Tolerability of enalapril initiation by patients with left ventricular dysfunction: Results of the medication challenge phase of the studies of left ventricular dysfunction

Tolerability of enalapril initiation by patients with left ventricular dysfunction: Results of the medication challenge phase of the Studies of Left Ventricular Dysfunction Although converting-enzyme inhibitors are useful for the treatment of congestive heart failure (CHF), there are concerns about adverse reactions especially on initiation of therapy. In the Studies of Left Ventricular Dysfunction, enalapril, 2.5 mg twice per day was given on an open-label outpatient basis for 7 days (mean 0.1, range 2 to 7, and median 7) as a prerandomization drug challenge to 7467 patients with left ventricular dysfunction (ejection fraction 10.35). Four hundred forty-four (5.93%) patients reported side effects, including symptoms attributed to hypotension (in 166 patients [2.2%]). The majority (346 [77.9%] of 444 and 129 [77.7%] of 166 with symptoms attributed to hypotension) of patients who reported side effects were willing to participate in the study and to continue receiving enalapril. Thus only 96 (1.3%) of 7467 patients (0.5% because of symptoms attributed to hypotension) were not willing to continue because of side effects, Women and patients of CHF class Ill or IV were more likely to report side effects. In conclusion, enalapril is well tolerated by patients with left ventricular dysfunction; treatment can be initiated on an outpatient basis in the majority of patients. (AM HEART J 1994;126:356-64.)

John B. Kostis, MD,* Brent J. Shelton, MSb Salim Yusuf, MBBS,C Melvin B. Weiss, MD,d Robert J. Capone, MD: Carl J. Pepine, MD,f Gilbert Gosselin, MD,z Francois Delahaye, MD, MPH,h Jeffrey L. Probstfield, MD,’ Linda Cahill, RN,j and Diana Dutton, RN,k for the Studies of Left Ventricular Dysfunction Investigators New Brunswick, N. J., Chapel Hill, N. C., Ontario and Quebec, Canada, Valhalla and Rochester, N. Y., Gainesville, Fla., Lyon, France, Seattle, Wash., and Portland, Ore.

Angiotensin-converting enzyme (ACE) inhibitors are being used in an increasing proportion of patients with left ventricular dysfunction with or without heart failure. They have been found to improve hemodynamic function without the occurrence of tolFrom the auniversity of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick; the %Jniversity of North Carolina at Chapel Hill; ‘McMaster University, Ontario; dWestchester County Medical Center, Valhalla; the TJniversity of Rochester Medical Center; the ‘University of Florida, Gainesville; CMontreal Heart Institute, Quebec; hHBpital Cardiologique, Lyon, France; ‘Fred Hutchison Cancer Research Center, Seattle; the juniversity of Washington, Seattle; and kOregon Health Sciences University, Portland. Received for publication Nov. 4, 1993; accepted Dec. 13, 1993. Reprint requests: John B. Kostis, MD, UMDNJ-Robert Wood Johnson Medical School. One Robert Wood Johnson Place, CNlS, New Brunswick, NJ 08903-0019: Copyright @ 1994 by Mosby-Year Book, Inc. 000%8703/94/$3.00 + 0 4/l/56670

356

erance, to relieve symptoms, to reduce the need for hospitalization, and to decrease mortality.l-l4 In addition, they have been found to decrease the chance of development of congestive heart failure (CHF) in patients with asymptomatic left ventricular dysfunction and to decrease the risk of acute myocardial infarction and hospitalization for angina pectoris.i5-I7 In the Studies of Left Ventricular Dysfunction (SOLVD), a short period of ACE inhibitor (enalapril) challenge (test dosing) was instituted to ensure that patients could tolerate the medication, to minimize self-withdrawals after randomization, and to examine more closely short-term tolerability for this agent. The majority of the patients received the drug on an outpatient basis. This report describes the tolerability of initiation of ACE inhibitor therapy with enalapril, 2.5 mg twice daily before randomization in the 7487 patients who were eligible for entry into SOLVD.

