Quinapril in Chronic Heart Failure
David B. Northridge and Henry J. Dargie
of quinapril are similar to those of other ACE inhibitors. In a large, multicenter, randomized, placebocontrolled study of 225 patients with mild to moderate CHF, 10 to 40 m g / d a y quinapril significantly improved clinical status and exercise capacity in a dose-related manner. The incidence of side effects did not differ significantly from that of placebo. The initial studies with quinapril are promising and warrant further clinical investigation of this compound. Am J Hypertens 1990;3:283S-287S
KEY WORDS: Quinapril, chronic heart failure.
D
uring the 1980s, angiotensin converting enzyme (ACE) inhibitors became widely accepted for the treatment of patients with chronic heart failure (CHF). ' However, there are still some questions regarding when these drugs should be introduced and which patients are most likely to benefit from treatment. Many of these issues are likely to be resolved during the 1990s, although further questions will undoubtedly arise. It is also likely that additional ACE inhibitors will be introduced during the 1990s, some of which may have potential advantages in CHF. The present article summarizes the indications for ACE inhibitor treatment in CHF, and reviews the available clinical data on the new ACE inhibitor, quinapril. 1 2
3
David B. Northridge, MD
RATIONALE FOR USING ACE INHIBITORS IN HEART FAILURE
From the Department of Cardiology, Western Infirmary, Glasgow, Scotland. Address correspondence and reprint requests to David B. Northridge, MD, Department of Cardiology, Western Infirmary, Glasgow, Scotland G i l 6NT.
Angiotensin converting enzyme inhibitors have beneficial acute and chronic hemodynamic effects in patients with CHF. ' The pattern of response differs from that of other so called "balanced" vasodilators. Angiotensin converting enzyme inhibition results in a fall in both right and left ventricular filling pressures in most pa4 5
6
Downloaded from http://ajh.oxfordjournals.org/ at University of New South Wales on July 8, 2015
Angiotensin converting enzyme inhibitors are now firmly established in the treatment of patients with chronic heart failure (CHF). Their beneficial acute and chronic hemodynamic effects are not associated with reflex tachycardia or drug tolerance. Angiotensin converting enzyme inhibitors produce symptomatic improvement and improve exercise capacity in all grades of heart failure. They also improve the prognosis of patients with severe heart failure. Quinapril is a recently introduced, nonsulfhydryl ACE inhibitor, whose intermediate half-life makes it well-suited for the treatment of patients with CHF. The acute and chronic hemodynamic effects
tients. ' However, in contrast to conventional vasodilators, there is no reflex tachycardia and only a relatively small increase in cardiac output. Furthermore, hemodynamic tolerance is much less common during ACE inhibitor therapy than is the case with other vasodilat o r s . This may be an important factor in the efficacy of the ACE inhibitors, since acute hemodynamic improvement does not predict clinical benefit. The fact that there is a delay of several weeks from the onset of treatment to the appearance of demonstrable clinical improvement suggests that chronic hemodynamic effects may be more relevant than an acute response. Large-scale clinical trials have provided compelling evidence supporting the use of ACE inhibitors in CHF (Table 1). The initial placebo-controlled studies in patients with moderate to severe CHF showed that an ACE inhibitor such as enalapril improves both symptoms and exercise capacity (Figure l ) , in addition to prolonging life. More recent studies have also demonstrated clinical efficacy in patients with milder C H F , ' ' as well as possible improvement in survival. ' Other large, multicenter clinical studies currently in progress (eg, the SOLVD study) should provide a definitive answer as to whether ACE inhibitors improve the prognosis in patients with mild to moderate CHF, as they do in severely symptomatic patients. The general trend towards the earlier use of ACE inhibitors in CHF has led to consideration of their use in asymptomatic patients, the objective being to delay or prevent the development of symptomatic CHF and to improve survival. Left ventricular (LV) function is strongly predictive of mortality in CHF, even in asymptomatic patients. Thus, patients with asymptomatic LV dysfunction have a poor prognosis, and the factors that lead to improved survival with ACE inhibitors (eg, reduction of ventricular arrhythmias and decreased progression to terminal C H F ' ) in symptomatic patients may also apply to patients with asymptomatic LV dysfunction. Angiotensin converting enzyme inhibitors have also been used in an attempt to reduce ventricular dilation following myocardial infarction (MI). ' The available clinical data suggest that these agents can favorably influence ventricular remodelling at this time. In the two studies published to date, the drugs were introduced relatively late (ie, between 7 and 28 days) post-MI. ' However, circulating levels of renin and angiotensin II 4 5
4-7
47
8
5
13
1 mo
FIGURE 1. Improvement of exercise time after one month of enalapril therapy.
14
15 16
17-19
16
12
15
20 21
20 21
TABLE 1. BENEFICIAL EFFECTS OF ACE INHIBITORS IN PATIENTS WITH CHF Symptoms
Severity of CHF
+ ++ ++
Mild Moderate Severe CHF = chronic heart
failure.
Survival ?
