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

Archive for May, 2017

Primary Care Corner with Geoffrey Modest MD: Steroid knee injections: do they help??

23 May, 17 | by gmodest

by Dr Geoffrey Modest

A recent article in JAMA found that regular injections of intra-articular steroids was associated with decreased knee cartilage volume and no real improvement in pain in patients with knee osteoarthritis (see doi:10.1001/jama.2017.5283).

​Details:

–140 patients with symptomatic knee osteoarthritis as well as synovitis by ultrasound (evidence of effusion synovitis, with suprapatellar pouch depth >2mm) were randomized to receiving intra-articular 1cc triamcinolone 40mg vs 1cc saline every 3 months for 2 years, both without local anesthetic

–mean age 58, 54% women, BMI 31, 65% white, mean hemoglobin A1c=6%, CRP 0.5

–all patients had radiographic evidence of Kellgren-Lawrence knee OA grade 2 or 3 (grade 2= definite osteophytes and possible joint space narrowing on anteroposterior weight-bearing radiograph; grade 3= multiple osteophytes, definite joint space narrowing, sclerosis, possible bony deformity)

–knee MRI was done at baseline and then annually

Results:

–there was greater cartilage loss with injected steroids (volume loss of 0.21 mm vs 0.10 mm with normal saline), though the amount of superficial fibrillations (fraying of the articular surface) was more common in the saline group (34% vs 13%)

–no significant difference between the groups in pain scores, or functional activities such as the 20 meter-walk time or the chair-to-stand time (these were all measured after asking patient to not take pain meds for 2 days prior to their evaluations)

–adverse events: overall more significant in saline group (63 vs 52, p=0.02), though no difference in what was considered treatment-related.  Cellulitis in one patient in the saline group, also hemoglobin A1c actually decreased significantly in the steroid group (-0.1% vs increase of 0.2% in the saline group, and this was controlling for BMI, radiographic DJD classification, sex). No difference in hypertension

Commentary:

–As noted in a recent blog on the lack of benefit of arthroscopy in patients with degenerative knee disease (see here​ ), knee DJD is remarkably common and a leading cause of  disability (and medical costs, largely for procedures)

–the physiologic rationale for intra-articular steroid injections is that DJD is typically associated with synovitis, with its associated elaboration of biochemical mediators having the potential for causing further joint destruction (collagenases, aggrecanases, cytokines). And local steroids might decrease the inflammation and this destructive cycle. Animal studies have supported this hypothesis. This study, utilizing MRI to assess the steroid effects on cartilage, seems better designed than prior studies which have used xrays, given how insensitive xrays are to assessing the radiolucent cartilage.

–so, how can one reconcile the conclusions of this study (negative impact on cartilage and no effect on pain) with the other studies finding pain improvement in the 4 weeks after the injection, an older but smaller study of 68 patients with the same basic protocol as in this study finding some benefit for pain, and with the huge anecdotal experience of benefit (steroid injections are done increasingly commonly)???

–these patients had pretty mild DJD, especially in terms of baseline symptoms, with a WOMAC pain score of 8.3. This score is based on 5 items (pain during walking, using stairs, in bed, sitting or lying, and standing upright, each with a score of 0-4, ranging from  None (0), Mild (1), Moderate (2), Severe (3), and Extreme (4); ie total maximum score of 20, with an average score of 8, as in the above study, being between mild and moderate.

–one issue with knee OA is how to define it or its progression objectively. The Framingham Study found a poor correlation between radiographic knee OA and symptoms (see Hannah MT. J Rheumatol 2000; 27: 1513, for example). And there is no accepted minimal clinically important difference for MRI cartilage measurement, as duly noted by the authors of this study. Also, I am concerned about the increase found in cartilage fibrillation found in the non-steroid group, since this early splitting of the tangential cartilage surface might harken more severe and clinically important cartilage changes over the somewhat longer term

–they only assessed pain relief at the 3-monthly evaluation, with no data on how patients fared in the first 1 or 2 months [and, in my pretty extensive experience with knee injections, probably around 1000 over the years, the vast majority of patients getting relief for the first few months, some much longer, and that relief translates into dramatic improvement in function and pain relief; ie they can walk and actually do things they couldn’t do before]

–there are even some literature (a meta-analysis of 38 studies) supporting saline injections as  helping with pain relief [ie, their control injections were not necessarily sham injections; saline itself may have some benefit. Which is an important difference. There seems to be a more profound placebo effect with injections than pills, so perhaps the real control for this injection study should be a needle in the joint with no meds injected???]

–and, in terms of generalizability of these results, it is important to stress that these patients had clinically mild knee OA at baseline, but still received injections every 3 months [not necessarily common clinical practice for those with mild-to-moderate symptoms], so their results might not apply to many patients who are actually getting knee injections for more severe, functionally limiting pain despite exercise/physical therapy/etc

–what about the decrease in cartilage thickness?? This is certainly concerning, though perhaps there are non-measured countervailing processes going on: are patients getting a lot of early pain relief [a good thing], but then using their knees more [walking, etc] which leads to more cartilage destruction through wear-and-tear???  And, though small, does the relative improvement in A1c in the steroid group reflect the patients’ ability to do more exercise?

 

So, how should this study affect clinical practice??

–my non-rigorously-tested finding, through loads of knee injections, is that 90+% of patients have much less pain and are able to function much better after injections, and I will continue to do injections

–that being said, injections should be accompanied with aggressive patient education around the importance of quadriceps strengthening exercises, which often help a lot [there were older studies suggesting this may not be true in patients with misaligned knees, perhaps from more severe DJD, where the patella does not track correctly and quad strengthening might exacerbate knee symptoms, but my sense is that this is relatively uncommon].  And some patients need a knee injection in order to do more exercise or physical therapy…

–other therapeutic options are sparse. Arthroscopic meniscal repair or joint lavage seems to do nothing . Physical therapy is important, but does not help many patients much (especially those who are frail, have advanced DJD, are unable to do the necessary home-based exercises,…). NSAIDs have a wide array of undesirable adverse effects, especially in the population with symptomatic knee OA, since they are typically older and have lots of comorbidities (and in this study, unlike NSAIDs, steroids were not associated with hypertension, for example)

–I also use the equivalent of 40 mg triamcinolone with 2cc of 1% lidocaine. This might have better efficacy (unknown to me) than just 1 cc of triamcinolone alone, since the added volume of the anesthetic may help the steroid reach more areas of the inflamed knee joint, and perhaps the anesthetic improves the pain relief beyond the steroid itself.

–after I have done a few knee injections, especially if there are diminishing returns (the first injections working for much longer than subsequent ones), I do discuss and recommend consideration of surgical management (usually knee replacement surgery)

–but I am certain that I will continue having patients, especially older ones, who often have serious medical comorbidities, who adamantly refuse surgery and really want repeated knee injections (even every 2-3 months) in order to function.  This study will change my practice in that I will discuss the issue of potential cartilage harm more forcefully than previously.

–one important general issue is my concern about the quick summaries of potentially clinically very important articles:  the one-line synthesis of this study was “Intra-Articular Corticosteroids Show No Benefit in Knee Osteoarthritis” in Physician’s First Watch/NEJM Journal Watch, and there was little more added in the few summary lines. I am very concerned that this type of analysis may undercut an important therapeutic modality for many patients, perhaps leading to fewer injections even though the patient may achieve very important pain relief and improved functioning/quality of life.  This brings up one of the reasons I do these blogs: we in primary care clinical practice are inundated with new articles (mostly drug-company sponsored) and new guidelines (often done by specialty societies whose members directly or indirectly are involved with drug companies, etc) on a daily basis. It is essentially impossible to keep up with the information onslaught. The summary services such as Journal Watch are really helpful in scanning the literature and alerting us to new articles/guidelines that might affect our clinical practice. But they may well have the very negative effect of dumbing down the literature to quick quips (sound bites?) that really make it impossible to figure out if a certain article or guideline really should apply to the patient sitting in front of us. My hope with these blogs is to look at a few of these articles that might well affect practice, give sufficient (and accurate) summaries of the methodology, types of patients involved, procedures done, and their results; then briefly put in my sense of how this article fits in with older literature and our model of disease physiology; and provide some specific concerns, if any, which might affect its clinical utility. This way, the reader can decide what they think about the article (or guideline), be able to review the specifics of the study​, even use my link to see the study itself for more details, and then figure out how or if they will integrate it into their practice

Primary Care Corner with Geoffrey Modest MD: Against arthroscopy for DJD of knees

16 May, 17 | by gmodest

by Dr Geoffrey Modest

The BMJ just published a systematic review comparing knee arthroscopy versus conservative management in patients with degenerative knee disease (see doi:10.1136/bmjopen-2017- 016114), an update of a prior review, adding ten new studies.

Details:

— 13 RCTs and 12 observational studies were included

— studies were diverse: the analysis included those with symptomatic degenerative knee disease, defined as persistent knee symptoms that affect quality of life and does not respond to conservative treatment, but with or without osteoarthritis and, in those getting arthroscopic surgery, “including any or all of debridement and/or partial  meniscectomy”.  Those with acute trauma were excluded.

Results:

— knee arthroscopy led to a very small reduction in pain in the first three months (mean difference 5.4 on 100 point scale), and very small or no pain reduction up to two years (mean difference of 3.1), high-certainty evidence. The MID (minimally important difference) being 12 points.

