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Renal/urol

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

6 Feb, 17 | by EBM

By Dr. Geoffrey Modest

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

Details:

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

Results:

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

Commentary:

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

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

Relevant past blogs:

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

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

Primary Care Corner with Geoffrey Modest MD: Hematuria Evaluation

2 Feb, 16 | by EBM

By Dr. Geoffrey Modest 

The Am College of Physicians just released an “advice for high-value care” regarding the assessment and workup of hematuria (see doi:10.7326/M15-1496​)​. Their points:

  • Though there are no recommendations to support performing hematuria screening (the USPSTF gives it an “I”, or insufficient evidence, rating), millions of patients get routine urine dipsticks and microscopic exams (though many of these tests may be done for other reasons as well, given the multitude of evaluations on a single dipstick). But 44-77% of primary care physicians have been endorsing the use of urinalysis in routine practice, though the % is decreasing over time.
  • Any episode of gross hematuria deserves more urologic attention, since the pretest probability of cancer or a clinically significant condition is high (>10-25%), vs asymptomatic microscopic hematuria–AMH (0.5-5.0%, but up to 20% in high-risk groups), though the prevalence of AMH is pretty high (0.9-18.0% of the adult population) large population-based case-control study of healthy adults found no difference in cancer incidence between those with and without dipstick-positive hematuria, with a sensitivity of screening of 2.9% and positive predictive value of 0.2-0.5% for cancer, undermining the rationale for screening
  • Most urologic societies recommend a microscopic exam if the urine dipstick is positive for blood, from a clean-catch midstream urine, with a positive finding being at least 3 RBCs/high-powered field [the Am Urological Assn (AUA) used to say there needed to be confirmation in 2 of 3 specimens, though now even 1 warrants further workup]
  • The AUA has a lower age threshold (35 years old) vs other societies (40-60 yo) as a target for further workup. the AUA suggests workup at any age if high risk (male sex; past/current smoking; occupational exposure such as chimney sweeps, nurses, waiters, aluminum/ship/petroleum workers, exposure to aromatic amines as in tobacco/dye/rubber/leather workers/hairdressers/printers; history of gross hematuria; irritative voiding symptoms of frequency/urgency; chronic UTIs; exposure to carcinogenic chemotherapy; chronic indwelling foreign body) — not sure what to make of this, since probably 70% of the population qualifies, e.g. being male and history of smoking.  and ??nurses, waiters are at high risk?
  • Further evaluation includes CT urography per the AUA, though the Canadian and Dutch guidelines promote ultrasound to decrease radiation exposure
  • The AUA still recommends complete urologic evaluation even in the presence of high-probability of underlying renal disorders (dysmorphic red cells, proteinuria, cellular casts, CKD, hypertension)
  • Also AUA suggests performing the full workup even if the patient is on antiplatelet or anticoagulant therapy
  • They do not suggest urinary cytologic evaluation or using the FDA-approved bladder cancer detection tests (lots of false positives and negatives)
  • Harms of AMH evaluation:
    • Anxiety, discomfort of cystoscopy, the uncommon complications of cystoscopy (infection in up to 3.7%, sepsis, urethral stricture); complications of CT urography (contrast nephropathy in 2% and up to 20% in higher risk patients with heart failure or CKD), cost
    • In terms of radiation exposure from CT urography, there is considerable variability depending on the scanner/imaging protocol, but is typically 20-30 mSv (with some centers in the 7-10 range, but some up to the 90 mSv range…). The National Research Council concluded that 10 mSv may have increased risk of cancer. The higher doses are projected to create 4 cancers per 1000 patients (see, for prior blogs in http://blogs.bmj.com/ebm/category/radiation/on the issue of radiation exposure.)

