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Archive for December, 2013

Primary Care Corner with Dr. Geoffrey Modest: ADHD drugs and Priapism

22 Dec, 13 | by EBM

see below from the FDA.  not just methylphenidate, but also seems to be an issue with  non-stimulant drug atomoxetine. sounds like it can be severe: average age 12.5 and 2 needing surgical intervention.

geoff

Safety Announcement

[12-17-2013]  The U.S. Food and Drug Administration (FDA) is warning that methylphenidate products, one type of stimulant drug used to treat attention deficit hyperactivity disorder (ADHD), may in rare instances cause prolonged and sometimes painful erections known as priapism. FDA continues to monitor the safety of drugs after they are approved, and, based on a recent review of methylphenidate products, we have updated the drug labels2 and patient Medication Guides to include information about the rare but serious risk of priapism. Patients who take methylphenidate and develop erections lasting longer than four hours should seek immediate medical treatment to prevent long-term problems with the penis.  If not treated right away, priapism can lead to permanent damage to the penis.

Priapism can occur in males of any age and happens when blood in the penis becomes trapped, leading to an abnormally long-lasting and sometimes painful erection. Younger males, especially those who have not yet reached puberty, may not recognize the problem or may be embarrassed to tell anyone if it occurs.  All male patients and their caregivers should be taught the signs and symptoms of priapism and the importance of seeking immediate medical treatment if it occurs.

Methylphenidate products are among the medicines that can be used to treat ADHD. One of the most common childhood brain disorders, ADHD can continue through adolescence and adulthood and causes symptoms such as difficulty staying focused and paying attention, difficulty controlling behavior, and hyperactivity. Medications such as methylphenidate used to treat ADHD benefit patients with the disorder by increasing focus, reducing impulsivity, and improving overall social functioning. Therefore, patients who have been prescribed a methylphenidate product should not stop taking it without first talking to their health care professionals. Table 1 lists methylphenidate products marketed in the United States.

In our review, the median age of patients taking a methylphenidate product who experienced priapism was 12.5 years (range 8 to 33 years). In a few patients, priapism occurred after an increase in the dosage of methylphenidate, but priapism has also occurred under other conditions, such as during short periods of time when the drug was stopped temporarily, when there was a longer than typical time between doses, or after stopping the drug permanently. Two patients required surgical intervention; one required shunt placement, and the other had to have needle aspiration of the corpus cavernosum.

The risk of priapism may cause some health care professionals toconsider switching patients to the non-stimulant drug Strattera (atomoxetine), another drug used to treat ADHD; however, atomoxetine has also been associated with priapism in young children, teenagers, and adults. Priapism appears to be more common in patients taking atomoxetine than in patients taking methylphenidate products. Health care professionals should be cautious when considering changing patients from methylphenidate to atomoxetine.

Amphetamine products are also used to treat ADHD, and we have received reports of priapism in four patients taking an amphetamine product.  However, whether the amphetamine products caused the  priapism is uncertain, because all of these patients had been taking other medications that are thought to cause priapism. Therefore, we cannot conclude that the use of amphetamine products can result in priapism.

Primary Care Corner with Dr. Geoffrey Modest: JNC Hypertension guidelines–simple goals

22 Dec, 13 | by EBM

So, here is my brief (ie, briefer than usual) review of JNC-8 (see doi:10.1001/jama.2013.284427). This is a short 14-page document, recommending the following:

–in people over 60 years old, initiate drug treatment to lower BP to <150/90 (but okay to keep at systolic<140 if already there based on prior guidelines and if well-tolerated, per expert opinion, though no clear benefit to doing so)

–in those younger than 60, begin drugs to lower diastolic <90, mostly based on really old studies from the 1970s, which only looked at diastolic blood pressure. This recommendation is stronger for those 30-59yo than 18-29yo (ie, no RCTs showing anything in the younger group)

–in those younger than 60yo, use a systolic goal of <140 (expert opinion, since lack of studies, as in last point)

–in those >18yo with CKD (chronic kidney dz, with GFR<60, or people of any age with alb/creat ratio >30), treat to lower BP to <140/90. this is based on expert opinion. No signif data that 130/80 prevents either cardiovasc or renal outcomes. JNC-8 not address those over 70yo with CKD, since the eGFR calculation models did not include them.

–those >18 yo with diabetes, use drugs to lower BP to <140/90. lack of evidence that lower BP helps

–for general non-black population, including those with diabetes, initial treatment should be thiazide-type diuretic, CCB (calcium channel blocker), ACE-I (ACE inhibitor) or ARB (angiotensin receptor blocker), noting that in some trials thiazide more effective than CCB or ACE-I (eg ALLHAT).

