Den gode artikel

Christian Torp-PedersenChristian Torp-Pedersen

Først ansøgning om penge: NIH

• Regn med at 2 bedømmere har Regn med at 2 bedømmere har læst ansøgningenlæst ansøgningen

• Regn med at resten af udvalget Regn med at resten af udvalget læser på dit læser på dit ””1 page summary1 page summary”” samtidigt med at de hører en samtidigt med at de hører en mundtlig gennemgang af en mundtlig gennemgang af en bedømmerbedømmer

Et godt abstract

• En, højst to sætninger som forklarer En, højst to sætninger som forklarer hvorfor dette er ekstremt vigtigthvorfor dette er ekstremt vigtigt

• Et kort metodeafsnit, det bliver næppe Et kort metodeafsnit, det bliver næppe læstlæst

• Et svulstigt resultatafsnit – et abstract Et svulstigt resultatafsnit – et abstract skal bestå af MANGE resultaterskal bestå af MANGE resultater

• En direkte konklusion på baggrund af de En direkte konklusion på baggrund af de resultater som er nævnt i abstract uden resultater som er nævnt i abstract uden for meget implikationfor meget implikation

Abstract a.m. John Camm

• A title with at least one A title with at least one ’’buzz wordbuzz word’’• A strong first sentenceA strong first sentence• A strong conclusionA strong conclusion• All that rest in the middle just All that rest in the middle just

becomes a blurrbecomes a blurr

DIAMONDDIAMOND

Danish Investigations of Arrhythmia and Mortality ON Dofetilide

MonthsMonths

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

00 1212 2424 3636

P=0.56P=0.56

Dofetilide - 311 deathsDofetilide - 311 deaths

Placebo - 317 deathsPlacebo - 317 deaths

Overall Survival - Intention to Treat

Dofetilide (n=762)Dofetilide (n=762)

Placebo (n=756)Placebo (n=756)

Su

rviv

al

Su

rviv

al

Overall RR 0.95, Overall RR 0.95, 95% CI 0.81–1.1195% CI 0.81–1.11

Arrhythmia requiringArrhythmia requiring treatment & withdrawaltreatment & withdrawal

00

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

00 11 22 33

P=0.79P=0.79

Cardiac deaths + resus. C.A.Cardiac deaths + resus. C.A.

11 22 33

P=0.78P=0.78

Recurrent MIRecurrent MI

3311 22

P=0.90P=0.90

YearsYears

Events in patients with AFEvents in patients with AF

00 11 22 33

P=0.71P=0.71

Secondary Endpoints

000.00.0

00 11 22 33

P=0.89P=0.89

Cardiac deathCardiac death

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

0.00.0

Dofetilide (n=762)Dofetilide (n=762)

Placebo (n=756) Placebo (n=756)

Even

t Fre

e P

rob

ab

ilit

yEven

t Fre

e P

rob

ab

ilit

y

YearsYearsYearsYears

YearsYears YearsYears

Ventricular Arrhythmia (Total)Ventricular Arrhythmia (Total)

*Number with resuscitated cardiac arrest-death in parenthesis

DofetilideDofetilidenn=762=762

12 (5–7)12 (5–7)

PlaceboPlacebonn=756=756

25 (11–2)25 (11–2) 0 (0–0)0 (0–0)TdP*TdP*

14 (6–2)14 (6–2) 17 (3–5)17 (3–5)VT*VT*

14 (3–11)14 (3–11)VF*VF*

RCA:RCA:

3838 1616

Death:Death:

311311

00

4 days4 days

>4 days>4 days1919

1919 44

1212

44

307307 317317

317317

TOTALTOTAL

4 days4 days

>4 days>4 days

TOTALTOTAL

Effect of Dofetilide on Atrial Fibrillation

35

11

0

10

20

30

40

50

Placebo Dofetilide

n=1125n=1125PP<0.001<0.001

28

84

0

25

50

75

100

Placebo Dofetilide

n=393n=393PP<0.001<0.001

No of patients enrolled in NSRNo of patients enrolled in NSRwho developed AFwho developed AF

No of patients enrolled in AFNo of patients enrolled in AFwho converted to NSRwho converted to NSR