volume 128, Number 2 American HearI Journal

METHODS SOLVD was a large multicenter, randomized, placebocontrolled clinical trial. Its primary objective wasto establish whether ACE inhibition with enalapril would decrease mortality in patients with left ventricular dysfunction (ejection fraction I 35%) . The study wascomposedof two trials: (I) a “treatment trial” conducted among patients with left ventricular dysfunction who required digitalis or diuretic agentsfor treatment of symptomatic CHF and (2) a “prevention trial” conducted among patients with left ventricular dysfunction who did not require diuretic agents or digitalis for treatment of symptomsor signsof CHF. The rationale, design, and methods of SOLVD have been described in detail.18Men and women aged 21 to 80 years with left ventricular ejection fraction 135 % measuredby contrast ventriculography, two-dimensional echocardiography, or radionuclide ventriculography within 3 months of the day of consentwereeligible for the study. Subjectswith serious diseaseslikely to cause death within the next 2 years, cardiac dysfunction not causedby left ventricular dysfunction (e.g. valvular, pericardial, or congenital heart disease),intolerance to enalapril, uncontrolled hypertension, acute myocardial infarction within 30 days of the scheduledbeginning of the study, or substantial likelihood of nonadherencewere excluded from the study. To decreasethe number of patients who would not be able to adhere to the study therapy becauseof inability to tolerate ACE inhibition, a 2- to 7-day prerandomization drug challenge period (test dosing) was included in the protocol. Thus patients meeting all inclusion criteria were given enalapril, 2.5 mg twice per day. Twenty-four hours later patients were called on the telephone and questioned as to whether major adverse reactions had occurred. The indications and limitations of this prerandomization adherence-screeningprocedure have been described.lg Patients were then seenin the clinic 2 to 7 days after starting to receive medication. At this time any adverseeffects were noted, and blood wasdrawn for hematocrit, white blood cell (WBC) and differential counts, and electrolyte, and creatinine analysis. In addition, heart rate and blood pressurewere recorded. These data and eligibility criteria were recorded on standardized forms at the first visit. After this visit the patients were given placebo for 14 to 17 days (mean 15 days) and then returned to the clinic for randomization. Statistical analyses. Paired t tests were used to detect changesin laboratory parameters.Multivariate regression models were used to determine independent effects on changesoccurring in blood urea nitrogen (BUN), serum creatinine, and serum potassium levels and in systolic blood pressure(SBP). Fisher’sexact test and Pearson’schi squaretest were usedin assessing the homogeneity of side effects amongthe levels of eachbinary and ordinal covariate. Logistic regressionanalysis was used to assessindependent effects in comparisonof the presenceor absence of sideeffects betweenmenand women,betweenNew York Heart Association (NYHA) functional classes(I or II vs III or IV), amongagecategories(<56,56 to 65, and >65), and amongtrials (nonrandomized patients and patients in the prevention, and treatment trials).

/Costis et al.

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RESULTS Patient population. Seven thousand four hundred eighty-seven eligible patients were given enalapril, 2.5 mg twice daily in the prerandomization enalapril challenge phase of SOLVD. Stroke occurred in 3 of these patients, and 4 (0.05? ) died within the 2- to 7-day period. These deaths were attributed to coronary thrombosis, cardiac arrhythmia, and in 2 patients, myocardial infarction. During the 15-day placebo prerandomization period, 34 (0.46 $;,) patients died. Thus initiation of enalapril therapy was not associated with an increased death rate. Of the remaining 7446 patients, 2569 were randomized into the treatment trial and 4228 into the prevention trial, and 649 were not randomized because of self-initiated withdrawal, noncompliance, or side effects. The average duration of enalapril therapy during test dosing was 6.0 -+ 2.3 days (median 7 days); the average age was 60 t 10 years (median 61 years); and the average ejection fraction was 27’ ; +_6’1;) (median 28%). Eighty-five percent of the population were men. Thirty percent of patients were taking digitalis, 39 16 diuretic agents, 22 C;’ both digit,alis and diuretic agents, 39 4‘; vasodilators, and 11”;~ all three classes of medication. Drug treatment was more frequent in the treatment trial (68’:;; digitalis, 86 “; diuretics, and 53 ?Gvasodilators) than in the prevention trial (13 “; , 17 c2, and 37 5, respectively). Nitrates were the most frequently used vasodilators. Eighty-nine patients were hospitalized to initiate enalapril therapy. These patients were in NYHA class IV, were concomitantly receiving a non-ACE inhibitor vasodilator, had serum sodium levels 5 130 mEq/L, or a combination of these characteristics, and their data are not included in this report. Experience with this subset of patients has already been reported.“’ This subset of 89 patients represents only a small proportion (1.25; ) of all of the patients who received enalapril therapy and only 1I ?; of the 806 patients who were classified as being in NYHA class IV, who were taking non-ACE inhibitor vasodilators, or who had serum sodium levels ~1.30 mEq/L. The others, 717 patients with these characteristics, were given enalapril on an outpatient basis and are included among the patients described in this report. Effect of enalapril on selected parameters. Enalapril use was associated with small but statistically significant (p < 0.01) reductions in heart rate and in WBC and neutrophil counts and with increases in BUN, serum creatinine, and potassium levels (Table I). Although most of these effects were st,at.istically significant by paired analysis in this very large study and occurred in patients in both the treatment and the prevention trials, they were quantit,;rtively very small

360

Kostis

et

al.

