We read with interest the paper by Iofina et al.[1] highlighting the
superior outcomes observed using sirolimus eluting stents (SES) versus
intra-coronary radiation therapy (IRT) for patients with in-stent
restenosis (ISR). This condition remains a significant source of morbidity
and need for repeat procedures and, up until recently, IRT has remained
the most proven treatment for ISR, with reported...
We read with interest the paper by Iofina et al.[1] highlighting the
superior outcomes observed using sirolimus eluting stents (SES) versus
intra-coronary radiation therapy (IRT) for patients with in-stent
restenosis (ISR). This condition remains a significant source of morbidity
and need for repeat procedures and, up until recently, IRT has remained
the most proven treatment for ISR, with reported restenosis rates below
20% in randomised studies.[2] The use of drug eluting stents (DES) has
more recently provided further optimism in the long term management of
such patients, particularly given the long term concerns of IRT including
late stent thrombosis and edge restenosis.
The angiographic binary in-lesion restenosis rate at six months of
11% in the SES group and 29% in the IRT group (p=0.046) identified by
Iofina et al.[1] is comparable to that in The Multicenter, Nonrandomised
Sirolimus-Eluting Stent in the Treatment of Patients With an In-Stent
Restenotic Native Coronary Artery Lesion (TROPICAL) study[3] that
enrolled 162 patients. Here, binary restenosis in the SES group was 9.7%
and the primary end point, in-lesion late loss at 6 month follow up, was
0.08 ± 0.49 mm (which compared favourably with the late loss in IRT trials
which has ranged from 0.22 ± 0.84 mm to 0.64 ± 0.69 mm).[3]
We recently reported the utility of adopting DES based therapies for
ISR with beneficial outcomes extending to 18 months of clinical follow-up.[4] In our observational study, the major adverse cardiac event (MACE)
rate was significantly lower in the SES compared with the IRT group (14% vs 40%, P=.03) at 18 months.[4] Furthermore, the use of SES for ISR
rather than IRT was associated with a significant reduction in the
procedure time (54 ± 20 min versus 88 ± 28 min p<0.001) with a
favourable reduction in the total radiation exposure to both patient and
operator.
Despite the non-randomised study design, Iofina et al.[1] offer
further credence for the use of SES for ISR. Certainly randomised studies
will be required to determine if drug-eluting stents are the best
contemporary treatment for ISR and this will be delineated by the
Sirolimus for In-stent ReStenosis (SISR) trial. In this ongoing trial,
preliminary analyses have demonstrated encouraging results for the use of
SES to treat native coronary ISR lesions with a target vessel failure
(TVF) rate at nine months of 12.4% in the SES group versus 21.6% in the
IRT group (p=0.023) and a target lesion revascularisation (TLR) rate of
8.5% in the SES group versus 19.2% in the IRT group (p=0.004).[5] Longer
term results are eagerly awaited.
References
1. Iofina E, Radke PW, Skurzewski P, Haager PK, Blindt R, Koch KC,
Hanrath P, vom Dahl J, Hoffmann R. Superiority of sirolimus eluting stent
compared with intracoronary beta radiation for treatment of in-stent
restenosis: a matched comparison. Heart. 2005;91:1584-9.
2. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary
gamma-radiation therapy to inhibit the recurrence of restenosis after
stenting. N Engl J Med. 2001; 344:250–256.
3. Neumann FJ, Desmet W, Grube E, et al. Effectiveness and safety of
sirolimus-eluting stents in the treatment of restenosis after coronary
stent placement. Circulation. 2005; 111:2107-11.
4. Barlis P, Horrigan MC, Chan RK, Ajani AE, Proimos G, Schumer W,
van Gaal WJ, Rowe M, Eccleston D, Yan BB, Mun Cheong Y, Oliver LE, Clark
DJ. What is the best contemporary treatment for in-stent restenosis?
Cardiovasc Revasc Med. 2005;6:179-81.
5. Holmes Jr DR. SISR. A prospective randomized comparison of the
sirolimus-eluting stent vs brachytherapy in patients with bare metal in-
stent restenosis. TCT 2005; October 16-21, 2005; Washington, DC
Old medical theories, like myths, never die. In every era, long after
the initial excitement evaporates, scientific theories that have not
gathered logical strength through increasing clinical associations are
recycled to address current perceptions. Such theories, like myths, offer
a vicarious resolution of the ignorances that lies between our
insecurities and our expectations.[1,2] Wilmshurst et al....
Old medical theories, like myths, never die. In every era, long after
the initial excitement evaporates, scientific theories that have not
gathered logical strength through increasing clinical associations are
recycled to address current perceptions. Such theories, like myths, offer
a vicarious resolution of the ignorances that lies between our
insecurities and our expectations.[1,2] Wilmshurst et al. recently suggest
once again that platelets may have a role in the pathogenesis of
migraine.[3] They base this impression on the seeming efficacy of the
combination of clopidogrel and aspirin in comparison to aspirin alone in
managing attacks of migraine with aura in patients who had undergone
closure of persistent foramen ovale or atrial septal defect; this salutary
effect of combined anti-platelet regimen is believed to work through an
effect on serotonin stores.
