Featured Post

Is the new professionalism and ACP's new ethics really just about following guidelines?

The Charter ( Medical Professionalism in the New Millennium.A Physician's Charter) did not deal with just the important relationship of ...

Friday, October 26, 2018

Cleveland Clinic article says the more fit live longer

Dr. Kyle Mandsager and colleagues at the Cleveland Clinic reported on the long term mortality  ( median followup of 8.4 years)  on 122,007 patients who were referred for symptom limited exercise treadmill testing.They were stratified by age and sex  into five cardiorespiratory  performance groups .(low,below average,above average,high and elite expressed as metabolic equivalent units (METs) which is 3.5 ml 02 uptake/kilogram/minute) which was estimated by treadmill incline and speed.

The 25th, 50th,75th and 97.7 percentiles were tabulated for age and sex .Low is defined as less than 25 th percentile and elite as greater than 97.7 th percentile.

They found that cardiorespiratory fitness (CRF) was "inversely associated with long term mortality with no observed upper limit of benefit. Cardiorespiratory  fitness is a modifiable indicator of long term mortality …"

We have another coarse grain study that could be used to support  the thesis that exercise is good and lots of exercise is better and you will live longer. I don't believe it is that simple.

 This study does not correlate exercise history with longevity rather it correlates exercise performance with longevity. Admittedly exercise performance or capability does correlate with exercise history but they are not exactly the same thing.  Further, while it may well be the case that CRF is modifiable and  that one can actually improve mortality by improving one's CRF their data does not direct address those point although I like to believe that proposition is true.

What is shown impressively in their Figure 1, is  the 10 year survival probability for the above average or the high group is about 95% ( just by my eyeballing the chart) versus the low group where the survival probability is slightly less than 80%

So how low is the low group in terms of exercise capability.For example in the 70-79 year age group the low group had a MET of less than 6. Some one in that category(assuming a reasonably functioning orthopedic and neuromuscular system)  could likely walk a mile in 15 minutes or complete Stage 1 of the Bruce treadmill protocol. 

What about a 40 year old? Subjects in the 40-49 year old group had a MET levels of less than 9.8. This corresponds to being able to finish Stage 2 and a bit into Stage 3 and be able to run a 12 minute mile.

Someone in the high category would have a MET value of 12.5 to 14.6 which corresponds to being able to reach Stage 5 on the Bruce  protocol and run a mile in 9 minutes.

The authors made comments that are headline attractors.  "The increase in all cause mortality associated with reduced CFR (low versus elite:adjusted HR,5.04:95% CI, 4.10--6.20;p<.002) was comparable to or greater than traditional risk factors." See figure 2 in their artcle for details of that comparison.<0 .001...was="" 2="" comparable="" compared="" diabetes="" esrd.="" factors.="" factors="" figure="" greater="" hypertension="" nbsp="" or="" p="" risk="" see="" smoking="" than="" the="" their="" to="" traditional="">

Skeptics of the thesis that there is a "U -shaped"curve relating risk of death to exercise level will perhaps find some comfort in their finding : "There was also no evidence to suggest relative harm associated with extreme levels of fitness in these subgroups of patients"In fairness I should add that no one has claimed that excessive fitness is deleterious but rather the claim has been that excessive exercise may be harmful, again realizing that fitness levels and exercise levels are highly correlated. 

I don't think anyone has claimed that being too fit is harmful to health or lowers longevity. 

Nitpicking aside, their data provide more fuel to the argument that exercise ( or at least CRF) is good and apparently the more the better.

1)Mandsager,k et al "Association of cardiorespiraory fitness with long-term mortality among adults undergoing exercise treadmill testing" JAMA Network open, 2018 1 (6)Oct 19


Friday, October 19, 2018

Changing status for use of aspirin in primary prevention of heart disease

In the not too distant past based in part  on the results of the Physicians Health Study (1989) and the Women's Health Study (2005) it seemed reasonable to recommend aspirin for cardiovascular disease prevention. Recommendations were typically based on various guidelines that were estimates of a person's risk based on various risk factors such as cholesterol level,Blood pressure, smoking status, family history, etc. Since age is a major risk factor many of elderly are taking low dose aspirin with or without a physicians's advice.Is that still a good idea?

Dr. Paul Ridker in an editorial in the NEJM (1) questions whether the old advice is still justified in light of more recent clinical trial data  and perhaps a changing risk baseline for the population in general. More people now are on medication for blood pressure,fewer smoke and many more now are taking statin drugs than they were at the times of the PHS and WHS.

In the same issue of NEJM 3 primary prevention trials were published. Only the trial in diabetic patients (the ASCEND trial) was there shown to be a statistically signficiant reduction in vascular events with asprin. A 12% reduction is vascular events was countered by a 29% increase in major bleeding and the all-cause mortality was the same in the control and the treatment groups.

