2017 DRUG RESEARCH

ROUNDUP
Get the latest research on the drugs and
clinical applications that concern you most
 April 2017

Dear Colleague
nejm journal watch Coverage of new drug-related evidence is an important feature of NEJM Journal
Cardiology Watch, helping us fulfill our mission to support clinicians efficient understanding
Emergency Medicine
of medical developments. Our 110 NEJM Journal Watch physician-editors regularly
Gastroenterology
survey more than 250 medical journals to identify the most important clinical re-
General Medicine
Hospital Medicine search and provide the clinical context you need to practice with confidence. As
Infectious Diseases part of this effort, we appraise a broad range of medication studies, choose those
Neurology with the most clinical impact, and summarize them, highlighting key points and
Oncology and Hematology identifying whats new.
Pediatrics andAdolescent Medicine
Psychiatry It can be a struggle to keep up with important developments in therapeutics. There-
Womens Health fore, weve compiled these NEJM Journal Watch articles covering topics in drug
research to thank you for your engagement in our clinician community. Weve
chosen summaries that address questions that arise frequently in practice and
that have helped us manage our own patients. We hope you enjoy this compilation
and find it useful in providing the best and most responsible patient care.

Allan S. Brett, MD
NEJM Journal Watch Editor-in-Chief

800.843.6356 | f: 781.891.1995 | nejmgroup@mms.org

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 2017 Drug Research Roundup

TABLE OF CONTENTS
Another Trial of Tamsulosin for Patients with Ureteral Stones 2

Consider Using TMP/SMX After Draining Uncomplicated Abscesses 3

Thiazide-Associated Hypercalcemia: A Population-Based Study 4

Another Look at Metformin and Vitamin B12 Deficiency 5

Net Effect of Warfarin for Patients with Atrial Fibrillation and Chronic Kidney Disease 6

Three Common Approaches to Smoking Cessation Are Roughly Equal in Efficacy 7

Testosterone for Older Men: A Group of Randomized Trials 8

Association Between Proton-Pump Inhibitors and Dementia? 9

Should We Withhold ACE Inhibitors Just Before Noncardiac Surgery? 10

Comparing Dabigatran, Apixaban, and Rivaroxaban in the Absence of Head-to-Head Trials 11

Oral Therapy for New-Onset Type 2 Diabetic Patients with Severe Hyperglycemia 12

How Long Do We Need to Treat CAP? 13

Should We Treat Patients with Isolated Calf Deep Venous Thrombosis? 14

Pregabalin Is Ineffective for Treating Sciatica Pain 15

Macrolide Antibiotic Therapy for Asthma Exacerbations? 16

Should Inhaled Steroids Be Used for Mild Intermittent Asthma? 17

NEJM Journal Watch is produced by NEJM Group, a division of the Massachusetts Medical Society.
2017 Massachusetts Medical Society. All rights reserved.
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EDITORS NOTE: Over the years, the pendulum has swung back and forth regarding the efficacy of alpha-
blockers (e.g., tamsulosin) in facilitating passage of ureteral stones. This study and a meta-analysis published
in 2016 suggest benefit for stones that measure 5 to 10 mm.

Another Trial of Tamsulosin for Patients with Ureteral Stones

Allan S. Brett, MD

The drug facilitated passage of 5- to 10-mm distal ureteral stones.

The efficacy of -blockers (e.g., tamsulosin) to facilitate passage of ureteral stones is unclear. In a 2014 meta-analysis
of mostly small studies, tamsulosin shortened time to stone passage, but study quality was not highly rated (Cochrane
Database Syst Rev 2014; 4:CD008509). In a subsequent large trial, tamsulosin was not superior to placebo, but stone
passage was not confirmed by imaging (NEJM JW Gen Med Jul 1 2015 and Lancet 2015; 386:341).
Now, in a double-blind, randomized trial conducted in five Australian emergency departments, 403 adults with
computed tomography (CT)confirmed distal ureteral stones received daily tamsulosin (0.4 mg) or placebo for
28 days. Stone size was <5 mm in 74% of patients and 5 to 10 mm in 26%; patients were excluded if stone size
exceeded 10 mm.

In patients with smaller stones, stone passage (confirmed by absence of stone on CT at 28 days) occurred with
equal frequency (90%) in the tamsulosin and placebo groups. In contrast, stones measuring 5 to 10 mm passed
significantly more often with tamsulosin than with placebo (83% vs. 61%). Median time to stone passage (i.e., time
to patient-reported stone retrieval or to a 48-hour pain-free period) was 7 days with tamsulosin and 11 days with
placebo (P=0.10); this endpoint was not reported separately for small and large stones. At 28 days, 13 patients (5 in
the tamsulosin group and 8 in the placebo group) had undergone urologic intervention. Pain scores were similar
in the tamsulosin and placebo groups throughout follow-up.

COMMENT
In this study, tamsulosin increased the probability that 5- to 10-mm distal ureteral stones would be passed. The
clinical importance of this finding depends on whether tamsulosin lowered overall need for invasive urologic in-
terventions (both during and after 28-day follow-up), but that outcome was not reported. Thus, the ultimate
clinical benefit remains speculative.

