Here are the last 20 additions to the PBrain (total entries as of now = 3726)


Effects of oral vs transdermal estrogen therapy on sexual function in early postmenopause: Ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS) (3707)
Taylor HS et al JAMA Intern Med 08-28-2017

The menopausal transition can adversely affect sexual function. In a study of hormonal treatments during early menopause, investigators randomized 727 healthy women (mean age, 53; within 3 years of last menstrual period) to placebo, transdermal estradiol (tE2; 0.050 mg released daily), or oral conjugated equine estrogen (oCEE; 0.45 mg daily). Sexual function was assessed over 4 years with the Female Sexual Function Inventory (FSFI; higher scores indicate better function). Features such as arousal, lubrication, and pain reduction were quantified with subscores.

Women in the placebo group experienced declines from baseline in FSFI score as well as subscores for lubrication and pain reduction. Compared with placebo, tE2 treatment was associated with modest improvements in FSFI (P=0.002), lubrication (P=0.001), and pain reduction (P=0.002). By contrast, oCEE treatment did not improve FSFI score relative to placebo (P=0.13). Women who received oCEE, but not tE2 or placebo, showed a large increase in circulating sex hormone binding globulin (SHBG) concentration.

Comment: Both oral and transdermal estradiol are effective for managing menopausal hot flashes and associated sleep disorders. This study indicates that transdermal estradiol may be superior to oral estradiol for improving sexual function (possibly because oral estradiol raises circulating SHBG and lowers free testosterone concentration, thereby adversely affecting libido). In observational studies involving postmenopausal women, transdermal estradiol compared with oral estrogen was associated with lower rates of venous thromboembolism, pulmonary embolism, and possibly stroke; thus, transdermal estradiol may have more benefits and fewer risks than oral estrogen. However, some women may prefer oral hormone therapy based on cost and convenience. When prescribing transdermal estradiol for postmenopausal women older than 50, I generally start with a dose of 0.0375 mg and, if necessary, increase the dose to 0.050 mg.


Do incidental hyperechoic renal lesions measuring up to 1 cm warrant further imaging? Outcomes of 161 lesions (3708)
Doshi AM et al AJR Am J Roentgenol 209:346 08-01-2017

When hyperechoic lesions are noted incidentally on renal ultrasound, additional imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) often can distinguish benign fat-containing angiomyolipomas from solid lesions that might represent renal cell carcinoma. But is additional imaging and surveillance necessary for very small hyperechoic lesions detected on ultrasound?

In this single-center retrospective study, researchers identified 161 patients (mean age, 63) who had incidentally-detected hyperechoic renal lesions measuring 1 cm or smaller on ultrasound and one or more follow-up imaging studies. In 58% of patients, lesions were consistent with angiomyolipoma on CT or MRI; in 12%, lesions were not seen on CT or MRI; and in 3%, they were not seen on follow-up ultrasound. In nearly all other cases, lesions remained stable during at least 2 years of follow-up imaging. However, two cases were deemed "indeterminate" (CT confirmed the lesion to be neither fat-containing nor cystic, but long-term follow-up was not available), and one case was presumed to represent a slow-growing renal cell carcinoma (it enlarged from 1.0 to 1.6 cm on CT at 2 years; the patient then was lost to follow-up).

COMMENT: Given that only three lesions were deemed to be indeterminate or suspicious for an enlarging renal cell carcinoma, the authors conclude that most hyperechoic renal lesions that are 1 cm or smaller might not require additional imaging. Nevertheless, they acknowledge that this decision should be individualized according to demographic and clinical factors. I would add that patient preference (either for or against further evaluation) also should play a role.


Tiotropium in early-stage chronic obstructive pulmonary disease (3709)
Zhou Y et al NEJM 377:923 09-07-2017

Long-acting bronchodilators are first-line therapy for patients with chronic obstructive pulmonary disease (COPD); numerous studies have shown that these drugs improve lung function, symptoms, and exacerbations in patients with moderate-to-severe disease. However as many as 80% of patients with COPD are stage 1 (forced expiratory volume in 1 second [FEV1], ≥80% of predicted value) or stage 2 (FEV1, 50% to 79% of predicted). Whether long-term bronchodilator therapy benefits these patients is unclear.

In an industry-funded study, 841 Chinese patients with stage 1 or 2 COPD were randomized to once-daily inhaled tiotropium or placebo. At baseline, mean postbronchodilator FEV1 was 78% of predicted, and mean postbronchodilator FEV1 to forced vital capacity ratio was 60%. After 2 years, mean prebronchodilator FEV1 in the tiotropium group was 157mL greater than that in the placebo group. In addition, secondary outcomes (annual decline in postbronchodilator FEV1, exacerbation rate, and quality of life) were better in the tiotropium group. Dry mouth and pharyngeal discomfort were more common in the tiotropium group.

Comment: Patients with stage 1 or 2 COPD who receive tiotropium have improved lung function and symptom scores and fewer exacerbations. A benefit was seen even in patients with group A symptoms (COPD Assessment Test ≤10, or ≤2 exacerbations in the past year). These findings will lower my threshold for starting tiotropium in a patient with mild symptoms or just a single recent exacerbation, but I still would not treat asymptomatic patients. In addition, we don't know if we can extrapolate these results to other long-acting bronchodilators.


Tocilizumab (Actemra) for Giant Cell Arteritis (3710)
Med Ltr Med Ltr 59:161 09-25-2017

The FDA has approved the interleukin-6 (IL-6) receptor antagonist tocilizumab (Actemra - Genentech) for subcutaneous (SC) treatment of giant cell arteritis in adults. It is the first drug to be approved in the US for this indication. Tocilizumab is also approved for treatment of rheumatoid arthritis, polyarticular or systemic juvenile idiopathic arthritis, and cytokine release syndrome.

THE DISEASE: Giant cell arteritis is a systemic large vessel vasculitis that usually occurs in adults >50 years old. It can cause blindness, stroke, and aortic aneurysm or dissection. High-dose corticosteroid therapy has been effective in inducing remission, but treatment must be continued for months or years, adverse effects can be severe, and relapses are common. Alternatives to glucocorticoid therapy have not been found to be effective in randomized, controlled trials.

MECHANISM OF ACTION: Tocilizumab is a humanized IL-6 receptor monoclonal antibody that competitively inhibits the binding of IL-6 to its receptors. IL-6 is a pro-inflammatory cytokine that is overproduced in patients with giant cell arteritis.

