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Archive for May, 2017

Primary Care Corner with Geoffrey Modest MD: Statins in the elderly?

26 May, 17 | by gmodest

by Dr Geoffrey Modest

​A post-hoc secondary analysis of data from the ALLHAT-LLT trial assessed the value of pravastatin, 40 mg per day, versus placebo in older patients, finding no benefit (see doi:10.1001/jamainternmed.2017.1442)

Details:

— the ALLHAT-LLT study, a community-based study which included 10,355 patients who had a fasting LDL level of 120 to 189 mg/dL and fasting triglycerides level < 350 mg/dL. 4546 were excluded for being younger than 65 and an additional 2942 because of baseline atherosclerotic disease, resulting in 1467 people in the pravastatin group and 1400 in usual care (UC)

— The intervention was open label pravastatin 40 mg per day versus UC. Mean follow-up 4.6 years

— mean age 71, 51% female, 40% white/31% Latino, 25% on aspirin/90% on anti-hypertensives/10% of women on estrogens, 22% current smokers, 51% diabetics, BMI 30, mean blood pressure 147/83

— baseline LDL was 148 mg/dL, decreasing to 109 mg/dL in those on pravastatin and 129 mg/dL in UC. The proportion taking statins was 78% versus 29%, respectively, by year 6 [ie, pretty large cross-over of patients]; this was more pronounced for participants 65 to 74 years old, where 32% of the UC group were taking a statin, though in those >75 yo, 15% were.

Results:

— all-cause mortality in pravastatin vs UC was non-significantly different for all adults 65 and older (HR 1.18, p=0.09), including nonsignificant HR of 1.08 those age 65 to 74, and 1.34 for those 75 years old or greater [ie nonsignificant trend to worse prognosis in group on pravastatin]

— coronary heart disease event rates were also not significantly different among the groups. No change with multivariable regression. No significant interaction between the treatment group and age.

Commentary:

— it is true that there are not rigorous data on older people and statin use, especially for adults greater than 75 years old, with much of the existing data being post-hoc analyses.

— One concern with the ALLHAT trial is that it was not a truly randomized controlled trial, with the control group being usual care. As a result, the 29% taking statins in the UC group might have been a very high risk group and thereby dilute the difference with the pravastatin group; and conversely 22% of those assigned to pravastatin did not take it (were they self-selected as healthier and less likely to have an atherosclerotic event??).  So ultimately, there was only a 20 mg/dL difference between the groups (and, pravastatin is one of the weaker statins). Another issue which may have disadvantaged the pravastatin group: among people 75 years and older, the mean systolic blood pressure was 150.6 mmHg in the pravastatin group and 147.5 mmHg in the UC group (p=0.01). Their finding of nonsignificant increases in overall mortality as well as in cardiovascular and stroke mortality, and heart failure event rates (all of which are strikingly contrary to the statin studies in younger people which show marked benefit of statins) suggest to me that intrinsic biases of the current ALLHAT study may have played an important role (though coronary heart disease rates were nonsignificantly lower in the pravastatin group)

–other issues: this was an open label study (with its attendant potential biases), did not include nonpharmacologic therapies of diet/exercise (and did those on statins stop doing these healthful behaviors because perhaps they found out from their clinicians that their lipids were better and they thought they didn’t need to continue the lifestyle changes, as was found in another statin study??), and those already on a statin were excluded from the study (those likely at higher cardiovascular risk, leaving the actual cohort at lower risk).

— There is reasonable theoretical benefit for using statins in the elderly: in people older than 65, about one half of all deaths are from atherosclerotic disease. And, statins reveal their effectiveness pretty quickly, within 6 months to a year.

— In general, although the relative risk of hyperlipidemia causing atherosclerotic disease in the elderly is lower than in younger people, the absolute risk in fact increases a lot with age.

— See blog , which reviews some of the data showing benefit of statins in the elderly, including a relatively recent meta-analysis of 8 trials, finding for example a 39% relative risk reduction for MI in those on statins, with number needed to treat of 24 for one year to prevent one MI. Relatively similar numbers for stroke prevention. Though these are mostly post-hoc subgroup analyses of bigger studies.