–for the general black population, including diabetics, initial treatment with thiazide or CCB. as with last point, the ALLHAT study weighed in heavily. (note that ACE-I/ARB is not initial choice in diabetics)

–for those >18 yo with CKD and htn, initial therapy should include ACE-I or ARB. Includes all patients, independent of race or diabetes. though the recommendation for black pts is expert opinion here. no data to support ACE-I or ARB if older than 75yo

–if BP goal above not achieved in 1 month, can either increase dose of initial drug or add another of the initial 4 classes, then a third drug from the list if still needed, but do not add combo of ACE-I plus ARB. Then can use drugs of other classes and consider referring to specialist if BP not achieved with the above strategy. (expert opinion)

So, pretty simple. only 2 goals. older people (>60yo) have target of <150/90. Everyone else <140/90

A few observations:

  1.  No preference in choice of initial meds between thiazide-type diuretics, CCBs, ACE or ARB.

–notable loss of b-blockers from list (I think justified by the cochrane anaylses showing inferior outcomes to other drugs)

–thiazides still listed in the main group, unlike with the NICE recommendations. hydrochlorothizide (most commonly prescribed) may not be the best, per prior blogs, but one issue with chlorthalidone is hypokalemia since only the 25mg dose is available to us in the US (recent study showed that chlorthalidone no worse than HCTZ in causing hypokalemia if give the 12.5mg dose). It is perhaps notable that there is as much new-onset diabetes with thiazides as with statins, though no comment here (mechanism??? — old studies posited that hypokalemia from the diuretics decreased b-cell insulin release, as documented in animal studies)

–These are just “guidelines” not to supercede clinical judgment, as stated. But no clear comment that we should look at underlying conditions to choose the antihypertensive (JNC-7 had chart, suggesting for example that b-blockers be used preferentially if patient is s/p MI or has CHF). I still think (and suspect committee members would agree) that we should look at underlying issues (not give diuretics in pt with hyperuricemia, give CCB if patient has raynaud’s…….), though not in guidelines

–they do not explicitly recommend starting with 2 drugs at the same time for anyone (and they do not stratify aggressiveness of therapy by initial blood pressure), though they do note that some on the panel did suggest 2-drug combo in those with bp>160/100.

  1. No detailed suggestions about which second meds to add. There are data from small studies which make some sense: if start with CCB or diuretic, then add ACE or ARB, since there is some synergy between the “volume-effective” meds in the first category and the “renin-effective” meds in the second. By the way, the NICE guidelines have lots of specific suggestions on order of meds, refractory hypertension treatment, when to work-up secondary causes, special cases of when to use specific meds.  It is a very long, detailed, highly referenced document, but does have much more info.  The good thing about JNC-8 is it’s briefness, easy interpretation (not a lot of nuance), and less complicated algorithm.
  1. No information about several newer approaches, also highlighted in the european guidelines ESC and NICE, such as the use of 24-hr ambulatory or home-based monitoring to help define hypertension. Also missing in the diagnosis of hypertension is any mention of the correct method of checking blood pressure, or explicit definition of hypertension/pre-hypertension (ie, JNC-7 perhaps appropriately focused on those with either systolic>130 or diastolic>80 as prehypertensive, likely to progress to hypertension, and suggesting aggressive lifestyle changes of wt loss, exercise, DASH diet, etc). Also no mention of workup of hypertension, when to look for secondary causes, etc.  There are very brief comments in the JNC-8 algorithm that lifestyle changes are important (no specific mention of wt loss, diet, exercise, salt or alcohol consumption, meds such as NSAIDs) but refers to other guidelines. I am concerned that one of the impeti (I think that is plural of impetus, from my Latin dabblings of the past) from these guidelines is to go directly to drugs (not that they say that, just that there is so minimal comment on lifestyle that it might reinforce it)
  1. Not sure how we mere mortals are to reconcile the different guideline suggestions. Should we not focus on diet, salt or alcohol consumption? For diabetics, should we use the new JNC-8 goal or the new American Diabetic Association goal of <140/80?  Given that guidelines lead to external agencies measuring adherence to guidelines (did you do enough A1C’s on your diabetic patients?? etc), which is the right blood pressure goal for diabetics? And which of these “performance measures” will they use to rate us on our report cards?
  1. One issue I have commented on in past blogs is that as we base more guidelines on evidence-based medicine (and this guideline was much more evidence-based than JNC-7, which was more expert opinion), we are in the trap of not having studies that really address the question we need answered.  For example, the recommendation to treat those over the ripe old age of 60 years to a higher BP goal is based on several studies which happened to choose a higher goal (eg, bring systolic down to 160 mmHg, or if already in the 160-180 range, bring it down 20 mmHg — there are no large, long-term studies stratifying older people to lower targets to see if they do better, though there was a short-term Japanese study that I sent out recently not showing any outcome difference)

Note that “this guideline was not endorsed by any federal agency or professional society prior to publication and thus is a departure from previous JNC reports” – including NHLBI. I am concerned that some of the new guidelines (eg the recent lipids one and this one) come out of specific specialty societies (who have their own issues and biases) and did not initially come out in draft form for comments (the AHRQ — agency for healthcare research and quality — always sends out drafts for public comment prior to releasing guidelines). To us guys in the trenches, the guidelines seem to have dropped down from heaven, and are rather jarring.

