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Den gode artikel
Christian Torp-Pedersen
Først ansøgning om penge: NIH
• Regn med at 2 bedømmere har læst
ansøgningen
• Regn med at resten af udvalget læser
på dit ”1 page summary” samtidigt med
at de hører en mundtlig gennemgang af
en bedømmer
Et godt abstract
• En, højst to sætninger som forklarer
hvorfor dette er ekstremt vigtigt
• Et kort metodeafsnit, det bliver næppe
læst
• Et svulstigt resultatafsnit – et abstract
skal bestå af MANGE resultater
• En direkte konklusion på baggrund af
de resultater som er nævnt i abstract
uden for meget implikation
Abstract a.m. John Camm
•
•
•
•
A title with at least one ’buzz word’
A strong first sentence
A strong conclusion
All that rest in the middle just becomes
a blurr
Danish Investigations of Arrhythmia and
Mortality ON Dofetilide
DIAMOND
Overall Survival - Intention to Treat
1.0
Dofetilide - 311 deaths
0.8
Dofetilide (n=762)
Survival
Placebo (n=756)
0.6
Placebo - 317 deaths
0.4
0.2
0.0
Overall RR 0.95,
95% CI 0.81–1.11
0
P=0.56
12
24
Months
36
Secondary Endpoints
Arrhythmia requiring
treatment & withdrawal
Cardiac deaths + resus. C.A.
Recurrent MI
1.0
Event Free Probability
0.8
0.6
0.4
0.2
P=0.79
P=0.78
P=0.90
0.0
0
1
Years
2
3
0
1
Cardiac death
1.0
Years
2
3
0
1
2
3
Events in patients with AF
0.8
Dofetilide (n=762)
Placebo (n=756)
0.6
0.4
0.2
0.0
Years
P=0.89
0
1
Years
2
P=0.71
3
0
1
Years
2
3
Ventricular Arrhythmia (Total)
Dofetilide
n=762
Placebo
n=756
TdP*
25 (11–2)
0 (0–0)
VT*
14 (6–2)
17 (3–5)
VF*
14 (3–11)
12 (5–7)
RCA: 4 days
>4 days
TOTAL
19
19
38
4
12
16
Death: 4 days
>4 days
TOTAL
4
307
311
*Number with resuscitated cardiac arrest-death in parenthesis
0
317
317
Effect of Dofetilide on Atrial Fibrillation
No of patients enrolled in NSR
who developed AF
50
40
No of patients enrolled in AF
who converted to NSR
100
35
30
n=1125
P<0.001
84
75
n=393
P<0.001
50
20
11
28
10
25
0
0
Placebo
Dofetilide
Placebo
Dofetilide
God dansk indledningt
Cardiac arrhythmias are common in patients with congestive heart failure (CHF),
contributing to both mortality and morbidity. The possibility of reducing morbidity has so
far been overshadowed by severe safety concerns with antiarrhythmic drugs. Some class
I drugs1 and the class III drug d-sotalol2 increase mortality in patients with myocardial
infarction. Amiodarone appeared to prolong life in one CHF study,3 but this finding was
not confirmed in Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure
study,4 which showed no effect on mortality. A neutral outcome was also found in two
other studies including some CHF patients.5,6 Amiodarone is frequently used to treat
arrhythmias in patients with CHF, but the considerable long term side effects limit its use.
Digoxin has demonstrated safety in CHF in the Digitalis Investigation Group trial7 and is
commonly used for rate control in atrial fibrillation associated with CHF.
Dofetilide is a selective inhibitor of the rapid component of the delayed rectifier, outward
potassium current (IKr), which prolongs the action potential duration and the effective
refractory period in a concentration dependent manner. Clinical studies have
demonstrated that the drug is effective in treating atrial fibrillation and flutter.8,9 As with
other class III anti-arrhythmic drugs, dofetilide can cause proarrhythmia but the
incidence is yet to be defined.
