Continuation and effectiveness of tadalafil once daily during a 6-month observational study in erectile dysfunction: the EDATE study.

AIMS: This was the first observational study evaluating treatment continuation, effectiveness and tolerability of tadalafil 5 mg once daily (TAD-OaD) in patients who chose and paid for treatment of erectile dysfunction (ED) in routine clinical practice. METHODS: Men ≥ 18 years with ED, treated previously with phosphodiesterase type 5 (PDE5)-inhibitor on-demand (PRN) or treatment-naïve, were enrolled at 59 sites. For patients prescribed TAD-OaD at baseline (T1), change in erectile function (IIEF-EF and GAQ) was documented after 1-3 (T2) and 4-6 (T3) months. The primary outcome was the probability to switch/discontinue from TAD-OaD, estimated by Kaplan-Meier (KM) product-limit method. Changes in IIEF-EF were evaluated using a mixed model for repeated measures adjusting for patient baseline characteristics. RESULTS: Of 975 men enrolled (median age 56.8 years, 33.7% with previous PDE5-inhibitor use), 778 were prescribed TAD-OaD, 135 TAD-PRN and 62 sildenafil or vardenafil PRN. During the 6-month longitudinal observation, 107 patients (13.8% of 778) switched or discontinued TAD-OaD-treatment. KM-rates (95%CI) for continuing TAD-OaD at 2, 4 and 6 months were 94.0% (92.3, 95.7), 88.3% (85.9, 90.6) and 86.3% (83.7, 88.9), respectively. The 25th percentile of time to switch/discontinuation of TAD-OaD was estimated as 31.1 weeks (lower 95%CI 30.3 weeks). At T3, IIEF-EF scores had increased by 7.1 (LSmean; 95%CI 5.8, 8.5) points; 91.3% of patients reported improved erections. The most frequently reported AE was headache (10 patients; 1.3%); no new/unexpected safety signals were observed. CONCLUSION: Under routine conditions, and when patients were involved in treatment decision-making, more than 86% of men starting/switching to tadalafil once daily (OaD) at baseline continued tadalafil OaD treatment for ≥ 6 months.

Value of prolonged scrotal drainage after penile prosthesis implantation: a multicenter prospective nonrandomized pilot study.

We aimed to understand the risks and benefits of post-inflatable penile prosthesis (IPP) implantation drainage and optimal duration. Our patients were divided into 3 groups: Group 1 (n = 114) had no drain placed, Group 2 had a drain placed for 24 h (n = 114) and Group 3 had a drain placed for 72 h (n = 117). Postoperative scrotal hematoma and prosthesis infection rates were compared between the groups. The patients from Group 3 demonstrated a statistically significant lower incidence of hematoma on the 10th postoperative day: (n = 1, 0.9%) compared to Group 2: (n = 11, 9.6%) and Group 1: (n = 8, 7%), (p = 0.013). However, on the 3rd postoperative day, there was a statistically significant lower incidence of hematoma in both Groups 3 and 2: (0.9% and 6.1%, respectively) vs. Group 1: (11.4%), (p = 0.004). Hematoma rates followed the same group order after the first day of surgery: 1.7% (n = 2), 5.3% (n = 6), and 8.8% (n = 10), respectively, (p = 0.05). Five patients (4.4%) in Group 1 and four patients (3.5%) in Group 2 developed an IPP associated infection, opposed to only a single patient (0.85%) in Group 3, (p = 0.210). We concluded that prolonged scrotal drainage for 72 h after virgin IPP implantation significantly reduces hematoma and infection rates.

Genetic association study of the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms and the risk to develop erectile dysfunction in a German ED population.

Erectile dysfunction (ED) is often associated with cardiovascular disorders such as hypertension, coronary heart disease, hypercholesterolaemia and diabetes mellitus. The genotypes in the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms have been identified as genetic risk factors for cardiovascular disorders. The association between the genotypes in these polymorphisms and the risk to develop ED was analysed. In 455 German ED patients and 111 age-matched healthy controls genotyping in the candidate polymorphisms was performed after DNA extraction from whole blood. Association studies between the genotype distribution in the control group in comparison with the ED-group and age of onset of the disease as well as erectile response to intracorporal prostaglandin injection in dependence of candidate polymorphism genotype were performed using the SPSS-Software(R). Genotype distribution of the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms was similar in the ED population and the healthy control group. The age of onset of the disease as well as the erectile response to intracorporal prostaglandin injection was independent of the genotypes in the three candidate polymorphisms. In contrast to the previous studies in this analysis, the risk to develop ED is not influenced by the genotypes in the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms.

