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Neuro- stroke

Primary Care Corner with Geoffrey Modest MD: Stroke and dementia, and artificial sweeteners

2 May, 17 | by

by Dr Geoffrey Modest

Two studies came out from the Framingham Heart Study database by the same authors in 2 different journals, one on the association between consuming artificially-sweetened beverages and the later development of stroke and dementia, and the other on sugary beverages and preclinical Alzheimer’s disease. I will divide these into 2 blogs.

An evaluation of the Framingham Heart Study Offspring cohort, with data from 1971 and evaluated over 9  examination cycles, found that artificially-sweetened soft drink consumption was associated with a higher risk of stroke and dementia (see DOI: 10.1161/STROKEAHA.116.016027).

 

Details

— 2888 participants >45yo were evaluated for incident stroke;  1484 who were >60yo were evaluated for incident dementia

— mean age 62 for the younger group and 45% men, 69 for the older group and 46% men

— beverage intake was quantified at cohort examinations 5 (1991-5), 6 (1995-8), and 7 (1998-2001). Total sugar-sweetened beverages included soft drinks, fruit juice, and fruit drinks.

— surveillance for incident events began at examination 7 and continued for 10 years

— there were 97 cases of incident stroke (82 ischemic), and 81 cases of incident dementia (63 consistent with Alzheimer’s)

 

Results:

— controlling for age, sex, education (for the dementia cohort), calorie intake, diet quality, physical activity, and smoking; when compared to a daily cumulative intake of 0 artificially-sweetened drinks per week:

— hazard ratio for ischemic stroke was 2.96 (1.26-6.97), p=0.01 (ie, about 3x higher). Relationship was strongest for ischemic stroke

— hazard ratio for Alzheimer’s disease 2.89 (1.18-7.07), p=0.02. There was also an association with all-cause dementia of similar magnitude, 2.47 (1.15-5.30), p=0.02. Both were statistically significant in the group having at least one drink per day.

— sugar-sweetened beverages were not associated with the stroke or dementia, only artificially-sweetened soft drinks

— the curves for event-free survival for both of these outcomes continued to decrease through year 10 (i.e. it was not plateauing), and there was a dose-response curve with the more artificially-sweetened soft drinks, the lower the event-free survival

— there was no interaction in the above analyses with waist-to-hip ratio, diabetes mellitus, or with the presence of apolipoprotein E4

— there was not much change in the associations when excluding diabetes from the analysis, given the potential interaction of those with diabetes drinking more artificially-sweetened beverages (diabetes was found to be only a partial mediator of the association).

 

Commentary:

— the Nurses’ Health Study and Health Professionals Follow-Up Study both reported a higher risk of incident stroke with greater consumption of sugar-and artificially-sweetened beverages. The above study is reported to be the 1st showing association between artificially-sweetened drinks and an increase in both all-cause dementia and Alzheimer’s.

— The above study predated the approval of Stevia

— there are studies which have shown that artificial sweeteners cause glucose intolerance in mice by altering the gut microbiome, and they are associated with glucose intolerance in humans. See here for a detailed review of these animal and human studies.

— Generalizability of these results: the Framingham study served as a model for epidemiologic studies given its long-term nature (began in 1948) and in the regular intensive follow-ups done over the years. However, it was limited by the lack of ethnic variation. It also was an observational study which limits drawing conclusions regarding causality.

 

So, bottom line (again): these no-calorie artificial sweeteners seem to be associated with significant problems, including glucose intolerance (despite the fact that we used to push diabetic patients to drink these over regular sodas). And there are suggestive data that they do not help even with weight loss (see here ). so, all in all, we should be promoting water as the best drink….

Primary Care Corner with Geoffrey Modest MD: The elusive search for afib in stroke patients; and an app

19 Apr, 17 | by

​​​​by Dr Geoffrey Modest

Atrial fibrillation is an important risk factor for current ischemic strokes, but may be hard to diagnose in those presenting in sinus rhythm. A reasonably large German study found that prolonged Holter monitoring picked up many more cases of atrial fibrillation than standard monitoring, the Find-AFRANDOMISED trial (see Wachter R. Lancet Neurol 2017; 16: 282–90).

Details:

–398 patients were recruited from 2013-2014 in 4 German centers, all with acute ischemic stroke and symptoms for 7 days or less, aged 60 years or older, in sinus rhythm and no history of atrial fibrillation (AF).

— Mean age 73, 40% women, 80% hypertension/27% diabetes/41% hyperlipidemia/18% current smoker/29% previous smokers/20% previous ischemic stroke/8% previous TIA/5% heart failure/10% MI/15% CAD/7% with ejection fraction <50%

— lacunar lesion on brain imaging found in 40%, cardioembolism 20%/small vessel disease 30%/stroke of unknown cause 50%, mean CHA2DS2-VASC score 4.8 (most in the 4-6 range), mean CHADS2 score 3.5 (50% in the 4-6 range). 197 patients were classified as having cryptogenic stroke; 201 as non-cryptogenic, mostly small vessel occlusion (118 pts) and cardioembolic stroke (75 pts)

— Those with severe ipsilateral carotid or intracranial artery stenosis were excluded

— patients were randomized into standard monitoring (at least 24 hours of rhythm monitoring: 188 of 198 patients had stroke unit telemetry for a median duration of 73 hours, and 149 of the 198 patients received additional Holter monitoring for a median of 24 hours) versus 10-day Holter monitoring at baseline, at 3 months, and at 6 months of follow-up. The initial Holter was done at a median of 3.5 days after symptom onset

— primary endpoint was the occurrence of atrial fibrillation or atrial flutter (lasting 30 seconds or longer) within 6 months after randomization and before stroke recurrence.

— secondary endpoints included: the detection of AF within 12 months, recurrence of stroke, systemic embolism or death within 12 months.

