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Archive for July, 2016

Primary Care Corner with Geoffrey Modest MD: 2016 HIV Treatment Guidelines

29 Jul, 16 | by EBM

By Dr. Geoffrey Modest

The International Antiviral Society–USA panel just released their 2016 recommendations for antiretroviral drugs for treatment and prevention of HIV infection in adults (see Gunthard HF. JAMA 2016; 316(2): 191; and this group did include several HIV luminaries, such as Paul Sax from Brigham & Women’s and Paul Volberding from UCSF).

Summary:

  • When to initiate therapy:
    • Everyone who has detectable virus, independent of CD4 count; and as soon as possible after acute HIV infection (to reduce the latent HIV reservoir, immune activation and perhaps protection against infection of central memory T cells)
    • Also in those with persistent undetectable virus without ART (antiretroviral therapy) if declining CD4 counts, which can occur in these “elite controllers”, since they have higher levels of immune activation and increased cardiovascular risk. [I had such a patient who died in his 40s from lung cancer and minimal smoking history. Though lung cancer can occur in such patients not infected with HIV, there is a higher risk of lung cancer in HIV patients, and my guess is that his “controlled HIV” off medications played a part. Unclear if meds would have helped, however]
    • Start ART as soon as possible in patients with opportunistic infections (OIs), with the possible exceptions of cryptococcal meningitis (data from resource-limited settings showed poorer results with early treatment, though using flucytosine here seems to improve results). Need careful monitoring with active TB, esp TB meningitis, which has higher rates of immune reconstitution inflammatory syndrome (IRIS).
  • Recommended initial regimens
    • Dolutegravir/abacavir (ABC)/lamivudine (3TC)
    • Dolutegravir plus tenofovir alafenamide (TAF)/embricitaine (FTC)
    • Elvitegravir/cobistat/TAF/FTC
    • Raltegravir/TAF/FTC
    • A couple of comments:
      • They replaced TDF (tenofovir disoproxil fumarate) with TAF because of increased bone loss and renal dysfunction/proximal renal tubular toxicity with TDF. However TAF should not be used with rifamycins and there are limited data on pregnant women. And TAF may have worse lipid profiles than TDF.  But they note that TDF is basically fine to use if well-tolerated, more available in coformulation (i.e. with FTC), and potential concerns that TAF really has no long term data.
      • Only use ABC if HLA-B*5701 negative. Also still use cautiously in those with high cardiovascular risk, since a few studies have suggested an association with MI
    • All of these above regimens use InSTIs (integrase strand transfer inhibitors). suggested non-InSTI-based regimens include:
      • Darunavir (boosted with cobicistat or ritonavir) plus TAF/FTC or TDF/FTC, or ABC/3TC
      • Efavirenz/TDF/FTC (which, by the way, is generic, is associated with similar efficacy to the above regimens when patients are able to tolerate it, and would lead to a $900 million annual savings in the US over the prior branded version of Atripla -this study was done in 2012 prior to the newer ?more expensive regimens…. and efavirenz/TDF/FTC has been my go-to regimen for about 20 years and has done really, really well overall)
      • Rilpivirine/(TAF or TDF)/FTC
  • Special populations:
    • Hep B coinfected
      • Use regimen with TAF or TDF, 3TC or FTC, and a 3rd med for the HIV
    • Pregnant women
      • Treat the woman to improve her own health and decrease her likelihood of neonatal transmission
      • AZT/3TC has the longest track record, though has more toxic effects
      • Raltegravir is the recommended InSTI
      • Boosted atazanavir/r daily or darunavir/r bid are recommended PIs
      • Efavirenz is the recommended NNRTI after the 1st 8 weeks of pregnancy. Though if woman is on it before pregnancy, best to continue to maintain virologic suppression
    • Hep C coinfected
      • Use HIV meds that do not interact with Hep C virus therapies. Consult current HCV treatment guidelines
      • At this point, recommended regimens include dolutegravir/ABC/3TC; and dolutegravir or raltegravir plus TAF/FTC.
        • Specifically, would now avoid regimens with NNRTIs, boosted PIs or elvitegravir/cobicistat
      • Renal disease
        • Monitor all patients for development of kidney disease with eGFR, urinalysis, testing for glycosuria and albuminuria or proteinuria when ART initiated, changed, or every 6 months when HIV RNA is stable
        • Worst offender seems to be TDF and especially in combo with boosted PIs [for unclear reasons, they do not comment that the D:A:D study, Mocroft A Lancet HIV 2016; 3: e23 found pretty equivalent declines in eGFR with atazanavir-r and lopinavir-r as with TDF]
        • Not use or dose-adjust TDF if creatinine clearance<60
        • Not use TAF if renal function gets worse (esp proximal tubule dysfunction) or if creat clearance <30
        • Renal transplant is okay if ESRD, since high expectation of high rates of patient and graft survival [though, I should add, there are data that those with CD4<200 fare less-well, to the point that one of my patients on dialysis cannot get a renal transplant until his CD4 is consistently above 200]
      • Osteoporosis/fractures
        • Patients may lose 2-6% of bone mineral density at the hip and spine in first 1-2 years. greater initial decline with TDF-containing regimens, so avoid in osteopenicpatients
  • CD4 count and primary OI prophylaxis
    • Prior guidelines for OI prophylaxis were based on CD4 counts
    • They feel that for patients achieving viral suppression with ART, the incidence of MAC (mycobacterium avium complex) has declined so much that primary prophylaxis is not recommended, though not enough data on PCP (pneumocysitis jirovecii pneumonia) so should still use prophylaxis (see my comment below)
  • Lab monitoring (not much change):
    • The usual: initial CD4, viral load, hepatitis serologies, comprehensive metabolic panel, urinalysis, STIs, lipids. Also genotype testing for resistance.  Recheck 4-6 weeks after starting ART. Then every 3 months for a year. Then can go every 6 months for adherent patients with suppressed virus. They also suggest checking HLA B*-5701 prior to initiating ABC treatment (though I do check it routinely on initial presentation in case I need to change meds later)
    • If pretreatment CD4<200, check every 3 months until viral load reliably suppressed and CD4>350 for 1 year. Then every 6 months until virus suppressed for at least 2 years and CD4>500
    • When virus suppressed for >2 years and CD4>500, repeat monitoring of CD4 unnecessary unless virologic failure (defined as viral load >200)
    • If viral load rebounds to >50, assess for causes of virologic failure (in particular medication adherence, and food-drug interactions)and repeat in 4 weeks
    • Typically virologic suppression occurs within 24 weeks of ART initiation
    • If virologic failure, check genotype (consider proviral DNA assays to estimate archived resistance if the viral load is below 500-1000, the limits of the regular genotype assay) and change ART meds (studies mostly suggest that viral loads in the 50-200 range should be monitored more closely, since the data are inconsistent about virologic failure)
    • Can do InSTI resistance testing if patient fails therapy and has not stopped ART for >1 month.
  • Engagement in care/adherence
    • Early diagnosis is important. We should use an opt-out strategy for testing (i.e., present testing to the patient as a usual lab test, allowing for patients to actively opt out of testing)
    • Retention in care is key: 30% of new HIV infections are in people with undiagnosed infections, 60% in those not engaged in care
    • Predictors of not being engaged in care include:
      • Substance use (and methadone maintenance programs/opioid substitution therapy are great ways to retain patients in HIV care)
      • Depression
      • Directly observed treatment is helpful (as in methadone programs or other daily contacts with patients)
    • Patient navigators and care coordinators help
  • Prevention (not much change):
    • Treatment as prevention is primary strategy
    • Pre-exposure prophylaxis (PrEP), especially if population has HIV incidence >2%/yr. can be daily TDF/FTC (which they prefer) or intermittent (see blogs below)
    • Immunize against hep A,B. Check for STIs. Follow at least every 3 months
    • Post-exposure prophylaxis as soon as possible after exposure (prior to test results, and within 72 hours per most guidelines). Use TDF/FTC plus raltegravir bid or dolutegravir daily and continue 28 days. Check HIV serologies at 4-6 weeks, 3 months, and 6 months later. Can also use TDF/FTC plus boosted darunavir or TDF/FTC/cobicstat/elvitegravir

