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Archive for September, 2013

Primary Care Corner with Geoffrey Modest MD: e-Cigs-good choice for smoking cessation, glamorizing use or both?

24 Sep, 13 | by EBM

the whole issue of e-cigarettes is pretty confusing. several of my patients have been using them with pretty significant cigarette quit rates even after stopping the e-cigarette. one of my patients brought in one (a BLU, as i remember), asking me what it contained.  after thoroughly scouring the e-cigarette and packaging, i could find no indication of what was inside the cigarette. there were a couple of articles that helped clarify the situation.

1. recent randomized controlled trial in lancet from new zealand. 657 adult smokers averaging 18 cigarettes/d randomized to 16mg e-cigarettes, 21mg nicotine patch, or placebo e-cigarette (no nicotine), beginning one week before quit date. only low intensity support provided — voluntary telephone counseling. (see verified abstinence after 6 months:

–7.3% with nicotine e-cigarettes

–5.8% with patches

–4.1% with placebo e-cigarettes

–median time to relapse was longer with nicotine e-cigs (35 days), vs 14 days with patches, 12 days with placebo e-cigs

–mean cigarette consumption also 2 cigarettes lower with nicotine e-cigs

–no diff in adverse events

achievement of abstinence was lower than anticipated for the power calculations, so unable to assess statistical superiority of nicotine e-cigs or patches to placebo e-cigs.

2. Time magazine article 9/30/13: Electronic cigarettes could save lives — or hook a new generation on nicotine, by Eliza Gray.  main points:

–20% of smokers have tried e-cigs

–e-cigs use a tiny metal coil to vaporize nicotine liquid

–appeal is that they do not have the >7000 additives of cigarettes, they do not smell like cigarettes to others, do not stain teeth, and are cheaper than cigarettes — bottle of 16mg nicotine costs $8, $38 for refillable e-cigarette (includes atomizer, rechargeable battery, and charger). the $8 bottle lasts for one week in a 1 ppd smoker, cheaper than the $10/day for a pack of cigarettes. non-rechargeable BLU costs $10, has 400 puffs or approx 1 1/2 packs of cigarettes equivalent

–rapidly growing market: $300M in retail sales last year, estimated to grow to $1.8B this year

–advertised as sexy (ads by katherine heigl and leonardo dicaprio), and safer

–at this point unregulated. no indication of ingredients. unregulated in terms of actual nicotine delivered. but as of October, FDA to regulate

–big players coming into the market (lorillard, reynolds, altria, british american tobacco), likely to squeeze out the current smaller makers. (and undoubtedly increase advertizing — FDA may come out with regulations on how and to whom the ads can be directed, whether legal to have internet sales, etc)

–fear is that these new e-cigs may re-glamorize smoking, discourage smokers from quitting entirely, and entice new smokers

–stores (called Vapers) popping up to sell these cigarettes. with different flavors (eg chocolate, tobacco, menthol), styles of e-cigs (cheaper ones which look more like cigarettes, rechargeable as above are much longer and look pretty different)

–the additives mentioned in e-cigs include propylene glycol (i guess it lowers a person’s freezing point), and still has aerated fine particles. unclear of the safety of the flavors or of other additives not mentioned

so, may be helpful for some current smokers to quit.  BUT, big concern about legitimizing/glamorizing cigarettes. increasing people who never smoked (and, we know that nicotine addiction is very powerful.  there are many patients who have told me and others that it is much easier to get off heroin or alcohol than cigarettes. some of the addiction is just the addiction to nicotine, some is the very positive effects of nicotine: wakes you up when you are sleepy; relaxes when you’re anxious; satiates when you are hungry; and withdrawal symptoms are not pleasant but better than heroin or alcohol — not that i am encouraging you to smoke….). and the e-cig companies are trying to make e-cigs feel like/taste like regular cigarettes. all in all, pretty scary.

Primary Care Corner with Geoffrey Modest MD: Most with PCN allergy will test negative for it and can be given PCN safely

12 Sep, 13 | by EBM

interesting study of patients who report prior history of penicillin allergy (see j hosp med 2013 DOI 10.1002/jhm.2036). 146 hospitalized patients with history consistent with IgE-mediated penicillin allergy were given penicillin skin testing (PST), which consisted of intradermal testing and, if negative, followed by test dose of oral penicillin.  they excluded patients with history of anaphylaxis. only one patient had a positive skin test. the remaining 145 with negative PST did fine with full course of oral penicillin. so negative predictive value of 100%. the results in this study, with <1% having positive PST, is lower than in some other studies, where it is as high as 20%.

study significant because there are many patients with history suggestive of IgE-mediated penicillin allergy (eg, hives, urticaria, laryngeal edema, …). the more specific the patient is about these symptoms, the more likely they have a true penicillin allergy, though on allergy testing vast majority are still negative. probably mostly because of waning IgE immunity (it appears that this waning immunity is real: very rare to have allergic symptoms on rechallenge with penicillin). the importance of sorting out true penicillin allergy is that  penicillin is cheap and easy to take — with alternatives often having much broader spectrum of activity (and likelier to lead to antibiotic resistance), be much more expensive (and may lead to dreaded prior approvals), may have more adverse effects, may require more invasive administration with associated adverse effects (IV therapy, PICC lines….).

