Erectile dysfunction in essential arterial hypertension and effects of sildenafil: results of a Spanish national study

AJH

2004; 17:139 –145

Erectile Dysfunction in Essential Arterial Hypertension and Effects of Sildenafil: Results of a Spanish National Study Pedro Aranda, Luis M. Ruilope, Carlos Calvo, Manuel Luque, Antonio Coca, and A´ ngel Gil De Miguel, for the Sildenafil Study Group Background: The aim of this study was to establish the prevalence of erectile dysfunction (ED) in hypertensive patients in specialized care hypertension units (SCHUs) and to assess the effectiveness and tolerability of sildenafil treatment. Methods: This was a multicenter, prospective, open, observational pharmacoepidemiology study conducted in 25 Spanish SCHUs. A total of 2130 men with essential hypertension under treatment were recruited. In a second phase, 291 subjects with a score ⱕ 21 in the Sexual Health Inventory for Men (SHIM) received sildenafil (50 mg/day) as required 30 to 60 minutes before sexual activity, and were evaluated by the International Index of Erectile Function (IIEF). Results: A total of 975 subjects (45.8%) had a score ⱕ 21 in the SHIM. In the second phase, sildenafil improved the score in the erectile function domain in 232 patients (83.2%). Severity of ED significantly improved (P ⬍ .001); severe (22.3% to 7.7%), moderate (23% to 5.6%),

A

and mild impairment (36.3% to 44.8%). The IIEF was normalized in 39.1% of patients who completed posttreatment IIEF. In all, 33 subjects (11.8%) failed to complete the study: two (0.7%) because of lack of efficacy, two (0.7%) intercurrent disease, 10 (3.6%) failure to return to the visits, three (1.1%) fear of therapy, four (1.4%) adverse effects requiring treatment discontinuation, and 12 (4.3%) protocol violations. No statistically significant association was found between the prevalence of adverse effects and antihypertensive treatment with single drug or combination therapy. Conclusions: A high incidence of ED was found in hypertensive patients from Spanish SCHUs. Sildenafil showed an excellent response and safety profile. Am J Hypertens 2004;17:139 –145 © 2004 American Journal of Hypertension, Ltd. Key Words: Sildenafil, hypertension, erectile dysfunction, prevalence, adverse effects.

rterial hypertension (HT) is the most relevant modifiable risk factor because of its high prevalence and significant contribution to cardiovascular morbidity and mortality.1 Although the different groups of antihypertensive drugs similarly lower blood pressure (BP),2 the choice of drug should contemplate not only antihypertensive efficacy and the capacity to counter cardiovascular and target organ damage, but also other factors that contribute to improve treatment compliance and quality of life in hypertensive patients. Erectile dysfunction (ED) is often found in hypertensive men, either as a result of atherosclerotic involvement

of the penile vessels and endothelial dysfunction secondary to HT and other risk factors associated to neurovegetative changes caused by HT-related conditions (diabetes mellitus), or because of side effects of the antihypertensive medication.3,4 In fact, ED may be a health marker in men ⬎40 years of age, facilitating the detection of undiagnosed underlying diseases.5 The results of the EDEM study suggested a prevalence of ED in the general population of 18.9%, as assessed by the erectile function domain of the International Index of Erectile Function (IIEF).6 Furthermore, some studies conducted in our setting reported a high prevalence of ED in patients with controlled HT (46.5%),

Received July 2, 2003. First decision August 5, 2003. Accepted September 5, 2003. From the Hospital Carlos Haya (PA), Ma´laga, Spain; Hospital 12 de Octubre (LMR), Madrid, Spain; Hospital General de Galicia (CC), Santiago de Compostela, Spain; Hospital Clı´nico San Carlos (ML), Madrid, Spain; Hospital Clinic i Provincial (AC), Barcelona, Spain; and Universidad Rey Juan Carlos (AGM), Madrid, Spain.

Supported by a grant from Pfizer Laboratories, Madrid, Spain. A complete list of participants in the Sildenafil Study Group is given in the Appendix. ´ ngel Gil de Miguel, Address correspondence and reprint requests to Dr. A Teaching and Research Unit, Rey Juan Carlos University, Preventive Medicine and Public Health Area, Health Sciences Department, Avda. De Atenas s/n, Alcorcon, Madrid 28922, Spain; e-mail: [email protected]

© 2004 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.