American

Table I. Hemodynamic

and biochemical data before and after administration

August 1994 Heart Journal

of enalapril Difference

Parameter

SBP (mm Hg) DBP (mm Hg) Heart rate (beats/min) Potassium (mEq/L) BUN (mg/dl) Creatinine (mg/dl) WBC (cells/mm3 X 106) Neutrophils (%) Values

are means Blood urea

BUN,

Postdrug

Predrug

t SEM. nitrogen;

DBP,

125.4 78.0 77.4 4.3 18.3 1.2 7.5 62.2

diastolic

blood

?I 17.6 + 10.4 ?I 13.0 + 0.4 + 6.8 + 0.3 -t- 2.11 + 10.4

pressure;

119.3 74.2 76.4 4.4 18.9 1.23 7.4 61.88

SBP, systolic

blood

Table II. Changes in laboratory parameters by New York

Heart Association functional class NYHA

I or II

NYHA

III

OF IV

P

Difference in BUN n

5907

+ 0.98 0.189 + 0.16 911

SEM 0.006 Difference in creatinine n 5867 Mean +0.02 SEM 0.003 Difference in SBP n 6087 Mean -6.28 SEM 0.185 BUN, Blood urea nitrogen; tolic blood pressure.

NYHA,

0.0195

902

+0.52 Mean SEM 0.058 Difference in potassium i;lean +0.07 5895

0.0001

0.016

New York

903 +0.03 0.007

0.1590

940 -5.10 0.481

0.0196

Heart

Association;

SBP, sys-

and probably not of clinical importance. The reduction in blood pressure was, however, more sizeable (6 mm Hg decrease in SBP and 4 mm Hg decrease in diastolic blood pressure; p < 0.0001 for both). A small proportion of patients showed marked changes in these variables. Marked changes were defined as changes of >20% from baseline (predrug) values. Thus 442 (6.5 %) of the patients had a decline of >20 % in their pre-drug SBP (mean decrease 36 & 9.0 mm Hg). Six hundred sixty (9.7%) patients had an increase of >20% in their predrug creatinine level (mean increase 0.37 + 0.27 mg/dl). Increase in potassium level by >20% was seen in 407 patients (59%)(mean increase 1.07 -t 0.30 mEq/L). Increase in BUN level by >20 % was observed in 1497 (21.8 % ) patients (mean increase 6.4 + 4.4 mg/dl). Changes in serum potassium, BUN, and creatinine

pressure;

rt 2 k 2 + f * It

(post-pre)

17.2 10.2 12.5 0.4 7.4 0.3 2.1 10.1 WBC, white

p

-6.1 k 14.51 -3.8 f 9.8 -1.0 + 10.6 0.1

+ 0.5

0.6 k 4.7 0.02 + 0.21 -0.1

f

1.5

-0.3 * 9.4 blood

Value

<0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.008

cell count.

concentrations and in SBP were at best weakly correlated with one another. The change in creatinine was correlated with the change in BUN by a Pearson coefficient of 0.267. Patients in NYHA class III or IV (compared with those in NYHA class I or II) had a more pronounced (but still very small) increase in potassium level (mean increases 0.16 and 0.07 mEq/L, respectively; p = 0.0001) and BUN level (mean increases 0.98 and 0.52 mg/dl, respectively; p = 0.02). On the other hand, patients in NYHA class I or II experienced larger decreases in SBP compared with those in NYHA class III or IV (mean decreases 6.3 and 5.1 mm Hg, respectively; p = 0.02, Table II). A multivariate regression model was used to describe the independent relations of certain covariates (age, WBC, ejection fraction, percentage of neutrophils, percentage of lymphocytes, hematocrit, serum sodium concentration, trial [treatment vs prevention, vs no randomization], NYHA class, sitting heart rate, and gender) with the change in the four parameters (BUN, creatinine, and potassium concentrations and SBP). By this analysis, the greatest increases in BUN and in potassium occurred in NYHA class III or IV patients compared with class I or II patients and in nonrandomized patients compared with those in the prevention or treatment trial. Significant decreases in SBP were more notable for NYHA class I or II than class III or IV. For each l-year increase in age, SBP decreased by 0.094 and BUN decreased by 0.0158 mg/dl. No differences were noted between patients in the prevention trial and the treatment trial. A unit increase in serum sodium level was associated with a decline of 0.005 mEq/L in potassium level. Women had a greater increase in creatinine levels than did men. See Table III for estimates and more detailed results. Reported side effects. In the prerandomization enalapril challenge, only 456 (6.1%) of 7487 reported one or more side effects. There were 533 side effects