Furyk JS et al. Distal ureteric stones and tamsulosin: A double-blind, placebo-controlled, randomized, multicenter trial.
Ann Emerg Med 2016 Jan; 67:86. (http://dx.doi.org/10.1016/j.annemergmed.2015.06.001)

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EDITORS NOTE: Although most uncomplicated skin abscesses respond to incision and drainage without need
for antibiotic therapy, adding a short course of trimethoprimsulfamethoxazole improved cure rates modestly in
this study. However, only 1 patient benefited for every 14 patients who received the antibiotic.

Consider Using TMP/SMX After Draining Uncomplicated

Abscesses
Ali S. Raja, MD, MBA, MPH, FACEP

Trimethoprimsulfamethoxazole led to a higher rate of cure, but even without antibiotics, the majority of abscesses
resolved.
The appropriate treatment for uncomplicated cutaneous abscesses is incision and drainage. Thus far, studies have
not shown any additional benefit from the administration of antibiotics. However, these studies may have been under-
powered to detect the benefit of antibiotics, given that cure rates after drainage alone are high.

These investigators performed a double-blinded, randomized, controlled trial of trimethoprimsulfamethoxazole

(TMP/SMX; 320 mg/1600 mg, twice a day for 7 days) versus placebo in 1247 patients with uncomplicated abscesses
that were detected by physical or ultrasonographic examination and were incised and drained. The primary outcome
was clinical cure of the abscess, evaluated 1 to 2 weeks after the weeklong treatment course.

In a modified intention-to-treat analysis, the TMP/SMX group had a significantly higher rate of clinical cure
(80.5% vs. 73.6%; P=0.005). In a per-protocol analysis of 1057 patients who completed at least 5 days of treatment and
had an in-person follow-up visit, the difference had even greater statistical significance (92.9% vs. 85.7%; P<0.001).
Patients in the TMP/SMX group had no serious adverse reactions to the medication.

COMMENT
It is notable that more than 85% of abscesses resolved after drainage alone; well-performed incision and drainage
is still the cornerstone of management of uncomplicated abscesses. However, I will be sharing these results with
my patients, and will prescribe the high-dose TMP/SMX used in this study for those who understand the poten-
tial gastrointestinal and other risks of the medication and desire a higher (but still not guaranteed) likelihood
of cure.

Talan DA et al. Trimethoprimsulfamethoxazole versus placebo for uncomplicated skin abscess. N Engl J Med 2016 Mar 3;
374:823. (http://www.nejm.org/doi/full/10.1056/NEJMoa1507476)

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EDITORS NOTE: Development of mild hypercalcemia during treatment with thiazide diuretics is not rare. This
study provides a nice overview, and suggests that in a nontrivial proportion of cases, the thiazide is unmasking
primary hyperparathyroidism.

Thiazide-Associated Hypercalcemia: A Population-Based Study

Allan S. Brett, MD

Primary hyperparathyroidism is often, but not invariably, present in these patients.

Thiazide diuretics can increase renal tubular reabsorption of calcium, resulting in hypercalcemia. However, thia-
zide-associated hypercalcemia also can represent unmasking of preexisting primary hyperparathyroidism (PHPT)
or incidental development of PHPT during thiazide therapy. Mayo Clinic researchers used their Olmsted County,
Minnesota, database to explore the incidence and features of thiazide-associated hypercalcemia that was identified
in 221 patients between 1992 and 2010.

Thiazide-associated hypercalcemia was more common in women than in men (incidence, 20 vs. 4 cases per
100,000 person-years), and incidence increased with age. Hypercalcemia was first noted a median of 4 years after
thiazide was started, and mean highest calcium level was 10.7 mg/dL (highest, 12.5 mg/dL). Serum parathyroid hor-
mone levels were elevated in 34% of patients and were in the upper half of the normal range in 43%. Among 83 patients
who stopped taking thiazides, serum calcium normalized in 24 patients and remained elevated in 59; PHPT was diag-
nosed subsequently in 48 of those 59 patients. Among 138 patients who continued thiazides, serum calcium normal-
ized in about half and remained only mildly elevated in the rest.

COMMENT
Because hypercalcemia in these patients was not evaluated and managed in systematic fashion, the frequencies of
various outcomes are only approximations. However, two take-home points are evident. First, underlying prima-
ry hyperparathyroidism is present in a fairly large proportion of patients with thiazide-associated hypercalcemia.
And second, because the hypercalcemia tends to be mild and nonprogressive, we can reasonably continue thiazide
therapy if compelling reasons exist to do so (e.g., hypertension that requires diuretic therapy for good control).

Griebeler ML et al. Thiazide-associated hypercalcemia: Incidence and association with primary hyperparathyroidism over two de-
cades. J Clin Endocrinol Metab 2016 Mar; 101:1166. (http://dx.doi.org/10.1210/jc.2015-3964)

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EDITORS NOTE: Metformin is the most widely prescribed oral agent for type 2 diabetes. It appears to be
associated with development of vitamin B12 deficiency, but the absolute incidence is quite low.