CLINICAL STUDIES: FDA approval of tocilizumab for giant cell arteritis was based on the results of a double-blind trial in 251 adults ≥50 years old with newly diagnosed or relapsing giant cell arteritis. Patients were randomized to tocilizumab 162 mg SC every week (n=100) or every other week (n=50) plus a 26-week prednisone taper, or to placebo plus a 26- (n=50) or 52-week (n=51) prednisone taper. The rate of sustained glucocorticoid-free remission (remission from week 12 through 52 and adherence to prednisone taper) was significantly greater in patients who received tocilizumab once weekly (56%) or every other week (53%) than in those who received placebo plus 26 weeks (14%) or 52 weeks (18%) of prednisone taper. The cumulative prednisone dose over the 52-week period was ~50% lower in those receiving tocilizumab than in those receiving placebo.

The effect of IL-6 inhibition with tocilizumab on vision loss and other ischemic events remains to be determined.

ADVERSE EFFECTS: Adverse effects in the clinical trial were similar in all of the groups. Serious adverse events occurred less frequently in patients treated with tocilizumab. Serious bacterial, fungal, and viral infections have been reported with use of tocilizumab. Testing for latent tuberculosis is required before starting the drug. Live vaccines should not be administered during tocilizumab therapy. Neutropenia, thrombocytopenia, and serum hepatic transaminase elevations have been reported with tocilizumab; dosage adjustment and/or discontinuation of the drug may be needed, based on severity. Use of tocilizumab for other indications has been associated with GI perforation; patients with a history of diverticulitis are at increased risk.

DRUG INTERACTIONS: In vitro data indicate that tocilizumab may reverse IL-6-mediated suppression of CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4, potentially decreasing serum concentrations of other drugs taken concurrently.5 In vivo studies have found that concurrent use of tocilizumab resulted in decreased serum concentrations of simvastatin (Zocor, and others) and omeprazole (Prilosec, and others). Other biologic agents should not be used concomitantly with tocilizumab.

DOSAGE, ADMINISTRATION, AND COST: The recommended dosage of tocilizumab for treatment of giant cell arteritis is 162 mg injected SC once weekly. Administration every other week may be considered for some patients. Tocilizumab should be given in combination with a tapering course of a glucocorticoid. The labeling states that it can be used alone after discontinuation of glucocorticoid therapy, but the duration of treatment is unclear. A 28-day supply of once-weekly tocilizumab (four 162-mg prefilled syringes) costs $3647.10.

CONCLUSION: In one controlled trial in patients with newly diagnosed or relapsing giant cell arteritis, addition of tocilizumab (Actemra) to tapered prednisone was significantly more effective than addition of placebo in achieving sustained remission and in reducing the cumulative dosage of prednisone. Its effect on the most serious complications of giant cell arteritis (blindness, stroke) remains to be determined. More data are needed to clarify the place of tocilizumab in the treatment of giant cell arteritis.


Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease (3711)
Eikelboom et al NEJM 377:1319 10-05-2017

METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months.

RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group.

CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events.

Editorial

From Journal Watch:

Aspirin remains the mainstay of secondary prevention for coronary artery disease; vitamin K antagonists are superior when added to aspirin or used alone for patients with acute myocardial infarction (MI), but excess bleeding has limited their use. In the manufacturer-sponsored, double-blind COMPASS trial, investigators enrolled 27,395 patients (mean age, 68; 22% women) with stable coronary artery disease to the direct-acting oral anticoagulant rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg daily), rivaroxaban (5 mg twice a day), or aspirin (100 mg daily). The primary outcome was cardiovascular death, stroke, or MI.

The study was stopped after 23 months of follow-up because of a significant advantage in efficacy for rivaroxaban plus aspirin. The primary outcome occurred in 4.1% of patients who received rivaroxaban plus aspirin, 4.9% who received rivaroxaban alone, and 5.4% who received aspirin alone. When bleeding events (3.1%, 2.8%, and 1.9%, respectively) were included in the analysis, the net clinical benefit remained significantly greater with rivaroxaban plus aspirin than with aspirin alone; rivaroxaban alone did not have a significant advantage over aspirin alone. Results were consistent across predefined subgroups including age, sex, geographic region, and race or ethnicity.

Comment: For patients with stable coronary artery disease, it appears that rivaroxaban plus aspirin improves cardiovascular outcomes at 2 years. Many patients who might benefit from this combination are already taking aspirin and other medications, and their ability to add another twice-daily drug to their regimen long-term may bear on how readily rivaroxaban plus aspirin is adopted in clinical practice. The current recommendation for patients with atherosclerotic disease is to remain on aspirin for life; it's unclear whether patients would need to remain on rivaroxaban plus aspirin for life as well. Furthermore, the additional cost of rivaroxaban is not insignificant.

From PL, 11/17:
Consider the new COMPASS trial in patients with stable CV disease. It's stirring up controversy and is a good example. It suggests that adding Xarelto (rivaroxaban) 2.5 mg BID to low-dose aspirin reduces the risk of a CV event versus aspirin alone with a p-value less than 0.001. This statistically significant p-value below 0.05 indicates that the treatment effect is likely real, and not due to chance. But don't rely on p-values alone to determine if results are clinically significant. They don't describe the size of the effect or the likelihood that a patient will have these results. Instead, look at the actual difference in outcomes to evaluate if results are clinically significant. Large studies often have the "power" to find very small differences that may not matter clinically. For example, adding Xarelto to aspirin reduces the risk of a CV event by just 1.3%. This translates to a number needed to treat (NNT) of 77 patients over about 2 years. Also weigh benefits versus risks. In this case, adding Xarelto to aspirin increases major bleeding by 1.2%, or a number needed to harm (NNH) of 83 patients over about 2 years. Also pay attention to the characteristics of the study patients to evaluate whether results apply in the "real world." For example, COMPASS included very few black patients, and excluded those at high bleeding risk or with severe heart failure. So what's the bottom line? Based on COMPASS, don't add low-dose, BID Xarelto to aspirin for secondary CV prevention. The chance of a benefit is similar to the risk of harm and results may not apply to many of your patients.


Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke (3712)
Mas et al NEJM 377:1011 09-14-2017

METHODS: In a multicenter, randomized, open-label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3.

RESULTS: A total of 663 patients underwent randomization and were followed for a mean (+/-SD) of 5.3 +/- 2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone.

CONCLUSIONS: Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation.

Editorial

From Journal Watch

Patent foramen ovale (PFO) occurs in about one of four patients, so attributing PFO as the cause of an otherwise cryptogenic stroke is often based on circumstantial evidence. Three clinical trials (CLOSURE I, PC, and RESPECT) failed to establish a role for PFO closure in preventing recurrent stroke. Accordingly, a 2016 American Academy of Neurology practice advisory recommended against routine PFO closure for patients with cryptogenic ischemic stroke. Now two new randomized trials and an exploratory analysis of extended follow-up from RESPECT are set to agitate the mix.

