eLetters

779 e-Letters

  • REACHing the wrong conclusion: residual confounding by indication

    Dear Professor Otto –

    In a recent edition of Heart, Potier et al reported the results of a large, observational analysis of the REACH registry[1]. The authors sought to retrospectively compare clinical outcomes in angiotensin receptor blocker (ARB), and angiotensin converting enzyme inhibitor (ACEi) treated patients, using propensity score matching to reduce confounding by indication. They conclude that treatment with ARB was more effective than with ACEi, across a wide spectrum of cardiovascular diseases and with regard to a number of different clinical outcomes. However, we believe that their methodology falls short of the standards expected from a well-conducted pharmacoepidemiological analysis[2].

    Although the REACH Registry is a well-powered cohort of patients at risk of adverse cardiovascular outcomes, several characteristics make it disadvantageous in the context of comparative drug efficacy analysis. Firstly, exposure to ACEi or ARB was established at baseline; all participants were prevalent users of these agents. Much evidence exists to suggest that bias is introduced by such an approach; the characteristics of prevalent users may be affected by the drug itself[3]. A new-user design would have eliminated such concerns.

    The indication for ACE inhibition and angiotensin receptor blockade differed greatly in this cohort of patients, recruited in 2003 and 2004. During this time, the evidence base for the use of ARBs was limited; most patients wo...

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  • Author response to Siniorakis et al.

    The authors thank Siniorakis et al. for highlighting the cardioprotective effect of enkephalins (ENK) as well as their potential role as biomarkers in post infarct heart failure (HF).[1] We had restricted our discussion around ENK and other vasoactive peptides to allow for a broader analysis of various concepts and also to comply with article length limitations. We note that the comments of Siniorakis et al. are consistent with the objective of our article, which is to highlight the potential role of other vasoactive pathways beyond that of the natriuretic peptide system when using sacubitril / valsartan in HF.[2] Indeed there is evidence to suggest that proenkephalin may be a prognostic indicator in acute heart failure.[3]

    References:
    1 Siniorakis E, Arapi S, Kaplanis I, et al. Cardioprotective effects of enkephalins and potential interference from neprilysin inhibitors. [Letter to Editor], Heart 2017.
    2 Singh JSS, Burrell LM, Cherif M, et al. Sacubitril/valsartan: beyond natriuretic peptides. Heart 2017.
    3 Ng LL, Squire IB, Jones DJ, et al. Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study. J Am Coll Cardiol 2017;69:56-69.

  • Use of preoperative neutrophil gelatinase-associated lipocalin to predicts acute kidney injury and mortality after cardiac surgery

    We read with great interest the recent article by Bulluck and colleagues regarding use of preoperative serum neutrophil gelatinase-associated lipocalin (sNGAL) to predict acute kidney injury (AKI) during hospitalisation and 1-year cardiovascular and all-cause mortality following adult cardiac surgery. They showed that preoperative sNGAL was an independent predictor of postoperative AKI and 1-year mortality. Although the valuable study has been actualized, two issues in methodology seem important to avoid any optimistic interpretation or misinterpretation of results.
    First, when using the KDIGO criteria to define and grade AKI, Bulluck et al1 used a time window of 72 h to include patients with different serum creatinine (sCr) increases from baseline, rather than 48 h, as specified by the guideline. Furthermore, it was unclear whether the sCr levels used for diagnosis and staging of AKI had been corrected based on perioperative fluid balance. The available evidence shows that not adjusting sCr levels for fluid balance may underestimate incidence of AKI after cardiac surgery, as a positive perioperative fluid balance may dilute sCr.2
    Second, this study only assessed the associations of preoperative sNGAL levels with the risks of postoperative AKI and 1-year mortality, but did not provide the true predictive performances of preoperative sNGAL. To determine discriminative ability of preoperative sNGAL for adverse postoperative outcomes, the receiver operating charac...

