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Responses of patients in heart failure to long-term oral verapamil administration

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... The experience related to the use of verapamil in heart failure is limited because of the known negative inotropic effect of the drug and the warning by the manufacturer concerning the risk of developing heart failure [40]. In a small study, Ferlinz and Gallo [41] demonstrated symptomatic deterioration in 4 of 10 patients with CHF on long-term verapamil therapy in spite of acute Calcium Channel Blockers in Heart Failure Cardiology 1998;89(suppl 1):38-46 41 hemodynamic improvement. The Danish study on the effect of verapamil on death or reinfarction [42] in survivors of acute myocardial infarction may provide some indirect but useful information regarding the effect of this calcium antagonist in patients with chronic heart failure. ...
... The experience related to the use of verapamil in heart failure is limited because of the known negative inotropic effect of the drug and the warning by the manufacturer concerning the risk of developing heart failure [40]. In a small study, Ferlinz and Gallo [41] demonstrated symptomatic deterioration in 4 of 10 patients with CHF on long-term verapamil therapy in spite of acute Calcium Channel Blockers in Heart Failure Cardiology 1998;89(suppl 1):38-46 41 hemodynamic improvement. The Danish study on the effect of verapamil on death or reinfarction [42] in survivors of acute myocardial infarction may provide some indirect but useful information regarding the effect of this calcium antagonist in patients with chronic heart failure. ...
... In summary, available informations demonstrate a strong vasodilatory effect of nisoldipine in patients with 42 Cardiology 1998;89(suppl 1): [38][39][40][41][42][43][44][45][46] Elkayam CHF resulting in decreased LV afterload and leads to augmentation of cardiac output and LV ejection fraction in some patients. These changes, however, result in either no or small changes in exercise capacity. ...
Article
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A considerable effort has been made in the last 15 years to evaluate the safety and efficacy of calcium channel blockers (CCBs) in the treatment of patients with chronic congestive heart failure (CHF). Available studies have provided strong evidence for a potential detrimental effect of the first-generation calcium antagonists in patients with CHF, indicating the need for great caution when these drugs are used in patients with significant depression of left ventricular systolic function. A number of second-generation CCB have demonstrated a strong vasodilatory effect and favorable hemodynamic action but failed to show a similar improvement in exercise capacity, morbidity and mortality. Moreover, drugs such as nicardipine and nisoldipine have resulted in a detrimental effect in some patients and, therefore, cannot be considered safe when used in patients with moderate-to-severe heart failure. Available information from the V-HeFT III study demonstrate a lack of an unfavorable effect of felodipine on exercise tolerance in patients with chronic heart failure. Although mortality rate was similar in both the felodipine and the placebo group, because of the relatively small number of patients in this study, no clear conclusion can be drawn regarding the effect of felodipine on mortality in patients with CHF. An encouraging signal regarding a potential role of CCB in the treatment of chronic heart failure has been provided by the recently completed PRAISE study. This prospective large-scale study demonstrated the safety of amlodipine, a long-acting dihydropyridine derivative, when used in patients with heart failure due to coronary artery disease. Furthermore, this study demonstrated a substantial reduction in mortality in patients with CHF due to nonischemic cardiomyopathy and provided a strong indication for a potential therapeutic benefit of amlodipine when added to standard CHF therapy in this patient population. No clear explanation is available at the present time regarding the reason for the deleterious effect demonstrated with some of the dihydropyridines and the contrasting benefit seen with amlodipine. Finally, more information regarding the safety and efficacy of dihydropyridines should become available in the next year. The PRAISE II study is ongoing and will provide further information regarding the therapeutic role of amlodipine in patients with nonischemic dilated cardiomyopathy. The MACH-1 study is evaluating the effect of mibefradil, a predominant T-type channel blocker with an ideal activity profile, on morbidity and mortality in patients with chronic CHF.
... The experience related to the use of verapamil in heart failure is limited because of the known negative inotropic effect of the drug and the warning by the manufacturer concerning the risk of developing heart failure [40]. In a small study, Ferlinz and Gallo [41] demonstrated symptomatic deterioration in 4 of 10 patients with CHF on long-term verapamil therapy in spite of acute Calcium Channel Blockers in Heart Failure Cardiology 1998;89(suppl 1):38-46 41 hemodynamic improvement. The Danish study on the effect of verapamil on death or reinfarction [42] in survivors of acute myocardial infarction may provide some indirect but useful information regarding the effect of this calcium antagonist in patients with chronic heart failure. ...
