Digit HF trial review presentation by a resident

Digit HF trial review presentation by a resident

1. Journal Presentation The Digit-HF Clinical Trial 1 Presenter : Dr Dibora Kebede (IMR3) Moderator : Dr Birhanu (Internist and cardiology fellow)

2. OUTLINE INTRODUCTION METHODS INCLUSION/EXCLUSION RANDOMIZATION OUTCOMES STATISTICAL ANALYSIS RESULTS DISCUSSION CRITICAL APPRAISAL 3

3. INTRODUCTION Heart failure remains a major cause of mortality and morbidity in industrial countries The course of this disease is characterized by repeated hospital admissions at relatively short intervals and a limited prognosis for survival Despite advances in HF treatment, HF remains a disabling disorder that severely affects patients’ prognosis and quality of life It is responsible for 1% to 2% of direct health costs in the Western industrialized nations

4. Cardiac glycosides have been used for the treatment of chronic HF for centuries. Current ( ESC) HF guidelines suggest treatment with cardiac glycosides as an option in patients with persistent symptoms despite optimal pharmacological. Prescription rates of cardiac glycosides of currently 20–25% in European and ≈10% in U.S. 5

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9. 10 METHODS In the main trial, patients with left ventricular ejection fractions of 0.45 or less were randomly assigned to digoxin ( 3397 patients) or placebo (3403 patients) in addition to diuretics and angiotensin-converting–enzyme inhibitors (median dose of digoxin, 0.25 mg per day; average follow-up, 37 months). In an ancillary trial of patients with ejection fractions greater than 0.45, 492 patients were randomly assigned to digoxin and 496 to placebo. RESULTS In the main trial , mortality was unaffected . There were 1181 deaths (34.8 percent ) with digoxin and 1194 deaths (35.1 percent ) with placebo ( risk ratio when digoxin was compared with placebo, 0.99 ; 95 percent confidence interval, 0.91 to 1.07; P = 0.80). In the digoxin group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure (risk ratio, 0.88; 95 percent confidence interval, 0.77 to 1.01; P = 0.06). There were 6 percent fewer hospitalizations overall in that group than in the placebo group, and fewer patients were hospitalized for worsening heart failure ( 26.8 percent vs. 34.7 percent; risk ratio, 0.72 ; 95 percent confidence interval, 0.66 to 0.79; P<0.001) CONCLUSIONS Digoxin did not reduce overall mortality , but it reduced the rate of hospitalization both overall and for worsening heart failure . These findings define more precisely the role of digoxin in the management of chronic heart failure

10. AIM OF THE STUDY To demonstrate that digitoxin preferably ranging at serum concentrations of 8–18 ng /mL on top of standard of care reduces the composite endpoint of all-cause mortality or first hospital admission for worsening HF

11. STUDY DESIGN Trial Design : Pragmatic , multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase IV trial Study was conducted between May 2015 to December 2024 across 65 German ,Austria and Serbia study site.

12. INCLUSION CRITERIA

13. EXCLUSION CRITERIA

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15. ENDPOINTS Primary Endpoint: Composite endpoint of time to all-cause mortality or hospital admission for worsening heart failure (whatever occurs first ) Admission for worsening heart failure is defined by presence of the following points together : 1.) Worsening of heart failure based on clinical judgment by the treating physician. 2 .) hospital stay overnight 3 .) i.v. -treatment with diuretics or vasoactive substances or inotropes .

16. Secondary Endpoints : Key secondary endpoints : 1 ) Time to all-cause mortality 2 ) Recurrent hospital admission for worsening heart failure and terminal event of all-cause mortality ENDPOINTS

17. Secondary endpoints : Cardiovascular mortality, Death from heart failure , Any non-cardiovascular death, Fatal or nonfatal myocardial infarction, stroke Any cardiovascular hospitalization , Hospital admission for any cause, Implantation of a cardioverter-defibrillator,cardiac-resynchronisation device, pacemaker, Sudden cardiac death , Change in functional capacity assessed by NYHA class and quality of life assessed by the SF-12. ENDPOINTS

18. SAFTEY OUTCOMES: Adverse Events : Adverse events (AEs), serious adverse events (SAEs) and laboratory abnormalities will be compared between the treatment groups. ENDPOINTS

19. ETHICAL CONSIDERATIONS The trial was conducted and is reported according to the principles of the Declaration of Helsinki and the guidelines for Good Clinical Practice. The study was conducted in compliance with the German Drug Law (AMG), the German GCP ordinance, ICH GCP guidelines, and other applicable ethical and regulatory requirement The protocol was approved by the national competent authority ( NCA)Authority Germany All the patients provided written informed consent The study is supported by the Federal Ministry of Education and Research (BMBF) under grant number: 01KG1303.

