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Primary Care Corner with Geoffrey Modest MD: Syncope Guidelines

13 Mar, 17 | by EBM

By Dr. Geoffrey Modest

Finally a guideline on syncope management (See http://www.onlinejacc.org/content/early/2017/03/03/j.jacc.2017.03.003​ ​, or 10.1016/j.jacc.2017.03.003), these from the Am Heart Assn/Am College of Cardiology. Many of us, I think, have been relying on suggestions from such sources as UpToDate, which are not rigorously evaluated and validated by at least a semi-independent association (the American Heart Association, though does have intrinsic potential biases for more cardiologic workup and investigation than a truly independent organization such as the National Institutes of Health in the US or National Institute for Health and Care Excellence NICE in the UK, does take the issue of upfront conflicts of interest more seriously than most other specialty groups, in this case with neither the chair nor vice-chair with any stated conflicts of interest, as well as 8 of the 15 committee members without stated conflicts).

Details:

  • Syncope is a common condition: estimates of prevalence as high as 41%, recurrent syncope in 13.5%. Mayo Clinic report of 19% prevalence in selected community residents over 45 years old (mean age of 62, more often in females, 22% vs 15%). Trimodal age distribution: first episode age 20, 60, or 80 yo. Different etiologies by age: older people more often associated with cardiac causes/meds/comorbidities: esp aortic stenosis, renal dysfunction, AV or left bundle-branch blocks, and meds associated with orthostatic hypotension. Also syncope in 12-15% of those with heart failure. younger people: more likely noncardiac
  • Initial evaluation:
    • History
      • Focus on prognosis, diagnosis, reversible or amelioratable factors, comorbidities, medication use, and patient/family needs
      • Prognostic factors depend on separating neural from cardiac causes (the latter being worse), assessing prodromal symptoms (e.g. the most common cause of syncope being vasovagal, a reflex syncope that has typical features of upright posture, exposure to emotional stress, pain; associated with diaphorsesis, warmth, nausea, pallor), family history, meds and comorbidities
    • PE
      • Especially orthostatic blood pressure and pulse changes, murmurs/gallops/rubs, basic neuro exam for focal abnormalities that would lead to a more detailed exam
    • ECG
      • Especially bradyarrhythmias with sinus pauses or high-grade conduction block; ventricular tachyarrhythmias. Or arrhythmogenic substrate (WPW, Brugada, long-QT syndrome, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy ARVC)
    • Then risk assessment
      • Stratify by cause of syncope/reversibility of underlying condition (vasovagal has better prognosis than heart failure with preserved ejection fraction, which is better than advanced cardiomyopathy, which is better than acute aortic dissection)
      • Data not really available on stratifying by high vs intermediate vs low-risk groups. There are some data on short and long-term risk factors (30 days after ER visit or 12 months later, showing the usual culprits
        • Short-term: male, older than 60 yo, no prodrome, prior palpitations, exertional syncope, history of structural heart disease, heart failure, cerebrovasc disease, fam history of sudden cardiac death, persistent bleeding, positive troponins
        • Long-term: many of same, but added diabetes, high CHADS-2 score, cancer, low GFR
        • And there are some studies suggesting “risk scores”, but they have different definitions of syncope, outcomes, etc., so not so practical, but typically include some of the above: age cutoff (45 or 65), abnormal ECG, prodrome, exertional, signs of volume depletion, etc.
      • Further testing: costly and often ineffective as a general rule and should be guided by the above initial exam. in particular, if the initial exam is not reasonably definitive:
        • Targeted blood testing:
          • CBC and lytes have low yield when done routinely, and should be guided by history/physical (moderate recommendation, nonrandomized trials)
          • Brain natriuretic peptide and troponins, uncertain evidence, though they do comment that BNP “is elevated in patients whose subsequent cause for syncope is determined to be cardiac”
        • If eval suggestive of cardiovascular abnormalities, consider further cardiac workup (not recommended as routine)
          • Transthoracic echo, if structural heart disease suspected, esp valvular disease, HCM, LV dysfunction (moderate recommendation, nonrandomized trials)
          • CT/MRI: MRI if suspect infiltrative disease such as sarcoid, or if suspect ARVC; CT esp if suspect pulmonary embolism (weak recommendation, nonrandomized trials)
          • Stress testing: esp if syncope during exertion (moderate recommendation​, limited design)
          • Cardiac monitoring: if suspected arrhythmia, choice dependent on likely timing of next syncope (Holter if likely in next 24-72 hours, others if longer). (moderate recommendation​, limited design). BUT they do push some for implantable cardiac monitors, which has the highest yield for those with no answer from noninvasive testing (moderate recommendation, with RCTs)
          • In-hospital monitoring: good to do telemetry
          • Electrophysiological studies: recommendations based on older studies. Can be useful in those with syncope from suspected arrhythmia, mostly useful in those with structural heart disease (yield of 50% vs 10%). (Moderate recommendation, nonrandomized trials)
          • Tilt-table testing: though they give this a moderate recommendation with RCTs to support, they do note that the utility is highest in patients with suspected recurrent vasovagal syncope, BUT there is overall only “moderate sensitivity, specificity, and reproducibility,” with “the presence of false-positives in controls”, and the diagnosis can typically be made through structured history taking as well and long-term cardiac monitoring.
        • If eval suggestive of neurogenic orthostatic hypotension, also not to be done routinely. Can be associated with multiple system atrophy, Parkinson’s, Lewy Body dementia, or peripheral autonomic dysfunction from diabetes, amyloidosis, immune-mediated neuropathies, hereditary sensory or autonomic neuropathies, inflammatory neuropathies. Less commonly with B12 deficiency, neurotoxins, porphyria, HIV or other infections
          • EEG during tilt-testing: patients can have both epileptic convulsions as well as pseudosyncope, which can be sorted out by doing tilt-testing with EEG monitoring (moderate recommendation​, limited design)
          • Head MRI and CT: no benefit in absence of focal neuro deficits or head injury
          • Carotid artery imaging: no benefit without focal neuro deficits
          • Plain EEG: no benefit unless symptoms suggestive of a seizure
        • Then treatment decision
          • There is a large section on guideline-based therapies for arrhythmias and structuralcardiac disorders, which i will not review here
          • Vasovagal syncope: patient education on diagnosis and triggers, lying down when symptoms begin (if sufficiently long prodrome), and in recurrent syncope:
            • Midodrine if no history of hypertension, heart failure or urinary retention. Studies suggest 43% reduction in symptoms. (moderate recommendation, RCTs)
            • Orthostatic training: e.g. repetitive tilt-table tests, or daily standing against a wall in the house for prolonged time periods (weak recommendation, RCTs)
            • Fludrocortisone, esp if inadequate response to fluids and salt (weak recommendation, nonrandomized trials)
            • Other approaches with weak recommendations include: b-blockers in those >42 years old (poor performance in younger patients), encouraging increased salt and fluid intake, decreasing meds that cause hypotension, SSRIs

