Den gode artikel

1. Den gode artikel Christian Torp-Pedersen

2. 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

5. 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

6. 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

7. Danish Investigations of Arrhythmia and Mortality ONDofetilide DIAMOND

8. Overall Survival - Intention to Treat 1.0 Dofetilide - 311 deaths 0.8 Dofetilide (n=762) Placebo (n=756) 0.6 Placebo - 317 deaths Survival 0.4 0.2 Overall RR 0.95, 95% CI 0.81–1.11 P=0.56 0.0 0 12 24 36 Months

9. Secondary Endpoints Arrhythmia requiring treatment & withdrawal Cardiac deaths + resus. C.A. Recurrent MI 1.0 0.8 0.6 0.4 0.2 P=0.79 P=0.78 P=0.90 0.0 0 1 2 3 0 1 2 3 0 1 2 3 Event Free Probability Years Years Years Cardiac death Events in patients with AF 1.0 0.8 Dofetilide (n=762) Placebo (n=756) 0.6 0.4 0.2 P=0.89 P=0.71 0.0 0 0 1 2 3 1 2 3 Years Years

10. 25 (11–2) 0 (0–0) TdP* 14 (6–2) 17 (3–5) VT* Ventricular Arrhythmia (Total) Dofetilide n=762 Placebo n=756 14 (3–11) 12 (5–7) VF* 19 4 RCA: £4 days 19 12 >4 days 38 16 TOTAL 4 0 Death: £4 days 317 307 >4 days 311 317 TOTAL *Number with resuscitated cardiac arrest-death in parenthesis

11. Effect of Dofetilide on Atrial Fibrillation No of patients enrolled in NSRwho developed AF No of patients enrolled in AFwho converted to NSR 50 100 84 n=1125 P<0.001 40 35 n=393 P<0.001 75 30 50 20 28 11 25 10 0 0 Placebo Dofetilide Placebo Dofetilide

12. 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)

13. 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.

14. 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.15,16Dofetilide 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.

15. Hvem er publikum?

16. Hvem er publikum? • En editor • To referees

17. Hvem er publikum? • En editor • To referees • Editor ved intet • Referees ved meget lidt

18. Introduktion • Et formål: At forklare hvorfor en travl editor skal læse videre • Fortæl hvorfor dit arbejde er nødvendigt

19. 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 …..

20. 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

21. 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 gøre

22. Resultater • Billeder er bedre end ord

23. Pfeffer 1992 - SAVE

28. R Sigmaplot Anderson, C - upubliceret

29. Vær loyal overfor protokollen Men ikke med teksten

30. Packer - 1996

33. 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

34. Statement of principal findings • This is the first study to demonstrate….Ikke alle tidsskrifter ønsker ”priority claims” • The principal finding of this study

35. 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 ….

36. Metodeforhold • Beskrive at ens metoder er optimale • Undgå at skuffe læseren – skriv eventuelle svagheder først:While the epidemiological approach has limitations, this study …….

37. Implication • Ekstremt vigtigt – et studie SKAL have konsekvenser. • Konsekvensen kan være klinisk, metodemæssigt, fremtidig forskning…..

38. 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.

39. Konklusion • Principal finding i ny indpakning

40. Svarbreve til tidsskrifter • Editor er doven • Risikoen for at det går tilbage til reviewer er stor • Reviewere har stadigt travlt

41. 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.

42. 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!

43. 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.

44. 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”.

45. 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.

46. 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 • 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. • 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. • 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.

47. 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 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).” 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.