Effects Of Digitalis Research Articles

Effect of Digitalis on ICD or CRT-D Recipients: A Systematic Review and Meta-Analysis

Digitalis has been widely utilized for heart failure therapy and several studies have demonstrated an association of digitalis and adverse outcome events in patients receiving implantable cardioverter defibrillators (ICDs) or cardiac resynchronization therapy defibrillators (CRT-Ds). Hence, we conducted this meta-analysis to assess the effect of digitalis on ICD or CRT-D recipients. We systematically retrieved relevant studies using the Cochrane Library, PubMed, and Embase database. A random effect model was used to pool the effect estimates (hazard ratios (HRs) and 95% confidence intervals (CIs)) when the studies were of high heterogeneity, otherwise a fixed effect model was used. Twenty-one articles containing 44,761 ICD or CRT-D recipients were included. Digitalis was associated with an increased rate of appropriate shocks (HR = 1.65, 95% CI: 1.46-1.86, p < 0.001) and a shortened time to first appropriate shock (HR = 1.76, 95% CI: 1.17-2.65, p = 0.007) in ICD or CRT-D recipients. Furthermore, the all-cause mortality increased in ICD recipients with digitalis therapy (HR = 1.70, 95% CI: 1.34-2.16, p < 0.01), but the all-cause mortality was unchanged in CRT-D recipients (HR = 1.55, 95% CI: 0.92-2.60, p = 0.10) or patients who received ICD or CRT-D therapy (HR = 1.09, 95% CI: 0.80-1.48, p = 0.20). The sensitivity analyses confirmed the robustness of the results. ICD recipients with digitalis therapy may tend to have higher mortality rates, but digitalis may not be associated with the mortality rate of CRT-D recipients. Further studies are required to confirm the effects of digitalis on ICD or CRT-D recipients.

The importance of calcium in the treatment of heart disease

Prof. G. Singer (Die rztliche Praxis, No. 5, 1929. Medizinisches Seminar) expresses itself in the sense that in some heart diseases with congestion both in the large and in the small circle (mainly with myodegenerations of the heart and aortic defects), when heart and diuretics do not work, - very often they achieve good results by introducing into the body simultaneously with digitalis (intravenously or per os) 10% calcium solution in the amount of 1 snt. 3 exclusively intravenously. Calcium, enhancing the effect of digitalis on the heart, at the same time moderates its side effects on the parasympathetic system and, according to the author, is a whip and reins for the digitalis (Die Peitsche und der Zgel).

Dermite de contact secondaire à l’application du laurier rose (Nerium oleander)

IntroductionNerium Oleander is a plant that usually grows in the Mediterranean area, which known by its systemic toxicity. Its cutaneous effects are not well known, with few publications in the literature. Here we report a case of a patient who presents an acute eczema following the local application of the Nerium oleander leaves. ObservationOur case was of a 21 years old male, He had no medical history especially atopy, or a previous use of plants. He have applied directly by friction the root of the Nerium Oleander on the cheeks and the chin, without any oral ingestion. Six hours later, he noticed a sudden onset of an ill-defined erythematous and edematous closet with intense itching, surmounted with Vesicles, bullae and oozing in the area of application of the plant, with a satisfactory evolution following the prescription of topical corticosteroid for 10 days and a barrier cream. DiscussionNerium Oleander is an ornamental plant that is very common in Morocco and it grows in wetlands. The active ingredients are cardiac glycosides. Oleandrine is the main toxic heteroside. Its topical use is commun in alternative medicine, for various disorders, especially Scabies, hemorrhoid, boils and hair loss. In our case, this plant was used for acne lesions. Anamnesis did not reveal the notion of exposure to another allergen. The toxicity of the Nerium Oleander is close to the effect of digitalis, among these effects we mentioned: cardiac effects, including conduction disorders, arrhythmias with a significant risk of circulatory collapse and sudden death, neurological effects with a risk of convulsions, digestive such as the irritation of oral mucosa, hyper salivation, nausea and vomiting or gastroenteritis. As well as malaise and shivering. ConclusionIn addition of the systemic effects of the Nerium Oleander, this observation reminds it methods of use, just as much as the non-negligible probability of occurrence of cutaneous reactions.

