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Archive for April, 2014

Primary Care Corner with Geoffrey Modest MD: ACE inhibitor vs ARB in diabetics??

30 Apr, 14 | by EBM

recent review/meta-anal of cardiovasc events/mortality in diabetic pts on ACE-I vs ARBs (see doi:10.1001/jamainternmed.2014.348). this analysis looked at 35 studies, mostly ACE-I vs placebo or active control (22 in all, 11 placebo, most of others with CCB) and ARBs vs placebo or active control  (13 in all, 9 placebo). results:

  –ACE-I reduced risk of all-cause mortality 13% [RR 0.87 (0.78-0.98)], cardiovasc deaths 17% [0.83 (0.70-0.99)], major CV events 14% [0.86 (0.77-0.95] with MI dec 21% [0.79 (0.65-0.95)] and heart failure 19% [0.81 (0.71-0.93)]. no diff in studies if comparison to placebo or active control.
–ARBs reduced CHF 30% [0.70 (0.59-0.82)], but no significant decrease in major CV events overall and no signif decrease in either of the mortality outcomes. similar results if compared to placebo or active med. olmesartan may be a bad actor (2 studies showed increased death rates); excluding these studies, the results for ARBs showed no real difference in heterogeneity
–neither showed dec in stroke.
–ACE-I treatment effect on all-cause and cardiac mortality not vary significantly with either starting baseline blood pressure or proteinuria, or the types of ACE-I used or diabetes

so, there are clear limitations to the study: very few head-to-head comparisons; no standardization in dosages, A1c levels, blood pressure targets; different background therapies; different primary endpoints of the studies. but this study does suggest that there may be non-equivalences between ACE-I and ARB (most of us use ACE-I first, largely because of Prior Authorization Phobia, then ARB if not tolerated — considering them pretty equivalent in that they both block the renin-angiotensin system but through different mechanisms.)  so, this study mostly supports what we are already doing, which in the local Boston culture is using mostly lisinopril as first-line med in diabetics (though data for ACE-I considerably less compelling in diabetics without microalbuminuria).

geoff

Primary Care Corner with Geoffrey Modest MD: New Vitamin D Articles

29 Apr, 14 | by EBM

vitamin D deficiency has been associated with many different medical conditions noted over the past decade, presumably related to there being vitamin d receptors on almost cell types in the body. in general, vitamin D supplementation has been shown to benefit rickets, fractures and falls (though recent meta-anal did not find consistent positive effect on bone density). there are also strong associations with multiple sclerosis, an array of autoimmune disorders, infections, cardiac disease, and cancer. there has been a slew of posts about vit d, some showing increased insulin sensitivity or improved lipids with vitamin d supplementation, one showing improved response to TB infection by antiTB drugs when simultaneously given vitamin D. the data on vitamin D and risk of non-skeletal diseases, however, is still unclear, and the 2011 endocrine society guidelines clearly recommend vitamin D only for the proven skeletal issues (see doi: 10.1210/jc.2011-0385)

one BMJ article was an umbrella review (systematic collection and eval of info from multiple systematic reviews and meta-analyses on all clinical outcomes assessed) was done of observational studies of associations between circulating vit D levels and clinical outcomes, along with meta-anal of RCTs on supplementation (see here). they assessed 107 reviews and 74 meta-anals, looking at 137 outcomes (!!). results:

–probable associations between high vit D concentrations or supplementation: decrease dental caries in kids, increased newborn birth weight at term, decreased PTH levels in patients with ESRD on dialysis (in contrast to previous reports, they did not find evidence that vitamin d by itself improves bone mineral density or reduces the risk of fracture of falls in older people).
–suggestive health benefits: decreased risk of colorectal ca, non-vertebral fx, cardiovasc dz, htn, ischemic stroke, cognition, depression (from cohort studies), BMI, metabolic syndrome, type 2 diabetes, SGA newborns, gestational diabetes
–no conclusion: a huge list, mostly everything except the above 2 categories (see their Table 6) also impressive associations in their Forest plot as figure 3 (though, these are all from observational studies!!); figure 4 (less impressive) is the RCT review, though most of which had very few participants, which pretty much reflects the “probable associations” point above.

