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Cardiol- arrhythmia

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

19 Apr, 17 | by gmodest

​​​​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).


–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.


— 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”)​


— 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)


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: Syncope Guidelines

13 Mar, 17 | by EBM

By Dr. Geoffrey Modest

Finally a guideline on syncope management (See​ ​, 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).


  • 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


  • 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 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, 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: Sudden Cardiac Death in Young Athletes in the U.S.

2 Dec, 16 | by EBM

By Dr. Geoffrey Modest

A recent article looked at the demographics and epidemiology of sudden death in young athletes from the United States National Registry from 1982-2011 (see Maron BJ. Am J Med (2016) 129, 1170).


  • 2406 athlete deaths were reported to the registry, of whom 842 had confirmed cardiovascular causes associated with exercise, and with autopsy examination.


  • Mean age 18, 89% male, 46% white/43% African-American or other minority. 25% of deaths were during competition, 39% during practice, 17% during recreational activity, 18% unassociated with physical activity. 66% were junior high or high school, 19% in college. 35% playing basketball, 30% football.
  • Mortality rate in males exceeded females by 6.5-fold (1:121,691 and 1:787,392 athlete-years, respectively; p <0.001)
  • Cause of sudden death:
    • Hypertrophic cardiomyopathy (HCM): 302 athletes (292 males, 10 females), 36% of cases. 152 in African-American/138 in white
    • Congenital coronary anomalies: 158 athletes (127 males, 31 females), 19% of cases. 77 in African-American/72 in white
    • Indeterminate cause with left ventricular hypertrophy/possible HCM (autopsy finding abnormal hearts with increased heart weight and mild left ventricular thickening): 77 athletes (73 males, 4 females), 9% of cases. 31 in African-American/40 in white
    • Myocarditis: 57 athletes (46 male, 11 female), 7% of cases. 24 in African-American/30 and white
    • Arrhythmogenic right ventricular cardiomyopathy: 43 cases (31 male, 12 female). 8 in African-American and 35 in white


  • The US National Registry of Sudden Death in Athletes prospectively assembles data on the deaths of young athletes in competitive athletics, for those engaged in organized team or individual sports requiring regular training and competition, and have had sudden death. [not sure how inclusive this registry is for those just doing recreational sports — those in noncompetitive athletics may be significantly underreported]
  • This study confirms that hypertrophic cardiomyopathy was by far the single most common cause of sudden death in athletes in the US and was far more common in males and females. Coronary artery anomalies, arrhythmogenic right ventricular cardiomyopathy, and prolonged QT syndrome (though the latter only occurred in 18 individuals, 2.1% overall) were more frequent percentagewise in females.
  • Overall hypertrophic cardiomyopathy was more common in African-Americans than in whites and least common in white females.
  • The significant increase in cardiac deaths in males over females (greater than 6-fold) was also found in the French national registry (30-fold difference, though for marathon running it was 6-fold).
  • Structurally normal hearts were found in less than 5% of the athletes.
  • For a review of the American Heart Association and the American College of cardiology guidelines, see .
  • Given the relatively high percentage of athletes dying from hypertrophic cardiomyopathy (and especially if you include those with LVH but considered to be indeterminate in terms of the specific HCM criteria), these data reinforce the American Heart Association recommendations for pre-participation screening (see or Maron BJ. JACC. 2014; 64: 1479). A brief review of the criteria:
    • The 14-element recommended screen for preparticipation in competitive athletes includes 7 items on personal history (chest discomfort on exertion, unexplained syncope or near syncope, excessive dyspnea or palpitations on exertion, heart murmur, elevated blood pressure, prior restriction from participating in sports, and prior testing of the heart by a physician), 3 on family history (sudden death before age 50 in at least one relative, disability from heart disease in a close relative prior to the age of 50, known history of specific cardiac diseases including hypertrophic cardiomyopathy, long QT syndrome, ion channelopathies, Marfan syndrome, clinically significant arrhythmias), and 4 items on physical exam including heart murmur likely to be organic, femoral pulses to exclude aortic coarctation, physical stigmata of Marfan’s, hypertension)
    • However, it is noted that personal/family history is often insensitive in identifying cardiac abnormalities, physical exam is often unremarkable (with some abnormalities only detectable by EKG, such as WPW or channel ionopathies), and even HCM is only detected by a murmur at rest in 25%, with an additional 50% on by Valsalva or cardiac exam while standing.
    • The EKG is sensitive but not so specific, given the number of false positives in young athletes
      • 5% of elite athletes have EKGs indistinguishable from HCM
      • The EKG is abnormal in more than 90% of people with HCM but the EKG changes are typically nonspecific (the specificity is about 50 to 60%, as per
      • The sensitivity and specificity for HCM is also largely determined by the cutpoints of voltages used in defining HCM. As noted, false-negative results occur in more than 10% of patients with documented HCM as well as more than 90% with congenital coronary anomalies. (Though 40% of sudden deaths in athletes in the Minnesota study were from diseases that could reliably be picked up by EKG)
      • The guidelines are more circumspect about using screening EKGs. Prior guidelines I’ve seen have been more strongly against using EKG. This one suggests that there are real concerns about the availability of trained people to read EKGs in younger people, there are lots of false positives leading to lots of echocardiograms (and potentially scaring/medicalizing the kids and families), and the cost to the system is quite high, given the large number of EKGs that would be done. And the issue in the US is different, for example, from the Italian data showing potential benefit from EKG screening, since that area of Italy (Veneto) had a very large % of sudden death from arrhythmogenic right ventricular cardiomyopathy which can be found on EKG more easily
    • The recommendations: use the 14 point screening guideline as above. Screening with 12 lead EKG’s may be considered in young healthy people age 12 to 25, not necessarily limited to athletes, mandatory and universal mass screening with EKG is not recommended for anyone.

So, sudden cardiac death, not surprisingly, is a pretty devastating though infrequent outcome for young and basically healthy kids.  My concerns are that sudden death clearly happens to those who are not super-competitive athletes (66% happened in junior high or high school; overall only 25% during competition and 39% during practice – and I’m not sure how complete the above database is, especially in those not in competitive athletics), and that these deaths are potentially preventable, to the extent that the questionnaire is reliable. I would not be surprised, for example, if the mortality in a kid with HCM were as great in an unfit 7th grader working hard on the basketball court for 15 minutes vs the remarkably fit varsity player…. It seems to me, given this, that we really should be screening all young kids with the questionnaire, perhaps on entry to junior high school, which really means also interviewing parents/guardians since kids are likely quite unreliable in knowing the specifics of the family history.

