 years; 63% male), 89% qualified with a stroke and 11% with a TIA. Compared with the reference period, the risk for major bleeding in the first 30 days was significantly increased with both aspirin plus dipyridamole (rate ratio, 1.94; absolute risk, 4.9 per 100 person-years) and aspirin plus clopidogrel (rate ratio, 1.98; absolute risk, 5.8 per 100 person-years). The time course of gastrointestinal (GI) bleeding mirrored that of major bleeding. Antiplatelet monotherapy (aspirin, clopidogrel, or dipyridamole) was not associated with any changes in risk for major bleeding over time. No regimen was associated with variation in intracerebral hemorrhage over time. Absolute risks for major bleeding were higher in patients age ≥65 than in younger patients.

Comment: This study is a useful reminder that dual antiplatelet therapy can increase the risk for systemic bleeding. The absolute early risk of 5 to 6 events per 100 patient-years (about 1 event per 200 patients per month) with dual antiplatelets is relatively low but not trivial. Greater use of GI-protective medication might reduce the risk for GI bleeding. It is reassuring that no regimen increased the degree of early intracerebral hemorrhage


Proton pump inhibitor use and risk of hip fractures among community-dwelling persons with Alzheimer's disease - A nested case-control study (3803)
Torvinen-Kiiskinen S et al Aliment Pharmacol Ther 47:1135 04-01-2018

Data are inconsistent regarding any association between use of proton-pump inhibitors (PPIs) and risk for bone fractures. To evaluate this potential relation, investigators used a nationwide Finnish database to perform a nested case-control study in community-dwelling patients with Alzheimer disease. Some 4800 patients with incident hip fractures were identified and matched to 19,000 controls without hip fractures (mean overall age, 84; 75% women). Data on PPI use were obtained from a nationwide prescription register.

Neither long-term (>1 year) nor cumulative PPI use was associated with excess risk for hip fractures - and current use showed a very small association that barely achieved statistical significance (odds ratio, 1.12; 95% confidence interval, 1.03-1.22). In addition, various PPIs showed no significant differences in associated fracture risk.

Comment:  Existing data about PPIs and fractures are mixed at best (and fraught with potential confounding). Heterogeneity among study populations, ascertainment methods, and control for interactions - as well as a very small effect magnitude - all cast doubt on meta-analyses. This study provides another example of an initially reported association between PPIs and long-term adverse events being refuted by subsequent findings. The modest, statistically marginal association with current PPI use may result from residual confounding, as current users were more likely to be women, to have comorbidities, and to use medications that raise fall risk. Appropriate use of PPIs should no longer be limited by concerns about fracture risk.


Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) (3804)
McDonald LC et al Clin Infect Dis 19; 66:e1 03-01-2018

Metronidazole is no longer recommended as first-line treatment for adults; nucleic acid testing alone is discouraged unless institutional guidelines limit the collection of specimens to those at increased risk for CDI.

Sponsoring Organization: Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

Target Audience: Infectious diseases physicians, gastroenterologists, hospitalists, clinical pharmacists, clinical microbiologists, and infection preventionists

Background and Objective: Since publication of the previous Clostridium difficile infection (CDI) guidelines in 2010, knowledge regarding epidemiology, testing, and treatment of CDI has progressed considerably. The new guidelines incorporate these advances. Pediatric populations are now covered by these recommendations as well.

The guidelines recommend two possible testing strategies:

Comment: Much has changed in the CDI world since 2010.The new guidelines are a needed update reflecting the growing role of FMT in patients with multiple recurrences of CDI and minimizing the role of metronidazole in adult CDI treatment. The two options for testing will, it is hoped, encourage hospital stakeholders to create local criteria discouraging the overtesting of patients with low clinical suspicion of CDI.