The ARRIVE trial was  a primary prevention trial in"high risk " subjects The intention-to-treat analysis showed that the primary outcome was the same in the control and aspirin groups. The primary outcome was a composite of stroke,heart attack,unstable angina,TIAs and death from CV causes.Gi bleeding was twice as common in the aspirin group.

The ASPREE trial was a primary prevention trial in subjects 70 years of age and older who were free of CV disease ,dementia or disability on entry into the study. After five years of 100 mg aspirin a day versus placebo there was no CV benefit .There was more GI bleeding with aspirin ( Hazard ratio of 1.39).

So unlike aspirin's well established  role in secondary CV disease prevention the benefit-risk ratio in primary prevention is ( in Ridker's words) "exceptionally small" . Dr. Ridker has been an advocate of statin use and it is not surprising  that he ends his commentary with: "Thus beyond diet maintenance,exercise, and smoking cessation,the best strategy for the use of aspirin in the primary prevention of cardiovascular disease may simply be to prescribe a statin instead."

1) Ridker, PM Should Aspirin be used for primary prevention in the post-statin era? NEJM 379;16 oct 18 2018. 1572

Saturday, October 13, 2018

More physical activity may be needed to prevent HF than some other CVD events

 The title is a reworded version of the title of the article which is designated as reference 2 in the footnotes.

There are  2 (at least 2) epidemiologic studies that indicate a linear dose-response relationship between physical activity (PA) and the risk of heart failure. While one study ( Pandy et al see below) does demonstrate a "modest" reduction in HF risk at a lower levels of PA, both studies report a more robust reduction in HF at higher exercise levels.

Pandy et al (Circulation 2015,, see ref 1 below) did a meta-analysis involving about 370  thousand subjects , 20 thousand of which developed HF over a 13 years period.They compared the HF risk in 3 categories based on level of exercise, namely 500 MET-min per week ,1000 MET-min per week and 2000 MET-min per week.

500 MET-min per week is equivalent to 2.5 hours of "moderate" exercise per week or 1.25 hours of "vigorous" exercise per week.Moderate is defined a exercise requiring 3-5.9 MET and vigorous as about 7 METS. (It requires about7 METS to run a 15 minute mile or to finish Stage 2 on the Bruce protocol treadmill exercise tests. One should be able to walk a fifteen minute mile with a 02 consumption of 5 METS.)

1000 MET-hrs per week is 5 hours of moderate or 2.5 hours of vigorous exercise per week and 2000 as twice that or 10 hours of moderate exercise per week. Yes, that does seem like a lot,

Both the 2008 US exercise  guidelines and the 2018 guidelines recommend at least 500 but state that more benefits accrue with higher levels .

Pandy reported a linear dose response with a "marked reduction in risk at very high doses of PA ( about 35%) at 2000 MET-min per week".This would be 10 hours of moderate or 5 hours ofvigorous aerobic activity.

Their data:
exercise level                                HF RF

500 MET minutes  per week            0.9 (0.87-0.92)
1000 "  " " " " " " " "                       0.81(0.77-0.80
2000 "  "   "   "" """""                     0.65 (0.58-0.73)

Quoting the authors; "Only a moderate reduction ( about 10%) risk in HF noted at the minimal ( US guidelines) recommended level,"

The authors offer a mechanistic explanation namely that CAD event risk reduction occurs at a lower level of exercise by reducing the usual suspect Risk factors (BP,Lipids,blood sugar control) while HF risk reduction occurs at a higher levels of exercise perhaps  by altering cardiac function and structure, i.e beneficial remodeling,perhaps mitigating the age related loss of left ventricular compliance

An earlier article Patel K, (Int J Cardiol 2013 see ref 2) had reached generally similar conclusions regarding the levels of exercise needed to decrease HR risk versus the amount adequate to  reduce general  CV risk,

Patel et al studied 5503 patients age 65 and older
During the 13 years of follow up incident HF developed in:
26% of those with little or no regular exercise
23% of those with "low"level of exercise
20% of those with "moderate"
19 % of those with high .

Low was defined a 1-499 Met-min per week
medium as 500-999
high as greater than 1000

The HRs for incident HF were:
low level exercise     0.87 (0.71-1.06)
medium                     0.68 (0.54-0.85) stat sig 
high                            0.60 (0.49-0.74) stat sig 

All exercise level groups had reduced HR for incident MI, stroke, and cardiovascular mortality but the lowest level group did not have a statistically significant  decrease in HF risk.

These 2 studies indicate that more exercise is associated with greater reduction in HF risk, although some  HF decrease was noted in the lowest exercise group in the Pandy study.