Primary Care Corner with Geoffrey Modest MD: Optimal blood pressure in patients with atrial fibrillation

30 Nov, 16 | by EBM

By Dr. Geoffrey Modest

It is unclear from the literature what the goal blood pressure should be in patients with atrial fibrillation, and this is not addressed by any of the guidelines. A post hoc analysis of the AFFIRM trial (Atrial Fibrillation Follow-up Investigation of Rhythm Management, a prospective trial assessing the strategy of rate versus rhythm control) looked retroactively at the relationship of achieved blood pressure and outcomes (see Badheka AO. Am J Cardiol 2014; 114: 727)).


  • 3947 patients in the trial were followed 6 years, noting their systolic and diastolic blood pressures (recorded after sitting quietly for at least five minutes) at baseline and at follow-up, divided into 10-mm Hg increments. The follow-up blood pressure was defined as the average of all available blood pressure measurements during each post-baseline visit
  • Mean age 69, and the following were significantly (and much) more frequent in patients who had lower blood pressure, with average percentages overall as follows:  60% in men, 70% hypertension, 40% coronary artery disease, 25% in patients with heart failure, 14% smoking
  • The endpoints assessed were all-cause mortality; the combination of all-cause mortality, ventricular tachycardia or fibrillation, pulseless electrical activity, significant bradycardia, stroke, major bleeding, MI, and PE as a composite secondary outcome.


  • All-cause mortality was observed in 614 people (15.6% of the group)
  • The incidence of all-cause mortality was lowest in those with BP 140/78 mm Hg, with a U-shaped curve. All-cause mortality was:
    • 9 fold higher in the group with systolic blood pressure <110; 1.9 fold higher in those with systolic greater >160
    • 3.9 fold higher in the group with diastolic <60; 1.8 fold higher in the group with diastolic >90
  • There was a similar U-shaped relationship to the composite secondary outcome.
  • Subgroup analyses also found a similar U-shaped curve with an increased all-cause mortality with blood pressure <110/60, including the following subgroups: whether or not they had CAD, hypertension, heart failure, or reduced ejection fraction.


  • One of the complicating factors in assessing the optimal blood pressure in patients with atrial fibrillation is that several of the drugs we use to control rate (e.g. beta-blockers and non-dihydropyiridine calcium channel blockers) also decrease blood pressure. So, one of the complicating factors in interpreting the association between lower blood pressure and increased mortality is inherent in this retrospective observational study: are those who require more medications to control their heart rate at a higher risk of death, just because their harder-to-manage atrial fibrillation is associated with higher mortality? And their higher incidence of hypotension merely reflects their need for more meds (which also lower their blood pressure) to control that rate???
  • Another large issue is the dramatic baseline comorbidities in those with lower blood pressure, reinforcing the fact that these were much sicker patients and raising questions as to whether the study could mathematically adjust for these covariates in their final analysis. The authors did control for age, history of hypertension, history of heart failure, history of MI or revascularization, history of stroke, diabetes, smoking status, use of warfarin, lipid-lowering therapy, diuretics, and which group they were randomized to in the AFFIRM  trial. However, given how apparently sick these patients with low blood pressure were, one wonders if there were other important variables not included (e.g. other medical conditions such as renal failure, or COPD –esp since those with lower BP also had lower BMI, or psychosocial conditions associated with higher mortality such as depression)???
  • And what really is the actual blood pressure in patients with atrial fibrillation? The automated blood pressure cuffs typically use an oscillometric methodology. Studies have shown that many of these cuffs are inaccurate in patients with atrial fibrillation (see DOI: 10.1111/jch.12545). And, a larger issue to me is that there is a large blood pressure variability between measurements in patients with atrial fibrillation, with one measurement picking up a particularly strong, forceful beat, leading to a systolic blood pressure that may be 30 to 40 mm Hg higher than other readings. Some people suggest averaging several recordings (??how many), but I have no idea whether this correlates with clinical events are not, what the best methodology for determining that clinically-relevant BP really should be, or what would be the optimal goal BP (which also requires a good clinical prospective study using a validated methodology. perhaps 24-hour ambulatory blood pressure monitoring with an approved and accurate automated cuff???). As mentioned, i have seen no guidelines address the blood pressure issue: either its measurement or management goals.
  • One issue that is found frequently in observational studies on hypertension is a J-shaped or U-shaped curve. Of note this tends not to be found in controlled trials (e.g. the SPRINT trial), suggesting that there may be a bias in the uncontrolled trials: those with lower blood pressure have higher mortality related to the fact that they have underlying diseases leading to both a lower blood pressure and higher mortality
  • Of note, there are some data suggesting that we do not need to be overly aggressive in controlling rate (see Van Gelder IC. N Engl J Med 2010; 362: 1363), which also raises the interesting question of whether those with aggressive rate control may have had increased mortality because their blood pressure was lower, balancing perhaps a clinical benefit of the lower rate (i.e. there might be some benefit for tighter rate control, but only in those who could achieve this without lowering their blood pressure too much). Unfortunately in this Van Gelder article they did not mention the achieved blood pressures in the 2 groups.
  • This AFFIRM article suggests that the target blood pressure in those with atrial fibrillation may be higher than in the general population. However, the methodologic issues above, to me, simply amplify the issue that there really are no good clinical data guiding us on either how to measure blood pressure or what the goal should be in those with atrial fibrillation….

Primary Care Corner with Geoffrey Modest MD: Rivaroxaban and Increased Intracranial Hemorrhage vs. Dabigatran

6 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent review compared the adverse effects of dabigatran and rivaroxaban, two of the NOACs (non-vitamin K antagonist oral anticoagulants) –see doi:10.1001/jamainternmed.2016.5954. This follows another report finding increased bleeding risks as well as MIs in post marketing case reports for dabigatran following its approval. This new report, funded by Medicare and the FDA, did find a significant increase in major bleeds from rivaroxaban over dabigatran.


  • Retrospective new-user cohort study of 118,891 patients with nonvalvular atrial fibrillation who were 65 years or older and enrolled in Medicare from 2011 to 2014. Patients were included if they had a diagnosis of atrial fibrillation or flutter and filled a first prescription for either drug in this time period. Excluded if they had less than six months of enrollment in Medicare, were younger than 65, were in a skilled nursing facility or nursing home.
  • 52,240 were on dabigatran and 66,651 were on rivaroxaban
  • 50% were 65 to 74-year-old/40% were 75 to 84-year-old, 47% female, 91% white/4% black, 33% with diabetes, 40% hyperlipidemia, 86% hypertension, 15% obese, 19% smoking, 15% with heart failure, 33% with CHADS2 score of 0 to 1, 40% with score of 2, 19% with score of 3; 10% with HAS-BLED score of 1, 54% score of 2, 29% score of 3.


