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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
June 11, 2011

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Even Short-Term NSAID Use Associated with Cardiovascular Events
Chemotherapy for Older Patients with Metastatic Colorectal Cancer
Does Cannabis Impair Cognition in Patients with Multiple Sclerosis?
FDA: 5-Alpha Reductase Inhibitors Associated with Increased Risk for
   High-Grade Prostate Cancer Diagnosis
France Suspends Use of Pioglitazone (Actos®)Based on 'Slight' Risk for Bladder Cancer
Curb Use of High-Dose Simvastatin, FDA Says
Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis
Two studies link omega-3s to lower diabetes risk; veggie omega-3s make a strong
   showing vs. omega-3 fish fats
Use of Dietary Botanical Supplements and Teas in U.S. Infants
Do PPIs Interfere with Aspirin's Antiplatelet Effect?
β-Blockers in COPD Patients
Levothyroxine and Fracture Risk in Elders
Five Lessons from Niaspan's Disappointing Study
AIM-HIGH Halted: A Death Knell for the HDL Hypothesis? Six Experts Weigh In
No Benefit of Aspirin or Statins in Pulmonary Arterial Hypertension
Endocrine Society Releases Guidance on Managing Vitamin D Deficiency
"Bath Salts" Intoxication

Circulation 2011 May 24; 123:2226
Even Short-Term NSAID Use Associated with Cardiovascular Events
Registry data show adverse effects of both selective cyclooxygenase-2 inhibitors and nonselective agents within the first week of treatment.
     Since 2007, practice guidelines have advised clinicians about the risks of nonsteroidal anti-inflammatory drug (NSAID) use in patients with known cardiovascular disease or at high risk for ischemic heart disease. However, whether short-term NSAID use (e.g., for less than a week) can worsen outcomes in such patients is unclear. Therefore, investigators used data from the Danish National Patient Registry to assess the impact of NSAID use in >83,000 patients (mean age, 68; 63% men) after hospitalization for first myocardial infarction (MI) from 1997 through 2006.
     More than 42% of the cohort received prescriptions for NSAIDs including ibuprofen (23%), diclofenac (13%), rofecoxib (5%), celecoxib (5%), and naproxen (2%). During follow-up, the primary outcome, a composite of death and recurrent MI, occurred in 42.1% of NSAID recipients. Compared with the overall study population, risk for a primary endpoint in NSAID recipients was significantly elevated in the first week of NSAID treatment (hazard ratio, 1.45), and the increase in risk remained significant throughout treatment (>90 days; HR, 1.55). In individual analysis, all NSAIDs except naproxen were associated with an increased risk for the primary outcome. Diclofenac conferred the highest risk, with a hazard ratio (3.26 in the first week of treatment) higher than that of rofecoxib, which was withdrawn from the U.S. market in 2004.
     Comment: In this large, national study, NSAIDs — many of which are available without a prescription — were associated with a 45% increase in risk for recurrent MI or death within the first week of treatment in post-MI patients. When NSAID treatment was continued for 3 months, the increase in risk rose to 55%. It appears that no NSAID, no matter how short the duration of use, is without possible cardiovascular side effects in patients with coronary artery disease.
JoAnne M. Foody, MD Published in Journal Watch Cardiology June 8, 2011
     Citation(s):Schjerning Olsen A-M et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: A nationwide cohort study. Circulation 2011 May 24; 123:2226. http://www.ncbi.nlm.nih.gov/pubmed/21555710?dopt=Abstract
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MM: Adjunctive treatments such as IV Glutathione have successfully decreased side effects of oxaliplatin, 5-FU, Folfox and cisplatin treatments. These adjuncts should not be ignored when trying to maximize dose and obtain optimal effects. If chemotherapy is going to be administered, then give the patient the best chance for success.
2011 May 21; 377:1749
Chemotherapy for Older Patients with Metastatic Colorectal Cancer
Older patients experienced limited added benefit from reduced-dose oxaliplatin or capecitabine.
     As with many solid-tumor malignances, colorectal cancer (CRC) is more common in older patients, who are often underrepresented in clinical trials and for whom application of standard therapies often leads to greater rates of toxicity. Moreover, recent studies have questioned whether older patients would receive the same benefits from contemporary oxaliplatin- and capecitabine-based treatments that younger patients achieve.
     To examine this issue, investigators from the Medical Research Council in the U.K. conducted a 2x2 factorial, randomized, phase III trial involving 459 older or frail patients (mean age, 74; WHO performance status, ≤2) with previously untreated, metastatic CRC. Patients were randomized to receive standard intravenous 5-fluorouracil (5-FU) with or without intravenous oxaliplatin or oral capecitabine with or without intravenous oxaliplatin. The starting doses of chemotherapy were 80% of standard therapy.
     Oxaliplatin recipients versus nonrecipients achieved nonsignificantly longer progression-free survival (PFS; the primary endpoint; 5.8 and 4.5 months), similar overall survival (OS) and overall toxicity, higher response rate (35% vs. 13%; P<0.0001), and less frequent quality-of-life (QOL) improvement (49% vs. 62%; P=0.04). Capecitabine recipients versus 5-FU recipients experienced similar QOL improvement (the primary outcome), PFS, OS, and response rate, but greater risk for grade ≥3 toxicity (P=0.03).
