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...
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 of those arrhythmias is an independent risk factor for ischemic stroke(4)(5).
The ultimate risk factor for left atrium-related cadiogenic thromboembolism is the documentation of a prothrombotic state in the left atrium and left atrial appendage(LAA), but this entails the use of an invasive strategy, namely, trans oesophageal echocardiography(TOE)(6). Recourse to this modality could be circumvented if a correlation cloud be shown to exist between LAFI and LAA abnormalities such as smoke, sludge, and thrombus. Already, the CHA2DS2 Vasc score has been shown to be significantly associated with TOE risk factors for thromboembolism(7). The next step is also to explore the potential association between LAFI and TOE risk factors for thrromboembolism .
Given the fact that echocardiographically documented left atrial strain has been shown to predict a prothrombotic state in patients with NVAF(8) it would also be worthwhile to explore a potential relationship between LAFI and left atrial strain, not only in NVAF ,but also in subjects with excessive atrial ectopic activity and in subjects with short-run atrial tachyarrhythmia. Furthermore, given the fact that atrial fibrosis(documented by late gadolinium enhancement magnetic resonance imaging[LGE-MRI]) has been shown to predict occurrence of incident atrial fibrillation in non-AF subjects of mean age 49(9), it might be informative to explore a correlation between LAFI and the extent and distribution of atrial fibrosis.
In conclusion, if LAFI proves to be significantly correlated with parameters of the prothrombotic state and also correlated with the extent and distribution of left atrial fibrosis, it might be the modality of choice for stratification of risk of left atrial-related cardiogenic thromboembolism either in NVAF or in patients with excessive atrial ectopic activity or short-run atrial tachyarrhytmia.
References
(1) Froehlich L., Meyre P., Aeschbacher S et al
Left atrial dimensions and cardiovascular outcomes in patients with and without atrial fibrillation: A systematic review and meta analysis
Heart 2019;doi:10.1136/heartjnl 2019-315174
(2) Lip GYH., Nieuwlaat R., Oisters R
Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach
CHEST 2010;137:263-272
(3)Azarbal F., Welles C., Wong JM et al
Association of CHA2DS2-Vasc and RCHADS2 scores with atrial dysfunction in patients with coronary heart disease(from the Heart and Soul Study)
Am J Cardiol 2014;113:1166-1172
(4) Marinheiro R., Parreira L., Amador P et al
Excessive atrial ectopic activity as an independent risk factor for ischemic stroke
Int J Cardiol 2017;240:226-230
(5) Yzamada S., Lin C-Y., Cahng S-L et al
Risk of stroke in patients with short-run atrial tachyarrhythmia
STROKE 2017;48:3232-3238
(6)Dinh T., Baur LH., Pisters R et al
Aspirin versus vitamin K antagonist treatment guided by transoesophageal echocardiography in patients with atrial fibrillation: a pilot study
Heart 2014;100;563-558
(7) Willens HJ., Gomez-Marin O., Nelson K et al
Correlation of CHADS2 and CHA2 DS2 Vasc scores with transesophageal echocardiography irisk factors for thromboembolism in a multi-ethnic United States population with nonvalvular atrial fibrillation
Journal of the American Society of echocardiography 2013;26:175-184
(8) Kupczynska K., Michalski BW., Miskowicc D et al
Association between left atrial function assessed by speckle-tracking echocardiography and the presence of atrial appendage thrombus in aptients with atrial fibrillation
Anatoll J cardiol 2017;18:15-22
(9) Siebramair J., Suksaranjit P., McGann CJ et al
Atrial fibrosis in non-atrial fibrillation individuals and prediction of atrial fibrillation by use of late gadolinium enhancement magbetic resonance imaging
J cardiovasc Electophysiol 2019;30:550-556
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
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
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
Under the heading "Changes in kidney function during intercurrent illness"(1) mention must be made of the risk of acute kidney injury when nonsteroidal anti inflammatory drugs(NSAIDs) are prescribed for acute gout, the latter complication(the equivalent of "intercurrent illness") sometimes documented as a consequence of diuretic use in congestive heart failure(CHF)(2). Coprescription of NSAIDs, diuretics, and angiotensin converting enzyme inhibitors(or angiotensin receptor blockers), so-called triple therapy, is associated with increased risk of acute kidney injury(rate ratio 1.31, 95% Confidence Interval 1.12 to 1.53)(3). This was shown in a nested case-control study which enrolled patients in whom hypertension was the indication for prescription of diuretics and/or angiotensin converting enzyme inhibitors(or angiotensin receptor blockers)(3), but might be equally applicable in the context of CHF. Additionally, among CHF patients who have a drug regime which includes spironolactone, the use of NSAIDs might increase the risk of hyperkalaemia. The rationale is that NSAIDs "interfere with the stimulatory effect of prostaglandins on the release of renin"(4). The risk of hyperkalaemia may be compounded by concurrent use of beta adrenergic blocking agents(4).