Migraine theory and therapy is a long chain of tenuously linked
assumptions coupled to serendipity of a high order.[4] Several lines of
evidence challenge the presumed pathogenetic link between platelets,
serotonin, and migraine as well as the conclusions of the authors: (i)
Platelet hyperaggregability has been noted in a range of other medical
conditions unrelated to migraine and is found with high levels of stress.
Stress affects the vast majority of the general population but migraine
afflicts only about one-fifth of humankind. (ii) Propranolol, the gold
standard migraine prophylactic agent, enhances platelet aggregability [5].
(iii) Contrary to the general impression, evidence for migraine
prophylactic value of aspirin is poor.[6] (iv) A negative correlation
exists between migraine and antibodies to phospholipids (the membrane-
binding moiety increasing platelet aggregability), suggesting a degree of
protection against development of migraine.[7] (v) Migraine headache has
been reported in patients with thrombocytopenia.[8] (vi) Although
platelet aggregation and adhesion are commonly increased in diabetes
mellitus, it is hypogylcaemia rather than hyperglycaemia that precipitates
migraine.[9] (viii) Menstrual migraine typically improves with pregnancy[10] but estrogens increase epinephrine induced platelet aggregation.[11]
(ix) Migraine-like headache is a sequela of cocaine use, [12,13]. but
cocaine inhibits platelet aggregation and dissociates preformed platelet
aggregates [14]. (x) Amitriptyline, a first-line migraine prophylactic
agent, unambiguously stimulates brain noradrenergic as well as
serotonergic function.[15] (xi) Development of carcinoid tumour remarkably
decreased migraine frequency and intensity leading to a complete remission
with postoperative recurrence.[16] (xii) Nicotine increases platelet
aggregation [17] but is considered relatively unlikely to lead to
migraine.[18] (xiii) Nitric oxide (and endothelium-derived relaxing
factor) putatively involved in vascular headaches associated with exercise
or infection inhibits platelet aggregation and adhesion.[8,19]
Proponents of the platelet theory of migraine postulate a parallel
between the platelet and the neuron by suggesting that platelet activation
mirrors trigeminovascular system inflammation. Believing that (peripheral)
platelet function tells us anything about brain neuronal function involves
complete suspension of scientific disbelief.[15] No systemic influence,
including platelet dysfunction, can rationalize the characteristic
lateralization (unilateral, bilateral or side-shift) of migraine
headache.[21] For internists, cardiologists, and neurologists (especially
researchers into primary headaches) familiar with the useful effect of
inhibition of platelet aggregation in cardiovascular and cerebrovascular
medicine, it is indeed difficult to concede that a similar benefit might
not be available to migraine patients. Nevertheless, if migraine has to
progress from a vaguely-understood syndrome to a properly defined disease,
theories that clutter our thinking need to be addressed squarely and
discarded. The platelet theory of migraine is one such concept that might
best be passed into history.
Wilmshurst et al.[3] have also reported increased frequency and
severity of migraine with aura attacks immediately following closure of
atrial shunts, a phenomenon that has important pathophysiological
implications. Yankowsky and Kuritzky have earlier reported on aggravation
of migraine with aura into a daily pattern with clocklike precision after
closure of an atrial septal defect (ASD).[21] Importantly, there is no
suggestion of a causal link between ASD and migraine but closure of ASD
appears to be associated with appearance or worsening of migraine with
aura.[3,21] In uncomplicated ASD, correction of the septal defect would
lead to decrease in the elevated right atrial pressure and plasma atrial
natriuretic peptide levels would decrease correspondingly.[22] ANP appears
to play a role as a counterregulatory hormone in many disorders
characterized by volume expansion, including hypertension; also,
orthostatic hypotension, a characteristic feature of migraine, is
associated with lower levels of ANP, and suggests that noradrenergic
hypofunction may be involved in the pathogenesis of migraine.[23,24] A
compensatory or adaptive function has been attributed to sympathetic
hypofunction associated adrenergic receptor hypersensitivity.[25] The fact
that migraine prophylactic agents such as beta-blockers or calcium
antagonists or clonidine invariably lower elevated blood pressures or tend
to maintain normotension – while only rarely causing symptomatic
hypotension – indicates that a low blood pressure is an adaptive feature
in migraine. Nausea and vomiting is another facet of a complex vasopressin
-mediated adaptive mechanism in migraine.[26,27]
Dramatic aggravation of migraine following atrial shunt closures indicates
substantial alteration of some physiological variable with prominent
circadian variation and a critical influence on the primary
pathophysiological process in migraine.[22] In ASD, the reduced filling
pressure of the left ventricle causes a smaller than normal stroke volume
and reduced cardiac output; consequently a relatively small aorta is
commonly seen. Following closure of large atrial shunts, immediate
improvement in left ventricular stroke volume and cardiac output occurs.