     Comment: This trial demonstrates the feasibility of conducting randomized clinical trials in older, debilitated patients, and it highlights that the use of combination chemotherapy in these patients should be selective. The potential benefit of oxaliplatin for greater antitumor response did not translate into significant differences in PFS or OS but resulted in potential detriments in QOL. Capecitabine resulted in greater risk for toxicity, indicating that the dose reduction of this agent in older and frail patients should be greater than those applied in this trial.
David H. Ilson, MD, PhD Published in Journal Watch Oncology and Hematology June 7, 2011
     Citation(s):Seymour MT et al. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): An open-label, randomised factorial trial. Lancet 2011 May 21; 377:1749.
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Neurology 2011 Mar 29; 76:1153
Does Cannabis Impair Cognition in Patients with Multiple Sclerosis?
Information-processing speed, executive function, and visuospatial perception were significantly worse among long-term cannabis users than among nonusers in a cross-sectional study of MS patients.
     Cannabinoids effectively relieve certain multiple sclerosis (MS) symptoms, such as muscle stiffness and spasms, and many MS patients use cannabis for that purpose (CNS Drugs 2011; 25:187). However, long-term or heavy cannabis use is associated with cognitive impairment in the general population, and cognitive impairment is also a feature of MS.
     Researchers used the Minimal Assessment of Cognitive Function in MS test battery to compare 25 MS patients who were long-term cannabis users (mean duration, 27 years; abstinent for ≥12 hours before testing) with 25 well-matched MS patients who had not used cannabis regularly (mean age in both groups, 44). Most of the cannabis group reported daily use.
     Cannabis users were significantly more impaired than nonusers on 6 of 11 measures, representing the cognitive domains of visuospatial perception, executive functioning, and information-processing speed — but not on the domains of learning and memory or verbal fluency. Cannabis users were twice as likely as nonusers to be classified as globally impaired. Differences between the two groups remained largely intact after adjustment for a range of potentially confounding factors. Cognitive performance was not correlated with duration of cannabis use, age that use started, urinary cannabinoid levels, or duration of abstinence.
     Comment: The findings of this well-executed study suggest that long-term, heavy cannabis use by MS patients may adversely affect cognition beyond the impairment associated with MS itself. However, given that most of the cannabis users initiated use during adolescence (on average, 14 years before MS diagnosis), their cognitive impairments are likely to have developed over a long period and to reflect residual impairment from recent use. Verbal learning and memory are consistently impaired in cannabis users in the general population — but not in this study relative to nonusing MS patients. Future studies could assess the cognitive performance of patients who start using cannabis only for therapeutic reasons after MS diagnosis. For now, clinicians should be aware that long-term cannabis use may worsen cognitive function in MS patients and should advise patients to weigh this risk against the potential for symptom relief.
— Nadia Solowij, PhD Dr. Solowij is a Senior Lecturer in the School of Psychology and Illawarra Health and Medical Research Institute, University of Wollongong, Australia.
Published in Journal Watch Neurology June 7, 2011
     Citation(s):Honarmand K et al. Effects of cannabis on cognitive function in patients with multiple sclerosis. Neurology 2011 Mar 29; 76:1153 http://www.ncbi.nlm.nih.gov/pubmed/21444900?dopt=Abstract
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FDA: 5-Alpha Reductase Inhibitors Associated with Increased Risk for High-Grade Prostate Cancer Diagnosis
The labels of 5-alpha reductase inhibitors (5-ARIs) are being changed to note an increased risk for being diagnosed with high-grade prostate cancer, the FDA announced on Thursday. The drugs (finasteride and dutasteride) are approved to treat benign prostatic hyperplasia and male pattern hair loss.
     The announcement came after the FDA reviewed data from two prostate cancer prevention trials. In one, finasteride (given daily for 7 years) was associated with a higher frequency of prostate cancers with Gleason scores between 8 and 10, compared with placebo (1.8% vs. 1.1%). In the other, dutasteride (given daily for 4 years) was also associated with more high-grade cancers relative to placebo (1% vs. 0.5%).
      The FDA recommends that physicians rule out prostate cancer before prescribing 5-ARIs for benign prostatic hyperplasia. Also, because these drugs lower prostate-specific antigen values, clinicians should be aware that if PSA increases while a patient is taking a 5-ARI — even if it is within the normal range — it may indicate the presence of prostate cancer

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France Suspends Use of Pioglitazone (Actos®)Based on 'Slight' Risk for
Bladder Cancer

     The antidiabetes drug pioglitazone (marketed in the U.S. as Actos) is to be taken off the market in France because of concerns over a "slightly increased risk" for bladder cancer, Bloomberg reports.
     In its announcement, the French drug agency AFSSAPS said that a French cohort of some 155,000 patients with diabetes who were exposed to pioglitazone, when compared with a nonexposed diabetic cohort, showed a statistically significant association between exposure to the drug and the incidence of bladder cancer.
     In September 2010 the FDA said it was following a 10-year epidemiological study of the association. Interim results showed an increased risk among patients with the longest exposures and the highest cumulative doses of Actos.