The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies
are two distinct studies investigating whether a reduction in mortality and morbidity can
be achieved by long term dofetilide treatment in patients with left ventricular systolic
dysfunction and either CHF or a recent myocardial infarction. This publication describes
the results of the congestive heart failure study (DIAMOND-CHF)
Prøver igen
Prevention of ventricular and supraventricular arrhythmias in patients with
congestive heart failure is an important goal with the object of reducing mortality
and morbidity. A series of antiarrhythmic drugs have been tested in clinical trials
without success. Thus, several class 1 drugs and the class III drug d-sotalol have
been demonstrated to be associated with increased mortality compared to
placebo. Amiodarone has in a single survival study been demonstrated to reduce
mortality, but this observation has not been confirmed in a series of other
studies. Amiodarone is associated with frequent side effects that may be serious,
and which has prevented the possibility of using this drug on a wide scale for
non- lifethreatening conditions. The Danish studies of arrhythmia and mortality
on dofetilide were designed to study the possibility of reducing mortality and
morbidity in patients with congestive heart failure using the novel class III
antiarrhythmic drug dofetilide. This is a selective inhibitor of the rapid component
of the delayed rectifier, outward potassium current (IKr), which prolongs the
effective refractory period. There is no effect on ATP dependent potassium
channels. Clinical studies have demonstrated that the drug is particularly
effective in treating patients with atrial arrhythmias. The target population in the
Diamond CHF study was high risk patients with congestive heart failure. To
ensure that the population would be as representative as possible of these
patients as seen in clinical practice screening of consecutive patients admitted to
hospital was specifically required. The primary endpoint was all cause mortality
and the possibility of reducing morbidity was studied by having hospitalisation for
worsening of heart failure as one secondary endpoint.
Final
Congestive heart failure is a serious disease that may be exacerbated by many factors unrelated to
ventricular dysfunction. One factor that is important in determining the symptoms and clinical course
of patients with severe congestive heart failure is the maintenance of normal sinus rhythm.
Unfortunately, atrial fibrillation (AF) is common in patients with heart failure and can impair exercise
tolerance and exacerbate symptoms by causing loss of atrial contraction, leading to hemodynamic and
thromboembolic consequences, or by increasing the rapidity of the ventricular response leading to
tachycardia and a shortened diastolic filling period.1–4 Although digitalis can attenuate the
ventricular response at rest, it fails to do so during exercise and thus does not eliminate the effect of
AF on exercise tolerance.5 In addition, previous studies have shown that AF increases the risk of
cardiovascular morbidity in patients with heart failure.6 Hence, prevention of AF or conversion of AF
are worthwhile goals in patients with congestive heart failure.
Currently available drug therapy to prevent or convert AF can have adverse effects that are possibly
detrimental in patients with heart failure, including an increase in mortality.7 Heart failure patients
receiving class I drugs for AF in the SPAF trial had a 3-fold increase in mortality and arrhythmic
deaths.7 Quinidine therapy has also been associated with a 3-fold increase in mortality.8 The only
exception has been the class III drug, amiodarone, which has been associated with favorable effects
in heart failure.9,10 However, this drug is frequently associated with serious cardiac and noncardiac
side effects.11
Dofetilide is a novel class III antiarrhythmic drug that selectively inhibits the rapid component of the
delayed rectifier potassium current (IKr) and prolongs the effective refractory period.12–14 As a pure
class III agent, it has no negative inotropic effects, even in patients with a markedly reduced left
ventricular ejection fraction.15 In addition, dofetilide has no effect on cardiac conduction or sinus
node function in patients with pre-existing cardiac disease.15,16 Dofetilide has been shown to convert
AF to sinus rhythm and is effective for maintaining sinus rhythm in 70% of patients for at least six
months.17,18
The DIAMOND-CHF (Danish Investigations of Arrhythmia and Mortality on Dofetilide) study was
designed to evaluate whether dofetilide affects survival or morbidity in patients with reduced left
ventricular (LV) function and congestive heart failure.
Hvem er publikum?
Hvem er publikum?
• En editor
• To referees
Hvem er publikum?
• En editor
• To referees
• Editor ved intet
• Referees ved meget lidt
Introduktion
• Et formål: At forklare hvorfor en travl
editor skal læse videre
• Fortæl hvorfor dit arbejde er nødvendigt
Praktisk introduktion
• En indledning som forklarer at dette er
EKSTEMT vigtigt
• Der er en afgrundsdyb mangel på vigtig
viden om dette emne!
• Derfor gjorde jeg/vi …..
