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.
Given the fact that acute myocardial infarction(AMI)(1), left bundle branch block(LBBB)(2), and pulmonary embolism(PE), are all age-related disorders, the authors of the recent study correctly highlighted the importance of including PE in the differential diagnosis of the association of suspected AMI and LBBB(2). For the purpose of identifying those patients who are most likely to have AMI the authors proposed the use of serum troponin as a rule-in criterion during the first 3 hours of hospital admission . By implication the inclusion of PE in the differential diagnosis should be deferred for at least 3 hours, and only activated in patients who do not have a raised serum troponin level.
However, in view of the fact that elevation in serum troponin may be a feature in the presentation of PE(4), and also in view of the fact that transient LBBB has been reported in a 59 year old patient with PE(5), the latter disorder should be included in the differential diagnosis of the association of acute coronary syndrome and LBBB. In the 59 year old patient who was reported with PE and LBBB, serial troponin levels were 0.38, 0.41, and 1.12 ng/ml(reference range 0-0.04)(5), arguably justifying early coronary angiography(2). That patient had neither pleuritic pain nor breathlessness to raise the index of suspicion for PE. Coronary angiography ruled out coronary artery occlusion, and helical computed tomography revealed extensive PE involving the main branches of both pul...
Given the fact that acute myocardial infarction(AMI)(1), left bundle branch block(LBBB)(2), and pulmonary embolism(PE), are all age-related disorders, the authors of the recent study correctly highlighted the importance of including PE in the differential diagnosis of the association of suspected AMI and LBBB(2). For the purpose of identifying those patients who are most likely to have AMI the authors proposed the use of serum troponin as a rule-in criterion during the first 3 hours of hospital admission . By implication the inclusion of PE in the differential diagnosis should be deferred for at least 3 hours, and only activated in patients who do not have a raised serum troponin level.
However, in view of the fact that elevation in serum troponin may be a feature in the presentation of PE(4), and also in view of the fact that transient LBBB has been reported in a 59 year old patient with PE(5), the latter disorder should be included in the differential diagnosis of the association of acute coronary syndrome and LBBB. In the 59 year old patient who was reported with PE and LBBB, serial troponin levels were 0.38, 0.41, and 1.12 ng/ml(reference range 0-0.04)(5), arguably justifying early coronary angiography(2). That patient had neither pleuritic pain nor breathlessness to raise the index of suspicion for PE. Coronary angiography ruled out coronary artery occlusion, and helical computed tomography revealed extensive PE involving the main branches of both pulmonary arteries(5).
The true prevalence of PE-related LBBB is not known. It might be more prevalent than implied by the occasional anecdote, where it is tachycardia-dependent(5), given the fact that PE, itself, is commonly characterised by sinus tachycardia(6). Conversely, sinus bradycardia is distinctly uncommon in PE(7)(8)(9)(10). Even more unusual is the transient resolution of pre-existing LBBB following the onset of PE, as was the case in a 61 year old man with coexisting deep vein thrombosis(DVT)(11). Accordingly, at the very least, the work-up of an elderly patient with the association of acute coronary syndrome and LBBB should include clinical evaluation for DVT, irrespective of troponin status.
I have no funding and no conflict of interest
References
(1) Sanchis-Gomar F., Perez-Quillis C., Leischik R., Lucia A
Epidemiology of coronary heart disease and acute coronary syndrome
Ann Transl Med 2016;4:256
(2) Nestelberger T., Cullen L., Lindahl B., Reichlin T., Greenslade JH., Giannitsis E., Christ M et al
Diagnosis of acute myocardial infarction in the presence of left bundle branch block
Heart 2019;doi:10.1136/heartjnl-2018-314673
(3) Heit JA., Spencer FA., White RH
The epidemiology of venous thromboembolism
J Thromb Thrombolysis 2016;41:3-14
(4) Lankeit M., Friesen D., Aschoff J., Delias C., HasenfuB G., Katus H et al
Highly sensitive troponin T assay in normotensive patients with acute pulmonary embolism
Eur Heart J 2010;31:1836-1844
(5) Kasmani R., Okoli K., Mohan G., Casey K., Ledrick D
Transient left bundle branch block: an unusual electrocardiogram in acute pulmonary embolism
Am J Med Sc 2009;337:381-382
(6) Raghav KPS., Makkuni P., Figuerdo VM
A review of electrocardiography in pulmonary embolism: recognising pulmonary embolism masquerading as ST-elevation myocardial infarction
Reviews in Cardiovascular Medicine 2011;12:157-163
(7) Khosravi A., Andalib E., Khaledifar A., Hajizadeh M., Nejati M., Behjati M
Pulmonary thromboembolism presenting with recurrent bradycardia and hypotension
National Research Institute of Tuberculosis and Lung Disease, Iran 2017;16:248-250
(8) Larsen TR., Ball TC
Chronic pulmonary embolism in a young athletic woman
Proc Bayl Univ Cent 2015;28:371-374
(9) Lee J-W., Cha S-I., Jung C-Y., Choi W-I., Jeon K-N et al
Clinical course of pulmonary embolism in lung cancer patients
Respiration 2009;78:42-48
(10) Catella P., Wiesel S., Siddiqui A., Chalhoub M
A rare case of pulmonary embolism induced symptomatic bradycardia
American Journal of Respiratory and Critical Care Medicine 2017;195:A5492
(11) Athar SM., Chin BSP., Flint EJ
Transient disappearance of left bundle branch block pattern ; an unusual ECG presentation of acute pulmonary embolism
Postgrad Med J 2002;78:555-558
We read the article by Godino et al describing the risk of non-revascularisation of a coronary chronic total occlusion (CTO) for the cardiac death, sudden cardiac death and sustained ventricular arrhythmias (SCD/SVA) with great interest 1. After reading in detail, we have the following comments.