Volume 128, Number 2 American Heart Journal

Table III. Results of multivariate

Kostis rt al.

regression modeling

Predictor Difference Trial N P T Age WBC Difference

in BUN

in potassium

Difference in creatinine Trial N P T Gender Female Male Age EF Sitting HR Difference in SBP Age Hematocrit Serum sodium

_Estimated coefficient squared

regression or least means

Estimated SEh!f

0.78 1.23

0.126 0.196

0.295 0.137 0.120 0.0059 0.0282 0.066 0.128 -0.006 0.006 -0.005

0.0075 0.0196 0.4810 0.0076 0.0141 0.012 0.019 0.0013 0.0027 0.0019

(NvsP) (NvsT) (P vsT)

0.073 0.032 0.030

0.0136 0.0063 0.0055

0.0031 0.0018 0.7360

(NvsP) (NvsT) (P vsT)

0.059 0.032 0.0010 0.0009 - 0.0004 NYHA I or II NYHA III or IV -0.094 -0.097 -0.144

0.0086 0.0057 0.0903 G.0004 0.0002 -6.77 -5.44 0.0179 0.0412 0.0590

0.0007

NYHA

I or II

1.50 0.70 0.80 0.0158 -0.069 NYHA I or II NYHA III or IV Hematocrit WBC Serum sodium

BUN, Blood urea nitrogen; EF, ejection fraction; HR, heart rate, N, nonrandomized systolic blood pressure; 7’, treatment trial; WBC, white blood cell count.

reported (Table IV). The most commonly reported side effect was dizziness, lightheadedness, or similar complaints attributed to hypotension (166 [2.2 % ] patients of the population). This rate was not higher in the 285 patients (2.1% ) in whom baseline SBP was
361

trial, NYHA,

- --__-

0.021”

0.0009

0.0001 0.0273 0.0046

0.0003 0.0345 0.0414 0.352 0.572 0.0001 0.0186 0.0145 New York Heart

P

Association;

0.0229

P, prevention

trial; SBP,

ty-six percent of these patients were willing to continue in the study. The majority (77.9 % ) of patients who reported side effects to enalapril were willing to participate in the study and to continue receiving enalapril if randomized to do so (Table IV). Thus only 98 (1.3%) of 7487 patients who returned for the second visit were not willing to continue receiving enalapril because of side effects. Women, patients with more severe CHF (NYHA class III or IV), and patients in the treatment trial were more likely to report side effects to enalapril (Tables IV through V). Women reported side effects more frequently than men (8.0 % vs 5.8%) p = 0.0029; adjusted odds ratio 1.28, p = 0.05; Table IV). Patients in the prevention trial reported side effects less frequently than did their treatment trial counterparts (4.3% vs 6.4% ; p < 0.001). Patients with more severe CHF (class III or IV) were more likely to report side effects than were patients with less severe (class I or II) symptoms (9.8% vs 5.4%) p < 0.0001; adjusted odds ratio 1.34, p = 0.031).

362

Kostis et al.

August 1994 Heart Journal

American

Table IV. Participants who reported side effects and participants who were willing to continue despite side effects (total cohort and by gender) All participants With side effects

Side effect

n

%

Willing

Women

Men

to continue

n

%

With side effects f%)

Symptomatic hypotension Altered taste Skin rash or pruritus Angioneurotic edema Cough Gastrointestinal symptoms Azotemia Stroke Hyperkalemia Other

166 75 52 3 10 70 11 3 1 129

2.20 1.00 0.69 0.04 0.13 0.93 0.15 0.04 0.01 1.72

129 68 39 1 9 54 3 0 0 98

77.71 90.66 75.00 33.33 90.00 77.14 27.27 0.00 0.00 75.96

2.72 1.72 1.18 0 0.4 1.54 0.4 0 0 1.81

Total with ~1 side effect (n) Total reported side effects (n) Attending visit 2 (n)

444 520

5.93 6.95 7487

346

77.93

7.97 9.69 1104

Willing to continue tw) 80.00 89.47 69.23 100.00 82.35 25.00 74.31 81.82

With side effects f%)

Willing to continue (%)

