Safety of Long-Term Use of Lisinopril for Congestive Heart Failure Christopher
Moyses,
MRCP, DM,
and Trevor J.C. Higgins,
PhD
S
Early clinical experience with lisinopril suggested that it was well tolerated in congestive heart failure (CHF). An analysis of data from > l,OOO patients treated with lisinopril has been performed to examine the long-term safety of lisinopril in CHF. Df these, 620 have been studied for up to nearly 4 years, and a further 440 have been studied in comparative trials for 3 months. When patients who received lisinopril or placebo for the same period were compared, the proportion of liiinopril patients reporting an adverse event was 44.1% compared with 39.4% on placebo. Over a 4.year period, 205 patients (33.1%) diiontinued treatment. About 33% of these died, 33% withdrew due to clinical adverse events, 21(3.4%) were withdrawn because of adverse laboratory findilyfs, and 56 (9.0%) withdrew for reasons unrelated to treatment. Sixteen patients (2-S%) withdrew because llsinopril was deemed ineffective. The most frequently reported drug-related adverse laboratory findings were increases in blood urea nitrogen, blood urea, serum creatinine, and plasma potassium. There appeared to be no differences in the pattern of adverse events with respect to the race of the patient. Elderly patients and those with the most severe forms of heart failure appeared to be at greater risk for an adverse event. Evaluation of the safety of liiinopril compared with enalapril, captopril, and diioxin in controlled clinical trials shows all the angiotensin-convertin% enzyme inhibitors to be equally well tolerated with a closely similar range of adverse events, suggesting that the satisfactory safety profile of liiinopril is shared by other drugs of this class. lisinopril appears to be well tolerated in the treatment of heart failure. (AmJCardiol199&70:91C-97C)
ince their introduction, the angiotensinconverting enzyme (ACE) inhibitors have become a cornerstone of the management of congestive heart failure (CHF).l There is now substantial evidence that the use of these drugs prolongs life2>3 as well as producing symptomatic improvement4,5 and improvements in hemodynamics.4,6 Indeed, as a class, the ACE inhibitors have been shown to be more effective in reducing mortality than some other vasodilator regimens.3 Because the-control of symptoms of these patients represents one of the therapeutic goals of treatment, the adverse effects of the drugs used in the management of CHF and the risk-benefit balance of therapy is an issue worthy of consideration. Adverse effects of treatment gathered from controlled clinical trials, in carefully selected and monitored patients, give much valuable information regarding the risks of treatment. Lisinopril (ICI 209,000) was first registered in 1987 and became available for general use in 1988. The early clinical trial experience with lisinopril in 311 patients with mild-to-moderate heart failure7 showed a mortality similar to that on placebo with causes of death typical of heart failure patients. The most commonly encountered adverse events were dizziness, diarrhea, and hypotension (Figure 1) and the major causes of discontinuation were hypotension, dizziness, renal impairment, rash, and diarrhea. Since that time, lisinopril has been further evaluated in controlled clinical trials in patients with CHF. As use of a new drug expands and its use becomes widespread in situations outside that of the controlled clinical trial, other unsuspected adverse effects may appear. The aim of this review is to assess the safety and tolerability of lisinopril as it applies specifically to the patient with CHF, both in controlled clinical trials and in the context of widespread general use.
From the Medical Research Department: ICI Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, United Kingdom. Address for reprints: Christopher Moyses, MRCP, DM, Medical Research Department, ICI Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TF, United Kingdom.
METHODS Patierrts:
Patients with CHF in clinical trials were in functional classes II-IV on the New York A SYMPOSIUM:
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Heart Association (NYHA) grading system, and the vast majority received concurrent treatment with diuretics and/or digitalis. Spontaneous reports of adverse events have concerned patients with a wide range of severity of heart failure who were taking a wide range of concurrent medications. S&fety assessment: This review of safety encompasses adverse events recorded during controlled clinical, trials, during open-label extension studies, and those arising from spontaneous reports during marketed use; the methods by which adverse reactions are collected in these situations are necessarily different. In the controlled clinical studies, involving 620 patients, adverse clinical experiences were sought at each visit in all studies, and the subjects were required to report any event that seemed unusual, whereupon they were questioned about the nature of each event. The clinical investigators were made aware of the result of earlier clinical studies, both by discussion and by use of a brochure containing information regarding lisinopril. An event was considered to be serious if it was a definite hazard or handicap to the patient and any relation between the adverse event and the use of lisinopril was graded by the investigator, using a 5point scale (definitely not, probably not, possibly, probably, or definitely drug related). All adverse events from these studies experienced by patients while taking lisinopril have been considered for inclusion in this review up to the time when the drug was first marketed. Except where indicated, this was irrespective of the opin-
ion of the investigator regarding any causal relationship to the use of lisinopril. Many of these controlled trials were extended so as to evaluate the safety of long-term exposure of patients to lisinopril, and additional patients were recruited into the controlled phases of the studies, thereby extending their power. As a result, a recent analysis of data from 620 patients treated with lisinopril has been possible. The scope of the present review encompasses long-term safety of lisinopril in the treatment of CHF, but because the occurrence of adverse events may be anticipated to increase with increased time of exposure to the drug, it is appropriate to consider the frequency of adverse events on lisinopril treatment compared with placebo during the initial 12-week doubleblind phase of the evaluation of the drug, as well as the effects of long-term exposure. In addition, 4 double-blind, parallel-group clinical studies, each of 12 week duration (vide infra), have recently been completed. This has provided tolerability data for lisinopril in a further 440 patients and has allowed comparison of lisinopril with enalapril, captopril, and digoxin. In the case of these studies, adverse events were reported only for the controlled phases of these trials. Once the drug is marketed, reliance is necessarily placed on spontaneous reports from physicians and information passed to the company by regulatory authorities who have been informed of adverse events by physicians in their own country. In the case of these reports, some information regarding the patient’s condition and other possible contributory factors, such as the other drugs being
IO 9-
8-
FIGURE l. Eariy achrerse experlewes occurring in 23% of patknts wlth CHF In the Rslnoprll and piacebotreatment groups. Filled bars = llslnoprll (n = 311); open bars = placebo (n = 104). CHF = congesthfe heart failure.
