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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
August 5, 2017

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Neonatal Tremors Caused by Vitamin D Deficiency
The Drug Expiration Date Myth
Why Are Generic Drugs Getting So Expensive?
Moderate Coffee Consumption and Mortality: Good News
How Do Women View the Benefits and Harms of Screening Mammography?
ASCO 2017 Report — Breast Cancer
An Association Between Vasectomy and Prostate Cancer?
Healthy Aging Is Less Likely When Weight Is Gained in Early and Middle Adulthood
Reducing Metabolic Adverse Effects of Antipsychotic Drugs: A New Approach
Multiple Sclerosis Shortens Lifespan by About 9 Years

Pediatrics 2017 Jul 26
Neonatal Tremors Caused by Vitamin D Deficiency
In a case report of two patients, neonatal shivers or tremors were most likely due to vitamin D deficiency.
Two authors in the pediatrics department at Howard University in Washington, D.C. present two cases of newborn infants who had tremors or “shivers.”
The first infant was born full term via spontaneous vaginal delivery without complications and was exclusively breast-fed. The initial outpatient newborn visit at 6 days of age revealed a healthy neonate. The mother expressed concern that the infant shivered “like he was cold.” She reported that she had seen the shivering in the newborn nursery as well. On day 12 of age, the neonate was seen in follow-up, by which time the shivering had worsened and was more sustained, lasting 2 to 2.5 minutes per episode. The infant then underwent an extensive evaluation at a referral hospital.
The differential diagnosis included seizures, neurologic abnormality, hypoglycemia, hypocalcemia, hypomagnesemia, hyperthyroidism, drug withdrawal, and sepsis. The only abnormality was a low 25-hydroxyvitamin D level (6 ng/mL). The mother admitted that she had not been giving vitamins to her infant nor had she ever taken prenatal vitamins. After starting the infant on 800 international units (IU) of vitamin D per day, the tremors resolved within 2 weeks.
The second infant was also born full term via normal spontaneous vaginal delivery. The mother reported taking prenatal vitamins. After delivery, the infant had a normal examination except for “occasional shudder” of the chin. Screening for hypoglycemia was negative. The vitamin D level was low (17 ng/mL). The infant was started on 800 IU of vitamin D per day and was lost to follow-up.
COMMENT: I usually avoid reviewing case reports but decided to do so after reading the details of the first case and the thorough work-up that was completed. The second case was a bit less compelling. However, given the right context (e.g., exclusive breast-feeding and/or lack of prenatal care) and persistent or worsening tremors or shuddering lasting beyond the first few days of life, I will now consider vitamin D deficiency in my differential diagnosis.
CITATION(S): Collins M and Young M.Benign neonatal shudders, shivers, jitteriness, or tremors: Early signs of Vitamin D deficiency. Pediatrics 2017 Jul 26; [e-pub].
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The Drug Expiration Date Myth
[Editor's Note: This is a great summary of the expiration date situation and discarding valuable drugs that are still effective. It can also apply to the beyond-use dates of compounded preparations. PLEASE READ THE ORIGINAL STORY.]
Pharmacies are required to toss expired drugs. Billions of dollars are routinely wasted, and it's driving up the cost of care for everyone.
Pharmacist/toxicologist Lee Cantrell tested drugs that had been expired for decades. Most of them are sufficiently potent to be used today. The box of prescription drugs had been stored in a back closet of a retail pharmacy for so long that some of them predated the 1969 moon landing. Most were 30 to 40 years past their expiration dates.
Cantrell contacted Roy Gerona, a UCSF researcher who specializes in analyzing chemicals. In his lab, Gerona ran tests on the decades-old drugs. The findings surprised both researchers: A dozen of the 14 compounds were still as potent as they were when they were manufactured, some at almost 100 percent of their labeled concentrations.
ProPublica has been researching why the U.S. healthcare system is the most expensive in the world and includes the following:

Experts estimate these activities cost about $765 billion a year—as much as a quarter of all the country's healthcare spending.