0895-7061/04/$30.00 doi:10.1016/j.amjhyper.2003.09.006

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although these studies were based on a sample of only 512 patients in the primary care setting.7 Sildenafil is the first of a new class of drugs shown to be active via the oral route for treating ED. It has been tested in hypertensive patients either not treated or treated with multiple antihypertensive drug therapies, with excellent clinical results and a good safety profile.8 –10 Therefore, this study was designed to evaluate the prevalence of ED in a large population of hypertensive men seen in specialized care hypertension units (SCHUs), and to assess the effectiveness and tolerability of sildenafil for the treatment of ED under conditions of routine clinical practice.

Methods A multicenter, prospective, open, noncomparative, noninterventional, observational pharmacoepidemiologic study was conducted in 25 Spanish SCHUs (annex I). Centers were included from all Spanish regions to ensure a patient sample representative of the overall Spanish population because the prevalence of ED is not homogeneous in the different regions. Study Population A total of 2130 men with primary hypertension (HT) receiving antihypertensive treatment were recruited during the study. This sample size ensured adequate statistical power for the two primary objectives of the study with a maximal confidence level of 98% and an ␣ error of 0.001; the final number of subjects was increased 25% to compensate for losses to follow-up. A first phase was intended to establish the prevalence of ED in the hypertensive male population treated in SCHUs. For this, the Sexual Health Inventory for Men (SHIM) was used.4,11 The SHIM is an abbreviated version of the International Index of Erectile Function (IIEF) including questions 2, 4, 5, 7, and 15 of the latter. It is used for its simplicity as a screening instrument in the clinical setting. An overall score of ⬍21 points defines a patient with signs of ED (sensitivity 0.98; specificity 0.88; positive predictive value 0.89; negative predictive value 0.95; ␬ index 0.85; for a 95% confidence interval).11 In a second phase, patients with SHIM scores of ⬍ 21 were invited to start treatment with sildenafil. The inclusion criteria in this second phase included having a stable partner, a SHIM score of ⬍21, age ⬎18 years, current treatment with 1, 2 or 3 antihypertensive drugs, and systolic and diastolic BP values of ⬍160 and 100 mm Hg, respectively. Patients with anatomic deformities of the penis were excluded, as were those receiving treatment with nitrites or nitric oxide donors, allergy to sildenafil or to any other component of the medicinal product, a history of retinitis pigmentosa, patients receiving previous medication for ED who were not willing to discontinue it during the study, patients in whom sexual activity was clinically not advisable because of unstable

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angina, uncontrolled severe heart failure, hypotension (systolic and diastolic BP values of ⬍90 and 50 mm Hg, respectively), or a recent history (⬍3 months) of stroke or acute myocardial infarction. All patients were studied according to a protocol including age, height, weight, and duration of ED. A complete clinical history was recorded, including sexual history, a physical examination, concomitant diagnoses and treatments, and the active ingredients and daily doses of their antihypertensive medication. The patients received sildenafil at an initial dose of 50 mg/day, as required, 30 to 60 min before sexual activity, and with a maximum recommended administration frequency of once every 24 hours. The patients remained in the study until sufficient time had elapsed to ensure the administration of 3 to 4 doses. The first two doses should be of 50 mg/day, and the patients continued with the same dose if they considered the treatment to be effective. If treatment was considered ineffective, the patient could increase the dose to 100 mg/day. Therapeutic response was evaluated by the IIEF12 before and after treatment. The IIEF consists of 15 questions grouped into five domains that assess erectile function (questions 1 to 5 and 15), satisfaction with intercourse (questions 6 to 8), orgasmic function (questions 9 and 10), sexual desire (questions 11 and 12), and overall satisfaction (questions 13 and 14). The overall score in the erectile function domain allows for classifying ED as severe (6 to 10 points), moderate (11 to 16 points), mild (17 to 25 points), or none (26 to 30 points). Treatment was considered effective when improvements were found in the erectile function domain and the patient responded affirmatively to the direct question: “Has sildenafil improved your erections? (yes/no)” regardless of the final dosage required by the patient. The patients were questioned about the administration dates, dosage, and the existence of possible adverse effects. In the event of such effects, their severity was recorded along with the resulting actions taken or consequences. To establish pre- and post-treatment statistical significance, Wilcoxon signed rank tests and McNemar’s test were used. All statistical tests were two-sided and were performed considering a maximal ␣ error of 5% (P ⬍ .05). The statistical analysis was carried out by the Preventive Medicine and Public Health Teaching and Research Unit of Rey Juan Carlos University (Madrid, Spain), using SPSS 10.0 software (SPSS Inc., Chicago, IL). Study performance and protocol were reported to the Spanish Medicines Agency, and each subject was included after written informed consent was obtained.

