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Cardiol – CAD

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 doi.org/10.1016/S0140-6736(17)30770-5)

 

Details:

— 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

 

Results:

— 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.

 

Commentary:

— 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.

Details:

— 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.

Results:

— 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.

Commentary:

–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 https://www.fda.gov/Drugs/DrugSafety/ucm475463.htm​ ), 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: 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.)

Details:

— 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

Results:

— 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

 Commentary:

— 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: Nature vs nurture: studies on lipids and NAFLD

6 Jun, 17 | by gmodest

by Dr Geoffrey Modest

2 recent articles found significant genetic associations with 2 common clinical conditions: hyperlipidemia and non-alcoholic fatty liver disease (NAFLD). I bring these up to make the point that, though there is often a genetic association with disease, usually this is not determinant and there is an important role for a healthy lifestyle both in preventing the disease from happening and treating it if it does happen.

***Whole genome sequencing of two populations on the island Crete found some genetic variants which were either completely new, or rare in other populations, including one associated with increased HDL levels, and  another with decreased triglycerides and VLDL levels (see DOI: 10.1038/ncomms15606)

 

Details:

–945 patients from Crete, and specifically from Mylopotamos and Pomak villages, had genome-wide association studies done to look for common-frequency variants with small-to-modest effect sizes, evaluating 29 million single nucleotides variants in the Pomak and Mylopotamos cohorts. These results were imputed and validated for the larger populations in the areas

–there were 17 genome-wide significant independent signals found, including 2 novel cardiometabolic associations:

— chr16:70790626 for increased high-density lipoprotein levels (explaining 3.24% of the phenotypic variance in the Mylopotamos cohort)

— rs145556679, associated with decreased triglycerides and VLDL, so far only found in the Mylopotamos cohort and no other worldwide cohort.

— rs13382259, associated with decreased diastolic blood pressure in the Pomak population

Commentary:          

–one advantage of looking at an isolated population is that low-frequency alleles will be amplified by the more limited gene pool

–though not commented on in the article, people from Crete are among the longest-livers in the world: Mylopotamos is called “Village of Long Life”. Of note, there is a similar genetic variant in isolated Amish populations in the United States. Interestingly, the people from Mylopotamos do eat a largely Mediterranean diet though their diet is high in animal fat, but with less atherosclerotic disease than would be predicted by their diet

***5-8% of lean people have evidence of NAFLD, despite the strong association with obesity. This study looked at 3 groups of patients stratified by BMI (see DOI: 10.1038/ajg.2016.318).  This is an Austrian study limited to Caucasian people; the prevalence of lean patients with NAFLD has been well-documented to be higher in Asian people but Caucasians had not been assessed previously. I am not sure about lean African Americans, though their overall prevalence of NAFLD is lower than either Latinos or white patients. This study was a subsample of the 2500 people in the Salzburg Colon Cancer Prevention Initiative study.

Details:

–187 nondiabetic patients were assessed by BMI groupings and had ultrasound evaluation:

–lean healthy: BMI <25, no steatosis, n=71

–age 56, 25male/46 female, bmi 22.7, whr 87 cm (waist-to-hip ratio), ALT 17, diabetes 0, impaired fasting glucose 13%, HDL 67/LDL 120/TG 86, A1c 5.4, adiponectin 13.8 [adiponectin has many functions but higher levels are associated with more insulin sensitivity], FIB4 score 1.2 [a noninvasive measure of hepatic fibrosis]

–lean NAFLD: BMI <25, steatosis, n=55

–age 61, 26male/29 female, bmi 23.6, whr 91 cm, ALT 21, diabetes 31%, impaired fasting glucose 20%, HDL 58/LDL 136/TG 117, A1c 5.5, adiponectin 10.4, FIB4 score 1.3

–obese NAFLD: BMI>30, steatosis, n=61

–age 63, 29male/32 female, bmi 32.7, whr 113 cm, ALT 28, diabetes 36%, impaired fasting glucose 32%, HDL 45/LDL 139/TG 169, A1c 5.8, adiponectin 8.9, FIB4 score 1.1

–all had oral glucose tolerance test,  serum metabolome, and genotyping for single-nucleotide polymorphisms (SNPs) associated with NAFLD

Results:

–lean NAFLD patients had fasting insulin levels similar to lean healthy ones, but did have markedly impaired glucose tolerance

–lean NAFLD patients  had a higher rate of the mutant PNPLA3 CG/GG variant vs lean healthy, 59% vs 35%.

–serum adiponectin levels were decreased in both NAFLD groups vs lean healthy (p<0.001 for both groups)

–metabolomics study showed variations in lysophosphatidylcholines, phosphatidylcholines, lysine, tyrosine and valine (several of these may have anti-inflammatory effects and increase insulin secretion, which could explain some of the differences in glucose tolerance between the groups)

–clinically no difference in lifestyle habits between the 2 lean groups, though the obese group did have more people consuming fast food at least once a week and had lower physical activity

Commentary:

–NAFLD is certainly much more prominent in those with obesity than in lean patients, though this does raise the question as to whether the prognosis is the same in these 2 BMI groups.  They did not do transient elastography (Fibroscans) or get liver histology in this study, though the lean NAFLD group did have the highest FIB4 score (suggesting more hepatic fibrosis, with a score of 1.3 being the cutpoint, suggesting that NAFLD is likely to be deleterious in this group)

–lean NAFLD patients were in between lean healthy and obese NAFLD in terms of metabolic derangements, though they did have much more impaired glucose tolerance than the lean healthy ones, and about 30% did have diabetes as defined by either fasting plasma glucose, impaired glucose tolerance, or A1c levels. The lower adiponectin levels in the two NAFLD groups further confirm their relative insulin resistance.