For all the above reasons, NSAIDs should be contraindicated in CHF patients with gout. The recommended alternatives include colcichine(5) and intraarticuoar corticosteroids(6), resp...
Under the heading "Changes in kidney function during intercurrent illness"(1) mention must be made of the risk of acute kidney injury when nonsteroidal anti inflammatory drugs(NSAIDs) are prescribed for acute gout, the latter complication(the equivalent of "intercurrent illness") sometimes documented as a consequence of diuretic use in congestive heart failure(CHF)(2). Coprescription of NSAIDs, diuretics, and angiotensin converting enzyme inhibitors(or angiotensin receptor blockers), so-called triple therapy, is associated with increased risk of acute kidney injury(rate ratio 1.31, 95% Confidence Interval 1.12 to 1.53)(3). This was shown in a nested case-control study which enrolled patients in whom hypertension was the indication for prescription of diuretics and/or angiotensin converting enzyme inhibitors(or angiotensin receptor blockers)(3), but might be equally applicable in the context of CHF. Additionally, among CHF patients who have a drug regime which includes spironolactone, the use of NSAIDs might increase the risk of hyperkalaemia. The rationale is that NSAIDs "interfere with the stimulatory effect of prostaglandins on the release of renin"(4). The risk of hyperkalaemia may be compounded by concurrent use of beta adrenergic blocking agents(4).
For all the above reasons, NSAIDs should be contraindicated in CHF patients with gout. The recommended alternatives include colcichine(5) and intraarticuoar corticosteroids(6), respectively. According to the American College of Physicians Clinical Practice Guideline moderate quality evidence shows that colcichine 1.2 mg followed by 0.6 mg after 1 hour can be as effective, for pain control, as 1.2 mg followed by 0.6 mg/h for 6 hours. The lower dose regime is associated with lower prevalence of diahrroea(23% vs 77%)(5). The alternative is the use of intra articular corticosteroids, advocated in Australia(6), but not licensed for use in the UK.
I have on funding and no conflict of interest
References
(1) Change in renal function associate with drug treatment in heart failure: national guidance
Heart June 2019
(2) Spieker LE., Ruschitzka FT., Luscher TF., Noll G
The management of hyperuricemia and gout in patients with heart failure
Eur J Heart Failure 2002;4:403-410
(3)Lapi F., Azoulay L., Yin H., Nessim SJ., Suissa S
Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with nonsteroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study
BMJ 2013;346:e8525
(4) Palmer BF
Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system
N Engl J Med 2004;351:585-592
(5) Qaseem A., Harris RP., Forciea MA., for the Clinical Guideline Committee of the American College of Physicians
Management of acute and recurrent gout: A clinical practice guideline for the American College of Physicians
Ann Intern Med 2017;166:58-68
(6) Robinson PC., Stamp LK
The management of gout: Much has changed
RACGP 2016;45:299-302
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
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.
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.
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.
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
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...
Show MoreGiven 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...
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...
Show MoreNotwithstanding 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 MoreUnder the heading "Changes in kidney function during intercurrent illness"(1) mention must be made of the risk of acute kidney injury when nonsteroidal anti inflammatory drugs(NSAIDs) are prescribed for acute gout, the latter complication(the equivalent of "intercurrent illness") sometimes documented as a consequence of diuretic use in congestive heart failure(CHF)(2). Coprescription of NSAIDs, diuretics, and angiotensin converting enzyme inhibitors(or angiotensin receptor blockers), so-called triple therapy, is associated with increased risk of acute kidney injury(rate ratio 1.31, 95% Confidence Interval 1.12 to 1.53)(3). This was shown in a nested case-control study which enrolled patients in whom hypertension was the indication for prescription of diuretics and/or angiotensin converting enzyme inhibitors(or angiotensin receptor blockers)(3), but might be equally applicable in the context of CHF. Additionally, among CHF patients who have a drug regime which includes spironolactone, the use of NSAIDs might increase the risk of hyperkalaemia. The rationale is that NSAIDs "interfere with the stimulatory effect of prostaglandins on the release of renin"(4). The risk of hyperkalaemia may be compounded by concurrent use of beta adrenergic blocking agents(4).
Show MoreFor all the above reasons, NSAIDs should be contraindicated in CHF patients with gout. The recommended alternatives include colcichine(5) and intraarticuoar corticosteroids(6), resp...
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...
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'
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...
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 enti...
Show MoreIn 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 MoreUnder 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...
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