At first, although the authors mentioned a little in the DISCUSSION, the effect of medications for the prevention of cardiac death and SCD/SVA may better be clarified in the subjects. As they stated, because those who received CTO lesion revascularisation tend to have longer dual antiplatelet therapy and receive more hospital visit for follow-up coronary angiography to recheck, there might be such confounding factors. For example, the third generation P2Y12 class of adenosine diphosphate (ADP) receptors inhibitor was approved in 2009 in Europe 2. How was its distribution compared to conventional clopidogrel treatment? And appropriate statin treatment would be also associated with plaque stability and reduced cardiac adverse events as well as the beta-blocker administration for the prevention of SCD/SVA 3. Because the follow-up period was long as up to 12-years, the difference of these medication strategies between two groups should be clarified. The same also applies to the used stent types. The importance of current manuscript would be much better after these concerns were clarified.
Second, the multivariate analysis of Table 3 contains 2 factors,...
We read the article by Godino et al describing the risk of non-revascularisation of a coronary chronic total occlusion (CTO) for the cardiac death, sudden cardiac death and sustained ventricular arrhythmias (SCD/SVA) with great interest 1. After reading in detail, we have the following comments.
At first, although the authors mentioned a little in the DISCUSSION, the effect of medications for the prevention of cardiac death and SCD/SVA may better be clarified in the subjects. As they stated, because those who received CTO lesion revascularisation tend to have longer dual antiplatelet therapy and receive more hospital visit for follow-up coronary angiography to recheck, there might be such confounding factors. For example, the third generation P2Y12 class of adenosine diphosphate (ADP) receptors inhibitor was approved in 2009 in Europe 2. How was its distribution compared to conventional clopidogrel treatment? And appropriate statin treatment would be also associated with plaque stability and reduced cardiac adverse events as well as the beta-blocker administration for the prevention of SCD/SVA 3. Because the follow-up period was long as up to 12-years, the difference of these medication strategies between two groups should be clarified. The same also applies to the used stent types. The importance of current manuscript would be much better after these concerns were clarified.
Second, the multivariate analysis of Table 3 contains 2 factors, “CTO not revascularised” and “left ventricular ejection fraction (LVEF)”. However, from Table1, there was significant difference in left ventricular ejection fraction between CTO-R group and CTO-NR group. Thus, I suspect that these 2 factors, “CTO not revascularised” and “LVEF” may have significant multicollinearity. From the METHODS section, the authors wrote that comprehensive set of covariates, based on clinical relevance at univariate analysis and data from previous investigations were used. However, how did you exclude the multicollinearity? If you use the variance inflation factor (VIF), you may better present the VIF of enrolled variables. Because I guess if you include both CTO-NR and LVEF into multivariate analysis, CTO-NR may be excluded and only LVEF was preserved after step-wise method, i.e, the difference of the prognosis may be attributed to only LVEF difference.
Disclosures
The authors have no conflict of interest related to the manuscript.
Acknowledgements
None.
References
1 Godino C, Giannattasio A, Scotti A, et al. Risk of cardiac and sudden death with and without revascularisation of a coronary chronic total occlusion. Heart 2019 Feb 21. pii: heartjnl-2018-314076. doi: 10.1136/heartjnl-2018-314076.
2 Mousa SA, Jeske WP, Fareed J. Antiplatelet therapy prasugrel: a novel platelet ADP P2Y12 receptor antagonist. Clin Appl Thromb Hemost 2010 ;16:170-6.
3 Park JJ, Chae IH, Cho YS, et al. The recanalization of chronic total occlusion leads to lumen area increase in distal reference segments in selected patients: an intravascular ultrasound study. JACC Cardiovasc Interv 2012 ;5:827-36.
Under the "diagnosis" heading the authors asserted that "hypothyroidism can be deemed the aetiology of pericardial effusion or cardiac tamponade if a high TSH level has been found, after excluding other secondary causes like a neoplastic, bacterial or an inflammatory process"(1).. I would add that, if the patient's hypothyroidism is of autoimmune aetiology, Addison's disease is a secondary cause that also requires urgent exclusion(2).
In one report, a 21 year old man presented with cardiac tamponade, in association with a TSH level of 17.9 microUnits/L(normal range 0.35-5.0 microUnits/L), and serum thyroxine and serum tri-iodothyronine levels which were both at the lower limit of the normal range. Serum cortisol, however, was 0.5 micrograms/dl(normal range 3.0-23.0 mcd/dl). Tests for thyroid and adrenal autoantibodies were positive, thereby fulfilling the criteria for Type 2 autoimmune polyglandular syndrome(Type-2 APS).
Comment
On the basis of the above observations the work-up of patients with pericardial effusion of presumed hypothyroid aetiology should include evaluation of adrenal function, because Addison's disease can, in its own right, be the underlying cause of cardiac tamponade(3). Furthermore, irrespective of hormonal status, pericardial effusion in a patient with Type 2 APS may ultimately be attributable to the "serositis" component of that syndrome, rendering the effusion capable of relapsing...
Under the "diagnosis" heading the authors asserted that "hypothyroidism can be deemed the aetiology of pericardial effusion or cardiac tamponade if a high TSH level has been found, after excluding other secondary causes like a neoplastic, bacterial or an inflammatory process"(1).. I would add that, if the patient's hypothyroidism is of autoimmune aetiology, Addison's disease is a secondary cause that also requires urgent exclusion(2).
In one report, a 21 year old man presented with cardiac tamponade, in association with a TSH level of 17.9 microUnits/L(normal range 0.35-5.0 microUnits/L), and serum thyroxine and serum tri-iodothyronine levels which were both at the lower limit of the normal range. Serum cortisol, however, was 0.5 micrograms/dl(normal range 3.0-23.0 mcd/dl). Tests for thyroid and adrenal autoantibodies were positive, thereby fulfilling the criteria for Type 2 autoimmune polyglandular syndrome(Type-2 APS).
Comment
On the basis of the above observations the work-up of patients with pericardial effusion of presumed hypothyroid aetiology should include evaluation of adrenal function, because Addison's disease can, in its own right, be the underlying cause of cardiac tamponade(3). Furthermore, irrespective of hormonal status, pericardial effusion in a patient with Type 2 APS may ultimately be attributable to the "serositis" component of that syndrome, rendering the effusion capable of relapsing or remitting irrespective of concurrent hormone replacement therapy(4).
