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Primary Care Corner with Geoffrey Modest MD: Blood Pressure Guidelines for Older Adults

27 Feb, 17 | by EBM

By Dr. Geoffrey Modest

The American College of Physicians and the American Academy of Family Physicians just published guidelines on the pharmacologic treatment of hypertension in adults over 60 yo, with both a systematic review and meta-analysis (see doi:10.7326/M16-1785), and a clinical practice guideline (see http://annals.org/aim/article/2598413/pharmacologic-treatment-hypertension-adults-aged-60-years-older-higher-versus )

Results:

  • They analyzed 46 publications representing 21 randomized controlled trials and 3 cohort studies
  • 9 trials show that intensive blood pressure treatment substantially improved outcomes in patients with moderate to severe hypertension, with SBP >160 mmHg. The data on lower systolic blood pressures also showed benefit but the results were less consistent.
  • Overall studies of patients achieving SBP <140 mmHg were similar to those that achieved 140, although the reduction in stroke risk was more consistent in the studies where patients achieved the higher SBP
  • In 6 trials comparing different treatment targets with 41,491 patients, treatment targets of SBP <140 mmHg or diastolic blood pressure of <85 mmHg were associated with only marginal benefit, with wide confidence intervals:
    • 14% nonsignificant reduction all-cause mortality, RR 0.86 (0.69-1.06)
    • 21% reduction in stroke, RR 0.79 (0.59-0.99)
    • 18% marginally significant reduction in cardiac events, RR 0.82 (0.64-1.00)
    • Because of their size and the event rates found, these analyses were dominated by the SPRINT and ACCORD trials. SPRINT (which excluded diabetics as well as those with SBP >180, prior stroke, urinary protein excretion >1 g per day or symptomatic heart failure/EF <35%) found marked reductions in mortality in cardiac events, though the ACCORD trial (which included only diabetics, though did achieve an SBP of 119 mmHg, similar to SPRINT) did not find any reduction in mortality or major cardiovascular events with intensive treatment [though other trials found benefit of hypertension treatment to be at least as strong in diabetics]. Also, the SPRINT trial stopped earlier than projected because of benefit, which, as mentioned in my blog on it noted below, will tend to exaggerate benefits and perhaps decrease finding risks.
  • Overall, tighter control “may prevent on average, roughly 10 to 20 events for every 1000 high-risk patients treated over 5 years across a population”
  • Harms of more intensive therapy: in general the evidence was relatively low to moderate strength, but did not find clear evidence of more renal, cognitive impairment, deterioration of quality-of-life/functional status, or increase in fractures or falls, though there was low-quality evidence for increase in syncope.

Recommendations:

  • Initiate treatments in adults over 60 years old who have systolic blood pressure persistently at or above 150 mmHg, to reduce the risk for mortality, stroke, and cardiac events (strong recommendation, high quality evidence).
  • Consider initiating or intensifying pharmacologic therapy in patients over 60 years old with a history of stroke or TIA to achieve a targeted systolic pressure of less than 140 mmHg to reduce the risk of recurrent stroke. (Weak recommendation, moderate quality evidence)
  • Consider initiating or intensifying pharmacologic treatment in some adults greater than 60 years old at high cardiovascular risk to achieve a target systolic pressure of less than 140 mmHg to reduce the risk of stroke and cardiac events. (Weak recommendation, low quality evidence)
  • And for all of these recommendations, the risks and benefits should be periodically discussed with the patient.

Commentary:

  • There are really no studies that include the real elderly. The SPRINT elderly subgroup (those patients over 75 at enrollment), still had a mean age of 80, with SD of only 4 years, so really does not inform my practice with lots of people in the 85-100 age range. one might glean from the above trials that the lower blood pressure may well be better, since there was no evidence that age mattered in the groups analyzed (again, not including the very old), subgroup analyses from SPRINT as well as the HYVET trials found that frailty did not matter, and there was more absolute benefit in those with higher cardiovascular risk (and age plays into that). But, at least my practice in the elderly and especially in the very old is to check orthostatics regularly (looking for both initial and standard orthostatic hypotension: See http://blogs.bmj.com/ebm/2016/05/20/primary-care-corner-with-geoffrey-modest-md-orthostatic-hypotension-revisited/for details), try to get home-based BP measurements (and preferentially use these to guide therapy, as long as I have confirmed that the patient measures blood pressure accurately and the cuff is accurate), and assess cognitive function more aggressively (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/ which is an Italian prospective study in patients mean age of 79 with some baseline cognitive impairment, finding that those in the lowest BP group (SBP<128 mmHg) had more cognitive decline than those with higher pressures)​. So, my guess (without data) is that the benefits will persist in the very old, though I suspect the harms will be greater (patients more frail, more comorbidities, and more sensitive to meds)
  • My major concern with these articles on tighter blood pressure control in general is that there is a tendency in clinical practice to attempt to achieve the goal blood pressure they achieved in the study. However, this brings up a few issues:
    • In general the studies have very specific ways that they measured the blood pressure. The general real-world approach, at least in my experience, is to have a medical assistant bring the patient into the room and measure the blood pressure/record it in the electronic medical record. I have consistently been measuring manual blood pressures myself for the past many years, typically with the patient sitting on the exam table and resting a few minutes while I write my notes in the other room, and often find striking differences from the recorded blood pressure, not uncommonly 30 to 40 mmHg difference. Although most often my recording is much less than that of the medical assistance, at times it is much more (the 118/68, which really is 190/110!!!). So in general I am concerned about relying on automated blood pressure recordings (which in general is less reliable in people with atrial fibrillation and arrhythmias, as well), though my main concern is that the patients, perhaps somewhat deconditioned, walk into the room and sit down without resting and have largely unreliable readings.
    • For example, in the SPRINT study, which did achieve lower blood pressure in the tight control group than often found in other trials (123/62, in the elderly subgroup), they measured the blood pressure as follows: the staff person would tell a patient that they needed to rest for 5 minutes before taking the blood pressure, would leave the room completely, would return but not speak a word with the patient and immediately take the blood pressure. Argument has been raised in the literature that the blood pressure measured in randomized controlled trials is typically 5 to 10 mmHg lower than the clinic-based blood pressure (i.e. a randomized trial with an achieved systolic blood pressure of 123, as above, may be equivalent to a clinic-based blood pressure of 130 or so). For details of the SPRINT trial, see http://blogs.bmj.com/ebm/2015/11/19/primary-care-corner-with-geoffrey-modest-md-tighter-blood-pressure-control-the-sprint-trial/, which reviews the results of the overall trial, as well as http://blogs.bmj.com/ebm/2016/06/02/primary-care-corner-with-geoffrey-modest-md-sprint-trial-elderly-subgroup-study-of-lower-blood-pressure-goal/ which looked at the predesignated subgroup of those greater than 75 years old).
    • There are also significant questions as to the general reliability of office-based blood pressure, both because of whitecoat hypertension as well as masked hypertension (see http://blogs.bmj.com/ebm/2016/12/12/primary-care-corner-with-geoffrey-modest-md-masked-hypertension/ , as well as the frequent observation that ambulatory blood pressure monitoring is much more predictive of clinical events, leading to the USPSTF and other international groups suggesting this is the preferred mechanism to diagnose hypertension (see http://blogs.bmj.com/ebm/2015/01/15/primary-care-corner-with-geoffrey-modest-md-uspstf-recs-on-ambulatory-blood-pressure-monitoring/
  • So, my real concern is that we may be basing important clinical decisions based on inaccurate data, and that we may be significantly over-treating (predominately) or under-treating hypertension, with their attendant potential adverse outcomes​

By the way, there was a review of intensive lowering of blood pressure in the elderly (defined as >65 yo), essentially simultaneous with the above, in the Journal of the American College of Cardiology, which identified only 4 studies (all included above) with 10,857 patients that met their criteria, finding that intensive blood pressure control with SBP <140 lead to a significant decrease in major cardiovascular events, including cardiovascular mortality and heart failure, but no difference in stroke or MI (see DOI: 10.1016/j.jacc.2016.10.077​). This exemplifies one of the points I made in my blog http://blogs.bmj.com/ebm/2016/11/21/primary-care-with-geoffrey-modest-md-lessons-ive-learned-from-looking-at-the-medical-literature/ , that systematic reviews and meta-analyses may well come to different conclusions based on their own inclusion and exclusion criteria, and that we in the trenches (who are responsible for reading and considering implementing important changes in clinical practice) really need to assess how those authors configured their analyses and the relevance of their conclusions to our clinical practice. Not a simple feat.

