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

26 May, 17 | by gmodest

by Dr Geoffrey Modest

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


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

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

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

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


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

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


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

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

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

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

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

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


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

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


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

27 Feb, 17 | by EBM

By Dr. Geoffrey Modest

The American College of Physicians and the American Academy of Family Physicians just published guidelines on the pharmacologic treatment of hypertension in adults over 60 yo, with both a systematic review and meta-analysis (see doi:10.7326/M16-1785), and a clinical practice guideline (see )


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


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


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

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

Primary Care Corner with Geoffrey Modest MD: SPRINT Trial: Elderly Subgroup Study of Lower Blood Pressure Goal

2 Jun, 16 | by EBM

By Dr. Geoffrey Modest

A subgroup analysis of the SPRINT trial found improved clinical outcomes in community-dwelling patients >= 75yo on intensive blood pressure control (see doi:10.1001/jama.2016.7050). For an overall review/critique of SPRINT, see


  • In brief, the SPRINT trial involved 9361 patients, mean age 68 (but they had a pre-designated subgroup >=75 yo), randomized to SBP goals of <120 vs <140 and achieving SBP of 121 vs 136, then finding a pretty dramatic clinical benefit in those with the more aggressive blood pressure goal. The researchers did not determine the antihypertensives used, but encouraged using those with known cardiovascular benefit (diuretics, calcium blockers, ACE/ARB)
  • The current study is of the 2636 people were over >=75 (mean age 79.9, 38% women, 75% white/17% black/7% Hispanic, baseline BP 142/71, 10% with orthostatic hypotension, creatinine 1.1 mg/dl, eGFR 63, total chol 182/HDL 56, 52% on statin, 10-yr Framingham risk score 25%, mean of 2 antihypertensives, 13% physically fit/55% less fit/32% frail)
  • Results in this older cohort, after 3.14 years (study terminated early):
    • Achieved blood pressure: 123.4/62.0 vs 134.8/67.2; those in the intensive group required average of 1 more antihypertensive (frail patients had SBP difference of 10.8 mm Hg, less fit 11.3 and fit 13.5 mmHg)
    • Primary composite outcome (nonfatal MI, acute coronary syndrome, nonfatal stroke, nonfatal acute decompensated heart failure, death from cardiovascular cause):
      • 102 events in intensive group (2.59%/yr) vs 148 (3.85%/yr) on standard therapy, a 34% reduction [HR 0.66 (0.51-0.85)]. Number-needed-to-treat for 3.14 years was 27
    • Secondary outcome (all-cause mortality):
      • 73 deathsin intensive group vs 107 on standard therapy, a 33% reduction [HR 0.67 (0.49-0.91)].  NNT for 3.14 years was 41
    • Rate of serious adverse events was not statistically different overall, with:
      • Hypotension in 2.4% in intensive vs 1.4% standard, nearly significant trend
      • Orthostatic hypotension at clinic visit in 21.0% vs 21.8%
      • Syncope in 3.0% vs 2.4%
      • Electrolyte abnormalities in 4.0 vs 2.7%, nearly significant trend
      • Acute kidney injury in 5.5 vs 4.0% (leading to hospitalization or were reported in hospital discharge summary), nearly significant trend
      • Injurious falls in 4.9% vs 5.5%
      • And, overall, no increase in the serious adverse events in the frail group

So, several points:

