Long-Term Effects of Indapamide: Final Results of a Two-Year Italian Multicenter Study in Systemic Hypertension

Long-Term Effects of Indapamide: Final Results of a Two-Year Italian Multicenter Study in Systemic Hypertension Gastone Leonetti, MD, Alessandro Rappelli, MD, Antonio Salvetti, MD, and Luigi Scapellato, MD

To evaluate the antihypertensive efficacy and tderability of a low-dose diuretic, indapamide, 2.5 mg once daily, was given to 246 patients with uncomplicated, mild to moderate hypertension for a period of 24 months. Blood pressure during sitting was l~~l/l~~lmmHg(meanfotandanl~ of the mean) at the end of the placebo tun-in period

and143f1~fland140~1/85flmmHg after 2 and 24 months, respectiveb heart rate was clhdcally unmodified (from 77 f 1 to 75 l 1 beats/ min). Total cholesterol, high-den&y cholesterol and serum triglycerides were unchanged, and uric acid increased significantly (from 262.0 f 6.5 to 377.7 f 56.5 mdjiter). A mild reduction in mm potassium (-0.36 f 0.03 mmoVliier) was observed after 2 and 6 months of therapy; however, the degree of reduction appeared to be lower than that from reported studies with other thiazide diiretics. The hncbnce of hypdcalemii (serum potassium <3.S mmol/llter) was highest in northem Italy (17%), intermediate in the central region (14%) and lowest in southern Italy (2%), although the absolute reduction in serum potassium was similar in all the geographic areas. Blood glucose tolerance was unchanged despite the changes in serum potasshan. The tolerability was good on the whole, with a tendency toward an improvement in the well-bdng of patients, most of whom were already asymptomatic before starting the study. (Am JCardiol1990;65~7H-71H)

I

n a previous publication,’ we have reported the preliminary results on tolerability and well-being of patients with mild to moderate hypertension during 1 year of treatment with indapamide. Since then, we have completed the study, which was scheduledfor a 2-year period, and this report presents the final results. The longer duration of the study allows for a better evaluation of the time courseof the antihypertensive efficacy of this agent and its impact on serum electrolytes, lipoproteins, and blood sugar tolerance as well as subjectivetolerability. It is generally acceptedthat untreated arterial hypertension is one of the major cardiovascular risk factors,2*3 and if blood pressure reduction is achieved there is a significant decreasein many, but not all, cardiovascular events,as shown in epidemiologic trials of the Veterans Administration Study,4 Australian Study,5 Medical ResearchStudy6and the EuropeanStudy in Elderly Hypertensives.’The minor reductions in coronary heart events in contrast to thosein cerebrovascularand renal eventsor congestiveheart failure havebeenhypothesizedto be due to changesin lipoproteins (an increasein total cholesterol, low-density lipoproteins and triglycerides, and a decrease in high-density lipoproteins [HDL]), serum electrolytes (a decreasein serumpotassiumand probably serummagnesium), and finally a reduced blood glucosetolerance. Thesemetabolic changesare mainly, or almost exclusively, associatedwith the use of thiazide diuretics.8*9This Italian multicenter study was performed with indapamide, a diuretic agent which alone or in combination has been shown to be equivalent to other antihypertensive agents.l”+l’ Indapamide was selectedbecauseof its pharmacokinetic characteristics (only 5% of the drug is excreted in the urine), l2 higher concentration at the vascular wa11,12 and pharmacodynamic properties (increased production of renal prostaglandin)’ 3 that reduce blood pressurewith minimal diuretic activity. METHODS

This Italian multicenter study (31 centers) followed up patients over a 2-year period. Three hundred forty-two patients of both genders,age range 19 to 77 years (mean f standard error of the mean 50.32 f 0.52), and a sitting diastolic blood pressurebetween95 and 115mm Hg after From the Istituto di Clmica Medica Generale e Terapia Medica, Uni- a l-month placeborun-in period, and with no contraindiversiti di Milano; Istituto di Patologia Medica e Metodologia Clinica., cations to the useof diuretics or 0 blockers,were admitted Universiti di Ancona; Cattcdra di Terapia Medica.Sistematica.,Clinica to the study and receiveda single daily administration of Medica I, Universiti di Pisa; and Divisione Medicina e Centro per lo indapamide, 2.5 mg. If, after 1 month of indapamide Studio e Terapia Ipertensione,OspedaleUmberto I, Siracusa,Italy. Address for reprints: ProfessorGastoneLeonetti, MD, Centro Fi- treatment, the sitting diastolic blood pressure was resiologia Clmica e Ipertensione,Via F. Sforza 35, 20122Milano, Italy. duced L5 mm Hg, patients continued to receiveindapaTHE AMERICAN JOURNAL OF CARDIOLOGY MAY 2. 1990