... The experience related to the use of verapamil in heart failure is limited because of the known negative inotropic effect of the drug and the warning by the manufacturer concerning the risk of developing heart failure [40]. In a small study, Ferlinz and Gallo [41] demonstrated symptomatic deterioration in 4 of 10 patients with CHF on long-term verapamil therapy in spite of acute Calcium Channel Blockers in Heart Failure Cardiology 1998;89(suppl 1):38-46 41 hemodynamic improvement. The Danish study on the effect of verapamil on death or reinfarction [42] in survivors of acute myocardial infarction may provide some indirect but useful information regarding the effect of this calcium antagonist in patients with chronic heart failure. ...
... In summary, available informations demonstrate a strong vasodilatory effect of nisoldipine in patients with 42 Cardiology 1998;89(suppl 1): [38][39][40][41][42][43][44][45][46] Elkayam CHF resulting in decreased LV afterload and leads to augmentation of cardiac output and LV ejection fraction in some patients. These changes, however, result in either no or small changes in exercise capacity. ...
Article
Full-text available
Patients with heart failure are particularly susceptible to the negative effects of calcium channel blockers because the failing heart demonstrates a defect in the delivery of calcium to the contractile proteins, and an attenuation of the normal sympathetic reflexes. Currently these drugs have no place in the treatment of heart failure caused by systolic dysfunction of the left ventricle. Calcium channel blockers should probably not be described for patients with coronary artery disease and left ventricular dysfunction. When the patient needs additional treatment for angina and beta-blockers or nitrates have not given satisfactory results, it may be appropriate to prescribe amlodipine or felodipine.
... The experience related to the use of verapamil in heart failure is limited because of the known negative inotropic effect of the drug and the warning by the manufacturer concerning the risk of developing heart failure [40]. In a small study, Ferlinz and Gallo [41] demonstrated symptomatic deterioration in 4 of 10 patients with CHF on long-term verapamil therapy in spite of acute Calcium Channel Blockers in Heart Failure Cardiology 1998;89(suppl 1):38-46 41 hemodynamic improvement. The Danish study on the effect of verapamil on death or reinfarction [42] in survivors of acute myocardial infarction may provide some indirect but useful information regarding the effect of this calcium antagonist in patients with chronic heart failure. ...
... The experience related to the use of verapamil in heart failure is limited because of the known negative inotropic effect of the drug and the warning by the manufacturer concerning the risk of developing heart failure [40]. In a small study, Ferlinz and Gallo [41] demonstrated symptomatic deterioration in 4 of 10 patients with CHF on long-term verapamil therapy in spite of acute Calcium Channel Blockers in Heart Failure Cardiology 1998;89(suppl 1):38-46 41 hemodynamic improvement. The Danish study on the effect of verapamil on death or reinfarction [42] in survivors of acute myocardial infarction may provide some indirect but useful information regarding the effect of this calcium antagonist in patients with chronic heart failure. ...
... In summary, available informations demonstrate a strong vasodilatory effect of nisoldipine in patients with 42 Cardiology 1998;89(suppl 1): [38][39][40][41][42][43][44][45][46] Elkayam CHF resulting in decreased LV afterload and leads to augmentation of cardiac output and LV ejection fraction in some patients. These changes, however, result in either no or small changes in exercise capacity. ...
Article
The rationale for the use of calcium channel blockers in patients with chronic heart failure lies in their vasodilator action, antiischemic effect, ability to lessen left ventricular diastolic dysfunction and data showing their effect in preventing progression of myocardial dysfunction in animals with cardiomyopathy. Despite initial studies reporting improvement of the hemodynamic profile with nifedipine, further evaluation showed variable results, with hemodynamic worsening seen in up to 29% of patients. Longer-term controlled studies evaluating symptoms and clinical status demonstrated worsening chronic heart failure in approximately 25% of patients within 8 weeks of nifedipine therapy. Although diltiazem has a lesser myocardial depressant effect and its short-term use was associated with less frequent hemodynamic and clinical worsening, long-term exposure to the drug in a large group of patients with chronic heart failure due to left ventricular systolic dysfunction after myocardial infarction resulted in an increased incidence of cardiac events, with worsening heart failure and death. The use of verapamil in a similar patient cohort showed the loss of its demonstrated protective effect in patients with clinical evidence of heart failure. In an attempt to improve the safety of calcium channel blockers, the following approaches were suggested: 1) use of second-generation drugs with less myocardial depressant effect; 2) concomitant use of angiotensin-converting enzyme inhibitors to prevent reported neurohormonal activation; and 3) development of drugs with favorable neurohormonal effects. These approaches led to mixed results.(ABSTRACT TRUNCATED AT 250 WORDS)
... In the congestive HF group, 4 patients had to be withdrawn because of clinical deterioration, while left ventricular function evaluated by serial echocardiographic examinations remained normal in the control group despite the negative inotropic effect of the drug. [13]. Chew et al. studied the effect of IV verapamil in 25 patients with coronary artery disease. ...
