833 e-Letters

  • Correction on Figure 1

    I submit this comment on the recent publication by Leung et al entitled “Non-inferiority trials in cardiology: what clinicians need to know” (1) which I believe has a slight error that merits correction.

    On Figure 1 in the original publication, the label says that Result E shows “New treatment inferior” but that is not a correct interpretation. The text in the footnote (“the upper bound of the 95% CI exceeds the predetermined non-inferior margin. Therefore, the new treatment is inferior to standard treatment”) is also incorrect. The data shown in Result E are not sufficient to declare a non-inferiority hypothesis met (the upper limit of the CI for relative risk is above the non-inferiority margin) but nor are they sufficient to declare the new treatment inferior (the lower limit of the CI for relative risk is below the null value). Therefore, the correct label for Result E is “New treatment neither inferior nor non-inferior.” The new treatment would only be declared inferior to the standard treatment in cases F and G (where the lower limit of the 95% CI for relative risk is above the null).


    1. Leung JT, Barnes SL, Lo ST, Leung DY. Non-inferiority trials in cardiology: what clinicians need to know. Heart 2019 [epub ahead of print]

  • Lifestyle modifications and their relationship with myocardial stiffness, atrial stiffness and atrial fibrosis

    Some of the risk factors for atrial fibrillation(AF) mentioned by the authors, such as hypertension, diabetes, sleep apnoea, older age, and lack of exercise, respectively(1), are also risk factors for myocardial stiffness(2)(3)(4)(5)(6). Myocardial stiffness, in turn, is a risk factor for atrial remodeling in the canine heart(7), and a parameter associated with paroxysmal AF in structurally normal human hearts(8). What is more, exercise has been shown to be capable of reversing myocardial stiffness, both in animals(9), and in human subjects(10).
    In the more specific context of left atrial stiffness, obesity has emerged as a risk factor for left atrial stiffness(11)(12). Among patients with obesity, hypertension, and diabetes, respectively, a link has been hypothesised between the twin entities of left ventricular stiffness and depressed atrial compliance, on the one hand, and the development of myocardial fibrosis.(12) . The authors of the latter hypothesis proposed that obesity, hypertension and diabetes generated a systemic proinflammatory state which culminated in the emergence of the coexistence of stiff cardiomyocytes and interstitial fibrosis(12). Furthermore, in a study where the assumption was made that the existence of low voltage areas was a surrogate for left atrial fibrosis, the presence of a left atrial low voltage burden exceeding 10% was shown to be associated with significantly(p < 0.0001) higher left atrial stiffness index((LASI)(13)....

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  • Biomarkers to enhance prognosis assessment in transcatheter aortic valve replacement: usefulness of CA125

    We have read with interest the review published by Goldsweig et al of predictors of readmission after transcatheter aortic valve replacement (TAVR) (1). We agree that identifying factors linked with a higher rate of readmission is of utmost importance. In this review, several clinical and procedural factors have been identified as predictors of adverse events after TAVR. However, the potential value of biomarkers for risk stratification in this setting has also been suggested in the literature. Several biomarkers have been tested for prognostic purposes; among them, we would like to highlight the role of Carbohydrate Antigen 125 (CA125). CA125 is a glycoprotein released by the mesothelial cells in response to increased hydrostatic pressures and/or inflammatory stimuli (2). Their levels are elevated in up to two-thirds of decompensated patients and correlated to parameters of clinical and echocardiographic congestion including pulmonary artery and right atrial pressures. Interestingly, its changes after discharge are strongly associated with the risk of adverse clinical events (2). In the setting of TAVR, baseline (pre-implant) CA125 levels were independent predictors of death and MACE (death, myocardial infarction, stroke, and readmission), even after adjusting for well-established prognostic factors, in an observational study (3). Interestingly, increases of CA125 at any time in the follow-up after TAVR were independently related to events, suggesting its usefulness not...

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  • Number needed to treat to harm

    This is a really important and interesting article. I would like to congratulate the authors with their work.

