Here are the last 20 additions to the PBrain (total entries as of now = 3705)


Non-steroidal anti-inflammatory drugs for spinal pain: A systematic review and meta-analysis (3686)
Machado GC et al Ann Rheum Dis 76:1269 07-01-2017

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed commonly for patients with low back and neck pain, randomized trials have not shown dramatic benefits. In this meta-analysis, researchers identified 35 randomized, placebo-controlled trials of NSAID therapy for acute or chronic low back pain or sciatica (33 trials) or neck pain (only 2 trials). Median study duration was 7 days; no study extended beyond 3 months. On 100-point pain scales, mean differences in pain relief between NSAIDs and placebo were 9.2 points for studies lasting less than 2 weeks and 7.7 points for studies lasting 2 weeks to 3 months. Outcomes were in this general range for both acute and chronic pain and for both nonsciatic and sciatic pain. About six patients had to be treated to alleviate pain in one patient (based on the assumption that a clinically meaningful difference is ≥10 points). For disability, mean differences between NSAIDs and placebo were also less than 10 points on 100-point scales.

Comment: These results confirm my clinical experience: Only a small proportion of patients with back pain or sciatica perceive benefit from NSAIDs, and some of the perceived benefit reflects placebo effects or the tendency for these conditions to fluctuate or improve. Moreover, in recent meta-analyses, acetaminophen was ineffective for low back pain (NEJM JW Gen Med May 1 2015 and BMJ 2015; 350:h1225) and opioids were only marginally effective (NEJM JW Gen Med Jul 15 2016 and JAMA Intern Med 2016; 176:958). Taken together, these meta-analyses paint a pessimistic picture of drug treatment for back pain.


Trial of tocilizumab in giant-cell arteritis (3687)
Stone JH et al NEJM 377:317 07-27-2017

Patients with giant-cell arteritis (GCA) generally are treated with high-dose steroids; once such treatment is started, tapering is difficult due to flares. Patients also often experience adverse effects from steroids. Steroid-sparing therapies include methotrexate, azathioprine, and hydroxychloroquine, but none of these are uniformly effective. In this 1-year, industry-sponsored, international study, 251 patients with GCA were randomized to receive subcutaneous tocilizumab (Actemra; weekly or every 2 weeks [biweekly]) or placebo. Tocilizumab patients tapered their steroid doses over 26 weeks. Placebo patients tapered their steroid doses over either 26 or 52 weeks.

Sustained remission at 52 weeks occurred in 56% of the weekly tocilizumab group, in 53% of the biweekly tocilizumab group, in 14% of the placebo group who tapered steroids over 26 weeks, and in 18% of the placebo group who tapered steroids over 52 weeks. In addition, median cumulative steroid doses in the two tocilizumab groups were 1862 mg, compared with 3296 mg in the 26-week placebo group and 3818 mg in the 52-week placebo group. Serious adverse events were higher in the placebo groups, although neutropenia occurred in 4% of tocilizumab patients, and one tocilizumab patient developed ischemic optic neuropathy that resolved with steroid therapy.

Comment: This is an impressive study, but several caveats exist: Risks of tocilizumab beyond 1 year of therapy are still to be determined, and only slightly more than half of tocilizumab patients sustained steroid-free remission at 1 year. I look forward to results of the 2-year open-label follow-up study in these patients. However, adding tocilizumab to the treatment options for patients with GCA is potentially practice changing.


Association between alendronate use and hip fracture risk in older patients using oral prednisolone (3688)
Axelsson KF et al JAMA 318:146 07-11-2017

Bisphosphonate drugs are recommended to prevent glucocorticoid-related fractures. Because the specific effect of these drugs on hip fracture incidence in steroid-treated patients is unclear, Swedish investigators conducted this retrospective study using a registry of older patients (age, ≥65) called "Senior Alert." Nearly all of these patients were enrolled during hospitalizations or were nursing home residents. Among patients in this database, 1802 took ≥5 mg of prednisolone daily for at least 3 months and started the bisphosphonate alendronate shortly after beginning steroid therapy; these patients were propensity-matched with 1802 patients who took prednisolone but no osteoporosis drug. About half the patients had diagnoses of either polymyalgia rheumatica or rheumatoid arthritis, and about 15% had diagnoses of osteoporosis. Median prednisolone dose was about 8 mg daily.

During average follow-up of 1.3 years, hip fracture incidence was significantly lower in alendronate recipients than in propensity-matched controls (10 vs. 27 fractures per 1000 person-years). Thus, for every 60 steroid-treated patients who took alendronate, roughly 1 fewer hip fractures occurred.