another BMJ article looked at either 25OHD levels or vit D supplementation and cause-specific mortality (see here). results:

–primary prevention observational studies: bottom vs top 1/3 of 25OHD levels (median 25OHD level in was 20.7 ng/ml):

–death from cardiovasc disease: RR 1.35 (1.13-1.61)
–death from cancer: RR 1.14 (1.01-1.29)
–death for non-vascular, non cancer:  RR 1.30 (1.07-1.59)
–all-cause mortality: RR 1.35 (1.22-1.49). there was a dose-response: as compared to people with 25OHD of 30, 21-29 with RR 1.07, 10-20 with RR 1.20, <10 with RR 1.50
–on subgroup analyses in observational studies, mortality higher in studies with lower baseline use of vitamin D supplements

–in RCTs, there were different RRs depending on type of vitamin D supplementation — all-cause mortality with vit D3 (cholecalciferol, from UVB radiation, supplement animal-derived) had RR 0.89 (0.80-0.99) and with vit D2 (ergocalciferol, plant-derived) RR=1.04 (0.97-1.11).
–with vit D2 supplementation, increased RR of mortality in studies with lower intervention doses and shorter average intervention periods. (this could be reverse causation: sicker patients, more likely to die sooner, may get less sun or take fewer supplements and therefore have lower 25OHD levels. also there is a report of patients finding decreased vit d with acute changes in systemic inflammatory response — eg see Am J Clin Nutr 2011;93:1006–11.

so, these studies confirm the many observational studies finding impressive associations between vitamin d levels and several clinical outcomes, including mortality.  but we really need good intervention studies to see if this pans out, or if potential confounders could explain the association (eg shared determinants, such as obesity, medical comorbidities or social status). Their figure 7, which looked at various subgroup analyses, showed a very consistent difference. but the studies do highlight risks, the most consistent being hypercalcemia, esp in the setting of chronic kidney disease.  there are ongoing RCT trials (eg VITAL trial of 26K men and women randomized to 2000 IU vit D3 assessing outcome of cancer, CAD, and stroke — due out in 2017). so, as with pretty much all nutritional studies, observational studies show positive effects of supplements, but the real proof needs big RCTs (though for vitamin d, i do think the observational data are pretty impressive, the basic physiology of having vitamin D receptors being everywhere, the limited data showing positive effects of vitamin D on immunologic function, and the low toxicity/cost of supplementation does make me check/treat low 25OHD levels, though will switch preferentially to D3 supplements given this last study).

geoff

Primary Care Corner with Geoffrey Modest MD: Big pharma – the beat goes on

25 Apr, 14 | by EBM

front page article in NY Times on excessive (extortive) costs of medical equipment/meds (see here). from my extrapolation (pretty crude) of their graph, between 1987 and 2008, outpatient costs have stayed flat at about $750, inpatient costs have gone down a bit from $1550 to $1400, while prescription drugs increased from $450 to $2200.

the article highlights type 1 diabetes and insulin pump therapy, though mentions the dramatic increase in costs for rheumatoid arthritis, etc [on that note, it was a great pleasure posting the blog on rheum arthritis drugs last june — will append to end of this blog]. they highlight a woman with an insulin pump. cost of pump $26,400. her cost after insurance $4224. monitor probes at $100 and need to be replaced every 6 days, disposable tubing replaceable every 3 days, 10 or so teststrips (which can be $1.50/strip),  and insulin which has sky-rocketed to $200/bottle essentially through monopoly pricing.

and, of course, she is mostly a captive audience, assuming she wants optimal treatment to decrease complications (which, in addition to improving her quality of life, saves the system huge amounts of money later on). the article adds that in “most other developed countries, with or without national health systems, provide free care and supplies for people with chronic diseases,… and they bargain hard with drug and device makers to bring down list prices”.  eg “the vial of insulin .. for $200 in an American pharmacy is typically bought by British pharmacists for under $30 and dispensed free.”