Commentary:

  • In terms of OI prophylaxis, I’m not sure I’m ready to stop MAC prophylaxis based just on viral suppression. I have seen a few patients on long-term ART with consistent viral suppression but who maintain very low CD4 counts (on the order of 50). The data supporting not using MAC prophylaxis is from a small study (see Yangco BG. AIDS Patient Care STDS 2014; 28(6): 280) of 41 patients eligible for MAC prophylaxis by CD4 count but not on it, put on ART with subsequent viral loads <1000, and finding no MAC infections. BUT, this was an observational study; of the only 11 MAC infections in the overall cohort (n=369), the infections happened 43-126 days after starting ART; and there are no data on how their CD4 counts changed after 1-2 months on therapy (i.e., did these patients remain below the 50 cells/mL level while on therapy???). The paper’s conclusion was “primary MAC prophylaxis may not be required for virologically suppressed patients with CD4<50 cells/ml”.  So, out of caution and without a clear study, I personally would still keep patients on prophylaxis until their CD4 counts increase sufficiently (>50).
  • A still unanswered and not so uncommon situation is immunologic failure: patients who continue to have viral suppression but have deterioration of their CD4 counts. I have had several patients with this, and my very anecdotal experience is that patients have a pretty sustained increase in CD4 when I have added/switched to dolutegravir.
  • So, this guideline reflects the fact that the treatment of HIV infection has been transformed more rapidly and dramatically than any treatment I have seen. It has gone from a disease with essentially 100% mortality, despite taking >30 pills/day with meds up to every 4-5 hours throughout the day and night, and lots of adverse reactions, to an essentially 100% treatable disease with 1 pill a day and no adverse reactions. In fact HIV infection is now much easier to treat than hypertension and much much easier than diabetes…

 

See:

http://blogs.bmj.com/ebm/2015/12/23/primary-care-corner-with-geoffrey-modest-md-hiv-therapy-without-nrtis/ for a blog on HIV therapy without NRTIs, in those intolerant or resistant

http://blogs.bmj.com/ebm/2015/10/05/primary-care-corner-with-geoffrey-modest-md-hiv-pre-exposure-prophylaxis/ for a blog on the PROUD trail of daily TDF/FTC as PrEP

http://blogs.bmj.com/ebm/2015/12/18/primary-care-corner-with-geoffrey-modest-md-on-demand-hiv-pre-exposure-prophylaxis/ for the IPERGAY trial of on-demand TDF/FTC PrEP

Primary Care Corner with Geoffrey Modest MD: Gonorrhea Resistance Increasing?

27 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A rather disturbing MMWR just came out finding that gonorrhea is becoming increasingly resistant to pretty much all of our current antibiotics (see http://www.cdc.gov/mmwr/volumes/65/ss/pdfs/ss6507.pdf ).

Details:

  • The Gonococcal Isolate Surveillance Project (GISP) has been around since 1986 and does sentinel surveillance of antimicrobial sensitivity for N. gonorrhoeae (GC). They check GC cultures and antibiotic susceptibility from the first 25 men with gonococcal urethritis attending each of the participating STD clinics at 27 sites in the US.
  • They are able to extract selected demographic and clinical data
  • Mean age 28, 58% Black/22% white/13%Hispanic-Latino; 37% MSM or MSMF (men who have sex with men, or both men and women)

Results:

  • 5093 isolates were collected in 2014 (all of the resistance patterns were more common in MSM)
    • 3% resistant to tetracyclines
    • 2% resistant to ciprofloxacin (increasing, though there was an initial dip after the CDC stopped recommending its use to treat GC)
      • 2% resistant to penicillin (plasmid-based, chromosomal, or both) — though CDC has not recommended using it for treatment of GC since 1989
    • But of major significance:
      • 5% had reduced susceptibility to azithromycin (0.6% in 2013):
        • In all geographic areas of the US, but most in the Midwest (Midwest about 4%, Northeast about 2.7%, rest about 2%)
        • In all groups of sex partners (MSM about 4.3%, MSMW about 3.2%, and MSW about 1.5%)
        • None of these azithro-resistant isolates had reduced ceftriaxone or cefixime susceptibility
      • 8% had reduced susceptibility to cefixime (0.4% in 2013)
      • 1% had reduced susceptibility to ceftriaxone (no change from 2013), though highest in Northeast (about 0.4%).
      • 38% of isolate exhibited resistance to some antibiotic;  and 10% to 2, 7% to 3 and 0.5% to 4 antibiotics

Commentary:

  • Gonorrhea is the 2nd most commonly reported notifiable disease in the US, with 350,062 cases reported in 2014
  • The role of GISP is especially important, since we have mostly gone to NAAT testing (nucleic acid amplification tests) instead of GC culture, and one needs to grow the GC in culture to test susceptibility
  • Though the numbers of resistant isolates to the azithro and ceftriaxone are still pretty low, it is important to remember that there is a critical threshold (inflection, or tipping point), where the prevalence leads to a dramatic increases in their transmission (which, from my rather distant memory is on the order of 8%). So the 4-fold increase in azithro resistance to 2.5% may be really foreboding
  • Limitations of the study: a big one is that only men with urethritis were tested (and MSM,MSMW were disproportionately represented); another is that we do need to see infectious diseases more and more through a global perspective. What is happening in the US is not isolated from the rest of the world. And though the resistance level to ceftriaxone is still relatively low in the US, in other areas the levels are much higher (the WHO report in 2014 found >25% resistance to 3rd generation cephalosporins in 3 of the 6 regions of the world. See http://blogs.bmj.com/ebm/2014/07/11/primary-care-corner-with-geoffrey-modest-md-whos-remarkable-scary-report/ for details.)  Also, with such low numbers of resistance reported by GISP (especially for ceftriaxone), sampling error could lead to rather large % changes in the numbers (only about 1% of the reported cases were actually sampled, and my guess is that there are many more cases of GC than those reported….)
  • CDC recommendations remain the same: treat GC with ceftriaxone 250mg IM plus azithro 1gm orally (the combined meds are synergistic and cover for each other’s resistance for now, since there are no reported cases of resistance to both). Use azithro 2g plus gentamicin or gemifloxacin if intolerant of cephalosporins. Cefixime had been considered an acceptable cephalosporin to use until 2012, when recommendations changed because of increasing cefixime The decreasing cefixime resistance reported now may not be significant, since it is not simultaneously decreasing in other areas of the world. It is still not recommended by the CDC.
  • And, the striking increase in azithromycin is very concerning because if it continues to increase, the mainstay of GC treatment will become increasingly ineffective, especially in the context of increasing cephalosporin resistance in much of the world. GC may become effectively resistant to all meds we currently have….

For a slew of blogs on antimicrobial resistance, see http://blogs.bmj.com/ebm/category/antimicrobial-resistance/

Primary Care Corner with Geoffrey Modest MD: USPSTF Diabetes Screening Misses Most People

26 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A study looked at the sensitivity/specificity of the current USPSTF guidelines for diabetes screening in a community setting, finding over half the cases are missed (see http://journals.plos.org/plosmedicine/article/asset?id=10.1371%2Fjournal.pmed.1002074.PDF ). The USPSTF in 2015 recommended diabetes screening for those aged 40-70 and who are overweight/obese.