Cardiac arrhythmias are common in patients with congestive heart failure Cardiac arrhythmias are common in patients with congestive heart failure (CHF), contributing to both mortality and morbidity. The possibility of reducing (CHF), contributing to both mortality and morbidity. The possibility of reducing morbidity has so far been overshadowed by severe safety concerns with morbidity has so far been overshadowed by severe safety concerns with antiarrhythmic drugs. Some class I drugs1 and the class III drug d-sotalol2 antiarrhythmic drugs. Some class I drugs1 and the class III drug d-sotalol2 increase mortality in patients with myocardial infarction. Amiodarone increase mortality in patients with myocardial infarction. Amiodarone appeared to prolong life in one CHF study,3 but this finding was not confirmed 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 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 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 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 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 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 Investigation Group trial7 and is commonly used for rate control in atrial fibrillation associated with CHF. fibrillation associated with CHF. Dofetilide is a selective inhibitor of the rapid component of the delayed Dofetilide is a selective inhibitor of the rapid component of the delayed rectifier, outward potassium current (IKr), which prolongs the action potential rectifier, outward potassium current (IKr), which prolongs the action potential duration and the effective refractory period in a concentration dependent duration and the effective refractory period in a concentration dependent manner. Clinical studies have demonstrated that the drug is effective in 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 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 drugs, dofetilide can cause proarrhythmia but the incidence is yet to be defined.defined.The Danish Investigations of Arrhythmia and Mortality ON Dofetilide The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies are two distinct studies investigating whether a reduction (DIAMOND) studies are two distinct studies investigating whether a reduction in mortality and morbidity can be achieved by long term dofetilide treatment 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 in patients with left ventricular systolic dysfunction and either CHF or a recent myocardial infarction. This publication describes the results of the congestive myocardial infarction. This publication describes the results of the congestive heart failure study (DIAMOND-CHF)heart failure study (DIAMOND-CHF)

God dansk indledningt

Prevention of ventricular and supraventricular arrhythmias in patients Prevention of ventricular and supraventricular arrhythmias in patients with congestive heart failure is an important goal with the object of with congestive heart failure is an important goal with the object of reducing mortality and morbidity. A series of antiarrhythmic drugs reducing mortality and morbidity. A series of antiarrhythmic drugs have been tested in clinical trials without success. Thus, several class 1 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 drugs and the class III drug d-sotalol have been demonstrated to be associated with increased mortality compared to placebo. Amiodarone associated with increased mortality compared to placebo. Amiodarone has in a single survival study been demonstrated to reduce mortality, has in a single survival study been demonstrated to reduce mortality, but this observation has not been confirmed in a series of other but this observation has not been confirmed in a series of other studies. Amiodarone is associated with frequent side effects that may studies. Amiodarone is associated with frequent side effects that may be serious, and which has prevented the possibility of using this drug be serious, and which has prevented the possibility of using this drug on a wide scale for non- lifethreatening conditions. The Danish studies on a wide scale for non- lifethreatening conditions. The Danish studies of arrhythmia and mortality on dofetilide were designed to study the of arrhythmia and mortality on dofetilide were designed to study the possibility of reducing mortality and morbidity in patients with possibility of reducing mortality and morbidity in patients with congestive heart failure using the novel class III antiarrhythmic drug congestive heart failure using the novel class III antiarrhythmic drug dofetilide. This is a selective inhibitor of the rapid component of the dofetilide. This is a selective inhibitor of the rapid component of the delayed rectifier, outward potassium current (IKr), which prolongs the delayed rectifier, outward potassium current (IKr), which prolongs the effective refractory period. There is no effect on ATP dependent effective refractory period. There is no effect on ATP dependent potassium channels. Clinical studies have demonstrated that the drug potassium channels. Clinical studies have demonstrated that the drug is particularly effective in treating patients with atrial arrhythmias. The is particularly effective in treating patients with atrial arrhythmias. The target population in the Diamond CHF study was high risk patients with target population in the Diamond CHF study was high risk patients with congestive heart failure. To ensure that the population would be as congestive heart failure. To ensure that the population would be as representative as possible of these patients as seen in clinical practice representative as possible of these patients as seen in clinical practice screening of consecutive patients admitted to hospital was specifically screening of consecutive patients admitted to hospital was specifically required. The primary endpoint was all cause mortality and the required. The primary endpoint was all cause mortality and the possibility of reducing morbidity was studied by having hospitalisation possibility of reducing morbidity was studied by having hospitalisation for worsening of heart failure as one secondary endpoint.for worsening of heart failure as one secondary endpoint.