Primary Care Corner with Geoffrey Modest MD: leisure time activity and lower cancer risk

27 Feb, 17 | by EBM

By Dr. Geoffrey Modest

There have been a plethora of articles in the past year on the beneficial effects of exercise. I will use the next several blogs to sample some of these.

One article looked at the beneficial effects of leisure-time physical activity on 26 cancer types (see doi:10.1001/jamainternmed.2016).

Details:

  • 44 million participants from 12 prospective US and European cohorts had self-reported leisure-time physical activity at baseline (1987 to 2004). Leisure-time physical activity levels were assessed as cohort-specific percentiles on a continuous basis. Hazard ratios are based on high vs low activity levels (comparing the 90th versus 10th percentiles of activity)
  • Median age 59 years, 57% females, BMI 26.
  • 186,932 participants with cancer were included in the analysis
  • Moderate activity in general was defined as intensity of >=3 more METS; vigorous activity as >=6 METS (see below for a definition for METS, or Metabolic Equivalents

Results:

  • There was a lower risk for 13 cancers with higher levels of leisure-time physical activity (the statistical models controlled for age, sex, smoking, alcohol, race/ethnicity, education; as well as specific risk factors for some cancers, such as hormone therapy, age at menarche, age at menopause, and parity for several of the female-only cancers, etc.):
    • Esophageal adenocarcinoma, decreased 42%, HR 0.58 (0.37-0.89)
    • Liver, decreased 27%, HR 0.73 (0.55-0.98)
    • Lung, decreased 26%, HR 0.74 (0.71-0.77)
    • Kidney, decreased 23%, HR 0.77 (0.70-0.85)
    • Gastric cardia, decreased 22%, HR 0.78 (0.64-0.95)
    • Endometrial, decreased 21%, HR 0.79 (0.68-0.92)
    • Myeloid leukemia, decreased 20%, HR 0.80 (0.70-0.92)
    • Myeloma, decreased 17%, HR 0.83 (0.72-0.95)
    • Colon, decreased 16%, HR 0.84 (0.77-0.91)
    • Head and neck, decreased 15%, HR 0.85 (0.78-0.93)
    • Rectal, decreased 13%, HR 0.87 (0.80-0.95)
    • Bladder, decreased 13%, HR 0.87 (0.82-0.92)
    • Breast, decreased 10%, HR 0.90 (0.87-0.93)
  • But there were higher risks of:
    • Malignant melanoma, increased 27%, HR 1.27 (1.16-1.40)
    • Prostate cancer, increased 5%, HR 1.05 (1.03-1.08): but specifically for non-advanced prostate cancer (HR 1.08), with no association for advanced prostate cancer (HR 0.99)
    • Cancers that did not reach statistical significance included non-Hodgkin’s lymphoma (though this was borderline significant at the P=0.05 level, with an 8% decrease with increased leisure-time activity), thyroid, gastric non-cardia, soft-tissue, pancreas, lymphocytic leukemia, ovary, and brain
    • Controlling for BMI decreased the statistical significance for esophageal carcinoma, and rendered the associations with endometrial cancer, liver and gastric cardia to be nonsignificant
    • Associations were generally similar with overweight/obese versus normal weight individuals
    • Smoking status modified  the association for lung cancer but not the other smoking-related cancers

Commentary:

  • This observational study found the quite impressive result that exercise was associated with major decreases in 13 cancers (10, after adjusting for BMI), and the decrease was 20+ % (i.e., really large) for 7 of them.
  • There are obvious concerns with such a study, including the fact that they compared only the top 10th percentile to the lowest 10th percentile of leisure-time activity, which also likely includes more unaccounted-for biases (e.g., those in the highest percentile group being much more likely to have generally healthy lifestyles, which may not be fully reflected in the multivariate analysis). Also, as with any meta-analyses, there are bound to be significant differences in the methodology of each individual study, making the strict combination of them less rigorous. The measures of physical activity were self-reported, and the cutpoints of high vs low varied between the individual studies. Also, some of the measurements (e.g. BMI) were considered as dichotomous variables (either above or below 25) which could conceal their true contribution (i.e. a BMI of 25.1 may confer a very different risk from a BMI of 35.1; on the other hand a BMI of 24.9 may not be so different from a BMI of 25.1)
  • Another issue is that leisure-time activity reflects only part of the picture. Many of the old studies only looked at leisure-time activity because they could not figure out how to incorporate work-related activity into the metric. Work-related activity requires very detailed analyses of individual workplaces, given that people doing the same job in different workplaces may have amounts of physical exertion, depending on such factors as degree of automation, how large the workplace is and what the division-of-labor is, and, in general, how the specific job was structured, including the role of labor unions requiring employers to decrease the intensity or potential risks of many jobs. Also, since leisure-time activity typically reflects voluntary participation that would reinforce the above-stated potential bias that these people lead generally healthier lifestyles.
  • Another recent systematic/meta-analysis (see http://dx.doi.org/10.1136/bmj.i3857)included 174 world-wide studies, looked at the levels of total physical activity (leisure-time, occupational, domestic, transportation) and the risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic strokes, finding:
    • Overall, major gains for all outcomes occurred at lower levels of physical activity (3000-4000 MET minutes/week)
    • Even 600 MET/week (the lowest level in the studies), had a 2% lower risk of diabetes (vs no reported physical activity)
    • But going from 600 to 3600 MET minutes/week reduced the risk additionally by 19%. further increases did not add much (e.g., 0.6% if increase from 9000 to 12000 MET minutes/week)
    • At higher levels of physical activity (>8000 MET minutes/week), they found:
      • 14% reduction in breast cancer
      • 21% reduction in colon cancer
      • 28% reduction in diabetes
      • 25% reduction in ischemic heart disease
      • 26% reduction in ischemic stroke
    • But, looking at the curves: for all endpoints but breast cancer, there was the most dramatic improvement going from about 1500 to 4000 MET minutes/week, with leveling off thereafter. For breast cancer, the curve showed a relatively linear decline with more activity. [Remember: this study included all physical activity: i.e. it is hard to translate the current US recommendation of 75-150 minutes/week of exercise into the above 1500-4000 MET minutes/week.]​
  • Potential mechanisms connecting exercise with decreased cancer include: decreased body fat (body fat could confer various risks, including increased estradiol levels; they did note that BMI did decrease the association with several cancers, however I would add that BMI is not the most specific measurement of body fat, and does not differentiate from the much more metabolically active and less healthy visceral fat from subcutaneous fat); also many/most hormonal systems are changed with exercise, including cortisol levels (which in themselves affect most other hormone levels), male and female sex steroids, insulin and insulin-like growth factors, and adipokines (and many of these hormone systems could be related to carcinogenesis, e.g. by altering immune function); as well as changes in inflammation, oxidative stress (which are especially related to  visceral fat), and the reduced colonic transit time which could affect colon cancer incidence.

So, a pretty quick and dirty study, but it does really reinforce the potential role of exercise in cancer prevention. This becomes even more of an issue given the predictions that the global cancer burden will increase dramatically (one model suggesting a doubling by the year 2030), especially as unhealthy lifestyles such as smoking and poor diet increase in resource-poor countries: there are increasing obesity trends and less physical activity as more people move to crowded and often quite polluted cities — these changes are associated with a pretty dramatic shift from mortality associated with infectious diseases to that associated with chronic, western-type diseases).