Effect of digitalis level on readmission and mortality rate among heart failure reduced ejection fraction patients

IntroductionDigitalis has been used for over 200 years to treat patients with heart failure, and evidence supports its use to improve clinical symptoms and quality of life, but not survival. The objective of this retrospective study was to evaluate the effects of digitalis on readmission and mortality in patients with heart failure with reduced ejection fraction (HFrEF) who were receiving current guideline recommended medical therapy. MethodsWe reviewed medical record data from a retrospective cohort study of 1047 patients admitted to the hospital from 2005 to 2014 with decompensated HFrEF. 244 received digitalis, at some point during patient trajectory, and 803 never received digitalis. The primary outcomes of interest were the length of stay in hospital, readmission rates after discharge at 1, 6, 12, and 24 months and the overall mortality rate, at the same time points. ResultsWe studied the effects of digitalis after adjusting for age, sex, race, potentially confounding comorbidities, and prescription medications. Digitalis treatment is associated with decreases in EF in patients with HFrEF (OR = −2.83, P < 0.001) and was associated with an increased readmission rate for any reason after discharge from the hospital at 6, 12, and 24 months, 53%, 34%, and 35%, respectively. No statistically significant difference was found between patients who received digitalis and those who did not (referent group) for the length of hospital stay and overall mortality rate. ConclusionDigitalis use is associated with increased re-admission rates for any reason following discharge from the hospital at 6, 12, and 24 months.

Long-Term Effects of Flosequinan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the PROFILE Trial After 24 Years

ObjectivesThe purpose of this clinical trial was to evaluate the long-term effects of flosequinan on the morbidity and mortality of patients with severe chronic heart failure. BackgroundFlosequinan was the first oral vasodilator to be used in the clinic to augment the effects of digitalis, diuretics, and angiotensin-converting enzyme inhibitors in heart failure. However, the drug activated neurohormonal systems and exerted both positive inotropic and chronotropic effects, raising concerns about its safety during long-term use. MethodsFollowing a run-in period designed to minimize the risk of tachycardia, we randomly assigned 2,354 patients in New York Heart Association functional class III to IV heart failure and with an ejection fraction ≤35% to receive long-term treatment with placebo or flosequinan (75 or 100 mg/day) in addition to their usual therapy. The primary outcome was all-cause mortality. ResultsThe trial was terminated after a recommendation of the Data and Safety Monitoring Board, because during an average of 10 months of follow-up, 192 patients died in the placebo group and 255 patients died in the flosequinan group (hazard ratio: 1.39, 95% confidence interval: 1.15 to 1.67; p = 0.0006). Flosequinan also increased the risk of disease progression, which was paralleled by drug-related increases in heart rate and neurohormonal activation. However, during the first month, patients in the flosequinan group were more likely to report an improvement in well-being and less likely to experience worsening heart failure. Similarly, during the month following drug withdrawal at the end of the trial, patients withdrawn from flosequinan were more likely than those withdrawn from placebo to report symptoms of or to require treatment for worsening heart failure. ConclusionsAlthough flosequinan produced meaningful symptomatic benefits during short- and long-term treatment, the drug increased the risk of death in patients with severe chronic heart failure.

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.

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. 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). 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.

Digitalis for treatment of heart failure in patients in sinus rhythm.

