I agree wholeheartedly with many of Dr Rawles' comments. There are
five components of delay in the "pain-to-needle" time. My editorial
focused on administration of thrombolytic therapy in the emergency
department, and as such I did not discuss other important components of
delay.
Patient delays in summoning medical assistance have proven to be very
difficult to influence. Delays in the arr...
I agree wholeheartedly with many of Dr Rawles' comments. There are
five components of delay in the "pain-to-needle" time. My editorial
focused on administration of thrombolytic therapy in the emergency
department, and as such I did not discuss other important components of
delay.
Patient delays in summoning medical assistance have proven to be very
difficult to influence. Delays in the arrival of medical assistance have
been improved by dispatching an ambulance immediately to the patient.
There may be further delays at the scene for history-taking, physical
examination and procedures to be undertaken, but these may prove
worthwhile if treatment can be expedited as a result. For instance, the
recording of an electrocardiogram may allow confirmation of the diagnosis
of threatened myocardial infarction, enabling pre-hospital thrombolysis to
be undertaken - and as Dr Rawles points out, this has real advantages.
Transport delays are essentially unmodifiable. This leaves delays in
hospital, which I discussed in my editorial.
I strongly support the use of pre-hospital thrombolysis in rural
areas[1] and in cases where transport delays are likely to exceed one
hour.[2]
The issue of just how many lives are saved per hour less of treatment
delay is controversial because no trials have randomised the timing of
thrombolysis. In the FTT overview, which examined all available data from
randomized trials of >1,000 patients, regression analysis showed that
there was an approximate straight-line relationship between treatment
delay and mortality, and we calculated that for every hour less of delay
prior to treatment, 1.6 lives were saved per 1,000 patients randomised.[3]
It is incorrect to simply connect the data points (including the 50%
reduction in the first hour in the GISSI-1 trial[4]) and to ascribe larger
reductions for each hour less of delay prior to treatment. In a weighted
regression analysis of eight trials, Boersma et al concluded that a one-
hour delay may result in 21 lives lost per 1,000 patients treated.[5]
In the GREAT trial, which was led by Dr Rawles, 311 patients who were
more than 30 minutes' travelling time away from hospital were randomised
to receive either pre-hospital or in-hospital thrombolysis. The "door-to-
needle" time of those treated in-hospital (which was the focus of my
editorial) was 87 minutes.[6] A meta-analysis of six pre-hospital
thrombolysis trials, including the GREAT trial, calculated that there was
a 17% reduction (95% confidence interval 2-30%) in short-term mortality
with pre-hospital thrombolysis, equating to about 16 lives saved per 1,000
patients treated.[7]
It should be noted that there were often marked door-to-needle delays
prior to in-hospital thrombolysis in these trials, meaning that the
overall difference in the time to treatment between pre- and in-hospital
thrombolysis was approximately 60 minutes. In the largest of these trials
(the European Myocardial Infarction Project, which randomized 5,469
patients) the difference was 55 minutes, but no significant reduction in
mortality was shown with pre-hospital thrombolysis, leading to the
conclusion that perhaps the difference has to be greater than this to
translate into a survival benefit.[8]
I believe that the appropriate paradigm is not actually "time from
onset of ischaemia to treatment", as Dr Rawles asserts, but rather, "time
from the onset of ischaemia to the opening of the infarct-related artery
and achievement of myocyte reperfusion". The primary goal of treatments
for patients with acute myocardial infarction should be to shorten this
time as much as possible.
Dr Rawles sees little point in reducing the door-to-needle time if
the patient has already taken an hour or more to get to the emergency
department, but I disagree. Any reduction in the delay between the onset
of ischaemia and opening of the infarct-related artery is important to
reduce mortality, preserve left ventricular function and improve quality
of life. Our goal, therefore, should be to reduce all components of delay
in the time from the onset of ischaemia to opening of the infarct-related
artery and achievement of myocyte perfusion.
Harvey D White
Cardiology Department
Green Lane Hospital
Auckland, New Zealand
References
(1) White HD. Prehospital thrombolysis [editorial]. NZ Med J. In
press 2001.
(2) White HD, Van de Werf FJJ. Thrombolysis for acute myocardial
infarction. Circulation 1998;97:1632-46.
(3) Fibrinolytic Therapy Trialists' (FTT) Collaborative Group.
Indications for fibrinolytic therapy in suspected acute myocardial
infarction: collaborative overview of early mortality and major morbidity
results from all randomised trials of more than 1000 patients. Lancet
1994;343:311-22.
(4) Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto
Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in
acute myocardial infarction. Lancet 1986;i:397-402.
(5) Boersma E, Maas ACP, Deckers JW, et al. Early thrombolytic
treatment in acute myocardial infarction: reappraisal of the golden hour.
Lancet 1996;348:771-5.
(6) The GREAT Group. Feasibility, safety, and efficacy of domiciliary
thrombolysis by general practitioners: Grampian Region Early Anistreplase
Trial. Br Med J 1992;305:548-53.
(7) Morrison LJ, Verbeek PR, McDonald AC, et al. Mortality and
prehospital thrombolysis for acute myocardial infarction: a meta-analysis.
JAMA 2000;283:2686-92.
(8) The European Myocardial Infarction Project Group. Prehospital
thrombolytic therapy in patients with suspected acute myocardial
infarction. N Engl J Med 1993;329:383-9.
The major factor influencing the outcome of thrombolytic therapy for
acute myocardial infarction is not door-to-needle time, as Harvey White
claims, but pain-to-needle time. The largest component of the overall
delay from onset to thrombolytic treatment is attributable to the
patient's delay in calling for medical help. There is then an appreciable
delay between calling for an ambulance or a doctor and arr...
The major factor influencing the outcome of thrombolytic therapy for
acute myocardial infarction is not door-to-needle time, as Harvey White
claims, but pain-to-needle time. The largest component of the overall
delay from onset to thrombolytic treatment is attributable to the
patient's delay in calling for medical help. There is then an appreciable
delay between calling for an ambulance or a doctor and arriving at the
hospital - the call-to-door time. Probably little can be done to shorten
patient delay, so in assessing the emergency response of the health-care
system to a patient with suspected acute MI, it is better to exclude that
element of the delay over which the system has no control and start the
audit clock when the patient first makes contact with any sector of the
health service. This is acknowledged in the National Service Framework for
coronary heart disease recently launched by the Government Department of
Health in England which lays down various standards to be met, including a
rigorous 60-minute call-to-needle time. This forces us to look out of the
front door of the hospital to see what avoidable delays are encountered by
the patient before arrival at hospital. There is not a lot of point in
"busting a gut" to achieve a door-to-needle time of <_30 minutes="minutes" if="if" the="the" patient="patient" has="has" already="already" taken="taken" an="an" hour="hour" or="or" more="more" to="to" get="get" emergency="emergency" department="department" after="after" summoning="summoning" help.="help." p="p"/> A recently published audit showed that with a "scoop and run" policy
in urban areas only 15% of patients had a call-to-needle time within 60
minutes.[1] By contrast, in an audit of prehospital thrombolysis, 75% of
call-to-needle times were within 60 minutes, and that was in a rural area.[2] So the message is that we have to look to prehospital thrombolysis to
maximise the potential benefit of early thrombolysis.