–the rate of the PNPLA3 allele were similarly high in both NAFLD groups, and much higher than in the lean healthy ones  (p=0.007). This does suggest that this genetic variant does seem to be associated with NAFLD independent of BMI (though not determinant, since 35% of the non-NAFLD people also had this allele). Unfortunately, there were no granular data presented to see if it were just this SNP which was responsible for the NAFLD, or if this subgroup happened to have a less healthy lifestyle. Would also be interesting to know if there were differences in their microbiomes as well, which is also affected by diet and exercise. See the multitude of prior blogs on NAFLD in the http://blogs.bmj.com/ebm/category/gi-liver/ category, or just type NAFLD in the search window.

The reason I am evaluating these articles is to raise the general points that:

–clinically, we should still be suspicious of these underlying medical issues in patients who do not seem to fit the phenotype: a younger thin and athletic person who has a bad lipid profile, a thin person with an increase in their ALT levels on liver function testing, or evidence of fatty liver disease or glucose intolerance.  All of these people may have underlying medical problems (respectively, atherosclerotic disease, NAFLD) which might well affect their longer term morbidity/mortality

–and some anecdotes to fill this in, reinforcing the genetic components:

–one of my residents a few decades ago was curious about the strikingly high incidence of ASCVD/MIs in thin, athletic men in their 40’s in his Indian community near Boston. These men had surprisingly low HDL levels

–and lots of people who are morbidly obese with A1c in the mid 4 range, yet many who are much less obese (and some normal weight) who are either pre-diabetic or diabetic; I have found glucose intolerance in several thin patients with family history of diabetes

–as another example showing that risk factors may be discordant from the clinical picture: though obesity is the dominant risk factor for obstructive sleep apnea, it is found in about 11% of men with normal weight and about 3% of women (overall it is 2-3 times more common in men)

–so, we should think about risk factors when we see patients, but not be swayed too heavily and keep open mind to these diagnoses. Genes may be the dominant player in some patients.

 

On the other hand, there is usually some interplay between nature and nurture. Helping patients develop healthy lifestyles may well counteract the potentially deleterious effect of the genes, or potentially lead to more aggressive preventative approaches (eg, earlier uses of statins to prevent cardiac disease, etc)

–one interesting and I think poignant example of the nature/nurture interplay is that of the US Pima Indians in Arizona, who reportedly have the highest rates of diabetes and obesity in the US (see Schulz. Diabetes Care 2006; 29: 1866). In 1890 their water supply was taken over by white settlers, making it impossible to continue their agrarian lives. The US government subsidized  the food supply with sugar and white flour, and the previously lean population developed obesity and diabetes. It turns out that a group of Pimas, speaking the same language and from the same genetic stock, live in remote areas of rural Mexico and continue to practice their traditional agriculture. These Mexican Pimas have similar lower levels of obesity as other non-Pimas living in the same remote areas (around 7% in men and 20% in women), and have rates of diabetes close to the other non-Pima Mexicans (6.9% vs 2.6%). But the US Pimas have diabetes rate of 38% —  more than 5-fold higher!!! (and 68% in men older than 45, 70% of women older than 45 and 82%of women older than 55), which tracks with prevalent obesity (mean BMI=34), as well as their dramatically lower levels of physical activity there. A pretty clear example of a strong genetic predisposition to diabetes which manifests itself in the setting of a nonhealthy lifestyle/obesity….

so, I think all of this points to the fact that there are often important genetic factors leading to disease,and we as clinicians dealing with individual patients should still be attuned to patients who do not exhibit the typical profile (eg, those with high predisposition to heart disease or have abnormal LFTs from NAFLD but appear to be young and fit, or those who have OSA but are also of normal weight). And healthy lifestyles may not just help with these targeted diseases but are generally beneficial (collateral benefit… see blogs showing likely benefit from cancer, Alzheimers etc etc)

See here  for projected decreased cancer risk from exercise

See here for projected cardiovascular benefit from cardiovascular fitness

See here  for dietary influences on Alzheimers

Or, a slew of blogs on the benefits of Mediterranean diets

Primary Care Corner with Geoffrey Modest MD: Hemoglobin A1c reduction and decreased cardiovascular event

8 May, 17 | by gmodest

​by Dr Geoffrey Modest

A recent cohort study found an association between those patients who achieved an early reduction in HbA1c with metformin and a significant reduction in subsequent cardiovascular events (see DOI: 10.2337/dc16-2271).

 

Details:

— a population-based cohort study in northern Denmark from 2000-2012 assessed 24,752 new-onset diabetics 6 months after initiating metformin therapy

— median age 62.5, 55% males. Median follow-up 2.6 years

— primary endpoint: subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA1c and other confounding factors (age, sex, year of starting metformin therapy, microvascular and macrovascular complications, obesity, alcoholism, antiplatelet drugs, statins, antihypertensives, psychiatric medications, achieved cholesterol target, and use of other unspecified glucose lowering therapy). socioeconomic status was adjusted by using education as a proxy.

 

Results:

— those who achieved A1c <6.5% tended to be older (> 70yo), female, and more likely to have initiated metformin later in the study (between 2010-2012), tended to have slightly more microvascular and macrovascular complications at baseline, take more preventative medications, and have less obesity. They also tended to have lower baseline A1c initially.