Their formal suggestions for “high-value care”:

  • Make sure to ask patients about gross hematuria as part of the review of systems
  • Do not do routine urinalysis in healthy, asymptomatic patients with primary intent to screen for cancer
  • If urinalysis is done and results positive for heme, do a microscopic exam of the urine, with 3 or more RBCs/hpf being abnormal
  • Refer for urologic evaluation if gross hematuria
  • Consider referral for cystoscopy and imaging in patients with AMH in the absence of a demonstrable benign cause [(e.g. menstruation, viral illness, vigorous exercise, UTI, etc), then repeat the urinalysis after that potential cause is no longer present (though some urology societies recommend up to 3 repeated urinalyses to confirm absence of a more serious cause)]
  • Pursue hematuria evaluation even if the patient is on anti-platelet or anti-coagulant therapy
  • Don’t get  urine cytology or use the newer tests for bladder cancer markers

So, a few points:

  • The change in the AUA guidelines to treat any single urinalysis finding hematuria as a basis for further workup (similar to any positive stool guaiac) is appropriate and a bit late, since there were studies I saw perhaps 25 years ago confirming that both renal and bladder cancers can produce intermittent hematuria. For this reason, I personally do perform 3 repeat urinalyses if there may be a confounding and benign cause (vigorous exercise, UTI, etc.), and especially so if there are risk factors for cancer as above (though working as a waiter or nurse was not on my list….). And it is important to understand the importance of gross hematuria, though it may be very intermittent and both the patient and clinician may not pay much attention to that (though beware of eating beets, or taking rifampin as a cause of red-colored urine). One study did find that in patients referred to urology for AMH, 20% had gross hematuria within the past 6 months on further questioning, without that having been ascertained by the primary care clinician.
  • Up to 1/3 of urine dipsticks are positive for heme but have negative microscopic exams (likely heme-positive from free hemoglobin, as from hemolysis, or myoglobin, or even from semen/sperm being present in the urine). And it makes sense that a microscopic exam be done on the same urine specimen when there is a heme-positive dipstick exam.
  • Primary care clinicians often under-refer to urology for AMH, even in situations of high cancer risk (lots of the risk factors above, including occupational, or even with gross hematuria). And the concern is that a detected bladder cancer is usually quite curable if early/superficial, and much less so when invasive. A SEER (surveillance, epidemiology and end-results)-Medicare dataset found that delaying the diagnosis of bladder cancer >9 months after a claim for hematuria had a much higher mortality than if < 3 months (median cancer-specific survival of 50.9 months vs 70.9 months (see Cancer, 2010: 116: 5235). And this delay in referral seems to be much greater in women
  • These guidelines do not discuss the most rational approach, in my opinion. It seems reasonable, though untested, to do a renal evaluation first. If there is evidence of a renal cause for hematuria (e.g., some combination of dysmorphic red cells, casts, proteinuria, renal dysfunction, abnormal radiologic assessment), I tend to pursue the renal workup at that point and consider referral to a nephrologist if the etiology remains unclear, there is progressive disease, the imaging study is concerning for a serious underlying pathology, etc. I am not convinced that everyone in this category needs cystoscopy…  But if the renal imaging is normal and there are no compelling reasons to consider a renal etiology, I absolutely support referral for cystoscopy and have occasionally picked up early transitional cell carcinomas. So, I am not sure that their algorithm to check “renal function testing, cystoscopy, and imaging” is appropriate. I should note that the 2012 AUA guidelines (go to URL: https://www.auanet.org/education/guidelines/asymptomatic-microhematuria.cfm​ ) does comment that even if a renal cause is likely because of these findings (they tend to focus too much on the less-reliable marker of RBC dysmorphism), “the presence of renal disease disease does not exclude a urologic process and evaluation should include assessment for urologic pathology”. Seems to me that Occam’s razor needs a sharpening….

Primary Care Corner with Geoffrey Modest MD: Interventions to prevent recurrent kidney stones

30 Jan, 15 | by EBM

By: Dr. Geoffrey Modest

The Am College of Physicians released a clinical practice guideline on interventions to prevent recurrent kidney stones (see doi:10.7326/M13-2908​).

