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

BMJ Evidence-Based Medicine – Join the Editorial Board

21 Jun, 17 | by Kelly Horwood, BMJ

We are changing the way the journal looks, feels, and operates. In order to do this well, we would very much like your help in delivering relevant, trustworthy, and impactful evidence-based content to as wide a range of frontline health professionals as possible.


We are planning to publish original evidence-based research, insights and opinions on what matters for health care, whilst focusing on the tools, methods, and concepts that are basic and central to practising evidence-based medicine. Our plan includes exciting developments in the types of articles that debate the uncertainties and controversies in evidence, and the research methods that educate and inform practice.  Our new clinical spotlight section will strive to disseminate relevant research: saving you time and improving your practice.


We are looking for health professionals and EBM researchers who are interested, and motivated, to enhance the practice and understanding of evidence-based healthcare.

We want BMJ Evidence-Based Medicine to be the go-to journal for solving the evidence translational problems that currently prevents uptake of evidence into practice.


If you would like to be part of the debate then we would like you to consider becoming an Editorial Board member


EDITORIAL BOARD members will have the opportunity to:

  • Author commentaries on the latest research that matters;
  • Contribute to series articles that offer relevant EBM insight;
  • Contribute to blog articles on the dedicated BMJ EBM site
  • Receive reduced rates to EvidenceLive and upcoming events
  • Receive regular evidence updates.
  • Contribute to peer review;
  • Receive online journal access,
  • Open access submission fees;


If you want to become a flagbearer for the EBM community then we’d very much like to hear from you. To apply please fill out the form here:


Professor Carl Heneghan

Editor in Chief, BMJ Evidence-Based Medicine

Primary Care Corner with Geoffrey Modest MD: Decreasing antibiotic resistance by stewardship program

21 Jun, 17 | by gmodest

by Dr Geoffrey Modest

A recent systematic review and meta-analysis found that hospital antibiotic stewardship programs significantly reduced the incidence of infections and colonization with antibiotic-resistant bacteria and C difficile infections (see S1473-3099(17)30344-4).



–32 studies in a meta-analysis with 9,056,241 in-hospital patient days and 159 estimates of incidence ratios (IRs) of target infections

–studies from 20 countries: US (5 studies), Japan (4), Germany (3), France (3). Most common design was before-after analyses

–most frequent stewardship  interventions:  audits in 59%, implementation of restrictive policies in 47%, co-implementation of stewardship programs with infection control measures (mostly hand hygiene) in 25%



–antibiotic stewardship programs reduced the incidence of and colonization with:

— multi-drug resistant gram-negative bacteria: 51% reduction; IR 0.49 (0.35-0.68), p<0.0001

–specifically, a 43% reduction in carbapenem resistance; IR 0.57 (0.40-0.81), p=0.0018; this was especially true for carbapenem-resistant Acinetobacter Baumannii, 56% reduction, and P aeruginosa, 29% reduction

— extended-spectrum b-lactamase-producing gram-negative bacteria: 48% reduction; IR 0.52 (0.27-0.98), p=0.04

— methicillin-resistant staph aureus (MRSA): 37% reduction; IR 0.63 (0.45-0.88), p=0.007

— c diff infections: 32% reduction; IR 0.68 (0.53-0.88), p=0.003

–antibiotic stewardship programs were more effective when implemented with hand-hygiene interventions: 66% reduction; IR 0.34 (0.21-0.54), p<0.001; in those without hand-hygiene interventions, there was a 17% reduction; IR 0.83 (0.71-0.98), p=0.03

–no difference in vancomycin-resistant enterococci, or quinolone-resistant and aminoglycoside-resistant gram-negative bacteria

–in terms of sites in the hospital:

–59% reductions in hematology-oncology departments

–23% reduction in ICUs

–22% reduction in medical departments

–in terms of types of stewardship interventions:

–antibiotic cycling: 51% reduction in antibiotic resistance; IR 0.49, p=0.003

–audits and feedback: 34% reduction; IR 0.66 p=0.0006

–antibiotic restriction: 23% reduction; IR 0.77, p=0.0003

–interventions generally became more effective over time: 10% reduction for 1980-2000; 21% reduction for 2001-5; 32% reduction for 2006-13



–various types of antibiotic stewardship programs have had success in other studies, including use of empirical therapy as suggested in treatment guidelines, de-escalation of therapy to more targeted/narrower spectrum antibiotics, switching from IV to po antibiotics, restriction of antibiotics, and bedside consultation

–a review of their table of the studies involved in the above meta-analysis shows that the various interventions in the studies pretty consistently decreased some infections

–it is noteworthy to reinforce the pretty striking effects of hand-hygiene in preventing bacterial resistance, including both MRSA and antibiotic-resistant gram-negatives. the hand-hygiene strategies used varied from: education, to replacement of handwashing with alcohol-based hand rubbing, to substitution of hand-directed soap dispensers with elbow-directed soap dispensers.

–other studies have shown decreases in mortality and antibiotic costs through stewardship programs.

–and, other studies have shown that using guideline-based empirical therapy was associated with a 56% reduction in mortality and using de-escalation strategies led to a 35% mortality reduction

–one key feature in the meta-analysis  probably was the high compliance/involvement of physicians, educational feedback, and close relationships between physicians and the stewardship team (the authors did not comment on non-physicians).

–this meta-analysis was limited by many issues, including study heterogeneity, difficulty in culling out single interventions in more detail, the potential for secular trends/differences over time, the inability to target the different specific hand-hygiene measures, and significant differences in individual study quality (2 studies were high quality, 26 moderate, 4 low)

so, I bring up this article for a few reasons, though it does not directly apply to outpatient practice (other than that we get the output of resistant bacterial strains as they migrate from the hospital to the community):

–there may be some lessons we could apply directly to primary care, eg:

–using more guideline-based antibiotic therapies

–being more diligent specifically in limiting antibiotic use for evidently viral illnesses (a large % of antibiotic use, as per blogs below)

–using more targeted and narrower-spectrum antibiotics (eg, avoiding cipro for UTIs)

​–spending more time discussing the potential consequences of antibiotic overuse with patient

​–making sure that patients understand the importance of taking complete courses of antibiotics when indicated

–making sure we optimize hand hygiene

​–and perhaps implementing a stewardship plan: the easiest plan, with pretty strong data above, would likely be simply audit and feedback to providers on a regular basis

–and, i think it is important for us to understand the gravity of the antibiotic-resistance issue and the likely development of increasing numbers of untreatable infections, and not just the weird ones that hang out in hospitals, but even just e. coli or n. gonorrheae (eg see blog  )

for blogs going into more detail on some of these issues:

(see here for the slew of blogs on antimicrobial resistance,  and see below for some more specific ones)