Results:

— after 6 months, 13.5 % were found to have atrial fibrillation in the enhanced monitoring group versus 4.5% in the standard group, absolute difference 9.0%, p=0.002, number needed to screen=11

— no patient with detected atrial fibrillation had a recurrent stroke or systemic embolization before the detection of atrial fibrillation within 6 months [by the way, this and another recent study I saw challenged the prior conventional wisdom that recurrrent strokes were much more common within the first week or two after the initial event]

— one of 27 patients in the enhanced monitoring group had atrial flutter

— the median duration of the longest AF episode during Holter monitoring was 5 hours, though one third lasted more than 24 hours and slightly less than one third < 6 minutes, and the number of episodes of atrial fibrillation detected ranged from 1 to 12

— review of their graph shows that the 1st 10 day Holter monitor picked up 18 patients, about ½  were picked up in the 1st 5 days; the 2nd  10-day monitor picked up an additional 6 with 2 picked up in the 1st 5 days; and the 3rd picked up one on the 8th day

— oral anticoagulation was given to all of the 39 patients who developed AF, more in the intervention group since more AF was picked up there

–clinical sequelae were found in 8 patients in the intervention group (5 recurrent strokes and 3 TIAs) and 14 in the control group (9 recurrent strokes and 5 TIAs), for rates of 3.7% vs 5.4%, nonsignificant (though this trial was underpowered for clinical outcomes, this finding does mirror that of the CRYSTAL-AF trial, which used an implantable cardiac monitor to pick up AF, finding 21% fewer events after 12 months). No cases of systemic embolization. No difference in picking up AF by age, sex, CHADS2, NIH Stroke Scale, symptoms at admission, or if the stroke was considered “cryptogenic”)​

Commentary:

— The rationale for looking aggressively for atrial fibrillation is that strokes from AF can be more severe, there is a high risk of recurrent strokes, and the detection of AF really changes therapy from antiplatelet drugs to oral anticoagulants, the latter decreasing the risk of recurrent strokes by 60 to 70%.  Since there are significant adverse events associated with these anticoagulants, it seems that their indications need to be pretty clear.

— The European Society of Cardiology recommends at least 72 hours of to monitoring, and also gives a Class IIa recommendation for implantable cardiac monitors (see Eur Heart J 2016; 37: 2893–962.)

— Review of the timing of AF pickups in the above study found that most (18/25, 72%) happened on the first 10-day cycle, and the pickup was reasonably evenly spread throughout the 10-day period; 6/25, (24%) were picked up in the second 10-day monitoring, again spread throughout the 10-day period; and one (4%) was near the end of the third 10-day period. This suggests to me that the monitoring should be for the entire 10-day periods, and that it is unlikely that a 4th 10-day period would be useful. The researchers in the above study suggested 7-10 days of monitoring within the first few days of symptom onset, and then repeating if higher risk (repeated cryptogenic strokes or embolic stroke of unknown source, frequent supravenrtricular ectopies, elevated natriuretic peptides, left atrial enlargement, or reduced atrial contractility).

–Holter monitoring has the advantage of being cheap, noninvasive, available, and able to be done within days of a cerebrovascular event.

so, very interesting study finding a significant number of patients having a stroke do in fact have AF on monitoring, and the more monitoring , the higher the pickup rate.  But hard to come to firm conclusions without a larger study powered sufficiently to assess clinical outcomes in order to see if AF pickup and treatment mattered (eg, is AF causative, or is it an innocent bystander which we know is common as age increases? and we also know that strokes themselves can cause cardiac arrhythmias, so which came first?) The other issues the larger trial could assess include:

​– what defines risky AF: eg, do really short episodes of AF matter (and what length does seem to matter?), and is this age-dependent?

— is there a number of AF episodes per 10-day monitoring that increase risk of stroke/TIA (and does that number vary depending on the length of AF episodes)? and, is this age-dependent?

— at what age should we do more aggressive monitoring (and should there be scaled amounts of monitoring based on different age groups, since AF is more common with increasing age)? is there an age where monitoring stops being clinically useful (either the AF doesn’t really increase risk that much, or the risks start to outweigh the benefits)?

the bottom line to me is that if we can show that picking up AF leads to improved clinical outcomes,  I would support more aggressive monitoring than the recommendations of the study authors: even though there were only 1 pickup during the third 10-day period, given how devastating a recurrent stroke can be, my inkling would be to support the 3 monitoring periods.

See here which argues for enhanced screening for atrial fibrillation overall (not just in people with strokes)

and  there are many blogs on atrial fibrillation treatment ( type atrial fibrillation in the search window)

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As an aside, there is a free app for iphones called Cardiio which displays one’s pulse (just place a finger lightly on the camera on the back of the iphone). In Europe, it is approved to diagnose AF, but the FDA has not approved it in the US at this point. But one can see one’s rhythm, and patients could be shown how to use it and assess for abnormalities which might be AF. Basically, a study found that in 1013 patients with hypertension, diabetes, and/or aged >65, the sensitivity for the full Cardiio (Cardio Rhythm) was 92.9% and the specificity was 97.7%, as compared to single-lead ECG tracings reviewed by 2 cardiologists (see Chan P-H. J Am Heart Assoc. 2016;5:e003428, or  doi: 10.1161/JAHA.116.003428), though the positive predictive value in this study was only 53.1%. I have played with the app a little and seems pretty impressive to me (ie, I can see a clear waveform, documentation of the pulse, and, at least for the few times I’ve done it, I seem to be in normal sinus rhythm. Though not sure what I’d find with three 10-day Holter monitor recordings…)

Primary Care Corner with Geoffrey Modest MD: Physical activity and decreased recurrent strokes

19 Jan, 17 | by EBM

By Dr. Geoffrey Modest

The SAMMPRIS trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) compared aggressive medical management of patients with intracranial stenosis and a non-disabling stroke/TIA, versus stenting plus aggressive medical management, finding that aggressive medical management was superior (see  doi 10.1212/WNL.0000000000003534​).​ In a prespecified analysis, they looked at the relationship between risk factor control during follow-up and outcomes in the aggressive medical arm.