Background:

–13% of men and 7% of women get kidney stones, and 35-50% have recurrence within 5 years without treatment
–80% are calcium oxalate or calcium phosphate or both
–Dietary efforts include increasing water intake, reducing dietary oxalate, reducing dietary animal protein and other purines, and maintaining normal calcium intake

Results of this systematic review:

–1 good quality and 28 fair-quality trials found insufficient evidence that assessing stone composition, or blood/urine chemistries reduces recurrences
–80 fair-quality trials of dietary interventions have found that:
–Increased fluid intake, reduced soft drink intake (esp. soda acidified by phosphoric acid, eg colas), and a high-calcium, low-protein, low-sodium diet reduce stone recurrences, though these studies were typically of low-quality and often with mixed results.
–One trial also found that low sodium intake (50 mmol/d) helped in patients with calcium oxalate stones.
–No trial specifically assessed low oxalate diet, though there was a trial finding benefit of high calcium (1200 mg/d) vs. low calcium diets (400 mg/d) — which has been attributed to dietary calcium binding oxalate in the gut and decreasing oxalate absorption.

Pharmacologic therapy:

–Thiazides — moderate-quality evidence from 6 fair-quality trials of 24.9% vs. 48.5% incidence of recurrent stones. no difference in type of thiazide. Though 8% vs. 1% withdrew for adverse reactions. ​ (In terms of dose — they note that these studies were done with higher dose thiazides. none with lower doses which have fewer adverse effects — it is evident that even low doses of thiazides increase serum calcium levels, though I could find no good data on dose-dependent calcium excretion. and I have prescribed lower dose thiazides with apparent good effect)
​–Citrates (which interfere with stone formation) — moderate-quality evidence in 5 trials of calcium stones with lower recurrence (11.1% vs. 52.3%). though 15% vs. 2% withdrew for adverse reactions.
–Allopurinol — moderate-quality evidence in 4 trials in patients with calcium oxalate stones of decreased recurrence (33.3% vs. 55.4%). no increase in adverse effects found.

So, their recommendations:

–Increase fluid intake spread throughout the day to achieve at least 2 L of urine/d (weak recommendation, low-quality evidence). They suggest avoiding colas (acidified by phosphoric acid) but not drinks acidified by citric acid (eg fruit-flavored sodas)
–Use drug monotherapy with thiazides, citrate or allopurinol in patients where increased fluid intake fails to reduce recurrent stones (weak recommendation, moderate-quality evidence)

So, a couple of comments:

1. Although I do give patients lists of high oxalate foods to avoid when they have calcium oxalate stones (and I do check stone chemistry analysis), my guess is that a more acceptable diet is the high calcium one, which I also recommend.
2. The issue of allopurinol. unclear what the mechanism is. 2 RCTs have found that patients who had hyperuricosuria put on allopurinol had fewer calcium oxalate stones, but an observational study found no difference in uric acid excretion in people with or without stones (observational study. controlled for some risk factors. but who knows?). Uric acid as nidus for stone formation (unclear). As most of you know by now, I am very concerned about food additives, and one of the obvious targets is high-fructose corn syrup, which is associated with dramatic increases in fructose consumption (currently about 25% of calories in the US, mostly from sodas, with increase from about 15 gm/d when fructose was consumed naturally from fruits to 73 gm/day now), has a different metabolism from glucose (which is converted into glycogen in the liver, vs. fructose, which is converted to fructose-1-phosphate and depletes the liver of phosphates, increases uric acid levels, increases small dense and more atherogenic LDL particles, and may increase insulin resistance). I have had some patients completely stop soda intake and have found pretty dramatic decreases in uric acid levels. So, this is now one of my dietary recommendations for those with kidney stones.