— this blog found that true penicillin allergy is really uncommon, and that we may therefore be using broad-spectrum antibiotics more often than necessary

this one reviewed ​the latest WHO categorization of resistant bacteria of international concern, and also has a general assessment of the lack of drug company investments in new antibiotics, and that the major use of antibiotics and development of resistance is actually from industrial non-therapeutic use of antibiotics in livestock. there are also links to other blogs on the effects of antibiotics on the microbiome and the significant prescribing of antibiotics for human  nonbacterial conditions (eg URIs, acute rhinosinusitis, pharyngitis, bronchitis)

and this one reviewed the WHO guidelines on treating sexually-transmitted infections in this era of antibiotic resistance

Primary Care Corner with Geoffrey Modest MD: ?Add PPI to aspirin in elderly

20 Jun, 17 | by gmodest

by Dr Geoffrey Modest

A prospective population-based cohort study of patients with vascular disease and on antiplatelet therapy (mainly low-dose aspirin) found a dramatic increase in the risk of bleeds in those over 75 years old, raising the question of whether we should be using proton-pump inhibitor (PPI) prophylaxis (see



— 3166 patients with vascular disease (defined as a 1st TIA, ischemic stroke, or MI and placed on antiplatelet therapy) in the Oxford Vascular Study from 2002 to 2012 were followed until 2013. 50% of the cohort were greater than 75 years old

— for the subgroup of patients < 75 years old:

— mean age 61, 65% male, 32% ischemic stroke/30% TIA/21% NSTEMI/17% STEMI, 97% on aspirin/3% nonaspirin antiplatelet therapy

— for those > 75 years old:

— mean age 83, 43% male, 42% ischemic stroke/27% TIA/23% NSTEMI/8% STEMI, 95% on aspirin/5% nonaspirin antiplatelet therapy

— the predominant aspirin formulation was 75 mg enteric-coated aspirin



— there were 405 1st bleeding events (187 major bleeds) during 13,509 patient years of follow-up in the cohort, at an average annual risk of 3.36%:

— 218 gastrointestinal

— 45 intracranial

— 142 other

— risk of non-major bleeding was unrelated to age, but major bleeding increased steeply with age, particularly in those > 75 years old, with no increase with age in patients < 70

— for those >75 yo vs <75 yo:

— major bleeding overall, HR 3.10 (2.27-4.24), p<0.0001 [ie, more than 3-fold the risk]

— fatal bleeds, HR 5.53 (2.65-11.54), p<0.0001

— major upper GI bleeds, HR 4.13 (2.60-6.57), p<0.0001; and fatal GI bleeds, HR 10.26 (4.37-24.13), p<0.0001.

— The annual risk of major bleeds increased steeply after age 70, reaching 4.1% at age 85 or older, with a similar pattern for both life-threatening and fatal bleeds. Those > 75 yo had more severe bleeds in those younger, p<0.0001. The outcome for nonfatal bleeds was also worse in the older group.

— Also, the proportion of those who survived extracranial bleeds which resulted in new or a sustained increase in disability increased with age, OR 12.8 (4.5-36.6), p<0.0001, comparing those > 75 vs <75 yo, especially in those with upper GI bleeds

— this analysis was similar if those on dual antiplatelet treatment (e.g. aspirin plus clopidogrel) were excluded

— the association of major bleeding with age were independent of sex, history of vascular disease, vascular risk factors, and history of peptic ulcer disease

— the absolute risks of major bleeding vs ischemic events increased with age. In the younger cohort this ratio was similar to those in prior aspirin trials. But the ratio increased from 0.19 in those younger than 75, to 0.32 in those 75 to 84, to 0.46 in those older than 85 [ie, the risk of major bleeds estimated to be attributable to antiplatelet treatment was approaching that of prevented ischemic events].

— The estimated number needed to treat (NNT) with routine PPIs to prevent one disabling or fatal upper GI bleed over 5 years would be 338 for individuals < 65 years old, but only 25 for individuals > 85 years old. The NNT to prevent one major upper GI bleed at 5 years was 80 for patients younger than 65, 75 for patients 65-74, 23 for patients 75-84 and 21 for patients greater than 85.



— given the high prevalence of vascular disease in people over 75, 40-66% of individuals in the US and Europe take aspirin or other antiplatelet drug for secondary prevention of vascular disease (and this does not include primary prevention use of aspirin!!!!). Guidelines in general do not recommend taking PPIs regularly, though a meta-analysis of randomized PPI trials vs placebo in patients on antiplatelet drugs, mostly aspirin, found a 74% reduction in upper GI bleeding (this was the number they used in estimating the preventive efficacy of PPIs above).

— The general basis for recommendations for use of antiplatelet agents is largely based on trials done in people < 75 years old (the mean age was 63, and most were < 75 yo).

— As a perspective in this study, PPIs would presumably only prevent upper GI  bleeds, though 60% of all bleeds and 48% of major bleeds in the above study were non-upper GI bleeds

— assumptions in the above study, as noted by the authors, are that the efficacy of PPIs would be similar for the prevention of any bleed vs major bleed, similar at different ages, and remain consistent over time.

— I am very concerned about the role of H Pylori infections in predisposing patients to upper GI bleeds when they are on NSAIDs.  An article in 1997 changed my practice to test and treat people prior to starting regular NSAID therapy (see Chan FKL Lancet 1997; 350: 975, which found that patients about to begin longterm NSAID therapy, had endoscopy, and those found to have asymptomatic H Pylori infection were then were randomized to either naproxen 750mg/d vs triple H Pylori therapy and then naproxen 750 mg/d, finding that on repeat endosopy 8 weeks later, 26% had ulcers in the naproxen only group whereas 3% had them after successful H Pylori treatment). Subsequently the 2008 Expert Consensus document by the Am Heart Assn and Am College of Gastroenterology recommended: “Testing for and eradicating H. pylori in patients with a history of ulcer disease is recommended before starting chronic antiplatelet therapy.”  (see JACC 2008; 52: 1502). And another more recent article finding that those on low-dose aspirin who had H Pylori infection which had  been eradicated had recurrent GI bleeds at the level of  average-risk patients (see Chan FKL. GASTROENTEROLOGY 2013;144:528–535​)


So, as per many prior blogs, I am concerned with long-term, wide-scale use of PPIs, in terms of significant adverse effects, as well as their profound effects on the microbiome. Given the rather compelling data from this study, it would be really great to have a randomized controlled trial in patients for both primary and secondary atherosclerotic disease prevention with aspirin, comparing PPI vs H2 blocker (fewer adverse longterm effects than PPIs) vs placebo, looking at both major GI bleeds as well as comparing them to the incidence of thromboembolic events. And, as per above comment, it would be great to either exclude those who were H Pylori positive, or treat them prior to aspirin therapy. My own practice in general, as mentioned in prior blogs, is to test and treat H Pylori infections, given their profound frequency in my patient population and the association with stomach cancer (I have had several older patients die from stomach cancer, which might have been prevented if H Pylori were diagnosed and treated earlier: eg see here ). Besides, it is always a tad unnerving when we have to prescribe a medication (which is not entirely benign) to counteract the effects of another medication.​ But, based on the study, it does seem reasonable to consider a PPI in those greater than 75 years old and on aspirin therapy.

