1 INTRODUCTION

Erectile dysfunction (ED) affects up to 77% of men worldwide,1, 2 of which approximately 55% are in their 60s.3 The presence of cardiovascular diseases and other risk factors (vascular inflammation, atherosclerosis, hyperlipidemia, hypertension, diabetes, smoking, and metabolic syndrome) contributes further to the development of ED.2 It has been estimated that about 68% of men with hypertension have some degree of ED.4 Given the high prevalence in older men of ED and cardiovascular comorbidities, the use of ED and concomitant antihypertensive medications (AHM) is often required.1, 5

Tadalafil is a long-acting, selective inhibitor of phosphodiesterase 5 (PDE5) used widely as first-line treatment for ED.6 It has also demonstrated efficacy and safety in the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH), with or without coexisting ED.7 Tadalafil is marketed either as-needed or once-daily dosing for the treatment of ED, and as once-daily for the treatment of BPH and BPH with ED.8 PDE5 inhibitors prevent degradation and facilitate accumulation of cyclic guanosine monophosphate in the cavernosum smooth muscle, which then mediates relaxation, vasodilation, and erection.6 PDE5 inhibitors are considered to be generally safe when used in combination with antihypertensive drugs,9 however, since PDE5 enzyme is found also in systemic arterial blood vessels, the inhibition may contribute to vasodilation of the systemic vasculature.10

The objective of this pooled analysis of clinical studies was to assess the incidence of hypotension-related treatment-emergent adverse events (TEAEs) and major adverse cardiovascular events (MACEs) in patients who received tadalafil (Cialis®, Eli Lilly and Company) concomitantly with AHM vs those receiving AHM alone (excluding alpha-blockers). This safety evaluation is the largest performed to date on tadalafil, and the focus on placebo-controlled, randomized, double-blind clinical trials allowed for an unbiased evaluation of the drug-drug interactions of the two medications.

2 METHODS 2.1 Source of clinical data

As of 31 May 2018, a total of 145 completed studies were identified in the Eli Lilly's Global Integrated Database (GID). Five studies (for which databases were not available; not part of the 145 studies), 69 clinical pharmacology studies, and four studies in healthy volunteers/mild ED patients were not included in the analysis.

The safety analysis was based on 72 Phase II–IV studies including randomized double-blind (placebo- or active-controlled) and open-label trials, either with parallel or cross-over arms (up to three-way crossovers). Dosage regimens of tadalafil included as-needed, once-daily, or a mix of both; doses ranged from 2 to 100 mg; and could be either fixed or titrated. Study periods varied from a single dose up to 24 months.

In this analysis, studies were categorized as either All placebo-controlled studies (including participants only from placebo-controlled trials) or All studies (including participants from both placebo-controlled and non-placebo-controlled studies).

2.2 Patient populations

All patients included in the analysis had a diagnosis of ED and/or BPH and received at least one dose of the investigational product (tadalafil or placebo). The patient population was determined by the inclusion/exclusion criteria of the original studies. ED studies enrolled males ≥18 years old who had a history of ED ≥3 months in duration, ranging in severity (mild, moderate, or severe) and etiologic classification (psychogenic, mixed, or organic). BPH studies enrolled males ≥45 years old having BPH-lower urinary tract symptoms for >6 months.

Included patients were categorized by indication and dose regimen as follows: ED as-needed; ED once-daily; BPH once-daily; All ED/BPH (combining all ED and BPH groups). Participants were also grouped by use of AHM (With concomitant AHM vs Without concomitant AHM), and by number of concomitant antihypertensive classes of medicines taken during the study period (0, 1, 2, ≥3). Patients receiving nitrates or ED therapy other than tadalafil were excluded as per original study exclusion criteria. Patients receiving alpha-blockers were also excluded from this analysis. Alpha-blockers are relegated to fourth or fifth treatment line for hypertension due to the risk of hypotensive and cardiac events,11-14 additionally, they may have a known orthostatic hypotension effect when co-administered with PDE5 inhibitors.9

2.3 Safety endpoints

TEAEs of hypotension/increased hypotensive effect and MACEs were the safety endpoints of interest. Coding of adverse events (AEs) collected during the clinical studies was updated to MedDRA version 23.1. TEAEs were those AEs that first occurred or worsened in severity during the treatment period. TEAEs were classified as non-serious or serious adverse events (SAE) and presented by system organ class/preferred term. TEAEs of hypotension/increased hypotensive effect were identified by the following preferred terms: hypotension; orthostatic hypotension; blood pressure ambulatory decreased; blood pressure decreased; blood pressure diastolic decreased; blood pressure systolic decreased; blood pressure orthostatic decreased; blood pressure orthostatic; dizziness; dizziness exertional; dizziness postural; presyncope; and syncope. MACEs were identified by two Standard MedDRA Queries (SMQ) (broad and narrow search): myocardial infarction and ischemic central nervous system vascular conditions, and/or the following five preferred terms: death; cardiac arrest; cardiac death; sudden cardiac death; sudden death.

