DOI 10.1378/chest.113.5.1272 1998;113;1272-1276Chest

 Naty, Salvatore Durante and Gennarino BorrelloCarmelindo M.E. Tranfa, Girolamo Pelaia, Rosa D. Grembiale, Saverio SalmeterolShort-term Cardiovascular Effects of

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Short-term Cardiovascular Effects ofSalmeterol*Carmelindo M.E. Tranfa, MD; Girolamo Pelaia, MD; Rosa D. Grembiaie, MD;Saverio Naty, MD; Salvatore Durante, MD; and Gennarino Borrello, MD

The occurrence of cardiovascular side effects is sometimes associated with the utilization ofP-adrenoceptor agonists. The most important causes of these undesirable pharmacologic actionsare as follows: (1) direct stimulation of cardiac p-adrenoceptors; (2) reflex activation ofadrenergic mechanisms due to peripheral vasodilation; (3) hypokalemia; and (4) hypoxemia. Theaim of this study was to evaluate the potential short-term, cardiovascular side effects ofsalmeterol, a long-acting and highly selective P2-adrenoceptor agonist. Eight volunteer healthysubjects and eight patients with reversible airway obstruction and without cardiovascularalterations were treated with 50 pg of salmeterol twice a day for 3 days and then with 100 pg ofsalmeterol twice a day for a further 3-day period. The 24-h ECG (Holter) monitoring andmeasurement of arterial BP, performed on the admission day and on the third and the sixth dayof pharmacologic treatment, showed that salmeterol did not produce any significant change inmean heart rate, number of supraventricular and ventricular premature complexes, and BP.Furthermore, no ECG abnormality related to myocardial ischemia was recorded during 24-hHolter monitoring. These data suggest that salmeterol, administered in regular and high dosesfor a short period, does not cause significant cardiovascular effects in both normal subjects andpatients with reversible airway obstruction. (CHEST 1998; 113:1272-76)

Key words: cardiovascular effects; Holter monitoring; salmeterol

Abbreviation: p-AR= p-adrenergic receptor

T nhaled P-adrenoceptor agonists are the most ef-¦*¦ fective bronchodilators currently available. How¬ever, stimulation of P-adrenergic receptors (P-AR)sometimes may also induce cardiovascular side ef¬fects,1"3 such as tachycardia, arrhythmias, prolonga¬tion of QT interval, and T-wave changes.

These effects, which are quite rare with the use ofinhaled P2-selective drugs, depend mainly on reflexrelease of catecholamines, secondaiy to peripheralvasodilation, and on direct activation of cardiac P-AR.The latter belong mostly to the Prsubtype, but some

P2-receptors coexist with the more numerous psub¬types in atria and left ventricle.4

Furthermore, hypoxemia and hypokalemia mayalso contribute to trigger the cardiac side effects ofP-adrenoceptor agonists.

*From the Faculty of Medicine (Drs. Tranfa, Grembiaie, andNaty), and the Faculty of Pharmacy (Dr. Pelaia), University ofCatanzaro, Italy; and the Center for Cardiac Rehabilitation (Drs.Durante and Borrello), "Mater Domini Hospital," Catanzaro,Italy.Manuscript received July 29, 1997; revision accepted October 7,1997.Reprint requests: C.M.E. Tranfa, MD, Cattedra di FisiopatologiaRespiratoria, Policlinico "Mater Domini," Via T. Campanella,88100 Catanzaro, Italy

Some studies have reported an increased incidenceof arrhythmias in patients who were treated with a

combination of p-adrenoceptor agonists and theophyl¬line.56 Other authors78 have shown that salbutamol,given alone by either inhaled route or oral administra¬tion, may induce a significant increase in heart rate. Onthe contrary, it has also been reported that inhaledbitolterol mesylate and oral (sustained-release) theoph¬ylline, given alone or in combination, do not elicitcardiotoxic effects.9 However, it cannot be ruled outthat a prolonged, either direct or reflex, stimulation ofcardiac p-AR by longer-acting p-adrenoceptor agonistsmay trigger undesirable cardiovascular effects.