Article
Full-text available
Purpose The 2021 European Society of Cardiology guidelines on acute and chronic heart failure (HF) recommend that non-dihydropyridine calcium channel blockers (NDCC) should be avoided in patients with HF with reduced ejection fraction. It also emphasizes that beta-blockers only be initiated in clinically stable, euvolemic patients. Despite these recommendations, NDCC and beta-blockers are often still employed in patients with AF with rapid ventricular response and acute decompensated HF. The relative safety and efficacy of these therapies in this setting is unclear. Methods To address the question of the safety and efficacy of NDCC and beta-blockers for acute rate control in decompensated HF, we provide a perspective on the literature of NDCC and beta-blockers in chronic HF with reduced and preserved ejection fraction and AF, including trials on the management of AF with rapid ventricular response with and without HF. Results Robust data demonstrates mortality benefits when beta-blockers are used in patients with chronic HF with reduced ejection fraction. The data that inform the contraindication of NDCC in HF with reduced ejection fraction are outdated and were not primarily designed to address the efficacy and safety of rate control of AF in patients with HF. Several studies indicate that for acute rate control, NDCC and beta-blockers are both efficacious therapies, especially in the setting of tachycardia-induced cardiomyopathy. Conclusion Future studies are needed to assess the safety and efficacy of beta-blockers and NDCC in both acute and chronic AF with HF with reduced and preserved ejection fraction.
... Краткосрочное назначение недигидропиридиновых АК пациентам с дисфункцией ЛЖ способно вызвать ухудшение клинического состояния [8][9][10][11], а длительное использование этих средств приводит к повышению риска декомпенсации ХСН, развития ИМ и смерти [12][13][14][15]. ...
Article
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The authors present the data on the potential of the combination of angiotensin-converting enzyme inhibitors and calcium channel antagonists in the treatment of hypertensive patients with chronic heart failure and preserved left ventricular ejection fraction. The informed choice of lisinopril, as a component of such a combination, is justified.
... Furthermore, if acute therapy is successful (especially if the selected agent also possesses positive RV lusitropic effects), the long-term clinical responses must be continuously monitored, since the drug that appears promising during acute invasive testing may not be able to sustain these favorable immediate aftermaths over the long run. Indeed, in one of our prior studies even severely compromised patients still responded well to the acute administration of verapamil [340], though managing to preserve the accrued therapeutic benefits (when they were switched over to long-term maintenance therapy with the comparable oral doses of this drug) for only a few months, followed by deterioration [344]. Similarly, the patient described here, serving as a suitable representative of the diagnostic and therapeutic venues that are now available in primary pulmonary hypertension, improved for a few months, but then also began to slowly weaken. ...
... Short-term treatment with verapamil, nifedipine, and diltiazem has produced clinical deterioration, 10,[17][18][19] and long-term therapy with these drugs has increased the risk of worsening heart failure, myocardial infarction, and death in patients with left ventricular dysfunction. 1,3,4,20 These adverse reactions have been attributed to the propensity of the drugs to depress cardiac contractility and activate endogenous neurohormonal systems, 21 but the importance of these mechanisms remains uncertain, since the deleterious actions may be *PϽ0.05 for the comparison with the placebo group. ...
Article
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Previous studies have shown that calcium-channel blockers increase morbidity and mortality in patients with chronic heart failure. We studied the effect of a new calcium-channel blocker, amlodipine, in patients with severe chronic heart failure. We randomly assigned 1153 patients with severe chronic heart failure and ejection fractions of less than 30 percent to double-blind treatment with either placebo (582 patients) or amlodipine (571 patients) for 6 to 33 months, while their usual therapy was continued. The randomization was stratified on the basis of whether patients had ischemic or nonischemic causes of heart failure. The primary end point of the study was death from any cause and hospitalization for major cardiovascular events. Primary end points were reached in 42 percent of the placebo group and 39 percent of the amlodipine group, representing a 9 percent reduction in the combined risk of fatal and nonfatal events with amlodipine (95 percent confidence interval, 24 percent reduction to 10 percent increase; P=0.31). A total of 38 percent of the patients in the placebo group died, as compared with 33 percent of those in the amlodipine group, representing a 16 percent reduction in the risk of death with amlodipine (95 percent confidence interval, 31 percent reduction to 2 percent increase; P=0.07). Among patients with ischemic heart disease, there was no difference between the amlodipine and placebo groups in the occurrence of either end point. In contrast, among patients with nonischemic cardiomyopathy, amlodipine reduced the combined risk of fatal and nonfatal events by 31 percent (P=0.04) and decreased the risk of death by 46 percent (P<0.001). Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.