What if the system is destroying drugs that are technically "expired" but could still be safely used?
It turns out that the FDA has long known the shelf life of some drugs can be extended, sometimes by years. For decades, the federal government has stockpiled massive stashes of medication, antidotes, and vaccines in secure locations throughout the country. The drugs are worth tens of billions of dollars and would provide a first line of defense in case of a large-scale emergency. Even though the government requires pharmacies to throw away expired drugs, it doesn't always follow these instructions itself. Instead, for more than 30 years, it has pulled some medicines and tested their quality.
The federal agencies that stockpile drugs, including the military, the CDC and the VA, have long realized the savings in revisiting expiration dates. Years ago, the FDA and DOD created the Shelf Life Extension Program. Each year, drugs from the stockpiles are selected based on their value and pending expiration and analyzed.
Pharmacist Marc Young, who helped run the extension program from 2006 to 2009, says it has had a "ridiculous" return on investment saving the federal government $600 million to $800 million because it did not have to replace expired medication.
An official with DOD, which maintains about $13.6 billion worth of drugs in its stockpile, says that in 2016 it cost $3.1 million to run the extension program, but it saved the department from replacing $2.1 billion in expired drugs. To put the magnitude of that return on investment into everyday terms: It's like spending a dollar to save $677.
A 2015 commentary in Mayo Clinic Proceedings, called " Extending Shelf Life Just Makes Sense," also suggested that drug companies could be required to set a preliminary expiration date and then update it after long-term testing. An independent organization could also do testing similar to that done by the FDA extension program, or data from the extension program could be applied to properly stored medications.
"The FDA will have to take the lead for a solution to emerge," he says. "We are throwing away products that are certainly stable, and we need to do something about it."
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Ann Intern Med 2017 Jul 4
Why Are Generic Drugs Getting So Expensive?
When market competition drops, generic drug prices rise (sometimes exorbitantly).
As the use of generic drugs has grown substantially to >85% of dispensed U.S. prescriptions, prices of some commonly prescribed generic drugs have also risen dramatically. In a retrospective cohort study of >1 billion prescription drug claims from >57 million patients within a database including 130 commercial health plans, investigators evaluated the effects of market competition on prices of 1120 generic drugs from 2008 to 2013. Using a structured scoring measure of market competition that incorporated number of generic drug manufacturers and market share for each manufacturer, they designated each drug as low-, medium-, or high-competition. Overall price (out-of-pocket cost + third-party payment) of dispensed generic prescriptions per quantity of drug dispensed was correlated with competition level, controlled for market size and baseline drug price.
Increases in mean generic drug prices were inversely proportional to competition level: 64% for low-competition drugs, 44% for medium-competition drugs, and 10% for high-competition drugs. Some low-competition drugs rose in price by >1000% in <6 years.
COMMENT: While this study demonstrates an obvious macroeconomic effect (i.e., manufacturer market competition for generic drugs has an impact on drug costs), the microeconomic effect on individual patients whose medical conditions rely on low-cost generic drugs can be great, especially for life-threatening conditions. Regulatory policies that encourage competition or limit monopoly manufacturers of generic drugs may be necessary — and vital — to achieve reasonable drug costs.
CITATION(S): Dave CV et al. High generic drug prices and market competition: A retrospective cohort study. Ann Intern Med 2017 Jul 4; [e-pub].
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Ann Intern Med 2017 Jul 11
Moderate Coffee Consumption and Mortality: Good News
Two studies confirm an association between coffee intake and lower risk for death in diverse populations.
Coffee contains antioxidants and other bioactive compounds that may have positive effects (e.g., reduced insulin resistance). Prior studies have suggested the protective effects of coffee; however, concerns over predominantly white U.S. participants as well as different coffee preparations from country to country have raised questions about the generalizability of these findings. Now, in two large cohort studies (one U.S., one European), researchers prospectively evaluated the effects of coffee intake in >700,000 participants (mean follow-up, 16 years). The U.S. cohort included minorities (e.g., black, Latino, Asian American) as well as whites, while the European cohort included 10 different countries. Each study adjusted for known and potential confounders.