  • The hypertension guideline trend has been for increasingly higher blood pressure goals in the elderly: the European guidelines target initiating treatment only if SBP>160 in those >80 yo; the JNC8 recommendations are for a target of 150 in those >60 yo
  • The SPRINT guidelines did have some really important exclusions: history of diabetes, symptomatic heart failure in past 6 months or LVEF <35%, clinical dementia, prevalent stroke, unintentional weight loss of >10%, an SBP of <110 mmHg after standing for 1 minute, or residing in a nursing home
  • Not surprisingly, the NNT was much lower in this trial than the overall SPRINT trial, given the higher event rate of this older group
  • And, reassuringly re: orthostatic hypotension, this subgroup analysis is pretty convincing that there was no increase, but they did exclude anyone with a standing SBP <110
  • But, a few caveats here:
    • The baseline BP was pretty low: mean 142/71. I would be hesitant to assume the same results would apply to those with baseline BP of 200/100
    • This is a much smaller cohort than the larger study, and the overall SPRINT study did find statistically significant though small increases in adverse effects in the intensive group: for hypotension, syncope, electrolyte disturbances, and acute kidney injury
    • They do not give a breakdown of the age distribution, nor do they do further subgroup analysis to know if the same benefit would apply to those 85 years old or older
    • They did not look at initial orthostatics (see )which may be more prevalent and important than the usual postural changes that they did assess.
    • I still remain concerned that the diastolic pressures are pretty low (62 range), given that it is in diastole that the coronaries perfuse, and this high risk group likely had some obstructive coronary disease. I do understand that these 3 year results did not show an increase in cardiovascular events/mortality, but I remain a tad skeptical
  • However, this issue of blood pressure goal in older people is really important clinically, since studies such as the Framingham Study have found that about 90% of elderly develop hypertension if they live long enough. Another study found that 75% of those 75 years old have hypertension
  • So, what makes sense for clinical practice?
    • I do think this study, despite above caveats, should inform clinical practice
    • As per my last blog, I do think it is really important to make sure the blood pressure reading we are basing decisions on is really accurate (make sure done correctly, use ambulatory/home monitors,…)
    • I would check orthostatics, including initial orthostatics, on all elderly patients given this lower goal
    • But that being said, I would strongly consider slowly decreasing systolic blood pressure in elderly patients to the low 120 range, with slow incremental med changes, in those with no prior history of diabetes, stroke, or standing BP <110 mm Hg (as excluded in the SPRINT trial).

Primary Care Corner with Geoffrey Modest MD: Exercise Benefits in Elderly at Lower Levels

17 Dec, 15 | by EBM

By Dr. Geoffrey Modest

A couple of concerns about the exercise prescriptions we give patients: How realistic are they are for the elderly; and when older people cannot do the moderate-to-vigorous activities recommended, is there benefit in less aggressive exercise? A systematic review and meta-analysis was recently done to answer these questions (see doi:10.1136/bjsports-2014-094306).


  • 9 prospective cohort studies were found, with 122,417 participants (73,745 women and 48,672 men, mean age 72.9, average cohort size 13,602, six cohorts were American/2 from Pacific region/1 Asian, follow-up of 9.8 years and with 18,122 deaths (14.8%)
  • They defined 4 activity levels, by Metabolic Equivalent of Task, or MET) minutes: inactive, low (1-499 MET-minutes), medium (500-999) and high (>1000)
  • Results, with inactive being the reference:
    • ​Low activity had a 22% reduction in mortality [RR 0.78 (0.71-0.87), p<0.0001]
    • ​Moderate  activity had a 28% reduction in mortality [RR 0.72 (0.65-0.80), p<0.0001]
    • High activity had a 35% reduction in mortality [RR 0.665 (0.61-0.70), p<0.001]
  • Most of this association was for a reduction in cardiovascular disease (i.e. 25% reduction in low, 26% medium and 40% high activity), though the reduction in cancer mortality was also significant (ie 11% reduction in low, 16% medium and 31% high activity)
  • There was a dose-response curve, with more exercise intensity having more mortality benefit. But, the greatest decrease in mortality was associated with increasing from inactivity to the lowest level, with gradually more benefit as the intensity increases further.
  • Women benefited more than men: for those performing low activity exercise — men had 14% mortality reduction vs 32% in women (??do men overestimate their amount of exercise and women underestimate it??)

So, a few points:

  • For further clarification of METs and MET-minutes, see​ . As a rough guide: sedentary/resting energy expenditure is 1 MET; moderate activity is 3-5.9 METs, and walking 3 miles per hour is 3.3 METs; high activity is >6.0 METs, and running at 10 minutes/mile is a 10 MET activity.
  • Approximately 60% of older people cannot do 150 min of moderate-to-vigorous activity/week
  • These 9 studies were observational, though they controlled for many risk factors for mortality, such as smoking, blood pressure, fasting blood sugar, lipids, parental history of heart disease, etc. (e.g., see JAMA 1989; 262: 2395). Others of the studies in the meta-analysis also controlled for depression, mobility, chronic diseases, BMI, alcohol, education, diabetes, early parental mortality, and even red meat consumption — though it varied from study to study. The power of this paper is that it combines many studies with many participants showing mortality benefit from lower amounts of physical activity, and in that way gets a bigger picture of the results than a single study can. But, as with all observational studies, are there unanticipated confounders?? (i.e., are there other factors not taken into account which predispose some people to have less activity but put them at higher mortality risk? Perhaps they have unanticipated neurologic conditions? Or have they fallen and are afraid to do exercise, but are at higher mortality risk because of a condition predisposing them to fall?)
  • But, despite this significant limitation (i.e., not having a randomized controlled study with allotment of individuals to differing levels of exercise and seeing what happens), perhaps the strongest message we can give patients is: exercise is good for you and you should do whatever you can (the concern is that by prescribing/insisting on too much exercise for an individual, some people end up doing nothing). I have had success in just getting people to walk 15-20 minutes/day (15 minutes of walking/day is the midpoint of the low activity group, with 250 MET-min), and some of them are able to increase that over time. And many people actually feel better after doing exercise…

Primary Care Corner with Geoffrey Modest MD: Rotator Cuff Repair in the Older People?

3 Dec, 15 | by EBM

By Dr. Geoffrey Modest

And yet another article suggests that we are doing too much surgery. This one is on nontraumatic rotator cuff tears in older patients (see J Bone Joint Surg Am. 2015;97:1729).


  • 160 patients (mean age 64, 50% female, 50% working, mean duration of symptoms 27 months) in Finland with 167 symptomatic, nontraumatic, isolated full-thickness supraspinatus tears were randomized into:
    • Group 1: physiotherapy– patients given written info and guidance on home-based exercise program. First six weeks aimed at improving glenohumeral motion and active scapular retraction; then static and dynamic exercises to improve scapular and glenohumeral muscle function until 12 weeks, then increased resistance and strength training until 6 months. Also 10 sessions of PT in outpatient facility to monitor progress.
    • Group 2: physiotherapy plus acromioplasty. PT as in group 1, plus arthroscopic acromioplasty (to reduce the friction between the supraspinatus and the acromion).
    • Group 3: group 2 plus anatomic repair of the ruptured tendon.
  • Primary outcome was Constant score (a combo of 4 scores: pain, ADLs, range of motion, and strength), recorded prior to intervention and after 3, 6, 12 and 24 months). Baseline Constant score was about 60 points. Scores are from 0-100.
  • All patients had repeat MRI at 2 years.

Results at 2 years:

  • Similar changes in Constant score between the groups at 2 years vs prior to intervention: 18.4 point improvement in group 1, 20.5 points in group 2, and 22.6 points in group 3. These changes not significantly different from each other.
  • No significant difference in visual analog scale for pain or patient satisfaction in the 3 groups (high patient satisfaction in all 3 groups: 89% in group 1, 95% in group 2, and 94% in group 3​).
  • Mean sagittal size of the tendon tear by MRI initially was approx 10.5 mm; at 2 years,  tendon tear size was significantly smaller in group 3 (4.2 mm, p<0.01) vs approx 11.0 mm in groups 1 and 2.
  • Rotator cuff repair and acromioplasty cost more….
  • On review of the Constant subscores:
    • Pain and ADL: significantly better in group 2 or 3, beginning at 3 months and continuing for the 2 years, but ROM and strength initially best in group 1 then equalized.
    • ​These differences were on the order of 2 points, where a 10 point difference is considered clinically important.


  • Rotator cuff tears are really common, up to 30% of those >60yo. They may be asymptomatic or lead to significant pain/shoulder dysfunction.
  • The tear thickness did increase slightly in groups 1 and 2 and decreased in group 3 (who had tendon repair). At 2 years, MRI-documented full thickness tear was found in 80% of groups 1 and 2, but 31% of group 3. Not sure what the clinical significance of this is.
  • Though there were statistical differences in the Constant subscores, especially pain and ADL, these numbers were small and the visual-analog scale for pain was no different amongst the groups.
  • The finding that there was no difference in these groups is reinforced by the considerable placebo effect of surgery in other studies.
  • Bottom line: conservative therapy seems to be a viable option for initial treatment in older patients with non-traumatic rotator cuff tears, though the patients probably would need to be pretty motivated to follow the PT program and have consistent support/guidance.​