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A SYMPOSIUM:

INDAPAMIDE

AND ANTIHYPERTENSIVE

STRATEGY

K+

TABLE I Questionnaire Evaluating the Incidence and Severity of Adverse Effects and Well-Being Self Evaluation Mood Physical activity Physrcal health Alertness Checklist of 19 Items

mEq/l

By visual scale

Possible answers Sadness Headache Sweating Cough Nasal obstruction Shortness of breath Cold extremities Dizziness Intestinaldysfunction Sleep dysfunction Skin rashes Unsteadiness Tiredness Faintness Nocturia Sexual activity Physical activity Feeling unwell Nausea

Often/rarely/never

- 1.0 J

Yes/No

6th

12th

18th

24th month

FIGURE 1. Sitting blood pressure (BP) during indapamide, 2.5 moddherapyforMmonthsinpatientswith mg-daay, mild to moderate hypwknsion. Values are express4 as mean f standard error of ths mean. Open bar, pretreatme slashed bar, dwing active treatment. All reductions ars statisticany signltlcant (**p
I 12th 15 %

24th month 11 %

scis&9,moanmeanstandardolrorofthomoan-vsprotroy **p
:W p < 0.01 active vs. basal

68H

I 6th

FIGURE 2. Serum potassium &ring indapamide, 2.5 mg once daily, monotherapy for 24 months in hypertensive patients. Vabes are expreswd as means f standard errw of the mean. @on bar, protroatmsnt; slashod bar, during active treatment; doffed ho, lowor value of normal range; bars Mow the ab

BP mmHg

2nd

I 2nd

K+ < 3.5 mEq/l ::;::: p < 0.01 acttve vs. basal

mide therapy for a further period of 1 month (responders), whereasthe other patients were withdrawn from the study (nonresponders).If the diastolic blood pressurein the responderswas still >95 mm Hg after 2 months of indapamide therapy, 100 mg of atenolol was added, whereasthe patients with a diastolic blood pressure<95 mm Hg continued to receiveonly indapamide. The blood pressurewas measuredwith a mercury sphygmomanometer after 5 minutes of rest in the seatedposition: systolic blood pressure was measured at the start and diastolic blood pressure was measured at the end (phase V) of Korotkoff sounds.The blood pressureregisteredwas the averageof 3 measurementstaken at 2- to 3-minute inter-

basal

I basal

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vals. The incidence of adverseeffects and the evaluation of well-being were investigated by means of a checklist and a self-administeredquestionnaire (Table I). The patients were seenmonthly during the first 6 months of the study and at 3-month intervals thereafter in the outpatient department. Blood pressure,heart rate, body weight, physical wellbeing,and the items on the checklist and the self-administered questionnairewerecheckedduring eachvisit. Laboratory tests (hematocrit, red and white blood cell counts, serum sodium,potassium,creatinine, uric acid, total cholesterol, high-density cholesterol, triglycerides, fasting and postprandial glucose,transaminases,alkaline phosphatase) and urinalysis were performed before and 2, 6, 12, 18 and 24 months after indapamide treatment. Of the 397 patients admitted to the run-in period, 342 satisfied the admission criteria and 248 of them (72%) had a diastolic blood pressure<95 mm Hg and a reduction >5 mm Hg after 2 months of monotherapy with indapamide. The results obtained in this group treated with indapamide alone for a 2-year period are reported. Statistical analysis: A 2-way analysis of variance (time, patients) wasused.For modal variables, the Friedman or a Cochran testswereused.The statistical calculation was doneon a VAX 785 (Digital Equipment Corporation). RESULTS Population: Of the 342 patients admitted to the study at the end of the run-in period who receivedindapamide, 2.5 mg once daily, as monotherapy for 2 months, 248 (72%) were responders(i.e., sitting diastolic blood pressure <95 mm Hg with a reduction of 15 mm Hg after treatment) and continued with the monotherapyregimen for the duration of the study. Forty-three patients (13%)