— those with the greatest point reductions in A1c tended to be younger, had lower prevalence of macrovascular complications, less comorbidity, and took fewer preventive medications. They also tended to have the highest baseline A1c and received more additional glucose lowering therapy.

— During the follow-up, there were 439 incident MIs, 594 strokes, and 1845 deaths.

— the risk of a primary end-point, compared with an achieved HbA1c <6.5% in the adjusted model, was:

— 6.5-7%: 18% increased risk, HR 1.18 (1.07-1.30)

— 7-7. 5%: 23% increased risk, HR 1.23 (1.09-1.40)

— 7.5-8%: 34% increased risk, HR 1.34 (1.14-1.57)

— >8%: 59% increased risk, HR 1.59 (1.37-1.84)

— these results were consistent for the individual outcomes, age groups, presence or absence of comorbidity at baseline, or socioeconomic status.

— the clearest association between higher A1c and worse clinical outcomes was in patients >70 years old.

— a 4% absolute decrease in HbA1c was associated with a 20% decreased risk of a primary outcome; lesser degrees of risk reduction were not statistically significant

 

Commentary:

— observational data from many studies are quite consistent that there is an increased risk of atherosclerotic disease in diabetics, and that this increase starts early in the prediabeticrange (eg A1c 5.5-6), especially in men, and increases with increasing A1c. The data on decreasing risk by lowering A1c is less clear, and seems to be dependent on the medication used. Some medications have some reasonable support for cardiovascular benefit, including metformin, pioglitazone, and GLP-1 agonists (I am very suspect about empaglifozin, see below). It is important to know that the published target of getting the A1c’s as low as possible, around 7% or even lower, are based on decreasing risk of microvascular complications found in several studies, not the really important macrovascular ones (80% of diabetics die from cardiovascular causes). Which is not to say that microvascular complications are not important…

–As noted in prior blogs, the ACCORD study questioned the utility of lower A1c targets for macrovascular protection but (I think) is overquoted and has led to a more lackadaisical approach to diabetes management. See blog noting that “A subgroup analysis of this ACCORD study actually found that those who achieved a lower A1c in fact did better (in terms of cardiovascular endpoints), all the way down to an A1c of 6!!, but as the number of meds needed in the attempt to lower the A1c increased, they had worse outcomes (i.e., those in the intensive therapy group who had medication-flogging to improve their A1c had worse outcomes even at a much higher A1c). See Riddle MC. Diabetes Care; 33:983.” Also see the blog which goes into more detail on ACCORD. So, my conclusion was that the lower the A1c, the better in terms of macrovascular complications in ACCORD, but only if this lower A1c can be achieved easily with meds (and, reinforcing the above comment, the choice of meds may be extremely important. For example, in the ACCORD study, 91% of those in the aggressive treatment arm took TZDs, and mostly rosiglitazone, known to increase cardiac mortality!!!. Interestingly in this current study, those >70yo did better cardiovascular-wise if their A1c were low with metformin, which suggests that age may not be the decisive factor in targeting A1c goals, but perhaps other things (comorbidities, longevity predictions), though my sense is that currently clinicians are somewhat more hesitant to be aggressive with older patients, quoting the ACCORD trial

–one peculiar aspect of this study to me was why did so many patients have high A1c’s 6 months after starting metformin? My clinical experience, with a few dozen new-onset diabetics (though not the 24.7K in this study), is that they uniformly respond to metformin with essentially normalization of their A1c, independent of how high their initial A1c was. Even patients with A1c’s in the 15-18% range decrease to <7% with just metformin 500 mg once a day. The purported explanation for this is that they have glucotoxicity, whereby the increased blood sugar leads to decreased insulin effectiveness (as shown, for example, in decreased insulin-mediated glucose uptake into muscle), and this is true in laboratory situations with both diabetics and nondiabetics.  Typically new-onset diabetics need insulin injections early on to help decrease the blood sugar, thereby decreasing the glucotoxicity for which their struggling pancreas cannot compensate with more insulin production, and then, when their blood sugars are lower, their marginal endogenous insulin reserves work. And in my experience exogenous insulin can uniformly be stopped, typically within 1-2 months, and some do not even need to continue the metformin (at least for months to years, when their pancreases get increasingly tired).

–and, why did those with high A1c’s 6 months after starting metformin do so poorly? was it simply poor glucose control? or, were those who did not achieve a low A1c fundamentally different from those who did, perhaps in unmeasured ways?? did they have diabetes longer, leading to more atherosclerosis (ie, was the increase in cardiovascular events really just lead-time bias, where those with longer duration of diabetes before diagnosis had more atherosclerotic disease just because they had diabetes for longer)? Or, is their diabetes fundamentally different: do the ones who easily achieve really low A1c levels have a different, “mild” type of diabetes and would not get heart disease for a really long time anyway, while others have great difficulty getting their diabetes controlled, have more complications, but the complications have nothing to do with the A1c level achieved but with the fact that they just have “aggressive” diabetes???