... However, it emerged that the long-term efficacy of vasodilator drugs was not related to their haemodynamic effects. For example, controlled trials of minoxidil (Franciosa et al., 1984) and the calcium antagonist vasodilators verapamil (Ferlinz & Gallo, 1984), nifedipine (Elkayam et al., 1990) and diltiazem (Goldstein etal., 1991) showed that patients treated with these agents were at greater risk of developing worsening heart failure and of dying from cardiovascular causes than those treated with placebo. In the case of the calcium antagonists this appears at least in part due to negative inotropic effects. ...
Article
1. Despite demonstrable benefits in terms of symptomatic relief and improvement in prognosis, even the best treatments of heart failure currently available fall short of being ideal. We review the basis for newer approaches to the treatment of heart failure and discuss some of the agents which capitalize on current understanding of the underlying patho-physiology. 2. Several drugs, old and new, are presently being investigated by major clinical trials. We also consider some of the difficulties related to the design and conduct of such trials and suggest how drugs might be better assessed in the future.
Article
The chemistry, pharmacology, pharmacokinetics, efficacy, and adverse effects of amlodipine are reviewed. Amlodipine belongs to the dihydropyridine subclass of calcium antagonists. Amlodipine is a potent peripheral and coronary vasodilator with high selectivity for vascular smooth muscle and minimal effect on myocardial contractility or cardiac conduction. Absorption after oral administration is slow, and the duration of action is long, with a half-life of 36-45 hours. Amlodipine has FDA-approved labeling for use in the treatment of hypertension, chronic stable angina, and vasospastic angina. The agent is also indicated for use in hypertensive or anginal patients who also have congestive heart failure due to systolic dysfunction (New York Heart Association classes II and III). Clinical trials suggest that effective 24-hour control of hypertension and angina is provided by once-daily administration of amlodipine 5-10 mg alone or in combination with other drugs. No clinically important drug interactions have been observed to date. Amlodipine has not shown any unfavorable effects on serum glucose or lipid levels. The most common adverse effect is peripheral edema. Amlodipine is effective and well tolerated when given alone or in combination with other drugs for the treatment of hypertension and angina. Amlodipine may offer advantages over verapamil, diltiazem, and nifedipine in patients with hypertension or angina with associated congestive heart failure due to systolic dysfunction.
Article
It has been proposed that worsening of heart failure with dihydropyridines, such as nicardipine, is related to the activation of the neuroendocrine system. To test this, we evaluated 20 patients with severe heart failure (mean age, 55 +/- 13 years; New York Heart Association functional class III; left ventricular ejection fraction, 18% +/- 8% on maintenance therapy with captopril, digoxin, and diuretics) who were randomized to nicardipine (60 or 90 mg/d) or placebo during a 4-month double-blind protocol. The following measurements were obtained at baseline, monthly, and at 4 months or last follow-up visit: rest and exercise radionuclide ventriculography, maximal treadmill time, 6-minute walking test distance, serum norepinephrine and aldosterone concentrations, and plasma renin activity. During the follow-up period, worsening of heart failure occurred in 6 patients in the nicardipine group and in 2 patients in the placebo group (p = 0.06). The maximal treadmill time for a 6-minute walking distance and exercise radionuclide ejection fraction at the last follow-up visit did not change in patients who did not deteriorate with heart failure in the placebo or nicardipine groups as compared with baseline values. In this study group of patients with severe heart failure receiving therapy with digoxin, captopril, and diuretics, nicardipine was associated with worsening heart failure without an apparent activation of the neurohormones. However, because of the small number of patients and a significant number of patients who deteriorated during the follow-up period, no definitive conclusions can be made.