K’ mEq” + 5.0

NORTH

CENTER

SOUTH

1

4.0 3.0 2.0

1 .o 0

- 1.0 J basal 24th

J

basal

17%

24th

- basal 24th month

14%

K’ < 3.5 mEq/l :w p < 0.01 active

2%

vs. basal

FlGURE3.Sennnpotadumkfondaffer~monU1saf i-i, 2.5 mg ollca daily, mosdher*yinthe3subSaathem it&y). Vabes 8re exgroup,(-,-dd lJhldaderlwefthemean.opcnb8~ pressedasmeanf ~;8&sbedb8~after24~d8ttedtim, lower due ef nemd hItereduc6mvsn.

r-e;

bars befow tbe abscissa,

abso-

had a reduction in diastolic blood pressure >5 mm Hg but the diastolic valueswere still >95 mm Hg, and therefore thesepatients receivedatenolollO0 mg in association with indapamide during the follow-up. Forty-five patients (13%) were nonrespondersand were discharged from the study, and 6 patients withdrew (5 were lost to follow-up and 1 patient died of a causeunrelated to hypertension and its treatment). Of the 248 patients who receivedindapamide, 2.5 mg monotherapy, 186 (75% of the respondersafter 2 months or 54% of the whole population admitted to the study) completed the 24 months of treatment. Of the 62 withdrawals, 54 were lost to follow-up, 3 had hypokalemia necessitatingwithdrawal, and another 5 discontinued for reasonsunrelated to the study. Blood pressure and heart rate: Pretreatment sitting blood pressureof the 248 patients who were treated with indapamide, 2.5 mg monotherapy, for the duration of the study was 165 f l/ 105 f 1 mm Hg (mean f standard error of the mean). This showed no difference from the blood pressureof the whole population who satisfied the

admissioncriteria at the end of the run-in period: 163 f l/104 f 1 mm Hg. Blood pressurewas 143 f l/88 f 1 mm Hg and 140 f l/85 f 1 mm Hg after 2 and 24 months of treatment, respectively (p 0.77 mmol/liter for total cholesterol were found in 22 patients (11 patients had an increase and 11 a decrease).An increase or decrease >0.26 mmol/liter for HDL cholesterolwas observedin a few patients (4 and 5, respectively). Average serum triglycerideswere unchangedand again only a few patients had changesin either direction >0.22 mmol/liter. Blood glucose: Average fasting and postprandial blood sugarwereunmodified during long-term treatment

TABLE II Plasma Concentrations Lipoprotein Cholesterol Monotherapy

of Creatinine &mol/liter), Uric Acid @mol/liter), Sodium (mmol/liter), Total and High-Density Levels (mmol/liter). and Triglycerides (mmol/liter) Before and During 24 Months of lndapamide Months

Basal Creatinine Uric Acid Sodium Total cholesterol HDL cholesterol Triglycerides

2

80.44 f 0.88 292.05 f 6.54 139f 1

5.51 f 0.08 1.24 f 0.02 48fl

1.51 f 0.05 134f5

Values are mean f standard

6

12

82.21 f 0.88

82.21 f 0.88

377.69 f 56.51 139fl 5.61 f 0.10

322.97 f 5.91 138fl 5.61 f 0.08

1.21 47 1.52 135

f f f f

0.02 1 0.05 5

1.27 f 0.02 49 f 1 1.54 f 0.04 137f4

18

82.21 f 1.76 318.81 f 6.54 138i 1 5.58 f 0.08 1.27 49 1.59 141

f f f f

0.02 1 0.05 5

24

83.09 f 323.57 f 138f 5.51 f

1.76 6.54 1 0.08

82.81 f 0.88 317.62 f 5.35 138+1 5.53 f 0.08

1.24 f 0.02 48fl 1.59 f 0.04 141 f 4

1.27 f 0.02 49f 1 1.51 f 0.04 134f4

error of the mean.