+ ++
are elevated within 48 h of MI. Infarct expansion and ventricular dilation also occur soon after an infarct and are well under way seven days postinfarction. Thus, greater benefit might be expected from the earlier introduction of ACE inhibitors after acute ML 22
WHICH DRUGS AND WHEN? While ACE inhibitors have been shown to be effective in CHF, their role in the management of patients with CHF has to be considered vis-a-vis that of other effective drug therapies—in particular, diuretics and digoxin. One randomized study demonstrated that a diuretic containing both furosemide and amiloride was as effective as an ACE inhibitor overall, and was more likely to prevent recurrence of pulmonary edema. In a different study, patients with symptomatic CHF despite diuretic therapy were randomized to treatment with either an increased dose of diuretic or the addition of an ACE inhibitor to the original diuretic therapy. The therapeutic outcome in patients receiving the high-dose diuretic was superior to that of the ACE inhibitor group. Finally, the addition of digoxin or captopril to standard diuretic therapy was compared to placebo in a recent, large multicenter study, The ACE inhibitor had little significant advantage over digoxin. While interesting, these studies were conducted in artificial circumstances and are of questionable relevance to clinical practice. In patients with decompensated CHF, the question is not whether to increase the dosage of a diuretic, commence digoxin therapy, or introduce treatment with an ACE inhibitor. Rather, all three approaches can be considered together. It is difficult to deny any patient with symptomatic CHF, despite an adequate dose of diuretic, the potential benefits of an ACE inhibitor. 23
24
13
Downloaded from http://ajh.oxfordjournals.org/ at University of New South Wales on July 8, 2015
9 - 1 1
12
Control
25,26
27
25 26
PHARMACOKINETICS AND HEMODYNAMIC EFFECTS OF QUINAPRIL Pharmacokinetics and Pharmacology Quinapril is a new ACE inhibitor currently available in several Euro pean countries. It possesses many of the properties dis cussed above that make it well-suited for the treatment of CHF (Table 2). Quinapril is a nonsulfhydryl-containing prodrug, which is hydrolyzed in the liver to the active metabolite, quinaprilat. In vitro studies have shown that quinaprilat is approximately three times as potent an inhibitor of the converting enzyme as quina pril. Quinapril is rapidly absorbed after oral administra tion, with peak plasma concentrations achieved within 1 h. It is rapidly hydrolyzed to quinaprilat, which reaches its peak plasma concentration 2 h after a single oral dose. Since plasma concentrations of quinaprilat 28
29
TABLE 2.
CHARACTERISTICS OF SELECTED ACE INHIBITORS Captopril Enalapril Lisinopril
Duration SH Group Prodrug
Short Yes No
Long No Yes
Quinapril
Very Long Intermediate No No No Yes
are fourfold higher than the parent compound during chronic oral dosing, the therapeutic effect of quinapril is primarily due to that of its more potent metabolite. Quinaprilat is excreted predominantly in the urine; hence, its clearance in patients with impaired renal func tion is reduced in direct proportion to creatinine clear ance. Quinapril produces potent ACE inhibition, while its shorter half-life suggests that it may be suitable for the treatment of CHF. The lack of sulfhydryl group may reduce the incidence of some adverse effects (eg, skin rashes, loss of taste) thought to be related to this chemi cal group. ' ' Quinapril can be administered in a dose of 5 to 40 mg daily. As with other ACE inhibitors, appro priate dose reductions are required in older patients or in those with renal impairment. 29
30
3 26 31
32
Acute and Chronic Hemodynamic Effects The acute hemodynamic effects of quinapril have been investi gated in two open-label, uncontrolled, single-dose stud ies. In the first study, 15 patients with severe heart fail ure received a 5 mg oral dose of quinapril. As might be expected from the pharmacokinetics of the drug, hemo dynamic effects occurred within 1 h of dosing, but the maximum changes were delayed for between 2 and 3 h postdosing. The hemodynamic effects were similar to those described for other ACE inhibitors. Specifically, there was a 44% decrease in LV filling pressure, a 2 1 % increase in cardiac output, a 28% decrease in systemic vascular resistance, and a 15% decrease in mean arterial pressure. However, there was no reflex tachycardia. The second study included 26 patients with moderate to severe CHF unresponsive to treatment with digoxin and diuretics. The maximal hemodynamic effects oc curred 4 h following a single oral dose of 2.5 to 10 mg quinapril. The acute effects were similar to the previous study: there was a 20% to 4 0 % decrease in filling pres sures, a 2 5 % increase in cardiac output, a 3 0 % decrease in both systemic vascular resistance and pulmonary vas cular resistance, and a 5 % decrease in mean arterial pressure. The chronic hemodynamic effects of quinapril (total daily doses of 5 to 30 mg/day given in at least two divided doses) were investigated in the same patients who participated in the latter acute hemodynamic study (Table 3). Of the original 26 patients, 19 were available for a second hemodynamic study after 16 weeks of quinapril therapy. The results showed that the initial 33
34
TABLE 3. RAP PAWP MAP
CHRONIC HEMODYNAMIC EFFECTS OF QUINAPRIL 1 I I
30% 35% 5%
SVR CO HR
MAP = mean arterial pressure; SVR = systolic CO = cardiac output; HR = heart rate.
j Τ ~ vascular
30% 20% resistance;
Downloaded from http://ajh.oxfordjournals.org/ at University of New South Wales on July 8, 2015
The number of ACE inhibitors licensed for use in CHF in the USA can be expected to increase dramatically over the next decade, and it is likely that all drugs in this class will be effective in this application. The decision as to which ACE inhibitor to select will therefore depend more on a drug's side effect profile than on its relative efficacy. In patients with CHF, the long-acting ACE in hibitors (eg, enalapril and lisinopril) are more likely to adversely affect biochemical markers of renal function than the shorter-acting drugs. However, the rele vance of the small reduction in glomerular filtration rate (GFR) is uncertain, since clinically significant renal im pairment is uncommon following the introduction of an ACE inhibitor in patients without renal artery stenosis. Hypotension following the first dose is an occasional problem with all ACE inhibitors. However, with longacting agents, the hypotension may take many hours to resolve and may require infusion of intravenous fluids and, occasionally, angiotensin II to restore the blood pressure. Hypotension may also occur with short-act ing ACE inhibitors, but tends to resolve much more rapidly. Finally, the long-acting ACE inhibitors are more likely to induce hyperkalemia, especially when coad ministered with potassium supplements or potassiumsparing diuretics. ' Therefore, the "ideal" ACE inhibi tor for the treatment of CHF should have a duration of action that is long enough to allow once- or twice-daily dosing, but short enough to permit some overnight re covery of GFR.