In the industry-sponsored Gore REDUCE trial, 664 patients with cryptogenic stroke and PFO (81% with moderate-to-large shunts, defined as >6 microbubbles within 3 cardiac cycles) were randomized in a 2:1 ratio to PFO closure plus antiplatelet therapy or antiplatelet therapy alone. After a median follow-up of 3.2 years, 6 of 441 (1.4%) PFO-closure recipients had a clinical ischemic stroke versus 12 of 223 (5.4%) antiplatelet-only recipients (P=0.002). New brain infarctions were identified in 22 of 383 PFO-closure patients (5.7%) versus 20 of 177 antiplatelet-only patients (11.3%; P=0.04), but this difference was primarily driven by clinically apparent strokes, as there was no significant difference in the incidence of silent brain infarcts. Atrial fibrillation occurred in 29 (6.6%) of 441 PFO-closure patients compared with 1 (0.4%) of 223 antiplatelet-only patients (P<0.001).

In CLOSE, 663 patients with cryptogenic strokes and PFO with atrial septal aneurysm (excursion >10 mm) or large interatrial shunt (>30 microbubbles) were randomized 1:1:1 to PFO closure plus antiplatelet therapy, antiplatelet therapy alone, or oral anticoagulation therapy. Strokes occurred in none of the 238 PFO-closure patients and 14 of 235 antiplatelet-only patients (P<0.001). In the PFO closure arm, 4.6% of patients developed atrial fibrillation compared with 0.9% in the antiplatelet-only arm (P=0.02). The incidence of recurrent stroke did not differ significantly between the antiplatelet-only and anticoagulation arms.

The primary analysis of the industry-funded RESPECT trial found no significant benefit with PFO closure after a median 2.1 years of follow-up. By contrast, in this new exploratory analysis, recurrent stroke rates after a median 5.9 years of follow-up were significantly lower in the PFO-closure group than in the medical arm (0.58 vs. 1.07 per 100 patient-years; P=0.046). Dropouts were more common with medical therapy, and choice of long-term antithrombotic therapy was at the site investigator's discretion.

COMMENT: Selecting only patients with atrial septal aneurysms or moderate-to-large shunts, excluding patients with lacunar strokes, and excluding transient ischemic attacks as an outcome may explain why we now see benefits of PFO closure that were not demonstrated previously. Cryptogenic stroke patients with these high-risk PFO features may benefit from PFO closure, but whether this benefit extends to less-selected patients remains unclear.

CITATION(S):

Søndergaard L et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 2017 Sep 14; 377:1033. (http://dx.doi.org/10.1056/NEJMoa1707404)

Mas J-L et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 2017 Sep 14; 377:1011. (http://dx.doi.org/10.1056/NEJMoa1705915)

Saver JL et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017 Sep 14; 377:1022. (http://dx.doi.org/10.1056/NEJMoa1610057)

Ropper AH.Tipping point for patent foramen ovale closure. N Engl J Med 2017 Sep 14; 377:1093. (http://dx.doi.org/10.1056/NEJMe1709637)


A randomized controlled trial of a CPR decision support video for patients admitted to the general medicine service (3713)
Merino AM et al J Hosp Med 12:700 09-01-2017

Code status discussions with hospitalized patients are necessary on admission, yet patients often have misconceptions about their options and expectations surrounding cardiopulmonary resuscitation (CPR) and other emergent procedures during cardiac or respiratory arrest. Investigators randomized 119 Veterans Affairs (VA) general medical patients (average age, 75) either to watch a 6-minute video (intervention group) or to discuss code status with the medical team (usual-care group). The video explained and visually illustrated the components and meaning of full code, do not resuscitate (DNR), and combined DNR/do not intubate (DNI); the video then showed a simulated code resuscitation that included CPR, defibrillation, and intubation.

Both intervention and usual-care patients completed surveys about their code-status preferences and offered opinions about their healthcare team. Patients who watched the video were significantly more likely to select combined DNR/DNI status (56% vs. 17%) and significantly less likely to choose full-code status (37% vs. 71%); three patients needed to watch the video to influence one patient's selection of a different code status.

Comment: In our experience, the quality of providers' communications with hospitalized patients about code status is quite variable. Ideally, video resources such as this one could promote more-informed patient decision making and could facilitate concordance between patient preference and provided care. Such tools should present options in a balanced and nonmanipulative manner and should be used as an adjunct to, and not a substitute for, direct patient-clinician communication. Note, however, that this VA population was predominantly older white men, which might limit the generalizability of the study results.

DNR Video


Association of thyroid function with life expectancy with and without cardiovascular disease: The Rotterdam study (3714)
Bano A et al JAMA Intern Med 09-18-2017

Some studies suggest that patients with high-normal thyroid function have excess risk for cardiovascular disease (CVD) and early death. In this population-based Dutch cohort study, 7785 adults (mean age, 65) without known thyroid disease (thyrotropin and free thyroxine [FT4] within normal reference ranges) were identified. Patients were divided into tertiles according to both thyrotropin and FT4 levels.

During median follow-up of 8.1 years, fatal or nonfatal adverse CVD events occurred in 10% of patients, and 17% died overall. Outcomes were as follows:

Comment: These results, and similar results of prior studies, might make us question how to manage patients who are receiving thyroid replacement therapy and who believe they feel better at higher replacement doses with suppressed thyrotropin. I am less likely to push replacement doses beyond a middle range of thyrotropin suppression based on symptoms alone.


Recurrent Ischemic Stroke: Strategies for Prevention (3715)
Oza et al AFP 96:437 10-01-2017

Recurrent strokes make up almost 25% of the nearly 800,000 strokes that occur annually in the United States. Risk factors for ischemic stroke include hypertension, diabetes mellitus, hyperlipidemia, sleep apnea, and obesity. Lifestyle modifications, including tobacco cessation, decreased alcohol use, and increased physical activity, are also important in the management of patients with a history of stroke or transient ischemic attack. Antiplatelet therapy is recommended to reduce the risk of recurrent ischemic stroke. The selection of antiplatelet therapy should be based on timing, safety, effectiveness, cost, patient characteristics, and patient preference. Aspirin is recommended as initial treatment to prevent recurrent ischemic stroke. Clopidogrel is recommended as an alternative monotherapy and in patients allergic to aspirin. The combination of clopidogrel and aspirin is not recommended for long-term use (more than two to three years) because of increased bleeding risk. Aspirin/dipyridamole is at least as effective as aspirin alone, but it is not as well tolerated. Warfarin should not be used for prevention of recurrent ischemic stroke.

