Monthly Archives: May 2014

Stable TSH can be rechecked in 2 years

Clinical Question

How much do seemingly stable thyroid tests vary over time?

Bottom Line

Most patients receiving thyroid replacement therapy with less than 125 mcg levothyroxine per day can wait 2 years before monitoring with thyroid stimulating hormone (TSH) if their level is normal. Fewer than 1 in 10 patients who take less than 125 mcg levothyroxine per day with a normal TSH level will have an abnormal laboratory value 1 year later. The likelihood goes up to 26.7% if the dosage is higher than 125 mcg levothyroxine per day. Patients with TSH levels closer to the upper or lower limits of normal will also be slightly more likely to have an abnormal value in 1 year. (LOE = 1b)


Pecina J, Garrison GM, Bernard ME. Levothyroxine dosage is associated with stability of thyroid-stimulating hormone values. Am J Med 2014;127(3):240-245.

Study Design: Cohort (retrospective)

Funding: Self-funded or unfunded

Setting: Outpatient (primary care)

Allocation: Unknown


These authors identified 715 patients (84% female, average age = 54 years) in a single primary care practice who were treated for hypothyroidism and had a normal TSH value (0.3 mIU/L – 5.0 mIU/L). They recorded all subsequent TSH levels in these patients for the following 6 years. Age, sex, body mass index, and history of chronic autoimmune thyroiditis were not associated with the development of a subsequent abnormal TSH level, but the dosage of levothyroxine was. Approximately 1 in 4 patients taking more than 125 mcg levothyroxine per day (26.7%) had an abnormal TSH level 1 year later. Most of the patients taking lower dosages (91.1%) had normal TSH levels 1 year later.

Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, MA

Compression stockings = placebo stockings in preventing post-thrombotic syndrome

POEMs Research Summaries

Clinical Question

Are compression stockings effective in preventing post-thrombotic syndrome in patients with deep vein thrombosis?

Bottom Line

Compression stockings are no better than placebo stockings in preventing post-thrombotic syndrome in patients after their first proximal deep vein thrombosis (DVT). (LOE = 1b)Bottom Line


Kahn SR, Shapiro S, Wells PS, et al, for the SOX trial investigators. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet 2014;383(9920):880-888.
Study Design: Randomized controlled trial (double-blinded)


Setting: Outpatient (any)



In this multicenter study, patients with their first proximal DVT were randomized to 2 years of compression stockings (30 to 40 mmHg gradient; n = 410) or placebo stockings (5 mmHg; n = 396). The stockings were given within 2 weeks of the DVT and were replaced every 6 months (sooner if they wore out, got torn, or the patient’s leg changed size). The researchers evaluated the patients at baseline and 1, 6, 12, 18, and 24 months. The patients did not wear their stockings to these visits (scheduled for the afternoon) to facilitate the evaluation of signs of post-thrombotic syndrome. The authors defined post-thrombotic syndrome as ipsilateral pain and swelling that lasted at least 1 month that was worse at the end of the day or with prolonged sitting or standing and better in the morning or with leg elevation. Overall, the rate of post-thrombotic syndrome was not statistically different in patients treated with compression stockings than in patients treated with placebo stockings (14.2% vs 12.7%; P = 0.6). These findings are strengthened in light of the potential bias introduced by the authors’ analytic approach.

Henry C. Barry, MD, MS
Michigan State University
East Lansing, MI

New anticoagulants vs. warfarin in A Fib: no clear winner

Clinical Question:

Are the newer anticoagulants safer or more effective than warfarin in patients with atrial fibrillation?

Bottom Line

In this meta-analysis, newer anticoagulants appear to be slightly more effective than warfarin in the short term (2 years) in preventing strokes of all kinds in patients with atrial fibrillation. However, they are no more effective than warfarin in preventing ischemic strokes, and they cause more gastrointestinal hemorrhage. The short-term nature of the included studies and a significant concern about publication bias suggests that the newer agents are by no means a slam dunk over warfarin. Since the patients taking warfarin only spent two thirds of their time in therapeutic range, perhaps efforts to improve performance may be a wiser use of resources. (LOE = 1a-)


Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383(9921):955-962.