— knee arthroscopy led to a very small improvement in function in the short term (4.9 on a 100-point scale) and very small or no improvement at two years (difference of 3.2), moderate-certainty evidence. The MID being 8 points.

— very low probability of serious complications after knee arthroscopy, low-quality evidence. The most common serious adverse effect was venous thromboembolism, at a rate of 5/1000, followed by infection at 2/1000.

 

Commentary:

–symptomatic degenerative knee disease is remarkably common after age 45, affecting about 25% of people, from osteoarthritis of the knee joint lining and/or menisci.

–arthroscopic knee surgery for DJD (degenerative joint disease) is the most common ambulatory orthopedic procedure in the US (and 9th most common of all ambulatory procedures), associated with transient improvement in pain but requiring activity restriction for 2-12 weeks.

–so, this study found  evidence of minimal benefit from knee arthroscopy at 3 months (not considered clinically significant), which decreased further over the next 2 years, for both pain and function.

–one recent study was cited as an impetus for this systematic review, which included 140 adults (mean age 50; duration of pain 15 months). Though 96% did not have definitive radiographic evidence of OA (osteoarthritis), 91% had MRI-documented meniscal degeneration grade 3a or 3b, which is the worst grade. Patients were randomized to exercise therapy alone vs arthroscopic partial meniscectomy (see doi.org/10.1136/bmj.i3740). For the exercise group:  progressive neuromuscular and strength exercises over 12 weeks, 2-3 sessions/week. For those getting surgery: instruction for home-based exercises 2-4x/day to regain knee ROM  and reduce swelling. For the primary outcomes, no difference in pain at 2 years, using the KOOS (knee injury and osteoarthritis outcome score) subscales on pain, other symptoms, function in sports and recreation, and knee related quality of life (also no difference at 3 months; but the exercise group had had greater improvement in all muscle strength variables at 3 months). On secondary analysis the meniscectomy group had lower pain scores at 12 months that was considered clinically significant (though the exercise group had greater muscle strength at that time). [However, this study does not really rule-out the possibility that meniscectomy with aggressive PT afterwards is superior to both of their interventions, since the therapy post-surgery was just the suggestion to do home-based exercises].

 

so, the current study comes to the same conclusions as prior analyses, but by adding 10 more studies reinforces those conclusions that arthroscopy is not generally indicated in those with degenerative knee disease. And, I think, it does apply well to primary care, since it did not limit patients to specific MRI or xray findings (and I get MRIs of patients with typical chronic knee pain only quite rarely; and in general the utility of xray itself is questioned, since there is a pretty poor correlation with symptoms per the Framingham Study), or even to specific clinical findings, but seems to apply simply to those with undifferentiated chronic knee pain not responsive to conservative treatment, but affecting quality of life.

Primary C|are Corner with Geoffrey Modest MD: Postmarketing adverse effects of drugs

15 May, 17 | by gmodest

by Dr Geoffrey Modest

A recent article in JAMA, which made it into the popular press (see http://gizmodo.com/a-third-of-new-drugs-have-adverse-effects-after-fda-app-1795048377​ ), assessed post-market safety events of new drugs approved by the FDA between 2001 and 2010, finding a large number of serious adverse events after the drugs were approved and on the market (Downing NS. JAMA 2017; 317(18): 1854)

Details:

— all new drugs and biologics approved by the FDA between 2001 and the end of 2010 were assessed, excluding diagnostic agents, sunscreens, and drugs not intended for use in the United States, with follow-up through February 28, 2017. They did not include labeling changes and dosage form discontinuations.

— 222 novel therapeutics were approved, 183 pharmaceuticals and 39 biologics.

— 47 (21.2%) were for cancer treatment and hematology

— 37 (16.7%) for infectious diseases

— 26 (11.7%) for cardiovascular disease diabetes and hyperlipidemia

— 77 (34.7%) of these drugs received priority reviews and 28 (12.6%) received accelerated approval

— 62 (27.9%) were designated as orphan products

— median total FDA review time was 311 days, but was less than 200 days for 54 novel therapeutics, and greater than 400 days for 34.2%. 52 (23.6%) were within 60 days of their regulatory deadline approval dates.

Results:

— 123 new post-market safety events occurred, including 61 boxed warnings, during a median follow-up of 11.7 years, and affecting 71 of these new drugs (32% of all new meds).

— Three medications (valdecoxib, tegaserod, efalizumab) were withdrawn from the market

— median time from approval to first post-market safety event was 4.2 years

— post-market safety events were significantly more frequent among biologics vs meds, incidence rate ratio (IRR) 1.93 (1.06-3.52, 0.032), p=0.03.

— Within the therapeutics, those for psychiatric diseases had the highest IRR of 3.78 (1.77-8.06), p<0.001. Drugs for the treatment of cancer and hematologic disease had the fewest post-market safety events, with safety events at 10 years being reported in 60.0% for the psychiatric drugs and 21.4% for the cancer/hematologic ones

those medications receiving accelerated approval had IRR= 2.20 (1.15-4.21), p=0.02, as well as those approved within 60 days of their statutory decision deadline with IRR= 1.90 (1.19 -3.05), p=0.008

— no difference in post-market safety events among those drugs which were first-in-class versus the look-alikes

Commentary:

— as a baseline during this period, the FDA assessment of safety of novel therapeutics seems tilted toward approval: the majority of key (“pivotal”) trials, which served as the basis of FDA approval, enrolled fewer than 1000 patients and had follow-up of only six months or less; and approval seemed to happen more often just before the deadline for that decision

— one issue that is not commented on, at least that I have seen, is that several pivotal studies are terminated early, prior to their expected date, because of evident benefit. Sometimes this benefit is highly statistically significant, though the absolute benefit is not so great. And, by stopping the studies earlier than anticipated, there’s even less time for adverse events to manifest themselves.

— The above article highlights the problems with relying on postmarketing drug surveillance (which obviously needs to continue), finding that 32% of medications had postmarket safety events, and half of these were boxed warnings (ie, were considered severe). An even bigger issue is the poor compliance of drug companies and medical device companies to do and report postmarketing findings, despite these being specific FDA conditions for their approval. A blog on FDA-approved medical devices found that <20% of FDA-required post-marketing studies were actually done. A JAMA letter confirmed similar numbers for drugs (see Fain K. JAMA 2013; 310 (2): 202)

— BUT, the biggest concern now is that it seems that the FDA is poised for major changes which would lead to even more accelerated drug approval overall (the above study found that accelerated approval was itself associated with a higher incidence of postmarketing adverse events). Of the many many issues concerning the current Trump administration, I would like to highlight two:

— Trump  is fundamentally anti-scientific and anecdotal in his approach. This is concretely manifested by his ready denial of climate change and replacing 5-9 scientists on the EPA board with representatives of industry, since they “understand the restrictive nature of regulations”, and is planning a 40% reduction in funding for the scientific component of the EPA. He thereby shuts himself off from the potential to analyze policy from a scientific instead of a political or “gut” viewpoint. (see http://www.cnn.com/2017/05/08/politics/epa-scott-pruitt-board/  for example).  In addition, his impetus to change the FDA, such that it leads to more rapid approval of medications, is grounded in an anecdotal example of a young girl with Pompe disease, a rare inherited disorder (which is even stranger since her father was in a position to found a company to develop enzyme replacement therapy). This rather extreme anecdote seems to him to justify really quick approval of drugs by the FDA, with less rigorous scientific evidence, and with the potential for real harm to lots of people.

— Trump just recently approved Scott Gottlieb as head of the FDA, with a commitment to get new drugs to the market sooner. Gottlieb is an advisor to several large pharmaceutical companies: “an unprecedented web of Big Pharma ties. He has spent most of his career dedicated to promoting the financial interests of the pharmaceutical industry”, per Dr. Michael Carome director of the Public Citizen’s Health Research Group (http://www.cnn.com/2017/03/10/politics/scott-gottlieb-donald-trump-fda/ ); the article also pointed out that “Gottlieb would be tasked by Trump with eliminating some of the regulatory burdens at the FDA”, getting new drugs to the market sooner.

 

So, I think that this postmarketing JAMA study and others suggest that the FDA may already be approving some drugs too quickly (and faster than their European counterpart), and this approval process is already slanted towards the drug companies (the studies are usually designed by the drug companies to get the outcomes they want through their own analyses of the results (see prior blogs, including a blog on empaglifozin and one on ezetimibe as cases in point ). And the current Trump administration changes are likely to make things a whole lot worse.  Even if there is a significant class action lawsuit and settlement against the drug company because of a severe adverse event found after FDA approval, even large settlement sums pale in comparison to the drug company profits from those drugs (at least in the cases I’ve seen).

 

Primary Care Corner with Geoffrey Modest MD: Osteoporosis treatment guideline

11 May, 17 | by gmodest

​by Dr Geoffrey Modest

The American College of Physicians just updated their clinical practice guideline on the treatment of low bone density/osteoporosis to prevent fractures in women and men (see doi:10.7326/M15-1361).