Now for something completely different. A different type of study published by CR de Fillippi from the Cardiovascular Health study ( reference 3) provides an interesting  insight regarding possible mechanism(s) by which more exercise is better in terms of HF risk reduction. 

They studied 2, 9333 subject free of HF at the onset and  who had normal values for two biomarkers, NT-Pro BNP and cTnT (troponin).They then measured these markers every 2 to 3 years and compared incident increase in those markers in groups divided by their exercise levels.(They quantitated exercise using  a particular system and used numerical scores to define groups and I was not able  to translate those values in to MET hrs to compare with the other 2 articles)

 They found compared with the participants with the lowest PA activity scores those with the highest (i.e. more exercise) had an low odds ratio of 0.50 (0.33-0.77) for a significant increase in NT proBNP and an OR of 0.3 for and increase in troponin.  Quoting  the authors "increased levels of NTProBNP and cTnT may reflect pathological precursors of hemodynamic stress and injury that are prevented by PA at some as yet more precisely defined level.

So how to put all this together.

An  appealing ( at least to me) mechanistic explanation is that an overall decrease in CV mortally and arguably a slight reduction in HF risk  can be brought about by modest exercise and even  perhaps slightly less  than modest levels  by reducing the usual suspect,traditional CVD risk factors.Modest here refers to about 500 MET hrs per week. but some studies have shown a decreased heart attack risk at even lower exercise levels.

A more robust risk reduction in HF risk (perhaps 20-35%) seems  to require higher levels of exercise  ( in the 1000 Met-hrs per week range and higher) by perhaps bringing about an advantageous remodeling of the heart or at least a mitigation of the deleterious remodeling of the heart than occurs with sedentary aging which in turn may predispose to the development of heart failure with preserved ejection fraction (HFpEF).

To the extent that CVD risk factor reduction can decrease heart attacks and the  accompanying reduction in   heart function some reduction in HF risk would be likely, i.e.some reduction in heart failure with reduced ejection fraction ( HFrEF). But at least half of cases of HF are not associated with decreased systolic function ( at least as measured by the ejection fraction  (EF)) but by the echocardiographic findings of decreased left ventricular compliance and distensibility which according to the work of Dr. Ben Levine and others at SW  Medical School in Dallas predispose to diastolic heart failure  (HFpEF) .That group suggests that at least 30 minutes of exercise 4 to five times a week might be sufficient to prevent that age related loss of cardiac compliance. ( see ref 4 below for more on this argument) and perhaps prevent at least some cases of HFpEF. It would be nice if as little as 30 minutes 5 times a week would be sufficient.

1)Pandy,A "Linear,dose dependent inverse association between PA(physical activity) and heart failure risk Circ. 115.132 p 1786-1794

2.Patel K. "Prevention of heart failure in older adults may require higher levels of physical activity than needed for other cardiovascular events." Int J Cardiol. 2013, Oct 168 (3) 1905-1909)

3)de Fillippi, CR "Physical activity, change in biomarkers of myocardial stress and injury, and subsequent heart failure risk in older adults. JAm Coll Cardiol.. 2012 Dec. 18;60 (24), 2539-47

4) Bhella, PS  "Impact of lifelong exercise "dose" on left ventricular compliance and distensibility"J Amer coll cardiology. 2014 , 64, no 12,p 1267  

Addendum 7/13/20 In the table of Pandy's data I had erroneously type Met hr instead of Met minutes.

Tuesday, October 09, 2018

2018 U.S. exercise guidelines-or how exercise is good for just about everything

The 2018 Physical Activity Guidelines Advisory Committee issued its report to the Secretary of HHS in February 2018.See here for link to full report.

Their prescription for exercise was unchanged from their 2008 recommendations.  They recommend 2.5 to 5 hours of moderate to vigorous exercise per week. This can also be expressed as 500 to 1000 Met-minutes per week. "Moderate" is defined as exercise requiring between 3 and 5.9 METS and "vigorous" as greater than 6 METS.

To put those numbers into perspective , consider than it would require about 7 METS to run a fifteen minute miles and about 5 METs to walk a fifteen minute mile and about 9 METS to run a 12 minute mile. It requires about 7 METS to complete Stage 2 on the Bruce treadmill protocol .A MET is 3.5 ml of oxygen per kilogram weight per minute. 

Now, about how exercise (physical activity or PA) is good for just about everything. 

The 2008 exercise guidelines reported that PA could lead to a reduction in risk of breast cancer and colon cancer . The 2018 reports adds the following cancers to those whose risk is reduced by PA :
bladder, lung, esophagus, endometrium and stomach.But reduction in heart disease risk is the major selling. point for an exercise program as well as decrease in diabetes and hypertension risk. 

The publication also offers evidence of a risk reduction for dementia and depression.

If the benefits of exercise could be achieved by a daily  pill, everyone would be taking it.