Physicians' attitudes towards androgen replacement therapy for male and female sexual dysfunction.

Androgen deficiency syndrome is a commonly diagnosed condition. The aim of this study was to investigate common clinical practices of specialists in the field of sexual medicine regarding androgen replacement treatment for men and women. Attendees of the 16th Annual Congress of the European Society of Sexual Medicine held in January 2014 in Istanbul, Turkey, were asked to participate in a survey during the congress days. A 24-item self-report, closed-question questionnaire was distributed. Three sections were accessed: sociodemographic data, professional background and personal practice patterns regarding androgen substitution in men and women. A total of 133 physicians (mean age 47 years; range 25-79) completed the survey. Responses were inconsistent regarding the lab tests used for primary evaluation of male androgen deficiency. The majority of participants (62%) recommended testosterone replacement therapy for symptomatic men with testosterone levels <8 nmol l(-1) (231 ng dl(-1)). Similarly, most physicians (88%) recognized a correlation between libido and testosterone levels in women. Only 42% and 53% reported they would prescribe testosterone to women with low libido, premenopausal and postmenopausal, respectively. This survey showed discrepancies among physicians regarding testosterone replacement therapy for men and women.

[Efficacy and tolerability of vardenafil within the time window of 6 hours after administration and beyond. Results of a clinical study carried out in 233 urological offices]. / Die Wirksamkeit und Verträglichkeit von Vardenafil im Zeitfenstervon sechs Stunden nach Einnahme und darüber hinaus. Ergebnisse einer klinischen Studie in 233 urologischen Praxen.

UNLABELLED: In the multicenter STEADY-(safety, tolerability, efficacy and impact on quality of life of vardenafil 10 mg in patients with erectile dysfunction)-study, 996 patients with erectile dysfunction were treated with vardenafil for a period of 12 weeks. The results within a time window of up to 6 hours post-administration and beyond (up to 12 hours) were evaluated. The effectiveness of vardenafil was analysed on the basis of the parameters Sexual Encounter Profile (SEP) 2 (vaginal penetration) and SEP3 (erection maintenance) as also the "erectile function score" and overall satisfaction. RESULTS: On the occasion of the first follow-up 4 weeks after the administration of vardenafil there was an appreciable improvement in all four parameters. Very high success rates were observed not only during the primarily investigated time window of 6 hours, but also beyond this (up to 12 hours). Satisfaction with sexual intercourse (SI) increased from 24.6% prior to treatment to 87.6% at the end of the 12-week treatment period. CONCLUSION: Under doctor's office conditions vardenafil was reliable and highly effective, already at the 10 mg dose, when the patients utilized its effect within a time window ranging from < 0.5 to 12 hours (tablet ingestion to SI). In addition, vardenafil was very well tolerated. Patient satisfaction with the treatment was reportedly very high.

Results from an online survey investigating ED patients' insights and treatment expectations.

Data suggest that the currently available therapies for erectile dysfunction (ED) do not meet all the patients' and their partners' expectations. The aim was to assess ED patients' treatment expectations for a variety of sex- and drug-related aspects such as importance of spontaneity, partner satisfaction, ideal onset of action and ideal duration of action. A total of n=1124 men with ED and n=410 healthy men, aged 30-75, participated in this online survey. The ED sample was further divided into patients currently undergoing treatment (CTG), patients who had been undergoing treatment in the past (PTG) and naïve patients (NG). The International Index of Erectile Function as well as a mix of study-specific questions was used. All groups considered 'maintaining an erection until the partner reaches orgasm' the most important aspect regarding erectile function. 'Being able to please the partner' was considered as the most important aspect for a fulfilled sex life. The majority of men (38.1%) further considered an onset of action of about 15 min to be desirable. In all, 95.9% further considered a duration of action up to 4 h to be desirable whereas approximately 71% of men considered a duration of more than 12 h to be too long. It seems that once the basic functional aspects related to erectile function have been covered, additional benefits such as 'spontaneity' and 'pleasing the partner' become important and may be critical for choosing the optimum individual treatment, to improve the sexual satisfaction and the adherence to the treatment.

