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ACP InternistWeekly



In the News for the Week of November 26, 2013




Highlights

Genotype testing for warfarin dosing may offer limited or no benefit

Genotyping for warfarin therapy has limited, if any, benefit, according to 3 recent studies and an editorial. More...

ABIM to appoint non-internists to its governance

The American Board of Internal Medicine (ABIM) has announced that it will begin including a non-internist member of the health team and a public member with a patient/caregiver perspective on each of its specialty boards. More...


Test yourself

MKSAP Quiz: 2-month history of fatigue, anorexia and weight loss

A 74-year-old woman is evaluated for a 2-month history of fatigue, anorexia, and a 6-kg (13.2-lb) weight loss. She was treated with chemotherapy for ovarian cancer 6 months ago. She also has hypertension managed with hydrochlorothiazide. Following a physical exam and lab results, what is the most likely cause of this patient's hyponatremia? More...


Hypertension

AHA, ACC, CDC issue science advisory on hypertension

The American Heart Association (AHA), American College of Cardiology (ACC), and Centers for Disease Control and Prevention (CDC) issued a recent science advisory on control of hypertension. More...


Diabetes

Chelation may reduce mortality, cardiovascular events in diabetics after MI

Chelation reduced cardiovascular disease events in patients with diabetes who had a previous myocardial infarction (MI), a recent study found. More...


From the College

Board of Regents announces results for 2014-2015 Chair-elect

At its November meeting, the Board of Regents elected Tanveer P. Mir, MD, MACP, of New York City as the 2014-2015 Chair-elect of the Board of Regents. More...


Cartoon caption contest

And the winner is …

ACP InternistWeekly has tallied the voting from its latest cartoon contest, where readers are invited to match wits against their peers to provide the most original and amusing caption. More...

Editorial note: ACP InternistWeekly will not be published next week due to the Thanksgiving holiday.


Physician editor: Daisy Smith, MD, FACP



Highlights


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Genotype testing for warfarin dosing may offer limited or no benefit

Genotyping for warfarin therapy has limited, if any, benefit, according to 3 recent studies and an editorial.

The research was presented at the American Heart Association's Scientific Sessions and appeared online Nov. 19 at the New England Journal of Medicine. In the first study, researchers randomized 1,015 U.S. inpatients and outpatients with a target international normalized ratio (INR) of 2.0 to 3.0 to receive doses of warfarin during the first 5 days of therapy that were determined either by a dosing algorithm including clinical variables and genotype data or only clinical variables. The dose of warfarin was double-blinded during the first 4 weeks of therapy.

At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, −0.2; 95% CI, −3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the 2 algorithms of 1 mg per day or more. Researchers concluded that there was no benefit of genotype-guided dosing of warfarin on time in the therapeutic INR range during the first month of treatment. The authors wrote, "Our results emphasize the importance of performing randomized trials for pharmacogenetics, particularly for complex regimens such as warfarin."

A second multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism found that pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. The researchers used a pharmacogenetic loading-dose algorithm that took into account the effect of CYP2C9*2, CYP2C9*3, and VKORC1 (−1639G→A) on warfarin.

A total of 455 warfarin-naive patients who had either atrial fibrillation or venous thromboembolism and required warfarin with a target INR of 2.0 to 3.0 were recruited from 3 U.K. centers and 2 in Sweden. In the study, 227 patients were randomized to the genotype-guided group and 228 to the control group. Patients in the genotype-guided group received warfarin doses per the pharmacogenetic algorithms for the first 5 days. Patients in the control group received a 3-day loading-dose regimen.

The mean percentage of time in the therapeutic range was 67.4% in the pharmacogenetic group, compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% CI, 3.3 to 10.6 percentage points; P<0.001). The pharmacogenetic group experienced significantly fewer incidences of excessive anticoagulation (INR ≥4.0) than the control group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).

The differences in the mean INR between the 2 groups were greatest soon after starting anticoagulation and waned during the 3-month follow-up period. The researchers wrote, "Our algorithmic strategy reduced the likelihood of excessive anticoagulation (INR ≥4.0) in the early stages of anticoagulation, while reducing the time to achieve a therapeutic INR, suggesting that genotype-guided dosing may not only prove to be safer but may also reduce the time required for stabilization when adopting a loading-dose strategy."