Another Look at Metformin and Vitamin B12 Deficiency

Allan S. Brett, MD

A study with as long as 13 years of follow-up supports this link.

Several studies have linked metformin to development of vitamin B12 deficiency (NEJM JW Gen Med Jul 1 2010 and
BMJ 2010; 340:c2181). Now, researchers provide additional data on this potential complication.

In the randomized Diabetes Prevention Program, 3200 adults at high risk for diabetes received metformin, placebo,
or intensive lifestyle modification for 3 years (NEJM JW Gen Med Mar 15 2002 and N Engl J Med 2002; 346:393). After
the trial was completed in 2002, participants were invited to a follow-up study in which the metformin group was of-
fered open-label metformin. Among 1700 participants with 5-year follow-up, prevalence of vitamin B12 deficiency
(203 pg/mL) at year 5 was significantly higher in the metformin group than in the placebo group (4% vs. 2%); at a
higher cutoff of 298 pg/mL, prevalences were 19% and 9%, respectively. Although differences between groups dimin-
ished after 13 years, years of metformin exposure still correlated with development of B12 deficiency at year 13. Patients
with metformin-related low B12 levels had elevated homocysteine levels (an expected finding in B12-deficient patients).

COMMENT
This study strengthens the case for metformin-induced reductions in vitamin B12 levels. However, the clinical im-
portance of this relation remains somewhat unclear: The researchers had no data on changes in red-cell mean
corpuscular volume (MCV), and participants responses on a standardized neuropathy screening instrument did
not correlate with vitamin B12 levels. Checking a serum B12 level if the MCV rises or if neuropathic symptoms de-
velop in a metformin-treated patient certainly is appropriate. However, whether we should monitor B12 status rou-
tinely in all metformin-treated patients remains unclear.

Aroda VR et al. Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study.
J Clin Endocrinol Metab 2016 Apr; 101:1754. (http://dx.doi.org/10.1210/jc.2015-3754)

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EDITORS NOTE: Atrial fibrillation is common in patients with chronic kidney disease. However, warfarin is
difficult to manage in these patients, and the newer direct oral anticoagulants are relatively contraindicated in
advanced renal disease. This study albeit observational helps to clarify the benefits and harms of warfarin
therapy in such patients.

Net Effect of Warfarin for Patients with Atrial Fibrillation and

Chronic Kidney Disease
Allan S. Brett, MD

In a meta-analysis, warfarin was beneficial for patients with nonend-stage CKD, but not for those with end-stage
CKD.
Atrial fibrillation (AF) and chronic kidney disease (CKD) coexist commonly. However, randomized trials of anti
coagulation for AF have excluded patients with severe CKD, and observational studies of the efficacy and safety of
anticoagulation in AF patients with CKD have yielded varying results. Now, researchers have conducted a meta-
analysis of 11 cohort studies in which investigators examined effects of warfarin in such patients.

In AF patients with nonend-stage CKD, warfarin was associated with lower risk for ischemic stroke or thrombo-
embolism (hazard ratio, 0.70), lower mortality (HR, 0.65), and no excess major bleeding risk, compared with no anti-
coagulation. In patients with end-stage CKD (i.e., patients receiving renal replacement therapy), warfarin was associ-
ated with no difference in risk for ischemic stroke or thromboembolism or for mortality and with higher risk for major
bleeding (HR, 1.30), compared with no anticoagulation.

COMMENT
This analysis suggests net benefit for warfarin anticoagulation in AF patients with nonend-stage CKD and net
harm in those with end-stage CKD. The analysis did not address the newer oral anticoagulants, which are not
recommended for use when glomerular filtration rate is <30 mL/minute/1.73 m2 (for dabigatran [Pradaxa] and
rivaroxaban [Xarelto]), <25 mL/minute/1.73 m2 (for apixaban [Eliquis]), and <15 mL/minute/1.73 m2 (for
edoxaban [Savaysa]).

Dahal K et al. Stroke, major bleeding, and mortality outcomes in warfarin users with atrial fibrillation and chronic kidney disease:
A meta-analysis of observational studies. Chest 2016 Apr; 149:951. (http://dx.doi.org/10.1378/chest.15-1719)

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EDITORS NOTE: This study reminds us that nicotine replacement therapy, when used consistently, compares
favorably to more expensive prescription pharmacotherapies for smoking cessation.

Three Common Approaches to Smoking Cessation Are Roughly

Equal in Efficacy
Thomas L. Schwenk, MD

Quit rates at 26 weeks were about 25% for varenicline, nicotine patches, or the combination of nicotine patches and
nicotine lozenges.
Several studies have shown superior effectiveness for varenicline (Chantix) or nicotine replacement combination therapy
(nicotine patches plus nicotine lozenges) over nicotine replacement monotherapy, but the two superior approaches
have not been compared directly. In this study, researchers randomized 1086 smokers (mean age, 48; mean daily
cigarettes, 17; mean smoking duration, 29 years) to one of three open-label 12-week interventions:

Varenicline alone (starting at 0.5 mg daily and titrated to 1 mg twice daily)

21-mg nicotine patches, tapered to 7-mg patches by 8 weeks

Nicotine patches as above, plus five 2-mg or 4-mg lozenges daily (depending on smoking history)

All regimens were adjusted as needed for side effects, and all participants received initial weekly counseling sessions.