Geoff

Primary Care Corner with Dr. Geoffrey Modest: “The Selling of Attention Deficit Disorder” (from the NYT)

16 Dec, 13 | by EBM

the NY times had a front-page story on “the selling of attention deficit disorder”, one of a recent series of health care expose-type articles (see http://www.nytimes.com/2013/12/15/health/the-selling-of-attention-deficit-disorder.html?nl=todaysheadlines&emc=edit_th_20131215&_r=0). their basic points:

–dramatic increase in diagnosis (made in 15% of high school aged children!! — second only to  asthma — with # of kids on meds increasing from 600K to 3.5M in past 20 years)

–increase in meds coincides with intensive drug company campaign to publicize syndrome and promote pills as therapy, including widespread advertising to parents/kids: using celebrities on TV to promote diagnosis, defining ADHD to include “childhood forgetfulness and poor grades as grounds for medication, that, among other benefits, can result in ‘schoolwork that matches his intelligence’ and ease family tension”, “subsidized 50,000 copies of a comic book that tries to demystify the disorder and uses superheroes to tell children, ‘medicines may make it easier to pay attention and control your behavior'”.

–(my comment): part of issue is that DSM-5 has broadened diagnosis of ADHD, expanding the age of diagnosis (used to be that dx had to be made by age 7, now it’s 12), and lowering the definition of when a kid is “impaired” but without specifics on the definition of degree of impairment, eg mild, moderate, severe). BMJ has a good editorial comment on DSM-5, noting that many more people diagnosed, lack of specific definitions of severity though 87% of those diagnosed in 2010 ended up on meds (though per DSM-5 those with only mild to moderate sx should have nonmedication behavioral approach), and 78% !!!! of the work group advisors for DSM-5 redefinition of ADHD had links to drug companies (see http://dx.doi.org/10.1136/bmj.f6172)

–drug company now targeting “adult ADHD” for publicity blitz, using popular musicians and the campaign: “it’s your ADHD — Own It”, and an on-line instrument which NY Time poll found that 1/2 of 1000 participants got result of either “ADHD possible or ADHD may be likely”. the Times comments on a psychiatrist promoting concept that ADHD is a lifelong disorder requiring life-long therapy (he received $45K from drug companies from 2010-2011). also, part of ad campaign is that since ADHD runs in families, parents of ADHD kids may need therapy. as an aside, there was a funny comment in the lancet several years ago in an editorial about adult ADHD (which they saw as basically a credible diagnosis in the U.S. and not the U.K.), where a U.S. med student was asked what was “normal” for patient, with the response that that happened when the physician did not look hard enough…..

–dr. joseph biederman, a child psychiatrist at harvard and MGH whose studies were frequently cited by drug companies, was involved in 2008 senate investigation on his research, which was subsidized by drug companies, and he was paid $1.6M in speaking and consulting fees.

–and, by the way, the name “Adderall” comes from ADD for all”

so, there are clear cases of ADHD in kids — i have treated many kids with severe dysfunction from ADHD with some pretty remarkable results.  the point is not to deny the existence or appropriate therapy to those kids in need. but there are clear adverse effects (not a benign drug as promoted by drug companies, but with potential for addiction and, though unusual, can have very severe adverse effects, such as psychosis/hallucinations, suicide). the extensive drug company blitz clearly led to dramatic profits for the drug company, akin to the drug-company sponsored “pain as the fifth vital sign” helped promote the widespread use of opiates, as per prior blog posts.

geoff

 

Primary Care Corner w/Dr. Geoffrey Modest: Choosing Wisely–Hematology

12 Dec, 13 | by EBM

as many as you know, several of the medical professional organizations have submitted a list of 5 suggestions which they feel would decrease the use of unnecessary tests or treatments.  the most recent addition is from the American Society of Hematology, which I am circulating even though I’m not sure it’s really helpful (they are focusing on very low hanging fruit). see http://bloodjournal.hematologylibrary.org/content/122/24/3879.full.pdf+html. in brief,

–In situations where RBC transfusions are necessary, transfuse the minimum number of units required to relieve symptoms of anemia or return the patient to a safe hemoglobin range (7-8 g/dL in stable noncardiac in-patients)  — [transfusing more than is necessary does not improve outcomes and increases the potential risk]