Full article


Mavyret and Vosevi - Two New Combinations for Chronic HCV Infection (3716)
Med Ltr Med Ltr 59:166 10-09-2017

The FDA has approved Mavyret (Abbvie) and Vosevi (Gilead), two new fixed-dose combinations of direct-acting antiviral (DAA) drugs, for treatment of chronic hepatitis C virus (HCV) infection caused by any of the six major HCV genotypes in patients without cirrhosis or with compensated cirrhosis. Both are approved for use in treatment-experienced patients. Mavyret is also approved for treatment-naive patients.

Both glecaprevir/pibrentasvir (Mavyret) and sofosbuvir/velpatasvir/voxilaprevir (Vosevi) are effective for treatment of hepatitis C virus (HCV) infection caused by all of the six major HCV genotypes and have produced sustained virologic responses in treatment-experienced patients who failed treatment with a direct-acting antiviral-based regimen. Mavyret is also FDA-approved for treatment-naive patients and for a treatment duration of only 8 weeks in treatment-naive and -experienced patients without cirrhosis.

Full article


Pancreatic Enzyme Replacement Products (3717)
Med Ltr Med Ltr 59:170 10-09-2017

Full article


Long-term oral bisphosphonate therapy and fractures in older women: The Women's Health Initiative (3718)
Drieling RL et al J Am Geriatr Soc 65:1924 09-01-2017

Although bisphosphonates' efficacy in preventing fragility fractures is well established, questions persist about optimal duration of use. Some 97,000 participants in the Women's Health Initiative (WHI) observational and randomized trials completed medication forms. Among a subgroup of 5120 women (mean age, 80; 94% white) with estimated 5-year hip fracture risk ≥1.5% and ≥2 years of self-reported bisphosphonate use, investigators assessed risk for incident fractures following various durations of bisphosphonate therapy (2 years, 3 to 5 years, 6 to 9 years, and 10 to 13 years).

During additional mean follow-up of 3.7 years, fracture rates were 2% for hip fractures, 3% for radius or forearm fractures, 5% for clinical vertebral fractures, and 26% for any clinical fracture. Adjusted analysis showed that, compared with 2 years of bisphosphonate use, 10 to 13 years of use was associated with a modestly but statistically significantly higher risk for any clinical fracture (hazard ratio, 1.29; 95% confidence interval, 1.07 to 1.57). Risks after 10 to 13 years of use were even higher for hip fractures (HR, 1.66) and clinical vertebral fractures (HR, 1.65), although these did not reach statistical significance, possibly because of the small numbers in these subgroups. Compared with 2 years' use, 3 to 5 and 6 to 9 years' use did not confer excess fracture risk overall or at specific sites.

Comment: This study - the largest to assess fracture risk in older, female, long-term bisphosphonate users - supports discontinuing therapy after 2 to 5 years. As an editorialist notes, whether (and when) to restart bisphosphonate therapy after a drug holiday depends on which agent has been used and the patient's underlying fracture risk.

Lyles KW.Have we learned how to use bisphosphonates yet? J Am Geriatr Soc 2017 Sep; 65:1902


Proton pump inhibitors and risk of mild cognitive impairment and dementia (3719)
Goldstein FC et al J Am Geriatr Soc 65:1969 09-01-2017

Patients continue to express concern about media reports stating that proton-pump inhibitor (PPI) use might cause cognitive impairment or dementia. In this latest study, researchers took advantage of prospectively collected data on 10,500 patients (mean age, 73) with normal cognition or mild cognitive impairment who were followed at 33 U.S. Alzheimer disease research centers. Participants underwent detailed structured cognitive assessments annually and were classified as using PPIs continuously, intermittently, or never. Follow-up ranged from 2 to 6 years.

In analyses adjusted for confounding demographic and clinical variables, PPI use (continuous or intermittent) compared with no PPI use was associated with significantly lower risk for progression from normal cognition to mild cognitive impairment, and from mild cognitive impairment to dementia. Hazard ratios for progression were roughly 0.80 for these outcomes. Histamine-2-receptor antagonist use also was associated with lower risk for cognitive impairment.

Comment: This study's strength is its robust longitudinal assessment of cognitive status at specialized research centers; in contrast, the first publicized study to suggest a PPI−dementia connection was derived from an administrative claims database with nonverified dementia diagnoses and inadequate adjustment for confounding variables (NEJM JW Gen Med Jun 15 2016 and JAMA Neurol 2016; 73:410). Although the protective effect of PPIs against cognitive decline found in the current study is difficult to explain, the findings provide reassurance that PPIs are unlikely to cause cognitive decline. A recent Finnish study with confirmation of dementia diagnoses reached similar conclusions (NEJM JW Gen Med Sep 15 2017 and J Gastroenterol 2017 Jul 11; [e-pub])


Methylphenidate for apathy in community-dwelling older veterans with mild Alzheimer's disease: A double-blind, randomized, placebo-controlled trial (3720)
Padala PR et al Am J Psychiatry 09-15-2017

Apathy, a prominent feature of Alzheimer disease, impairs motivation, reduces spontaneous behavior, and has been associated with a heavier caregiver burden. In a 12-week trial, investigators randomized 60 community-dwelling male veterans with mild Alzheimer disease and apathy to methylphenidate (target dose, 10 mg twice daily) or placebo (mean age, 77; mean Mini-Mental State Exam [MMSE] score, 24; >90% white).

Participants did not have active psychosis, frontotemporal dementia, or current major depression, although 58% had depressive symptoms. About 85% had hypertension, and 47% had coronary artery disease. Polypharmacy was common (cholinesterase inhibitors, 63%; antidepressants, 55%; memantine, 30%).

Significant improvements for methylphenidate vs. placebo were first seen at 4 weeks for overall apathy scores; at 8 weeks for the behavior, cognition, and motivation domains of apathy; and at 12 weeks for depression and emotion scores, MMSE scores, activities of daily living, and caregiver burden. Adverse events and serious adverse events were similar in the groups, with only one serious event possibly attributable to medication.