From blog of 1/3/17 on cardiovascular fitness as a vital sign:

  • As a quick guide to METs:
    • Light activity (<3 METs): includes walking 2.5 mph (2.9 METs)
    • Moderate activity (3-6 METS): includes walking 3.0 mph (3.3 METs), walking 3.4 mph (3.6 METs), stationary biking (light effort) 5.5 METs
    • Vigorous activity (>6 METs):  jogging (7.0 METs), calisthenics/pushups/situps (8.0 METs), rope jumping (10.0 METs)​

Primary Care Corner with Geoffrey Modest MD: vitamin B12 and diabetic autonomic neuropathy

23 Feb, 17 | by EBM

By Dr. Geoffrey Modest

A recent Danish study found that vitamin B12 deficiency was associated with diabetic cardiovascular autonomic neuropathy, CAN (see Hansen CS. J Diabetes Complic. 2017; 31(1); 202)

​Details:

  • 469 type II diabetic patients were screened for CAN by several measures, as well as for peripheral neuropathy.
  • Mean age 59, 60% male, diabetes duration 10 years, 5% excessive alcohol consumption, 12% smokers, BMI 32, blood pressure 132/82, 6% on vitamin B12 supplementation (though 16% in those in the highest B12 quartile), 80% on lipid-lowering drugs, 75% on metformin, 4% on PPIs alone and 10% on the combination with metformin, 40% on insulin
  • CAN was measured after a 5-minute supine resting period:
    • Heart rate variability (HRV)
    • 3 tests assessing cardiovascular autonomic reflexes:
      • Lying-to-standing test
      • Deep breathing test (E/I ratio), a measure of heart rate variation during deep breathing [which is affected by an abnormality in the parasympathetic nervous system]
      • Valsalva
    • Peripheral neuropathy was measured electronically by vibration sensation

Results:

  • B12 level varied from the lowest quartile mean of 190 to the highest quartile of 486 pmol/l
  • Serum levels of B12 were significantly lower in those on metformin or proton pump inhibitors, p <0.001.
  • Higher level of B12 were significantly associated with a lower odds ratio of CAN, p=0.04
  • A 25 pmol/l higher level of vitamin B12, adjusted for age, sex, diabetes duration, and alcohol consumption, was associated with:
    • 6% lower level of CAN diagnosis, odds ratio 0.94 (0.88-1.00, p= 0.034)
    • An increase of E/I ratio of 0.21% (p= 0.038)
    • A decrease in resting heart rate of 0.25 bpm (p= 0 .025)
  • No association between B12 levels and decreased vibration/peripheral neuropathy

Commentary:

  • Cardiovascular autonomic neuropathy is very common in patients with type II diabetes, ranging in prevalence from 20 to 65% and increasing with length of diabetes. CAN is also an independent predictor of cardiovascular mortality and morbidity. But CAN may well be overlooked clinically until a patient is symptomatic, typically late in its course.
  • Vitamin B12 deficiency is also quite common in diabetics, with estimates from 2-33%, potentially mediated in part by the use of metformin through a not-so-well understood mechanism. This relationship is both metformin dose-dependent and treatment duration dependent, and may be measurable in as little as 4 months after the onset of use. In addition, the frequent use of proton pump inhibitors may decrease vitamin B 12 levels. Another potential and common mechanism for B12 deficiency in older patients is the age-associated decrease in several digestive enzymes, leading to the inability to liberate B12 from foods thereby decreasing its absorption (studies have found b12 deficiency in 10-25% of elderly, typically asymptomatic).
  • This was an observational study, therefore it is difficult to attribute causation. In addition, there is no compelling evidence that correcting B12 deficiency decreases the likelihood of CAN [one Indian population-based study of healthy elderly showed that B12 supplementation in those deficient led to normalization of decreased heart rate variability (see Sucharita S. Autonoom Neurosci 2012; 168 (1-2); 66)].
  • Also, the effect of B12 deficiency on CAN in the study was not particularly large. Part of this is that there were very few patients (0.6% of their population) who they defined as having vitamin B12 deficiency (that being below 125 pmol/l in this study, though many consider the cutpoint to be <148 pmol/l, which translates to <200 pg/ml), so the lowest quartile had lots of patients who were probably not actually B12 deficient. And the likely reason for the low B12 deficiency rates was that the standard clinical practice in that area was to check B12 levels in patients every other year. They did not test for methylmalonic acid or homocysteine, which might have been relevant in those with borderline B12 deficiency (35% had B12 levels between 125 and 250 pmol/l, though others consider borderline to be between 148 and 221 pmol/l​, or 200-300 pg/ml). Also, the fact that the effect was particularly evident for the E/I ratio with deep breathing suggests that a parasympathetic abnormality may predominate, and parasympathetic denervation is in fact typically the first abnormality in CAN, leading to increased sympathetic tone.
  • Of note, several different studies, but not all, show that those with peripheral neuropathy associated with B12 deficiency do improve with B12 supplementation, though the degree of improvement tracks inversely with both the extent and duration of disease.

So, my take on this is that given the clear importance of vitamin B12 for several aspects of health (neurologic, psychiatric, hematologic), and that some of these manifestations may be pretty subtle/very hard to detect early on, I personally think it makes sense to check vitamin B12 levels in the elderly as well as those on metformin and PPIs. And now, perhaps more so in diabetics overall, perhaps when they reach the ripe old age of 50 or so.

Primary Care Corner with Geoffrey Modest MD: opiate prescribing in the elderly and subsequent dependence

22 Feb, 17 | by EBM

By Dr. Geoffrey Modest

Two important articles were just published in NEJM which I think should stimulate a change in clinical practice regarding prescribed opiates.

————————————————————————————

One article assessed the relative importance of physician prescribed opiates and the subsequent use of opioids in the elderly (see Barnett ML. N Engl J Med 2017; 376: 663).

Details:

  • Retrospective analysis of a random 20% sample of continuously-enrolled Medicare beneficiaries who had an emergency department (ED) visit from 2008-2011, and had not received opioid prescription for the prior six months
  • Mean age 69, 65% female, 76% white, 50% also on Medicaid, 37% disabled, mean of 3.5 chronic conditions (most commonly hypertension in 78%, hyperlipidemia in 70%, acute MI in 50%, depression 40%, diabetes 38%, COPD 28%), with 38% from the South/24% Midwest/20% Northeast/17% West
  • ED physicians at the hospitals were classified as either high-intensity or low-intensity opioid prescribers, according to their quartile of prescribing rates at that same hospital.
  • The rates of continued opioid use were compared, defined as 180 days supplied in the 12 months after that ED visit

Results:

  • 215,678 patients received treatment from low-intensity and 161,951 from high-intensity prescribers. The overall clinical characteristics of the patients treated by these different providers were very similar.
  • Within individual hospitals, the opioid prescribing rates varied by the type of providers: 7.3% versus 24.1% (p<0.001), for the low versus high-intensity prescribers. There was minimal correlation between the physicians’ prescribing rate and the median initial dose of the opioid prescribed.
  • There was a 30% increase in long-term use of opioids by patients treated by the high-intensity prescribers, adjusted odds ratio 1.30 (1.23-1.37), p<0.001. The number-needed-to-harm was 49 patients receiving an opioid prescription leading to one excess long-term opioid user.
  • There was a stepwise increase in long-term opioid use, tracking with increased quartiles of physician prescribing rates.
  • Those patients seeing a high-intensity opioid prescriber had higher rates of subsequent hospital encounters (a 3% significant increase) and encounters for fall or fracture (a 7% significant increase), with no difference in non-opioid-related encounters

Commentary:

  • It is notable that the rates of hospitalizations for opioid overdoses in the elderly Medicare population has quadrupled from 1993 to 2012.
  • It is also quite concerning that the elderly are more likely to have adverse consequences from even therapeutic doses of opioids, including more sedation, falls, fractures, and death from any cause.
  • Although this was an observational study, which limited the rigor of its conclusions or its ability to determine causality, these researchers seem to have done an excellent job of including huge numbers of patients, comparing providers in the same institution with each other, and controlling well for likely comorbidities of the patients (though they don’t have a clear assessment of the intensity of the pain of the individual patients, it does seem unlikely that patients would be assigned to high-intensity opioid prescribers just because they had more pain and thereby creating a bias in the study)
  • As noted in several prior blogs, one of my major concerns about opioid prescribing is the dearth of good clinical evidence. This leads to a not so infrequent clinical conundrum: what to do with an elderly patient who has significant chronic pain, perhaps from osteoarthritis, to the point that they have very limited function and extremely poor quality of life. Perhaps a trial of NSAIDs does not help (and NSAIDs have their own attendant morbidities), and neither does acetaminophen nor topical or other adjuvant therapies. Perhaps they have had multiple steroid injections with diminishing or limited effectiveness. And perhaps they are not interested in surgery, or are not healthy enough for it. As a result, to improve their quality of life and after extensive discussion of adverse effects, I have sometimes prescribed tramadol or codeine or even low-dose oxycodone, often in combination with other adjuvant therapies, with excellent clinical and quality-of-life results. And, I think that is in the patients’ best interests and is appropriate care. Even in patients who are 90+ years old.
  • However, this article does reinforce the peril of prescribing opiates to the elderly. Given that the patients given opiates did not seem to differ clinically from those not given opiates, it pretty clearly suggests that we as providers may be playing a significant role in creating long-term opiate users. Our experience in Boston has shown pretty dramatic changes in ED opiate prescribing over the past couple of years. During that time period of this study, it was unusual for one of my patients who had gone to the ED for pain not to come home with an opiate prescription, even if they explicitly stated to the ED doctor that they did not want or need these meds. That is no longer the case. And we should all take seriously studies which show, for example, that even renal colic, considered one of the more severe pains, seems to respond to NSAIDs similarly to opiates (e.g., see Teichman JMH. New Engl J Med. 2004; 350: 684). And many patients do well with NSAIDs post-op (my clinical observation).
  • Although the study targeted older patients, it is consistent with a prior blog in which adolescents with low risk of illicit drug dependence but given legitimate prescription opiates as 12th graders (for surgery, etc.), were up to 3-fold more likely to have opiate use disorder at age 23 (see http://blogs.bmj.com/ebm/2015/11/10/primary-care-corner-with-geoffrey-modest-md-prescribed-opioids-and-future-prescription-opioid-misuse-in-teens/​ )

Given that clinicians seem to be more consciously decreasing/limiting their opiate prescriptions and more hesitant to start opiates, there not only may be fewer prescription opiates available on the street, but also fewer patients requesting/needing continued opiate prescriptions subsequently. So, the more optimistic take on this issue of opiate dependence is perhaps that the future is bright/there may be fewer people with opioid dependence going forward.