And the benefit of earlier thrombolysis is very much greater than the
1.6/1000/h quoted. For reasons given elsewhere the FTT estimate is wrong,[3] and the best estimate we have of the time related benefit is more
that 10 times as great, at 21/1000/h.[4]
References
(1) Birkhead JS, et al. Trends in the provision of thrombolytic
treatment between 1993 and 1997. Heart 1999;82:438-42.
(2) Rawles J, et al. Call to needle times after acute myocarial infarction
in urban and rural areas in northeast Scotland: prospective observation
study. BMJ 1998;317:576-8.
(3) Rawles J. What is the likely benefit of earlier thrombolysis? Eur Heart J 1996;17:991-5.
(4) Boersma E, et al. Early thrombolytic treatment in acute myocardial
infarction: reappraisal of the golden hour. Lancet 1996;348:771-5.
I am grateful to Dr Turner and Dr Bryson for their interest in our
Editorial.
I think they are right, all PFOs are "not equal". As stated in
the editorial, there is only
conclusive data that large patent foramen ovale capable of passage of more
than 20 micro bubbles
without provocative manouvers are implicated in crytogenic stroke. It
seems reasonable to
infer that the situation with d...
I am grateful to Dr Turner and Dr Bryson for their interest in our
Editorial.
I think they are right, all PFOs are "not equal". As stated in
the editorial, there is only
conclusive data that large patent foramen ovale capable of passage of more
than 20 micro bubbles
without provocative manouvers are implicated in crytogenic stroke. It
seems reasonable to
infer that the situation with decompression illness is comparable and that
a small PFO may be
entirely benign .
As you are aware, transoesophageal echocardiography has become an
accepted initial
investigation for possible atrial septal abnormality. I absolutely agree
that this is probably
misguided particularly as incomplete valsalva manoeuvres are achieved
during sedation. I
believe this discrepancy explains the variation in the screening data
comparing
transoesophageal echocardiography and transcranial doppler. We have been
investigating this
issue in Oxford over the last year and we will be presenting data at the
British Cardiac
Society which demonstrates that transthoracic echocardiography with
valsalva manoeuvre is the
initial investigation of choice when screening for patent foramen ovale
capable of causing
clinical events. Transoesophageal echocardiography should be reserved for
detailed anatomical
assessment in the minority of patients that require closure.
We have concerns about the role of troponin measurements in the recently published guidelines on the management of acute coronary syndromes not associated with ST elevation on the ECG.[1] We feel that following the guideline in its present form will blunt the usefulness of troponin measurements as a decision support tool.
The recommended decision limits seem to reflect an insufficiently critical appraisal...
We have concerns about the role of troponin measurements in the recently published guidelines on the management of acute coronary syndromes not associated with ST elevation on the ECG.[1] We feel that following the guideline in its present form will blunt the usefulness of troponin measurements as a decision support tool.
The recommended decision limits seem to reflect an insufficiently critical appraisal of cardiac troponin assay technology and the clinical diagnostic studies supporting their use. The limit of normality for the latest generation of troponin T and I assays, defined as the 97.5th centile for normal health volunteers, lies below the minimal detectable concentration (MDC) for troponin assays. The standard definition of MDC is in terms of signal noise for the zero calibrant (usually two standard deviations). A more realistic assessment of assay sensitivity is the functional sensitivity (FS), which is the lowest concentration in serum, which can be measured with acceptable precision and is always higher than MDC. Measurements made between FS and MDC will have a considerable analytical uncertainty, which will increase as MDC is approached. The clinical significance of using a decision cut-off at the extreme of analytical performance will vary depending on the clinical characteristics or pre-test risk of the group of patients being tested and the question being asked.
Troponin measurements are used within the guidelines to establish the diagnosis of an acute coronary syndrome and as an adjunct to risk stratification. Comparison of clinical diagnostic studies on troponin is complicated by lack of definition of patient groups, changing methodology and lack of comparability between troponin T and I assays and also between different troponin I assays. The earliest clinical diagnostic studies used a qualitative point of care testing device for troponin T with a sensitivity of about 0.2ug/L[2] The reported clinical decision point for studies using quantitative troponin T has virtually always been 0.1ug/L representing the 99.6th centile of a large reference population using the first generation assay,[3] which had some cross reactivity with muscle troponin. This limit has been retained by the manufacturer for the third generation assay, although comparative data for the 99.6th centile has not been published. However, the highest value found in 1951 healthy test subjects using the third generation assay is 0.037ug/L[4] In diagnostic studies elevation of troponin above 0.1ug/L in the absence of any other evidence of myocardial ischaemia is presumed to be evidence of minor myocardial damage (MMD) classified as being a part of the spectrum of acute coronary syndromes.
Minor elevations of troponin have been associated with a number of conditions such as heart failure, renal failure, pulmonary embolism and are common in hospitalised patients not known to have an acute coronary syndrome, presumably reflecting MMD[5] [6] of varied aetiology. But troponin levels in these patient groups seem to identify a poor general prognosis rather than a coronary prognosis in the absence of clinical indicators for an acute coronary syndrome.[7] The poor prognosis identified by troponin in renal failure patients is longer term[7] than that seen in acute coronary syndromes. In heart failure[8-10] troponin rise has been noted in 25% to 89% of patients and is linked to severity. Such studies simply reinforce the notion that not all myocardial injury is ischaemic.
There is a lack of good evidence supporting cut-offs lower than 0.1ug/L for the diagnosis of acute coronary syndromes. Extension of the definition of MMD down to the MDC of troponin is ahead of the evidence and may present chest pain management programmes with serious logistic problems by eroding the specificity of the test for identifying acute coronary syndromes.
Within the context of recommendation 4, an undetectable troponin is used as the most sensitive available technique for excluding myocardial damage. The use of a very low troponin level as a "rule out" criterion is understandable. However, in the absence of any other objective evidence for ischaemic heart disease, minor elevations of troponin have unproven diagnostic utility, especially in the context of patients with other pathology. Recommendation 3 allows the diagnosis of an acute coronary syndrome to be made on the basis of a detectable troponin alone and risk stratification is based on the troponin level. But, virtually all of the evidence for the prognostic value of troponin is for patients with acute coronary syndromes diagnosed on the basis of ECG criteria[11][12] including sub-studies of FRISC,[13] TRIM,[14]GUSTO,[15-17] and TIMI[18] which were designed as interventional studies. Clearly, the interpretation of any result needs to be done in the context of clinical presentation but that can be very non-specific in the context of emergency medicine departments.