Details:

–treatment options

–bisphosphonates: high quality evidence that they reduce vertebral, nonvertebral and hip fractures in postmenopausal osteoporotic women (specifically shown with alendronate, risedronate, and zolendronic acid; ibandronate shown to reduce radiologic vertebral fractures; zoledronic acid reduces vertebral fractures in osteoporotic men). [BUT, these differences in bisphosphonates probably reflects the studies that have been done and may not indicate true differences between these meds. eg, we tend to assume that all ACE inhibitors are similar without specific studies showing true equivalence. Though it may not be true…..]. Adverse events: low-quality evidence that they can be associated with atypical subtrochanteric fractures (FDA issued warning), though very uncommon, in 1.78/100K in women taking bisphosphonates for <2 years, and up to >100/100K if >7 years (though these numbers pale in relation to fractures prevented in high risk patients). also, low quality evidence for osteronecrosis of the jaw (also rare). older concerns about atrial fibrillation were not found in newer studies. similarly with MI. but high-quality evidence of association with mild upper GI symptoms; hypocalcemia, flu-like symptoms, uveitis, and episcleritis with zoledronic acid; myalgias/joint symptoms with ibandronate and zoledronic acid. uncertain risk for cancer

​–denosumab (monoclonal antibody which prevents the development of osteoclasts through RANKL inhibition): high quality evidence that it reduces radiographic vertebral, nonvertebral and hip fractures  in post-menopausal women. Adverse events: high-quality evidence for mild upper GI symptoms; moderate quality evidence of increased risk of infection, (eg bacterial cellulitis, though no increase in serious infections); rash/eczema. also rate atypical femoral fracture and osteonecrosis of the jaw through 8 years of therapy

–teriparatide (hormone fragments of PTH):  high quality evidence that ​it reduces radiographic vertebral and nonvertebral fractures in post-menopausal women. Adverse events: high-quality evidence of association with mild upper GI symptoms, headache, hypercalcemia. also renal effects, hypercalciuria.

–SERMs (selective estrogen receptor modulators): high quality evidence that ​raloxifene reduces vertebral fractures in osteoporotic women, but non-statistically-significant decrease in risk of nonvertebral or hip fractures. Adverse events: high-quality evidence of hot flashes, thromboembolic events (incl pulmonary embolism, cerebrovascular death)

–estrogens: moderate quality evidence that ​it does not reduce fractures in postmenopausal women (a change in recommendations, based on newer data on postmenopausal women with established osteoporosis). Adverse events: high-quality evidence of association with cerebrovascular and thromboembolic events; higher incidence of breast cancer

​–calcium and vitamin D: moderate quality evidence​ that calcium or vitamin D alone has uncertain effect on fracture risk. Adverse events: probably no increase in MI with calcium (though shown in one analysis). increased risk of hypercalciuria with vitamin D

–physical activity: insufficient data to show conclusively that there is benefit for preventing fracture risk. no studies looking at comparative benefit of physical activity vs other interventions [though data show that physical activity can regulate bone maintenance and stimulate bone formation, increasing mineral content, and improving muscle strength (which protects the bone)]

–comparative benefits of above meds: insufficient head-to-head studies. and network meta-analysis to assess likely differences between meds did not find any

-recommendations:

​–offer pharmacotherapy for women with known osteoporosis with alendronate, risedronate, zoledonic acid, or denosumab, to reduce risk of hip and vertebral fractures. strong recommendation, high-quality evidence

–treat osteoporotic women with pharmacologic therapy for 5 years. weak recommendation, low-quality evidence​​. the studies to support this excluded patients with severe osteoporosis (total hip BMD in the beginning T-score worse than -3.5),  or whose total hip BMD at 5 years was lower than their baseline. and post-hoc analysis found that those with pre-existing fractures or T <-2.5 after 5 years of therapy may benefit from continued treatment

–offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinically recognized osteoporosis. weak recommendation, low-quality evidence​

–do NOT do bone mineral density (BMD) monitoring during the 5-year drug treatment period for osteoporosis in women. weak recommendation, low-quality evidence​.

–do NOT use estrogens or raloxifene in post-menopausal women in the treatment of osteoporosis. strong recommendation, moderate-quality evidence​

–make decision whether to treat women >65yo with osteopenia who are at high risk for fracture based on discussion, fracture risk profile, and benefits/harms/cost of meds. weak recommendation, low-quality evidence​ (there are some studies on post-hoc analysis suggesting those with T scores near the osteoporosis range finding that treatment with risedronate significantly reduced the risk for fragility fractures by 73%

 

Commentary:

–osteoporosis is exceedingly common: 200 million people worldwide, and 54 million in the US have osteoporosis or low bone density (50% of Americans >50yo are at risk for osteoporotic fractures). also, huge economic impact on health care system: $25.3 billion/yr by 2025.

–risk factors (per the article): age, female sex, menopause, hypogonadism or premature ovarian failure, low body weight, history of parental hip fracture, ethinicity (white people at higher risk), prior fracture (clinical or not), prior fracture with minimal trauma (“fragility” fracture), rheumatoid arthritis, smoking, alcohol (>2 drinks/d), low BMD, vitamin D deficiency, low calcium intake, hyperkyphosis, falling, immobilization, long term use of some meds (glucocorticoids, anticoagulants, anticonvulsants, aromatase inhibitors, cancer chemotherapies, gonadotropin-releasing hormone agonists). by the way, older studies have suggested that the compilation of risk factors of body weight/BMI, smoking, alcohol, and ethnicity only account for aoubt 15% of the risk variability (ie,  patients with lots of these risk factors  may well have normal BMDs and vice versa)

–BMD definitions: T-score in postmenopausal women and men >50yo is 2.5 SD below the young female adult mean (reported as worse than -2.5). BUT only 1/2 of the people with osteoporotic fractures have this low a BMD (which is probably because the BMD is a quantitative assessment of the amount of calcium in a cross-section of bone and does not reflect the internal qualitative structure of the bone). And, on the other side, osteoporotic patients on bisphosphonates with no improvement in BMD still have large reductions in fractures. There is also the Z-score, which compares people to those of the patient’s age and sex, and those better than -2.0 are “within the expected range for age”. The FRAX score (see https://www.sheffield.ac.uk/FRAX/tool.jsp and has been used about 5 million times, per the website) combines clinical risk factors, which can include BMD but does not need it, though data on benefit of FRAX are lacking. the threshold to treat varies by health care system and by clinical judgment, but rough guidelines, eg from the North American Menopause Society (see osteoporosis NAMS 2010 in dropbox, or DOI: 10.1097/gme.0b013e3181cdd4a7) is at least 20% for major osteoporotic fracture or at least 3% for hip fracture.

–in terms of physical activity, there are a slew of observational studies showing benefit, reasonable mechanistic support (the more one stresses one’s bones, the stronger they are; and conversely the less stressed, as through immobilization or prolonged bed rest esp in the elderly, the weaker). But it turns out that drug companies, the major sponsors of studies these days, are less interested in this nonpharmacologic modality. and, practically, it is probably unethical to randomize people to exercise vs not and follow them for years, given the multitude of exercise benefits, physically and mentally… and there are no real comparative effectiveness trials of the different meds because, I would guess,  drug companies choose the low bar of placebo control for their studies instead of comparing to another active med in order to maximize the likelihood for benefit and FDA approval.

–also, there really are limited data on treatment of men

— I would also add to the list of risk factors: HIV and some HIV meds (eg tenofovir disoproxil fumarate) and renal failure, as well as other medical conditions (hyperparathyroidism, monoclonal gammopathy and myelomas, etc)

–in terms of stopping therapy, I have been repeating the BMD after 5 years of therapy and continuing with bisphosphonates if the T-score is worse than pre-treatment or if it is more than about -2.5 to -2.7, after discussion with patients.  I am concerned that some clinicians are just stopping the bisphophonates at 5 years without reassessing the patient with another BMD, based on not knowing the exclusions or posthoc analysis of the relevant studies, which may put some patients at significant risk (see blog)

 

so, seems to me to be pretty reasonable recommendations overall. I do have lots of women on bisphosphonates without adverse effects, including into well-advanced age. The rationale here is that the risk of falls increases with age, as does the risk of hip osteoporosis. And the benefit of bisphosphonates in terms of fracture protection is evident within 11 months, and 8 months in those >70yo (see DOI 10.1007/s40266-016-0344-7).

 

see prior blog for a more detailed review of the studies on stopping bisphosphonates after 5 years.

Primary Care Corner with Geoffrey Modest MD: Management of incidental pulmonary nodules

10 May, 17 | by gmodest

by Dr Geoffrey Modest

​The Fleischner Society guidelines for the management of incidental pulmonary nodules found on CT scans was just updated, involving international input from radiologists, pulmonologists, surgeons, pathologists (see doi:10.1148/radiol.2017161659​).

 

Details:

–the guidelines refer to incidental pulmonary nodules found by CT scan in those >35yo, not for patients at high risk (eg in those with cancer who might have mets, or those getting CTs for screening purposes)

–the minimum threshold size leading to  recommendation for nodule follow-up is if the estimated cancer risk is >1% (arbitrarily chosen)

–follow-up CTs should use low-radiation techniques, no more than 3 mGy in a standard sized person, in order to reduce radiation exposure, esp in patients likely to receive many of them.