———————————————————————————————————————-

An editorial highlighted the huge public health threat of fentanyl (see Frank RG. N Engl J Med 2017; 376:605), making several important points:

  • Fentanyl-related deaths have been increasing dramatically, especially in the eastern United States: from 2628 in 2012, to 5544 in 2014, with 41% of heroin-related deaths involving fentanyl
  • Fentanyl is mixed with a multitude of street drugs, including heroin, MDMA (methylenedioxymethamphetamine), OxyContin, Xanax, and Narco (acetaminophen-hydrocodone). A recent Canadian analysis found that 89% of seized counterfeit OxyContin tablets contained fentanyl
  • Fentanyl is cheap, going for $3500 per kilogram, as compared to $65,000 per kilogram for heroin (and this is despite heroin’s declining prices, which had made it much more attractive in the streets than prescribed opiates, such as Percocet)
  • This all further supports harm reduction strategies, especially since most who die from fentanyl overdose are unaware they are taking it, including: improved monitoring of street drugs for fentanyl, drug enforcement approaches which emphasize use reduction (e.g., not targeting buyers with syringes, which may actually increase the risk of needle sharing and other higher-risk behaviors, etc.), improved access to treatment programs, improved access to naloxone (which, as per prior blogs, may need a higher dose for fentanyl overdoses).

Commentary:

  • This article highlights the devastating and escalating effects of illicit fentanyl, apparently largely produced in China, emphasizing appropriately the importance of harm reduction as a key strategy
  • Of note, I had been unaware that fentanyl was mixed with so many different street drugs, and not just with heroin. This article highlighted how widespread fentanyl-lacing can be, and this message needs to be transmitted to our drug-using population.​

For relevant recent blogs:

http://blogs.bmj.com/ebm/2017/02/10/primary-care-corner-with-geoffrey-modest-md-increasing-deaths-from-opioids/ highlights the increasing opiate death rates, esp from fentanyl

http://blogs.bmj.com/ebm/2016/06/29/primary-care-corner-with-geoffrey-modest-md-tai-chi-for-knee-oa-mindfulness-for-chronic-pain/ describes a study looking at Tai Chi and mindfulness to treat chronic pain

http://blogs.bmj.com/ebm/2016/04/05/primary-care-corner-with-geoffrey-modest-md-meds-for-oa-including-placebo/ is an interesting study finding that even placebo works pretty well for chronic pain from osteoarthritis and, in general http://blogs.bmj.com/ebm/category/pain/​ for a slew of articles on chronic pain and opiates, with descriptions and critiques of published guidelines

 

Primary Care Corner with Geoffrey Modest MD: understated cervical cancer mortality and hpv in men

16 Feb, 17 | by EBM

By Dr. Geoffrey Modest

2 recent articles looked at US cervical cancer mortality and hpv infections in men.

  1. The New York Times reported a huge racial gap in cervical cancer deaths in the United States (see https://www.nytimes.com/2017/01/23/health/cervical-cancer-united-states-death-toll.html?_r=0 ). They referred to an article which calculated a much higher death rate from cervical cancer overall in the US than previously found, with an increased disparity between black and white women (see DOI: 10.1002/cncr.30507).

Details:

  • The age-standardized rate for cervical cancer death reported by the National Center for Health Statistics from 2000-2012 was 3.2/100K in white women and 5.7/100K in black women
  • However, these results were not corrected for the prevalence of hysterectomies, and given that hysterectomies are significantly more common in black women, the above statistics understated the cervical cancer death rates (since these cancers are essentially eliminated in people who’ve had hysterectomies for benign reasons, especially if the cervix is removed).

Results:

  • The overall prevalence of hysterectomies was 20% for women >20 years old, higher in black women for all ages between 45-69, peaking for both white and black women at ages 65-69, but this peak hysterectomy rate was 58% of black women vs 43% of white women [remarkably high numbers overall and shockingly so for older black women!!]
  • Correcting for the prevalence of hysterectomies, the mortality rate was 10.1/100K in black woman and 4.7/100K in white women.
  • Based on this, the disparity in mortality rates was underestimated by 44% over the published NCHS numbers.
  • The highest corrected rate was in black women > 85 years, with a death rate of 37/100K vs 11/100K for white women!!!
  • Using this corrected analysis, the rate of cervical cancer deaths in white women decreased at 0.8% per year, whereas for black women the annual decrease was 3.6%.

Commentary:

  • Each year more than 12,000 women in the US are diagnosed with cervical cancer and more than 4000 women die from it.
  • For the women in this study, the likelihood of a supracervical hysterectomy (i.e., leaving the cervix) was <2% (data from before 2004), though now is closer to 4-7.5%. So more individual data, even if available, would not have altered the results much
  • Cervical cancer is largely preventable through screening, and screening rates may be lower in poor and minority areas, although published results on this are equivocal. The data are clearer that black women tend to present with more advanced disease and may receive different treatments than white women, e.g. less surgery and more radiation for the same stage of cancer. For example, a recent large study of more than 15,000 patients with advanced cervical cancer found that more than half did not receive treatment considered to be standard of care, mostly those who were black and poor.
  • The corrected cervical cancer mortality rates in black American women is similar to those of many resource-poor countries in Latin America, Asia (excluding Japan), the Caribbean, and Africa (including sub-Saharan Africa). For white women, their corrected cervical mortality rates are similar to those of Europe, Australia, and Japan
  • The corrected mortality is significantly higher in black vs white women in all age groups, except those aged 20-29 and 35-39 (though increases pretty dramatically in women older than this)
  • Some of the methodologic weaknesses of the study include the potential for biases related to incomplete data and the merging of 2 unrelated databases with very different methodologies. The data on age-standardized death rates came from the National Center for Health Statistics (they also looked at the SEER database, which did not include every state and notably did not include Louisiana), whereas the data on hysterectomy prevalence came from the Behavioral Risk Factor Surveillance System survey, which is based on interviews.
  • It was quite striking to me when I was working in Chicago many many years ago that a very large number of my middle-aged to older black female patients had had hysterectomies when living in the Southern US, but were unaware they even had the surgery (many reported having had some surgery, but were never told that the doctors had done a hysterectomy). We were told that this was a not uncommon method of enforced birth control for black women…. So, since some were unaware they even had the surgery (and may be part of the older women now), the racial disparity may be even greater.

So, it is quite striking that black women in the United States have such a high death rate from cervical cancer. And, perhaps a real concern is that with the repeal of the Affordable Care Act, which does cover such screenings, there may be less access for many people for appropriate screenings. In addition, I am very concerned that the upcoming, likely attacks on Planned Parenthood and other clinics providing cervical cancer screening etc., will decrease access especially for poor women and women of color.