Results A total of 2130 patients with a mean age of 55.5 ⫾ 7.3 years (range 25 to 75 years) and a mean time since the diagnosis of HT of 8.8 ⫾ 4.2 years were recruited into the

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141

Table 1. Cardiovascular characteristics and therapeutic scheme Hypertensive Population (n ⴝ 2130) Cardiovascular Risk Factors n

Sildenafil Group (n ⴝ 291)

Cardiovascular Complications %

n

Type 2 DM Dyslipidemia

722 618

33.9 CHD 29 Stroke

234 56

Smoking Obesity

256 660

12 31

36 311

Heart failure* CRF†

Antihypertensive Drugs %

n

11 ACEI 2.5 AIIA Calcium channel 1.6 blockers 14.6 ␤-blockers ␣-blockers Diuretics

128 69 123 81 87 96

Antihypertensive Regimen % 44 One drug 23.7 Two drugs Three or more 42.3 drugs 27.8 29.9 33

% 32.7 35.9 31.3

ACEI ⫽ angiotensin converting enzyme inhibitor; AIIA ⫽ angiotensin II antagonists; CHD ⫽ coronary heart disease; CRF ⫽ chronic renal failure; DM ⫽ diabetes mellitus. * New York Heart Association II/III; † Moderate-Severe Chronic Renal Failure.

study. Table 1 lists the most frequently associated cardiovascular risk factors and complications found in these patients. A total of 975 patients (45.8%) had a SHIM score of ⱕ21. All patients were invited to start treatment with sildenafil; however, only 291 patients were finally included in the second study phase (29.8%), and the rest (n ⫽ 684; 70.2%) were not included despite SHIM scores of ⬍21. Of these individuals, 413 (60.5%) refused to participate in the second phase and 271 (39.5%) had some contraindication for sildenafil treatment (concomitant nitrate administration, heart failure, or severe multisystemic vascular impairment). The patients included in the second phase had a mean age of 57.3 ⫾ 8.8 years (21.1% were ⱖ65 years), a median SHIM score of 13 points (range 21), an average time with treated HT of 4.8 ⫾ 2.7 years, and a mean systolic and

diastolic arterial pressure of 147.5 ⫾ 12 and 88 ⫾ 6 mm Hg, respectively. Mean body mass index (BMI) was 28.4 ⫾ 3.7 kg/m2. The estimated mean duration of ED was 3.48 ⫾ 2.8 years. Table 1 shows the antihypertensive treatment and therapeutic regimen received by the patients. Twelve patients (4.1%) were excluded from the analysis on the grounds that they failed to complete the initial IIEF. The patients treated with sildenafil showed a median IIEF score of 37 (range 57). Of these, 45 patients (16.2%) acknowledged no attempt at sexual intercourse or activity in the 4 preceding weeks. In turn, 22.3%, 23.0%, and 36.3% had severe, moderate, and mild ED, respectively, whereas 2.2% showed no dysfunction in the erectile function domain of the IIEF (Fig. 1A). The distribution of ED according to age, BMI, the duration of HT subjected to treatment, the number of antihypertensive drugs, and the two most prevalent risk factors are shown in Table 2.

FIG. 1. Erectile dysfunction (ED) severity (A) and median scores for IIEF and its domains (B) before and after treatment. *P ⬍ .001).