Primary Care Corner with Geoffrey Modest MD: Canagliflozin decreases macrovasc disease???

19 Jun, 17 | by gmodest

by Dr Geoffrey Modest

Another study assessed the role of a sodium-glucose co-transporter 2 inhibitor, this time canagliflozin, and its effects on cardiovascular and renal outcomes in patients with type II diabetes (see DOI: 10.1056/NEJMoa1611925 ). A drug company supported study.


— this report involved 2 trials with 10,142 participants with type II diabetes and high cardiovascular risk, randomized to canagliflozin vs placebo, followed a mean of 188.2 weeks. All had HgbA1c between 7 and 10.5%, had a history of symptomatic atherosclerotic cardiovascular disease, or were at least 50 years old and had 2 or more risk factors (which included diabetes of at least 10 years duration). Patients were from 667 centers in 30 countries. 96% participants completed the trial.

— mean age 63, 36% women, mean duration of diabetes 13.5 years, 78% white/13% Asian/3% black, 18% current smoker, 90% history of hypertension/14% heart failure/56% CAD/19% cerebrovascular disease/21% peripheral vascular disease (66% overall had a history of cardiovascular disease), 2% amputation, BMI 32, blood pressure 137/78, A1c 8.2%, 70% with normal albuminuria/22% microalbuminuria/8% macroalbuminuria

— baseline diabetes therapy: 50% insulin/43% sulfonylurea/77% metformin/4% GLP-1 inhibitors/12% DPP-4 inhibitors

— the 2 studies overall were similar, though in one study patients received canagliflozin 300 mg vs canagliflozin 100 mg vs placebo, the other canagliflozin 100 mg with an optional increase to 300 mg vs placebo

— primary outcome: composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.


— for those on canagliflozin (vs placebo):

— the use of other antihyperglycemic agents was 9.3% lower.

— HgbA1c -0.58%, BMI -1.60, blood pressure -4/-1 mmHg (p<0.001 for all comparisons). LDL and HDL were higher with canagliflozin, though the ratio was similar

— the primary outcome was lower with canagliflozin, 26.9 vs 31.5 per 1000 patient-years, a 14% decrease with HR 0.86 (0.75-0.97), p<0.001 for noninferiority, p=0.02 for superiority

— these outcomes were broadly consistent across prespecified subgroups, though those on baseline diuretics did significantly better (34%, HR 0.66, p<0.001) and those not on diuretics had a trend to doing worse

— the pre-specified secondary renal outcomes (progression of proteinuria with >30% increase and a change from either normoalbuminuria to microalbuminuria or from micro to macroalbuminuria) overall were not statistically significant, however there seemed to be a possible benefit of canagliflozin in terms of progression of albuminuria, HR 0.73 (0.67-9): regression of albuminuria with HR 0.60, as well as for the composite outcome of the sustained 40% reduction in eGFR plus need to renal replacement therapy plus death renal causes, HR 0.60 (0.47-0.77)

— adverse reactions: overall 7% less common in those on canagliflozin, but of note there were twice the number of amputations, 6.3 vs 3.4 participants per 1000 patient-years, HR 1.97 (1.41-2.75), in 71% at the level of the toe or metatarsal, and especially those with a prior history of amputation or peripheral vascular; fracture risk was also higher, occurring in 15.4 vs 11.9 per thousand patient years, p=0.02; and, as per prior studies of SGLT-2 inhibitors, there were more cases of osmotic diuresis, volume depletion, and mycotic genital infections in women in those on canagliflozin, though not urinary tract infections.


–reviewing their graphs, there were several major differences in the groups of canagliflozin:

–the HgbA1c was significantly lower, was down to 7.5 by week 26, slowly increased to 7.8 by week 150, and ultimately to around 8.0 by week 300. placebo was pretty consistently around 8.2-8.3

–mean weight decreased to 87kg with canagliflozin but remained around 89-90 kg with placebo

–blood pressure was 131/74 with canagliflozin but 136/76 with placebo

–the graphs for cardiovascular events:

–deaths from cardiovascular causes, nonfatal MI or nonfatal stroke: curves separated at around 52 weeks of treatment, then paralleled after 104 weeks

–death from cardiovascular causes: nonsignficant. curves initially separated favoring canagliflozin then merged together after 260 weeks

–nonfatal stroke: also nonsignificant and similar to cardiovascular deaths

–nonfatal MI: also nonsignificant, though did separate after 104 weeks and remained separate

–other outcomes:

–death from any cause: nonsignificant

–heart failure hospitalizations: signficantly better with canagliflozin, HR 0.67 (0.52-0.87) with separation early, by 26 weeks

–renal: clear benefit beginning by 78-104 weeks for progression of albuminuria and the composite of 40% reduction in eGFR, requirement for renal replacement therapy or death from renal causes [though it seems that lowering A1c itself seems to be renoprotective from many studies, and those on canagliflozin had lower A1c levels!!!]

–it is unclear how much of the benefit from canagliflozin is related to the protective effects of this drug, given the substantial differences in HgbA1c, weight and blood pressure. the change in renal outcomes would largely be expected from these differences, as per many prior studies (unfortunately the authors did not compute the expected effect attributable to these A1c changes, but they would certainly go a long way to explaining the differences). and the differences in macrovascular outcomes (their primary outcomes) similarly may be explained largely by these differences in the constellation of better A1c, blood pressure, and weight loss in the canagliflozin group

–also, there is no comment in the article or the supplementary materials about the differences in treatment in the placebo group: they comment that the use of other antihyperglycemic agents was 9.3% lower with canagliflozin but do not comment on what additional meds were used in the placebo group. was it potentially harmful agents (eg rosiglitazone)? more sulfonylureas (which do not seem to help and may hurt cardiovascular outcomes)? more GLP-1 agonists (which would make their results more impressive, given that these do seem to be cardioprotective)

–and it is concerning about the increase in both amputations and fractures with canagliflozin.  Bones do not seem to fare well.

–also, see prior blogs on another SGLT2 inhibitor empaglifozin, where I found the study also quite flawed. And, it is important to remember, these SGLT-2 trials were both drug-company sponsored. and, it would not be so surprising to find that these trials are designed to achieve the results that the drug companies would like….  for example, they could have designed this canagliflozin trial so that the A1c levels in both the drug and placebo groups matched!!!! we could then sort out how much of the problem was related to the A1c differences and how much to the drugs used (they would also need to describe what drugs were used….)

so, how to proceed?

