You don't need to be signed in to read BMJ Blogs, but you can register here to receive updates about other BMJ products and services via our site.

Archive for November, 2015

Primary Care Corner with Geoffrey Modest MD: Drug Company Shenanigans, This Time With Generics

19 Nov, 15 | by EBM

By Dr. Geoffrey Modest

The Boston Globe had a front page article on a relatively new face of drug companies’ relentless, seemingly inexorable pursuit of profit, this time extending more into generics. A recent blog mentioned a few generics with unconscionable price increases, noting that Daraprim (pyrimethamine) had a dramatic increase in cost (though this was apparently decreased after public outrage), as well as doxycylcine going from $20/bottle in 2013 to $1849 eighteen months later (see http://blogs.bmj.com/ebm/2015/09/30/primary-care-corner-with-geoffrey-modest-md-and-the-drug-company-shenanigans-continue/ ). The new Boston Globe article comments on several generic drugs increasing by up to 75 times their price over the past 2 years (see http://www.bostonglobe.com/business/2015/11/06/generic-drug-price-increases-alarm-insurers-providers-and-consumers/H3iA9CSxAUylnCdGjLNKVN/story.html?s_campaign=email_BG_TodaysHeadline&s_campaign=​  ). I will include below the examples they gave, since they did not come out in the link provided.

Details:

  • Globe examples (comparing 2013 to 2015 prices):
    • Amitryptyline 100 mg, was $0.04/pill in 2013, now $1.03 (a 2,475% increase)
    • Captopril 12.5 mg was $0.11/pill, now $0.91 (a 727% increase)
    • Digoxin 0.25 mcg was  $0.12, now $0.98 (a 717% increase)
    • Tetracycline 250 mg was $0.06, now $4.60/pill (a 7,567% increase)
    • Clobetasol, a very potent topical steroid, increased from $0.27/gram to $4.15/gram (a 1496% increase), meaning that a 30 gram tube went from around $8 to $125!!!
  • Generics comprise 80% of all prescriptions, so I guess it is not so surprising that the drug companies are targeting these drugs. And even though they are not nearly the price of the new hepatitic C drugs, many people are on these meds and often for a long time.
  • A survey by the National Community Pharmacists Association found “that virtually all were grappling with ‘large upswings’ in the costs of generics, with ‘overnight’ price changes sometimes exceeding 1,000 percent”
  • The issue is that drug prices are not regulated in the US (as opposed to many other countries), so there are no constraints on drug company price setting. And, there is no way that we guys in primary care have the time or ability to track these daily huge changes in pricing. And the issue is made worse by increasing mergers (e.g. the recent one of the generic-maker Teva Pharmaceuticals buying the generics division of Allergan PLC of Ireland in a $40.5B deal), decreasing the potential for competition
  • In case you thought that overall the drug companies are fair and responsible, and that they incur great R&D costs to develop new and really important drugs, see doi: 10.1136/bmj.e4348​, which highlights how few really significant innovative drugs are actually developed (only a small minority, on the order of 10-15% are not simply look-alike drugs, such as yet another ACE inhibitor), that 80% of basic research costs actually come from public sources, and that the drug companies have a remarkably inflated assessment of the costs of drug development (which, of course, they highlight whenever questioned about the high cost of drugs). And, of course, with regard to generics, there is $0 in R&D…

So, what’s wrong with this picture???

Primary Care Corner with Geoffrey Modest MD: Tighter Blood Pressure Control? The SPRINT Trial

19 Nov, 15 | by EBM

By Dr. Geoffrey Modest

So, the SPRINT study (Systolic Blood Pressure Intervention Trial) was finally released at the Am Heart Assn meeting (see prior blog http://blogs.bmj.com/ebm/2015/09/28/primary-care-corner-with-geoffrey-modest-md-aggressive-blood-pressure-management/ ), along with all of its details (see DOI: 10.1056/NEJMoa1511939). This was a large study looking at 2 different blood pressure targets and the associated clinical outcomes. The study was sponsored by the NIH/NHBLI (as opposed to the more usual drug company sponsors of studies).

Details:

  • 9361 patients (mean age 67.9, mean age of those >75 was 79.8; 30% non-Hispanic black, 11% Hispanic, 58% white, baseline BP 140/78, total chol 190 mg/dl, HDL 53, 52% on aspirin, 14% current smokers, BMI 30, 1.8 BP meds used) with systolic blood pressure (SBP) of 130-180 mmHg and an increased risk of cardiovascular disease (defined as one or more of: clinical or subclinical cardiovascular disease such as coronary artery calcium score, LVH or low ankle-brachial index, but excluding those with stroke; chronic kidney disease CKD with eGFR 20-59; 10-year risk of CVD of >15% by Framingham risk score; or >75 yo — 61% qualitfied by Framingham risk score, 28% each by age>75 or CKD), study in 102 clinical sites in the US, including Puerto Rico. All of the elderly in the study were from the community, not assisted living or nursing homes
  • The actual inclusion criteria for blood pressure were a tad more complex: SBP 130-180 mmHg on 0-1 med, 130-170 on up to 2 meds, 130-160 on up to 3 meds, or 130-150 on up to 4 meds. no diastolic inclusion criteria
  • Patients with diabetes, stroke and other conditions mentioned below were excluded
  • Randomized to achieve a systolic of <120 mmHg vs a target of <140mmHg.
  • The goal of the trial was not to test different med strategies, but to allow flexibility in the meds used. But, they did encourage using meds with the strongest CVD outcome data (thiazide-type diuretics, calcium blockers, ACE-I/ARBs). Thiazides-type diuretics were preferred as first line agents (preferentially chlorthalidone), loop diuretics in those with advanced kidney disease, b-blockers for those with coronary artery disease. amlodipine was the preferred calcium channel blocker. they also reinforced lifestyle changes
  • Primary composite outcome was: MI, other acute coronary syndromes, stroke, heart failure or death from cardiovascular causes
  • Proposed followup up of 6 years

Results:

  • ​The achieved SBPs were 121.4 mmHg and 136.2 in the intensive and standard treatment groups. Mean diastolic was 68.7 mmHg in the intensive and 76.3 in standard groups
  • Mean number of BP meds used was 2.8 in intensive and 1.8 in standard groups
  • Primary composite outcome occurred in 1.65% per year in the intensive group and 2.19%/year in the standard group, with an HR=0.75 (0.64-0.89), p<0.001
    • Heart failure HR=0.62 (0.45-0.84), p=0.002
    • ​Death from cardiovasc cause HR=0.57 (0.38-0.85), p=0.005
    • All-cause mortality HR=0.73 (0.60-0.90), p=0.003
    • No significant difference in MI, acute coronary syndrome, stroke
    • ​In those with normal baseline renal function, >30% reduction in eGFR to <60 was more common in those on intensive therapy, HR=3.49 (2.44-5.10), p<0.001
    • And, in general the curves showed improvement beginning about 1 year after therapy started, increased over the next 3 years, then plateaued
  • Subgroup analysis: basically no statistically significant difference by prior hx of CKD, age < or >75, sex, race, previous hx of cardiac disease, or baseline systolic pressure
  • Rates of serious adverse events were higher in those in the intensive group: hypotension (2.4 vs 1.4%), syncope (2.3 vs 1.7%), electrolyte disturbances (10.1 vs 7.4%), acute kidney injury or failure (4.1 vs 2.5%), but not injurious falls, and orthostatic hypotension more common in standard treatment group (18.3 vs 16.1%)
  • ​Study stopped early, after 3.26 years, because of statistically significant benefit

So, this is a really good study, showing pretty clearly that for the group overall, and several of the subgroups, there was a clear benefit of a lower blood pressure target. There are a few issues of note:

  • One of the most significant exclusions in this study was patients with diabetes. This clearly undermines the generalizability of the results, since hypertension and diabetes tend to run together for physiologic reasons (50% of patients with hypertension have diabetes and 80% of diabetics have hypertension: hypertension is associated with insulin resistance, and in therefore part of the Metabolic Syndrome; insulin causes renal sodium retention and contributes to hypertension). So, excluding diabetics effectively excludes a very large % of patients with hypertension. Other important exclusions affecting the study’s generalizability include: all participants were >50yo, none had SBP>180 mmHg, none had a prior stroke or had predominantly diastolic hypertension (though they did treat diastolic hypertension to <90 mmHg). Other exclusions included those with urinary protein excretion>1g/d, and symptomatic heart failure or EF<35%.
  • This study did not look at potentially subtle adverse effects of tighter blood pressure control, especially in the elderly. For example, an Italian study found that elderly with mild cognitive impairment had more rapid cognitive decline with lower achieved blood pressure (see http://blogs.bmj.com/ebm/2015/04/23/primary-care-corner-with-geoffrey-modest-md-too-low-blood-pressure-and-cognitive-decline-in-elderly/ ). Also, many elderly have initial orthostatic hypotension (vs the usual one, which in this study is defined as blood pressure after standing one minute — as described in the remarkably long and complete supplementary materials) and initial orthostasis is much more common than the usual one (see http://blogs.bmj.com/ebm/2014/12/18/primary-care-corner-with-geoffrey-modest-md-orthostatic-hypotension/ ).  They did in fact find more hypotension and syncope in the intensive treatment group, though more usual orthostatic hypotension in the standard group. This divergence in findings suggests that usual orthostatic hypotension is a less useful marker of the real clinical outcomes than initial orthostatic hypotension.  All of this raises the concern about falls, broken hips, even subtle cognitive deterioration — huge quality-of-life changes which might be more important to the patient than the potential decrease in cardiac events.
  • Although it makes sense to stop a trial early because of clear benefit, there is a very important potential downside (which I personally have never seen stated): a longer-term study allows us to see if there are important adverse events that do not become manifest in the foreshortened study: perhaps renal disease related to more aggressive blood pressure control really becomes clinically evident after 5-8 years (and they did find a short-term increase in CKD in this study). Or there are more falls/broken hips (which in this short study did not qualify as “injurious falls”, though there was more hypotension and syncope). Or there is more cognitive decline. So, stopping a study early as in this case focuses on the benefits of the intervention and minimizes the potential for finding longer-term risks (of course, some studies may be stopped early because of adverse events, but the point is that we are looking at potentially lifelong therapies and a short study may not really illuminate the long-term risks).
  • There are clear concerns about basing treatment strategies on clinic blood pressures. The USPSTF has finally come out with strong recommendations about the use of home-based or ambulatory blood pressure monitoring as more relevant markers of future clinical events​ (see http://blogs.bmj.com/ebm/2015/01/15/primary-care-corner-with-geoffrey-modest-md-uspstf-recs-on-ambulatory-blood-pressure-monitoring/ )
  • But, that all being said, I was concerned that the JNC-8 recommendations for BP treatment was surprisingly simplistic (though simple guidelines are much easier to adopt overall, I was pretty concerned about not incorporating reasonable data that diabetics, those with renal failure, etc., needed tighter control) — See http://blogs.bmj.com/ebm/2013/12/22/primary-care-corner-with-dr-geoffrey-modest-jnc-hypertension-guidelines-simple-goals/ for a review of JNC-8.  I do think that the pendulum swung a little far from the much more stringent goals in prior JNC guidelines. It is really great to have the SPRINT trial as a large, randomized intervention trial actually achieving a real difference in achieved blood pressures and showing a clear benefit (for example, one of the largest prior trials, the HOT, or Hypertension Optimal Treatment trial, only achieved a 2.9/3.1 BP difference between the groups, so was not so useful clinically).
  • So, bottom line, I do think the SPRINT trial fills a large gap in our knowledge about blood pressure goals. But there are a few caveats: we should be very vigilant around issues of orthostatic hypotension (i.e., regularly checking orthostatics, including initial orthostatic hypotension) and cognitive decline, especially in the elderly; and that we probably should use more home-based or formal ambulatory blood pressure monitoring more to make sure that the blood pressure is not a lot lower than it appears to be on clinic visit. But, given these issues, it seems pretty clear that we really should try to achieve lower blood pressure goals than in JNC-8.  My review of the supplemental materials indicate that at least some of these issues will be evaluated, including looking specifically at dementia, cognitive decline and MRI changes in the brain (e.g., small vessel ischemic changes) and published in future articles.