Digitalis glycosides have been in clinical use for the treatment of heart failure (HF) for longer than 200 years. In recent years, several trials have been conducted to address concerns about their efficacy and toxicity. To examine the effectiveness of digitalis glycosides in treating HF in patients with normal sinus rhythm. To examine the effects of digitalis in patients taking diuretics and angiotensin-converting enzyme inhibitors; in patients with varying severity and duration of disease; in patients with prior exposure to digitalis versus no prior exposure; and in patients with "HF due to systolic dysfunction" versus "HF with preserved ejection fraction." Searches on the following databases were updated in May 2013: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Dissertation Abstracts. Annual meeting abstracts of the American Heart Association, the American College of Cardiology, and the European Society of Cardiology were searched from 1996 to March 2013. In addition, reference lists provided by the pharmaceutical industry (GlaxoSmithKline and Covis Pharma) were searched. Included were randomized placebo-controlled trials of 20 or more adult participants of either sex with symptomatic HF who were studied for seven weeks or longer. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of HF such as acute ischemic heart disease or myocarditis was present. Articles selected from the searches described above were evaluated in a joint effort of the review authors. The staff of the Cochrane Heart Group ran searches on the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE. No new studies were identified in the updated searches. Thirteen studies (7896 participants) are included, and major endpoints of mortality, hospitalization, and clinical status, based respectively on 8, 4, and 12 of these selected studies, were recorded and analyzed. The data show no evidence of a difference in mortality between treatment and control groups, whereas digitalis therapy is associated with lower rates of both hospitalization and clinical deterioration. The largest study, in which most participants were taking angiotensin-converting enzyme inhibitors, showed a significant rise in "other cardiac" deaths, possibly due to arrhythmias. However collectively, these findings were based on studies done before beta-blockers, as well as angiotensin receptor blockers and aldosterone antagonists, became widely used to treat HF. The literature indicates that digitalis may have a useful role in the treatment of patients with HF who are in normal sinus rhythm. New trials are needed to elucidate the importance of the dosage of digitalis and its usefulness in the era of beta-blockers and other agents shown to be effective in treating HF.

A new indication for digoxin: To enable introduction and dose-escalation of ß-blocker therapy in severe heart failure

After over two centuries of usage, digoxin is still being prescribed in modern therapeutics in cardiology. However, since the publication of the DIG trial [1], there have been debates about its use because of the neutral primary all-cause mortality endpoint. Subsequent analyses of the data showed that lower doses of digoxin produced beneficial survival benefits [2]. Since the positive inotropic effects of digitalis have been shown mostly at higher doses [3], a question has been raised regarding how digoxin could possibly produce beneficial effects if used at low doses.

Phase II trial of second-line erlotinib and digoxin for nonsmall cell lung cancer (NSCLC)

Phase II trial of second-line erlotinib and digoxin for nonsmall cell lung cancer (NSCLC) Fadi Kayali, Muhamad A Janjua, Damian A Laber, Donald Miller, Goetz H KloeckerUniversity of Louisville, James Graham Brown Cancer Center, Louisville, KY, USABackground: In vitro digoxin sensitizes cancer cells to the induction of apoptosis by chemotherapy. Inhibition of the Na/K-ATPase enzyme by ouabain disturbs the intracellular ion composition of cancer cells, altering cellular homeostasis. This suggests that inhibition of the Na/K pump results in cellular sensitization of malignant but not benign cells to the induction of apoptosis. Epidemiologic studies have also shown beneficial effects of digitalis in breast cancer incidence. At ASCO (American Society of Clinical Oncology) 2007 our group presented a Phase II study showing encouraging results by adding digoxin to biochemotherapy for melanoma. Erlotinib is one of the standard second-line treatments for nonsmall cell lung cancer (NSCLC), with a response rate (RR) of 10%. This study's hypothesis was that adding digoxin to erlotinib will improve the RR and time to progression (TTP) in NSCLC.Methods: Patients with progressive disease (PD) after chemotherapy were enrolled if they had an ECOG (Eastern Cooperative Oncology Group) score from 0 to 2 and good organ function. Daily erlotinib 150 mg and digoxin 0.25 mg were taken by mouth. The digoxin dose was adjusted to keep levels between 1 and 2 ng/mL. Computed tomography scans were done every 6 weeks. Treatment continued until PD or significant toxicity occurred.Results: Patient accrual lasted from March 2006 until August 2008 and was stopped early at the time of interim analysis. Twenty-eight patients were enrolled, and 24 who completed at least 6 weeks of therapy are presented here. All patients had unresectable NSCLC stage III/IV at diagnosis. Median age was 61 (34–78), 14 were female, 17 had prior radiation (not involving the target lesions), 23 had one prior chemotherapy, and one subject had two. Only one patient was a never-smoker. Histologies were 50% adenocarcinoma, 30% squamous, and 20% unspecified. One patient had a partial response, nine had stable disease, and 14 had progressive disease. The median TTP was 61 days (9–366) and median survival 157 days (9–844). Side effects were similar to erlotinib single agent with no treatment-related mortality. There were no unexpected or increased adverse events related to digoxin.Conclusions: Digoxin did not increase the response rate of erlotinib in the treatment of progressive NSCLC. The TTP and survival seen in this study were similar to the published results with erlotinib alone. This combination does not warrant further clinical studies in NSCLC.Keywords: metastatic lung cancer treatment, digitalis, erlotinib