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TABLE I Demographic Receiving Lisinopril
Data
for Heart
Failure
Patients
TABLE II Frequency 2 1% of Heart Failure
No. Patients Total
Double-Blind,
Placebo-Controlled
476 144
Age (yr) 18-34 35-44 45-54 55-64 65-81
20 49 119 244 188 58.5
age (yr)
(77%) (23%) (3%) (8%) (19%) (39%) (30%)
Race Caucasian Black Other
540 (87%) 66 (11%) 14 (2%)
Etiology Coronary heart disease Valvular heart disease Cardiomyopathy Hypertension Other Unknown
226 43 220 43 40 48
(36%) (7%) (35%) (7%) (6%) (8%)
Duration of heart failure < 1 year 1-5 years 6-10 years 110 years Unknown
216 256 64 33 51
(35%) (41%) (10%) (5%) (8%)
New York Heart I II Ill IV Unknown
Association
class 1 (0.2%) 198 (32%) 299 (48%) 71(11%) 51 (8%)
used, may be missing or inadequately reported. Additionally, when some adverse effects of treatment are well recognized and are already listed in the prescribing information for the drug, there may be a reluctance on the part of physicians to report these adverse effects, with a consequent emphasis (of uncertain extent) on reporting unusual or unexpected adverse events. RESULTS Patients The demographic characteristics of the population of 620 patients are presented in Table I. Duration of treatment with lisinopril ranged from a single dose to approximately 4 years. The mean duration of treatment was 321 days overall. Total exposure to lisinopril was 199,112 patient days. The lisinopril-treated population was predominantly male and 69% of the population was aged 255 years. The majority (87%) were Caucasian. The most common causes of heart failure were coronary artery disease (36%) or cardiomyopathy (35%); 41% of patients had had heart failure for l-5 years but 35% of the popula-
Adverse Taking
Events Lisinopril
Occurring During
in
Studies Lisinopril (n = 313) %
620
Sex Male Female
Mean
(%)
of Clinical Patients
Placebo (n = 155) %
Death
2.9
5.2
Body as a whole Abdominal pain Asthenia Chest pain Edema Malaise Orthostatic effects Syncope Cardiovascular system
2.2 3.8 3.2 1.0 1.3 1.0 1.3
1.9 3.2 1.3 0.6 0.0 0.0 0.6
1.6 5.1 1.0 1.0
3.2 0.6 0.0 0.0
Digestive system Diarrhea Nausea Vomiting
4.2 2.6 1.3
1.9 5.2 0.6
Metabolic/nutrition/immune Weight gain
1.0
0.0
13.4 5.1 1.0
4.5 3.9 0.0
2.2 3.2 1.0
2.6 4.5 1.3
Skin and skin appendages Alopecia Erythema Pruritus Rash
1.0 1.0 1.0 1.9
0.6 0.6 1.9 0.6
Urogenital system Renal dysfunction
1.0
0.0
Angina pectoris Hypotension Orthostatic hypotension Palpitation
Nervous/psychiatric Dizziness Headache Paresthesia Respiratory system Cough Dyspnea Upper respiratory
infection
tion had the syndrome for < 1 year. The majority of the patients had NYHA class II or III heart failure. Comparison with placebo: Data comparing the incidence of adverse effects on lisinopril to that on placebo during 12 weeks of double-blind treatment are shown in Table II. Adverse events are categorized by the body system in which they occurred. Most frequently affected were the body as a whole, the nervous and psychiatric system, the cardiovascular system, and the respiratory and digestive systems. When patients who received lisinopril and placebo for the same period were considered, the percentage of lisinopril patients who reported an adverse event (44.1%) was similar to that percentage reporting adverse events on placebo (39.4%). The most frequently reported adverse events on lisinopril were dizziness, hypotension, headache, diarrhea, and asthenia. Interestingly, death, heart failure, dyspnea, and nausea were seen on placebo more frequently than on lisinopril therapy. A SYMPOSIUM:
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TABLE Body
III
Incidence
of Adverse
Events
Affecting
Different
Systems* Lisinopril (n = 620) %
Body System Body as a whole Cardiovascular Digestive
(includes
deaths)
system
Hemic
26.5 21.1 16.3
system
0.5
Endocrine and lymphatic
system
0.6
Metabolic/nutritional/immune Musculoskeletal Nervous
3.5
system
7.7
and psychiatric
21.6
system
20.3
Respiratory
Skin and skin appendage
9.7
The senses
4.0
Urogenital *Mean
the
duration
system of exposure
7.1 to lisinopril
was 321 days.
Extended use of liiinopril: In the extended use of lisinopril for up to 4 years, the most frequently affected body systems were the body system as a whole, the cardiovascular, respiratory, nervous and psychiatric, and digestive systems (Table III). The most frequently reported adverse events were dizziness, dyspnea, chest pain, asthenia, cough, diarrhea, hypotension, and nausea (Figure 2). Some of these events are also characteristic of the patient population with CHF and for this reason many of the reports of some adverse effects, e.g., dyspnea, were only rarely considered to be drug related by the attending physician. Deaths and discontinuation of therapy: Of the 620 patients treated with lisinopril, 73 (11.8%) died during the survey period. Overall, 205 patients discontinued lisinopril treatment (33.1%). About 33% of these patients died and about 33% with-
drew due to adverse clinical events. Of the patients who stopped treatment, 21 (3.4%) were withdrawn because of adverse laboratory test results; 16 (2.6%) withdrew because lisinopril was deemed ineffective, and 56 (9.0%) were withdrawn for reasons unrelated to treatment. The major causes of death during lisinopril therapy were the same as those reported in the earlier smaller scale surveys,7~8 primarily sudden death, myocardial infarction, worsening CHF, and cardiogenic shock. Only 2 deaths (1 sudden death and 1 renal failure) were thought to be possibly drug-related by the attending physicians. The most frequent clinical events necessitating withdrawal are depicted in Figure 2, along with the most frequently reported adverse events. Hypotension, dizziness, and rash were the most common causes of discontinuation of lisinopril in CHF patients. Serious nonfatal adverse events: Serious, but nonfatal, adverse events were experienced by 110 of 620 patients (17.7%). Some of these patients subsequently died, but these adverse events were usually distinct from the final cause of death. Adverse laboratory findings: The major changes observed in laboratory parameters believed to be drug-related were increases in blood urea nitrogen, blood urea, and serum creatinine (Table IV). Increases in serum potassium are an anticipated effect of ACE inhibitors, due to their action in suppressing aldosterone release. Changes in liver enzyme titers and in urinary protein excretion are features encountered in patients with CHF and have been observed in the use of other ACE inhibitors.g
FIGURE 2. Adverse experiences occurring In 23% of heart failure patients treated wlth Ilslnoprll. The frequency of adverse events is shown In filled bars and wtthdrawab by open bars. lhe total number of patlents was 020 and maan duratlon of treatment was 321 days.