From Prescriber's Letter, 4/18:

You'll see a shift in meds to treat Clostridium difficile in adults, due to new guidelines from Infect Dis Soc of America (IDSA). Metronidazole has been the standard for treating C. diff, with oral vancomycin often saved for severe or recurrent infections. But about one in 4 patients relapse after a first C. diff episode. Lean toward vancomycin for initial treatment and recurrences. A month after treatment, one more patient will have resolution of diarrhea for every 10 patients treated with vancomycin instead of metronidazole. Treat an initial C. diff bout with oral vancomycin QID for 10 days. But if diarrhea recurs, use an extended taper. For example, after the initial 10-day course, give vancomycin BID for a week, daily for a week, then once every 2 to 3 days for up to 8 weeks. Prescribe Firvanq oral vancomycin solution. It's grape flavored and costs about $125 for 10 days, versus $600 for generic vancomycin caps. It's still okay to use metronidazole for mild infections, such as white count 15,000 or less and creatinine below 1.5 mg/dL, especially if cost of vancomycin is a barrier. Metronidazole is TID and costs about $15 for 10 days. But repeat courses could lead to neurotoxicity, dizziness, ataxia, confusion, etc. Save fidaxomicin (Dificid) for patients who relapse after vancomycin. Recurrence rates may be lower than vancomycin in some patients, but 10 days of BID fidaxomicin cost about $3,700. Refer for fecal transplant when patients have 3 or more C. diff episodes, to restore a healthy GI flora. Don't discourage probiotics if patients want to try one to prevent C. diff while taking an antibiotic, in combo with usual C. diff treatment, or to prevent recurrent C. diff. Suggest a product with Saccharomyces boulardii (Florastor, etc) or Lactobacillus species (Culturelle, etc). To prevent C. diff, continue to limit antibiotics, especially clindamycin, quinolones, etc. Also stop unnecessary PPIs. Don't use a stool test to see if C. diff has cleared, patients may remain asymptomatic carriers after treatment.


Efficacy of foot orthoses for the treatment of plantar heel pain: A systematic review and meta-analysis (3805)
Rasenberg N et al Br J Sports Med 03-19-2018

Although plantar fasciitis usually is a self-limited condition, it is frustrating for patients and clinicians because it can interfere with activity for weeks or months, and most treatments are not helpful. In this systematic review and meta-analysis, researchers examined the efficacy of foot orthoses, which often are recommended for treating patients with plantar fasciitis (called "plantar heel pain" in this analysis).

Reviewers identified 20 randomized trials in which foot orthoses were compared with sham orthoses, other treatments, or no treatment. Although some studies showed modest improvement with orthoses at single follow-up time points, the overall results showed no significant short- or long-term benefit for custom-made or prefabricated orthoses (beyond the symptom improvement experienced by control groups).

Comment: According to this meta-analysis, foot orthoses are largely ineffective. Patients should be aware of these findings before purchasing custom-made orthoses, which can be quite expensive. Stretching exercises and inexpensive ready-made silicone heel inserts probably are worth trying in most cases, although evidence supporting these interventions also is limited. Finally, although most patients who present with stated complaints of heel pain do have the syndrome of plantar fasciitis, we should not overlook other less common causes of heel pain, such as Achilles tendinopathy and calcaneal bursitis (which present with posterior, rather than plantar, tenderness).


Fluoroquinolone use and risk of aortic aneurysm and dissection: Nationwide cohort study (3806)
Pasternak B et al BMJ 360:k678 03-08-2018

Fluoroquinolones are associated with tendinopathy and tendon rupture (NEJM JW Gen Med Jan 1 2013 and Am J Med 2012; 125:1228.e23). The presumed mechanism is stimulation of matrix metalloproteinase activity, which results in degradation of collagen and extracellular matrix structural components. Because excessive metalloproteinase activity also is involved in the pathophysiology of aortic aneurysm, Swedish researchers performed a registry-based study to explore a possible association between fluoroquinolone use and aortic aneurysm or dissection. About 306,000 fluoroquinolone treatment episodes (78% ciprofloxacin) were propensity score-matched to the same number of amoxicillin treatment episodes in middle-aged or older adults (age, ≥50).

Within 60 days of the date that a prescription was filled, rates of aortic aneurysm or dissection were 1.2 cases per 1000 person-years for fluoroquinolone and 0.7 cases per 1000 person-years for amoxicillin - a significant difference. The estimated absolute difference was 82 cases of aortic aneurysm or dissection by 60 days per 1 million treatment episodes.