Comment: With the usual caveat that retrospective observational studies generally do not prove causality, this study suggests that alendronate can prevent hip fractures in older patients who take daily glucocorticoids. However, whether these results apply to average community-dwelling outpatients is unclear, because the database was composed largely of recently hospitalized patients and nursing home residents. An American College of Rheumatology guideline on glucocorticoid-induced osteoporosis bases its recommendations for bisphosphonate therapy on patient age, steroid duration and dose, and presence of other osteoporosis risk factors (Arthritis Care Res [Hoboken] 2010; 62:1515).


Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): A randomised, double-blind, placebo-controlled trial (3689)
Gibson PG et al Lancet 07-04-2017

Macrolide antibiotics have antibacterial, antiviral, and anti-inflammatory effects and thus have generated interest for treating patients with asthma. Australian researchers evaluated azithromycin as add-on therapy in a randomized trial that involved 420 adults (median age, 60) with asthma not controlled with inhaled corticosteroids and long-acting bronchodilators. Participants received azithromycin (500 mg) or placebo thrice weekly for 48 weeks.

Azithromycin patients had significantly fewer moderate or severe exacerbations than did placebo patients (1.07 vs. 1.86 per person-year). Fewer exacerbations were seen for both eosinophilic and neutrophilic asthma, and fewer azithromycin patients had at least one exacerbation (44% vs. 61%). Asthma-related quality of life improved significantly in the azithromycin group. Diarrhea (but no other potentially drug-related adverse effect) was more common with azithromycin; sputum cultures of azithromycin patients showed a nonsignificant increase in azithromycin-resistant bacteria.

Comment: This study shows that azithromycin is effective in preventing asthma exacerbations in patients whose disease is not controlled by typical inhaled corticosteroids and long-acting β-agonist therapy, but long-term antibiotic resistance is a concern. An editorialist notes that azithromycin should be reserved for patients at highest risk for exacerbations and restricted to peak respiratory distress months in autumn and winter. Whether azithromycin's benefit was mediated by preventing respiratory infections, enhancing viral inactivation, or other anti-inflammatory effects is unclear. Given that we have specific treatments for patients with severe allergic and eosinophilic asthma (omalizumab [Xolair]) and anti-interleukin [IL]-5 monoclonal antibodies, respectively), azithromycin might be especially attractive for patients with neutrophilic asthma. In my allergy/asthma specialty practice, I will try azithromycin in those patients with continued exacerbations despite high-dose corticosteroid/long-acting β-agonist and tiotropium (Spiriva) therapy who aren't candidates for biologics.


Probiotics for Gastrointestinal Conditions: A Summary of the Evidence (3690)
Wilkins et al AFP 96:170 08-01-2017

Probiotics contain microorganisms, most of which are bacteria similar to the beneficial bacteria that occur naturally in the human gut. Probiotics have been widely studied in a variety of gastrointestinal diseases. The most-studied species include Lactobacillus, Bifidobacterium, and Saccharomyces. However, a lack of clear guidelines on when to use probiotics and the most effective probiotic for different gastrointestinal conditions may be confusing for family physicians and their patients. Probiotics have an important role in the maintenance of immunologic equilibrium in the gastrointestinal tract through the direct interaction with immune cells. Probiotic effectiveness can be species-, dose-, and disease-specific, and the duration of therapy depends on the clinical indication. There is high-quality evidence that probiotics are effective for acute infectious diarrhea, antibiotic-associated diarrhea, Clostridium difficile-associated diarrhea, hepatic encephalopathy, ulcerative colitis, irritable bowel syndrome, functional gastrointestinal disorders, and necrotizing enterocolitis. Conversely, there is evidence that probiotics are not effective for acute pancreatitis and Crohn disease. Probiotics are safe for infants, children, adults, and older patients, but caution is advised in immunologically vulnerable populations.

Full article which includes a list of brandname products with contents, as well as which probiotics are supported by data for which condition.


Post-bariatric surgery patients: Your role in their long-term care (3691)
Kreykes et al JFP 66:356 06-01-2017

Full article


Bipolar disorder: Making the Dx, selecting the right Rx (3692)
Wells et al JFP 66:375 06-01-2017

Provides a nice table of medications for bipolar I and II with level of evidence supporting them.

Full article


Oral Agent Offers Relief from Generalized Hyperhidrosis (3693)
Jarrett et al JFP 66:392 06-01-2017

Summary of an article that found benefit in treating hyperhidrosis with oxybutinin 2.5 to 7.5 mg.

Full article


Porphyria (3694)
Bissell et al NEJM 377:862 08-31-2017

Full article


Stroke: Secondary Prevention of Ischemic Events (3695)
Morris et al JFP 66:420 07-01-2017

The major area that I find confusing is antiplatelet therapy - primarily because the data is murky and inconsistent. For most patients who do not need anticoagulation (warfarin or NOAC), aspirin 81 mg is a fine choice. After a stroke with significant intracranial arterial stenosis, DAPT with asprin and clopidogrel for 90 days is recommended. Clopidogrel alone is a reasonable option - especially if the patient had a stroke while taking aspirin. Longterm DAPT is not suggested. Comment: My own experience suggests either DAPT or warfarin is suggested for vertebrobasilar disease.