–also, unfortunately, in the above study there were obvious important unmeasured factors, including smoking, BMI, diet, physical activity, social support, patient motivation, etc. which really could affect their results. And there may also have been an inherent bias that clinicians tried to get better blood sugar control in patients who were healthier and they felt had a better prognosis, so actually had less cardiovascular disease because of that? (this is hard to sort out in an observational study as this one)

—  As a side issue, studies like this one from Denmark, as well as others from most European countries, showcase the advantages of their having extensive medical databases, linkages to prescription data, linkages to social/demographic data, and nearly 100% followup.  The US, with the most expensive medical system in the world, unfortunately pales in comparison (?reflecting different priorities in public health???)…

 

so, why do I bring up this article, given the above limits of the interpretability of such an observational study?  a few reasons:

–I think there probably is value to more aggressive diabetes treatment to lowering cardiovascular events (and, again, this is what kills diabetic patients). and I think the results of the ACCORD trial weigh much too heavily on the various guidelines, since this study (i think) was quite flawed

–I think that we should really move towards using diabetes medications which have the clearest cardiovascular benefit (eg metformin, GLP-1 agonists, as opposed to insulin and sulfonylureas) as a priority, vs just focusing on achieving the best “number” for our A1c’s (untested, just my thought), though it is clear that A1c level is important for the microvascular complications

–I think studies like this one should stimulate us to question our model of disease (diabetes, here). Is it one disease or a combination of different ones with different outcomes but we lump them together (sort of like breast cancer: some are really aggressive and spread even before we can even detect them. some slowly increase in size and are easily treated but may not change life expectancy much…..)?

–and, I think it is a clinically useful and important intellectual activity to look at studies like this one (which I do think has some validity) in order to reflect on and critique the study; think about its potential biases, assumptions and limitations to its generalizability; and figure out if or how it should be incorporated into our understanding of the disease and how we should treat patients (though oftentimes these studies raise more questions than they answer, but maybe the questions are more advanced as we see more studies and get more data…..).  This is one of my main impeti (?plural for impetus) for doing these blogs. I think that overall in medicine we are deluged/overwhelmed daily with huge numbers of medical articles, guidelines, etc. And my concerns are that in many cases we just hear about/read the bottom line: does the med work?? etc. And the studies are mostly funded by drug companies. And they design them to optimally get the result they want. And many of the details of the study are buried in the text (and, more and more, buried in the supplemental material, for which one needs either a subscription to the journal or access to a medical library, but in any event takes even longer to sort out). See empagliflozin blog listed below as one of many examples of what I think is a poorly designed drug-company sponsored study. And nowadays the drug companies seem to have greater access to the media, who also publish a not-so-in-depth review, and they certainly have much more access to direct-to-consumer advertising, both of which may push us to prescribe these drugs.  So, all in all, it is getting much harder to read the onslaught of medical information critically, decipher it, and apply it appropriately. And I hope these blogs help a little …..

 

See here and here for blogs critiquing the empaglifozin study, suggesting that the accepted cardiovascular benefit is not so clear when one scratches the surface of the article. It also comments on the benefits found with metformin and pioglitazone in other studies.  Though I should add that the FDA does have warnings about these SGLT-2 inhibitors (such as empagliflozin) causing acute renal injury, ketoacidosis, urosepsis/pyelonephritis, and genital mycotic infections  (see https://www.fda.gov/Drugs/DrugSafety/ucm475463.htm)

 

See blog on liraglutide, a GLP-1 agonist, which I think really does have significant cardiovascular benefit, as well as powerfully lowering A1c levels

Primary Care Corner with Geoffrey Modest MD: Statin myopathy and vitamin D deficiency

1 May, 17 | by gmodest

by Dr Geoffrey Modest

A recent editorial provided reasonably convincing evidence that there is a relationship between low vitamin D levels and statin associated muscle symptoms, SAMS (see Glueck CJ. Atherosclerosis. 2017; 256: 125). See article for the references.

 

Details/summary of data:

— one study showed an inverse relationship between CK levels and vitamin D levels in patients on simvastatin, independent of symptoms

— a non-blinded study with high-dose vitamin D to normalize serum levels found that up to 95% of 134 patients with SAMS were free of muscle symptoms on reinstating statins, and this continued for up to 24 months later (the last time point measured)

— another trial of 150 patients with SAMS with a median vitamin D of 21ng/ml and given vitamin D supplements found that 87% were successfully able to restart their statins and remain symptom-free for 24 months

— a meta-analysis of 2420 patients documented that vitamin D levels tend to be lower in patients with SAMS; several other studies have confirmed that in patients with SAMS and low vitamin D levels, repleting the vitamin D levels leads to about 90% being able to tolerate rechallenge with statins

 

Commentary:

— SAMS is quite frequent, varies somewhat depending on the statin use/dose, but is reported in about 10% of patients.

— Myopathy is also a reasonably common symptom of vitamin D deficiency

— there are studies which suggest that even those with intolerable muscle symptoms from 3 or more statins, only 43% had muscle symptoms on rechallenge (and 27% had muscle symptoms only on placebo, 17% had symptoms to neither drug). ie, there is likely a pretty big placebo effect. Though the 90+% success rates with vitamin D noted above are a bit eye-popping.

— so, a provocative editorial. Clearly, especially in light of the potentially large placebo effect, and in light of the importance of statins in preventing clinical cardiovascular outcomes, there should be a well-designed randomized control trial to assess the true benefit of vitamin D repletion in those with SAMS who are vitamin D deficient. It is notable in several of the uncontrolled studies, increasing vitamin D even in patients with levels in the low 20 ng/ml range was effective, which is actually above what the Endocrine Society defines as deficient, <20 ng/ml. so, it makes sense in future RCTs to look at those patients who have SAMS and with 25-OH vitamin D levels <30 ng/ml or so to see if vitamin D supplementation helps, or perhaps in all-comers to see if there is a 25-OH vitamin D threshold.  The meta-analysis mentioned above found that the difference in vitamin D levels in those with and without SAMS was 28 vs 35 ng/ml.