  • 2537 had a primary outcome of thromboembolic stroke (n=306), intracranial hemorrhage (176), or major extracranial bleeding (1209) including major GI bleeding (1018) and mortality (846).
  • Rivaroxaban vs. dabigatran was associated with:
    • 19% reduction in thromboembolic stroke, HR= 0.81 (0.65 to 1.01). Nonsignificant. This translates to 1.8 fewer cases of thromboembolic stroke per 1000 person-years
    • 65% increase in intracranial hemorrhage, HR 1.65 (1.20 to 2.26).  AIRD (adjusted incidence rate difference): 2.3 excess cases per 1000 person-years
    • 48% increase in major extracranial bleeding, HR 1.48 (1.32 to 1.67). AIRD = 13.0 excess cases per 1000 person-years; including 40% increase in major gastrointestinal bleeding, HR 1.40 (1.23 to 1.59). AIRD of 9.4 excess cases per 1000 person-years
    • 15% increase in overall mortality, HR 1.15 (1.00 to 1.32), borderline significant at p=0.051, AIRD of 3.1 excess cases per 1000 person-years. In patients 75 years or older or with CHADS2 score greater than 2, the excess risk was significant (27% and 24% increases, respectively).
    • The excess rate of intracranial hemorrhage exceeded the attributed reduced rate of thromboembolic stroke (the latter actually didn’t reach statistical significance)


  • As I have mentioned in several prior blogs, I am very concerned about the widespread adoption and use of NOACs in non-valvular atrial fibrillation. I believe there was significant drug company malfeasance in both the design and presentation of the data. See blogs referenced at the end for more information. This is not to say that NOACs are decidedly bad, just that the studies on which their approval were based were seriously flawed, perhaps largely because of the drug company cover-ups.
  • As a point of reference, in a large meta-analysis of warfarin in patients with a fib, intracranial hemorrhage occurred in 6 patients on warfarin vs. 3 on control, with n= 2900); and extracranial hemorrhage with warfarin was less than 0.3% per year(see Hart RG. Ann Intern Med 2007; 146:857).
  • It was interesting that more cardiologists prescribed rivaroxaban than family practitioners. Not sure what this reflects. Sensitivity analysis did not show that the patients on rivaroxaban were sicker. Perhaps the cardiologists were aware of the post marketing studies on the harms of dabigatran. Perhaps they were more influenced by the ROCKET-AF study of rivaroxaban(which has been criticized for using defective INR machines, see blogs and NEWS FLASH below). It is important to note that there are no head-to-head comparisons of these different NOAC medications
  • It is perhaps significant that the curves for intracranial hemorrhage, major GI bleeding, and mortality diverged during the follow-up period, though there was convergence on the event rate for thromboembolic strokes (i.e.: increasing problems without increasing benefits).
  • One wonders if some of the increased incidence of bleeding with rivaroxaban is that it actually has the same half-life as dabigatran of about 12 hours, but is dosed at once a day, whereas dabigatran is dosed twice a day
  • The study is limited by several factors. It is a retrospective analysis, and cannot have the rigor of the conclusions of a well conducted randomized trial. Also the mean duration of on treatment follow-up was only four months, though they did have a reasonable representation of those on meds at least 6 to 8 months.
  • So, to me this huge acceptance of NOACs over warfarin (which certainly has its well-known drawbacks) seems more to reflect drug company shenanigans and heavy-duty marketing than clear benefit, and with attendant risks (though i have occasionally prescribed them, e.g. when patients were spending long periods of time in other countries without access to INR monitoring).

For blogs on NOACs, best to go to, which has blogs on the rivaroxaban study (ROCKET-AF) using  defective INR machines in those patients on warfarin, a huge Swedish study showing safety and efficacy of warfarin when patients were mostly in the appropriate therapeutic range, and a slew of articles on drug company malfeasance in promoting dabigatran when internal drug company memos for example showed that they knew that drug levels actually should be monitored (though this went against their main selling point: that one would not have to  monitor levels vs warfarin), as well as the study mentioned above about post-marketing serious adverse events of dabigatran, with the comment that “the Institute for Safe Medication Practices reported that dabigatran was responsible for more serious adverse events than 98.7% of all medications” [and it seems to be better than rivaroxaban, at least by the above study!!!!!]. I also continue to be concerned about the lack of easy access to reversal agents for the NOACs, especially in smaller hospitals outside of large academic centers.

*********NEWS FLASH********

  • There was a new investigative report by Deborah Cohen in BMJ last week (she seems to have spear-headed many of the really great reports in BMJ about drug company malfeasance), stating that the drug company (Janssen) actually knew that the INR testing devices were faulty in the ROCKET AF study (which single-handedly propelled rivaroxaban into blockbuster status), yet withheld this information from the FDA. It turns out that the increased intracranial bleeding with warfarin might have been related to the fact that 33% of actual laboratory readings of INR were above 4, yet the defective point-of-care machines gave an INR on the same sample of between 2-3 (see doi: 10.1136/bmj.i5131)

Primary Care Corner with Geoffrey Modest MD: ACE Inhibs Decrease Conduction System Disease

11 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A secondary analysis of the ALLHAT hypertension study (see doi:10.1001/jamainternmed.2016.2502 ) found that patients in the lisinopril arm had decreased development of cardiac conduction system disease, which the authors suggested was due to lisinopril’s anti-inflammatory and antifibrotic properties.


  • ALLHAT was a community-focused hypertension study in 623 North American sites with 3 medication arms: lisinopril, amlodipine, and chlorthalidone. There was also a lipid component, and patients with fasting LDL 120-189 mg/dl (or 100-129 if known atherosclerosis) were randomized to pravastatin vs placebo. Follow-up 5 years
  • 21,004 people: 56% men, mean age 66.5, 92% white/6% black, baseline BP=174/98, BMI 28, Framingham risk score 22%, 16% smokers


  • 1114 developed conduction system disease: LBBB in 389, RBBB in 570, intraventricular conduction delay in 155
  • lisinopril vs chlorthalidone: 19% reduction in developing conduction system disease [HR 0.81 (0.69-0.95, p=0.01] with lisinopril
  • Amlodipine was non-significantly different from lisinopril