EFFECTS OF QUINAPRIL ON HEART FAILURE SYMPTOMS AND EXERCISE CAPACITY The effects of chronic dosing with quinapril were investigated in a 12 week, double-blind study in 225 patients with mild to moderate heart failure (New York Heart Association (NYHA) functional class II or III). The patients were randomized to one of four groups: placebo, 5 mg quinapril twice daily, 10 mg quinapril twice daily, or 20 mg quinapril twice daily. Patients who were already taking a diuretic and/or digoxin continued to do so, but no dosage changes were made during the 12week study period. Clinical assessments were made regularly, and bicycle exercise tests were performed at baseline and after 6 and 12 weeks of treatment. The NYHA functional class improved in approximately 5 0 % of the quinapril-treated patients, compared with 3 0 % of patients in the placebo group. Clinical benefit was more marked in Class III than in Class II patients at the start of the study. An increase in exercise capacity had occurred by week 6, and was even more marked at week 12. The improvement with 10 and 20 mg quinapril twice daily was significantly greater than that with placebo, whereas the increase in exercise time in the group receiving 5 mg quinapril twice daily was not statistically significant. By the end of the study, the improvement observed with 20 mg quinapril twice daily was significantly greater than that associated with 10 mg quinapril twice daily. Quinapril was well-tolerated, and there were no serious adverse effects or deaths. Minor side effects in the quinapril-treated groups were no more common than in the placebo group and included cough, dizziness and gastrointestinal symptoms. A small increase in serum creatinine occurred in three patients, but did not require discontinuation of quinapril therapy. This large, carefully-controlled study provides evidence that quinapril is both efficacious and extremely well-tolerated in the treatment of mild to moderate CHF. This was also the first study to suggest a dose response for the clinical effects of an ACE inhibitor in heart failure. 35
SUMMARY The ACE inhibitors have become a well-established option for the treatment of chronic heart failure. Agents in this class produce sustained hemodynamic and clinical improvement, while simultaneously improving survival. These drugs should be regarded as part of a therapeutic strategy that needs to be tailored to the needs of the individual patient, and which may also include nondrug treatment, diuretics, digoxin and, ultimately, heart transplantation. Quinapril is a new ACE inhibitor whose therapeutic effects are due primarily to the action of its active metabolite, quinaprilat. The beneficial acute and chronic hemodynamic effects of quinapril are similar to those of other ACE inhibitors. The maximal hemodynamic effect of quinapril may be delayed for up to 4 h after the first dose, making prolonged observation mandatory, especially in older patients or in those with hepatic impairment. Quinapril has been shown to produce clinical benefits in mild to moderate CHF, possibly in a dose-related manner. Its intermediate half-life decreases the risk of significant renal impairment. The initial studies with quinapril in the treatment of CHF are promising. REFERENCES 1.
Editorial: Angiotensin converting enzyme inhibitors in the treatment of heart failure. Lancet 1985;ii:811-812.
2.
Packer M: Converting enzyme inhibitors for severe chronic heart failure: views from a skeptic. Int J Cardiol 1985;7:111-120.
3.
Ball SG, Robertson JIS: A need for new converting enzyme inhibitors. Br Med J 1985;290:180-181.
4.
Packer M, Medina N, Yushak M, et al: Hemodynamic pattern of response during long-term captopril therapy for severe chronic heart failure. Circulation 1983; 68:803-812.
5.
Sharpe DN, Murphy J, Coxon R, et al: Enalapril in patients with chronic heart failure: a placebo controlled randomized, double blind study. Circulation 1984; 70:271-278.
6.
Packer M, Medina N, Yushak M: Contrasting hemodynamic responses in severe heart failure: a comparison of captopril and other vasodilator drugs. Am Heart J 1982;104:1215-1223.
7.
Bayliss J, Norell MS, Canega-Anson R, et al: Clinical importance of the renin angiotensin system in chronic heart failure: double blind comparison of captopril and prazosin. Br Med J 1985;290:1861-1865.
8.
Massie BM, Kramer BL, Topic N: Lack of relationship between short-term hemodynamic effects of captopril and subsequent clinical responses. Circulation 1984; 69:1135-1141.
9.
Cleland JGF, Dargie HJ, Hodsman GP, et al: Captopril in heart failure: a double blind controlled trial. Br Heart J 1984;52:530-535.
10.