Signaling through the Na/K-ATPase: implications for cardiac fibrosis

the cardiotonic effects of digitalis have been exploited in clinical practice for many years. However, while the existence of endogenous digitalis-like substances (also called cardiotonic steroids) has been accepted for some time, their exact chemical nature has been only recently demonstrated ([1][

Phase II trial of second-line erlotinib and digoxin in patients with non-small cell lung cancer (NSCLC)

e19077 Background: There is laboratory evidence that digoxin sensitizes cancer cells to the induction of apoptosis by chemotherapy. Inhibition of the Na/K-ATPase enzyme by ouabain disturbs the intracellular ion composition of cancer cells, altering cellular homeostasis. This suggests that inhibition of the Na/K pump results in cellular sensitization of malignant, but not benign cells to induction of apoptosis. Epidemiologic studies also have shown beneficial effects of digitalis in breast cancer incidence. At ASCO 2007 our group presented a phase II study showing encouraging results by adding digoxin to bio-chemotherapy for melanoma. Erlotinib is one of the standard second-line treatments for NSCLC with a response rate (RR) of 10%. This study hypothesized, that adding digoxin to erlotinib may improve the RR and time to progression (TTP) in NSCLC. Methods: This was a phase II trial using daily 150 mg erlotinib and digoxin 0.25 mg. The digoxin dose was adjusted to keep levels between 1–2 ng/ml. Patients with progressive disease (PD) after chemotherapy were enrolled, if they had an ECOG 0–2 and good organ function. CT scans were done every 6 weeks. Treatment continued until PD or significant toxicity occurred. Results: Patient accrual lasted from 3/06–8/08 and was stopped early at time of interim analysis. Twenty eight patients were enrolled and 24, who completed at least 6 weeks of therapy, are presented here. All patients had unresectable stage III/IV at diagnosis. Median age was 61 (34–78), 14 were female, 17 had prior radiation (not involving the target lesions), 23 had one prior chemotherapy and 1 subject had two. Only one patient was a never smoker. Histologies were 50% adenocarcinoma, 30% squamous and 20% unspecified. One patient had a PR, 9 SD, and 14 PD. The median TTP was 61 days (9–366) and median survival 157 days (9–844). Side effects were similar to erlotinib single agent with no treatment related mortality. There were no unexpected or increased adverse events related to digoxin. Conclusions: Digoxin did not increase the response rate of erlotinib in the treatment of progressive NSCLC. TTP and survival seen in this study were similar to the published results with erlotinib alone. This combination does not warrant further clinical studies in NSCLC. No significant financial relationships to disclose.