  • It was interesting that in this study no one developed lesser conduction system abnormalities such as 1st degree AV block, LAFB, or incomplete RBBB, which suggests that there might be a different pathophysiology than simply a progression of conduction system dysfunction (e.g. progressive fibrosis of Lev). The data on progression of 1stdegree AV block, for example, are mixed, with some long term studies finding this to be a benign condition, but some studies (e.g. Framingham Study) did find that an increase in atrial fibrillation (HR 2.1), likelihood of progression to require a pacemaker (HR 2.9) and higher all-cause mortality (HR 1.4): see Cheng S. JAMA 2009; 301(24): 2571.
  • LBBB and RBBB are clearly associated with increased cardiac mortality, as well as the potential progression to complete heart block
  • Lisinopril was better than chlorthalidone in this secondary analysis, controlling for an array of clinical variables, including demographics, BMI, smoking, aspirin use, diabetes, CAD, LVH, lipids. And this wasdespite the fact that the achieved blood pressure reduction was inferior with lisinopril.
  • Concerns about the study:
    • This is a secondary analysis, and there was some selection bias (those who received serial EKGs were more likely to be men and white, not have diabetes, and to be on aspirin)
    • >40% of all  participants were on at least one additional step 2 or step 3 drug, which brings up 2 issues:
      • The choice of the second and third agents was prescribed (either atenolol, clonidine or reserpine as step 2, hydralazine as step 3) and these were not standard community practice even at that time, at least in the Boston area (e.g.: adding atenolol to lisinopril was not done much then, since that combo was felt to be less synergistic, both being renin-active agents. The other agents were not used much at all)
      • There were no granular data presented separating out patients just on lisinopril as a single agent vs those on lisinopril in combination. This is problematic if lisinopril plus one of the second line meds did have some synergistic effect in combination for preventing conduction system abnormalities. So, for example, maybe the lisinopril did nothing alone, but did so only in combination with another med. in that case the conclusion that lisinopril is good for protecting the conduction system would be erroneous.
    • If lisinopril were protective, why would that be the case?
      • I think positing the anti-inflammatory effect is a bit of a stretch, since those on pravastatin (a pretty potent anti-inflammatory) had no protection and in fact a trend to worse conduction system disease outcomes
      • Clearly the issue is not lowering the blood pressure per se, since the lisinopril group had less BP improvement
      • My guess is that the issue was decreasing LVH, since LVH was the strongest single predictor of incident conduction system disease in multivariate analysis. (The association with lisinopril above did control for LVH, but only LVH at baseline. And only by the relatively poorly sensitive EKG). And, ACE inhibitors/ARBs are the best agents for reversing LVH. Also, LVH itself does have significant mortality associated with it, which is decreased when an antihypertensive agent decreases EKG-determined LVH (see the LIFE trial, Dahlof B. Lancet 2002; 359: 995, which showed that the ARB losartan was better than atenolol in decreasing cardiac events, but that with LVH regression by either drug, there were fewer cardiac events – i.e., it was the LVH regression that mattered, not the drug. unfortunately, they did not report on conduction system dysfunction). The data on reversal of LVH is almost as good for calcium blockers (e.g. amlodipine) as with ACE inhibitors (e.g. lisinopril). Diuretics (like chlorthalidone) are significantly less likely to reverse LVH.
    • So, my conclusions:
      • This study reinforces my use of dihydropyridine calcium channel blockers as my first drug for hypertensive patients. As mentioned in several prior blogs, I am concerned with using hydrochlorothiazide as the initial agent (the most commonly used one), since its durability over 24 hours is quite limited (see blog below), and this ALLHAT secondary analysis reinforces not using a diuretic. Amlodipine has a much longer duration of action and has much less blood pressure variability (perhaps an additional clinical benefit). This was pretty much the conclusion of NICE, in their 2011 analysis, suggesting that all Afro-Caribbean hypertensive individuals and all white people >55yo have a calcium channel blocker as the first agent. They do suggest an ACE inhibitor if white and <55yo (mostly because of the higher likelihood of high renin hypertension in this  group), though they also supported using chlorthalidone (but not hydrochlorothiazide)
      • And, as in the LIFE study, the current study does support preferentially using an ACE inhibitor or ARB for those with LVH by EKG (and, I would extend this to echo LVH). Though, again, amlodipine (or other dihydropyridine calcium channel blockers) are also reasonable. (i.e., the 2011 NICE guidelines are basically upheld by this study….)


See which showed that HCTZ has poor 24-hr duration, with chlorthalidone being much better

Primary Care Corner with Geoffrey Modest MD: Warfarin in Nonvalvular Atrial Fibrillation

13 May, 16 | by EBM

By Dr. Geoffrey Modest

Over the years, I have sent out several blogs about the drug company shenanigans/malfeasance in studies promoting NOACs (non-vitamin K antagonist oral anticoagulants) — See link at bottom. Here is a large study suggesting the benefits of warfarin (See doi:10.1001/jamacardio.2016.0199 ). The authors note that studies finding NOAC superiority were in comparison to warfarin where the times-in-therapeutic range (TTR) varied from 55.2% to 64.9%. In the current study researchers looked at the relative effectiveness of warfarin for patients with atrial fibrillation (AF) as it varied with TTR. Data are from a large Swedish registry.


  • Retrospective, multicenter cohort study of 40,449 patients
  • 40% women, mean age 73, mean CHA2DS2-VASc (see below) score 3.3, TTR<70% in 43%, hypertension 60%, heart failure 30%, renal failure 4%, excessive alcohol use 2%, history of falls 8%, prior major bleed 6%, MI 21%, diabetes 18%, stroke 19%, TIA 8%
  • 4311 patients also on aspirin with the warfarin, with the concomitant diseases/risk factors about the same as the overall cohort except that 43% had a prior MI (vs 17% just on warfarin)


  • Annual all-cause mortality 2.19% (2.07-2.31), intracranial bleed 0.44% (0.39-0.49)
  • Comparing those with TTR <70% vs >70% (all are annual rates)
    • All-cause mortality was 4.35% vs 1.29%
    • Any major bleed was 3.81 vs 1.61%, with intracranial bleed 0.72 vs 0.34%; GI bleed 1.26 vs 0.56%
    • Any thromboembolism was 4.41 vs 2.37%, MI 1.90 vs 0.98%, venous thromboembolism (VTE) 0.24 vs 0.09%, and arterial embolism 2.52 vs 1.41% [thromboembolism defined as: stroke, TIA, peripheral arterial emboli, venous thromboembolism, MI]
  • The role of INR variability (dividing those around the median of higher vs lower variability in their cohort): comparing high vs low
    • All-cause mortality was 2.94% vs 1.50%
    • Any major bleed was 3.04 vs 1.47%, with intracranial bleed 0.51 vs 0.38%; GI bleed 1.05 vs 0.50%
    • Any thromboembolism was 3.48 vs 2.46%, with MI 1.53 vs 0.96%, VTE 0.16 vs 0.11%, and arterial embolism 1.98 vs 1.51%
  • For those with TTR >70%, INR variability did not matter
  • For those on aspirin
    • All-cause mortality was 2.57% vs 2.13%
    • Any major bleed was 3.07 vs 2.04%, with intracranial bleed 0.62 vs 0.41%; GI bleed 1.16 vs 0.67%
    • Any thromboembolism was 4.90 vs 2.12%, with MI 1.53 vs 0.96%, VTE 0.19 vs 0.12%, and arterial embolism 2.72 vs 1.54%
  • For those with renal failure, intracranial bleed more than twice as common, with HR 2.25 (1.32-3.82)
  • The strongest predictor of intracranial bleeding was renal failure