An important caveat to interpretation of raised TSH levels is that, in the presence of primary hypoadrenalism, a raised serum TSH does not necessarily signify coexistence of primary hypothyroidism. On its own, primary hypoadrenalism can cause elevation of serum TSH which reverts to the normal range during the course of corticosteroid replacement therapy(5). In the latter report a 26 year old man with Addison's disease had a documented pretreatment serum TSH of 32 microUnits/L. Over a 2 year period of corticosteroid replacement therapy his serum TSH progressively fell to 2.5 microUnits/L, without concomitant thyroid replacement therapy. During that period both his serum thyroxine and serum tri-iodothyronine levels remained well within the normal range(5).
Finally, even in the presence of the coexistence of raised serum TSH and subnormal serum thyroxine clinicians should remain vigilant for type 2 APS, notwithstanding the fact that an identical biochemical scenario was depicted by the authors of the clinical vignette(1). In one case report a 24 year old man had a diagnosis of primary hypothyroidism characterised by serum thyroxine 40 nmol/L(normal 60-140 nmol/L), tri-iodothyronine 1.2 nmol/L(normal 1.6-3.0 nmol/L), and serum TSH 90 microUnits/L. However, he deteriorated after commencing thyroid replacement therapy, and this deterioration proved to be attributable to coexisting Addison's disease. Thyroxine was stopped, and he received corticosteroid replacement therapy instead. Over a period of 18 months of corticosteroid replacement therapy he experienced clinical improvement, and his thyroid function tests reverted to the normal range without the benefit of concomitant thyroid replacement therapy(6).
References
(1)Chahine J., Ala CK., Pantalone KM., Klein AL
Pericardial diseases in patients with hypothyroidism
Heart 2019;0:1-7,doi 10.1136/heartjnl-2018-314528
(2) Bacal A., Mathew G., Pyle J., Pauwaa S., Kazi M
Cardiac tamponade as initial presentation of autoimmune ployglandular syndrome type 2
AACE Clinical Case Reports 2018;4:e195-e198
(3) Torfoss D., von der Lippe E., Jacobsen D
Cardiac tamponade preceding adrenal insufficiency-an unusual presentation of Addison's disease: a report of two cases
Journal of Internal Medicine 1997;241:525-528
(4) Tucker WS., Niblack GD., McLean RH., Alspaught MA., Wyatt RJ., Jordan SC et al
Serositis with autoimmune endocrinopathy: Clinical and immunogenetic features
Medicine 1987;66:138-147
(5) Candrina R., Giustina G
Addison's disease and corticosteroid-reversible hypothyroidism
J Endocrinol Invest 1987;10:523-524
(6) Burrows AW
Reversible hypothyroidism after steroid replacement for Addison's disease
Postgrad Med J 1981;57:368-370
In their prospective cohort study of 165,411 primary care patients, Akyea et al. claim that suboptimal responders on statin treatment will experience significantly increased risk of future cardiovascular disease (CVD)(1). As many cardiovascular events may heal without serious health problems, we consider mortality as the most important outcome. Among the 80,802 patients with optimal cholesterol lowering, 821 (1.01 %) died from CVD. Among the 84,609 patients with suboptimal cholesterol-lowering 873 (1.03 %) died. This means that to prevent one cardiovascular death by optimal cholesterol lowering you have to increase the degree of lowering in 5,000 patients for six years. This is hardly a benefit because several independent researchers have reported that serious side effects from statin treatment are much more common than reported in the statin trials (2). The small numbers reported in the trial reports are achieved by excluding participants who suffer from side effects of the drug during a few weeks long run-in period before the start of the trial. That this is an effective method to lower the number of side effects appeared in the IDEAL trial where this method wasn´t used and where a high statin dose was compared with a low dose, because in that trial almost half of the participants in both groups suffered from serious side effects (2).
Furthermore, Akyea et al. have not reported total mortality in the two groups. This failure may introduce another bias because tota...
In their prospective cohort study of 165,411 primary care patients, Akyea et al. claim that suboptimal responders on statin treatment will experience significantly increased risk of future cardiovascular disease (CVD)(1). As many cardiovascular events may heal without serious health problems, we consider mortality as the most important outcome. Among the 80,802 patients with optimal cholesterol lowering, 821 (1.01 %) died from CVD. Among the 84,609 patients with suboptimal cholesterol-lowering 873 (1.03 %) died. This means that to prevent one cardiovascular death by optimal cholesterol lowering you have to increase the degree of lowering in 5,000 patients for six years. This is hardly a benefit because several independent researchers have reported that serious side effects from statin treatment are much more common than reported in the statin trials (2). The small numbers reported in the trial reports are achieved by excluding participants who suffer from side effects of the drug during a few weeks long run-in period before the start of the trial. That this is an effective method to lower the number of side effects appeared in the IDEAL trial where this method wasn´t used and where a high statin dose was compared with a low dose, because in that trial almost half of the participants in both groups suffered from serious side effects (2).
Furthermore, Akyea et al. have not reported total mortality in the two groups. This failure may introduce another bias because total mortality was higher in at least seven
statin trials (AFCAPS/TEXcaps, ASPEN, TNT, SPARCL, DEBATE, SEAS and GISSI-HF) (2).
A relevant question is also whether the higher risk among those with suboptimal cholesterol lowering was due to their higher cholesterol or whether they have been more stressed than the optimally treated patients because in a recent study by Song et al (3) stress related disorders were strong predictors of CVD. This fact induces yet another bias in the study by Akyea et al. because several studies have shown that stress may raise serum cholesterol substantially (4-7), and stress may increase the risk of CVD in many other ways (8). We consider that mental stress is the most likely explanation of the difference because a recent review of the medical literature has documented that the general view about the role of cholesterol in CVD does not satisfy any of Bradford Hill´s criteria for a medical hypothesis (2).
1. Akyea RK, Kai J, Qureshi N, et al. Heart 2019;0:1–7. doi:10.1136/heartjnl-2018-314253
2. Ravnskov U, de Lorgeril M, Diamond DM, et al. LDL-C does not cause cardiovascular disease: a comprehensive review of current literature. Exp Rev Clin Pharmacol 2018;11:959-70. doi: 10.1080/17512433.2018.1519391.
