Lisinopril

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Abstract
Following establishment of its efficacy in hypertension and congestive heart failure, the ACE inhibitor lisinopril has now been shown to reduce mortality and cardiovascular morbidity in patients with myocardial infarction when administered as early treatment. The ability of lisinopril to attenuate the detrimental effects of left ventricular remodelling is a key mechanism; however, additional cardioprotective and vasculoprotective actions are postulated to play a role in mediating the early benefit. The GISSI-3 trial in > 19 000 patients has demonstrated that, when given orally within 24 hours of symptom onset and continued for 6 weeks, lisinopril (with or without nitrates) produces measurable survival benefits within 1 to 2 days of starting treatment. Compared with no lisinopril treatment, reductions of 11% in risk of mortality and 7.7% in a combined end-point (death plus severe left ventricular dysfunction) were evident at 6 weeks. Advantages were apparent in all types of patients. Thus, those at high risk — women, the elderly, patients with diabetes mellitus and those with anterior infarct and/or Killip class >1 — also benefited. These gains in combined end-point events persisted in the longer term, despite treatment withdrawal after 6 weeks in most patients. At 6 months, the incidence rate for the combined end-point remained lower than with control (a 6.2% reduction). The GISSI-3 results concur with those from recent large investigations (ISIS-4, CCS-1, SMILE) of other ACE inhibitors as early management in myocardial infarction. However, the results of the CONSENSUS II trial (using intravenous enalaprilat then oral enalapril) were unfavourable in some patients. These findings, together with the development of persistent hypotension and, to a lesser extent, renal dysfunction among patients in the GISSI-3 trial, have prompted considerable debate over optimum treatment strategies. Present opinion generally holds that therapy with lisinopril or other ACE inhibitors shown to be beneficial may be started within 24 hours in haemodynamically stable patients with no other contraindications; current labelling in the US and other countries reflects this position. There is virtually unanimous agreement that such therapy is indicated in high-risk patients, particularly those with left ventricular dysfunction. The choice of ACE inhibitor appears less important than the decision to treat; it seems likely that these benefits are a class effect. Lisinopril has a tolerability profile resembling that of other ACE inhibitors, can be given once daily and may be less costly than other members of its class. However, present cost analyses are flawed and this latter point remains to be proven in formal cost-effectiveness analyses. In conclusion, early treatment with lisinopril (within 24 hours of symptom onset) for 6 weeks improves survival and reduces cardiovascular morbidity in patients with myocardial infarction, and confers ongoing benefit after drug withdrawal. While patients with symptoms of left ventricular dysfunction are prime candidates for treatment, all those who are haemodynamically stable with no other contraindications are also eligible to receive therapy. Lisinopril and other ACE inhibitors shown to be beneficial should therefore be considered an integral part of the early management of myocardial infarction in suitable patients. Left ventricular remodelling follows a myocardial infarction and in some patients precedes potentially lethal heart failure. Damage to the cellular and structural components of the heart causes ventricular thinning and expansion of the infarct zone. These events predispose susceptible patients to ventricular enlargement and dysfunction. There is accumulating evidence, although not completely consistent, that the renin-angiotensin-aldosterone system in general and angiotensin II (AII) in particular is a primary modulator of these processes. By inhibiting the actions of AII, ACE inhibitors would be expected to modify such deleterious effects. As demonstrated by the large GISSI-3 trial, lisinopril attenuates ventricular enlargement when therapy is begun within 24 hours of symptom onset and continued for 6 weeks in patients with myocardial infarction (see also Clinical Efficacy summary). At 6 weeks, left ventricular end-diastolic volume increased by a significantly smaller amount with lisinopril than with no lisinopril (and end-systolic volume tended to show this effect), particularly in the presence of significant left