Primary Care Corner with Geoffrey Modest MD: Exercise Benefit in Elderly

17 Nov, 15 | by EBM

By Dr. Geoffrey Modest

A systematic review/meta-analysis was recently published in the British Journal of Sports Medicine on the protective effects of even low amounts physical exercise in those >60yo (see doi:10.1136/bjsports-2014-094306). Current recommendations are for 150 min of moderate-intensity or 75 min of vigorous-intensity physical activity/week, as measured by the metabolic equivalent task (MET, which describes the intensity of energy expenditure for specific activities). For reference, resting energy expenditure is 1 MET, moderate activity is 3-5.9 METs (e.g. brisk walking) and vigorous activity is >6 METs (e.g., running). The MET-minute calculation is simply the sum of the #METs x #minutes x #days done/week for each of the activities. Studies suggest that there is substantial health benefits by performing 500-1000 MET-minutes/week (mortality benefit of 20-30%), the range suggested by the above recommendations.


  • 9 cohort studies included with 122,417 participants (60% women, mean age 72.9), and followed 9.8 years
  • 18122 deaths during follow-up period (14.8%)


  • Low amounts of moderate-to-vigorous physical activity (MVPA), expending 1-499 MET-min/wk, was associated with a 22% reduction in mortality risk [RR=0.78 (0.71-0.87), p<0.0001], though there was a difference between men (a 14% reduction in morality risk  [RR=0.86 (0.80-0.94), p<0.001]), as compared to women (a 32% reduction [RR 0.68 (0.63-0.74 p<0.00001]) –all of these RR’s are adjusted for age, sex, overweight, smoking, elevated BP, diabetes, plasma cholesterol, cardiovascular and chronic disease, cancer, depression, educational level and self-reported health
  • More extensive MVPA (expending 500-999 MET-min/wk), was associated with further mortality benefit of 28% in those following current recommendations of 150 min of moderate-intensity or 75 min of vigorous intensity physical activity/week) [RR=0.72 (0.656-0.80), p<0.0001]
  • Even more extensive exercise (>1000 MET-min/wk) had a 35% reduction in mortality [RR=0.65 (0.61-0.70), p<0.0001]
  • Of note, the relative benefit from the individual studies for each of the target exercises (low-dose, medium-dose and high-dose) were pretty consistent, even though the studies varied widely in participants (6 were from the US/2 from the Australia/one Asian).
  • The benefit was most dramatic in comparing those with low amounts of MVPA vs inactivity, with smaller incremental benefit as the amount of physical activity increased.
  • Subgroup analysis found mortality benefit in cardiovascular disease was the most profound in those doing 1-499 MET min/week of MVPA (a 25% decrease in mortality), going up to 500-999 MET min/week (decreased mortality insignificantly improved to 26%), and going to >1000 MET min/week (a more impressive decrease of 40%). For cancer the relative numbers were 11%, 16% and 31%.

One concern is that 60% of older adults are not able to achieve the 150 min/week as recommended.​ So,

  • This study reinforces that there is still significant benefit to less-than-recommended exercise duration, both for men and women (though this is more impressive in women than men as noted above). By this meta-analysis, we should not be rigid in recommending the 150 min/week of exercise (since that really may be too much for some people and ultimately result in no exercise being done). So, the real clinical issue for us is to convince those >60yo to just do exercise, as much as they can reasonably do, recognizing that most of the benefit seems to be achieved even with small exercise duration. One issue for those of us in the northern climates is to plot a strategy with the patient to exercise in the colder months. I have had some success in suggesting walking up and down stairs for 10-15 minutes/day. There are a few studies also finding that even light intensity exercise (1.6-2.9 METs) has health benefits over being sedentary.
  • An issue in a meta-analysis of observational studies is the question of reverse causation: is it that the healthier people tend to do more exercise, but the real increased longevity is because they are healthier, regardless of their doing exercise? The above meta-analysis did seem to control for chronic conditions and self-reported health status, making reverse causation less likely.
  • So, given all of this, and as several recent blogs have reinforced, I do think that one of the most important things we do for patients, including the elderly, is to reinforce and help patients eat well and exercise, and the above study suggests that we try to negotiate a reasonable exercise program and not simply prescribe one that meets the recommendations….