3. Song H, Fang F, Arnberg FK et al. Stress related disorders and risk of cardiovascular disease: population based, sibling controlled cohort study. BMJ 2019;365:l1255.
4. Friedman M, Rosenman RH, Carroll V. Changes in the serum cholesterol and blood-clotting time in men subjected to cyclic variation of occupational stress. Circulation 1958;17:852-61.
5. Thomas PD, Goodwin JM, Goodwin JS. Effect of social support on stress-related changes in cholesterol level, uric acid level, and immune function in an elderly sample. Am J Psychiatry 1985;142:735-7.
6. Grundy SM, Griffin AC: Effects of periodic mental stress on serum cholesterol levels. Circulation 1959;19:496-8.
7. Muldoon MF, Bachen EA, Manuck SB et al. Acute cholesterol responses to mental stress and change in posture. Arch Intern Med 1992;152:775-80.
8. Thrall G, Lane D, Carroll D, Lip GY. A systematic review of the effects of acute psychological stress and physical activity on haemorheology, coagulation, fibrinolysis and platelet reactivity: Implications for the pathogenesis of acute coronary syndromes. Thromb Res 2007;120:819-47.
The conclusion of this article was twofold: 1) approximately half of primary care patients put on statins did not achieve at least a 40% reduction in LDL-Cholesterol (the sub-optimal group) and 2) those who did (the optimal group) had fewer cardiovascular incidents over the next (approximately six) years.
Table 1 in the paper shows that the sub-optimal group have 1.43 times the “alcohol misuse” of the optimal group. There is no more information on alcohol consumption beyond this. Were the alcohol misusers also far less likely to be non or moderate drinkers and far more likely to be heavy and frequent drinkers?
The smoking information shows that, from the limited information available, the sub-optimal group were 25% more likely to be smokers. However, there is no smoking information for 96% of patients. There is no activity information – were the drinking/smokers more likely to be sedentary? Were they more likely to be obese?
There were more men in the sub-optimal group. The sub-optimal patients were more likely to be poorly-controlled diabetics and less likely to have hypertension treated.
Correspondence with the researchers confirmed that the HRs in Table 2 were not adjusted for anything other than age and baseline LDL-Cholesterol. They were not adjusted for alcohol misuse, or smoking, or gender, or any other lifestyle factors that were known to be different between the two groups – even with vast amounts of missing information.
The conclusion of this article was twofold: 1) approximately half of primary care patients put on statins did not achieve at least a 40% reduction in LDL-Cholesterol (the sub-optimal group) and 2) those who did (the optimal group) had fewer cardiovascular incidents over the next (approximately six) years.
Table 1 in the paper shows that the sub-optimal group have 1.43 times the “alcohol misuse” of the optimal group. There is no more information on alcohol consumption beyond this. Were the alcohol misusers also far less likely to be non or moderate drinkers and far more likely to be heavy and frequent drinkers?
The smoking information shows that, from the limited information available, the sub-optimal group were 25% more likely to be smokers. However, there is no smoking information for 96% of patients. There is no activity information – were the drinking/smokers more likely to be sedentary? Were they more likely to be obese?
There were more men in the sub-optimal group. The sub-optimal patients were more likely to be poorly-controlled diabetics and less likely to have hypertension treated.
Correspondence with the researchers confirmed that the HRs in Table 2 were not adjusted for anything other than age and baseline LDL-Cholesterol. They were not adjusted for alcohol misuse, or smoking, or gender, or any other lifestyle factors that were known to be different between the two groups – even with vast amounts of missing information.
The entire differences between the groups for CVD events were credited to statins/the degree of cholesterol-lowering. None to lifestyle differences. This should be corrected, as it is wrong and misleading.
This study has already been inappropriately quoted in the media which is what the public read and misinformation is propagating. The authors need to take some responsibility for failing to point out that the dosing of the statins prescribed (most likely archaic low dose simvastatin) isn't analysed and long term compliance isn't addressed in this ' primary prevention population based longitudinal non interventional study'
Cardiologists are going to inundated with questions from patients with coronary disease on statins who have misinterpreted information which is incomplete and misrepresented - the title of the study needs to be highlighted 'Initiation of statins' is well put and needs to be remembered. The study cannot address the 'ongoing management' of cardiovascular risk with appropriate cardiovascular investigation of patients and optimization of preventative strategies as this study does not address this crucial aspect.
It is already well proven that only moderate to high dose statin therapy has a proven biological anti-atherogenic effect so that low doses initiated in general practice are actually ineffective and this is what the study shows NOT that statins are ineffective but that medical practice of blanket prescribing of low doses of statins is ineffective without monitoring of response and ongoing titration to achieve evidence based targets. This omission from the conclusions needs to be corrected and it ne...
This study has already been inappropriately quoted in the media which is what the public read and misinformation is propagating. The authors need to take some responsibility for failing to point out that the dosing of the statins prescribed (most likely archaic low dose simvastatin) isn't analysed and long term compliance isn't addressed in this ' primary prevention population based longitudinal non interventional study'
Cardiologists are going to inundated with questions from patients with coronary disease on statins who have misinterpreted information which is incomplete and misrepresented - the title of the study needs to be highlighted 'Initiation of statins' is well put and needs to be remembered. The study cannot address the 'ongoing management' of cardiovascular risk with appropriate cardiovascular investigation of patients and optimization of preventative strategies as this study does not address this crucial aspect.
It is already well proven that only moderate to high dose statin therapy has a proven biological anti-atherogenic effect so that low doses initiated in general practice are actually ineffective and this is what the study shows NOT that statins are ineffective but that medical practice of blanket prescribing of low doses of statins is ineffective without monitoring of response and ongoing titration to achieve evidence based targets. This omission from the conclusions needs to be corrected and it needs to be emphasized that patients with cardiovascular disease on proper high dose statins are not part of this study at all.
We are grateful for the comments by David P Foley, Zoe Harcombe and Uffe Ravnsker on our paper.