Full article


Safety of Long-Term PPI Use (3696)
Med Ltr Med Ltr 59:131 08-14-2017

Nice review of the issues with PPI use. Fracture: Nurses' Health Study failed to find an association after confounding variables were accounted for. No link to osteoporosis has been found. Hypomagnesemia: RR of 1.43 in one large study - but it is quite uncommon. Kidney disease: Mechanism unknown, but association has been noted (RR 1.45 after 14 years. B12 deficiency: Risk appears to be higher in women and younger people. Pneumonia: Questionable association. C diff: Questionable association. Dementia: One prospective study suggested RR of 1.45 in patients over 75 taking PPI, but Nurses' Health Study did not find an association with dementia.

Full article


Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): A prospective cohort study. (3697)
Dehghan M et al Lancet 08-28-2017

Standard dietary advice to restrict total fat and saturated fatty acids (<30% and <10% of total energy, respectively) is based largely on a few observational studies conducted years ago in North America and Europe. However, recent meta-analyses have shown no association, or an inverse relation, between saturated fatty acid intake and total mortality and adverse cardiovascular (CV) events.

Researchers conducted detailed analyses of the diets of more than 135,000 people with a range of income levels in 18 countries on five continents. Participants were sorted into quintiles based on percentage of dietary energy derived from carbohydrates; protein; and total, saturated, monounsaturated, and polyunsaturated fats. Median follow-up was 7.4 years. After adjustment for education, smoking, physical activity, diabetes, urban versus rural location, total energy intake, and geographic region, higher carbohydrate intake was associated with higher risk for overall mortality and non-CV-related death but was not associated with major adverse CV events assessed individually or as a group. Conversely, higher intakes of total, saturated, monounsaturated, and polyunsaturated fats were associated with lower risk for overall and non-CV-related death and were not associated with adverse CV events (other than an inverse relation between saturated fat intake and stroke).

Comment: Data from this large, diverse international cohort does not support current dietary guidelines that recommend restricting total and saturated fats. The findings suggest that people who eat high carbohydrate diets might benefit from substituting fats for some of their carbohydrates.


Effect of intensive blood-pressure treatment on patient-reported outcomes (3698)
Berlowitz DR et al NEJM 377:733 08-24-2017

In the landmark SPRINT study, nondiabetic hypertensive patients at high risk for adverse cardiovascular (CV) outcomes were treated to achieve intensive or standard systolic blood pressure (BP) targets (<120 vs. <140 mm Hg). During average follow-up of 3.3 years, a composite adverse CV outcome occurred significantly less frequently in the intensively treated group (5.2% vs. 6.8%; NEJM JW Gen Med Dec 15 2015 and N Engl J Med 2015; 373:2174). But two important questions remain: First, because side effects of BP medications can affect general well-being, did intensive treatment have an adverse effect on quality of life, compared with standard treatment? And second, because about 60 people had to be treated intensively to prevent one adverse CV event (reflecting the 1.6 percentage-point benefit), is intensive treatment cost-effective? SPRINT investigators now have addressed these questions.

SPRINT participants periodically completed standardized questionnaires that assessed physical and mental health quality of life and depression. Scores changed very little during the trial, with no significant differences between the intensive- and standard-treatment groups. Cost-effectiveness was estimated with simulation models that included SPRINT outcomes plus other estimates of costs, risks, and benefits beyond the limited SPRINT time frame, and utilities (i.e., numerical representation of quality of life in various health states). Across varying estimates and assumptions, the incremental cost of intensive treatment (per quality-adjusted-life-year gained) was often

Comment: Reassuringly, quality of life was not impaired, on average, by intensive BP treatment. Moreover, the cost-effectiveness estimates are within the willingness-to-pay thresholds often considered to be acceptable in the U.S. But we should keep two things in mind: First, SPRINT participants were high-risk patients, and second, the average achieved systolic BP in the intensive-treatment group (121.5 mm Hg) remained higher than the target. Extrapolating SPRINT results to lower-risk patients, or treating more aggressively to get everyone below 120 mm Hg, potentially could negate these favorable quality-of-life and economic outcomes.


No association between proton pump inhibitor use and risk of Alzheimer's disease (3699)
Taipale H et al Am J Gastroenterol 2017 Jul 11; 06-11-2017

When a widely publicized 2016 study from Germany reported an association between use of proton-pump inhibitors (PPIs) and dementia, many PPI users were alarmed and asked their physicians about it (NEJM JW Gen Med Jun 15 2016 and JAMA Neurol 2016; 73:410). That study had several flaws: It came from an administrative claims database, dementia diagnoses were not confirmed, and adjustment for confounding variables was limited. Now, two new studies - both with substantial adjustment for confounding variables - have been published.

