Immunomodulatory properties of antihypertensive drugs and digitalis glycosides.

INTRODUCTION: The role of chronic inflammatory process in the pathogenesis or exacerbation of hypertension has been already acknowledged. AREAS COVERED: Therefore, one can speculate that hypotensive drugs may exert some of their therapeutic effects due to immunomodulatory properties. So far, this assumption has been tested in different studies, and the resulting knowledge is summarized in the current review article that is dedicated to different groups of antihypertensives, namely calcium channel blockers, beta blockers, as well as other less commonly used medications, such as hydralazine, alfa-2 receptor agonists, diazoxide, doxazosin, aliskiren, and sodium nitroprusside. Articles were found in the Pubmed by entering the name of a specific drug/group of drugs with the words: immunology, cellular response, humoral response, inflammation, interleukin. The 2000-2021 range was used to search for all drugs except propranolol (1980-2021) and calcium blockers (1990-2021). EXPERT OPINION: Observed decrease in serum/plasma concentration of proinflammatory cytokines, and CRP along with lower expression of adhesion molecules on immune cells strongly suggest that these drugs possess immunomodulatory properties, which seems to be crucial in the medical practice, especially in the therapy of hypertensive patients with other accompanying inflammatory-based diseases, such as type II diabetes, developed metabolic syndrome, allergies or autoimmunity.

Integrated specialized atrial fibrillation clinics reduce all-cause mortality: post hoc analysis of a randomized clinical trial.

AIMS: An integrated chronic care programme in terms of a specialized outpatient clinic for patients with atrial fibrillation (AF), has demonstrated improved clinical outcomes. The aim of this study is to assess all-cause mortality in patients in whom AF management was delivered through a specialized outpatient clinic offering an integrated chronic care programme. METHODS AND RESULTS: Post hoc analysis of a Prospective Randomized Open Blinded Endpoint Clinical trial to assess all-cause mortality in AF patients. The study included 712 patients with newly diagnosed AF, who were referred for AF management to the outpatient service of a University hospital. In the specialized outpatient clinic (AF-Clinic), comprehensive, multidisciplinary, and patient-centred AF care was provided, i.e. nurse-driven, physician supervised AF treatment guided by software based on the latest guidelines. The control group received usual care by a cardiologist in the regular outpatient setting.After a mean follow-up of 22 months, all-cause mortality amounted 3.7% (13 patients) in the AF-Clinic arm and 8.1% (29 patients) in usual care [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.23-0.85; P = 0.014]. This included cardiovascular mortality in 4 AF-Clinic patients (1.1%) and 14 patients (3.9%) in usual care (HR 0.28; 95% CI 0.09-0.85; P = 0.025). Further, 9 patients (2.5%) died in the AF-Clinic arm due to a non-cardiovascular reason and 15 patients (4.2%) in the usual care arm (HR 0.59; 95% CI 0.26-1.34; P = 0.206). CONCLUSION: An integrated specialized AF-Clinic reduces all-cause mortality compared with usual care. These findings provide compelling evidence that an integrated approach should be widely implemented in AF management.

The sodium pump and digitalis drugs: Dogmas and fallacies.

The sodium pump (Na/K-ATPase) is a plasma membrane enzyme that transports Na+ and K+ against their physiological gradients in most eukaryotic cells. Besides pumping ions, the enzyme may also interact with neighboring proteins to activate cell signaling pathways that regulate cell growth. Digitalis drugs, useful for the treatment of heart failure and atrial arrhythmias, inhibit the pumping function of Na/K-ATPase and stimulate its signaling function. In the current field of research on the sodium pump and digitalis drugs, some issues that are commonly accepted to be well established are not so, and this may impede progress. Here, several such issues are identified, their histories are discussed, and their open discussions are urged. The covered unsettled questions consist of (a) the suggested hormonal role of endogenous digitalis compounds; (b) the specificity of Na/K-ATPase as the receptor for digitalis compounds; (c) the relevance of the positive inotropic action of digitalis to its use for the treatment of heart failure; (d) the conflicting findings on digitalis-induced signaling function of Na/K-ATPase; and (e) the uncertainties about the structure of Na/K-ATPase in the native cell membrane.