 

Bottom line: statins are important for many patients, SAMS is common as is vitamin D deficiency, there are likely other benefits from vitamin D sufficiency anyway, vitamin D supplementation is pretty benign and inexpensive, so to me it seems reasonable at this point to try vitamin D supplementation in patients who are intolerant of statins because of SAMS, even if there baseline levels seem pretty good.

 

see here for an array of blogs on vitamin d.

 

Primary Care Corner with Geoffrey Modest MD: Chest pain prediction tool

28 Apr, 17 | by gmodest

by Dr Geoffrey Modest

The second article on the ED evaluation of chest pain involved an instrument to predict/stratify cardiac risk, finding it to be quick, reliable and efficient (see doi:10.7326/M16-1600).

Details:

–Nine Dutch hospitals assessed the HEART instrument prospectively to evaluate unselected patients presenting to EDs with chest pain, in a sequence where every 6 weeks, 1 hospital was randomly switched to using the instrument. Publicly-funded study.

–3648 patients (1827 receiving usual care, 1821 HEART care)

–Exclusion criteria included evident ST-segment elevation MI.

–The HEART score is based on History, Electrocardiogram, Age, Risk Factors, and Troponin levels , with each having a score range of 0-2 (go to https://www.mdcalc.com/heart-score-major-cardiac-events for HEART score calculator):

–score of 0-3 is low-risk, and the patient was to be discharged with reassurance

–score of 4-6 is intermediate-risk, with recommendation for hospitalization for observation and investigation

–score of 7-10 is high-risk, and prompted invasive treatment

–But, physicians could overrule the score’s recommendation

–primary outcome: incidence of MACE (major adverse cardiac events) within 6 weeks, including: MI (with or without ST-segment elevation), unstable angina, percutaneous coronary intervention, CABG, >50% stenosis treated conservatively, or death from any cause

Results:

–low HEART score found in 715 (39%); intermediate in 231 861(47%), and high in 190 (11%)

— MACE within 6 weeks, after using HEART was 1.3% lower than during usual care (ie non-inferior):

–HEART: 18.9%

–usual care: 22.2%

–Usual care: 405 patients (22.2%): 9 (0.5%) cardiovascular death, 400 (21.9%) with cardiac ischemia, 290(15.9%) with significant stenosis

–breakdown of MACE by HEART score:

–low score: 14 patients (2.0%): 1 (0.1%) cardiovascular death, 10 (1.4%) with cardiac ischemia, 10 (1.4%) with significant stenosis

–intermediate score: 175 patients (20.3%): 2 (0.2%) cardiovascular death, 162 (18.8%) with cardiac ischemia, 117 (13.6%) with significant stenosis

–high score: 140 patients (73.7%): 2 (1.1%) cardiovascular death, 143 (75.3%) with cardiac ischemia, 102 (11.8%) with significant stenosis

–no difference in early discharge, readmissions, recurrent ED visits, outpatient visits, or visits to general practitioners

–BUT, nonadherence to protocol occurred in 313 of 1766 (18%) of patients, 291 of 715 (41%) of low-risk patients and 22 of 190 (12%) of high risk patients. Nonadherence for low-risk patients consisted of prolonged observation or hospitalization after presentation at the ED in 80% of them, a 2nd troponin measurement in  58%, and stress exercise testing in 18%. No data were presented on outcomes of those patients who are on-protocol vs those who were outside of the protocol

— overall, for the low-risk patients (39% of the total), the HEART score was 99% sensitive in identifying these patients as low risk and eligible for early discharge.

Commentary:

–only 20% of patients coming to the ED with chest pain have acute coronary syndrome. But one of the difficulties is that about 50% with acute coronary syndrome do not have classic symptoms. And 2-6% of patients with acute coronary syndrome are missed by current practice.

–Overall in the Netherlands (and other countries), management is conservative and 2/3 of the patients with chest pain get admitted. So, this study adds to the data that using a prescribed simple instrument (HEART in this case, hs-cTnT in the previous blog) can lead to efficient and safe risk-stratification

–one interesting contradiction in these 2 studies is that the HEART score represents much more “gray area”, as opposed to the all-or-none issue with the single high-sensitivity troponin test in the last blog. And per the HEART protocol, the pretty common clinical situation of someone who is 45yo, has a history of hypercholesterolemia/ hypertension/diabetes, some non-specific ECG changes but only a slightly suspicious cardiac history and a normal troponin (and most hospitals in this study used a high-sensitivity assay) would have a HEART score of 4, leading to admission. And a person aged 65 with the same risk factors and a normal ECG and troponin would similarly be admitted. Maybe that is reasonable, but these people would be missed by using the single hs-troponin level as in the last study. In this regard, it would be useful to know if there should be different ratings in the HEART scale: ie, if someone has a HEART count of 3 (low-risk) with a high troponin, do they really have the same risk of MI or ACS as someone with the same count but a normal troponin? Or alternatively, is there a difference between those with the same intermediate risk of 4 or 5 with a normal troponin vs a high one? It would be useful to see more granular data from the HEART study the assess post-hoc how important the troponin component was.

— Overall, the study was impressive in that included 9 different hospitals of different types, had 99.9% follow-up, and its design allowed within-hospital comparisons. And, they captured all of the clinically relevant major cardiac adverse outcomes.