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  • Cardioprotective effects of enkephalins and potential interference from neprilysin inhibitors

    To the Editor, Singh et al¹ refer to cardiocirculatory effects of sacubitril/valsartan beyond those related to the activation of the natriuretic peptide system. Sacubitril, by inhibiting neprilysin (NEP), upregulates various vasoactive peptides, with enkephalins (ENK) performing a major role among them. It is not by chance that PARADIGM-HF trial, which established the novel NEP inhibitor, bestows NEP with the name ‘enkephalinase’, since the latter catalyzes the degradation of ENK. Singh et al¹ concentrate on the sacubitril-related augmentation of substance P, bradykinin and adrenomedullin, while they refrain from referring to ENK. ENK and proenkephalins, their precursors, are endogenous opioids, ligands to delta and kappa opioid receptors (ORs), which are abundant in the neural system as well as in the myocardium. The endogenous opioid system exerts a significant antinociceptive action in the heart, as we deduce by observations in animal and human models². An important field where ENK have already demonstrated their cardioprotective role, is reperfusion-related ischemia, with myocardial infarction, coronary artery by pass and angioplasty constituting the principal clinical equivalents in this setting³. In all the above mentioned conditions, ENK are overexpressed, both in the neural system and locally in the myocardium. ENK action during reperfusion ischaemia is exerted via various pathways. In detail, they increase intracellular Ca²+ levels, while, simultaneously, they ope...

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  • Older Chinese patients will benefit more from treatment for erectile dysfunction

    We read with great interest this paper which demonstrated erectile dysfunction (ED), not only as a preclinical predictor of cardiovascular disease (CVD), treatment for ED. But also has a role in a reduced mortality and heart failure hospitalization1.However, a multi-country and region population-based survey indicated that the majority of Asian men have never sought treatment for ED because of cultural factors or sexual conservatism2.
    Unfortunately, this situation is more serious in China. A multi-center investigation of 3327 subjects showed that although the proportion of severe cases (IIEF<8) among the Chinese elderly is the highest in all age groups, most elderly men are reluctant to visit the hospital just for the loss of erectile function (EF). They consider the loss of libido and EF with increasing age to be a natural process of aging3. Moreover, even the old men who seek help for ED were more concerned about the side effects of Western medicine (e.g., PDE5i); only a few of them (19%) used Western medicine as the first choice4. Furthermore, Chinese physicians seldom ask patients about their sexual health during routine consultations, their neglect of the health education about ED also aggravated this vicious circle2, 4.
    Hence, there is a substantial need for promoting Andersson et al 's 1 findings on health education of elderly ED patients in China. The improved awareness and cultural factors would lead more Chinese elderly to visit the hospi...

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  • Do Beta Blockers really reduce the mortality in patients with HFPEF?

    I do welcome the systemic review and meta-analysis on drug treatment effects on outcomes in heart failure with preserved ejection fraction, by Dr Zheng and co-workers.(1) I do note the authors' definition of HFPEF as having a left ventricular ejection fraction of >40% as per the suggestions of the American Guidelines.(2) They acknowledge the difficulties posed by those with LVEF 40-49% where the evidence base is largely lacking with the exception of the more recent sub-study of CHARM data in those with LVEF in the above mid-range.(3)
    I have however an issue with their inclusion of the SENIORS study data.(4) Although the mean LVEF of those labelled as HF with preserved LVEF was 49%, the patients included as those with preserved left ventricular ejection fraction, were those with LVEF>35%. This calls into question as to whether the positive effect on mortality of beta-blockers in this trial was caused by the impact of including patients with LVEF 35-40% within this group. I am sure that the authors would agree that the positive impact of the beta-blockers on the mortality of patients with LVEF 35-40%, is un-controversial.(4) While another publication from the SENIORS study group found no statistically significant difference between those deemed HFREF and those deemed HFPEF. We do know that the comparison here may be flawed for the above mentioned issue.
    I would therefore, encourage the authors to reconsider their firm conclusion about the effectivenes...

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  • Is traumatic intracranial hemorrhage a specific risk factor of atrial fibrillation ?

    We read the study of Wei-Shiang Lin et al.[1] with a great interest. In their large-scale cohort retrospective study, they found that traumatic intracranial hemorrhage was associated with an increased risk of atrial fibrillation (AF) and hypothesized that inflammation and/or secondary cardiac insult due to the traumatic brain injury (TBI) may cause AF. Nevertheless, several points should be discussed. First, acute inflammation is well-known to be related to AF in trauma patients. The risk of new-onset AF is reasonably expected to occur at the acute phase following the trauma. This point has already been previously demonstrated to occur during the days following cardiac surgery or septic shock onset.[2] In the same way, cardiac insult occurs at the very early phase of TBI and the consecutive cardiac systolic dysfunction was reported to be reversible within the first week after the trauma. [3] In this perspective, how to explain that the risk of AF persists one year after the trauma? It would be very helpful if the authors could provide data on the delay between the day of trauma and the day of new-onset AF. Furthermore, inflammation and cardiac dysfunction are related to the TBI severity and it would be valuable to know whether the more severe TBI patients are more prone to develop AF than mild or moderate TBI. Finally, in their statistical model, the authors have taken into account comorbidities which are also known to favor AF. But others factors, such as sepsis and relat...