Comment: These results bear replication in larger samples and both sexes. Still, the study suggests several clinically important points. First, treating apathy might help to reduce depressive symptoms, but apathy and depression should be distinguished from each other and warrant separate attention. Second, in these elderly patients with hypertension and cardiovascular disease, adverse effects were no more frequent for modestly dosed methylphenidate than for placebo. Third, improvements occurred within 4 weeks for apathy but more gradually in other psychological and functional areas. Fourth, cognitive improvements at 12 weeks were comparable to those reported for cholinesterase inhibitors. Overall, treating apathy with methylphenidate may benefit both patients with mild Alzheimer disease and their caregivers.


ffects of withdrawing &#945;1-blocker from combination therapy with &#945;1-blocker and 5&#945;-reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A prospective and comparative trial using ur (3721)
Matsukawa Y et al J Urol 198:905 10-01-2017

The two most commonly used drug treatments for urinary symptoms related to benign prostatic hyperplasia (BPH) have complementary mechanisms of action. An α-blocker (e.g., tamsulosin, silodosin) relaxes prostatic and bladder-neck smooth muscle tone and thus works quickly; in contrast, 5α-reductase inhibitors (e.g., finasteride, dutasteride) reduce prostate size gradually over many months. Researchers sought to determine whether patients receiving both drugs eventually could drop α-blockers without experiencing symptom relapse.

In a trial from Japan, 140 men with BPH-related symptoms and prostatic enlargement (volume, ≥30 cc) began treatment with both silodosin and dutasteride; significant improvements in mean symptom scores and urodynamic measurements were documented at 12 months. Patients then were randomized to continue combination therapy or to continue dutasteride and stop silodosin. During an additional 12 months of follow-up, mean improvements in symptom scores and urodynamic measurements were maintained, with no significant differences between groups.

Comment: This study suggests that, after 12 months of combination therapy for BPH-related urinary symptoms in patients with documented prostate enlargement, withdrawal of the α-blocker usually will not exacerbate symptoms. Based on these results, I'll be more likely to stop α-blockers in patients who've received at least 1 year of combination therapy; if symptoms worsen in occasional patients, α-blockers always can be restarted.


Malignant neoplasms in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors, tocilizumab, abatacept, or rituximab in clinical practice: A nationwide cohort study from Sweden (3722)
Wadstrom H et a JAMA Intern Med 09-18-2017

Some data have suggested an association between biologics and excess risk for nonmelanoma skin cancers in patients with rheumatoid arthritis (RA; NEJM JW Dermatol Mar 2016 and BMJ 2016; 352:i262), but risks for other malignancies are unknown. In this Swedish study, researchers used national healthcare registries to examine incident malignancy rates in 22,500 RA patients who initiated treatment between 2006 and 2015 with biologics (tocilizumab [Actemra], abatacept [Orencia], rituximab [Rituxan], or an anti-tumor necrosis [TNF] agent), 46,000 RA patients who initiated conventional disease-modifying antirheumatic drugs (DMARDs), and 107,500 people in a general-population comparator group.

Risk for first invasive solid or hematologic malignancies or skin cancers was similar in both treatment groups (biologics and DMARDs) and in the population-based control group, except for a small excess risk for cutaneous squamous cell cancer in abatacept-treated patients.

Comment: Follow-up was relatively short (<10 years for non-anti-TNF biologics), and the researchers did not address risk for recurrence of previous malignancies, which is a major concern for rheumatologists. However, this study is reassuring to both rheumatologists and patients, and it reinforces my policy of asking all patients who are taking biologics to see a dermatologist periodically.


Chronic cough: Evaluation and Management (3723)
Michaudet et al AFP 96:575 11-01-2017

Although chronic cough in adults (cough lasting longer than eight weeks) can be caused by many etiologies, four conditions account for most cases: upper airway cough syndrome, gastroesophageal reflux disease/laryngopharyngeal reflux disease, asthma, and nonasthmatic eosinophilic bronchitis. Patients should be evaluated clinically (with spirometry, if indicated), and empiric treatment should be initiated. Other potential causes include angiotensin-converting enzyme inhibitor use, environmental triggers, tobacco use, chronic obstructive pulmonary disease, and obstructive sleep apnea. Chest radiography can rule out concerning infectious, inflammatory, and malignant thoracic conditions. Patients with refractory chronic cough may warrant referral to a pulmonologist or otolaryngologist in addition to a trial of gabapentin, pregabalin, and/or speech therapy. In children, cough is considered chronic if present for more than four weeks. In children six to 14 years of age, it is most commonly caused by asthma, protracted bacterial bronchitis, and upper airway cough syndrome. Evaluation should focus initially on these etiologies, with targeted treatment and monitoring for resolution.

Full article


Rivaroxaban or aspirin for extended treatment of venous thromboembolism (3724)
Weitz JI et al NEJM 03-18-2017

The duration of guideline-recommended antithrombotic therapy for patients with venous thromboembolism (VTE) ranges from 3 months to indefinite, depending on whether the VTE is provoked or unprovoked and on patients' bleeding risks (NEJM JW Emerg Med Feb 2016 and Chest 2016; 149:315). For long-term prevention of recurrent VTE, options include warfarin, direct-acting oral anticoagulants, and aspirin; among the anticoagulants, guidelines recommend direct-acting anticoagulants over warfarin, unless substantial renal impairment is present. Indirect comparisons suggest that direct-acting oral anticoagulants are more effective than aspirin but are more likely to cause serious bleeding. Now, we have a head-to-head, randomized, double-blind trial.

Industry-supported researchers enrolled 3396 adults with VTE; half had isolated deep venous thrombosis, and half had pulmonary embolism. All patients had completed 6 to 12 months of anticoagulation. VTE was considered to be provoked in about 60% of patients and unprovoked in 40%. Patients received daily rivaroxaban (Xarelto; 20 mg), rivaroxaban (10 mg), or aspirin (100 mg). All patients had creatinine clearance ≥30 mL/minute. At 1 year, rates of symptomatic recurrent VTE with 20-mg rivaroxaban, 10-mg rivaroxaban, and aspirin were 1.5%, 1.2%, and 4.4%, respectively; differences between rivaroxaban and aspirin were significant. The difference in event rates between rivaroxaban and aspirin was somewhat larger for unprovoked VTE (≈1.6% vs. 5.6%) than for provoked VTE (≈1.2% vs. 3.6%). Rates of major bleeding were similar in the three groups (0.5%, 0.4%, and 0.3%).

Comment: For extended treatment to prevent recurrent VTE, rivaroxaban is more effective than aspirin, with similar safety. For patients with unprovoked VTE, roughly 25 patients would need to be treated with rivaroxaban (compared with aspirin) for 1 year to prevent one VTE event. Whether the benefit-harm tradeoff would be preserved beyond 1 year is unknown. Interestingly, this trial suggested a small benefit for extended therapy even in patients whose initial VTEs were provoked. Finally, note that only the 20-mg dose currently is FDA-approved for extended treatment after VTE; the 10-mg dose is approved only for short-term prophylaxis after hip or knee replacement.