Study Design: meta analysis of RCT’s

Funding: self-funded or unfunded

Allocation: unknown


The authors of this study and the editors of Lancet did a fairly abysmal job in communicating how this study was conducted. The abstract claims the authors searched a single database to identify phase randomized trials comparing newer anticoagulants with warfarin in patients with atrial fibrillation. However, the methods section reports the authors conducted a prespecified analysis of 4 studies and doesn’t describe a thing about the search strategy. Additionally, the authors don’t include data on ximelagatran, which was pulled because of safety concerns. The authors pooled the data for nearly 72,000 patients with atrial fibrillation who received one of the newer anticoagulants (dabigatran, rivaroxaban, apixaban, or edoxaban; n = 42,411) or warfarin (n = 29,272). The authors evaluated the outcomes by intention to treat “when possible,” but made no adjustments for performing multiple analyses. Two of the four trials included nearly one third of the patients with CHADS2 scores of 0 to 1, which is a group that may not need anticoagulation. Overall, approximately one fourth of the patients had paroxysmal atrial fibrillation. The median duration of follow-up was 2.2 years and the warfarin-treated patients were in therapeutic range only two thirds of the time. Patients receiving the newer agents had a lower risk of stroke or systemic embolic events than patients taking warfarin (3.1% vs 3.8%; relative risk = 0.81; number needed to treat (NNT) =148; 95% CI, 103 – 261). There was no statistically significant differences in the rate of ischemic stroke or myocardial infarction. Patients taking the newer agents had fewer hemorrhagic strokes (0.4% vs 0.9%; NNT = 220; 170 – 308) and intracranial hemorrhages (0.7% vs 1.4%; NNT = 132; 108 – 169). Furthermore, all-cause mortality was slightly lower in patients receiving the newer agents (6.9% vs 7.7%; NNT = 129; 84 – 279). However, patients taking newer agents had more gastrointestinal bleeding (2.6% vs 2%; number needed to treat to harm = 185; 128 – 335). Although the study was unfunded, the authors had heavy ties to industry, which may explain their sloppiness in describing their methods. For example, they don’t even try to evaluate the potential for publication bias, an issue especially important since industry-sponsored studies have a long track record of not finding their way to publication.

Henry C. Barry, MD, MS
Michigan State University
East Lansing, MI

Treatment of low T not risk free

Testosterone and Cardiovascular Risk

The Medical Letter on Drugs and Therapeutics • March 3, 2014 (Issue 1437) p. 17

Read our blog post on this topic (posted below)

Prompted by the recent publication of 2 retrospective studies, the FDA has announced that it is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products.1

The first study examined the records of 8709 men with low testosterone levels (<300 ng/dL) who underwent coronary angiography between 2005 and 2011; 1223 of these men started testosterone therapy after a median of 531 days following coronary angiography. Three years after coronary angiography, the Kaplan-Meier estimated cumulative percentages of men who died or had a myocardial infarction (MI) or ischemic stroke were 26% of those treated with testosterone and 20% of those who were not treated with the hormone, a hazard ratio of 1.29 (95% CI 1.04-1.58; P=0.02).2 The second study compared the rate of nonfatal MI during the 90 days after filling a prescription with the rate in the prior year in 56,000 men given a prescription for testosterone and in 167,000 given a phosphodiesterase type 5 inhibitor (sildenafil [Viagra] or tadalafil [Cialis]). In the testosterone group as a whole, the post / pre-prescription rate ratio was 1.36, but in men ≥65 years old it was 2.19 and in younger men with a history of heart disease it was 2.90. In men who received a prescription for sildenafil or tadalafil, the rate ratio was 1.08 for all ages, 1.15 for those ≥65 years old, and 1.40 for younger men with a history of heart disease.3 A recent meta-analysis of randomized, placebo-controlled trials of testosterone therapy also found an increased risk of cardiovascular-related events in men treated with the hormone (odds ratio [OR] 1.54; 95% CI 1.09-2.18); an analysis by funding source found that the risk was greater in trials not funded by the pharmaceutical industry (OR 2.06 vs. 0.89).4

 Testosterone Replacement Therapy

The next (March 3, 2014) issue of The Medical Letter will include a short article on the cardiovascular risks of testosterone replacement therapy. The impetus for this piece was a Drug Safety Communication from the FDA announcing that the agency was investigating the risk of stroke, heart attack, and death in men taking FDA-approved replacement products.

Testosterone is popular. A 2011 article in The Medical Letter mentioned 4 transdermal products (3 gels and a patch), one buccal tablet, and 2 injectable formulations. A 2013 editorial in The New England Journal of Medicine estimated that nearly $2 billion per year are spent on these products. Undoubtedly some of those dollars are spent on the FDA-approved indication, which is hypogonadism (defined by testosterone serum concentrations <300 ng/dL), but I suspect that many or most of them come from young men seeking to enhance their appearance or their athletic prowess and older men trying to regain the energy and sexual prowess of youth, without regard for their serum testosterone levels.

Testosterone actually can increase feelings of wellbeing, strength, physical performance, muscle mass, and libido. But is it safe? The main concern with prescribing the hormone has been whether it could promote the growth of prostate cancer. Androgen deprivation through surgical or medical castration is a standard treatment for the disease, but there is no convincing evidence that testosterone replacement therapy increases the risk of prostate cancer. A 2006 study published in the Journal of the American Medical Association described prostate biopsies obtained at baseline and after 6 months of testosterone replacement therapy in 40 elderly men with hypogonadism; no treatment-related change was observed in prostate histology.