Precipitation of migraine following closure of atrial septal defect [3,21]
suggests that a higher stoke volume / cardiac output might worsen or
unmask a migrainous diathesis.[22,28]
The theoretical basis for a non-neuronal non-vascular origin of
migraine has been recently elucidated.[29] A selective involvement of the
ophthalmic division of the trigeminal nerve is likely in migraine and
other primary headaches; mechanical deformation of the corneo-scleral
envelope by ocular choroidal venous congestion and rise of intraocular
pressure (IOP) has been proposed to underlie both the scintillating
scotoma as well as the headache of migraine.[29,30] In contrast to the
brain, the eye is a low-volume but far more highly vascularized organ; the
eye is anatomically less capable of accommodating any sudden increase in
stroke volume. The cardiac output increasing effect of closure of larger
atrial shunts is somewhat comparable to the immediate peripheral arterial
perfusion enhancing effect of glyceryl trinitrate (GTN) manifest by
flushing of face and throbbing headache.[31] GTN is the best available
experimental human model for migraine; it generally causes migraine
headache a few hours after consumption,[32] at which time substantial
venous pooling likely develops at the ocular choroidal venous plexus in
migraine patients due to an intrinsic regional ocular sympathetic
hypofunction. Propranolol, atenolol, metoprolol, nadolol, clonidine,
flunarizine, and verapamil lower the IOP, further supporting the nexus
between migraine, autonomic dysfunction, and intraocular pressure.[29]
Immediate aggravation of migraine attacks after closure of atrial shunts
spontaneously regresses after a few months;[21] ocular tissue creep at the
level of the corneo-scleral envelope likely dissipates the headache-
provoking effect of increased cardiac output in patients with ASD.[29]
Like trait or basal autonomic function, endogenous pain control
mechanism, and corneo-scleral distensibility, increase in cardiac output
after atrial shunt closure is likely to be a highly variable,
idiosyncratic function; these important confounding features might well
explain the results of the studies of Wilmshurst et al.[3]
References
1. Gupta VK. Migrainous stroke: are antiphospholipid antibodies
pathogenetic, a biological epiphenomenon, or an incidental laboratory
aberration? Eur Neurol 1996;36:110-111.
2. Lévi-Strauss C. Then structural study of myth; in Lévi-Strauss C
(ed): Structural Anthropology. Harmondsworth, Peregrine, 1977, pp 206-231.
3. Wilmshurst PT, Nightingale S, Walsh KP, W L Morrison WL.
Clopidogrel reduces migraine with aura after transcatheter closure of
persistent foramen ovale and atrial septal defects. Heart 2005;91:1173-1175.
21. Yankovsky AE, Kuritzky A. Transformation into daily migraine with
aura following transcutaneous atrial septal defect closure. Headache
2003;43:496-498.
22. Gupta VK. Closure of atrial septal defect and migraine.
Headache;2004:44:291-292.
23. Gotoh F. Komatsumoto S, Araki N, Gomi S. Noradrenergic nervous
activity in migraine. Arch Neurol 1984;41:951-5.
24. Araki N. Autonomic nervous activity in migraine [abstract].
Rinsho Shinkeigaku 1995;35:1336-1338.
25. Boccuni M, Alessandri M, Fusco BM, Cangi F. The pressor
hyperresponsiveness to phenylephrine unmasks sympathetic hypofunction in
migraine. Cephalalgia 1989;9:239-245.
26. Gupta VK. Conceptual divide between adaptive and pathogenetic
phenomena in migraine: nausea and vomiting. Brain 2004;127:E18.
27. Gupta VK. A clinical review of the adaptive potential of
vasopressin in migraine. Cephalalgia 1997;17: 561-569.
28. Gupta VK. Percutaneous closure of patent foramen ovale reduces
the frequency of migraine attacks. Neurology 2004;63:1760-1761
29. Gupta VK. Migrainous scintillating scotoma and headache is ocular
in origin: a new hypothesis. Med Hypotheses 2005 (In press).
30. Gupta VK. Glyceryl trinitrate and migraine: nitric oxide donor
precipitating and aborting migrainous aura. J Neurol Neurosurg Psychiatry
(22 October 2005). Available
at: http://www.jnnp.com/cgi/eletters/76/8/1158#708.
31. Thomsen LL, Iversen HK, Brinck TA, Olesen J. Arterial supersensitivity
to nitric oxide (nitroglycerin) in migraine sufferers. Cephalalgia
1993;13:395-9.