So, a few issues:

  • These data, though not from a prospective, randomized study, do reflect more of a real-world community setting.
  • The results for patients in good control (TTR>70%) is actually better than in the “pivotal NOAC studies”.
  • In terms of the issue of using the combo of warfarin and aspirin:
    • I am very concerned about the increased serious adverse events with this combination (see , which looks at several observational studies on aspirin plus warfarin for patients with AF and CAD, all showing much higher risks (e.g., bleeding) without any clear benefit. The PREFER trial (see De Caterina, R. Heart 2014; 100: 1625) looked at a large European registry of patients with AF and found that 95% of those on dual antiplatelet and anticoagulation therapy did NOT have an “accepted indication” (i.e.: acute coronary syndrome or stenting –and, this is the current recommendation of the European Society of Cardiology guidelines in AF: anticoagulant therapy only except in these indications).
    • In the above Swedish study, only 2.6% of those on additional aspirin had a clear indication for this therapy. And this study really supported NOT using aspirin, given the higher mortality, higher MI/VTE/arterial embolism, and much higher bleeding risk (though, as noted, this was not an RCT, had many more patients with prior MI, so it is not so surprising that there was an increase in these thrombotic events. But twice the level of major bleeds???  And 50% more thrombotic events??? Is aspirin really useful?? I personally have stopped aspirin in my patients on warfarin, based on the prior blog)
  • So, my bottom line: this Swedish study confirms the utility of warfarin in patients with nonvalvular AF, though clearly differentiates its advantages in those in good control (INR in range >70% of the time) vs not. I do have trouble with the NOACs overall, given the noted drug company issues in my prior blogs and the lingering concern that if they are in an accident, reversal agents are not widely available. But I have occasionally used NOACs in patients who are leaving the country and cannot get their INR checked, or it is just too difficult to get the INR in range despite best efforts all around, often including home-based nursing care/checking the INR at home. That being said, the clear majority of my patients on warfarin are definitely in the >70% TTR category and seem to be doing just fine…. (though I do need to monitor them frequently, but, then again, most of them have significant cardiac and other morbidities, and my guess is that the increased monitoring/health system contact is actually a positive thing)

CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 75 years [doubled], diabetes mellitus, stroke [doubled]–vascular disease, age 65-74 years, and sex category [female])

For older blogs, see: goes through the antithrombotic therapy guidelines but also reviews the history of drug company malfeasance with the NOACs, which really make me uneasy about using them…

Primary Care Corner with Geoffrey Modest MD: Atrial Fibrillation and Lower BP

24 Mar, 16 | by EBM

By Dr. Geoffrey Modest

Although there have been many studies confirming a role of hypertension in the development of atrial fibrillation (AF), a secondary analysis of the LIFE trial gives insight into the effects of achieving different levels of blood pressure on the frequency of development of AF (see Hypertension. 2015;66:368). The LIFE trial (Lancet. 2002;359:99) used 2 different hypertensive agents (losartan and atenolol) in patients with EKG-documented LVH to assess differences in clinical outcomes.


  • 8831 hypertensive patients (mean age 66.6, 45% male, 6% Black race, 13% with diabetes, 18% ischemic heart disease, 7% MI, 5% stroke, 15% smokers, BMI 28), with EKG LVH and no history of AF, in sinus rhythm on baseline EKG, were randomly assigned to losartan or atenolol, and followed 4.6 years
  • Patients with in-treatment achieved SBP ≤ 130 mmHg (lowest quintile at last measurement in the study) were compared to those with SBP 131-141 vs those with ≥​142


  • New onset AF developed in 701 patients (7.9%)
  • In multivariate analyses (controlling for age, sex, race, DM, history ischemic heart disease/MI/heart failure, serum glucose/creatinine/microalbumin, prior BP therapy), comparing achieved SBP of ≥​142 mmmHg:
    • Achieved SBP of ≤​130 mmHg was associated with a 40% lower risk of AF (18-55%, p=0.001)
    • Achieved SBP of 131-141 mmHg was associated with a 24% lower risk of AF (7-38%,  p=0.007)
  • ​For each 10mmHg decrease in SBP:  13% lower risk of AF (9-17%, p<0.001)
  • ​And, no difference in benefit of lower SBPand AF in those > or <60yo
  • But, lowering SBP to ≤125 mmHg was no longer associated with reduced risk of AF (all achieved SBPs less than 125 were nonsignificantly related to the development of AF, though the hazards ratio trended to increasing risk with progressively lower SBP)

So, a few points:

  • Although the LIFE cohort included only patients with LVH on EKG, it has the advantage of using 2 different BP meds with 2 different mechanisms of actions. This makes it more likely that it is the achieved blood pressure which correlated with the development of AF. (With only one medication, one might wonder if the association was the blood pressure lowering effect or perhaps some other unrelated effect of the med).
  • But, one concern here is that those on losartan had somewhat lower likelihood of developing AF (in those who developed AF, 46.2% were on losartan vs 50.6% on atenolol). And we know from the LIFE study that those on losartan had more regression of their LVH than those on atenolol, and this was the purported reason that in the overall LIFE trial there were overall fewer cardiac events in the losartan group. In fact, the incidence of cardiac events in the LIFE study overall was equivalently lower in both the losartan and atenolol groups when there was regression of LVH, but regression was more common in the losartan group. So, it may be that looking at the post-hoc analysis of hypertensive patients with LVH and their likelihood of developing AF might not be so generalizable to hypertensives without LVH (.e., if the development of AF were at least partly related to LVH on EKG).
  • Prior articles have had somewhat mixed results: the Cardio-Sis trial (Lancet. 2009;374:525) found statistically fewer cases of new onset AF in those on tighter control (achieved SBP of 131.9 mmHg was better than 135.6), though another study did not (Am J Hypertens. 2008;21:1111)
  • So, this trial adds to the argument that more dramatic lowering of the blood pressure may have another positive effect: decreasing the likelihood of developing AF. And, of course, this is a really important clinical endpoint (stroke, other emboli, risks of prolonged anticoagulation and/or cardiac procedures, risk of sudden cardiac death and heart failure, risk of cognitive decline, …). though there were also limitations of the SPRINT trial (see​ , which did not include diabetics but did find a pretty much all-endpoint benefit of tighter control at an achieved SBP of 121 mmHg), this current study does add to the literature suggesting more aggressive goals of therapy, with SBP target in the 125-130 mmHg range, at least in those with EKG-LVH. Though, it should be added, that this study had too few diabetics to make a meaningful argument about their blood pressure goal, and another recent blog (see ) assessed a systematic review finding that the goal for diabetics should perhaps be higher than others, with a target of 140/75-80. And I will add my usual caveat to be less aggressive with elderly, since postural hypotension/risk of falls is so common(?autonomic dysfunction, see and too low a blood pressure can be associated with cognitive decline (see ).