Primary Care Corner with Geoffrey Modest MD: Increasing Mortality of US White Population

18 Nov, 15 | by EBM

By Dr. Geoffrey Modest

​The NY Times had a striking article from 2 Princeton economists (including Angus Deaton, who just won the Nobel Prize in Economics) finding that white Americans aged 45-54 with no more than a high school education had an increase in death rates, largely attributed to​ suicides and substance abuse from alcohol and prescription opiates. In terms of racial comparisons, white Americans have a mortality rate of 415/100K, African-Americans are at 581/100K (though the gap is closing), and Hispanics have a much lower rate of 262/100K. For the NY Times article, see http://www.nytimes.com/2015/11/03/health/death-rates-rising-for-middle-aged-white-americans-study-finds.html?emc=edit_th_20151103&nl=todaysheadlines&nlid=67866768&_r=0 . The full article is also freely available (see doi: 10.1073/pnas.1518393112​).

Will summarize the article in more detail:

  • If the white mortality rate in those 45-54 had continued to decline at the rate it was from 1979-1998, 488,500 deaths would have been avoided in the period 1999-2013. This loss of life is comparable to lives lost during the AIDS epidemic though mid-2015.
  • Between 1970 and 2013, there was a 44% overall decrease in mortality for those 45-54 yo, attributed to behavioral change, prevention and treatment. Similar changes were seen in other wealthy countries. In the US, this was a decrease of 2%/year. But after 1998, in contrast to other rich countries’ mortality rates which continued to decline at 2%/yr, the mortality rates for US non-Hispanic whites rose by 0.5%/yr. See the first graph below: all groups (including US Hispanic) are trending down, with the solitary exception of US whites​ (in graph, USW=US whites, USH=US Hispanics).
  • The increases in mortality were largely in US whites with high school degree or less (37% increased mortality over 1999-2013, with an increase of 134/100K) and less so for those with some college but no BA (31%) and those with BA or more (32%).
  • In those 45-54 group, mortality was dramatically increased for drug and alcohol poisonings, but also for suicides and chronic liver diseases, with not much change for diabetes and decreased mortality from lung cancer (see 2nd graph below). In 2013, drug overdoses were highest in white non-Hispanic, and death from cirrhosis and chronic liver disease fell for blacks and rose for whites.
  • The increased mortality in white non-Hispanics increased for each 5 year grouping from age 30 to 64, but the increases were most dramatic in the 45-54 groupings (see last graph on below). Not shown was those 65-74, who continued to have decreased mortality at 2%/yr.
  • Morbidity increased in parallel to mortality: overall, comparing data from 1997-99 to 2011-13, there were significant changes in self-assessed health status, pain, psychological distress, difficulties with activities of daily living, and alcohol use. For example, one in three white non-Hispanics aged 45-54 reported chronic joint pain in 2011-13. The Kessler six questionnaire, which assessed serious mental illness, increased from 3.9% to 4.8% of respondants. There were significant decreases (2-3% range) in walking 1/4-mile, climbing 10 steps, standing or sitting for 2h, shopping, and socializing with friends; and the activities overall were limited by physical and mental health issues. Of note, though obesity played a role, increases in midlife morbidity increased both in those with BMI >30 and those <30.
  • “Concurrent declines in self-reported health, mental health, and ability to work, increased reports of pain, and deteriorating measures of liver function all point to increasing midlife distress.”​

So, pretty impressive/depressing. The CDC estimates that for each prescription pain killer death in 2008, there were 10 admissions for abuse, 32 ER visits for misuse/abuse, 130 people who were abusers or dependent, and 825 nonmedical opiate prescription users (so, mortality is really just the tip of the iceberg in terms of the full societal effects). One aspect in the current discourse not really addressed is the effects of economic insecurity and lack of adequate social supports in the US (it is notable that the economic downturn was worldwide over the past 7-8 years, but the increases in mortality were confined to the US). And the greatest change was in non-Hispanic whites with little education (unclear why US Hispanics did relatively better, but there may have been less of a dramatic change in their economic and social well-being during the downturn, as well as differences in social/community supports. International surveys indicate that overall Latin Americans have higher subjective well-being, despite lower incomes). Just raises yet again the 1879 Virchow quote: “Don’t crowd diseases (epidemics) point everywhere to deficiencies of society?”

Primary Care Corner With Geoffrey Modest MD: New HIV-1 Drug Approved by FDA

17 Nov, 15 | by EBM

By Dr. Geoffrey Modest

The FDA just approved a new single pill for the treatment of HIV-1. Genvoya (the new drug) is basically the same drug as Stribild (elvitegravir 150mg, cobicistat 150mg, emtricitabine 200mg and tenofovir disoproxil fumarate, or TDF,  300mg), but changes the TDF to tenofovir alafenamide 10mg (TAF). This is really a good evolution, since data over the last few years has confirmed that TAF has similar antiviral efficacy to TDF but much less renal toxicity and bone loss. The current FDA approval is for HIV-1 patients who are treatment-naive, over 12 years old, weighing more than 35 kg, as well as for adults with suppressed viral loads (<50 copies/ml) on a stable antiretroviral regimen. TAF has a much lower tenofovir dose than TDF, has lower blood levels, but higher intracellular levels (where the HIV-1 replicates). There is an accompanying boxed-warning that it can cause lactic acidosis and severe hepatomegaly with steatotosis, either of which can be fatal, and that it is not approved to treat hepatitis B infection. Common side effect is nausea. Genvoya is not recommended for patients with severe renal impairment (undefined), though can be used in those with moderate renal impairment. The European Union also approved its use in September. For the full but brief FDA press release, see http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm471300.htm​ .