Obesity: When to Consider Medication (3725)
Saunders 2017-10-01 10-01-2017

This article includes a nice table comparing various drugs, effectiveness in clinical trials, adverse effects, and a "good candidate/bad candidate" discussion. However, I was surprised to find no discussion of cost. The main authors apparently have no involvement with pharmaceutical companies, but I still found the discussion very much weighted toward medication treatment for obesity in spite of limited efficacy.

Full article


Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines (3726)
Whelton PK et al J Am Coll Cardiol 11-13-2017

Background: In 2003, the National Institutes of Health (NIH) issued its last guideline on hypertension (Seventh Joint National Committee [JNC7]; NEJM JW Gen Med Jun 15 2003 and JAMA 2003; 289:2560). In 2014, the JNC8 guideline - written by an expert panel no longer affiliated with NIH - was published (NEJM JW Gen Med Jan 15 2014 and JAMA 2014; 311:507). Now, the ACC and AHA have issued a new guideline, intended to be the U.S. standard of care.

Key Recommendations

Comment: This guideline is a 194-page document (currently online) that addresses a broad spectrum of topics, including BP measurement, secondary hypertension, and managing hypertension in patients with comorbidities. But the big changes - heavily influenced by results of the SPRINT study (NEJM JW Gen Med Dec 15 2015 and N Engl J Med 2015; 373:2103) — are those in the bulleted list above.

First, the new categories will label many more people as having elevated BP or frank hypertension. In JNC7, systolic thresholds for so-called prehypertension, stage 1 hypertension, and stage 2 hypertension were 120 mm Hg, 140 mm Hg, and 160 mm Hg, respectively; diastolic thresholds were 80 mm Hg, 90 mm Hg, and 100 mm Hg, respectively. The downstream consequences of telling people with BP of 120/70 mm Hg that their BP is “elevated” are unknown.

Second, in the new guideline, hypertension treatment is based on both BP thresholds and 10-year overall CV risk. Younger and middle-aged people without other substantial risk factors who are labeled as having stage 1 hypertension (130–139/80–89 mm Hg) generally will have estimated 10-year CVD risk <10%, and lifestyle modification (but not drug therapy) will be recommended for them. However, nearly all older people with BP in this range will be candidates for drug therapy, because the risk calculator gives them 10-year CV risk >10% based on age alone.

Consider, for example, a healthy white 65-year-old male nonsmoker with a BP of 130/80 mm Hg, total cholesterol level of 160 mg/dL, HDL cholesterol of 60 mg/dL, LDL cholesterol of 80 mg/dL, and fasting blood glucose of 80 mg/dL - all favorable numbers. The calculator estimates his 10-year CV risk to be 10.1%, making him eligible for BP-lowering medication under the new guideline. To my knowledge, no compelling evidence exists to support drug therapy for this person, and, keep in mind, several studies have suggested that the ACC/AHA risk calculator overestimates risk in certain populations. In addition, a recent guideline from the American College of Physicians and the American Academy of Family Physicians (NEJM JW Gen Med Apr 15 2017 and Ann Intern Med 2017; 166:430) recommends - as did JNC8 - a systolic BP treatment threshold of 150 mm Hg for average-risk older people (age, ≥60).

In the new guideline, the authors discuss accurate measurement of BP in the office and encourage home or ambulatory monitoring to identify white-coat hypertension. Unfortunately, proper office measurement (e.g., seated position for at least 5 minutes in a quiet and relaxed setting, proper positioning of the arm, repeat measurements after several minutes in some cases) is the exception and not the rule in most primary care practices. BP lability is common with both office-based and home readings, making it difficult to say, "your blood pressure is X" (a single number that represents the patient's "true" BP).

I'm not going to change my practice until I weigh responses to this guideline from a broad range of experts. In the end, initiating drug therapy in patients with BPs near treatment thresholds should reflect shared decision-making between clinicians and patients.


Here are the last 10 additions to the PBrain by date


Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines (3726)
Whelton PK et al J Am Coll Cardiol 11-13-2017

Background: In 2003, the National Institutes of Health (NIH) issued its last guideline on hypertension (Seventh Joint National Committee [JNC7]; NEJM JW Gen Med Jun 15 2003 and JAMA 2003; 289:2560). In 2014, the JNC8 guideline - written by an expert panel no longer affiliated with NIH - was published (NEJM JW Gen Med Jan 15 2014 and JAMA 2014; 311:507). Now, the ACC and AHA have issued a new guideline, intended to be the U.S. standard of care.

Key Recommendations

Comment: This guideline is a 194-page document (currently online) that addresses a broad spectrum of topics, including BP measurement, secondary hypertension, and managing hypertension in patients with comorbidities. But the big changes - heavily influenced by results of the SPRINT study (NEJM JW Gen Med Dec 15 2015 and N Engl J Med 2015; 373:2103) — are those in the bulleted list above.

First, the new categories will label many more people as having elevated BP or frank hypertension. In JNC7, systolic thresholds for so-called prehypertension, stage 1 hypertension, and stage 2 hypertension were 120 mm Hg, 140 mm Hg, and 160 mm Hg, respectively; diastolic thresholds were 80 mm Hg, 90 mm Hg, and 100 mm Hg, respectively. The downstream consequences of telling people with BP of 120/70 mm Hg that their BP is “elevated” are unknown.

Second, in the new guideline, hypertension treatment is based on both BP thresholds and 10-year overall CV risk. Younger and middle-aged people without other substantial risk factors who are labeled as having stage 1 hypertension (130–139/80–89 mm Hg) generally will have estimated 10-year CVD risk <10%, and lifestyle modification (but not drug therapy) will be recommended for them. However, nearly all older people with BP in this range will be candidates for drug therapy, because the risk calculator gives them 10-year CV risk >10% based on age alone.

Consider, for example, a healthy white 65-year-old male nonsmoker with a BP of 130/80 mm Hg, total cholesterol level of 160 mg/dL, HDL cholesterol of 60 mg/dL, LDL cholesterol of 80 mg/dL, and fasting blood glucose of 80 mg/dL - all favorable numbers. The calculator estimates his 10-year CV risk to be 10.1%, making him eligible for BP-lowering medication under the new guideline. To my knowledge, no compelling evidence exists to support drug therapy for this person, and, keep in mind, several studies have suggested that the ACC/AHA risk calculator overestimates risk in certain populations. In addition, a recent guideline from the American College of Physicians and the American Academy of Family Physicians (NEJM JW Gen Med Apr 15 2017 and Ann Intern Med 2017; 166:430) recommends - as did JNC8 - a systolic BP treatment threshold of 150 mm Hg for average-risk older people (age, ≥60).