Methods
•
•
•
•
Kan som ofte hackes fra andre artikler
Husk at skrive ALLE sætninger om
Et kedeligt afsnit som altid kan forkortes
Statistik – skriv HVILKE metoder der
anvendes, og ikke om HVORDAN de
anvendes
Results
• Præsentere populationen
• Undgå at gentage oplysninger
• Logisk opdeling – helst med små
overskrifter
• Kom kritik i forkøbet med
”Analyses of sensitivity”
”Other analyses”
• Det centrale budskab skal være grafisk
– hvis det overhovedet kan lade sig
Resultater
• Billeder er bedre end ord
Pfeffer 1992 - SAVE
Variables
Homozygocity
Other combinations of
Homozygocity
for both
sequence
for both
G:G and C:C
variants
A:A and T:T variants
variants
(n=1249)
(n=88)
128.7
129.3
132.5
(124.9-132.4)
(128.3-130.2)
(129.1-135.9)
81.2
81.5
84.1
(78.9-83.5)
(80.9-82.0)
(82.0-86.2)*
66.1
65.1
67.4
(63.9-68.4)
(64.5-65.7)
(65.4-69.5)*
123.1
125.4
129.1
(120.2-125.9)
(124.7-126.1)
(126.5-131.6)†‡
72.2
73.3
76.0
(70.3-74.1)
(72.8-73.8)
(74.3-77.7)†‡
69.1
70.6
72.3
(67.1-71.1)
(70.1-71.1)
(70.5-74.2)§
(n=73)
Office systolic BP, mm Hg
Office diastolic BP, mm Hg
Office heart rate,
beats/min
Mean 24-hr systolic BP, mm Hg
Mean 24-hr diastolic BP, mm Hg
Mean 24-hr heart rate,
beats/min
Double homozygocity for
BP-raising variants
0.02
0.01
Others
0
Density
0.03
0.04
Double homozygocity for
BP-lowering variants
75
100
125
150
Mean 24-hour ambulatory systolic blood pressure
175
R
Sigmaplot
Anderson, C - upubliceret
Vær loyal overfor protokollen
Men ikke med teksten
Packer - 1996
Discussion
• Statement of principal findings
• Relation til andre studier – Husk ikke blot
at skrive at andre fundet hist og pist, men
fremhæv svaghederne og dermed
indirekte egen styrke
• Metodeforhold
• Styrker og Svagheder
• Implikation
• Konklusion
Statement of principal findings
• This is the first study to demonstrate….
Ikke alle tidsskrifter ønsker ”priority
claims”
• The principal finding of this study
Relation til andre studier
• Undgå generelle sætninger:
Similar findings have also been found
by ……
• Skriv hellere: A small study by ….
Using a different technique ….
An older study ….
Metodeforhold
• Beskrive at ens metoder er optimale
• Undgå at skuffe læseren – skriv
eventuelle svagheder først:
While the epidemiological approach has
limitations, this study …….
Implication
• Ekstremt vigtigt – et studie SKAL have
konsekvenser.
• Konsekvensen kan være klinisk,
metodemæssigt, fremtidig forskning…..
Man arbejder med hver sætning!
• These results demonstrate that the risk
of cancer for all insulins was neutral
after 1 year, but the confidence
intervals remains high for humans
insulins because of power.
• The power to examine human insulins
was low, but for all other insulins the
risk of cancer was neutral after 1 year.
Konklusion
• Principal finding i ny indpakning
Svarbreve til tidsskrifter
• Editor er doven
• Risikoen for at det går tilbage til
reviewer er stor
• Reviewere har stadigt travlt
Sørg for at de kun skal læse ET
dokument EN gang
• Start med et svulstigt takkebrev
• Første kommentar af første reviewer
• Egne kommentarer til dette
• Manuskript tidligere version
• Manuskript nuværende version
Afsnit skal være så tydelig markeret at
det er helt intuitivt hvad der er reviewer
kommentarer, hvad der er svar o.s.v.
Svar!!
• Henvis gerne tilbage – aldrig frem
• Lav aldrig gentagelser
• Lav gerne ligegyldige rettelser:
”Nevertheless, in order to clarify this
further ......”
• Vær trods alt dette HELT klar i mælet
når en kommentar tilbagevises – dette
skal kun være i yderste nød!