A couple of comments:

  • Though the FDA warned against using Genvoya for hepatitis B, there are actually some small studies finding TAF is as good as TDF for treating hepatitis B (see Journal of Hepatology, 2015-03-01, Volume 62, Issue 3, Pages 533-540).  I.e., my guess is that they mean that we should not use Genvoya for sole hepatitis B infections, though it does sound reasonable to me to use Genvoya for those with a combo of HIV and hepatitis B (as I have been doing with prior HIV regimens that have TDF/FTC as a component). But I would follow the hepatitis B viral load closely, just to be sure.
  • My understanding is that the FDA approval was based on a few studies, including a non-inferiority study just released in the Lancet Infectious Diseases journal. There they looked at 1443 patients who were on one of 4 TDF-based regimens, were virologically suppressed, and had eGFR >50 ml/min, then randomized them to either the combo of elvitegravir/cobicistat/emtricitabine/TAF (i.e. Genvoya) vs continuing their prior meds (seeorg/10.1016/S1473-3099(15)00348-5). Bottom line: at 48 weeks, viral suppression with Genvoya was 97%, vs 93% if continued their old meds. Hip and spine bone mineral density, as well as GFR and proteinuria, were better with TAF (Genvoya) than in those on the TDF-based meds, though there were more adverse events in the TAF group (mostly not related to the drug, such as URIs, with somewhat fewer Grade 3 or 4 adverse events — 9% vs 11% with TDF). Nausea was present in 5% of those on Genvoya.
  • So, finally, TAF will be hitting the approved-drug lists. Hopefully in other forms as well (e.g., just replacing the TDF in Truvada, which is TDF and emtricitabine, with TAF). We’ll see what the cost will be….​

For other blogs on tenovofir in HIV, see:

http://blogs.bmj.com/ebm/2015/04/17/primary-care-corner-with-geoffrey-modest-md-updated-hiv-guidelines-2015/ which reviews the current guidelines and highlights stribild as one of the preferred initial drugs

http://blogs.bmj.com/ebm/2015/07/23/primary-care-corner-with-geoffrey-modest-md-tenofovir-nephrotoxicity/ which comments on how best to screen for tenofovir nephrotoxicity

Primary Care Corner with Geoffrey Modest MD: Exercise Benefit in Elderly

17 Nov, 15 | by EBM

By Dr. Geoffrey Modest

A systematic review/meta-analysis was recently published in the British Journal of Sports Medicine on the protective effects of even low amounts physical exercise in those >60yo (see doi:10.1136/bjsports-2014-094306). Current recommendations are for 150 min of moderate-intensity or 75 min of vigorous-intensity physical activity/week, as measured by the metabolic equivalent task (MET, which describes the intensity of energy expenditure for specific activities). For reference, resting energy expenditure is 1 MET, moderate activity is 3-5.9 METs (e.g. brisk walking) and vigorous activity is >6 METs (e.g., running). The MET-minute calculation is simply the sum of the #METs x #minutes x #days done/week for each of the activities. Studies suggest that there is substantial health benefits by performing 500-1000 MET-minutes/week (mortality benefit of 20-30%), the range suggested by the above recommendations.

Details:

  • 9 cohort studies included with 122,417 participants (60% women, mean age 72.9), and followed 9.8 years
  • 18122 deaths during follow-up period (14.8%)

Results:

  • Low amounts of moderate-to-vigorous physical activity (MVPA), expending 1-499 MET-min/wk, was associated with a 22% reduction in mortality risk [RR=0.78 (0.71-0.87), p<0.0001], though there was a difference between men (a 14% reduction in morality risk  [RR=0.86 (0.80-0.94), p<0.001]), as compared to women (a 32% reduction [RR 0.68 (0.63-0.74 p<0.00001]) –all of these RR’s are adjusted for age, sex, overweight, smoking, elevated BP, diabetes, plasma cholesterol, cardiovascular and chronic disease, cancer, depression, educational level and self-reported health
  • More extensive MVPA (expending 500-999 MET-min/wk), was associated with further mortality benefit of 28% in those following current recommendations of 150 min of moderate-intensity or 75 min of vigorous intensity physical activity/week) [RR=0.72 (0.656-0.80), p<0.0001]
  • Even more extensive exercise (>1000 MET-min/wk) had a 35% reduction in mortality [RR=0.65 (0.61-0.70), p<0.0001]
  • Of note, the relative benefit from the individual studies for each of the target exercises (low-dose, medium-dose and high-dose) were pretty consistent, even though the studies varied widely in participants (6 were from the US/2 from the Australia/one Asian).
  • The benefit was most dramatic in comparing those with low amounts of MVPA vs inactivity, with smaller incremental benefit as the amount of physical activity increased.
  • Subgroup analysis found mortality benefit in cardiovascular disease was the most profound in those doing 1-499 MET min/week of MVPA (a 25% decrease in mortality), going up to 500-999 MET min/week (decreased mortality insignificantly improved to 26%), and going to >1000 MET min/week (a more impressive decrease of 40%). For cancer the relative numbers were 11%, 16% and 31%.

One concern is that 60% of older adults are not able to achieve the 150 min/week as recommended.​ So,

  • This study reinforces that there is still significant benefit to less-than-recommended exercise duration, both for men and women (though this is more impressive in women than men as noted above). By this meta-analysis, we should not be rigid in recommending the 150 min/week of exercise (since that really may be too much for some people and ultimately result in no exercise being done). So, the real clinical issue for us is to convince those >60yo to just do exercise, as much as they can reasonably do, recognizing that most of the benefit seems to be achieved even with small exercise duration. One issue for those of us in the northern climates is to plot a strategy with the patient to exercise in the colder months. I have had some success in suggesting walking up and down stairs for 10-15 minutes/day. There are a few studies also finding that even light intensity exercise (1.6-2.9 METs) has health benefits over being sedentary.
  • An issue in a meta-analysis of observational studies is the question of reverse causation: is it that the healthier people tend to do more exercise, but the real increased longevity is because they are healthier, regardless of their doing exercise? The above meta-analysis did seem to control for chronic conditions and self-reported health status, making reverse causation less likely.
  • So, given all of this, and as several recent blogs have reinforced, I do think that one of the most important things we do for patients, including the elderly, is to reinforce and help patients eat well and exercise, and the above study suggests that we try to negotiate a reasonable exercise program and not simply prescribe one that meets the recommendations….