Commentary:

  • Though CBC and lytes do have a low yield, I personally will continue to do them regularly, since they are cheap/easy and may unexpectedly lead to an important intervention by finding an unexpected anemia or hypokalemia, etc.
  • I would reinforce the importance of manually checking baseline and orthostatic blood pressure. See (See http://blogs.bmj.com/ebm/2016/05/20/primary-care-corner-with-geoffrey-modest-md-orthostatic-hypotension-revisited/for more studies on orthostatic hypotension, including the finding that initial hypotension on standing is in fact much more common than standard orthostatic hypotension after a couple minutes)
  • In terms of vasovagal syncope, which is so common: if the patient has baseline lowish blood pressure which decreases on standing, I do recommend fluids and salt (with limited effect though), and there was a recent article not included in the guidelines above which did show benefit of fludrocortisone (see http://blogs.bmj.com/ebm/2016/09/22/primary-care-corner-with-geoffrey-modest-md-fludrocortisone-for-vasovagal-syncope/), which I have used on several patients, sometimes with midodrine, to good effect.​
  • As noted, the guidelines do go through lots of details on the treatment of the cardiac conditions associated with syncope, and can be referenced in the paper itself.​

So, overall I think this is a very useful guideline, which appropriately minimizes routine testing beyond the history, physical and EKG (though, as mentioned, I do usually check a CBC and lytes even in otherwise asymptomatic patients).

Primary Care Corner with Geoffrey Modest MD: Early Activity After Concussion?

26 Jan, 17 | by EBM

By Dr. Geoffrey Modest

A large Canadian study looked at outcomes in kids according to whether there was strict rest versus different levels of physical activity in the week after a concussion (see doi:10.1001/jama.2016.17396​ ).

Details at initial exam:

  • 2413 participants aged 5 to 18 with acute concussion completed the questionnaires in the emergency room, at day 7, and at day 28 post-injury. The researchers assessed persistent postconcussive symptoms (PPCS, defined as at least 3 new or worsening individual symptoms vs preconcussion status) to see how that varied according to the amount of physical activity begun within 7 days of the ED visit.
  • Mean age 11.8 years, 39% female, arrived at ED a median of 8.7 hours after injury, 24% lost consciousness (11% >3 minutes), 2% had seizure, 8% had prior concussions lasting more than a week.
  • 49% appeared dazed and confused, 41% answered questions slowly, 14% repeated the questions, 21% were forgetful.
  • Parental report of headache in 87%, nausea in 59%, balance problem in 44%, dizziness in 70%, drowsiness 73%, increased sleeping 35%, sensitivity to light or noise 37%, irritability 27%, sadness 40%, seemed mentally foggy 40%, increased fatigue 75%, poor concentration 37%, acts more emotional 40%