The researchers noted that the study looked at time in the therapeutic range, rather than the clinical outcomes of bleeding and thrombosis. It was underpowered to detect a reduction in bleeding events, and it did not use a double-blind design. The majority of patients were of European ethnic background, and algorithms specific to ethnic groups will need to be developed. They added the caveat that it is not yet clear whether these results would translate to better clinical outcomes.

A third study addressed genotype-guided therapy with acenocoumarol or phenprocoumon, which are not approved for use in the United States. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). The percentage of time in the therapeutic range during the first 4 weeks after starting treatment was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences between the 2 groups for several secondary outcomes, nor for bleeding or thromboembolic events.

An editorial concluded that the 3 trials showed that pharmacogenetic testing either isn't useful when prescribing vitamin K agonists or is, at best, marginally so, given the cost and effort required.

The editorialist wrote, "Perhaps we should concentrate on improvements in the infrastructure for INR testing, including better communication among the laboratory, the physician, and the patient (e.g., through social media); in the use of formal algorithms for dosing, without concern for genotype; in patient adherence to therapy and possibly more responsibility for dosing being assumed by the patient; and in increased diligence by medical and paramedical personnel in testing, monitoring, and dosing on the basis of the INR, given the high percentage of medical mismanagement associated with these anticoagulant agents."


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ABIM to appoint non-internists to its governance

The American Board of Internal Medicine (ABIM) has announced that it will begin including a non-internist member of the health team and a public member with a patient/caregiver perspective on each of its specialty boards.

Additionally, in an effort to ensure that board governance represents the voice of the physician in practice, the ABIM council also voted that each of the specialty boards will include a minimum of 1 practitioner whose primary practice is in a non-university, community setting. The organization recently announced its decision in a press release.

"As a physician who practiced in a community-based setting for nearly 30 years, I know that community-based physicians face different demands and expectations from those who work primarily in a university setting," said Richard J. Baron, MD, MACP, president and CEO of ABIM, in the press release. "Although ABIM has been actively recruiting non-academic physicians for Board positions for years, requiring it now in the membership composition of the Specialty Boards signifies the importance of ensuring their voice will be represented in the design of Certification and Maintenance of Certification."

ABIM will begin a search for the clinician and public board members through a call for nominations. The board of directors and the ABIM council are part of a new governance structure that was announced in July.

The ABIM board of directors oversees the overall strategic direction of the organization and supports efforts to make Maintenance of Certification and the certification credential relevant and valuable to the broader health care community and to all the internists who participate in it. The ABIM council guides the policies and procedures for Certification and Maintenance of Certification in all of the disciplines of internal medicine.



Test yourself


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MKSAP Quiz: 2-month history of fatigue, anorexia and weight loss

A 74-year-old woman is evaluated for a 2-month history of fatigue, anorexia, and a 6-kg (13.2-lb) weight loss. She was treated with chemotherapy for ovarian cancer 6 months ago. She also has hypertension managed with hydrochlorothiazide.

mksap.gif

On physical examination, temperature is 36.2 °C (97.2 °F), blood pressure is 132/75 mm Hg without postural changes, pulse rate is 86/min without postural changes, and respiration rate is 14/min. BMI is 23. There are no neurologic findings. Estimated central venous pressure is less than 5 cm H2O. Cardiac and pulmonary examinations are normal. There is no peripheral edema.