Cleland JGF, Dargie HJ, Ball SG, et al: Effects of enalapril in heart failure: a double blind study of effects on exer-
Downloaded from http://ajh.oxfordjournals.org/ at University of New South Wales on July 8, 2015
favorable hemodynamic responses had been maintained and that there was no evidence of hemodynamic tolerance. These preliminary reports suggest that quinapril produces beneficial acute and chronic hemodynamic effects in moderate to severe CHF. The maximal hemodynamic changes occur two to four hours after the initial dose. Since these were both open-label studies, however, the results should be interpreted with some caution. Furthermore, the hemodynamic effects are expressed as maximum changes only, which tend to exaggerate the responses to a drug. Therefore, further hemodynamic studies are indicated, ideally using an active control such as an alternative ACE inhibitor or a conventional vasodilator.
cise performance, renal function, hormones and meta bolic state. Br Heart J 1985;54:305-312. Captopril Multicentre Research Group: A placebo con trolled trial of captopril in refractory chronic congestive heart failure. J Am Coll Cardiol 1983;2:755-763.
12.
The CONSENSUS Trial Study Group: Effects of enala pril on mortality in severe congestive heart failure: re sults of the Co-operative North Scandinavian Enalapril Survival Study (CONSENSUS). Ν Engl J Med 1987;316:1429-1435.
13.
The Captopril-Digoxin Multicentre Research Group: Co operative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA 1988;259:539-544. Kromer EP, Riegger GAJ, Liebau G, et al: Effectiveness of converting enzyme inhibition (enalapril) for mild con gestive heart failure. Am J Cardiol 1986;57:459-462.
14. 15.
Kleber FX: Influence of captopril on life expectancy in chronic congestive heart failure. Herz 1987;125(suppl I):38-45.
16.
Newman TJ, Maskin CS, Dennick LG, et al: Effects of captopril on survival in patients with heart failure. Am J Med 1988;84:140-144.
17.
Dargie HJ, Cleland JGF, Leckie BJ, et al: Relation of ar rhythmias and electrolyte abnormalities to survival in patients with severe chronic heart failure. Circulation 1987;75(suppl IV):98-107.
18.
Gradman A, Decdwania P, Cody R, et al: Predictors of total mortality and sudden death in mild to moderate heart failure. J Am Coll Cardiol 1989;14:564-570.
19.
Franciosa JA, Wilen M, Ziesche S, et al.: Survival in men with severe chronic left ventricular failure due to either coronary artery disease or idiopathic dilated cardiomyo pathy. Am J Cardiol 1983;51:831-833.
24.
Cowley AS, Stainer K, Wynne RD, et al: Symptomatic assessment of patients with heart failure: double blind comparison of increasing doses of diuretics and captopril in moderate heart failure. Lancet 1986;ii:770-772.
25.
Packer M, Lee WH, Yushak RN, et al: Comparison of captopril and enalapril in patients with severe chronic heart failure. Ν Engl J Med 1986;315:847-853.
26.
Powers ER, Chiaramida A, DeMaria AN, et al: A double blind comparison of lisinopril with captopril in patients with symptomatic congestive heart failure. J Cardiovasc Pharmacol 1987;9(suppl 3):S82-S88.
27.
Cleland JGF, Dargie HJ, McAlpine H, et al: Severe hypo tension after first dose of enalapril in heart failure. Br Med J 1985;291:1309-1312.
28.
Kaplan HR, Taylor DG, Olson SC, et al: Quinapril—A preclinical review of the pharmacology, pharmacoki netics and toxicology. Angiology 1989;40:335-350.
29.
Olson SC, Horvath AM, Michniewicxz BD, et al: The clinical pharmacokinetics of quinapril. Angiology 1989;40:351-359.
30.
Begg EJ, Bailey RR, Lynn KL, et al: The pharmacokinetics of angiotensin converting enzyme inhibitors in patients with renal impairment. J Hypertension 1989;7(suppl 5):529-532.
31.
Edwards CRW, Padfield PL: Angiotensin converting en zyme inhibitors: past, present, and bright future. Lancet 1985;i:30-34.
32.
Schnaper HW: The management of hypertension in older patients. J Cardiovasc Pharmacol 1990;15(suppl 2):S56-S61.
33.
Holt P, Majim J, Sowton E: The acute haemodynamic effects of quinapril, a new non-sulphydryl angiotensin converting enzyme inhibitor in patients with severe con gestive cardiac failure. Eur J Clin Pharmacol 1986;31:914.
20.
Sharpe N, Murphy J, Smith H, et al.: Treatment of pa tients with symptomless left ventricular dysfunction after myocardial infarction. Lancet 1988;i:255-259.
21.
Pfeffer MA, Lamas GA, Vaughan DE, et al: Effect of captopril on progressive ventricular dilation after anterior myocardial infarction. Ν Engl J Med 1988; 319:80-85.
34.
Banas JS: Preliminary haemodynamic report of the effi cacy and safety of quinapril in acute and chronic treat ment of patients with congestive heart failure. Angiology 1989;40:396-404.
22.
McAlpine HM, Morton JJ, Leckie B, et al: Neuroendo crine activation after acute myocardial infarction. Br Heart J 1988;60:117-124.
35.
Riegger GAJ: The effects of ACE inhibitors on exercise capacity in the treatment of congestive heart failure. J Cardiovasc Pharmacol 1990;15(suppl 2):S41-S46.
23.
Richardson A, Bayliss J, Scriven AJ, et al: Double blind
Downloaded from http://ajh.oxfordjournals.org/ at University of New South Wales on July 8, 2015
11.
comparison of captopril alone against furosemide plus amiloride in mild heart failure. Lancet 1987;ii:709-711.