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Curb Use of High-Dose Simvastatin, FDA Says
Because of an increased myopathy risk, the FDA recommends limiting the use of simvastatin at the 80-mg level, the highest approved dose.
The FDA advises physicians to:

     The agency is changing the drug's label to characterize certain drugs as being contraindicated for use with simvastatin because they can increase the level of simvastatin. Those drugs are: itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, and danazol.
     In addition, the following drugs should not be used with simvastatin doses higher than 10 mg: amiodarone, verapamil, and diltiazem. And finally, amlodipine and ranolazine should not be used with doses higher than 20 mg.

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Lancet Neurol 2011 May; 10:436
Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis
Among children with acute demyelination, low vitamin D levels, past infection with the Epstein-Barr virus, and the HLA-DRB1*15 allele were associated with development of MS.
     Researchers sought to identify risk factors for multiple sclerosis (MS) among children with incident central nervous system demyelination. They prospectively studied 302 children (aged <16 years) who presented within 90 days after demyelination-symptom onset to one of 23 centers in Canada.
     During a median follow-up of 3 years, 63 children (21%) developed MS. Older age at onset of demyelination symptoms (12 vs. 9 years) was associated with significantly increased risk for MS. Among children who presented with multifocal deficits, those with encephalopathy were significantly less likely than those without encephalopathy to develop MS. Oligoclonal bands in cerebrospinal fluid were more common among children who developed MS than among those who did not (60% vs. 15%).
     Development of MS was associated with lower vitamin D serum concentration, previous Epstein-Barr virus infection and anti-EBNA1 titers, and the presence of one or more HLA-DRB1*15 alleles. MS was diagnosed in significantly more children with all three of these risk factors than in children with none of these risk factors (57% vs. 5%).
     Comment: One goal of this study was to evaluate very early demyelination, when environmental factors are linked closely in time with disease development. The findings provide useful prognostic information to help clinicians distinguish between the pediatric demyelinating diseases of MS and acute disseminated encephalomyelitis. The authors offer a helpful risk-stratification algorithm to guide counseling and follow-up in clinical practice.
Robert T. Naismith, MD Published in Journal Watch Neurology May 3, 2011
     Citation(s):Banwell B et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: A prospective national cohort study. Lancet Neurol 2011 May; 10:436. http://www.ncbi.nlm.nih.gov/pubmed/21459044?dopt=Abstract
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Article from Vital Choices Newsletter http://newsletter.vitalchoice.com/e_article002123188.cfm?x=bjwWlQg,b1h1R7NC)
June 6, 2011 Omega-3s Linked to Lower Diabetes Risk
Two studies link omega-3s to lower diabetes risk; veggie omega-3s make a strong showing vs. omega-3 fish fats
by Craig Weatherby
     Cell and animal research on omega-3s and diabetes show that these essential fats exert genetic influences similar to diabetes drugs … without adverse side effects.  These documented “nutrigenomic” effects should help deter diabetes … but while generally positive, the evidence from human clinical and diet-health studies remains mixed. The positive side of the scale just got added weight from two investigations published this week in the American Journal of Clinical Nutrition.
     Both of these diet-health epidemiological studies link higher omega-3 intakes to lower diabetes risk. And surprisingly, plant-source omega-3s seemed to equal or exceed the benefits of seafood-source omega-3s.
Smaller but stronger of the two studies favors seafood omega-3s
     In the smaller but more reliable of the two studies, Harvard researchers studying more than 3,000 older adults for a decade linked high blood levels of omega-3s to a substantially reduced risk of diabetes. Their findings applied to seafood-source, “marine” omega-3s (EPA and DHA) and plant-source omega-3s (ALA) alike.
     The body converts plant-source omega-3 ALA into EPA and DHA … the only omega-3s we humans actually need to survive and thrive. But the body can only turn from one to 10 percent of dietary ALA into omega-3 EPA and DHA ... which explains the generally far greater health benefits associated with seafood and fish oils. The Boston-based team tested blood levels of omega-3 EPA and DHA among 3,088 older men and women – mean age 75 years – and compared those levels with the volunteers’ health status after 10 years (Djoussé L, Biggs ML, Lemaitre RN et al. 2011).
     Surprisingly, compared with high levels of seafood-source omega-3s, the Harvard team linked high blood levels of plant-source omega-3 ALA to a slightly greater risk reduction … a 43 percent cut in the risk of developing diabetes within 10 years, versus a 36 percent drop. Importantly, higher omega-3 levels were still linked to lower diabetes risk after the results were adjusted to account for factors like weight and exercise habits. Singapore study favors plant-source omega-3s … but relies on shakier data A larger, Singapore-based study published simultaneously in the same journal linked high intake of plant-source omega-3 ALA to a 22 percent cut in diabetes risk during one decade of follow up. Surprisingly, no risk reduction was seen among those with the highest estimated intakes of marine omega-3s.