Expression of nitric oxide-sensitive guanylyl cyclase subunits in human corpus cavernosum.

The muscles of the corpus cavernosum of the penis relax in response to stimulation of non-adrenergic, non-cholinergic nerves or nitric oxide (NO)-donating drugs to elicit erection. It is generally assumed that NO mediates this effect via activation of soluble guanylyl cyclase and a subsequent increase in cyclic guanosine 3', 5'-monophosphate concentration. However, there are no data on the expression of this enzyme in human corpus cavernosum. The purpose of the present study was the molecular characterization of NO-sensitive guanylyl cyclase in human corpus cavernosum. RNA was extracted from tissue samples obtained from seven patients undergoing penile prosthetic surgery or correction of penile deviation. Reverse transcriptase-polymerase chain reaction (RT-PCR) with specific primers for the subunits of NO-sensitive guanylyl cyclase was performed, and PCR products were subcloned and sequenced. Specific amplification products encoding the alpha(1), beta(1), alpha(2), and beta(2) subunits were detected. In addition, we isolated a transcript encoding a novel variant beta(2) subunit. To test whether this novel transcript arises by alternative splicing or whether it is encoded by a separate gene, a 4000-bp clone of the corresponding genomic DNA sequence was isolated. Sequence analysis suggests that the novel beta(2) variant arises by alternative splicing from the same gene as the beta(2) subunit on chromosome 13. In conclusion, our findings suggest the presence of different subunit mRNAs of NO-sensitive guanylyl cyclase in human corpus cavernosum.

One-year prophylactic efficacy and safety of pantoprazole in controlling gastro-oesophageal reflux symptoms in patients with healed reflux oesophagitis.

BACKGROUND: Pantoprazole is a benzimidazole derivative which selectively inhibits the proton pump H+. K+-ATPase necessary for the final step in gastric acid secretion. AIM: To investigate the tolerability and the prophylactic effect of pantoprazole 40 mg once daily on relapse in patients whose reflux oesophagitis had been healed. METHODS: The safety of pantoprazole 40 mg once daily was assessed in an open 1-year trial on 222 patients whose reflux oesophagitis had been healed with omeprazole or pantoprazole. Relapse was defined as endoscopically-confirmed reflux oesophagitis (at least Grade I), with endoscopies being performed for patients experiencing 3 consecutive days of disease-specific symptoms. RESULTS: Kaplan-Meier survival analysis at 6 and 12 months gave estimated treatment failure rates of 2% and 6% from confirmed relapses (per-protocol), and of 9% and 30% for a worst-case group (all withdrawals counted as failures). The only population shift in laboratory variables was a doubling of the median serum gastrin level over the first 6 months; thereafter it stabilized. Fifty-four (24%) patients experienced adverse events; 15 of these withdrew. Serious adverse events were reported for 12 patients. CONCLUSIONS: Pantoprazole appears to be highly effective and to have a good safety profile for long-term prophylaxis of reflux oesophagitis.

Presence of PGE1 binding determines the erectile response to PGE1.

The clinical benefit of PGE1 in erectile dysfunction in men is well proven, while other species including non-human primates show almost no response. The reason for that difference is still unclear. We examined PGE1 binding in human surgical material (n=27) and from transsexual surgery (n=7) as well as rhesus (n=10) and cynomolgus monkeys (n=8) corpus cavernosum tissue. Erection was judged after intracavernous injection of PGE1 in men (10 microg) and in monkeys (5 microg). Human corpus cavernosum shows high- (binding capacity 24.7+/-3.3 pmol/mg protein) and low-affinity (binding capacity 77.4+/-7.3 pmol/mg protein) PGE1 binding sites. Oestrogen (3 mg/day) for more than one month before transsexual surgery decreases receptor density significantly. In rhesus and cynomolgus monkeys no high-affinity binding could be detected, while they respond on PGE1 with slight tumescence only. These findings indicate a significant correlation between corpus cavernosum PGE1 receptor density and the erectile response.