Impact of Digitalis Use on Mortality in Japanese Patients With Non-Valvular Atrial Fibrillation　- A Subanalysis of the J-RHYTHM Registry.

BACKGROUND: Because the influence of digitalis use on the death of patients with non-valvular atrial fibrillation (NVAF) remains controversial, a subanalysis of the J-RHYTHM Registry was performed.Methods and Results:A consecutive series of outpatients with AF from 158 institutions was enrolled and followed for 2 years or until the occurrence of an event. Among 7,406 patients with NVAF, 7,018 (age, 69.7±10.0 years; men, 71.1%) with information on antiarrhythmic drug and digitalis use at baseline were divided into 2 groups based on digitalis use. The influence of digitalis on death was investigated using a propensity score-matching model. In 802 patients treated with digitalis, all-cause death was significantly higher than in 6,216 patients with no digitalis use during the 2-year follow-up period (4.4% vs. 2.4%, unadjusted P<0.001). Digitalis use was significantly associated with all-cause death in the crude model (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.28-2.68, P=0.001). However, after propensity score-matching, the association was not significant (HR 1.31, 95% CI 0.70-2.46, P=0.405). Older age, male sex, heart failure, coronary artery disease, and lower body mass index were significantly associated with all-cause death in NVAF patients treated with digitalis. CONCLUSIONS: Digitalis use was not independently associated with all-cause death, and several clinical confounding factors might contribute to increased mortality in NVAF patients treated with digitalis.

Digitalis therapy is associated with higher comorbidities and poorer prognosis in patients undergoing ablation of atrial arrhythmias: data from the German Ablation Registry.

BACKGROUND: Digitalis glycosides are employed for rate control of atrial fibrillation. Recent studies suggested potential harmful effects of digitalis monotherapy and combination with antiarrhythmic drugs. The aim of the present study was to assess the prevalence and potential impact of digitalis therapy on outcome in patients undergoing catheter ablation of supraventricular arrhythmias. METHODS AND RESULTS: The German Ablation Registry is a nationwide, prospective registry with a 1-year follow-up investigating 12,566 patients receiving catheter ablations of supraventricular arrhythmias in 52 German centres. The present analysis focussed on pharmacotherapy in 8608 patients undergoing catheter ablation of atrial tachycardia, atrial fibrillation, or atrial flutter. Patients receiving digitalis therapy (n = 417) were older and presented a significantly increased prevalence of comorbidities including coronary artery disease, heart failure, diabetes, and pulmonary disease. One-year mortality was significantly higher in digitalis-treated patients (4.7% vs. 1.3%, p < 0.001), most strikingly in patients undergoing ablation of atrial flutter. This effect was maintained after adjustment for important risk factors. Similar results were obtained for as the combined endpoint of death, myocardial infarction, stroke and major bleeding (6.6% vs. 2.7%, p < 0.001), and non-fatal rehospitalisations (54.1% vs. 45.1%, p = 0.001). CONCLUSION: In the present study of patients undergoing catheter ablation of supraventricular arrhythmias, an association of digitalis therapy with increased mortality and an increased rate of other severe adverse events were observed. The results from this 'real-life' registry are consistent with previously published studies. However, whether digitalis therapy promotes a poorer prognosis or may just serve as a marker for this aspect cannot be thoroughly interpreted.

Impact of the duration of the evidence-based medicine use in acute heart failure: A nationwide cohort study.