Downloaded from http://ajh.oxfordjournals.org/ at University of New South Wales on July 8, 2015
David B. Northridge and Henry J. Dargie
of quinapril are similar to those of other ACE inhibitors. In a large, multicenter, randomized, placebocontrolled study of 225 patients with mild to moderate CHF, 10 to 40 m g / d a y quinapril significantly improved clinical status and exercise capacity in a dose-related manner. The incidence of side effects did not differ significantly from that of placebo. The initial studies with quinapril are promising and warrant further clinical investigation of this compound. Am J Hypertens 1990;3:283S-287S
KEY WORDS: Quinapril, chronic heart failure.
D
uring the 1980s, angiotensin converting enzyme (ACE) inhibitors became widely accepted for the treatment of patients with chronic heart failure (CHF). ' However, there are still some questions regarding when these drugs should be introduced and which patients are most likely to benefit from treatment. Many of these issues are likely to be resolved during the 1990s, although further questions will undoubtedly arise. It is also likely that additional ACE inhibitors will be introduced during the 1990s, some of which may have potential advantages in CHF. The present article summarizes the indications for ACE inhibitor treatment in CHF, and reviews the available clinical data on the new ACE inhibitor, quinapril. 1 2
3
David B. Northridge, MD
RATIONALE FOR USING ACE INHIBITORS IN HEART FAILURE
From the Department of Cardiology, Western Infirmary, Glasgow, Scotland. Address correspondence and reprint requests to David B. Northridge, MD, Department of Cardiology, Western Infirmary, Glasgow, Scotland G i l 6NT.
Angiotensin converting enzyme inhibitors have beneficial acute and chronic hemodynamic effects in patients with CHF. ' The pattern of response differs from that of other so called "balanced" vasodilators. Angiotensin converting enzyme inhibition results in a fall in both right and left ventricular filling pressures in most pa4 5
6
Downloaded from http://ajh.oxfordjournals.org/ at University of New South Wales on July 8, 2015
Angiotensin converting enzyme inhibitors are now firmly established in the treatment of patients with chronic heart failure (CHF). Their beneficial acute and chronic hemodynamic effects are not associated with reflex tachycardia or drug tolerance. Angiotensin converting enzyme inhibitors produce symptomatic improvement and improve exercise capacity in all grades of heart failure. They also improve the prognosis of patients with severe heart failure. Quinapril is a recently introduced, nonsulfhydryl ACE inhibitor, whose intermediate half-life makes it well-suited for the treatment of patients with CHF. The acute and chronic hemodynamic effects
tients. ' However, in contrast to conventional vasodilators, there is no reflex tachycardia and only a relatively small increase in cardiac output. Furthermore, hemodynamic tolerance is much less common during ACE inhibitor therapy than is the case with other vasodilat o r s . This may be an important factor in the efficacy of the ACE inhibitors, since acute hemodynamic improvement does not predict clinical benefit. The fact that there is a delay of several weeks from the onset of treatment to the appearance of demonstrable clinical improvement suggests that chronic hemodynamic effects may be more relevant than an acute response. Large-scale clinical trials have provided compelling evidence supporting the use of ACE inhibitors in CHF (Table 1). The initial placebo-controlled studies in patients with moderate to severe CHF showed that an ACE inhibitor such as enalapril improves both symptoms and exercise capacity (Figure l ) , in addition to prolonging life. More recent studies have also demonstrated clinical efficacy in patients with milder C H F , ' ' as well as possible improvement in survival. ' Other large, multicenter clinical studies currently in progress (eg, the SOLVD study) should provide a definitive answer as to whether ACE inhibitors improve the prognosis in patients with mild to moderate CHF, as they do in severely symptomatic patients. The general trend towards the earlier use of ACE inhibitors in CHF has led to consideration of their use in asymptomatic patients, the objective being to delay or prevent the development of symptomatic CHF and to improve survival. Left ventricular (LV) function is strongly predictive of mortality in CHF, even in asymptomatic patients. Thus, patients with asymptomatic LV dysfunction have a poor prognosis, and the factors that lead to improved survival with ACE inhibitors (eg, reduction of ventricular arrhythmias and decreased progression to terminal C H F ' ) in symptomatic patients may also apply to patients with asymptomatic LV dysfunction. Angiotensin converting enzyme inhibitors have also been used in an attempt to reduce ventricular dilation following myocardial infarction (MI). ' The available clinical data suggest that these agents can favorably influence ventricular remodelling at this time. In the two studies published to date, the drugs were introduced relatively late (ie, between 7 and 28 days) post-MI. ' However, circulating levels of renin and angiotensin II 4 5
4-7
47
8
5
13
1 mo
FIGURE 1. Improvement of exercise time after one month of enalapril therapy.
14
15 16
17-19
16
12
15
20 21
20 21
TABLE 1. BENEFICIAL EFFECTS OF ACE INHIBITORS IN PATIENTS WITH CHF Symptoms
Severity of CHF
+ ++ ++
Mild Moderate Severe CHF = chronic heart
failure.
Survival ?