Therefore, we decided to study, by means of 24-hECG recording in both healthy subjects and patientswith reversible bronchial obstruction, the possibleonset of tachycardia, arrhythmias, and other sideeffects, after inhalation of regular and high doses ofthe long-acting salmeterol xinafoate, a partial agonistat P2-AR with the highest P2-selectivity of any of thecurrently available p-sympathomimetics.10

Materials and Methods

Eight volunteer healthy subjects (five male and three female,29 to 43 years of age, mean±SD: 33.5±4.1) and eight patients

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with reversible airway obstruction (4 male and 4 female, 18 to 61years of age, mean±SD: 40.5±12.8) documented by an increasein FEVl9 within 20 min after inhalation of 200 pg of salbutamol,both >12% and 200 mL,11 were enrolled in this study. Treatmentwith inhaled and oral P2-adrenoceptor agonists was withheld for24 h, anticholinergic agents for 12 h, and slow-release theophyl¬line for 36 h. Patients taking inhaled/oral corticosteroids or

cromoglycates continued this treatment at a constant dosethroughout the study. Smoking and use of caffeine-containingdrinks were not allowed during the trial.Each subject was studied throughout a 7-day period, according

to the following experimental design.

First DayOn the admission day, baseline pulmonary function tests

(flow-volume curve), bronchodilator response, blood gas (oxygen,carbon dioxide) analysis, baseline 24-h ECG ambulatory moni¬

toring (Holter ECG; Model 2448; Ela Medical; Montrouge,France), recording of arterial BP by a mercury sphygmomanom-eter (FC-110; Focal; Tokyo, Japan), and determination of serumlevels of some electrolytes (Na+, K+, Mg2+) were performed.Lung volumes and expiratory flows were obtained using a

pneumotachometer (MasterLab; Jaeger; Wurzburg, Germany)and the highest value of three consecutive measurements was

chosen. Holter ECG was performed with the subject wearing a

set of electrodes taped to the chest and carrying a portablerecording device; the 24-h monitoring was then analyzed by a

computer system (Anatec S; Ela Medical).

Second DayAfter baseline registration of FEVl5 50 |jLg (two puffs) of

salmeterol was administered by metered-dose aerosol. FEV]_measurements were repeated 2 h thereafter. Inhalation of 50 pg(two puffs) of salmeterol was repeated 12 h after the first drugadministration.

Third DayAdministration of salmeterol was continued following the same

schedule of the second day (inhalation of 50 pg of salmeteroltwice a day).

Fourth DayAdministration of salmeterol was continued following the same

schedule of the second and third day. Furthermore, Holter ECGwas performed, serum electrolyte levels were measured, andarterial BP was determined 2 h after the first drug inhalation.

Fifth DayAfter baseline registration of FEVls 100 |xg (four puffs) of

salmeterol was administered by metered-dose aerosol. FEVXmeasurements were repeated 2 h thereafter. Inhalation of 100 u_g(four puffs) of salmeterol was repeated 12 h after the first drugadministration.

Sixth DayAdministration of salmeterol was continued following the same

schedule of the fifth day.

Seventh DayAdministration of salmeterol was continued following the same

schedule of the fifth and sixth day. Furthermore, Holter ECG

was performed, serum electrolyte levels were measured, andarterial BP was determined 2 h after the first drug inhalation.

This protocol was approved by the institutional review boardfor human studies and an informed written consent was obtainedfrom each of the 16 subjects.

Statistical AnalysisThe Student's t test for paired data was used for statistical

comparison of the results; a p value <0.05 was considered as

significant.