–these SGLT2 inhibitors possibly do decrease cardiovascular events (at least this has been shown for 2 different ones, though I think both studies are pretty flawed, as above). it should be kept in mind that  the FDA does warn about ketoacidosis and severe urosepsis with these drugs (see​ ), and there are reports of acute kidney injury as well as a pretty high incidence of genital mycotic infections.​

–i personally am still more impressed with the studies on GLP-1 agonists. they seem to be cardioprotective, I am consistently shocked at how well they work in lowering A1c levels, and they are quite targeted (the most common problem I have seen is GI, though a few cases of itchy rash/apparent allergy to one of them, though subsequent use of another was well-tolerated). And, they have been around for a long time ( exenitide has been used in Europe for >10 years).

Primary Care Corner with Geoffrey Modest MD: Does glucose home-monitoring help???

15 Jun, 17 | by gmodest

by Dr Geoffrey Modest

A recent article added to some prior literature suggesting that glucose self-monitoring is not so effective in type II diabetics not on insulin (see doi:10.1001/jamainternmed.2017.1233 ).



— 450 patients were enrolled in this pragmatic, open label randomized trial, of which 418 completed the final visit. All were in established primary-care relationships in North Carolina, had a hemoglobin A1c between 6.5% and 9.5%, and were randomized into one of 3 wings: no self-monitoring of blood glucose (SMBG), once daily SMBG, or once daily SMBG with enhanced patient feedback including automatic tailored messages delivered via the meter that were intended to educate and motivate patients with an algorithm that took into account the blood glucose value, time of day, and relationship to food intake.

— Median age 61, 46% male, 33% black/62% white, 60% high school or some college/34% college or higher, BMI 33, 38% with low health literacy, mean duration of diabetes 6 years, 3 comorbidities, current use of SMBG 75%, diabetic meds were metformin 80%/sulfonylurea 36%/TZD 5%/DPP-4 inhibitor 9%

— baseline hemoglobin A1c 7.6%

— Primary outcomes were: hemoglobin A1c level and health-related quality of life at 52 weeks



— testing adherence declined in both of the SMBG groups (though more so in the group with messaging!): daily testing overall going from around 95% initially to 60% at 12 months; for the no SMBG group, 24% tested at least a few times/month and only 9% tested less than once/month

— follow-up hemoglobin A1c’s were:

— no SMBG: baseline 7.52, follow-up 7.55

— SMBG, no messaging: 7.55, follow-up 7.49

— SMBG, with messaging: 7.61, follow-up 7.51

— there was no significant difference between hemoglobin A1c levels across all 3 groups (p=0.74), with estimated adjusted mean A1c difference:

— SMBG with messaging vs no SMBG: -0.09% (-0.31% to 0.14%)

— SMBG vs no SMBG: -0.05% (-0.27% to 0.17%) [as a reference here, a 0.5% difference (10x this difference) is considered to be clinically significant]

— there was no significant difference in health-related quality of life.

— there was no significant difference in adverse events including frequency of hypoglycemia, healthcare utilization, or insulin initiation

— there was no significant difference in almost all of the secondary outcomes, including the diabetes empowerment scale, diabetes treatment satisfaction scale, and the communication assessment tool.



— prior studies have been mixed on the role of SMBG in non-insulin using patients, though more than 75% do regular SMBG

–there were several limitations of the study, many noted by the authors: this study really reflected whether it was useful to continue SMBG, since most patients had already been doing so (ie, not whether initiating SMBG mattered for those not doing so); and there was a selection bias in that all participants were willing to be randomized into a group not using SMBG. Also, about 40% in the daily testing group stopped doing so (though not sure what that means, since they don’t say whether this is decreasing testing to 6x/week or 1x/month…)


the bottom line here: I think that it can be useful to have some home-based glucose monitoring for a few reasons, including fuller details on blood sugar swings during the day, with the potential:

–to elucidate to the patient what tends to make the blood sugar go up or down (eg, it was the last meal with rice which raised the blood sugar, or doing exercise lowered it….). This real-time feedback can well inform the patient on what lifestyle issues either improve or worsen blood sugars, leading to appropriate tweaking of them. in my experience, after suggesting to patients that they monitor their blood sugar 1-2 hours after a meal, that the patients are better able to identify triggers to higher blood sugars. and, sometimes, they are able to modify their diets

–to adjust medications to cover these higher or lower levels, if lifestyle changes would not help

–but I think that the main message from this study, as well as prior ones, is that our primary focus as clinicians should not be primarily to strongly encourage/berate patients about checking their blood sugars at home, but to focus on lifestyle changes and medication adherence. as I have mentioned in prior blogs, I think that diabetes treatment is one of the hardest issues I deal with in clinical medicine. it brings to the fore the multitude of issues and obstacles to treating this complicated disease, including the difficulty in eating well/exercising (access to good foods, ability/time to cook healthy meals, access to good exercise venues including safe streets to walk on/time to do so in our overprogrammed lives, and generally competing with a culture and with persuasive advertising to eat poorly, sit at home watching TV, work 2 jobs to survive, etc, which are perhaps the most important underpinnings for our diabetes epidemic.)  these are the hard issues for our patients, and i think the primary ones to focus on. And really focusing on  the importance of SMBG​ can actually dilute/divert this pivotal message of the importance of lifestyle changes.

Primary Care Corner with Geoffrey Modest MD: Monitor BP effects by ABPM?? SPRINT trial

14 Jun, 17 | by gmodest

by Dr Geoffrey Modest

The SPRINT hypertension study assessed different blood pressure targets on clinical outcomes, finding the lower the pressure, the better. A subsequent ambulatory blood pressure substudy of SPRINT looked at the relationship between the achieved ambulatory versus clinic-based blood pressures (see DOI: 10.1161/HYPERTENSIONAHA.116.08076.)