Primary Care Corner with Geoffrey Modest MD: Breast Cancer Risk and Mediterranean Diet

16 Nov, 15 | by EBM

By Dr. Geoffrey Modest

The PREDIMED study was a large dietary intervention trial which assessed different diets and looked at the subsequent development of invasive breast cancer (see JAMA Intern Med. 2015;175(11):1752-1760​). This was a single-blind randomized controlled field trial done in Spain from 2003-2009 looking at several different outcomes (see below). Breast cancer was a prespecified secondary outcome in women without a prior history of breast cancer.

Details:

  • 4282 women aged 60-80 at high cardiovascular risk  (mean age 67.7, BMI 30.4, 3% on hormone replacement therapy) were randomized to a Mediterranean diet supplemented with EVOO (extra-virgin olive oil), Mediterranean diet supplemented with mixed nuts, or a control diet with advice to decrease fat intake (the Mediterranean diet groups got free supplementary foods; after the first 3 years the researchers became more aggressive in outreach to the control group in an attempt to make the contacts from researchers more equal) and were followed a median of 4.8 years.
  • Achieved diet composition was pretty similar for total calories (approx 2000/d), % protein, % carbs, % fiber, % polyunsaturated fats, though there were strong trends for increased monounsaturated fats in both Mediterranean diets, a-linolenic acid in the nut diet, % EVOO in the EVOO diet (22%, vs 12.5% in the nut diet and 8.8% in low fat, but there was concomitant different % refined olive oil in the EVOO diet of 0.8% vs 5.9% in the nut diet and 6.7% in low fat: i.e., the total % of energy from olive oils was actually not so different between the groups). There was a pretty similar consumption of saturated fats (9.8% of energy in each of the Mediterranean diets and 8.8% in the low fat one).

Results:

  • 35 confirmed cases of invasive breast cancer
    • 1/1000 person-years in those on Mediterranean diet with EVOO
    • 8/1000 person-years in those on Mediterranean diet with mixed nuts
    • 9/1000 person-years in those on the low fat diet
  • Multivariable-adjusted hazard ratios:
    • Mediterranean diet with EVOO vs control: HR 0.32 (0.13-0.79)
    • Mediterranean diet with nuts vs control: HR 0.59 (0.26-1.35)  [ie, not significant]
    • Analyzing by annual cumulative updated dietary exposure: each additional 5% of calories from EVOO: HR 0.72 (0.57-0.90)

I have sent out a few previous blogs on the PREDIMED diet: one showing that the Mediterranean diet supplemented with EVOO was associated with lower likelihood of developing atrial fibrillation (see http://blogs.bmj.com/ebm/2014/06/24/primary-care-corner-with-geoffrey-modest-md-olive-oil-and-atrial-fibrillation/ ), one showing that this diet was associated with primary prevention of coronary artery disease (see http://blogs.bmj.com/ebm/2014/01/21/primary-care-corner-with-geoffrey-modest-md-mediterranean-diet-and-cad-primary-prevention/​ ), and one finding lower likelihood of developing diabetes (see http://blogs.bmj.com/ebm/2014/01/21/primary-care-corner-with-geoffrey-modest-md-mediterranean-diet-for-diabetes-prevention/ ).There was another PREDIMED study finding improved cognition in those on either of the Mediterranean diets (see  J Neurol Neurosurg Psychiatry 2013;84:1318–1325)

So, this present study does raise several issues:

  • There were a small numbers of events, so the results need to be confirmed by larger, longer-term RCTs.
  • The amount of EVOO consumed was pretty significant: there was a statistical benefit only in those consuming >15% of their cumulative energy intake from EVOO and increasing benefit with higher intakes.
  • ​It is unclear from this study design whether the benefit was from the high mono-unsaturates associated with olive oils overall, or to the higher concentration of polyphenols in EVOO (though the actual achieved olive oil consumption, as noted above, supports more the role of EVOO itself, since the actual total % of energy from all olive oils was pretty similar between the groups). There are some other data suggesting that some of the olive oil monounsaturates are associated with antiproliferative effects on human oncogenes and with decreased DNA oxidative damage. But olive oil polyphenols from EVOO have some effect in “inhibition of tumor growth and proliferation, migration, and invasiveness of breast cancer cells in vitro and in vovo breast cancer models” as well as increased apoptosis of cultured breast cancer cells.
  • ​One important point here is that this was a randomized intervention trial. Prior epidemiologic studies have found mixed results on the role of fat in increasing breast cancer risk, but these have been observational studies (the data are more consistent for alcohol as a “dietary” risk factor). The choice of the Mediterranean diet in PREDIMED was because of observational data that heart disease and breast cancer, for examples, are lower in Mediterranean countries than in the US or Northern/Central Europe. A secondary outcome of the old Lyon Diet Heart Study, a 4 year study of 605 patients with coronary heart disease, had found a 56% risk reduction for total deaths and a 61% risk reduction for cancers, though not specifically breast cancer, in those on Mediterranean diet vs low fat diet (see Arch Intern Med 1998; 158:1181).
  • ​But this study does raise, I think, the important point that a healthy diet has an array of benefits throughout the body. We in medicine are often so focused on one part of the body (should we lower the cholesterol to prevent heart disease?) that we may miss the big picture (in this case, the Mediterranean diet seems to be good for the heart, the brain, the pancreas, etc.). And this myopia in part leads to the finding in patients who take statins that they actually eat worse than before the statins (well, after all, the patient is taking a statin, their lipids are pristine, so all is good) — instead of our continuing to reinforce the multitude of known (and unknown but likely) benefits of eating healthfully.​

Primary Care Corner with Geoffrey Modest MD: Potassium Sparing Diuretics and Metabolic Changes

16 Nov, 15 | by EBM

By Dr. Geoffrey Modest

There has been a lot of controversy about the role of diuretics in the treatment of hypertension, with their not being in the first line therapy list of NICE (National Institute for Health and Care Excellence in the UK) and sometimes not used in the US as the initial agent because of adverse effects (hyperglycemia, hypokalemia, etc.). In this context, there was a short-term but quite impressive study in Lancet Diabetes&Endocrinology looking at their adverse effects in hypertensive patients assigned to hydrochlorothiazide, amiloride, or the combination in a government-supported study (see doi.org/10.1016/S2213-8587(15)00377-0).