     In the Singapore study, an international team led by Andrew Odegaard of the University of Minnesota linked plant-source omega-3s – but not marine omega-3s – to reduced diabetes risk over time. Odegaard’s group recruited 43,176 healthy, ethnically Chinese Singaporeans of both genders, aged 45 to 74, and then questioned them about their eating habits and followed them for 10 years. Their analysis linked high ALA intake to a 22 percent drop in diabetes risk … after accounting for weight, exercise, and other factors. However, as the authors wrote, omega-3s from fish were not tied to any reduction in diabetes risk: Omega-3 FAs [fatty acids] from marine sources were not associated with [lower or higher] diabetes risk, whereas non-marine omega-3 FA intake was strongly associated [with reduced diabetes risk].” (Brostow DP et al. 2011)
     Interestingly, neither omega-6 fat intake nor the omega-6/omega-3 intake ratio was associated with any change in the risk of developing type 2 diabetes. Still, this large Singapore study is likely less reliable than the smaller Harvard investigation. Why? Instead of measuring people’s omega-3 blood levels, the Singapore study authors could only estimate omega-3 intakes, based people’s responses to diet questionnaires. The sheer size of the Singapore study adds statistical strength to its outcomes … but this advantage is significantly undercut by use of a much less reliable methodology.
Is omega-3 ALA really responsible … or just a marker for healthy lifestyle?
     Why didn’t omega-3 from fish reduce diabetes risk in the large Singapore-based study?
     Unlike EPA and DHA from seafood, some lab research suggests that omega-3 ALA might improve body cells' sensitivity to insulin, the hormone that regulates blood sugar. However, as lead author Andrew Odegaard told Reuters, people who consume a lot of ALA – which is concentrated in flaxseed, walnuts, canola oil, and dark, leafy greens – are likelier to have healthier, plant-rich diets, hence healthier lifestyles overall. He added that while his team tried to adjust their analysis to account for those variables, it’s feasible that ALA intake is a “marker” for other anti-diabetes factors. Odegaard noted that if fish is deep-fried and served alongside unhealthful fare like French fries and sweet soda, this could easily cancel out any beneficial effect from omega-3s.
     Sources: Brostow DP, Odegaard AO, Koh WP, Duval S, Gross MD, Yuan JM, Pereira MA. Omega-3 fatty acids and incident type 2 diabetes: the Singapore Chinese Health Study. Am J Clin Nutr. 2011 May 18. [Epub ahead of print]. Djoussé L, Biggs ML, Lemaitre RN, King IB, Song X, Ix JH, Mukamal KJ, Siscovick DS, Mozaffarian D. Plasma omega-3 fatty acids and incident diabetes in older adults. Am J Clin Nutr. 2011 May 18. [Epub ahead of print] doi: 10.3945/ajcn.111.013334. Djoussé L, Gaziano JM, Buring JE, Lee IM. Dietary omega-3 fatty acids and fish consumption and risk of type 2 diabetes. Am J Clin Nutr. 2011 Jan;93(1):143-50. Epub 2010 Oct 27. Hodge AM, English DR, O'Dea K, Sinclair AJ, Makrides M, Gibson RA, Giles GG. Plasma phospholipid and dietary fatty acids as predictors of type 2 diabetes: interpreting the role of linoleic acid. Am J Clin Nutr. 2007 Jul;86(1):189-97. Odegaard AO, Koh WP, Butler LM, Duval S, Gross MD, Yu MC, Yuan JM, Pereira MA. Dietary patterns and incident type 2 diabetes in chinese men and women: the singapore chinese health study. Diabetes Care. 2011 Apr;34(4):880-5. Epub 2011 Feb 17. Vessby B, Aro A, Skarfors E, Berglund L, Salminen I, Lithell H. The risk to develop NIDDM is related to the fatty acid composition of serum cholesterol esters. Diabetes 1994;43:1353-7. Wang L, Folsom AR, Zheng ZJ, Pankow JS, Eckfeldt JH. Plasma fatty acid composition and incidence of diabetes in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr 2003;78:91-8. Wang L, Folsom AR, Zheng ZJ, Pankow JS, Eckfeldt JH; ARIC Study Investigators. Plasma fatty acid composition and incidence of diabetes in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr. 2003 Jul;78(1):91-8.
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2011 Jun; 127:1060
Use of Dietary Botanical Supplements and Teas in U.S. Infants
Nearly 10% of surveyed mothers reported giving botanical remedies to their infants.
     Estimates of dietary botanical supplements and tea use in national samples of U.S. children range from 1% to 4%, but the rate of use in infants only is unknown. Researchers analyzed data from a nationwide survey of about 3000 mothers of healthy infants who received 10 questionnaires during their infants' first year about infant feeding practices and oral intake of dietary botanical supplements (any plant-based remedy) or any tea during the previous 2 weeks. Most respondents were white, middle income, and college educated.
     Nine percent of mothers reported at least once that their infants had been given dietary botanical supplements or tea; 3.6% reported this activity more than once. About 2% of infants received botanical supplements or tea during their first month. Maternal use of these products and Hispanic ethnicity were significantly associated with giving botanical supplements and tea to infants. The most commonly administered products were gripe water, chamomile, teething tablets, and tea. The most common reasons for giving these products to infants were to help with fussiness, digestion, colic, relaxation, and teething. The most common sources of information about botanical products were friends and relatives, healthcare professionals, and the media.