Mulcahy's article is an interesting update on the subject of silent
myocardial ischemia.[1] He postulates that ambulatory ST segment
monitoring does not add significantly to the finding of exercise testing, because it would occur almost exclusively in patients with a positive result in the ischemia exercise test.
In a German multicentre study, we have analyzed both exercise test
and ambulat...
Mulcahy's article is an interesting update on the subject of silent
myocardial ischemia.[1] He postulates that ambulatory ST segment
monitoring does not add significantly to the finding of exercise testing, because it would occur almost exclusively in patients with a positive result in the ischemia exercise test.
In a German multicentre study, we have analyzed both exercise test
and ambulatory ST segment findings in 239 hypertensive patients. ST
segment depression was defined as 1 mm for limb or chest recordings V1 to
V6 without angina in an incremental cycle ergometry and 1 mm horizontal or
descending ST segment depression, 1 min duration, without angina pectoris,
in ambulatory ST detection. Eighteen patients had ST segment depression
only in the exercise test, 23 only in ambulatory ST detection and 28
patients had ST segment depression with both methods. The ambulatory ECG
was combined with a 24-h ambulatory blood pressure device with the
capability of additional blood pressure recording triggered by ST segment
analysis.
At the time of ST segment depression, all parameters except diastolic
blood pressure were significantly lower in the ambulatory ST detection
compared to the corresponding parameters at the time of ST segment
depression in the exercise test in the group with ST-segment depression
with both methods (systolic blood pressure: 148 + 19 vs. 188 +/- 35 mmHg;
heart rate: 93 +/- 12 vs. 120 +/- 21 beat/min.; double product: 13,714 +/-
2315 vs. 22,992 +/- 3985 mmHg/min).[2] Other groups have also reported a
substantially lower ischemic threshold in the ambulatory ST segment
detection than that measured during the exercise test.[3,4]
Furthermore, it has previously been reported that patients with
negative exercise test may have silent myocardial ischemia in the
ambulatory ST segment monitoring, a finding which was associated with
increased cardiovascular morbidity.[5,6] We therefore agree with these
groups that the two methods of detecting ischemia do not replace but
complement each other.
References
1. Mulcahy DA. The return of silent myocardial ischemia? Not really.
Heart 2005;91:1249-1250.
2. Uen S, Weisser B, Un I, Baulmann J, Vetter H, Mengden T. A
comparison of ischemic threshold as determined by exercise test and
Cardiotens monitoring in hypertensive patients. J Hypertens 2005 June,
volume 23, supplement 2, S166.
3. Benhorin J, Banai S, Moriel M, Gavish A, Keren A, Stern S, Tzivoni
D. Circadian variation in ischemic threshold and their relation to the
occurrence of ischemic episodes. Circulation 1993 Mar; 87(3):808-14.
4. Quyyumi AA, Panza JA, Diodati JG, Lakatos E, Epstein SE. Circadian
variation in ischemic threshold: a mechanism underlying the circadian
variation in ischemic events. Circulation 86 (1992) 22-24.
5. Gaetano AL, Alessandro M, Vincenzo P, Guiseppe C, Domenico C,
Filippo C, Attilio M: Ischemic-like ST-segment changes during Holter
monitoring in patients with angina pectoris and normal coronary arteries
but negative exercise testing. Am J Cardiol 79 (1997) 1-6.
6. Raby KE, Barry J, Treasure CB, Hirsowitz G, Fantasia G, Selwyn AP.
Usefulness of Holter monitoring for detecting myocardial ischemia in
patients with nondiagnostic exercise treadmill test. Am J Cardiol 72(12)
(1993) 889-893.
We have read the article[1] with great interest. Selection of the 23
patients is not clearly mentioned here. There is a lack of some other
information too. Once the chest pain started, after what time those
patients were selected for angioplasty? What was the percentage of lumen
narrowing or stenosis? Was the stenosis complicated or not? What was the
material used for primary angioplasty?
We have read the article[1] with great interest. Selection of the 23
patients is not clearly mentioned here. There is a lack of some other
information too. Once the chest pain started, after what time those
patients were selected for angioplasty? What was the percentage of lumen
narrowing or stenosis? Was the stenosis complicated or not? What was the
material used for primary angioplasty?
Rapid time to treatment with thrombolytic therapy is associated with
lower mortality in patients with acute myocardial infarction (MI). Study[2] suggests that physicians and health care systems should work to
minimize door-to-balloon times and that door-to-balloon time should be
considered when choosing a reperfusion strategy. Time from acute MI
symptom onset to first balloon inflation and by time from hospital arrival
to first balloon inflation (door-to-balloon time) plays an important role
in management of MI.