–do not test for thrombophilia in adult patients with venous thromboembolism occurring in the setting of major transient risk factors (e.g. surgery, trauma, or prolonged immobility) — [the correlation between positive tests of thrombophilia and actual clinical events is quite imperfect, with a lot of false positives.  Therefore, testing when not clinically indicated may lead to inappropriately prolonged duration of anticoagulation]

–Do not use inferior vena cava filters routinely in patients with acute venous thromboembolism — although there are indications for IVC filters (eg acute venous thromboembolism with a contraindication to anticoagulation, PE despite appropriate therapeutic anticoagulation, and massive PE with poor cardiopulmonary reserve), there is no evidence of their utility for primary prophylaxis of a PE.  There was a recent report of 6000 patients undergoing bariatric surgery which found that prophylactic IVC filters actually increased the risk of death or disability. When IVC filters are indicated, it is recommended that retrievable filters are used and should be removed if the risk for PE has resolved]

–do not administer plasma or prothrombin complex concentrates for nonemergent reversal of vitamin K antagonists (i.e. outside of the setting of major bleeding, intracranial hemorrhage, or anticipated emergent surgery) — [aggressive reversal of the effects of vitamin K antagonist is both costly and potentially harmful.  For non-bleeding patients with an INR greater than 10, even though there are no randomized control trials, these patients can usually be managed safely by administering small doses of vitamin K rather than blood products]

–limit surveillance CT scans in asymptomatic patients after curative-intent treatment for aggressive lymphoma — [as noted in a plethora of prior emails/blogs, CT scans are not benign since the attendant radiation may well increase the risk of malignancy over the long-term.  Review of the literature shows no survival benefit from surveillance CT scans of asymptomatic aggressive non-Hodgkin’s lymphoma survivors.  Relapses are heralded in general by clinical symptoms.  There is no evidence of a survival benefit if a relapse is detected on a routine scan]

 

geoff

Primary Care Corner with Dr. Geoffrey Modest: vitamin B12 deficiency with acid suppressive therapy

12 Dec, 13 | by EBM

Although gastric acid is required to cleave vitamin B12 from ingested dietary proteins, and the same parietal cells that produce acid also produce intrinsic factor, studies have been mixed as to whether acid suppressive therapy leads to low vitamin B-12 levels. a large community-based case-controlled study was done by Kaiser Permanente North California comparing 26,000 patients with an incident diagnosis of vitamin B12 deficiency with 185,000 without (see doi:10.1001/jama.2013.280490).  Results:

 

–Vitamin B12 deficiency was more commonly diagnosed in patients with at least a 2 year supply of PPIs compared to nonusers (OR, 1.65).

–among people taking PPIs for at least 2 years, those on a higher dose (greater than 1.5 pills per day) had a higher OR of 1.95, as compared to those who were on lower doses of less than 0.75 pills per day, with OR of 1.63, and a statistically significant trend.

–a similar trend was found with people on H2 blockers, though there was no increased risk in those taking less than 0.75 pills per day.  The odds ratios were also significantly less than with PPIs.

–In addition, there was an increasing trend of vitamin B12 deficiency with longer duration of use of PPIs, but no trend with H2 blockers
–The strength of the association between PPI use and B12 deficiency decreased with discontinuation of the PPI

–The association between PPIs and B12 deficiency was strongest among those who were younger, especially those younger than 30 years of age.  The association was also stronger for women than men.  No differences by race/ethnicity.  No difference if diagnosis of GERD or not.

 

so, although the study was not a randomized controlled trial, it has the benefit of being very large, did find that the likelihood of B12 deficiency increased with higher potency of acid suppression (PPI>H2 blocker) and higher doses of the PPI, more likely with longer duration of taking the PPI, decreased on stopping PPI,  and was more profound than with other conditions known to be associated with B12 deficiency such as thyroid disease.  There there also is a reasonably plausible mechanism. This again reinforces that PPI’s are very strong drugs and should be used only when necessary — prior studies have shown that it is pretty uncommon for patients initially put on PPIs to be “stepped-down” to less aggressive therapies (H2 blockers or calcium tablets), reinforcing the “step-up” approach of starting with less potent and increasing potency as clinically needed (though i also do find that even in this case, over time some patients can be down-titrated)

 

geoff

Primary Care Corner with Dr. Geoffrey Modest: More on new AHA lipid/statin guidelines–are they a disservice to patients?