    I do have one question with regard to figure 3B. The numbers needed to treat to harm (NNTH) in this table seem to have counterintuitive values, for instance see the value from the direct thrombin inhibitor, which is listed as 153, with a corresponding OR of harm of 2.63. This NNTH value is more or less equal to that of aspirin, which has a listed NNTH of 155, however, its corresponding OR for harm is much lower, namely 1.07. Similarly, the point estimate of the NNTH for standard dose Xa is 270 which is higher than that listed for low dose Xa inhibitor (187), while the respective ORs for harm show that standard-dose Xa inhibitor has a higher odds for harm. I realize that there is a possible logical explanation for these counterintuitive results, namely that the base rates of the placebo/observation condition vary significantly, but that would not be expected. Could the authors elaborate on this? Thank you very much in advance.

  • The number needed from a non-significant result

    This is our response to a concern raised by a reader regarding the estimates and credible intervals of those numbers needed to treat to harm presented in our article titled “Extended treatment of venous thromboembolism: a systematic review and network meta-analysis.”

    First, we confirm that data published in the Journal are valid and correct.

    We also like to thank the reader to point it out as a number needed (either for benefit or harm) derived from an effect estimate that crosses the unity has been intuitively challenging to visualize (Hutton JL. Br J Haematol. 2009;146:27-30). Because it is given by the reciprocal of the absolute risk difference, a number needed can never include zero but straddles plus and minus infinity ∞ when the absolute risk difference include zero. By the frequentist approach based on inverting the confidence interval of the absolute risk difference, it represents that the number needed encompasses two disjoint regions: one from upper confidence interval to plus ∞ and the other from lower confidence interval to minus ∞ (Altman DG. BMJ. 1998;317:1309-12). Some had argued that for those non-significant results, a number needed should be presented as a single number without its confidence interval as it includes the possibility of no benefit or harm (McQuay HJ. Ann Intern Med. 1997;126:712-20). Other had suggested that it should not be reported when being non-significant (McAlister FA. CMAJ. 2008;179:549-53).

    Our analyses with t...

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  • CHADS2 score and prediction of stroke in heart failure

    Given the fact that some of the patients studied by Chou et al were characterised by the coexistence of , at least, four CHADS2 parameters, namely, Congestive heart failure, Hypertension, Age 75 or more, and Diabetes(1), it is to be expected that some of those patients will have stenotic cerebrovascular disease(both intracranial and extracranial)(2). In the latter study of 780 subjects presenting with stroke in the presence of nonvalvular atrial fibrillation(NVAF), concomitant cerebrovascular stenosis of 50% or more was identified in 231 patients. Multivariate analyses showed that CHADS2 score was an independent predictor of concomitant cerebral atherosclerosis(Odds Ratio 3.121; 95% Confidence Interval 1.770 to 5.504), and also a predictor of the presence of proximal stenosis at the symptomatic artery(OR, 3.043; 95% CI 1.458 to 6.350)(2).
    When the CHADS2 score is associated with coronary heart disease(CHD) , as might have been the case in 1475 of the heart failure patients studied by Chou et al(1), CHADS2 predicts stroke in the total absence of NVAF(3). In the latter study, over a period of 5821 person-years of follow up, 40 out of 916 non anticoagulated patients with stable CHD and no NVAF suffered an ischaemic stroke/transient ischaemic attack. Compared with those with low(0-1) CHADS2 scores, those with progressively higher CHADS2 scores had a stepwise significant increase in rates of stroke/TIA(3). This increase in stroke rate might, arguably, hav...

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  • LTFT trainees: electrophysiology’s loss

    On reading Dobson et al’s enlightening article we were saddened but not surprised to hear that nationally, there were no cardiology LTFT trainees training in electrophysiology (EP). Of course, it remains unclear as the relationship here: do trainees planning LTFT avoid EP, or do EP trainees fear reducing their hours will prove challenging?

    Either way, this represents a great shame for both trainees and subspecialty. For trainees, the fulfilment of electrophysiological problem-solving and skilful intervention should be accessible to all regardless of hours worked. For the subspecialty, a growth in diversity of electrophysiologists as well as flexible working seems very sensible to ensure the continued growth of the subspecialty and its long-term sustainability. Ongoing initiatives by the BCS, BHRS, EHRA and others continue to advocate for a diverse and flexible workforce in EP, and we applaud these efforts.