In a study[3] showed that, patients with AMI treated at hospitals
with high or intermediate volumes of primary angioplasty had lower
mortality with primary angioplasty than with thrombolysis, whereas
patients with AMI treated at hospitals with low angioplasty volumes had
similar mortality outcomes with primary angioplasty or thrombolysis. To
prevent restenosis or reinfarction in previously stenosed coronary vessels
drug eluting stent (paclitaxel-eluting stent) proves superior to bare
metal stent.[4] In patients with in-stent restenosis, sirolimus- or
paclitaxel-eluting stents is superior to conventional balloon angioplasty
for the prevention of recurrent restenosis. Sirolimus-eluting stents may
be superior to paclitaxel-eluting stents for treatment of this disorder.[5]
Reference:
1. Should primary angioplasty be available for all patients with an ST
elevation myocardial infarction? A de Belder. Heart 2005;91:1509-1511;
doi:10.1136/hrt.2004.059485.
2. Christopher P. Cannon; C. Michael Gibson; Costas T. Lambrew; David A.
Shoultz; Drew Levy; William J. French; Joel M. Gore; W. Douglas Weaver;
William J. Rogers; Alan J. Tiefenbrunn
Relationship of Symptom-Onset-to-Balloon Time and Door-to-Balloon Time
With Mortality in Patients Undergoing Angioplasty for Acute Myocardial
Infarction
JAMA, Jun 2000; 283: 2941 - 2947.
3. David J. Magid; B. Ned Calonge; John S. Rumsfeld; John G. Canto; Paul
D. Frederick; Nathan R. Every; Hal V. Barron; for the National Registry of
Myocardial Infarction 2 and 3 Investigators
Relation Between Hospital Primary Angioplasty Volume and Mortality for
Patients With Acute MI Treated With Primary Angioplasty vs Thrombolytic
Therapy
JAMA, Dec 2000; 284: 3131 - 3138.
4. Gregg W. Stone; Stephen G. Ellis; Louis Cannon; J. Tift Mann; Joel D.
Greenberg; Douglas Spriggs; Charles D. O'Shaughnessy; Samuel DeMaio;
Patrick Hall; Jeffrey J. Popma; Joerg Koglin; Mary E. Russell; for the
TAXUS V Investigators
Comparison of a Polymer-Based Paclitaxel-Eluting Stent With a Bare Metal
Stent in Patients With Complex Coronary Artery Disease: A Randomized
Controlled Trial
JAMA, September 14, 2005; 294: 1215 - 1223.
5. Adnan Kastrati; Julinda Mehilli; Nicolas von Beckerath; Alban Dibra;
Jörg Hausleiter; Jürgen Pache; Helmut Schühlen; Claus Schmitt; Josef
Dirschinger; Albert Schömig; for the ISAR-DESIRE Study Investigators
Sirolimus-Eluting Stent or Paclitaxel-Eluting Stent vs Balloon Angioplasty
for Prevention of Recurrences in Patients With Coronary In-Stent
Restenosis: A Randomized Controlled Trial. JAMA, January 12, 2005; 293:
165 - 171.
Intra-country variation versus inter-country variation in pre-hospital care management of acute MI with ST elevation is worrisome
matter. Thanks to R C Welsh et al. for wring the article. ST elevation
acute MI needs early treatment with fibrinolysis therapy as early
possible.
Study[1] shows that time management is the key of ST elevation MI.
Rapid time to treatment with thrombolytic therapy...
Intra-country variation versus inter-country variation in pre-hospital care management of acute MI with ST elevation is worrisome
matter. Thanks to R C Welsh et al. for wring the article. ST elevation
acute MI needs early treatment with fibrinolysis therapy as early
possible.
Study[1] shows that time management is the key of ST elevation MI.
Rapid time to treatment with thrombolytic therapy is associated with lower
mortality in patients with acute myocardial infarction (MI). More rapid
time to reperfusion results in lower mortality in the strategy of primary
angioplasty.
Increased mortality and delay in door-to-balloon time longer than two hours (present in nearly 50% of this cohort) suggests that physicians and
health care systems should work to minimize door-to-balloon times and that
door-to-balloon time should be considered when choosing a reperfusion
strategy. Door-to-balloon time also appears to be a valid quality-of-care
indicator.
References:
1. Christopher P. Cannon; C. Michael Gibson; Costas T. Lambrew; David A.
Shoultz; Drew Levy; William J. French; Joel M. Gore; W. Douglas Weaver;
William J. Rogers; Alan J. Tiefenbrunn
Relationship of Symptom-Onset-to-Balloon Time and Door-to-Balloon Time
With Mortality in Patients Undergoing Angioplasty for Acute Myocardial
Infarction
JAMA, Jun 2000; 283: 2941 - 2947.
The data presented in Welsh et al.'s paper assessing variations in
practice across the 12 countries in the ASSENT 3 PLUS trial may not be
representative of UK practice since each of the four constituent countries
of the UK have distinct health systems.
In England and Wales, both of which have national standards for the
care of STEMI patients -National Service Frameworks- and in which all 130...