Primary Care Corner with Geoffrey Modest MD: Rivaroxaban, Is It Really Better Than Warfarin for Non-valvular Atrial Fib?

16 Feb, 16 | by EBM

By Dr. Geoffrey Modest

The BMJ spotlight team (actually Deborah Cohen, associate editor) just released another investigation into poorly-regulated drug-company-supported studies which have led to large changes in clinical practice and large profits for drug companies (see BMJ 2016;352:i575). This one is a challenge to the ROCKET-AF study (see N Engl J Med 2011;365:883-91), which was the single study leading to FDA approval for rivaroxaban, a​ direct thrombin inhibitor, by showing that although it was as good as warfarin in patients with non-valvular atrial fibrillation in preventing strokes, there were fewer episodes of intracranial and fatal bleeds. Of note, rivaroxaban is now the world’s best-selling new anticoagulant. However, it turns out that the ROCKET-AF study relied on defective point-of-care INR machines which gave falsely low INR levels, thereby leading the researchers to increase the warfarin dosing and perhaps predisposing patients to more bleeding.


  • BMJ found that the INR devices used had been recalled in December 2014 because the FDA issued their highest level recall notice finding that these devices could give “clinically significantly lower” INR values. The device manufacturer Alere had received 18,924 reports of malfunction and 14 serious injuries, dating back to 2002 (prior to the ROCKET-AF trial starting)
  • September 2015: BMJ asked ROCKET investigators about the device recall. No direct response, just one from the drug company that they were unaware of the recall.
  • The European Medicines Agency (EMA, the European equivalent of the FDA) in April 2015 did not know these devices were used in the ROCKET-AF study, and called for an independent investigation into direct oral anticoagulants. The company claimed that the results of ROCKET-AF were still valid after conducting some sensitivity analyses. No independent investigation has happened to date.
  • But, as per Harlan Krumholz, a cardiologist at Yale, “the study should be considered of uncertain validity until a more thorough review can be  done”, and to have “an investigation by an independent group of experts to quickly determine if there are grounds for retraction [of the study]”.
  • In looking back at the original FDA approval for rivaroxaban, 2 primary reviewers had expressed concern about the warfarin control and recommended that the drug not be approved, stating “ROCKET provides inadequate information to assess the relative safety and efficacy of [rivaroxaban] in patients whose warfarin administration can be well-controlled”
  • BMJ asked the ROCKET researchers if those patients who had major bleeds had had laboratory INRs checked. None responded.
  • It turns out that at the 12-week and 24-week time-periods, there were simultaneous measurements of INR by device and a central lab, though this data has not been released.
  • There was a rebuttal by the investigators to the above BMJ charges (see DOI: 10.1056/NEJMc1515842). The investigators did post-hoc analyses using the FDA recall criteria [medical conditions that the FDA thought might lower the INR value of the device: anemia with hematocrit >30%, and conditions which raised fibrinogen levels (acute inflammation, chronic inflammatory conditions, severe infection, cancer or end-stage renal disease]. Results of the post-hoc analysis were mixed:
    • ​In those without recall conditions: no significant difference in strokes with rivaroxaban vs warfarin; more intracranial hemorrhages, fatal or critical organ bleeding with warfarin; more GI bleeding overall with rivaroxaban
    • In those with recall conditions (and presumably on unnecessarily higher doses of warfarin): decreased stroke in those on rivaroxaban but only in the per-protocol patients; no difference in intracranial hemorrhages, fatal/critical organ bleeding; more GI bleeding with rivaroxaban.

So, these articles bring up several issues:

  • It is a little unsettling to me that rivaroxaban was approved based on only one drug company-sponsored study
  • I’m not sure what to make of the post-hoc analysis by the investigators. Surprisingly, they seem to show fewer adverse events in those without the FDA-designated recall conditions, though interestingly in those patients with those conditions, rivaroxaban​seemed a bit worse on clinical bleeding. But are those recall conditions complete? Many older studies, for example, found a relationship between smoking and high fibrinogen levels (to the point that many posited that the main mechanism of smoking causing heart disease was mediated by fibrinogen, and that stopping smoking quickly reversed much of the increased CAD risk because smoking’s effect on fibrinogen levels reversed so quickly). Smoking was not on the recall list. Are there other unknown conditions which lead to aberrancies in the device INRs?Or are there other unknown biases which can happen in a post-hoc analysis? It would be interesting to know the relationship between the laboratory INR measurements at the 12 and 24-week times and the results of the point-of-care devices. And what the correlation was on an individual basis between these discrepancies and the positive and negative clinical outcomes. And, I would strongly support an independent review.
  • A prior BMJ issue and several other studies have suggested that dabigatran also may have many more adverse events than reported and that there were drug company shenanigans; in particular the drug company covered up evidence suggesting that there needed to be blood monitoring, despite the main selling point for the drug being that no drug monitoring was necessary, as opposed to warfarin and the need to follow INRs, (see As a result of the BMJ and other articles about dabigratan, at the end of 2015 both the EMA and FDA held meetings to see if there was a need to monitor blood levels of direct anticoagulants and adjust the dose as necessary to maximize benefits/minimize harms.
  • This raises the issue that the FDA historically has been less aggressive in regulating devices than meds. Typically, once one device is accepted, there is much less overview on similar products (new devices just need to be “substantially equivalent” or similar to ones already on the market). And, the issue of rivaroxaban highlights that approval of meds may well require studies using not-so-well-regulated devices which could potentially dramatically affect the results. And, this is compounded by the selection bias favoring the drugs: positive studies of drugs are published at a much higher rate than negative studies. And once a drug company has a positive study (as with ROCKET-AF), there is little incentive to do further confirmatory studies after a drug is approved.
  • So, yet again, I am very hesitant to prescribe these newer meds, given huge conflicts-of-interest, the large numbers of cases of drug companies hiding results they do not like, the decreasing authority and efficacy of the FDA in monitoring new drugs (e.g., see ), and the increasing reliance on post-marketing surveillance, which seems to happen only pretty rarely (e.g., see ). I continue to use warfarin as my preferred anticoagulant, and I use the close monitoring of INRs (which in rock stable patients, can actually be done on an every 2-3 month basis) as a means to check-in with these patients, who are typically medically-complex anyway.

