A Dose-Finding Study of the Hemodynamic Effect of lsosorbide Dinitrate Spray in

Congestive Heart Failure Robert Klein, MD, and Tali Sharir, MD

A dose-finding study of the hemodynamic effect of a new formulation of isosorbkle dinitrate (ISDN) spray was performed in 12 patients with chronic congestive heart failure. Doses of 1.2S,2.5,5.0 mg and placebo, as 1 squirt, were randomly given to ail patients. Hemodynamic measurements were performed by a Swan-Gang catheter before and at 30 seconds and 1, 5, lo,20 and 30 minutes after drug administration and every 30 minutes thereaf- ter, until return of heniodynamic variables to base- line. Hemodynamic improvement evident as de- creases in right-sided pressures and an imrease in cardiac output was observed within 1 minute from administration of ISDN spray, and peaked at 5 min- utes. Near maximal effect was achieved by the 2.5 mg dose. Thus, 2.5 mg of ISDN spray (new formu- lation) produces rapid, near-maximal hemodynam- ic improvement in patients with congestive heart failure.

(Am J Cardioi 1990;65:39J-42J)

From the Cardiology Department, Rebecca Sieff Hospital, Zefat, Israel.

Address for reprints: Robert Klein, MD, Cardiology Department, Rebecca Sieff Hospital, Zefat, Israel.

T he most rapid conventional therapy for relief of symptoms in angina pectoris and dyspnea asso- ciated with heart failure is sublingual administra-

tion of nitrates in tablet form. However, even the rapidly acting sublingual tablets require a few minutes before onset of effect. Peak plasma levels are achieved about 2 minutes after dissolution of the tablet.’ Moreover, the time required for dissolution of the tablet (which varies from patient to patient) further delays the onset of action. In elderly patients with a dry mouth this problem may be more pronounced.

Nitrate spray has been established as a form of rapid administration of nitrates in patients with angina pecto- ris, chronic congestive heart failure and pulmonary ede- ma.2-4 Nitroglycerin and isosorbide dir&rate (ISDN) sprays are available. 2~5 They have been shown to act as rapidly as, or even more rapidly than, sublingual nitrate tablets.

A new formulation of an ISDN spray in a hydrophilic solution with improved biovailability is now available. This report describes a dose-finding study of the hemody- namic effect of this new spray in patients with chronic congestive heart failure.

METHODS Patients: Twelve patients (8 men and 4 women, aged

42 to 75 years [medium age 681) were studied. All had chronic congestive heart failure for a period of 16 months. Ten of the patients were in New York Heart Association functional class III and 2 patients were in class II. The cause of heart failure was coronary artery disease in all cases. The inclusion criteria were: heart failure due to coronary, hypertensive or primary myocar- dial disease; heart failure of 16 months’ duration; stable hemodynamic condition for 13 months before the trial; functional class II to III left ventricular filling pressure I18 mm Hg at rest; previous documented response to vasodilators; age 40 to 75 years; and left ventricular ejec- tion fraction 135%, determined by radionuclide ventric- ulography or left ventriculography during cardiac cathe- terization. The exclusion criteria were: acute myocardial infarction within 3 months from trial; unstable angina pectoris or poorly controlled chronic stable angina pecto- ris; uncontrolled systemic hypertension; chronic obstruc- tive pulmonary disease with pulmonary hypertension; life-threatening ventricular arrhythmias; artificial cardi- ac pacemaker; sick sinus syndrome; essential treatment with long-acting nitrates or other vasodilators; predomi-

THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 4, 1990 39J

A SYMPOSIUM: ADVANCES IN NITRATE THERAPY (PART 2)

50-

35- I”

E 30-

25-

20-

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0 Placebo A 1.25 mg * 2.50 mg n 5.00 mg

30 -

25 -

20 -

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E 15-

10 -

5 I I I I I I I I I I 0 0.5 1 3 5 10 20 30 45 60

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Minutes after application

0 Placebo A 1.25 mg * 2.50 mg W 5.00 mg

40J THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

FIGURE 1. Mean pulmonaryarterialprersure; ChWW+SOVerlhauWithpbceboMdi~ dlnitrate spray.

FIGURE 2. Puhonmy capilky wedge presup cbngfmoverlhourwithplacehandi~ dinitrato spray.

FIGURE 3. Kghl alrial premure: dNngetsoverl hour*placebomdisosorbh dinitrate epray.

FIGURE 4. Cardiac ou@uk changes over 1 hour with placebo and immrbide dinitrate spray.

4.6 -

g 4.4-

4.2 -

4.0 -

3.8 -

3.6 ,I

0 0.5 1 3 5 10 20 30 45 60

Minutes after application

0 Placebo A 1.25 * 2.50 n 5.00 mg mg mg

nant right heart failure with peripheral edema being the main sign of heart failure; cardiac valvar disease; any active pulmonary, systemic, hepatic, renal or metabolic disease; and mental impairment.