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Overall, 3.4% of patients were withdrawn from treatment because of adverse laboratory findings. Most of these were considered to be drug-related by the investigators. Changes in hematologic values and elevations in serum creatinine, serum potassium, and urinary protein have been observed during the treatment of CHF patients with other ACE inhibitors, notably captopril and enalapril.lO-l2 During the course of these studies, 9 of 582 patients (1.6%) had hemoglobin values < 10 g/dL, or 6.2 mmol/liter. None was discontinued, and in 3 patients the values returned to normal during the observation period. One of 584 patients (0.2%) had total white blood cell counts < 2,500 mm3. This was considered an isolated observation, and the white blood cell count was > 2,500 mm3 during the rest of the study. Two of 350 (0.6%) had a platelet count < 100,000 mm3. Of 591 patients 34 (5.8%) had serum creatinine > 2.5 mg/dL (221 mmol/liter). Elevation of serum creatinine, especially when ACE inhibitor treatment is combined with diuretic treatment in CHF patients, is well established.i1>12 The clinically important elevations occurred most often in patients with abnormal values at baseline and were frequently transient in nature. Of 292 patients 9 (3.1%) had urinary protein excretion > 1,000 mg/24 hour. Most of these patients exhibited the abnormality during baseline therapy. One patient was withdrawn. Special grouw of age, race, renal function, and severity of heart failure: The adverse events encountered during these studies have been examined with respect to subsets of patients who might be considered to represent a different risk from treatment with lisinopril compared with the general population. In order to consider the possibility that the elderly were at a particular risk from treatment with this drug, the total study population (620) was divided into those aged 265 years (n = 188) and < 65 years (n = 432): 18% of the elderly subgroup and 15% of the younger patients continued treatment for >2 years, and the mean duration of treatment was 347 and 310 days for the elderly and the young subsets, respectively. Although the incidence of death or nonfatal serious events does not seem substantially different between the 2 groups, the elderly appear to be at a higher risk of discontinuation due to an adverse event. Of the 620 patients in the studies, only 66 were Black. However, no apparent differences between
Finding Hematocrit
reduced
% of Patients
in Whom
Drug-Related Investigator
by
Measured
All Patients
0.6
Blood
urea nitrogen
increased
Blood
urea increased
1.3
7.7
increased
13.9
2.3
3.0
6.2
10.9
Serum
creatinine
Serum
bilirubin
0.6
0.9
Serum
AST increased
1.1
4.4
Serum
ALT increased
0.9
3.4
Serum
uric acid increased
1.7
5.0
Serum
potassium
3.0
4.8
24.hour
urinary
4.3
4.3
increased
increased protein
increased
*Mean duration of treatment 32 1 days ALT = alanine aminatransferase; AST = asparateaminotransferase.
the Black and Caucasian patients were observed with respect to the safety of lisinopril treatment. Renal function has been an important issue in the use of ACE inhibitors since their introduction, and abnormalities of renal function are not uncommon in the general CHF patient population. Thus, the safety of lisinopril in the renally impaired patients is of particular interest. The total population was divided into those with baseline serum creatinine levels r 1.6 and < 1.6 mg/dL. Patients with more advanced renal failure (> 2.5 mg/dL) were excluded from clinical study and so systematic information regarding the safety of lisinopril in this subgroup of patients is lacking at present. A subset of 85 patients with serum creatinine 2 1.6 mg/dLwere treated for a mean period of 432 days and 420 patients with normal renal function (serum creatinine < 1.6 mg/dL) were treated for a mean of 334 days (in 115 patients the baseline serum creatinine values were not known). Although the incidence of death appears lower in those with renal impairment than in those with normal renal function, the incidence of adverse events, including nonfatal serious ones appeared to be higher in those with renal impairment. When the patients were stratified by severity of CHF using their baseline NYHA grades, it was observed that the incidence of adverse experiences of all severities, as well as the incidence of death, tended to increase with the severity of CHF. This finding would be anticipated from existing knowledge of the risks of death from heart failure.13 When the duration of treatment with lisinopril was taken into account, the incidence of death, espeA SYMPOSIUM:
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cially in the NYHA class IV patients, seemed somewhat lower than previously reported.14 Comparative safety: Four recently reported double-blind, parallel-group clinical trials (see Bach and Zardini, Zannad et al, Herlitz, and Sloman elswhere in this symposium) in which lisinopril has been compared with captopril (2 trials), enalapril and digoxin have provided data on comparative safety (Figure 3). The most frequent adverse events appear to be common to all 4 drugs and may reflect the symptoms of CHF as much as the effects of therapy. The ACE inhibitors all have a remarkably similar adverse-event profile, suggesting that the adverse events seen in these trials reflect class effects of these drugs. One particular feature of these comparative data deserves comment. In a comparative study of lisinopril and captopril (see Bach and Zardini in this symposium) it was noted that blood urea and serum creatinine values were affected to a similar extent by both the long-acting and short-acting ACE inhibitor, suggesting that sustained ACE inhibition is not generally associated with impaired renal function in heart failure patients. Spontaneous reports of adverse events: The spontaneous reports so far received from general clinical worldwide use of lisinopril in heart failure suggest a pattern of adverse events similar to that observed in this clinical trial population, which has been the subject of intense study and which is reported here. Reports of adverse events cluster most frequently in: the genitourinary system,where deterioration in renal function, including renal failure, is the most prominent adverse event; in the
cardiovascular system where hypotension, including first-dose hypotensive events, is the more frequent observation; and in adverse reactions involving the skin, where rashes and angioedema are reported. Isolated cases of thrombocytopenia and neutropenia have been reported, although in such cases the data are inadequate to establish any causal link with the drug. DISCUSSION
Previous evaluations of lisinopril have demonstrated it to be well tolerated in the treatment of CHF.718This report is based on increased numbers of patients studied and increased duration of treatment with lisinopril and also encompasses general use of the drug in the uncontrolled situation. Data collected in the open-label use of lisinopril without a placebo control tend to increase artificially the incidence of adverse events recorded during treatment. As heart failure is of a generally symptomatic nature, longer follow-up periods tend to lead to the recording of more adverse events. Because of the number of drugs being taken by heart failure patients, it is more difficult to assign a causal relation between an adverse event experienced by a patient and lisinopril treatment. Overall, this review of safety and tolerability of lisinopril in heart failure leads to the conclusion that it is generally well tolerated in such patients and that clinical adverse events usually do not require discontinuation of therapy. The incidence of death in patients with heart failure is 2.9% in those treated with lisinopril, compared with an
RGURE 3. inddence of adverse events occurring in > 1% of heart failure patients in controlled comparative trials of iisinoprii, enaiaprli, captoprii, and digoxin. Deaths, woreening heart failure, and reeuRing hospRaiizations have beee omitted.