THE AMERICAN JOURNAL OF CARDIOLOGY MAY 2. 1990

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Blood sugar mgldl 120

I1

100

Symptomatic

patients (n) 0 Placebo N 12th month n 24th month

m 80 s

m p _____-E-----G

-____+ _____a------Z

Postprandial

.z 60

Fasting

75 t 40 e 2 20

80 70

n ,

60 basal

2nd

6th

,

,

12th

18th

,

Headache

Vertigo Nausea Fatigue Unstea- Abdominal diness discomfort

24th month

FIGURE 5. Numbew of symptomatic

FIGURE 4. Fasting and posfprandial blood ghose behre and dwing 24 monfhs of hlapamida, 2.5 mg once daily, monothsrapy. Dashed line, fading; solid he, postprandial glucose. Vabssaroexpressdasmeanf standademwofthemean.

with indapamide (Fig. 4): only 2 patients had an increase and 2 a decreasein blood glucose >l.l 1 mmol/liter. Serum uric acid (Table II): Serum uric acid significantly increased during long-term indapamide therapy with a peak after 2 months of therapy (from 292.0 f 65 to 377.7 f 56.5) and lower values thereafter. Tolerabilii and well-being: The tolerability of indapamide treatment was evaluated by meansof a checklist including 19 items and a self-assessment questionnaireto evaluate mood, physical feeling, activity and alertness (Table I). In all, there wasan improvement,or no change, in the symptomsevaluated from the checklist during active treatment. The number of patients who complained of adverseeffects was lower during indapamide therapy than during the run-in period (Fig. 5). The physical wellbeing, assessedfrom 19 items of the checklist, was unchanged in 79%, improved in 15%and worsenedin 6%; the senseof well-being was unmodified in 64%,improved in 25% and worsened in 11%. Sexual function was unchangedin 88%and improved in almost all the remaining patients. The improvement was maximal during the first year of treatment; however,patients who werewithdrawn from the study or lost to follow-up were not included in the analysis and this may falsely improve the results. DISCUSSION

In this Italian multicenter study, we haveinvestigated the antihypertensive efficacy, the impact on serum electrolytes, lipoproteins and blood glucose tolerance, and finally the influence on well-being of indapamide, 2.5 mg oncedaily, as monotherapy. To achievethis aim, we have admitted to the study only patients with mild and moderate arterial hypertension (who representmost of the hypertensivepatients), and for ethical reasonsonly patients classified as responders(i.e., patients attaining a sitting diastolic blood pressure<95 mm Hg and a reduction >5 mm Hg after 2 months of therapy) were followed-up for 24 months. The antihypertensive efficacy of indapamide, 2.5 mg oncedaily, in our population of mild and moderatehypertensivepatients was satisfactory.After 2 months of treatment, 72% of the patients admitted to the study were classified as responders,according to the criteria of our 70H

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

patients for some of the mosthquenWyreqo&dadverseeffectsbefure(openhtrs) and after 12 (s&shed ims) and 24 monfhs (#Wed bars) of indapamido, 2.5 mg once daily, nlamhrapy.

study, and this result is in agreementwith that reportedin 2 other multicenter studies.14v’5 The percentage of respondersstill remains >60% if we select diastolic blood pressure<90 mm Hg as a more strict criterion for the definition of “responders.” The percentageof responders waslower at the end of the 24 months of therapy (54% of the whole population admitted to the study), but the difference between the values after 2 and 24 months is predominantly due to the fact that 54 patients werelost to follow-up. Although we do not know the specific reasons that induced thesepatients to abandonthe study, it seems unlikely that a treatment failure was the main cause, becauseblood pressurewas consistently reduced for the duration of the study in the patients defined asresponders after 2 months of therapy and regularly followed up thereafter (Fig. 1). The blood pressure reductions observedafter 2 and 24 months were -2O/-17 and -23/ -20 mm Hg, respectively. As expected,becauseof the pharmacodynamicaction of diuretics, indapamide causeda reduction in the serum potassiumlevel, which was0.34 f 0.03 mmol/liter in our patients, almost maximal after 2 months of treatment and only slightly greater thereafter. The reduction in serum potassiumduring long-term treatment with indapamide was lower than that reported with the other diuretics, apart from potassium-sparing agents. However, diuretics were previously prescribedat doseshigher than currently recommended.In our study, the final percentage of patients with serum potassiumlevels <3.5 mmol/ liter was 11%.Three patients were withdrawn becauseof a reduction in serumpotassiumlevelsconsidereddangerous by their physicians. In another patient the serum potassiumlevel was <3.0 mmol/liter. The significanceof the reduction in plasmapotassiumdiffered in the 3 different geographic areas of the country: The pretreatment averageplasma potassiumlevel was lowest in the northem part of Italy, intermediate in the central part, and highest in the southernpart of the country. Becauseof the different pretreatment levels,the sameaveragereduction in plasmapotassiumlevel resultedin a greater percentage of patients with a plasma potassium level <3.5 mmol/ liter in the northern part of Italy comparedwith the other regions. Also, the reduction in plasma potassium levels causedby indapamide was already evident and maximal