Both American and UK guidelines for the treatment of cholesterol,[1,2] recommend monitoring percent reduction in low-density lipoprotein cholesterol (LDL-C) among patients initiating statins as an indication of response and adherence. Our recently published paper [3] examined LDL-C reduction among patients initiating statins in the real-world setting.
With regard to the points raised:
Why didn’t you analyse the possible reasons for the observed ‘findings’?
Our study was not designed to establish causality so we are unable to analyse possible reasons for the observed findings. We are, however, undertaking further research to establish these latter.
David P Foley notes in his response, ‘it is already well proven that only moderate to high dose statin therapy has a proven biological anti-atherogenic effect’. However, it is important to avoid any erroneous impression that patients are started on low dose statins in primary care. As shown in Table 1, most patients in this study were actually prescribed moderate and high potency statins (70.9% in the sub-optimal responders compared to 81.8% in the optimal responders).
A study by Vupputuri et al,[4] examined LDL-C reduction and adherence among high-risk patients initiating statins in a real-world setting using electronic health records of 1,066 patients in the US. Of patients with high adherence...
We are grateful for the comments by David P Foley, Zoe Harcombe and Uffe Ravnsker on our paper.
Both American and UK guidelines for the treatment of cholesterol,[1,2] recommend monitoring percent reduction in low-density lipoprotein cholesterol (LDL-C) among patients initiating statins as an indication of response and adherence. Our recently published paper [3] examined LDL-C reduction among patients initiating statins in the real-world setting.
With regard to the points raised:
Why didn’t you analyse the possible reasons for the observed ‘findings’?
Our study was not designed to establish causality so we are unable to analyse possible reasons for the observed findings. We are, however, undertaking further research to establish these latter.
David P Foley notes in his response, ‘it is already well proven that only moderate to high dose statin therapy has a proven biological anti-atherogenic effect’. However, it is important to avoid any erroneous impression that patients are started on low dose statins in primary care. As shown in Table 1, most patients in this study were actually prescribed moderate and high potency statins (70.9% in the sub-optimal responders compared to 81.8% in the optimal responders).
A study by Vupputuri et al,[4] examined LDL-C reduction and adherence among high-risk patients initiating statins in a real-world setting using electronic health records of 1,066 patients in the US. Of patients with high adherence in the study, 42.3% still did not achieve the LDL-C target, compared to 54.7% and 79.7% of those with intermediate and low-statin adherence.
Statin potency and adherence might explain some of the variations observed in LDL-C response. We, however, believe there might be other mediating variables or influences and we seek to find these in our on-going research.
This paper needs to be corrected to adjust for lifestyle differences.
Standard and recognised practice in peer-reviewed quantitative research studies is to report a baseline description of the study population including the proportion of missing variables.
The selection of potential covariates to adjust in our statistical model was therefore not determined simply by the observed patient characteristics that were found to be different between the two patient groups as suggested by Zoe Harcombe. The inclusion of all clinical and other related variables in a model, regardless of significance, in order to control for confounding can lead to unreliable estimates of effects and large standard errors.
An acceptable and appropriate approach for selection of potential covariates was used in our paper. A list of 31 potential variables (list provided in supplementary file of the paper) including alcohol misuse, smoking, gender were systematically and objectively assessed. The potential covariates that met the criteria outlined in the methods section, according to change in estimation criterion of effect estimator by 5% or more,[5] were selected for adjustment in the final regression models. Most of the 31 variables explored did not meet this criterion.
Questionable benefit of increasing the degree of cholesterol lowering
Our paper highlights the benefit of statins in reducing future cardiovascular disease (CVD) risk for both optimal and sub-optimal responders. For every 1 mmol/l fall in LDL-C, there was a 6% lower risk of CVD in those with < 40% reduction in LDL-C, compared to a 13% drop in those who attained the recommended 40% or more reduction. In a Cochrane Review by Taylor et al, reductions in all‐cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins.[6]
In relation to stress-related disorders as strong predictors of CVD, we note stress-related disorders show substantial comorbidity with other psychiatric disorders [7]. In our paper, severe mental illness was one of the potential covariates (Supplementary file – Appendix 1) assessed but was not found to be significantly associated with the exposure and outcome in our study.
To conclude, we would emphasise the main message from our paper. In the real-world primary care setting, optimal lowering of LDL-C is not observed within 2 years in over half of patients and these patients will experience significantly increased risk of future CVD. There is therefore a need for monitoring of LDL-C response and consideration of ongoing titration and appropriate management to achieve the recommended reduction in LDL-C.
References:
1. National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification. London: : National Institute for Health and Care Excellence 2016.
2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:S1-45. doi:10.1161/01.cir.0000437738.63853.7a
3.Akyea RK, Kai J, Qureshi N, et al. Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease. Heart 2019;:heartjnl-2018-314253. doi:10.1136/heartjnl-2018-314253
4. Vupputuri S, Joski PJ, Kilpatrick R, et al. LDL cholesterol response and statin adherence among high-risk patients initiating treatment. Am J Manag Care 2016;22:e106-15.
5. Maldonado G, Greenland S. Simulation study of confounder-selection strategies. Am J Epidemiol 1993;138:923–36.
6. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease (Review). Cochrane Database Syst Rev Published Online First: 2013. doi:10.1002/14651858.CD004816.pub5.www.cochranelibrary.com
7. Song H, Fang F, Arnberg FK, et al. Stress related disorders and risk of cardiovascular disease: population based, sibling controlled cohort study. BMJ 2019;365:l1255. doi:10.1136/bmj.l1255
Notwithstanding the high costs and lack of reimbursement associated with the use of positron emission tomography/computed tomography(PET/CT) in suspected cardiac implantable electronic device (CIED) infection(1), the ability of this modality to distinguish between infective and non infective vegetations is a powerful argument for its inclusion in the workup of suspected CIED. Evidence of the ability to make this distinction comes from two sources(2)(3). Firstly, in a retrospective study of 177 transoesophageal echocardiographic studies performed on 153 consecutive patients, a visible mass was observed on a device lead in 25 instances. In 11 studies this was a lead vegetation, in 13 instances only lead strands were seen, and in one instance a lead vegetation coexisted with a lead strand. Nevertheless, 18 of the 25 patients with lead-associated masses had no other evidence of infection. In that study the presence or absence of infection was adjudicated by three clinical investigators who independently reviewed all available clinical data without knowledge of the echocardiographic results(2). In another study, 63 consecutive patients(mean age 68.6) with suspected CIED were evaluated both by echocardiography(tranasthoracic and transoesophageal) and by PET/CT. Echocardiography was associated with a positive predictive value(PPV) of 83.3%, and a negative predictive value(NPV) of 69.2%. For PET/CT, PPV and NPV amounted to 100% and 93.9%, respectively(3). The additional ut...