— unfortunately, one major problem with this study was that ED physicians were hesitant to send low-risk patients home, though the final analysis showed non-inferiority to this approach. Given the high number of patients who were treated by protocol, and the rather dramatic outcome differences between the low-risk and the higher-risk categories, it seems that this tool worked quite well

So, these last 2 blogs are pretty encouraging that we may soon be able to risk-stratify patients with chest pain adequately (the accepted false negative rate on chest pain work-ups in the ED, whether appropriate or not, is in the 2% range, similar to what this study found). Would be great to have a point-of-care high-sensitivity troponin test (per the last blog), though this study suggests that using the HEART tool even without a troponin level might bring the risk above the low-risk category for some patients (leading to direct referral to the ED), or, alternatively, categorize the patient as low risk if they have 1 point or less on the HEART scale (leading to discharge and close followup), because even adding 2 points in those with an elevated troponin would not matter.  This, of course, should be tested in a well-conducted study to see if it were valid.

Primary Care Corner with Geoffrey Modest, MD: Single troponin to r/o MI

27 Apr, 17 | by gmodest

by Dr Geoffrey Modest

Two articles recently came out in the Annals of Internal Medicine which looked at simple and efficient ways to rule out acute myocardial infarction in patients with chest pain who go to the emergency room. This blog will deal with an article looking at a single measurement of high-sensitivity troponin (see doi:10.7326/M16-2562). Tomorrow, I will review an article looking at a somewhat more complex algorithm.

Details:

— 9241 patients who presented to the emergency dept with possible acute coronary syndrome were evaluated in this collaborative meta-analysis from 11 prospective cohort studies in Europe, New Zealand, and Australia. A publicly-funded study,

— 64% male, mean age 61

— Prevalence of acute MI range from 7-23% with an overall prevalence of 15%

— Study exclusion criteria were pretty consistent across the studies, but those with renal failure requiring dialysis were excluded in 3 of the studies and atypical presentations in one study

— 2 studies did not perform a 2nd troponin measurement on some low risk patients, but in general 2nd troponin levels were drawn for clinical care purposes and later outcome adjudication, at least 6 hours after symptom onset. 9 of the included studies were classified as having a high risk of bias due to reported nonconsecutive nonrandom patient selection (e.g. not recruiting patients 24 hours a day, 7 days a week, esp in some of the smaller hospitals where the resources were lacking) or exclusions due to missing data

–Overall 2825 patients (30.6%) were classified as low risk, defined as no new ischemia on ECG and high sensitivity cardiac troponin T (hs-cTnT) measurement below the limits of detection, <0.005 mcg/L

Results:

— 14 (0.5%) of the low-risk patients had an acute myocardial infarction during hospitalization (primary outcome), with the test performing at a sensitivity of 98.7% (96.6%-99.5%). In 7 of these 14 cases the time between symptom onset and blood sampling was < 3 hours (< 2 hours in 4 cases). The pooled negative predictive value was 99.3% (96.5%-100%)

— major adverse cardiac events (MACE) or death within 30 days (secondary outcome) occurred 21 times (including index admission for acute MI) after a negative index test result. Overall test sensitivity was 98.0% (94.7%-99.3%).

— A total of 126 (1.3%) of patients died within the 30 day follow-up. But no low-risk patients died.

Commentary:

— 10 to 20% of patients who present to the ED with suspected cardiac-related chest pain have an acute MI.

— Prior studies have shown that the hs-cTnT below the limits of detection reliably detects those patients who may be safely discharged from the ED for outpatient management, and this is been incorporated into European guidelines (eg NICE guidelines, updated 2016, state: “consider performing a single high-sensitivity troponin test only at presentation to rule out NSTEMI”). A few retrospective analyses have suggested the utility of a single hs-cTnT below detectable level in ruling out an acute MI, however the studies were considered to be methodologically flawed

— One advantage of the current study is that it was carried out in several different countries and with several different baseline patient cardiac risk and comorbidities, as well as differing prevalence of acute MI and the proportion of patients identified as low risk. This makes the conclusion more potentially generalizable.

— 50% of those in the low-risk group who actually had an acute MI after the negative troponin had their troponin level checked prior to 3 hours after symptom onset.  This reinforces the recommendation of checking a 2nd troponin level in this group (ie, if checked <3 hours after symptom onset) if the first one were negative, as per the European guidelines.

— the specificity of hs-cTnT was poor, as expected, since increased troponin levels are not specific to an MI

— unfortunately, these researchers when unable to access patient-specific data to further elucidate the specifics of those patients who had false negative rates (beyond the too-early troponin testing).

–this hs-cTnT assay has been used in Europe for years, but was just approved for use in the US this year (I am not sure how available it is or how often it is used at this point).

So, this study and the one tomorrow raise the potential that in the not-so-distant future, low-risk patients may be able to be efficiently evaluated and discharged from the ED. And this hopefully would also apply to community-based settings as well. their email addresses, i can add them to the list

 

Primary Care Corner with Geoffrey Modest MD: Cardiovascular Fitness — a new vital sign?

19 Jan, 17 | by EBM

By Dr. Geoffrey Modest

A recent scientific statement from the American Heart Association stresses the importance of assessing cardiorespiratory fitness (CRF) as part of the risk assessment for cardiovascular disease (see DOI: 10.1161/CIR.0000000000000461)​.