Adherence rates were about 45% for all interventions at 8 weeks. In intent-to-treat analyses, quit rates (assessed
by self-report and confirmed by exhaled carbon monoxide) were similar for all three interventions: about 35% at
4 weeks, about 30% at 12 weeks, about 25% at 26 weeks, and about 20% at 52 weeks. Overall frequency of side effects
was similar across groups, but insomnia, somnolence, and nausea were most common with varenicline, and itching
and rash were most common with nicotine.

COMMENT
These results call into question the alleged superiority of varenicline and nicotine replacement combination therapy
over nicotine replacement monotherapy. All pharmacotherapeutic approaches to quitting appear to be similarly
effective when combined with structured support and follow-up.

Baker TB et al. Effects of nicotine patch vs varenicline vs combination nicotine replacement therapy on smoking cessation at
26 weeks: A randomized clinical trial. JAMA 2016 Jan 26; 315:371. (http://dx.doi.org/10.1001/jama.2015.19284)

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EDITORS NOTE: This large, randomized trial of testosterone supplementation in men with age-related low
testosterone levels was conducted rigorously and was sponsored by NIH (and not the pharmaceutical industry).
However, its duration (only 1 year) was unfortunately too short for drawing conclusions about long-term safety.

Testosterone for Older Men: A Group of Randomized Trials

Allan S. Brett, MD

At 1 year, some patients had benefited modestly.

In a recent trial, testosterone therapy did not improve sexual function or quality of life in older men with low serum
testosterone levels, but participants were not enrolled according to any particular symptoms (NEJM JW Gen Med
Sep 15 2015 and JAMA 2015; 314:570). Now, in an NIH-supported group of randomized, double-blind studies (the
Testosterone Trials [TT]), researchers have focused on symptomatic older men (age, 65) with two serum testoster-
one levels that averaged <275 ng/dL. Qualifying symptoms were decreased libido (for the Sexual Function Trial),
difficulty walking or climbing stairs (for the Physical Function Trial), or fatigue (for the Vitality Trial); men were
enrolled only if these symptoms were verified by standardized assessment tools. Patients with recent cardiovascular
events or uncontrolled hypertension were excluded.

Altogether, 790 men received testosterone gel or placebo for 1 year. For primary endpoints, results with active
treatment (compared with placebo) were as follows:

Sexual function scores improved significantly both in the Sexual Function Trial and among all TT participants,
but improvement was only about 0.6 points on a 12-point scale.

A small increase in the proportion of men whose 6-minute walk distance improved by 50 meters (about 8 per-
centage points at 12 months) was not significant in the Physical Function Trial but was significant among all TT
participants.

The proportion of men who improved by 4 points on a 52-point fatigue scale did not increase significantly either
in the Vitality Trial or among all TT participants.

Several secondary endpoints favored testosterone therapy. Frequencies of adverse events with testosterone and placebo
generally were similar, but testosterone recipients were more likely to develop polycythemia (2% vs. 0%) and increased
prostate-specific antigen levels (6% vs. 2%).

COMMENT
On average, testosterone therapy improved sexual and physical function modestly in symptomatic older men with
low testosterone levels, but the proportion of men who benefited was low. Moreover, patients were highly selected
according to age, testosterone levels, and fairly restrictive enrollment criteria: About 50,000 men were screened
to enroll the 790 participants. Although these results could justify testosterone treatment in men who meet the
studys enrollment criteria, patients should understand that benefits were rather limited, and long-term safety
remains unclear.

Snyder PJ et al. Effects of testosterone treatment in older men. N Engl J Med 2016 Feb 18; 374:611.
(http://dx.doi.org/10.1056/NEJMoa1506119)
Orwoll ES. Establishing a framework does testosterone supplementation help older men? N Engl J Med 2016 Feb 18; 374:682.
(http://dx.doi.org/10.1056/NEJMe1600196)

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EDITORS NOTE: This observational study attracted considerable media attention, and patients on proton pump
inhibitors are now asking whether the drugs will increase their risk for dementia. Patients need to understand
that this study likely had substantial confounding and cant prove cause-and-effect, but it provides an opportunity
to make sure the patient really has an indication for PPI therapy.

Association Between Proton-Pump Inhibitors and Dementia?

Allan S. Brett, MD

An observational study that suggested this association has considerable limitations.

In February 2016, a study that linked proton-pump inhibitors (PPIs) to dementia was published online and attracted
considerable media attention. Because patients who use PPIs continue to ask their physicians about this presumed
dementia risk, we thought it worthwhile to revisit the study (the original article now has been published in print).
Drawing from an insurance claims database, researchers compared older (age, 75) regular PPI users (3000) with
older PPI nonusers (71,000); patients had no history of dementia at baseline. During about 6 years of follow-up, risk
for a new diagnosis of dementia was significantly higher among PPI users than among nonusers (hazard ratio, 1.44).