 

Single solid nodules

— <6 mm (a larger size than prior guidelines): no further follow-up studies (grade 1C, strong recommendation, low- or very-low quality of evidence). Those at higher risk (see below), such as suspicious morphology or upper lobe location has optional recommendation to repeat CT but not before 12 months (small risk by waiting this long and earlier study might provide false reassurance)

— 6-8mm and low clinical risk (see below): follow-up 6-12 months, depending on size, morphology and patient preference (grade 1C, strong recommendation, low- or very-low quality of evidence​). usually one follow-up exam is sufficient, though optional one at 18-24 months. For those at higher risk, this additional 18-24 month follow-up is recommended.  (strong recommendation, moderate quality of evidence​)​. average risk of cancer 0.5-2%

— >8mm: same recommendation independent of risk: CT at 3 months, PET/CT, or tissue sampling (grade 1A, strong recommendation, high quality of evidence). average risk of cancer 3%

Multiple solid nodules

–dominant nodule <6mm: same as with single (Grade 2B, weak recommendation, moderate quality of evidence​)​.

–6-8 mm: same as with single, but initial follow-up CT at 3-6 months (optional follow-up at 18-24 months if low risk, recommended if high risk). Grade 1B, strong recommendation, moderate quality of evidence​​.

–>8 mm: same as 6-8mm

Single subsolid nodules

–ground glass nodule: <6mm, no routine follow-up; >6mm, CT at 6-12 months to confirm persistence, then every 2 years for 5 years​. (grade 1B; strong recommendation, moderate-quality evidence). Approximately 10% grow and 1% progress to adenocarcinoma, in a study done in Asian population.

–part solid nodule: <6mm, no routine follow-up; >6mm, CT at 3-6 months to confirm persistence (could be infectious and resolve). If solid component remains <6mm, annual CT for 5 years  (grade 1C; strong recommendation, low- or very-low-quality evidence). If solid component >6mm, highly suspicious for cancer (grade 1B; strong recommendation, moderate quality evidence.)

Multiple subsolid nodules

–<6mm: CT at 3-6 months. If stable, consider repeat at 2 and 4 years (grade 1C; strong recommendation, low- or very-low-quality evidence)

–>6mm: CT at 3-6 months. if persistent, consider diagnosis of multiple primary adenocarcinomas (grade 1C; strong recommendation, low- or very-low-quality evidence). subsequent management depends on most suspicious nodule.

 

risk factors for malignancy:

–nodule size is the dominant risk factor

–nodules are classified as solid, pure ground glass, and part-solid. BUT huge inter- and intra-observer disagreements (correct classification of nodules as solid or sub-solid was found in only 58% of cases!!). Those with marginal spiculation are more likely to be malignant (OR 2.2-2.5), though this is not really a binary finding, and no threshold of the degree of spiculation has been defined

–nodule location: upper lobes, and esp right upper lobe, more likely to be cancer, with odds ratio of about 2.0  Adenocarcinomas and mets are more likely peripheral, and squamous cell cancers are more near the hila. Small nodules in perifussural or subpleural areas often are lymph nodes

–nodule multiplicity: increased risk of cancer as number of nodules increases from 1 to 4, but decreases with >4 (more likely prior granulomatous infection)

–nodule growth rate: solid cancers double their volume (a 26% increase in diameter) in 100-400 days; subsolid nodules (eg, primary adenocarcinomas) have average doubling times of 3-5 years: hence the longer follow-up time for those with subsolid nodules

–emphysema/fibrosis: emphysema is independent risk factor for cancer. Old studies found about 3x increase. NLST  (National Lung Screening Trial, which led to current screening recommendations for smokers) found incidence of 25 cancers/1000 screened in those with emphysema and 7.5/1000 in those without. Both emphysema-predominant COPD and increasing severity of centrilobular emphysema increase the risk of cancer. As does pulmonary fibrosis (esp idiopathic pulmonary fibrosis, with HR 4.2)

​–age/demographics: rare <40yo, and increases each decade of life. Women may be at higher risk in a few studies: esp if lower BMI and lower educational level, but also a higher cancer risk in women with nonsolid nodules. Family history  is a risk factor both in smokers and never-smokers, with RR 1.5-1.8 if an affected sibling. Also higher in black men and native Hawaiian men at lower levels of smoking.

–tobacco/exposures. 10- to 35-fold increased risk in smokers. passive smokers also with increased risk, but less so. smoking mostly associated with squamous cell cancers. incidence of adenocarcinomas is increasing over time, esp for female nonsmokers, but unclear effect of smoking on this and smoking not included as a risk factor for adenocarcinomas. other inhaled carcinogens noted as cancer risk factors include asbestos, uranium and radon. [silicosis may be, but not shown conclusively, per my reading. similar with beryllium exposure. and, no doubt, others]

–the categories of risk used in this guideline are from the American College of Chest Physicians (these are spelled out, with a mathematical equation including the variety of risk factors:

–low-risk: estimated cancer risk (<5%), found typically in those of young age, less smoking, smaller nodule size, regular margins, and location other than upper lobe

–high risk (>5%), more often if older age, heavy smoking, larger nodule size, irregular or spiculated margins, and upper lobe location

–one not-so-uncommon clinical situation is the patient who has an abdominal CT, where the CT finds a small lung nodule (<6mm), but only the lower part of the lungs is visualized. If patient is low risk, no further follow-up recommended. If intermediate size (6-8mm), follow-up CT of the complete chest after 3-12 months depending on clinical risk.  If larger nodule or suspicious characteristics, full chest CT right away for further evaluation

 

Commentary:

–with increasing use of CT scans, lots of lung nodules are found. in US adults between 2006-14, more than 4.8 million had at least one chest CT, with >1.5 million nodules identified, and 63K lung cancers diagnosed within 2 years.

–I would personally include as higher risk any patients with industrial exposures esp if there is evidence of distorted lung parenchyma (eg fibrosis, as by silicosis), especially since other causes of fibrosis are higher risk (emphysema, idiopathic pulmonary fibrosis). and I would be more inclined to follow them more closely, as well as caution them about avoiding any other exposures more aggressively (smoking, etc).

–they do not mention HIV in this guideline (they refer to immunocompromise as creating higher likelihood of infection, no mention of cancer), but there are observational studies of 2- to 4-fold increased risk of lung cancer at younger age and lower smoking exposure: I had a patient who was an elite controller, who had an undetectable viral load, high CD4 count off any antiretroviral meds, minimal smoking history, but who died in his late 40s from lung cancer. My review of the literature found this phenomenon not so uncommon, even in patients with good immunologic response to antiretrovirals.  so I would add HIV, controlled or not, as potential risk factor

–I am very concerned about radiation exposure (as per many prior blogs). Above they mention that the repeat CT scans done should produce only 3 mGy of radiation exposure. LDCT, low-dose CT used for screening smokers, is 1.5 mSv, which from my search is the same as 1.5 mGy, whereas a diagnostic chest CT is about 7-8 mGy, and a chest xray about 0.1 mGy. So the recommended radiation dose for the follow-up repeat CT is less than 1/2 that of a regular diagnostic CT. I’m not sure exactly what that means. Is the follow-up CT different from a diagnostic CT?? Or are they recommending new CT scanners which deliver less radiation, but may not be available in many places (and might limit the generalizability or utility of their algorithm, since more cancers may be created by the higher radiation exposure)? There was an article about a new Toshiba CT scanner which delivers around 4 mGY: see https://www.technologyreview.com/s/510861/ct-scanner-delivers-less-radiation/​ , which may be what they are referring to….

–BUT, one concern I have is that the additional radiation exposure from multiple CTs (even from lower radiation ones) might have an even higher risk of causing cancer in patients with baseline abnormal lungs. The data on radiation exposure and cancer, from what I can find, is largely mathematical modeling based on people with normal lungs (eg Einstein AJ JAMA 2007; 298: 317, as well as here , here , and here). My guess, though not addressed in anything I have seen, is that those with diseased lungs are at higher risk of radiation-related lung cancer, and that risk may be much higher than estimates from the current mathematical models of people with normal lungs (eg, maybe the underlying lung pathology is associated with inflammation and fibrosis which is associated with significant chromosomal damage, etc, which puts the lungs at higher cancer risk from further damage by radiation??? sort of a multiple-hit theory??)

 

So, I think this guideline is helpful for us in primary care. Given the rather low bar to get CT scans these days and the frequent finding of difficult-to-interpret incidental “abnormalities” found, it is useful to have some sense of how to interpret and follow the findings, and why. of course, there are real concerns about the radiation exposure, but at least these guidelines are more lenient than prior ones (larger size cutpoint of when to do followup CTs, and less aggressive followup than before)​

 

 

Primary Care Corner with Geoffrey Modest MD: Higher allopurinol dosages for gout

9 May, 17 | by gmodest

by Dr Geoffrey Modest

A recent New Zealand study assessed the efficacy and safety of higher allopurinol doses in patients with pretty severe gout and comorbidities (see doi: 10.1136/annrheumdis-2016-210872​).

Details:

–183 patients with gout and taking creatinine clearance (CrCL)-based allopurinol therapy were randomized to continuing routine care vs monthly escalating allopurinol dose to achieve a target serum urate level of <6 mg/dL. Non-blinded study, patients followed 12 months

–mean age 60, 87% male, mean duration of gout 17 years, creatinine 1.58, CrCL 60, BMI 35, 44% palpable tophi, 38% on colchicine/13% NSAIDs/13% on prednisone. 34% diabetic/72% hypertensive/57% hyperlipidemic, 43% cardiovascular disease

–52% had CrCL <60ml/min, 13% CrCL <30 ml/min

–mean baseline serum urate level (SU) was 7.15 mg/dL on mean allopurinol dose of 269 mg/d.