In one study, researchers took advantage of a database that includes all people in Finland with formally diagnosed Alzheimer disease. Prior PPI use was similar in the 70,000 Alzheimer patients and 280,000 age- and sex-matched controls without Alzheimer disease. No consistent dose-response relation was seen between PPI use and Alzheimer disease. Another analysis involved nearly 14,000 women (mean age, 61) from the prospective observational U.S. Nurses' Health Study who underwent 20-minute self-administered tests of cognition. In participants with prior use of PPIs but not histamine-2-receptor antagonists (H2RAs), PPI use and cognitive scores were not related. However, among those with prior use of H2RAs but not PPIs, an association between H2RA use and poorer cognitive scores was noted.

Comment: The study from Finland is especially important, because it is population-based and because Alzheimer disease was diagnosed according to specified protocols. The U.S. study (which addresses performance on a brief cognitive test, but not dementia) is less informative but still reassuring; however, the association between H2-receptor antagonists and poorer cognitive performance was unexpected and requires further study. In any case, we still don't have decisive evidence that PPIs cause Alzheimer disease or facilitate its development.

Additional source: Lochhead P et al. Association between proton pump inhibitor use and cognitive function in women. Gastroenterology 2017 Jul 17


Association of beta-blocker use with less prevalent joint pain and lower opioid requirement in people with osteoarthritis (3700)
Valdes AM et al Arthritis Care Res (Hoboken) 69:1076 07-01-2017

Adrenergic neurotransmission is involved in pain pathways, and several animal and human studies suggest that β-blockers have antinociceptive effects. Given these observations, U.K. researchers examined associations between β-blocker use and pain in a cohort of 873 patients with hip or knee osteoarthritis and hypertension; 40% of these patients were taking β-blockers.

On a standardized scale, β-blocker users were significantly less likely than nonusers to have at least moderate joint pain (34% vs. 42%). In analyses adjusted for various demographic and clinical characteristics, at least moderate joint pain remained significantly less likely among β-blocker users (odds ratio, 0.68). β-blocker users also were significantly less likely than nonusers to be taking opioid analgesics. No other antihypertensive class (i.e., diuretics, calcium-channel blockers, angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers) was associated with attenuated pain.

Comment: Managing pain is difficult in older arthritic patients, given the many contraindications to nonsteroidal anti-inflammatory drugs and opioids. β-blockers recently have dropped to second-tier therapy for hypertension, but if this intriguing finding - a possible analgesic effect of β-blockers - can be corroborated, it could become a relative indication for earlier β-blocker use in hypertensive patients with osteoarthritic pain.


Comparative effectiveness of high-dose versus standard-dose influenza vaccination on numbers of US nursing home residents admitted to hospital: A cluster-randomized trial (3701)
Gravenstein S et al Lancet Respir Med 07-20-2017

In previous studies, high-dose influenza vaccine provided better protection than standard-dose vaccine against laboratory-confirmed influenza in Medicare-eligible individuals. To study high-dose vaccine effectiveness in a high-risk, frail population, investigators conducted an industry-supported trial assessing respiratory-related hospital admissions in long-stay nursing home residents aged 65 years and older. They cluster-randomized 823 nursing homes in 38 U.S. states to facility-wide use of standard-dose or high-dose (4 times more antigen) vaccine for the 2013-2014 influenza season. Half of the nursing homes were also given free standard-dose vaccine for staff.

Among more than 38,000 patients for whom Medicare hospital claims were available, the incidence of respiratory-related hospital admissions was significantly reduced in residents of facilities randomized to high-dose rather than low-dose vaccine (3.4% vs. 3.9% over 6 months). Incidence of all-cause hospitalization in the entire population of about 53,000 was also significantly lower in residents of high-dose vaccine facilities than in residents of low-dose facilities. Rates of death and of decline in function did not differ by vaccine group. Staff vaccination rates were about 55% in all groups.

Comment: In these nursing home residents, high-dose influenza vaccine reduced hospitalization risk compared with standard-dose vaccine. The difference was significant but not dramatic; however, the trial was conducted in a year when the predominant circulating strain was A(H1N1)pdm09. During seasons with A/H3N2 strain predominance, overall hospitalization rates were two to four times higher than in this study, so these findings could represent a conservative estimate of benefit. Editorialists note the absence of laboratory confirmation of outcomes, which moderates the possible causal link between the favorable results and influenza per se. They also note that other effective choices are now available for adults aged 65 and older, with the approval of adjuvanted influenza vaccine and a recombinant protein vaccine (NEJM JW Infect Dis Sep 2017 and N Engl J Med 2017 Jun 22; 376:2427).