Results:

  • 1677 (69.5%) participated in early physical activity, 736 (30.5%) had no physical activity:
    • Light aerobic exercise (e.g. walking, swimming, or stationary cycling) in 795 (32.9%)
    • Sport-specific exercise (e.g. running drills in soccer or skating drills in ice hockey) in 214 (8.9%)
    • Noncontact drills (e.g. complex passing drills) in 143 (5.9%)
    • Full contact practice (e.g. normal training activities) in 106 (4.4%)
    • Full competition (e.g. normal game play) in 419 (17.4%)
  • PPCS at 28 days occurred in 733 people (30.4%)
  • The incidence of PPCS at 7:
    • Those who engaged in early physical activity: 523 (31.3%) were symptom-free and 803 (48%) had at least three persistent or worsening postconcussive symptoms.
    • Those not engaging in physical activity: 584 (79.5%) had at least three persistent or worsening postconcussive symptoms
  • The incidence of PPCS at 28 days, by propensity score matching:
    • Early physical activity: 28.7% versus 40.1% for no physical activity
    • Among those symptomatic at day 7, the incidence of PPCS:
      • Light aerobic activity: absolute risk benefit of 6.5% over no activity
      • Moderate activity: absolute risk benefit 14.3% over no activity
      • Full contact activity: absolute risk benefit 16.8% over no activity

Commentary:

  • Pediatric concussion guidelines uniformly recommend an initial period of cognitive as well as physical rest after a concussion. These recommendations include modification of school attendance and mental activities as well as avoidance of any physical activity until postconcussive symptoms have returned to baseline, and then a gradual resumption of activities. However, there is no actual evidence to support these recommendations: they reflect a concern for preventing harm.
  • It is, however, very clear from the literature, that re-injury and recurrent concussions are deleterious.
  • This study, though quite large, is an observational study. They did propensity score matching as a means to mathematically control for differences between the different groups of activity level, in an attempt to decrease the inherent bias in an observational study (by mathematically adjusting the groups for likely relevant variables). It was notable that of the 20 items that they asked parents initially (e.g. headache, balance problem, drowsiness, etc., as noted above), there really was not much difference between the groups that performed physical activity and those that did not. However, this study still does not rise to the same evidence quality as a randomized controlled trial (i.e., mathematically modeling is just not the same…). A further caveat is that they did not look at cognitive rest, and it is conceivable that those who did not do any physical activity had much more cognitive activity, and it was the cognitive activity actually caused an increase in PPCS (not so likely, but possible). Also, the cutpoint of beginning exercise within the first 7 days of injury is arbitrary. It would be useful to see data on when exercise was started, perhaps over the first 3 weeks post-concussion and stratified by the initial concussion scores, to see what was the optimal timing or degree of exercise postconcussion
  • It was also impressive that there was an apparent dose-response curve: those that did more activity seemed to benefit the most
  • There really are an array of reasons that might support the conclusions of the study: for some children having to avoid all activity creates significant dysphoria (being the parent of two kids who had concussions, I can attest that not participating in sports created a lot of unhappiness) which can account for some of the psychological symptoms such as fatigue, poor concentration, irritability, etc. As a contrary issue, it is quite clear in the literature that physical activity is important for skeletal health, cardiorespiratory fitness, improvement in symptoms of depression, anxiety, self-esteem, cognitive performance, and academic achievement. In addition, exercise may well lead to improved cerebral blood flow and promote neuro-plasticity,
  • The study is very important in challenging a long-held, though not rigorously demonstrated, view about dealing with injury, in this case concussion. Similarly, for a long time, we were all advised to limit any activity at all for patients with low back pain, for a minimum of two weeks. That also seemed prudent at the time, but turned out to be the antithesis of what we should have been doing. And in these cases, I think this conception that rest is the right prescription really undercuts the power of exercise in preserving and restoring health.

So, based on the study as well as some others, it seems to make sense to have a gradual resumption of physical activity as soon as tolerated after an acute concussion, but avoiding activities that might risk re-injury, given how much better kids did who resumed exercise within a week after a concussion. However, it certainly makes sense to have a real randomized controlled trial to assess the optimal degree of physical activity and its timing after concussion, as well as specific characteristics of the concussion which might dictate different exercise programs. And, also to look at the effect of cognitive rest (which, i think, may be nearly impossible in our technological era, given the intense cognitive stimulation of smartphones, electronic devices, etc.)

For prior blogs: http://blogs.bmj.com/ebm/2015/02/03/primary-care-corner-with-geoffrey-modest-md-concussion-a-less-aggressive-approach/ for another study suggesting more rapid introduction of physical activity; or http://blogs.bmj.com/ebm/2014/09/09/primary-care-corner-with-geoffrey-modest-md-need-for-safe-sustainable-sports/​ for a study looking at the time-course of postconcussive symptoms in kids seen in the Boston children’s hospital ED

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.

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