American College of Physicians: Internal Medicine — Doctors for Adults ®


In the News
for the Week of 9-28-10


Test yourself

  • MKSAP Quiz: fatigue, constipation, polyuria and hypertension

FDA update

  • Rosiglitazone restricted to patients who can’t take other drugs

Preoperative care

  • Preprocedural statins reduce risk of postprocedure cardiovascular events


  • Tiotropium improves asthma symptoms as well as salmeterol

Patient self-management

  • Quick phone calls show same effect as group classes for heart failure

Physician payments

  • Still time to file a claim for UnitedHealth Group settlement

From the College

  • New guides explain health care reform law

Cartoon caption contest

  • Vote for your favorite entry

Physician editor: Darren Taichman, FACP


Antipsychotic drugs linked to VTE risk

Antipsychotic drugs may increase risk for venous thromboembolism (VTE), especially in new users, according to a new study.

Researchers in the United Kingdom performed a case-control study using a national primary care database to examine the possible relationship between antipsychotic drugs and VTE risk. Patients who had a first VTE between Jan. 1, 1996 and July 1, 2007 were matched with four or fewer controls according to age, calendar time, practice and sex. The main outcome measures were odds ratios for VTE associated with use of antipsychotic drugs, adjusted for comorbid conditions, and concomitant exposure to other drugs. The study results were published early online Sept. 21 by BMJ.

The authors identified 25,532 eligible cases, 15,975 with deep venous thrombosis and 9,557 with pulmonary embolism, and 89,491 matched controls. Cases were more likely to have a high BMI than controls, were more likely to live in a socially disadvantaged area, and were more likely to be taking other drugs that could increase VTE risk. Among cases and controls, 0.4% had schizophrenia, 0.3% had bipolar disorder, and 1.0% had dementia, while eight cases and 31 controls had more than one of these disorders.

Risk for VTE was 32% higher in patients who had received a prescription for antipsychotic drugs in the past 24 months compared with those who hadn’t (adjusted odds ratio [OR], 1.32 [95% CI, 1.23 to 1.42]). At greater risk were patients who had just started taking an antipsychotic within the last three months (adjusted OR, 1.97 [95% CI, 1.66 to 2.33]), those who were taking atypical versus conventional drugs (adjusted OR, 1.73 [95% CI, 1.37 to 2.17] vs. 1.28 [95% CI, 1.18 to 1.38]), and those who were taking low- versus high-potency drugs (adjusted OR, 1.99 [95% CI, 1.52 to 2.62] vs. 1.28 [95% CI, 1.18 to 1.38]). Absolute risks were low, the authors found, estimating that antipsychotic drugs would account for four additional VTE cases per 10,000 patients over a year of treatment in all age groups and 10 additional VTE cases per 10,000 patients in those over 65 years of age.

The study was limited by its observational design, the authors noted. For example, they were unable to determine why most patients were prescribed antipsychotics. However, they concluded that antipsychotic drugs are associated with an increased risk for VTE and that further research on this association is warranted. An accompanying editorial advised doctors to consider the low absolute risk in clinical decision making and said that the results don’t support the use of antithrombotic prophylaxis in patients taking antipsychotics without any other risk factors. However, the editorialists wrote, clinicians should be alert for “the best candidates for antipsychotic treatment, such as those people with the lowest vascular risk profile who may respond to short term and low dose treatment with antipsychotics because of individual pharmacogenetic characteristics, and those who may be more susceptible to developing side effects as a result of individual vascular risk factors possibly interacting with antipsychotics.”


Screening mammograms work, but effects are modest, study finds

Screening mammography helps reduce deaths from breast cancer, but its effects are modest, according to a new study.

Researchers used data from the Norwegian breast cancer screening program to quantify screening mammography’s effect on breast cancer mortality. Norway began its breast cancer screening program in 1996 in select counties and rolled it out geographically over the next nine years, offering mammography every two years to women between 50 and 69 years of age. The staggered rollout of the screening program allowed the authors to identify and analyze four groups of women, two of which lived in counties with or without screening from 1996 through 2005 (screening group and nonscreening group) and two of which mirrored these groups from 1986 through 1995 and served as historical comparisons (historical screening group and historical nonscreening group). The primary outcome measured was the incidence-based rate of death from breast cancer. The study results appear in the Sept. 23 New England Journal of Medicine.