Prøver igen

Congestive heart failure is a serious disease that may be exacerbated by many factors 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 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 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 maintenance of normal sinus rhythm. Unfortunately, atrial fibrillation (AF) is common in patients with heart failure and can impair exercise tolerance and exacerbate symptoms patients with heart failure and can impair exercise tolerance and exacerbate symptoms by causing loss of atrial contraction, leading to hemodynamic and thromboembolic by causing loss of atrial contraction, leading to hemodynamic and thromboembolic consequences, or by increasing the rapidity of the ventricular response leading to 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 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 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 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 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 failure.6 Hence, prevention of AF or conversion of AF are worthwhile goals in patients with congestive heart failure.with congestive heart failure.Currently available drug therapy to prevent or convert AF can have adverse effects that 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 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 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 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, 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 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.11is frequently associated with serious cardiac and noncardiac side effects.11Dofetilide is a novel class III antiarrhythmic drug that selectively inhibits the rapid Dofetilide is a novel class III antiarrhythmic drug that selectively inhibits the rapid component of the delayed rectifier potassium current (component of the delayed rectifier potassium current (IIKr) and prolongs the effective Kr) and prolongs the effective refractory period.12–14 As a pure class III agent, it has no negative inotropic effects, 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, 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-dofetilide has no effect on cardiac conduction or sinus node function in patients with pre-existing cardiac disease.15,16existing cardiac disease.15,16 Dofetilide has been shown to convert AF to sinus rhythm 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 and is effective for maintaining sinus rhythm in 70% of patients for at least six months.17,18months.17,18The DIAMOND-CHF (Danish Investigations of Arrhythmia and Mortality on Dofetilide) study 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 was designed to evaluate whether dofetilide affects survival or morbidity in patients with reduced left ventricular (LV) function and congestive heart failure.reduced left ventricular (LV) function and congestive heart failure.

Final

Hvem er publikum?

Hvem er publikum?

• En editorEn editor• To refereesTo referees

Hvem er publikum?

• En editorEn editor• To refereesTo referees

• Editor ved intetEditor ved intet• Referees ved meget lidtReferees ved meget lidt

Introduktion

• Et formål: At forklare hvorfor en Et formål: At forklare hvorfor en travl editor skal læse videretravl editor skal læse videre

• Fortæl hvorfor dit arbejde er Fortæl hvorfor dit arbejde er nødvendigtnødvendigt

Praktisk introduktion

• En indledning som forklarer at En indledning som forklarer at dette er EKSTEMT vigtigtdette er EKSTEMT vigtigt

• Der er en afgrundsdyb mangel på Der er en afgrundsdyb mangel på vigtig viden om dette emne!vigtig viden om dette emne!

• Derfor gjorde jeg/vi …..Derfor gjorde jeg/vi …..

Methods

• Kan som ofte hackes fra andre Kan som ofte hackes fra andre artiklerartikler

• Husk at skrive ALLE sætninger omHusk at skrive ALLE sætninger om• Et kedeligt afsnit som altid kan Et kedeligt afsnit som altid kan

forkortesforkortes• Statistik – skriv HVILKE metoder der Statistik – skriv HVILKE metoder der

anvendes, og ikke om HVORDAN de anvendes, og ikke om HVORDAN de anvendesanvendes

Results

• Præsentere populationenPræsentere populationen• Undgå at gentage oplysningerUndgå at gentage oplysninger• Logisk opdeling – helst med små Logisk opdeling – helst med små

overskrifteroverskrifter• Kom kritik i forkøbet medKom kritik i forkøbet med

””Analyses of sensitivityAnalyses of sensitivity””””Other analysesOther analyses””

• Det centrale budskab skal være grafisk – Det centrale budskab skal være grafisk – hvis det overhovedet kan lade sig gørehvis det overhovedet kan lade sig gøre

Resultater

• Billeder er bedre end ordBilleder er bedre end ord

Pfeffer 1992 - SAVE

Variables Homozygocity

for both

G:G and C:C

variants

(n=73)