Article
Prospective controlled clinical trials with cardiovascular events and mortality as end points are needed to provide clinicians with a fully informed choice of optimal hypertensive therapy. Seven trials (six of them still ongoing) have provided insight into the effects of the third-generation calcium antagonist, amlodipine, on mortality and end-organ damage in patients with hypertension or other forms of cardiovascular disease. The completed PRAISE study has addressed the safety of amlodipine in patients with advanced heart failure (CHF). The trial showed that amlodipine does not increase mortality or morbidity in CHF patients and significantly reduces the risk for these end points in patients whose CHF has a nonischemic etiology. The PRAISE-2 study is now under way to further evaluate the benefits of amlodipine in nonischemic CHF patients. The ALLHAT trial compares the effects of standard diuretic treatment with three alternative treatments (amlodipine, lisinopril, and doxazosin) on the incidence of fatal coronary artery disease (CAD) and nonfatal myocardial infarction (MI) in 40,000 hypertensive patients. The ASCOT trial compares the effects of amlodipine +/- perindopril with atenolol +/- bendrofluazide on fatal CAD and nonfatal MI in 18,000 high-risk patients. The PREVENT trial tests a similar hypothesis, looking at the effects of amlodipine on arterial atherosclerotic lesions, and the AASK trial is evaluating the effects of amlodipine on renal disease. The PRAISE trial has provided valuable information on the safety and efficacy of amlodipine in preventing death and disability in patients with CHF. The six ongoing trials will provide important additional information on the effect of amlodipine in patients with heart disease of other etiologies.
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Myocarditis has been shown to be a common cause of cardiomyopathy and is believed to account for 25% of all cases in human beings. Unfortunately, the disease is difficult to detect before a myopathic process ensues. Treatment of myocarditis-induced heart failure includes the standard regimen of diuretics, digoxin, angiotensin-converting enzyme inhibitors, and currently, beta-adrenergic blockers. Treatment of myocarditis itself is dependent on the etiology of the illness. Treatments under investigation include immunosuppressants, nonsteroidal antiinflammatory agents, immunoglobulins, immunomodulation, antiadrenergics, calcium-channel blockers, angiotensin-converting enzyme inhibitors, nitric oxide inhibition (e.g., aminoguanidine), and antiviral agents. Despite advances in treatment, more work needs to be done in the early detection of myocarditis. Additionally, better means need to be established for distinguishing between viral and autoimmune forms of the disease, so that appropriate treatment can be instituted.
Article
Although calcium channel blockers have not been shown to be beneficial for the treatment of patients with heart failure, a recent clinical trial demonstrated a favorable effect of amlodipine on the survival of patients with heart failure resulting from nonischemic dilated cardiomyopathy. We investigated the effects of amlodipine on a murine model of congestive heart failure induced by the M variant of encephalomyocarditis virus (EMCV). Four-week-old male DBA/2 mice were inoculated with EMCV and administered amlodipine, diltiazem, or vehicle PO for 2 weeks. The heart weight-to-body weight ratio and the histopathological grades of myocardial lesions were significantly lower and survival was significantly increased in the amlodipine-treated group (P < .01, P < .05, and P < .05, respectively) than in the control group. In vitro, amlodipine added to murine J774A.1 macrophages concomitant with EMCV inhibited nitrite formation in a concentration-dependent manner, but diltiazem did not. Furthermore, NG-monomethyl-L-arginine, an inhibitor of NO synthesis, decreased myocardial lesions significantly in this murine model. Immunohistochemistry revealed that the number of cells stained with antibody against an inducible NO synthase decreased significantly in the amlodipine-treated group compared with that in the control group (P < .01). Amlodipine appears to have a protective effect against myocardial injury in this animal model of congestive heart failure. The therapeutic effect of amlodipine may be in part resulting from inhibition of overproduction of NO.
Article
Therapy with angiotensin-converting enzyme inhibitors and nonselective vasodilators (hydralazine and isosorbide dinitrate) has become accepted treatment in patients with symptomatic, chronic congestive heart failure (CHF), and has been demonstrated in large clinical trials to ameliorate symptoms, improve exercise performance, and reduce cardiac mortality. Nevertheless, the management of patients with CHF remains a therapeutic challenge. The second Vasodilator-Heart Failure Trial (V-HeFT II) showed that the average 2-year mortality with enalapril (18%) was significantly lower than that with hydralazine-isosorbide dinitrate (25%) but, somewhat surprisingly, the nonspecific vasodilators produced significantly more improvement in exercise performance and left ventricular function. Such data suggest that improvement in symptoms, hemodynamics, and survival may not be afforded by the use of a single class of vasodilator therapy, but might be optimized by the combined use of different agents. This report describes the rationale and design of V-HeFT III, a multicenter, prospective, randomized, double-blind, placebo-controlled trial comparing the effects of chronic oral extended-release felodipine (felodipine ER) 2.5 to 5 mg twice daily, when added to a stable regimen of enalapril and loop diuretics, with or without digoxin, on exercise performance, morbidity, and mortality in patients with New York Heart Association functional class II to III CHF followed for a minimum of 12 weeks. Felodipine is a second-generation dihydropyridine calcium antagonist with a high degree of vascular selectivity which, in the doses used in this study, exerts its systemic arterial effect by decreasing peripheral vascular resistance without producing negative inotropic effects. The results of V-HeFT III may shed important light on the role of additive vasodilator therapy in the management of patients with CHF.