Overall, data from 40,075 women with breast cancer were analyzed. For women in the screening group compared with the historical screening group, breast cancer death was reduced by 7.2 deaths per 100,000 person-years (rate ratio, 0.72; 95% CI, 0.63 to 0.81; P<0.001). For women in the nonscreening group compared with the historical nonscreening group, breast cancer death was reduced by 4.8 deaths per 100,000 person-years (rate ratio, 0.82; 95% CI, 0.71 to 0.93; P<0.001). The authors calculated a relative reduction in mortality of 10% in the screening group (P=0.13), concluding that the screening-related mortality difference between the current and historical groups was 2.4 deaths per 100,000 person-years, one-third of the total reduction of 7.2 deaths. Breast cancer mortality also decreased significantly in women who were too young or too old for screening mammography, a finding the authors attributed to care from a multidisciplinary breast cancer management team established as part of the nationwide screening program.

The authors pointed out that their study’s total follow-up was only 8.9 years, possibly not long enough to detect the screening mammography program’s full potential benefit, and that some of the women in the nonscreening group may have had mammograms that weren’t recorded, among other limitations. However, they concluded that only a third of the reduced breast cancer mortality in their study could be directly attributed to screening mammography, and that medical care provided by an interdisciplinary team may also have had an important effect. An accompanying editorial agreed, saying that the study results “help confirm that the decision about whether to undergo screening mammography is, in fact, a close call.” Given the evidence that the benefit of screening mammography is modest, the editorialist wrote, “the time has come for it to stop being used as an indicator of the quality of our health care system.”


Test yourself

MKSAP Quiz: fatigue, constipation, polyuria and hypertension

A 45-year-old man is evaluated for a 3-month history of fatigue, constipation, and polyuria. He also has a 5-year history of hypertension. Current medications are losartan and diltiazem.

Physical examination findings, including vital signs, are normal.

Laboratory studies:

Calcium 11.4 mg/dL (2.85 mmol/L)
Creatinine 1.1 mg/dL (97.2 µmol/L)
Glucose, fasting 88 mg/dL (4.9 mmol/L)
Phosphorus 2.2 mg/dL (0.71 mmol/L)
Thyroid-stimulating hormone 1.2 µU/mL (1.2 mU/L)

Measurement of which of the following levels should be done next?

A) Calcitonin
B) 25-Hydroxy vitamin D
C) Parathyroid hormone
D) Parathyroid hormone–related protein

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


FDA update

Rosiglitazone restricted to patients who can’t take other drugs

The use of rosiglitazone (Avandia) will be restricted to patients who cannot control their diabetes using other medications, the FDA announced last Thursday.

Manufacturer GlaxoSmithKline (GSK) will be required to develop a restricted access program, under which rosiglitazone will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take pioglitazone (Actos). Physicians who prescribe rosiglitazone will have to attest to and document their patients’ eligibility, according to the FDA press release. Patients will be required to review statements describing the cardiovascular safety concerns associated with the drug.

Current users of the drug will be able to continue taking rosiglitazone if they appear to be benefitting and they acknowledge their understanding of the potential risks. The FDA also ordered GSK to convene independent scientists to review the results of the RECORD study. During the FDA review of RECORD, questions arose about potential bias in identifying cardiovascular events due to the study’s open-label design, FDA administrators wrote in a perspective published Sept. 23 in the New England Journal of Medicine.

The FDA leaders also explained the reasoning behind their restriction of rosiglitazone. The evidence of the drug’s risks was not definitive but “there was no reliable evidence to refute these cardiovascular safety concerns,” the article said. Less regulation, such as a label change, would not provide adequate assurance that use of the drug would be limited to appropriate patients. However, removing the drug from the market would take away the glycemic control benefits seen by patients who have reasons not to take pioglitazone. For example, the FDA’s recently announced investigation of an association between pioglitazone and bladder cancer may dissuade patients with a history of that disease from taking pioglitazone, the article noted.


Preoperative care

Preprocedural statins reduce risk of postprocedure cardiovascular events

Using statins before invasive procedures significantly reduces the risk of postprocedural myocardial infarction, but not death, a new meta-analysis found.