Dual activity of the H1-H2 domain of the (Na++K+)-ATPase

(Na++K+)-ATPase is a target receptor of digitalis (cardiac glycoside) drugs. It has been demonstrated that the H1-H2 domain of the α-subunit of the (Na++K+)-ATPase is one of the digitalis drug interaction sites of the enzyme. Despite the extensive studies of the inhibitory effect of digitalis on the (Na++K+)-ATPase, the functional property of the H1-H2 domain of the enzyme and its role in regulating enzyme activity is not completely understood. Here we report a surprise finding: instead of inhibiting the enzyme, binding of a specific monoclonal antibody SSA78 to the H1-H2 domain of the (Na++K+)-ATPase elevates the catalytic activity of the enzyme. In the presence of low concentration of ouabain, monoclonal antibody SSA78 significantly protects enzyme function against ouabain-induced inhibition. However, higher concentration of ouabain completely inactivates the (Na++K+)-ATPase even in the presence of SSA78. These results suggest that the H1-H2 domain of the (Na++K+)-ATPase is capable of regulating enzyme function in two distinct ways for both ouabain-sensitive and -resistant forms of the enzyme: it increases the activity of the (Na++K+)-ATPase during its interaction with an activator; it also participates in the mechanism of digitalis or ouabain-induced inhibition of the enzyme. Understanding the dual activity of the H1-H2 domain will help better understand the structure–function relationships of the (Na++K+)-ATPase and the biological processes mediated by the enzyme.

It could have happened to Van Gogh: a case of fatal purple foxglove poisoning and review of the literature

Although death owing to the toxic effects of the therapeutic Digitalis lanata extract, digoxin has been reported, there are no reported cases of fatal Digitalis purpurea (digitoxin) plant intoxication in humans in the literature. We describe a case of ingestion of Digitalis purpurea in a 64-year-old man, which was fatal despite administration of Digibind. A review of the literature and aspects of management of plant digitalis poisoning are discussed.

Role of Digitalis in the Contemporary Management of Systolic Heart Failure in African Americans

Introduction: The effects of digitalis in patients with systolic heart failure (SHF) have not been evaluated in the era of contemporary medical therapy including the use of beta blockers. In the African-American Heart Failure Trial (A-HeFT), the fixed-dose combination of isosorbide dinitrate/hydralazine (FDC I/H) decreased mortality and morbidity and improved patient reported functional status in self-identified black patients with SHF stabilized on contemporary heart failure (HF) therapy. Objective: We investigated the effect of digitalis in A-HeFT. Methods: A pre-specified Kaplan-Meier survival analysis was performed to determine the effect of FDC I/H compared to placebo with or without the use of digitalis (n = 1050). Analogous retrospective analyses within the FDC I/H and placebo groups were performed. Results: In A-HeFT, 62% of patients received digitalis at baseline. Patients receiving digitalis had lower systolic BP (125 vs. 128 mmHg), diastolic BP (76 vs. 78 mmHg), and qualifying LV ejection fraction (23.3 vs. 25.6%). Concomitant medications were comparable for either ACEI or ARB (93%) and beta blockers (87%). Digitalis users had significantly higher use of diuretics (94 vs. 89%) and spironolactone (45 vs. 29%). Compared to placebo, FDC I/H was associated with 53% improvement in survival (p < 0.01), and a 32% decrease in death or first HF hospitalization (p < 0.01) in patients treated with digitalis. There was a trend for an increase in all-cause mortality in patients receiving digitalis (Table) that was noted in the placebo group (HR = 1.65; 95% CI 0.91-2.76; p = 0.102) and not the FDC I/H group (HR = 1.02; 95% CI 0.50-2.10; p = 0.96). Digitalis use was associated with a significant increase in the risk of mortality or first heart failure hospitalization. Conclusions: FDC I/H improved outcomes in patients with HF independent of the use of digitalis. Within the limitations of sub-group analysis, our data indicate that the use of digitalis was not associated with beneficial effects on morbidity and mortality in black patients with SHF receiving contemporary therapy.Tabled 1Effect of Digitalis on Outcomes in All A-HeFT PatientsOutcomeHazard Ratio95% CIRisk Increasep ValueDeath1.380.88-2.1138%0.166Death or 1st HF Hospitalization1.381.06-1.7438%0.015 Open table in a new tab