Article
During the last 50 years, physicians have developed three distinct conceptual models of heart failure that have provided a rational basis for the treatment of the disease. In the 1940s through the 1960s, physicians regarded heart failure principally as an edematous disorder and formulated a cardiorenal model of the disease in an attempt to explain the sodium retention of these patients. This model led to the widespread use of digitalis and diuretics. In the 1970s and 1980s, physicians viewed heart failure principally as a hemodynamic disorder and formulated a cardiocirculatory model of the disease in an attempt to explain patients' symptoms and disability. This model led to the widespread use of peripheral vasodilators and the development of novel positive inotropic agents. Now, in the 1990s, physicians are beginning to think about heart failure as a neurohormonal disorder in an attempt to explain the progression of the disease and its poor long-term survival. This new conceptual framework has led to the widespread use of converting-enzyme inhibitors and the development of beta blockers for the treatment of heart failure. Which conceptual model most accurately describes the syndrome of heart failure and leads physicians to utilize the most effective treatment? This paper critically reviews the available evidence supporting and refuting the validity of all three models of heart failure. We conclude that, to varying degrees, all three approaches provide useful, but incomplete, insights into this physiologically complex and therapeutically challenging disease.
Article
This article examines trials of the use of two types of drugs in the treatment of myocardial infarction: angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists. ACE inhibitors are an established treatment for hypertension and heart failure and have been shown to reduce mortality from heart failure and after myocardial infarction. Six large studies have been carried out. In 1 in which an ACE inhibitor was given 3-16 days after infarction in patients with an ejection fraction < 40%, mortality was reduced by 17%. In a second study of patients who had evidence of heart failure and were followed up for 15 months, treatment with ACE inhibitors was given 3-10 days after myocardial infarction and mortality was reduced by 27%. Two other studies of 11,000 and 50,000 unselected patients with myocardial infarction showed only marginal clinical benefit. Calcium antagonists were introduced to treat hypertension and angina pectoris. In trials with patients with heart failure, the results have not been encouraging, and in some patients these agents seem to be harmful. Recently, long-acting calcium antagonists have become available, and these may avoid the deleterious effects of short-acting drugs. Since calcium antagonists act on smooth muscle, they may increase myocardial blood flow to improve function after "stunning" or "hibernation." This idea was investigated with a long-acting dihydroyridine calcium, antagonist in a randomized double-blind, placebo-controlled study (Doppler Flow, Echocardiography, and Functional Improvement Assessment of Nisoldipine Therapy-I--DEFIANT I), and a further study is being carried out. At present the widespread use of calcium antagonists after infarction is not recommended.
Chapter
Für die Therapie der chronischen Herzinsuffizienz mit Calciumantagonisten zusätzlich zur Standardtherapie mit ACE-Hemmern, Diuretika und Digitalis liegen hinsichtlich der Morbidität und Belastbarkeit nur wenige Langzeitstudien vor. Hinsichtlich der Mortalität sind bisher keine ausreichend großen Studien abgeschlossen. Kurzwirksame Caliumantagonisten mit ausgeprägter peripherer Vasodilatation und reflektorischer Aktivierung des sympatho-adrenergen Systems verstärken die prognostisch ungünstigen Effekte der sympatho-adrenergen Aktivierung in der chronischen Herzinsuffizienz. Allerdings konnte in kleineren Studien insbesondere für die chronische Herzinsuffizienz ohne koronare Herzerkrankung durch eine zusätzliche Therapie mit Calciumantagonisten der neueren Generation wie Amlodipine und Felodipine eine Verbesserung der Symptomatologie und Morbidität erzielt werden. Hinsichtlich der Mortalität sind auch hier die vorliegenden Studien zu klein. Somit sind Calciumantagonisten für die Therapie der chronischen Herzinsuffizienz bisher sicher nicht die Therapeutika der ersten Wahl. Allerdings muß in speziellen Konstellationen an die Calciumantagonisten gedacht werden.