Notwithstanding the high costs and lack of reimbursement associated with the use of positron emission tomography/computed tomography(PET/CT) in suspected cardiac implantable electronic device (CIED) infection(1), the ability of this modality to distinguish between infective and non infective vegetations is a powerful argument for its inclusion in the workup of suspected CIED. Evidence of the ability to make this distinction comes from two sources(2)(3). Firstly, in a retrospective study of 177 transoesophageal echocardiographic studies performed on 153 consecutive patients, a visible mass was observed on a device lead in 25 instances. In 11 studies this was a lead vegetation, in 13 instances only lead strands were seen, and in one instance a lead vegetation coexisted with a lead strand. Nevertheless, 18 of the 25 patients with lead-associated masses had no other evidence of infection. In that study the presence or absence of infection was adjudicated by three clinical investigators who independently reviewed all available clinical data without knowledge of the echocardiographic results(2). In another study, 63 consecutive patients(mean age 68.6) with suspected CIED were evaluated both by echocardiography(tranasthoracic and transoesophageal) and by PET/CT. Echocardiography was associated with a positive predictive value(PPV) of 83.3%, and a negative predictive value(NPV) of 69.2%. For PET/CT, PPV and NPV amounted to 100% and 93.9%, respectively(3). The additional utility of PET/CT is the ability to detect "unsuspected extracardiac sites of infection in up to 23% of patients with device-related sepsis"(4), thereby facilitating the fulfilment of Duke criteria for infective endocarditis(5). In those instances where the sensitivity of PET/CT is suboptimal that shortcoming is largely attributable to prior antibiotic use(6). Furthermore, negative PET/CT also identifies a group of patients who have excellent outcome without device extraction(6).
I have no funding, and no conflict of interest.
References
(1) DeSimone DC., Sohali MR., Mulpuru SK
Contemporary management of cardiac implantable electronic device infection
Heart 2019;105:961-965
(2)Downey BC., Juselius WE.,Pandian NG., Estes NAM., Link MS
Incidence and significance of pacemaker and implantable cardioverter-defibrillator lead masses discovered during transesophageal echocardiography
PACE 2011;34:679-683
(3) Erba PA., Sollini M., Conti U., Bandera F., Tascini C., De Tommasi SM
Radiolabeled WBC scintigraphy in the diagnostic work up of patients with suspected device-related infections
JACC Cardiovascular Imaging 2013;6:1075-1086
(4) Gutierrez-Carretero E., Rezaei K., Rodriguez-Mora F., de Alarcon A
Infections on cardiovascular implantable electronic devices: A critical review
Medical Research Archives 2019;Issue 3;page 1 to 64
(5) Tak T., Shukla S
Molecular diagnosis of infective endocarditis: a helpful addition to Duke criteria
Clin Med Res 2004;2:206-208
(6) Sarrazin J-F., Phillippon F., Trottier M., Tessier M
Role of radionuclide imaging for diagnosis of device and prosthetic valve infections
World Journal of Cardiology 2016;8:534-546
In the context of suspected cardiac implantable electronic device infection a fundamental flaw in transoesophageal echocardiography(TOE) is that this modality does not distinguish between infective and non infective masses situated on the electronic device lead. For example, in one study 25 patients who underwent TOE were shown to have either a lead vegetation(11 cases) or lead strands(13 cases) or both(1 case). Nevertheless, 18 of of those 25 patients proved, after exhaustive evaluation, to have no evidence of infection(1). According to a recent report, however, guided biopsy of a lead-associated mass, by means of a biotome, can facilitate the distinction between an infective versus non infective device-related mass. In Case 1 of that report an 80 year old woman with a pacemaker presented with mild leucocytosis in the setting of a recent dental procedure, but was afebrile. Transoesophageal echocardiography(TOE) disclosed a 1.6 X 1.0 cm mass on her right atrial lead. Using femoral access and fluoroscopic guidance the mass was biopsied under TOE guidance. The mass proved to be a thrombus with irregular fragments of soft tissue. The gram stain showed no polymorphonuclear cells and the tissue culture confirmed no growth. Case 2 in that report was a 29 year old man with an implantable cardioverter-defibrillator in the setting of intermittent fever and night sweats. TOE revealed a 2.9 cm X 1.2 mass encasing the device lead. A single blood culture grew a Propionib...
In the context of suspected cardiac implantable electronic device infection a fundamental flaw in transoesophageal echocardiography(TOE) is that this modality does not distinguish between infective and non infective masses situated on the electronic device lead. For example, in one study 25 patients who underwent TOE were shown to have either a lead vegetation(11 cases) or lead strands(13 cases) or both(1 case). Nevertheless, 18 of of those 25 patients proved, after exhaustive evaluation, to have no evidence of infection(1). According to a recent report, however, guided biopsy of a lead-associated mass, by means of a biotome, can facilitate the distinction between an infective versus non infective device-related mass. In Case 1 of that report an 80 year old woman with a pacemaker presented with mild leucocytosis in the setting of a recent dental procedure, but was afebrile. Transoesophageal echocardiography(TOE) disclosed a 1.6 X 1.0 cm mass on her right atrial lead. Using femoral access and fluoroscopic guidance the mass was biopsied under TOE guidance. The mass proved to be a thrombus with irregular fragments of soft tissue. The gram stain showed no polymorphonuclear cells and the tissue culture confirmed no growth. Case 2 in that report was a 29 year old man with an implantable cardioverter-defibrillator in the setting of intermittent fever and night sweats. TOE revealed a 2.9 cm X 1.2 mass encasing the device lead. A single blood culture grew a Propionibacterium species thought to be a contaminant. The device-associated mass was biopsied using the same technique as in Case 1. Histology of the biopsy specimen revealed "pieces of fibrin mixed with neutrophils harboring calcification, consistent with an infectious etiology". Lead extraction was undertaken. Culture of the extracted lead tip was positive for Propionibacterium, thereby disproving the previous hypothesis that the organism was a contaminant. The authors of the case reports stress that the safety of this technique still needs further investigation. Furthermore, performing a biopsy using this technique carries a risk of lead dislodgement(2).