Primary Care Corner with Geoffrey Modest MD: 3 Heart Failure Articles of Note

20 Jan, 16 | by EBM

By Dr. Geoffrey Modest

There were 3 useful articles in the JACC-Heart Failure journal which I think are useful in primary care

  1. This article (see​) looked at the target for b-blocker (BB) use in patients with heart failure and reduced ejection fraction (EF, <35%) within the HF-ACTION study, the largest trial of BB use involving 2331 medically stable outpatients and showing benefit from a structured aerobic exercise program over 2.5 years (see JAMA 2009; 301(14): 1439). The issue addressed is titration of the BB dose: the HF-ACTION and other trials have found that just lowering the heart rate (HR) improves mortality but raise the question of whether that explains the full BB effect, or is the achieved dose of the BB more important.


  • 2320 patients (mean age 60, 28% female, 32% black, BMI 30, 62% NYHA Class II, 50% ischemic cardiomyopathy, EF 25%, SBP 110 mmHg, resting HR 70, 80% in sinus rhythm).
  • Divided into 2 groups: those on high dose carvedilol (>=25mg/d) vs low dose (<25 mg/d); and those with high heart rate (>=70 bpm) vs low (<70 bpm)


  • All-cause death or all-cause rehospitalization (all with adjusted HR values)
    • High vs low dose BB, hazard ratio 0.87 (0.77-0.99), p=0.03, i.e. 13% decrease in deaths/hospitalizations
    • High vs low HR, hazard ratio 11 (0.98-1.24), p=0.09, nonsignificant
    • And looking at the combination, adding HR to the analysis added no significant value
  • There was a significant 21% decrease in all-cause death as well as a 23% decrease in cardiovascular death or heart failure rehospitalization with high-dose BB. HR was not significant for any of the outcomes in either unadjusted or adjusted analyses. Part of the reason for the lack of significance is the relatively low number of events, under powering the study.
  • The association between BB dose and the above clinical outcomes was independent of the baseline HR
  • There was no significant difference in the biomarker NT-proBNP between these groups, though there was more of a decrease in the biomarker in the high BB dose group, though nonsignificant. Related to small numbers?

So, this study reinforces maximizing the BB dosage, even in those with HR<70bpm. I’m not sure what the BP was for this group (not reported), but the high numbers of patients in the community not on optimal BB doses (in the 80-90% range!!) reflect perhaps a less aggressive approach to therapy than seems warranted. I should add the caveat that this is a post-hoc analysis, and as such is potentially limited by confounding.


  1. A meta-analysis of 11 studies looking at the progression of asymptomatic heart failure (HF) to symptomatic HF, over an average of 7.9 years (see org/10.1016/j.jchf.2015.09.015), assessing both those with ALVSD (asymptomatic left ventricular systolic dysfunction), and ALVDD (asymptomatic left ventricular diastolic dysfunction).


  • 11 studies identified with 5,369 patients. 5 with ALVSD, 3 with ALVDD, and 4 with both
  • ALVSD somewhat variably defined, but typically ejection fraction (EF)<30-50%


  • ALVSD: absolute risk of progression to symptomatic HF was 8.4/100 person-years (4.0-12.8 per 100 person-years); adjusted relative risk was 4.6 (2.2-9.8)
  • ​ALVDD: absolute risk of progression to symptomatic HF was 2.8/100 person-years (1.9-3.7 per 100 person-years); adjusted relative risk was 1.7 (1.3-2.2)
  • In controls (no ventricular dysfunction): absolute risk of progression to symptomatic HF was 1.04/100 person-years (0.0-2.2 per 100 person-years)
  • ​Per a 1-SD change in EF, there is an overall 38% increased risk of developing clinical HF [RR=1.38 (1.14-1.67]
  • The main predictors of progression were: age, sex, blood pressure, diabetes, and BMI

So, it is pretty clear that asymptomatic LV dysfunction is associated with a significant risk of becoming symptomatic, more so in those with reduced systolic function, and with increasing risk as the EF decreases. Studies have shown that asymptomatic LV dysfunction is also associated with reduced survival, and interventions as with ACE inhibitors prevent or delay the development of symptomatic HF and decreases mortality.


  1. Looking at the CIBIS-ELD trial (Cardiac Insufficiency Bisoprolol Study in Elderly), researchers assessed the tolerability and efficacy of bisoprolol vs. carvedilol in symptomatic (at least NYHA class 2) patients > 65 yo with either HFrEF (heart failure with reduced ejection fraction) or HFpEF (heart failure with preserved EF) —​.


  • 626 patients with HFrEF (mean age 73, 26% women, 61% NYHA class 2/32% class 3, 15% with peripheral edema, mean HR 75, mean BP 134/80, BMI 27, EF 35%, NT-proBNP 968; CAD in 68%, dilated cardiomyopathy in 19%, hypertension in 80%, 9% smokers, 48% with MI) and 250 with HFpEF (mean age 73, 66% women, 76% NYHA class 2/23% class 3, 35% with peripheral edema, mean HR 71, mean BP 146/80, BMI 29, EF 59%, NT-proBNP 253; CAD in 33%, dilated cardiomyop in 2%, hypertension in 90%, 8% smokers, 18% with MI) were randomized to bisoprolol vs carvedilol, with a goal to up-titrate to the target or maximally tolerated dose
  • Carvedilol started at 6.25mg bid with target of 25 mg bid (or 50mg bid in those with body weight >85kg); bisoprolol was 2.5mg daily with target of 10mg daily, with biweekly dose doubling
  • Titration was to be over 6 weeks (8 weeks for those >85kg and on 50mg carvediol), then 4 week maintenance period