Relevant prior blogs:

http://blogs.bmj.com/ebm/2016/10/17/primary-care-corner-with-geoffrey-modest-md-cervical-screening-guidelines-from-asco/ which reviews the American Society of Clinical Oncology guidelines

http://blogs.bmj.com/ebm/2016/10/12/primary-care-corner-with-geoffrey-modest-md-cervical-cancer-screening-less-frequently/ presents data from a study in the Netherlands, suggesting that negative cervical HPV screening in women over age 40 supports a strategy of screening every 10 years

http://blogs.bmj.com/ebm/2014/10/29/primary-care-corner-with-geoffrey-modest-md-whither-the-pelvic-again/ which was a review of urinary screening for HPV, with my concern that clinicians will be doing far fewer pelvic exams (which certainly has its pluses, since these can be invasive and uncomfortable procedures for women), but with the caveat that I have seen several younger clinicians feeling less comfortable doing pelvic exams even when clinically indicated

http://blogs.bmj.com/ebm/2016/07/18/primary-care-corner-with-geoffrey-modest-md-pap-smears-post-hysterectomy-in-hiv-positive-women/ presents a study suggesting that we should do Pap smears in HIV patients, even post-hysterectomy

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  1. Another article came out looking at the prevalence of genital HPV infections as well as vaccination rates in US adult men, from the National Health and Nutrition Examination Survey (NHANES) of 2013- 2014 (see doi:10.1001/jamaoncol.2016.6192).

Details:

  • NHANES collects information of representative cross-section samples of the US population.
  • 1868 men aged 18 to 59 were examined and DNA was extracted from self-collected penile swab specimens for HPV genotype.
  • Demographic and vaccination information was gathered by self-report.

Results:

  • The overall general HPV infection prevalence in males aged 18-59 was 45.2% (i.e., 34.8 million men). bimodal pattern, with peaks age 28-32 and another 58-59
  • The infection prevalence with at least one high risk HPV subtype by DNA testing was 25.1%
  • The overall prevalence of infection for subtypes covered by the HPV-9 valent vaccine was 15.1% (the 9-valent vaccine covers 90% of subtypes responsible for cervical cancer in women)
  • The specific very high-risk subtype prevalences: 4.3% for HPV-16 (3.3 million men), 1.7% for HPV-18 (1.3 million men)
  • In vaccine-eligible men, the prevalence of infection with at least one HPV strain targeted by the HPV-4 valent vaccine was 7.1% and by the HPV 9-valent vaccine was 15.4%
  • Among vaccine-eligible men, HPV vaccination coverage was 10.7% (i.e. more than 25 million vaccine-eligible men did not receive the vaccination)

Commentary:

  • HPV is the most commonly known sexually transmitted infection in the US. An estimated 79 million people in the US are infected with HPV, half of new infections occurring before age 24. There was a study about 10 years ago finding that 50% of women in their first year at college acquired HPV infection. In men, an estimated 160,000 are infected annually with low-risk HPV infections
  • In men, an estimated 9000 HPV-related cancers occur annually, responsible for 63% of penile cancers, 91% of anal cancers and 72% of oropharyngeal cancers (the oral HPV infection rates are around 10% for men and 4% for women). HPV can also cause recurrent respiratory papillomatosis
  • Men seem to clear HPV infection pretty quickly, with a study of 290 men finding that the 12-month risk of acquiring a new infection was 29%, with the median time to clearance being 5.9 months (Giuliano AR. J Infect Dis 2008; 198: 827). So, it seems likely that the point prevalence in the above study significantly understates the life-time acquisition rate for HPV, which is similar to that of women.
  • BUT, the major public health issue for men is that they can transmit this infection to women, potentially leading to cervical cancer, with a significant morbidity and mortality (as in first article above)
  • The CDC therefore published their recommendations for HPV vaccination: females aged 11 to 26; males aged 11 to 21, but from 21-26 being “recommended for persons with a risk factor (medical, occupational, lifestyle, or other indication”). Probably makes sense to support male vaccination till age 26, similar to the female recommendations

So, bottom line: these studies are very concerning, since on the one hand HPV infections are wide-spread and the number of unvaccinated men who are vaccine-eligible is staggering; on the other hand, cervical cancer death rates are quite high in the US and with a pretty dramatic black-white differential.

Primary Care Corner with Geoffrey Modest MD: Is Mammography Useful?

14 Feb, 17 | by EBM

By Dr. Geoffrey Modest

This blog will bring up 2 recent studies suggesting the lack of efficacy of mammography screening coupled with significant overdiagnosis.

  1. An article a couple of years ago looked at screening mammography in the US, with 10 year follow-up of breast cancer incidence and mortality (see Harding C. JAMA Intern Med 2015; 175: 1483).

Details:

  • This was an ecological study of 16,120,349 women 40 years of older who resided in 547 counties reporting in the Surveillance, Epidemiology, and End Results (SEER) cancer registries during the year 2000.
  • 53,207 had a diagnosis of breast cancer and were followed for 10 years.
  • The researchers looked at the extent of the screening in each county, and the results of both breast cancer incidence and mortality (the latter being defined as women diagnosed with breast cancer in the year 2000 who had died from the disease during the 10 year follow-up period). Overall, in the 547 counties, the overall 10-year incidence based mortality was 47.2 per 100,000 cases diagnosed in 2000.

Results:

  • There was a strong positive correlation between the extent of mammography screening and the breast cancer incidence (P<0.001)
  • But, there was no relationship between screening and breast cancer mortality.
  • Each increase of 10 percentage points in the extent of screening was accompanied by:
    • A 16% increase in breast cancer diagnoses, RR 1.16 (1.13- 1.19)
    • Not even a trend to a change in breast cancer deaths, RR 1.01 (0.96-1.06)
  • Analyzing by tumor size, screening led to a higher incidence of small breast cancers (<= 2 cm), but not with a decreased incidence of larger breast cancers (>2 cm )
  • Each increase of 10 percentage points in screening is associated with:
    • A 25% increase in the incidence of small breast cancers, RR 1.25 (1.18- 1.32)
    • A 7% increase in the incidence of larger breast cancers, RR 1.07 (1.02- 1.12)
  • The following figure shows that as the proportion of women had a mammogram in the past two years, the incidence of breast cancer diagnoses increased significantly yet the 10-year mortality did not budge

Commentary:

  • So, pretty powerful large-scale epidemiologic study, finding that mammography led to a large increase in the diagnosis of small cancers, but there was no decline in the detection of larger cancers. This may be the reason why there was no significant difference in the overall death rate from breast cancer by doing mammography screening.
  • What does this mean? It may mean that there are a subset of very aggressive small cancers which spread and cause clinical disease and mortality, and that screening is didn’t help for these. And that a very large number of small cancers that are picked up by mammography are in fact “overdiagnosed” (defined as: tumors that would not have become clinically evident in the remaining lifetime without screening).
  • One would have expected that if screening did pick up small tumors earlier, that over time the diagnosis of larger and less treatable cancers should decrease. It is quite concerning that the number of larger breast cancers in fact continued to increase over the study. And, of course, the goal of screening is to reduce mortality, which was not found in the study. One additional finding was that increased screening would lead to more breast conserving surgical procedures; however they found no evidence of a decrease in extensive mastectomies.
  • Without getting into a lot of detail, the authors present reasonable arguments that this is not just lead-time bias, or ecological bias (this latter happens when looking at group data and assuming that it applies to the individual who may or may not have had a mammogram). Also, there was no association between mortality rates even comparing those counties with much higher breast cancer incidence, reducing the potential bias of comparing counties with very different incidences of breast cancer. But, they also did not have data on women who had therapy or what the risk factors were for the women who developed breast cancer. Also, this was just a 10-year follow-up, and patients may well live more than 10 years with newer therapies, but I would have expected some evident benefit of screening by 10 years (and at least a trend to benefit…)
  • There have been several important changes in technology over the past several decades, some of which may make older studies less applicable now (these older studies are the ones on which current mammogram recommendations are based). On the one hand, the sensitivity of our screening methods is greater and we are picking up much smaller tumors; and, perhaps these smaller tumors are more likely to regress than the larger ones picked up previous, leading to increased overdiagnosis. On the other hand, treatments have improved a lot, and the risk/benefit equation may have changed some. Given the potential harms of overdiagnosis (including surgery, radiotherapy, and chemotherapy), we should be looking at the new balance. In addition, there are interesting advances in genomic profiling, which are helpful in determining how aggressive a tumor is likely to be as well as how intensive therapy should be

So, a large study like this offers interesting insights, especially when looking at likely overdiagnosis (which one cannot determine in an individual patient). As with all screening tests (e.g. PSA), it would be really useful to figure out how to risk stratify patients, with more aggressive screening in those at higher risk. That is much more likely to show benefit for screening then with screening the general population.

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  1. A more recent article look specifically at breast cancer overdiagnosis by mammography screening in Denmark (see doi:10.7326/M16-0270)). The study looked at women aged 35 to 84, from 1980 to 2010.

