1I Heart 'The
failure: to digitalise or not? view against
Harvey D . White Specialisr in Cardiovascular Research, Coronary Care Unit, Green Lane Hospital, Auckland, New Zealand.
Abstract: Despite extensive clinical experience the role of digoxin is still not well defined. In patients with atrial fibrillation digoxin is beneficial for ventricular rate control. For patients in sinus rhythm and heart failure the situation is less clear. Digoxin has a narrow therapeutic:toxic ratio and concentrations are affected by a number of drugs. Also, digoxin has undesirable effects such as increasing peripheral resistance and myocardial demands, and causing arrhythmias. There is a paucity of data from well-designed trials. The trials that are available are generally small with limitations in design and these show variation in patient benefit. More convincing evidence is required showing that digoxin improves symptoms or exercise capacity. Furthermore, no trial has had sufficient power to evaluate mortality. Pooled analysis of the effects of other inotropic drugs shows an excess mortality and there is a possibility that digoxin may increase mortality after myocardial infarction (MI). Angiotensin-converting enzyme (ACE) inhibitors should be used first as they are safer, do not require blood level monitoring, modqy progression of disease, relieve symptoms, improve exercise rolerance and reduce mortality. Caution should be exercised in using digoxin until large mortality trials are completed showing either benefit or harm. Until then digoxin should be considered a third-line therapy. (Aust NZ J Med 1992; 22: 626-630.) Key words: Digoxin, ACE inhibirors.
INTRODUCTION igoxin has played a prominent role in the treatment of heart failure for over 200 years' and is one of the most commonly prescribed drugs, yet there are no convincing clinical data that it is beneficial, and it may actually cause harm in some patients by increasing myocardial demands, peripheral resistance and arrhythmias. Its role in current therapies must be evaluated in the light of the total evidence of benefit, risk and cost, and compared to other treatments available. Decisions to prescribe medications should be based on good evidence from clinical trials showing that patients benefit, not on laboratory measurements of mechanisms of possible benefit.
D
Digoxin therapy for patients in sinus rhythm may be less effective and less safe than alternative therapy, and digoxin should now be considered a third-line drug. There is a great need for a large mortality trial of digoxin therapy.
EVIDENCE THAT DIGOXIN IS BENEFICIAL Clearly digoxin improves the contractility of isolated muscle stripsY2and in humans there are several studies which show improved symptomatic tatu us.^-^ However, individual studies should not be selected, and if the total data are evaluated the results are ~onflicting.~-' ' Furthermore, almost all studies are withdrawal studies where patients who
Correspondence to: Dr H . D. White, Coronary Care Unit, Green Lane Hospital, Auckland 1003, New Zealand.
626
Aust NZ J Med 1992; 22
HEART FAILURE AND DIGOXIN
TABLE 1 Desirable Effects of Medications for Heart Failure
0 Relieve symptoms 0 Improve exercise capacity I3 Improve quality of life fl Reduce mortality U Improve natural history 0 Safe G Not expensive
have already been shown to be tolerant and perhaps to benefit from digoxin therapy are withdrawn and symptomatic status is then evaluated, or parallel studies where patients who are already on digoxin are continued on this therapy and another treatment is compared in patients who have digoxin This is an inappropriate trial design and would not be acceptable if we were, for example, evaluating therapies for angina or arrhythmias. T h e appropriate design is a prospective, randomised, double-blind, placebocontrolled trial evaluating hard endpoints in patients who have not been on digoxin before. Desirable endpoints of patient benefit are listed in Table 1. Of all the withdrawal studies, deterioration in symptomatic status occurred in < 5% when digoxin was T h r e e placebo-controlled randomised trials have shown no improvement in exercise c a p a ~ i t y . ~ .There ' . ~ have been two studies where digoxin apparently improved exercise capacity. l o . ' ' However, these results are questionable as the patients who improved on digoxin were already on digoxin at baseline and the well-known training effect of repeated exercise testing may explain the benefit shown. In the trial by Lee et al. there was improved symptomatic status as measured by an improved heart failure score (X-ray, clinical) but the same numbers of patients deteriorated during the control and active phases. On retrospective analysis the use of a third heart sound and enlarged heart were predictors of patient benefit. However, several recent trials have been unable to prospectively validate these criteria for benefit and it cannot be recommended from these latter studies that patients with large hearts and a third heart sound will benefit most with digoxin therapy.S.R-'o No trial has had the statistical power to evaluate the effect of digoxin on the survival of patients with chronic heart failure. There is a desperate need for such a trial. Fortunately such a trial is now underway (Digitalis Investigation Group) and planning to randomise 7000 patients with clinical heart failure and ejection fractions 145% and HEART FAILURE AND DIGOXIN
I
TABLE 2 Clinical Effects of Digoxin Toxicity Gastrointestinal anorexia, nausea. vomiting Neurological headache, fatigue, malaise neuralgic pain. disorientation. confusion, delirium. seizures. visual symptoms Cardiac arrhythmias including paroxysmal atrial tachycardia and ventricular tachycardia heart block Other g ynacomastia
patients who are already on diuretics and Angiotensin-converting enzyme (ACE) inhibitors will be randomised to either digoxin or placebo. Patients will be followed for two-four years and the primary endpoint is total mortality.