Results

Normal SubjectsThe individual characteristics of the eight healthy

subjects and their bronchodilator response to salme¬terol (measured 2 h after drug administration), ex¬

pressed as percent changes in FEV1? are shown inTable 1. Salmeterol induced a slight, but not signif¬icant, increase in FEVp

Comparative evaluation of the individualdata recorded in each subject before and aftersalmeterol administration, at both daily doses of 100and 200 pg, did not show any significant changeeither in 24-h average heart rate, expressed as

beats per minute (baseline vs salmeterol 100 and200 pg: mean±SD= 75.25±11.67; 80.12±8.49; and

Table 1.Subject Characteristics and Percent Changesin FEVj 2 h After Inhalation of 50 and 100 pg of

Salmeterol Xinafoate*

Subject No./

Sex/Age, yr

BaselineFEV!, %Predicted

% FEVjChanges 2 h

After S

50jxg 100 \xg

l/M/332/F/343/M/324/M/295/F/326/M/437/F/338/M/32

Mean 33.50SD 4.119/M/29

10/F/18ll/F/3912/F/6113/F/4814/M/4015/M/4316/M/46

Mean 40.50SD 12.84

116110104111101110125105110.25

7.5971.973.175.077.078.466.659.669.471.376.13

0+ 3+20

+4+ 1001.251.58

+28.6+32.2+26.2+ 17.0+38.0+ 30.8+41.0+ 34.931.097.47

0+5+5+4+4+40

+53.372.13

+33.4+33.1+28.6+21.3+40.0+35.4+49.0+ 36.534.668.08

*S=salmeterol. No. 1 to 8=normal subjects; No. 9 to 16=patientswith reversible airway obstruction.

CHEST/113/5/MAY, 1998 1273

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79.50± 10.06, respectively) (Fig 1), or in the 24-hnumber of supraventricular and ventricular pre¬mature complexes (baseline vs salmeterol 100 and200 pg: mean±SD=41.37±31.91; 47.00±56.41;and 55.87±48.75, respectively) (Fig 2). Further¬more, no significant change in systolic and diastolicarterial BP (Table 2) was detected. Finally, no ECGabnormality related to myocardial ischemia was re¬

corded during 24-h Holter monitoring performedbefore and after salmeterol administration.

Patients With Reversible Airway Obstruction

The individual characteristics of the eight patientswith reversible airway obstruction and their bron¬chodilator response to salmeterol (measured 2 hafter drug administration), expressed as percentchanges in FEVjl, are shown in Table 1. Salmeterolinduced a significant increase in FEV1 (p<0.05) atboth single doses of 50 and 100 pg.No significant changes in 24-h average heart

rate (baseline vs salmeterol 100 and 200 pg:mean±SD=62.25±10.63; 68.12±9.57; and 69.25±8.34, respectively) (Fig 3), as well as in the 24-hnumber of supraventricular and ventricular prema¬ture complexes (baseline vs salmeterol 100 and 200pg: mean±SD= 30.00±35.32; 27.37±31.73; and39.50±43.43, respectively) (Fig 4), and in systolicand diastolic arterial BP (Table 2), were observedwith both salmeterol daily doses of 100 and 200 |xg.Furthermore, no ECG abnormality related to myo¬cardial ischemia was recorded during 24-h Holtermonitoring performed before and after salmeteroladministration.

In both groups, salmeterol did not produce anysignificant change in either Pa02 or PaC02 values,

O S 100 meg S 200 meg

S 200 meg

Figure 1. Effects of salmeterol xinafoate (S) on 24-h averageheart rate (HR) in eight normal subjects.

Figure 2. Effects of salmeterol (S) on the 24-h number ofsupraventricular and ventricular premature complexes (PCs) ineight normal subjects.

or serum levels of sodium, potassium, and magne¬sium (data not shown). Furthermore, no cardiovas¬cular symptom was reported by any of the subjectsenrolled in the study.