in terms of outpatient care, when should testing be indicated???  i would think of it if the patient’s therapy would be significantly better with penicillin than other drugs (eg, syphilis, rheumatic heart disease prophylaxis), or if frequent penicillin-sensitive infections requiring abx. with IgE-mediated penicillin allergies, there may be issues with prescribing some other, structurally-similar antibiotics, such as cephalosporins, carbapenems (eg imipenem) or monobactams (eg aztreonam). studies with cephalosporins show that in fact serious allergic reactions are rare (2%) in patients who are skin-test positive for penicillin. one confounding issue here is that patients allergic to one antibiotic are more likely to be allergic to another (multiple drug allergy syndrome) — ie, patients with true penicillin allergy are more likely to have reaction to other antibiotics whether they are structurally similar to penicillin or not.  one of the most interesting findings was how rare it was to have true penicillin allergies, even though penicillin allergy is the most common medication allergy reported by patients.


Primary Care Corner with Geoffrey Modest MD: New diabetes drugs (DPP-4-Is) lower A1C, not cardiac events

10 Sep, 13 | by EBM

2 new articles in NEJM from the european society of cardiology congress looked at cardiac outcomes after improved A1c levels with 2 different DPP-4 inhibitors

1. saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor vs placebo given to 16.5K patients with DM2 with hx or at risk for CAD events (high risk: men >54 yo or women >59yo, with at least one of: dyslipidemia, htn, active smoking) followed 2.1 yrs. other dm meds adjusted per physicians. primary endpoint of composite of cardiovascular death, MI or ischemic stroke. secondary endpt of above plus hosp for heart failure, coronary revasc, or unstable angina. (see DOI: 10.1056/NEJMoa1307684 ). drug company sponsored study

–fasting glucose levels lower in saxagliptin group; A1c also lower (7.5% vs 7.8% at year 2, with 36.2% vs 27.9% having A1c<7% by the end of the trial) — all highly significant.  associated decrease in albumin/creat ratio.

–primary endpt in 7.3% in saxagliptin vs 7.2% in placebo group   — nonsignificant

–secondary endpt in 12.8% vs 12.4% — also nonsignificant, though statistically more patients were hospitalized for heart failure (3.5% vs 2.8%) with saxagliptin

–more hypoglycemia with med. no diff in pancreatitis, though infrequent event. (important, since exanitide assoc with pancreatitis in recent study: see dm exenatide and pancreatitis jamaintmed 2013 in dropbox or doi:10.1001/jamainternmed.2013.2720) .  the DPP-4 inhibitors inhibit breakdown of GLP-1 (exenatide is a GLP-1 agonist)

2.   alogliptin (another DPP-4 inhibitor) vs placebo given to 5400 pts with acute coronary syndrome (acute MI or hosp for unstable angina within past 15-90 days), followed median 18 months. primary endpt of composite of cardiovasc death, nonfatal MI or nonfatal stroke. secondary endpt same, with addition of urgent revasc due to unstable angina (see DOI: 10.1056/NEJMoa1305889). drug company sponsored study

–A1c lower with alogliptin vs placebo (initial median of 8%, decreased to 7.7% with med vs no change with placebo) — highly significant

–primary outcome in 11.3% if pts on alogliptin vs 11.8% on placebo — nonsignificant

–no diff in adverse events, including pancreatitis

it seems to be pretty consistent using different types of hypoglycemic agents that lowering A1C is associated with decreased development or progression of certain microvascular outcomes (though for nephropathy, most of the studies are looking at the surrogate marker of microalbumenuria and not renal failure). however, most diabetics die from macrovascular causes. metformin pretty clearly decreases cardiac deaths. the data are less clear with sulfonylureas/insulin (eg, huge retrospective VA study showing cardiac mortality is about 1/2 with metformin compared to sulfonylureas, see Ann Intern Med. 2012;157:601-610 and below). so, this makes it problematic in using A1C as a surrogate marker for macrovascular clinical diabetes outcomes. and some of the agents may lower A1C but increase cardiac mortality (rosiglitazone), or heart failure (thiazolidinediones) and perhaps DPP-4 inhibitors (above). i bring these articles up mostly to reinforce that it is problematic using surrogate markers (eg A1C) instead of real clinical outcomes.  these were pretty short-term studies, and the difference in A1c was not dramatic though highly significant, but these are high risk patients.  in the VA study noted below, the outcome curve diverged within 2 years, showing metformin benefit.