Other combinations of

sequence

variants

(n=1249)

Homozygocity

for both

A:A and T:T variants

(n=88)

Office systolic BP, mm Hg 128.7

(124.9-132.4)

129.3

(128.3-130.2)

132.5

(129.1-135.9)

Office diastolic BP, mm Hg 81.2

(78.9-83.5)

81.5

(80.9-82.0)

84.1

(82.0-86.2)*

Office heart rate,

beats/min

66.1

(63.9-68.4)

65.1

(64.5-65.7)

67.4

(65.4-69.5)*

Mean 24-hr systolic BP, mm Hg 123.1

(120.2-125.9)

125.4

(124.7-126.1)

129.1

(126.5-131.6)†‡

Mean 24-hr diastolic BP, mm Hg 72.2

(70.3-74.1)

73.3

(72.8-73.8)

76.0

(74.3-77.7)†‡

Mean 24-hr heart rate,

beats/min

69.1

(67.1-71.1)

70.6

(70.1-71.1)

72.3

(70.5-74.2)§

Mean daytime systolic BP, mm Hg 129.0

(126.1-131.9)

130.9

(130.2-131.6)

134.9

(132.2-137.5)†‡

Mean daytime diastolic BP, mm Hg 76.5

(74.5-78.5)

77.2

(76.7-77.7)

80.3

(78.4-82.1)‡║

Mean daytime heart rate, beats/min 72.8

(70.7-74.9)

73.6

(73.1-74.1)

75.7

(73.8-77.6)*§

Mean nighttime systolic BP, mm Hg 108.4

(105.3-111.6)

112.3

(111.5-113.1)¶

114.9

(112.1-117.7)†

Mean nighttime

diastolic BP, mm Hg

61.6

(59.6-63.6)

63.7

(63.2-64.2)

65.5

(63.7-67.3)║

Mean nighttime

heart rate, beats/min

60.4

(58.2-62.5)

63.5

(62.9-64.0)#

64.9

(62.9-66.9)†

00.

010.

020.

030.

04D

ensi

ty

75 100 125 150 175

Mean 24-hour ambulatory systolic blood pressure

Double homozygocity forBP-lowering variants

Others

Double homozygocity for BP-raising variants

R

Sigmaplot

Anderson, C - upubliceret

Vær loyal overfor protokollen

Men ikke med teksten

Packer - 1996

Discussion

• Statement of principal findingsStatement of principal findings• Relation til andre studier – Husk ikke Relation til andre studier – Husk ikke

blot at skrive at andre fundet hist og blot at skrive at andre fundet hist og pist, men fremhæv svaghederne og pist, men fremhæv svaghederne og dermed indirekte egen styrkedermed indirekte egen styrke

• MetodeforholdMetodeforhold• Styrker og SvaghederStyrker og Svagheder• ImplikationImplikation• KonklusionKonklusion

Statement of principal findings

• This is the first study to This is the first study to demonstrate….demonstrate….Ikke alle tidsskrifter ønsker Ikke alle tidsskrifter ønsker ””priority priority claimsclaims””

• The principal finding of this studyThe principal finding of this study

Relation til andre studier

• Undgå generelle sætninger:Undgå generelle sætninger:Similar findings have also been Similar findings have also been found by ……found by ……

• Skriv hellere: A small study by …. Skriv hellere: A small study by …. Using a different technique ….Using a different technique ….An older study ….An older study ….

Metodeforhold

• Beskrive at ens metoder er Beskrive at ens metoder er optimaleoptimale

• Undgå at skuffe læseren – skriv Undgå at skuffe læseren – skriv eventuelle svagheder først:eventuelle svagheder først:While the epidemiological While the epidemiological approach has limitations, this approach has limitations, this study …….study …….

Implication

• Ekstremt vigtigt – et studie SKAL Ekstremt vigtigt – et studie SKAL have konsekvenser.have konsekvenser.

• Konsekvensen kan være klinisk, Konsekvensen kan være klinisk, metodemæssigt, fremtidig metodemæssigt, fremtidig forskning…..forskning…..

Man arbejder med hver sætning!