Comment: This large study, in which confounding was minimized through propensity-score matching, adds to a growing body of evidence that fluoroquinolone use is associated with excess risk for aortic aneurysm or dissection. The results are biologically plausible given the mechanisms discussed above.


MRI-targeted or standard biopsy for prostate-cancer diagnosis (3807)
Kasivisvanathan V et al NEJM 03-19-2018

Multiparametric magnetic resonance imaging (MRI) of the prostate provides anatomic, functional, and vascular information; it can be used to guide biopsy decisions in men undergoing prostate-specific antigen (PSA) screening (NEJM JW Gen Med Feb 15 2017 and Lancet 2017; 389:815). In this multicenter trial, 500 men with suspected localized prostate cancer (based on PSA level or digital rectal examination) were randomized either to standard biopsies (10-12 cores) guided by transrectal ultrasound, or to multiparametric MRI-targeted evaluation. In the latter group, only those patients whose MRI results were equivocal or suggestive of cancer underwent biopsy (targeted to abnormal areas on MRI).

Key findings were as follows:

Comment: Multiparametric MRI-targeted evaluation lowers the biopsy rate and identifies higher-grade prostate cancers more accurately than does conventional biopsy using nontargeted transrectal ultrasound. Thus, MRI appears to facilitate more-optimal evaluation of patients with suspected localized prostate cancer. However, it adds another layer of complexity to the downstream effects of PSA screening - a practice that itself remains controversial. -Allan S. Brett, MD


Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: The SPACE randomized clinical trial (3808)
Krebs EE et al JAMA 319:872 03-06-2018

Although most clinical guidelines recommend against opioids for patients with chronic back and musculoskeletal pain, opioids still are prescribed frequently for these conditions. In this randomized trial, conducted in the Minneapolis Veterans Affairs system, researchers randomized 240 patients (mean age, 58; mostly men) with moderate-to-severe chronic back pain or hip or knee osteoarthritis pain to flexible opioid or nonopioid regimens. Patients who were receiving long-term opioid therapy were excluded, as were those with substance abuse disorders or poor prognoses.

Opioid regimens started with immediate-release morphine or oxycodone or hydrocodone/acetaminophen and progressed to sustained-action morphine or oxycodone or transdermal fentanyl, all titrated to 100-mg morphine-equivalents, as needed. Nonopioid regimens started with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) and progressed to tricyclic antidepressants, gabapentinoids, topical analgesics, serotonin-norepinephrine reuptake inhibitors, and tramadol as needed. Patients pursued nonpharmacologic treatments as desired. Both groups were monitored in-person monthly until stable; subsequently, patients were monitored every 1 to 3 months (usually by telephone).

At 12 months, improvement in pain-related function was similar between the two groups. Pain intensity was significantly lower in the nonopioid group than in the opioid group, although this improvement was of borderline clinical significance. The opioid group had significantly more medication-related symptoms; adverse events did not differ between groups.

Comment: This nonblinded trial mimics real-life practice with its patient heterogeneity and wide range of medication choices. No benefit, and some potential harm, seems to be associated with use of opioids in patients with chronic back or osteoarthritis pain. Note, however, that several of the medications used by patients in this study's control group - including acetaminophen, NSAIDs, and gabapentinoids - also are ineffective or minimally effective in patients with chronic low back pain (NEJM JW Gen Med Jan 1 2018).


Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children (3809)
Goldenberg JZ et al Cochrane Database Syst Rev 12:CD006095 12-19-2017

Hospitalization and antibiotic use are major independent risk factors for Clostridium difficile-associated diarrhea (CDAD), and probiotic prophylaxis can lessen CDAD's occurrence (NEJM JW Gastroenterol May 2017 and Gastroenterology 2017; 152:1889), but guidelines have not yet endorsed broad use of this preventive intervention.

In this meta-analysis of 31 randomized trials that involved >8500 patients (7000 were inpatients, 7800 were adults, 1100 were children, and 2500 had baseline CDAD risk >5%), significant effects on CDAD incidence for probiotics compared with control (placebo or no probiotic) were:

Comment: Moderate-quality evidence supports a significant protective effect of probiotics against CDAD. Probiotics should not be given to patients who are immunocompromised, are pregnant, are in intensive care, or have prosthetic heart valves or certain preexisting gastrointestinal disorders (e.g., inflammatory bowel disease, ostomy). For most other hospitalized patients who receive antibiotics during hospitalization, prescribing 20 to 50 billion colony forming units of probiotics daily (starting within 24-48 hours of antibiotic initiation) can prevent CDAD.