Details:

  • 227 patients were analyzed, with risk factors recorded at baseline, 30 days, 4 months, and then every 4 months for up to 32 months.
  • Aggressive medical therapy included aspirin 325 mg per day along with clopidogrel 75 mg daily for the first 90 days, as well as treating the systolic blood pressure and LDL cholesterol to target (see below). Secondary risk factors included the non-HDL cholesterol, hemoglobin A1c in diabetics, smoking, weight management, and physical activity. Coaching on healthy lifestyle behaviors was done at regularly scheduled times throughout the follow-up
  • Target for risk factors:
    • Cholesterol: LDL <70 mg/dl (47% in target over the course of the study)
    • Blood pressure: systolic blood pressure < 140, or <130 if diabetic (53% in target)
    • Hemoglobin A1c < 7% if diabetic (42% in target)
    • Smoking cessation (65% target)
    • Weight management (if initial BMI 25-27, target <25;  initial BMI >27, target 10% weight loss; 19% in target)
    • Physical activity, assessed using the 8 point Physician-based Assessment and Counseling for Exercise (PACE) questionnaire (target score 4-8; 44% in target), where:
      • PACE 3= trying to do vigorous or moderate exercise but not exercising regularly
      • PACE 4= moderate exercise (brisk walking or slow cycling for at least 10 minutes at a time) <5 times per week or vigorous exercise (jogging or fast cycling for at least 20 minutes at a time) <3 times a week
      • PACE 6= at least 30 minutes of moderate exercise a day for at least 5 days a week for the past 6 months or more

Results:

  • At 3 years, the likelihood of the endpoint of a recurrent stroke, MI, or vascular disease in multivariate analysis, controlling for the above risk factors:
    • Higher PACE score decreased the likelihood by 40% [OR 0.6 (0.4 0.8)], with a dose effect for exercise (i.e., more exercise, more benefit)
    • Blood pressure, cholesterol, as target variables (i.e., dichotomized to above and below target) were nonsignificant. smoking, BMI, and hemoglobin A1c were also not significant
    • For recurrent ischemic stroke as the only endpoint at 3 years:
      • PACE had a highly significant odds ratio of 6.7 (2.5- 18.1)
      • LDL overall was not statistically significant as a dichotomized variable, though there was a significant odds ratio of 1.1 (1.0- 1.3) looking at it as a continuous variable, for each increase of 10 mg/dL)
      • Systolic blood pressure was similarly nonsignificant though had a significant odds ratio 1.2 (1.0- 1.6) as a continuous variable, for each increase of 10 mmHg
      • Hemoglobin A1c for diabetic patients had an odds ratio of 2.3 (1.0-5.0)
      • Smoking, BMI remained nonsignificant

Commentary:

  • Patients with intracranial atherosclerotic stenosis are at particularly high risk of recurrent stroke. Other trials had found that poorly controlled blood pressure and elevated cholesterol are important risk factors for this. The above SAMMPRIS trial was an NIH-funded trial for intensive risk factor management, evaluating patients within 30 days of a TIA or non-disabling stroke caused by a 70-99% stenosis of a major intracranial artery. And the primary outcomes were stroke, MI or vascular death within 30 days after enrollment, as well as ischemic stroke in the territory of the qualifying artery beyond 30 days
  • Although the study did show that controlling blood pressure and cholesterol were important for reducing vascular events, the independent effect of physical activity was considerably stronger for the prevention of recurrent vascular events, and especially for recurrent ischemic stroke. Other studies had shown that exercise decreased mortality among stroke patients and decreased the incidence of incident stroke among healthy people.
  • Although the above trial was an observational trial, and there is certainly a potential bias from post-stroke depression, they did note that the percentage of patients involved in physical activity increased from 32% at 30 days to 56% at the 4-month follow-up visit, perhaps reflecting the focus on lifestyle modification by the researchers. This increase in exercise would make less likely but not eliminate the potential depression bias.
  • One side concern in post-stroke patients is how rapidly to lower blood pressure. This study did suggest that in those enrolled within 30 days of a TIA or nondisabling stroke, they did better with more intensive blood pressure control (33.8% had blood pressure at the target at baseline, increasing to 47.6% at 30 days). As in another study, they did not find that diabetes, weight, or smoking cessation were significantly related to recurrent vascular events, though part of this may be due to lack of power to detect a significant effect.
  • The likely mechanisms for the positive effect of exercise include augmented arterial blood to the brain (including collaterals), improvement in other risk factors (HDL, insulin resistance, blood pressure), and decreased arterial stiffness.

So, this post hoc analysis (but of a prespecified endpoint) demonstrated the remarkable predictive power of exercise for fewer recurrent vascular events; and this relationship was increasingly evident as the amount of exercise increased. Unfortunately, they did not look at dietary interventions as part of their lifestyle modification. But, to me, bottom line is that we should be aggressively encouraging patients to increase their exercise as much as possible if they have intracranial-arterial stenosis causing a TIA or nondisabling stroke, as well as prescribing the usual culprits to control blood pressure, lipids, and give an antiplatelet drug.

Primary Care Corner with Geoffrey Modest MD: CPAP Does Not Reduce Cardiovasc Risk

3 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent article looked at patients with moderate-to-severe obstructive sleep apnea (OSA) and documented cardiovascular disease (CVD), finding no reduced risk of adverse cardiovascular outcomes by using CPAP (see DOI: 10.1056/NEJMoa1606599).

Details:

  • 2717 patients aged 45-75 who had moderate-to-severe OSA as well as coronary or cerebrovascular disease were randomized to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group)
  • Mean age 61, 81% male, 64% Asian/25% white, 51% with coronary artery disease/49% cerebrovascular disease, 79% hypertensive, 44% stroke, 33% MI, 30% diabetic, 15% smokers, 78% on BP meds/57% statins/75% aspirin/27% diabetic meds, BMI 29, apnea-hypopnea index (AHI) 29 (moderate-to-severe obstructive sleep apnea), 84% snoring almost every day, but minimal daytime sleepiness
  • Primary composite end point was: death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack
  • Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood.
  • Results:
    • In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night (in beginning 4.4, decreasing to 3.5 hours/night by 12 months), and the mean AHI decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up, reflecting good control. 42% adhered to treatment for >4 hrs/night.
    • After a mean follow-up of 3.7 years:
      • Primary end-point event occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) [HR 1.10; (0.91 to 1.32) P = 0.34]. No significant effect on any individual or other composite cardiovascular end point was observed, and the trend was actually for more events in the CPAP group.
      • CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood, with greater reductions in anxiety and depression (25-30% lower). no difference in road-traffic accidents or accidents caused by injury
    • No difference in subgroups: region (China vs other), age, sex, severity of OSA, BMI, daytime sleepiness, type of CVD, diabetes.
    • There were differences in patient characteristics in those who used CPAP > vs < 4 hours/night: more were Caucasian/European, men, had baseline CAD, hypertension, and fewer had TIA/stroke. Using propensity-score matching, there were 86 events in the CPAP group and 98 in usual-care: non-significant (i.e., no benefit even in the subgroup who used CPAP for > 4 hours/night)

