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Archive for September, 2014

Primary Care Corner with Geoffrey Modest: Smoking cessation with combo varenicline and nicotine patches

30 Sep, 14 | by EBM

I have posted a few blogs in the past year or so on the potential of the combination of varenicline plus nicotine patch. This is not an intuitive combo, since varenicline​ blocks with high affinity the nicotinic cholinergic receptor a4b2, presumably the principal mediator of nicotine dependence, both blocking nicotine effects but also with some agonist activity — though there may be other important receptors involved as well. JAMA published the largest study on the combo (see DOI:10.1001/jama.2014.7195). South African study of 435 smokers randomized to 12-week intervention of varenicline plus placebo patch vs. varenicline plus nicotine patch.


–Nicotine or placebo patch (15-mg nicotine patch, left on for 16h/day) begun 2 weeks before target quit date (TQD). Varenicline begun 1 week before. All continued until week 12 after TQD. Varenicline begun with usual up-titration (as per the chantix starter packet), and similarly tapered down in the last week.

–Mean age of patients was 46.3, mean smoking 16 cigarettes/d, 26.5 years of smoking with therefore 21 pack-years smoking, 1.5 previous quit attempts. 62% completed the study

–Primary endpoint: the % of people able to maintain complete abstinence from smoking for the last 4 weeks of treatment. Secondary endpoint was point prevalence of abstinence at 6 months. Continuous rate of abstinence from weeks 9-24, and adverse events. Tobacco abstinence determined by carbon monoxide measurements at TQD​ and up to 24 weeks later

–Combo treatment associated with higher continuous abstinence rate at 12 weeks (55.4% vs 40.9%; OR 1.85 [1.19-2.89], p=0.007); and at 24 weeks (49.0% vs 32.6%; OR 1.98 [1.25-3.14], p=0.004); and point prevalence abstinence at 6 months (65.1% vs 46.7%; OR 2.13 [1.32-3.43], p=0.002). Interestingly, the combo therapy did not decrease nicotine craving more than varenicline alone.

–More nausea in combo group, as well as sleep disturbance, skin reactions (mostly from the patch), constipation, and depression; but only skin reactions reached statistical significance (14.4% vs 7.8%, p=0.03). The varenicline alone group had more abnormal dreams and headaches (non-significant). Overall mean weight gain was 3.0 kg in the combo group and 2.2 kg with varenicline alone.

So, very impressive abstinence rates with combo therapy. combo therapy overall is better than monotherapy (even combo of long-acting nicotine patches with short-acting nicotine gum/lozenges, as well as combo of patches with bupropion). It would be interesting to have head-to-head comparison of varenicline/patch vs. bupropion/patch vs. combo patch/gum to find the most advantageous combination.  But this study, I think, is an important one, adding a potent combo therapy to help people decrease the most significant preventable cause of morbidity/mortality from cardiovasc and respiratory diseases.


Primary Care Corner with Geoffrey Modest MD: Dark Chocolate helps with peripheral arterial disease (PAD)

29 Sep, 14 | by EBM

A recent article on the impressive role of dark chocolate in improving walking for patients with PAD (see DOI: 10.1161/JAHA.114.001072). I can’t resist it: so many bad things going on around the world and here is a chance to trumpet a universal (or nearly so) positive. So, in this remarkably important study (albeit small, with only 20 patients, mean age 69, 85% with hypertension, 30% diabetes, 90% dyslipidemia, 80% former smokers, 60% on ACE-I, 100% on statins, 95% on anti-platelet drugs), they measured maximal walking distance (MWD) and maximal walking time (MWT) in those randomly given 40 g of dark chocolate (>85% cocoa) vs. 40 g of mild chocolate (<=35% cocoa) in single-blind cross-over design study, checking the MWD and MWT at baseline and 2 hours after chocolate ingestion. And…