 

So, there really should be high quality randomized controlled studies of statin use in the elderly. The pathophysiology of atherosclerosis and the mechanics of statin use would suggest significant benefit for the elderly, even within 6 months of initiating statin therapy, and with minimal likely adverse effects. However, the current information is basically from post-hoc secondary analyses. Given our aging population and their high mortality rates from atherosclerotic disease, it really makes sense to have large rigorous studies. In the meantime, I will continue to treat the elderly with statins on an individual basis, having had (I think) good success: several elderly patients with severe CAD who have lived for decades on statins, dying in their mid 90s, and only one patient with an adverse effect/intolerance.

Also, as I mentioned in a recent blog, I am really concerned that the wrong message is getting out to clinicians: Physician’s First Watch and NEJM Journal Watch stated “Pravastatin Doesn’t Improve Clinical Outcomes in Seniors” . I think these sound-bite type analyses do in fact dumb-down the process of critical analysis of potentially important clinical articles, reinforcing (by omission) that the results of this study sound pretty definitive and thereby perhaps convincing some clinicians to stop prescribing statins. This approach is ahistorical (ie, omits the wealth of prior data suggesting benefit), and tends to reinforce the conception that the newest study trumps (perhaps bad term) all of the older studies (ironically, in this case, this study was based on a post-hoc analysis of a really old study, though I do think that in general newer studies tend to be accepted by us disproportionately, and inappropriately in some cases)

 

Primary Care Corner with Geoffrey Modest MD: Cellulitis treatment

25 May, 17 | by gmodest

by Dr Geoffrey Modest

 

Given the emergence of methicillin-resistant Staphylococcus aureus (MRSA), there are concerns about what empiric therapy to prescribe for skin infections, including cellulitis. A recent article in JAMA assessed the utility of adding trimethoprim-sulfamethoxazole (TMP-SMX) to cephalexin in treating uncomplicated cellulitis (see doi:10.1001/jama.2017.5653).

Details:

— 5 US emergency departments participated in an outpatient double-blind study of 500 patients >12 years old with cellulitis but without wound, purulent drainage, or abscess, seen from 2009-2012.

— Median age 40, 58% male, 57% white/35% black/1% Asian, symptom duration 3 days, 20% with a history of fever in the week prior to enrollment, 56% of infections were in the lower extremity/24% upper extremity/9% trunk abdomen or back/6% head or neck/4% groin or buttocks, 11% diabetics; mean length and width of erythema was 13 x 10 cm

— Bedside ultrasound was used to exclude abscess

— patients were randomized to cephalexin 500 mg 4 times a day plus TMP-SMX 160 mg/800 mg twice a day for 7 days, vs cephalexin plus placebo for 7 days

— primary outcome was clinical cure,  defined as an absence of fever, increase in erythema >25%, swelling, or tenderness at days 3-4; no decrease in erythema, swelling, or tenderness at days 8-10; and the presence of no more than minimal erythema, swelling, or tenderness at days 14-21.

Results:

— in a per-protocol analysis, which was limited to those patients who had a physical follow-up at 14-21 days after enrollment and took to at least 75% of medication doses: clinical cure at 14-21 days occurred in 182 (83.5%) of those assigned to cephalexin plus TMP-SMX, versus 165 (85.5%) in those on cephalexin alone, nonsignificant

— in the modified intention-to-treat population (participants took at least one dose of study medication, had an in-person or telephone assessment at the test of cure visit, and included those who withdrew from the trial or were lost to follow-up), clinical cure occurred in 189 of 248 patients (76.2%) in the combination group and 171 (69.0%) in the cephalexin group, a difference of 7.3% (-1.0% to 15.5%) p=0.07, almost but not quite significant. However in the more specific modified intention-to-treat analysis including those who took at least one dose of medications and had an in-person follow-up evaluation at any time during the study (ie, not including those who were lost to follow-up etc), the clinical cure rates were 83.8% in those on combined therapy and 82.8% of those with cephalexin alone, nonsignificant

— Adverse events, including the secondary outcome of overnight hospitalization, recurrent skin infections, and similar skin infections in household contacts through weeks 7-9, did not differ significantly. However, one patient on TMP-SMX did have acute-on-chronic kidney injury that resolved.