Laboratory studies:

Blood urea nitrogen 5 mg/dL (1.8 mmol/L)
Serum creatinine 0.4 mg/dL (35.4 µmol/L)
Electrolytes:
Sodium 128 mEq/L (128 mmol/L)
Potassium 3.8 mEq/L (3.8 mmol/L)
Chloride 90 mEq/L (90 mmol/L)
Bicarbonate 25 mEq/L (25 mmol/L)
Glucose 60 mg/dL (3.3 mmol/L)
Osmolality 266 mosm/kg H2O
Cortisol (8 AM) 20 µg/dL (552 nmol/L) (normal range, 5-25 µg/dL [138-690 nmol/L])
Thyroid-stimulating hormone 1.3 µU/mL (1.3 mU/L)
Urine studies:
Osmolality 50 mosm/kg H2O (normal range, 300-900 mosm/kg H2O)
Potassium 15 mEq/L (15 mmol/L) (normal range for women, 17-164 mEq/L [17-164 mmol/L])
Sodium 12 mEq/L (12 mmol/L) (normal range for women, 15-267 mEq/L [15-267 mmol/L])

Which of the following is the most likely cause of this patient's hyponatremia?

A: Hypovolemia
B: Low solute intake
C: Measurement error (pseudohyponatremia)
D: Primary adrenal insufficiency

Click here or scroll to the bottom of the page for the answer and critique.


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Hypertension


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AHA, ACC, CDC issue science advisory on hypertension

The American Heart Association (AHA), American College of Cardiology (ACC), and Centers for Disease Control and Prevention (CDC) issued a recent science advisory on control of hypertension.

The advisory stated that system-level approaches will be needed to reduce hypertension prevalence in the U.S., involving the following factors:

  • identifying all patients eligible for management,
  • monitoring at the practice/population level,
  • increasing patient and clinician awareness,
  • providing an effective diagnosis and treatment guideline,
  • systematically following up patients for initiation and intensification of therapy,
  • clarifying roles of clinicians to implement a team approach,
  • reducing barriers for patients to receive and adhere to medications and implement lifestyle modifications and
  • leveraging electronic medical record systems to support these steps.

As part of a multipronged approach, the AHA, ACC and CDC developed a treatment algorithm intended to apply to the largest number of hypertensive patients while being flexible and detailed enough to support individualized therapy. The algorithm divides patients into those with stage 1 hypertension (systolic blood pressure 140 to 159 mm Hg or diastolic blood pressure 90 to 99 mm Hg) and stage 2 hypertension (systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg). In the first group, a trial of lifestyle modification and consideration of thiazide therapy are recommended. In the second group, 2 drugs are preferred in addition to lifestyle modifications: thiazide and an angiotensin-converting enzyme (ACE) inhibitor, angiotensin-receptor blocker, or calcium-channel blocker, or consideration of an ACE inhibitor and calcium-channel blocker.

The algorithm also offers a step-by-step method for rechecking and reviewing blood pressure, as well as ways to encourage patients who successfully control their blood pressure and actions to take when blood pressure is not at goal. The science advisory and algorithm were published by Hypertension on Nov. 15 and are available free of charge online.



Diabetes


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Chelation may reduce mortality, cardiovascular events in diabetics after MI

Chelation reduced cardiovascular disease events in patients with diabetes who had a previous myocardial infarction (MI), a recent study found.

The Trial to Assess Chelation Therapy (TACT) included 1,708 patients age 50 or over with a history of MI, of whom 633 had diabetes mellitus. Patients were randomized to 40 infusions of either ethylene diamine tetraacetic acid (EDTA) chelation or placebo, and they were followed for a median of 55 months. Results were published by Circulation: Cardiovascular Quality and Outcomes on Nov. 19.

Patients without diabetes saw no significant benefit from the EDTA chelation therapy; however, patients with diabetes had a substantial reduction in cardiovascular events. In the diabetic subgroup, the study's primary end point (death, reinfarction, stroke, coronary revascularization or hospitalization for angina) was 25% in the active group versus 38% in the placebo group (hazard ratio [HR], 0.59; 95% CI, 0.44 to 0.79), a finding that remained significant after adjustment. The number needed to treat to reduce 1 primary end point over 5 years was 6.5.

The study authors concluded that EDTA chelation markedly reduced cardiovascular events in post-myocardial infarction patients age 50 and over with diabetes. They cautioned that these results were from a subgroup, although a prespecified one, of a larger trial, so they require replication. The authors speculated as to the possible mechanism of the effect, suggesting that metals bind to glycation end products, accumulating in tissue and promoting inflammation. The fact that the survival and event curves continued to separate long after the intervention stopped suggests that removal of the metals may have had long-term benefit for the patients.