The data presented in Welsh et al.'s paper assessing variations in
practice across the 12 countries in the ASSENT 3 PLUS trial may not be
representative of UK practice since each of the four constituent countries
of the UK have distinct health systems.
In England and Wales, both of which have national standards for the
care of STEMI patients -National Service Frameworks- and in which all 130
hospitals caring for heart attack patients participate in the national
audit of myocardial infarction, use of emergency ambulance services as
opposed to the requirement to contact a primary care physician first,
suggested by Welsh et al. as a reason for UK delay, was as reported by
Birkead et al. in 2002-03 67% of patients with a final diagnosis of an
acute coronary syndrome called for an emergency ambulance and 16.2%
contacted the primary care practitioner.
Norris[1] reports that most out of hospital cardiac arrest occurs in
the home, but that as patients usually have premonitory symptoms, there is
an opening for education about these symptoms and how to act to avoid
delay and subsequent mortality. Although there is clearly a need to
educate the public at large to call an ambulance if they witness what
could be a heart attack or cardiac arrest, less is k...
Norris[1] reports that most out of hospital cardiac arrest occurs in
the home, but that as patients usually have premonitory symptoms, there is
an opening for education about these symptoms and how to act to avoid
delay and subsequent mortality. Although there is clearly a need to
educate the public at large to call an ambulance if they witness what
could be a heart attack or cardiac arrest, less is known about what is
effective in reducing individual delay time.
Our systematic review of interventions to reduce delay in patients
with suspected heart attack[2] concluded that there was little evidence
that community-wide media campaigns or one to one educational
interventions reduced delay time.
Supporting evidence came mainly from before and after studies; no RCT
provided positive results, suggesting a need for caution in attributing
any reported effects to the actual intervention. The methodological
quality of studies was generally poor and few studies reported mortality
data. While most studies reported pre-intervention baselines, few had a
reasonable post intervention follow-up-period (which should be measured in
years not months). The best RCT[3] with a large sample in an 18 month
intervention which included both a media campaign and a one-to-one
intervention with people at higher risk was negative. Few studies reported
the intervention in sufficient detail to draw any conclusions about which
elements were effective.
We now know about many potential psycho-social, clinical and
environmental factors that are associated with extended delay.[4] Most of
the interventions that have been tested are educational and education
alone has repeatedly been shown not to be an effective method for changing
behaviour. It is seems likely that we need to spend more time designing
cognitive-behavioural supportive interventions for patients, and
importantly their family or carers, then assessing these in a well
controlled RCT and using qualitative techniques to elicit which part, if
any, of the intervention led to appropriate actions. Once validated an
intervention might best be delivered through rehabilitation programmes,
NSF clinics and discharge planning. As Norris et al have shown there is
huge potential for saving lives.
Jill F Pattenden Robert J Lewin BHF Care and Education Research Group, Dept of Health Sciences,
University of York
References
1. RM Norris on behalf of the UK Heart Attack Study (UKHAS)
Collaborative Group. Heart 2005; 91 1537-1540.
2. Kainth A, Hewitt A, Pattenden J, Sowden A, Duffy S, Watt I, Thompson D,
Lewin R. A systematic review of interventions to reduce delay in patients
with suspected heart attack. Emergency Medicine Journal. 2004;21:506-508.
3. Luepker RV, Raczynski JM, Osganian s et al. Effect of a community
intervention on patient delay and emergency medical service use in acute
coronary heart disease: the rapid early action for coronary treatment
(REACT) trial. JAMA 2000; 284:60-67.
4. Pattenden J, Watt I, Lewin RJ et al. Decision making processes in people
with symptoms of acute myocardial infarction:qualitative study. BMJ
2002;324:1006-9.
We thank Dr Tom Quinn for his interest in this manuscript. His letter
addresses the realities of intra-country variation versus inter-country
variation in pre-hospital care. Dr Quinn appropriately points out in his
letter to the editor that the United Kingdom is made up of distinct
nations with distinct health systems. We have recognized this issue in the
manuscripts limitations section, “Because our stu...
We thank Dr Tom Quinn for his interest in this manuscript. His letter
addresses the realities of intra-country variation versus inter-country
variation in pre-hospital care. Dr Quinn appropriately points out in his
letter to the editor that the United Kingdom is made up of distinct
nations with distinct health systems. We have recognized this issue in the
manuscripts limitations section, “Because our study is based on a non-
randomized assessment of variation in process of care across international
boundaries in selected centres participating in ASSENT 3 PLUS, it may not
be generally representative of the standard of pre-hospital care in the
respective country and therefore has inherent limitations”. It is
encouraging that the past practice of contacting a primary care physician
prior to activate the emergency medical services is being modified,
specifically in England and Wales, with direct activation of the emergency
medical system and more expedited care.
Since myocardial infarction (MI) was redefined five years ago(1),
focus has been on troponins. However, with the consensus document the
presence of an abnormal Q wave has also been redefined, but this change
appears to have created only little controversy. Abnormal Q waves are
still considered a definite objective sign of an established MI, and in
this connection, the history of the patient is often in...