Bulbocavernosus reflex latencies and somatosensory evoked potentials after pudendal nerve stimulation in the diagnosis of impotence.

The bulbocavernosus reflex (BCR) was examined in 39 normal potent men and in 252 patients with impaired potency of varying aetiology. For BCR evaluation minimum, maximum and mean latencies, the temporal dispersion in ten successive responses, together with minimum and maximum side differences from simultaneous recordings of the left and right bulbocavernosus muscles were determined. Pathological findings were detected in 125 patients. Somatosensory evoked potentials (SSEPs) recorded from the scalp after stimulation of the penile dorsal nerves and the terminal branches of the pudendal nerve were investigated in 30 controls and in 246 patients. An abnormal SSEP was found in 63 patients.

Current perspectives on intracavernosal pharmacotherapy for erectile dysfunction.

Thirty percent of males afflicted with erectile dysfunction (ED) do not respond to oral drugs, another 15% reveal contraindications to currently available therapy, and a subset of patients actually prefer injection therapy due to its predictable short time-to-onset of erection and reliable rigidity compared to oral drugs. This paper provides both a historical and current perspective on intracavernosal therapy and reviews the popular injectable therapeutic agents that are currently used for the treatment of ED. Emphasis is placed on the efficacy, mechanism of action and side effect profiles of approved and experimental injectable pharmacotherapy for ED. International Journal of Impotence Research (2000) 12, Suppl 4, S91-S100.

Transurethral alprostadil with MUSE (medicated urethral system for erection) vs intracavernous alprostadil--a comparative study in 103 patients with erectile dysfunction.

A comparative study in 103 unselected patients with erectile dysfunction between MUSE up to 1000 micrograms and intracavernous Alprostadil (Prostavasin) up to 20 micrograms provided total response-rates of 43% (MUSE) vs 70% (Prostavasin). Complete rigid erections were reached in 10% (MUSE) vs 48% (Prostavasin). The average end-diastolic flow values in the deep penile arteries ranged between 9.2-9.4 cm/s after MUSE and 4.5-4.8 cm/s after i.c. Alprostadil confirming the investigator's assessment, that in the vast majority of patients MUSE were not able to induce a complete cavernous smooth muscle relaxation. In terms of side effects the reported penile pain/ burning-rate after MUSE was 31.4% compared to 10.6% after i.c. Alprostadil. In addition after MUSE clinically relevant systemic side-effects like dizziness, sweating and hypotension occurred in 5.8% with syncope in 1%. No circulatory side-effects were encountered after i.c. Alprostadil. Urethral bleeding after MUSE-application was observed in 4.8%. Due to the superior efficacy and lower side-effects self-injection therapy with Alprostadil remains the 'Gold Standard' in the management of male impotence. MUSE should be reserved for a subset of patients suffering from erectile dysfunction.

IC351 (tadalafil, Cialis): update on clinical experience.

IC351 (tadalafil, trade name Cialis) is a new representative compound of the second generation of selective phosphodiesterase 5 (PDE-5) inhibitors. The selectivity ratio vs PDE-5 is more than 10 000 for PDE-1 through PDE-4 and PDE-7 through PDE-10 and 780 for PDE-6. In the European daily-dosing trial, the efficacy rates were up to 93% for successful intercourses with completion in the 50-mg dose in patients with mild to moderate erectile dysfunction (ED). In two different dose-ranging studies with 2-25 mg taken as needed, efficacy rates of up to 88% improvement in erections and up to 73% successful intercourses with completion were achieved. In a placebo-controlled, fixed-dose (10- and 20-mg) trial in diabetic patients, improved erections of 56% and 64% were reported compared with 25% after placebo. Drug-related adverse effects, with headache in up to 23% of patients (placebo, up to 17%), dyspepsia in up to 11% (placebo, up to 7%), back pain in up to 4.7% (placebo, 0%), and myalgia in up to 4.1% (placebo, up to 2.4%), were mostly mild to moderate. Neither drug-related serious cardiovascular adverse events nor color vision disturbances were encountered. The long half-life (>17 h), with a comfortably long window of opportunity, releases couples from the need to plan sexual activities and therefore provides the highest amount of spontaneity for sexual activities.