COMMENT
Media coverage of this study did not adequately emphasize that most observational studies including this
one do not establish cause and effect. One problem is that the researchers controlled for only a few potentially
confounding variables; they did not control for alcohol use or cigarette smoking, which could be associated with
both PPI use and propensity for dementia. Additionally, type of dementia was not specified for most patients.
Patients who take PPIs for valid reasons (e.g., those with peptic ulcer or severe reflux symptoms, and those who
take PPIs for guideline-recommended ulcer prophylaxis) should not stop taking the drugs because of this study.
However, this study and others that raise concerns about various potential adverse effects might motivate
patients who take PPIs for no good reason to discontinue them.

Gomm W et al. Association of proton pump inhibitors with risk of dementia: A pharmacoepidemiological claims data analysis.
JAMA Neurol 2016 Apr; 73:410. (http://dx.doi.org/10.1001/jamaneurol.2015.4791)

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EDITORS NOTE: An important element of preoperative consultation is to advise patients on which of their
medications should be taken just before surgery and which should be omitted. This is probably the best study to
date on whether we should hold ACE inhibitors and ARBs on the morning of noncardiac surgery.

Should We Withhold ACE Inhibitors Just Before Noncardiac Surgery?

Allan S. Brett, MD

In an observational study, withholding angiotensin-convertingenzyme inhibitors was associated with fewer adverse
events.
For patients who take angiotensin-convertingenzyme (ACE) inhibitors and undergo noncardiac surgery, some ob-
servational studies suggest that continuing the ACE inhibitors on the morning of surgery is associated with excess risk
for intraoperative hypotension. However, the evidence is not decisive, and the 2014 American College of Cardiology/
American Heart Association guideline on management of patients undergoing noncardiac surgery concludes that
continuation of ACE inhibitors or angiotensin-receptor blockers (ARBs) perioperatively is reasonable (Circulation
2014;130:e278).

Now, researchers have addressed this issue using data from a prospective cohort study of patients (age, 45) who
underwent noncardiac surgery and required overnight hospital admission. Among 4802 patients who used ACE inhib-
itors or ARBs routinely, 74% took the drug during the 24 hours before surgery; the drug was withheld in the remain-
ing 26%. The following outcomes were noted:

The primary composite outcome (death, stroke, or myocardial injury defined by perioperative rise in troponin
level) occurred in 12.0% of patients whose ACE inhibitor or ARB was withheld and in 12.9% of those whose drug
was continued; after adjustment for potentially confounding variables (including preoperative blood pressure and
use of other antihypertensive drugs), the relative risk for this outcome was significantly lower in the drug-withheld
group (RR, 0.82; P=0.01).

Incidence of intraoperative hypotension was lower in the drug-withheld group than in the drug-continued group
(23.3% vs. 28.6%); in adjusted analyses, relative risk was significantly lower in the drug-withheld group (RR, 0.80;
P<0.001).

Clinical and surgical factors were not associated substantially with continuing versus withholding ACE inhibitors
or ARBs; thus, most decisions to withhold the drugs likely were arbitrary and based on clinician preference.

COMMENT
This analysis doesnt carry the authority of a randomized trial, but the authors conclusion that we should con-
sider withholding ACE inhibitors and ARBs before noncardiac surgery is reasonable. They note that anesthe-
sia-related blunting of sympathetic vascular tone might increase reliance on the renin-angiotensin system to
maintain blood pressure intraoperatively.

Roshanov PS et al. Withholding versus continuing angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers be-
fore noncardiac surgery: An analysis of the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation prospective cohort.
Anesthesiology 2017 Jan; 126:16. (http://anesthesiology.pubs.asahq.org/article.aspx?articleid=2572372)

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EDITORS NOTE: Clinicians now have a choice of several direct-acting oral anticoagulants for patients with
atrial fibrillation and venous thromboembolism. In this observational analysis that was quite rigorously adjusted
for confounding, apixaban seemed to be associated with less bleeding.

Comparing Dabigatran, Apixaban, and Rivaroxaban in the Absence

of Head-to-Head Trials
Allan S. Brett, MD

In an observational study, apixaban was associated with the least major bleeding.
U.S. clinicians have a choice of four direct-acting oral anticoagulants (DOACs), but head-to-head trials are lacking. In
this observational study, Mayo Clinic researchers used an insurance database to compare effectiveness and safety of
the three most-commonly prescribed DOACs (dabigatran [Pradaxa], apixaban [Eliquis], and rivaroxaban [Xarelto]) in
patients with nonvalvular atrial fibrillation. Using propensity-score matching, demographically and clinically similar
cohorts were created for each two-way comparison: The rivaroxabandabigatran comparison had 15,800 patients in
each group, and the apixabandabigatran and apixabanrivaroxaban comparisons had about 6500 patients in each
group. Results were published in two separate articles.