Ann Intern Med. 2012;157:601-610:  Retrospective VA study of 250K patients with diabetes started on metformin (155K) or sulfonylurea (98K) — see dm rx metf vs sulfon VA annals 2012 in dropbox.  5 yrs of followup data, with adjusted increased risk of CVD outcomes (acute MI or stroke) 21% higher in those on sulfonylurea than metformin.  Divergence of curves after 2 years.  Since VA study, 95% men and 75% white. Glyburide with 25% increase and glipizide with 15% increase.  These results are consistent with very old University Group Diabetes study, UKPDS and others (which have led to suggestion that metformin be first-line therapy).

Reasons for inc morality in sulfonylureas — they note increased weight, increased lipids, and increased incidence of hypoglycemia. I would add increased hyperinsulinemia. Several studies, best of which is the Quebec study about 10-15 years ago, which found that hyperinsulinemia is epidemiologically linked to CAD to at least the same extent as hyperglycemia (and indepedently). Likely attributable to the effect of insulin on platelet adherence, trophic increases in smooth muscle (part of atherogenic process), local increases in HMG-CoA reductase activity, and, as i remember, increases in endothelial dysfunction.  In this light, not surprising that glipizide, which is short-acting and causes less hyperinsulinemia, seems to be better than glyburide (and probably should be the perferred sulfonylurea used, as suggested in some recent reviews).  Also, this model would suggest that other medications which decrease the hyperinsulinemia may be better (eg, i would guess that exanitide would be physiologically better than insulin injections … Though we need to look at long-term data, and, i have been wrong more than once in guessing like this).




Primary Care Corner with Geoffrey Modest MD: Conundrum–Ankle-Brachial index not recommended but Periph arterial disease important and under-diagnosed

10 Sep, 13 | by EBM

US Preventive Services Taskforce just published their guidelines for peripheral arterial disease screening with ankle-brachial index (ABI) — see link: they do not find sufficient evidence to recommend routine screening, though point out:


–PAD common, with recent NHANES survey showing that 5.9% of US population >40 years old have ABI <0.9, most of whom are asymptomatic

–PAD is a marker for coronary heart disease (approx 2-fold increased risk – see  JAMA. 2008;300(2):197-208, which found twice the 10-year mortality in those with PAD), and is independent of traditional risk factors. adding PAD to the framingham risk score would result in reclassification of patient risk as follows: for men, who get more PAD at an earlier age, 19% were reclassified, mostly by a normal ABI resulting in high risk decreasing to intermediate risk; in women, there was a 36% reclassification rate, mostly from low to intermediate or high risk based on low ABI) — but there are no data that this reclassification and potentially changed treatment would affect clinical outcomes. one study in JAMA (2010; 303(9):841-8) did not show that aspirin was effective in general population with low ABI. USPSTF comments that there are no studies addressing lipid-lowering in patients without known diabetes or CAD (one point of the guidelines is whether the testing would alter therapy; diabetics and patients with CAD should already be on lipid-lowering meds and probably aspirin anyway). [there actually are a couple of studies – one small study of patients with severe PAD who did have a survival benefit with statins and another larger study of patients also found a mortality benefit, but this study had patients with many different underlying medical problems (44% with CAD) and didn’t perform subgroup analysis. so, there are some data suggesting statins do confer cardioprotection in those with PAD.]


coincidentally, the european cardiology conference this month reported the results of the REACH trial (reduction of atherothrombosis for continued health) registry in patients with symptomatic PAD. full report not available for evaluation,  but i am bringing it up given the above guidelines.  basically:

–5861 patients with established symptomatic PAD assessing 4-year data.

–primary outcome (localized) — worsening claudication or new episode of critical limb ischemia, revascularization or amputation.  secondary outcome (systemic) — cardiovascular death, nonfatal MI and nonfatal stroke.

–3643 on statin and 2218 not. (note: this is not an intervention trial)

–adverse limb outcomes:  occurred in 22% of those on statin and 26.2% not on statin (unadjusted rates), with 14.7 vs 18.2% with worsening claudication or critical limb ischemia; 18.2% vs 21.7% with revascularization; 3.8% vs 5.6% with amputation

–adverse systemic outcomes: 19.6 vs 20.3% with total cardiovasc outcomes; 17.3 vs 19.7% all-cause mortality; 11.4 vs 12.4% cardiovascular mortality; 5 vs 4.6% nonfatal MI; 6 vs 6.8% nonfatal stroke.  — unclear how statistically significant this is. [though these numbers don’t show much improvement with statins, unlike the 25-30% risk reduction in the CAD trials]


so, what makes sense here???  it is true from several studies that PAD is associated with CAD. one would think this to be true whether the PAD were symptomatic or not. adding PAD to the framingham risk score seems to reclassify a lot of people. and statins do seem to improve walking distances and decrease need for limb revascularization. (also, see article showing that ramipril increases walking distances in dropbox, or JAMA. 2013;309(5):453-460).  i would suggest the following:


–would not screen for PAD in asymptomatic patients, given the above-noted lack of good data.

–statins should be part of treatment for symptomatic PAD (one reason i brought this study up is the pretty surprising finding that >1/3 of the patients in this registry with symptomatic PAD were not on statins), esp if LDL is >100.



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