Bulbocavernosus-reflex latencies and pudendal nerve SSEP compared to penile vascular testing in 669 patients with erectile failure and other sexual dysfunction.

The purpose of this current study was to find out the coincidence of pathological penile vascular supply with pathological data in Bulbocavernosusreflex latency (BCR-L) measurements and Pudendal Nerve SSEP (PudSSEP) recordings. Six hundred and sixty-nine males (642 with erectile dysfunction, 27 with different sexual disturbances) (mean age 49.3 y, range 17-76 y) underwent consecutively a battery of neurophysiological investigations together with pharmacotesting of cavernous bodies combined with duplex sonography of penile arteries. Pathological vascular findings were indicated in 286 men (43%), pathological neurophysiological findings in 264 men (39%). Normal findings in both investigations (vascular and neurophysiological) were encountered in 252 men (38%); 131 men (19%) revealed pathological data exclusively in the neurophysiological parameters, 153 (23%) exclusively in the vascular parameters and 133 (20%) in both. The highest percentages of pathological findings were observed in patients with diabetes mellitus (110 out of 131, 88%) and patients who had sustained pelvic trauma or surgery (36 out of 44, 82%), in contrast to the lowest percentage in patients with a proven psychogenic etiology (10 out of 38, 26%). Somewhat surprising was the rather high proportion of vascular impairment in patients with defined neurological diseases such as alcohol abuse (20 out of 51, 43%), polyneuropathy (PNP) of various etiology (9 out of 19, 47%), lumbosacral radiculopathies (26 out of 65, 40%), and CNS diseases (24 out of 52, 46%), about half of them coinciding with pathological neurophysiological findings. Even if the validity of BCR-L measurement and PudSSEP recordings in the assessment of neurogenic impotence was controversely discussed, we conclude that in a large number of impotent males both neurogenic and vascular factors are responsible for the onset of erectile dysfunction.

Intracavernous Alprostadil Alfadex--an effective and well tolerated treatment for erectile dysfunction. Results of a long-term European study.

Long-term efficacy and safety of Alprostadil-Alfadex (EDEX/VIRIDAL) in intracavernous self-injection therapy for chronical erectile failure was investigated in a four year running multicenter European trial. Of the 16,886 protocolled injections 93% (15,713) resulted in rigid erections followed by successful sexual intercourse. Reported side effects by patients were prolonged erections > 6 h only occurring during the first year in 1.2% (2 out of 162), painful erections in 29% (47 out of 162) during the first year and decreasing to 12.1% by year 4, hematomas, neither requiring therapeutic measures nor impeding sexual performance in 33.3% (54 out of 162) in year 1 with a decrease to 12.1% by year 4, fibrotic penile alterations such as nodules, plaques or deviations in 11.7% (19 out of 162) with spontaneous healing in 48% (9 out of 19). Of the 162 patients involved in this trial 54 completed the 4 y. Of the 54 completers 91.4% considered the tolerability good or very good and were satisfied or very satisfied with self-injection therapy with Alprostadil-Alfadex. The respective rates of the female partners were 51.7% very satisfied and 39.7% satisfied. These data of the world-wide longest running prospective trial with a vasoactive drug in self-injection therapy provided impressive proof that Alprostadil-Alfadex represents a very effective and safe treatment for erectile dysfunction of both psychogenic and organogenic origin.

The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial.

Vardenafil, a novel selective phosphodiesterase type 5 inhibitor, was evaluated in its first large-scale at-home trial. A total of 601 men with mild to severe erectile dysfunction (ED) were enrolled in this multi-centre, randomized, double-blind, placebo-controlled trial of 12 weeks of treatment with either placebo or 5, 10 and 20 mg of vardenafil. Primary endpoints were Q3 (vaginal penetration) and Q4 (maintenance of erection) of the International Index of Erectile Function (IIEF). In the intent-to-treat population (n=580), the changes from baseline for 5, 10 and 20 mg vardenafil (1.2, 1.3 and 1.5, respectively) were all improved (P<0.001) over placebo (0.2) for Q3 and were similarly improved for Q4 (1.4, 1.5 and 1.7) compared to placebo (0.5) (P<0.001). All vardenafil doses improved all IIEF domains compared to placebo (P<0.001). The percentage of successful intercourses was between 71 and 75% for the three vardenafil doses. For the 20 mg dose, 80% of the patients experienced improved erections (GAQ) compared to 30% for placebo. Most frequent treatment-emergent adverse events were headache (7-15%), flushing (10-11%) and up to 7% for dyspepsia or rhinitis. Vardenafil treatment resulted in a high efficacy and low adverse-event profile in a population with mixed ED etiologies.