this also brings up the trawling that medical suppliers do directly to patients and to us guys: faxing us papers to sign to give new “and better” equipment for patients (no charges for the equipment included, of course), soliciting patients to ask us for a motorized scooter or wheelchair, or a recent patient of mine: he had type 2 diabetes but needed a 3-day continuous glucose monitor to figure out why his A1c was so high despite his multiple well-controlled fingersticks taken many different times of the day; i was then confronted by the company doing the monitor to see if i would sign an order for him to get an insulin pump!!!! (again with no mention of the exorbitant charge)…

Rheumatoid arthritis blog from june 2013:

NEJM with recent article on therapy for rheumatoid arthritis refractory to methotrexate as single agent (mean dose 20mg/wk), comparing adding on sulfasalazine (titrate up to 2 gm/d) plus hydroxychloroquine (400 mg/d) to adding on etanercept. (see DOI: 10.1056/NEJMoa1303006).  353 pts from VA hospitals.

 –no difference in clinical scores (ACR20 and ACR50) at either 34 or 48 weeks
–no diff in radiographic progression at 48 weeks
–similar improvement in functional outcomes
–similar number of adverse events (GI mostly with triple therapy, infections more with etanercept)

 so, there are many potential advantages in the triple therapy: it is a lot cheaper, it has been around for a long time (one concern is that the TNF inhibitors may cause long-term problems, like cancer, by their profound immunologic effects — and is associated with more infections in the short-term), and rheum arthritis can again be treated in the primary care setting (i had treated many RA patients in the past, but have been referring them to rheumatology because of the imperative to treat early and aggressively, esp with the new-fangled biologics…..)

geoff

Primary Care Corner with Geoffrey Modest MD: Aspirin for noncardiac surgery not help

24 Apr, 14 | by EBM

recent followup study to the original POISE trial in the lancet, which found that pre-op b-blockers (metoprolol) did not improve post-surgical outcomes after noncardiac surgery in high risk vascular patients (risks outweighed benefits). NEJM had recent article on aspirin (see doi: 10.1056/NEJMoa1401105). in this trial 10K patients from 23 countries at risk for vascular complications (>45yo, with history of at least one of: CAD, PAD, stroke, major vasc surgery, or over age 70 with high risk of CAD) and about to undergo noncardiac surgery were assigned either aspirin vs placebo or clonidine vs placebo. for the aspirin group, they assessed 2 subgroups, those who were not previously on aspirin (initiation stratum, 5628 pts) and those previously on aspirin (continuation stratum, 4382 pts). those in the initiation group were given ASA 200mg just before surgery and 100mg/d after for 30 days. those in the continuation group stopped their regular aspirin 7 days before surgery, then received 200mg aspirin pre-op and then 100 mg/d for 7 days, then continued their regular aspirin regimen. primary outcome=composite of death or nonfatal MI at 30 days. results:

–baseline: age 69, 53% male, 33% with hx of vascular disease, 65% received prophylactic anticoagulation for 3 days post-op
–primary outcome in 7% in the aspirin group and 7.1% in placebo (non-significant)
–major bleeding in 4.6% in aspirin group and 3.8% placebo (significant with HR 1.23)
–no diff between the aspirin strata (somewhat more acute kidney injury in the continuation stratum and decreased risk of stroke in  the initiation stratum. no diff in MI

so, rationale for study is that post-surgical period is assoc with MI and with platelet activation (which might predispose to coronary artery thrombosis and might be prevented with ASA). one concern in this study design was that there are some observational data of increased thrombotic risk if stop aspirin before surgery. this was not found in this study. another issue, not commented upon directly, is whether low-dose aspirin is sufficient. this comes up with diabetics. for example, the well-designed POPADAD study (see doi:10.1136/bmj.a1840) looked at very high risk patients (diabetes and peripheral arterial disease) and found that ASA 100mg/d did not prevent cardiovascular events or mortality, and at that time raised the question whether low-dose aspirin was sufficient in diabetics who have really sticky platelets (and, i believe, led to downgrading of am diab assn recommendations from “recommend aspirin” to “consider aspirin”). so, higher dose aspirin, other antiplatelet drug. to me there are a couple of take-home messages: low-dose aspirin is not sufficient to cover high risk patients with noncardiac surgery (and increases bleeding), so should not be used; and it appears to be safe in this large study to just stop the aspirin a few days before surgery, without worrying about rebound thrombosis.