— 36 patients had treatment failure with cephalexin plus TMP-SMX: 10 (28%) were found to have an abscess the time of clinical failure and 9 (25%) developed an opening of the skin and purulent drainage

— 60 patients overall had treatment failure with clinical evidence of infection and had material available for culture: 41 (68%, and 10% of the per-protocol population) had MRSA, 8 (13%) had MSSA, and 3% streptococcal species, with no difference between treatment groups in the proportion having MRSA during follow-up.

— Post hoc subgroup analyses showed no difference between the groups if the patients had a history of fever or not, had diabetes, or by the size of the erythema.

Commentary:

— cellulitis is a common outpatient issue, and a difficult one because it is usually impossible to find the causative organism. b-hemolytic strep is often considered the cause, and the 2014 guidelines from the Infectious Diseases Society of America suggest choosing an antibiotic against Streptococci if there is no evidence of systemic signs of infection, penetrating trauma, evidence of MRSA elsewhere, or injection drug use. However, it is common for clinicians to cover MRSA infection in patients with cellulitis, given how widespread these infections are and how standard antibiotic therapy as with cephalosporins do not cover these MRSA infections.

— it is not so surprising that TMP/SMX does not add much to the treatment of cellulitis overall, since it does not provide much coverage for b-hemolytic strep, the presumed major causative organism

— One concern with this type of ED-based study is the higher likelihood of lower levels of medication adherence. They found that of the patients who took at least one dose of medications, only 52% were 100% adherent to the full regimen and 25% took 76-99% of their doses. This nonadherence was 3-fold higher in the cephalexin only group, for unclear reasons. But, the per-protocol analysis (ie those who took the meds) showed no difference between the outcomes of the treatment groups. I should add that some in this per-protocol group might have taken as little as 75% of their prescribed antibiotics, and this seems to me to be an arbitrary number. Which brings up the issue that some of these patients, in their most aggressively treated group, may actually have had insufficient antibiotic therapy. It would have been useful to have more granular data here assessing outcomes by finer gradations of medication adherence.

— Of note, of 36 patients who had treatment failure in the combined antibiotic group, over half had an abscess or skin opening/purulent discharge; and 71% of 28 in those on cephalexin alone. 10% of the patients who had clinical failure but had taken at least 75% of medication doses did have MRSA, which does suggest that even in patients with no clinical or ultrasound evidence of an abscess, there might well be MRSA (though, again, was this MRSA created or selected-for by taking insufficient quantities of antibiotics to cure the infection??) And this number is likely to be higher in many clinical settings, where cellulitis is defined exclusively clinically and without the use of ultrasound. It is somewhat reassuring that the treatment failures were similar in that both treatment groups had MRSA, though it seems that the numbers were too low to draw definitive conclusion.

–clearly from this study, there is a fine line between cellulitis and abscess formation. Even many of those who did not have an ultrasound-detectable abscess at the initiation of the study ultimately did develop fluid collections or skin opening with purulent discharge. And the proportion of patients with unknown fluid collections in our health center, for example, is undoubtedly higher than in this study since we do not have a bedside ultrasound machine (which limits the generalizability of this study in these settings). Again, it would have been interesting to have more granular data about the baseline characteristics of those who developed abscess/purulent discharge in this study and if there were any predictive models for them, since those who have abscesses are much more likely to have MRSA and should be treated differently. For one thing, those who are basically healthy (no immunocompromise, lots of comorbidities) who have no systemic symptoms and especially with small abscesses (eg <2cm) do just as well with incision and drainage and without antibiotics at all. And if antibiotics are indicated, they should cover MRSA.

 

so, this article, though not obviously generalizable to all settings (eg no ultrasound in many settings, perhaps higher medication adherence in primary care setting), does suggest reasonably strongly that TMP/SMX does not add much to the treatment of clinical cellulitis. Though imperfect, the per-protocol analysis does support this conclusion. Therefore, I think it is very reasonable to treat patients with cellulitis but without systemic symptoms/immunocompromise/etc just with a cephalosporin, thereby avoiding the unusual but occasionally severe adverse reactions of TMP/SMX, but with the caveat that there be close followup. Other studies have found that 90% of patients with cellulitis have significant clinical  improvement within 3 days, so that might be a reasonable target for a return visit. On the other hand, it seems reasonable to me to use the combo therapy in a patient who has a low probability for coming for follow-up, especially if one cannot rule-out a small abscess for lack of an ultrasound, where I would imagine that MRSA is more likely…

 

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….

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