Now we have a cardiovascular signal. Is it weak or is it strong? The next issue of The Medical Letter will shed some light on that question, but the large long-term controlled trial we need to really know the answers to all of our questions about testosterone replacement therapy is nowhere in sight.

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Diagnosis and Treatment of Benign Positional Vertigo

NEJM Resident E-Bulletin

Benign Paroxysmal Positional Vertigo
Clinical Practice

J.-S. Kim and D.S. Zee

Benign paroxysmal positional vertigo (BPPV) is by far the most common type of vertigo, with a reported prevalence between 10.7 and 64.0 cases per 100,000 population and a lifetime prevalence of 2.4%.

What are the typical presentation, epidemiology, and risk factors for the development of BPPV?

The condition is characterized by brief spinning sensations, usually lasting less than 1 minute, which are generally induced by a change in head position with respect to gravity. Vertigo typically develops when a patient gets in or out of bed, rolls over in bed, tilts the head back, or bends forward. Even though patients with BPPV occasionally report persistent dizziness and imbalance, a careful history taking almost always reveals that their symptoms are worse with changes in head position. Many patients also have nausea, sometimes with vomiting. Attacks of BPPV usually do not have a known cause, although cases may be associated with head trauma, a prolonged recumbent position (e.g., at a dentist’s office), or various disorders of the inner ear. Spontaneous remissions and recurrences are frequent; the annual rate of recurrence is approximately 15%. Patients with BPPV are at increased risk for falls and impairment in the performance of daily activities. The prevalence of idiopathic BPPV is increased among elderly persons and among women, with peak onset between 50 and 60 years of age and a female-to-male ratio of 2:1 to 3:1.

What is the underlying pathophysiological process in BPPV?

The fundamental pathophysiological process in BPPV involves dislodged otoconia from the macula of the utricular otolith that enter the semicircular canals. When there is a change in the static position of the head with respect to gravity, the otolithic debris moves to a new position within the semicircular canals, leading to a false sense of rotation. BPPV usually arises from the posterior semicircular canal, which resides in the most gravity-dependent area of the labyrinth; this type of BPPV accounts for 60 to 90% of all cases.

Q. How is the diagnosis made in patients with BPPV that involves the posterior canal?

A. In patients with BPPV that involves the posterior canal, nystagmus is typically induced with the use of the Dix–Hallpike maneuver. In this maneuver, with the head turned to one side at angle of 45 degrees, the patient is moved from a sitting position to supine position, with the head hanging below the examination table. The induced nystagmus is upbeat and ipsiversive torsional (the upper pole of the eyes beats toward the side of the affected [lower] ear). When there is movement of otolithic debris (canalolithiasis) in the posterior canal away from the cupula, the endolymph flows away from the cupula, stimulating the posterior canal. The nystagmus usually develops after a brief latency period (2 to 5 seconds), resolves within 1 minute (typically within 30 seconds), and reverses direction when the patient sits up. With repeated testing, the nystagmus diminishes, owing to fatigability. If the otoconia become attached to the cupula (cupulolithiasis), the evoked nystagmus is similar to that observed in canalolithiasis but is usually longer in duration. A positive response to the Dix–Hallpike maneuver, in which the nystagmus beats in the correct direction, is the standard for diagnosing BPPV involving the posterior canal.

Table 2. Diagnosis and Treatment of Benign Paroxysmal Positional Vertigo According to the Affected Canal.

Table 2

Figure 1. Use of the Dix–Hallpike Maneuver to Induce Nystagmus in Benign Paroxysmal Positional Vertigo Involving the Right Posterior Semicircular Canal.

Dix Hallpike maneuver

Q. How is BPPV treated?

A. BPPV typically resolves without treatment. A prospective longitudinal study showed that the median interval between the onset of symptoms and spontaneous resolution in untreated patients was 7 days when the horizontal canal was affected and 17 days when the posterior canal was affected. However, canalith-repositioning maneuvers can be used to treat BPPV promptly and effectively. Medications are primarily used to relieve severe nausea or vomiting. For example, Epley’s canalith-repositioning maneuver was designed to flush mobile otolithic debris out of the posterior canal and back into the vestibule. The otoconia move around the canal with each step of the maneuver and eventually drop out into the vestibule, where they can be resorbed. Each position should be maintained until the induced nystagmus or vertigo dissipates, but always for at least 30 seconds. The success rate with Epley’s maneuver is about 80% after one session and increases to 92% with repetition up to four times. The Semont maneuver can also be used to treat BPPV involving the posterior canal.

Figure 2. Epley’s Canalith-Repositioning Maneuver for the Treatment of Benign Paroxysmal Positional Vertigo Involving the Right Posterior Semicircular Canal.

Epley's Maneuver

Figure 3. Semont’s Repositioning Maneuver for Benign Paroxysmal Positional Vertigo Involving the Right Posterior Semicircular Canal

Semont meneuver