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incidence of 5.2% in the control group treated with placebo during 12-week double-blind trials. This contrasts with the very early clinical experience that showed a very similar mortality rate for both lisinopril and placebo. The most frequent clinical adverse experiences observed are dizziness, dyspnea, chest pain, asthenia, cough, diarrhea, and hypotension. The percentage of heart failure patients discontinuing lisinopril due to an adverse clinical event within a treatment period of 4 years is ll%, and this was attributable primarily to hypotension, dizziness, and lack of response. The most frequently reported adverse laboratory findings in lisinopril-treated patients included elevations in blood urea nitrogen or blood urea, serum creatinine, and serum potassium. Changes in laboratory values in lisinopril-treated patients were generally minor and seldom resulted in discontinuation of therapy. Although the overall incidence of adverse events was generally higher in patients receiving longterm therapy with lisinopril, reflecting the longer exposure to the drug, there were no unusual or unexpected adverse events. Many of those that occurred have also been recorded for other ACE inhibitors and may well be class related.14 No outstanding differences with regard to the safety of lisinopril have been observed in older versus younger patients, Black versus White patients, or in those with renal impairment or severe heart failure. A recent comparative study of lisinopril and captopril (see Bach and Zardini in this symposium) has shown no difference between the 2 drugs with regard to blood urea and serum creatinine values. This observation suggests that use of the longeracting ACE inhibitor was not generally associated with renal impairment, as was suggested by the early work of Packer et all5 using higher doses of ACE inhibitors and diuretics. In an earlier comparative study, Giles et all6 demonstrated a greater tendency for lisinopril to increase blood urea nitrogen values than did captopril, although the
drugs did not differ significantly in their tendency to increase serum creatinine. In conclusion, this survey of data on 620 patients together with new, additional comparative data on a further 440 patients in double-blind trials and > 3 years of spontaneous reports confirms earlier observations7js regarding the generally well-tolerated nature of lisinopril when used once daily for the treatment of CHF in addition to established therapy with digitalis and/or diuretics. REFERENCES 3.. Braunwald E. ACE inhibitors-a cornerstone of the treatment of heart failure. N Engl J Med 1991;325:351-353. 2. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Co-operative North Scandmatian Enalapd Survival Study (CONSENSUS). N Engl JMed 1987;316:142%1435. 3. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wang M. A comparison of enalapril with hydralazineisosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl JMed 1991;325:303-310. 4. Reigger AJ. ACE inhibitors in congestive heart failure. Car&&y 1989; 76(suppl2):42-49. 5. Rucinska EJ. Enalapril in the treatment of congestive heart failure: effects on signs, symptoms and mortality. Acta Cardiol1991;46:231-246. 6. Dickstein K, Aarsland T, Woie L, Abrahamsen AM, Fyhrquist F, Cummings S, Gomez HJ, Hagen E, Kristianson K. Acute haemodynamic and hormonal effects of lisinopril (MK 521) in congestive heart failure. Am Heart J 1986;112:121-129. 7. Rush JE, Merrill DD. The safety and tolerability of lisinopril in clinical trials. .I Cardiovasc Phamacol1987;9(suppl3):S9%SlO7. 6. Cameron HA, Higgins TX. Clinical experience with lisinopril observations on safety and tolerability. J Hum H~&Yz.s 1989;3(suppl 1):177-186. 9. Todd PA Goa KL. Enalaprib an update of its pharmacological properties and therapeutic use in congestive heart failure. Drug 1989;37:141-161. 10. GriiTmg GT, Melby JC. Enalapril (MK-421) and the white cell count and haematocrit. Lancet 1982;i:1361. 1L Packer M, Lee WH, Medma N, Yushak M, Kessler PD. Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Ann Intern A4ed 1987;106:34&354. l2. Warner NJ, Rush JE. Safety profiles of the angiotensin converting enzyme inhibitors. Drugs 1988;35(suppl5):8%97. 3.3. Kannel WB, Savage D, Castelli WP. Cardiac failure in the Framingham Study: Twenty year follow-up. In: Braunwald E, Hock MD, Watson .I, eds. Congestive Heart Failure: Current Research and Clinical Applications. New York: Grune and Stratton, 1982:15-30. 14. Borek M, Charlap S, Frishman WH. Angiotensin converting enzyme inhibitors in heart failure. Med Clin NorthAm 1989;73:315-338. 15. Packer M, Lee WH, Yushak M, Me&ma N. Comparison of captopril and enalapril in patients with severe chronic heart failure. N Engl J Med 1986315: 847453. 16. Giles TD, Katz R, Sullivan JM, Wolfson P, Haugland M, Kirlin P, Powers E, Rich S, Hacksaw B, Chiaramida A, Rouleau JL, Fisher MB, Pigeon J, Rush MD. Short- and long- acting angiotensin converting enzyme inhibitors: a randomized trial of lisinopril versus captopril in the treatment of congestive heart failure. JAm Co11 Cardiol 1989;13:1240-1247.