Both cohorts showed significant inverse associations between amount of coffee consumed and mortality. U.S. coffee drinkers who consumed ≥2 cups daily attained almost 20% relative risk reduction (RRR) in mortality compared with those drinking no coffee; European coffee drinkers of ≥2 cups daily exhibited RRRs of 7% to 10% (women) and 12% to 14% (men). Coffee-associated lower mortality was seen across all U.S. ethnic minorities and European countries; among nonsmokers, former smokers, and current smokers; and for caffeinated or decaffeinated coffee.
COMMENT: These studies provide support that moderate coffee intake (2–5 cups daily) is safe and associated with reduced risk for death, probably in a dose-dependent fashion. If you're still debating the health benefits of coffee for your patients, you may want to do it over a cup of joe.
CITATION(S): Park S-Y et al. Association of coffee consumption with total and cause-specific mortality among nonwhite populations. Ann Intern Med 2017 Jul 11; [e-pub].
Gunter MJ et al. Coffee drinking and mortality in 10 European countries: A multinational cohort study.Ann Intern Med 2017 Jul 11; [e-pub].
Guallar E et al. Moderate coffee intake can be part of a healthy diet. Ann Intern Med 2017 Jul 11; [e-pub].
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JAMA Intern Med d 2017 Jun 26
How Do Women View the Benefits and Harms of Screening Mammography?
Large survey shows U.S. women are more likely to be aware of screening's benefits than its harms.
Many breast cancers detected with screening mammography represent overdiagnosis (NEJM JW Womens Health Feb 2017 and Ann Intern Med 2017; 166:313); indeed, such screening has not substantially reduced breast cancer-specific mortality. Are women aware of this? Investigators analyzed survey data from >400 U.S. women (age range, 40–59) regarding their knowledge and perceived importance of the benefits and harms associated with screening mammography. Respondents were asked to rate the personal importance of the potential benefits (e.g., saving lives, earlier treatment, peace of mind) or harms (e.g., false-positive findings, anxiety, unnecessary treatment) of mammography. Among participants, 56% reported having a mammogram during the past year, 29% less recently, and 14% never.
Nearly all respondents had knowledge of all the listed benefits of mammography; in contrast, less than one third were aware of risks for overdiagnosis and overtreatment. About 55% of respondents said the benefits of mammography were “very important” to them, whereas only 15% said the harms were very important.
COMMENT: The investigators note that the discrepancy between women's awareness of benefits and harms of mammography may reflect a lack of balanced information from clinicians, news media, and advocacy groups. Accordingly, their findings point to opportunities for education at population and individual levels. As we have learned with vaccination, helping the public reach a balanced, evidence-based perspective can be challenging.
CITATION(S): Yu J et al. Women's awareness and perceived importance of the harms and benefits of mammography screening: Results from a 2016 national survey. JAMA Intern Med 2017 Jun 26; [e-pub].
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ASCO 2017 Report — Breast Cancer
William J. Gradishar, MD
Highlights of the latest treatments
At this year's annual meeting of the American Society of Clinical Oncology (ASCO 2017), held June 3 to 7 in Chicago, investigators discussed the latest findings in cancer research. The editors of NEJM Journal Watch Oncology and Hematology were on hand to report highlights of the conference. Here, Editor-in-Chief William J. Gradishar, MD, reviews key presentations on new breast cancer treatments. All meeting abstracts can be viewed in the ASCO meeting library.
Abemaciclib for HR-positive/HER2-Negative Metastatic Breast Cancer
The approach to treating patients with ER-positive metastatic breast cancer has changed in the last couple of years with adoption of strategies partnering endocrine therapy with targeted therapy, such as an mTOR inhibitor or CDK4/6 inhibitors. The approved CDK4/6 inhibitors, palbociclib and ribociclib, extend progression free-survival (PFS) for patients when combined with endocrine therapy versus endocrine therapy alone. These two CDK4/6 inhibitors are generally well tolerated, with asymptomatic neutropenia being the most adverse event.