  • Mean daily dose of bisoprolol after titration was 4.93 mg in the HFpEF and 5.01 in HFrEF groups; for carvedilol it was 25.3 and 29.1 respectively) — nonsignificant differences (19% of HFpEF vs 27% with HPrEF reached target dose, regardless of treatment group, which was significant)
  • ​It took longer to uptitrate those with preserved EF (12%) vs reduced EF (5%)
  • Similar HR reductions, at 7 bpm in both those with preserved and reduced EFs. BP decreased more with the preserved EF group (14/5 mmHg) vs reduced (8/4)
  • NYHA functional class improvement:
    • Reduced EF group had 34% improvement vs preserved EF group (decrease of 31% vs 18%): 23% improvement (p<0.001  for comparison), and no diff if on carvedilol vs bisoprolol
  • 6-minute walk distances and physical quality of life measures improved in the HFrEF group but no change in HFpEF groups (20 vs 4 meters).
  • In 3 measures of quality of life (SF-36 PFS, SF-36 PCS and SF-36 MCS, reflecting physical functioning, physical component, and mental component): there was only a significant change in the HFrEF group only
  • ​Echo for systolic function: mean EF improved in those with reduced EF from 35% to 39% by week 12, no change in the preserved group.
  • ​Echo for diastolic function: mean E/e’ and left atrial volume index not change in either group, but E/A mitral flow did increase in those with preserved EF [i.e., BBs did not change any markers of diastolic function in either those with preserved or reduced EF), and no difference between the BBs]
  • ​Adverse effects: more in HFpEF patients (79%) vs HFrEF (58%), with p<0.001 for difference, mostly bradycardia (20% vs 11%), dizziness (15% vs 4%), and fatigue (18% vs 4%)

So, one of the major conundrums in treating HF is that about 50% have HFpEF (preserved EF), with increasing prevalence over time. This group in general has the same overall prognosis as those with reduced EF. And we have minimally effective treatments as compared with those with reduced EF. On the surface, BBs would seem to be reasonable drugs (they decrease BP, decrease LVH, decrease HR, and decrease ventricular arrhythmias — a leading cause of death in this group). This study did not find any really significant differences between using bisoprolol vs carvedilol, either in tolerability or efficacy. But there were real differences between those with reduced EF (easier ability to titrate dose up, more improvement in NYHA functional class and measures of quality of life, walking distance, EF, fewer adverse events) and much less in those with preserved EF (more decrease in HR, BP, and no real clinical improvement). This was a short-term study, and without a placebo group,


So, why do I bring up these 3 articles?

  • HF is really common (5.7 million US adults, lifetime risk in a young adult being 20%), has a substantial morbidity/mortality, and there are lots of people with asymptomatic HF (3-4x the number with symptomatic).
  • The first article found that for those with reduced EF, trying to push BB to the targeted dose (which, unfortunately, does not happen so often in community practice), seems to confer the most benefit
    • The treatment algorithm is pretty straightforward (diuretics as needed, then ACE/ARB, then BB, then aldosterone antagonists; though can use hydralazine/isosorbide dinitrate in African-Americans and those not tolerant of ACE/ARBs), but these meds all lower blood pressure, and in my experience the not-so-uncommon limiting factor is that the blood pressure can’t abide this many agents at full dose, leaving us some unanswered questions:
      • What are the priority agents (in general the studies have assumed this medication order, but if the blood pressure is low, which individual agent is the most effective?)
      • Is it better to have low doses of multiple agents vs maxing out the meds in a specific order (studies do suggest that low doses of meds are useful)?
    • And another issue is hyperkalemia. Though the diuretics help counter this, all the other meds make it worse. And this is especially an issue in diabetics (not-so-uncommon), where hyperkalemia is more often an issue.
      • Again, should we give a little of many agents or push individual agents in a particular order? (E.g. my experience is that BBs are less hyperkalemic than the ACE/ARB or aldo antagonists. I should add that the CIBIS III trial did find that starting BBs first seems to be equivalent in outcome to ACE/ARBs, but the advantage of ACE/ARB first is that they work faster, and BBs can cause worsening heart failure in the short-term, further supporting starting first with ACE/ARB to better optimized initial treatment)
    • The second article found that those with asymptomatic HF have a real risk of progression to symptoms, more-so in those with reduced EF (systolic dysfunction). And these asymptomatic people, a very common issue, are at much higher risk of morbidity and mortality, raising:
      • The potential possibility that we should be screening more routinely for asymptomatic LV dysfunction, then doing interventions to improve the function and potentially decrease both the likelihood of symptomatic HF and mortality. Seems like a useful study to do, since the prevalence, morbidity and mortality of HF is so profound. But at this point it is not clear that early identification and treatment changes any clinical outcomes.
      • And, it reinforces the likely benefit of preventing ventricular dysfunction in the first place: decreasing systolic dysfunction by decreasing cardiovascular risk factors, the development of nonischemic cardiomyopathies (e.g. decreasing stress, treating infections such as chagas, lyme early and aggressively, etc.); and decreasing diastolic dysfunction (also treating hypertension, stress, development of myocardial ischemia)
    • And the third article, though actually a short-term tolerability study, highlights the difficulty of treating those with preserved EF, though it should be pointed out that this was a short-term study and the mechanism of disease in those with preserved EF is different from those with reduced EF (i.e., it may take longer to reverse the cardiac remodeling in those with preserved EF)
      • ​But the bigger and more relevant/longer-termstudies do not find the same benefit with current treatment of those with preserved EF as in those with reduced EF, though there are some data that ARBs decrease hospitalizations (CHARM-Preserved trial) and that spironolactone decreases hospitalizations and (secondary analysis) deaths in those with high BNP levels (TOPCAT trial) though with a fair amount of hyperkalemia
      • In fact, treatment of those with preserved EF is pretty much several decades behind where we are with patients with reduced EF (where we were basically using loop diuretics and digoxin for symptom control, without improving mortality)
      • e., we really need better drugs (and reinforcing the above interventions to decrease the development of left ventricular dysfunction with preserved EF to the extent we can)
    • But my experience is that treating HF, esp. in those with reduced EF, is really easy to do in the primary care setting in the vast majority of patients and that there is really a very remarkable response to the meds with the above-noted algorithm (I have had several patients with shockingly low EFs in the 10-15% range who function totally normally for more than 10 years…). And we can also provide symptom control for the majority of those with preserved EF, using diuretics, ACE/ARB, ?spironolactone (which are more effective than BBs anyway in improving left ventricular size and shape), and BBs as needed to help control HR, anginal symptoms, and BP. Treating HF one of the more rewarding primary care interventions, since patients pretty regularly respond so well clinically to these interventions and feel much better so rapidly.

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