Since myocardial infarction (MI) was redefined five years ago(1),
focus has been on troponins. However, with the consensus document the
presence of an abnormal Q wave has also been redefined, but this change
appears to have created only little controversy. Abnormal Q waves are
still considered a definite objective sign of an established MI, and in
this connection, the history of the patient is often insufficient(2). For
decades the Minnesota criteria in different editions have been used
worldwide, but a set of generally accepted international
electrocardiographic criteria for an established MI have so far not been
available. Therefore, we welcome the joint European-American
initiative(1).
However, using the new definition of an abnormal Q wave we recently
demonstrated an increase in the proportion of patients categorized as
having an established MI(3). This observation may result in additional
patient examinations and a change in outcome measures of clinical and
epidemiological trials. Finally, the redefinition may have consequences of
psycho-social importance to the individual patient. Of interest, the new
definition of an abnormal Q wave has been interpreted differently in
recent Danish guidelines and in the series "Education in Heart"(4, 5).
This, of course, is not appropriate and may cause confusion. A definition
should be unambiguous.
There exist no generally accepted set of rules defining how small the
rate of false positive and false negative diagnoses should be in order to
be "acceptable". This decision should preferably be based on a careful
clinical judgement. In the present case, we propose that the false
positive rate should be equal to the false negative rate and be <10-
15%.
Finally, cardiologists and other physicians treating patients with
ischemic heart disease should be familiar with the new Q wave definition
(Table 1)1 in order to cope with the clinical dilemmas it may give rise
to.
Table 1 Electrocardiographic changes in established MI
1. Any QR wave in leads V1 through V3 ≥ 30 ms (0.03 s);
abnormal Q wave in lead I, II, aVL, aVF or V4 through
V6 in any two contiguous leads and at least 1 mm in depth.
References
1. Myocardial infarction redefined--a consensus document of the joint
european society of cardiology/american college of cardiology committee
for the redefinition of myocardial infarction. Eur Heart J. 2000;21:1502-
1513
2. Ammar KA, Kors JA, Yawn BP, Rodeheffer RJ. Defining unrecognized
myocardial infarction: A call for standardized electrocardiographic
diagnostic criteria. Am Heart J. 2004;148:277-284
3. Jensen JK, Ovrehus K, Moldrup M, Mickley H, Hoilund-Carlsen PF.
Redefinition of the Q wave - is there a clinical problem? Am J Cardiol.
2005:Accepted
4. Grande P, Holmvang L. Akut koronart syndrom. Dansk Cardiologisk
Selskab. 2004
5. French JK, White HD. Clinical implications of the new definition of
myocardial infarction. Heart. 2004;90:99-106
Hsi et al. propose absence or presence of gyceryl trinitrate (GTN)-
induced headache as a possibly useful clinical tool to assist in the
initial risk stratification of patients with chest pain [1]. Several
issues merit attention:
1. The mechanism of action of GTN in precipitation of headache in
patients – regardless of status of the coronary circulation – is unknown.
Hsi et al. propose absence or presence of gyceryl trinitrate (GTN)-
induced headache as a possibly useful clinical tool to assist in the
initial risk stratification of patients with chest pain [1]. Several
issues merit attention:
1. The mechanism of action of GTN in precipitation of headache in
patients – regardless of status of the coronary circulation – is unknown.
2. Excluding patients with a known history of chronic headache adds
little in terms of mechanistic clarity about headache-provocation by GTN.
3. It is difficult to understand why -- as suggested by Hsi et al. --
nitrates should selectively dilate coronary arteries more than cerebral
arteries in patients with obstructive coronary artery disease (CAD). With
established obstructive CAD, the only component that is significantly
reversible is spasm. Second, regional distribution of GTN does not depend
on distribution of atherosclerotic lesions. It is understandable that
within one anatomical region, critically obstructive atherosclerotic
lesions might overperfuse (luxury overperfusion or steal syndrome) lesion-
free arteries but to apply the same principle across different regions is
speculative.
4. To reciprocally link CAD with cerebral circulation is a unique [1]
albeit logically challenging research premise. It is a rare case in which
a patient with atypical anginal pain might manifest a typical reassuring
response to GTN; in any case since the response is but subjective, it is
hardly advisable to lower the index of suspicion. To modify the index of
suspicion on the basis of occurrence of headache following GTN
administration does not appear to be a scientifically sound approach.