a separate report looked at giving clonidine 0.2 mg just before surgery and then for next 3 days, with rationale that there is marked activation of the sympathetic nervous system during and after noncardiac surgery, and this should be blocked centrally with clonidine. if anything, in this trial clonidine was worse than placebo (signif increase in nonfatal cardiac arrest) and more hypotension (48% vs 37%)

geoff

 

Primary Care Corner with Geoffrey Modest MD: Academic med centers & drug company boards

23 Apr, 14 | by EBM

JAMA had an interesting/disturbing letter documenting extensive representation of Academic Medical Centers on the boards of the largest pharmaceutical companies (see doi:10.1001/jama.2013.284925 ).  47 of the largest 50 pharmaceutical companies in the world were evaluated based on 2012 data. Findings:

–40% of the drug companies had a least one board member who was in a leadership position at an Academic Medical Center.
–16 of the 17 US companies (94%) had at least one such board member.
–And, on reviewing the data provided in the article, Harvard/Partners/Mass General were quite well represented, being on 3 different boards and making    an average of about $320,000 for those individuals.  Unfortunately, the names of the specific individuals involved was withheld.

As I have mentioned before, there has been a fundamental shift in medical research over the past 30 years or so.  Prior to Ronald Reagan, the vast majority of research and publications in the refereed journals was funded by public money, such as the NIH.  Reagan cut back on funding for the public sector and promoted the private sector as the major funder, creating the current situation with the vast majority of articles in those journals are funded  by pharmaceuticals or medical device makers.  One issue that I noted in my review of the new AHA lipid guidelines, is that not only are the recommendations potentially tainted by scientists on the guideline committees receiving drug company money, but that even which studies performed are dictated largely by the drug companies (for example, a study trying to show the efficacy of ezetimibe by comparing it in combination with simvastatin versus placebo in patients with carotid artery disease, is a useless self-serving study and would only be funded by a drug company).  This JAMA article raises the stakes higher.  These are large amounts of money (average $312,564)  being given directly to the leadership of Academic Medical Centers to serve on the drug company board, which has direct fiduciary responsibility to shareholders to ensure the financial success of the company.

Paul Levy, former CEO of Beth Israel Hospital in Boston, wrote a blog also noting that this degree of complicity between the academic Medical Center’s and the drug companies is abhorrent, see here

geoff

Primary Care Corner with Geoffrey Modest MD: Mammograms, again

22 Apr, 14 | by EBM

the boston globe ran a story earlier this month pointing out the marginal benefit of mammography from a recent analysis –see below, but they had a thoughtful summary (see here)

the article came out in JAMA (see doi:10.1001/jama.2014.1398) and reinforces the not-so-great efficacy of mammog screening, confirming what i posted in several blogs. they did literature search finding 8 large RCTs (all done between the 1960s and 1990s, which may be an issue: see below) finding a 15-20% decreased breast cancer mortality. another meta-anal from canadian task force found 19% decrease after 11.4 yrs of followup. the new JAMA data (see tables below) includes the relative risk (RR), absolute risk reduction (ARR), overdiagnosis (detected tumors on screening that would never become clinically evident. mostly DCIS, but some suggestion that may also be some invasive cancer diagnoses). this article is available for free, so i am reproducing their results below.

table 1: pooled results from RCTs on mortality reductions with mammog screening by age group