Commentary:

  • The indications for CPAP seem to continue to decrease over time. There is pretty good documentation that OSA is associated with hypoxemia and sympathetic stimulation, elevated blood pressure especially in the AM, inflammation, oxidative stress, metabolic syndrome/insulin resistance/type 2 diabetes (which seems to independent of the obesity common in both conditions), 2-3x increased risk of NAFLD (also apparently independent of obesity/diabetes), hypercoagulation, right-sided heart failure. There are several observational studies suggesting that there is an association with cardiovascular events (esp stroke). And there are studies finding that using CPAP lowers the blood pressure, but only a little (2-3 mmHg, but can be up to 6-7 mmHg in those with resistant hypertension, though a recent RCT found a 3-4mmHg decrease); and improves insulin sensitivity and endothelial function. And observational studies show that it lowers cardiovascular events in those adherent to treatment. Another study found a 64% relative and 28.5% absolute risk reduction in those using CPAP in a nonrandomized but prospective 6 year study, concluding “OSA treatment should be considered for primary and secondary cardiovascular prevention, even in milder OSA” (see Buchner NJ. Am J CritCare Med 2007; 176 (12): 1274), advocating for more aggressive CPAP usage.
  • The concerns about CPAP are: that OSA is remarkably common, including 20-30% of males and 10-15% of females, though this depends on how OSA is defined and what the cutpoints are for the AHI (these percentages are if one uses an AHI>5/hour cutpoint); OSA seems to be much more common in those with underlying cardiovascular disease, cited at 40-60%; but CPAP is a pretty significant intervention (very difficult for many patients to use CPAP machines/uncomfortable, and in this study, the average was only 3.3 hours/night, which is similar to general clinical practice). Using CPAP therefore only makes sense if there is real clinical improvement.
  • A prior study was done in Spain (see Barbe F. JAMA 2012; 307(20): 2161) which randomized 357 patients to CPAP, 366 control. All patients had AHI of  >= 20/hr and no significant daytime symptoms; and they excluded anyone with prior cardiovascular event (i.e., much lower cardiovascular risk than those in the current study). In this 4-year study, as with the above study, there was no difference in cardiovascular events. Of note there was no difference in events when assessing those with the highest AHI levels or % of time with SaO2 <90%. Median CPAP usage was 5 hours, but those who used the CPAP >4 hours did have a 28% [HR 0-.72 (0.52-0.98), p=0.04)] lower incidence of hypertension or cardiovascular event. But looking specifically at cardiovascular events, there was a nonsignificant trend to lower CVD events (I should add here that 60% used the CPAP>4 hours, and this more adherent group may have done other healthy changes to decrease their risk of cardiovascular events. and these healthier things may have influenced the outcome more than the CPAP). Similarly if look at amount of time with SaO2<90%, the less time the fewer events.
  • So, overall, this current study showed very little cardiovascular benefit in many patients at high risk for CVD events and with pretty severe OSA. Although it is true that people used the CPAP only for 3-4 hours/night, this seems to be pretty much the range of usual CPAP usage, and they did find a dramatic decrease in AHI. My sense is that the indications for CPAP, a pretty significant and difficult intervention for many patients, have decreased considerably over time (early commentators suggesting that we should use it to prevent right-heart failure, or improve hypertension control, or decrease cardiovascular events/metabolic syndrome, etc.). Now, by far the major argument for CPAP for the vast majority of people, it seems to me, is for symptom control when patients are not sleeping well and having daytime somnolence or functional/psychological impairment(depression/anxiety, etc.) from inadequate sleep.

Primary Care Corner with Geoffrey Modest MD: Aspirin Right After TIA/Stroke

7 Jun, 16 | by EBM

By Dr. Geoffrey Modest

A meta-analysis challenged the published statistic of the protective effect of aspirin after a TIA or ischemic stroke, showing that the effect of aspirin is much greater than believed, especially if given within days of the event (see doi.org/10.1016/S0140-6736(16)30468-8 ).

Details:

Background:

  • Risk of recurrent stroke is 10% in the week after a TIA or minor stroke
  • But many patients delay seeking medical attention for days-to-weeks after these events
  • In the UK, 1/2 of recurrent strokes happen prior to seeking medical attention
  • Pre-hospital use of self-administered aspirin is often discouraged for fear of exacerbating intracerebral bleed
  • BUT, hemorrhage is a rare cause of TIAs and is in <5% of minor strokes
  • There are minimal data from RCTs on the effect of aspirin after TIA or minor stroke, with only observational data on the effect of aspirin on early benefits after TIA or minor stroke
  • 12 trials with 15,778 participants comparing aspirin vs placebo for secondary prevention of ischemic stroke, all with data on recurrent vascular events within 12 weeks of randomization. the data from these trials were reanalyzed, looking at individual patient outcomes

Results:

  • Aspirin vs placebo reduced the 6 week risk of:
    • Ischemic stroke by 58% [(HR 0.42 (0.32-0.55), p<0.0001)]; 84 of 8452 on aspirin, vs 175 of 7326
    • Disabling or fatal ischemic stroke by 71% [(HR 0.9 (0.2-0.42), p<0.0001)]; 36 of 8452 on aspirin, vs 110 of 7326
    • And, greatest benefit was in those put on aspirin within 2 weeks à for disabling or fatal ischemic stroke the risk was decreased by 93%:  [(HR 0.07 (0.02-0.31), p=0.004)]; 2 of 6691 on aspirin, vs 23 of 5726
  • The effect of aspirin on recurrent strokes was partly by reduction in severity (by modified Rankin Score, 58% decrease), and was independent of dose, patient characteristics, or etiology of TIA/stroke
  • There was still some benefit at 6-12 weeks after the initial event, but none after 12 weeks
  • In the 3 trials (40,531 people) in people with major acute stroke, recurrent ischemic stroke at 14 days was mostly in patients with less severe baseline deficits and was 63% less by the 2nd day after starting treatment [(HR 0.37 (0.25-0.57), p<0.0001)]
  • In terms of the dreaded complication of intracerebral hemorrhage, there was no difference between those on aspirin vs control at 12 weeks (3 of 4125 on aspirin vs 5 of 4137 in control group), though there was a trend to more events in those on high-dose aspirin
  • The effect of aspirin on preventing recurrent ischemic strokes was independent of the dose (low dose = <100mg/d, high-dose = >300 mg).
  • Also no difference if patient diabetic, hypertensive, or if current smoker
  • Also no difference in patients with atrial fibrillation at baseline (HR 0.28 (0.087-1.00), p=0.0508), or in those with lacunar strokes [I could not find the data on this in the supplementary materials, so cannot comment further]
  • Dipyridamole plus aspirin vs aspirin alone (7 trials, with 6602 participants)
    • No difference in risk of ischemic stroke or their severity in first 12 weeks (OR=0.90)
    • But after 12 weeks, there was a 24% decreased risk [(OR 76 (0.63-0.92), p=0.005)], particularly for disabling or fatal ischemic strokes [(OR 0.64 (0.49-0.84), p=0.001)]

Conclusion:  It seems that aspirin worked much better when given as soon as possible (in the above analysis, in the 0-2 weeks after a TIA or minor stroke), and also pretty dramatically reduced the severity of a further ischemic stroke when that happens (in the 70% range), also with the greatest reduction when given within the first 2 weeks. Dipyridamole did nothing early on, but the combo with aspirin was superior to aspirin in the long-term.

So, this poses the difficult clinical conundrum: how do we reach out to patients to make sure they get aspirin therapy as soon as they have one of these minor events: a resolved TIA or a minor stroke, for which many a denier type may just write-off and not seek care. This brings up several issues:

  • It is likely much safer/preferable to reinforce/have public health initiatives to educate patients to seeking care as soon as possible after any stroke-like symptoms. And to reduce obstacles to care: this would likely happen more often if there were universal coverage for health care, and if there were not the rather daunting co-pays that people may be confronted with if they go to an ER.
  • The UK did a major public education campaign (Oxford Vascular Study), showing that there was there was a major improvement in patients having a major stroke seeing emergency attention within 3 hours and simultaneous decrease in people just making future medical appointments; but for TIA and minor stroke, there was not much difference in either of these, suggesting that reaching those with TIA/minor stroke and convincing them to seek urgent medical attention is not so easy. (Graphs in the supplemental material of this study)
  • Given the low likelihood of there being a cerebral hemorrhage causing the TIA/minor stroke (and this study found no increase in the 12-week risk of intracerebral hemorrhage on low dose aspirin vs control), it seems that there would be pretty clear benefit to the public health imperative: self-administer aspirin as soon as possible after a patient has symptoms suggestive of TIA/minor stroke (though, again, being assessed in the ER is the preferable action). And it should be emphasized that the most dramatic effect of aspirin in those with TIA/mild stroke, a 93% reduction, was in preventing of disabling or fatal subsequent ischemic strokes.
  • And, I do try to use the combo of aspirin/dipyridamole over just aspirin if the patient can tolerate it (it is twice a day and has more adverse effects) but is pretty expensive (though, both aspirin and dipyridamole are really, really old meds….), since the data do suggest some more efficacy over plain low-dose aspirin. But with this data, I think it is likely to be more useful to start aspirin right away (cheaper and better tolerated), just to make sure the patient has the aspirin in their system as soon as possible, and then transition to the combo aspirin/dipyridamole over the next couple of months (making sure the patient reverts to aspirin if the combo causes any problems).

Primary Care Corner with Geoffrey Modest MD: Home Blood Pressure Monitoring

3 May, 16 | by EBM

By Dr. Geoffrey Modest

A Japanese study was just done of hypertensive patients, comparing clinic blood pressure readings to home-based monitoring, and finding that home-based monitoring was better overall, especially for coronary artery disease. (See Kario K. J Am Coll Cardiol 2016; 67: 1519).

Details:

  • 21,591 treated hypertensive patients (mean age 64.9, 51% women, BMI 24, mean followup 2.02 years) were followed in the HONEST study.
  • Patients were asked to measure their home BP (HBP) twice in the AM and twice in the PM on 2 different days in each measurement period and average the 2 measurements for each timeframe; done at 1, 4, 16 weeks, then at 6, 12, 18, and 24 months
  • Clinic blood pressure CBP) was done by the “usual methods of each institution”, without further clarification

Results:

  • 127 strokes (2.92/1000 patient-years) and 121 CAD events (2.78/1000 patient-years)
  • For strokes:
    • Higher incidence if morning home systolic BP (HSBP) ≥145 mmHg vs <125 mmHg [HR 6.01 (2.85-12.68)]. There was a graded increase in strokes as the morning HSBP increased, reaching significance at the 145-155 range (HR 3.97), then increasing in the ≥155 range to HR 12.57.
    • Higher incidence if clinic systolic BP (CSBP) ≥150 mmHg vs <130 mmHg [HR 5.85 (3.17-10.67)]. There was a graded increase in strokes as the morning CSBP increased, reaching significance at the 150-160 range (HR 4.88), then increasing in the ≥160 range to HR 14.17.
  • For CAD events (defined as MI and angina with coronary revascularization):
    • Higher incidence if morning HSBP ≥145 mmHg vs <125 mmHg [HR 6.24(2.82-13.84)]. There was a graded increase in strokes as the morning HSBP increased, reaching significance at the 145-155 range (HR 4.15), then increasing in the ≥155 range to HR 12.61.
    • Higher incidence if CSBP ≥150 mmHg vs <130 mmHg [HR 3.51 (1.71-7.20)]. There was a graded increase in strokes as the morning CSBP increased, reaching significance only at the ≥160 range to HR 8.82.
    • In terms of diastolic BP, there were only significant increases in stroke in the ≥90 mmHg group by HBP, and ≥95 mmHg group by CBP. No difference in CAD events in any diastolic BP group.
  • There did not appear to be a J-shaped curve in the relationship between HBP and stroke or CAD events (the numbers of events at the lower blood pressures was pretty small, so wide confidence intervals for these outcomes, but there was no apparent increase as the morning SBP decreased to 110 mmHg)
  • A statistical analysis (goodness-to-fit) found that for stroke events, both HSBP and CSBP predicted events pretty equally. BUT for CAD events, the morning HSBP far outperformed the CSBP