–dose escalation group: increase allopurinol monthly, 50mg if CrCL <60ml/min, otherwise 100mg, to achieve target SU level

Results:

–mean change in SU was -0.34 mg/dL in the control group (?better med adherence by being in the study) vs -1.5 mg/dL in the dose escalation group (p<0.001). This separation was achieved within about 4 months, though took 7 months in those with CrCL <60.

–at month twelve: 32% of controls and 69% in dose escalation group achieve SU <6 mg/dL; this SU level was achieved in each of the last 3 visits in 14% vs 59% (odds ratio, OR=8.0)

–no difference in gout flares or tophus size during the study

–adverse events: 25 in controls, 35 in 22 dose escalation patients . Only one adverse event considered likely to be related to allopurinol, in a patient in the dose escalation group who had high INR after starting warfarin for elective mitral valve replacement.

–mild elevations of LFTs in both groups, and a few had moderate increases in GGT

–no difference in renal function between the groups (increases from their baselines). Both groups had about 10% of patients getting >20% decrease in CrCL, but similar numbers of patients actually had improvement in CrCL.

–no difference in other lab tests, including CBC (and eosinophilia)

Commentary:

–one presupposition for this study is that it is important to treat SU levels to specific targets. Several groups, including the American College of Rheumatology in 2012 (see DOI 10.1002/acr.21772) and the European League Against Rheumaone blogtism (EULAR) in 2016 (http://dx.doi.org/10.1136/annrheumdis-2016-209707​ ), suggest targets of SU levels <6mg/dL in those with recurrent gout and <5 mg/dL in those with severe gout (tophi, chronic arthropathy, frequent attacks). However, there is a counterargument: one blog  questions the validity of treating-to-target for SU levels, noting that there are no studies looking at the clinical outcome of titrating to different targets in an RCT. Observational studies do confirm that those with SU levels <6 have fewer gout flares, but we do not really have the data to make a truly informed decision. These conclusions questioning treating-to-target were similar to the 2016 the AHRQ analysis of the data on the management of gout (see another blog)

–allopurinol is FDA-approved to a dose of 800mg, though in the pretty remote past I had a patient with tophaceous gout on even higher levels than that in an attempt to dissolve the extensive tophi (and this was done not uncommonly for those with very high SU levels, probably often due to inborn errors of metabolism), and overall many patients were on higher doses of allopurinol to achieve SU levels <6. However, doses >300mg/d seem to be rarely used more recently, as confirmed in a 2006 study. The concern about higher doses has been adverse effects, including the pretty rare allopurinol hypersensitivity syndrome (fever, rash, eosinophilia, hepatic abnormalities, renal failure, found in <0.1%, so this current study was not powered to detect this), which typically occurs in the first 2 months of therapy and is more common in those with higher starting doses or CKD, and perhaps with concomitant thiazide therapy

–EULAR guidelines comment that it is best to start with allopurinol 100mg/d in those with normal renal function, then increase every 2-4 weeks to achieve the SU target. but, with the most usual prescribed allopurinol dose of 300mg/d, only 50-70% reach the 6 mg/dL target; and those on up to 600-800 mg/d had a 75-80% chance to achieving that target. Starting at a low dose with slow increments seems to reduce the likelihood of gout flares from the allopurinol, and decreases the risk of severe cutaneous reactions. In those with renal impairment, allopurinol should be renal-dosed, starting at 50mg, and  the maximal dose of allopurinol should be adjusted by creatinine clearance in order to decrease the likelihood of severe cutaneous reactions.  If the SU level is not adequately controlled on high-dose allopurinol, consider adding a uricosuric, or consider switch to feboxustat, which seems more effective in patients with CKD. The American College of Rheumatology suggested continued gradual allopurinol dose escalation above the CrCL-based doses to achieve target SU level, with no maximum dose, though they specifically comment that in patients with CKD, it’s okay to exceed 300mg/d.

–not sure how to interpret the lack of clinical improvement in the current study (gout flares, tophi) in those on higher dose allopurinol, though the true separation of SU levels began after 4 months of therapy, so only 8 months of pretty much sustained SU differences between the groups, and only 5 months in those with renal compromise. The lack of benefit from high dose allopurinol is consistent with the observed finding that SU lowering drugs have no clinical effect for 6 -12 months. But why is this? why did a patient of mine with 2+ months of SU level of 4.4 mg/dL on meds have a gout flare?? Not so clear. Part of this may be that patients put on allopurinol can have an increase in gout flares in the first 3-6 months (and, EULAR recommends gout prophylaxis for 6 months after starting urate-lowering therapy), which could counterbalance a protective effect in other patients (no data provided in this study, but perhaps concomitant colchicine prophylaxis could help sort this out). Also, this study did not attempt to achieve SU <5mg/dL, which really is the goal recommended as the target for those with tophaceous or severe gout as in this study (ie, their target was perhaps too high)

— this blog  comments on the role of decreasing fructose intake in lowering uric acid levels (and I have seen some pretty impressive results from stopping sodas), as well as the effect of antihypertensives on SU levels and gout (losartan, especially, but also calcium channel blockers, especially amlodipine, decrease SU levels.)

–also, as a perhaps important side issue, there may also be cardiovascular benefits from  lowering SU levels (see this blog)

 

so, CKD does not seem to be a contraindication for using higher doses of allopurinol, especially when slowly titrating up doses to achieve SU in target range, as shown in this population of patients with pretty severe gout and lots of comorbidities. The next step is to have some studies with real clinical outcomes, ideally targeting different levels of SU for patients with different severities of gout, and with concomitant preventive therapy for the first 6 months.​ to the list

Primary Care Corner with Geoffrey Modest MD: Hemoglobin A1c reduction and decreased cardiovascular event

8 May, 17 | by gmodest

​by Dr Geoffrey Modest

A recent cohort study found an association between those patients who achieved an early reduction in HbA1c with metformin and a significant reduction in subsequent cardiovascular events (see DOI: 10.2337/dc16-2271).

 

Details:

— a population-based cohort study in northern Denmark from 2000-2012 assessed 24,752 new-onset diabetics 6 months after initiating metformin therapy

— median age 62.5, 55% males. Median follow-up 2.6 years

— primary endpoint: subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA1c and other confounding factors (age, sex, year of starting metformin therapy, microvascular and macrovascular complications, obesity, alcoholism, antiplatelet drugs, statins, antihypertensives, psychiatric medications, achieved cholesterol target, and use of other unspecified glucose lowering therapy). socioeconomic status was adjusted by using education as a proxy.

 

Results:

— those who achieved A1c <6.5% tended to be older (> 70yo), female, and more likely to have initiated metformin later in the study (between 2010-2012), tended to have slightly more microvascular and macrovascular complications at baseline, take more preventative medications, and have less obesity. They also tended to have lower baseline A1c initially.

— those with the greatest point reductions in A1c tended to be younger, had lower prevalence of macrovascular complications, less comorbidity, and took fewer preventive medications. They also tended to have the highest baseline A1c and received more additional glucose lowering therapy.

— During the follow-up, there were 439 incident MIs, 594 strokes, and 1845 deaths.

— the risk of a primary end-point, compared with an achieved HbA1c <6.5% in the adjusted model, was:

— 6.5-7%: 18% increased risk, HR 1.18 (1.07-1.30)

— 7-7. 5%: 23% increased risk, HR 1.23 (1.09-1.40)

— 7.5-8%: 34% increased risk, HR 1.34 (1.14-1.57)

— >8%: 59% increased risk, HR 1.59 (1.37-1.84)

— these results were consistent for the individual outcomes, age groups, presence or absence of comorbidity at baseline, or socioeconomic status.

— the clearest association between higher A1c and worse clinical outcomes was in patients >70 years old.