ventricular asynergy. Ejection fraction (EF) did not change significantly; however, the percentage of patients with EF ≤35% (but who did not have clinical signs of congestive heart failure) was lower in lisinopril recipients. According to post-hoc analyses, which require caution in their interpretation, this was also true in high-risk groups (the elderly, those with Killip class >1 and patients with anterior infarcts). Lisinopril increased peak oxygen consumption during exercise and improved left ventricular diastolic function in other investigations in small numbers of patients with coronary artery disease. Of interest is the finding that lisinopril reduced the in-hospital incidence of sustained ventricular tachycardia (sVT) and sVT plus ventricular fibrillation in the GISSI-3 trial. A direct electrophysiological action is unlikely. Lisinopril had no effect on potentially arrhythmogenic serum noradrenaline (norepinephrine) levels, although amelioration of sympathetic activity has been demonstrated for other ACE inhibitors. Other potential cardio- and vasculoprotective effects observed with lisinopril in vitro, in animals, or in humans in some instances, include the following: (i) reductions in left ventricular mass and attenuation of necrotic cell damage; (ii) antioxidant effects; and (iii) increases in bradykinin levels and stimulation of prostacyclin synthesis. Evidence is equivocal for antiplatelet effects or enhancement of fibrinolysis. The possible contribution of these activities to the mechanism of lisinopril in myocardial infarction is undetermined at present. Bioavailability of lisinopril is about 20 to 28% in patients with myocardial infarction, similar to that for healthy individuals but greater than the value of 16% recorded for patients with congestive heart failure. Peak serum lisinopril concentrations are reached at about 8 hours after a single 2.5 or 5mg dose in most patients with suspected myocardial infarction. Absorption of lisinopril is not influenced by food. The apparent volume of distribution for lisinopril is 124L and the drug is not bound to plasma proteins. Lisinopril is not metabolised. Rather, it is excreted unchanged by renal mechanisms which probably include tubular secretion and reabsorption in addition to glomerular filtration. The elimination half-life (t1/2p) of lisinopril is 12.6 hours in healthy volunteers. Most of a dose of lisinopril is eliminated in an early phase, but the drug is still detectable in the later phase, which has a t1/2 of about 30 hours. Steady-state is reached within 2 to 3 days. Mean renal clearance in patients with myocardial infarction is 3.11 L/h for a 2.5mg dose and 3.76 L/h for a 5mg dose. Clearance of lisinopril in patients with myocardial infarction, as in the elderly and patients with congestive heart failure, is slower than in healthy individuals. Patients with renal impairment require dosage adjustment according to creatinine clearance. Lisinopril provides early and prolonged benefits in mortality and cardiovascular morbidity when administered within 24 hours of symptom onset and continued for 6 weeks in patients with acute myocardial infarction. The GISSI-3 trial, conducted in more than 19 000 patients, demonstrated an 11% reduction in risk of all-cause mortality and a 7.7% decrease in combined end-point events (death plus severe left ventricular dysfunction) at 6 weeks, compared with no lisinopril (patients were given thrombolytics, β-blockers and aspirin and were allowed to receive nitrates as standard coronary care). Most survival gain is accrued within the first few days. Indeed, survival appears to be improved as early as day 1 of lisinopril treatment, as shown by divergent survival curves and reductions in types of cardiac deaths compared with control (no lisinopril). However, no statistics are available for the 1-day data. A sustained, albeit somewhat smaller, benefit in mortality plus cardiovascular morbidity is evident at 6 months despite lisinopril withdrawal after 6 weeks: the incidence of combined end-point events was reduced by 6.2%. The combination of lisinopril plus nitrates produced a significant improvement vs standard care (a 17% mortality risk reduction at 6 weeks and an 8.7% decrease in the combined end-point at 6 months). The lack of demonstrable efficacy with nitrates alone obscures their role in this indication. Lisinopril was associated with improved survival independently of the effects produced by thrombolytics, β-blockers or aspirin. Patients at the greatest risk also benefit from early treatment with lisinopril. Women, the