• These results demonstrate that the These results demonstrate that the risk of cancer for all insulins was risk of cancer for all insulins was neutral after 1 year, but the neutral after 1 year, but the confidence intervals remains high for confidence intervals remains high for humans insulins because of power.humans insulins because of power.

• The power to examine human insulins The power to examine human insulins was low, but for all other insulins the was low, but for all other insulins the risk of cancer was neutral after 1 year.risk of cancer was neutral after 1 year.

Konklusion

• Principal finding i ny indpakningPrincipal finding i ny indpakning

Svarbreve til tidsskrifter

• Editor er dovenEditor er doven• Risikoen for at det går tilbage til Risikoen for at det går tilbage til

reviewer er storreviewer er stor• Reviewere har stadigt travltReviewere har stadigt travlt

Sørg for at de kun skal læse ET dokument EN gang

• Start med et svulstigt takkebrevStart med et svulstigt takkebrev• Første kommentar af første reviewerFørste kommentar af første reviewer• Egne kommentarer til detteEgne kommentarer til dette• Manuskript tidligere versionManuskript tidligere version• Manuskript nuværende versionManuskript nuværende version

Afsnit skal være så tydelig markeret at Afsnit skal være så tydelig markeret at det er helt intuitivt hvad der er reviewer det er helt intuitivt hvad der er reviewer kommentarer, hvad der er svar o.s.v.kommentarer, hvad der er svar o.s.v.

Svar!!

• Henvis gerne tilbage – aldrig fremHenvis gerne tilbage – aldrig frem• Lav aldrig gentagelserLav aldrig gentagelser• Lav gerne ligegyldige rettelser: Lav gerne ligegyldige rettelser:

””Nevertheless, in order to clarify this Nevertheless, in order to clarify this further ......further ......””

• Vær trods alt dette HELT klar i mælet Vær trods alt dette HELT klar i mælet når en kommentar tilbagevises – når en kommentar tilbagevises – dette skal kun være i yderste nød!dette skal kun være i yderste nød!

The editor:The editor:  We wish to thank HEART for giving us a comprehensive review We wish to thank HEART for giving us a comprehensive review

and for giving us the opportunity to have a revised manuscript and for giving us the opportunity to have a revised manuscript evaluated. Below we have replied to each of the comments evaluated. Below we have replied to each of the comments given by the referees. A principal issue is whether a “clinical given by the referees. A principal issue is whether a “clinical diagnosis” of diabetes can be accepted. Ideally diabetes diagnosis” of diabetes can be accepted. Ideally diabetes should be defined by international criteria, but this is rarely should be defined by international criteria, but this is rarely available in studies of clinical epidemiology. The majority of available in studies of clinical epidemiology. The majority of the literature on clinical epidemiology of diabetes in patients the literature on clinical epidemiology of diabetes in patients with heart failure and patients with ischemic heart disease with heart failure and patients with ischemic heart disease relies on similar definitions as those we have used.relies on similar definitions as those we have used.

  We hope you will consider the revised manuscript suitable for We hope you will consider the revised manuscript suitable for

publication in HEART.publication in HEART.  In the following reviewer comments are indicated in In the following reviewer comments are indicated in italicitalic and our and our

reply in reply in bold bold text. Changes to the manuscript are shown in text. Changes to the manuscript are shown in normal text.normal text.

Sød mand!

-- The definition of new onset diabetes is also -- The definition of new onset diabetes is also confusing. The authors should confusing. The authors should

try to indicate how many patients fulfilled the try to indicate how many patients fulfilled the standard definition of diabetes standard definition of diabetes

through the study. The results refer to 2 different through the study. The results refer to 2 different types of new onset diabetes. types of new onset diabetes.

This is also confusingThis is also confusing  Our reply: We acknowledge that our definition Our reply: We acknowledge that our definition

of new onset diabetes may be difficult to read of new onset diabetes may be difficult to read and we have prepared a new section. There and we have prepared a new section. There are NOT 2 types of new onset diabetes in this are NOT 2 types of new onset diabetes in this manuscript – but the predefined endpoint of manuscript – but the predefined endpoint of “diabetes related adverse event” and “new “diabetes related adverse event” and “new onset diabetes”.onset diabetes”.