— the SPRINT study randomized patients to aggressive vs less aggressive blood pressure control, achieving a systolic of 121 mmHg versus 136 mmHg, respectively. The primary clinical outcome (MI, acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes) was 25% less frequent in those having tighter control. (see here for details)

— in the current ancillary study on ambulatory blood pressure monitoring (ABPM), they performed ABPM at the 27-month study visit in a subgroup of 897 SPRINT participants

— for this ancillary study, mean age 71, 29% female, 66% white/28% black/3% Hispanic, BMI 30, 46% never smoker, 38% nondrinker/26% moderate drinker/10% heavy drinker, 21% CVD at baseline, eGFR 67, LDL 108/HDL 53/triglycerides 100, number of antihypertensive meds at the 27 month visit = 2.9 with 78% on ACE-I/ARB, 60% on calcium-blocker, 76% diuretics, 40% beta-blocker

— at the 27 month clinic visit:

— clinic-based systolic 120 mmHg

— nighttime ABPM systolic 116 mmHg

— daytime ABPM systolic 127 mmHg

— 24-hour ABPM systolic 123 mmHg



— for those on intensive therapy:

— decreased clinic-based systolic BP by 16.0 mmHg

— decreased nighttime systolic BP by 9.6 mmHg

— decreased daytime systolic BP by 12.3 mmHg

— decreased 24 hour systolic BP by 11.2 mmHg

–there was poor agreement in participants between clinic-based systolic BP and daytime systolic ABPM



— the role of ABPM continues to evolve, with studies documenting its strong association with cardiovascular and renal clinical events. Data for the last decade or so have pretty convincingly shown that ambulatory blood pressure is more predictive of cardiovascular events than clinic-based blood pressure, leading ultimately to the USPSTF promoting ABPM in their most recent guidelines (see , and my blog on it )

— One issue with the SPRINT study has been the rather eclectic way they measured the clinic-based blood pressure, reducing its generalizability to our clinical practice (see here which comments on their approach). One advantage of ABPM is that it is an equalizer, where the target blood pressure is pretty reproducible from one ambulatory monitor to another, and does not depend on measuring blood pressure in a clinic setting based on a very structured and likely unreproducible methodology (even without the strict regimen in SPRINT, how many of us check blood pressures after the patient has been resting quietly in a dark room for 5 minutes??)

— Unfortunately, there are relatively limited data on ambulatory blood pressure monitoring as a means to follow up patients with hypertension on treatment. There are some studies which do suggest that it is useful: a Brazilian study (see Salles GF. AchInternMed.2008;168:2340), which looked prospectively at 556 patients with resistant hypertension for 4.8 years, found that ambulatory blood pressure monitoring predicted clinical endpoints, and that clinic-based blood pressure did not. And in fact 40% of those with clinic-based “resistant hypertension” did not even have hypertension on ABPM (adding to the studies finding that even “appropriately” documented clinic-based blood pressure is really a poor predictor, and sometimes pretty irrelevant, especially as compared to ABPM: see here for an array of blogs on this, including the quite impressively documented and  prescient recommendations from NICE in the UK in their 2011 guidelines


So, this study adds further to the imperative to use ABPM, especially in those patients with blood pressures near the goal (ie, the patient with 200/110 mmHg can just be treated….). And, though much less well documented (but easier for many) to use home-based measurements. This study helps reinforce the utility of ABPM in those being treated (again, I would assume, especially so if the achieved blood pressure is pretty close to goal: eg the Brazilian study above on refractory hypertension finding no benefit for clinic-based blood pressures did not have granular data, but I would assume that those way above goal continued to need adjustment of their meds independent of the ABPM reading, and those near goal were more likely to be in-range with ABPM even though the clinic-based pressures were high.


And, again, this study does raise a pretty basic concern: how often do our accepted clinical approaches (in this case clinic-based blood pressures) not really reflect the reality of actual clinical outcomes, yet are passed down over time and accepted? Which all reinforces the importance of constantly challenging our existing models. Another example which I have commented on recently is with A1c as a surrogate marker for diabetes and macrovascular complications, suggesting that the issue may be less with the A1c achieved than with the medications we choose to put patients on, and it is probably most important to choose ones that have documented cardioprotection (see here )

Primary Care Corner with Geoffrey Modest MD: Opioidsx3, and drug company shenanigans to boot

13 Jun, 17 | by gmodest

by Dr Geoffrey Modest

This is a triple blog on a few recent developments in the opioid world.

  1. The FDA just announced that they are seeking removal of Opana ER, long-acting oxymorphone hydrochloride, “based on its concern that the benefits of the drug may no longer outweigh its risks”. [And certainly many of us thought it was ridiculous to approve it from the start. We have all been through this scene before with oxycontin…].  The FDA found (not so surprisingly) that there was a shift in its route of abuse from nasal to injection after the product was reformulated (it had been reformulated “to make it more resistant to physical and chemical manipulation for abuse by snorting or injecting”….).   This increase in injection use has been associated with outbreaks of HIV, hepatitis C and some cases of thrombotic microangiopathy. And if the company refuses to remove the drug from the market voluntarily, the FDA will formally require its removal by withdrawing its approval. (see see​  )


  1. the NY Times had an article on 6/10/17 highlighting the increasing role of the internet in buying opiates (they highlight fentanyl), using the “dark web sites” whereby the drugs can be bought anonymously using a special browser, buying the drugs with virtual (untrackable) currencies like bitcoin. A couple of 13-year olds were also highlighted, who had gotten the drugs this way. The reporter commented that “the leading dark net market, AlphaBay, had >21,000 listing for opioids and >4100 for fentanyl and similar drugs from dozens of dealers large and small”. see ​


  1. another NY Times article on vivitrol (extended-release injectable naltrexone), suggested lots of drug company shenanigans (see ). Basically,

–it is being marketed very aggressively (billboards, buses, subways)

–there are no head-to-head studies with buprenorphine to show its relative effectiveness (and the company seems to not have the least interest in doing those studies)

–it is more expensive than suboxone (eg, 3-fold) [though I should add that naltrexone is an old generic drug, used in the past with some limited success for alcohol dependence, reformulated as an extended release injection but with a dramatic increase in cost]

​–the studies supporting its use are weak: eg a Russian study of 250 patients, where 1/2 failed to stay abstinent for 6 months, though it was better than placebo. And this study and another had very high dropout rates (50% range)

–the new head of Health and Human services, tom price, “ignored widely accepted science” and is praising vivitrol as “the future of opioid treatment”, since the other meds (methadone and buprenorphine​, which work really well) simply “substitute for illicit drugs”

–not shockingly, the drug company Alkermes has been spending millions of dollars in contributions to officials involved in dealing with the opioid crisis (primarily spending money on them vs the usual: doctors and medical associations). it spend $19 million on federal lobbying since the drug was approved in 2010, and $222,521 in political contributions to congress last year

–the company even provides free shots to inmates, with the hope that they will continue to get them when out of jail (??getting people hooked on vivitrol??). And, this has worked pretty well: sales of $58.5M in first quarter in 2017, up 33%, 1/2 from Medicaid, and with huge expansion of Medicaid coverage for it (was 15 programs in 2012 in 9 states, now 450 programs in 39 states).

–and, this promotion of vivitrol may be very harmful: in the setting of the ongoing opioid crisis, and trump’s plan to spend $1 billion for new addiction and treatment programs over the next 2 years, trump and price could really undercut very effective treatments for a largely untested one that appeals more to them, perhaps both financially and ideologically (ie, a lock-step response of “just say no to opioids” without looking at the science or studies)….