2.13 0.88 0.61 0.05 0.09 0.83 0.11 0.05 0.02 1.71

77.20 91.07 76.92 33.33 83.33 75.47 28.57 0.00 0.00 74.31

5.58 6.48 6376

76.97

Table V. Participants who reported side effects and participants who were willing to continue despite side effects (by New York Heart Association functional class) NYHA III or IV

NYHA I or II

Side effect Symptomatic hypotension Altered taste Skin rash or pruritus Angioneurotic edema Cough Gastrointestinal symptoms Azotemia Stroke Hyperkalemia Other Total with 21 side effect fn) Total reported side effects fn) Attending visit 2 (4

With side effects (%)

Willing to continue (%)

1.83 0.95 0.70 0.05 0.11 0.88 0.13 0.03 0 1.61

77.77 88.52 77.77 33.33 85.71 80.35 25.00 0.00

5.38 6.29 6391

79.07

A slightly higher percentage (79%) of patients in NYHA class I or II were willing to continue taking enalapril than were those of class III or IV (74%) (Table V). DISCUSSION

This study demonstrates that enalapril, 2.5 mg twice per day initiated as outpatient therapy was tolerated very well by the majority of the 7487

74.75

With side effects (%)

% willing to continue (%I

4.75 1.38 0.69 0 0.30 1.38 0.30 0.10 0.10 2.57

77.08 100.00 57.14

9.79 11.57 1011

73.74

100.00 64.28 33.33 0.00 0.00 80.77

patients with systolic left ventricular dysfunction who were eligible for the SOLVD project. Patients with left ventricular dysfunction, especially those with CHF and taking diuretic agents, are considered by somelo-ls* 20-24to be at higher risk for side effects. Many physicians thus have used caution when initiating therapy with ACE inhibitors by hospitalizing patients or by using a shorter-acting agent to avoid prolonged early hypotension. The SOLVD experi-

Kostis et al.

ence demonstrates that therapy with a long-acting ACE inhibitor (enalapril) can be initiated safely on an outpatient basis in the majority of patients with left ventricular dysfunction with or without CHF symptoms. Only 98 (1.3%) of the 7487 eligible patients were not enrolled because of side effects. This very 10~ percentage results in part from the low probability of the development of side effects and from the willingness of the majority (78%) of participants who reported side effects during test dosing to continue receiving enalapril even though they had had a side effect. This finding implies that the majority of side effects were acceptable to the patients. It is likely that some of the side effects reported were the result of inherent patient symptoms or “placebo effects” because this phase of SOLVD did not include a parallel placebo group. GI complaints, altered taste, and skin rash may belong in this category because significant differences in these side effects were not reported in the randomized phase of the studies.131 i5 Symptomatic hypotension was observed in both the prerandomization and the randomization phases of SOLVD. The short duration of administration may not have allowed side effects that develop over time to become apparent. This limitation may account for the low rate of cough as a side effect. In the randomized phase of SOLVD, cough was reported more frequently by patients randomized to enalapril than by those randomized to placebo.13 Women and patients with more severe CHF were more likely to report side effects than were men or patients in NYHA class I or II. The increased rate of reported side effects by women and patients with more severe CHF was generally observed across the spectrum of side effects. However, it is noteworthy that the difference in reported symptomatic hypotension between NYHA class groups (I or II vs III or IV) were more pronounced (risk ratio 2.59) than the difference in this side effect between men and women (relative risk 1.28). The opposite was true when skin rash (relative risk 9.99 vs 1.93), taste alteration (1.45 vs 1.95), and GI symptoms (1.57 vs 1.86) were considered. Changes in laboratory parameters observed after initiation of enalapril usually were clinically trivial but statistically significant. Although in a small but not negligible proportion of patients marked (i.e., >20% of baseline value) changes were observed, in the majority of cases these changes did not prevent the patient from continuing in the study. Only 12 (0.16%) of 7487 patients were excluded because of abnormal results in laboratory tests (11 because of azotemia and 1 because of hyperkalemia).

363

The major implication of this report is that in patients with left ventricular dysfunction, including those with class III or IV CHF, init,iation of ACE inhibitor therapy in an outpatient setting is safe and very well tolerated. There appears to be no need for hospitalization or for initiation of t.herapy with short-acting ACE inhibition even in patients taking diuretic agents and vasodilating agents unless specific reasons are present. A limitation of the study is that the patients in SOLVD were carefully selected by experienced investigators according to specific criteria and thus may not represent the spectrum of patients who receive ACE inhibition in clinical practice. Closer supervision may be needed for patients with azotemia or hypotension. REFERENCES

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