I have no funding and no conflict of interest
References
(1) Downey BC., Juselius WE., Pandian NG., Estes NAM., Link MS
Incidence and significance of pacemaker and implantable cardioverter-defibrillator lead masses discovered during transosophageal echocardiography
PACE 2011;34:679-683
(2)Chang D., Gabriels J., Laighold S., Williamson AK., Isnail H., Epstein LM
A novel diagnostic approach to a mass on a device lead
Heart Rhythm Case Reports doi.org/10.1016/hrcr.2019.03.001 Article in Press
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.
Given the fact that acute myocardial infarction(AMI)(1), left bundle branch block(LBBB)(2), and pulmonary embolism(PE), are all age-related disorders, the authors of the recent study correctly highlighted the importance of including PE in the differential diagnosis of the association of suspected AMI and LBBB(2). For the purpose of identifying those patients who are most likely to have AMI the authors proposed the use of serum troponin as a rule-in criterion during the first 3 hours of hospital admission . By implication the inclusion of PE in the differential diagnosis should be deferred for at least 3 hours, and only activated in patients who do not have a raised serum troponin level.
Show MoreHowever, in view of the fact that elevation in serum troponin may be a feature in the presentation of PE(4), and also in view of the fact that transient LBBB has been reported in a 59 year old patient with PE(5), the latter disorder should be included in the differential diagnosis of the association of acute coronary syndrome and LBBB. In the 59 year old patient who was reported with PE and LBBB, serial troponin levels were 0.38, 0.41, and 1.12 ng/ml(reference range 0-0.04)(5), arguably justifying early coronary angiography(2). That patient had neither pleuritic pain nor breathlessness to raise the index of suspicion for PE. Coronary angiography ruled out coronary artery occlusion, and helical computed tomography revealed extensive PE involving the main branches of both pul...
To the Editor
We read the article by Godino et al describing the risk of non-revascularisation of a coronary chronic total occlusion (CTO) for the cardiac death, sudden cardiac death and sustained ventricular arrhythmias (SCD/SVA) with great interest 1. After reading in detail, we have the following comments.
Show MoreAt first, although the authors mentioned a little in the DISCUSSION, the effect of medications for the prevention of cardiac death and SCD/SVA may better be clarified in the subjects. As they stated, because those who received CTO lesion revascularisation tend to have longer dual antiplatelet therapy and receive more hospital visit for follow-up coronary angiography to recheck, there might be such confounding factors. For example, the third generation P2Y12 class of adenosine diphosphate (ADP) receptors inhibitor was approved in 2009 in Europe 2. How was its distribution compared to conventional clopidogrel treatment? And appropriate statin treatment would be also associated with plaque stability and reduced cardiac adverse events as well as the beta-blocker administration for the prevention of SCD/SVA 3. Because the follow-up period was long as up to 12-years, the difference of these medication strategies between two groups should be clarified. The same also applies to the used stent types. The importance of current manuscript would be much better after these concerns were clarified.
Second, the multivariate analysis of Table 3 contains 2 factors,...
Under the "diagnosis" heading the authors asserted that "hypothyroidism can be deemed the aetiology of pericardial effusion or cardiac tamponade if a high TSH level has been found, after excluding other secondary causes like a neoplastic, bacterial or an inflammatory process"(1).. I would add that, if the patient's hypothyroidism is of autoimmune aetiology, Addison's disease is a secondary cause that also requires urgent exclusion(2).
Show MoreIn one report, a 21 year old man presented with cardiac tamponade, in association with a TSH level of 17.9 microUnits/L(normal range 0.35-5.0 microUnits/L), and serum thyroxine and serum tri-iodothyronine levels which were both at the lower limit of the normal range. Serum cortisol, however, was 0.5 micrograms/dl(normal range 3.0-23.0 mcd/dl). Tests for thyroid and adrenal autoantibodies were positive, thereby fulfilling the criteria for Type 2 autoimmune polyglandular syndrome(Type-2 APS).
Comment
On the basis of the above observations the work-up of patients with pericardial effusion of presumed hypothyroid aetiology should include evaluation of adrenal function, because Addison's disease can, in its own right, be the underlying cause of cardiac tamponade(3). Furthermore, irrespective of hormonal status, pericardial effusion in a patient with Type 2 APS may ultimately be attributable to the "serositis" component of that syndrome, rendering the effusion capable of relapsing...
In their prospective cohort study of 165,411 primary care patients, Akyea et al. claim that suboptimal responders on statin treatment will experience significantly increased risk of future cardiovascular disease (CVD)(1). As many cardiovascular events may heal without serious health problems, we consider mortality as the most important outcome. Among the 80,802 patients with optimal cholesterol lowering, 821 (1.01 %) died from CVD. Among the 84,609 patients with suboptimal cholesterol-lowering 873 (1.03 %) died. This means that to prevent one cardiovascular death by optimal cholesterol lowering you have to increase the degree of lowering in 5,000 patients for six years. This is hardly a benefit because several independent researchers have reported that serious side effects from statin treatment are much more common than reported in the statin trials (2). The small numbers reported in the trial reports are achieved by excluding participants who suffer from side effects of the drug during a few weeks long run-in period before the start of the trial. That this is an effective method to lower the number of side effects appeared in the IDEAL trial where this method wasn´t used and where a high statin dose was compared with a low dose, because in that trial almost half of the participants in both groups suffered from serious side effects (2).
Furthermore, Akyea et al. have not reported total mortality in the two groups. This failure may introduce another bias because tota...