— a 4% absolute decrease in HbA1c was associated with a 20% decreased risk of a primary outcome; lesser degrees of risk reduction were not statistically significant

 

Commentary:

— observational data from many studies are quite consistent that there is an increased risk of atherosclerotic disease in diabetics, and that this increase starts early in the prediabeticrange (eg A1c 5.5-6), especially in men, and increases with increasing A1c. The data on decreasing risk by lowering A1c is less clear, and seems to be dependent on the medication used. Some medications have some reasonable support for cardiovascular benefit, including metformin, pioglitazone, and GLP-1 agonists (I am very suspect about empaglifozin, see below). It is important to know that the published target of getting the A1c’s as low as possible, around 7% or even lower, are based on decreasing risk of microvascular complications found in several studies, not the really important macrovascular ones (80% of diabetics die from cardiovascular causes). Which is not to say that microvascular complications are not important…

–As noted in prior blogs, the ACCORD study questioned the utility of lower A1c targets for macrovascular protection but (I think) is overquoted and has led to a more lackadaisical approach to diabetes management. See blog noting that “A subgroup analysis of this ACCORD study actually found that those who achieved a lower A1c in fact did better (in terms of cardiovascular endpoints), all the way down to an A1c of 6!!, but as the number of meds needed in the attempt to lower the A1c increased, they had worse outcomes (i.e., those in the intensive therapy group who had medication-flogging to improve their A1c had worse outcomes even at a much higher A1c). See Riddle MC. Diabetes Care; 33:983.” Also see the blog which goes into more detail on ACCORD. So, my conclusion was that the lower the A1c, the better in terms of macrovascular complications in ACCORD, but only if this lower A1c can be achieved easily with meds (and, reinforcing the above comment, the choice of meds may be extremely important. For example, in the ACCORD study, 91% of those in the aggressive treatment arm took TZDs, and mostly rosiglitazone, known to increase cardiac mortality!!!. Interestingly in this current study, those >70yo did better cardiovascular-wise if their A1c were low with metformin, which suggests that age may not be the decisive factor in targeting A1c goals, but perhaps other things (comorbidities, longevity predictions), though my sense is that currently clinicians are somewhat more hesitant to be aggressive with older patients, quoting the ACCORD trial

–one peculiar aspect of this study to me was why did so many patients have high A1c’s 6 months after starting metformin? My clinical experience, with a few dozen new-onset diabetics (though not the 24.7K in this study), is that they uniformly respond to metformin with essentially normalization of their A1c, independent of how high their initial A1c was. Even patients with A1c’s in the 15-18% range decrease to <7% with just metformin 500 mg once a day. The purported explanation for this is that they have glucotoxicity, whereby the increased blood sugar leads to decreased insulin effectiveness (as shown, for example, in decreased insulin-mediated glucose uptake into muscle), and this is true in laboratory situations with both diabetics and nondiabetics.  Typically new-onset diabetics need insulin injections early on to help decrease the blood sugar, thereby decreasing the glucotoxicity for which their struggling pancreas cannot compensate with more insulin production, and then, when their blood sugars are lower, their marginal endogenous insulin reserves work. And in my experience exogenous insulin can uniformly be stopped, typically within 1-2 months, and some do not even need to continue the metformin (at least for months to years, when their pancreases get increasingly tired).

–and, why did those with high A1c’s 6 months after starting metformin do so poorly? was it simply poor glucose control? or, were those who did not achieve a low A1c fundamentally different from those who did, perhaps in unmeasured ways?? did they have diabetes longer, leading to more atherosclerosis (ie, was the increase in cardiovascular events really just lead-time bias, where those with longer duration of diabetes before diagnosis had more atherosclerotic disease just because they had diabetes for longer)? Or, is their diabetes fundamentally different: do the ones who easily achieve really low A1c levels have a different, “mild” type of diabetes and would not get heart disease for a really long time anyway, while others have great difficulty getting their diabetes controlled, have more complications, but the complications have nothing to do with the A1c level achieved but with the fact that they just have “aggressive” diabetes???

–also, unfortunately, in the above study there were obvious important unmeasured factors, including smoking, BMI, diet, physical activity, social support, patient motivation, etc. which really could affect their results. And there may also have been an inherent bias that clinicians tried to get better blood sugar control in patients who were healthier and they felt had a better prognosis, so actually had less cardiovascular disease because of that? (this is hard to sort out in an observational study as this one)

—  As a side issue, studies like this one from Denmark, as well as others from most European countries, showcase the advantages of their having extensive medical databases, linkages to prescription data, linkages to social/demographic data, and nearly 100% followup.  The US, with the most expensive medical system in the world, unfortunately pales in comparison (?reflecting different priorities in public health???)…

 

so, why do I bring up this article, given the above limits of the interpretability of such an observational study?  a few reasons:

–I think there probably is value to more aggressive diabetes treatment to lowering cardiovascular events (and, again, this is what kills diabetic patients). and I think the results of the ACCORD trial weigh much too heavily on the various guidelines, since this study (i think) was quite flawed

–I think that we should really move towards using diabetes medications which have the clearest cardiovascular benefit (eg metformin, GLP-1 agonists, as opposed to insulin and sulfonylureas) as a priority, vs just focusing on achieving the best “number” for our A1c’s (untested, just my thought), though it is clear that A1c level is important for the microvascular complications

–I think studies like this one should stimulate us to question our model of disease (diabetes, here). Is it one disease or a combination of different ones with different outcomes but we lump them together (sort of like breast cancer: some are really aggressive and spread even before we can even detect them. some slowly increase in size and are easily treated but may not change life expectancy much…..)?

–and, I think it is a clinically useful and important intellectual activity to look at studies like this one (which I do think has some validity) in order to reflect on and critique the study; think about its potential biases, assumptions and limitations to its generalizability; and figure out if or how it should be incorporated into our understanding of the disease and how we should treat patients (though oftentimes these studies raise more questions than they answer, but maybe the questions are more advanced as we see more studies and get more data…..).  This is one of my main impeti (?plural for impetus) for doing these blogs. I think that overall in medicine we are deluged/overwhelmed daily with huge numbers of medical articles, guidelines, etc. And my concerns are that in many cases we just hear about/read the bottom line: does the med work?? etc. And the studies are mostly funded by drug companies. And they design them to optimally get the result they want. And many of the details of the study are buried in the text (and, more and more, buried in the supplemental material, for which one needs either a subscription to the journal or access to a medical library, but in any event takes even longer to sort out). See empagliflozin blog listed below as one of many examples of what I think is a poorly designed drug-company sponsored study. And nowadays the drug companies seem to have greater access to the media, who also publish a not-so-in-depth review, and they certainly have much more access to direct-to-consumer advertising, both of which may push us to prescribe these drugs.  So, all in all, it is getting much harder to read the onslaught of medical information critically, decipher it, and apply it appropriately. And I hope these blogs help a little …..

 

See here and here for blogs critiquing the empaglifozin study, suggesting that the accepted cardiovascular benefit is not so clear when one scratches the surface of the article. It also comments on the benefits found with metformin and pioglitazone in other studies.  Though I should add that the FDA does have warnings about these SGLT-2 inhibitors (such as empagliflozin) causing acute renal injury, ketoacidosis, urosepsis/pyelonephritis, and genital mycotic infections  (see https://www.fda.gov/Drugs/DrugSafety/ucm475463.htm)

 

See blog on liraglutide, a GLP-1 agonist, which I think really does have significant cardiovascular benefit, as well as powerfully lowering A1c levels

Primary Care Corner with Geoffrey Modest MD: Sugary beverages and Alzheimer’s

4 May, 17 | by gmodest

​​​The second study from the Framingham Study Offspring cohort database found that increased intake of sugary sweet beverages was associated with lower total brain volume by MRI and poorer performance on neuropsychological testing (see doi.org/10.1016/j.jalz.2017.01.024 ). For first study, see here

Details:

–4276 participants had neuropsychological testing and 3846 had brain MRI imaging

–mean age 54, 46% male, 21% high school degree/31% some college/46% college grads, systolic BP 121 mmHg/17% on BP treatment, total chol 194/HDL 57, 8% diabetes, 2% atrial fibrillation, 10% current smoker, waist-to-hip ratio 0.9 (the WHO defines abdominal obesity as >0.90 for men and >0.85 for women)

–total consumption of sugary beverages:

–< 1x/d in 56%

–1-2 x/d in 29%

–> 2x/d in 15%

–31% consumed fruit juice ≥​​ 1x/d

–diet soft drinks were consumed more regularly than sugar-sweetened ones:  49% no diet soft drinks, 35% up to 6/wk, 16% ≥​​ 1/d

–total calorie intake 1942 cal/d, but increased from 1782 in those consuming <1 sugary beverage/d, to 2007 if 1-2/d, to 2413 if >2/d; similarly, saturated fat increased from 22 to 24 to 27 g/d

Results:

–as compared to consuming <1 sugary beverage/day, higher intake was associated with:

–lower brain volume (more so if >2/d than1-2/d)

–poorer performance on memory tests: both immediate and delayed recall

–lower hippocampal volume, borderline significant [the hippocampus is the part of the brain that consolidates short-term information into long-term memory]

–daily fruit juice intake was associated with:

–lower total brain volume, hippocampal volume, and poorer immediate and delayed recall

— however, none of these associations reached statistical significance in the most highly adjusted model, which included not just age, sex, caloric intake, education, blood pressure, smoking, cardiovascular disease, or cholesterol, but also included saturated fat, trans fat, dietary fiber, and physical activity.

— Diet soft drinks had only a small effect on total brain volume and on poor performance on the test of similarities but not other memory tests.

— Essentially no difference in subclinical markers of vascular brain injury (silent brain infarcts and white-matter hyperintensity volume)

Commentary:

–11 million metric tons of sugar were consumed by Americans in 2016 (per the US Dept of Agriculture)

–a recent blog  highlighted the remarkable statistic that “on average 26.3% of US adults consume at least one sugar-sweetened beverage daily, up to 41.4% in Mississippi, the highest of states, and that soda by itself was consumed by 24.5% of those 18-34 yo, and 47.4% in Mississippi). And a NHANES study (Welsh JA. JAMA 2010; 303(15): 1490) found that on average, 15.8% of calories came from added sugars, and that >25% of the patients got >25% of their total energy from added sugar.”