Details:

  • Studies since the 1950s have consistently found that CRF is a strong and independent marker of cardiovascular risk as well as all-cause mortality, adjusting for age and the other standard risk factors. This is been found in healthy men and women, those with known or suspected cardiovascular disease, and those with the co-morbidities of obesity, type 2 diabetes, hypertension, and hyperlipidemia. In many studies CRF is a more powerful predictor of mortality risk than traditional cardiovascular risk factors. It has even been shown to be a more powerful risk predictor than ST-segment depression, cardiovascular symptoms, or hemodynamic responses.
  • The survival benefit in 13 studies showed that each 1-MET (metabolic equivalent) higher CRF, a small increment, was associated with a marked 10-25% improvement in survival. And, one study found that men who improved from unfit to fit between two successive examinations had a reduction in mortality risk of 44% relative to those who remained unfit in both exams (i.e., those with higher CRF have dramatic clinical benefit)
  • As a quick guide to METs:
    • Light activity (<3 METs): includes walking 2.5 mph (2.9 METs)
    • Moderate activity (3-6 METS): includes walking 3.0 mph (3.3 METs), walking 3.4 mph (3.6 METs), stationary biking (light effort) 5.5 METs
    • Vigorous activity (>6 METs):  jogging (7.0 METs), calisthenics/pushups/situps (8.0 METs), rope jumping (10.0 METs)
  • Of note, even though the most dramatic differences in all-cause and cardiovascular mortality were found comparing the most fit to the least fit subjects (70% and 56% respectively), the greatest increase in mortality benefit was in comparing the least fit group to the next least fit category
  • A recommendation in the paper is that CRF should become an accepted “vital sign”, and should be part of the standard clinical encounter
  • CRF also is associated with heart failure exacerbations and mortality, with one study finding that for every 6% increase in CRF over three months there was a 4% lower risk of cardiovascular mortality or hospitalization, and an 8% decrease risk of cardiovascular mortality or heart failure hospitalization (for example, see http://blogs.bmj.com/ebm/2016/11/09/primary-care-corner-with-geoffrey-modest-md-vigorous-exercise-helps-those-with-heart-failure/ which shows the benefit of vigorous exercise in patients with heart failure and reduced ejection fraction), timing of cardiac transplantation, preoperative surgical risk prediction (including studies of abdominal aortic aneurysm repair, liver transplant, lung cancer resection, upper GI surgery, intra-abdominal surgery, bariatric surgery, coronary artery bypass grafting). And interventions seem to help: in patients waiting for CABG surgery, those randomized into an exercise training group had superior outcomes to the control group, with a reduced rate of perioperative complications and shorter hospital stays. And observational studies have also shown that men with higher CRF had 68% lower stroke mortality, controlling for standard risk factors.
  • There were a few studies showing that those with a higher level of CRF had a reduced risk of developing dementia or Alzheimer’s, one study showing a 36% lower risk of developing dementia in those with the highest quartile of CRF. Higher levels of CRF are also associated with lower measures of anxiety or depression symptoms
  • Many studies have shown decreased risk of development of prediabetes, metabolic syndrome, and type 2 diabetes in those with higher CRF, again with the biggest difference in those going from lower CRF to the moderate range.
  • Lower levels of CRF at a younger age are also associated with a higher risk of disability at an older age. For example one study of obese adults with type 2 diabetes found that after four years, improvement of CRF decrease the likelihood of developing disability
  • Added value of CRF to the traditional risk calculators:
    • Several analyses have looked at various ways of incorporating the additional value of CRF. In one 30-year study of patients with stage II hypertension, the 30 year risk of cardiovascular mortality was 18.4% in those with low CRF versus 10.1 present in those with high CRF (i.e., a huge difference)
    • Overall, adding CRF to the traditional risk stratification led to actual CVD and all-cause mortality outcomes being correctly reclassified through the risk predictor as being decreased 23.3% and 20.6% respectively through correctly reclassifying patients as higher risk, and 55.8% and 46.0% respectively for correctly reclassifying patients as lower risk. The overall changes reflected a 30.5% and 24.5% correct reclassification for all-cause mortality, with larger changes in correctly reclassifying patients as lower risk because of CRF. [e., those at apparently high risk by a traditional risk calculator, in reality have significantly lower risk if they are more fit; there are changes apparent in the other direction as well, but less emphatically so]. Also as a point of comparison, when looking at the nontraditional risk factors, such as coronary artery calcium scores  (which seems to be the best of the lot), the level of correct reclassification from the traditional risk calculators is much lower
  • So, how does one measure CRF?
    • The most accurate and standardized quantification of CRF is through CPX (cardiopulmonary exercise testing), a combination of conventional exercise testing with ventilatory expired gas analysis
    • A step below that is to look at achieved treadmill speed/grade and duration, making sure the patient does not hold the hand rails
    • Another approach is to look at submaximal exercise testing or the 6-minute walk test to assess distance walked (walking <350 meters is associated with high risk).
    • And the easiest overall/least time-consuming/cheapest/easiest to implement is to do nonexercise prediction calculations. These are not standardized at this point, and each study seems to have somewhat different calculators. Perhaps the best is to use the one by Nes BM. Med Sci Sports Exerc 2011; 43: 2024, which incorporated an assessment of patient reported physical activity, age, waist circumference, and resting heart rate, and this is one of the studies which included a lot of people (n= 2067 men and 2193 women) and looked at actual clinical outcomes, finding that 90.2% of women and 92.5% of men in the lowest two quartiles of fitness were correctly classified. Their questions for physical activity included: frequency of exercise (never, <1x/wk, 1x/wk, 2-3x/wk, >3x/wk), intensity (“no sweat/heavy breathing, “heavy breath and sweat”, “push myself to exhaustion”), and duration (<15 in, 15-30 min, 30-60 min, >60 min).
    • Overall exercise recommendations:
      • Type: exercise should involve major muscle groups (legs, arms, trunk) that is continuous and rhythmic (e.g. brisk walking, jogging, cycling, swimming, rowing)
      • Intensity: moderate and/or vigorous intensity relative to the persons capacity
      • Frequency: at least five days per week of moderate or three days per week of vigorous intensity exercise
      • Time: 30 to 60 minutes per day (150 minutes per week) of moderate and 20 to 60 minutes per day (75 minutes per week) of vigorous exercise. Of note between 10 and 20 minutes can be beneficial in previously inactive people
      • Amount: a target of 500 to 1000 MET-min/wk
      • Pattern: one continuous session per day or multiple sessions per day of greater than 10 minutes each. Less than 10 minutes may work in deconditioned individuals.