Discussion

The results of our short-term trial have shown thatinhaled salmeterol, at both daily doses of 100 and200 pg, did not induce cardiovascular side effects ineither normal subjects or patients with reversibleairway obstruction during the 6 days of pharmaco¬logic treatment. In particular, 24-h Holter ECGmonitoring demonstrated that salmeterol did notcause any clinically relevant change either in theaverage heart rate or in the number of supraventric¬ular and ventricular premature complexes. Further¬more, no ECG alteration related to myocardial isch¬emia was recorded and no significant modification ofsystolic and/or diastolic arterial BP was detected.Our data are consistent with those of other au¬

thors. Analyzing the results of a multicenter studyinvolving about 700 asthmatic patients, Britton etal12 did not find any significant change in systolic anddiastolic BP or ECG pattern during several monthsof treatment with either salbutamol (200 pg qid) or

salmeterol (50 pg bid). Furthermore, an analogousmulticenter trial performed by Pearlman et al,13including 234 asthmatics randomly assigned to threedifferent groups (placebo, salbutamol, and salmet¬erol groups), showed no significant difference amongthe groups in the occurrence of supraventricularand/or ventricular ectopy during 24-h ambulatoryECG.

Several factors may account for the lack of cardio-

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Table 2.BP Values Recorded Before and 2 h After Inhalation of 50 and 100 pg of Salmeterol Xinafoate*

Subject No.

Systolic BP, mm Hg Diastolic BP, mm HgBaseline S50 pg S 100 \xg Baseline S 50 |xg S 100 |xg

12345678

MeanSD910111213141516

MeanSD

12010511011011014011590112.5014.14

120110115140105110130120118.7511.57

11010011011010013511095108.7512.17

120115115145105110125120119.3712.08

12012012011095140115120117.5012.54

125110110145110110130120120.0012.82

657070808085806574.377.76

807070807070808075.005.34

707070808090807076.257.44

757070857070808075.005.98

708075807090807076.877.04

807570857075808076.875.30

*For explanation of abbreviations, see Table 1 footnotes.

vascular side effects observed in our study. It ispossible that the stimulation of cardiac P-AR in¬duced by salmeterol does not reach the threshold ofclinical relevance because it is not sufficient to cause

significant modifications of heart rate, rhythm,and/or oxygen consumption. In fact, plasma levels ofsalmeterol after inhalation are very low and, more¬

over, most cardiac P-ARs belong to the P^subtype.Another factor might concern the potential develop¬ment of receptor homologous desensitization subse¬quent to a prolonged activation of cardiac P-AR. In

fact, a reduced responsiveness of P-AR may theoret¬ically occur as a consequence of a continuous or

repeated exposure to a P-adrenoceptor agonist.14In conclusion, according to the results of our trial,

essentially based on Holter ECG monitoring and BPmeasurements, a short-term treatment with bothregular and high doses of salmeterol does not appearto induce cardiovascular side effects in either normalsubjects or patients with reversible airway obstruc¬tion. This suggests that the long-lasting stimulationof P-AR occurring during bronchodilator therapy

Baseline BI S 100 meg BS S 200 meg

Figure 3. Effects of salmeterol xinafoate (S) on 24-h averageheart rate (HR) in eight patients with reversible airway obstruc¬tion.

? Baseline CZJ S 100 meg IH S 200 meg

Figure 4. Effects of salmeterol (S) on the 24-h number ofsupraventricular and ventricular premature complexes (PCs) ineight patients with reversible airway obstruction.

CHEST/113/5/MAY, 1998 1275

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with salmeterol should not represent a significantrisk for subjects with no preexistent cardiovascularalteration. However, further long-term studies are

still needed to confirm our preliminary findingsconcerning salmeterol safety.

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DOI 10.1378/chest.113.5.1272 1998;113; 1272-1276Chest

Salvatore Durante and Gennarino BorrelloCarmelindo M.E. Tranfa, Girolamo Pelaia, Rosa D. Grembiale, Saverio Naty,

Short-term Cardiovascular Effects of Salmeterol

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