20. 1253 patients were screened 1240 patients underwent randomization and assigned in a 1:1 ratio to receive either digitoxin or placebo . 1212 were included in the mITT Randomization was stratified according to sex , NYHA functional class (II, III, or IV ), trial site , the presence or absence of atrial fibrillation ,and previous treatment with cardiac glycosides Each patient received a unique code ,which corresponded to either digitoxin or placebo in identical-looking blister packs. RANDOMIZATION

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23. STATISTICAL ANALYSIS The sample size was calculated to provide 80% power to detect a hazard ratio (HR) of 0.811 for the primary endpoint assuming an event rate occur in 26% patient in digitoxin and 31 % placebo (734 events)within 24 months with RR of 20%. A two -sided Type I error rate of 0.05 was used . The target sample size was initially set at 2190 patients to account for potential loss of patients in the per-protocol analysis. All randomized patients were included in the primary analysis , regardless of whether they adhered to the treatment regimen . ( mITT ) Efficacy analyses were performed in a modified intention-to-treat population

24. Primary Endpoint Analysis: Time-to-first Event Analysis The primary endpoint (death from any cause or hospitalization for worsening heart failure) was analyzed using Cox proportional hazards models . superiority was demonstrated if the lower boundary of the 95% CI for the HR was less than than <1 . Secondary endpoint Analyses: the superiority of digitoxin to placebo with respect to the total number of deaths from any cause and hospitalizations for worsening heart failure was analyzed in a negative binomial model STATISTICAL ANALYSIS

25. RESULTS: BASELINE CHARACTERISTICS 26

26. RESULTS: BASELINE CHARACTERISTICS 27

27. RESULTS: PRIMARY END POINT The rate of events in the digitoxin group was 12.8 events per 100 patient-years , while the rate in the placebo group was 15.7 events per 100 patient-years . Hazard ratio for death or first hospital admission for worsening heart failure, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03 ) Absolute risk reduction 4.6% Number needed to treat:-22

28. RESULTS: PRIMARY END POINT

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30. RESULTS: SECONDARY OUTCOMES Death from any cause occurred in 167 patients ( 27.2%; 7.8 deaths per 100 patient-years) in the digitoxin group and 177 ( 29.5 %; 8.9 deaths per 100 patient-years) in the placebo group hazard ratio, 0.86 ; 95% CI, 0.69to 1.07; threshold for noninferiority , 1.303; P<0.001

31. A first hospitalization for worsening heart failure occurred in 172 patients ( 28.1%; 9.1 events per 100 patient years ) in the digitoxin group and 182 patients ( 30.4 %; 10.8 events per 100 patient-years) in the placebo group hazard ratio, 0.85 ;( 95% CI, 0.69 to 1.05) RESULTS: SECONDARY OUTCOMES

32. Serious adverse event occurred in 29 patients ( 4.7%) in the digitoxin group and 17 patients ( 2.8%) in the placebo group these events included cardiac disorders in 21 patients (3.4%) and 11 patients (1.8%),respectively Adverse events led to discontinuation of digitoxin or placebo in 56 patients (9.1%) and 61 patients (10.2%), RESULTS: SAFETY OUTCOMES

33. Among patients with chronic heart failure and reduced ejection fraction, the incidence of a primary-outcome event was significantly lower with digitoxin than with placebo. The treatment effect of digitoxin on the primary outcome appeared to be consistent among prespecified subgroups . A post hoc analysis of the DIG trial indicated a beneficial effect of digoxin at low concentrations in serum with respect to death from any cause or hospitalization for worsening heart failure. This effect appears to be similar to the this trial DISCUSSION

34. The finding suggest that digitoxin remain clinically relevant in the modern era of HFrEF therapy ,on top of ACEi/ARNI, B-blocker, MRA ,and SGLT2 inhibitor The absence of mortality benefit is similar to DIG trial, where digoxin didn’t reduced overall survival Digitoxin may have role as an adjunctive therapy ,especially in patient with low blood pressure and in those with higher resting HR DISCUSSION

35. Strengths : Randomized, double-blind ,placebo-controlled trial design Longer median follow up(3 years) Contemporary background therapy Represent a common HFrEF population Consistent effect direction Not sponsored by Pharmaceutical DISCUSSION

36. Limitations : 1,Underpowered particularly for secondary outcome 2,Lack generalizability 2 , Protocol Amendments 3,Composite endpoint driven more by hospitalization 4,Digitoxin availability DISCUSSION

37. 39 QUESTION AND COMMENT QUESTION AND COMMENT QUESTION AND COMMENT

38. YES CAN’T TELL NO Remark Did the trial address a clearly focused issue ?  Was the assignment of patients to treatment randomized?  Were all of the patients who entered the trial properly accounted for at its conclusion?  Were patients, health care workers and study personnel ‘blind’ to treatment?  Were the groups similar at the start of the trial?  Aside from the experimental intervention, were the groups treated equally?  Are the results statistically and clinically significant?  For primary out come Can the results be applied to the local population?  Are the benefits worth the harms and costs?  CRITICAL APPRAISAL 40

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