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  • Evidence in special situations and patient groups continues to increase

    Dear Editor,

    We have read the article by dr. Ghannam with interest. We appreciate their summary of the available data on anticoagulant treatment in special patient populations. However, with the rapidly increasing evidence in this field, some recent relevant studies were not mentioned.
    For instance, in patients undergoing cardioversion, the authors suggest treatment with VKA or rivaroxaban, based on the statement that this is the only available NOAC studied prospectively in this setting. Last year, the data of the ENSURE-AF with edoxaban were presented, which provide similar evidence for the use of edoxaban in this setting (1). Furthermore, the recently published EMANATE-AF study adds solid evidence for the use of apixaban in this setting (2).
    Similarly, in patients undergoing catheter ablation, the RE-CIRCUIT study published earlier this year provides very reassuring prospective data on the uninterrupted use of dabigatran in patients undergoing catheter ablation (3), yet this is not mentioned in the article. At the ESC in 2017, the data of the RE-DUAL PCI study provide insight in different strategies on how to combine dabigatran with single or dual antiplatelet therapy in patients undergoing percutaneous coronary interventions (4). Similar data for rivaroxaban were described in the PIONEER study (5), and the results of the ongoing AUGUSTUS study with apixaban are expected within the next years.
    In summary, the very large number of patients studied...

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  • Does antibiotic prophylaxis really prevent streptococci infective endocarditis?

    To the Editor,
    We read with interest the work presented by Cahill et al. [1] in which the authors evaluate the impact of antibiotic prophylaxis to prevent bacteremia and infective endocarditis in patients undergoing dental procedures. The analysis was performed based on 36 studies, including 21 bacteremia studies, five case controls and cohort studies, and 10 time trend studies.
    It is generally well established that dental cares cause bacteremia, and that most are due to streptococcal strains [1,2]. It is, consequently, reasonable to think that prescribing antibiotics before dental cares decreases the incidence of such bacteremia. Globally, the discordant results between the different kinds of studies analyzed in the paper by Cahill et al. [1] are clearly insufficient to conclude that antibiotic prophylaxis prevents bacteremia due to streptococci. In our view, this observation can be explained by the fact that dental care is not the only cause of streptococcal bacteremia. Indeed, such bacteremia are extremely common, and it has been demonstrated that they can occur after chewing and after brushing in patients with periodontitis (cumulatively in 25% and 20% of cases, respectively) [2]. It is, therefore, fairly unlikely that bacteremias due to dental cares are more responsible for endocarditis than other kinds of bacteremias. In practice, this implies that the only reasonable antibiotic prophylaxis to prevent almost every bacteremia due to oral streptococci wou...

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  • Chocolate intake and risk of atrial fibrillation

    Chocolate intake and risk of atrial fibrillation

    Dear Editor,

    We have read with great interest the paper “Chocolate intake and risk of clinically apparent atrial
    fibrillation: the Danish Diet, Cancer, and Health Study” by Elizabeth Mostofsky and coworkers [1] and we found their conclusion of importance with a view to clinical prevention.

    With reference to the findings reported in the paper, we would like to make the following contribution to the discussion. In a recent analysis performed on 650 healthy women in pre-menopausal age (age range 45-54 years) chocolate intake was higher in women in the low quartile of adherence to Mediterranean Diet (low Med Score). This subgroup of women showed a lower ABI index compared to women with higher Med Score. The analysis of sources of antioxidants showed a greater intake from fruit and vegetables in the higher quartiles of Med Score. Coffee and tea were similarly distributed among the quartiles of Med Score [2]. Analysis from diet recall had the major limitation of missing data regarding out-of-mealtime snacking and drinking.
    In Mediterranean countries, wine is a strong antioxidant source and the synergistic effect of drinking wine during meals and antioxidant bioavailability is well known. We clearly understand that nutritional habits in Northern Europe differ from Mediterranean ones. However, we would like to underline that in a Mediterranean lifestyle characterized by high intake of antioxidants,...

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