Primary Care Corner with Geoffrey Modest MD: Testosterone, again

24 Jan, 15 | by EBM

By: Dr. Geoffrey Modest 

There have been a couple of articles on testosterone:

1. Article in j clin endocrinology and metabolism on testosterone therapy for men with type 2 diabetes (T2D) and low testosterone levels (see doi: 10.1210/jc.2014-1872). 88 men aged 35-70 (ave age 62) with A1c <8.5%, total testosterone (TT) < 346 ng/dl (they specifically were looking for men with low normal testosterone levels, and excluded those with TT < 144), with mild to moderate “aging male symptoms” and erectile dysfunction, randomized to 40 weeks of IM testosterone undecanoate 1000 mg or placebo, assessing their AMS (aging male symptoms score, a validated 17-item scale to assess 3 domains: somatovegetative, psychological, and sexual), as well as sexual desire and erectile function. This analysis was a secondary one; with the primary study finding in these men that testosterone injections did not lead to any change in glucose metabolism (insulin resistance or glycemic control) or visceral adiposity (for that study see: Diabetes Care 2014;37:2098–2107). Results of current analysis:

–Testosterone injections did in fact increase TT levels

–No difference in the AMS score with testosterone injections

–No difference in sexual desire (interestingly, those on IM testosterone actually had reduced erectile function)

–Although the utility of free testosterone levels is debated, they found that 72% of the men had low free testosterone and there was no difference in results for them vs.. those with low TT

–Symptoms overall were worse at baseline if men were depressed or if had micro vascular complications (neither of these correlated with TT levels)

–The authors are careful to note that their conclusions do not apply to symptomatic men with unequivocally low testosterone levels, and that their results for men with less severe androgen deficiency were somewhat at odds with some other studies

Note: 30-50% of aging, obese men with T2D have low TT, though the vast majority has only mildly decreased TT (as in this study). In observational studies, 55-70% of those with low TT levels have symptoms of androgen deficiency, but 50-55% of those with normal TT had similar symptoms. So, I think this study is relevant to us because it highlights the importance (and high prevalence) of depression as a likely cause of sexual dysfunction, and the lack of significant efficacy of testosterone therapy. The data for clinical benefit of testosterone therapy in older men is very mixed, with best data for improving libido, though no significant change in erectile function or sexual satisfaction. As a result, the Institute of Medicine’s committee on testosterone concluded that there is insufficient evidence to recommend that testosterone treatment of older men have any well-established benefit. The number of testosterone prescriptions has increased dramatically in the last several years — this study reinforces the lack of real utility for testosterone replacement therapy for the majority of men (with the exception of those with profound TT deficiency, eg a man with symptoms consistent with testosterone deficiency — eg decreased libido, mood, osteoporosis, energy plus a TT level measured between8-10AM and less than 300 ng/dL, and this test should be repeated/confirmed 2x more before giving meds since there are significant daily variations in TT). And there are real risks to testosterone therapy.

2. The Endocrine Society came out with a clinical practice guideline for androgen therapy in women (see doi: 10.1210/jc.2014-2260). They basically recommend:

–Do not diagnose androgen deficiency in healthy women because of lack of well-defined syndrome and lack of data correlating symptoms with androgen levels. And don’t use testosterone routinely in those with hypopituitarism, adrenal insufficiency, etc.

–Do not use testosterone therapy for infertility; sexual dysfunction (other than “hypoactive sexual desire syndrome”, which studies suggest may respond to short term testosterone therapy, though endogenous testosterone levels do not predict response to therapy even in this “syndrome”); cognitive, cardiovascular, metabolic, or bone health; or general well-being

–Not use dehydroepiandrosterone​

–AND, none of these testosterone preparations are available in the US for women, women frequently develop very high serum testosterone levels on therapy, and long-term safety data are lacking (though it seems that the testosterone equivalent doses for women is about 10% of those used in men).