Age Total events in group/total number       Mammog grp           Control grp RR with
mammog
 ARR with mammog Number needed to screen
39-49 448/152300 625/195919 0.85 (0.75-0.96) 0.0005 1904
50-59 361/78465 410/69849 0.86 (0.75-0.99) 0.0007 1339
60-69 110/19093 155/18377 0.68 (0.54-0.87) 0.0027 377
70-74 42/5073 36/4859 1.12 (0.73-1.72 NA NA

 

table 2: estimated benefits and harms of mammog screening in 10,000 women with annual mammog over 10 year period

Age # Diagnosed with invasive unnecessary breast ca or DCIS over 10 yrs # Breast ca deaths in next 15 yrs # Deaths averted with screen over next 15 yrs Overdiagnosis during 10 yrs # With >=1 false pos during 10 yrs # With >=1 biopsy during 10 yrs
40 190 27-32 1-16 ?-104 6130 700
50 302 56-64 3-32 30-137 6130 940
60 438 87-97 5-49 64-194 4970 980

(note: the “# of breast ca deaths in next 15 yrs” column is the number who would die even if they were screened)

they point out that these studies were of women of average risk and the benefit would likely be greater if women at higher risk. for example 4 microsimulation (ie mathematical) models found that women 40-49 with Gail model score twice average and given biennial screen would have same ratio of benefit/harm as woman>50 with average risk.

so, this is a very complex issue. this article confirms the pretty paltry benefits of mammography screening (although average lifetime risk of breast cancer is 12.3%, aggressive mammog screening will avoid breast cancer mortality in only 3-32 of 10,000 women screened in their 50’s, with 6130 having false positives, 940 getting biopsies, 30-137 with overdiagnosed breast cancers) and does not include the fact that treatment is much better now than when the studies were done, and does not even mention that all these mammograms are likely (by mathematical modeling) to create some cancers. also important to note that the differences in breast cancer mortality do not translate into differences in all-cause mortality (prob in part because the numbers saved by mammog is really so small). attempts at provider/patient shared-decision-making so far have probably not been adequate (eg, no change in mammog ordering after USPSTF came out with guidelines to decrease mammogs to every other year and only in women 50-74.  also, boston globe comments on 2010 study of 460 women, where >96% reported that MD discussed benefits of screening but <20% discussed risks).  be aware that the suggestion of doing individualized risks, esp those 40-50 yo, (Gail model etc) makes sense mathematically, but there are no real-world data. also that the array of imputed breast cancer risk factors (inc BMI, dec bone density, smoking, alcohol, estrogen/androgen exposure, late age of first pregnancy…) are absent in 60% of women with breast cancer.  which also (again) raises the elephant-in-the-room: the huge numbers of industrial toxins in our environment, food chain, water… which may well be a really major cause of breast cancer (the vast vast majority never adequately tested, but we do know of many so far which have hormonal stimulatory  effects on breast tissue). but in the context of mammog, i think it makes sense to discourage women under 50 from getting mammog, and doing mammog every 2 year in women aged 50-74 (there are pretty good data that every other year testing is just about as sensitive and fewer false positives… and also less radiation)

geoff

Primary Care Corner with Geoffrey Modest MD: Tylenol #3 vs vicodin for acute pain — no difference

16 Apr, 14 | by EBM

here is a lay-press article of a study (to be printed) comparing patients coming to the ER with the acute traumatic extremity pain to assess the short-term efficacy of tylenol #3 (codeine/acetaminophen  30/300) vs vicodin (hydrocodone/acetaminophen 5/500) given as a 3 day supply.  no difference. both decreased pain score by 50%.  see here

geoff

Primary Care Corner with Geoffrey Modest MD: Rosiglitazone and the FDA

15 Apr, 14 | by EBM

one of the BMC preceptors asked for my assessment of the shenanigans around rosiglitazone and what we should do (thanks, dan).  so, here is my sense:

1. FDA initially restricted rosiglitazone because of very large meta-anal showing increased cardiac events

2. the RECORD study (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of glycemia in Diabetes study) did not find increased cardiac risk after 3.75 yrs.  re-eval was done at 5.5 years just published in August (see doi.org/10.1016/j.ahj.2013.05.004).  see point 3 below, but the FDA gives lots more weight to this type of trial looking at cardiac outcomes, vs secondary analyses