For preventing stroke or systemic embolism, all three drugs performed similarly. However, for overall major bleed-
ing requiring hospital admission, the following statistically significant differences were noted:

More events with rivaroxaban than with dabigatran (about 1 more per 100 person-years)

Fewer events with apixaban than with dabigatran (about 1 fewer per 100 person-years)

Fewer events with apixaban than with rivaroxaban (about 2 fewer per 100 person-years)

For gastrointestinal bleeding (responsible for most major bleeding events), findings closely paralleled those for overall
major bleeding listed above. For the small number of intracranial bleeding episodes, significantly more events oc-
curred with rivaroxaban than with dabigatran (0.53 vs. 0.26 per 100 person-years; P=0.02); no significant differences
were found for the other two pairwise comparisons.

COMMENT
Apixaban was associated with less major bleeding than the other two drugs in this observational study. However,
patients to whom these drugs were prescribed could have differed in subtle ways that were not captured by pro-
pensity matching. Another way to address absence of head-to-head trials is network meta-analysis, in which
outcomes of randomized DOAC-versus-warfarin trials are compared indirectly with each other. Several network
meta-analyses also have suggested similar efficacy but less major bleeding with apixaban than with the oth-
er two agents in patients with atrial fibrillation.

Noseworthy PA et al. Direct comparison of dabigatran, rivaroxaban, and apixaban for effectiveness and safety in nonvalvular atrial
fibrillation. Chest 2016 Dec; 150:1302. (http://dx.doi.org/10.1016/j.chest.2016.07.013)
Abraham NS et al. Gastrointestinal safety of direct oral anticoagulants: A large population-based study. Gastroenterology 2016
Dec 31; [e-pub]. (http://dx.doi.org/10.1053/j.gastro.2016.12.018)

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EDITORS NOTE: When a patient presents with newly diagnosed diabetes and severe hyperglycemia
(e.g., glucose level >300 mg/dL), there is a knee-jerk temptation to start insulin immediately. But this
study shows that many of these patients can be managed with oral medication.

Oral Therapy for New-Onset Type 2 Diabetic Patients with Severe

Hyperglycemia
Allan S. Brett, MD

Two oral regimens were effective in patients with blood glucose levels between 300 and 450 mg/dL.
An American Diabetes Association guideline (Diabetes Care 2016; 39 [Suppl 1]:1) recommends insulin therapy for
most patients with type 2 diabetes who present initially with severe hyperglycemia (i.e., blood glucose level, 300 mg/
dL); however, oral regimens also can be effective. In this study, researchers enrolled 100 adults with newly diagnosed
type 2 diabetes, glucose levels of 300 to 450 mg/dL, and no evidence of ketoacidosis or hyperosmolar symptoms. Pa-
tients were randomized to receive one daily dose of either extended-release glipizide (10 mg) or a fixed combination
of 5-mg saxagliptin plus 2000-mg metformin (Kombiglyze XR). The study was funded by the maker of Kombiglyze.

At initial diagnosis, mean glucose level was 342 mg/dL, and mean glycosylated hemoglobin (HbA1c) was 11%. All
patients received diabetes education and had close follow-up at a diabetes center. At 12 weeks, glycemic control im-
proved substantially in nearly all patients in both groups (mean blood glucose level, about 130 mg/dL; mean HbA1c,
about 7%). Prevalence of hypoglycemia (glucose level, <70 mg/dL) was greater with glipizide than with saxagliptin/
metformin (24% vs. 8%), but severe hypoglycemia (<50 mg/dL) did not occur in either group.

COMMENT
Oral therapy is an acceptable option for clinically stable, newly diagnosed type 2 diabetic patients with blood
glucose levels between 300 and 450 mg/dL. Regimens can be adjusted during follow-up, depending on patients
glycemic response to initial treatment and the extent to which they modify diet and physical activity. The take-
home message should not be that Kombiglyze (cash price, about US$5,000 annually) is the drug of choice; for
selected motivated patients, I have even used metformin monotherapy successfully in this setting.

Amblee A et al. Combination of saxagliptin and metformin is effective as initial therapy in new-onset type 2 diabetes mellitus with
severe hyperglycemia. J Clin Endocrinol Metab 2016 Jun; 101:2528. (http://dx.doi.org/10.1210/jc.2015-4097)

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EDITORS NOTE: Hospitalized patients with community-acquired pneumonia often receive lengthy courses
of antibiotics; even patients who can be discharged within a few days are often prescribed another week of
outpatient oral antibiotics. This study shows that many patients require only a 5-day course.

How Long Do We Need to Treat CAP?

Richard T. Ellison III, MD

A multicenter study found that 5 days of antibiotic treatment was comparable to longer treatment for hospitalized
patients with community-acquired pneumonia.
Concerns regarding antibiotic resistance and the adverse impact of antibiotics on the microbiome have led to increasing
interest in defining the minimal duration of antibiotic therapy necessary to treat infections. Spanish investigators have
now assessed whether a 5-day antibiotic course, as suggested in the Infectious Diseases Society of America treatment
guidelines for community-acquired pneumonia (CAP), is as effective as longer treatment. Patients hospitalized for
CAP at four Basque-region teaching hospitals were randomized to an intervention group or a control group. Patients
in the intervention group received only 5 days of antibiotic treatment if they had been afebrile and clinically stable for
48 hours. In control group patients, therapy duration was determined by the treating physician.