Show MoreThe conclusion of this article was twofold: 1) approximately half of primary care patients put on statins did not achieve at least a 40% reduction in LDL-Cholesterol (the sub-optimal group) and 2) those who did (the optimal group) had fewer cardiovascular incidents over the next (approximately six) years.
Table 1 in the paper shows that the sub-optimal group have 1.43 times the “alcohol misuse” of the optimal group. There is no more information on alcohol consumption beyond this. Were the alcohol misusers also far less likely to be non or moderate drinkers and far more likely to be heavy and frequent drinkers?
The smoking information shows that, from the limited information available, the sub-optimal group were 25% more likely to be smokers. However, there is no smoking information for 96% of patients. There is no activity information – were the drinking/smokers more likely to be sedentary? Were they more likely to be obese?
There were more men in the sub-optimal group. The sub-optimal patients were more likely to be poorly-controlled diabetics and less likely to have hypertension treated.
Correspondence with the researchers confirmed that the HRs in Table 2 were not adjusted for anything other than age and baseline LDL-Cholesterol. They were not adjusted for alcohol misuse, or smoking, or gender, or any other lifestyle factors that were known to be different between the two groups – even with vast amounts of missing information.
The enti...
Show MoreThis study has already been inappropriately quoted in the media which is what the public read and misinformation is propagating. The authors need to take some responsibility for failing to point out that the dosing of the statins prescribed (most likely archaic low dose simvastatin) isn't analysed and long term compliance isn't addressed in this ' primary prevention population based longitudinal non interventional study'
Show MoreCardiologists are going to inundated with questions from patients with coronary disease on statins who have misinterpreted information which is incomplete and misrepresented - the title of the study needs to be highlighted 'Initiation of statins' is well put and needs to be remembered. The study cannot address the 'ongoing management' of cardiovascular risk with appropriate cardiovascular investigation of patients and optimization of preventative strategies as this study does not address this crucial aspect.
It is already well proven that only moderate to high dose statin therapy has a proven biological anti-atherogenic effect so that low doses initiated in general practice are actually ineffective and this is what the study shows NOT that statins are ineffective but that medical practice of blanket prescribing of low doses of statins is ineffective without monitoring of response and ongoing titration to achieve evidence based targets. This omission from the conclusions needs to be corrected and it ne...
We are grateful for the comments by David P Foley, Zoe Harcombe and Uffe Ravnsker on our paper.
Both American and UK guidelines for the treatment of cholesterol,[1,2] recommend monitoring percent reduction in low-density lipoprotein cholesterol (LDL-C) among patients initiating statins as an indication of response and adherence. Our recently published paper [3] examined LDL-C reduction among patients initiating statins in the real-world setting.
With regard to the points raised:
Why didn’t you analyse the possible reasons for the observed ‘findings’?
Our study was not designed to establish causality so we are unable to analyse possible reasons for the observed findings. We are, however, undertaking further research to establish these latter.
Show MoreDavid P Foley notes in his response, ‘it is already well proven that only moderate to high dose statin therapy has a proven biological anti-atherogenic effect’. However, it is important to avoid any erroneous impression that patients are started on low dose statins in primary care. As shown in Table 1, most patients in this study were actually prescribed moderate and high potency statins (70.9% in the sub-optimal responders compared to 81.8% in the optimal responders).
A study by Vupputuri et al,[4] examined LDL-C reduction and adherence among high-risk patients initiating statins in a real-world setting using electronic health records of 1,066 patients in the US. Of patients with high adherence...
Notwithstanding the high costs and lack of reimbursement associated with the use of positron emission tomography/computed tomography(PET/CT) in suspected cardiac implantable electronic device (CIED) infection(1), the ability of this modality to distinguish between infective and non infective vegetations is a powerful argument for its inclusion in the workup of suspected CIED. Evidence of the ability to make this distinction comes from two sources(2)(3). Firstly, in a retrospective study of 177 transoesophageal echocardiographic studies performed on 153 consecutive patients, a visible mass was observed on a device lead in 25 instances. In 11 studies this was a lead vegetation, in 13 instances only lead strands were seen, and in one instance a lead vegetation coexisted with a lead strand. Nevertheless, 18 of the 25 patients with lead-associated masses had no other evidence of infection. In that study the presence or absence of infection was adjudicated by three clinical investigators who independently reviewed all available clinical data without knowledge of the echocardiographic results(2). In another study, 63 consecutive patients(mean age 68.6) with suspected CIED were evaluated both by echocardiography(tranasthoracic and transoesophageal) and by PET/CT. Echocardiography was associated with a positive predictive value(PPV) of 83.3%, and a negative predictive value(NPV) of 69.2%. For PET/CT, PPV and NPV amounted to 100% and 93.9%, respectively(3). The additional ut...
Show MoreIn the context of suspected cardiac implantable electronic device infection a fundamental flaw in transoesophageal echocardiography(TOE) is that this modality does not distinguish between infective and non infective masses situated on the electronic device lead. For example, in one study 25 patients who underwent TOE were shown to have either a lead vegetation(11 cases) or lead strands(13 cases) or both(1 case). Nevertheless, 18 of of those 25 patients proved, after exhaustive evaluation, to have no evidence of infection(1). According to a recent report, however, guided biopsy of a lead-associated mass, by means of a biotome, can facilitate the distinction between an infective versus non infective device-related mass. In Case 1 of that report an 80 year old woman with a pacemaker presented with mild leucocytosis in the setting of a recent dental procedure, but was afebrile. Transoesophageal echocardiography(TOE) disclosed a 1.6 X 1.0 cm mass on her right atrial lead. Using femoral access and fluoroscopic guidance the mass was biopsied under TOE guidance. The mass proved to be a thrombus with irregular fragments of soft tissue. The gram stain showed no polymorphonuclear cells and the tissue culture confirmed no growth. Case 2 in that report was a 29 year old man with an implantable cardioverter-defibrillator in the setting of intermittent fever and night sweats. TOE revealed a 2.9 cm X 1.2 mass encasing the device lead. A single blood culture grew a Propionib...
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