It is of interest that the PRISM[19] study, which looked at the effectiveness of the platelet receptor inhibitor Tirofiban in acute coronary syndromes, found no benefit in patients with troponin T levels in the range zero to 0.1ug/L compared with levels greater than 0.1ug/L and possibly greater benefit in the range 0.1 - 0.24ug/L compared with higher levels. Similar results were obtained for troponin I. This suggests that different levels of troponin characterise different pathological events and that the cut-point adopted may be of therapeutic significance.
Samples from the TIMI IIB sub-study18 were recently examined using three different troponin I methods with cut-offs at or near the limit of detection and were found to give similar results with a two fold increase in risk associated with a positive result. The TRIM sub-study found decision points down to 0.05ug/L troponin T[13] clinically useful. The effect of lowering the cut-point in a diagnostic study will depend on the number of test subjects reclassified by the change and will be sensitive to case mix. In these studies the number reclassified was small and the cases were highly selected. Such dichotomization of data does not allow analysis of various cut-offs for risk stratification. Unfortunately, lack of comparability between assays complicates the transferability of data from clinical studies and discourages the use of multiple prognostic decision points and encourages interest in touchstones such as MDC and FS. The real issue, however, is how to use troponin measurements to tailor appropriate treatment and requires strata of decision points.
The study by the FRISC[13] group using troponin T assay with an upper limit of normal reported as 0.06ug/L and a detection limit of 0.04ug/L showed that risk was positively related to the level of troponin T. There was approximately a five fold difference in risk between the lowest (less than 0.06ug/L) and the highest (greater than 0.62ug/L) quintile and a two to three fold difference between the less than 0.06ug/L and the 0.06 to 0.18ug/L groups. A study using a Troponin I assay in the TIMI IIIB[11] study came to similar conclusions. The FRISC study group has tended to retain the same troponin T stratification with the low risk group being less than 0.06 when integrating risk with the results of exercise testing[20][21] and inflammatory markers.[22]
Assigning risk, as in the guideline, to patients with marginally elevated troponin levels (0.01-0.1ug/L ) and no independent confirmatory evidence for myocardial ischaemia goes beyond the available evidence. The diagnostic return and practicality of using the MDC as a diagnostic decision point in the context of managing chest pain in the general medical/emergency medicine setting needs to be critically scrutinised. Even an undetectable troponin does not exclude the presence of severe coronary artery disease as a cause of symptoms and as the guideline points out, no patient with established coronary artery disease is at no risk. It is important to make a clinically useful and practical prognosis based on evidence.
It is becoming accepted that the distinction between non Q wave infarction and unstable angina is artificial because they have a similar pathogenesis and require similar clinical management strategies. However, the troponin level reliably signifying ischaemic MMD on which the diagnosis depends needs further study. The latest generation of troponin assays has improved sensitivity and specificity and there is some justification for lowering the limit of normality but the impact of changing decision thresholds needs to be subjected to clinical studies.
The National Academy of Clinical Biochemistry[23] Standards of Laboratory Practice in the United States supports this view but have nevertheless recommended the use of the 97.5th centile of the normal range as a cut-off. However, they also support the use of multiple sample times for cardiac markers, which is not common practice in the UK and not recommended in the guideline. Sequential sampling is more likely to identify the peak troponin and improve discrimination from low background noise, although that advantage is lost using a zero cut-off.
Therefore, the use of a decision level at the extreme of assay performance, which overlaps with normality and morbid conditions and which identifies a degree of MMD of uncertain pathological significance, seems premature. Since this is a very important issue, it would be better to design studies specifically to address clinical management issues rather than exploiting interventional studies, which by necessity have highly selected patient groups. The lowest prognostic risk category identified by the FRISC[13] group was less than 0.06ug/L. We suggest 0.05ug/L troponin T as an interim practical round number decision point for low risk stratification and "rule-in" test for an acute coronary syndrome, which approximates to the FS of the test. At least this is a level of troponin T that can really be measured. Intermediate risk would be between 0.05 and 0.1ug/l. Calibration problems with troponin I assays create problems in deriving equivalent decision points but the FS could be a common interim approach. Although the use of MDC or FS as decision points is a potential way of improving the comparability of diagnostic performance between different troponin assays, this is no substitute for commercial calibration protocols designed to improve the comparability of assays.
MW France*, G Cook, CJ Seneviratne, G Burrows, B Keevil, P Lewis, J McMurray, K Carolan, A Kirkpatrick
*Corresponding author: Department of Clinical Biochemistry Manchester Royal Infirmary CMHT, Oxford Road Manchester M13 9WL, UK
Tel: 0161 276 4284 Fax: 0161 276 4586
mfrance@labmed.cmht.nwest.nhs.uk
Greater Manchester Clinical and Laboratory Audit Group on the use of Cardiac Markers in Ischaemic Heart Disease.
Supported by a grant from the North West Regional Office Education Directorate and Manchester Health Authority.
References
(1) British Cardiac Society Guidelines and Medical Practice Committee and Royal College of Physicians Clinical Effectiveness and Evaluation Unit. Guideline for the management of patients with acute coronary syndromes without persistent ECG ST segment elevation. Heart 2001;85:133-142.
(2) Wu AHB, Lane PL. Metaanalysis in Clinical Chemistry: Validation of Cardiac Troponin T as a marker for Ischemic Heart Diseases. Clin Chem 1995;41:1228-1233.
(3) Muller-Bardorff M, Hallermayer K, Schroder A, Ebert Ch, Gerhardt W, Katus HA. Improved TroponinT ELISA specific for cardiac Troponin T isoform: assay development and analytical and clinical validation. Clin Chem 1997;43:458-466.
(4) Multicentre evaluation: data on file at Roche.
(5) Barasch E, Kaushik V, Gupta R, Ronen P, Hartwell B. Elevated cardiac troponin levels do not predict adverse outcomes in hospitalized patients without clinical manifestations of acute coronary syndromes. Cardiology 2000;93:1-6.
(6) Giannitsis E, Muller-Bardorff M, Kurowski V, Weidtmann B, Wiegand U, Kampmann M. Independent prognostic value of troponin T in patients with confirmed pulmonary embolism. Circulation 2000;102:211-217.