Sodium pumps: ouabain, ion transport, and signaling in hypertension

TO THE EDITOR: A recent Editorial Focus in this journal (7) addresses the newly recognized role of the sodium pump as both an ion transport protein and a hormone receptor with its own signaling cascade. The relative importance of the cardiotonic steroids (CTS) as endogenous signaling hormones versus their ability to inhibit the sodium pump is of great interest. Indeed, the article noted that “although all digitalislike compounds inhibit Na-K-ATPase-mediated transport, they differ considerably in terms of their hypertensive effects.” The author concludes that “these findings do not support the prevailing hypothesis that the pathophysiological effect of digitalis results from inhibition of . . . transport activity.” This implies that the hypertensive effect of CTS may be due to the action of these agents as regulators of signal transduction, entirely unrelated “to its (Na-K-ATPase’s) role as an ion pump.” The discoveries related to Src kinase-mediated signal transduction by Na-K-ATPase add a new dimension to the view that the endogenous cardiotonic steroids comprise a novel hormone system. Nevertheless, the view that CTS induced hypertension is unrelated to inhibition of ion transport is inconsistent with published reports. Regrettably, the Editorial Focus does not cite key articles that support the conclusion that CTS hypertension is secondary to inhibition of sodium pumps. It is true that the tendency of certain CTS to induce hypertension does not correlate with their relative potency as Na-KATPase inhibitors (8, 9). The most obvious comparison is that ouabain induces hypertension while digoxin (1, 9) and a digitoxigenin derivative, PST-2238 (4), are antihypertensive. This need not imply that ouabain’s effect on blood pressure is unrelated to inhibition of Na transport. Instead, these data are consistent with the interpretation that some CTS have mixed agonist/antagonist properties. Viability of the hypothesis that enhancement of cytoplasmic Ca 2 responses by ouabain is related to inhibition of Na-KATPase relies on the secondary effect of Na on Na/Ca exchange. There is now direct evidence that elevation of blood pressure is a consequence of reduced transport activity of the ouabain-sensitive Na-K-ATPase 2-isoform (2, 3, 10) and the resultant Ca 2 gain mediated by Na/Ca exchange (3, 5, 10). Moreover, reduced 2 expression leads to murine hypertension (10). The vascular myogenic effect of that model is prevented by the Na/Ca exchange inhibitor SEA0400 (10). A key role for Na/Ca exchange is revealed by the observation that SEA0400 lowers blood pressure in ouabain-induced hypertension and other forms of salt-dependent hypertension, but not salt-independent hypertension (5). These findings demonstrate that ouabain’s hypertensive effect depends on its inhibition of the Na-K-ATPase and Ca 2 gain via Na/Ca exchange. Thus Src signaling, alone, appears to be insufficient to raise blood pressure in ouabain-induced hypertension although an accessory role is not excluded. Comparison of the effect of reduced expression of the 2 Na-K-ATPase (6) with that of low-dose ouabain on cell signaling may be a useful way to determine the roles of altered Na and Ca 2 in mediating the effects of ouabain on Src kinase signaling.

Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data

Objective:In heart failure, digitalis increases exercise capacity and reduces morbidity, but has no effect on survival. This raises the suspicion that the inotropic benefits of digitalis may be counteracted by...

Contemporary Use of Digoxin in the Management of Cardiovascular Disorders

Digitalis is the oldest compound in cardiovascular medicine that continues to be used in contemporary clinical practice.1 Evidence supporting the beneficial effects of digoxin on hemodynamic, neurohormonal, and electrophysiological parameters has been accumulated from >200 years of clinical experience and research (Table 1).2 View this table: TABLE 1. Effects of Digoxin Digoxin was approved for heart failure in 1998 under current regulations by the Food and Drug Administration on the basis of the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED), Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme (RADIANCE), and Digitalis Investigators Group (DIG) clinical trials.3–5 It was also approved for the control of ventricular response rate for patients with atrial fibrillation. The most recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend digoxin for symptomatic chronic heart failure for patients with reduced systolic function (Class IIa recommendation: weight of evidence/opinion is in favor of usefulness/efficacy), preserved systolic function (Class IIb: usefulness/efficacy is less well established by evidence/opinion), and/or rate control for atrial fibrillation with a rapid ventricular response (Class IIa).6 The new Heart Failure Society of America guidelines for heart failure provide similar recommendations.7 Despite its relatively recent approval by the Food and Drug Administration and the guideline recommendations, digoxin use is decreasing in patients with heart failure.8 In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry, only 30% of patients with left ventricular systolic dysfunction were being treated with digoxin before admission. Digoxin was added in only 8% of patients before discharge despite the fact that they had signs and symptoms of heart failure while receiving diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs) and β-blockers.9,10 This decrease in digoxin use is likely the result of several factors. …

Gender-specific prescription for cardiovascular diseases?