The 150 control patients had a significantly longer median antibiotic course than the 162 intervention patients
(10 days vs. 5 days). However, rates of clinical success (resolution or improvement of pneumonia-related and CAP-
related signs and symptoms without further antibiotics) were comparable between groups at both day 10 (49% of con-
trols vs. 56% of intervention patients) and day 30 (89% and 92%, respectively). The results were comparable in both
intention-to-treat and per-protocol analysis and at all levels of CAP severity. In secondary analyses, in-hospital
mortality was comparable between groups, but readmission within 30 days was more common in control patients.

COMMENT
These findings clearly support a 5-day antibiotic course for hospitalized patients with CAP who have a prompt
response to treatment. Important caveats in considering the findings are that patients requiring ICU care were
excluded, and approximately 80% of the patients received a quinolone, so the applicability to other antibiotic
regimens is uncertain.

Uranga A et al. Duration of antibiotic treatment in community-acquired pneumonia: A multicenter randomized clinical trial.
JAMA Intern Med 2016 Jul 25; [e-pub]. (http://dx.doi.org/10.1001/jamainternmed.2016.3633)

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2017Guideline
Drug Research Roundup
Watch Update JWatch.org

EDITORS NOTE: Finally, we have a reasonably large randomized trial that sheds light on the pros and cons
of anticoagulating patients with isolated deep vein thrombosis of the calf.

Should We Treat Patients with Isolated Calf Deep

Venous Thrombosis?
Allan S. Brett, MD

In a randomized trial, treatment did not improve outcomes.

For isolated deep venous thrombosis (DVT) of the calf, American College of Chest Physicians guidelines suggest
(1) anticoagulation in patients with severe symptoms or risk factors for proximal extension, and (2) in lower-risk
patients, repeat ultrasound imaging during 2 weeks, plus anticoagulation for those whose DVTs extend proximally
(Chest 2016; 149:315). However, data to inform these decisions are limited. In this double-blind trial, researchers in
Europe randomized 259 adults with first acute isolated symptomatic calf DVTs, diagnosed by ultrasound, to receive
either the low-molecular-weight heparin nadroparin (not available in the U.S.) or placebo for 6 weeks; follow-up
visits with repeat ultrasound were scheduled at 3 to 7 days and at 6 weeks. Patients with active cancer or previous
venous thromboembolic disease were excluded. About half of the patients had reversible risk factors (i.e., estrogen
therapy or recent surgery, immobilization, or prolonged travel).

The primary composite outcome (proximal extension of calf DVT, contralateral proximal DVT, or pulmonary
embolism at 6 weeks) occurred in 3% of nadroparin patients and 5% of placebo patients a nonsignificant differ-
ence. Outcomes were similar at 3 months. Major bleeding occurred in 4% of nadroparin patients and no placebo
patients (P=0.03). No participant died.

COMMENT
According to the authors, this study is the first placebo-controlled, randomized treatment trial for isolated calf
DVT. The results suggest that, for patients like those enrolled in this trial, initial anticoagulation is unnecessary if
a second ultrasound examination is done within a week to screen for proximal extension. With its sample size, the
study was underpowered to detect a several percentage point benefit for anticoagulation, but it did remind us of
bleeding risks during an even relatively brief course of anticoagulation.

Righini M et al. Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): A randomised, double-blind,
placebo-controlled trial. Lancet Haematol 2016 Nov 7; [e-pub]. (http://dx.doi.org/10.1016/S2352-3026(16)30131-4)

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2017Guideline
Drug Research Roundup
Watch Update JWatch.org

EDITORS NOTE: The growing opioid epidemic has pushed clinicians to look for nonopioid options for
treatment of pain. Off-label prescribing of gabapentin and pregabalin for various painful disorders including
sciatica has increased substantially. But in a well-done randomized trial, pregabalin had no effect beyond
placebo.

Pregabalin Is Ineffective for Treating Sciatica Pain

Allan S. Brett, MD

In a placebo-controlled study, pregabalin was associated with no benefit and excess side effects.
Gabapentin and pregabalin (Lyrica) are prescribed frequently for lumbosacral radicular pain, despite a lack of evi-
dence that they are effective for this condition. In this randomized trial from Australia, researchers randomized
209 patients with sciatica to receive either pregabalin (titrated from 150 mg to 600 mg, depending on response and
side effects) or placebo for as long as 8 weeks. At enrollment, duration of pain had been 1 week to 1 year (mean,
2 months); all patients had pain radiating below the knee and either dermatomal pain distribution, motor or sensory
deficit, or diminished reflex. The primary outcome was leg pain at 8 weeks.

Improvement in the mean leg-pain score at 8 weeks actually was slightly greater in the placebo group than in the
pregabalin group (decrease of 3.0 vs. 2.6 points, from a mean baseline of 6.1 on a 10-point scale), but the difference
was not statistically significant; pain scores remained similar in the two groups at 1 year. Moreover, the groups did not
differ on any secondary outcome (e.g., ratings of disability, quality of life, and global perceived effect). However, the
frequency of side effects was significantly higher with pregabalin than with placebo dizziness was most common
(40% vs. 13%).