Details:

  • Retrospective analysis of electronic health record data of 50,515 adult primary care patients seen between 2008-2010 in 6 health centers in the Midwest and Southwest, followed for up to 3 years (median 1.9). [This screening was prior to the 2015 USPSTF guidelines]
  • 18,846 (37%) were >40 yo; 33,537 (66%) were overweight or obese; 39,061 (77%) were racial/ethnic minorities (35% Black, 334% Hispanic, 9% other)
  • They excluded patients with dysglycemia (glucose intolerance or diabetes) at baseline
  • They then compared the actual findings of dysglycemia (by the usual fasting or post-prandial sugar/A1c) criteria with who would have not been screened if adhering to the later-published 2015 USPSTF guidelines

Results:

  • 29,946 (59%) had a glycemic test within 3 y of follow-up
  • 8,478 of them developed dysglycemia (78% by using the A1C criteria)
  • 12,679 (25%) of the 50,515 patients overall would have been eligible for screening per the 2015 USPSTF guidelines
    • Overall sensitivity of the guidelines was 45.0% (43.9-46.1%)
    • Overall specificity was 71.9% (71.3-72.5%)
    • PPV was 38.8% and NPV was 76.8%
    • Subgroup analysis:
      • Compared to normal weight: overweight people had 31% more dysglycemia; obese 145% increase
      • PCOS 124% increase
      • Dramatic increases in dysglycemia in those with increasing number of diabetes risk factors (the Am Diabetes Assn risk factors as noted below)
    • On multivariate analysis, significant associations with the development of dysglycemia: age >40, overweight/obese, nonwhite race/ethnicity, hypertension, PCOS, history of gestational diabetes, family history of diabetes
    • Dysglycemia cases in racial/ethnic minorities were significantly less likely to be eligible for USPSTF-guideline based screening, though they had higher odds for developing dysglycemia (OR for Black patients 1.24; Hispanic 1.46). The sensitivity for different racial/ethnic groups was:
      • White: 54.5%
      • Black: 50.3%
      • Hispanic/Latino: 37.7%
      • And the lower sensitivity in racial/ethnic minorities reflects the greater proportion of patients who developed dysglycemia at a normal weight and under 40 yo (e.g., 20% of Hispanic/Latino patients of normal weight developed dysglycemia, as well as 31% of those <40yo)

Commentary:

  • Diabetes is really common: from the USPSTF document: “approximately 86 million Americans aged 20 years or older have IFG or IGT. Approximately 15% to 30% of these persons will develop type 2 diabetes within 5 years if they do not implement lifestyle changes to improve their health”
  • Many studies over the last several decades in several different countries show that intensive lifestyle interventions can prevent or at least delay the development of diabetes, with reasonable argument that this would significantly decreased the associated micro- and macrovascular morbidity. This strongly supports the likely utility of screening/potential for earlier intervention.
  • It should be noted that the Am Diabetes Assn has much more expansive guidelines (see http://care.diabetesjournals.org/content/suppl/2015/12/21/39.Supplement_1.DC2/2016-Standards-of-Care.pdf , p16) for testing asymptomatic adults:
    • All overweight (BMI >25, or >23 in Asian-Americans) with at least one additional risk factor: physical inactivity, first-degree relative with diabetes, members of high-risk ethnic group (African American, Latino, Native American, Pacific Islander), women who had baby >9 # or had gestational diabetes, hypertension, HDL <35 or triglyceride >250, other clinical condition associated with diabetes (e.g. acanthosis nigricans), history of CVD
    • In absence of above, everyone at age 45
  • The NICE guidelines in the UK focus on those at high diabetes risk, independent of obesity (see https://www.diabetes.org.uk/Documents/About%20Us/What%20we%20say/Position%20Statement%20-%20Early%20identification%20of%20people%20with%20Type%202%20diabetes%20(Nov%202015).pdf )
  • There are clear limitations of this study. This was not a prospective study of all-comers to assess the prevalence of dysglycemia, along with individual risk factors. And even in the PLoS analysis, they do not disaggregate the issues of age<40 and normal weight (i.e., it is not entirely clear if normal weight people who also are <40 yo have a significant incidence of dysglycemia). [On my brief search, I was quite surprised at how little epidemiological data was available on the prevalence of glucose intolerance in the US population, including different ethnicities/other subgroups.]
  • My experience absolutely reflects the results of the PLoS study: we find many people who have either glucose intolerance or diabetes who would not qualify under the current USPSTF guidelines (I have been using the Am Diabetic Assn guidelines, though I should add that in our health center, a very large % of our patients under age 40 do qualify for testing by these guidelines). However, though this study is not definitive, it really raises the ante: it seems that a fair number of patients under 40yo or with normal weight have dysglycemia. And it seems to me that the benefits (early reinforcement of intensive lifestyle changes) far outweigh the risks….

By Dr. Geoffrey Modest MD: AHA List of Meds to Avoid in Patients with Heart Failure

22 Jul, 16 | by EBM

By Dr. Geoffrey Modest

The American Heart Association has published a long article on medications which could cause or exacerbate heart failure (HF). For the complete text, see http://circ.ahajournals.org/content/circulationaha/early/2016/07/11/CIR.0000000000000426.full.pdf)

  • HF is the leading hospital discharge diagnosis in patients >65yo. This group has a very high medication burden (given their age and the likelihood that they have multiple risk factors and medical comorbidities), and on average are on 6.8 medications/d with 10.1 doses/d, not including OTCs (over-the-counter meds) and CAMs (complementary and alternative meds). In one study, 88% of HF patients used OTCs and 35% herbal supplements/63% vitamins. These multiple meds expose patients to more adverse drug effects, exacerbated by the increased likelihood for drug-drug interactions
  • These are the commonly used primary care drugs listed in the article:
    • NSAIDs – pretty well-documented increases in HF precipitation and exacerbation, including both the nonselective and COX-2 inhibitors
    • Anesthetics and oncology drugs – will not comment much, since not such a primary care issue, but many can affect cardiac function or exacerbate heart failure (an array of direct cardiotoxins, as well as those that cause peripheral vasodilation, hypotension, increased sympathetic nervous system activity)
    • Metformin – initial concerns about lactic acidosis (a carry-over from phenformin, its no-longer-available relative associated with severe lactic acidosis and frequent deaths). BUT the FDA in 2006 removed HF as a contraindication for metformin, noting that in patients with HF, “the risk of metformin-associated lactic acidosis was minimal and similar to that of other diabetes mellitus medications in patients with HF and that metformin was associated with an overall reduction in mortality” (my emphasis). There is still some concern about using metformin in unstable HF patients or those hospitalized for HF, and they cite the 2016 Am Diabetes Assn guidelines as the source (for further analysis of this, see my commentary below).
    • TZDs and DPP-4 inhibitors for diabetes – reasonable data against using these meds in patients with HF
    • The array of antiarrhythmics with negative inotropy (flecainide, esp inthose with existing LV dysfunction; disopyramine; sotalol; dronedarone)
    • Antihypertensives:
      • Calcium channel blockers (diltiazem, verapamil, nifedipine). [The nifedipine issue is a little unclear to me: a small study (n=21) found worsening of HF. For its cousin amlodipine, an initial study actually found benefit for amlodipine in those with HF, however not replicated in a follow-up study, but there was no overall harm. There is more peripheral edema and pulmonary edema with both of these drugs, so I would be hesitant to use them acutely in patients with unstable HF, but for unclear reasons nifedipine but not amlodipine are on the AHA list. Not sure why the difference
      • a-blockers (prazosin, doxazosin): cause vascular smooth muscle relaxation and increased HF (e.g. ALLHAT trial)
      • Centrally-acting a-agonists: (clonidine). Small studies actually show some improvement in patients with HF, by decreasing sympathetic tone and improving hemodynamics, but the potential for bradycardia and AV dissociation are of concern
    • Selective a1-blockers (tamsulosin, etc.): seem to be associated with increased HF hospitalizations, esp if not getting concomitant b-blockers (suggesting unopposed a1 stimulation could lead to b1-receptor stimulation, with increases in renin/aldo, and edema). No clear data that there are HF exacerbations, but still a concern and should be used cautiously
    • Itraconazole, though terbenifine also has liver toxicity but is not associated with HF and is not on the list
    • Albuterol (from decreased b-receptor responsiveness with continued use)
    • Cilostazol: associated with increased heart rate, PVCs/nonsustained ventric tach, though no data showing increased risk of arrhythmias in those with HF. But best to avoid
    • Stimulants (amphetamines, etc.): increase blood pressure, reports of sudden death, acute coronary syndromes, MI, etc. But large epidemiological studies do not confirm excess of serious cardiovasc events
    • Anti-epileptics: carbamazepine is associated severe LV dysfunction seen clinically only with overdoses, though there is potential for hypotension, bradycardia, AV block; pregabalin is associated with peripheral edema, perhaps from direct vascular effects and not from HF (as with dihydropyridine calcium channel blockers) though some HF case reports
    • Antipsychotics: both typical and atypical are associated with sudden cardiac death, arrhythmias, prolonged QTc intervals, tachycardia and hypotension
    • Antidepressants:
      • Tricylcic antiderpressants are associated with tachycardia, postural hypotension, AV conduction, increased QTc, and can be associated with cardiomyopathies.
      • Citalopram is associated with increased QTc, though very rare case reports of torsades, and hard to disentangle the many other meds being taken by patients in these case reports that could also cause torsades. Also, the limited case report data suggest no citalopram dose-relationship
    • Anti-parkinsons meds: valvular regurgitation with pergolide or cabergoline. Limited similar data on bromocriptine. But large epidemiological studies did not find much harm
    • Bipolar meds: lithium is associated with bradyarrhythmias, PVCs, AV block, T-wave depression, cardiomyopathy.
    • Hydroxychloroquine: 70 cases of cardiotoxicity
    • OTC meds: a few of the bad actors above (e.g. NSAIDs) are available OTC, along with vasoconstrictors (phenylephrine/pseudephedrine) which can cause cardiotoxicity, sympathomimetics (asthma meds), and many OTCs are formulated with lots of sodium (cough/cold meds, gaviscon)
    • CAMs: some of clear concern (ma-haung, an ephedra-like product which can cause increased blood pressure and heart rate), even vitamin E >= 400IU has been associated with HF. Some CAMs have significant interactions with cardiovasc meds used for HF (especially grapefruit juice, St. John’s wort, black cohosh). The major concern is the lack of studies showing the safety of the vast majority of CAMS