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Table 2. IIEF score distribution before and after treatment IIEF Before Treatment Characteristic Age (yr) ⬍45 45–54 55–64 ⬎65 BMI (kg/m2) ⬍26 26–30 ⬎30 Duration of HT under treatment (yr) 0–2 3–5 ⬎6 Antihypertensive drugs One Two Three or more Diabetes No Yes Dyslipidemia No Yes Total

<25 points

IIEF After Treatment

McNemar
s Test P

>25 points

<25 points

>25 points

95.2% 98.8% 98.2% 98.3%

4.8% 1.2% 1.8% 1.7%

55.6% 54.4% 59.8% 75%

44.4% 45.6% 40.2% 25%

⬍ ⬍ ⬍ ⬍

100% 97.3% 96.7%

0% 2.7% 3.3%

67.7% 59.2% 56.6%

32.3% 40.8% 43.4%

⬍ .001 ⬍ .001 ⬍ .001

97.1% 100% 98.5%

2.9% 0% 1.5%

55.6% 61% 67.2%

44.4% 39% 32.8%

⬍ .001 ⬍ .001 ⬍ .001

97.8% 99% 96.5%

2.2% 1% 3.5%

64.9% 58.4% 61%

35.1% 41.6% 39%

⬍ .001 ⬍ .001 ⬍ .001

97.9% 97.4%

2.1% 2.6%

59.1% 72.7%

40.9% 27.3%

⬍ .001 ⬍ .01

98.2% 96.1% 97.8%

1.8% 3.9% 2.2%

62.1% 55.6% 60.9%

37.9% 44.4% 39.1%

⬍ .001 ⬍ .001 ⬍ .001

.05 .001 .001 .001

BMI ⫽ body mass index; HT ⫽ Hypertension; IIEF ⫽ International Index of Erectile Function.

All patients started treatment with a dose of 50 mg. This dose could be increased to 100 mg if considered appropriate, as was decided by 59 patients (21.1%). In all, 33 patients (11.8%) failed to complete the study. Two patients (0.7%) withdrew from the study because of lack of efficacy and two (0.7%) because of intercurrent disease. Ten patients (3.6%) did not return to the follow-up visits. Three patients (1.1%) withdrew from the study because of fear of treatment, four (1.4%) because of adverse effects requiring sildenafil discontinuation, and 12 (4.3%) because of protocol violations. The median IIEF score after treatment was 60 (range 70), with a significant improvement compared to the pretreatment score (P ⬍ .001); a median increase of 19 points was recorded (range 70). Sildenafil treatment improved the score in the erectile function domain in 232 patients (83.2%). The median erectile function score increased from 14 points (range 27) to 24 points (range 29) (P ⬍ .001). Similarly, in relation to questions 3 and 4 of the erectile function domain of the IIEF, improvements in score were recorded in 69.2% and 76% of the patients, respectively. The severity of ED improved significantly (P ⬍ .001) after treatment, with a reduction in the percentage of hypertensive patients with severe (from 22.3% to 7.7%), moderate (23% to 5.6%), and mild ED (36.3% to 44.8%), and with IIEF normalization in 39.1% of hypertensive patients who completed the post-treatment IIEF (Fig. 1A).

In contrast, 81.7% of the patients answered affirmatively to a direct question about improvement in erectile function in relation to treatment. The efficacy of sildenafil for improving erectile function could be determined only in the 237 patients who fully completed the erectile function domain of the IIEF and who answered the direct question regarding improved erectile function in relation to treatment. Of these subjects, 208 (87.8%) gave an affirmative answer to this question and also showed a score increase in this domain (74.6% of all recruited patients). The efficacy of sildenafil was significantly lower in patients with a high BMI, reaching 93.5% in patients with BMI ⬍26 kg/m2, 89.5% in those with BMI 26 to 30 kg/m2, and 76.5% in patients with BMI ⬎30 kg/m2 (P ⬍ .05). No significant differences were found between sildenafil efficacy and the use of one, two, or more antihypertensive drugs. Orgasmic function (questions 9 and 10 of the IIEF) improved significantly (P ⬍ .001), with a median of 5.5 (range 10) to 8 (range 10). Similar considerations applied to satisfaction with intercourse (questions 6, 7 and 8 of the IIEF) and sexual desire (questions 11 and 12 of the IIEF), for which median scores increased from 7 (range 13) to 11 (range 15), and from 6 (range 8) to 7 (range 8), respectively (P ⬍ .001). Finally, overall satisfaction (questions 13 and 14 of the IIEF) also improved significantly (P ⬍