3. so, they lifted their restriction.

but,…

1. rosiglitazone is not nearly as good as pioglitazone for lipids. for example, a study of 400 people off all other diabetes meds were randomized to pioglitazone vs rosiglitazone. results at 24 weeks:

–no diff in A1c
–fasting TG significantly reduced with pioglit but increased with rosiglit
–HDL increased in both groups but significantly more with pioglit
–LDL increased with both, more with rosiglit, and (perhaps most important) LDL particle size was larger with pioglit (it is the small, dense LDL particles that are more oxidizable and seem to cause the real problems: inciting inflammation, causing monocytes to differentiate to tissue macrophages, and it is only the oxidized LDLs that bind to the scavenger receptor on the macrophages and lead to uptake of lipids and formation of foam cells)

 2. unlike rosiglit which has the rather striking adverse events on the initial meta-anal, pioglit has one of the few studies showing actual cardiovascular benefit. the PROACTIVE study (see here) was a prospective RCT of 5238 pts with diabetes with evident macrovascular disease. after 3 years, primary composite endpoint of all-cause mortality, nonfatal MI (including silent MI), stroke, acute coronary syndrome, surgical intervention on heart or legs, amputation) was nonsignificantly better with pioglit.  But, secondary outcome of all-cause mortality, nonfatal MI and stroke was a very significant 16% reduction. [a bit strange that they used these primary/secondary outcomes: their secondary outcome is more objective by not including decisions about surgical intervention, etc.  Each of the secondary endpoints were better with pioglit, though interestingly silent MIs were the same].

3. the RECORD study  specifically looked at cardiac outcomes with rosiglit.  4447 pts with A1C >7 randomly assigned to adding rosiglit, sulfonylurea (if failed metformin), or metformin (if failed sulfonylurea) with 5.5 yr followup, looking at cardiovasc or unknown cause of death, MI, or stroke. No diff in primary endpoints. but small number of events. high dropout rate. and significantly more patients in the rosiglit group on statins (55% vs 46%)!!

4. as an aside, the ACCORD trial, which looked at tighter vs less tight control of diabetes, found that there was increased mortality in the tighter control group.  but it turns out that in the tighter control group, there was an increase in the use of TZDs from 58 to 91%, almost all rosiglit….

so, seems pretty clear to me that if you are going to use a TZD, pioglitazone is the only one to use….  it has much better effect on lipids and the PROACTIVE study showed clinical cardiovasc benefit, esp given the dearth of diabetes drugs leading to decrease in macrovascular events (ie, metformin really is the only med with clearcut evidence). both pioglit and rosiglit do lead to more significant heart failure, so should be used cautiously.

geoff

Primary Care Corner with Geoffrey Modest MD: New atrial fibrillation guidelines

11 Apr, 14 | by EBM

new guidelines on management of atrial fibrillation from am heart assn and am acad of cardiol (see doi: 10.1016/j.jacc.2014.03.022). long article, so will summarize a few of the newer or more significant recommendations:

1. antithrombotic therapy — individualized/shared decision-making.

 –warfarin if mechanical valve (range 2-3 or 2.5-3.5, depending on type of valve/location).
–for patients with nonvalvular afib with prior stroke, TIA, or CHA2DS2–VASc score of 2 or greater, recommend oral anticoag. [note they are not using the older CHADS2 score.  see below for the CHA2DS2–VASc instrument.]  options: warfarin with INR 2-3 (level of evidence A); or dabigatran, rivaroxaban, or apixaban (level of evidence B) [ie, they added these factor Xa inhibitors to the list.  though i have sent out recent blogs on the apparent understating of risks of dabigatran in particular]. not use dabigatran in patients with mechanical valves or dabigatran and rivoraxaban if ESRD or hemodialysis
–they still recommend INR monitoring at least weekly til INR in range, then at least monthly [though, fyi, there was a recent article suggesting that rock-stable patients could be checked every 3 months]
–for patients with nonvalvular AF and CHA2DS2–VASc score of 0, “it is reasonable to omit antithrombotic therapy”. for a score of 1, can do nothing, use aspirin, or anticoagulate [they are downgrading the recommendation that aspirin should be used in low risk patients, given relative paucity of studies — SPAF is only study showing benefit of aspirin alone]