Commentary:

  • My concerns:
    • They lump together clear cardiotoxins, with documented meds which lead indirectly to HF exacerbations (NSAIDs), with really beneficial meds with little data suggesting adverse HF effects (e.g. metformin). Though they do defend their list by citing important studies, and they duly note that there are differing levels of HF concern, I fear that when the lists are published and widely spread, these major differences may be blurred over and may lead to fear of using important and helpful meds. And many of the above AHA concerns are based more on theoretical issues and not hard data (e.g. carbamazepine).
    • In terms of their listing metformin:
      • There are pretty impressive small studies showing benefit for metformin in those with HF. But the AHA listed that it was potentially a cause of problems (lactic acidosis) especially in those with unstable or hospitalized with HF. They cite the ADA recommendations, which cite a 2013 comparative safety and effectiveness study (see Eurich D. Circ Heart Fail. 2013; 6: 395), which not only did not cite any data on metformin use in such patients (and did not recommend against metformin use in these patients), but notes no increased risk of lactic acidosis overall and that metformin was associated with a small reduction in all-cause hospitalizations in those with HF (including those with LVEF <30%) and chronic kidney disease!!!
      • There are animal data suggesting that metformin improves cardiac function (decreases oxidative stress, improves insulin resistance, prevents progression of HF, improves cardiac structure/function/survival, attenuates LV remodeling and improves cardiac mechanical efficiency….)
      • And, in their assessment of the “Magnitude of HF induction or precipitation” they classify of metformin as being a “major” risk with the possible mechanism being “lactic acidosis”, which seems to me to be pretty unwarranted. especially since the studies overall and the FDA do not support an increase in lactic acidosis
    • But, this brings up an issue in medicine: carrying over information which may be distorted in one paper (the ADA recommendations), though on looking at the actual source, there was no such data or conclusion. I definitely see articles where the abstract distorts the conclusions from the actual study and, as above, where the supporting references for a statement in fact do not support the statement. I think this is less frequent now than several decades ago, but is still an issue (as in this metformin case)
  • So, bottom line: I am concerned that this list could be used indiscriminately to avoid using important drugs, even though the different drugs are noted to have markedly differing levels of potential problems. Clearly there is a difference between drugs directly related to clinical HF and those with potential mechanisms but little clinical data. And I would add that there is a real difference between some very important drugs clinically (e.g. nifedipine/amlodipine, where the importance of lowering blood pressure and the attendant clinical benefits may far outweigh the potential adverse effects), and those drugs which either have not a huge clinical impact or there are safer alternatives (e.g., for onychomycosis, I do not use itraconazole anymore, mostly terbenafine; or citalopram, where there are no good clinical data that these really are bad, but there are so many alternatives that can be used, such as sertraline). And, even in terms of metformin (my biggest concern in this AHA list), I personally would still be careful using it in patients with unstable HF, since there is not much of an upside (no real harm in waiting a short time when the patient is unstable, though I would use it at low dose in those who are chronically unstable and with okay renal function, see blog below) and there is the potential (though not well-documented) downside of lactic acidosis. However, if the drug is on the above list, it certainly does make sense to watch these patients a bit more closely.

For more blogs on metformin, see http://blogs.bmj.com/ebm/2016/04/26/primary-care-corner-with-geoffrey-modest-md-fda-changes-metformin-guidelines/ , which includes the revised and much more lenient FDA recommendations on metformin use in those with kidney disease, as well as other blogs (showing, for example, that metformin induces changes in the microbiome leading to decreased insulin resistance).

Primary Care Corner with Geoffrey Modest MD: Lung Cancer Screening for Smokers, an Individual Risk-Based Approach

20 Jul, 16 | by EBM

By Dr. Geoffrey Modest

The USPSTF strongly recommends low-dose chest CT (LDCT) annual screening for ever-smokers with >30 pack-year smoking history aged 55-80 or until they are 15 years after stopping smoking, based on the 3-year National Lung Screening Trial (NLST). JAMA just published an article evaluating the use of risk models/individual risk-based strategies to help focus the LDCT intervention (see  doi:10.1001/jama.2016.6255). By looking at individual lung cancer risk beyond the criteria of NLST, they actually found relatively higher risk in some patients with a low risk by NLST (and therefore no screening done in NLST or offered by USPSTF) but a low risk for many included in the USPSTF guidelines. Of note, there is no currently accepted validated risk tool for lung cancer for population screening.

Details:

  • They looked at 3 databases: the CXR-only wing of the NLST (2002-2009), the ever-smokers control group of the Prostate, Lung, Colorectal, and Ovarian cancer screening trial (PLCO, 1993-2009), and the National Health Interview Survey (NHIS, 1997-2001)
    • PLCO: 155K US men and women 55-74 yo had 4 annual CXRs and found no benefit from screening CXR in smokers
    • NLST randomized 53.5K smokers aged 55-74 with at least 30 pack-years smoking to LDCT vs CXR and found 20% decrease in lung cancer mortality by LDCT
    • NHIS: 87.5K people followed in annual cross-sectional US group from 2004, with linkage to the National Death Index. This database from 1997-2001 was used to validate the lung cancer death model. Then the model was applied to a more contemporary US population (NHIS 2010-2012) looking at all ever-smokers aged 50-80, which included 18,643 people, 52% male, 72% white/15% black/9% Hispanic, 55% post-high school education, 32% with BMI>30, 36% current smoker and 26% <10 pack-yrs, 21% 10-20, 15% 20-30, 14% 30-40, 24% >40; 67% had quit >15 years; 98% no family history, 7% had emphysema.
  • They assessed an array of characteristics from these databases (including age; education; sex; race; smoking intensity, duration, and quit-years; BMI; family history of lung cancer; self-reported symptoms of emphysema) to develop risk-based models for lung cancer incidence and deaths, then applied that to the later NHIS database.