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143

Table 3. Frequency and severity of adverse effects of sildenafil treatment (n ⫽ 291) Adverse Effect

n

%

Mild

Moderate

Headache Flushing Tachycardia Nasal congestion Diarrhea Dysuria Chest pain

11 3 2 1 1 1 1

3.8 1.0 0.7 0.3 0.3 0.3 0.3

3 1 2 1 1 1

8

.001) from a median score of 5 (range 8) to 8 (range 8) (Fig. 1B). Finally, 16 patients (5.5%) experienced side effects, with a predominance of headache (n ⫽ 11; 3.8%) and flushing (n ⫽ 3; 1%), tachycardia (n ⫽ 2; 0.7%), nasal congestion (n ⫽ 1; 0.3%), chest pain (n ⫽ 1; 0.3%), diarrhea (n ⫽ 1; 0.3%), and dysuria (n ⫽ 1; 0.3%). The severity of side effects is shown in Table 3. Four patients withdrew from the study because of adverse effects: two for moderate headache, and one each for moderate headache and severe flushing, and mild tachycardia. No statistically significant association was found between the prevalence of the side effect and single drug or combination antihypertensive treatment.

Discussion The study results show a high prevalence of ED (45.8%), representative of the Spanish male population with hypertension.1 This is not surprising if one considers that apart from age (mean 55.5 ⫾ 7.3 years), other cardiovascular risk factors frequently associated with HT also contribute to ED, such as diabetes, dyslipidemia, or smoking13 (Table 1). A negative effect is also exerted by certain antihypertensive drug groups2– 4,14 and by changes in atherosclerosis progression induced by HT.15 Moreover, the fact that these patients are evaluated in a SCHU should also be taken into account. The 279 patients treated with sildenafil were significantly older on average than the overall hypertensive population surveyed (57.3 ⫾ 8.8 v 55.5 ⫾ 7.3 years) (P ⬍ .001), and 59 patients (21.1%) were ⬎ 65 years of age. They also had a significantly lower median SHIM score, 13 v 15 points (P ⬍ .001), which could suggest an increased severity of ED. In contrast, the prevalence of cardiovascular risk factors and of cardiovascular and cerebrovascular complications was greater in the overall sample (Table 1); such increased risk could have represented a contraindication to inclusion of many of the patients in the study. In percentage terms, the use of antihypertensive drugs in these patients differs from that seen in the general Spanish population with hypertension. The two main reasons for this could possibly be the fact that a vast majority of these patients are taking two or more antihypertensive

Severe 1

1

drugs (Table 1), and that these patients faithfully reproduce the percentage use of such drugs in SCHUs. Among patients who considered sildenafil to be effective, the majority (79.6%) used the 50-mg dose of sildenafil. In 20.4% of patients the dose had to be increased to 100 mg (except one patient who required 75 mg) to achieve treatment benefit. As mentioned elsewhere,8,16,17 no significant reductions in BP were seen, and no changes were required in the dose or number of antihypertensive agents used in any of the patients. Likewise, sildenafil was seen to be equally effective, regardless of the type of antihypertensive agent or the need for antihypertensive treatment with one or multiple drugs.9,18 –20 All IIEF dimensions improved significantly after sildenafil treatment (Fig. 1B). Erectile dysfunction and its severity improved significantly. A substantial reduction was recorded in the percentages of patients with severe or moderate ED, with a significant increase in the proportion of individuals with no ED according to the IIEF scores (Fig. 1A). This high percentage of IIEF normalization should also be analyzed taking into account that in 101 patients, ED severity was less than in the rest of the patients at the start. In any case, the results obtained can be considered very positive for the vast majority of the patients. These findings have been supported by another placebo-controlled study performed by Mancia et al,21 in which 568 hypertensive patients with ED taking two or more antihypertensive drugs responded to sildenafil after 6 weeks of treatment with a significant improvement in erectile function and satisfaction with intercourse, in the opinion of both the patients and their partners. Finally, as reported in other studies,18,21,22 clinical tolerability was good, with side effects in only 5.7% of cases, and treatment discontinuation due to this cause in only four patients. In this same line, Baumann and Burkart10 recently reported that sildenafil was well tolerated in hypertensive patients on combined antihypertensive treatment, based on the analysis of 35 clinical trials including ⬎8000 patients. In our study there were no cardiovascular events in either the overall sample or in the 18 patients (6.18%) diagnosed with ischemic heart disease. Although sexual intercourse may slightly increase the risk of an ischemic