In the new guideline, the authors discuss accurate measurement of BP in the office and encourage home or ambulatory monitoring to identify white-coat hypertension. Unfortunately, proper office measurement (e.g., seated position for at least 5 minutes in a quiet and relaxed setting, proper positioning of the arm, repeat measurements after several minutes in some cases) is the exception and not the rule in most primary care practices. BP lability is common with both office-based and home readings, making it difficult to say, "your blood pressure is X" (a single number that represents the patient's "true" BP).

I'm not going to change my practice until I weigh responses to this guideline from a broad range of experts. In the end, initiating drug therapy in patients with BPs near treatment thresholds should reflect shared decision-making between clinicians and patients.


Chronic cough: Evaluation and Management (3723)
Michaudet et al AFP 96:575 11-01-2017

Although chronic cough in adults (cough lasting longer than eight weeks) can be caused by many etiologies, four conditions account for most cases: upper airway cough syndrome, gastroesophageal reflux disease/laryngopharyngeal reflux disease, asthma, and nonasthmatic eosinophilic bronchitis. Patients should be evaluated clinically (with spirometry, if indicated), and empiric treatment should be initiated. Other potential causes include angiotensin-converting enzyme inhibitor use, environmental triggers, tobacco use, chronic obstructive pulmonary disease, and obstructive sleep apnea. Chest radiography can rule out concerning infectious, inflammatory, and malignant thoracic conditions. Patients with refractory chronic cough may warrant referral to a pulmonologist or otolaryngologist in addition to a trial of gabapentin, pregabalin, and/or speech therapy. In children, cough is considered chronic if present for more than four weeks. In children six to 14 years of age, it is most commonly caused by asthma, protracted bacterial bronchitis, and upper airway cough syndrome. Evaluation should focus initially on these etiologies, with targeted treatment and monitoring for resolution.

Full article


Mavyret and Vosevi - Two New Combinations for Chronic HCV Infection (3716)
Med Ltr Med Ltr 59:166 10-09-2017

The FDA has approved Mavyret (Abbvie) and Vosevi (Gilead), two new fixed-dose combinations of direct-acting antiviral (DAA) drugs, for treatment of chronic hepatitis C virus (HCV) infection caused by any of the six major HCV genotypes in patients without cirrhosis or with compensated cirrhosis. Both are approved for use in treatment-experienced patients. Mavyret is also approved for treatment-naive patients.

Both glecaprevir/pibrentasvir (Mavyret) and sofosbuvir/velpatasvir/voxilaprevir (Vosevi) are effective for treatment of hepatitis C virus (HCV) infection caused by all of the six major HCV genotypes and have produced sustained virologic responses in treatment-experienced patients who failed treatment with a direct-acting antiviral-based regimen. Mavyret is also FDA-approved for treatment-naive patients and for a treatment duration of only 8 weeks in treatment-naive and -experienced patients without cirrhosis.

Full article


Pancreatic Enzyme Replacement Products (3717)
Med Ltr Med Ltr 59:170 10-09-2017

Full article


Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease (3711)
Eikelboom et al NEJM 377:1319 10-05-2017

METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months.

RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group.

CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events.

Editorial

From Journal Watch:

Aspirin remains the mainstay of secondary prevention for coronary artery disease; vitamin K antagonists are superior when added to aspirin or used alone for patients with acute myocardial infarction (MI), but excess bleeding has limited their use. In the manufacturer-sponsored, double-blind COMPASS trial, investigators enrolled 27,395 patients (mean age, 68; 22% women) with stable coronary artery disease to the direct-acting oral anticoagulant rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg daily), rivaroxaban (5 mg twice a day), or aspirin (100 mg daily). The primary outcome was cardiovascular death, stroke, or MI.

The study was stopped after 23 months of follow-up because of a significant advantage in efficacy for rivaroxaban plus aspirin. The primary outcome occurred in 4.1% of patients who received rivaroxaban plus aspirin, 4.9% who received rivaroxaban alone, and 5.4% who received aspirin alone. When bleeding events (3.1%, 2.8%, and 1.9%, respectively) were included in the analysis, the net clinical benefit remained significantly greater with rivaroxaban plus aspirin than with aspirin alone; rivaroxaban alone did not have a significant advantage over aspirin alone. Results were consistent across predefined subgroups including age, sex, geographic region, and race or ethnicity.

Comment: For patients with stable coronary artery disease, it appears that rivaroxaban plus aspirin improves cardiovascular outcomes at 2 years. Many patients who might benefit from this combination are already taking aspirin and other medications, and their ability to add another twice-daily drug to their regimen long-term may bear on how readily rivaroxaban plus aspirin is adopted in clinical practice. The current recommendation for patients with atherosclerotic disease is to remain on aspirin for life; it's unclear whether patients would need to remain on rivaroxaban plus aspirin for life as well. Furthermore, the additional cost of rivaroxaban is not insignificant.

From PL, 11/17:
Consider the new COMPASS trial in patients with stable CV disease. It's stirring up controversy and is a good example. It suggests that adding Xarelto (rivaroxaban) 2.5 mg BID to low-dose aspirin reduces the risk of a CV event versus aspirin alone with a p-value less than 0.001. This statistically significant p-value below 0.05 indicates that the treatment effect is likely real, and not due to chance. But don't rely on p-values alone to determine if results are clinically significant. They don't describe the size of the effect or the likelihood that a patient will have these results. Instead, look at the actual difference in outcomes to evaluate if results are clinically significant. Large studies often have the "power" to find very small differences that may not matter clinically. For example, adding Xarelto to aspirin reduces the risk of a CV event by just 1.3%. This translates to a number needed to treat (NNT) of 77 patients over about 2 years. Also weigh benefits versus risks. In this case, adding Xarelto to aspirin increases major bleeding by 1.2%, or a number needed to harm (NNH) of 83 patients over about 2 years. Also pay attention to the characteristics of the study patients to evaluate whether results apply in the "real world." For example, COMPASS included very few black patients, and excluded those at high bleeding risk or with severe heart failure. So what's the bottom line? Based on COMPASS, don't add low-dose, BID Xarelto to aspirin for secondary CV prevention. The chance of a benefit is similar to the risk of harm and results may not apply to many of your patients.