+ ++
are elevated within 48 h of MI. Infarct expansion and ventricular dilation also occur soon after an infarct and are well under way seven days postinfarction. Thus, greater benefit might be expected from the earlier introduction of ACE inhibitors after acute ML 22
WHICH DRUGS AND WHEN? While ACE inhibitors have been shown to be effective in CHF, their role in the management of patients with CHF has to be considered vis-a-vis that of other effective drug therapies—in particular, diuretics and digoxin. One randomized study demonstrated that a diuretic containing both furosemide and amiloride was as effective as an ACE inhibitor overall, and was more likely to prevent recurrence of pulmonary edema. In a different study, patients with symptomatic CHF despite diuretic therapy were randomized to treatment with either an increased dose of diuretic or the addition of an ACE inhibitor to the original diuretic therapy. The therapeutic outcome in patients receiving the high-dose diuretic was superior to that of the ACE inhibitor group. Finally, the addition of digoxin or captopril to standard diuretic therapy was compared to placebo in a recent, large multicenter study, The ACE inhibitor had little significant advantage over digoxin. While interesting, these studies were conducted in artificial circumstances and are of questionable relevance to clinical practice. In patients with decompensated CHF, the question is not whether to increase the dosage of a diuretic, commence digoxin therapy, or introduce treatment with an ACE inhibitor. Rather, all three approaches can be considered together. It is difficult to deny any patient with symptomatic CHF, despite an adequate dose of diuretic, the potential benefits of an ACE inhibitor. 23
24
13
Downloaded from http://ajh.oxfordjournals.org/ at University of New South Wales on July 8, 2015
9 - 1 1
12
Control
25,26
27
25 26
PHARMACOKINETICS AND HEMODYNAMIC EFFECTS OF QUINAPRIL Pharmacokinetics and Pharmacology Quinapril is a new ACE inhibitor currently available in several Euro pean countries. It possesses many of the properties dis cussed above that make it well-suited for the treatment of CHF (Table 2). Quinapril is a nonsulfhydryl-containing prodrug, which is hydrolyzed in the liver to the active metabolite, quinaprilat. In vitro studies have shown that quinaprilat is approximately three times as potent an inhibitor of the converting enzyme as quina pril. Quinapril is rapidly absorbed after oral administra tion, with peak plasma concentrations achieved within 1 h. It is rapidly hydrolyzed to quinaprilat, which reaches its peak plasma concentration 2 h after a single oral dose. Since plasma concentrations of quinaprilat 28
29
TABLE 2.
CHARACTERISTICS OF SELECTED ACE INHIBITORS Captopril Enalapril Lisinopril
Duration SH Group Prodrug
Short Yes No
Long No Yes
Quinapril
Very Long Intermediate No No No Yes
are fourfold higher than the parent compound during chronic oral dosing, the therapeutic effect of quinapril is primarily due to that of its more potent metabolite. Quinaprilat is excreted predominantly in the urine; hence, its clearance in patients with impaired renal func tion is reduced in direct proportion to creatinine clear ance. Quinapril produces potent ACE inhibition, while its shorter half-life suggests that it may be suitable for the treatment of CHF. The lack of sulfhydryl group may reduce the incidence of some adverse effects (eg, skin rashes, loss of taste) thought to be related to this chemi cal group. ' ' Quinapril can be administered in a dose of 5 to 40 mg daily. As with other ACE inhibitors, appro priate dose reductions are required in older patients or in those with renal impairment. 29
30
3 26 31
32
Acute and Chronic Hemodynamic Effects The acute hemodynamic effects of quinapril have been investi gated in two open-label, uncontrolled, single-dose stud ies. In the first study, 15 patients with severe heart fail ure received a 5 mg oral dose of quinapril. As might be expected from the pharmacokinetics of the drug, hemo dynamic effects occurred within 1 h of dosing, but the maximum changes were delayed for between 2 and 3 h postdosing. The hemodynamic effects were similar to those described for other ACE inhibitors. Specifically, there was a 44% decrease in LV filling pressure, a 2 1 % increase in cardiac output, a 28% decrease in systemic vascular resistance, and a 15% decrease in mean arterial pressure. However, there was no reflex tachycardia. The second study included 26 patients with moderate to severe CHF unresponsive to treatment with digoxin and diuretics. The maximal hemodynamic effects oc curred 4 h following a single oral dose of 2.5 to 10 mg quinapril. The acute effects were similar to the previous study: there was a 20% to 4 0 % decrease in filling pres sures, a 2 5 % increase in cardiac output, a 3 0 % decrease in both systemic vascular resistance and pulmonary vas cular resistance, and a 5 % decrease in mean arterial pressure. The chronic hemodynamic effects of quinapril (total daily doses of 5 to 30 mg/day given in at least two divided doses) were investigated in the same patients who participated in the latter acute hemodynamic study (Table 3). Of the original 26 patients, 19 were available for a second hemodynamic study after 16 weeks of quinapril therapy. The results showed that the initial 33
34
TABLE 3. RAP PAWP MAP
CHRONIC HEMODYNAMIC EFFECTS OF QUINAPRIL 1 I I
30% 35% 5%
SVR CO HR
MAP = mean arterial pressure; SVR = systolic CO = cardiac output; HR = heart rate.
j Τ ~ vascular
30% 20% resistance;
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The number of ACE inhibitors licensed for use in CHF in the USA can be expected to increase dramatically over the next decade, and it is likely that all drugs in this class will be effective in this application. The decision as to which ACE inhibitor to select will therefore depend more on a drug's side effect profile than on its relative efficacy. In patients with CHF, the long-acting ACE in hibitors (eg, enalapril and lisinopril) are more likely to adversely affect biochemical markers of renal function than the shorter-acting drugs. However, the rele vance of the small reduction in glomerular filtration rate (GFR) is uncertain, since clinically significant renal im pairment is uncommon following the introduction of an ACE inhibitor in patients without renal artery stenosis. Hypotension following the first dose is an occasional problem with all ACE inhibitors. However, with longacting agents, the hypotension may take many hours to resolve and may require infusion of intravenous fluids and, occasionally, angiotensin II to restore the blood pressure. Hypotension may also occur with short-act ing ACE inhibitors, but tends to resolve much more rapidly. Finally, the long-acting ACE inhibitors are more likely to induce hyperkalemia, especially when coad ministered with potassium supplements or potassiumsparing diuretics. ' Therefore, the "ideal" ACE inhibi tor for the treatment of CHF should have a duration of action that is long enough to allow once- or twice-daily dosing, but short enough to permit some overnight re covery of GFR.