Clostridium difficile Summary (3810)
Kney Various 04-22-2018

Metronidazole is no longer recommended as first-line treatment for adults; nucleic acid testing alone is discouraged unless institutional guidelines limit the collection of specimens to those at increased risk for CDI.

Sponsoring Organization: Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

Target Audience: Infectious diseases physicians, gastroenterologists, hospitalists, clinical pharmacists, clinical microbiologists, and infection preventionists

Background and Objective: Since publication of the previous Clostridium difficile infection (CDI) guidelines in 2010, knowledge regarding epidemiology, testing, and treatment of CDI has progressed considerably. The new guidelines incorporate these advances. Pediatric populations are now covered by these recommendations as well.

The guidelines recommend two possible testing strategies:

Comment: Much has changed in the CDI world since 2010.The new guidelines are a needed update reflecting the growing role of FMT in patients with multiple recurrences of CDI and minimizing the role of metronidazole in adult CDI treatment. The two options for testing will, it is hoped, encourage hospital stakeholders to create local criteria discouraging the overtesting of patients with low clinical suspicion of CDI.

From Prescriber's Letter, 4/18:

You'll see a shift in meds to treat Clostridium difficile in adults, due to new guidelines from Infect Dis Soc of America (IDSA). Metronidazole has been the standard for treating C. diff, with oral vancomycin often saved for severe or recurrent infections. But about one in 4 patients relapse after a first C. diff episode. Lean toward vancomycin for initial treatment and recurrences. A month after treatment, one more patient will have resolution of diarrhea for every 10 patients treated with vancomycin instead of metronidazole. Treat an initial C. diff bout with oral vancomycin QID for 10 days. But if diarrhea recurs, use an extended taper. For example, after the initial 10-day course, give vancomycin BID for a week, daily for a week, then once every 2 to 3 days for up to 8 weeks. Prescribe Firvanq oral vancomycin solution. It's grape flavored and costs about $125 for 10 days, versus $600 for generic vancomycin caps. It's still okay to use metronidazole for mild infections, such as white count 15,000 or less and creatinine below 1.5 mg/dL, especially if cost of vancomycin is a barrier. Metronidazole is TID and costs about $15 for 10 days. But repeat courses could lead to neurotoxicity, dizziness, ataxia, confusion, etc. Save fidaxomicin (Dificid) for patients who relapse after vancomycin. Recurrence rates may be lower than vancomycin in some patients, but 10 days of BID fidaxomicin cost about $3,700. Refer for fecal transplant when patients have 3 or more C. diff episodes, to restore a healthy GI flora. Don't discourage probiotics if patients want to try one to prevent C. diff while taking an antibiotic, in combo with usual C. diff treatment, or to prevent recurrent C. diff. Suggest a product with Saccharomyces boulardii (Florastor, etc) or Lactobacillus species (Culturelle, etc). To prevent C. diff, continue to limit antibiotics, especially clindamycin, quinolones, etc. Also stop unnecessary PPIs. Don't use a stool test to see if C. diff has cleared, patients may remain asymptomatic carriers after treatment.


Here are the last 10 additions to the PBrain by date


Clostridium difficile Summary (3810)
Kney Various 04-22-2018

Metronidazole is no longer recommended as first-line treatment for adults; nucleic acid testing alone is discouraged unless institutional guidelines limit the collection of specimens to those at increased risk for CDI.

Sponsoring Organization: Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

Target Audience: Infectious diseases physicians, gastroenterologists, hospitalists, clinical pharmacists, clinical microbiologists, and infection preventionists

Background and Objective: Since publication of the previous Clostridium difficile infection (CDI) guidelines in 2010, knowledge regarding epidemiology, testing, and treatment of CDI has progressed considerably. The new guidelines incorporate these advances. Pediatric populations are now covered by these recommendations as well.