So, a few points

  • This study supports the importance of home-based blood pressure readings. There is much more data for ambulatory blood pressure monitoring (ABPM), with most but not all studies finding much better predictive value than clinic based measurements, leading to the NICE guidelines in the UK strongly recommending either ABPM or HBP in 2011, and the USPSTF following suit in 2015 [see http://blogs.bmj.com/ebm/2015/11/02/primary-care-corner-with-geoffrey-modest-md-uspstf-guidelines-on-blood-pressure-screening/which reviews the USPSTF screening recommendations for blood pressure and includes a Grade A recommendation to screen outside of the clinical setting, but also see a review (Hodgkinson J. BMJ 2011; 342:d3621).
  • But this study adds the following useful insights:
    • They focused on the AM blood pressures, since several studies have looked at blood pressure variability and found that blood pressure tends to be highest in the morning and the incidence of cardiovascular events and strokes is similarly higher then (presumably related to increased activation of the RAS system and increased platelet function/thrombotic tendency). So, from this study which generally found superior predictive value of home-based BP monitoring (especially for CAD), it makes sense for patients to focus just on the morning blood pressures as the decision point on therapy (it turns out in their data that the evening HSBP was also predictive of stroke events but not CAD events). Overall, looking at CSBP or evening HSBP underestimates CAD risk.
  • It should be emphasized how important it is to check the home BP cuff (I ask patients to bring it in, and I simultaneously check one arm as they check the other, then vice versa)
  • One other advantage of home based monitoring is that it empowers the patients around their medical care. In fact, a JAMA study showed that patients who take their BP at home have better blood pressure control (see http://blogs.bmj.com/ebm/2015/10/13/primary-care-corner-with-geoffrey-modest-md-bp-self-monitoringself-titrating-decreases-bp/ )
  • So, my bottom line: I really do follow the HBP, which I have lots of patients do (some insurers cover the monitor, otherwise good monitors are about $50, should be appropriately sized upper arm cuffs, and many of my patients have had their kids get one for them). If the patient cannot do HBP monitoring, I ask them to go to a local pharmacy, sit quietly for a few minutes, then check their BP and record it. And I usually do not treat high blood pressure in the clinic if the home pressure is okay (and is done correctly by the patient and with a BP cuff which I find is accurate).

Primary Care Corner with Geoffrey Modest MD: Atrial Fibrillation – Should We Look Harder For It?

2 Dec, 15 | by EBM

By Dr. Geoffrey Modest

Over the years, I have had several patients who have presented with significant strokes related to previously-undetected atrial fibrillation (AF). I have also had a couple of patients with dementia and no evident prior stroke, who on workup have had multiple small infarcts, again possibly related to AF. In this light, there was an interesting editorial in JAMA (see JAMA 2015; 314: 1911) ​ raising the question of whether we should be screening regularly for AF. Although not part of their argument, I think that the potential and not clearly well-defined relationship between AF and cognitive decline may be part of the incentive to screen (see below). Their argument is basically (all references are in the text):

  • AF is really common (1 in 4 lifetime risk in those >40, with 0.5% age 40, increasing to up to 15% at age 80)
  • Treatment is pretty effective: oral anticoagulation (OA) reduces stroke risk by 2/3 and mortality by 1/3, with relatively small risk of major bleeding (hence the use of pretty universal guidelines to anticoagulate if the CHA2DS2-VASc score is 2 or greater)
  • The effectiveness of OA is much more impressive than many of the other recommended screening activities/interventions
  • AF is a common cause of stroke: a recent Swedish Stroke survey of 94K patients with ischemic stroke found AF in 31K of them, which is probably an underestimate (see Stroke 2014; 45: 2599)
  • So, can asymptomatic AF be picked up by screening??
    • A systematic review found that in 123K patients, a single screen using either pulse palpation or EKG found undiagnosed AF in 1% of people overall and 1.4% of those >65yo.
    • The European Society of Cardiology 2012 guidelines on AF recommended routine checking the pulse of patients >=65 years of age, followed by an electrocardiogram as needed, for the timely detection of AF.
    • There are cheap handheld or smartphone EKG-type devices which may be useful. Preliminary studies suggest an AF pickup of 1.5-3.0%, all of whom qualified for OA.
  • Prognosis of incidental AF
    • A UK study found people with incidentally detected asymptomatic AF had stroke rate of 4% in 1.5 years and all-cause mortality of 7% in those untreated. Those on warfarin had stroke and death rates of 1% and 4% respectively
  • Cost-effectiveness
    • ​Smartphone based screening in those 65-85yo: $4066 per quality-adjusted life-year gained, $20,695 per stroke prevented (i.e., better than most preventative interventions). This age group has high incidence of AF and essentially all people >65 would qualify for OA
  • The authors suggest that we in the US follow the European guidelines and check the pulse during office visits.

So, AF has potentially devastating consequences, with significant morbidity and mortality. A few points:

  • The relationship between AF and multi-infarct dementia (MID) is not clear, and AF is not listed as a risk factor for MID by the NIH. But there was a population-based study (Rotterdam Study) which followed 6514 patients aged >55 and found a strong association between dementia and impaired cognitive function in those who developed AF and were <67 yo (see http://blogs.bmj.com/ebm/2015/10/30/primary-care-corner-with-geoffrey-modest-md-atrial-fibrillation-and-dementia/). A recent article on AF and cognition (see Stroke 2015;46:3316-3321) noted that:
    • The mechanism is unclear (?multiple small emboli, ?AF-associated cerebral hypoperfusion)– and, evidently, if the mechanism were the latter, it would be hard to attribute the cognitive decline to AF, since there would not necessarily be dectectable infarcts on brain imaging.
    • There have been meta-analyses (see Neurology 2011; 76:914, Ann Intern Med 2013; 158: 338) finding >2-fold increased risk of cognitive impairment in those with AF and subsequent stroke.
    • A few meta-analyses have found a 40% increased risk of dementia in those with AF and without stroke (see Heart Rhythm 2012; 9: 1761).
    • But, as we know, associations are not necessarily causal, and AF/dementia do have shared risk factors.
    • ​And, one of my concerns is that in many of these studies, our measurement of dementia (e.g. Mini-mental state exam) is a very blunt instrument and does not pick up subtle changes which may be very significant for the person at that time, and ultimately over years, progress to our definition of dementia.
  • Given the potential devastation of stroke/cognitive impairment, as well as the potential damage from other peripheral emboli, it seems to me that we should have a randomized controlled intervention study looking at treatment for AF and its overall effects. For that study, there would need to be some agreement on the following:
    • What is AF?  Is it a random pick-up on a routine exam (i.e., 1-minute evaluation for an irregular pulse and then followed by an EKG)? Is it a 24-hour Holter monitor, or a 30-day event monitor??? (clearly there are people with very intermittent, paroxysmal AF who have clinical emboli, and checking a pulse is going to find those with sustained AF predominantly)
    • ​What is cognitive decline? This study should include doing a more extensive evaluation for subtle cognitive decline (e.g., the Cardiovascular Health Study did look at a few instruments, including the Modified MMSE and Digit Symbol Substitution Test, as well as telephone interviews, finding those with incident AF had faster and earlier onset cognitive decline — see Neurology 2013; 81: 119).
  • But at this point, I will continue doing what I have been doing: pretty much always checking my own manual blood pressures on patients, after waiting several minutes in a reasonably relaxed atmosphere (as per prior blogs). In this setting I sometimes do pick up AF (and, by the way, the automated cuffs are pretty unreliable for blood pressure measurement in those with AF, further supporting checking manual blood pressures in those >50yo or so). But I will now add on checking the pulse for irregularities, and then follow the guidelines for treatment when I find AF. And, perhaps more aggressive assessments for AF than pulse-checking at the time of exams should be done (given the high prevalence of AF, especially in our aging population, a more intensive AF assessment such as Holter monitoring could be a very cost-effective strategy, especially given the dramatic quality-of-life issues associated with stroke/dementia). But this would need studies to determine.

Primary Care Corner with Geoffrey Modest MD: Carotid Occlusion and Just Medical Therapy

22 Oct, 15 | by EBM

By Dr. Geoffrey Modest

The USPSTF recently restated their prior recommendation to NOT check for asymptomatic carotid stenosis (see Ann Intern Med. 2014;161:356-362​). This is based both on the potential risks of both screening and treatment, and some studies showing decreased benefit: current medical therapy may be associated with fewer strokes than when the initial studies on carotid endarterectomy were done. These older studies had found that in patients with asymptomatic carotid stenosis, carotid endarterectomy when done in a referral facility with consistently low peri-procedural morbidity/mortality, the procedure decreased the overall risk of strokes by about 50%. As a consequence of these earlier studies, a study in​2011 found that more than 90% of carotid interventions were for asymptomatic carotid stenoses in the US Medicare population (vs 0% in Denmark!!). One of the concerns about medical management of internal carotid stenosis was that progression to occlusion was likely devastating. A new study in JAMA Neurology confirmed that the current medical therapies are in fact associated with much lower progression to carotid occlusion, and that occlusion itself was rarely associated with clinical stroke, further supporting the USPSTF recommendation (See doi:10.1001/jamaneurol.2015.1843).

Details:

  • Retrospective review of data from 2 stoke prevention clinics in Canada from 1990 (when they began annual carotid ultrasound surveillance) until 2013, looking at ipsilateral stroke or TIA, death from ipsilateral stroke, or death from unknown cause
  • 3681 patients in the database (mean age 66, 71% men, 78% hypertensive with mean BP 148/80 presumably on meds, 68% hyperlipidemic), with carotid stenosis measured by ultrasound/Doppler

Results:

  • 316 (8.6%) were asymptomatic before an index occlusion that occurred during the observation period
  • Of these 316 patients, 13% had prior MI, 21% diabetes, 22% smoked/ 53% had quit smoking/12% never smoked
  • 80% of these occlusions occurred prior to 2002, when medical therapy was less intensive, with decreasing frequency over time (254 cases before 2002, 39 in 2002-7, and 7 after 2010)
  • ​Only 1 patient had an ipsilateral stroke at the time ofcarotid occlusion, and 3 had ipsilateral stroke during follow-up (all before 2005)
  • Of the 316 who had a carotid occlusion, 71 died over mean of 7.2 years after the occlusion, with the major known causes being MI (16%), cancer (13%), sudden death (11%), sepsis (11%), though 23% were of unknown cause
  • The total carotid plaque area was significantly related inversely to event-free survival, as was age and male sex (but not the % of stenosis)
  • ​Similar results were found for contralateral occlusion

So, a few issues:

  • This observational study is consistent with others that suggest that optimal medical therapy seems to be strongly associated with decreases in carotid artery stenosis progression, and that the effect of complete occlusion is not as dire as feared (likely thanks to the rich collateral circulation in the brain).
  • I think the presence of carotid stenosis, whether symptomatic or not, should trigger an aggressive medical response, since atherosclerotic disease in the carotids is a marker of atherosclerotic disease elsewhere (including the coronaries, i.e. it is a “coronary artery disease equivalent”).
  • The cornerstones of this aggressive medical response should include lifestyle interventions (diet, exercise, not smoking), as well as high-potency statins, optimizing blood pressure and diabetes control, and antiplatelet drug therapy (see doi.org/10.1016/j.jacc.2014.12.045).
  • There is a recently started 2-center study which will formally answer the question of medical vs surgical management: the CREST-2 trial (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Study) is a 4-year trial which will compare maximal medical therapy vs that plus carotid endarterectomy in one wing, and that plus carotid stent in the other, with results expected by December 2020.
  • But, for now, it the data support not screening for asymptomatic carotid stenosis and that the primary treatment is aggressive lifestyle and medical management.