elderly (>70 years), and patients with Killip class 2 or 3, anterior infarcts or diabetes mellitus experienced reductions in at least 1 measure of outcome at 6 weeks and/or 6 months. Benefit was thus demonstrated in all patient categories, including individuals with Killip class 1 who comprised the majority of patients in GISSI-3. Lisinopril is associated with an adverse events profile typical of ACE inhibitors. Headache, dizziness, diarrhoea and cough are experienced most frequently. The low incidence of lisinopril withdrawal due to cough in the GISSI-3 trial (0.5%) may relate to the short period of treatment. Older patients with congestive heart failure, but not those with hypertension, have experienced more frequent adverse events than younger patients during lisinopril therapy. General tolerability data for elderly patients with myocardial infarction are not available from GISSI-3. Persistent hypotension occurs with lisinopril and other ACE inhibitors. This event developed significantly more frequently with lisinopril than with no lisinopril in the pilot study for GISSI-3, and hypotension in general was the main reason for treatment discontinuation in GISSI-3 (9.7% of patients). However, mortality did not increase proportionately in the subgroup of patients who experienced hypotension. Likewise, the risk of renal dysfunction rises in patients receiving lisinopril, especially in high-risk patients, but a proportional rise in mortality was not observed in these patients in GISSI-3. Renal dysfunction developed in 1.8% of all lisinopril recipients in GISSI-3 and caused drug withdrawal in 4.2% of elderly patients. Other potentially serious adverse events are rare. The incidence of angioedema during lisinopril therapy has ranged from 0.06% to 0.6% in patients with indications other than myocardial infarction, as reported in the literature, but was low (0.01%) in GISSI-3. Anaemia was documented in 0.58% of patients, most with hypertension, in a UK postmarketing study. Although cost-minimisation studies to date have suggested a possible cost advantage for lisinopril over some other ACE inhibitors, these types of analyses are of limited clinical value unless all outcomes and other costs are equal. Furthermore, acquisition costs vary greatly across markets. The issue of cost effectiveness thus requires evaluation in formal analyses: a cost effectiveness analysis of an ‘all patients’ treatment strategy versus a selective approach is ongoing. Lisinopril does not appear to have an additive adverse hypotensive effect when combined with β-blockers, as shown by GISSI-3. The risk of hyperkalaemia is increased by concomitant potassium-sparing diuretics, and diuretics in general can predispose patients receiving lisinopril to development of renal impairment. Lisinopril can cause lithium toxicity by reducing lithium clearance. In the early management of acute myocardial infarction, lisinopril may be administered orally within the first 24 hours of symptom onset in haemodynamically stable patients with no other contraindications. Treatment must be conducted under medical supervision in a hospital setting. The currently recommended dosage of lisinopril is 5mg as a first dose, 5mg 24 hours later, 10mg at 48 hours after the first dose, then 10mg once daily. Duration of treatment is 6 weeks; patients should then be reassessed and treatment continued if warranted by the presence of other conditions (e.g. hypertension, left ventricular dysfunction or congestive heart failure). Lisinopril dosage should be decreased to 2.5mg in patients with systolic blood pressure (SBP) ≤120mm Hg. If hypotension develops (SBP ≤100mm Hg) the daily maintenance dosage may be 5mg, with a temporary decrease to 2.5mg if required. Persistent hypotension (SBP ≤90mm Hg for ≥1 hour) necessitates lisinopril discontinuation. Lisinopril should be used with caution in patients with, or at risk of, hyperkalaemia or renal impairment. The dosage is reduced in patients with renal dysfunction (creatinine clearance ≤30 ml/min/1.73m2 or serum creat-inine levels ≥2 mg/dl). Use of ACE inhibitors in the early and late management of myocardial infarction is gaining widespread acceptance as results of large mortality trials are examined and assimilated into treatment protocols. Lisinopril is a non-sulfhydryl ACE inhibitor with established efficacy in congestive heart failure and hypertension. More recently, publication of the GISSI-3 study has centred attention on lisinopril in the early management of acute myocardial infarction. This indication is the sole topic of this review.