A SYMPOSIUM:
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Moyses,
MRCP, DM,
and Trevor J.C. Higgins,
PhD
S
Early clinical experience with lisinopril suggested that it was well tolerated in congestive heart failure (CHF). An analysis of data from > l,OOO patients treated with lisinopril has been performed to examine the long-term safety of lisinopril in CHF. Df these, 620 have been studied for up to nearly 4 years, and a further 440 have been studied in comparative trials for 3 months. When patients who received lisinopril or placebo for the same period were compared, the proportion of liiinopril patients reporting an adverse event was 44.1% compared with 39.4% on placebo. Over a 4.year period, 205 patients (33.1%) diiontinued treatment. About 33% of these died, 33% withdrew due to clinical adverse events, 21(3.4%) were withdrawn because of adverse laboratory findilyfs, and 56 (9.0%) withdrew for reasons unrelated to treatment. Sixteen patients (2-S%) withdrew because llsinopril was deemed ineffective. The most frequently reported drug-related adverse laboratory findings were increases in blood urea nitrogen, blood urea, serum creatinine, and plasma potassium. There appeared to be no differences in the pattern of adverse events with respect to the race of the patient. Elderly patients and those with the most severe forms of heart failure appeared to be at greater risk for an adverse event. Evaluation of the safety of liiinopril compared with enalapril, captopril, and diioxin in controlled clinical trials shows all the angiotensin-convertin% enzyme inhibitors to be equally well tolerated with a closely similar range of adverse events, suggesting that the satisfactory safety profile of liiinopril is shared by other drugs of this class. lisinopril appears to be well tolerated in the treatment of heart failure. (AmJCardiol199&70:91C-97C)
ince their introduction, the angiotensinconverting enzyme (ACE) inhibitors have become a cornerstone of the management of congestive heart failure (CHF).l There is now substantial evidence that the use of these drugs prolongs life2>3 as well as producing symptomatic improvement4,5 and improvements in hemodynamics.4,6 Indeed, as a class, the ACE inhibitors have been shown to be more effective in reducing mortality than some other vasodilator regimens.3 Because the-control of symptoms of these patients represents one of the therapeutic goals of treatment, the adverse effects of the drugs used in the management of CHF and the risk-benefit balance of therapy is an issue worthy of consideration. Adverse effects of treatment gathered from controlled clinical trials, in carefully selected and monitored patients, give much valuable information regarding the risks of treatment. Lisinopril (ICI 209,000) was first registered in 1987 and became available for general use in 1988. The early clinical trial experience with lisinopril in 311 patients with mild-to-moderate heart failure7 showed a mortality similar to that on placebo with causes of death typical of heart failure patients. The most commonly encountered adverse events were dizziness, diarrhea, and hypotension (Figure 1) and the major causes of discontinuation were hypotension, dizziness, renal impairment, rash, and diarrhea. Since that time, lisinopril has been further evaluated in controlled clinical trials in patients with CHF. As use of a new drug expands and its use becomes widespread in situations outside that of the controlled clinical trial, other unsuspected adverse effects may appear. The aim of this review is to assess the safety and tolerability of lisinopril as it applies specifically to the patient with CHF, both in controlled clinical trials and in the context of widespread general use.
From the Medical Research Department: ICI Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, United Kingdom. Address for reprints: Christopher Moyses, MRCP, DM, Medical Research Department, ICI Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TF, United Kingdom.
METHODS Patierrts:
Patients with CHF in clinical trials were in functional classes II-IV on the New York A SYMPOSIUM:
HEART
FAILURE
MANAGEMENT
91c
Heart Association (NYHA) grading system, and the vast majority received concurrent treatment with diuretics and/or digitalis. Spontaneous reports of adverse events have concerned patients with a wide range of severity of heart failure who were taking a wide range of concurrent medications. S&fety assessment: This review of safety encompasses adverse events recorded during controlled clinical, trials, during open-label extension studies, and those arising from spontaneous reports during marketed use; the methods by which adverse reactions are collected in these situations are necessarily different. In the controlled clinical studies, involving 620 patients, adverse clinical experiences were sought at each visit in all studies, and the subjects were required to report any event that seemed unusual, whereupon they were questioned about the nature of each event. The clinical investigators were made aware of the result of earlier clinical studies, both by discussion and by use of a brochure containing information regarding lisinopril. An event was considered to be serious if it was a definite hazard or handicap to the patient and any relation between the adverse event and the use of lisinopril was graded by the investigator, using a 5point scale (definitely not, probably not, possibly, probably, or definitely drug related). All adverse events from these studies experienced by patients while taking lisinopril have been considered for inclusion in this review up to the time when the drug was first marketed. Except where indicated, this was irrespective of the opin-
ion of the investigator regarding any causal relationship to the use of lisinopril. Many of these controlled trials were extended so as to evaluate the safety of long-term exposure of patients to lisinopril, and additional patients were recruited into the controlled phases of the studies, thereby extending their power. As a result, a recent analysis of data from 620 patients treated with lisinopril has been possible. The scope of the present review encompasses long-term safety of lisinopril in the treatment of CHF, but because the occurrence of adverse events may be anticipated to increase with increased time of exposure to the drug, it is appropriate to consider the frequency of adverse events on lisinopril treatment compared with placebo during the initial 12-week doubleblind phase of the evaluation of the drug, as well as the effects of long-term exposure. In addition, 4 double-blind, parallel-group clinical studies, each of 12 week duration (vide infra), have recently been completed. This has provided tolerability data for lisinopril in a further 440 patients and has allowed comparison of lisinopril with enalapril, captopril, and digoxin. In the case of these studies, adverse events were reported only for the controlled phases of these trials. Once the drug is marketed, reliance is necessarily placed on spontaneous reports from physicians and information passed to the company by regulatory authorities who have been informed of adverse events by physicians in their own country. In the case of these reports, some information regarding the patient’s condition and other possible contributory factors, such as the other drugs being
IO 9-
8-
FIGURE l. Eariy achrerse experlewes occurring in 23% of patknts wlth CHF In the Rslnoprll and piacebotreatment groups. Filled bars = llslnoprll (n = 311); open bars = placebo (n = 104). CHF = congesthfe heart failure.