— Interestingly, there was not much of an association between sugar intake and vascular brain injury, despite studies showing that sugar consumption is associated with cardiovascular disease. Instead the current study found a more profound association with several markers of preclinical Alzheimer’s disease. This is also found in mice, where sucrose intake is associated with increased tau phosphorylation, amyloid-beta aggregation, hippocampal atrophy, and reduced brain-derived neurotrophic factor, BDNF. In the Framingham study cohort, these researchers have found that one standard deviation increase in BDNF was associated with a 33% lower risk of Alzheimer’s disease, suggesting that BDNF might be a factor in mediating the association between dietary sugar and Alzheimer’s. Other studies have found that impaired glucose tolerance and chronically elevated blood glucose are associated with poor memory, perhaps related to changes in the hippocampal volume and microstructure

— as a clinical perspective, daily fruit juice intake was equivalent to 1.5 years of brain aging in terms of  total brain volume and 3.5 years of brain aging for the delayed memory scores. And, relative to no intake, consuming more than 3 sugar-sweetened soft drinks per week was associated with lower brain volume equivalent to 2.6 years of brain aging, and lower immediate memory recall equivalent to 13.0 years!!!

— this trial also highlights the potentially bad effects of fruit juice, noting that the general public underestimates the sugar content of fruit juice by an average of 48%, even though 100% fruit juice, without added sugar, contains lots of fructose with negligible fiber content

— see here which reviews the sordid (ie not so sweet) history of the sugar industry in promoting sugar and shifting the blame away from sugar in increasing heart disease, dental caries, etc, since the 1950s, despite lots of scientific evidence to the contrary
–and, a couple of more references on lifestyle and cognitive function:

— lower adherence to a Mediterranean diet has been associated with increased brain volume loss, supplementing other studies finding higher incidence of clinical dementia related to lifestyle issues, especially diet and exercise (see review)

​– a just published systematic review/meta-analysis of exercise interventions for cognitive function in adults older than 50, found that physical exercise improved cognitive function regardless of the cognitive status of the participants. This was true for both aerobic and resistance exercise of at least moderate intensity with the duration of 45 to 60 minutes per session, done on as many days of the week as feasible (see doi.10.1136/bjsports-2016-096587.)

so, these 2 articles (including the earlier one) confirm and extend the bad health effects of excess sugar and artificial sweeteners to include adverse effects on cognition and stroke. These studies are observational ones from the Framingham Heart Study, and therefore do not definitively confirm causality, but they do add to the growing literature on their adverse effects on the brain. And, in terms of lifestyle interventions, over the years I have found that it is much easier to help people stop sodas and juices, substituting water, than other dietary interventions.​ The low-hanging fructose….

Primary Care Corner with Geoffrey Modest MD: New heart failure guidelines

3 May, 17 | by gmodest

These guidelines update the 2013 guideline for the management of heart failure, focusing on biomarkers, new therapies for both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved injection fraction (HFpEF), as well as new information on managing comorbidities including anemia, hypertension, and sleep apnea; and some new insights into the prevention of heart failure (see DOI: 10.1161/CIR.0000000000000509). This guideline is a 2nd part to the 2016 guideline on new therapies, which included recommendations for the angiotensin receptor-neprilysin inhibitor valsartan/sacubitril (an ARNI) and the sinoatrial node modulator ivabradine. Seven of 17 on the AHA committee members had ties to drug companies, though neither the chair nor vice chair did. My comments are embedded in the text

Biomarkers:

— B-type natriuretic peptide (BNP) and N-terminal pro-B type natriuretic peptide (NT-proBNP) track similarly for both the presence and severity of heart failure, and either can be used, though not interchangeably

— it is important to note that BNP, but not NT-proBNP, is a substrate for neprilysin, and therefore the ARNI  increases BNP levels. So, in studies using the ARNI, the NT-proBNP levels were reduced, associated with improved clinical outcomes [ie, it makes sense to use the NT-proBNP if starting the ARNI]

— several studies have found that these biomarkers assist in the diagnosis or exclusion of heart failure as a cause of symptoms such as dyspnea or weight gain in the setting of chronic ambulatory heart failure, or in the setting of acute heart failure decompensation.

— This still are no clear, consistent data showing that these biomarkers improve mortality or cardiovascular outcomes, so there is no specific recommendation regarding biomarker-guided therapy or the utility of serial measurements of these biomarkers in reducing hospitalization or deaths

— other biomarkers include troponins I and T, which may be elevated in chronic or acute decompensated heart failure, and do have prognostic significance in the setting acute heart failure

— and there are a slew of newer biomarkers (e.g., some reflecting inflammation, oxidative stress, vascular dysfunction, myocardial and matrix remodeling, myocardial fibrosis), which have in some studies predictive value for hospitalizations and deaths, and may have incremental prognostic value over the currently accepted biomarkers, but there need to be more studies on them

— the STOP-HF study, an unblinded single center study evaluating patients who are at risk for heart failure because of hypertension, diabetes, or nonvascular disease but without systolic dysfunction or symptomatic heart failure at baseline, patients were randomized to screening BNP testing versus usual care, finding that those with BNP levels > 50, who then had echocardiograms and team-based therapy including a cardiovascular specialist, had reduced composite endpoint of asymptomatic left ventricular dysfunction with or without newly diagnosed heart failure.

Biomarkerrecommendations:

— for patients at risk for developing heart failure, natriuretic peptide screening followed by team-based care can be useful in preventing heart failure. strength of recommendation IIa, moderate quality evidence

— for patients hospitalized with heart failure, a predischarge natriuretic peptide can be useful to establish a postdischarge prognosis, based on observational studies showing that those who did not have a significant decrease in these levels during hospitalization had worse outcomes. [This could key clinicians to more aggressive post-discharge management, though no specific biomarker thresholds for changes have been tested prospectively ,and they do not mention studies documenting the effectiveness of this approach]. Grade IIa recommendation, moderate quality evidence

— measurement of other biomarkers (e.g. soluble ST2 receptor, galectin-3, high-sensitivity troponin) may be considered for additional risk stratification. Grade IIb, moderate strength of evidence

HFrEF (for Stage C, symptomatic failure):

— overall clinical strategy is to use an ACE inhibitor or ARB or ARNI, along with beta blocker and aldosterone antagonist in selected patients, to reduce morbidity and mortality. Grade I recommendation, high quality evidence

— both ACE inhibitors and ARBs are recommended in patients with prior or current symptoms of chronic heart failure to reduce morbidity and mortality, with ARBs being recommended in patients who are ACE inhibitor intolerant because of cough or angioedema. Grade I recommendation, high quality evidence [I remain concerned about using ARBs in patients with angioedema, since I have seen 2 patients admitted to the ICU with angioedema in this situation, and there are many more in the literature, though I realize that small studies have found this not to be a problem, and there is no clear mechanistic reason why it should happen, other than those with ACE inhibitor-induced angioedema may be more generally allergic to other medications]

— ARNI is recommended in patients with chronic symptomatic HFrEF who tolerate ACE inhibitors or ARB, to further reduce morbidity and mortality, based on a study comparing ARNI versus enalapril showing improved clinical outcomes with the ARNI. Grade I recommendation, high quality evidence

— but, ARNI should not be used in conjunction with either ACE inhibitors or ARBs, and is associated with higher incidence of angioedema (and studies have shown that the combination of it with an ACE inhibitor is associated with unacceptable levels of angioedema and significant morbidity). As a result of this high incidence of angioedema with this combination, subsequent studies have excluded patients with a history of angioedema, so the recommendation is not to use the ARNI in patients with any history of angioedema, just to be safe. Black patients and smokers seem to be particularly at risk. The recommendation is that initiating ANRI should be at least 36 hours after terminating ACE inhibitors. [ARNI  seems to be a good drug clinically, but I am concerned about the fact that inhibition of the neprilysin enzyme, which has multiple biological targets, creates the potential for more downstream adverse effects detected over time]

— although not in a formal recommendation, in the flowchart they do promote the hydralazine-nitrate combination in black patients, and they do support ICD usage in patients with NYHA class II to IV heart failure and LVEF <35%; and cardiac resynchronization therapy in these same patients as with ICD but have a QRS interval greater than 150 ms and left bundle branch pattern

–Ivabradine, a selective inhibitor of the If current in the sinoatrial node, is useful for heart rate reduction, and has been found to be beneficial in reducing heart failure hospitalizations for patients with symptomatic stable chronic HFrEF on otherwise maximal management including a beta blocker at maximum tolerated dose, are in sinus rhythm, and have a heart rate>70 at rest. This is based on an RCT of patients with NYHA class II to IV HFrEF (though class IV HFrEF was not well represented), LVEF <35% and in sinus rhythm (though some had paroxysmal atrial fibrillation). However, as they note, only 25% of patients in the study were on optimal doses of beta blocker therapy, so they recommend starting ivabradine only in patients on maximal doses of beta blockers). grade IIa recommendation, with only moderate quality evidence

— there is a useful table of the maximal doses of drugs as well as the mean doses achieved in the clinical trials, with the following sampling:

— enalapril, maximum dose 10 to 20 mg BID, mean dose in trials 16.6 mg a day

— lisinopril, maximum dose 20 to 40 mg daily, mean dose and trials 35 mg per day

— losartan, maximum dose 50 to 150 mg a day, mean dose and trials 129 mg a day

— valsartan maximum dose 160 BID, mean dose and trials 254 mg a day

— carvedilol, maximum dose 50 mg b.i.d., mean dose in trials 37 mg a day

— metoprolol extended release, maximum dose 200 mg a day, mean dose in trials 159 mg day