POTENTIAL FOR HARM Withering learned from his close bedside observations that the dose of digoxin must be exact, that it should be given for a short time and that cases should be chosen carefully.' The cases most likely to benefit were those 'where the pulse is feeble or intermitting, the countenance pale, the lips livid, the skin cold, the swollen belly soft and fluctuating, or the anasarcous limbs readily pitting under the pressure of the finger'. Withering may have been describing patients with atrial fibrillation and he probably recognised that the benefit for patients in sinus rhythm was less. Digoxin has a very narrow therapeutic:toxic ratio and some patients may be very sensitive to developing toxicity. Clinical side-effects can occur despite dose adjustments for body size and renal function. Table 2 lists the most common mani-
TABLE 3 Factors that Influence Sensitivity to Digoxin Type and severity of underlying cardiac disease Changes in electrolytes hypokalaemia or hyperkalaemia hypomagnesaemia hypercalcaemia hyponatraemia Acid base imbalance Concomitant drug adminisfration anaesthetics catecholamines and sympathornimetics antiarrhythmic agents Thyroid status Renal function Autonomic nervous system tone Respiratory disease ~
Aust
NZ J Med 1992; 22
~~
627
nagnitude ood level
s volume of distribution Decreases renal and nonrenal clearance nrenal clearance
? 70-100% T 70-100% t 40-100 ? 15O/o
?
T 30% ? 50%
renal clearance
festations." There are a number of well recognised factors that sensitise patients to digoxin (Table ,).I2 Drug interactions with digoxin are common and may interact through several mechanisms. Table 4 lists some medications commonly used in patients with cardiac disease that may affect digoxin levels. Measurement of digoxin levels is thus mandatory for patients in sinus rhythm and the cost of the test and the inconvenience and time involved for both doctors and patients must be considered in assessing the benefit and cost of digoxin therapy. There have been a number of studies investigating the role of digoxin after infarction. In two of these trials there was the suggestion that mortality was in~reased,'~.'~ whereas four other trials, although finding a higher mortality among digoxin-treated patients, accounted for differences by a higher incidence of adverse baseline risk factors.lS-lsThe mechanism of this possible adverse effect could relate to arrhythmogene~is'~or increased myocardial demands due to increased contractility or increased peripheral resistance2' aggravating ischaemia. There is therefore concern that, overall, digoxin may be harmful in this setting, and more randomised trials are required. Pooled analysis of trials with other inotropic agents shows a 2x increase in mortality, p
failure: to digitalise or not? view against
Harvey D . White Specialisr in Cardiovascular Research, Coronary Care Unit, Green Lane Hospital, Auckland, New Zealand.
Abstract: Despite extensive clinical experience the role of digoxin is still not well defined. In patients with atrial fibrillation digoxin is beneficial for ventricular rate control. For patients in sinus rhythm and heart failure the situation is less clear. Digoxin has a narrow therapeutic:toxic ratio and concentrations are affected by a number of drugs. Also, digoxin has undesirable effects such as increasing peripheral resistance and myocardial demands, and causing arrhythmias. There is a paucity of data from well-designed trials. The trials that are available are generally small with limitations in design and these show variation in patient benefit. More convincing evidence is required showing that digoxin improves symptoms or exercise capacity. Furthermore, no trial has had sufficient power to evaluate mortality. Pooled analysis of the effects of other inotropic drugs shows an excess mortality and there is a possibility that digoxin may increase mortality after myocardial infarction (MI). Angiotensin-converting enzyme (ACE) inhibitors should be used first as they are safer, do not require blood level monitoring, modqy progression of disease, relieve symptoms, improve exercise rolerance and reduce mortality. Caution should be exercised in using digoxin until large mortality trials are completed showing either benefit or harm. Until then digoxin should be considered a third-line therapy. (Aust NZ J Med 1992; 22: 626-630.) Key words: Digoxin, ACE inhibirors.
INTRODUCTION igoxin has played a prominent role in the treatment of heart failure for over 200 years' and is one of the most commonly prescribed drugs, yet there are no convincing clinical data that it is beneficial, and it may actually cause harm in some patients by increasing myocardial demands, peripheral resistance and arrhythmias. Its role in current therapies must be evaluated in the light of the total evidence of benefit, risk and cost, and compared to other treatments available. Decisions to prescribe medications should be based on good evidence from clinical trials showing that patients benefit, not on laboratory measurements of mechanisms of possible benefit.
D
Digoxin therapy for patients in sinus rhythm may be less effective and less safe than alternative therapy, and digoxin should now be considered a third-line drug. There is a great need for a large mortality trial of digoxin therapy.
EVIDENCE THAT DIGOXIN IS BENEFICIAL Clearly digoxin improves the contractility of isolated muscle stripsY2and in humans there are several studies which show improved symptomatic tatu us.^-^ However, individual studies should not be selected, and if the total data are evaluated the results are ~onflicting.~-' ' Furthermore, almost all studies are withdrawal studies where patients who
Correspondence to: Dr H . D. White, Coronary Care Unit, Green Lane Hospital, Auckland 1003, New Zealand.