(7) Mockel M, Schindler R, Knorr L, Muller C, Heller G, Stork TV, Frei U. Prognostic value of troponin T and I elevations in renal disease patients without acute coronary syndromes: a 9 month outcome analysis. Nephrol Dial Transplant 1999;14:1489-1495.
(8) Chen YN, Wei JR, Zeng LJ, Wu MY. Monitoring of troponin I in patients with acute heart failure. Ann Clin Biochem 1999;36:433-437.
(9) Setsuta K, Seino Y, Takahashi N, OgawaT, Sasaki K, Harada A, Takano T, Kishida H, Hayakawa H. Clinical significance of elevated levels of cardiac troponin T in patients with chronic heart failure. Am J Cardiol 1999;84:608-611.
(10) La Vecchia L, Mezzena G, Zanolla L, Paccanaro M, Varotto L, Bonnano C, Ometto R. Cardiac troponin T as diagnostic and prognostic marker in severe heart failure. J Heart Lung Transplant 2000;19:644-652
(11) Antman EM, Tanasijevic MJ, Thompson B, Schactman M, McCabe CH, Cannon CP, Fischer GA, Fung AY, Thompson C, Wybenga D, Bruanwald E. Cardiac specific Troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342-1349.
(12) Galvani M, Ottani F, Ferrini D, Ladenson JH, Destro A, Baccos D, Rusticali F, Jaffe AS. Prognostic influence of elevated values of cardiac Troponin I in patients with unstable angina. Circulation 1997;95:2053-2059.
(13) Lindahl B, Per Venge MD, Wallentin L for the FRISC Study Group. Relation between Troponin T and the risk of subsequent cardiac events in unstable coronary artery disease. Circulation 1996;93:1651-1657.
(14) Luscher MS, Thygesen K, Ravkilde J, Heikendorff L, for the TRIM study group. Applicability of cardiac Troponin T and I for early risk stratification in unstable coronary artery disease. Circulation 1997;96:2578-2585.
(15) Ohman EM, Armstrong PW, Christenson RH, Granger CB, Katus HA, Hamm CW, O'Hanesian MA, Wagner GS, Kleiman NS, Harrel FE, Califf RM, Topol EJ for the Gusto IIa investigators. Cardiac Troponin T levels for risk stratification in acute myocardial ischaemia. N Engl J Med 1996;335:1333-1341.
(16) Newby KL, Christenson RH, Ohman M, Armstrong PW, Thompson TD, Lee KL, Hamm CW, Katus HA, Cianciolo C, Granger CB, Topol EJ, Califf RM for the GUSTO-IIa investigators. Value of Serial Troponin T measures for early and late risk stratification in patients with acute coronary syndromes. Circulation 1998;98:1853-1859
(17) Ohman EM, Armstrong PW, White HD, Granger CB, Wilcox RG, Weaver WD, Gibler WB, Stebbins AL, Ciancolo C, Califf RM, Topol EJ for GUSTO III investigators. Risk stratification with a point of care cardiac Troponin T test in acute myocardial infarction. Am J Cardiol 1999;84:1281-1286.
(18) Morrow DA, Rifai N, Tanasijevic MJ, Wybenga DR, De Lemos JA, Antman EM. Clinical efficacy of three assays for cardiac Troponin I for risk stratification in acute coronary syndromes: A Thrombolysis In Myocardial Infarction (TIMI) IIB Substudy. Clin Chem 2000;46:453-460
(19) Heeschen C, Hamm CW, Goldman B, Deu A, Langenbrink L, White HD for the PRISM study investigators. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of Tirofiban. Lancet 1999;354:1757-1762.
(20) Lindahl B, Andren B, Ohlsson J, Venge P, Wallentin L. Risk stratification in unstable coronary artery disease. Additive value of troponin T determinations and pre-discharge exercise tests. FRISK study group. Eur Heart J1997;18:762-770.
(21) Safstrom K, Lindahl B, Swahn E. Risk stratification in unstable coronary artery disease--exercise test and troponin T from a gender perspective. FRISC study group. Fragmin during instability in coronary artery disease. J Am Coll Cardiol 2000;35:1791-1800.
(22) Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long term mortality in unstable coronary artery disease. FRISC Study Group. N Eng J Med 2000;343:1139-1147.
(23) Wu HB, Apple FS, Gibler B, Jesse RL, Warshaw MM, Valdes R. National Academy of Clinical Biochemistry Standards of Laboratory Practice: Recommendations for the use of cardiac markers in coronary artery diseases. Clin Chem 1999;45:1104-1121.
We were interested to read the review about the exciting topic of
patent foramen ovale (PFO).[1]
The authors raise the interesting conundrum that has prevented PFO
being considered an important abnormality - How can a problem affecting
one-quarter of all individuals be associated with disease? Indeed with
regard to decompression illness (DCI) the authors state that whilst many
divers have a PFO,...
We were interested to read the review about the exciting topic of
patent foramen ovale (PFO).[1]
The authors raise the interesting conundrum that has prevented PFO
being considered an important abnormality - How can a problem affecting
one-quarter of all individuals be associated with disease? Indeed with
regard to decompression illness (DCI) the authors state that whilst many
divers have a PFO, few get clinical manifestations of DCI. A solution to
this apparent conundrum has been forthcoming. Whilst the prevalence of
probe patent PFO is 27%,[2] the prevalence of a PFO allowing the passage
of >25 bubbles following contrast injection is much lower, and was
found to be 4.9% in the control group of a recent study.[3] However for
patients with a history of acute neurological DCI it was ten-fold higher
(49%).
Only 1.3% of people have a PFO >10mm at post-mortem,[2] whilst
in 32 patients with a history of stroke (4 patients) or DCI (28 divers),
that have undergone PFO closure, the defects ranged in stretched diameter
from 9-16mm (mean 12mm).[4] Hence large PFO (>10mm) is uncommon in
the general population but very common in these divers.
Thus while it may
be reasonable to accept a small defect as being physiological, a large
defect should be considered pathological and is certainly associated with
some forms of DCI.
In addition the authors state that transoesophageal echocardiography
(TOE) is superior to transthoracic echocardiography (TTE) for detecting
PFO. Whilst TOE provides the best anatomical data, it is possible (and
not uncommon) to have no evidence of a right-to-left shunt on TOE but have
a large one at TTE following a Valsalva. This is mainly because it is not
possible to perform an adequate Valsalva during a TOE. To maximise any
right-to-left shunt a sustained Valsalva is needed, and imaging should
continue following its abrupt release. The physiological basis for this
is that during the Valsalva both right and left atrial pressures rise
initially, then, due to a reduction in venous return to the thorax both
begin to fall. On sudden release the left atrial pressure falls further
as reduced pulmonary venous return persists for a few cardiac cycles,
whilst there is a rapid return of right atrial pressure. Thus the
greatest pressure gradient may be achieved immediately after Valsalva
release due to a reduction in left atrial pressure rather than being
solely due to an increase in right atrial pressure.