 

Primary Care Corner with Geoffrey Modest MD: Guidelines for incontinence

23 Jan, 15 | by EBM

By: Dr. Geoffrey Modest 

The Am College of Physicians released practice guidelines for the nonsurgical management of urinary incontinence in women (see doi:10.7326/M13-2410​).

Baseline issues:

–urinary incontinence is really common: 25% in women aged 14-21; 44-57% in middle-aged and postmenopausal women aged 40-60; 75% in those >75 yo (though likely that these numbers reflect under-reporting)

–risk factors: pregnancy, pelvic floor trauma after vaginal delivery, menopause, hysterectomy, obesity, UTI, functional and/or cognitive impairment, chronic cough, constipation

–2 main types: stress incontinence from urethral sphincter failure with increased intra-abdominal pressure (e.g. from laughing, coughing, sneezing) and urge incontinence from involuntary loss of urine from compelling urge to void. There are also mixed incontinence and overactive bladder (with urinary urgency with or without incontinence, typically with frequency and nocturia). No comment in guidelines on overflow incontinence.

Most women do not volunteer that they are incontinent — clinicians need to ask!!

 Recommendations:

  1. Stress incontinence: first-line treatment is pelvic floor muscle training — e.g. Kegel exercises (strong recommendation, high-quality evidence).

–these exercises work well (5 times more effective than no active treatment) and NNT (number needed to treat) in pooled data is 2. Added use of biofeedback using a vaginal electromyography probe also works with NNT of 3 (low-quality evidence, but high quality evidence for urge incontinence). Insufficient data for other treatments (pessaries, other devices).

  1. Urge incontinence: bladder training – e.g. progressively lengthening the time between voiding(strong rec, moderate-quality evidence).

–low-quality evidence that bladder training improves urge incontinence (NNT=2), data on complete continence was insufficient

  1. mixed incontinence: both pelvic floor muscle and bladder training (strong rec, moderate-quality evidence)

–using both trainings, NNT=6 to achieve continence, NNT=3 to improve continence

  1. NOT use systemic meds for stress incontinence

–as opposed to systemic drugs, vaginal estrogen preparations do help (NNT=5). One low-quality study found additional efficacy of vaginal estrogens plus Kegel’s. (They did not comment that vaginal estrogens are only for postmenopausal women, though I’m sure that’s what they meant, and their 2 references are for postmenopausal women).

  1. Use meds for urge incontinence if bladder training unsuccessful. Choose med by tolerability, adverse effect profile, ease of use, and cost (strong rec, high-quality evidence)

— There was moderate-to-high quality evidence that the following antimuscarinic agents achieved continence with NNT=8-9: darifenacin (Enablex), fesoterodine (Toviaz), oxybutynin, solifenacin (Vesicare), tolterodine, and trospium.

–of these, I tend to use trospium first (prior review a few years ago found higher likelihood of success, see Ann Intern Med. 2012;156:861-874), then the other 2 generics: tolterodine and oxybutynin (tolterodine is my second choice, since it seems to be better tolerated). The present guidelines do not find much difference between these 3 (though I also find that sometimes when one does not work, another does). There is moderate-quality evidence that fesoterodine achieved continence more than tolterodine.

–if these fail, consider using the b3-adrenoreptor agonist mirabegron (Myrbetriq), which has moderate-quality evidence that it works with NNT=12 (I have never used this, so cannot personally comment)

​–most common adverse events from antimuscarinics were dry mouth, constipation, blurred vision. Also insomnia (esp. with oxybutynin). Dizziness (esp. with trospium). Drug discontinuation rates from adverse effects were higher for fesoterodine and oxybutynin than tolterodine.

  1. Weight loss and exercise help for obese women with urge incontinence

So, I think this is a reasonable approach. Begin with non-pharmacologic therapies (which seem to work really well for about 1/2 of the women I’ve seen), then progress to meds if needed. Topical estrogens also decrease UTI recurrences in women with atrophic vaginitis and frequent UTIs, which commonly goes along with incontinence (i.e., both are common in postmenopausal women). And I have almost always found significant improvement with one of the generic antimuscarinics: trospium, tolterodine, oxybutynin.