BACKGROUND: Several randomized control trials have established that drugs can decrease the heart failure (HF) rehospitalization in patients with HF. However, limited studies have investigated the duration of medicine use to decrease the rehospitalization period in the real world. Hence, this study aims to investigate whether the evidence-based medicine decreases the HF rehospitalization in different treatment intervals in the clinical practice. METHOD: We examined patients admitted with acute HF from the National Health Insurance Research Database in Taiwan. In addition, the major adverse cardiovascular events (MACE) were the composite endpoints of the in-hospital mortality and rehospitalization after 1 year. Furthermore, we analyzed the medicine use to decrease 14 days and 1, 6, and 12 months' HF rehospitalization. RESULTS: Overall, we examined 11,012 patients. The use of the renin-angiotensin system (RAS) blockers [hazard ratio (HR), 0.58; P < 0.01], ß-blocker (HR, 0.67; P < 0.01), spironolactone (HR, 0.63; P < 0.01), and digitalis (HR, 0.67; P < 0.01) associated with the lower in-hospital mortality rate. The Cox regression analysis revealed that RAS blocker (HR, 0.86; P < 0.01) and ß-blocker (HR, 0.71; P < 0.01) were independent predictors for MACE. Although RAS blockers declined rehospitalization to 6 months, ß-blocker decreased the rehospitalization rate after 1 month use and the benefit persisted till 12 months. Furthermore, digitalis only lowered rehospitalization to 14 days. CONCLUSION: This study suggests that the use of evidence-based medicine is associated with lower MACE for patients with HF, and these drugs could play vital roles in different periods to decrease the rehospitalization in the clinical setting.

Clinical Use of Digitalis: A State of the Art Review.

The history of digitalis is rich and interesting, with the first use usually attributed to William Withering and his study on the foxglove published in 1785. However, some knowledge of plants with digitalis-like effects used for congestive heart failure (CHF) was in evidence as early as Roman times. The active components of the foxglove (Digitalis purpurea and Digitalis lanata) are classified as cardiac glycosides or cardiotonic steroids and include the well-known digitalis leaf, digitoxin, and digoxin; ouabain is a rapid-acting glycoside usually obtained from Strophanthus gratus. These drugs are potent inhibitors of cellular membrane sodium-potassium adenosine triphosphatase (Na+/K+-ATPase). For most of the twentieth century, digitalis and its derivatives, especially digoxin, were the available standard of care for CHF. However, as the century closed, many doubts, especially regarding safety, were raised about their use as other treatments for CHF, such as decreasing the preload of the left ventricle, were developed. Careful attention is needed to maintain the serum digoxin level at ≤ 1.0 ng/ml because of the very narrow therapeutic window of the medication. Evidence for benefit exists for CHF with reduced ejection fraction (EF), also referred to as heart failure with reduced EF (HFrEF), especially when considering the combination of mortality, morbidity, and decreased hospitalizations. However, the major support for using digoxin is in atrial fibrillation (AF) with a rapid ventricular response when a rate control approach is planned. The strongest support of all for digoxin is for its use in rate control in AF in the presence of a marginal blood pressure, since all other rate control medications contribute to additional hypotension. In summary, these days, digoxin appears to be of most use in HFrEF and in AF with rapid ventricular response for rate control, especially when associated with hypotension. The valuable history of the foxglove continues; it has been modified but not relegated to the garden or the medical history book, as some would advocate.

The Beat Goes On: The Story of Five Ageless Cardiac Drugs.

This article traces the history of 5 cardiac drugs-Aspirin, Atropine, Digitalis, Nitroglycerine, and Quinidine-that have been in continuous use for centuries and some for longer. Four of the 5 started life as botanicals and 4 have as also served widely varied functions far removed from their current purposes. Collectively, they have played a role in the history of royalty, religious leaders, assassinations and military campaigns in addition to their place in medical therapy. Their present clinical status has evolved from long-term clinical observation without the need for controlled clinical trials, detailed statistical analyses or FDA approvals. This review of their background illustrates the varied means by which markedly different substances from widely separated sources can come together to participate in the management of circulatory disorders.

[New pharmacologic therapies for chronic heart failure]. / Neue medikamentöse Therapieansätze bei chronischer Herzinsuffizienz.