–it is consistently scary how our system works, in this case likely from greasing the palms of the officials. And it really could lead to vivitrol leapfrogging above buprenorphine or methadone in our political climate. i (and everyone else i know) are generally really impressed with the effectiveness of buprenorphine, including in its long-term use in patients. and it is so safe, as compared to other opiates (and most other meds….).

–getting rid of Opana ER, which many states in the US attempted initially but unsuccessfully​ to block, is a feather in the cap of FDA (it had seemed unlikely that the current FDA leadership would take such a strong position)

–the issue of the dark web is truly scary by making these drugs so much easier to access and so anonymously (eg by kids sitting at home but with internet access).

Primary Care Corner: Hyperuricemia and cardiometabolic disease

12 Jun, 17 | by gmodest

​A recent study suggested that hyperuricemia itself predicts the development of several cardiac risk factors, including hypertension and hyperlipidemia (see doi: 10.1161/HYPERTENSIONAHA.116.08998.)


— 5899 Japanese subjects were enrolled who at baseline did not have overweight/obesity (BMI>25), hypertension (>140/90 after resting quietly for 5 min), diabetes (meds or A1c>6.4), and dyslipidemia (LDL >140, HDL <40, and/or TG >150), as well as any history of gout or hyperuricemia on medications, or chronic kidney disease with the eGFR <60. [ie, a pretty normal cohort medically]

— 282 men and 133 women had  hyperuricemia defined as serum uric acid (SUA) > 7 mg/dL in men or >6 mg/dL in women

— Mean age 47, 1864 men, there was small but statistically significant differences between those with hyperuricemia versus normal SUA at baseline (e.g. in men, BMI 22.4 vs 21.8, blood pressure 116/73 vs 114/72, eGFR 87 vs 82, albumin 4.5 vs 4.4, with similarly small differences in women) though there was a more convincing difference in drinking habits at 72% vs 62%).

— SUA on average was 7.65 in hyperuricemic men vs 5.59 in those with SUA <7; 6.44 in hyperuricemic women vs​ 4.20 in those with SUA < 6

— patients had an initial exam in 2004, and a follow-up exam in 2009


— hyperuricemia was associated with an increased cumulative incidence of (all OR’s expressed as per SUA increase of 1 mg/dL):

— hypertension, 14.9% vs 6.1% (p<0.001), odds ratio (OR) of 1.5 [ie, the OR is much higher in those with much higher SUA levels]

— dyslipidemia, 23.1% vs 15.5% (p<0.001), OR of 1.3

— chronic kidney disease, 19.0% vs 10.7% (p<0.001), OR of 1.3

— overweight/obesity, 8.9% vs 3.0% (p<0.001),  OR of 1.5

— diabetes, 1.7% vs 0.9% (p<0.001), OR 1.5

–in the above, there were some differences between men and women: there was no increase in diabetes in men (though in women was 2.3% vs 0.5%, with p=0.011); and in women no increase in dyslipidemia (though in men 5.2% vs 19.2%, p=0.020) or overweight/obesity (trend in women with p=0.08, but in men was 11.0% vs 4.9%, p<0.001)

— multivariate analysis:

–model 1 (controlling for age, sex, and smoking/drinking), all looking at OR and p value per SUA increase of 1gm/dL:

–hypertension increased with OR of 1.4, p<0.001

–dyslipidemia increased with OR of 1.3, p<0.001

–CKD increased with OR of 1.3, p<0.001

–model 2 (controlling also for eGFR), all looking at OR and p value per SUA increase of 1gm/dL:

–hypertension increased with OR of 1.5, p<0.001

–diabetes increased with OR of 1.5, p=0.004

–dyslipidemia increased with OR of 1.3, p<0.001

–CKD increased with OR of 0.9, p=0.006 [ie, lower odds ratio]

–overweight/obesity increased with OR of 1.4, p<0.001

–model 3 (also controlling for BMI), all looking at OR and p value per SUA increase of 1gm/dL:

–hypertension increased with OR of 1.4, p<0.001

–diabetes increased with OR of 1.4, p=0.01

–dyslipidemia increased with OR of 1.2, p<0.001

–CKD increased with OR of 0.9,  p=0.004

–overweight/obesity increased with OR of 1.1,  p nonsignificant


— this study is particularly interesting because it isolates any of the cardiometabolic issues ​from hyperuricemia, which have historically been conflated with them, by choosing people who had hyperuricemia initially but none of these issues at baseline and following them 5 years later. It has been quite unclear what the directionality is (or if it exists): does hyperuricemia in fact lead to these medical problems, or do these issues lead to hyperuricemia through its effects on insulin resistance (leading to the various components of the metabolic syndrome), and renal vasoconstriction and reduced GFR (leading to decreased renal uric acid excretion). Or are both hyperuricemia and cardiometabolic risk factors both related to a third entity, perhaps insulin resistance. Animal studies have supported the role of uric acid as causal in these conditions. This study would have been stronger if they had intermediate exams, not just at the beginning and 5 years later, but still would not answer the issue of causality definitively.

— one big issue with multivariate adjustment (as a general issue), which really comes to the fore in this study, is that it really depends on the variables being independent. For example, controlling for eGFR even within the <60 range and finding no significant relationship between SUA and developing CKD does not necessarily mean that there really is no relationship. Perhaps a mild reduction of eGFR within the normal range is leading to reduced excretion of SUA (and higher blood levels) from this mild decrease in GFR itself (so controlling for eGFR may create the perhaps erroneous impression that SUA is unrelated). Or, controlling for BMI within the normal range may similarly not show that SUA elevation is not predictive of subsequent overweight/obesity, since mild increases of BMI may be associated with some increased insulin resistance leading to higher BMI in the future. So, I would not attach much significance to models 2 or 3 above.


so, this study complements and adds to the previously noted association between hyperuricemia and cardiovascular disease (see blogs noted below). However, one can still not definitively show causation, because the hyperuricemia could be an innocent bystander associated with the real cause.