5. It is currently not known why GTN might precipitate primary
headaches such as migraine or cluster headache or non-primary headaches
one hour after administration. A peculiar as yet undefined neuroantomic
susceptibility seems to underlie provocation of headache following GTN
administration; the headache response is neither uniform nor predictable
indicating the importance of idiosyncratic features. To understand the
biological basis of GTN-headache headache we have to reflect on the time
elapsed between its sublingual administration and onset of headache. In my
experience, some patients given GTN for suspected CAD (angina or
infarction) develop a headache variant (not migrainous or cluster
headache) within 10-15 minutes or earlier. It is a common practice to
accept occurrence of headache as indicative of sufficient generalized and
coronary vasodilatation and to ask the patient to expel the remaining part
of the tablet.
6. Onset of migraine after GTN manifests a significantly longer
prodrome [2]. The physiological system(s) primarily affected in migraine
must necessarily be afforded a considerable (but limited and exhaustible)
degree of protection by homeostatic defense mechanisms, thereby allowing
the subject to continue to function despite the stressful stimulus or
situation; this protection is obviously unlimited or inexhaustible in the
majority of the general population who are not susceptible to migraine [3]
or GTN-induced non-migrainous headache. Opposing the headache-provoking
effects of GTN is the parallel activation of a composite adaptive system
comprised of vasopressin release coupled to hyperfunction of the
sympathetic (noradrenergic) and serotonergic systems [4]. Pain of angina
pectoris or acute myocardial infarction is commonly associated with a
pronounced hyperactivation of the sympathetic nervous system that might
underlie the fact that not all patients given GTN develop headache.
7. The assumption that a diffuse cerebral vasodilatation underlies
GTN-induced headache is open to debate. Propranolol and verapamil have
opposite actions on intracranial circulation, decreasing and increasing
it, respectively; yet both agents are used commonly for prevention of
migraine [5], the prototypic primary vascular headache. Atenolol, nadolol,
or verapamil do not cross the blood-brain-barrier and do not influence any
neuronal function, whether central (brain, peripheral neural or central-
peripheral neuronal connections). Migraine prevention does not involve
critical alteration of either any known brain neuronal function or of
cerebrovascular circulation [5, 6]. Finally, the vasodilator sildenafil
can induce migraine without initial dilatation of the middle cerebral
artery [7].
8. GTN-induced ocular choroidal venous congestion may underlie the
headache of migraine [8]; GTN associated rapid ophthalmic arterial
vasodilatation may underlie cluster headache [9]. Headaches that do not
fit into strictly defined definitive primary categories [10] may reflect
attenuated or incomplete forms of such headaches.
As the letter of Professor Cheng testifies, the index idea seems
attractive and even persuasive. Nevertheless, where one starts often
affects where one ends. Belief in any hypothesis is a powerful philosophic
commitment, one that can lead forward as well as to nowhere. Worse, the
need to believe can impede scientific progress by coming up with data that
challenge and defy logic and cannot be integrated into an intelligible
synthesis. That GTN might cause headache more frequently in patients with
normal coronary arteries [1] is a hypothesis that challenges rational
thinking. The best biological explanation for the statistically valid
results of this study may lie in the differences between the test and
control cohorts. CAD positive patients were over a decade older than CAD
negative patients; also, the sex ratio was markedly skewed between the two
cohorts, with the percentage of male patients being far higher in the CAD
positive group (Table 1). While CAD progresses with age particularly in
males, the migrainous tendency in adulthood primary affects females
(F:M=5:1).
References
1. Hsi DH, Roshandel A, Singh N, Szombathy T, Meszaros. Headache
response to gylceryl trinitrate in patients with and without obstructive
coronary artery disease. Heart 2005;91:1164-1166.
4. Gupta VK. A clinical review of the adaptive potential of
vasopressin in migraine.
Cephalalgia 1997;17:561-569.
5. Gupta V. Silent or non-clinical infarct-like lesions in the
posterior circulation territory in migraine: brain hypoperfusion or
hyperperfusion? Brain 2005 (In press).
6. Gupta VK. Migraine, cortical excitability and evoked potentials: a
clinico-pharmacological perspective. Brain 2005;128:E36.
7. Kruuse C, Thomsen LL, Birk S; Olesen J. Migraine can be induced by
sildenafil without changes in middle cerebral artery diameter. Brain 2003
;126:241-7.
8. Gupta VK. Glyceryl trinitrate and migraine: nitric oxide donor
precipitating and aborting migrainous aura. J Neurol Neurosurg Psychiatry
Published online (24 October 2005). Available at :
http://jnnp.bmjjournals.com/cgi/eletters/76/8/1158
10. Headache Classification Subcommittee of the International
Headache Society. The Interrnational Classification of Headache Disorders.
2nd edition. Cephalalgia;2004;24 (Suppl 1):9--160.
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Dear Ediutor
Hsi et al. propose absence or presence of gyceryl trinitrate (GTN)- induced headache as a possibly useful clinical tool to assist in the initial risk stratification of patients with chest pain [1]. Several issues merit attention:
1. The mechanism of action of GTN in precipitation of headache in patients – regardless of status of the coronary circulation – is unknown.
2. Exc...
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