Chocolate_-_stonesoup–dark chocolate increased MWD by 11% (p<0.001) and MWT by 15% (p<0.001). MWD increased from 110.7m to 122.2m, MWT  from 124.8 to 142.2 seconds. also flow-mediated dilation doubled (p=0.003)
–dark chocolate also increased serum NOx​ by 57% (p<0.001) and decreased serum isoprostanes by 23% (p=0.01), and sNOX2-dp by 37% (p<0.001)
–no change in above after milk chocolate

There are some data suggesting that oxidative stress as well as endothelial dysfunction, reduced glucose-oxidation, accumulation of toxic metabolites, impaired nitric oxide generation (above study measured the metabolic endproducts of serum nitrite and nitrate, or NOx) play a role in intermittent claudication. Cocoa is rich in polyphenols, which induce arterial dilation (by lowering activation of NOX2, catalytic substrate of NADPH oxidase, which acts as a vasoconstrictor — above study measured the sNOX2-dp, the serum NOX2-derived protein). This study suggests that dark chocolate down-regulates NOX2-mediated oxidative stress (perhaps mediated by the polyphenols). Other data note increased arterial dilation in smokers with dark chocolate.

Of note, these very positive changes were after only 40 g of dark chocolate. Just imagine the effects of a much higher dose? Continuous infusion? This study does not undermine the most important PAD therapies: stopping smoking and exercise; it just raises the possibility of combo therapies — eating dark chocolate instead of smoking, or eating dark chocolate while walking.


Primary Care Corner with Geoffrey Modest MD: Cessation of smokeless tobacco and mortality post-MI

23 Sep, 14 | by EBM

Circulation published an article from Sweden on the profound effect of cessation of smokeless tobacco on post-MI mortality (see DOI: 10.1161/CIRCULATIONAHA.113.007252). they assessed all patients who were <75 years old and admitted to CCUs for MI between 2005-9 (the database included the vast majority of Swedish hospitals). They followed patients for 2.1 years post-MI to assess the relative difference in mortality in the 675 who quit snus (their form of oral snuff) vs 1799 who continued using.


–83 people died in the 2.1 years of follow-up

–Mortality rate in those who quit snus was 9.7/1000 person-years; Mortality rate in those who continued snus was 18.7/1000 person-years

–Adjusted for age and gender, the mortality rate HR was 0.51 (0.29-0.91) for quitters; In multivariable-adjusted model, the HR was 0.57 (0.32-1.02)

–these results were remarkably similar to those who quit smoking, with HR 0.54 (0.42-0.69)

Sweden has the highest prevalence of snuff use, though the overall snuff market is highest in the US (1.7 billion cans/yr, and growing at 5%/yr). Nicotine levels in Swedish snuff is similar to US (though, they do pasteurize it and lower the carcinogenic nitrosamines). Snuff (and snus) is associated with endothelial dysfunction, and increased blood pressure, heart rate and adrenaline, and perhaps increased risk of heart failure. Animal studies suggest an increase in ventricular arrhythmias post-MI.

There are caveats to the study:

–All patients were recruited 2 months post-MI (ie, we do not have data on nonsurvivors, though prior data suggest that snus users have a higher MI mortality)

–Many patients used both snus and smoked (though above controlled mathematically for smoking status, but the actual % of patients who never smoked but used snus was small)

–This was not an intervention study but a prospective observational one

–Those who continued to use snus were less likely to participate in a cardiac rehab program.

Nonetheless, this study highlights the potential cardiotoxicity and mortality associated with smokeless tobacco and the potential to halve the risk of subsequent mortality through cessation and reinforces the importance for us to be as aggressive in helping patients quit smokeless tobacco as we are with smokers.


Primary Care Corner with Geoffrey Modest MD: Benefits of physical activity in elderly

17 Sep, 14 | by EBM


The LIFE study (Lifestyle Interventions and Independence for Elders) is a multicenter study to assess the effects of physical activity in prevention of major mobility disabilities in older adults (see DOI:10.1001/jama.2014.5616).

Background: Mobility (ability to walk without assistance) is important for independent functioning and is inversely related to morbidity, disability and mortality.