The interest of the scientific and medical community on the impact of cardiovascular diseases in women has significantly grown in the last few years. Cardiovascular disease is indeed the leading cause of death among both women and men, even if this unequivocal epidemiological observation had not been taken into the right consideration in the past. Although cardiovascular diseases are equally important in men and women, gender differences in the clinical manifestation and progression of the disease have been demonstrated. The understanding of these differences is of crucial importance for the improvement of the clinical management of cardiovascular diseases and for the development of possible new gender-specific diagnostic and therapeutic options. Women, for many years, have been underrepresented in randomized clinical trials and only recently there has been a significant increase in the number and proportion of women who participate in these studies. Accordingly, the possibility of different responses to pharmacological therapy in women and in men has recently emerged as part of the gender-related issues of cardiovascular disease. The review by Jochmann et al. 1 addresses the gender differences in pharmacokinetics, pharmacodynamics, and physiology which may contribute to a different response to cardiovascular drugs in women when compared with men. The authors analysed several clinical trials of cardiovascular drugs which involved a significant proportion of women as well as the studies which specifically addressed the issue of gender differences in pharmacokinetics and pharmacodynamics of agents utilized for prevention and treatment of cardiovascular disease. It is interesting to note that of the 300 new drug applications received by the Food and Drug Administration (FDA) between 1995 and 2000, only 163 included an analysis according to gender. However, 11 of these drugs showed a difference in pharmacokinetics between men and women. 2 The differences between women and men in the response to drugs are related to a lower body weight, smaller organ sizes, and a higher proportion of fat in women when compared with men. In addition, hormone levels and differences in metabolism may affect absorption and elimination of drugs in women. 2 The cytochrome P450 (CYP) enzymes are responsible for the metabolism of most cardiovascular drugs, including many antiarrhythmics, and beta-blockers. Genetic polymorphisms in the expression of several CYP enzymes involved in drugs metabolism may influence the manifestation of adverse events and the efficacy of several agents. Gender differences in enzymes’ activity have been demonstrated for several CYP metabolized drugs, including diltiazem, nifedipine, and verapamil, with a significantly increased activity in women when compared with men. Gender differences in the elimination of drugs may also play a role, as the glomerular filtration rate is lower in women than in men, even after adjustment for body size. 2 All these differences may account for gender effects on both adverse reactions and efficacy of cardiovascular drugs. In the DIG trial, it has been shown that women affected by heart failure who received digoxin had a higher mortality than those receiving placebo. 3 This effect was not observed in men. Notably, only 2.3% of men compared with 3.4% of women had digoxin concentrations .2.0 ng/mL. The observation that the oral clearance of digoxin, a drug mostly eliminated by the kidney, is lower in women than in men may partially explain these different effect of digitalis on mortality. Women have a greater risk of developing some specific adverse drug reactions than men. The prevalence of druginduced torsades des pointes is higher in women than in men. A review of reported cases of cardiovascular drugrelated torsades des pointes showed a female prevalence of 70%. 4 Among patients who received dl-sotalol, torsades des pointes developed in 1.9% of males and in 4.1% of females, and proarrhythmia associated with the administration of erythromycin was also more common in women than in men, as shown by the Food and Drugs Administration database, where 67% of subjects who experienced lifethreatening arrhythmias were females. 5 Female gender is associated with a longer QT interval corrected for heart rate (QTc), an effect which is not present at birth and

