DIGOXIN TOXICITY.pptx, Treatment of Digoxin Toxicity, Ecg Changes in Digoxin Toxicity.

Digoxin Toxicity, ECG Changes,
Treatment of Digoxin Toxicity, ECG in Digoxin Toxicity,

1. DR HASAN MAHMUD IQBAL MBBS, BCS, MACC, MD (CARDIOLOGY). 01 VOL. 71, NO. 10, 2018 Digoxin and Mortality in Patients With Atrial Fibrillation A Journal Article Presentation.

2. ORIGINAL INVESTIGATION

3. INVESTIGATORS.… 02 Renato D. Lopes, MD, PHD, MHS , Roberto Rordorf , MD, Gaetano M. De Ferrari, MD, Sergio Leonardi , MD, MHS, Laine Thomas, PHD, Daniel M. Wojdyla , MS,Peter Ridefelt , MD, PHD,John H. Lawrence, MD, Raffaele De Caterina , MD, PHD,Dragos Vinereanu , MD, PHD, Michael Hanna, MD,Greg Flaker, MD, Sana M. Al- Khatib , MD, MHS, Stefan H. Hohnloser , MD,John H. Alexander, MD, MHS, Christopher B. Granger, MD, Lars Wallentin , MD, PHD for the ARISTOTLE Committees and Investigators Lopes et al. From the Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina,USA .

4. INTRODUCTION: Digoxin, a well-established drug in cardiovascular medicine, is widely used in patients with atrial fibrillation(AF). Current guidelines recommend digoxin for rate control in patients with AF, particularly those with concomitant heart failure. Digoxin has been evaluated in patients with heart failure and sinus rhythm but no randomized controlled trial has assessed digoxin’s long-term efficacy or safety in patients with AF. 03

5. In an effort to address this gap, several observational analyses, including post hoc analyses from clinical trials, registries, and meta-analyses, have recently been published. These studies have provided conflicting results, possibly due to varying patient populations and analytical methods. Digoxin has a narrow therapeutic window, and its levels are markedly influenced by drug–drug interactions and comorbidities. A major limitation of all previous studies examining the safety of digoxin in patients with AF is the lack of serum digoxin concentration measurements necessary to define a possible dose–response relationship. 04

6. A post hoc analysis of the DIG (Digitalis Investigation Group) trial in 1,171 patients with heart failure but not AF suggested that the serum digoxin concentration was directly related to mortality, with reduced mortality among patients with low digoxin levels (between 0.5 and 0.8 ng /ml ) and increased mortality among patients with levels >1.1 ng /ml. 05

7. The present study explored the association between digoxin use, serum digoxin concentration, and mortality in patients with AF in the ARISTOTLE trial. ( Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) 06

8. They analyzed whether this association was modified by the presence of heart failure, serum digoxin concentration, biomarkers, concomitant medications, or any other clinical or laboratory characteristics associated with digoxin use, serum digoxin concentration and mortality. The efficacy and safety of apixaban versus warfarin were also assessed according to digoxin use. 07

9. 08 They performed a post hoc digoxin subgroup analysis of the ARISTOTLE trial, which compared apixaban with warfarin for the prevention of stroke or systemic embolism in patients with AF and at least 1 additional risk factor for stroke. The primary efficacy outcome was stroke or systemic embolism. The primary safety outcome was major bleeding according to the International Society on Thrombosis and Haemostasis criteria. Clinical events, including cause of death, were adjudicated on the basis of prespecified criteria by a clinical events committee unaware of randomized treatment. All patients provided written informed consent, and approval by the appropriate ethics committees was obtained at all sites. Methods..

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15. 13 Heart failure was a subgroup of interest and was pre-specified in the statistical analysis plan. It was recorded in the case report form and defined as symptomatic congestive heart failure within 3 months or history of heart failure and/or a left ventricular ejection fraction (LVEF) 40% or less than 40% and/or moderate or severe left ventricular dysfunction. Digoxin concentrations were analyzed in serum samples obtained The analyses were performed at the Department of Clinical Chemistry, Uppsala University, Uppsala,Sweden .