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TABLE I Demographic Receiving Lisinopril
Data
for Heart
Failure
Patients
TABLE II Frequency 2 1% of Heart Failure
No. Patients Total
Double-Blind,
Placebo-Controlled
476 144
Age (yr) 18-34 35-44 45-54 55-64 65-81
20 49 119 244 188 58.5
age (yr)
(77%) (23%) (3%) (8%) (19%) (39%) (30%)
Race Caucasian Black Other
540 (87%) 66 (11%) 14 (2%)
Etiology Coronary heart disease Valvular heart disease Cardiomyopathy Hypertension Other Unknown
226 43 220 43 40 48
(36%) (7%) (35%) (7%) (6%) (8%)
Duration of heart failure < 1 year 1-5 years 6-10 years 110 years Unknown
216 256 64 33 51
(35%) (41%) (10%) (5%) (8%)
New York Heart I II Ill IV Unknown
Association
class 1 (0.2%) 198 (32%) 299 (48%) 71(11%) 51 (8%)
used, may be missing or inadequately reported. Additionally, when some adverse effects of treatment are well recognized and are already listed in the prescribing information for the drug, there may be a reluctance on the part of physicians to report these adverse effects, with a consequent emphasis (of uncertain extent) on reporting unusual or unexpected adverse events. RESULTS Patients The demographic characteristics of the population of 620 patients are presented in Table I. Duration of treatment with lisinopril ranged from a single dose to approximately 4 years. The mean duration of treatment was 321 days overall. Total exposure to lisinopril was 199,112 patient days. The lisinopril-treated population was predominantly male and 69% of the population was aged 255 years. The majority (87%) were Caucasian. The most common causes of heart failure were coronary artery disease (36%) or cardiomyopathy (35%); 41% of patients had had heart failure for l-5 years but 35% of the popula-
Adverse Taking
Events Lisinopril
Occurring During
in
Studies Lisinopril (n = 313) %
620
Sex Male Female
Mean
(%)
of Clinical Patients
Placebo (n = 155) %
Death
2.9
5.2
Body as a whole Abdominal pain Asthenia Chest pain Edema Malaise Orthostatic effects Syncope Cardiovascular system
2.2 3.8 3.2 1.0 1.3 1.0 1.3
1.9 3.2 1.3 0.6 0.0 0.0 0.6
1.6 5.1 1.0 1.0
3.2 0.6 0.0 0.0
Digestive system Diarrhea Nausea Vomiting
4.2 2.6 1.3
1.9 5.2 0.6
Metabolic/nutrition/immune Weight gain
1.0
0.0
13.4 5.1 1.0
4.5 3.9 0.0
2.2 3.2 1.0
2.6 4.5 1.3
Skin and skin appendages Alopecia Erythema Pruritus Rash
1.0 1.0 1.0 1.9
0.6 0.6 1.9 0.6
Urogenital system Renal dysfunction
1.0
0.0
Angina pectoris Hypotension Orthostatic hypotension Palpitation
Nervous/psychiatric Dizziness Headache Paresthesia Respiratory system Cough Dyspnea Upper respiratory
infection
tion had the syndrome for < 1 year. The majority of the patients had NYHA class II or III heart failure. Comparison with placebo: Data comparing the incidence of adverse effects on lisinopril to that on placebo during 12 weeks of double-blind treatment are shown in Table II. Adverse events are categorized by the body system in which they occurred. Most frequently affected were the body as a whole, the nervous and psychiatric system, the cardiovascular system, and the respiratory and digestive systems. When patients who received lisinopril and placebo for the same period were considered, the percentage of lisinopril patients who reported an adverse event (44.1%) was similar to that percentage reporting adverse events on placebo (39.4%). The most frequently reported adverse events on lisinopril were dizziness, hypotension, headache, diarrhea, and asthenia. Interestingly, death, heart failure, dyspnea, and nausea were seen on placebo more frequently than on lisinopril therapy. A SYMPOSIUM:
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TABLE Body
III
Incidence
of Adverse
Events
Affecting
Different
Systems* Lisinopril (n = 620) %
Body System Body as a whole Cardiovascular Digestive
(includes
deaths)
system
Hemic
26.5 21.1 16.3
system
0.5
Endocrine and lymphatic
system
0.6
Metabolic/nutritional/immune Musculoskeletal Nervous
3.5
system
7.7
and psychiatric
21.6
system
20.3
Respiratory
Skin and skin appendage
9.7
The senses
4.0
Urogenital *Mean
the
duration
system of exposure
7.1 to lisinopril
was 321 days.
Extended use of liiinopril: In the extended use of lisinopril for up to 4 years, the most frequently affected body systems were the body system as a whole, the cardiovascular, respiratory, nervous and psychiatric, and digestive systems (Table III). The most frequently reported adverse events were dizziness, dyspnea, chest pain, asthenia, cough, diarrhea, hypotension, and nausea (Figure 2). Some of these events are also characteristic of the patient population with CHF and for this reason many of the reports of some adverse effects, e.g., dyspnea, were only rarely considered to be drug related by the attending physician. Deaths and discontinuation of therapy: Of the 620 patients treated with lisinopril, 73 (11.8%) died during the survey period. Overall, 205 patients discontinued lisinopril treatment (33.1%). About 33% of these patients died and about 33% with-
drew due to adverse clinical events. Of the patients who stopped treatment, 21 (3.4%) were withdrawn because of adverse laboratory test results; 16 (2.6%) withdrew because lisinopril was deemed ineffective, and 56 (9.0%) were withdrawn for reasons unrelated to treatment. The major causes of death during lisinopril therapy were the same as those reported in the earlier smaller scale surveys,7~8 primarily sudden death, myocardial infarction, worsening CHF, and cardiogenic shock. Only 2 deaths (1 sudden death and 1 renal failure) were thought to be possibly drug-related by the attending physicians. The most frequent clinical events necessitating withdrawal are depicted in Figure 2, along with the most frequently reported adverse events. Hypotension, dizziness, and rash were the most common causes of discontinuation of lisinopril in CHF patients. Serious nonfatal adverse events: Serious, but nonfatal, adverse events were experienced by 110 of 620 patients (17.7%). Some of these patients subsequently died, but these adverse events were usually distinct from the final cause of death. Adverse laboratory findings: The major changes observed in laboratory parameters believed to be drug-related were increases in blood urea nitrogen, blood urea, and serum creatinine (Table IV). Increases in serum potassium are an anticipated effect of ACE inhibitors, due to their action in suppressing aldosterone release. Changes in liver enzyme titers and in urinary protein excretion are features encountered in patients with CHF and have been observed in the use of other ACE inhibitors.g
FIGURE 2. Adverse experiences occurring In 23% of heart failure patients treated wlth Ilslnoprll. The frequency of adverse events is shown In filled bars and wtthdrawab by open bars. lhe total number of patlents was 020 and maan duratlon of treatment was 321 days.