     Comment: In this study, reported use of dietary botanical supplements and teas in infants of predominantly white, middle-income mothers was higher than estimates from studies of all U.S. children, and Hispanic mothers were nearly twice as likely as white mothers to report infant botanical product use. Although no good evidence exists to support the effectiveness of these remedies for the nonspecific symptoms reported in this study, I do consider them to be safe, with caveats. For example, gripe water –– a mixture that often includes bicarbonate, ginger, dill, fennel, and chamomile –– occasionally contains alcohol or sucrose. One case of Pseudomonas sepsis from a foreign version of gripe water has been reported. I recommend asking parents about use of botanicals for their infants and warning them to read labels for undesirable ingredients and to be aware of possible, although rare, contamination. Botanical supplements are not regulated by the FDA.
Cornelius W. Van Niel, MD Published in Journal Watch Pediatrics and Adolescent Medicine
June 8, 2011
     Citation(s):Zhang Y et al. Feeding of dietary botanical supplements and teas to infants in the United States. Pediatrics 2011 Jun; 127:1060.
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BMJ 2011 May 11; 342:d2690
Do PPIs Interfere with Aspirin's Antiplatelet Effect?
Cardiovascular risk was higher in myocardial infarction patients who received proton-pump inhibitors along with aspirin.
     Proton-pump inhibitors (PPIs) are prescribed widely to prevent peptic ulcers in patients taking aspirin. PPIs, however, can lower aspirin absorption, which, in turn, could attenuate aspirin's antiplatelet effect. In this retrospective study, Danish investigators assessed the effect of PPI therapy on adverse cardiovascular (CV) events in nearly 20,000 aspirin-treated patients who survived 30 days after a first myocardial infarction (MI). Notably, clopidogrel-treated patients were excluded.
     During 1-year follow-up, 3400 patients (17%) experienced recurrent MI, stroke, or CV-related death. In a propensity-score matched model (which is designed to compensate for confounding factors and baseline differences), risk for the combined endpoint of CV-related death, MI, and stroke was significantly higher among PPI users than among nonusers (hazard ratio, 1.6). Similar results were obtained for secondary outcomes of all-cause death (HR, 2.4), CV-related death (HR, 2.2), and MI (HR, 1.3) but not for stroke. No differences in risk were observed for lansoprazole, omeprazole, and esomeprazole. Histamine-2 (H2)-antagonist use was not associated with elevated CV risk.
     Comment: In this study, PPI use was associated with elevated risk for adverse CV events in aspirin-treated patients after a first MI. Although these results echo recent concerns about an interaction between PPIs and clopidogrel, a large randomized trial (in which 70% of participants had acute coronary syndromes) ultimately showed that PPIs did not raise risk for adverse CV events in clopidogrel-treated patients (JW Cardiol Oct 6 2010). Because the current study's results could be explained by residual confounding (e.g., if generally sicker patients are more likely to receive PPIs than healthier patients), further research is needed to prove the existence of a clinically meaningful interaction between PPI and aspirin.
Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine June 9, 2011
     Citation(s):Charlot M et al. Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: Nationwide propensity score matched study. BMJ 2011 May 11; 342:d2690. (http://dx.doi.org/10.1136/bmj.d2690)
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BMJ 2011 May 10; 342:d2549
β-Blockers in COPD Patients
Four-year mortality was lower among patients with chronic obstructive pulmonary disease who received β-blockers.
     Clinicians sometimes are reluctant to prescribe β-blockers for patients who have chronic obstructive pulmonary disease (COPD) because of concern that these drugs might precipitate bronchospasm. In this retrospective cohort study, investigators assessed the effects of β-blockers on exacerbations, hospital admissions, and mortality in 6000 Scottish patients (mean age at diagnosis, 69) with COPD.
     A total of 819 patients used β-blockers. After a mean follow-up of 4.4 years (during which one third of patients died), β-blocker use was associated with 22% lower all-cause mortality. Mortality with β-blockers was lower regardless of patients' concurrent inhaled therapies (i.e., steroid, long-acting β2-agonist, anticholinergic, or combination therapy). Notably, β-blockers had no adverse effects on lung function.
     Comment: These results, which suggest β-blockers lower 4-year mortality in patients with COPD, are consistent with those of a prior study (JW Hosp Med Jul 12 2010). The findings are not surprising: About 90% of the β-blockers used in the study were cardioselective (e.g., atenolol, metoprolol), which are well tolerated by patients with COPD (Cochrane Database Syst Rev 2005; 4:CD003566), and many COPD patients also have heart disease, for which β-blockers are beneficial.
Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine June 9, 2011
     Citation(s):Short PM et al. Effect of β blockers in treatment of chronic obstructive pulmonary disease: A retrospective cohort study. BMJ 2011 May 10; 342:d2549. (http://dx.doi.org/10.1136/bmj.d2549)
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BMJ 2011 Apr 28; 342:d2238
Levothyroxine and Fracture Risk in Elders
Higher doses and current or recent use were associated with elevated risk.
     Elders with hypothyroidism require lower doses of levothyroxine for replacement than do younger people. However, many elders are overtreated and, as a result, develop iatrogenic hyperthyroidism — a risk factor for fracture. In this case-control study, investigators assessed the effects of levothyroxine dose on fracture risk among 214,000 Canadians (age, ≥70; mean age, 82) who were prescribed levothyroxine between 2002 and 2007.