Details:

  • Patients were 18-80 yo, withclinic systolic BP (SBP) >140 mmHg or home SBP >130 mmHg, and at least one other component of the metabolic syndrome, and excluding patients with known diabetes.
  • 441 patients were enrolled (mean age 62; 42% female; 89 kg; BMI 31; 9% smokers; clinic BP 155/91; home BP 150/86; 89% on ACE-I/ARB, 15% b-blocker, 42% calcium channel blocker, with mean of 1.5 BP meds; 33% with impaired glucose tolerance; serum potassium 4.1 mmol/L; and 99% had central obesity as a component of the metabolic syndrome, defined as men with waist circumference > 94 cm and women >80 cm)
  • For the modified intention-to-treat analysis 132 patients were randomized to amiloride 10mg, 134 to hydrochlorothiazide (HCTZ) 25mg, and 133 to amiloride/HCTZ combo pill with 5mg amiloride/12.5mg HCTZ for 12weeks, then double the initial dose of the meds for each group for another 12 weeks.

Results:

  • (Primary outcome): 2-hr results of oral glucose challenge test. Mean changes from baseline were
    • ​amiloride: -0.35 mmol/L (6.3 mg/dL) [i.e. got better]
    • amiloride and HCTZ: -0.22 mmol/L (4 mg/dL) [i.e. got better]
    • HCTZ: +0.20 mmol/L (+3.6 mg/dL) [i.e. got worse], so the net increase in those on HCTZ vs amiloride/HCTZ combo was 0.42 mmol/L (7.6 m/dL) higher
  • Other outcomes:
    • Clinic SBP: amiloride –baseline 153.8, at 12 weeks 140.8, at 24 weeks 135.4; combo baseline 156.2, at 12 weeks 136.7, at 24 weeks 133.4; HCTZ baseline 154.4, at 12 weeks 140.3, at 24 weeks 135.8 (difference of about 4.0 mm Hg lower SBP with combo over HCTZ, and significant at p=0.018 at 24 weeks
    • Home SBP: amiloride –baseline 149.3, at 12 weeks 138.3, at 24 weeks 134.4; combo baseline 150.6, at 12 weeks 136.1, at 24 weeks 132.3; HCTZ baseline 148.8, at 12 weeks 138.5, at 24 weeks 135.0 (difference of about 3.5 mmHg lower with combo over HCTZ, and significant at p=0.011 at 24 weeks
    • ​Potassium: with amiloride increased from 4.09 baseline  to 4.55 at 12 weeks and 4.61 at 24 wks, with combo increased from 4.16 baseline to 4.31 at 12 weeks, then back down to 4.14 at 24 weeks, and with HCTZ decreased from 4.21 baseline to 3.97 at 12 weeks then to 3.79 at 24 weeks (so, diff between combo and HCTZ was 0.46 on average, p<0.0001, though note that the combo did not lead to much of a change at 24 weeks when people were on double dose of the med)
    • ​Uric acid: overall essentially no change with amiloride, and equivalent changes with either HCTZ or the combo, increasing from a baseline of approx 345 mmol/L (5.88 mg/dL) to approx 385 mmol/L (6.47 mg/dL)
    • LDL did not change significantly with either HCTZ or the combo (which actually differs from prior studies finding some increase in LDL with thiazides)
  • ​Adverse events (overall numbers were not different, around 65%, between groups), but for hyperkalemia: 4.8% with amiloride (highest K was 5.8 mmol/L), and 2% with the combo (most in the 5.0-5.3 range, though they did not give the specifics). Most common adverse events were dizziness in 6% amiloride, 10% in combo, 11% HCTZ; muscle spasms in 9% amiloride, 9% of combo and 7% of HCTZ, and rest were <9%.

So, synthesis of all of these numbers above:

  • The combo pill was associated with improved blood pressure control over HCTZ (by systolic of about 4 mmHg), there was slight improvement in 2 hr glucose (difference with HCTZ of 7.6 mg/dL), and potassium was rarely elevated and only mildly so from an average baseline of 4.1 (though, remember that these were nondiabetic patients. the glucose effect may be more in diabetics)
  • ​Why does this happen: for the blood pressure, it is not unexpected to get some synergy between HCTZ and amiloride: thiazides cause sodium excretion in the distal tubule, and potassium-sparing diuretics prevent sodium reabsorption in the cortical collecting tubules. And, there are old experimental data showing that hypokalemia is associated with impaired insulin secretion by the b-cells of the pancreas (purported mechanism that b-cells have an ATP-dependent K channel, and that with higher K levels, more gets into the cells, leading to enhanced calcium-mediated release of insulin).
  • This study used a higher dose of HCTZ than we often use in the US, with its attendant increase in metabolic disarray. However, as I have pointed out in other blogs, there is an argument that the more-commonly prescribed 12.5 mg dose has inferior 24-hour effectiveness and lacks robust data confirming benefit in preventing clinically-relevant outcomes  (see doi:10.1016/j.jacc.2010.07.053).  It may also be of significance that there are no clinical outcome data that I know of/remember on the HCTZ/amiloride type combo drugs (though I doubt that outcomes would be worse, given the decrease in several potentially bad adverse events, such as hypokalemia or hyperglycemia)
  • ​In the past, I have usually prescribed the combination pill when patients have baseline potassium in the mid 3 range or lower. This study shows that not only does it seem safe to use the combo pill at higher potassium levels, but that there seem to be better outcomes (lower blood pressure and fewer metabolic sequelae). This study is pretty short-term (24 weeks), but does add to the argument for the combo pill over HCTZ alone for many patients (though, personally I still tend to follow the NICE guidelines of using a dihydropyridine calcium channel blocker for older and non-white patients, and use ACE-I in those who are <55yo and white. Unless there are other reasons to use a diuretic). And the potassium-sparing effect are also magnesium sparing (i.e. one loses less magnesium in the urine)

Primary Care Corner with Geoffrey Modest MD: Prescribing Alcohol to Diabetics?