Now, in the MONARCH 2 study (abstract 1000), Sledge and colleagues have evaluated the efficacy and safety of a third CDK4/6 inhibitor, abemaciclib, in patients with HR-positive, HER2-negative metastatic breast cancer who had disease progression on first-line endocrine therapy and who had not received chemotherapy. Patients were randomized to receive fulvestrant with or without abemaciclib.
PFS was prolonged with abemaciclib plus fulvestrant versus fulvestrant alone (16.4 vs. 9.3 months; P<0.0000001). The combination was generally well tolerated, but gastrointestinal symptoms were more common with abemaciclib than what was observed with palbociclib and ribociclib in other trials. Abemaciclib is likely to be the third CDK inhibitor approved in the near future, posing the challenge of how to optimally use these drugs.
Neoadjuvant Pembrolizumab for HER2-Negative Breast Cancer
Checkpoint inhibitors have demonstrated an anti-tumor signal in breast cancer in recent trials, but they have not been approved for breast cancer treatment despite being approved to treat other diseases, such as melanoma and lung cancer. Part of the challenge may be that breast cancer has a “middling” mutational load or expression of neo-antigens, compared with other malignancies.
The I-SPY platform incorporates an adaptive design in the neoadjuvant setting to quickly drop compounds that would appear to have limited success in a larger trial and to proceed with more promising drugs. This approach was used by Nanda and colleagues (abstract 506) to evaluate the role of the immune checkpoint inhibitor pembrolizumab combined with weekly paclitaxel versus paclitaxel alone prior to doxorubicin and cyclophosphamide in the neoadjuvant setting for patients with HER2-negative disease.
The pathological complete response (pCR) rate was higher for patients receiving pembrolizumab than for patients receiving paclitaxel alone (controls) among those with HER2-negative disease (46% and 16%, respectively) as well as among those with HER2-negative/ER-negative disease (60% and 20%) and HER2-negative/ER-positive disease (34% and 13%).
These results signal the promise of checkpoint inhibitors in patients with breast cancer in both the metastatic and adjuvant setting. Numerous trials with a variety of agents in the metastatic disease setting and the adjuvant setting are ongoing. All that remains to complete the story are the data.
Adjuvant Pertuzumab plus Trastuzumab for HER2-Positive Early Disease
The provisional approval of pertuzumab (along with trastuzumab and chemotherapy) by the FDA in the neoadjuvant setting for patients with HER2-positive disease was based on a high pCR rate that was observed in clinical trials. To provide a definitive randomized clinical trial in the adjuvant setting, von Minckwitz and colleagues conducted the long awaited APHINITY trial (abstract LBA500 and NEJM JW Oncol Hematol Aug 2017), in which patients with early stage breast cancer were randomized postoperatively to chemotherapy with trastuzumab for 1 year or chemotherapy with both trastuzumab and pertuzumab for 1 year.
With follow-up of <4 years, patients receiving dual HER2 targeting with trastuzumab and pertuzumab had a superior PFS compared with those receiving trastuzumab (difference, 1.7%; P=0.045). The benefit of pertuzumab was observed across subgroups, but was greatest in patients with node-positive disease (difference, 3.2%) and in those with ER-negative disease (difference, 2.3%).
The addition of pertuzumab to adjuvant chemotherapy and trastuzumab may offer the greatest benefit for those with high-risk disease, whereas those with lower risk disease could avoid the addition of pertuzumab to their adjuvant regimen.
Olaparib for Patients with HER2-Negative BRCA-Mutated Disease
PARP (poly ADP-ribose polymerase) inhibitors have been in development for several years and offer the prospect of a significant anti-tumor effect, particularly in BRCA-mutated tumors. PARPs bind to areas of DNA damage and set up the “scaffolding” to recruit other DNA repair enzymes. In tumor cells that already have DNA repair limitations due to a BRCA mutation, affecting other mechanisms of DNA repair with a PARP inhibitor can lead to cell death. The oral PARP inhibitor olaparib was reported in a small study (Lancet 2010; 376:235) to have anti-tumor activity as a single agent in BRCA-mutated, metastatic breast cancer (objective response rate, 41%).