— 1635 sedentary men and women 70-89 yo (mean 79), average BMI of 30, 74% White, 20% African-American, 4% Latino, with physical limitations but were able to walk 400 m, were randomized to structured moderate-intensity physical activity (2 center-based visits/week and home-based activity 3-4 times/week with goal of 150 min/week walking, and strength, flexibility, and balance training) or health education program (weekly workshops of health education during the first 26 weeks and then monthly, focusing on prevention, screening, negotiating the healthcare system, but NOT physical activity). Participants recruited from the community.  They were followed for 2.6 years.

–Primary outcome: Major mobility disability, defined as inability to complete a 400-m walk test within 15 minutes without sitting or help from another person or a walker, though they could stop up to 1 minute for fatigue.

–The physical activity group attended 63% of scheduled sessions, excluding medical leave (59% had medical leave at least once)

–Physical activity group increased activity by 138 minutes per week to 218 min/week. Health education group increased 34 minutes to 115 min/week

–The difference was 40 min/week for moderate physical activity, as assessed by accelerometry, throughout the followup period

–Persistent mobility disability (defined as 2 consecutive major mobility disability determinations) in 120 of those in physical activity group (14.7%) vs 162 in the health ed group (19.8%), with HR of 0.72 (0.57-0.91)

–Major mobility disability or death in 264 (32%) of physical activity group and 309 (38%) in health ed group, with HR 0.82 (0.70-0.97)

–The subgroup with lower physical function at baseline (Short Physical Performance Battery <8) had the most benefit in terms of major mobility disability (HR=0.75). No difference if stratify post-hoc by cognitive ability.

–No difference in safety/adverse events between the groups, though should be pointed out that physical activity group non-significantly trended to having more serious events (if exercise does unmask subclinical heart failure, etc)

–Cost of intervention was $4900/participant over 2.6 years.

So, though did rely on self-reported activities, this was a pretty impressive RCT in that a not-so-expensive intervention begun in already mobility-impaired elderly for only 2.6 years (though average life-expectancy was 9 years) significantly decreased development of major mobility disability.  Though no evident benefit on clinical outcomes in this short-term study in mobility-impaired elderly, this study confirms data on younger people and those without pre-existing mobility limitations (ie, there seem to be benefits for pretty much everyone). Exercise does improve several important physiologic effects, including improved lipids (increase HDL, decrease LDL), and decrease in CRP, fibrinogen, blood viscosity,  plasminogen activator inhibitor-1, platelet aggresation/adhesion, blood pressure, diabetes, osteoporosis, obestiy, colon and breast cancer, anxiety, depression, functional decline, falls/functional limitations, cardiovascular disease and stroke…..

In addition, another recent study in people over 65 found that exercise also decrease heart rate variability, an assessment of autonomic function and in several studies found to be associated with risk of heart disease (see DOI:10.1161/CIRCULATIONAHA.113.005361). In this 5-year study, 985 people in the Cardiovascular Health Study (mean age 71, 40% male, 66% White, 36% with > high school education, 10% smokers, resting heart rate of 67, 45% with htn, 16% diabetes), looking at amount of physical activity (observational study) and heart rate variability by 24-hour Holter monitor (done at baseline at at 5 years).


–Greater leisure-time activity, walking distance, and walking pace were each associated prospectively with an array of measured more favorable indices of heart rate variability, both in those with the highest reported physical activity and in those whose physical activity increased over time.

So, this study in the elderly confirms others in younger patients, that physical activity (perhaps modulated through reduced sympathetic activity) results in less heart rate variability, which might be an additional mechanism for the positive clinical effect of exercise.