Serum 25-hydroxyvitamin D insufficiency in search of a bone disease (3702)
Shah S et al J Clin Endocrinol Metab 102:2321 03-30-2017

Although many afflictions have been attributed to vitamin D deficiency, bone disease (i.e., osteomalacia) is the clinical entity with the strongest causal link to vitamin D deficiency. In this study, Australian researchers sought to identify the 25-hydroxyvitamin D (25[OH]D) level below which abnormal bone physiology becomes evident. Data were obtained from a large cohort of 12,000 adults and from a smaller cohort of 150 adults who underwent more extensive testing. Patients with hypercalcemia or renal disease were excluded.

Across 25(OH)D levels ranging from 12 to 60 ng/mL (30 to 150 nmol/L), there was a weak inverse relation between 25(OH)D and serum parathyroid hormone (PTH), and a weak positive relation between 25(OH)D and serum calcium. However, a significant breakpoint was evident at a threshold 25(OH)D level of less than 12 ng/mL: Serum calcium levels became distinctly lower and PTH levels became distinctly higher. The smaller cohort showed no significant correlations between 25(OH)D levels and markers of bone turnover (collagen- and procollagen-related peptides) or bone integrity (i.e., bone density, mineralization, and porosity); however, the small sample size provided limited statistical power for the latter findings.

Comment: In the U.S., many laboratories define 25(OH)D levels <20 ng/mL (50 nmol/L) as deficient, and levels between 20 and 30 ng/mL (50−75 nmol/L) as "insufficient" (J Clin Endocrinol Metab 2011; 96:1911). However, the current study authors believe their data justify a cutoff of 12 ng/mL (30 nmol/L) for deficiency, and they challenge the idea of a specific insufficiency range. This study might not settle the controversy about the optimal cutoff for deficiency, but it supports my concern that many clinicians push vitamin D supplementation excessively, without evidence of clinical or physiological benefit.


Menopausal Hormone Therapy and Long-Term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials (3703)
Manson et al JAMA 318:927 09-12-2017

Full article

Editorial


Exercise Stress Testing: Indications and Common Questions (3704)
Garner et al AFP 96:293 09-01-2017

Exercise stress testing is a validated diagnostic test for coronary artery disease in symptomatic patients, and is used in the evaluation of patients with known cardiac disease. Testing of asymptomatic patients is generally not indicated. It may be performed in select deconditioned adults before starting a vigorous exercise program, but no studies have compared outcomes from preexercise testing vs. encouraging light exercise with gradual increases in exertion. Preoperative exercise stress testing is helpful for risk stratification in patients undergoing vascular surgery or who have active cardiac symptoms before undergoing nonemergent noncardiac surgery. Exercise stress testing without imaging is the preferred initial choice for risk stratification in most women. Sensitivity and specificity increase with the use of adjunctive imaging such as echocardiography or myocardial perfusion imaging with single-photon emission computed tomography. Exercise stress testing is rarely an appropriate option to evaluate persons with known coronary artery disease who have no new symptoms less than two years after percutaneous intervention or less than five years after coronary artery bypass grafting. The Duke treadmill score has excellent prognostic value for exercise stress testing. Imaging is not necessary if patients are able to achieve more than 10 metabolic equivalents on exercise stress testing. Exercise stress testing is not indicated before noncardiac surgeries in patients who can achieve 4 metabolic equivalents without symptoms.

Full article


Thrombophilia Testing and Venous Thrombosis (3705)
Connors NEJM 377:1177 09-21-2017

Ordering thrombophilia tests is easy; determining whom to test and how to use the results is not. Although inherited and acquired thrombophilias are acknowledged to increase the risk of venous thromboembolism (VTE), the majority of patients with VTE should not be tested for thrombophilia. Data showing the clinical usefulness and benefits of testing are limited or nonexistent, as are data supporting the benefit of primary or secondary VTE prophylaxis based on thrombophilia status alone. Testing for inherited thrombophilia is controversial, with some arguing that these tests should never be performed. No validated testing guidelines have been published. The American College of Chest Physicians does not give guidance on thrombophilia testing in its ninth edition of clinical practice guidelines for antithrombotic therapy or its 2016 VTE update, whereas the American Society of Hematology's 2013 Choosing Wisely campaign recommends not testing for thrombophilia in adults with VTE who have major transient risk factors. According to the most comprehensive guide, Clinical Guidelines for Testing for Heritable Thrombophilia, published by the British Committee for Standards in Haematology, "It is not possible to give a validated recommendation as to how such patients (and families) should be selected" for testing. Although similar guidelines advise limiting testing to a narrow range of specific clinical situations and patients, the recommendations are not uniform.5-9 These recommendations have been developed in response to indiscriminate testing practices and misconceptions regarding the role of thrombophilia status in the management of VTE.