Heart failure is a disease with a high prevalence and incidence. New therapeutic approaches are needed to prevent the onset of heart failure and to reduce the high morbidity and mortality associated with this disease. An optimized therapy of arterial hypertension in patients with risk factors and the use of the SGLT2 inhibitor empagliflozin in type 2 diabetics are proven strategies to prevent heart failure. The therapeutic options in heart failure with preserved ejection fraction are still insufficient. In heart failure with reduced ejection fraction sacubitril/valsartan, the first approved angiotensin receptor-neprilysin inhibitor, is superior to an angiotensin converting enzyme (ACE) inhibitor. Whether digitalis affects the prognosis in heart failure remains unclear; however, serum concentration should be targeted at the lower therapeutic range. Iron supplementation in heart failure with reduced systolic function and iron deficiency improves symptoms and quality of life.

Association of digitalis treatment with outcomes following myocardial infarction in patients with heart failure or evidence of left ventricular dysfunction: an analysis from the High-Risk Myocardial Infarction Database Initiative.

BACKGROUND: Contradictory findings have been reported regarding the safety and efficacy of digitalis in patients recovering from acute myocardial infarction (MI). We studied the association of digitalis use with long-term and short-term prognosis in patients presenting with an acute MI complicated with heart failure (HF), left ventricular dysfunction, or both. METHODS AND RESULTS: Using the High-Risk MI Database Initiative combining data from 4 major clinical trials, totaling 27,673 patients, we investigated the association between digitalis use at baseline (3093 patients with digitalis and 24,580 without) with the rate of all-cause death, sudden cardiac death, cardiovascular death, HF hospitalization and the combination of the latter two, over a mean follow-up time of 2.7 years. Patients with and without atrial fibrillation (AF) were studied separately. After a propensity score-based analysis, among patients without AF, those receiving digitalis experienced a higher rate of all-cause [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.42-1.67] and sudden cardiac death (HR 1.65, 95% CI 1.44-1.89), compared to those not receiving digitalis; similar results were found for the other 3 endpoints (all HR around 1.6). In contrast, in AF patients, digitalis had a milder effect on all outcomes (all HR ≤ 1.12), with significant association only for the composite endpoint (HR 1.10, 95% CI 1.00-1.21, p = 0.049); comparable results were obtained at 30 days. Finally, the detrimental effect associated with digitalis use appeared to be more pronounced in patients with ejection fraction ≥ 40%. CONCLUSIONS: In MI survivors with HF and/or systolic dysfunction, digitalis was associated with a significant increased risk of death in patients without AF with mild to neutral associations for patients with AF. These findings raise concerns regarding the safety of digitalis in MI survivors with HF, especially for those without AF.

[Digitalis, a drug to be scrapped?] / La digitale: un farmaco da rottamare?

We performed a comprehensive review of the scientific literature on the use of digoxin in heart failure and atrial fibrillation. In congestive heart failure (CHF) there is only one randomized trial with a statistical sample sufficiently large. In this trial (DIG trial), which enrolled patients with systolic left ventricular dysfunction in sinus rhythm, digoxin had a neutral action on mortality and modestly reduced the overall need of hospitalization. The study was conducted in the pre-beta-blocker era and, therefore, it has a doubtful application to the current clinical context. There are no randomized trials on atrial fibrillation, either with or without heart failure. Several observational and retrospective studies and meta-analysis have shown an association between the use of digoxin and increased mortality about 20%. Both in the European and American guidelines, even in class I recommendations, evidence is not supported by randomized or observational trials, but just by experts' opinions. Digoxin use in CHF and atrial fibrillation is related to the physician's clinical judgment, based more on consolidated custom that on established scientific evidence. In our opinion, this therapy should be withdrawn until new randomized controlled trials will provide evidence of its efficacy. Two trials have been planned to this aim. Also the issue of toxicity threshold is still unresolved; digoxinemia values should be <1 ng/ml if digoxin is used, to avoid overdosing and toxicity with increased mortality.