Primary Care Corner with Geoffrey Modest MD: Medication errors with liquid meds in kids

11 Sep, 14 | by EBM

Medication adherence issues are one of the most pervasive primary care conundrums. I must admit that I always cringe a bit whenever I write for liquid meds for kids, hoping that the pharmacist can appropriately explain how to take the meds and give the appropriate measuring device. (There are other types of educational issues gone awry, evidenced by parents instilling the oral liquid antibiotics directly into the ear, or people taking suppositories by mouth….). So, in this light, there was a study done in New York assessing medication errors and the potential utility of “advanced counseling” in decreasing these errors (see 10.1016/j.acap.2014.01.003).


No clear marking to allow dose titration


Several studies have found that 40% of caregivers make errors in giving kids liquid meds. More if low levels of health literacy, or limited English proficiency. The language used in the instructions can also be confusion (writing “5ml” instead of “1 teaspoon” may be difficult for some parents; or using kitchen teaspoons instead of measuring spoons leads to dosing errors). Use of “advanced counseling skills” can help, eg asking the parent to describe how they will give the med, provider demonstration esp coupled with patient demonstration, use of pictures/drawings do help… but are underutilized.


–287 patients <9 yo from 2 urban New York public hospital ERs prescribed liquid meds. Parents were asked about the quality of counseling they received and/or a dosing instrument. Primary endpoint was observed dosing error, defined as >20% deviation from what was prescribed. Variables controlled for include: parent age, language, country, ethnicity, socioeconomic status, education, health literacy as assessed by Short Test of Functional Health Literacy in Adults, child age and their chronic disease status. cross-sectional analysis.

–41.1% of parents made dosing errors (81.4% underdosed, and 18.6% overdosed the med). Advanced counseling was provided to 33.1%, measuring instruments provided to 19.2%.

–97.6% of parents received some counseling in ER or pharmacy. 15% received both advanced counseling and medication instrument; 4.2% instrument only, 18.1% advanced counseling only, 62.7% neither

–Advanced counseling associated with decreased errors (30.5% vs 46.4%); instrument provision also associated with decreased errors (21.8% vs 45.7%)

–Combo of advanced counseling and instrument provision decreased odds of error, as compared to neither (20.9% vs 47.8%), with adjusted odds ratio of 0.3.

–Subgroup analysis did find that the combo strategy was significant only for those who spoke English, and those with adequate health literacy (there were essentially the same odds ratios of benefit for each of these interventions individually but were not statistically significant, perhaps because of small sample sizes)

Evidence shows that advanced counseling strategies work and have the support of the AMA and other professional organizations. However, most patients/parents in this study (and, i would imagine, in most practices) do not receive such counseling regularly. Pharmacists, at least in Massachusetts, are supposed to instruct parents in detail and provide measuring instruments, though unclear what the actual details or quality of that input really is.  The current study is limited, based on patients self-report and with likely biases, but it does highlight a very important problem inherent in outpatient medications — medication non-adherence is responsible for a huge amount of morbidity/mortality (eg, many hypertension studies find about 50% non-adherence rates) and the complexity of the medication regimens leads to more errors and non-adherence. Kids prescribed liquid meds have even more complex regimes than simply taking pills.



Primary Care Corner with Geoffrey Modest MD: Need for safe, sustainable sports

9 Sep, 14 | by EBM

study from boston children’s hosp looking at kids aged 11-22 coming into ER with acute concussion (see assessed duration and course of post-concussive symptoms. not much info in the literature previously about the time-course of symptoms. all pts had blunt head trauma with either alteration of mental status or new symptoms of headache, nausea, vomiting, dizziness, fatigue, drowsiness, blurred vision, memory or concentration difficulty, and no evidence of intracranial hemorrhage. exclusion criteria included glascow coma score <13, skull/long bone fracture, coexisting abdominal/thoracic injury, too much cognitive disability to fill out the questionnaire. Rivermead Post-concussion symptoms questionnaires were given in ER and at 1,2,4,6,8,12 weeks after ER visit.  results:

–235 patients completed at least 1 follow-up questionnaire. mean age 14, 60% male, 22% with loss-of-consciousness,  34% had concussion from collision, 41% from fall, 19% struck by object, 64% from playing sports. 23% had imaging done