Article
During the past 10 years, more than 80 orally active vasodilator and inotropic agents have been tested in the clinical setting to evaluate their potential utility in the treatment of chronic heart failure. Although the initial reports of all of these drugs suggested that each represented a major therapeutic advance, only three agents--digoxin, captopril and enalapril--have produced consistent long-term hemodynamic and clinical benefits in these severely ill patients. Most of the other drugs that have been tested have not (to date) distinguished themselves from placebo therapy in large-scale, controlled trials, even though these agents produce hemodynamic effects that closely resemble those seen with digitalis and the converting-enzyme inhibitors. These observations suggest that the hemodynamic derangements that characteristically accompany the development of left ventricular dysfunction cannot be considered to be the most important pathophysiologic abnormality in chronic heart failure. Although cardiac contractility is usually depressed in this disease, positive inotropic agents do not consistently improve the clinical status of these patients. Similarly, although the systemic vessels are usually markedly constricted, drugs that ameliorate this vasoconstriction do not consistently relieve symptoms, enhance exercise capacity or prolong life. Hence, correction of the central hemodynamic abnormalities seen in heart failure may not necessarily provide a rational basis for drug development, and future advances in therapy are likely to evolve only by attempting to understand and modify the basic physiologic derangements in this disorder.
Article
The systemic vasodilatory actions of the calcium antagonists make them potentially attractive for use as afterload reducing agents in patients with left ventricular failure. However, unlike other vasodilator drugs, these drugs also exert a direct negative inotropic effect on the myocardium. Clinical data suggest a limited role for the calcium antagonists as vasodilator therapy in patients with heart failure.
Article
Calcium antagonists impede the entry of calcium into myocytes and inhibit myocardial contraction. Calcium antagonists differ in their relative negative inotropic potency and can provoke baroreceptor stimulation that modulates left ventricular (LV) performance. Calcium antagonists are uniformly well tolerated in patients with normal LV function. Use of these agents in patients with suspected LV function impairment has yielded results ranging from hemodynamic improvement to clinical deterioration and increased mortality. Reports of clinical deterioration when calcium antagonists were combined with beta blockers underscore the importance of reflex adrenergic support for the myocardium. Although calcium antagonists are potent vasodilators and produce short-term hemodynamic improvement, they are not useful as primary treatment in patients with congestive heart failure (CHF). They may have a place in the treatment of coexistent problems in patients with LV dysfunction. Short-term use of calcium antagonists for myocardial ischemia or rapid atrial fibrillation is probably safe in the presence of LV dysfunction and overt CHF. Calcium antagonists appear to have a role in the treatment of patients with diastolic dysfunction of diverse etiologies.
Article
The presence of calcium ions is essential to the normal function of the cardiovascular system. Drugs such as calcium antagonists can modulate the interaction between these ions and specific cells at different levels, interfering with myocardial contraction and relaxation, vascular tone, specific conduction tissues and neuromuscular function. Vascular beds play a crucial role in adjustment of myocardial function to different body oxygen requirements; compensatory mechanisms in congestive heart failure (CHF) involve the vascular system to a large extent and paradoxically may worsen myocardial performance. Vasodilating drugs represent an important step forward in achieving better symptomatic results in CHF patients, and may also increase their survival. Of the different classes of vasodilator drugs calcium antagonists may represent an attractive alternative due to their anti-ischaemic and antiarrhythmic effects. Despite the overall good response to the acute use of these drugs in CHF, long term studies in which first generation calcium antagonists (nifedipine, diltiazem, verapamil) were used have produced disappointing results. Their main drawbacks were negative inotropism, lack of preload reduction and activation of neurohormonal mechanisms with a subsequent adverse effect on cardiovascular function, the latter effect being the most significant. A few long term studies, of between 1 and 52 months, have not demonstrated a consistent improvement in functional class in spite of apparently good initial results. The second generation of calcium antagonists have more potent and selective vasodilating properties with less negative inotropic effects; these properties might justify their use in the therapy of CHF, but no clear recommendations can be given due to the lack of large, long term, controlled studies. Overall, the existing clinical trials with calcium antagonists in CHF have not proved the superiority of this group of drugs when compared to other vasodilators. If the aetiology of CHF is related to the presence of coronary artery disease or arterial hypertension, calcium antagonists might be considered as additional therapeutic options. Diastolic dysfunction may be corrected or improved and coronary tone may be diminished, both of which may lead to a better myocardial oxygen supply. Systolic myocardial function must be evaluated in CHF patients before starting therapy with calcium antagonists in order to avoid possible deleterious effects. Further studies may shed more light on this matter and may indicate decisively whether or not calcium antagonists should play a role in the therapeutic pharmacological arsenal of selected CHF patients.