The study was limited by an unexpectedly high dropout rate, but it was higher among placebo patients than intervention patients, which would cause an underestimation of the intervention's effect. The results support the initiation of more trials of chelation in patients with diabetes and vascular disease, the authors said. In the meantime, there is not yet sufficient evidence to support routine use of chelation for these patients, they concluded.



From the College


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Board of Regents announces results for 2014-2015 Chair-elect

At its November meeting, the Board of Regents elected Tanveer P. Mir, MD, MACP, of New York City as the 2014-2015 Chair-elect of the Board of Regents. Dr. Mir will assume the position of Chair at the conclusion of the Annual Business Meeting at Internal Medicine 2015 in Boston. More information about Dr. Mir will be provided in the March ACP Internist, when the results of the election of new Regents and President-elect are reported.



Cartoon caption contest


.
And the winner is …

ACP InternistWeekly has tallied the voting from its latest cartoon contest, where readers are invited to match wits against their peers to provide the most original and amusing caption.

acpi-20131126-cartoon.jpg

"When hospice doctors round late ... "

This issue's winning cartoon caption was submitted by Alejandro Ovalle, MD, FACP. Thanks to all who voted! The winning entry captured 42.5% of the votes.

The runners-up were:

"This concierge medicine gig is getting a little bit out of control."

"I hear dead people."


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MKSAP Answer and Critique



The correct answer is B: Low solute intake. This item is available to MKSAP 16 subscribers as item 27 in the Nephrology section. More information is available online.

This patient has hypotonic hyponatremia due to low solute intake. Her history of anorexia and weight loss, in conjunction with clinical euvolemia and both low plasma and low urine osmolality and sodium, supports this diagnosis. Because some solute excretion by the kidney is required for urinary water excretion, this patient's low solute intake is limiting her ability to excrete free water, leading to hypotonic hyponatremia as her water intake exceeds her ability to excrete urinary water.

The absence of physical examination findings suggesting hypovolemia, including postural changes in blood pressure and pulse, decreases the likelihood of hypovolemic hyponatremia in this patient. In patients with hypovolemia, urine osmolality typically exceeds 400 mosm/kg H2O, which reflects increased tubular water resorption under the influence of antidiuretic hormone.

Pseudohyponatremia is characterized by a low serum sodium concentration due to measurement in a falsely large volume; an interfering substance displaces the liquid component of the sample, similar to ice cubes in a pitcher. The most common space-occupying substances are lipids and paraproteins. Measured plasma osmolality is normal in pseudohyponatremia and cannot be accounted for by increases in other solutes such as glucose, urea, or alcohols. The low measured plasma osmolality and the absence of an osmolal gap are consistent with hypotonic hyponatremia and exclude the diagnosis of pseudohyponatremia.

Hyponatremia is found in most patients with primary adrenal insufficiency, reflecting both mineralocorticoid deficiency and increased vasopressin secretion caused by cortisol deficiency. The absence of hypotension, hypovolemia, hyperkalemia, and a relatively high morning serum cortisol level does not support a diagnosis of primary adrenal insufficiency.

Key Point

  • Low solute intake can cause hypotonic hyponatremia.

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Test yourself

A 50-year-old man is evaluated in follow-up for a recent diagnosis of cirrhosis secondary to nonalcoholic steatohepatitis. He has a history of asthma, type 2 diabetes mellitus, hyperlipidemia, and obesity. His current medications are inhaled fluticasone, montelukast, insulin glargine, insulin lispro, simvastatin, and lisinopril. Following a physical exam, lab studies, and upper endoscopy, what is the most appropriate treatment?

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MKSAP 16 Holiday Special:  Save 10%

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Maintenance of Certification: What if I Still Don't Know Where to Start?

Because the rules are complex and may apply differently depending on when you last certified, ACP has developed a MOC Navigator. This FREE tool can help you understand the impact of MOC, review requirements, guide you in selecting ways to meet the requirements, show you how to enroll, and more. Start navigating now.