A Valsalva sustained
enough to reduce venous return to the thorax cannot be achieved with a TOE
probe in the mouth. Thus to state that a patient does not have a right to
left shunt a TTE bubble study must be performed even if a TOE has been
negative. For divers we would not consider a TOE indicated if a properly
performed TTE bubble study had been negative.
Anatomical detail of a PFO
is of technical interest with regard to device closure, but the functional
consequence (ie, the right to left shunt) is the information of relevance
in deciding if a PFO is of clinical consequence.
In light of the evidence demonstrating large PFO (>25 bubbles
crossing to the left) to be causally related to DCI and stroke, we believe
that such PFOs are pathological and should be sought by bubble-contrast
TTE. For those with large PFO and a history of DCI, who wish to continue
unrestricted diving, closure using a percutaneous device should be
offered. Interestingly we recently closed a PFO in a young man with no
history of DCI. He had a history of ventricular septal defect repair and
was referred for an echocardiogram with bubble contrast by his Diving
Medical Examiner. He was found to have a very large right to left shunt
(hundreds of bubbles crossing to the left). The United Kingdom Health and
Safety Executive (HSE) refused to grant him an unrestricted professional
diver medical certificate unless the PFO was closed, despite there being
no history of DCI during his extensive amateur diving career. It would
appear therefore that the HSE also consider large PFO to be an important
abnormality, even in the absence of any history.
References
(1) Alp N et al. Heart 2001;85(3):242-4.
(2) Hagen PT et al. Mayo Clin Proc 1984;59:17-20.
(3) Wilmshurst P, Bryson P Clin Sci 2000;99:65-75.
Fallon and colleagues reported no association between serum
homocysteine and coronary heart disease in the Caerphilly cohort study,[1]
and contrasted their result with the "positive results" shown in other
studies including our own BUPA (British United Provident Association)
cohort study of 21,520 men.[2] Fallon and colleagues may be incorrect in
interpreting their results as negative. They express them as...
Fallon and colleagues reported no association between serum
homocysteine and coronary heart disease in the Caerphilly cohort study,[1]
and contrasted their result with the "positive results" shown in other
studies including our own BUPA (British United Provident Association)
cohort study of 21,520 men.[2] Fallon and colleagues may be incorrect in
interpreting their results as negative. They express them as an odds ratio
for a homocysteine increase of one standard deviation which, from table 2
in their paper, is given as 1.4 mmol/L. Our positive result yielded an
odds ratio of 1.33 for a 5 mmol/L increase in serum homocysteine after
adjustment for the two confounding factors identified in our study
(namely systolic blood pressure and apolipoprotein B) and a 95% confidence
interval of 1.22-1.59 (p<_0.001. this="this" is="is" equivalent="equivalent" to="to" an="an" odds="odds" ratio="ratio" of="of" _1.08="_1.08" for="for" a="a" serum="serum" homocysteine="homocysteine" increase="increase" _1.4="_1.4" mmol="mmol" l="l" virtually="virtually" identical="identical" their="their" own="own" point="point" estimate="estimate" which="which" depending="depending" on="on" the="the" statistical="statistical" analysis="analysis" used="used" lay="lay" between="between" _1.07="_1.07" and="and" _1.12="_1.12" table="table" _4.="_4." effect="effect" appears="appears" be="be" similar="similar" that="that" from="from" positive="positive" studies="studies" but="but" there="there" source="source" uncertainty.="uncertainty." standard="standard" deviation="deviation" surprisingly="surprisingly" small="small" it="it" was="was" _3.9="_3.9" in="in" controls="controls" bupa="bupa" study.="study." if="if" were="were" materially="materially" larger="larger" than="than" value="value" cited="cited" results="results" caerphilly="caerphilly" study="study" would="would" indeed="indeed" inconsistent="inconsistent" with="with" those="those" correct="correct" two="two" consistent.="consistent." helpful="helpful" authors="authors" could="could" clarify="clarify" this.="this." p="p"/> Fallon and colleagues, in reviewing the "positive" studies, state
that in our study we "did not control for smoking" and that "omitting to
control for confounders may lead to false positive results". This
statement misrepresents our results. We state in our paper that we
examined the effect of smoking, that it was not significantly associated
with serum homocysteine and so was not a source of confounding, and that
there was therefore no reason to adjust for it in estimating the odds
ratio of death from ischaemic heart disease according to homocysteine
level. Had we adjusted for smoking, the odds ratio would change to 1.26;
this is still significantly above 1.0 (p=0.005), and the difference
between the estimates of 1.33 and 1.26 could readily be due to chance
alone. The reason that smoking was a confounding factor in the Caerphilly
Study but not in the BUPA Study may be that the BUPA cohort, unlike most
others, shows a high level of socio-economic homogeneity. Smoking is
related to social class and may be a marker of other causes of heart
disease that are socio-economically related.
NJ Wald (Corresponding author)
HC Watt
MR Law
BUPA Epidemiological Research Group Department of Environmental and
Preventive Medicine Wolfson Institute of Preventive Medicine Barts and
The London School of Medicine and Dentistry Charterhouse Square, London EC1M 6BQ, UK
DG Weir
J McPartlin
Department of Clinical Medicine Trinity College, St James's
Hospital Dublin 8, Ireland
JM Scott
Department of Biochemistry, Trinity College
References
(1) Fallon UB, Ben-Shlomo Y, Elwood P, Ubbink JB, Davey Smith G.
Homocysteine and coronary heart disease in the Caerphilly cohort: a 10
year follow up. Heart 2001;85:153-8.
(2) Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM.
Homocysteine and ischaemic heart disease: results of a prospective study
with implications on prevention. Arch Intern Med 1998;158:862-7.
We wish to thank Professor Wald and colleagues for highlighting an error
in our paper.1 We misreported the standard deviation for total
plasma homocysteine concentration (tHcy) in table 2 so that this was, as
Wald infers, too small. This error occurred because our analyses were based
on the log transformed data. The true value of the back-transformed standard
deviation is between 3.4 and 4.8...
We wish to thank Professor Wald and colleagues for highlighting an error
in our paper.1 We misreported the standard deviation for total
plasma homocysteine concentration (tHcy) in table 2 so that this was, as
Wald infers, too small. This error occurred because our analyses were based
on the log transformed data. The true value of the back-transformed standard
deviation is between 3.4 and 4.8 mmol/l (see
amended table 2). For the analysis in table 4, one standard deviation in
log transformed tHcy is equivalent to 4.3 mmol/l
tHcy. None of the effect estimates are changed. This means that our results
are not consistent with those of the BUPA cohort study.2 We
fully agree that our data cannot exclude a small positive association between
homocysteine and CHD, however it does not support the likelihood that homocysteine
is a strong risk factor for CHD within this cohort.