Study design: This was a randomized, double-blind, crossover, placebo-controlled dose-finding study. After screening procedures the patients were hospitalized in the cardiac unit. They received 1 squirt of a new formulation of an oral spray of ISDN (Schwarz Pharma, Monheim, Federal Republic of Germany) at a dose of 1.25,2.5 and 5.0 mg, and placebo. After each dose, hemodynamic measurements were performed through a Swan-Ganz thermodilution catheter (inserted 112 hours before ad- ministration of the first dose) at 0.5,1,3,5, 10,20,30,45 and 60 minutes after administration, or for a longer peri- od until return of the hemodynamic variables to the base- line level.

Analysis of data: The hemodynamic data were ana- lyzed separately for each treatment of the study and compared with the control measurements of that day. A

magnitude-time graph of activity was derived from the data for each day. Total activity of each treatment was measured by the difference integral to baseline. Confir- matory analysis was performed by l-sided paired t tests using Bonferroni-adjusted p values. The multiple signifi- cance level was 5%. Exploratory data analyses were per- formed for heart rate and adverse reaction.

RESULTS All patients completed the study. Placebo had no sig-

nificant effect. In all, hemodynamic improvement, evi- dent mainly as a reduction in pulmonary arterial, pulmo- nary capillary wedge and right atria1 pressures and an increase in cardiac output, was observed after adminis- tration of the spray. A significant effect was observed at 1 minute after administration and peaked at 5 to 10 min- utes, remained relatively stable between 10 and 20 min- utes and declined thereafter (Fig. 1 to 5).

The hemodynamic effect of the 2.5-mg dose was near maximal and significantly greater than that of the 1.25-

FIGURE 5. Systemic vasuh resiu changesover1hourwithpkeboandi~ dldrab spray.

u: 2000- E 0 0 1800- I

2 1600-

1400-

1200-

1000 1 , , , , , I I 1 I 1 0 0.5 1 3 5 10 20 30 45 60

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THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 4, 1990 41J

A SYMPOSIUM: ADVANCES IN NITRATE THERAPY (PART 2)

mg dose, which was not significant for all parameters in all time points where the effect of the 2.5 mg was signifi- cant. The 5.0-mg dose did not have a significantly greater effect than 2.5 mg.

No serious adverse effects were observed.

DISCUSSION Our results confirm the rapid onset of action of the

new formulation of ISDN spray in patients with chronic congestive heart failure. The new spray is similar to older formulations of nitroglycerin and ISDN spray.1-3,6 The rapid onset of action and the fact that the patient does not have to hold the drug sublingually for several minutes make the spray an important alternative to sublingual administration of nitrate tablets.

This dose-finding study also confirmed that although some hemodynamic improvement is produced by 1.25 mg, the optimal dose is 2.5 mg. The effect of this dose is not significantly different from that of the 5.0-mg dose in time to onset, magnitude and duration of the effect.

Although sublingual tablet administration is consid- ered the most rapid conventional method for relief of pain in angina pcctoris and of dyspnea in congestive heart failure, its effect is not immediate and it has certain limitations. When given sublingually as tablets, nitrates reach peak plasma levels 12 minutes after dissolution of the tablet.7 This time, however, shows marked interpa- tient variability. The dissolution process takes approxi- mately 1 minute and it increases the time required

to achieve peak plasma levels by approximately one half.

The dissolution time depends on numerous factors. It may be prolonged in the elderly, in regions with high temperatures and in patients with a dry mouth. Dis- tressed patients with dyspnea or severe chest pain may find it difficult to hold the tablet under their tongues. In dependent patients the nurse has to follow the patients for several minutes until the tablet dissolves, and to take care that the drug will not be swallowed. These problems are avoided by the use of spray. Our findings with the new ISDN spray fulfill these expectations.

In conclusion, the new ISDN spray is an effective and safe short-term treatment for patients with chronic con- gestive heart failure. The optimal dose is 2.5 mg.

REFERENCES 1. Schneeweiss A. Nitroglycerin. In: Schnceweiss A, cd. Drug Therapy in Cardio- vascular Diseases. Philadelphia: Lea & Febiger, 1986:5-28. 2. R&sin LH, Landau E, Darawshi A. More rapid relief of pain with isosorbide dinitrate oral spray than with sublingual tablets in elderly patients with angina pectoris. Am J Cardiol I 988,6/:2Em3E. 3. Schneeweiss A, Marmor A, Plich M, Alpert JS. ISDN spray in comparing heart failure. Am J Cardiol 3987;S9:848-852. 4. Wildfeurer A. Aspect pharmaccutische entwickhmg eines neuen oralen ISDN spray. Therapiewoche 1982;32:6/41-6349. 5. Parker JO, Vankoughnett KA, Farrell B. Nitroglycerin lingual spray: clinical efficacy and dose-response relation. Am J Cardiol 1986;57:1-5. 6. Marchionni N, De Bari M, Ferrucci L, Moschi G, Schneeweiss A. Compara- tive study of time-course of hemodynamic effect of isosorbide dinitrate spray and sublingual tablets in patients with pulmonary congestion. Cardiouasc Drugs Ther 1988;2:529-532. 7. Armstrong PW, Armstrong JA, Marks GS. Blood level after sublingual nitro- glycerin. Circulation 1979;59.585-588.

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