Results:

  • Hazard Ratios for lung cancer incidence (will only mention the really significant ones)
    • Age, very highly correlated with lung cancer incidence (HR 80) and lung cancer death (HR 432)
    • Pack-years smoking:
      • 30-40: HR 1.63 for lung cancer incidence; 1.74 for lung cancer death
    • 90% of the CT-preventable lung cancer deaths are likely preventable by screening only 49% of US ever-smokers aged 50-80
    • One remarkable finding: in the risk-based model to USPSTF, 36% of the USPSTF-eligible smokers would not be screened (5-year lung cancer risk, 1.3%; NNS, 647), and would be replaced by 36% high-risk smokers (5-year lung cancer risk, 3.2%; NNS, 226) who did not meet the USPSTF criteria (mostly because they were African-American, lower BMI, less educated; 22% smoked <30 pack-years but tended to be longer-term smokers (>45 years, but 61% smoked <1/2  pack-per-day), and 14% quit > 15 years ago but were high intensity smokers, almost all having >30 pack-years and 53% >45 pack-years ).e., following the USPSTF recommendations, instead of an individual risk-based approach (incorporating more than just the smoking history), would both over-screen many low-risk people and not screen some of the high risk ones.
  • The lung cancer incidence model was validated by the chest x-ray groups of the NLS and PLCO of ever-smokers; the lung cancer death model was validated in the 1997-2001 NHIS and in the PLCO x-ray group of ever-smokers
  • Lung cancer mortality, by this model, was 24% lower than expected in the NLST x-ray group
  • Based on the NHIS 2010-2012 data, there was an estimated 43.4 million ever-smokers aged 50-80 in the US.
  • Screening the 9 million ever-smokers eligible by the USPSTF criteria for LDCT: the estimate was to prevent 46,488 deaths over 5 years
  • But screening 9 million of the highest risk group by the risk-based population would prevent 55,717 deaths (9229 more)
    • So, in this risk-based model NNS (number-needed-to-screen to prevent a death) was 162 vs 194 with USPSTF, with fewer false-positives (116 vs 133), all with p<0.001
    • And if one used the USPSTF NNS of 194 and applied that to the highest risk of the risk-based group (with risk >1.9%) [i.e., increasing the screening by the risk-based analysis to equal the NNS from USPSTF], then 3.1 million more people would be screened and then 62,382 deaths would be prevented. This increase to 12.1 million would also not have an increase in numbers of false positives.

Commentary:

  • So, this study did a good job developing risk models and validating them through several US cohorts, thereby suggesting that they are pretty robust and transportable. The models seemed to be more efficient than the USPSTF recommendations in terms of identifying higher risk individuals, decreasing lung cancer incidence and mortality, and decreasing the false-positive rates from LDCTs.
  • In the NLST itself, 88% of CT-prevented lung cancer deaths occurred in the 60% of those at highest risk and there were 64% with false positive results; only 1% of the lung cancer deaths occurred in the 20% at the lowest risk (see Kovalchik SA. N Engl J Med 2013; 369: 245). In fact, if one looks at those with normal LDCT in the initial NSLT, there was a dramatically lower risk of lung cancer development or death (see blog at end), to the point that I am strongly considering stopping LDCT after a couple of negative scans.
  • A few limitations of the risk-based study:
    • There is the assumption that the 20% decreased mortality in NSLT-eligible would apply to the NSLT-ineligible that would be included in the risk-based strategy.
    • The NHIS cohort only has data on lung cancer mortality not incidence, so the above risk-based model for mortality was validated only by the 2 research studies (PLCO and NLST x-ray only groups)
    • Confining the LDCTs to the high risk only, by using the risk-model, may be associated with more complications from procedures and surgery (these people are generally at higher surgical risk), so might distort the risk:benefit calculations from NLST
  • The risk-based approach does have some improvement in decreasing lung cancer deaths from 46488/9 million screened to 55717/9 million, which is increasing absolute numbers from 5.2 to 6.1/1000 screened. Still pretty small numbers.
  • So, as per my prior blogs on the USPSTF recommendations, I think they way-over interpreted NLST by extending a 3 year study (with decreasing pickup of incident lung cancers by the 3rd year), to the potential for 25 years of annual screening and the attendant high radiation exposure, to extending the upper age limit from 74 in NLST to 80, and then to codifying a single but good study into routine practice though the absolute risk reduction was relatively small (62 deaths per 100,000 person-years). The current individual risk-based approach suggests that there are many high risk patients who would not be screened by the USPSTF criteria, and many on the USPSTF list who are actually quite low risk and likely do not benefit much from the screening. I hope (and sort of expect) that the current USPSTF guidelines will be reviewed and reconsidered at some point in the next couple of years… And, it is important to remember that, as pointed out in the other blogs, lung cancer is not even close to being the primary killer associated with smoking (heart disease from smoking being much more prevalent, and COPD, etc. rating pretty high as well). And focusing on lung cancer screening may dilute the bigger message (i.e., it would be pretty awful if patients who had a normal LDCT felt that smoking was not really so bad for them, and it was okay to continue smoking…) see older blogs below for more on this.

See: http://blogs.bmj.com/ebm/2016/04/05/primary-care-corner-with-geoffrey-modest-md-need-annual-low-dose-chest-cts/ which analyzes a retrospective study from NLST finding that those with an initial normal LDCT had about 35% lower rates of lung cancer incidence and mortality

http://blogs.bmj.com/ebm/2015/01/24/primary-care-corner-with-geoffrey-modest-md-uspstf-lung-cancer-screening-revisited/ is a critique of NLST, especially its perhaps overenthusiastic acceptance and extensions by USPSTF

Primary Care Corner with Geoffrey Modest MD: Pap Smears Post-Hysterectomy in HIV Positive Women

18 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A rather striking retrospective study was just published from 2 clinics in Texas, showing a high rate of vaginal intraepithelial neoplasia (VAIN) and vaginal cancer in HIV-infected women with no prior history of abnormal cytologic screening and who had a hysterectomy for conditions other than cervical dysplasia and cancer (see Smeltzer S. Obstet Gynecol 2016; 128: 52).

Details:

  • 68 providers, 4 of whom did regular pap screening, with 1827 HIV-positive women seen in 2015. Rate of pap testing was 47%
  • 238 women were seen between 2000-2015 with a history of HIV, previous hysterectomy, and no previous abnormal Pap test results
  • Median follow-up time for the Pap test was 16 years.
  • Results:
    • 164 (69%) had normal Pap test results
    • 12 (5%) had results showing atypical cells of undermined significance and human papillomavirus-positive
    • 55 (23.1%) had results showing low-grade squamous intraepithelial lesion
    • 7 (2.9%) had results showing high-grade squamous intraepithelial lesion
    • Of those who underwent biopsy for abnormal pap tests:
      • 15 (28%) had normal results
      • 23 (43%) had VAIN 1
      • 9 (16%) had VAIN 2
      • 7 (13%) had VAIN 3
      • No patients had invasive vaginal cancer.
    • No demographic risk factor was associated with the abnormal Pap test results after hysterectomy (race, smoking history, alcohol history, illegal drug use). Also no association with a specific indication for the hysterectomy (fibroids vs pelvic pain vs bleeding). The story was mixed on HIV-related risk factor (though overall there was not much difference in CD4 or viral load between those with normal vs abnormal paps, within 6 months of the pap abnormalities there was a significant deterioration: median CD4 was 573 vs 364, and viral load was 248 vs 400, all values with p<0.001)
    • Older patients and higher viral load significantly increased the risk of development of an abnormal Pap test result. For example, the patients with viral load values greater than 400 had approximately two times the risk of developing an abnormal Pap test result than those lower than 400; the adjusted hazard ratio of 2.1 (95% CI 1.2–3.5). In terms of age: 30-38yo HR 2.2, 38-44yo HR 3.8, >44yo HR 6.3
    • No difference in time to abnormal Pap test result was noted with antiretroviral use, or by CD4.