13 Nov, 15 | by EBM

By Dr. Geoffrey Modest

An Israeli study was just published in which adults with type 2 diabetes were randomized to drinking wine vs water, and an array of cardiometabolic  parameters were assessed (see Ann Intern Med. 2015;163:569-579​) — the CASCADE trial: CArdiovaSCulAr Diabetes & Ethanol trial, which just goes to show you that you can develop an acronym pretty easily for just about anything.

9087-glasses-of-red-and-white-wine-isolated-on-a-white-background-pv

Details:

  • 224 patients (baseline: mean age 60, 69% men, BMI 30.0, HDL 1.12 mmol/L or 43.5 mg/dL, LDL 2.41 mmol/L or 93.0 mg/dL, cholesterol/HDL ratio 4.1, fasting plasma glucose 150.4 mg/dL or 8.3 mmol/L, HgbA1C=6.9%, BP 137/78, waist circumference 105 cm, and mean positive metabolic syndrome criteria was 3.1 of 5) were randomly assigned to 150ml of mineral water, white wine or red wine with dinner daily for 2 years. Previously, these subjects had drunk no more than 1 drink of alcohol/week (mean 2.3 g/d)
  • All followed a Mediterranean diet without calorie restriction
  • They also looked at alcohol metabolism/ ADH1B polymorphism, where 36% were CC, 38% were CT and 26% were TT (the TT polymorphism of ADH1B is also called ADH1B*2 rs1229984, and is associated with much faster hepatic clearance of alcohol); and assessed the homeostatic model assessment of insulin resistance score (HOMA-IR, a measure of insulin resistance), which was 5.0 at baseline

Results:

  • Those on red wine vs water had: increased HDL [0.05 mmol/L (0.04=0.06), or 2.0 mg/dl (1.6-2.2), p<0.001] and apolipoprotein A1 [0.03 g/L (0.01-0.06),p=0.05], and decreased total cholesterol/HDL ratio by 0.27 [(-0.52 to -0.01), p=0.039]. Those drinking white wine were not significantly different from water in terms of lipid changes (except that, interestingly, both the red and white wine drinkers did have decreases in triglycerides by .09 mmol/L or 7.9 mg/dL with white wine and -0.1 mmol/L and 12.0 mg/dL with red wine). White wine, but not red wine, was associated with significant decreases in fasting plasma glucose levels (decreased 1.0 mmol/L, or 17.2 mg/dL) and HOMA-IR scores.
  • Only when looking at the slow alcohol metabolizers (ADH1B*1 carriers), both red and white wine had better fasting plasma glucose, HOMA-IR​, and hemoglobin A1C levels similarly
  • ​And, sleep quality improved in those drinking wine (p=0.040)
  • But no difference in blood pressure, adiposity, liver function, drug therapy, symptoms, or quality of life
  • Overall, red wine led to decrease in number of components of the metabolic syndrome by 0.34 [(-0.68 to -0.001), p=0.049], not with white wine

So, there are a few issues here

  • There have been many studies and meta-analyses from observational trials suggesting that moderate amounts of alcohol ingestion are cardioprotective, largely attributed to the alcohol content itself. For more discussion of this, see http://blogs.bmj.com/ebm/category/alcohol/ for blogs on alcohol, and http://blogs.bmj.com/ebm/2015/02/20/primary-care-corner-with-geoffrey-modest-md-moderate-alcohol-and-cardioprotection/​ which argues that the attributable benefits from even small amounts of alcohol consumption are likely related to inherent biases in the observational data collection.
  • This study is the first I’ve seen where there is an actual intervention done. Of course, the intervention is not really through a randomized controlled trial since I suspect that those drinking wine were in fact aware that it was not mineral water. And, one wonders if there might have been other changes in the diet related to drinking wine with the meal, though all were instructed in Mediterranean diet guidelines – i.e., they did not monitor the actual dietary composition, and the glass of wine could have altered the choices or quantities of foods consumed.
  • As noted in prior blogs, not all HDL is the same, and there are nonfunctional and even pro-inflammatory variants (see http://blogs.bmj.com/ebm/2014/11/24/primary-care-corner-with-geoffrey-modest-md-hdl-a-negative-risk-factor-or-cholesterol-efflux/ , and will append an older blog on pro-inflammatory HDL at the bottom). So, looking at HDL numbers may not necessarily translate to cardioprotection.
  • If the findings of the study are indeed valid, they suggest that the effect of wine on diabetic markers is basically through the alcohol itself (since both red and white wine improve the diabetes markers especially in the slow metabolizers who have more sustained blood alcohol levels), while the lipid effects were more evident with red wine, suggesting that its particular components may be protective (perhaps the phenolic compounds: resveratrol and quercetin), perhaps through their antioxidant, endothelial or antiplatelet actions (though in general it is felt that the quantity of these in red wine is insufficient to achieve therapeutic effects)
  • So, interesting study, though I don’t think it provides definitive answers to the question. I.e., I’m not ready to suggest alcohol to patients yet… (and, per the 5/14/12 blog, the real answer will come from looking at real clinical events and not the surrogate markers of changes in cholesterol, since alcohol also increases the proinflammatory variant).

Here is blog from 5/14/12

Although the vast majority of epidemiologic 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. The clinical trial of Torcetrapib, a cholesterol 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 Harvard school public health (see doi:10.1161/JAHA.111.000232). 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 atherosclerosis independent of the LDL itself. They looked at the data from 2 large epidemiologic studies — Nurses health study (NHS, 121K female nurses) and the health professionals follow-up study (HPFS, 52K males), looked at stored serum and assessed the HDL C-III relation to cardiac events.