Now, in the OlympiAD trial (abstract LBA4 and NEJM JW Oncol Hematol Aug 2017), Robson and colleagues evaluated the use of olaparib versus standard chemotherapy in patients with HER2-negative (ER-positive or triple-negative) breast cancer and a known or suspected BRCA mutation. Patients were required to have received prior anthracyclines and taxane therapy and up to two lines of prior chemotherapy in the metastatic disease setting.
PFS (the primary endpoint) favored olaparib versus chemotherapy (7.0 vs. 4.2 months; P<0.009). PFS also seemed to be better in patients who had not received prior platinum therapy. The objective response rate also favored olaparib (69% vs. 31%), but survival was similar with either treatment. Adverse effects of any grade with olaparib were manageable, with nausea, anemia, vomiting, fatigue, and neutropenia being most common. Based on these data, olaparib stands a good chance to be approved as the first PARP inhibitor for treatment of BRCA-mutated disease. Many other PARP inhibitors are also being developed as breast cancer therapies.
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JAMA Intern Med 2017 Jul 17
An Association Between Vasectomy and Prostate Cancer?
A meta-analysis casts doubt on this enduring belief.
A 30-year debate about the association of vasectomy with excess risk for prostate cancer has been fueled by studies of variable quality and with mixed results. In this meta-analysis, researchers addressed study quality: They evaluated 53 studies (16 cohort, 33 case-control, and 4 cross-sectional) that involved about 15 million patients; only 9 cohort studies, 7 case-control studies, and no cross-sectional studies were categorized as having low risk for bias.
When analyses of the cohort studies were restricted to those with low risk for bias, a barely statistically significant excess risk for incident prostate cancer of any type (relative risk, 1.05) was noted. Using the same criteria for case-control studies revealed no significant association of vasectomy with excess prostate cancer. When all studies were included, fatal, high-grade, or advanced prostate cancer was not statistically significantly associated with vasectomy although the point estimates for incidence were similar to those for overall prostate cancer.
COMMENT: The authors concluded that the strength of association between vasectomy and any prostate cancer declined as the quality of the studies improved. They calculated that, at most, only 0.5% of prostate cancers could be associated with vasectomy, and no association existed for high-grade, advanced, or fatal prostate cancers. Although the slight uncertainty probably should be disclosed to patients who are considering vasectomy, I do not think it should be influential in decision making.
CITATION(S): Bhindi B et al. The association between vasectomy and prostate cancer: A systematic review and meta-analysis. JAMA Intern Med 2017 Jul 17; [e-pub].
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JAMA 2017 Jul 18; 318:255
Healthy Aging Is Less Likely When Weight Is Gained in Early and
Middle Adulthood

Several chronic diseases occurred more commonly in those who gained as little as 2.5 (5.5lbs) to 10.0 kg (22lbs).
Mean weight gain in U.S. adults is about 1 to 2 pounds annually during early and middle adulthood. In this study, investigators followed about 118,000 young and middle-aged adults enrolled in two large national studies of healthcare professionals (mean age at enrollment, ≈45) to assess the consequences of weight gain. Participants recalled their weight at age 18 (for women) or 21 (for men) and were weighed at age 55. Every 2 years after age 55, participants were evaluated for onset of major chronic diseases.
At age 55, women had gained a mean 12.6 kg (28 lbs), and men had gained a mean 9.7 kg. Significant associations were noted between weight gain and incidence of most major chronic diseases. For example, gain of ≥20 kg (vs. maintaining stable weight) was associated with 8-fold and 11-fold higher risks for developing type 2 diabetes in men and women, respectively; weight gain of 2.5(5.5lbs) to 10 kg (22lbs) doubled risk for diabetes. After weight gain of 10 (22lbs) to 20 kg (44lbs), likelihood of healthy aging (defined as absence of major chronic disease, cognitive difficulties, and physical limitations) declined by 44% for women and by 34% for men.