16. STATISTICAL ANALYSIS. Patients using and those not using digoxin, overall and within the heart failure groups, were compared by using the Fisher exact tests and the Wilcoxon rank sum test for categorical and continuous variables, respectively. Two different analyses were implemented: a prevalent user analysis and an incident (new) user analysis. Both analyses included mortality endpoints(all-cause, cardiovascular, non-cardiovascular, and sudden cardiac death) and hospitalization for heart failure. 14

17. RESULTS… A total of 17,897 patients (98% of the overall population) from ARISTOTLE had information available on baseline digoxin use and heart failure status. Of those, 5,824 (32.5%) were taking digoxin at baseline, and 6,693 (37.4%) had concomitant heart failure. A total of 680 (11.7%) patients using digoxin at baseline stopped digoxin before the end of the trial. 15

18. RESULTS… BASELINE DIGOXIN USE AND OUTCOMES: Baseline digoxin use was not associated with higher all-cause mortality Similar results were seen for patients with and without heart failure. Rates of cardiovascular mortality (2.61 vs. 1.58 per 100 patient-years; adjusted HR: 1.11; 95% CI: 0.93 to 1.32; p ¼ 0.2363), as well as sudden cardiac death (1.08 vs. 0.59 per 100 patient-years; HR: 1.27; 95% CI: 0.96 to 1.67; p ¼ 0.0941), were numerically higher in patients using digoxin versus not using digoxin. 01

19. SERUM DIGOXIN CONCENTRATIONS AND OUTCOMES… Serum digoxin concentrations at baseline were measured in 4,434 (76.1%) patients taking digoxin. Baseline characteristics of the patients with and without digoxin concentration data available were similar. Median serum digoxin concentrations were significantly higher in patients who died compared with those who survived (median: 0.62 [25th, 75th percentiles: 0.39, 1.01] ng /ml vs. 0.55 [25th, 75th percentiles: 0.16, 0.86] ng /ml; p < 0.0001). 16

20. 17 For patients with digoxin levels < 0.9 ng /ml [76% of patients for whom digoxin measurement was available] there was no increased risk of death compared with those not on digoxin. For patients with levels 0.9 or >0.9ng/ml and <1.2 ng /ml there was a 16% increased risk of death compared with those not on digoxin. For patients with digoxin levels 1.2 ng /ml or >1.2ng/ml there was a significant 56% increased risk of death compared with those not on digoxin. Very Important slide…

21. For each 0.1-ng/ml increase in baseline serum digoxin concentration, a 4% higher risk of overall mortality was recorded. Baseline serum digoxin concentrations were also significantly associated with a higher risk of cardiovascular death and sudden death for each 0.5-ng/ml increase. 18

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25. In Conclusion… The study showed that digoxin use at baseline was not independently associated with increased mortality in patients with AF at risk for stroke. However, in patients with AF currently taking digoxin, the risk of death was independently related to serum digoxin concentration and was highest in patients with concentrations 1.2 ng /ml or >1.2 ng /ml. There was an independent association between serum digoxin concentration and mortality, with a “dose related effect” that is consistent with a plausible causal association between digoxin concentrations and risk of death. 22

26. These observations were strengthened by the finding that, after using a robust risk-set matching approach based on a time-dependent propensity score, the risk of death was greatest early after initiation of digoxin in previous nonusers, particularly with respect to sudden cardiac death. Finally, contrary to what has been shown previously for patients with heart failure in sinus rhythm, they found that initiating digoxin in patients with AF was significantly associated with an increased risk of heart failure hospitalization, primarily among patients with previous heart failure. These findings indicate that digoxin should be used with caution and with monitoring of its serum concentration in patients with AF and preferably avoided if symptoms can be alleviated with other treatments. 23