Commentary:

  • Incorporating CRF reflects a more individualized physiologic approach (assessing the constellation of how well the heart, lung, circulation, and oxygen extraction by muscles works). It is clear from epidemiologic data that on a community basis, as well as individual basis, the traditional risk factors of smoking, hypertension, hyperlipidemia, and diabetes confer an increased risk of cardiovascular disease. However, CRF is a truly specific individual physiologic risk factor, reflecting how these risk factors and more play out in the individual’s body. For example, hypertension itself confers different levels of individual risk dependent on CRF.
  • One note of caution: there is no uniformity in clinical practice as to which of the traditional risk calculators is the best: the Am Heart Association/Am College of Cardiology just published an updated tool, including a spreadsheet calculator (see org/10.1161/CIR.0000000000000467 for the article, and http://circ.ahajournals.org/highwire/filestream/234917/field_highwire_adjunct_files/0/Appendix_Users_Guide_Spreadsheet.xlsfor the spreadsheet to calculate risk. BUT, this tool also needs to be validated in different populations prior to being accepted (also, see http://blogs.bmj.com/ebm/2015/08/05/primary-care-corner-with-geoffrey-modest-md-comparison-of-the-2013-accaha-lipid-guidelines-to-atpiii/ for a critique of the 2013 ACC/AHA lipid guidelines.)
  • Interestingly, several studies suggest that CRF is a more potent predictor of cardiovascular disease than any of the individual risk factors we have incorporated into our predictive models
  • Why is CRF so important? There are several explanations: improved traditional cardiovascular risk profiles (though most of the studies did control for the major ones we know), changes in autonomic tone that may reduce arrhythmogenic risk, fewer thrombotic events (exercise decreases fibrinogen levels, for example), improved endothelial function, lower levels of visceral adiposity/improved insulin sensitivity, lower levels of inflammation, as well as perhaps improved mental health and sense of well-being. And, there might be important positive changes in the gut microbiome with exercise, which is clear in animal models, less clear in humans where those who exercise tend to eat differently from those who do not, so hard to control well).
  • I should add a couple of caveats here: it is important not to confound fitness with doing lots of exercise; a significant component of fitness (on the order of 30+%) is genetic and not related to regular exercise. And most of the studies above are observational, not intervention studies (i.e., only a few actually randomized patients to exercise programs vs none and looked at long-term outcomes. Though the one on pre-surgery exercise programs was pretty impressive. And, the overall data on the benefits of exercise overall are quite robust)
  • For ballpark figures, those with a CRF level less than 5 METs have a particularly high risk of mortality, whereas those with CRF levels of greater than 8 to 10 METS seem to have much more protection. And, more than half the reduction in all-cause mortality occurs between those who are least fit (e.g. CRF less than 5 METs) and those in the next least fit group (e.g. CRF 5-7METS); i.e., benefits for cardiorespiratory fitness are particularly strong in those people in the least fit as compared to the next higher category (i.e., one does not need to be an Olympic athlete to achieve the benefits)

So, the key points here are:

  • Cardiorespiratory fitness is an independent in additive risk assessor for total and cardiovascular mortality
  • Improving CRF dramatically decreases cardiovascular and all-cause mortality
  • This clinical improvement is especially profound in those who are the least fit, finding a greater than 50% risk reduction by moving one step up to the next least fit group. An increase in CRF of only one MET is associated with the 10 to 20% decrease in mortality rate
  • There is a reasonable argument based on studies that have been done to propose that a simple, non-exercise based calculator should be added as a vital sign. This could easily be measured by nonclinical staff and would provide clinicians important information to help encourage patient-specific exercise programs. This should to be evaluated more completely in different populations to assess its generalizability. However, even without those studies, given the documented benefits of exercise and the dramatic relationship in the above studies of CRF as a risk predictor, I personally will ask patients about CRF more and further reinforce the importance of exercise as part of a healthy lifestyle.

For other blogs on exercise, see http://blogs.bmj.com/ebm/category/exercise/

Primary Care Corner with Geoffrey Modest MD: FDA broadens indication for empagliflozin to include cardiovascular protection!!!

8 Dec, 16 | by EBM

By Dr. Geoffrey Modest

The FDA just extended the indication for the diabetes drug empagliflozin (Jardiance) to include reducing cardiovascular mortality in those with diabetes and cardiovascular disease. Their press release (see http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.htm ) states that they looked at postmarketing data, though their original approval 2 years ago indicated that they requested 5 years of post-marketing data.

See my prior blog critiquing the original study leading to FDA approval ( http://blogs.bmj.com/ebm/2015/12/21/primary-care-corner-with-geoffrey-modest-md-empaglifozin-the-good-and-the-bad/ )

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