Details:

  • Denmark had a perhaps unique opportunity to look at the results of mammography screening both because it has rigorous databases (the Danish Breast Cancer Group, DBCG, and the Danish Cancer Registry, DCR) as well as a 17-year screening program which involved 20% of the population aged 50 to 69. This differential access to mammography screening allowed for real-world comparisons to a large, essentially randomized non-screening populations. Clinical breast exams were not included.
  • The DBCG database included 90,665 women aged 35 to 94 who were diagnosed with invasive breast cancer, and 4267 diagnosed with DCIS
  • For the mammography group in DBCG, they divided tumors into two groups: large (>20 mm) and small (<20 mm), considering the large tumors as “advanced” because they are equivalent to T2 or greater in the TNM classification system
  • The screening routine, somewhat different from what we do in the US, was biennial screening with a 2-view mammography on the first round, with 1-view mammography at subsequent screens except for women with dense breasts who always received a 2-view mammogram.
  • The DCR provided individual data on tumor size in women with invasive breast cancer.

Results:

  • For women aged 35 to 69: in non-screening areas the incidence of advanced cancer increased throughout the observation period.
  • For women 70 to 84: in the non-screening areas the incidence of advanced cancer also increased throughout the observation period, and was most pronounced in the later years.
  • The incidence of non-advanced tumors increased in the screening versus prescreening periods, incidence ratio 1.49 (1.43- 1.54), i.e. a 49% increase
  • Looking just at nonadvanced tumors, there were 711 invasive tumors and 180 cases of DCIS that were overdiagnosed in 2010 (overdiagnosis rate of 48.3% including DCIS and 38.6% excluding DCIS
  • There was no reduction in the incidence of advanced cancers through mammography screening.
  • Their conclusion: “it is likely that one in every three invasive tumors in cases of DCIS diagnosed and women offered screening represents overdiagnosis (incidence increase of 48.3%)”

Commentary:

  • This study is quite remarkable since it is reasonably close to a really large-scale randomized controlled trial, in which for 17 years 20% of women got mammograms and the rest didn’t. And there was no difference in advanced breast cancers through consistent mammography screening
  • See below for other blogs on the poor utility of mammography screening, also showing almost no decrease in breast cancer mortality but large numbers of overdiagnosed mammogram-detected cancer.
  • A lot of the “overdiagnosis” is from DCIS (about 25% of all new breast cancer diagnoses), which the National Cancer Institute now classifies as a “noninvasive condition” (an observational study of 108,196 women with DCIS in the SEER registries found an overall breast cancer death rate of 3.3% over 20 years, similar to the general population: see Narod SA. JAMA Oncol 2015; 1(7):888
  • All of this reinforces the fact that early detection of breast cancer is fraught. For breast cancer, there are 230,815 diagnoses/year in women, 2109 in men; and 40,860 breast cancers deaths/year in women and 464 in men, and affects 1 in 8 women!!!; yet mammography screening has perhaps minimal benefit. Which really brings up the issue of prevention (which, it turns out, does not get much funding). As noted in prior blogs, one big unknown is the prevalence of industrial toxins (many of which are estrogenic, including pesticides, BPA, others used in plastics, etc etc) which are in our environment and may well be carcinogenic. Large numbers of new chemicals are being used and thousands of new ones are introduced each year with minimal attempts to look at potential toxicity. In addition, it is reasonably clear from the studies that healthy diet, weight control, and exercise are helpful. It seems to me that it would likely be much more useful to devote our national resources into preventing breast cancer by regulating environmental toxins and promoting healthy lifestyles than attempting early detection.

See http://blogs.bmj.com/ebm/2016/10/13/primary-care-corner-with-geoffrey-modest-md-radiologist-variability-in-mammography-readings/ which documents the quite remarkable discordance in radiologists’ reading of breast densities

See http://blogs.bmj.com/ebm/2014/02/13/primary-care-corner-with-geoffrey-modest-md-mammography-another-hit/​ for the 25-year results from the Canadian National Breast Screening Study finding NO benefit from mammography screening but that 22% of mammography-detected breast cancers were overdiagnosed.

See http://blogs.bmj.com/ebm/2014/04/22/primary-care-corner-with-geoffrey-modest-md-mammograms-again/ for a 2014 meta-analysis, finding that mammography yielded very small changes in breast cancer mortality (e.g. screening women in their 50s would lead to 3-32/10,000 decrease in breast cancer mortality, but have 6130 false positive and 30-137 overdiagnoses)​. As mentioned above, these studies were older ones.

Primary Care Corner with Geoffrey Modest MD: Dramatic Increase in Influenza Activity

14 Feb, 17 | by EBM

By Dr. Geoffrey Modest

The CDC just published their influenza update, showing that it is now widespread in 43 states for the week ending 2/4/17 (see https://www.cdc.gov/flu/weekly/).

Details:

  • There are very high levels of flu activity in the South and Southeast, and most of New England (though not so much in MA, NH, VT)
  • 20 reported pediatric deaths so far, 5 in the last week
  • 21% of the samples sent to the lab have been positive for flu
  • 88% are influenza A, and of these 92% are subtype H3; and a subsample found it to be the same H3N2 strain which is covered by the vaccine
  • None of the samples tested showed resistance to neuraminidase inhibitors (e.g. oseltamivir, zanamivir or peramivir), though rare international cases have shown resistance to these meds, both to H1N1 and H3N2
  • Hospitalization rates from flu since October 2016 have been 24.3/100K. The vast majority in these have been in those >65yo (113.5/100K), and a review of 796 cases (11.7%) found that 95% had at least one reported underlying medical condition, mostly cardiac, respiratory, metabolic disorders (esp. diabetes), or neurologic disorders; with most common ones being asthma, chronic lung disease, and multiple sclerosis or muscular dystrophy

Commentary:

  • There are no data in this report at the apparent effectiveness of the current vaccine (i.e., were these cases of flu mostly in those not getting the vaccine??), though it is reassuring that that the match of vaccine subtypes did indeed reflect those of the current outbreak
  • One concern raised a few months ago was that there may be waning immunity after vaccination. The vaccine is available earlier than before, typically at the end of the summer, with instructions from the CDC and local health department to vaccinate people right away. But it seems that influenza outbreaks are occurring most often in the feb-april time-period. And, a study of the 2011/12 season showed that those immunized <3months before the flu outbreak had 53% vaccine effectiveness, whereas those immunized more than 3 months before had  only 12% effectiveness. (See Peabody RG. Euro Surveill. 2013 18(5):pii=20389)
  • It seems reasonable to continue giving the vaccine even now  in the midst of this outbreak, though there is about a 2 week period prior to its being effective. And to consider chemoprophylaxis, especially given the susceptibility of the current subtypes (see https://www.cdc.gov/mmwr/pdf/rr/rr6001.pdf for more info on chemoprophylaxis)

Primary Care Corner with Geoffrey Modest MD: Increasing Deaths From Opioids

10 Feb, 17 | by EBM

By Dr. Geoffrey Modest

The CDC just published their report tracking drug and opioid-involved overdose deaths in the United States from 2010 to 2015 (see https://www.cdc.gov/mmwr/volumes/65/wr/mm655051e1.htm?s_cid=mm655051e1_x​ ).

Details:

  • Background: from 1999 to 2014 there was a tripling of drug overdose deaths, with 47,055 total drug deaths in 2014, and 60.9% involved an opioid. During 2013-2014, deaths from natural/semisynthetic prescribed opioids [this class includes natural opioids (morphine and codeine), and semisynthetic opioids (oxycodone, hydrocodone, hydromorphone, and oxymorphone)] increased slightly, but there was a rapid increase in deaths from heroin and “synthetic opioids other than methadone” (including tramadol, fentanyl).
  • In 2015, there were 52,404 drug overdose deaths including 33,091 (63.1%) involving an opioid. This death rate calculates to 16.3/100000 population (it was 12.3/100000 population in 2010, a 33% increase)
  • From 2014 to 2015 the death rate from “synthetic opioids other than methadone”, which includes fentanyl, increased by 72.2%, and heroin death rates increased by 20.6%. Natural/semisynthetic opioid death rates increased by 2.6%, but methadone death rates decreased by 9.1%
  • The rates of death involving heroin and “synthetic opioids other than methadone” increased among all demographic groups, regions, and most states (Florida and South Carolina had both decreasing and then increasing trends during this time: Florida decreased from 2010 to 2013 and then increased til 2015; South Carolina decreased from 2010 to 2012 and then increased til 2015)
  • The largest absolute rate increases in deaths from “synthetic opioids other than methadone” occurred in Massachusetts, New Hampshire, Ohio, Rhode Island, and West Virginia. The largest percent increases in rates occurred in New York (135.7%), Connecticut (125.9%) and Illinois (120%). The largest absolute rate increases in heroin deaths were in Connecticut, Massachusetts, Ohio, and West Virginia, and the largest percentage increases were in South Carolina (57.1%), North Carolina 46.4%, and Tennessee (43.5 percent)