27. Take Home Message: In patients with AF taking digoxin, the risk of death was independently related to serum digoxin concentration and was highest in patients with concentrations 1.2 ng /ml or > 1.2ng/ml. Initiating digoxin was independently associated with higher mortality in patients with AF, regardless of heart failure. 24

28. THANK YOU ALL… 01

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30. Table 1 summarizes the clinical differences between patients taking and not taking digoxin among those with and without heart failure. 01

31. Digoxin toxicity , also known as  digoxin poisoning , is a type of  poisoning  that occurs in people who take too much of the medication  digoxin  or eat plants such as  foxglove  that contain a similar substance. [1] [2]  Symptoms are typically vague. [1]  They may include vomiting, loss of appetite,  confusion , blurred vision, changes in color perception, and decreased energy. [1]  Potential complications include an  irregular heartbeat , which can be either  too fast  or  too slow . [1] Toxicity may occur over a short period of time following an  overdose  or gradually during long-term treatment. [1]  Risk factors include  low potassium ,  low magnesium , and  high calcium . [1]  Digoxin is a medication used for  heart failure  or  atrial fibrillation . [3] An  electrocardiogram  is a routine part of diagnosis. [2]  Blood levels are only useful more than six hours following the last dose. [1] Activated charcoal  may be used if it can be given within two hours of the person taking the medication. [1]   Atropine  may be used if the heart rate is slow while  magnesium sulfate  may be used in those with  premature ventricular contractions . [2]  Treatment of severe toxicity is with  digoxin-specific antibody fragments . [1]  Its use is recommended in those who have a serious dysrhythmia, are in  cardiac arrest , or have a potassium of greater than 5  mmol /L. [1]  Low blood potassium or magnesium should also be corrected. [1]  Toxicity may reoccur within a few days after treatment. [1] 01

32. Digoxin toxicity is often divided into acute or chronic toxicity. In both of these toxicity, cardiac effects are of the greatest concern. With an acute ingestion, symptoms such as nausea,  vertigo , and vomiting are prominent. On the other hand, nonspecific symptoms are more predominate in chronic toxicity. These symptoms include fatigue, malaise, and visual disturbances. [5] The classic features of digoxin toxicity are nausea, vomiting, abdominal pain, headache, dizziness, confusion, delirium, vision disturbance (blurred or yellow vision). It is also associated with cardiac disturbances including  irregular heartbeat ,  ventricular tachycardia ,  ventricular fibrillation , sinoatrial block and  AV block . [6] 01

33. ECG In digoxin toxicity, the finding of frequent premature ventricular beats (PVCs) is the most common and the earliest dysrhythmia. Sinus bradycardia is also very common. In addition, depressed conduction is a predominant feature of digoxin toxicity. Other  ECG changes that suggest digoxin toxicity include bigeminal and trigeminal rhythms, ventricular bigeminy , and bidirectional ventricular tachycardia. [5] 01

34. Treatment: The primary treatment of digoxin toxicity is  digoxin immune fab , which is an antibody made up of anti-digoxin  immunoglobulin  fragments. This antidote has been shown to be highly effective in treating life-threatening signs of digoxin toxicity such as hyperkalemia, hemodynamic instability, and arrhythmias. [11]  Fab dose can be determined by two different methods. First method is based on the amount of digoxin ingested whereas the second method is based on the serum digoxin concentration and the weight of the person. [10] Other treatment that may be used to treat life-threatening arrhythmias until Fab is acquired are  magnesium ,  phenytoin , and  lidocaine . Magnesium suppresses digoxin-induced ventricular arrhythmias while phenytoin and lidocaine suppresses digoxin-induced ventricular automaticity and delay afterdepolarizations without depressing AV conduction. In the case of an abnormally slow heart rate ( bradyarrhythmias ),  Atropine ,  catecholamines  ( isoprenaline  or  salbutamol ), and/or temporary  cardiac pacing  can be used. [8 01

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