Primary Care Corner with Geoffrey Modest MD: Medication in Elderly with Comorbidities

21 Oct, 15 | by EBM

By Dr. Geoffrey Modest

BMJ printed a new population-based cohort study looking at guideline-recommended drugs and deaths in older adults with multiple chronic conditions (see BMJ 2015;351:h498). These guidelines were typically based on randomized control studies with younger people and a single chronic condition.


  • 8578 older adults (mean age 77 with 36% >80yo, 59% women, 87% white), having multiple chronic conditions: hypertension (HTN)  92%, hyperlipidemia (HL) 77% , diabetes (DM) 40% , coronary artery disease (CAD) 39%, depression (DEP) 26%, heart failure (HF) 20%, atrial fibrillation (AF) 19%, chronic kidney disease (CKD) 12%, and thromboembolic disease 6%.
  • Data were from Medicare Current Beneficiary Survey cohort, a nationally representative sample of Americans >65yo, followed through 2011
  • The 9 study drugs: RAS blockers (ACE-I or ARBs) were used in 54%, statins in 53%, thiazides 47%, b-blockers 47%, calcium channel blockers (not differentiated by class) in 33%, SSRIs/SNRIs 21%, warfarin 14% , metformin 14%, clopidogrel 13%. 54% took at least 3 of the 9 study drugs. Mean total number of drugs (including nonstudy drugs) was 10. They also tracked changes in meds over the study period
  • Median follow-up of 24 months. 15% (1287) people died during follow-up.


  • Mortality over the 24 months: 27% in those with AF, 19% with CAD, 17% with DM, 33% with HF, 11% with HL, 15% with HTN
  • For the specific drugs (all of below were statistically significant), the HR for mortality was:
    • ​b-blockers: adjusted HR of 0.59 for AF, 0.70 for CAD,  0.68 for HF, and 0.48 for combo of AF/CAD/HL/HTN, 0.59 for HF/CAD/HL/HTN [note: an HR of 0.59 means a 41% decrease in mortality]
    • Statins:  HR 0.75 for CAD, 0.75 for DM, 0.68 for HL, and 0.65 for combo DM/CAD/HL/HTN, 0.68 for HF/CAD/HL/HTN, 0.70 for DEP/CAD/HL/HTN
    • Calc channel blockers: HR 0.78 for AF, 0.85 for HTN, and 0.69 for DM/CAD/HL/HTN, 0.71 for AF/CAD/HL/HTN and 0.72 for HF/CAD/HL/HTN
    • Thiazides: no significant benefits for HTN or any of the combo comorbidities
    • RAS blockers: 0.72 for HF, 0.80 for HTN, 0.82 for CAD, and 0.73 for AF/CAD/HL/HTN, 0.77 for HF/CAD/HL/HTN
    • Clopidogrel: no significant benefit for AF or CAD, or any of the combos (aspirin use could not be tracked in this database)
    • SSRI/SNRI: no significant benefit for DEP or any of the combos
    • Metformin: no significant benefit for DM or any of the combos
    • Warfarin: 0.69 for AF, 0.44 for thromboembolic dz, but no benefit for any of the combos​

So, this study, I think, is important for several reasons:

  • It largely reinforces what we are already doing, treating older patients with comorbidities based on the usual randomized controlled trials which typically limited the age range to younger patients and those usually limited to a single disease (e.g., excluding those with renal failure, etc.). And, of course, as people get older, they regularly and routinely develop multiple comorbid conditions
  • The study shows that in patients with multiple common comorbidities, the usual medications do improve mortality, even in a pretty short-term 2-year study. And the association between drug use and mortality was pretty similar across patterns of coexisting comorbidities, suggesting that similar benefits were evident despite the presence of comorbidities. This last finding supports the utility of randomized control trials limited to a single disease and then being applied more generally, at least in the above diseases/medications.​​
  • Although there is empirical evidence that observational studies usually have similar results to controlled intervention studies (see Cochrane Database Syst Rev 2014;4:MR000034), one has to remain somewhat skeptical that there could be unexpected biases. This study was quite good in that it incorporated certain social comorbidities (e.g. functional level, amount of time in the hospital, and living in a nursing facility), but still is open to the potential for other potential biases
  • For example, it is pretty clear that many of the cardiac meds do well. The hardest one for me to accept is that metformin does not have clear benefit, though on each analysis, there was a clear non-significant trend to benefit. My guess is that there is a strong selection bias here: those who are sicker do not get metformin. My bet is that they have a little (or lot) of renal dysfunction, or heart failure, etc., which scare the providers away from using metformin, leaving only the healthier elderly on it (and with a lower likelihood of showing mortality benefit in the healthier subgroup over a short 2-year study).  [Though, there are strong arguments that metformin is still a safe drug in many of these cases, esp. at a lower dose: See]
  • There have been increasing studies showing that, for example, anticoagulation for the very common condition of atrial fibrillation seems to be safer in the elderly than we thought in the old days, and I do have several patients into their late 80’s/early 90’s doing very well on them. And we know that the benefits of statins are typically evident within 6 months of starting them (based on studies of mostly younger people but some elderly) – i.e., these drugs seem to work well and are pretty well tolerated in the elderly.
  • So, bottom line, this study provides some pretty strong scientific rationale for continuing to treat elderly patients with their common multiple medical conditions with the same meds we have been using based on studies of younger people with single diseases. ​But, it is also important to bear in mind that this study only looked at mortality, which is not the only important end-point….

Primary Care Corner with Geoffrey Modest MD: Implantable Cardioverter Defibrillators in the Hospitalized Elderly

27 Aug, 15 | by EBM

By Dr. Geoffrey Modest

There was a pretty striking analysis of large numbers of elderly patients inappropriately receiving implantable cardioverter defibrillators (ICDs) during acute hospitalizations (see doi: 10.1136/bmj.h3529​)


  • The US implants more ICDs than any other country: 133,262 implants in 2009: 434 new implants/1M people, 1.5x higher than the second largest implanter
  • The age of implantation is slowly increasing, with average now of 74 yo
  • The major trials finding ICD efficacy were in outpatients with stable heart failure, with a mean age of 60 in the SCD-HeFT and 64 in MADIT II trials (in this latter study, there was no difference if symptomatic NYHA class 2-3 symptomatic or asymptomatic). The 23-31% survival benefit in these studies became apparent after 1-1.5 years.
  • But 1/3 of older Medicare beneficiaries have ICDs implanted during hospital admissions for heart failure or other acute co-morbidities
  • The current indications for AICD use for primary prevention include those at high risk of life-threatening ventricular tach or fib despite optimal med therapy (b-blocker, ACE-I), such as those with symptomatic cardiomyopathy (NYHA class 2-3) and LVEF (left ventricular ejection fraction) <35%, or those 40 days post-MI who are asymptomatic with LVEF <30%
  • Not much data in elderly: a substudy of MADIT-II found that those 121 people randomized to an ICD who were >75yo had only a non-significant mortality benefit.


  • This was a retrospective cohort study of 23,111 Medicare recipients who had a history of heart failure, were hospitalized with an acute condition, and were considered eligible for ICD therapy for primary prevention, e.g. with EF <35%. 5258 received ICD and 17,853 did not. Over 90% had the index admissions for heart failure. Follow-up 2.8 years. 53% died.
  • Mean age 80 in those not getting ICD and 75.5 in those getting one. Other differences: higher likelihood of ICD if male, lower LVEF (25% vs 29%), less psych comorbidites, more diabetes, ischemic heart failure, stroke.


  • Crude survival curves showed improvement in survival in the first few months only, no difference thereafter (see figure at the bottom). Matching patients with an ICD vs not by high dimension propensity scoring revealed no statistically significant benefit from ICDs.
  • Subgroup analysis: no statistical difference in cardiac mortality by history of non-recent MI (though there was a 37% lower total mortality). No diff in group with LBBB or by BNP levels. Those >81 yo did do better (RR 0.78, 0.65-0.93), though only 12% received an ICD

So, a few points:

  • A large number of ICDs are put in during acute hospitalizations, which had not been studied. Hospitalized patients are pretty different from stable outpatients: they may be more likely to die from heart failure itself (and ICDs don’t do much for that) instead of arrhythmia. This finding may be similar to the studies of patients admitted with MIs and getting early ICD placement: there was no benefit as compared to waiting 30-40 days and there were more non-sudden cardiac deaths in those getting early ICDs, those least likely to benefit from an ICD. Hence the recommendation to wait 40 days.
  • The benefit for this Medicare population was entirely within the first few months after ICD implantation (as per graph below). This result differs strikingly from the VA and MADIT-2 studies showing benefit only after 1-1.5 years, suggesting that in the Medicare study above there was a significant selection bias to ICDs in healthier patients (i.e., They did better in the next 4 months because they were healthier and therefore more likely to get an ICD). This also could explain the improved response in those >80 yo, where only 12% got the ICDs.
  • As an aside, other data show that women get ICDs less frequently than men, but there are other studies finding that they have lower risk of sudden cardiac death and are more likely to have complications for ICD implantation.
  • This study brings up a few issues: the most striking to me is the use of ICDs in acutely hospitalized patients, mostly hospitalized for heart failure, with no data to support that approach, and the observational data from this quite large Medicare study now going against it. ICDs clearly subject patients to adverse events and the system to very high costs (as another aside, I did have an 80+ year old patient who had a very large MI and the got an ICD, who for many years thereafter lived in fear of the ICD shocking him and therefore limited his activities significantly). The second big issue is the migration of indications from well-documented (those in their mid-60s) to much older individuals, based only on observational data, and not a lot of that.

implantable cardioverter defbrillators

Primary Care Corner with Geoffrey Modest MD: Spicy Foods and Mortality

13 Aug, 15 | by EBM

By Dr. Geoffrey Modest

A large epidemiologic study from 10 diverse areas in China looked at total and cause specific mortality in those eating spicy foods (see BMJ 2015;351:h3942).


  • Spices (esp capsaicin) have antibacterial activity and modify the intestinal microbiome (no clear data on exactly how the microbiome is altered, or to what effect)
  • Capsaicin has been studied in small populations or experimental conditions, finding it has anti-obesity, antioxidant, anti-inflammatory, anti-cancer, antihypertensive effects, and improves glucose homeostasis.​
  • Ingestion of hot red pepper decreases the appetite of both Asian and white people (?decreasing obesity-related morbidity/mortalitychili-61898_640)
  • A large ecological study has found higher spice consumption is associated with lower cancer incidence (these are rough-and-dirty studies which just show that in areas of high spice consumption there is less cancer, without the specifics showing individuals who eat spice have less cancer)

Details of this study:

  • 199,293 men and 288,082 women aged 30-79, without known cancer, heart disease or stroke at baseline, had an initial food questionnaire including consumption frequency of spicy foods, then followed 7.2 years (3.5M person-years of followup) between 2004-2013.
  • mean age 50, BMI 23, 5% diabetic, 35% hypertensive
  • 11,820 men and 8404 women died during this time period
  • those who consumed more spicy foods were from more rural areas (48% of low consumers, 82% high), more likely to smoke (57% vs 70% for men and 1.8 vs 3.0% for women) and drink alcohol (27% vs 47% men and 1.2 vs 3.8% women), and more frequently consumed red meat, vegetables and fruits (though not huge differences in these numbers).  Most common spice was fresh or dried chili peppers
  • Absolute mortality rates (in deaths/1000 person years):
    • ​6.1 for those eating spicy foods <1x/week
    • 4 for those eating spicy foods 1-2x/week, adjusted hazard ratio compared to those <1x/week=0.90 (0.84-.96)
    • 3 for those eating spicy foods 3-5x/week, adjusted hazard ratio compared to those <1x/week=0.86 (0.80-.92)
    • 8 for those eating spicy foods 6-7x/week, adjusted hazard ratio compared to those <1x/week=0.86 (0.82-.90) — ie, a 14% relative risk reduction
    • The above numbers adjusted for underlying hepatitis, smoking, prevalent diabetes or hypertension, red meat or vege consumption, alcohol, SES, BMI, physical activity, family history
    • Overall, women did better than men, with a 20% risk reduction, vs 10% for men
  • The relationship between eating spicy food was stronger in those not consuming alcohol (p=0.033 for interaction). somewhat stronger benefit if eating fresh vs dried chili peppers
  • Inverse relations also noted for deaths due to cancer, ischemic heart disease, and respiratory diseases