The guidelines recommend two possible testing strategies:

Comment: Much has changed in the CDI world since 2010.The new guidelines are a needed update reflecting the growing role of FMT in patients with multiple recurrences of CDI and minimizing the role of metronidazole in adult CDI treatment. The two options for testing will, it is hoped, encourage hospital stakeholders to create local criteria discouraging the overtesting of patients with low clinical suspicion of CDI.

From Prescriber's Letter, 4/18:

You'll see a shift in meds to treat Clostridium difficile in adults, due to new guidelines from Infect Dis Soc of America (IDSA). Metronidazole has been the standard for treating C. diff, with oral vancomycin often saved for severe or recurrent infections. But about one in 4 patients relapse after a first C. diff episode. Lean toward vancomycin for initial treatment and recurrences. A month after treatment, one more patient will have resolution of diarrhea for every 10 patients treated with vancomycin instead of metronidazole. Treat an initial C. diff bout with oral vancomycin QID for 10 days. But if diarrhea recurs, use an extended taper. For example, after the initial 10-day course, give vancomycin BID for a week, daily for a week, then once every 2 to 3 days for up to 8 weeks. Prescribe Firvanq oral vancomycin solution. It's grape flavored and costs about $125 for 10 days, versus $600 for generic vancomycin caps. It's still okay to use metronidazole for mild infections, such as white count 15,000 or less and creatinine below 1.5 mg/dL, especially if cost of vancomycin is a barrier. Metronidazole is TID and costs about $15 for 10 days. But repeat courses could lead to neurotoxicity, dizziness, ataxia, confusion, etc. Save fidaxomicin (Dificid) for patients who relapse after vancomycin. Recurrence rates may be lower than vancomycin in some patients, but 10 days of BID fidaxomicin cost about $3,700. Refer for fecal transplant when patients have 3 or more C. diff episodes, to restore a healthy GI flora. Don't discourage probiotics if patients want to try one to prevent C. diff while taking an antibiotic, in combo with usual C. diff treatment, or to prevent recurrent C. diff. Suggest a product with Saccharomyces boulardii (Florastor, etc) or Lactobacillus species (Culturelle, etc). To prevent C. diff, continue to limit antibiotics, especially clindamycin, quinolones, etc. Also stop unnecessary PPIs. Don't use a stool test to see if C. diff has cleared, patients may remain asymptomatic carriers after treatment.


Relationship between clinic and ambulatory blood-pressure measurements and mortality (3798)
Banegas JR et al NEJM 378:1509 04-19-2018

Some research suggests that 24-hour ambulatory blood pressure (BP) predicts cardiovascular (CV) outcomes more accurately than does clinic BP. Now, Spanish researchers provide additional insights drawn from a national primary care-based registry. The study included 64,000 adults (mean age, 58) who had guideline-specified indications for 24-hour ambulatory BP monitoring and who were followed for a mean 5 years. Patients were categorized as having sustained hypertension (elevated clinic and ambulatory readings), white-coat hypertension (elevated clinic but not ambulatory readings), masked hypertension (elevated ambulatory but not clinic readings), or normotension.

During follow-up, all-cause and CV-related mortality were 6% and 2%, respectively. Both clinic and ambulatory BP measurements (systolic and diastolic) were associated, in graded fashion, with excess all-cause and CV-related mortality. However, in models in which clinic BP was adjusted for ambulatory BP (and vice versa), ambulatory BP predicted mortality more strongly. Interestingly, masked hypertension predicted CV mortality as strongly as did sustained hypertension (whether or not patients were receiving treatment at the time of BP measurement). White-coat hypertension in untreated patients was associated with excess mortality, whereas the white-coat pattern in treated patients was not.

Comment: This study validates the utility of 24-hour ambulatory BP measurement as a stronger prognostic tool than clinic measurement. Limitations include the fact that only baseline BP measurement and baseline drug-treatment status were used to predict outcomes; thus, the study didn't tell us how subsequent drug treatment of patients with the various hypertensive phenotypes (sustained, white-coat, and masked) affects outcomes. Moreover, many clinicians base treatment decisions on readings from patient-owned home BP units. Self-monitoring appears to be valuable (NEJM JW Gen Med Apr 12 2018; [e-pub] and Lancet 2018; 391:949), but additional research on how those readings compare with 24-hour ambulatory readings would be useful.