Patients with unprovoked VTE have a significantly increased risk of recurrence, as compared with patients who have provoked VTE, with roughly a 10% risk in the first year after anticoagulant therapy is stopped and with a cumulative risk of 40% at 5 years and more than 50% at 10 years.33 Although patients with unprovoked VTE may have thrombophilia, the risk of recurrence is not influenced by factor V Leiden and the prothrombin gene mutation, which are common inherited thrombophilias.

Full article


Here are the last 10 additions to the PBrain by date


Thrombophilia Testing and Venous Thrombosis (3705)
Connors NEJM 377:1177 09-21-2017

Ordering thrombophilia tests is easy; determining whom to test and how to use the results is not. Although inherited and acquired thrombophilias are acknowledged to increase the risk of venous thromboembolism (VTE), the majority of patients with VTE should not be tested for thrombophilia. Data showing the clinical usefulness and benefits of testing are limited or nonexistent, as are data supporting the benefit of primary or secondary VTE prophylaxis based on thrombophilia status alone. Testing for inherited thrombophilia is controversial, with some arguing that these tests should never be performed. No validated testing guidelines have been published. The American College of Chest Physicians does not give guidance on thrombophilia testing in its ninth edition of clinical practice guidelines for antithrombotic therapy or its 2016 VTE update, whereas the American Society of Hematology's 2013 Choosing Wisely campaign recommends not testing for thrombophilia in adults with VTE who have major transient risk factors. According to the most comprehensive guide, Clinical Guidelines for Testing for Heritable Thrombophilia, published by the British Committee for Standards in Haematology, "It is not possible to give a validated recommendation as to how such patients (and families) should be selected" for testing. Although similar guidelines advise limiting testing to a narrow range of specific clinical situations and patients, the recommendations are not uniform.5-9 These recommendations have been developed in response to indiscriminate testing practices and misconceptions regarding the role of thrombophilia status in the management of VTE.

Patients with unprovoked VTE have a significantly increased risk of recurrence, as compared with patients who have provoked VTE, with roughly a 10% risk in the first year after anticoagulant therapy is stopped and with a cumulative risk of 40% at 5 years and more than 50% at 10 years.33 Although patients with unprovoked VTE may have thrombophilia, the risk of recurrence is not influenced by factor V Leiden and the prothrombin gene mutation, which are common inherited thrombophilias.

Full article


Menopausal Hormone Therapy and Long-Term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials (3703)
Manson et al JAMA 318:927 09-12-2017

Full article

Editorial


Exercise Stress Testing: Indications and Common Questions (3704)
Garner et al AFP 96:293 09-01-2017

Exercise stress testing is a validated diagnostic test for coronary artery disease in symptomatic patients, and is used in the evaluation of patients with known cardiac disease. Testing of asymptomatic patients is generally not indicated. It may be performed in select deconditioned adults before starting a vigorous exercise program, but no studies have compared outcomes from preexercise testing vs. encouraging light exercise with gradual increases in exertion. Preoperative exercise stress testing is helpful for risk stratification in patients undergoing vascular surgery or who have active cardiac symptoms before undergoing nonemergent noncardiac surgery. Exercise stress testing without imaging is the preferred initial choice for risk stratification in most women. Sensitivity and specificity increase with the use of adjunctive imaging such as echocardiography or myocardial perfusion imaging with single-photon emission computed tomography. Exercise stress testing is rarely an appropriate option to evaluate persons with known coronary artery disease who have no new symptoms less than two years after percutaneous intervention or less than five years after coronary artery bypass grafting. The Duke treadmill score has excellent prognostic value for exercise stress testing. Imaging is not necessary if patients are able to achieve more than 10 metabolic equivalents on exercise stress testing. Exercise stress testing is not indicated before noncardiac surgeries in patients who can achieve 4 metabolic equivalents without symptoms.

Full article


Porphyria (3694)
Bissell et al NEJM 377:862 08-31-2017

Full article


Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): A prospective cohort study. (3697)
Dehghan M et al Lancet 08-28-2017

Standard dietary advice to restrict total fat and saturated fatty acids (<30% and <10% of total energy, respectively) is based largely on a few observational studies conducted years ago in North America and Europe. However, recent meta-analyses have shown no association, or an inverse relation, between saturated fatty acid intake and total mortality and adverse cardiovascular (CV) events.

Researchers conducted detailed analyses of the diets of more than 135,000 people with a range of income levels in 18 countries on five continents. Participants were sorted into quintiles based on percentage of dietary energy derived from carbohydrates; protein; and total, saturated, monounsaturated, and polyunsaturated fats. Median follow-up was 7.4 years. After adjustment for education, smoking, physical activity, diabetes, urban versus rural location, total energy intake, and geographic region, higher carbohydrate intake was associated with higher risk for overall mortality and non-CV-related death but was not associated with major adverse CV events assessed individually or as a group. Conversely, higher intakes of total, saturated, monounsaturated, and polyunsaturated fats were associated with lower risk for overall and non-CV-related death and were not associated with adverse CV events (other than an inverse relation between saturated fat intake and stroke).