Researchers chose randomized, controlled trials of patients who underwent an invasive procedure and had been randomized to statin therapy or control. Control meant placebo, usual care or low-dose statin therapy. Invasive procedures were defined as percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) or noncardiac surgical procedures, including vascular surgery. The researchers performed a literature search of the MEDLINE, Cochrane and databases from inception to February 2010 for studies in which statins were initiated before procedures and clinical outcomes were reported. Twenty-one trials with a total of 4,805 patients met their selection criteria. The results were reported in the Sept. 28 Journal of the American College of Cardiology.

The use of preprocedural statins significantly reduced postprocedural myocardial infarction (MI) compared with control (risk ratio [RR] 0.57; 95% CI, 0.46 to 0.70; P<0.0001). A 5.8% absolute risk reduction occurred after PCI (P<0.0001) and a 4.1% risk reduction after noncardiac surgical procedures (P=0.004), but there was no such reduction after CABG. The risk reduction for PCI occurred when statin therapy was initiated approximately one to seven days before the procedure, while statins started about four weeks before noncardiac surgical procedures reduced postoperative MI. There was no significant reduction in all-cause mortality with preprocedure statin use. Preprocedure statins also reduced post-CABG atrial fibrillation: Among the CABG studies, postoperative atrial fibrillation was 19% in the statin arm and 37% in the control arm (RR 0.54; 95% CI, 0.43 to 0.68; P<0.0001).

The authors concluded from the analysis that preprocedural statin therapy is beneficial, but noted that it's difficult to determine the type and dose of statins to use, or how long they should be used before a procedure. The PCI and surgical studies both used a wide variety of drugs and doses. Still, in the PCI studies, 56% of the weight of analysis came from trials with use of atorvastatin at 40 mg or more; 58% of the CABG studies' analysis entailed use of atorvastatin at 20 mg or more; and 91% of the analysis of noncardiac surgery trials entailed use of 80-mg doses of fluvastatin, they said. As for the finding that using statins preoperatively didn't reduce post-CABG MI, the authors noted the trials they found were small and involved low doses of statins, thus the issue deserves further study.



Tiotropium improves asthma symptoms as well as salmeterol

Tiotropium bromide and salmeterol caused similar improvements in asthma symptoms when added to an inhaled glucocorticoid, according to a new NIH trial.

The three-way, double-blind, triple-dummy crossover trial included 210 adults with asthma. The effectiveness of adding tiotropium (which is currently approved for chronic obstructive pulmonary disease, but not asthma) was compared to doubling the dose of inhaled glucocorticoid or adding salmeterol. Compared to the doubled glucocorticoid, tiotropium increased morning peak expiratory flow (PEF) by 25.8 liters per minute (P<0.001), and was also superior in evening peak expiratory flow, proportion of asthma-control days, prebronchodialotor forced expiratory volume in one second (FEV1) and daily symptom scores. Tiotropium was noninferior to salmeterol on all of the study's outcomes, and did significantly better on prebronchodilator FEV1 (a difference of 0.11 liters, P=0.003).

Because the study was short (14 weeks) and included a small number of patients, it wasn't possible to examine the rate of asthma exacerbations or long-term safety issues, the study authors cautioned. The findings should not be considered clinically directive until additional studies with greater statistical power are conducted, according to the authors. The study was published in the Sept. 23 New England Journal of Medicine.

However, some clinicians have already begun substituting tiotropium for salmeterol and other long-acting beta-antagonists in patients who remain symptomatic on low doses of inhaled glucocorticoids, an accompanying editorial noted. This study provides encouraging results for such patients, although more data are needed to determine whether tiotropium and possibly other long-acting anticholinergic agents are effective and safe alternatives. Several other trials are currently exploring this possibility, the editorialist said.


Patient self-management

Quick phone calls show same effect as group classes for heart failure

An intensive program to teach self-management skills to heart failure patients didn't improve outcomes over a simple educational effort.

The trial included 902 patients from the Chicago area with mild to moderate heart failure who were randomized to one of two interventions. The education group received 18 educational tip sheets in the mail over the course of a year, with follow-up phone calls to check their comprehension of the information. The patients in the self-management group received the same tip sheets during group meetings in which they were also taught self-management skills to implement the advice. The study was published in the Sept. 22/29 Journal of the American Medical Association.

After two to three years of follow-up, there were no significant differences between the groups on any of the study’s endpoints: death, heart failure hospitalization, all-cause hospitalization or quality of life. Previous smaller trials have also failed to find benefit in teaching self-management skills to heart failure patients, the study authors noted. However, it's still not entirely clear that these interventions are ineffective, the authors concluded. Subgroup analyses showed a trend suggesting that self-management counseling may be beneficial for low-income patients.