Commentary:

  • No guidelines suggest regular pap screening for women with a hysterectomy, unless the hysterectomy was done for cancer or precancerous lesions
    • USPSTF, Am Cancer Society, ACOG, etc are against routine screening in these women overall:  “The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (cervical intraepithelial neoplasia [CIN] grade 2 or 3) or cervical cancer”, giving it a “D” recommendation
      • However, I should add that old studies did find a non-zero but low risk of vaginal abnormalities in women in the general population getting a pap smear post-hysterectomy for benign causes (see Pearce KF. N Engl J Med 1996; 335: 1559, which noted that of 9610 vaginal smears, atypical squamous cells of undetermined significance (ASCUS) occurred in 52 (0.5%); low-grade squamous intraepithelial lesion in 44 (0.5%); high-grade squamous intraepithelial lesion in 6 (0.1%); and squamous-cell carcinoma in 2 (0.02%). In 5 women, biopsies revealed vaginal intraepithelial neoplasia type I or II; there were no biopsy-proved cases of vaginal cancer. The probability of an abnormal Pap smear in this group of women was 1.1 percent, and the positive predictive value of the Pap test for detecting vaginal cancer was 0.Mean time to get potentially significant intraepithelial lesions was 19 yrs. Because of the age of this study, there was no information about HIV or HPV status.
    • There are very limited data and no clear recommendations on pap testing in HIV-positive women having a hysterectomy for benign reasons.
  • There are several unanswered questions (which really should be studied).
    • This Texas study was a retrospective analysis with limited data collected and there are no data I’ve seen on the effect of interventions on changing actual clinical outcomes in abnormalities picked up by routine screening
    • We know that HPV infection tends to persist in HIV-positive men and women, with attendant increased risk of anal and cervical cancers. It would be great if there were prospective data looking at HPV status and vaginal paps in women. In the above study, the ASCUS findings were associated with HPV. My guess is that HPV is the culprit and that it seems reasonable to consider HPV and/or pap screening in women with HPV infection at the time of hysterectomy and later if at risk for getting an HPV infection. But this should be studied. And it is really important that we pursue HPV vaccination rigorously in young women (and men).
      • Since there was a deterioration of HIV markers (CD4 and viral load) within 6 months of the abnormal pap, perhaps should we be doing selective paps on those with HIV deterioration, or at certain levels of these counts. Again, it would be good to know prospectively if changes in HIV markers consistently preceded vaginal cytology abnormalities.
      • This study was done in a single population/demographic area. Is it generalizable?
      • Is there any relationship between numbers of sexual partners, partners infected with HIV, etc. and the development of VAIN?
    • So, this study does throw a bit of a wrench into conventional wisdom. It is pretty clear that there is more of a risk for vaginal cytologic abnormalities in women with HIV who get a hysterectomy for benign reasons than we had thought, and that recommendations be reconsidered given the relatively benign test (pap), and further work-up (biopsy). To me, it is not unreasonable to assume that for a woman with significant abnormalities on vaginal biopsy and with pathological deterioration on observation/local therapy, that definitive therapy be considered.
    • But, at this point, it does seem reasonable to do vaginal pap smears on women with HIV and hysterectomy for benign reasons. Unclear what interval. But it seems from the data that these are not very aggressive or rapidly progressive evolution from VAIN to cancer, so likely that they could be done every several years.

Primary Care Corner with Geoffrey Modest MD: W-3 Fatty Acids Decrease Heart Disease

15 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A meta-analysis including 19 studies and >45K individuals from 16 countries supported a small but significant cardiovascular benefit for both seafood and plant-derived w-3 fatty acids (see doi:10.1001/jamainternmed.2016.2925).

Details:

  • 19 studies from 16 countries (US, Australia, Costa Rica, UK, Italy, Finland, Sweden, Singapore, France, Ireland, Germany…) with  45,637 individuals and 7973 total CHD (coronary heart disease), 2781 fatal CHD and 7157 nonfatal MI events (the studies did not all break down the CHD events the same way, so these numbers do not add up)
  • Median baseline age 59, 63% male, BMI 26, up to 30% current smokers. Most were white, though some studies had racial/ethnic diversity. Overall alcohol consumption, mostly up to 1 drink/d. Fish oil supplements used infrequently. Median 10 year of follow-up
  • Assessed biomarkers for w3 polyunsaturated fatty acids (measured in whole plasma or tissue, which turned out to be better predictors than adipose tissue and cholesterol ester estimates):
    • Seafood-derived: eicosapentaenoic acid (EPA; 20:5w-3), docosapentaenoic acid (DPA; 22:5w-3), and docosahexaenoic acid (DHA; 22:6w-3)
    • Plant-derived: a-linolenic acid (ALA; 18:3w-3)
  • Results: significant associations were as follows, with multivariate-adjusted analyses, per 1-SD increase in the biomarkers:
    • ALA:
      • Fatal CHD: 9% decrease, RR 91 (95%CI, 0.84-0.98)
    • DPA:
      • Fatal CHD: 10% decrease, RR 90 (95%CI, 0.85-0.96)
      • Total CHD: 6% decrease, RR 0.94; 95%CI, 0.90-0.99),
    • DHA:
      • Fatal CHD: 10% decrease, RR 90 (95%CI, 0.84-0.96)
    • EPA:
      • Only reached borderline significant benefit

Commentary:

  • The prior studies on w-3 polyunsaturated fatty acids and CHD events are a bit mixed, with many methodologic problems (including relying on dietary recall), and few have looked at plant-derived w-3’s
  • Though there was no comment on what “fully-adjusted multivariate analysis” meant, likely because the studies varied, there was a comment that “No significant differences in associations of ω-3 PUFA biomarkers with incident CHD events were observed by age, sex, ω-6 PUFA (linoleic acid or arachidonic acid) concentrations, type 2 diabetes status, statin use, regular aspirin use, year of biomarker sampling, or (for ALA) EPA, DPA, and DHA concentrations”
  • In terms of biological plausibility, there are randomized controlled trials showing these w-3 fatty acids lower triglyceride levels, blood pressure, heart rate, and improve endothelial function, membrane stabilization through changes in lipid composition (which could decrease ischemia-mediated ventricular fibrillation, and possibly explain why the clinical improvement was more evident for fatal events) and myocardial oxygen demand, all of which could translate into improved clinical cardiac outcomes.
  • One highlight in the above study is the equal association of the plant-derived ALA to the seafood-derived rest of them: there are also data showing ALA decreases thrombosis, arrhythmias and inflammation, and improves endothelial function. And for much of the world, plant-derived w-3 is more affordable and accessible. By my review, the best single source of ALA is flaxseed, then also canola oil, and walnuts (esp. English). Other pretty high sources (actually, better than fish on a weight basis when comparing to the fish w -3’s) include soybeans, oats (germ), dried beechnuts and butternuts).
  • There were some interesting subgroup analyses, showing that Chinese and African-American individuals may benefit more from w-3. ?why ?genetic component. ?how the food was prepared (minimally cooked vs deep-fried, etc.). It was also interesting that taking statins or aspirin did not affect the overall outcomes much, since they accomplish at least some of the positive biological effects as the w-3’s.
  • I am always concerned about looking at single foods or food additives. In part because we eat a variety of foods, vitamins, etc., and there are likely interactions between the food components as well as optimal balances of different ones. And, even though this study was perhaps the best of the w-3 ones I’ve seen (in the sense that it combined lots of different studies from different areas, looked at hard-evidence both of actual w-3 levels in the body (vs dietary recall) as well as hard clinical endpoints, and seemed methodologically rigorous), there is always concern about the causal relationships in observational studies (i.e., did those who ate more w-3’s also do more other healthful behaviors (eat less red meat, eat more natural foods, do  more exercise, etc.)?
  • So, I do think this study adds to and deepens the literature that w -3’s are good for you (and, contrary to some prior articles/concerns, it seems that w -6’s did not counteract the benefits of the w-3’s).

 

Primary Care Corner with Geoffrey Modest MD: Long Term Alendronate Effectiveness and Safety

14 Jul, 16 | by EBM

By Dr. Geoffrey Modest

There have been concerns that long-term alendronate use could lead to more complications, such as subtrochanteric femur fractures, but a recent Danish registry study was reassuring (See doi: 10.1136/bmj.i3365).