Comment: Data from this large, diverse international cohort does not support current dietary guidelines that recommend restricting total and saturated fats. The findings suggest that people who eat high carbohydrate diets might benefit from substituting fats for some of their carbohydrates.


Effect of intensive blood-pressure treatment on patient-reported outcomes (3698)
Berlowitz DR et al NEJM 377:733 08-24-2017

In the landmark SPRINT study, nondiabetic hypertensive patients at high risk for adverse cardiovascular (CV) outcomes were treated to achieve intensive or standard systolic blood pressure (BP) targets (<120 vs. <140 mm Hg). During average follow-up of 3.3 years, a composite adverse CV outcome occurred significantly less frequently in the intensively treated group (5.2% vs. 6.8%; NEJM JW Gen Med Dec 15 2015 and N Engl J Med 2015; 373:2174). But two important questions remain: First, because side effects of BP medications can affect general well-being, did intensive treatment have an adverse effect on quality of life, compared with standard treatment? And second, because about 60 people had to be treated intensively to prevent one adverse CV event (reflecting the 1.6 percentage-point benefit), is intensive treatment cost-effective? SPRINT investigators now have addressed these questions.

SPRINT participants periodically completed standardized questionnaires that assessed physical and mental health quality of life and depression. Scores changed very little during the trial, with no significant differences between the intensive- and standard-treatment groups. Cost-effectiveness was estimated with simulation models that included SPRINT outcomes plus other estimates of costs, risks, and benefits beyond the limited SPRINT time frame, and utilities (i.e., numerical representation of quality of life in various health states). Across varying estimates and assumptions, the incremental cost of intensive treatment (per quality-adjusted-life-year gained) was often

Comment: Reassuringly, quality of life was not impaired, on average, by intensive BP treatment. Moreover, the cost-effectiveness estimates are within the willingness-to-pay thresholds often considered to be acceptable in the U.S. But we should keep two things in mind: First, SPRINT participants were high-risk patients, and second, the average achieved systolic BP in the intensive-treatment group (121.5 mm Hg) remained higher than the target. Extrapolating SPRINT results to lower-risk patients, or treating more aggressively to get everyone below 120 mm Hg, potentially could negate these favorable quality-of-life and economic outcomes.


Celiac Disease and Nonceliac Gluten Sensitivity: A Review (3682)
Leonard et al JAMA 318:647 08-15-2017

Observations: Celiac disease is a gluten-induced immune-mediated enteropathy characterized by a specific genetic genotype (HLA-DQ2 and HLA-DQ8 genes) and autoantibodies (antitissue transglutaminase and antiendomysial). Although the inflammatory process specifically targets the intestinal mucosa, patients may present with gastrointestinal signs or symptoms, extraintestinal signs or symptoms, or both, suggesting that celiac disease is a systemic disease. Nonceliac gluten sensitivity is diagnosed in individuals who do not have celiac disease or wheat allergy but who have intestinal symptoms, extraintestinal symptoms, or both, related to ingestion of gluten-containing grains, with symptomatic improvement on their withdrawal. The clinical variability and the lack of validated biomarkers for nonceliac gluten sensitivity make establishing the prevalence, reaching a diagnosis, and further study of this condition difficult. Nevertheless, it is possible to differentiate specific gluten-related disorders from other conditions, based on currently available investigations and algorithms. Clinicians cannot distinguish between celiac disease and nonceliac gluten sensitivity by symptoms, as they are similar in both. Therefore, screening for celiac disease must occur before a gluten-free diet is implemented, since once a patient initiates a gluten-free diet, testing for celiac disease is no longer accurate.

Conclusions and Relevance: Celiac disease and nonceliac gluten sensitivity are common. Although both conditions are treated with a gluten-free diet, distinguishing between celiac disease and nonceliac gluten sensitivity is important for long-term therapy. Patients with celiac disease should be followed up closely for dietary adherence, nutritional deficiencies, and the development of possible comorbidities.

Full article


Safety of Long-Term PPI Use (3696)
Med Ltr Med Ltr 59:131 08-14-2017

Nice review of the issues with PPI use. Fracture: Nurses' Health Study failed to find an association after confounding variables were accounted for. No link to osteoporosis has been found. Hypomagnesemia: RR of 1.43 in one large study - but it is quite uncommon. Kidney disease: Mechanism unknown, but association has been noted (RR 1.45 after 14 years. B12 deficiency: Risk appears to be higher in women and younger people. Pneumonia: Questionable association. C diff: Questionable association. Dementia: One prospective study suggested RR of 1.45 in patients over 75 taking PPI, but Nurses' Health Study did not find an association with dementia.