9 Dec, 13 | by EBM

 

 

several people have asked what i consider a reasonable approach to lipid management. i have been following the lipid literature at this point for several decades, since i have always felt that heart disease was a manifestation of our industrialized society and abnormal lipids (from the attendant changes in lifestyle) was a principal component of atherosclerotic disease. my approach over the past decade or so involves developing a general sense of atherosclerotic risk as follows:

 

–the major part of the overall gestalt of a person’s risk is the traditional risk factors: age, smoking, hypertension, and lipids (with smoking being the strongest remedial component — we can’t do a lot about age).
–existence of atherosclerotic disease to me is an indication for very aggressive lipid management, independent of the lipid levels. in this category i have always included strokes (data on positive effect of statins is at least a decade old), as well as PAD or other atherosclerotic vascular disease (eg, renal artery stenosis, carotid stenosis). although the data are quite robust that LDL is bad and HDL protective, there are important gradations here: some LDL is less bad than others (large LDL in the large Quebec study had 1/3 the atherosclerotic risk of small dense LDL) and a minority of people have a pro-inflammatory HDL (see below for an old post, but HDL can be bad). and, the most important issue is not community data finding that LDL is bad etc, but the individual patient, and a person with atherosclerotic disease is telling me that they are prone to more…. (this is like the value of TSH, as a reflection of the individual person’s thyroid status, as opposed to T4 levels, which are a range reflecting the normal distribution for the community).
–diabetes is a reasonable atherosclerotic equivalent. as mentioned in my really long blog on recent AHA guidelines, there are some patients with very high HDLs and very low LDLs. there are no studies in the literature of this group that i am aware of, and i have not been pushing statins on them, but overall i do support the basic Am Diab Assn guideline to give statins to all diabetics over age 40 with 1 additional risk factor (ie, the default should be to give a statin, since there is such a high risk of ASCVD, except in a few cases, as above). interestingly, the AHA guidelines do not include people with glucose intolerance, though they have almost as high a risk as several other risk factors (eg, a prospective european study found for CAD risk: men in 5-5.4 range had 56% increased risk, 5.5-5.9 100% increase, known diabetes 382%; women not significant til 6.6-4 with 129% increase and 5-fold increase if known diabetes. (see doi:10.7326/0003-4819-141-6-200409210-00006). these numbers for men with A1c in the 5.5-5.9 range are not so different from those with PAD, for example. i have been checking A1c’s for years on patients as part of my cardiovasc risk stratifier, and i do incorporate glucose intolerance into my gestalt of who to treat.
–there are other risk factors to consider, including microalbuminuria in nondiabetics and even early renal disease (creat above 1.4). i think the data on coronary artery calcium score is quite strong (and is an individual marker of disease), but i will not do this given the radiation exposure. hs-crp is also reasonable (the JUPITER study was very impressive, though interestingly, the hs-crp added nothing in the subgroup who were stratified by coronary calcium scores. maybe hs-crp is a cheap and nontoxic alternative to coronary artery calcium???). at this point i have not incorporated hs-crp into my ASCVD risk assessment, and i do not check for microalbuminuria regularly, except in people with hypertension or diabetes. even aortic sclerosis in some studies is associated with increased risk.
–HDL is still important, to my view (interesting that AHA does not discuss HDL, though it is still part of its risk calculator!!). for primary prevention, i usually use the framingham cutpoint of total cholesterol/HDL ratio of 4 (there have been lots of studies validating the total chol/HDL ratio as a much better predictor of clinical events than LDL). for patients on statins, the Treating to New Targets study (TNT) found that an achieved LDL >100 with the highest quintile of HDL, >55, had the same rate of clinical events as those with LDL <70 with the lowest quintile of HDL, <38 — see LINK TO SLIDES BELOW SLIDE #4 and comment below –so, i still treat to an LDL target, which is modified by the achieved HDL, though i realize in some studies that the rate of protection by statins was independent of the initial LDL, but analysis of many studies shows cardioprotection is related to the achieved LDL (one can easily argue that these are secondary anaylses and not as statistically rigorous, but that’s all we have… and i do find it ironic that AHA is such a stickler for LDL goal studies (ie, the lack of multiple studies with differing LDL goals), yet applies their calculator on groups with absolutely no data (eg the 45 yo African-American male as mentioned in the longer blog with a total cholesterol of 130 and HDL of 70, and well-controlled BP on meds (SBP=130) qualifies for moderate intensity statin…..)
–so, based on this, who do i treat? first, pretty much everyone gets the diet and exercise discussion, with pretty good data suggesting that these are helpful in preventing heart disease as well as in secondary prevention. second, the framingham data has shown that the risk of heart disease is higher in patients with a little of several risk factors (the relationship is more than just additive) than in those with even a quite high single risk factor. so, someone who smokes and has glucose intolerance will probably get a statin, unless their lipids are remarkably good (again, if they have any evidence of atherosclerotic disease, they get a statin anyway)

 

i do realize that this “gestalt” is not exactly quantitative, but probably better (to me) to have some integrated approach which assesses different risk factors (which, from studies, do have attributable risks — eg, risk from different A1c levels is as above) than to put together a quantitative risk calculator which does not have sufficient data but spews out a “number” (eg the 45yo african american with controlled hypertension and pristine lipids).