Evaluation and Treatment of Male Hypogonadism (3797)
Sargis et al JAMA 319:1375 04-03-2018

Full guideline


Tinnitus Summary (3796)
Many Many 04-01-2018

The American Tinnitus Association can be found at www.ata.org.

Tinnitus from NEJM, 3/29/18 (Bauer) - provides a nice review of causes and treatments (or lack thereof).

Clinical Practice Guideline: Tinnitus from Otolaryngology: Head Neck Surg 151:S1, 2014.


Cessation of ureteral colic does not necessarily mean that a ureteral stone has been expelled (3799)
Hernandez N et al J Urol 199:1011 04-01-2018

We know that a painful ureteral stone has passed if the patient brings it to us. But what about patients whose pain resolves but who don't retrieve their stones? In this single-center retrospective study, researchers identified 52 patients who met the following criteria: acute ureteral colic, stone confirmed by imaging, follow-up within several weeks, and no pain during the 72 hours prior to the follow-up visit.

At the follow-up encounters (which occurred an average of 35 days after the acute presentations), 26% of these pain-free patients still had ureteral stones (seen on plain film, ultrasound, computed tomography, or ureteroscopy). Most of these patients did not have microscopic hematuria. Imaging confirmed passage of stones in the remaining 74% of patients.

Comment: In this study of patients whose acute ureteral colic resolved but who didn't retrieve their stones, the ureteral stone persisted in about one quarter of patients at 1 month. The authors argue for repeat imaging in such patients, so that those with ongoing obstruction and hydronephrosis can be identified and treated. Among patients who don't pass their stones, it's unclear why pain resolves in some but persists in others.


Spironolactone versus clonidine as a fourth-drug therapy for resistant hypertension: The ReHOT randomized study (Resistant Hypertension Optimal Treatment) (3801)
Krieger EM et al Hypertension 71:681 04-01-2018

Resistant hypertension is an infrequent but difficult-to-manage clinical problem. After prescription of the common frontline drugs (diuretic, angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker, and calcium-channel blocker), the most suitable drug to add is uncertain. In the ReHOT study (Resistant Hypertension Optimal Treatment), researchers in Brazil compared spironolactone and clonidine as a fourth drug in patients with resistant hypertension.

In the two-phase study, 1597 hypertensive patients were treated with ≤3 drugs for 12 weeks, and 187 patients (11.7%) were identified as having resistant hypertension. Compared with the other patients, those with true resistant hypertension had higher incidences of stroke and diabetes and lower glomerular filtration rates. Of this group, 162 were randomized to spironolactone or clonidine; mean daily doses were 40 mg and 0.35 mg, respectively.

The primary combined endpoint of blood pressure (BP) control during office measurement (less than 140/90 mm Hg) and 24-hour ambulatory BP monitoring was not different between the two groups. Only 21% of patients achieved normal BP levels. On secondary endpoints, spironolactone was associated with greater decreases than clonidine in 24-hour systolic and diastolic BP and diastolic daytime ambulatory BP. Analyses limited to patients with greater than 80% adherence to drugs showed similar trends on the primary outcome. The rates of adverse effects were low for both drugs.

Comment - Cardiology - Joel M. Gore, MD: In this multicenter trial, more than 1 of 10 hypertension patients had resistant hypertension. Clonidine was not superior to spironolactone as a fourth-drug therapy. As the authors note, because spironolactone is taken once daily, it should be considered the better choice for patients with resistant hypertension who require a fourth drug.

Comment - General Medicine - Allan S. Brett, MD: Here's another reason to avoid clonidine. In some patients considered to have resistant hypertension, the "resistance" actually reflects poor adherence to their medication regimens, sometimes for understandable reasons (e.g., financial constraints in uninsured, impoverished populations). Adding clonidine can be risky, given the severe rebound hypertension that can occur in such patients when clonidine is started or stopped abruptly and unpredictably.