Recurrent Ischemic Stroke: Strategies for Prevention (3715)
Oza et al AFP 96:437 10-01-2017

Recurrent strokes make up almost 25% of the nearly 800,000 strokes that occur annually in the United States. Risk factors for ischemic stroke include hypertension, diabetes mellitus, hyperlipidemia, sleep apnea, and obesity. Lifestyle modifications, including tobacco cessation, decreased alcohol use, and increased physical activity, are also important in the management of patients with a history of stroke or transient ischemic attack. Antiplatelet therapy is recommended to reduce the risk of recurrent ischemic stroke. The selection of antiplatelet therapy should be based on timing, safety, effectiveness, cost, patient characteristics, and patient preference. Aspirin is recommended as initial treatment to prevent recurrent ischemic stroke. Clopidogrel is recommended as an alternative monotherapy and in patients allergic to aspirin. The combination of clopidogrel and aspirin is not recommended for long-term use (more than two to three years) because of increased bleeding risk. Aspirin/dipyridamole is at least as effective as aspirin alone, but it is not as well tolerated. Warfarin should not be used for prevention of recurrent ischemic stroke.

Full article


ffects of withdrawing &#945;1-blocker from combination therapy with &#945;1-blocker and 5&#945;-reductase inhibitor in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A prospective and comparative trial using ur (3721)
Matsukawa Y et al J Urol 198:905 10-01-2017

The two most commonly used drug treatments for urinary symptoms related to benign prostatic hyperplasia (BPH) have complementary mechanisms of action. An α-blocker (e.g., tamsulosin, silodosin) relaxes prostatic and bladder-neck smooth muscle tone and thus works quickly; in contrast, 5α-reductase inhibitors (e.g., finasteride, dutasteride) reduce prostate size gradually over many months. Researchers sought to determine whether patients receiving both drugs eventually could drop α-blockers without experiencing symptom relapse.

In a trial from Japan, 140 men with BPH-related symptoms and prostatic enlargement (volume, ≥30 cc) began treatment with both silodosin and dutasteride; significant improvements in mean symptom scores and urodynamic measurements were documented at 12 months. Patients then were randomized to continue combination therapy or to continue dutasteride and stop silodosin. During an additional 12 months of follow-up, mean improvements in symptom scores and urodynamic measurements were maintained, with no significant differences between groups.

Comment: This study suggests that, after 12 months of combination therapy for BPH-related urinary symptoms in patients with documented prostate enlargement, withdrawal of the α-blocker usually will not exacerbate symptoms. Based on these results, I'll be more likely to stop α-blockers in patients who've received at least 1 year of combination therapy; if symptoms worsen in occasional patients, α-blockers always can be restarted.


Obesity: When to Consider Medication (3725)
Saunders 2017-10-01 10-01-2017

This article includes a nice table comparing various drugs, effectiveness in clinical trials, adverse effects, and a "good candidate/bad candidate" discussion. However, I was surprised to find no discussion of cost. The main authors apparently have no involvement with pharmaceutical companies, but I still found the discussion very much weighted toward medication treatment for obesity in spite of limited efficacy.

Full article


Tocilizumab (Actemra) for Giant Cell Arteritis (3710)
Med Ltr Med Ltr 59:161 09-25-2017

The FDA has approved the interleukin-6 (IL-6) receptor antagonist tocilizumab (Actemra - Genentech) for subcutaneous (SC) treatment of giant cell arteritis in adults. It is the first drug to be approved in the US for this indication. Tocilizumab is also approved for treatment of rheumatoid arthritis, polyarticular or systemic juvenile idiopathic arthritis, and cytokine release syndrome.

THE DISEASE: Giant cell arteritis is a systemic large vessel vasculitis that usually occurs in adults >50 years old. It can cause blindness, stroke, and aortic aneurysm or dissection. High-dose corticosteroid therapy has been effective in inducing remission, but treatment must be continued for months or years, adverse effects can be severe, and relapses are common. Alternatives to glucocorticoid therapy have not been found to be effective in randomized, controlled trials.

MECHANISM OF ACTION: Tocilizumab is a humanized IL-6 receptor monoclonal antibody that competitively inhibits the binding of IL-6 to its receptors. IL-6 is a pro-inflammatory cytokine that is overproduced in patients with giant cell arteritis.

CLINICAL STUDIES: FDA approval of tocilizumab for giant cell arteritis was based on the results of a double-blind trial in 251 adults ≥50 years old with newly diagnosed or relapsing giant cell arteritis. Patients were randomized to tocilizumab 162 mg SC every week (n=100) or every other week (n=50) plus a 26-week prednisone taper, or to placebo plus a 26- (n=50) or 52-week (n=51) prednisone taper. The rate of sustained glucocorticoid-free remission (remission from week 12 through 52 and adherence to prednisone taper) was significantly greater in patients who received tocilizumab once weekly (56%) or every other week (53%) than in those who received placebo plus 26 weeks (14%) or 52 weeks (18%) of prednisone taper. The cumulative prednisone dose over the 52-week period was ~50% lower in those receiving tocilizumab than in those receiving placebo.

The effect of IL-6 inhibition with tocilizumab on vision loss and other ischemic events remains to be determined.

ADVERSE EFFECTS: Adverse effects in the clinical trial were similar in all of the groups. Serious adverse events occurred less frequently in patients treated with tocilizumab. Serious bacterial, fungal, and viral infections have been reported with use of tocilizumab. Testing for latent tuberculosis is required before starting the drug. Live vaccines should not be administered during tocilizumab therapy. Neutropenia, thrombocytopenia, and serum hepatic transaminase elevations have been reported with tocilizumab; dosage adjustment and/or discontinuation of the drug may be needed, based on severity. Use of tocilizumab for other indications has been associated with GI perforation; patients with a history of diverticulitis are at increased risk.

DRUG INTERACTIONS: In vitro data indicate that tocilizumab may reverse IL-6-mediated suppression of CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4, potentially decreasing serum concentrations of other drugs taken concurrently.5 In vivo studies have found that concurrent use of tocilizumab resulted in decreased serum concentrations of simvastatin (Zocor, and others) and omeprazole (Prilosec, and others). Other biologic agents should not be used concomitantly with tocilizumab.

DOSAGE, ADMINISTRATION, AND COST: The recommended dosage of tocilizumab for treatment of giant cell arteritis is 162 mg injected SC once weekly. Administration every other week may be considered for some patients. Tocilizumab should be given in combination with a tapering course of a glucocorticoid. The labeling states that it can be used alone after discontinuation of glucocorticoid therapy, but the duration of treatment is unclear. A 28-day supply of once-weekly tocilizumab (four 162-mg prefilled syringes) costs $3647.10.

CONCLUSION: In one controlled trial in patients with newly diagnosed or relapsing giant cell arteritis, addition of tocilizumab (Actemra) to tapered prednisone was significantly more effective than addition of placebo in achieving sustained remission and in reducing the cumulative dosage of prednisone. Its effect on the most serious complications of giant cell arteritis (blindness, stroke) remains to be determined. More data are needed to clarify the place of tocilizumab in the treatment of giant cell arteritis.


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