 

after i was putting the above together, there was an interview in Medscape Cardiology today of 2 of the AHA committee members, to which i feel compelled to respond (sorry, this post is getting longer…). the passages are from the medscape article:

 

Dr Donald Lloyd-Jones, the cochair of the guidelines on the assessment of cardiovascular risk, said the evidence for treating to target simply isn’t there, but that doesn’t mean repeated measurements of LDL cholesterol won’t be needed.
“There have been no clinical trials in which they’ve taken an approach where they’ve titrated medication dosing to achieve a certain LDL level,” said Lloyd-Jones. “We just haven’t had those trials designed or performed yet. So we just couldn’t endorse that kind of approach. And yet, we’re not abandoning the measurement of LDL cholesterol, because it’s perhaps our best marker of understanding whether patients are going to achieve as much benefit as they can for the dose of statin they can tolerate. For the clinician, it’s also a very important marker of adherence.”
BUT….
1. unfortunately, it is true there are not lots of data from studies (which, by the way, are done by drug companies, so they choose which study to do — there is not some overarching coherent strategy to doing studies, unfortunately).
2. interpretation of the existing studies have found a consistent relationship between LDL levels achieved and cardiac events (this is, of course, a secondary analysis, though rather consistent). i have attached a powerpoint  link(first slide at link below) of one analysis of the results (from the TNT reference in next point).
3. the Treating to New Targets study, as mentioned, did compare atorvastatin 10 to 80mg (see N Engl J Med 2005;352:1425-35). the second slide shows pretty clearly that clinical events were significantly fewer with atrovastatin 80mg vs 10mg. slide 3 from a subsequent TNT article (see N Engl J Med 2007;357:1301-10) shows pretty clearly on secondary analysis that the achieved LDL was associated with cardiac events (the lower, the better), AND it didn’t matter if on atorvastatin 10mg or 80mg. slide 4 shows that the achieved HDL, when combined with the achieved LDL, significantly affects the subsequent cardiac risk (this is the graph of data from point above on HDL).
Dr Neil Stone, the chair of the expert panel who wrote the guidelines, said there were some problems with treating to goal, specifically in patients who were treated close but not exactly to target.
“In secondary prevention, what if your patient is on high-intensity statin therapy and gets an LDL-cholesterol level of 78 [mg/dL] and is adhering to an excellent lifestyle?” said Stone. “From our point of view, there is a large body of evidence that says he’s actually doing as good a job as he can possibly do. If he has to get to an optional goal of under 70 [mg/dL] as some would advocate, it means adding on medicines for which there is not proven benefit.”
In addition, the panel said that the use of LDL-cholesterol targets might result in the overtreatment of patients with nonstatin drugs. These other agents have not been shown to reduce the risk of atherosclerotic cardiovascular disease.
BUT …

 

1. i totally agree that there are no good large scale studies showing benefit of adding anything to a statin, and that some meds (eg ezetimibe) may be harmful. but that does not mean that we should not be treating to an LDL target (perhaps modified some by the HDL, as above), just that we may need to titrate the statin. so, the AHA chart (in my prior blog post) which clumps several “high intensity” regimens together (atorvastatin 40-80mg or rosuvastatin 20-40mg) should perhaps revert to the old way: if atorvastatin 40mg does not achieve the target, we should augment the intensity of therapy, moving to atorvastatin 80mg, or up to rosuvastatin 40mg. then call it quits. (of course, continuing to reinforce wt loss, diet, exercise…)
2. there are some pretty interesting drugs probably coming out which MAY have impressive clinical efficacy (eg, the PCSK9 inhibitors), and we may (???soon) have additional potent drugs in the armamentarium.

 

sorry if you think i am perseverating on this. i do, however, think these guidelines overall do a disservice (though, as i mentioned in the really long prior post, there are some very positive changes as well). let me know your thoughts.

 

geoff

 

PRIOR POST

 

 

 

Although the vast majority of epidemiol studies have found HDL to be cardioprotective, there have always been some concerns.  HDL is comprised of a diverse group of lipoproteins with significant metabolic heterogeneity.  there were a few older studies finding a “pro-inflammatory HDL”, which predisposed people to heart disease (see my lipid powerpoint, slide 106, which cites small studies from 2003 and 2009). the clinical trial of Torcetrapib, a cholest ester transfer protein inhibitor, dramatically increased HDL but was not cardioprotective. the researchers suggested that the HDL was somehow deformed. (this large torcetrapib trial overwhelmed a meta-analysis last year in BMJ, suggesting no benefit to raising HDL). in any event, there is a likely very illuminating article from harv school pub health. they had found before that there was occasionally a small apolipoprotein (apo C-III) on some lipoproteins causing a pro-inflammatory and atherogenic response. on LDL particles, this apo C-III caused increased coronary athero independent of the LDL itself. they looked at the data from 2 large epidem studies — Nurses health study (NHS, 121K female nurses) and the health professionals followup study (HPFS, 52K males), looked at stored serum and assessed the HDL C-III relation to cardiac events.  results:

 

. 14% of of women in NHS had HDL with apo C-III; 11% of men in HPFS had apo C-III

 

. Overall, each standard deviation increase in HDL was assoc with a 21% dec in cardiac events; but for patients without apo C-III, there was a 34% decrease in events and for those with apo C-III there was a statistically significant 18% increase.