Proton pump inhibitor use and risk of hip fractures among community-dwelling persons with Alzheimer's disease - A nested case-control study (3803)
Torvinen-Kiiskinen S et al Aliment Pharmacol Ther 47:1135 04-01-2018

Data are inconsistent regarding any association between use of proton-pump inhibitors (PPIs) and risk for bone fractures. To evaluate this potential relation, investigators used a nationwide Finnish database to perform a nested case-control study in community-dwelling patients with Alzheimer disease. Some 4800 patients with incident hip fractures were identified and matched to 19,000 controls without hip fractures (mean overall age, 84; 75% women). Data on PPI use were obtained from a nationwide prescription register.

Neither long-term (>1 year) nor cumulative PPI use was associated with excess risk for hip fractures - and current use showed a very small association that barely achieved statistical significance (odds ratio, 1.12; 95% confidence interval, 1.03-1.22). In addition, various PPIs showed no significant differences in associated fracture risk.

Comment:  Existing data about PPIs and fractures are mixed at best (and fraught with potential confounding). Heterogeneity among study populations, ascertainment methods, and control for interactions - as well as a very small effect magnitude - all cast doubt on meta-analyses. This study provides another example of an initially reported association between PPIs and long-term adverse events being refuted by subsequent findings. The modest, statistically marginal association with current PPI use may result from residual confounding, as current users were more likely to be women, to have comorbidities, and to use medications that raise fall risk. Appropriate use of PPIs should no longer be limited by concerns about fracture risk.


Efficacy of foot orthoses for the treatment of plantar heel pain: A systematic review and meta-analysis (3805)
Rasenberg N et al Br J Sports Med 03-19-2018

Although plantar fasciitis usually is a self-limited condition, it is frustrating for patients and clinicians because it can interfere with activity for weeks or months, and most treatments are not helpful. In this systematic review and meta-analysis, researchers examined the efficacy of foot orthoses, which often are recommended for treating patients with plantar fasciitis (called "plantar heel pain" in this analysis).

Reviewers identified 20 randomized trials in which foot orthoses were compared with sham orthoses, other treatments, or no treatment. Although some studies showed modest improvement with orthoses at single follow-up time points, the overall results showed no significant short- or long-term benefit for custom-made or prefabricated orthoses (beyond the symptom improvement experienced by control groups).

Comment: According to this meta-analysis, foot orthoses are largely ineffective. Patients should be aware of these findings before purchasing custom-made orthoses, which can be quite expensive. Stretching exercises and inexpensive ready-made silicone heel inserts probably are worth trying in most cases, although evidence supporting these interventions also is limited. Finally, although most patients who present with stated complaints of heel pain do have the syndrome of plantar fasciitis, we should not overlook other less common causes of heel pain, such as Achilles tendinopathy and calcaneal bursitis (which present with posterior, rather than plantar, tenderness).


MRI-targeted or standard biopsy for prostate-cancer diagnosis (3807)
Kasivisvanathan V et al NEJM 03-19-2018

Multiparametric magnetic resonance imaging (MRI) of the prostate provides anatomic, functional, and vascular information; it can be used to guide biopsy decisions in men undergoing prostate-specific antigen (PSA) screening (NEJM JW Gen Med Feb 15 2017 and Lancet 2017; 389:815). In this multicenter trial, 500 men with suspected localized prostate cancer (based on PSA level or digital rectal examination) were randomized either to standard biopsies (10-12 cores) guided by transrectal ultrasound, or to multiparametric MRI-targeted evaluation. In the latter group, only those patients whose MRI results were equivocal or suggestive of cancer underwent biopsy (targeted to abnormal areas on MRI).

Key findings were as follows:

Comment: Multiparametric MRI-targeted evaluation lowers the biopsy rate and identifies higher-grade prostate cancers more accurately than does conventional biopsy using nontargeted transrectal ultrasound. Thus, MRI appears to facilitate more-optimal evaluation of patients with suspected localized prostate cancer. However, it adds another layer of complexity to the downstream effects of PSA screening - a practice that itself remains controversial. -Allan S. Brett, MD


Treatment of Osteoporosis (3787)
Cotts et al JAMA 319:1040 03-13-2018

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