     After average follow-up of 3.8 years, 22,000 participants (88% women) experienced fractures. When remote levothyroxine use (stopped >180 days before index date) was used for comparison, current use and recent past use (stopped within 15–180 days of index date) were associated with significantly elevated risks for fracture (odds ratios, 1.9 and 1.3, respectively) after adjustment for multiple confounders. Daily dose among current levothyroxine users also affected risk; when low doses of levothyroxine (<0.04 mg) were used for comparison, high doses (>0.09 mg) and medium doses (0.04–0.09 mg) were associated with significantly elevated risk for any fracture (ORs, 3.5 and 2.6, respectively). Results were similar for hip fracture alone and for both sexes.
     Comment: In this study, current and recent levothyroxine use were associated with elevated fracture risk in elders. Furthermore, dose-response relations were observed. A major limitation of the study is lack of data about thyroid-stimulating hormone (TSH) levels used to guide levothyroxine dosing. Nevertheless, the findings remind us to monitor patients who are receiving levothyroxine and to avoid suppressed TSH levels, which indicate iatrogenic hyperthyroidism.
Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine May 17, 2011
     Citation(s):Turner MR et al. Levothyroxine dose and risk of fractures in older adults: Nested case-control study. BMJ 2011 Apr 28; 342:d2238. (http://dx.doi.org/10.1136/bmj.d2238)
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Five Lessons from Niaspan's Disappointing Study
Adapted from a post on Dr. Harlan Krumholz's Outcomes blog at Forbes.com
     Comparative effectiveness research has attracted attention in the healthcare debate. Critics charge that these studies are designed to restrict choice, stifle innovation, and keep useful but expensive therapies from patients. But when this research is done well, it can overturn conventional wisdom about understudied drugs and demonstrate that patients are receiving ineffective — or even harmful — treatments. Isn't more knowledge about benefits and harms of treatment alternatives just what patients need?
     Last month, we saw a widely publicized example of comparative effectiveness research done well. The National Institutes of Health (NIH) produced a gem of a study with critical implications for clinical decision making and future research. In the study, called AIM-HIGH, researchers sought to determine whether adding Niaspan (Abbott Laboratories' extended-release niacin) to statin therapy benefits patients with cardiovascular disease.
     The AIM-HIGH investigators enrolled 3414 patients with cardiovascular disease, low HDL cholesterol levels, and high triglyceride levels. All patients received simvastatin and additionally were assigned randomly to Niaspan or placebo. In a press release, the investigators announced that the trial was stopped after average follow-up of about 3 years (more than 1 year earlier than planned) because no hint of benefit was seen at this point. Although the results have not yet been published, enough information has been released to give us a good picture of the study. There was even a suggestion of harm — more strokes in the Niaspan group — but that might have been a chance occurrence.
     This study exemplifies comparative effectiveness research that should be embraced by patients, clinicians, industry, payers, and government. Here are five reasons:

1. The study targeted an important area of uncertainty for patients. Niaspan is a popular drug that raises HDL cholesterol levels and lowers triglyceride levels. In 2010, its worldwide sales approached US$1 billion. Unfortunately, we do not know whether the drug lowers risk for heart disease or stroke — or lengthens survival — when added to statins and other modern cardiovascular therapies. The only large study of niacin (not the extended-release formulation) was conducted more than 30 years ago. Drugs that modify risk factors do not always affect clinical outcomes in predictable ways.
2. Too often, studies compare one therapy with an inferior therapy. But in this study, Niaspan add-on therapy was compared with an appropriate alternative — simvastatin therapy, designed to achieve LDL cholesterol levels between 40 and 80 mg/dL. The study replicated a typical clinical scenario in which clinicians and patients must decide whether adding an unproven medication to an already proven therapy is worthwhile.
3. The conclusions of the study did not go beyond the evidence. The press release focused on the absence of benefit with Niaspan but did not generalize further to other drugs that might raise HDL cholesterol levels. Each drug must be tested separately because it could have distinctive effects on human biology. Even within a class, we have seen marked differences in risk profiles of drugs: Consider the recent examples of rosiglitazone (Avandia) and pioglitazone (Actos). Also, the investigators noted that the results should not be extrapolated to other patient populations. What this study can say is that niacin was not beneficial in a relatively high-risk population.
4. Both the NIH and Abbott were involved in the study. The investigators were wise to include Abbott, because the company tested its own product and relieved taxpayers from paying the entire bill (Abbott paid more than half the $52 million in study costs). Abbott should be commended for supporting the study: No pharmaceutical company should want to sell a product that does not help patients. Abbott has not criticized the study.
     Involvement of the NIH was also important, because it assured the study's credibility. The NIH has impeccable research credentials, with policies and procedures that protect scientific integrity and transparency. Unfortunately, concerns about misbehavior in data manipulation and the publication process have tainted many industry-sponsored trials.
5. The study had close oversight by a data safety monitoring board. Members of the board were the only people allowed to see results as the study progressed. Their decision to stop the study was based on statistical certainty that Niaspan would not show benefit with further follow-up. Oversight by an independent group, which is not controlled by the sponsors and is accountable to participants, is essential.