during the first 2 months of treatment, whereas no further significant reductions were found thereafter. The different levels of pretreatment plasma potassium are probably attributable to different dietary habits. Plasma sodium levels did not change significantly. In the present study, in accordance with other reports,r6.i7no significant changesoccurred in total cholesterol, HDL cholesterol and serum triglycerides. Mild changes in both directions were present in only a few patients. Conversely,there was an increasein the level of uric acid, which reached a maximum after 2 months of treatment and was slightly lower thereafter. Fasting and postprandial blood glucose levels were unchanged during treatment with indapamide and only minor and clinically irrelevant changeswere observedin a few patients. The absenceof significant changesin blood glucoseduring long-term treatment with indapamide is in agreementwith other studies in diabetic18J9and nondiabetic20,21hypertensive patients. The lack of diabetogenic effect of indapamide may possiblybe due to minor reduction in serum potassium or a protective action on carbohydrate metabolism resulting from the differencesin the molecular structure of indapamide comparedwith other diuretics (many oral antidiabetic agents have a common sulfonylurea structure). Although we cannot exclude that our data might be biased by a sequential effect, the tolerability and wellbeing of long-term monotherapy with indapamide, evaluated by a checklist of 19 items and self-assessmentof physical fitness,wasgood on the whole. In our population of patients with predominantly asymptomatic mild or moderate hypertension, there was no significant worsening and possibly a tendency toward an improvement of symptoms and a positive senseof well-being. In conclusion, our study with indapamide as monotherapy in hypertensive patients shows that blood pressure control wasobtained in 75%of the patients who were respondersto indapamide monotherapy after 2 months and were therefore eligible for the monotherapy followup of 24 months. This blood pressurecontrol is associated with (1) a good tolerance and a trend toward an improvement in well-being; and (2) a biochemical pattern characterized by a slight increasein uric acid, a mild decreasein plasma potassium, and no changesin serum lipids and glucose tolerance. REFERENCES 1. Leonetti G, Rappelli A, Salvetti A, Scapellato L. Tolerability and well-bemg with indapamide in the treatment of mild-moderate hypertension. Am J h4ed 1988:84:suppl 1 B:59-64. 2. Kannel WB, Dawber TR, Kagan A. Factors in the development of coronary heart disease: six year follow-up experience. Ann intern Med /961;55:33-60. 3. Kannel WB, Dawber TR. Hypertension cardiovascular disease: The Framingham study. In: Onesti G, Kim KE, Moyer JH, eds. Hypertension Mechanism and Management. New York: Grune & Stratton, 1973;93-110. 4. Veterans Administration Cooperative Study Group on Antihypertensive Agents: effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressure averaging 90 through I I4 mm Hg. JAMA 1970;2i3:1143-1152. 5. Australian Therapeutic Trial in Mild Hypertension: a live year controlled drug trial. Lancet 1980;1:126/-1267. 6. Medical Research Council Working Party on mild hypertension. Coronary heart disease in Medical Research Council trial of treatment of mild hypertension. Br Ham .J 1988;59:364-378.

7. Amery A, Brixko P, Clement D. De JF, Leonetti G. O’Malley K, Strasser M, Dollery C. Forette F, Hamdy R, Tuomilehto J, Williams B. Mortality Working Party on high blood pressure

Schaepdryver A, Fagard R, Forte J, Henry T, Birkenhager W, Bulpitt C, Dcruyttere Joossens JV. Lund-Johansen P, Petrie J, and morbidity results from the European in the elderly trial. Lancer /985;/:/349-

13.54. 8. Goldmann AI, Steele BW. Schnaper HW, Fitz AE, Frolich ED. Perry MH. Serum lipoproteins during chlorthalidone therapy. JAMA /980;244:169/-1695. 9. Ames RP. Hill P. Raised serum lipid concentration during diuretic treatment of hypertension: a study of predictive indexes. C/in Sri Mel Med 1978;55:3/ /s-3/4s. lO.Anavekar NA, Ludbrooke A, Louis WJ, Doyle AE. Evaluatmn of indapamide in the treatment of hypertension. J Cardiooasc Pharmacol 1979:1:389-394. 11. Houde M, Carriere S. Efficacy of indapamide in monotherapy or with betablocker in the treatment of moderate hypertension. C‘urr Med Res Opin

1983;8:suppl3:68-76. 12. Campbell DB. Taylor and metabolism

AR, Hopkins of indapamide: a review.