Digitalis use and risk of gastrointestinal cancers: A nationwide population-based cohort study.

BACKGROUND: Gastrointestinal cancers are characterized by a male predominance, suggesting a role of sex hormones. We hypothesized that digitalis medication, due to its estrogenic properties, decreases the risk of male-predominated gastrointestinal cancers. RESULTS: Long -term digitalis use (≥2 years) was followed by decreased risk for several gastrointestinal cancers, but associations were statistically significant only for liver cancer (hazard ratio [HR]=0.40, 95% confidence interval (CI) 0.16-0.98). Short-term (<1 year) use was associated with an increased risk of esophageal squamous cell carcinoma (HR=1.79, 95% CI 1.01-3.17), colorectal cancer (HR=1.72, 95% CI 1.57-1.89), gallbladder cancer (HR=1.93, 95% CI 1.04-3.59), and pancreatic cancer (HR=1.33, 95% CI 1.00-1.76), but no such increase was found among long-term users. METHODS: We performed a nationwide population-based cohort study in Sweden. Participants included 156,385 individuals using digitalis and a reference group of 551,933 users of organic nitrates between 2005 and 2013, who were identified in the Swedish Prescribed Drug Register. New diagnoses of gastrointestinal cancers were identified from the Swedish Cancer Register. Hazard ratios of gastrointestinal cancers in digitalis users compared to users of organic nitrates were calculated from Cox proportional hazards regression with adjustment for sex, age, municipality of residence and comorbidity. CONCLUSIONS: This study suggests a decreased risk of male-predominated gastrointestinal cancers, particularly of liver cancer, in long-term users of digitalis. Short-term use may be associated with an increased risk of esophageal squamous cell carcinoma, colorectal cancer, gallbladder cancer, and pancreatic cancer.The use of digitalis as preventive or therapeutic agents remains to be fully evaluated.

Epidemiology of overdose episodes from the period prior to hospitalization for drug poisoning until discharge in Japan: An exploratory descriptive study using a nationwide claims database.

BACKGROUND: Little is known about the nationwide epidemiology of the annual rate, causative substance, and clinical course of overdose-related admission. We aimed to describe the epidemiology of overdose episodes from the period prior to hospitalization for drug poisoning until discharge to home. METHODS: We assessed all cases of admission due to overdose (21,663 episodes) in Japan from October 2012 through September 2013 using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. RESULTS: The annual rate of overdose admission was 17.0 per 100,000 population. Women exhibited two peaks in admission rates at 19-34 years (40.9 per 100,000) and ≥75 years (27.8 per 100,000). Men exhibited one peak in the admission rate at ≥75 years (23.7 per 100,000). Within 90 days prior to overdose, ≥60% and ≥9% of patients aged 19-49 years received a prescription for benzodiazepines and barbiturates, respectively. In addition, 59% of patients aged ≥75 years received a prescription for benzodiazepines prior to overdose, 47% had a history of congestive heart failure, and 24% had a diagnosis of poisoning by cardiovascular drugs. The proportion of patients with recent psychiatric treatments decreased with age (65.1% in those aged 35-49 years and 13.9% in those aged ≥75 years). CONCLUSIONS: The findings emphasize the need for overdose prevention programs that focus on psychiatric patients aged 19-49 years who are prescribed benzodiazepines or barbiturates and on non-psychiatric patients aged ≥75 years who are prescribed benzodiazepines or digitalis.

In Carthage ruins: the illness of Sir Winston Churchill at Carthage, December 1943.

This paper reviews Churchill's illness in Carthage in December 1943. It was characterised by fever that lasted 6 days, left lower lobe pneumonia and two episodes of atrial fibrillation. He was managed in a private villa by Lord Moran, his personal physician, with the assistance of two nurses and the expert advice of colleagues. Sulphadiazine and digitalis leaf were prescribed and Churchill recovered. It is remarkable that, despite the severity of his illness, he continued to direct the affairs of State from his bed.