Primary Care Corner with Geoffrey Modest MD: Dabagratan, again

30 Jan, 15 | by EBM

By: Dr. Geoffrey Modest 

There have been a slew of articles recently promoting dabigatran and the direct acting thrombin inhibitors, and a remarkable number of articles in the on-line throw-away journals (delete-away??), like MedPage, interviewing leading researchers (many on the pharma dole) extolling the virtues of these medications. Recent articles include:

1. A meta-analysis noting that dabigatran, rivaroxaban, apixaban and edoxaban are non-inferior to vitamin K antagonists in stroke prevention for patients with atrial fibrillation, assessed the endpoints of all-cause and vascular mortality along with safety issues (see DOI:10.1111/jth.12651).

–71,683 patients with nonvalvular atrial fibrillation (from 4 RCTs , with follow-up of 1.8-2.8 years) found significant declines in all-cause mortality by 11% with NNT=132 (p<0.0001) and vascular mortality by 12%, NNT =189 (p<0.0001)​, with a striking decrease in mortality from bleeding (RR 0.54, p<0.0001, esp. intracranial bleeding with RR 0.42, p<0.00001)

2. A meta-analysis were done of the efficacy and treatment of acute venous thromboembolism — VTE (see doi:10.1001/jama.2014.10538). they assessed 8 strategies, though this was a “network meta-analysis”, mathematically combining different studies, since there were no direct comparisons of them. Strategies included: unfractionated heparin (UFH), low-molecular weight heparin (LMWH) in combo with vitamin K antagonists (VKA), LMWH with dabigatran or edoxaban, rivaroxaban, apixaban, and LMWH alone.

–45 studies with 45K patients, 22 comparing UFH-VKA with LMWH-VKA. only 6 studies looked at the new agents (2 with rivaroxaban, 2 with dabigatran, one each with edoxaban and apixaban), median follow-up of 3 months.
–Compared with LMWH-VKA, UFH-VKA associated with increased risk of recurrent VTE (HR 1.42), with proportion of patients with recurrent VTE over the 3 months: UFH-VKA 1.84%, LMWH-VKA 1.30%. so, no statistically signif diff for efficacy in any of these strategies, except UFH-VKA (which did badly)
–Risk of major bleeding event: rivaroxaban with 0.49%, apixaban 0.28%, LMWH-VKA 0.89%, with apixaban being the only one with statistically significant decrease in bleeding

BUT, a study released by JAMA Internal Medicine assessed retrospectively the Medicare pharmacy and medical claims for 1302 people on dabigatran used in atrial fibrillation vs. 8102 on warfarin (see doi:10.1001/jamainternmed.2014.5398). This was a real-world post-marketing study, assessing major and minor bleeding events (major= intracranial hemorrhage, hemoperitoneum, hosp visits/admits for hematuria, GI or other hemorrhage).

–Dabigatran associated with higher risk of bleeding than warfarin– 32.7% vs. 26.5%, with HR 1.30 (CI 1.20-1.41) for any bleeding event, major bleeding 9.0% vs. 5.9%, with HR 1.58. GI bleeding​ 17.4% vs. 10.0%, with HR 1.58 (CI 1.36-1.83), though risk of intracranial bleeding lower with dabigatran, 0.6% vs. 1.8%, with HR 0.32 (CI 0.20-0.50)​
–The risk of major bleeding with dabigatran was especially high in certain subgroups: African Americans had more bleeding with dabigratan with HR 2.12, and patients with chronic kidney disease had an increase with HR 2.07. the increased rate of intracranial bleeds was only higher in warfarin in white patients older than 75 (no diff in those

So, what does this all mean? I posted several blogs on dabigatran, some showing drug company malfeasance in promoting it, both withholding data and their own sense that levels should be monitored (the big push for this drug was that you didn’t need to do INRs, so it was easy for patients and providers). Also an article on increase in MI and ACS. and one on post marketing surveillance and increased bleeding with dabigatran. the current article on the Medicare population confirms (at least to me) the importance of post-marketing surveillance. All-too-often, there are serious adverse effects of meds (eg COX-2 inhibitors such as vioxx….) that are not found on initial studies, either legitimately through the gaps of statistical analysis or drug company malfeasance (or both). Some may be due to study design or to the cloistered setting of the academic medical center and selection biases. In any event, post-marketing analysis provides larger numbers of real-world patients on the med. As noted below, one of the big issues with direct thrombin inhibitor bleeding, unlike warfarin, is that there is no antidote/ability to reverse the effect.

Primary Care Corner with Geoffrey Modest MD: Obesity paradox and stroke

27 Aug, 14 | by EBM

the “obesity paradox” found in several studies is that normal or underweight people have higher mortality, esp if they have chronic diseases. overall, studies with longer-term databases have found this to be less true, suggesting reverse causality: those with lower weight may disproportionately include people with underlying diseases causing them to lose weight. the current study, a large study with a remarkably good/complete database, adds to this (see doi:10.1001/jamaneurol.2014.1017). results:

–71617 patients admitted to Danish hospitals from 2003-2012 with a stroke, with information on BMI in 53,812. looked at deaths likely caused by the index stroke (if the death occurred within the first week or month after the stroke), and recorded in the Danish Stroke Register (coverage felt to be >80% complete).

–mean age 71.2, 47% women, 8% hemorrhagic stroke, mean BMI=25.7, with 10% underweight, 39% normal wt, 35% overwt, and 17% obese.

–within the first week of stroke, 4373 pts died with 3334 (4.7% of total) dying of stroke. no difference in risk of death from stroke by BMI (except in the underweight group)

–within first month, 7878 died and 5512 (7.7%) from stroke. no difference in risk of death from stroke by BMI (except in the underweight group)

–those with the lowest BMI tended to have the most severe stroke (stroke severity score), even controlling for age, sex, stroke subtype, cardiovasc risk factors, civil and socioeconomic status.

–BUT, there was an inverse relationship between BMI and age of admission for stroke — as compared to normal weight patients, those overweight had stroke 3 years earlier and obese 6 years earlier.

so, in general this study supports recommendation to achieve a normal body weight, despite the mixed messages from some of the other studies. the issue with underweight individuals continues to be muddied. this group (likely) includes normal underweight people (who might actually have a lower stroke mortality) along with some with significant medical or mental illnesses associated with both underweight and higher mortality.

geoff

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