Table 2
Serum total homocyst(e)ine and potential confounding variables for
CHD in the control group
Linear
regression
95%
confidence interval (p value)
Beta
coefficient*
Age
(per 5 years)
0.033
0.01
to 0.05 (0.001)
Blood
pressure
systolic BP (per 10 mm/Hg)
0.0046
-0.003
to 0.01 (0.2)
diastolic BP (per 10 mm/Hg)
-0.0016
-0.29
to 0.19 (0.8)
Dietary
factors
†alcohol (per SD in ml/day)
-0.044
-0.062
to -0.02 (
folate (per SD in microg/day)
-0.056
-0.07
to- 0.03 (
†B12 (per SD in microg/day)
-0.053
-0.07
to -0.03 (
B6 (per SD in mg/day)
-0.035
-0.05
to -0.01 (
Blood
lipids
total cholesterol (per SD in mmol/l)
-0.021
-0.03
to -0.004 (0.01)
HDL cholesterol (per SD in mmol/l)
-0.019
-0.03
to -0.002 (0.02)
†triglycerides (per SD in mmol/l)
-0.010
-0.05
to 0.01 (0.03)
Clotting
factors
fibrinogen (per SD in g/l)
-0.002
-0.014
to 0.20 (0.7)
Body
mass index (10 kg/m2)
-0.10
-0.15
to -0.06 (
Creatinine
(per SD in micromol/l)
0.57
0.03
to 0.07 (
Smoking
Serum
tHcy (microm/l)
SD
never smoked
11.3
3.4
ex smoker
11.7
4.7
current smoker
12.1
4.8
ANOVA
p=0.01
Difference
in means
Serum
tHcy (microm/l) (SD)
t
Test p value
Hypertensive
11.9
(4.8)
Normotensive
11.7
(4.7)
0.2
Manual
social class
11.9
(4.8)
Non-manual
social class
11.6
(4.6)
0.2
Angina
12.2
(4.9)
No
angina
11.7
(4.7)
0.2
ECG
ischaemia
11.9
(3.6)
Normal
ECG
11.8
(4.7)
0.6
*Change in homocysteine
(natural log) per unit change in CHD risk factor. †Log transformed. ANOVA, analysis of
variance; BP, blood pressure; HDL, high density lipoprotein; tHcy, total
serum homocyst(e)ine concentration.
Criteria for selecting confounders is controversial. We believe that
the choice of confounders should be based on a priori knowledge
of exposure and disease associations, rather than any arbitrary statistical
level or stepwise procedure.3 Previous studies have documented
a strong positive dose response relationship between smoking and tHcy concentration.4
Smoking leads to 21% attenuation of the association in the BUPA cohort,
and given the way in which measurement imprecision dilutes our ability
to statistically adjust risk associations5 this suggests a substantial
degree of confounding.
The best evidence regarding homocysteine and CHD risk comes from studies
of genetic polymorphisms related to homocysteine metabolism. Individuals
homozygous for the thermolabile variant of the methylenetetrahydrofolate
reductase (MTHFR) gene (T/T) have homocysteine levels about 2.6 mmol/l
higher than those homozygous for the wild type (C/C) gene, and a relative
risk of CHD of 1.11 (95% confidence intervals 0.91-1.37)6. Thus
for a 5 mmol/l higher level of homocysteine
the BUPA study yields a relative risk of 1.33 (1.22-1.59), the Caerphilly
study 1.12 (0.98-1.27) and the MTHFR studies 1.22 (0.83-1.83). These are
all compatible with a small positive association. The MTHFR studies provide,
of course, far better evidence than observational studies which have measured
homocysteine, such as the BUPA and Caerphilly cohorts. Through "Mendelian
randomisation"7 they test, essentially, the unconfounded association
between homocysteine and CHD risk. In the observational studies of measured
homocysteine and CHD risk, extensive confounding is possible and indeed
probable. This is unlikely with genetic studies, although theoretically
possible due to population stratification or the MTHFR polymorphisms being
in linkage disequilibrium with other loci influencing disease risk. Conventional
epidemiological studies have a limited future8 and resources
should be put into either randomised trials of homocysteine manipulation
or further studies utilising Mendelian randomisation.
Una B Fallon
Yoav Ben-Shlomo
George Davey Smith
Department of Social Medicine
University of Bristol, Canynge Hall
Whiteladies Rd, Bristol BS8 2PR, UK
References
(1) Fallon UB, Ben Shlomo Y, Elwood P, Ubbink JB, Smith GD. Homocysteine
and coronary heart disease in the Caerphilly cohort: a 10 year follow up.
Heart 2001;85:153-8.
(2) Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott et al.
Homocysteine and ischemic heart disease: results of a prospective study
with implications regarding prevention. Arch Intern Med 1998;158:862-7.
(3) Rothman KJ, Greenland S. Modern Epidemiology. 2nd ed. USA: Lippincott
Williams & Wilkins, 1998.
(4) Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug
JE et al. Total plasma homocysteine and cardiovascular risk profile.
The Hordaland Homocysteine Study. JAMA 1995;274:1526-33.
(5) Phillips AN, Smith GD. Bias in relative odds estimation owing to
imprecise measurement of correlated exposures. Stat Med 1992;11:953-61.
(6) Brattstrom L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate
reductase gene mutation leads to hyperhomocysteinemia but not to vascular
disease: the result of a meta-analysis. Circulation 1998;98:2520-6.
(7) Gray R, Wheatley K. How to avoid bias when comparing bone marrow
transplantation with chemotherapy. Bone Marrow Transplant 1991;7(Suppl
3):9-12.
(8) Smith GD, Ebrahim S. Epidemiology-is it time to call it a day? Int
J Epidemiol 2001;30:1-11.
We read with interest Professor Treasure's recent paper on the
cardiovascular surgical aspects of Marfan syndrome.[1] We wish to add to
the discussion by raising the significant cardiovascular risks faced by
Marfan patients during pregnancy, a problem that he touched on in a
previous editorial.[2] This is an important and controversial issue in the
management of adult cardiovascular manifestations of Marfa...
We read with interest Professor Treasure's recent paper on the
cardiovascular surgical aspects of Marfan syndrome.[1] We wish to add to
the discussion by raising the significant cardiovascular risks faced by
Marfan patients during pregnancy, a problem that he touched on in a
previous editorial.[2] This is an important and controversial issue in the
management of adult cardiovascular manifestations of Marfan syndrome,
which is not mentioned in his recent and otherwise excellent review.