Previous:

Because the diabetes-related adverse events also Because the diabetes-related adverse events also included events (hyperglycemia, decreased included events (hyperglycemia, decreased glucose tolerance) that were not necessarily glucose tolerance) that were not necessarily diabetes, we subsequently defined a new endpoint diabetes, we subsequently defined a new endpoint retrospectively, new onset diabetes. This endpoint retrospectively, new onset diabetes. This endpoint included all patients who either had either an included all patients who either had either an adverse event coded as diabetes mellitus or adverse event coded as diabetes mellitus or diabetic coma, or who had started chronic medical diabetic coma, or who had started chronic medical therapy with insulin or oral antidiabetic medication therapy with insulin or oral antidiabetic medication or who had at least 2 random blood glucose or who had at least 2 random blood glucose readings above 11.2 mmol/L (random glucose was readings above 11.2 mmol/L (random glucose was measured 4 times during the first year and measured 4 times during the first year and thereafter once a year). In patients in whom only a thereafter once a year). In patients in whom only a single high random glucose measurement was single high random glucose measurement was reported, we queried the investigator whether the reported, we queried the investigator whether the patient had diabetes. If confirmed, the presence of patient had diabetes. If confirmed, the presence of an endpoint was noted. an endpoint was noted.

Revised

• Because the diabetes-related adverse events also included events Because the diabetes-related adverse events also included events (hyperglycemia, decreased glucose tolerance) that were not necessarily (hyperglycemia, decreased glucose tolerance) that were not necessarily diabetes, we subsequently defined a new endpoint retrospectively, new onset diabetes, we subsequently defined a new endpoint retrospectively, new onset diabetes. This was considered present if diabetes. This was considered present if

1.1. A clinical diagnosis of diabetes was reported. If the investigator reported an 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 adverse event coded as diabetes mellitus or diabetic coma, or if the patients had started chronic medical therapy with insulin or oral glucose lowering had started chronic medical therapy with insulin or oral glucose lowering therapy. therapy.

2.2. If the patient had at least 2 random blood glucose reading above 11.1 mmol/L. 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 Random glucose was measured 4 times during the first year and thereafter once a year. Random glucose was measured by the investigator using the once a year. Random glucose was measured by the investigator using the local laboratory. Blood glucose was requested, but in some cases plasma local laboratory. Blood glucose was requested, but in some cases plasma glucose may have been reported. For this reason we used the conservative glucose may have been reported. For this reason we used the conservative estimate of 11.1 as the cut-off.estimate of 11.1 as the cut-off.

3.3. If adverse event reporting was unclear/contradictory from the original case 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 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 additional page was sent to the investigators requesting to review the patient file and confirm the existence of diabetes, give the date diabetes was file and confirm the existence of diabetes, give the date diabetes was diagnosed and tick the following possibilities: need for diabetic medication, diagnosed and tick the following possibilities: need for diabetic medication, repeated high blood glucose results, a positive oral glucose tolerance test, 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 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 least one of the tick boxes was answered as yest was the patient classified as diabetic.diabetic.

Results and discussionResults and discussion- Mortality reduction was NOT significant in diabetic patients. The reading of - Mortality reduction was NOT significant in diabetic patients. The reading of the abstract, and discussion suggests otherwise. This should be correctedthe abstract, and discussion suggests otherwise. This should be corrected  Our reply: The last sentence in the result section of the abstract reads: “Our reply: The last sentence in the result section of the abstract reads: “Both Both

diabetics and non-diabetics at baseline had a similar reduction in mortality with carvedilol diabetics and non-diabetics 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).”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 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 line of unity. We consider the statement that mortality reduction was similar appropriate because there was no interaction. In response to this comment – appropriate because there was no interaction. In response to this comment – and in response to referee 2 – we have changed the conclusion of the abstractand in response to referee 2 – we have changed the conclusion of the abstract

  Old abstract conclusion:Old abstract conclusion:ConclusionConclusion – In patients with chronic heart failure, carvedilol is associated with less – In patients with chronic heart failure, carvedilol is associated with less

development of new onset diabetes compared to metoprolol. Carvedilol is superior to 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. metoprolol in improving long-term outcomes in both diabetic and non-diabetic patients.

  Revised version:Revised version:ConclusionConclusion - This study demonstrates both a high prevalence and incidence of diabetes in - 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 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. occur during treatment with metoprolol than during treatment with carvedilol.