COMMENT: These results are not surprising but do provide some details on risks associated with even moderate weight gain that could be used to counsel patients.
CITATION(S): Zheng Y et al. Associations of weight gain from early to middle adulthood with major health outcomes later in life. JAMA 2017 Jul 18; 318:255.
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JAMA Psychiatry 2017 Jul; 74:719
Reducing Metabolic Adverse Effects of Antipsychotic Drugs: A New Approach
A medication used for type 2 diabetes showed promise in obese and prediabetic patients taking antipsychotic drugs.
People with schizophrenia are vulnerable to metabolic disorders. Glucagon-like peptide-1 (GLP-1) receptor agonists, a new class of agents used to treat type 2 diabetes, increase insulin secretion and, at higher doses, reduce weight, without affecting insulin receptors. Investigators in Denmark conducted an industry-sponsored, 16-week, randomized, placebo-controlled trial of subcutaneous liraglutide, a GLP-1 agonist, in 103 patients with schizophrenia spectrum disorders treated with clozapine or olanzapine, the two antipsychotic drugs with the highest incidence of weight gain and metabolic disturbances.
All participants had elevated body-mass index values and prediabetes (e.g., elevated fasting blood sugar or glycosylated hemoglobin [HgbA1c] levels) but not diabetes; 96 patients completed the trial. Oral glucose tolerance tests normalized in almost four times as many liraglutide patients as placebo patients (number needed to treat, 2). Compared with placebo, liraglutide was associated with 5.3 kg more weight loss and 4.1 cm greater decrease in waist circumference, with large effect sizes. Liraglutide was also associated with greater decreases in HgbA1c and significant improvements in lipid profiles.
COMMENT: GLP-1 agonists are generally well-tolerated, and some sustained-release formulations under study for diabetes improve compliance. These results in patients who already were obese and prediabetic while taking medications that are very likely to cause or exacerbate these problems raise the possibility of a useful adjunctive medication in the treatment of psychosis.
CITATION(S): Larsen JR et al. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder: A randomized clinical trial. JAMA Psychiatry 2017 Jul; 74:719.
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Neurology 2017 Jul 7
Multiple Sclerosis Shortens Lifespan by About 9 Years
MS patients are at increased risk for early death, although their life expectancy has improved over the past 4 decades.
Investigators in Sweden evaluated age and cause of death for 29,617 patients with multiple sclerosis (MS) diagnosed between 1968 and 2012, matched 1:10 to those without MS. During the study period, 32% of the MS patients and 20% of the non-MS patients died.
Compared with their matched control counterparts, MS patients had higher overall mortality (median lifespan, approximately 76 years vs. 85 years). MS patients were at higher risk for death from respiratory disease (hazard ratio, 5.1) and infectious disease (HR, 4.1). Suicide was more likely in those with MS (HR, 1.9). Those diagnosed before the age of 18 (HR, 10.2), and those aged 18 to 40 (HR, 4.9), had particularly higher mortality than their control counterparts, compared with those diagnosed after age 40.
Mortality in MS patients declined relative to non-MS patients over the study interval (HR, 6.5 in the 1970s and 1980s; HR, 2.1 in the 2000s). Relative mortality due to cardiovascular disease, respiratory failure, infections, and suicides all declined over time.
COMMENT: Although most patients with MS will live into their 70s, they are at increased risk for complications associated with decreased mobility. Patients who accumulate disability are at risk for more complications and an earlier death. Survival curves suggest that some 10% die before the age of 60. Deaths caused by infections and respiratory failure were most common, and suicide was higher than in the control population. Mortality compared to the general population appears to be improving, perhaps due to better diagnostic methods and treatments. It will be interesting to see in future analyses whether an increase in treatment options favorably impacts mortality.
CITATION(S): Burkill S et al. Mortality trends for multiple sclerosis patients in Sweden from 1968 to 2012. Neurology2017 Jul 7; [e-pub].

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