 

. looking at the effect of apo C-III in multivariate analysis of other risk factors (all of below statistic signif):

 

compared to pts with normal wt, overwt and obesity were assoc with 7% and 12% lower levels of HDL without apo C-III — ie, overwt/obesity with lower of the good HDL.

 

alcohol assoc with 3% higher levels of both HDL types

 

smokers had 1% higher levels  of HDL with apo C-III (the bad one)

 

premenopausal women had 9% higher levels of HDL without apo C-III, as did postmenop women on estrogen replacement therapy, vs other postmenop women.

 

per SD increase in triglycerides,  8% lower HDL without apo C-III and 15% increase in HDL with apo C-III

 

per SD increase in A1C, 4% increase in HDL with apo C-III

 

(ie, several of these risk factors which depress HDL also lead to more HDL with apo C-III)

 

geoff

lipid slides

 

Primary Care Corner with Dr. Geoffrey Modest: Oral Hep C treatment–good news

9 Dec, 13 | by EBM

there have been a slew of articles over the past 2-3 years on non-interferon based therapy for hepatitis c. the latest one in the lancet is prescient in that it actually found a great oral regimen just as the FDA is about to approve a couple of new drugs for hepatitis c (see http://dx.doi.org/10.1016/S0140-6736(13)62121-2). in this open-label drug-company sponsored study 100 patients with hepatitis C infection at the Texas Liver Institute were assigned to 5 different therapies, and assessed for the sustained virologic response 12 weeks after the therapy ended (SVR12). All patients had genotype 1 hepatitis C. Groups 1-3 below consisted of 60 non-cirrhotic treatment-naïve patients and groups 4 and 5 were 40 patients with or without cirrhosis but had previously failed a protease-inhibitor regimen. Patients were given a combination pill of sofosbuvir 400mg qd (a nucleotide polymerase inhibitor hopefully to be released later this week by the FDA) plus ledipasvir 90mg qd (an NS5A inhibitor), with or without ribivarin. The groups and the responses are as follows:

For 60 noncirrhotic treatment-naïve patients
–sofosbuvir plus ledipasivir for 8 weeks: SVR12 in 19 of 20 patients (95%)
–sofosbuvir plus ledipasivir plus ribavirin for 8 weeks: SVR12 in 21 of 21 patients (100%)
–sofosbuvir plus ledipasivir for 12 weeks: SVR12 in 18 of 19 patients (95%)

for 40 patients who had virologic failure after receiving a protease-inhibitor regimen
–sofosbuvir plus ledipasivir for 12 weeks: SVR12 in 18 of 19 patients (95%)
–sofosbuvir plus ledipasivir plus ribavirin for 12 weeks: SVR12 in 21 of 21 patients (100%)

adverse reactions: 48% had at least one adverse reaction, the highest being in those also given ribavirin. The most common adverse effects were nausea, anemia, URI, and headache, most felt to be of only mild severity. Anemia was only noted in those patients on ribavirin. No patient discontinued therapy because of an adverse reaction

in terms of these dramatic responses, there was (not surprisingly) no difference in response by previous treatment history, presence or absence of ribavirin in the regimen, presence or absence of cirrhosis, IL28B genotype, baseline viral load, or race. Almost all patients, however, had genotype 1a (about 85%).

so, really amazing results, adding onto remarkable progress over the past several years. the vast majority of hep c infections in the US are genotype 1, which historically was remarkably resistant to really awful therapy (48 weeks of interferon and ribavirin, which was not only awful in terms of adverse effects and length of therapy — ie, if tolerated, patients basically lost one year of productive life — but also only had a 25% efficacy). this study, if repeated with a larger group of patients with longer followup and at multiple sites, raises the very distinct possibility of patients taking 1 combo pill once a day for 8 weeks and getting rid of hep c completely and without significant adverse effects. pretty dramatic progress.

geoff

Primary Care Corner with Dr. Geoffrey Modest: atrial fibrillation and weight reduction