The 25% reduction in events expected by the study design may also have been excessively optimistic, the authors said. In that case, the trial may have been too small to find a treatment benefit. Another explanation is that the follow-up telephone calls received by the education group were more effective than expected, and that patients may have received self-management assistance during these contacts, an accompanying editorial speculated.

The intervention offered to the self-management group involved considerable cost and inconvenience to the patients, the editorialists said. They suggested that future efforts will likely involve electronic media rather than in-person meetings, and that medical professionals should continue to consider the possibilities of patients as participants in their own health care.


Physician payments

Still time to file a claim for UnitedHealth Group settlement

There is still time for physicians who qualify to file a claim for the $350 million UnitedHealth Group settlement, involving low payments for out-of-network care.

The AMA is sponsoring a webinar to help physicians learn how to determine whether they qualify. Interested physicians must act quickly, as claims must be submitted by Oct. 5.

Additional information about filing is also available on the AMA website.


From the College

New guides explain health care reform law

The College has released two new publications in an effort to help bring clarity to the many internists and patients who are still grappling with the multitude of changes taking place as a result of the health care reform legislation.

Jointly with AARP, ACP has developed a brochure aimed at helping patients and their families understand how the changes will affect them. The College has also updated An Internist’s Practical Guide to Understanding Health Reform, written to help internists understand the provisions of the law that will most affect them.

Additional information is available online.


Cartoon caption contest

Vote for your favorite entry

ACP InternistWeekly's cartoon caption contest continues. Readers can vote for their favorite caption to determine the winner.

"Worst case of pedal edema I’ve ever seen."

"Welcome to New Age Podiatry Associates, where we treat the foot as if it were the whole person."

"Sorry, we don’t admit de feet."

Go online to pick the winner, who receives a $50 gift certificate good toward any ACP program, product or service. Voting continues through Monday, Oct. 4, with the winner announced in the Oct. 5 issue.


MKSAP Answer and Critique

The correct answer is C) Parathyroid hormone. This item is available to MKSAP 15 subscribers as item 14 in the Endocrinology and Metabolism module.

This patient’s parathyroid hormone (PTH) level should be determined next. Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting. The first step in the diagnosis of hypercalcemia is determination of the PTH level with an assay for intact PTH. If the PTH level is high or “inappropriately” normal, primary hyperparathyroidism is the diagnosis. If the PTH level is suppressed, a search for other entities that cause hypercalcemia must be conducted.

Calcitonin is secreted by thyroid parafollicular C cells. This serum level is elevated in patients with medullary thyroid cancer or C-cell hyperplasia. Calcitonin tends to lower the calcium level by enhancing cellular uptake, renal excretion, and bone formation. The effect of calcitonin on bone metabolism is weak and only relevant in pharmacologic amounts. Measurement of serum calcitonin is not indicated in a patient with hypercalcemia.

One of the ways in which PTH increases the serum calcium level is by upregulation of the 1a-hydroxylase enzyme, which stimulates conversion of vitamin D to its most active form, 1,25-dihydroxy vitamin D. This form of vitamin D increases the percentage of dietary calcium absorbed by the intestine. Body stores of vitamin D are assessed by measuring the 25-hydroxy vitamin D level, which has a long half-life. Measurement of this patient’s 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D levels may be appropriate if the parathyroid hormone level is suppressed or if further evaluation suggests concomitant vitamin D deficiency and hyperparathyroidism (a frequent association, particularly in elderly patients). At this time, however, such measurement is not indicated.

Humoral hypercalcemia of malignancy results from the systemic effect of a circulating factor produced by neoplastic cells. The hormone most commonly responsible for this syndrome is parathyroid hormone–related protein (PTHrP). This peptide’s N-terminal shares many homologic features with PTH and most, if not all, of the metabolic effects of PTH. Tumors that elaborate PTHrP are most commonly squamous cell carcinomas, such as those of the lung, esophagus, and head and neck. This patient has no evidence of cancer, which makes measurement of the PTHrP level inappropriate at this time. The diagnosis of humoral hypercalcemia of malignancy can often be made in the absence of PTHrP measurements if a compatible malignancy, hypercalcemia, and suppressed parathyroid hormone level are present.

Key Point

  • The most common cause of hypercalcemia in the outpatient setting is hyperparathyroidism.

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