Historical Vignettes in Heart Failure

“The Foxglove when given in very large and quickly-repeated doses, occasions sickness, vomiting, purging, giddiness, confused vision, objects appearing green or yellow; increased secretion of urine, with frequent motions to part with it, and sometimes inability to retain it; slow pulse, even as slow as 35 in a minute, cold sweats, convulsions, syncope, death…. “The directions therefore required an additional attention to the state of the pulse, and it was moreover of consequence not to repeat the doses too quickly, but to allow sufficient time for the effects of each to take place, as it was found very possible to pour an injurious quantity of the medicine, before any of the signals for forbearance appeared. “Let the medicine therefore be given in the doses, and the intervals mentioned above:—let it be continued until either acts on the kidneys, the stomach, the pulse, or the bowels; let it be stopped upon the first appearance of any of these effects, and I will maintain that the patient will not suffer from the exhibition, nor the practitioner be disappointed in any reasonable expectation…. “…I beg leave to deduce a few inferences, which I apprehend the facts will fairly support. That the digitalis will not universally act as a diuretic. That it does do so more generally than any other medicine. That it will often produce this effect after every other probable method has been fruitlessly tried. That if it fails, there is but little chance of any other medicine succeeding. That in proper doses, and under the management now pointed out, it is mild in its operation, and gives less distur bances to the system, than squill, or almost any other active medicine. That when dropsy is attended by palsy, unsound viscera, great debility, or other complication of disease, neither digitalis, nor any other diuretic can do more than obtain a truce to the urgency of the symptoms; unless by gaining time, it may afford opportunity for other medicines to combat and subdue the original disease. That the digitalis may be used with advantage in every species of dropsy, except the encysted. That it may be made subservient to the cure of diseases, unconnected with dropsy. That is has a power over the motion of the heart, to a degree yet unobserved in any other medicine, and that this power may be converted to salutary ends.”1 Withering's book1 describes his experience with digitalis in detail, including the evaluation of the dose response and the description of the beneficial and toxic effects of the drug. In this passage at the end of the book, Withering gives an account of the kinds of patients with dropsy who might respond to digitalis, clearly summarizes the side effects and signs of overdose, covers the method of securing an optimal dose by dose titration against the onset of the first adverse effect in an individual patient, and finally, he lists the inferences of his experience. The latter demonstrates that although Withering thought digitalis was mainly a diuretic, he also thought it had cardiac activity when he stated: “… has a power over the motion of the heart, to a degree yet unobserved in any other medicine, and that this power may be converted to salutary ends.” More than 200 years have passed since the publication of Withering's masterpiece, and digitalis is still in use today for the treatment of heart failure. We have learned more about the effects of digitalis, but the principles of its use clearly elucidated in the book have withstood the passage of time. Withering's book represents one of the first clinical trials and the first piece of what today is called evidence-based medicine. The only treatment utilized at that time was bloodletting, so the introduction of digitalis in the medical armamentarium represented a defining moment in the treatment of heart failure and was a real triumph in the practice of medicine.

Triggering of Ventricular Tachycardia by Meteorologic and Emotional Stress: Protective Effect of -Blockers and Anxiolytics in Men and Elderly

A circadian pattern with a morning peak and the triggering role of emotional stress have been suggested for ventricular arrhythmias. After controlling for participant baseline characteristics and medication used, the authors studied the association of emotional upset, physical activity, and meteorologic parameters with occurrence of ventricular tachycardia (VT) in 457 Croatian participants aged 11-88 years consecutively assigned to undergo continuous 24-hour Holter monitoring. In 2001, multivariate analysis of possible VT precipitators was performed separately for men, women, those aged <65 years, and those aged >64 years. A U-shaped pattern of wind speed (either very weak or very strong), rising relative air moisture, falling atmospheric pressure, and emotional upset were independent predictors of VT episodes in all participant subgroups. Positive association of VT with higher atmospheric temperature or pressure was observed in women and elderly. After adjustment for external triggers, a circadian variation in VT episodes persisted in women (p = 0.01) and those aged <65 years (p < 0.0001) only. A protective effect of beta-blockers and anxiolytics was especially apparent for men and elderly, as well as an adverse effect of digitalis in women. Results suggest that meteorologic and emotional stress could be considered external triggers of VT, with age- and sex-dependent susceptibility.