EFFECTS OF QUINAPRIL ON HEART FAILURE SYMPTOMS AND EXERCISE CAPACITY The effects of chronic dosing with quinapril were investigated in a 12 week, double-blind study in 225 patients with mild to moderate heart failure (New York Heart Association (NYHA) functional class II or III). The patients were randomized to one of four groups: placebo, 5 mg quinapril twice daily, 10 mg quinapril twice daily, or 20 mg quinapril twice daily. Patients who were already taking a diuretic and/or digoxin continued to do so, but no dosage changes were made during the 12week study period. Clinical assessments were made regularly, and bicycle exercise tests were performed at baseline and after 6 and 12 weeks of treatment. The NYHA functional class improved in approximately 5 0 % of the quinapril-treated patients, compared with 3 0 % of patients in the placebo group. Clinical benefit was more marked in Class III than in Class II patients at the start of the study. An increase in exercise capacity had occurred by week 6, and was even more marked at week 12. The improvement with 10 and 20 mg quinapril twice daily was significantly greater than that with placebo, whereas the increase in exercise time in the group receiving 5 mg quinapril twice daily was not statistically significant. By the end of the study, the improvement observed with 20 mg quinapril twice daily was significantly greater than that associated with 10 mg quinapril twice daily. Quinapril was well-tolerated, and there were no serious adverse effects or deaths. Minor side effects in the quinapril-treated groups were no more common than in the placebo group and included cough, dizziness and gastrointestinal symptoms. A small increase in serum creatinine occurred in three patients, but did not require discontinuation of quinapril therapy. This large, carefully-controlled study provides evidence that quinapril is both efficacious and extremely well-tolerated in the treatment of mild to moderate CHF. This was also the first study to suggest a dose response for the clinical effects of an ACE inhibitor in heart failure. 35
SUMMARY The ACE inhibitors have become a well-established option for the treatment of chronic heart failure. Agents in this class produce sustained hemodynamic and clinical improvement, while simultaneously improving survival. These drugs should be regarded as part of a therapeutic strategy that needs to be tailored to the needs of the individual patient, and which may also include nondrug treatment, diuretics, digoxin and, ultimately, heart transplantation. Quinapril is a new ACE inhibitor whose therapeutic effects are due primarily to the action of its active metabolite, quinaprilat. The beneficial acute and chronic hemodynamic effects of quinapril are similar to those of other ACE inhibitors. The maximal hemodynamic effect of quinapril may be delayed for up to 4 h after the first dose, making prolonged observation mandatory, especially in older patients or in those with hepatic impairment. Quinapril has been shown to produce clinical benefits in mild to moderate CHF, possibly in a dose-related manner. Its intermediate half-life decreases the risk of significant renal impairment. The initial studies with quinapril in the treatment of CHF are promising. REFERENCES 1.
Editorial: Angiotensin converting enzyme inhibitors in the treatment of heart failure. Lancet 1985;ii:811-812.
2.
Packer M: Converting enzyme inhibitors for severe chronic heart failure: views from a skeptic. Int J Cardiol 1985;7:111-120.
3.
Ball SG, Robertson JIS: A need for new converting enzyme inhibitors. Br Med J 1985;290:180-181.
4.
Packer M, Medina N, Yushak M, et al: Hemodynamic pattern of response during long-term captopril therapy for severe chronic heart failure. Circulation 1983; 68:803-812.
5.
Sharpe DN, Murphy J, Coxon R, et al: Enalapril in patients with chronic heart failure: a placebo controlled randomized, double blind study. Circulation 1984; 70:271-278.
6.
Packer M, Medina N, Yushak M: Contrasting hemodynamic responses in severe heart failure: a comparison of captopril and other vasodilator drugs. Am Heart J 1982;104:1215-1223.
7.
Bayliss J, Norell MS, Canega-Anson R, et al: Clinical importance of the renin angiotensin system in chronic heart failure: double blind comparison of captopril and prazosin. Br Med J 1985;290:1861-1865.
8.
Massie BM, Kramer BL, Topic N: Lack of relationship between short-term hemodynamic effects of captopril and subsequent clinical responses. Circulation 1984; 69:1135-1141.
9.
Cleland JGF, Dargie HJ, Hodsman GP, et al: Captopril in heart failure: a double blind controlled trial. Br Heart J 1984;52:530-535.
10.