Commentary:

  • The above includes 28 states with high quality reporting on death certificates, including specific drugs involved in overdoses. [Seems like all states should be tracking this. And this is why our national statistics and epidemiologic studies pale in comparison to western European countries, where they have large and inclusive national registries. Would be great to fix this…. much better data to act on]
  • Deaths from illicitly-manufactured fentanyl were probably largely responsible for the increase in deaths attributed to “synthetic opioids other than methadone” and were largely concentrated in eight of the 27 states examined. Actual fentanyl prescribing rates did not change during this time [confirming that this was likely illicitly-manufactured]
  • Factors likely involved in these changes include:
    • My guess is that the decrease in overdoses due to methadone is related to more vigorous efforts by the federal and state governments to limit its use in chronic pain. This shows that targeted strategies seem to work.
    • The smaller increase in natural/semisynthetic opioid deaths may also be related to changes in policies/education, use of the prescription drug monitoring program, and legislative changes in naloxone prescription and distribution.
    • The implementation of harm reduction strategies, including syringe exchange programs, increased access to naloxone, more available medication assisted treatments, strategies to reduce the transmission for hepatitis C and HIV, etc., are likely very important in decreasing the extremely important sequelae of drug use
    • But, ironically, it seems that as there is less availability of prescription opioids in opioid prescribing, many patients are taking some more dangerous but now much cheaper drugs such as heroin, which may well be laced with fentanyl (i.e., these opioid substitutes may be being used more, and these may even be more fatal, such as by the increase in fentanyl-related deaths).
  • So, the bottom line here for me is that single targeted measures (decreasing methadone prescribing) can lead to shifts in drug usage with potentially even worse clinical outcomes. Which really speaks to the need to deal with the underlying problems of poverty, lack of hope/avenues to advancement felt by many young (and old) people, lack of positive social supports, poor quality education for many, increasing income inequalities, etc. etc. etc.
  • As I have mentioned in several blogs, including one which evaluated/critiqued the CDC guideline for prescribing opioids for chronic pain (see past blogs below), the issue of chronic pain control is often one of the most difficult clinical issues we encounter in primary care. There are very clear examples (at least to me) of patients who need chronic opioids to function and lead reasonably normal lives. And several need very high doses (for a multitude of reasons, likely including genetic differences in mu receptors). There also are pretty clear examples of clinicians overprescribing opioids, from surgeons/emergency rooms as well as from primary care, and these can have profound social sequelae, such as drug diversion and opioid-related deaths. And, there are whole group of people in the middle, where it is not entirely clear and is a judgment call by the treating clinicians. The first two groups are easier to deal with; this middle group where there is more uncertainty about the need for opiates is quite challenging clinically and more socially concerning given the reality of the explosion of illicit drug use and deaths.
  • I would also like to mention again a prior blog finding that 12th graders prescribed opioids by clinicians (e.g. for surgery) but were considered beforehand to have a very low likelihood of using illicit drugs in the future per a standardized and validated questionnaire, had a much higher rate of opioid abuse at age 23 than a similar group who were not prescribed these opioids (see below).

Past blogs:

http://blogs.bmj.com/ebm/category/pain/ for the array of blogs on opiates and chronic pain

http://blogs.bmj.com/ebm/2016/03/25/primary-care-corner-with-geoffrey-modest-md-new-cdc-guidelines-for-opiate-prescribing/ for a critique of the CDC guidelines

http://blogs.bmj.com/ebm/2015/11/10/primary-care-corner-with-geoffrey-modest-md-prescribed-opioids-and-future-prescription-opioid-misuse-in-teens/ for the blog on 12th graders at low risk of addiction by a validated questionnaire, then getting prescribed opiates, finding that by age 23, there was a 33% increased risk of opioid misuse

Primary Care Corner with Geoffrey Modest MD: Metformin in those with CKD, CHF, CLD

6 Feb, 17 | by EBM

By Dr. Geoffrey Modest

A systematic review from the VA synthesized data on use of metformin in patients with chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment (see doi:10.7326/M16-1901). The goal was to assess all-cause mortality, major adverse cardiac events (MACEs), and other outcomes in patients with these underlying diseases (patients with these diseases having been the ones in whom the FDA initially had warned against using metformin).

Details:

  • 17 observational studies that included patients with CKD, CHF, or CLD with hepatic impairment were analyzed. These studies compared patients on diabetes regimens that included Metformin vs those that did not.

Results:

  • CKD
    • 6 studies were included, with sample sizes ranging from 1246 to 11,481 patients, median age ranging from 65 to 76. Only one study reported median daily metformin dose (1100 to 1900 mg in the different subgroups)
    • All-cause mortality
      • 22% lower for patients on metformin, HR 0.78 (0.63-0.96)
      • 2 studies reported CKD severity subcategories:
        • eGFR of 30 to <45 had neither benefit nor harm
        • eGFR of 30 to 60 had clear benefit of around 38%
        • eGFR <30 (one study) had neither benefit nor harm
      • MACEs:
        • 2 studies were evaluated, finding no difference in outcomes with metformin in the subgroups of patients with eGFR <45
        • And much, much more hypoglycemia in those on non-metformin-based regimens (specifically, glyburide or insulin)
      • CHF
        • 11 observational studies were included, with sample sizes from 346 to 13,930 patients, median age 55 to 77 years old. No studies included median metformin dose
        • All-cause mortality:
          • 22% lower for patients on metformin, HR 0.78 (0. 71-0.87)
          • 2 studies reported CHF severity subcategories:
            • One study looked at LVEF, finding that both an LVEF of 30-39% and LVEF<30% had a nonsignificant 13% decreased mortality; another study looked at patients with LVEF < 40%, finding a nonsignificant 21% decrease
          • MACEs:
            • The relative chance of readmission for CHF during follow-up was 13% lower for patients on metformin: HR 0.87 (0.78-0.97)
            • The relative risk for cardiovascular mortality was 23% lower in those on metformin (their figure shows that the three studies that looked at this found statistically significant improvement with metformin, but their overall summary said it was nonsignificant?????)
          • CLD
            • 3 observational studies included, with sample sizes ranging from 82 to 250 patients, median age 60-61. No studies reported median metformin dose.
            • All cause mortality:
              • The one study with low risk of bias (n=250) found significantly longer survival: HR 0.43 (0.24-0.78), regardless of cirrhosis severity. Post hoc analysis found a positive association between metformin and survival only in those with nonalcoholic steatohepatitis, though the number of patients in the other subgroups was small.
            • The other studies in those with moderate-to-high risk of bias showed a trend to lower all-cause mortality with metformin

Commentary:

  • Metformin is accepted as the first line drug for diabetes in the US and other countries that I know of. It is such a good and appropriate drug, given both its positive effects on diabetes (including its being weight-neutral or leading to weight loss) as well as data suggesting decreased cardiovascular disease and all-cause mortality. As a result, many clinicians have been using it despite FDA precautions/contraindications, with estimates that 20-30% of patients have been prescribed metformin who have had these precautions/contraindications. The FDA itself has been progressively relaxing these restrictions. In 2006 they removed CHF as a contraindication (though acute or unstable CHF remains a precaution). In addition in 2016, the FDA changed the warning for CKD to be based on eGFR instead of creatinine, making approximately 1 million additional patients with moderate CKD eligible to receive metformin. See blogs noted below for other studies promoting the use of metformin.
  • Most of the above conclusions were based on studies which had low strength-of-evidence, moderate risk-of-bias. However there was consistency in their finding that metformin therapy was associated with reduced all-cause mortality among patients with moderate CKD, CHF, or CLD; fewer CHF admissions among those with moderate CKD or CHF; and a much lower hypoglycemia rate among those with moderate CKD
  • There are other concerns about a meta-analysis such as above, including the fact that they don’t have data on doses of metformin for most studies, what other medications were being used in addition to metformin (the studies did not have rigorous details about which patients were on which other hypoglycemic medications), whether there was “confounding by indication” (where people might have been selected to be on or off metformin based on unknown individual clinical considerations), or even more than baseline data on metformin use in most studies (i.e. patients may have started on metformin but somewhere during the study had stopped it; or alternatively patients may have started off metformin but then put on it during the course of the study)