It is well recognised that, apart from the 50% risk of passing on
this autosomal dominant condition, pregnancy itself is associated with
increased risk of cardiovascular, most particularly aortic, events.[3] [4]
The majority of patients with no or only mild aortic dilatation have an
uncomplicated and uneventful pregnancy.[5] However, the higher risk of
catastrophic cardiovascular events in women with moderate to severe aortic
or mitral valve pathology, and particularly in those with evidence of
significant aortic dilatation, necessitates very close multidisciplinary
monitoring during pregnancy, with timely intervention to safeguard the
wellbeing of both mother and foetus.
Before pregnancy, any woman with a diagnosis of Marfan syndrome
should be evaluated clinically and echocardiographically to assess the
degree of cardiovascular symptoms and pathology. If at most, the
cardiovascular problems are mild, and the aortic root diameter is under 4
cm,[3] then female Marfan patients wanting children should be counselled
to reproduce early if possible, with warning of a small but potential risk
during pregnancy. Those with significant cardiovascular problems and/or a
dilated aortic root should be counselled against pregnancy. Despite this,
controversy remains with respect to those asymptomatic women with an
aortic root diameter between 4-5 cm who, mindful of the potential risks,
wish to become pregnant. The choice remains between offering pre-
conception prophylactic surgery, and that of allowing pregnancy to take
place with reassurance of a stringent and regular high-risk follow-up in a
dedicated multidisciplinary unit. The former choice poses the dilemma of
inflicting peri- and post-operative surgical morbidity in an otherwise
young and healthy individual whose aorta may not necessarily ever dilate
to a point requiring surgery. The latter risks accelerated aortic
dilatation, possibly complicated by dissection, during pregnancy and the
need for aortic surgery with maternal and foetal morbidity.
During pregnancy, any patient with Marfan syndrome requires regular
echocardiography to check valvular pathology and any significant increase
in aortic dimensions. Cardiovascular complications can occur early on in
pregnancy as significant cardiac output and plasma volume changes can be
seen as early as the 6th gestational week.[3] Due to the ability of beta-
blockers to slow the rate of aortic dilatation,[6] their continued use is
recommended in Marfan women during pregnancy.[7]
When possible, labour should be allowed to proceed naturally to a
vaginal delivery, but there should be a low threshold for caesarean
section in the event of foetal mal-position, distress or significant
maternal hypertension. Epidural anaesthesia is recommended in order to
minimise the rise in blood pressure accompanying pain and anxiety of
labour. It may also be prudent to administer prophylactic antibiotics in
women with evidence of mitral valve prolapse in the context of the low but
potentially serious consequence of bacteraemia associated with
instrumental delivery.
Finally, whilst the majority of female Marfan patients go through
pregnancy without significant problems, it is important to keep in mind
that no Marfan patient can be reassured of an event free pregnancy. Major
aortic events have been described in Marfan patients with normal aortic
roots in and out of pregnancy.[8] [9]
Kumud Dhital
Eric Rosenthal
Adult Congenital Heart Disease Clinic
Guy's Hospital St Thomas Street
London SE1 9RT, UK
References
(1) Treasure T. Cardiovascular surgery for Marfan syndrome. Heart
2000;84:674-8.
(2) Treasure T. Elective replacement of the aortic root in Marfan's
syndrome. Br Heart J 1993;69:101-3.
(3) Pyeritz RE. Maternal and fetal complications of pregnancy in the
Marfan syndrome. Am J Med 1981;71:784-90.
(4) Lipscomb KJ, Smith JC, Clarke B, et al. Outcome of pregnancy in
women with Marfan's syndrome. Br J Obstet Gynaecol 1997;104:201-6.
(5) Rossiter JP, Repke JT, Morales AJ, et al. A prospective
longitudinal evaluation of pregnancy in the Marfan syndrome. Am J Obstet
Gynecol 1995;173:1599-606.
(6) Shores J, Berger KR, Murphy EA, et al. Progression of aortic
dilatation and the benefit of long-term b-adrenergic blockade in Marfan's
syndrome. N Engl J Med 1994;330:1335-41.
(7) Elkayam U, Ostrzega E, Shotan A, et al. Cardiovascular problems
in pregnant women with the Marfan syndrome. Ann Intern Med 1995;123:117-
22.
(8) Rosenblum NG, Grossman AR, Gabbe SG, et al. Failure of serial
echocardiographic studies to predict aortic dissection in a pregnant
patient with Marfan's syndrome. Am J Obstet Gynecol 1983;146:470-1.
(9) Murgatroyd F, Child A, Poloniecki J, et al. Does routine
echocardiographic assessment of the aortic root diameter help predict the
risk of dissection in the Marfan syndrome? Eur Heart J 1991;12;410.
We agree that cystic medial necrosis may in a small number
of patients be the cause of spontaneous coronary artery dissection.[1]
However, the pathogenesis of spontaneous coronary artery dissection
remains
poorly understood. Indeed, no uniform histological findings have been
identified and it is improbable that a single mechanism operates in all
these
patients. Our patient had none of the featur...
We agree that cystic medial necrosis may in a small number
of patients be the cause of spontaneous coronary artery dissection.[1]
However, the pathogenesis of spontaneous coronary artery dissection
remains
poorly understood. Indeed, no uniform histological findings have been
identified and it is improbable that a single mechanism operates in all
these
patients. Our patient had none of the features of Marfans syndrome, and as
there was no histopathological analysis, the aetiology remains a subject
of
speculation.
The high mortality associated with this condition necessitates urgent
coronary angiography to confirm the diagnosis. In patients surviving the
initial episode, and subsequently remain asymptomatic, medical therapy is
safe and compatible with good long term outlook. However, in those with
ongoing symptoms of myocardial ischaemia consideration should be given to
coronary revascularisation, though technically difficult in some cases, as
the only means to improve outcome in this usually fatal condition.
Reference
(1) Basso C, Morgagni GL, Thiene G. Spontaneous coronary artery
dissection: a neglected case of acute myocardial ischaemia. Heart
1996;75:451-4.
Of the paper-based coronary heart disease (CHD) risk prediction
methods, the modified Sheffield tables,[1] which include the patient's
HDL cholesterol, and the revised charts published by the joint British
societies[2] most accurately classify subjects' risks. In our evaluation
of their performance,[3] the only statistically significant difference
between them was the lower specificity of the modi...