Primary care corner with Dr. Geoff Modest: FDA testosterone alert

3 Feb, 14 | by EBM

here is the Jan 31 FDA alert about testosterone (also see link: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm384225.htm):

AUDIENCE: Cardiology, Urology, Family Practice

ISSUE: FDA is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products. We have been monitoring this risk and decided to reassess this safety issue based on the recent publication of two separate studies that each suggested an increased risk of cardiovascular events among groups of men prescribed testosterone therapy. FDA is providing this alert while it continues to evaluate the information from these studies and other available data. FDA will communicate final conclusions and recommendations when the evaluation is complete.

BACKGROUND: Testosterone is a hormone essential to the development of male growth and masculine characteristics. Testosterone products are FDA-approved only for use in men who lack or have low testosterone levels in conjunction with an associated medical condition.

RECOMMENDATION: At this time, FDA has not concluded that FDA-approved testosterone treatment increases the risk of stroke, heart attack, or death. Patients should not stop taking prescribed testosterone products without first discussing any questions or concerns with their health care professionals. Health care professionals should consider whether the benefits of FDA-approved testosterone treatment is likely to exceed the potential risks of treatment. The prescribing information in the drug labels of FDA-approved testosterone products should be followed.

i just posted about one of the studies (from PLoS) last week, the other one being a recent one in JAMA (see doi:10.1001/jama.2013.280386). in the jama study they looked retrospectively of 8700 men in the VA with low testosterone levels (<300 ng/dL) who had coronary angiography in the years 2005-2011. findings:

–1223 of these men started testosterone an average of 531 days after cath (20% with prior hx MI, 50% with diabetes, 80% with known CAD). those on testosterone tended to be younger and have fewer comorbidities. the testosterone levels were also lower (176) in those put on testosterone therapy vs those not (207)

–after 3 years, those who were on testosterone: 25.7% had an event (all-cause mortality, MI, or stroke) vs 19.9% not on testosterone, finding a 29% increase in events in those on testosterone. no relation between those with or without coronary artery disease. (unlike some prior studies, the increase in events did not happen soon after starting testosterone, but after 3 years). no diff in the VA group with baseline cardiovasc risk factors in those who had/did not have events.

speculated mechanisms for testosterone and cardiovasc disease: testosterone increases platelet thromboxane A2 receptor density and platelet aggregation; dihydrotestosterone (a metabolite) increases smooth muscle proliferation and expression of vascular cell adhesion molecule 1; testosterone worsens sleep disordered breathing in those with OSA. (all of these are potentially directly assoc with cardiovasc dz)

so, nothing definitive, and the FDA alert is an alert, albeit a lukewarm one. but my sense is that there are enough data to reinforce being wary, at least only prescribing testosterone if there is a clear clinical indication, and letting patients know that there is a potential link.

geoff

Primary Care Corner with Geoff Modest MD: BP goal in kidney disease

23 Oct, 13 | by EBM

there seems to be several recent recommendations suggesting higher BP goals than JNC7.  the american diabetes assn set the new goal at 140/80, given the results of the ACCORD trial. the european society of cardiology came out with guidelines which i sent out before (see  doi:10.1093/eurheartj/eht151 ), which in brief set their goals as:

–systolic bp < 140 in patients with low-to-mod cardiovasc risk and those with diabetes (best data) as well as those with hx stroke/TIA, coronary art dz, diabetic or nondiabetic chronic kidney dz, without differentiating the presence of proteinuria (less good data)

–in elderly <80yo with SBP >160, decrease SBP to 140-150 range

–in fit elderly <80, SBP <140 should be considered (though i would add to check orthostatics in elderly esp with the lower goal, as well as checking symptoms). in fragile elderly, individualize goal

–in elderly >80yo and SBP>160, goal of 140-150 range

–DBP <90 in all, <85 in diabetics but 80-85 is safe

 

the quality of date for these recommendations is quite variable, as they note.