3 Dec, 13 | by EBM

epidemiologic studies have found an association between obesity and atrial fibrillation (4-5% increased risk per each 1-unit inc in BMI), presumably mediated through the association of obesity with several factors which could predispose to atrial fibrillation, including diastolic dysfunction, a pro-inflammatory state, atrial enlargement, abnl autonomic function, and atrial structural and electrical remodeling. a randomized control trial was done in Australia to see if weight reduction would alter the course of atrial fibrillation (doi:10.1001/jama.2013.280521). 150 pts with BMI >27 (mean 33) randomized to intensive wt management (8 weeks of modified very low calorie diet of800-1200 kcal, followed by low glycemic index meals, along with written exercise plan of walking or cycling 45 min 3x/wk) vs control (written and verbal nutrition and exercise advice, with fish oil 3g/d) x 13 months. results (comparing intervention vs control):

–wt loss of 14.3 vs 3.6 kg, waist circumf dec 17cm vs 5 cm, BMI dec 5.6 vs 1.3 units

–biochem markers: hsCRP dec from 2.5 o 1.3 vs 2.3 to 1.9; chol changes not signif, but consistently better with intervention group (inc of HDL and dec in LDL)

–BP: dec 3/2 vs 1/1 mm Hg (significant)

–atrial fib assessment: atrial fib severity score (AFSS: scale of symptomatic afib frequency, duration and global assessment of severity, with range from 3.25 to 30) decreased 11.8 vs 2.6; 7-d ambulatory cardiac monitor found decrease in those with at least one episode of afib from 65% to 21% vs 57% to 56%, total number of episodes dec from 3.3 to 0.62 vs 2.8 to 2.0, total duration of afib from 1176 min to 491 vs 1394 to 1546 min.

–echo showed dec in interventricular septal thickness of 1.1 vs 0.6mm and left atrial area of 3.5 to 1.9 cm2

–of note the intervention group did have more people start metformin, lipid lowering drugs, BP drugs and had less alcohol consumption

so, impressive data that this intervention led to dramatic decreases in atrial fib in overwt people with existing afib.  hard to disentangle what helped the most: wt loss or hypertension control or decreased drinking (or even perhaps using metformin: diabetes in recent study increased afib risk 50%, and in the current study those in the intervention group had similar blood sugars as the controls but significantly decreased insulin levels).  yet another study that lifestyle interventions help…

geoff

Primary Care Corner with Dr. Geoffrey Modest: You are what you (‘re mother) eats

3 Dec, 13 | by EBM

editorial in today’s new york times citing research suggesting that, even in utero, the type of food affects subsequent eating habits and perhaps obesity (see link: http://www.nytimes.com/2013/12/02/opinion/bad-eating-habits-start-in-the-womb.html?ref=opinion&_r=0). several interesting points:

–babies from mothers who ate healthily (varied diet) during pregnancy were subsequently more open to wide food range as children and adults. dietary patterns track from early childhood and once these patterns are formed, hard to change later

–researchers found that there are “sensitive periods” when taste preference develops, one of which is before 3 1/2 months of age (ie prior to infants getting solid foods). this therefore supports breast-feeding, since the infants are exposed to more flavor variety than is in formula.  Maybe this early “sensitive period” is evolutionarily sound, since kids then encode for later life which foods they prefer to eat and are healthier. and maybe eating these foods may have a positive emotional impact later in life.

–australian study found that maternal exposure to junk food (energy-dense, high fat, palatable) led to children subsequently preferring these foods

–in rodents junk food exposure in utero and through breast milk led to less sensitive reward pathway in brain (ie, pregnant mothers fed fruit loops, cheetos, nutella had offspring with desensitization of the opioid receptor to sweet and fatty foods, presumably leading to increased tendency to ingest lots of junk foods to get the same “high” [maybe this ties in with the plethora of chronic pain/opiate emails/blogs i’ve sent out recently???? more addictive behaviors later in life?????], and perhaps to subsequent obesity

–in human babies, sweets have an analgesic effect (cry less, leave their hands in cold water longer), but in obese children sweets have less of an analgesic effect (supporting the opiate receptor desensitization finding in rodents noted above)

–so, hard to square claims by the food industry that it is personal responsibility in food choices  is even harder to support since pretty unlikely that kids in utero and in infancy really have the ability to make a personal decision….. this claim is pretty spurious anyway, given the conscious and unconscious effects of advertising by food makers and the physical inaccessibility to good food in the “food deserts”, such as the inner city or much of rural America.

the data above, not so surprisingly, supports the importance of a good, basic diet, minimizing prepared foods, food additives, food substitutes, etc. ie, eat pretty much what your grandmother would have told you to eat.

but, as with all such studies, there is not a 100% correlation between early nutrition and subsequent eating habits of kids and adults.  but i just wish that in my case more than 33.33% of my dear offspring ate some vegetables….. (and they were all breast-fed, good food with mostly fruits and vegetables, early childhood exposure to many different styles of cooking and differing flavors, almost no junk food… and they were even free-range to boot).

geoff

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