So, a couple of comments:

  • This is a large epidemiologic study, subject to the usual caveats: concerns about adequacy of consumption data (only one initial dietary assessment, and self-reported; also those with high chili consumption likely used other unmeasured spices and ingredients) and adequacy of outcome data (quality of death reports). Also, hard to separate the non-measured differences between those living in more rural than more urban settings (and the difference in spicy food consumption was pretty striking in the different settings). Though it is notable that the high spicy food consumers did have some not-so-great lifestyle parameters (smoking alcohol, red meat). And, perhaps most importantly, epidemiologic studies preclude determining that a relationship is causal
  • In this study, there was a threshold: when people consumed spicy foods 1-2x/week, they achieved almost all of the benefit
  • But my real bottom line is that I should now add fresh chilies to my dark chocolate snacks.

[Here are a couple of the blogs on chocolate: and ]​

Primary Care Corner with Geoffrey Modest MD: Post-op Delirium in Elderly

12 Aug, 15 | by EBM

By: Dr. Geoffrey Modest

A recent study found a significant relationship between inflammatory markers and the development of delirium post-operatively (see doi:10.1093/gerona/glv083). This study assessed 566 patients >70yo undergoing major noncardiac surgery from the Successful Aging after Elective Surgery Study (SAGES), and compared 12 different cytokine levels in those patients who developed delirium vs not. Funded by the National Institute on Aging.


  • Inflammatory markers have been linked to a variety of outcomes in the elderly, including frailty, dementia and cognitive decline, as well as several medical diseases (diabetes, heart disease…)
  • Delirium is associated with systemic inflammatory states (eg, infections), perhaps related to inflammation-related breakdown of blood-brain barrier, microglial activation, and neuroinflammation.

Details of this study:

  • Mean age 77, 56% female, vascular comorbidity approx 45%, General Cognitive Performance mean of 55 (this is a composite measure reflecting vulnerability to delirium, which to my reading is a scale normalized to 50 for the elderly, with a score of 50 roughly correlating to an MMSE of 26, and a score of 55 correlating with 28)
  • Cytokines were measured at 4 times in all patients: pre-op (PREOP), post-anesthesia (PACU), post-op day 2 (POD2), and post-op day 30 (POD1M)
  • This was a case-control study matched for age, sex, surgery type, baseline cognition, vascular comorbidity, apo E genotype
  • Delirium was assessed by the Confusion Assessment Method algorithm
  • There was a 3-stage approach: a discovery cohort (n=272, comparing 39 matched pairs of delirium cases vs no-delirium controls), a replication cohort (36 matched pairs from the remaining SAGES sample), and a combo of these 2 (with 75 matched pairs).
  • Results:
    • The most consistently elevated statistically significant cytokines in the different cohorts:
      • IL-2, especially on POD2
      • IL-6 (the most elevated, and dramatically so), esp POD2
      • IL-12 was decreased, mostly POD1M
      • TNF-a (tumor necrosis factor alpha) and VEGF (vascular endothelial growth factor): both peaking on POD2
      • The association was found in all the cohorts, though less impressively in the replication cohort

This study confirms some previous studies finding an association between cytokines and delirium. In other studies IL-6 has been found to be associated with age-related frailty and dementia. IL-2 regulates growth and differentiation of T cells and affects the development of the immune system and also seems to induce blood-brain barrier dysfunction. A strength of the current study is that it had a real baseline cytokine measurement (some of the studies of patients with hip fractures could have had cytokine increases based on the trauma. This study was in patients getting elective surgery). Also, the cytokines measured in the current study did not include acute phase reactants.

So, delirium is a pretty awful disease for patients and family, with increased mortality, increased hospital stays with their attendant morbidity and cost, high rates of institutional placement, and perhaps even high risk of subsequent dementia. This study provides both a potential means to identify patients at high risk of delirium early, and could ultimately lead to new medications to prevent delirium (all to be determined). I did send out a previous blog on the efficacy of melatonin-like meds in preventing delirium (see )

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