Of the paper-based coronary heart disease (CHD) risk prediction
methods, the modified Sheffield tables,[1] which include the patient's
HDL cholesterol, and the revised charts published by the joint British
societies[2] most accurately classify subjects' risks. In our evaluation
of their performance,[3] the only statistically significant difference
between them was the lower specificity of the modified Sheffield tables,
which in turn gives them a significantly higher false positive rate than
the joint British societies' charts [3.8% (95% confidence interval 2.4 -
5.2%) vs 1.2% (0.5 - 1.9%)]. In context, false positive means a subject
whose 10 year CHD risk calculated with the Framingham equation is
<_30 but="but" who="who" is="is" scored="scored" by="by" the="the" risk="risk" table="table" chart="chart" as="as" having="having" a="a" of="of" _30="_30" or="or" higher.="higher." use="use" modified="modified" sheffield="sheffield" tables="tables" rather="rather" than="than" joint="joint" british="british" societies="societies" charts="charts" will="will" necessity="necessity" lead="lead" to="to" higher="higher" prescribing="prescribing" costs="costs" and="and" we="we" think="think" that="that" this="this" may="may" be="be" some="some" importance="importance" purchasers="purchasers" health="health" care.="care." p="p"/> Nonetheless, Wallis et al are quite correct in their assertion that
calculated CHD risks in the false positives identified by the modified
Sheffield tables approach the 30% risk threshold, and therefore treating
these patients may be no bad thing. Since the Sheffield group were
instrumental in setting the 30% treatment threshold in the first place, it
is interesting that they now believe that this risk level is
"conservative", by which we imagine they mean it is too high. The
rationale for choosing the current 30% threshold was based on the
Sheffield group's assessment of the affordability of statin treatment at
various risk levels.[4] Costs of treatment are heavily dependent upon the
price of the drugs, which have fallen substantially since the original
risk threshold was set. We agree with the Sheffield group that the 30%
risk threshold is now too high. However, we believe that it would be more
transparent were the CHD risk threshold for primary prevention to be
formally reduced, rather than covertly lowering it by using a risk
prediction method with a poor specificity.
Lower risk thresholds can be accommodated with the current joint
British charts, but the Sheffield tables would have to be drafted again.
We are also not convinced that the ability of the Sheffield tables to be
reproduced on a 'single page' is a particularly persuasive argument: the
latest edition of the British National Formulary seems to have been able
to publish the joint British societies' charts, in full and in colour.
AF Jones WA Bartlett
Department of Clinical Biochemistry, Birmingham Heartlands and
Solihull NHS Trust Birmingham B9 5SS, UK
FL Game
Department of Diabetes and Endocrinology, Nottingham City Hospital
Hucknall Road, Nottingham NG5 1PB, UK
GR Bayly
Department of Chemical Pathology, Bristol Royal Infirmary Bristol
BS2 8HW, UK
References
(1) Wallis EJ, Ramsay LE, Ul Haq IU, et al. Coronary and
cardiovascular risk estimation for primary prevention: validation of the
new Sheffield table in the 1995 Scottish health survey population. BMJ
2000;320:671-76.
(2) Wood D, Durrington P, Poulter N, et al. Joint British
recommendations on prevention of coronary heart disease in clinical
practice. Heart 1998;80(Suppl 2):S1-S29.
(3) Jones AF, Walker J, Jewkes C, et al. Comparative accuracy of
cardiovascular risk prediction methods in primary care patients. Heart
2001;85:37-43.
(4) Haq IU, Ramsay LE, Pickin DM, et al. Lipid-lowering for
prevention of coronary heart disease:what policy now? Clin Sci
1996;91:399-413.
Dear Editor,
I agree wholeheartedly with many of Dr Rawles' comments. There are five components of delay in the "pain-to-needle" time. My editorial focused on administration of thrombolytic therapy in the emergency department, and as such I did not discuss other important components of delay.
Patient delays in summoning medical assistance have proven to be very difficult to influence. Delays in the arr...
The major factor influencing the outcome of thrombolytic therapy for acute myocardial infarction is not door-to-needle time, as Harvey White claims, but pain-to-needle time. The largest component of the overall delay from onset to thrombolytic treatment is attributable to the patient's delay in calling for medical help. There is then an appreciable delay between calling for an ambulance or a doctor and arr...
Dear Editor,
I am grateful to Dr Turner and Dr Bryson for their interest in our Editorial.
I think they are right, all PFOs are "not equal". As stated in the editorial, there is only conclusive data that large patent foramen ovale capable of passage of more than 20 micro bubbles without provocative manouvers are implicated in crytogenic stroke. It seems reasonable to infer that the situation with d...
We have concerns about the role of troponin measurements in the recently published guidelines on the management of acute coronary syndromes not associated with ST elevation on the ECG.[1] We feel that following the guideline in its present form will blunt the usefulness of troponin measurements as a decision support tool.
The recommended decision limits seem to reflect an insufficiently critical appraisal...
We were interested to read the review about the exciting topic of patent foramen ovale (PFO).[1]
The authors raise the interesting conundrum that has prevented PFO being considered an important abnormality - How can a problem affecting one-quarter of all individuals be associated with disease? Indeed with regard to decompression illness (DCI) the authors state that whilst many divers have a PFO,...
Fallon and colleagues reported no association between serum homocysteine and coronary heart disease in the Caerphilly cohort study,[1] and contrasted their result with the "positive results" shown in other studies including our own BUPA (British United Provident Association) cohort study of 21,520 men.[2] Fallon and colleagues may be incorrect in interpreting their results as negative. They express them as...
We wish to thank Professor Wald and colleagues for highlighting an error in our paper.1 We misreported the standard deviation for total plasma homocysteine concentration (tHcy) in table 2 so that this was, as Wald infers, too small. This error occurred because our analyses were based on the log transformed data. The true value of the back-transformed standard deviation is between 3.4 and 4.8...
We read with interest Professor Treasure's recent paper on the cardiovascular surgical aspects of Marfan syndrome.[1] We wish to add to the discussion by raising the significant cardiovascular risks faced by Marfan patients during pregnancy, a problem that he touched on in a previous editorial.[2] This is an important and controversial issue in the management of adult cardiovascular manifestations of Marfa...
Dear Editor,
We agree that cystic medial necrosis may in a small number of patients be the cause of spontaneous coronary artery dissection.[1] However, the pathogenesis of spontaneous coronary artery dissection remains poorly understood. Indeed, no uniform histological findings have been identified and it is improbable that a single mechanism operates in all these patients. Our patient had none of the featur...
Dear Editor,
Of the paper-based coronary heart disease (CHD) risk prediction methods, the modified Sheffield tables,[1] which include the patient's HDL cholesterol, and the revised charts published by the joint British societies[2] most accurately classify subjects' risks. In our evaluation of their performance,[3] the only statistically significant difference between them was the lower specificity of the modi...
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