— isosorbide/hydralazine, maximum dose 40 mg isosorbide dinitrate with 100 mg hydralazine TID, mean dose achieved not available

— spironolactone, maximum dose 25 mg daily or BID, mean dose in trials 26 mg a day

— eplerenone, maximum dose 50 mg a day, mean dose in trials 42.6 mg a day

HFpEF

— systolic and diastolic blood pressures should be controlled in accordance with current clinical guidelines, to prevent morbidity. Grade I recommendation, strength of evidence moderate

— diuretics should be used to relieve symptoms due to volume overload in patients with symptomatic HFpEF. Grade I, a low level of evidence

— coronary revascularization is reasonable in patients with symptomatic CAD that is felt likely to have an adverse effect on their HFpEF. Grade IIa, low level of evidence

— management of atrial fibrillation according to guidelines is reasonable to improve symptomatic heart failure. Grade IIa, low level of evidence

— use of beta blockers, ACE inhibitors, and and ARBs in patients with hypertension is reasonable to control blood pressure. Grade IIa, low level of evidence [a study found that ARBs might decrease hospitalizations for HFpEF patients], Grade IIb, moderate level of evidence

— it is reasonable in patients with symptomatic HFpEF to use aldosterone receptor antagonists to decrease hospitalizations in patients who have ejection fraction >45%, elevated elevated BNP levels or heart failure admission within one year, estimated GFR >30, creatinine 2.5 mg/dL, and potassium <5 mEq/l (see here ). Grade IIb, moderate level of evidence

— use of nitrates, phosphodiesterase-5 inhibitors, and nutritional supplements are not recommended, felt to have no benefit

Anemia

–in those with NYHA class II or III heart failure and iron deficiency (ferritin <100ng/ml, or 100-200 if transferrin saturation <20%), intravenous iron therapy may improve functional status, based on 3 studies. In general patients did not have severe anemia (eg FAIR-HF trial, NEJM 2009; 361: 2436) had mean hemoglobin of 11.9 g/dL, MVC 92, ferritin 52, transferrin sat 18%), finding improved symptoms, functional capacity and quality of life (and, on further analysis, this was independent of having anemia).  Grade IIb, moderate level of evidence. No data on oral iron supplementation. And no benefit from erythropoietin-stimulating agents. so only intravenous iron recommended at this point.

 

Hypertension

–optimal blood pressure in those at increased risk of heart failure is <130/70, from the SPRINT trial of patients >75yo, established vascular disease or CKD, or Framingham Risk Score >15%, showing decrease in new onset heart failure, though they note that this goal is an approximation because office BP is typically about 5-10 mmHg higher than in this trial (see here, for issues about the unusual methodology of the SPRINT trial which limit its direct generalizability, and here for review/critique of the SPRINT trial subset in elderly). Grade I, moderate level of evidence.

— goal of systolic <130 in those with HFrEF, Grade I, expert opinion. Not tested in RCTs

— goal of systolic <130 in those with HFpEF. Avoid nitrates. Preferred choice ACE inhibitors, ARBs, and possibly ARNI, Grade I, expert opinion. Limited data to support

 

Sleep-disordered breathing

–perform sleep assessment in those with NYHA class II-IV heart failure and suspicion of sleep-disordered breathing or excessive daytime sleepiness, Grade IIa, not much data, but a study of patients with chronic heart failure found 61% had either central or obstructive sleep apnea, but treatments are different and one needs to know which one the patient has.

–in patients with cardiovascular disease and OSA, CPAP may be reasonable to improve sleep quality and daytime sleepiness, Grade IIb, moderate quality evidence.

— in patients with central sleep apnea and class II-IV HFrEF, using servo-ventilation treatment causes harm!! (higher mortality)

–[this recommendation befuddles me a bit: it is true that people with symptomatic OSA who use CPAP have better sleep quality and function better. But that is true if they have heart disease or not. And the study they quote (ORBIT-AF) just showed that those with atrial fib plus OSA and put on CPAP had less progression to more permanent atrial fib. Not sure that means much clinically, and this was not a study in heart failure patients. I assume that this section was added to highlight that sleep studies are indicated when people are not sleeping well (though this happens with heart failure a lot), and that we NOT go the servo-ventilation route if it is central sleep apnea, but that CPAP is okay for OSA. Which I guess is a reasonable point, but bringing in the atrial fib study in those not in heart failure seems a bit off-track.]

Commentary:

— although HFpEF seems to have pretty much the same prevalence as well as morbidity/mortality as HFrEF, it is quite striking how poorly equipped we are to provide great therapy. Personally I have had pretty good success with adding on spironolactone in patients with severe, resistant disease to help with symptoms and decrease multiple admissions.

— As noted in prior blogs, treating patients effectively with HPrEF has been one of the major advances in therapeutics over the last several decades. In my experience these patients do exceptionally well overall, can be treated effectively in the primary care setting, and do very well over the long-term and into very old age. I recently had a patient to had a severe MI at age 72, was resuscitated, maintained a left ventricular ejection fraction which never exceeded 10%, was basically asymptomatic with optimal heart failure therapy, and ultimately died over 20 years later..

— these guidelines do add some important new recommendations, especially: further promoting the use of natriuretic peptide​ biomarkers and integrating them more into care, considering using them to identify and manage patients at high risk of heart failure, and there seems to be value in checking iron levels in those with HFrEF​ even without anemia [I will integrate that into my approach to care, though will deviate to using oral supplementation if iron deficient]. And, as mentioned, I think these guidelines help us manage heart failure patients in a primary care setting, which I have found to be incredibly successful and satisfying for me (and I think for my patients)….

Primary Care Corner with Geoffrey Modest MD: Stroke and dementia, and artificial sweeteners

2 May, 17 | by gmodest

by Dr Geoffrey Modest

Two studies came out from the Framingham Heart Study database by the same authors in 2 different journals, one on the association between consuming artificially-sweetened beverages and the later development of stroke and dementia, and the other on sugary beverages and preclinical Alzheimer’s disease. I will divide these into 2 blogs.

An evaluation of the Framingham Heart Study Offspring cohort, with data from 1971 and evaluated over 9  examination cycles, found that artificially-sweetened soft drink consumption was associated with a higher risk of stroke and dementia (see DOI: 10.1161/STROKEAHA.116.016027).

 

Details

— 2888 participants >45yo were evaluated for incident stroke;  1484 who were >60yo were evaluated for incident dementia

— mean age 62 for the younger group and 45% men, 69 for the older group and 46% men

— beverage intake was quantified at cohort examinations 5 (1991-5), 6 (1995-8), and 7 (1998-2001). Total sugar-sweetened beverages included soft drinks, fruit juice, and fruit drinks.

— surveillance for incident events began at examination 7 and continued for 10 years

— there were 97 cases of incident stroke (82 ischemic), and 81 cases of incident dementia (63 consistent with Alzheimer’s)

 

Results:

— controlling for age, sex, education (for the dementia cohort), calorie intake, diet quality, physical activity, and smoking; when compared to a daily cumulative intake of 0 artificially-sweetened drinks per week:

— hazard ratio for ischemic stroke was 2.96 (1.26-6.97), p=0.01 (ie, about 3x higher). Relationship was strongest for ischemic stroke

— hazard ratio for Alzheimer’s disease 2.89 (1.18-7.07), p=0.02. There was also an association with all-cause dementia of similar magnitude, 2.47 (1.15-5.30), p=0.02. Both were statistically significant in the group having at least one drink per day.

— sugar-sweetened beverages were not associated with the stroke or dementia, only artificially-sweetened soft drinks

— the curves for event-free survival for both of these outcomes continued to decrease through year 10 (i.e. it was not plateauing), and there was a dose-response curve with the more artificially-sweetened soft drinks, the lower the event-free survival

— there was no interaction in the above analyses with waist-to-hip ratio, diabetes mellitus, or with the presence of apolipoprotein E4

— there was not much change in the associations when excluding diabetes from the analysis, given the potential interaction of those with diabetes drinking more artificially-sweetened beverages (diabetes was found to be only a partial mediator of the association).

 

Commentary:

— the Nurses’ Health Study and Health Professionals Follow-Up Study both reported a higher risk of incident stroke with greater consumption of sugar-and artificially-sweetened beverages. The above study is reported to be the 1st showing association between artificially-sweetened drinks and an increase in both all-cause dementia and Alzheimer’s.

— The above study predated the approval of Stevia

— there are studies which have shown that artificial sweeteners cause glucose intolerance in mice by altering the gut microbiome, and they are associated with glucose intolerance in humans. See here for a detailed review of these animal and human studies.

— Generalizability of these results: the Framingham study served as a model for epidemiologic studies given its long-term nature (began in 1948) and in the regular intensive follow-ups done over the years. However, it was limited by the lack of ethnic variation. It also was an observational study which limits drawing conclusions regarding causality.

 

So, bottom line (again): these no-calorie artificial sweeteners seem to be associated with significant problems, including glucose intolerance (despite the fact that we used to push diabetic patients to drink these over regular sodas). And there are suggestive data that they do not help even with weight loss (see here ). so, all in all, we should be promoting water as the best drink….

EBM blog homepage

Evidence-Based Medicine blog

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



Creative Comms logo

Latest from Evidence-Based Medicine

Latest from EBM