2. treat atrial flutter the same way

3. in terms of rate control, rate <80 is reasonable for symptomatic management (mostly by b-blocker or nondihydropyridine calcium channel blocker). but (per new study) resting heart rate <110 may be reasonable if patient asymptomatic and LV systolic function normal [my caveat here: i have a patient with baseline normal heart function, in afib and with mitral valve replacement, who developed severe symptomatic tachycardia-mediated cardiomyopathy at heart rate of 110, with LVEF of <20%, completely reversed after 2-3 months of lowered ventricular rate — this is supposed to happen at somewhat higher rates, on the order of 130, but either it can happen at lower rates or this patient had higher rates at other times of the day. in any event, i am hesitiant to target 110 from this anecdotal experience. and my many patients with afib do fine at rates in the 80s…]. in pts with exertional symptoms, consider checking pulse with exertion and titrating meds.

4. consider AV nodal ablation if medical management inadequate and rhythm control not achievable

5. consider cardioversion, esp if persistent sx with rate control, younger pt, hx of tachycardia-mediated cardiomyop, first episode of afib, or if afib precipitated by acute illness. if afib >48hrs, then 3 weeks of anticoagulation before (or can do TEE and if negative, cardiovert right away).  then, in any case, anticoag for 4 weeks after [no change in these recs]

6. hypertrophic cardiomyopathy: anticoagulate independent of CHA2DS2–VASc score. antiarrhythmics to prevent recurrent afib, or catheter ablation if not tolerated/not work

7. they note the efficacy of radiofreqency catheter ablation to maintain sinus rhythm, esp in younger patients with paroxysmal afib and little structural heart disease. [there was a recent JAMA article on the RAAFT-2 trial (see  doi:10.1001/jama.2014.467) which randomized 60+ patients with mean age 55 to antiarrhythmic drugs (mostly flecainide, and propafenone) vs radiofrequency ablation, followed 24 months, and found that radiofreq ablation led to 55% vs 72% developing atrial tachyarrhythmia > 30 sec on monitoring, and 47% vs 59% having recurrence of symptomatic atrial arrhythmia.

for the new guidelines, there were industry ties for vice-chair and 4 of 14 members of committee

of note, risk factors for developing AF include increasing age, htn, dm, MI, valv heart dz, chf, obesity, OSA, smoking, alcohol, hyperthyroidism.  there was an intriguing recent RCT in JAMA finding that wt loss decreases afib symptom burden and severity, number of episodes and cumulative duration of afib. also decrease in intraventricular septal thickness (see doi:10.1001/jama.2013.280521)

 

also, fyi,  B-type natriuretic peptide or N-terminal pro- B-type natriuretic peptide are elevated in paroxysmal or persistent afib, in absence of chf.

CHA2DS2–VASc (max 9 points):

–CHF  –1 point
–HTN –1 point
–age>= 75 yo  –2 points
–DM  –1 point
–stroke/TIA/thromboemboli  –2 points
–vasc dz (prior MI, PAD, aortic plaque)  –1 point
–age 65-74  –1 point
–female sex  –1 point

geoff

Primary Care Corner with Geoffrey Modest MD: Marijuana psych effects

9 Apr, 14 | by EBM

a recent animal study assessed the effects of cannabinoid receptor stimulation on adolescent rats, finding  brain changes similar to those found in schizophrenia (see  here). this study adds physiologic plausibility to the observed increased incidence of psychosis in human marijuana users in observational cohort studies (see below). given the current remarkable increase in marijuana potency, increasing usage overall, and new legalization, i thought it was useful to review some of the newer data on adverse effects, concentrating on the psych ones. it is notable that the onset of both addiction-related syndromes and psychosis typically occur in adolescence. in the rat study (i will not go into all of the gory details):