Article
Therapeutic approaches to the management of heart failure have traditionally focused on shortterm hemodynamic and symptomatic goals, but present evidence suggests that most therapeutic decisions have long-term consequences. Treatment may change the rate of disease progression, modify the need for additional therapy, influence the number of hospitalizations, and alter the risk of death. However, there may be little relation between a drug's short-term effect on cardiac function or cardiovascular symptoms and its long-term effect on survival. Some therapeutic interventions favorably influence the outcome of patients with heart failure, even though they exert negative inotropic effects; others adversely affect the outcome of patients, even though they markedly improve cardiac performance. This discordance might be explained if the most important predictor of response to a therapeutic intervention in heart failure were the effect of the pharmacologic agent on neurohormonal systems rather than on hemodynamic variables. In general, drugs that decrease the effects of the sympathetic nervous system (digitalis glycosides) and the renin-angiotensin system (angiotensin-converting enzyme [ACE] inhibitors) reduce the risk of worsening heart failure. Conversely, drugs that potentiate the effects, or increase the activity, of the sympathetic nervous system (phosphodiesterase inhibitors) or the renin-angiotensin system (calcium antagonists) increase cardiovascular morbidity and mortality. These observations suggest that physicians should no longer focus on short-term hemodynamic or symptomatic goals in the treatment of heart failure but, instead, should manage patients to improve both the quality and quantity of life.
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Because physicians have traditionally considered heart failure to be a hemodynamic disorder, they have described the syndrome of heart failure using hemodynamic concepts and have designed treatment strategies to correct the hemodynamic derangements of the disease. However, although hemodynamic abnormalities may explain the symptoms of heart failure, they are not sufficient to explain the progression of heart failure and, ultimately, the death of the patient. Therapeutic interventions may improve the hemodynamic status of patients but adversely affect their long-term outcome. These findings have raised questions about the validity of the hemodynamic hypothesis and suggest that alternative mechanisms must play a primary role in advancing the disease process. Several lines of evidence suggest that neurohormonal mechanisms play a central role in the progression of heart failure. Activation of the sympathetic nervous system and renin-angiotensin system exerts a direct deleterious effect on the heart that is independent of the hemodynamic actions of these endogenous mechanisms. Therapeutic interventions that block the effects of these neurohormonal systems favorably alter the natural history of heart failure, and such benefits cannot be explained by the effect of these treatments on cardiac contractility and ejection fraction. Conversely, pharmacologic agents that adversely influence neurohormonal systems in heart failure may increase cardiovascular morbidity and mortality, even though they exert favorable hemodynamic effects. These observations support the formulation of a neurohormonal hypothesis of heart failure and provide the basis for the development of novel therapeutic strategies in the next decade.
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The long-term effect of calcium channel blockers on chronic heart failure is disappointing, probably because of reflex sympathetic activation through arterial vasodilation. However, nilvadipine may be beneficial for treatment of chronic heart failure since this drug has minimal effects on sympathetic activation. In this study, the effects of 12-week administration of nilvadipine or placebo on symptoms of heart failure and cardiac function were investigated in 23 patients with mild-to-moderate chronic heart failure in a double-blind trial. The patients were randomly assigned to either a nilvadipine group (16 mg daily) or a placebo group. Intergroup comparisons did not show significant differences in any parameters. Serious adverse effects were not observed during the study. Thus, this study failed to show any beneficial effect of nilvadipine in the long-term treatment of patients with chronic heart failure. We conclude that the long-term administration of nilvadipine (16 mg daily) is neither effective nor harmful in the treatment of patients with chronic heart failure.
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Improvement of pharmacotherapy led to a reduction of morbidity and mortality in heart failure patients in recent years. Therapy for chronic systolic heart failure should include ACE-inhibitors and beta-blockers, in the case of fluid overload diuretics. In patients with persisting symptoms cardiac glycosides should be added. Spironolactone is indicated in patients in NYHA class III-IV. If ACE-inhibitors or beta-blockers are not tolerated or contraindicated AT1-receptor-blockers should be considered as second line drugs. Evidence-based therapy strategies can improve prognosis in heart failure but medication has to be individualised for every patient according to comorbidity.
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