Full article


Menopause and Hormone Replacement Therapy (3678)
PL PL 24:43 08-01-2017

More women will use hormone therapy to manage menopausal symptoms. Hormone therapy (HT) used to be popular in the 1980s and 1990s. Then it fell out of favor about 15 years ago when the big Women's Health Initiative trial found that estrogen plus progestin increased the risk of breast cancer, CV disease, and dementia in older women.

Now the pendulum is swinging again, due to new evidence and re-analysis of older data. Consider these factors to help women with moderate to severe menopausal symptoms decide if HT makes sense. Age and time since final period. Consider HT for bothersome menopausal symptoms in healthy women under age 60, or within 10 years of their last period. The benefits of improved quality of life and prevention of bone loss seem to outweigh risks. Plus some studies suggest that using estrogen alone in women under 60 is linked to a lower risk of heart disease. But don't start systemic HT in women over age 60 or 10 years past menopause due to higher risk of stroke, MI, and dementia.

Breast cancer. Risk is usually low. Using estrogen and a progestin for 4 to 5 years is linked to one more case of breast cancer per 1,000 women/yr. Estrogen alone for up to 7 years doesn't seem to increase risk. Be careful using systemic HT in women at high risk for breast cancer due to a strong family history or BRCA gene mutations. Continue to avoid systemic HT in breast cancer survivors. But a low-dose vaginal estrogen may be okay for severe genitourinary symptoms in women who aren't taking an aromatase inhibitor (letrozole, etc).

Cardiovascular risk. Avoid systemic HT in women with multiple CV risks or a history of stroke, MI, or venous thrombosis. But it's okay to use low-dose, short-term HT for severe menopausal symptoms in women with diabetes or controlled hypertension. If hormone therapy isn't appropriate, consider nonhormonal options, such as an SSRI or SNRI for hot flashes, or a vaginal moisturizer (Replens, etc) plus a lubricant for vaginal symptoms.

Women will ask you about hormone therapy (HT) options and how long to continue them for menopausal symptoms. Choice of treatment. For hot flashes, consider a systemic estrogen - oral, transdermal, or vaginal ring (Femring). Think about a patch, gel, or spray to possibly lower the risk of blood clots. Use the lowest dose possible to control symptoms and explain it can take up to 12 weeks to see the full effect. Consider cost, convenience, and patient preference. For example, start with an estradiol patch (Climara, etc) 0.025 mg once a week, oral estradiol (Estrace, etc) 0.5 mg daily, oral conjugated estrogens (Premarin) 0.3 mg daily, or estradiol vaginal ring (Femring) 0.05 mg every 90 days.

For women with a uterus, add a progestin or use a combo product (Activella, CombiPatch, etc) to reduce the risk of endometrial hyperplasia. The nonprogestin combo Duavee is also an option.

For vaginal symptoms alone, try a low-dose vaginal estrogen cream (Estrace Cream, etc), tablet (Vagifem, etc), or Estring. A progestin isn't needed since these have minimal systemic absorption. Keep the vaginal rings straight with the phrase, "a ring is bigger than a string." Femring provides a higher dose for systemic effects, Estring is a lower dose for local effects.

Duration of therapy. Don't automatically stop systemic HT after 5 years or when women reach a specific age. Instead, discuss whether to continue HT with women at least annually and periodically try to lower the dose or stop it. Try to taper systemic HT doses over several months before stopping it to possibly reduce the risk of recurrent symptoms. Be aware, low-dose vaginal estrogen can be continued indefinitely.


Probiotics for Gastrointestinal Conditions: A Summary of the Evidence (3690)
Wilkins et al AFP 96:170 08-01-2017

Probiotics contain microorganisms, most of which are bacteria similar to the beneficial bacteria that occur naturally in the human gut. Probiotics have been widely studied in a variety of gastrointestinal diseases. The most-studied species include Lactobacillus, Bifidobacterium, and Saccharomyces. However, a lack of clear guidelines on when to use probiotics and the most effective probiotic for different gastrointestinal conditions may be confusing for family physicians and their patients. Probiotics have an important role in the maintenance of immunologic equilibrium in the gastrointestinal tract through the direct interaction with immune cells. Probiotic effectiveness can be species-, dose-, and disease-specific, and the duration of therapy depends on the clinical indication. There is high-quality evidence that probiotics are effective for acute infectious diarrhea, antibiotic-associated diarrhea, Clostridium difficile-associated diarrhea, hepatic encephalopathy, ulcerative colitis, irritable bowel syndrome, functional gastrointestinal disorders, and necrotizing enterocolitis. Conversely, there is evidence that probiotics are not effective for acute pancreatitis and Crohn disease. Probiotics are safe for infants, children, adults, and older patients, but caution is advised in immunologically vulnerable populations.

Full article which includes a list of brandname products with contents, as well as which probiotics are supported by data for which condition.