The editor:
We wish to thank HEART for giving us a comprehensive review and for
giving us the opportunity to have a revised manuscript evaluated.
Below we have replied to each of the comments given by the referees.
A principal issue is whether a “clinical diagnosis” of diabetes can be
accepted. Ideally diabetes should be defined by international criteria,
but this is rarely available in studies of clinical epidemiology. The
majority of the literature on clinical epidemiology of diabetes in patients
with heart failure and patients with ischemic heart disease relies on
similar definitions as those we have used.
We hope you will consider the revised manuscript suitable for publication
in HEART.
In the following reviewer comments are indicated in italic and our reply in
bold text. Changes to the manuscript are shown in normal text.
Sød mand!
-- The definition of new onset diabetes is also confusing. The
authors should
try to indicate how many patients fulfilled the standard
definition of diabetes
through the study. The results refer to 2 different types of
new onset diabetes.
This is also confusing
Our reply: We acknowledge that our definition of new
onset diabetes may be difficult to read and we
have prepared a new section. There are NOT 2
types of new onset diabetes in this manuscript –
but the predefined endpoint of “diabetes related
adverse event” and “new onset diabetes”.
Previous:
Because the diabetes-related adverse events also
included events (hyperglycemia, decreased glucose
tolerance) that were not necessarily diabetes, we
subsequently defined a new endpoint retrospectively,
new onset diabetes. This endpoint included all patients
who either had either an adverse event coded as
diabetes mellitus or diabetic coma, or who had started
chronic medical therapy with insulin or oral antidiabetic
medication or who had at least 2 random blood glucose
readings above 11.2 mmol/L (random glucose was
measured 4 times during the first year and thereafter
once a year). In patients in whom only a single high
random glucose measurement was reported, we
queried the investigator whether the patient had
diabetes. If confirmed, the presence of an endpoint was
noted.
Revised
•
Because the diabetes-related adverse events also included events (hyperglycemia,
decreased glucose tolerance) that were not necessarily diabetes, we subsequently
defined a new endpoint retrospectively, new onset diabetes. This was considered
present if
1. A clinical diagnosis of diabetes was reported. If the investigator reported an adverse
event coded as diabetes mellitus or diabetic coma, or if the patients had started
chronic medical therapy with insulin or oral glucose lowering therapy.
2. If the patient had at least 2 random blood glucose reading above 11.1 mmol/L.
Random glucose was measured 4 times during the first year and thereafter once a
year. Random glucose was measured by the investigator using the local laboratory.
Blood glucose was requested, but in some cases plasma glucose may have been
reported. For this reason we used the conservative estimate of 11.1 as the cut-off.
3. If adverse event reporting was unclear/contradictory from the original case report
forms (such as the reporting of a single high blood glucose reading) and additional
page was sent to the investigators requesting to review the patient file and confirm
the existence of diabetes, give the date diabetes was diagnosed and tick the following
possibilities: need for diabetic medication, repeated high blood glucose results, a
positive oral glucose tolerance test, repeated high fasting glucose. Only when a date
(at least month/year) and at least one of the tick boxes was answered as yest was
the patient classified as diabetic.
Results and discussion
- Mortality reduction was NOT significant in diabetic patients. The reading of
the abstract, and discussion suggests otherwise. This should be corrected
Our reply: The last sentence in the result section of the abstract reads: “Both diabetics and nondiabetics at baseline had a similar reduction in mortality with carvedilol compared to metoprolol (RR
0.85; CI 0.69-1.06 and RR 0.82; CI, 0.71-0.94, respectively).” We clearly show that the
confidence limits for patients with diabetes cross the line of unity. We consider the
statement that mortality reduction was similar appropriate because there was no
interaction. In response to this comment – and in response to referee 2 – we have changed
the conclusion of the abstract
Old abstract conclusion:
Conclusion – In patients with chronic heart failure, carvedilol is associated with less development of new
onset diabetes compared to metoprolol. Carvedilol is superior to metoprolol in improving long-term
outcomes in both diabetic and non-diabetic patients.
Revised version:
Conclusion - This study demonstrates both a high prevalence and incidence of diabetes in patients with
heart failure over a course of 5 years. New onset diabetes was more likely to occur during treatment
with metoprolol than during treatment with carvedilol.