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Overall, 3.4% of patients were withdrawn from treatment because of adverse laboratory findings. Most of these were considered to be drug-related by the investigators. Changes in hematologic values and elevations in serum creatinine, serum potassium, and urinary protein have been observed during the treatment of CHF patients with other ACE inhibitors, notably captopril and enalapril.lO-l2 During the course of these studies, 9 of 582 patients (1.6%) had hemoglobin values < 10 g/dL, or 6.2 mmol/liter. None was discontinued, and in 3 patients the values returned to normal during the observation period. One of 584 patients (0.2%) had total white blood cell counts < 2,500 mm3. This was considered an isolated observation, and the white blood cell count was > 2,500 mm3 during the rest of the study. Two of 350 (0.6%) had a platelet count < 100,000 mm3. Of 591 patients 34 (5.8%) had serum creatinine > 2.5 mg/dL (221 mmol/liter). Elevation of serum creatinine, especially when ACE inhibitor treatment is combined with diuretic treatment in CHF patients, is well established.i1>12 The clinically important elevations occurred most often in patients with abnormal values at baseline and were frequently transient in nature. Of 292 patients 9 (3.1%) had urinary protein excretion > 1,000 mg/24 hour. Most of these patients exhibited the abnormality during baseline therapy. One patient was withdrawn. Special grouw of age, race, renal function, and severity of heart failure: The adverse events encountered during these studies have been examined with respect to subsets of patients who might be considered to represent a different risk from treatment with lisinopril compared with the general population. In order to consider the possibility that the elderly were at a particular risk from treatment with this drug, the total study population (620) was divided into those aged 265 years (n = 188) and < 65 years (n = 432): 18% of the elderly subgroup and 15% of the younger patients continued treatment for >2 years, and the mean duration of treatment was 347 and 310 days for the elderly and the young subsets, respectively. Although the incidence of death or nonfatal serious events does not seem substantially different between the 2 groups, the elderly appear to be at a higher risk of discontinuation due to an adverse event. Of the 620 patients in the studies, only 66 were Black. However, no apparent differences between
Finding Hematocrit
reduced
% of Patients
in Whom
Drug-Related Investigator
by
Measured
All Patients
0.6
Blood
urea nitrogen
increased
Blood
urea increased
1.3
7.7
increased
13.9
2.3
3.0
6.2
10.9
Serum
creatinine
Serum
bilirubin
0.6
0.9
Serum
AST increased
1.1
4.4
Serum
ALT increased
0.9
3.4
Serum
uric acid increased
1.7
5.0
Serum
potassium
3.0
4.8
24.hour
urinary
4.3
4.3
increased
increased protein
increased
*Mean duration of treatment 32 1 days ALT = alanine aminatransferase; AST = asparateaminotransferase.
the Black and Caucasian patients were observed with respect to the safety of lisinopril treatment. Renal function has been an important issue in the use of ACE inhibitors since their introduction, and abnormalities of renal function are not uncommon in the general CHF patient population. Thus, the safety of lisinopril in the renally impaired patients is of particular interest. The total population was divided into those with baseline serum creatinine levels r 1.6 and < 1.6 mg/dL. Patients with more advanced renal failure (> 2.5 mg/dL) were excluded from clinical study and so systematic information regarding the safety of lisinopril in this subgroup of patients is lacking at present. A subset of 85 patients with serum creatinine 2 1.6 mg/dLwere treated for a mean period of 432 days and 420 patients with normal renal function (serum creatinine < 1.6 mg/dL) were treated for a mean of 334 days (in 115 patients the baseline serum creatinine values were not known). Although the incidence of death appears lower in those with renal impairment than in those with normal renal function, the incidence of adverse events, including nonfatal serious ones appeared to be higher in those with renal impairment. When the patients were stratified by severity of CHF using their baseline NYHA grades, it was observed that the incidence of adverse experiences of all severities, as well as the incidence of death, tended to increase with the severity of CHF. This finding would be anticipated from existing knowledge of the risks of death from heart failure.13 When the duration of treatment with lisinopril was taken into account, the incidence of death, espeA SYMPOSIUM:
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cially in the NYHA class IV patients, seemed somewhat lower than previously reported.14 Comparative safety: Four recently reported double-blind, parallel-group clinical trials (see Bach and Zardini, Zannad et al, Herlitz, and Sloman elswhere in this symposium) in which lisinopril has been compared with captopril (2 trials), enalapril and digoxin have provided data on comparative safety (Figure 3). The most frequent adverse events appear to be common to all 4 drugs and may reflect the symptoms of CHF as much as the effects of therapy. The ACE inhibitors all have a remarkably similar adverse-event profile, suggesting that the adverse events seen in these trials reflect class effects of these drugs. One particular feature of these comparative data deserves comment. In a comparative study of lisinopril and captopril (see Bach and Zardini in this symposium) it was noted that blood urea and serum creatinine values were affected to a similar extent by both the long-acting and short-acting ACE inhibitor, suggesting that sustained ACE inhibition is not generally associated with impaired renal function in heart failure patients. Spontaneous reports of adverse events: The spontaneous reports so far received from general clinical worldwide use of lisinopril in heart failure suggest a pattern of adverse events similar to that observed in this clinical trial population, which has been the subject of intense study and which is reported here. Reports of adverse events cluster most frequently in: the genitourinary system,where deterioration in renal function, including renal failure, is the most prominent adverse event; in the
cardiovascular system where hypotension, including first-dose hypotensive events, is the more frequent observation; and in adverse reactions involving the skin, where rashes and angioedema are reported. Isolated cases of thrombocytopenia and neutropenia have been reported, although in such cases the data are inadequate to establish any causal link with the drug. DISCUSSION
Previous evaluations of lisinopril have demonstrated it to be well tolerated in the treatment of CHF.718This report is based on increased numbers of patients studied and increased duration of treatment with lisinopril and also encompasses general use of the drug in the uncontrolled situation. Data collected in the open-label use of lisinopril without a placebo control tend to increase artificially the incidence of adverse events recorded during treatment. As heart failure is of a generally symptomatic nature, longer follow-up periods tend to lead to the recording of more adverse events. Because of the number of drugs being taken by heart failure patients, it is more difficult to assign a causal relation between an adverse event experienced by a patient and lisinopril treatment. Overall, this review of safety and tolerability of lisinopril in heart failure leads to the conclusion that it is generally well tolerated in such patients and that clinical adverse events usually do not require discontinuation of therapy. The incidence of death in patients with heart failure is 2.9% in those treated with lisinopril, compared with an
RGURE 3. inddence of adverse events occurring in > 1% of heart failure patients in controlled comparative trials of iisinoprii, enaiaprli, captoprii, and digoxin. Deaths, woreening heart failure, and reeuRing hospRaiizations have beee omitted.