626
Aust NZ J Med 1992; 22
HEART FAILURE AND DIGOXIN
TABLE 1 Desirable Effects of Medications for Heart Failure
0 Relieve symptoms 0 Improve exercise capacity I3 Improve quality of life fl Reduce mortality U Improve natural history 0 Safe G Not expensive
have already been shown to be tolerant and perhaps to benefit from digoxin therapy are withdrawn and symptomatic status is then evaluated, or parallel studies where patients who are already on digoxin are continued on this therapy and another treatment is compared in patients who have digoxin This is an inappropriate trial design and would not be acceptable if we were, for example, evaluating therapies for angina or arrhythmias. T h e appropriate design is a prospective, randomised, double-blind, placebocontrolled trial evaluating hard endpoints in patients who have not been on digoxin before. Desirable endpoints of patient benefit are listed in Table 1. Of all the withdrawal studies, deterioration in symptomatic status occurred in < 5% when digoxin was T h r e e placebo-controlled randomised trials have shown no improvement in exercise c a p a ~ i t y . ~ .There ' . ~ have been two studies where digoxin apparently improved exercise capacity. l o . ' ' However, these results are questionable as the patients who improved on digoxin were already on digoxin at baseline and the well-known training effect of repeated exercise testing may explain the benefit shown. In the trial by Lee et al. there was improved symptomatic status as measured by an improved heart failure score (X-ray, clinical) but the same numbers of patients deteriorated during the control and active phases. On retrospective analysis the use of a third heart sound and enlarged heart were predictors of patient benefit. However, several recent trials have been unable to prospectively validate these criteria for benefit and it cannot be recommended from these latter studies that patients with large hearts and a third heart sound will benefit most with digoxin therapy.S.R-'o No trial has had the statistical power to evaluate the effect of digoxin on the survival of patients with chronic heart failure. There is a desperate need for such a trial. Fortunately such a trial is now underway (Digitalis Investigation Group) and planning to randomise 7000 patients with clinical heart failure and ejection fractions 145% and HEART FAILURE AND DIGOXIN
I
TABLE 2 Clinical Effects of Digoxin Toxicity Gastrointestinal anorexia, nausea. vomiting Neurological headache, fatigue, malaise neuralgic pain. disorientation. confusion, delirium. seizures. visual symptoms Cardiac arrhythmias including paroxysmal atrial tachycardia and ventricular tachycardia heart block Other g ynacomastia
patients who are already on diuretics and Angiotensin-converting enzyme (ACE) inhibitors will be randomised to either digoxin or placebo. Patients will be followed for two-four years and the primary endpoint is total mortality.
POTENTIAL FOR HARM Withering learned from his close bedside observations that the dose of digoxin must be exact, that it should be given for a short time and that cases should be chosen carefully.' The cases most likely to benefit were those 'where the pulse is feeble or intermitting, the countenance pale, the lips livid, the skin cold, the swollen belly soft and fluctuating, or the anasarcous limbs readily pitting under the pressure of the finger'. Withering may have been describing patients with atrial fibrillation and he probably recognised that the benefit for patients in sinus rhythm was less. Digoxin has a very narrow therapeutic:toxic ratio and some patients may be very sensitive to developing toxicity. Clinical side-effects can occur despite dose adjustments for body size and renal function. Table 2 lists the most common mani-
TABLE 3 Factors that Influence Sensitivity to Digoxin Type and severity of underlying cardiac disease Changes in electrolytes hypokalaemia or hyperkalaemia hypomagnesaemia hypercalcaemia hyponatraemia Acid base imbalance Concomitant drug adminisfration anaesthetics catecholamines and sympathornimetics antiarrhythmic agents Thyroid status Renal function Autonomic nervous system tone Respiratory disease ~
Aust
NZ J Med 1992; 22
~~
627
nagnitude ood level
s volume of distribution Decreases renal and nonrenal clearance nrenal clearance
? 70-100% T 70-100% t 40-100 ? 15O/o
?
T 30% ? 50%
renal clearance
festations." There are a number of well recognised factors that sensitise patients to digoxin (Table ,).I2 Drug interactions with digoxin are common and may interact through several mechanisms. Table 4 lists some medications commonly used in patients with cardiac disease that may affect digoxin levels. Measurement of digoxin levels is thus mandatory for patients in sinus rhythm and the cost of the test and the inconvenience and time involved for both doctors and patients must be considered in assessing the benefit and cost of digoxin therapy. There have been a number of studies investigating the role of digoxin after infarction. In two of these trials there was the suggestion that mortality was in~reased,'~.'~ whereas four other trials, although finding a higher mortality among digoxin-treated patients, accounted for differences by a higher incidence of adverse baseline risk factors.lS-lsThe mechanism of this possible adverse effect could relate to arrhythmogene~is'~or increased myocardial demands due to increased contractility or increased peripheral resistance2' aggravating ischaemia. There is therefore concern that, overall, digoxin may be harmful in this setting, and more randomised trials are required. Pooled analysis of trials with other inotropic agents shows a 2x increase in mortality, p