Effects of digitalis on mortality in a large cohort of implantable cardioverter defibrillator recipients: results of a long-term follow-up study in 1020 patients.

AIMS: The effects of digitalis on mortality in patients with structural heart disease are controversially discussed. We aimed to assess the effects of digitalis administration in implantable cardioverter defibrillator (ICD) recipients. METHODS AND RESULTS: This retrospective analysis comprises 1020 consecutive patients who received an ICD at our institution and who were followed for up to 10 years (median 37 months). A total of 438 patients were receiving digitalis at the time of ICD implantation and 582 did not. Patients on digitalis were more often in atrial fibrillation and had more often a prolonged QRS duration of ≥120 ms, a severely impaired left ventricular ejection fraction, and higher New York Heart Association (NYHA) classification heart failure. Crude Kaplan-Meier analysis demonstrated significantly higher mortality in patients on digitalis (HR = 2.47; 95% CI 1.87-3.25; P = 0.001). After adjustment for patient characteristics found statistically significant in adjusted Cox regression analysis (age, gender, NYHA classification, and QRS duration of ≥120 ms), a HR of 1.65 remained (95% CI 1.14-2.39; P = 0.01). Patients on digitalis died more often from cardiac arrhythmic and cardiac non-arrhythmic causes than patients not on digitalis (P = 0.04). There was no difference in mortality between patients receiving digitoxin and those receiving digoxin (HR = 1.55; 95% CI 0.74-3.25; P = 0.25). CONCLUSION: In this large ICD patient population, digitalis use at baseline was independently associated with increased mortality even after careful adjustment for possible confounders. Digitalis should be used with great caution in this population.

Sudden Cardiac Death in Patients With Atrial Fibrillation: Insights From the ENGAGE AF-TIMI 48 Trial.

BACKGROUND: Recent findings suggest that atrial fibrillation is associated with sudden cardiac death (SCD). We examined the incidence, characteristics, and factors associated with SCD in patients with atrial fibrillation. METHODS AND RESULTS: SCD was defined as witnessed death ≤60 minutes from the onset of new symptoms or unwitnessed death 1 to 24 hours after being observed alive, without another known cause of death. Predictors of SCD were examined using multivariate competing risks models. Over 2.8 years (median), 2349 patients died (40.5 per 1000 patient-years), of which 1668 (71%) were cardiovascular deaths. SCD was the most common cause of cardiovascular death (n=749; median age 73 years; 70.6% male). Most SCD events occurred out of hospital (92.8%) and without prior symptoms (66.0%). Predictors of SCD included low ejection fraction, heart failure, and prior myocardial infarction (P<0.001 for each). Additional significant baseline predictors of SCD, but not of other causes of death, included male sex, electrocardiographic left ventricular hypertrophy, higher heart rate, nonuse of beta blockers, and use of digitalis. The latter was associated with SCD in patients with or without heart failure (adjusted hazard ratio 1.55 [95% CI 1.29-1.86] and 1.56 [95% CI 1.14-2.11], respectively; Pinteraction=0.73). The rate of SCD was numerically but not statistically lower with edoxaban (1.20% per year with lower dose edoxaban; 1.28% per year with higher dose edoxaban) compared with warfarin (1.40% per year). CONCLUSION: SCD is the most common cause of cardiovascular death in patients with atrial fibrillation and has several distinct predictors, some of which are modifiable. These findings may be considered in planning research and treatment strategies for patients with atrial fibrillation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00781391.

What's Wrong with Evidence-Based Medicine?

Medicine in the last decades of the twentieth century was ripe for a data sweep that would bring systematic analysis to treatment strategies that seemingly had stood the test of time but were actually unvalidated. Coalescing under the banner of evidence-based medicine, this process has helped to standardize care, minimize error, and promote patient safety. But with this advancement, something of the art of medicine has been lost.