Details:

  • 61990 men and women 50-94 yo on alendronate, in the Danish prescription registry from 1996-2007, which holds almost 20 years of drug exposure data, were linked to all fracture outcomes treated in-hospital.
  • Mean age 72, 83% women, baseline major osteoporotic fracture 31%, diabetes 5%, CKD 1%, chronic pulmonary disease 19%, prednisolone in past year 25%
  • 2 nested case-control studies: one looked at those with hip fractures and compared them to 3 controls matched for age, sex, year of starting treatment, and follow-up time; the other similarly-controlled looked at subtrochanteric/femur shaft (ST/FS) fracture but matched to 5 controls.
  • All alendronate dosing was at 70 mg/week. Mean follow-up 6.9 years (range 0-17.9)
  • Results: [though of those who took their meds regularly, only 30% (18,242) completed 5 years of treatment, 4% (2465) completed 10 years, and only about 1000 completed >=14 years]
    • Incident ST/FSfracture in 1428 people, at rate of 3.4/1000 person-years (CI 3.2-3.6)
    • Incident hip fracture in 6784 people, at rate of 16.2/1000 person-years (CI 15.8-16.6)
    • Higher medication adherence and longer term use of alendronate led to 27% decreased risk of hip fracture [HR 0.73 (0.68-0.78), p<0.001]
    • Longer term alendronate usage was associated with decreased risk of hip fracture:
      • 5-10 dose years: HR 0.75 (0.67-0.83), p<0.001
      • >10 dose years: HR 0.74 (0.56-0.97), p=0.03
    • There was no association of ST/FS fracture with cumulative use of alendronate in those taking alendronate >10 years (in fact, there was a 57% reduced risk of subtrochanteric femur fractures and no change in shaft fractures), or in those currently taking it vs past users, though the likelihood of ST/FS was higher in those with comorbidities including diabetes, chronic lung disease, and those on proton pump inhibitors (PPIs).
    • The NNT (number-needed-to-treat for an additional 5 year to prevent one additional fracture) was 38, and the NNH (number-needed-to-harm by causing a ST/FS fracture in one person with an additional 5 years of therapy) was 1449.

Commentary:

  • There has been concern that using prolonged bisphosphonates could lead to more problems with atypical femur fractures, and, perhaps related to that, the usage of these meds has decreased by 50% in the US and similarly in the European Union
  • The above Danish study is observational, and therefore subject to biases. So, hard to make a firm recommendation. Potential biases and limitations include:
    • The registry was almost exclusively of North Europeans. There is some concern that some groups (e.g. South Asians) may be at higher risk of atypical femur fractures
    • They did not look at osteonecrosis of the jaw, another uncommon event related to bisphosphonates
    • The consequences/morbidity of an atypical hip fracture can be high, though typically less than that of a regular hip fracture
    • The above data were more impressive in those patients who adhered more to treatment with alendronate, and this group might be different from the general population (perhaps educational differences, or this group was convinced they were at higher risk of fracture and took the meds more often, etc.)
    • They did not have data on calcium/vitamin D intake.
  • In the Danish study, assuming a worst-case scenario (i.e., 100% of the ST/FS fractures are atypical/related to alendronate, there was 0 background rate of these fractures, and comparing the upper 95% confidence limit in the harm:benefit models rather than the observed 50% rate), there was still a clear benefit of alendronate for up to 13 years (and part of the issue beyond that is that there were so few patients on the med for >11 years that the confidence intervals were quite wide)
  • There are some data from a randomized trial (see Bone, HG. N Engl J Med. 2004; 350: 1189) where a subset of postmenopausal women were randomized to stopping alendronate after 5 years or continuing another 5 years, finding some decrease in BMD and increase in markers of bone turnover in the former group but no significant difference in fractures (except for slightly higher risk of fractures detected by x-ray and some nonsignificant decrease in height loss). But it is important to note that women at higher risk of fracture were excluded(either T-scores below -3.5, or T-score after 5 years which was worse than their baseline). No one in either group developed jaw osteonecrosis, and bone biopsies showed no qualitative abnormalities.
  • So, the above data are impressive, suggesting that continued alendronate, even up to 14+ years, is associated with continued decrease in hip fracture risk and no real change in ST/FS. My approach, which is reinforced by this Danish study, is to put all patients with an osteoporotic fracture or a BMD less than -3.5 on long-term therapy (which in several cases has been in the 15 year range so far). For the others, I check a BMD after 5 years, and if their BMD is worse than their initial one, I continue with the alendronate. And, the ones that I stop the alendronate in, I recheck their BMD in 2-3 years to make sure it is not deteriorating (my bias is that this is a pretty benign therapy overall, the functional/quality-of-life consequence of a hip fracture or a painful vertebral fracture can be quite significant, and, especially in a younger person with a long life expectancy, the further deterioration in BMD and increase in bone turnover markers on stopping the alendronate, as in the N Engl J Med trial, is concerning in the long-term even if no significant increase in these fractures happened in the next 5 years that they studied). The above Danish study was reassuring that long-term alendronate was associated with a continued 30% decrease risk of hip fracture and there was no increase in subtrochanteric and femoral shaft fractures
  • And, I will add my longstanding tirade that it is really important to down-titrate PPIs whenever possible, given the multitude of well-defined adverse effects including decrease in BMD/ 30% increase in fractures (in a large meta-analysis). I have found that most of my patients are able to downgrade to H2 blockers or calcium tablets, if not able to get off the meds completely

See http://blogs.bmj.com/ebm/2016/01/28/primary-care-corner-with-geoffrey-modest-md-guidelines-on-length-of-bisphosphonate-therapy/ for the American Society for Bone and Mineral Research guidelines on the length of bisphosponate therapy, which goes into further depth on the randomized controlled trials, and is not so different from my assessment above, just that the Danish trial does give further reassurances for using longer-term bisphosphonates.

Primary Care Corner with Geoffrey Modest MD: SES and Mortality

13 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A recent Swedish study found that socioeconomic status (SES) was independently associated with mortality, cardiovascular disease, and cancer in patients with type 2 diabetes (see doi:10.1001/jamainternmed.2016.2940).

Details:

  • 217,364 people <70 yo, with type 2 diabetes in the Sweden National Diabetes Register (from 2001-2011), assessing all-cause, cardiovascular, diabetes-related and cancer mortality.
  • Median age 58, 60% male
  • 10% from non-Western countries: of these, 10% Latin America/Caribbean, 17% East or South Asia, 60% Middle East/North Africa, 14% sub-Saharan Africa
  • Results (all adjusted for age, sex, duration of diabetes, marital status, income level, educational level, country of birth. further adjustment for smoking, HbA1c, eGFR, BMI, diabetes treatment, albuminuria, heart failure, MI, stroke, stage 5 CKD, and baseline cancer did not affect the associations much):
    • 19,105 all-cause deaths: 60% cardiovascular, 37% diabetes-related, 34% cancer-related
    • Marital status: comparing married vs single, overall 13.0 deaths /1000 vs 18.82 deaths/1000
      • 27% decreased all-cause mortality [HR 0.73 (0.70-0.77)]
      • 33% decreased cardiovasc mortality [HR 0.67 (0.63-0.71)]
      • 38% decreased diabetes-related mortality [HR 0.62 (0.57-0.67)]
      • No difference in cancer-related mortality, other than 33% decreased risk for prostate cancer [HR 0.67 (0.50-0.90)]
    • Income: comparing lowest to highest income quintiles, overall 8.92 deaths /1000 vs 18.33 deaths/1000. This risk varied continuously as income level changes
      • 71% increased all-cause mortality [HR1.71 (1.60-1.83)]
      • 87% increased cardiovasc mortality [HR 1.87 (1.72-2.05)]
      • 80% increased diabetes-related mortality [HR 1.80 (1.61-2.01)]
      • 28% increased cancer-related mortality [HR 1.28 (1.14-1.44)]
    • Income: comparing non-Western immigrants to native Swedes (with covariate adjustment)
      • 45% decreased all-cause mortality [HR 0.55 (0.48-0.63)]
      • 54% decreased cardiovasc mortality [HR 0.46 (0.38-0.56)]
      • 62% decreased diabetes-related mortality [HR 0.38 (0.29-0.49)]
      • 28% decreased cancer-related mortality [HR 0.72 (58-88)]
    • Education: comparing college/university degree vs 9 yrs or less education. this risk varied continuously as educational level increased
      • 15% decreased all-cause mortality [HR 0.85 (0.80-0.90)]
      • 16% decreased cardiovasc mortality [HR 0.84 (0.78-0.91)]
      • 16% decreased cancer-related mortality [HR 0.84 (0.76-0.93)]