     The challenge now is to act on the AIM-HIGH findings. The released information should be considered to be reliable enough to inform patients that adding Niaspan to statin treatment does not lower risk, regardless of its effects on HDL cholesterol and triglyceride levels. Although we will learn more details when the results are published formally, every patient on this drug — and every patient for whom this drug is contemplated — should be aware of these findings.
     This is exactly the kind of comparative effectiveness study that we need. We are now better informed about Niaspan than we were just a few weeks ago. Better information should lead to better decisions: That's an outcome we should all embrace.
— Harlan M. Krumholz, MD, SM Published in Journal Watch General Medicine June 7, 2011
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AIM-HIGH Halted: A Death Knell for the HDL Hypothesis? Six Experts Weigh In
Raising HDL levels with niacin failed to affect clinical outcomes.
     The randomized AIM-HIGH trial tested the addition of high-dose, extended-release niacin to statins in individuals who are at risk for cardiovascular events and have well-controlled LDL levels, but also have low HDL and elevated triglyceride levels. In the wake of the National Heart, Lung, and Blood Institute's early termination of AIM-HIGH, the editors of CardioExchange, an online forum for cardiology news and discussion, posed the following question to one of the principal investigators of AIM-HIGH and to five other experts from the cardiovascular-medicine and scientific communities:
     Is the halting of AIM-HIGH the death knell for the "HDL hypothesis": the idea that clinical benefit can be achieved by raising HDL-cholesterol levels?
     The interviewees' responses prompted a lively conversation, which you can access and join by registering for CardioExchange.
     No, emphatically, this trial does not sound the death knell for the HDL hypothesis.
VA-HIT clearly showed 10 years ago that gemfibrozil can reduce death, MI, and stroke, absent any LDL change. But the baseline LDL in VA-HIT was 111 mg/dL; in AIM-HIGH it was 71 mg/dL — a huge difference. We must continue to pursue research in higher-risk ACS and acute-MI patients whose HDL levels are low — and perhaps include more de novo or statin-naive patients, as we often see in real-world practice. —William E. Boden, MD, co–principal investigator of the AIM-HIGH trial; Medical Director of Cardiovascular Services, Kaleida Health; Chief of Cardiology, Buffalo General Hospital and Millard Fillmore Gates Circle Hospital; Professor of Medicine and Preventive Medicine, University at Buffalo
     Another one bites the dust! As I have maintained before, HDL is a very complex molecule that is involved in many metabolic pathways. Simply modifying the molecule qualitatively or quantitatively is not ipso facto going to translate into cardioprotective effects. It is hard to argue that a randomized, controlled, outcomes-based trial is not an important tool to bust myths and entrenched beliefs! —Sanjay Kaul, MD, Director, Cardiology Fellowship Training Program, Cedars-Sinai Medical Center, Los Angeles; Professor of Medicine, UCLA School of Medicine
     The discontinuation of this trial is disappointing. Of course, judging from a press release alone is extremely difficult for someone not associated with the study. Did the complexity of the relatively small study population of 1718 Niaspan-treated participants — with heterogeneous risk factors (metabolic syndrome, high blood pressure, diabetes) and varying drug treatments (e.g., with and without ezetimibe) — influence the conclusion that niacin was not effective in preventing heart attacks and strokes? If so, how? (It's somewhat surprising to see the ILLUMINATE trial [JW Cardiol Nov 5 2007] mentioned in the NIH press release without noting that off-target effects are likely to have played a major role in that study's results.) —Monty Krieger, PhD, Whitehead Professor of Molecular Genetics, Department of Biology, Massachusetts Institute of Technology (basic-science researcher who discovered the first HDL receptor)
     The hypothesis is not dead, but it is certainly on life support. It is clear that HDL "raising" is too simplistic and that HDL "manipulation" is a more appropriate potential therapeutic target. Nevertheless, the enticing combination of niacin plus statin therapy to improve cardiovascular risk has been dealt a serious blow. It can be resurrected only by a convincing subgroup analysis from AIM-HIGH or by a clear benefit demonstrated in
HPS2-THRIVE. —Amit Khera, MD, MSc, Assistant Professor, UT Southwestern Medical Center
     The HDL hypothesis may still be viable from the standpoint of future research, but this study is another disappointment to all of us who hope to further improve outcomes in patients at risk for cardiovascular disease. From the perspective of contemporary clinical care, we must step back and recognize that the evidence for lipid-modifying therapy, in terms of meaningful patient outcomes, supports only the use of statins, with little current role for agents that raise HDL. Other lipid-modifying therapies, including niacin (which failed in AIM-HIGH) and fibrates simply should not be used regularly, if at all. My perspective would change if a study or studies showed that lipid-modifying therapies that raise HDL have important clinical benefits beyond improving a patient's lab-test result. —Frederick A. Masoudi, MD, MSPH, FACC, FAHA, Associate Professor of Medicine, University of Colorado Denver; Denver Health Medical Center
     This study does not overturn the strong evidence from animal models that some forms of HDL raising are likely beneficial. Nor does it prove that other approaches that involve both LDL lowering and HDL elevation, such as CETP inhibition, will fail. AIM-HIGH showed that the HDL-raising effect of extended-release niacin does not benefit patients whose LDL is tightly controlled at 40 to 80 mg/dL. This could indicate that the anti-atherogenic effects of HDL are not important in the absence of an ongoing atherogenic stimulus. Or it may imply that niacin's particular mechanism of HDL elevation, which is unknown, is not beneficial. The data highlight, once again, the importance of testing specific hypotheses in carefully designed clinical trials. —Alan R. Tall, MD, Tilden Weger Bieler Professor of Medicine, Columbia University School of Medicine.