24. 13.

LeBel M, Grose JH, prostaglandin production

YW, Williams JRB. Pharmacokinetics Curr Med Rrs Opin 1977;5:supp/ 1:/3-

Belleau LJ, Langlois S. Effects of indapamide on renal in hypertensive patients. C‘urr Med Re.7 Opin 1983;

8:suppl 3:81-86. 14. Abbou CB. Efficacy

and tolerance of indapamide in essential hypertension. Curr Med Res Opin 1985:9:494-497. 15. Mimran A, Zambrowski JJ, Coppolani T. The antihypertensive action of indapamide: results of a French multicenter study of 218 ambulant patients. Postgrad Med J 1981:57:suppl 2:60-63. 16. Gerber A. Weidmann P, Bianchetti MG, Ferrier C, Laederach K. Mordasim R. Serum lipoproteins during treatment with the antihypertensive agent indapamide. Hypertension 1985:7:suppl 11:164-169. 17. Meyer-Sabellek W, Gotzen R, Heltr J, Arntz HR, Schulte KL. Serum lipoprotein levels during long term treatment with indapamide. Hypertmsiou

1985;7:suppl11:170-174. 18. Roux P, Court&s H. Blood mide in hypertensive 19. Osei T, Holland and glucdregulation

sugar regulation during treatment with indapadiabetics. Postgrad Med J 1981:57:suppl 2:70-72. G, Falko JH. Indapamide. Effectson apoprotein. lipoprotcm. in ambulatory diabetic patients. Arch Intern Med 1986.

146:1973-1977. 20. Ferrara LA,

Giumetti D, Fasano ML, Sore S, lannuzzi A. Strarrullo P. Mancini M. Once-a-day indapamide therapy in hypertension. Effects on the heart and peripheral arterial circulation. Jpn Heart J 1983:24:73/-737. 21. Royer RJ. Progress in the treatment of hypertension: a multlcentre study of indapamide in 442 patients. Cur Med Res Opin /977;5:supp/ /:/5/-156.

ADDITIONAL

PARTICIPANTS

The following is a list of those who participated in the Indapamide Italian Multicenter Study, with their respective cities or towns in parentheses:G. P. Benetti, M. Fossati,A. Castelnuovo(Merate); S. Boni, S. Cosentini, A. Meani (Cassanod’Adda); M. Lombardo, V. Colloca M. Reitani (Niguarda, Milano); G. Mariotti, C. All; (Cinisello Balsamo); C. Mazzola, M. Meregalli, M. Valsecchi (Casatenovo);A. Monteverde, P. Occhipinti, M. Minola (Carita, Novara); C. Pasotti, A. Capra, P. Gandolli (Voghera); E. Marras, M. G. Deledda (Oristano); M. Pittalis (Nuoro); M. Rimini, C. Fonnesu (Alghero); P. L. Cella, M. Lunardi (Barga); P. Innocenti, M. Iardella, P. Pambiaco(Carrara); A. Carnicelli, N. Giomi, R. Lenzi (Cecina); A. Bini, V. Mazzoni, S. Mainardi (Empoli); S. Ambrosoli, A. Caiaza, F. Ghisoni (Fidenza): P. D. Ricci, F. Ricci (Lucca); A. Pesola, G. Cosentino (Viareggio); L. Lucentini, M. Errico, M. Freda, F. Puzzolante (S. G. Rotondo); P. Saba,F. Giuntoli, A. Scalambrino (Pescia); G. Federigi, R. Pacini (Pistoia); E. Pallone, E. Ferrari, L. Rossi (Piombino); G. Pagni, R. Coretese (Sarzana); G.C. Saba (Seravezza); L. Papi, C. Sighieri, G. Caste110(Volterra); M. Lera, P. Locci (Camaiore); C. Del Prato, S. Gramenzi, N. Lecis (La Spezia); S. Bonaventura,C. Incontro (Lentini); F. Briguglio, E. Briguglio (Messina); I. Ottaviano, S. Burrafato (Ragusa); A. Pittera (Catania); V. Rosano,B. Milan0 (Vibo V.) THE AMERICAN JOURNAL OF CARDIOLOGY MAY 2, 1990

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