  • The role of coexisting high-grade carotid artery stenosis in aetiopathogenesis of NVAF-associated stroke

    Given the fact that high-grade carotid artery stenosis(CAS)(50% or more stenosis) is an independent risk factor for stroke in patients with coexisting nonvalvular atrial fibrillation(NVAF)(1), the optimum management of NVAF patients who have symptomatic CAS should be included among the key outstanding research questions enumerated by the authors of the recent review(2). In one study high-grade CAS was prevalent in 12%-14% of NVAF patients aged 71-80(3).. When high-grade CAS gives rise to amaurosis fugax , transient ischaemic attack(TIA), or stroke, the urgent priority is to mitigate the risk of subsequent occurrence of disabling stroke. That priority should prevail irrespective of presence or absence of coexisting NVAF. Strategies to mitigate that risk include initiation of dual antiplatelet therapy(4)(5) followed by interventional treatment of the CAS itself(6).
    For patients in whom symptomatic CAS coexists with NVAF, when the latter is associated with a CHA2DS2-Vasc score that justifies oral anticoagulation to mitigate the risk of cardioembolis stroke , coprescription of oral anticoagulants has to be included in the management strategy. Furthermore after interventional treatment of symptomatic CAS, secondary prevention of neurological events(including stroke) necessitates long term antithrombotic medication with aspirin(5). Concurrently , in the presence of coexisting NVAF, long term primary prevention of cardioembolic stroke necessitates long...

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  • A role for echocardiography when pulmonary embolism presents atypically

    Echocardiography has been shown to generate decisive diagnostic information when pulmonary embolism(PE) presents atypically with paradoxical cerebral embolism in the absence of concurrent PE-related stigmata such as dyspnoea, chest pain, or haemoptysis(1)(2), and also in those cases where the atypical presentation is one which simulates ST segment elevation myocardial infarction(STEMI) in the absence of paradoxical coronary artery embolism(3).
    The following are some anecdotal report which exemplify the diagnostic role of echocardiography:-
    A 32 year old man presented with a stroke , but no concurrent breathlessness or clinical signs of deep vein thrombosis(DVT). Transthoracic echocardiography(TTE) revealed intracardiac thrombus and also a thrombus in the main pulmonary artery. A subsequent Doppler examination revealed a DVT in the right lower limb(1).
    In another report, a 55 year old man presented with a stroke and no concurrent breathlessness. However, he had a blood pressure of 70/40 mm Hg and an elevated serum troponin of 0.07 ng/ml(normal < 0.03 ng/ml). TTE revealed a "positive bubble study" which was followed up with a transoesopahageal echocardiogram(TOE) which showed a patent foramen ovale(PFO). A subsequent Duplex study revealed right lower limb DVT.. His management included intracardiac surgery, which revealed biatrial thrombus straddling a patent foramen ovale. An extensive pulmonary thrombus was also discovered(...

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  • A timely change of focus

    The focus on left atrial dimensions in the risk stratification of patients with atrial fibrillation(AF) and also in those without AF(1), is a timely departure from the prevailing preoccupation with AF-related risk stratification strategies such as the CHA2 DS2-Vasc score which do not include evaluation of left atrial function(2), notwithstanding the hypothesis that the predictive ability of the CHADS2 index to stratify stroke risk may be mechanistically linked to severity of left atrial dysfunction(3). In the latter study left atrial functional index(LAFI) was the parameter utilised to evaluate left atrial function. Regression analysis showed that mean LAFI significantly(p < 0.001) decreased across tertiles of CHADS2(42.8, 37.8, 36.7). After adjustment for age, sex, race, and other parameters , high CHADS2 remained significantly associated with the lowest quartile of LAFI(Odds Ratio 2.34). For every point increase in CHADS2 the LAFI decreased by 4 %. Secondary analyses using CHA2 DS2 Vasc score replicated these results(3). In view of these observations LAFI is a potential modality to risk stratify nonvalvular atrial fibrillation(NVAF) subjects such as those with CHA2DS2 Vasc score of zero , who might otherwise be ineligible for thromboprophylaxis with oral anticoagulants. LAFI could even be utilised to evaluate eligibility for thromboprophylaxis in patients with excessive atrial ectopic activity or short-run atrial tachyarrhythmis, given the fact that each...

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