Published in Journal Watch Cardiology June 8, 2011
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Circulation 2011 May 18
No Benefit of Aspirin or Statins in Pulmonary Arterial Hypertension
Neither reduced thromboxane B2 levels nor improved lipid profiles had any effect on 6-minute walk distances.
     Most therapies for pulmonary arterial hypertension (PAH) target prostacyclin, nitric-oxide, and endothelin-1 levels; however, abnormal platelet activation, oxidative stress, and inflammation also play a role in poor outcomes. Therefore, investigators conducted a randomized, factorial study to determine whether aspirin, simvastatin, or both would improve 6-minute walk distances in patients with PAH.
     The trial was designed to include 92 subjects, but it was stopped early after just 65 were enrolled because of futility with regard to achieving the primary endpoint with simvastatin. Overall, 6-month results showed no difference in 6-minute-walk distance between either aspirin and placebo or simvastatin and placebo, despite significant improvements in thromboxane B2 levels and lipid levels, respectively. Compared with placebo recipients, simvastatin recipients had a worse 6-minute-walk distance and an increase in dyspnea, although neither finding reached statistical significance. In addition, and not surprisingly, a trend was seen toward more major bleeding episodes with aspirin than with placebo. Neither treatment had any effect on secondary endpoints including N-terminal proB-type natriuretic peptide (NT-proBNP) level and quality of life.
     Comment: In this small study, neither aspirin nor simvastatin improved 6-minute walk distance, NT-proBNP level, or quality of life in patients with isolated pulmonary arterial hypertension. Given the large number of patients with PAH, mechanistic and clinical trials of other therapeutic approaches are warranted.
JoAnne M. Foody, MD Published in Journal Watch Cardiology June 8, 2011
     Citation(s): Kawut SM et al. on behalf of the ASA-STAT Study Group. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation 2011 May 18; [e-pub ahead of print]. (http://dx.doi.org/10.1161/CIRCULATIONAHA.110.015693
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Endocrine Society Releases Guidance on Managing Vitamin D Deficiency
     People at high risk for vitamin D deficiency (e.g., Hispanics, blacks, pregnant women, obese individuals) should be screened for low vitamin D levels, but population screening is not recommended, according to new guidelines from the Endocrine Society published in the Journal of Clinical Endocrinology and Metabolism.
     Circulating serum levels of 25-hydroxyvitamin D below 20 ng/mL should be considered deficient, the society says.
     The society also offers recommended dietary intakes for at-risk groups, as well as guidance on using vitamin D2 or D3 supplements for treatment. It recommends against using supplementation to prevent cardiovascular disease or death or to enhance quality of life
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MMWR Morb Mortal Wkly Rep 2011 May 20; 60:624.
"Bath Salts" Intoxication
Investigation into a cluster of cases in Michigan leads to characterization of this new recreational drug.
     In early 2011, a Michigan poison control center received reports of several patients injecting, inhaling, or ingesting "bath salts" as recreational drugs. Purchased at a local store, the "bath salts," which have no legitimate use for bathing, contained the stimulant compounds 3,4-methylenedioxypyrovalerone (MDPV) or 4-methylmethcathinone (mephedrone). Subsequent statewide investigation identified 35 patients (age range, 22–50) who presented to emergency departments with "bath salt" intoxication during 5 months.
     Nearly half of patients had histories of psychiatric illness, and 69% had self-reported histories of drug abuse. Ninety-one percent presented with neurological symptoms (e.g., mydriasis, motor automatisms), 77% exhibited cardiovascular symptoms (e.g., hypertension, tachycardia), and 49% showed psychological symptoms (e.g., delusions, hallucinations, agitation, paranoia). One patient was dead on arrival, and 17 were admitted (9 to intensive care). Most patients were treated with benzodiazepines and observed; all recovered uneventfully.
     Comment: The Drug Enforcement Administration has identified "bath salts" as a drug of concern. For emergency providers, the emergence of this new drug of abuse should lead to questions about use of "bath salts" when patients present with psychiatric, cardiovascular, and neurological symptoms consistent with stimulant use. Treatment is the same as for other sympathomimetics — titrated doses of benzodiazepines and general supportive measures.
Diane M. Birnbaumer, MD, FACEP Published in Journal Watch Emergency Medicine
June 3, 2011
     Citation(s):Centers for Disease Control and Prevention (CDC). Emergency department visits after use of a drug sold as "bath salts" — Michigan, November 13, 2010–March 31, 2011. MMWR Morb Mortal Wkly Rep 2011 May 20; 60:624.

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