Cleland JGF, Dargie HJ, Ball SG, et al: Effects of enalapril in heart failure: a double blind study of effects on exer-
Downloaded from http://ajh.oxfordjournals.org/ at University of New South Wales on July 8, 2015
favorable hemodynamic responses had been maintained and that there was no evidence of hemodynamic tolerance. These preliminary reports suggest that quinapril produces beneficial acute and chronic hemodynamic effects in moderate to severe CHF. The maximal hemodynamic changes occur two to four hours after the initial dose. Since these were both open-label studies, however, the results should be interpreted with some caution. Furthermore, the hemodynamic effects are expressed as maximum changes only, which tend to exaggerate the responses to a drug. Therefore, further hemodynamic studies are indicated, ideally using an active control such as an alternative ACE inhibitor or a conventional vasodilator.
cise performance, renal function, hormones and meta bolic state. Br Heart J 1985;54:305-312. Captopril Multicentre Research Group: A placebo con trolled trial of captopril in refractory chronic congestive heart failure. J Am Coll Cardiol 1983;2:755-763.
12.
The CONSENSUS Trial Study Group: Effects of enala pril on mortality in severe congestive heart failure: re sults of the Co-operative North Scandinavian Enalapril Survival Study (CONSENSUS). Ν Engl J Med 1987;316:1429-1435.
13.
The Captopril-Digoxin Multicentre Research Group: Co operative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA 1988;259:539-544. Kromer EP, Riegger GAJ, Liebau G, et al: Effectiveness of converting enzyme inhibition (enalapril) for mild con gestive heart failure. Am J Cardiol 1986;57:459-462.
14. 15.
Kleber FX: Influence of captopril on life expectancy in chronic congestive heart failure. Herz 1987;125(suppl I):38-45.
16.
Newman TJ, Maskin CS, Dennick LG, et al: Effects of captopril on survival in patients with heart failure. Am J Med 1988;84:140-144.
17.
Dargie HJ, Cleland JGF, Leckie BJ, et al: Relation of ar rhythmias and electrolyte abnormalities to survival in patients with severe chronic heart failure. Circulation 1987;75(suppl IV):98-107.
18.
Gradman A, Decdwania P, Cody R, et al: Predictors of total mortality and sudden death in mild to moderate heart failure. J Am Coll Cardiol 1989;14:564-570.
19.
Franciosa JA, Wilen M, Ziesche S, et al.: Survival in men with severe chronic left ventricular failure due to either coronary artery disease or idiopathic dilated cardiomyo pathy. Am J Cardiol 1983;51:831-833.
24.
Cowley AS, Stainer K, Wynne RD, et al: Symptomatic assessment of patients with heart failure: double blind comparison of increasing doses of diuretics and captopril in moderate heart failure. Lancet 1986;ii:770-772.
25.
Packer M, Lee WH, Yushak RN, et al: Comparison of captopril and enalapril in patients with severe chronic heart failure. Ν Engl J Med 1986;315:847-853.
26.
Powers ER, Chiaramida A, DeMaria AN, et al: A double blind comparison of lisinopril with captopril in patients with symptomatic congestive heart failure. J Cardiovasc Pharmacol 1987;9(suppl 3):S82-S88.
27.
Cleland JGF, Dargie HJ, McAlpine H, et al: Severe hypo tension after first dose of enalapril in heart failure. Br Med J 1985;291:1309-1312.
28.
Kaplan HR, Taylor DG, Olson SC, et al: Quinapril—A preclinical review of the pharmacology, pharmacoki netics and toxicology. Angiology 1989;40:335-350.
29.
Olson SC, Horvath AM, Michniewicxz BD, et al: The clinical pharmacokinetics of quinapril. Angiology 1989;40:351-359.
30.
Begg EJ, Bailey RR, Lynn KL, et al: The pharmacokinetics of angiotensin converting enzyme inhibitors in patients with renal impairment. J Hypertension 1989;7(suppl 5):529-532.
31.
Edwards CRW, Padfield PL: Angiotensin converting en zyme inhibitors: past, present, and bright future. Lancet 1985;i:30-34.
32.
Schnaper HW: The management of hypertension in older patients. J Cardiovasc Pharmacol 1990;15(suppl 2):S56-S61.
33.
Holt P, Majim J, Sowton E: The acute haemodynamic effects of quinapril, a new non-sulphydryl angiotensin converting enzyme inhibitor in patients with severe con gestive cardiac failure. Eur J Clin Pharmacol 1986;31:914.
20.
Sharpe N, Murphy J, Smith H, et al.: Treatment of pa tients with symptomless left ventricular dysfunction after myocardial infarction. Lancet 1988;i:255-259.
21.
Pfeffer MA, Lamas GA, Vaughan DE, et al: Effect of captopril on progressive ventricular dilation after anterior myocardial infarction. Ν Engl J Med 1988; 319:80-85.
34.
Banas JS: Preliminary haemodynamic report of the effi cacy and safety of quinapril in acute and chronic treat ment of patients with congestive heart failure. Angiology 1989;40:396-404.
22.
McAlpine HM, Morton JJ, Leckie B, et al: Neuroendo crine activation after acute myocardial infarction. Br Heart J 1988;60:117-124.
35.
Riegger GAJ: The effects of ACE inhibitors on exercise capacity in the treatment of congestive heart failure. J Cardiovasc Pharmacol 1990;15(suppl 2):S41-S46.
23.
Richardson A, Bayliss J, Scriven AJ, et al: Double blind
Downloaded from http://ajh.oxfordjournals.org/ at University of New South Wales on July 8, 2015
11.
comparison of captopril alone against furosemide plus amiloride in mild heart failure. Lancet 1987;ii:709-711.
Downloaded from http://ajh.oxfordjournals.org/ at University of New South Wales on July 8, 2015