 –rats with persistent stimulation of the cannabinoid 1 receptor, but only during specific windows of adolescence (ie, only in early or mid adolescence and not during late adolescence or adulthood), develop a long-lasting prefrontal cortex disinhibition, with a functional downregulation of GABAergic transmission. One key finding is that this disinhibition is enduring into adulthood in rats but only if stimulated during these susceptible developmental times of early to mid adolescence.
–other studies find an important role of impaired GABA transmission in schizophrenia

an older lancet study provided a meta-analysis of longitudinal studies to assess the relationship between marijuana use in adolescence and psychosis (see here). although these were observational studies (so can’t really draw ironclad conclusions), these studies were long-term, so as to minimize the likelihood of reverse causality (eg, patients with imminent psychosis using more marijuana) and are not related to the acute, transitory, psychotic-like effect of acute marijuana usage. their findings:

–after thorough literature search, 7 cohort studies identified which were population-based longitudinal studies, including 2 birth cohorts from Dunedin
–there was a consistent relationship in these studies, finding an average 41% increased risk of schizophrenia (or schizophreniform disorder) with cannabis use. the most rigorous studies (swedish study and dunedin study) found an odds ratio of 2.58.
–6 studies looked at cannabis use frequencies, consistently finding that increased usage was associated with increased risk (50-200% increase)
–the Dunedin study found a stronger effect of cannabis on psychotic symptoms in those who used cannabis prior to age 16
–several studies assessed the presence of psychotic symptoms lasting longer than one month and another only looked at hospital admissions for schizophrenia, making acute intoxication as cause of psychotic symptoms unlikely
–by eliminating patients with known psychosis or predisposition to psychosis at baseline, controlling for up to 60 potential covariates (other substance use, mental health problems, personality traits, sociodemographic markers, etc), and following cohort for years before using cannabis, there was less likelihood for reverse causality (eg, Dunedin study adjusted for psychotic symptoms at age 11, looked at cannabis and psychosis measures at age 15 and 18)
–data on depression/affective disorders, suicidal thoughts, anxiety were examined separately, but marijuana usage was less consistently associated than for psychosis

 so, these 2 studies suggest that :

–especially during early adolescence (in rats and humans) there seems to be increased risk of long-term psychotic effects of marijuana use and this increase is dose-dependent.
–the implications seem pretty profound, since 20% of young people report using marijuana at least once a week and this increased use reported now is especially during early adolescence
–there can never be a randomized controlled trial of marijuana use and psychotic outcomes to prove causation.  but, this meta-analysis is one of the most careful i have seen, and the results are consistent over the several studies analyzed.
–in light of the physiologic possibility (in rats) and the potential increase in psychosis for the huge numbers of human marijuana users (40% of young adults report using marijuana in UK, which translates into a possible 14% of all psychotic outcomes might have been avoidable if marijuana not used), the better part of valor would be to inform young patients of psychosis as a potentially very serious complication of marijuana use.

 another review from the lancet (see here) reviewed the adverse effects of non-medical use of marijuana.  for psych effects, they note the well-accepted impairment in cognitive function in regular users, also noting deficits in verbal learning, memory and attention in heavy users (duration, frequency of use, cumulative dose of THC). there seems to be at least partial recovery after 2 years of abstinence in some but not all studies. also reported are structural brain changes (reduced hippocampus and amygdala volume in chronic users), as well as poor school performance, and early school leaving, with their attendant social consequences. again, most of this is based on observational studies, so cannot posit a direct causal relationship.

but, on the other hand, the American Academy of Neurology published guidelines on complementary/alternative medicine in multiple sclerosis, noting that cannabis has been shown to decrease spasticity and pain (excluding central neuropathic pain), and the spray seems to work for spasticity symptoms, pain and urinary frequency, though cannabis unlikely to improve objective measures of spasticity or urinary symptoms (see DOI 10.1212/WNL.0000000000000250).

geoff

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