— But, based on these studies, it seems reasonable to me to check SUA levels for 2 reasons (and I have been doing so pretty regularly):

— there are important lifestyle risk factors for increased SUA levels, especially fructose intake. I have been successful in a few cases of working with patients to decrease their consumption of sodas and other products with high fructose corn syrup, often finding pretty dramatic decreases in SUA levels (eg from the 8.5 range to the 7 range). And decreasing alcohol consumption

— In addition, I also think it would be reasonable to be even more aggressive in primary prevention of cardiac disease in those patients who have high SUA levels, both in terms of discussing the importance of healthy lifestyles and also having a lower threshold for starting meds. And the meds chosen might be different: eg, using losartan (but not other ARBs) or amlodipine/nifedipine for hypertension, since these lower SUA levels: see below.

a Danish study suggested that treating hyperuricemia in those with allopurinol led to fewer cardiovascular events

— another study provides an interesting evolutionary perspective on hyperuricemia, as well as a Taiwanese study finding a dramatic decrease in cardiovascular events by treating hyperuricemia

–here is my very brief blog on antihypertensives and uric acid from 2012, predating the bmj website:

— large study of general practices in UK, looking at 25K pts with gout. I had seen some older studies finding that losartan (but NOT other arb’s or ace-I’s) lower uric acid levels.  In this large UK database, they found a 19% dec risk of clinical gout with losartan (compared to other hypertensive pts), 13% with ccbs (21% dec with amlodipine, 13% with nifed, and 14% with dilt), with inc gout risk with diuretics, b-blockers, ace-I’s, other arb’s besides losartan.  They note in their discussion some studies (which I looked at and are pretty small…) find that ccbs (esp nifed and amlod) and losartan are uricosuric and decrease serum uric acid levels.  See doi:10.1136/bmj.d8190 ).  there have been some recent reports that high fructose corn syrup is perhaps the largest (or close to it) dietary component which increases uric acid.

Primary Care Corner with Geoffrey Modest MD: Chronic pain and dementia

8 Jun, 17 | by gmodest

by Dr Geoffrey Modest

​​The MMWR recently published the finding that the age-adjusted rates of Alzheimer’s deaths have increased in 41 states and the District of Columbia from 1999 to 2014 (see ).


— Alzheimer’s disease is the 6th leading cause of death United States, accounting for 3.6% of all deaths in 2014

— 93,541 Alzheimer’s deaths occurred in the US in 2014, at an age-adjusted rate of 25.4 deaths per 100K population. This represents a 54.5% increase over 1999, when the rate was 16.5 deaths per 100K (44,536 deaths).

— Most deaths occur in nursing home or long-term care facility (though this was a decrease from 67.5% in 1999, to 54.1% in 2014). The number of deaths in a hospital declined from 14.7% in 1999 to 6.6% in 2014,; the percent who died at home increased from 13.9% in 1999 to 24.9% in 2014. In addition, 6.1% died in a hospice facility in 2014.

— the specific Alzheimer’s death rate per 100K population increased among those to age 75 to 84 from 129.5 to 185.6 per 100K population, as well as in those >85 years old, from 601.3 to 1006.8 per 100K population.

— Overall, the death rates were higher among all age groups, both sexes, all races/ethnicities, urban/rural, and in almost every state. But they were particularly high for women and non-Hispanic whites

— age-adjusted rates for the 50 states and DC range from 7.0 to 29.8 per 100K in 1999, and from 10.7 to 43.6 per 100K in 2014


— this MMWR report is based on death certificates, which are not necessarily accurate and may be influenced by the prevailing culture and the US system of reporting.  In particular, the death certificate-based data derive from what the patients’ clinicians decide is the major cause of death, which in my experience is often a best-guess after the fact. and this is likely influenced by several nonclinical factors, including the acceptability of Alzheimer’s disease itself as a cause of death (which may have increased in this time period, at least partly explaining the noted increase), or even the influence of the funeral home directors. In addition, there may be very real issues with deciding if Alzheimer’s is truly the responsible condition: the definitive diagnosis is in fact histopathologic, though there are clinical definitions of reasonable accuracy, but many clinicians may be hesitant to use this label (is it truly accurate??) and avoid coding it; also, at what degree of cognitive impairment does it reach the threshold to go on a death certificate? (and that threshold is likely very different from one clinician to another)

— And, this increased incidence of Alzheimer’s also raises the question of potentially modifiable factors in the development of Alzheimer’s, which may have changed over time. For example, obesity, diet, physical activity, perhaps medications, and levels of education have been found to be associated with Alzheimer’s. See blogs 

— one profound implication of an increasing incidence of Alzheimer’s disease is the tremendous effects on others, and especially the paid and unpaid caregiver burden. And this stresses the need for additional resources to educate and train caregivers in the care of Alzheimer’s patients, as well as providing respite care and case management



another article just came out suggesting an association between persistent chronic pain and memory decline/dementia, in a longitudinal cohort of elders (see doi:10.1001/jamainternmed.2017.1622).



–10,065 community-dwelling older adults in the Health and Retirement Study, who were at least 62 years old in 2000 and answered questionnaires on pain and cognition; they were followed through 2012 with sequential questionnaires

— 60% female, median age 73 at baseline.

— 10.9% had persistent moderate-to-severe pain at baseline (n= 1120), 76% female (versus 58% female in the nonpain group), 86% white/8% black/5% Hispanic, 58% ever-smokers, 45% nonmarried/non-partnered

— comorbidities (all with differences with p<0.001): hypertension (61% in pain group, 48% comparison)/diabetes (20% pain, 14% comparison) lung disease (14% pain, 8% comparison), heart disease (37% pain, 25% comparison), stroke (13% pain, 8% comparison), depression (50% pain, 20% comparison), alcohol use (less in pain group overall, 68% reporting none versus 53% in comparison), difficulty doing more than 1 ADL (46% pain, 12% comparison)

— primary outcomes included memory score (a compilation of several cognitive tests, by the patient or proxy) and dementia probability score (a different cognitive test which estimates the chance that an individual would reach the DSM3 or 4 diagnostic criteria for dementia

–the fully adjusted model controlled for: demographic measures (age, sex, race/ethnicity), education level, current or former tobacco use, medical comorbidities of self-reported hypertension/diabetes/cancer/chronic lung disease/heart disease/stroke, household financial status, marital status, current alcohol use, and depressive symptoms


— of the elderly who reported pain on the initial intake evaluation, 69% reported pain subsequently (persistent pain)

— after covariate adjustment, persistent pain was associated with a 9.2% (2.8% – 15.0%) more rapid memory decline as compared to those without persistent pain

— after 10 years, there was a 15.9% higher relative risk of inability to manage medications, and 11.8% higher relative risk of inability to manage finances independently

— adjusted dementia probability increased 7.7% faster (0.55%-14.2%) in those with persistent pain, an absolute 2.2% increase in dementia probability


— the prevalence of chronic pain increases with age, affecting 25 to 33% of older adults. Also the recovery from chronic pain is less likely in older people. Older people with chronic pain are also more likely to be consumed by their chronic pain, reporting pain as affecting their subjective health status

— pain in the elderly has been reported to be more likely to be associated with falls, functional impairment, and cognitive decline/dementia in prior studies. But these are largely cross-sectional, observational studies at a point in time, and not a longitudinal study as above.