COMMENT
Pregabalin does not relieve pain associated with sciatica and should not be prescribed for this purpose; presum-
ably, the same holds true for the related drug gabapentin. This finding is not surprising: Although pregabalin has
some efficacy and is FDA-approved for use in patients with postherpetic neuralgia or diabetic peripheral
neuropathy, the pathogenesis of pain in those conditions is different from that of radicular pain.

Mathieson S et al. Trial of pregabalin for acute and chronic sciatica. N Engl J Med 2017 Mar 23; 376:1111.
(http://dx.doi.org/10.1056/NEJMoa1614292)

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2017Guideline
Drug Research Roundup
Watch Update JWatch.org

EDITORS NOTE: Patients with asthma exacerbations are often given antibiotics on the premise that an
antibiotic-responsive infection might have triggered the episode. This study debunks that premise; antibiotics
should not be given unless the patient also has evidence of pneumonia or bacterial sinusitis.

Macrolide Antibiotic Therapy for Asthma Exacerbations?

David J. Amrol, MD

Azithromycin did not improve symptoms or lung function.

Respiratory viral infections such as rhinovirus are an important cause of asthma exacerbations. Some studies suggest
atypical infections with Mycoplasma pneumoniae or Chlamydophila pneumoniae also can cause asthma symptoms,
but data conflict about whether treating these infections with antibiotics improves outcomes.

In a multicenter U.K. study, 199 adults with asthma exacerbations that required systemic corticosteroids were ran-
domized to azithromycin (500 mg for 3 days) or placebo in addition to usual care. Sputum cultures, serology, or nasal/
pharyngeal swabs were positive for bacteria or atypical bacteria in 11% of patients; viral polymerase chain reaction
assays were positive in 18% of patients. Asthma symptoms, quality of life, and lung function during 10-day follow-up
did not differ between the azithromycin and placebo groups or in subgroup analysis of patients with positive bacterial
or atypical bacterial tests.

COMMENT
These results confirm current asthma guideline recommendations that counsel against antibiotics for patients
with routine asthma exacerbations. The study also confirms that we still are overusing antibiotics in asthma, be-
cause the investigators noted for every 1 patient randomized, another 10 were excluded because antibiotics already
had been started by primary care physicians.

Johnston SL et al. Azithromycin for acute exacerbations of asthma: The AZALEA randomized clinical trial. JAMA Intern Med
2016 Sep 19; [e-pub]. (http://dx.doi.org/10.1001/jamainternmed.2016.5664)

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2017Guideline
Drug Research Roundup
Watch Update JWatch.org

EDITORS NOTE: In general, short-acting rescue inhaled bronchodilators are considered sufficient in
management of patients with mild asthma. Although this study suggested that some patients with mild asthma
might benefit from low-dose daily inhaled corticosteroid, the number needed to treat to benefit one patient is
extremely high.

Should Inhaled Steroids Be Used for Mild Intermittent Asthma?

David J. Amrol, MD

Recommending inhaled steroids routinely would be premature, although a small proportion of these patients might
benefit.
Current U.S. guidelines</Hyperlink> recommend inhaled steroids (ICS) as first-line treatment for patients with per-
sistent asthma; however, for patients with normal lung function, rare exacerbations, and symptoms fewer than thrice
weekly, only as-needed, short-acting bronchodilators are recommended. This approach is universally accepted, but it
is not based on clinical evidence. In the START trial, researchers examined the effectiveness of low-dose budesonide
within 2 years of diagnosis in adults and children with mild asthma (200304280000006>NEJM JW Pediatr Adolesc
Med Jun 2003 and Lancet 2003; 361:1071).

In this post hoc analysis of START data, researchers evaluated 4098 patients with symptoms fewer than 3 days
weekly who were randomized to daily budesonide (400 g in adults; 200 g in children) or placebo. Budesonide
recipients had fewer severe asthma-related events that required emergency treatment and systemic steroids (9 fewer
per year per 1000 patients), fewer courses of oral steroids (90 fewer per year per 1000 patients), and 1% less loss of
post-bronchodilator forced expiratory volume in 1 second (FEV1) after 3 years. Symptom scores improved minimally
with budesonide; mortality was similar between groups.

COMMENT
This study calls into question our current approach to managing intermittent asthma. Even patients with rare
symptoms can experience exacerbations and loss of lung function over time. But is it worth treating a patient daily
for 10 years to prevent one exacerbation requiring oral steroids? An editorialist notes that, although fixed airflow
limitation was reduced slightly in START, a 5-year extension of the trial (designed to evaluate lung function de-
cline) didnt show any protective benefit of ICS. So, although we should discuss ICS treatment with patients who
have intermittent asthma, we shouldnt espouse universal treatment based on this analysis.

Reddel HK et al. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom
frequency: A post-hoc efficacy analysis of the START study. Lancet 2016 Nov 29; [e-pub].
(http://dx.doi.org/10.1016/S0140-6736(16)31399-X)
Papi A and Fabbri LM. Management of patients with early mild asthma and infrequent symptoms. Lancet 2016 Nov 29; [e-pub].
(http://dx.doi.org/10.1016/S0140-6736(16)32111-0)

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