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cardiac event,23 current evidence suggests that sildenafil does not increase cardiovascular risk in certain groups of patients with cardiovascular disease, and an algorithm has been proposed as an aid to decision making in the treatment of ED among patients with cardiovascular disease.24,25 In these patients, the risk of myocardial infarction or unstable angina does not seem to increase with sildenafil treatment.22,26 –28 In a recent study involving 23 patients with clinically stable congestive heart failure, sildenafil was considered to improve exercise capacity, reducing heart rate and probably improving O2 consumption.29 Sildenafil could also have an effect by dilating epicardial coronary arteries,as well as improving endothelial dysfunction and inhibiting platelet activation, as deduced from the results reported by Halcox et al30 for a sample of 24 patients with clinically stable coronary disease who received a single 100-mg dose. In conclusion, data from this study show a high prevalence of ED in the Spanish hypertensive population, and an excellent therapeutic response and clinical safety with sildenafil treatment in these patients.

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Murcia); Rodrı´guez Pe´ rez, Jose´ Carlos (H. Ntra. Sra. del Pino, Las Palmas); Rodrı´guez Rodrı´guez, Javier (H. Gregorio Maran˜ o´ n, Madrid); Romero, Ramo´ n (H. Can Ruti, Badalona); Rubio Clemente, Felipe (H. Clı´nico de Salamanca, Res. Virgen de la Vera); Ruilope, Luis Miguel (H. 12 de Octubre, Madrid); San Roma´ n Montero, Jesu´ s Ma (Universidad Rey Juan Carlos, Madrid); Sa´ enz de Castro, Saturnino (H. Marque´ s de Valdecilla, Santander); Servicio de Nefrologı´a (H. de Cruces, Bilbao); Sulima´ n Jarabe, Nataji (H. Clı´nico, Valladolid); Torres Carballada, Alberto (H. La Paz, Madrid); Tovar, Jose´ L. (H. Vall d’Hebro´ n, Barcelona); Villatoro Ferres, Juan (H. General, Castello´ n).

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2.

Appendix: Sildenafil Study Group Sponsor: Spanish Society of Hypertension—Spanish League Against Arterial Hypertension (SEH-LELHA). Participants: Aranda, Pedro (H. Carlos Haya, Ma´ laga); Calvo Go´ mez, Carlos (H. General de Galicia); Cardenete, Francisco (H. Puerta del Mar, Ca´ diz); Coca, Antonio (H. Clinic i Provincial, Barcelona); Courel Barrio, Miguel (Hospital Xeral, Vigo); Ferna´ ndez Andrade, Carlos (H. Virgen del Rocı´o, Sevilla); Ferna´ ndez Vega, Francisco (H. Central de Asturias); Ferna´ ndez Giraldiz, Elvira (H. Arnau Vilanova, Le´ rida); Gil de Miguel, Angel (Universidad Rey Juan Carlos, Madrid); Godoy Rocati, Diego (H. General, Valencia); Gonza´ lez Cruz-Cervellera, Alfonso (H. General, Valencia); Lo´ pez Vidriero, Emilio (H. Gregorio Maran˜ o´ n, Madrid); Luque Otero, Manuel (H. Clı´nico Universitario San Carlos, Madrid); Maceira Cruz, Benito (H General, Sta. Cruz de Tenerife); Marco Franco, Julio E. (H. Son Dureta, Palma de Mallorca); Martı´nez, Isabel (H. De Galdakano); Martı´nez Ameno´ s, (H. de Bellvitge, Barcelona); Mora Macia` (Fundacio´ n Puigvert, Barcelona); Nieto Iglesias, Javier (H. Ntra. Sra. de Alarcos, Ciudad Real); Olivar, Josefina (H. Virgen de la Macarena, Sevilla); Olivares Martı´n, Jesu´ s (H. General, Alicante); Palacios, Gema (Unidad Me´ dica—Pfizer, Madrid); Pe´ rez Ben˜ asco, Vicente (Hospital Princesa de Espan˜ a, Jae´ n); Plana, Jaume (H. Comarcal de los Camilos, San Pedro de Rivas, Barcelona); Redo´ n, Jose´ (H. Clı´nico, Valencia); Rejas, Javier (Unidad Me´ dica–Pfizer, Madrid); Rivera Guzma´ n, Francisco Javier (Hospital Provincial, Co´ rdoba); Robles Pe´ rez, Roberto (H. Infanta Cristina, Badajoz); Rodicio, Jose´ Luis (H. 12 de Octubre, Madrid); Rodrı´guez Girone´ s Lausı´n, Manuel (H. Virgen de la Arrixaca,

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