–although there are some very important advantages of the current longitudinal study, there are some evident limitations in terms of the extent of the data collected:  lack of data on the source/site of the persistent pain, or even of  the degree of the medical or psychological comorbidities. Also, there were very significant differences in the baseline characteristics of those with and without persistent pain, both medical and psychosocial (especially for depression and impaired ADLs, but also for all of the major medical comorbidities), or even the medications or other therapies prescribed. So, even though they adjusted for many potential confounders, they really did not have the database to control well for them, and there are likely other unknown (and therefore uncontrolled) factors involved.

— there were also no data specifically on the types of pain medications given. There is concern that use of opioids, for example, might affect cognition, perhaps exacerbated by concomitant disability, depression, etc. However, another study of patients with chronic pain getting NSAIDs found about the same amount of cognitive effect as with opioids. I would however add that several of the adjuvant pain medications (gabapentin, pregabalin, tricyclics, etc) may have significant effects on cognition. and SSRIs or SNRIs themselves, if used to treat depression or pain, can also affect cognition (studies are mixed on this)

–there is a plausible mechanism for the association of persistent pain and cognitive decline. Stress, depression, and even sleep deprivation have been found to affect cortisol secretion, and perhaps through that, can lead to neurologic changes, including decreased neuronal density/function in the hippocampus, with decreased ability to form new memories.

–and there may be other associated changes in those with persistent pain which were not accounted for but could affect cognitive health: eg, physical exercise, diet (ability to shop, cook food, etc), limitations in social interactions/increased social isolation


so, though these studies are both significantly flawed, it is clear that dementia is really prevalent, that it is likely increasing overall and especially so as the population ages, that there are very significant medical and social costs (especially on the caregivers), that many lifestyle measures likely provide benefit (as per prior blogs, see below), and that chronic pain by itself may be associated with the increased incidence and progression of dementia.  In this latter case, I think it is important, especially in the elderly, to treat pain but preferably with nonsystemic medications, avoiding the multitude of toxic effects of NSAIDs (cardiac, renal, GI, etc, to which the elderly are likely more susceptible), opiates, and the typical adjuvants (gabapentin, tricyclics, etc). Perhaps it is best to treat with physical therapy and psychosocial therapies (cognitive behavioral therapy, mindfulness therapy, stress reduction therapies, etc) and/or with injections or topical medications. and, as I have mentioned many times, injections into joints, trigger points, muscle spasms, etc often really help the pain and improve the function, often for a very long time.



blog on article finding that prescribing opiates to the elderly is associated with subsequent opiate dependence

article on cognitive behavioral therapy for low back pain

study on tai chi and another on mindfulness for chronic pain

Primary Care Corner with Geoffrey Modest MD: Low-dose hypertension therapy

7 Jun, 17 | by gmodest

by Dr Geoffrey Modest

A recent meta-analysis assessed 42 trials comparing low-dose (one-quarter dose) antihypertensive therapy versus placebo, finding some efficacy and essentially no adverse events at this low dose (See DOI: 10.1161/HYPERTENSIONAHA.117.09202).


— 42 trials were identified involving 20,284 participants

— 37 comparisons evaluated quarter-dose therapy versus placebo

— 7 comparisons were of dual quarter-dose therapy versus placebo

— 1 comparison of quadruple quarter-dose therapy versus placebo

— standard full-dose therapy for some of the commonly prescribed medications were:

— atenolol 50 mg

— metoprolol 100 mg

— carvedilol 25 mg

— amlodipine 5 mg

— verapamil 240 mg

— lisinopril 20 mg

— enalapril 20 mg

— valsartan 80 mg

— candesartan 8 mg

— hydrochlorothiazide 25 mg



— quarter-dose therapy versus placebo led to a 4.7/2.4 mmHg improvement (p<0.001)

— dual quarter-dose therapy was associated with a 6.7/4.4 mmHg improvement versus placebo (p<0.001), as effective as standard-dose monotherapy

— quadruple quarter-dose therapy versus placebo (only one study) found a blood pressure reduction of 22.4/13.1 mmHg (p<0.001)

— adverse events in both the single and dual quarter-dose therapies were not significantly different from placebo and had significantly fewer adverse events compared to standard-dose monotherapy



— the studies used in this meta-analysis were quite old, the average being published to 17 years ago, and 85% had eligibility criteria based on diastolic blood pressure alone.

— It is important to realize that this study only looked at office-based blood pressure targets, not clinical outcomes. For example, beta-blockers are now out of favor because of a few meta-analyses showing little benefit in terms of clinical outcomes. And some commonly used meds are not included (eg losartan).

— Some of the older JNC recommendations, perhaps based on some of these studies, did raise the issue of combining low-dose medications versus increasing a single medication, given the synergy in blood pressure lowering of the combination and the significant decrease in adverse events

— there was also an interesting meta-analysis from 2009 (see Wald DS. Am J Med 2009; 122: 290), looking at 42 trials with 10,968 participants, finding that doubling the dose of thiazides, beta blockers, ACE inhibitors, calcium channel blockers, and the summation of all of these classes of antihypertensives led to only 22% of the equivalent incremental effect of adding a 2nd agent (though calcium channel blockers did a little better than others, especially ACE inhibitors). This study really reinforces my own anecdotal experience, that doubling the dose of lisinopril, amlodipine, etc seems to have much less blood pressure lowering effect than adding a 2nd agent (e.g going from lisinopril 10 mg to 20 mg has pretty consistently a lower incremental value than adding low-dose hydrochlorothiazide to the lisinopril 10 mg, which has the added benefit of being available as a single combination pill). Sort of similar to statins where the most significant cholesterol-lowering is at the lowest dose (I have a patient on 1/3 of atorvastatin 10mg, ie 3.3 mg, with impressive lipid lowering). There was also another study finding that half-dose therapy was about 80% as effective as compared to full standard-dose therapy.

In a prior blog on the increased efficacy of chlorthalidone over hydrochlorothiazide, I lamented the fact that chlorthalidone was only available as 25 mg in the United States, that that dose was associated with significant hypokalemia, and that the pill was too small to cut easily. One of my readers commented that he actually took one quarter of the pill, did not find it difficult to cut the pill, and his blood pressure was well-controlled with that.


So, I do realize these meta-analyses are based on old studies, but it does seem to have validity, and is reinforced by my own clinical experience. Based on the study comparing doubling the dose versus combination medications, my practice has been to double the dose of the medication only if there is a compelling other reason (such as trying to decrease the level of proteinuria by maximizing ACE inhibitor dose) or if the medication is well-tolerated and the patient is pretty close to the target blood pressure.

EBM blog homepage

Evidence-Based Medicine blog

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

Creative Comms logo

Latest from Evidence-Based Medicine

Latest from EBM