 

specifically for kidney disease,  KDIGO (kidney disease– improving global outcomes) came out with guidelines in 2012 suggesting goal of 140/90 in patients without proteinuria and 130/80 if either micro or macroalbumenuria present. in this light, there was a recent retrospective analysis in the annals looking at massive VA database of patients with chronic kidney dz and all-cause mortality, stratified by achieved systolic and diastolic blood pressures (see Ann Intern Med. 2013;159(4):233-242. doi:10.7326/0003-4819-159-4-201308200-00004).  650K almost all men stratified into 96 different blood pressure groupings (from <80/40 to >210/110) in 10mmHg increments.  they used eGFR calculations using the Chronic Kidney Disease Epidemiology Collaboration equation. findings:

–average age 73.8, 2.7% female, mean BMI 29

–pretty sick population with 43% having CAD, 43% diabetes,15% cerebrovasc dz, 15% CHF and mean eGFR 50.  62% CKD stage 3A (eGFR 45-59) or 3B (30-45). not much albumenuria, with microalb/creat ratio median of 40.

–mean baseline SBP 135 and DBP 72 (though not explicitly stated, this is pretty undoubtedly the mean baseline on lots of meds)

–240K deaths recorded

–the best mortality outcomes were with syst bp 140-160 and diast bp 80-90. no diff in group with proteinuria (though not much proteinuria overall) – see graph in article

–“U”-shaped curve, with mortality pretty similar if DBP 60 or 100. SBP 120 or 180.

–so, their conclusion: optimal bp in the 130-159/70-89 range. and “it may not be advantageous to achieve ideal SBP at the expense of lower-than-ideal DBP in adults with CKD”

 

impressive with huge numbers of people and lots of deaths, so able to stratify by many blood pressure groupings. but:

–this is observational retrospective study, without even clean information on blood pressures prior to being put on meds

–eGFR is not so accurate, esp in older group

–the issue of diastolic hypotension is pretty murky. the higher mortality in those with lower DBP may well represent the group of patients with isolated systolic hypertension initially with a wide pulse pressure (several studies show that pts with high pulse pressures have much higher mortality, presumably related to the fact that they have stiff arteries from atherosclerotic dz). even the intervention studies in the elderly with isolated systolic hypertension (eg SHEP) are not so easy to interpret, since those with initially low DBP do worse in both the intervention and placebo groups!!– is it because of the low DBP itself (reflecting more advanced atherosclerotic disease and arterial stiffness) or because of lowering the DBP too much (and decreasing coronary blood flow in patients at high risk of CAD). given these concerns, the SHEP trial concluded that there may be increased mortality with DBP<60 (but as noted, this is true in the untreated group as well). in fact, the achieved bp in SHEP was 143/68, with significant decrease in stroke and close to significant decrease in cardiovasc dz.  other studies suggest increased risk of stroke if DBP<65. my caveat here is that most patients with isolated systolic blood pressure put on antihypertensives have much more significant lowering of their systolic than diastolic pressures (and the goal of the hypertension in elderly of achieving SBP in the 140-150 range is usually attained without lowering DBP too much). the decrease in clinical events by lowering the systolic blood pressure at least to the 140-150 range is consistent throughout the studies, but we should make sure that we treat the individual patient (watching for signs of decreased coronary perfusion, decreased mental functioning, orthostatic hypotension, etc) and use that as the ultimate guide. there are no data that i know of for treating patients with baseline high systolic pressures and very low diastolics, such as 180/55, though i would do so cautiously. (if any of you know of studies, please let me know and i will send it around).

 

so, this study is interesting and seemed to get a lot of play, but really does not add that much insight.  i am mostly mentioning it to bring up the complicated issue above.

 

geoff

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