Results:

  • 14% 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%
  • 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, overweight and obesity were associated with 7% and 12% lower levels of HDL without apo C-III – i.e., overwt/obesity with lower of the good HDL.
    • Alcohol was 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

(i.e., several of these risk factors which change HDL also lead to more HDL with apo C-III)

 

Primary Care Corner with Geoffrey Modest MD: Prescribed Opioids and Future Prescription Opioid Misuse in Teens

10 Nov, 15 | by EBM

By Dr. Geoffrey Modest

Given the increasingly concerning issue of prescription opioid misuse, there was a disturbing article in Pediatrics finding that even appropriate use of prescription opiates in teenagers is associated with future opioid misuse (see  DOI: 10.1542/peds.2015-1364).

Details:

  • Prospective data from nationally representative cohorts of 6,220 12th-graders, followed up through age 23, in the Monitoring the Future study.
  • Initial survey data included questions on “legitimate” use of opioids, to see if the teens had ever taken narcotics because “a doctor told you to use them”, as well as use of marijuana/cigarettes/non-medically prescribed opiates/barbituates/alcohol, whether they disapproved regular use of marijuana, and some demographic and school performance questions. They also asked if in the last 12 months they had on one or more occasions taken “narcotics other than heroin on your own — that is, without a doctor telling you to take them”, followed by a list of brand-named and generic opiate pills, as well as questions about why they were taken (“to relax or relieve tension” or “to feel good or get high”)

Results:

  • Legitimate opioid use by grade 12 significantly predicted future opioid misuse later (increased 33%), 69% of the teens doing so to feel good/get high, or relax/relieve tensions.
  • This association was particularly strong in those 12th graders who are “least expected to misuse opioids”, including those who had disapproved or strongly disapproved of regular marijuana use and those without a history of baseline drug misuse. Teens in some of the lowest predicted risk strata for future opioid misuse (in the 1.75-3% probability) had a 3-fold increased opioid misuse if they had MD opiate prescriptions by 12th grade. Those in the 3-5% probability stratum had a doubling of opioid misuse later. There was no significant association of opioid misuse after being given legitimate opioid prescriptions in either the lowest risk group (0-1.75%) or in any of the groups with >5% risk. [For those unaware: the lowest risk stratum in this study was largely comprised of minority teens, which mirrors some other studies finding lower prevalence of opioid misuse among minority adolescents].

So, pretty impressive but observational study. Clearly there are a complex array of psychosocial factors involved in opioid misuse. But this study raises the question of whether us guys giving opioids to kids increases that risk. One reasonable inference from this study is that we should minimize giving opioid prescriptions to the most absolutely needy indications and at the lowest possible dose. In many cases NSAIDs or acetaminophen will suffice (e.g. studies show that NSAIDs work pretty much as well as opiates for kidney stone pain, reputedly one of the most severe pains).

Primary Care Corner with Geoffrey Modest MD: Drug Companies, Even More Shenanigans

10 Nov, 15 | by EBM

By Dr. Geoffrey Modest

The NY Times had a rather telling editorial 10/20/2015 about drug company shenanigans (see http://www.nytimes.com/2015/10/20/business/drug-makers-sidestep-barriers-on-pricing.html?emc=edit_th_20151020&nl=todaysheadlines&nlid=67866768&_r=0 ). It turns out that there is a prescription drug on the market called “Duexis”, which is a combination of ibuprofen and famotidine (both over-the-counter and cheap drugs) and costs $1500/month. Since insurers are hesitant to pay this amount for the drug, the drug company (Horizon Pharma) circumvents the issue by having a mail-order specialty pharmacy (“Prescriptions Made Easy”) affiliated with the drug company simply mail the med to the patient and then deal with the insurance companies.

A few details:

  • Horizon has increased the price 10-fold since it was introduced in late 2011.
  • Duexis has had a 72% increase in sales volume in the first half of this year compared with first half of last year, which translates to an increase of 131% to $73.1M.
  • Horizon also purchased the drug Vimovo, a combo of naproxen and Nexium, in 2013 and immediately raised the price 600%, further doubling it more recently, so the price is pretty equivalent to Duexis.
  • 71% of Duexis prescriptions and 61% of Vimovo went through the Prescriptions Made Easy program
  • One interesting sideline there is that a pharmacist’s wife was prescribed Vivomo, his pharmacy could not get the insurance company to approve it, but a specialty pharmacy (Linden Care) was able to send his wife the meds for a $10 copay (the specialty pharmacies do give copay assistance, decreasing the cost to the patient. This is illegal for Medicare and other federal programs since it unfairly prompts using very expensive drugs at a huge cost to the system. So, these specialty-pharmacy drug programs are marketed only to commercially insured patients.) [The 2 largest pharmacy benefit managers (Express Scripts and CVS Health) will not pay for Duexis an Vimovo.]​
  • Not surprisingly, other drug companies are doing the same: Valeant Pharmaceuticals International (making the news lately for its huge price increases and is being pursued by the feds — for another NY Times editorial, see http://www.nytimes.com/2015/10/27/opinion/is-valeant-pharmaceuticals-the-next-enron.html?emc=edit_th_20151027&nl=todaysheadlines&nlid=67866768&_r=0) uses their specialty pharmacy Philidor Rx Services.
  • Specialty pharmacies typically dispense complex drugs for rare genetic disorders, cancer, multiple sclerosis, but the ones used by Horizon and Valeant are dispensing common drugs for acne, toenail fungus and arthritis pain.​

So, needless to say, this brings up several issues:

  • One of the main issues here is that patients have little say into what medications are prescribed. They entrust their providers to choose the most appropriate meds (as is reasonable, though unfortunately some providers are swayed by the drug companies’ advertising and incentives inappropriately)
  • Another rather perverse feature is that the patient copay for Duexis is actually cheaper for patients than buying the over-the-counter meds (though way more expensive for the health care system)
  • Also most of us in primary care are unaware of the price of meds. Even if we knew the price at one time, these prices often increase dramatically and quickly, and I would wager few of us track these changes.
  • And, bottom line, our health care system is moving further and further away from the goal of providing high quality care as our raison d’etre.​

EBM blog homepage

Evidence-Based Medicine blog

Analysis and discussion of developments in Evidence-Based Medicine Visit site



Creative Comms logo

Latest from Evidence-Based Medicine

Latest from EBM