Commentary:

  • This study complements many prior studies from many countries over the past many decades showing that SES is a powerful predictor of morbidity and mortality, including both the development of and mortality from diabetes
  • Sweden provides not just a large and rigorous database for analysis (clinical as well as individual-level data on risk factors and socioeconomic variables), but a country where SES has minimal effect on access to and use of health care services. For example, being hospitalized in Sweden costs approximately $10/day independent of the level of care or the number/type of interventions done. Immigrants in general receive evidence-based treatments earlier than native Swedes!!!
  • Clearly there are limits to drawing definitive conclusions from an observational study. For example, some important covariates were not measured (e.g., alcohol intake, amount of smoking). Perhaps others as well.
  • So, an important aspect of this study in Sweden was that there appeared to be relatively equal access to medical care in all groups. This again reinforces the concept that health care is much more than medical care, and health outcomes really depend a lot on broader social issues (and, this is in a country with a much larger social safety net and more extensive social programs/support networks than the United States, for example). In terms of the potential mechanism leading to increased mortality in those with lower SES, one might posit that their attendant stress is associated with many potentially adverse hormonal changes (especially as mediated by the known stress-related increase in cortisol), coupled with perhaps less healthy eating habits, lack of social supports/community cohesion: all possibly leading to increased morbidity and mortality.

Some other SES blogs:

http://blogs.bmj.com/ebm/2016/04/28/primary-care-corner-with-geoffrey-modest-md-bmi-height-and-socioeconomic-status/ which found (through Mendelian randomization) that SES was related both to the individual’s height and BMI, and that part of the association was mediated through genetics, but mostly through social factors.

http://blogs.bmj.com/ebm/2016/04/26/primary-care-corner-with-geoffrey-modest-md-life-expectancy-and-income/ found a striking relationship in the US between income and life expectancy.

And, for those readers who are microbiome-oriented, http://blogs.bmj.com/ebm/2015/08/11/primary-care-corner-with-geoffrey-modest-md-early-life-stress-in-mice-changes-in-microbiome-and-later-anxiety/ which showed that early life stresses in mice leads to long-lasting adverse changes in microbiota

Primary Care Corner with Geoffrey Modest MD: ACE Inhibs Decrease Conduction System Disease

11 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A secondary analysis of the ALLHAT hypertension study (see doi:10.1001/jamainternmed.2016.2502 ) found that patients in the lisinopril arm had decreased development of cardiac conduction system disease, which the authors suggested was due to lisinopril’s anti-inflammatory and antifibrotic properties.

Details:

  • ALLHAT was a community-focused hypertension study in 623 North American sites with 3 medication arms: lisinopril, amlodipine, and chlorthalidone. There was also a lipid component, and patients with fasting LDL 120-189 mg/dl (or 100-129 if known atherosclerosis) were randomized to pravastatin vs placebo. Follow-up 5 years
  • 21,004 people: 56% men, mean age 66.5, 92% white/6% black, baseline BP=174/98, BMI 28, Framingham risk score 22%, 16% smokers

Results:

  • 1114 developed conduction system disease: LBBB in 389, RBBB in 570, intraventricular conduction delay in 155
  • lisinopril vs chlorthalidone: 19% reduction in developing conduction system disease [HR 0.81 (0.69-0.95, p=0.01] with lisinopril
  • Amlodipine was non-significantly different from lisinopril

Commentary:

  • It was interesting that in this study no one developed lesser conduction system abnormalities such as 1st degree AV block, LAFB, or incomplete RBBB, which suggests that there might be a different pathophysiology than simply a progression of conduction system dysfunction (e.g. progressive fibrosis of Lev). The data on progression of 1stdegree AV block, for example, are mixed, with some long term studies finding this to be a benign condition, but some studies (e.g. Framingham Study) did find that an increase in atrial fibrillation (HR 2.1), likelihood of progression to require a pacemaker (HR 2.9) and higher all-cause mortality (HR 1.4): see Cheng S. JAMA 2009; 301(24): 2571.
  • LBBB and RBBB are clearly associated with increased cardiac mortality, as well as the potential progression to complete heart block
  • Lisinopril was better than chlorthalidone in this secondary analysis, controlling for an array of clinical variables, including demographics, BMI, smoking, aspirin use, diabetes, CAD, LVH, lipids. And this wasdespite the fact that the achieved blood pressure reduction was inferior with lisinopril.
  • Concerns about the study:
    • This is a secondary analysis, and there was some selection bias (those who received serial EKGs were more likely to be men and white, not have diabetes, and to be on aspirin)
    • >40% of all  participants were on at least one additional step 2 or step 3 drug, which brings up 2 issues:
      • The choice of the second and third agents was prescribed (either atenolol, clonidine or reserpine as step 2, hydralazine as step 3) and these were not standard community practice even at that time, at least in the Boston area (e.g.: adding atenolol to lisinopril was not done much then, since that combo was felt to be less synergistic, both being renin-active agents. The other agents were not used much at all)
      • There were no granular data presented separating out patients just on lisinopril as a single agent vs those on lisinopril in combination. This is problematic if lisinopril plus one of the second line meds did have some synergistic effect in combination for preventing conduction system abnormalities. So, for example, maybe the lisinopril did nothing alone, but did so only in combination with another med. in that case the conclusion that lisinopril is good for protecting the conduction system would be erroneous.
    • If lisinopril were protective, why would that be the case?
      • I think positing the anti-inflammatory effect is a bit of a stretch, since those on pravastatin (a pretty potent anti-inflammatory) had no protection and in fact a trend to worse conduction system disease outcomes
      • Clearly the issue is not lowering the blood pressure per se, since the lisinopril group had less BP improvement
      • My guess is that the issue was decreasing LVH, since LVH was the strongest single predictor of incident conduction system disease in multivariate analysis. (The association with lisinopril above did control for LVH, but only LVH at baseline. And only by the relatively poorly sensitive EKG). And, ACE inhibitors/ARBs are the best agents for reversing LVH. Also, LVH itself does have significant mortality associated with it, which is decreased when an antihypertensive agent decreases EKG-determined LVH (see the LIFE trial, Dahlof B. Lancet 2002; 359: 995, which showed that the ARB losartan was better than atenolol in decreasing cardiac events, but that with LVH regression by either drug, there were fewer cardiac events – i.e., it was the LVH regression that mattered, not the drug. unfortunately, they did not report on conduction system dysfunction). The data on reversal of LVH is almost as good for calcium blockers (e.g. amlodipine) as with ACE inhibitors (e.g. lisinopril). Diuretics (like chlorthalidone) are significantly less likely to reverse LVH.
    • So, my conclusions:
      • This study reinforces my use of dihydropyridine calcium channel blockers as my first drug for hypertensive patients. As mentioned in several prior blogs, I am concerned with using hydrochlorothiazide as the initial agent (the most commonly used one), since its durability over 24 hours is quite limited (see blog below), and this ALLHAT secondary analysis reinforces not using a diuretic. Amlodipine has a much longer duration of action and has much less blood pressure variability (perhaps an additional clinical benefit). This was pretty much the conclusion of NICE, in their 2011 analysis, suggesting that all Afro-Caribbean hypertensive individuals and all white people >55yo have a calcium channel blocker as the first agent. They do suggest an ACE inhibitor if white and <55yo (mostly because of the higher likelihood of high renin hypertension in this  group), though they also supported using chlorthalidone (but not hydrochlorothiazide)
      • And, as in the LIFE study, the current study does support preferentially using an ACE inhibitor or ARB for those with LVH by EKG (and, I would extend this to echo LVH). Though, again, amlodipine (or other dihydropyridine calcium channel blockers) are also reasonable. (i.e., the 2011 NICE guidelines are basically upheld by this study….)

 

See http://blogs.bmj.com/ebm/2016/05/04/primary-care-corner-with-geoffrey-modest-md-chlorthalidone-is-better-than-hctz-for-hypertension/ which showed that HCTZ has poor 24-hr duration, with chlorthalidone being much better

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