–headache (85%), fatigue (64%), dizziness (61%) and taking longer to think (58%), poor concentration (52%) were most common presenting symptoms

–sleep disturbance, frustration, forgetfulness and fatigue were most common symptoms during follow-up:

–at day 7: 77% with some symptoms, with 69% having headache, 60% fatigue, 57% poor concentration, 54% taking longer to think, 44% light sensitivity, 44% forgetfulness, 43% noise sensitivity, and 30+% with restlessness, irritability, frustration, nausea, blurry vision

–at day 28: 32% with some symptoms, with 25% having headache, 22% fatigue 18% taking longer to think, and 10+% with dizziness, light sensitivity, frustration, irritability, restlessness, forgetfulness, dizziness, noise sensitivity, sleep disturbance

–at day 90: 15% with some symptoms, with 3+% with dizziness, fatigue, headache, poor concentration, taking longer to think.

–median days of symptoms: most of above lasted 10-12 days. longest were: fatigue 13d, light sensitivity 13d, sleep disturbance 16d, poor concentration 14d, taking longer to think 13d, frustration 14d, irritability 16d, and restlessness 12d

–physical symptoms mostly improved over time, but cognitive/emotional ones increased by day 7, then declined. 18% reported worse school performance after the concussion and only 8% returned to full athletic activity (64% reporting no athletic activity at all, except walking)

so, there are clear limitations to this study (self-reported symptoms, lack of control group), but pretty impressive how long the symptoms last. especially an issue for school-aged kids. as a firm believer in the importance of exercise, i find it unfortunate on both sides of the picture: first the high incidence of concussions (numbers are difficult to know, with definitional and reporting problems, but cited as high as 20+% of high schoolers who participate in sports), with the attendant long-lasting physical and cognitive/emotional problems); and second the finding that after a concussion, a significant majority reported no real athletic activity (at least for the 90-day mark). all of this speaks to the need for safe, sustainable sports through high school, with modifications to reduce the rather high risk of concussion and its sequelae (including the low likelihood, in this study, of returning to athletic activity).


Primary Care Corner with Geoffrey Modest MD: Low-risk prostate cancer and specialist recommendations

8 Sep, 14 | by EBM

interesting study of perceptions and suggestions of US radiation oncologists and urologists on the effectiveness of active surveillance for patients with prostate cancer (see Med Care 2014;52: 579–585). baseline is that there are general concerns that prostate cancer is greatly overtreated, and that active surveillance (AS) is appropriate (and in fact recommended) for low-risk prostate cancer (clinically localized disease, PSA in 4-10 range, Gleason 6 or less). results:

–national survey of radiation oncologists and urologists about perceptions of AS, done from nov 2011 to april 2012, with 717 completing survey

–71.9% thought AS effective and 80% thought it was underused

–BUT for a case patient of a 60yoM  diagnosed with low-risk prostate cancer, these specialists recommended radical prostatectomy in 44.9%, brachytherapy in 35.4% and AS only in 22.1%. though specialists in academic med centers more likely to recommend AS, with OR 2.35.

–and, lest anyone is surprised, urologists vs radiation oncologists were more likely to recommend surgery (OR of 4.19) and less likely to recommend radiation treatment (OR 0.13 for brachytherapy and OR 0.11 for external beam radiation)

so, 230K patients are diagnosed each year with prostate cancer. and estimated 100K with clinically-localized disease, qualifying for AS. clinical guidelines do recommend AS with close disease monitoring by frequent PSA tests, digital rectal exams and  biopsies; but most patients are treated with XRT or surgery and only 10% get AS. clearly, a key barrier to AS is that the specialists involved in the care of these patients (radiation oncologists, urologists) are in fact more aggressive than the recommendations (and, indeed, more aggressive than what they even said — that up to 80% thought AS was underused). given their inherent conflicts-of-interest, seems to me that primary care providers (and general oncologists) should be stronger advocates for patients with low-risk prostate cancer.



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