The 'effectiveness' scale--therapeutic outcome of pharmacologic therapies for ED: an international consensus panel report.

Despite availability of outcome measures and scales for assessing erectile dysfunction (ED) treatment efficacy, guidelines are not available for assessing broader therapeutic outcomes or defining treatment failure in ED. An International Consensus Advisory Panel was convened to develop guidelines, definitions and a new algorithm for evaluating treatment effectiveness in ED. These new guidelines are recommended for use in both research and clinical practice. A multidisciplinary, international panel, consisting of 11 senior researchers and clinicians, was convened to address pertinent issues concerning therapeutic outcome assessment for ED. The panel utilized a modified Delphi method of consensus development and proposed a new model for outcomes assessment. This model is inherently testable, using existing instruments and current methods of assessment. Following a comprehensive literature review and discussion, the Panel recommended adoption of a new treatment effectiveness conceptual framework or theoretical model for assessing therapeutic outcomes in ED. Treatment effectiveness is presumed to be a combined function of two other factors, treatment response and treatment satisfaction. Treatment response is based on the combined assessment of efficacy and tolerability, and treatment satisfaction on the combined assessment of patient and partner satisfaction. Taken together, these two domains define an overall domain of treatment effectiveness. This therapeutic index would be derived by independently assessing treatment efficacy and satisfaction by means of event logs, questionnaires or the more typical patient interview methods. In conclusion, the Ad Hoc Advisory Consensus Panel recommends adoption of a new framework or conceptual model for conducting ED outcome trials or clinical research. The concept of 'treatment effectiveness' is proposed as a new 'umbrella concept' or distal outcome to be evaluated.

Noradrenaline release in human corpus cavernosum and its modulation via presynaptic alpha 2-adrenoceptors.

Strips of human corpus cavernosum were incubated with 3H-noradrenaline and subsequently superfused with physiological salt solution containing desipramine and corticosterone. The electrically (0.66 Hz) evoked tritium overflow was abolished by tetrodotoxin or omission of Ca2+ from the superfusion fluid. The alpha 2-adrenoceptor agonist B-HT 920 (6-allyl-2-amino-5, 6, 7, 8-4H-thiazolo-5,4-d-azepine), inhibited the evoked overflow, whereas the alpha 1-adrenoceptor agonist, methoxamine, was ineffective. The alpha 2-adrenoceptor antagonist, rauwolscine, facilitated the evoked tritium overflow. It is concluded that the stimulation-evoked release of noradrenaline from the sympathetic nerve fibres of the human corpus cavernosum is modulated via presynaptic alpha 2-adrenoceptors.

[Echo morphology of testicular tumors]. / Echomorphologie der Hodentumoren.

The ultrasound and histological findings of 130 testicular tumours were compared; these included 56 seminomas, 49 teratomas, 16 mixed tumours, five Leydig cell tumours, three lymphomas and one metastasis. There was only a slight tendency to low echo homogeneous structure with seminomas and low echo irregular structure with teratomas and mixed tumours. Cystic components, or strongly echogenic structures, were found in 20 to 30% of primary testicular malignant tumours, but these findings were non-specific. Cystic lesions were found at histology to be due to necroses, haemorrhage or specific tumour cysts. Strongly echogenic appearances correlated with calcification, fibrosis or bone or cartilage development. There were no specific sonographic criteria suitable for the identification of specific tumour types.

[DSA and conventional angiography compared in the angiographic diagnosis of impotence]. / DSA und konventionelle Angiographie im Vergleich bei der angiographischen Diagnostik der Impotentia coeundi.

Twenty-three patients complaining of impotence were examined angiographically as part of their investigation. In all patients, DSA as well as conventional angiography was carried out. The purpose of this investigation was to compare the two methods with regard to their diagnostic value. By means of sequential analysis it was shown that, with an error level of 10%, DSA was superior to conventional angiography.