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incidence of 5.2% in the control group treated with placebo during 12-week double-blind trials. This contrasts with the very early clinical experience that showed a very similar mortality rate for both lisinopril and placebo. The most frequent clinical adverse experiences observed are dizziness, dyspnea, chest pain, asthenia, cough, diarrhea, and hypotension. The percentage of heart failure patients discontinuing lisinopril due to an adverse clinical event within a treatment period of 4 years is ll%, and this was attributable primarily to hypotension, dizziness, and lack of response. The most frequently reported adverse laboratory findings in lisinopril-treated patients included elevations in blood urea nitrogen or blood urea, serum creatinine, and serum potassium. Changes in laboratory values in lisinopril-treated patients were generally minor and seldom resulted in discontinuation of therapy. Although the overall incidence of adverse events was generally higher in patients receiving longterm therapy with lisinopril, reflecting the longer exposure to the drug, there were no unusual or unexpected adverse events. Many of those that occurred have also been recorded for other ACE inhibitors and may well be class related.14 No outstanding differences with regard to the safety of lisinopril have been observed in older versus younger patients, Black versus White patients, or in those with renal impairment or severe heart failure. A recent comparative study of lisinopril and captopril (see Bach and Zardini in this symposium) has shown no difference between the 2 drugs with regard to blood urea and serum creatinine values. This observation suggests that use of the longeracting ACE inhibitor was not generally associated with renal impairment, as was suggested by the early work of Packer et all5 using higher doses of ACE inhibitors and diuretics. In an earlier comparative study, Giles et all6 demonstrated a greater tendency for lisinopril to increase blood urea nitrogen values than did captopril, although the
drugs did not differ significantly in their tendency to increase serum creatinine. In conclusion, this survey of data on 620 patients together with new, additional comparative data on a further 440 patients in double-blind trials and > 3 years of spontaneous reports confirms earlier observations7js regarding the generally well-tolerated nature of lisinopril when used once daily for the treatment of CHF in addition to established therapy with digitalis and/or diuretics. REFERENCES 3.. Braunwald E. ACE inhibitors-a cornerstone of the treatment of heart failure. N Engl J Med 1991;325:351-353. 2. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Co-operative North Scandmatian Enalapd Survival Study (CONSENSUS). N Engl JMed 1987;316:142%1435. 3. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wang M. A comparison of enalapril with hydralazineisosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl JMed 1991;325:303-310. 4. Reigger AJ. ACE inhibitors in congestive heart failure. Car&&y 1989; 76(suppl2):42-49. 5. Rucinska EJ. Enalapril in the treatment of congestive heart failure: effects on signs, symptoms and mortality. Acta Cardiol1991;46:231-246. 6. Dickstein K, Aarsland T, Woie L, Abrahamsen AM, Fyhrquist F, Cummings S, Gomez HJ, Hagen E, Kristianson K. Acute haemodynamic and hormonal effects of lisinopril (MK 521) in congestive heart failure. Am Heart J 1986;112:121-129. 7. Rush JE, Merrill DD. The safety and tolerability of lisinopril in clinical trials. .I Cardiovasc Phamacol1987;9(suppl3):S9%SlO7. 6. Cameron HA, Higgins TX. Clinical experience with lisinopril observations on safety and tolerability. J Hum H~&Yz.s 1989;3(suppl 1):177-186. 9. Todd PA Goa KL. Enalaprib an update of its pharmacological properties and therapeutic use in congestive heart failure. Drug 1989;37:141-161. 10. GriiTmg GT, Melby JC. Enalapril (MK-421) and the white cell count and haematocrit. Lancet 1982;i:1361. 1L Packer M, Lee WH, Medma N, Yushak M, Kessler PD. Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Ann Intern A4ed 1987;106:34&354. l2. Warner NJ, Rush JE. Safety profiles of the angiotensin converting enzyme inhibitors. Drugs 1988;35(suppl5):8%97. 3.3. Kannel WB, Savage D, Castelli WP. Cardiac failure in the Framingham Study: Twenty year follow-up. In: Braunwald E, Hock MD, Watson .I, eds. Congestive Heart Failure: Current Research and Clinical Applications. New York: Grune and Stratton, 1982:15-30. 14. Borek M, Charlap S, Frishman WH. Angiotensin converting enzyme inhibitors in heart failure. Med Clin NorthAm 1989;73:315-338. 15. Packer M, Lee WH, Yushak M, Me&ma N. Comparison of captopril and enalapril in patients with severe chronic heart failure. N Engl J Med 1986315: 847453. 16. Giles TD, Katz R, Sullivan JM, Wolfson P, Haugland M, Kirlin P, Powers E, Rich S, Hacksaw B, Chiaramida A, Rouleau JL, Fisher MB, Pigeon J, Rush MD. Short- and long- acting angiotensin converting enzyme inhibitors: a randomized trial of lisinopril versus captopril in the treatment of congestive heart failure. JAm Co11 Cardiol 1989;13:1240-1247.
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