But, bottom line, these studies reinforce not just the safety of metformin in what had previously been considered concerning underlying comorbidities, but strongly suggest a significant benefit of metformin-based regimens. I.e., there really is an imperative to use metformin as the first-line therapy. We know through our clinical practice that metformin’s major adverse reactions are GI. This is clearly less the case in those on lower doses or if metformin is taken with meals. The somewhat skimpy data suggest that much of the benefit of metformin is conferred by much less than full doses (one oft-repeated quote is that about 80% of the benefit of metformin is by giving 1000mg vs 2000mg). My personal experience is that many people get much better glucose control on just 500mg once a day (which is my starting dose, though I leave it there if there is good control, as happens pretty frequently), and I even have a person on 250mg (1/2 tablet) because of GI intolerance, who seems to get benefit…

Relevant past blogs:

http://blogs.bmj.com/ebm/2015/01/23/primary-care-corner-with-geoffrey-modest-md-metformin-in-renal-failure/ is a systematic review of studies in patients with chronic kidney disease, finding for example no cases (as in, zero) of lactic acidosis in 70,490 patient-years on metformin

http://blogs.bmj.com/ebm/2016/04/26/primary-care-corner-with-geoffrey-modest-md-fda-changes-metformin-guidelines/​  which gives the updated FDA changes for metformin prescribing in those with CKD, with reference to a study of 813 patients with creatinine >6 who did NOT have increased mortality on low dose metformin (<= 500 mg/d), as well as the study finding that metfomrin induces changes in the microbiome, which leads to decreased insulin resistance.

Primary Care Corner with Geoffrey Modest MD: 30-day hospital readmission rates, ?? an appropriate QI marker

30 Jan, 17 | by EBM

By Dr. Geoffrey Modest

A recent NIH study looked at the effect of the Medicare Hospital Readmissions Reduction Program (HRRP) on 30-day readmission rates after hospitalizations for acute myocardial infarction, congestive heart failure, or pneumonia, and in particular looking at whether the previously lowest performing hospitals improved more than the higher performing ones after the introduction of HRRP  (see doi:10.7326/M16-0185).

Details:

  • 15,170,008 Medicare patients discharged alive from US acute care hospitals between 2000 and 2013.
  • Mean age 79.5, 54% female, 85% white/10% black/4.7% other race, 19% admitted with acute MI/45% CHF/36% pneumonia, 52% discharged to home/18% to home with care/23% to nursing home, average length of stay 6 days, 25% rural hospitals/65% private nonprofit/9% major teaching hospitals, overall observed readmission rate 23%.
  • HRRP penalties for 30-day readmission rates were: 0% for the highest performing hospitals, 0-0.5% for average performing hospitals, 0.5-0.99% for low performing hospitals, and >1% for the lowest performing ones.
  • Of 2868 hospitals serving 1,109,530 Medicare discharges annually, 30.1% were highest performers, 44.0% were average performers, 16.8% were low performers, and 9.0% were lowest performers

Results:

  • Overall risk-standardized readmissions increased by an estimated 0.5 per 10,000 discharges per year prior to the passage of HRRP, then decreased by 76.6 per 10,000 discharges per year after passage.
    • For acute MI, risk-standardized readmissions decreased by 23.7 per 10,000 discharges per year before passage, then by 99.3 per 10,000 discharges per year after passage
    • For CHF, risk-standardized readmissions increased by 5.1 per 10,000 discharges per year before the passage and then decreased by 84.7 per 10,000 after.
    • For pneumonia, risk-standardized admissions increased by 3.1 per 10,000 discharges per year before passage and then decreased by 48.2 per 10,000 after.
  • After controlling for pre-HRRP trends, readmissions per 10,000 discharges that were averted and attributable to the law were:
    • 6 for the highest performing hospitals
    • 8 for the average performers
    • 4 for the low performers
    • 1 for the lowest performers

Commentary:

  • It does seem that after passage of the law, there was a pretty dramatic decrease in the 30-day readmission rate among all hospitals, but especially among those that had been the lowest performers.
  • It should be pointed out that the data overall on the utility of financial incentives in changing the “quality of care” metrics is pretty mixed. This study found that the lowest performing hospitals were able to change the most; however, other studies of financial incentives have not shown this to be true, often attributed to the fact that these hospitals had insufficient infrastructure to implement change. Also, this does raise the ideological concern that using financial incentives to make change in fact reinforces the conception and actuality in the US that health care is just a business and not a fundamental human right that should be managed as in most other industrialized (and may less resource-rich) countries: an essential governmental social program such as education.
  • However, and the reason I bring up the study, is that it really brings up to me some concerns about quality goals, especially when looking at surrogate markers.
    • For A1c: as mentioned in several blogs, using a target A1c goal is fraught with potential downsides
      • For patients who have really erratic blood sugars (often because of lack of dietary consistency), just increasing meds to lower the A1c (and get “credit” for better care) may well lead to significantly poorer real-world outcomes from hypoglycemia (e., over treating patients at times when their blood sugars are already low).
      • Some of the meds that decrease A1c may actually increase clinical morbidity (rosiglitazone increasing cardiac disease, —  see the many blogs on other new but concerning meds at: http://blogs.bmj.com/ebm/category/diabetes/ )
      • And those who use A1c as a metric do not include actual clinical outcomes as part of their assessment.
    • In terms of hospital 30-day readmission rates, there certainly should be a mechanism to make sure that hospitals don’t just discharge and readmit patients as a means to increase their earnings (e., getting paid for 2 admissions instead of 1), but there is also a real down-side to focusing on decreasing the readmission rate:
      • Hospitals are dangerous places to be because:
        • They are crawling with resistant bacteria
        • There is a tendency/imperative to do lots of testing for things that we in outpatient medicine might just observe and workup later as needed (this is due to several issues: specialists are often involved in the hospitalized patient’s care, and studies have shown that specialists order more tests than generalists; and, even if there is a lowish probability of a problem, it does in some ways make sense to get more tests in hospitalized patients to see what is going on, since putting off the tests might prolong the hospitalization. But the net result of more testing is the likelihood of more adverse events (either because of the test itself, or because of the downstream further testing/procedures for false positive findings)
        • And those who use hospital readmission rates as a metric do not include actual clinical outcomes as part of their assessment.​ interestingly, when there have been doctors’ strikes and dramatic decreases in hospital admissions, as in 1976 in California as well as others, there has been an attendant lower mortality (and, that is a clinical outcome…..)
      • So, I think it makes sense to avoid unnecessary hospitalizations, and, I would think, to keep the length-of-stay as short as possible
      • My practice until 2 years ago (when our health center was still doing in-patient rounding) was to discharge patients as soon as I felt they were stable (often during my rounding early the morning after their admission) when I felt they had a roughly 80% chance of doing well at home, but with aggressive outpatient follow-up (home visits, or seeing them in clinic the next day, ). And my experience was that it was really uncommon for patients to be readmitted. But with the incentives being strongly to avoid readmissions, I am afraid that might translate into longer in-hospital observation and lengths-of stay (at least it was clear that I discharged patients much sooner than the house staff would have, in large part because I could assure timely and appropriate outpatient follow-up). The point here is that we should be developing coherent integrated systems of care that would allow decreased hospitalizations overall, and lower lengths-of-stay if possible when hospitalizations happen. and, not simply using a single marker of “quality” for the complex and often highly individual decisions on how long to keep a patient in the hospital (for example, the same patient who is homeless or does not have adequate home supports may need to stay in the hospital longer appropriately.)
      • ​And, the other side of the issue: if a patient is really sick with end-stage heart failure, , they are likely to be readmitted within 30 days perhaps no matter what happens (though, of course, we should do as aggressive outpatient management as we can). And their being home as much as possible may have important value to them: being with family, in a friendly and supportive environment, etc., even if they are aware they might be back in the hospital soon

So, the real issue is how does one blend the need for some quality control issues (better care for diabetics or decreasing hospitalizations, in the above examples) but avoid using a blunt instrument (a1c levels, 30-day readmissions) which may well decrease real quality care????  This is certainly not easy to do by large-scale data-mining, looking just at numbers (a1c’s) or billing (readmission rates), but I think really requires looking at individual patients to see what an appropriate a1c might be for them, or whether they were really discharged too early and needed readmission because of poor clinical judgment. If you send me their emails, I can add them to the list

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