Potentially clinically significant abnormal (PCSA) vital sign results, identified by diastolic blood pressure (DBP) and systolic blood pressure (SBP), were also evaluated. PCSA DBP reading was defined as <45 mmHg or a maximum decrease >20 mmHg, and PCSA SBP was defined as <85 mmHg or a maximum decrease>30 mmHg from baseline.

2.4 Statistical analysis

Data were presented for each indication-dose regimen category (ED as-needed; ED once-daily; BPH once-daily; All ED/BPH) by concomitant AHM status, study group (All placebo-controlled studies; All studies) and treatment received (placebo vs tadalafil; tadalafil).

Demographic and baseline characteristics were summarized in descriptive statistics only. Duration of treatment exposure was summarized descriptively as a quantitative variable and categorically for categories between ≥1 day and ≥2 years. The total exposure in person-years was also calculated.

The incidence of hypotension-related TEAEs and MACEs, respectively, was evaluated in both All placebo-controlled studies and All studies groups, and reported as the number (%) of patients with the event. The confidence interval (CI) of the incidence was calculated by Clopper-Pearson method. A comparison of the incidence between tadalafil and placebo was conducted for All placebo-controlled studies. A logistic regression model was used to calculate the odds ratios (OR) of tadalafil/placebo for different concomitant AHM status with 95%CIs and associated p-values. The model included the fixed terms of treatment group, status of concomitant AHM, and their interaction. In addition, the interaction (ratio of ORs of tadalafil/placebo) between treatment group and concomitant AHM was evaluated by exact logistic regression.

The number (%) of patients with at least one PCSA value for SBP/DBP during the post-baseline treatment period was analyzed in All placebo-controlled studies group.

A descriptive overview of hypotension-related TEAEs and treatment-emergent MACEs was provided for both All placebo-controlled studies and All studies groups, reporting any AEs of interest; treatment-related AEs; serious AE; AE leading to death; and AE leading to permanent study treatment discontinuation.

3 RESULTS 3.1 Safety data extraction and patient disposition

Safety data were extracted from 72 Phase II–IV clinical studies of tadalafil used for ED or BPH patients (Figure 1). Based on prior/concomitant medications reported in study case report forms, patients were identified as with or without concomitant AHM. A total of 15 030 and 22 825 patients were included in the analyses for All placebo-controlled studies and All studies groups, respectively. Of these, patients receiving tadalafil with concomitant AHM were 3088 and 6868, respectively (Table 1). A summary of demographic characteristics and treatment exposure is shown in Table 2. Overall, demographic features were similar between patients included in the two study groups. Patients receiving concomitant AHM were older, with the majority being in the age group 45 to <65 years (44.9–71.5%) and had slightly higher body mass index (BMI) than those who were not receiving AHM, regardless of the study category. Overall, the incidence of cardiovascular disorders (cardiac disorder, cerebrovascular disorder, other vascular disorders) was higher in patients receiving concomitant AHM (90.7–95.3%) compared with no AHM (10.9–16.0%). Those receiving concomitant AHM had also higher incidence of severe ED (organic etiology), regardless of the study category. The number of patients not receiving concomitant AHM was two- to three-fold higher than those receiving concomitant AHM. In both study groups, most patients used only one AHM (Table 3); across the All ED/BPH category in the All studies group (n = 22 832), the percentage of those taking one concomitant antihypertensive was 16.6% (n = 3788), followed by 9.6% (n = 2194) and 3.9% (n = 884) receiving 2 or ≥3 concomitant AHM, respectively. The most frequently used AHMs were angiotensin-converting-enzyme (ACE) inhibitors in ED studies and calcium channel blockers in BPH once-daily category. Other commonly prescribed classes of AHM included angiotensin receptor blockers (ARB), beta-blockers, diuretics, and centrally acting sympathomimetics.

Study selection (PRISMA flowchart). Abbreviations: BPH, benign prostatic hyperplasia; ED, erectile dysfunction

TABLE 1. Patient disposition by concomitant use of AHM and study category Without concomitant AHM With concomitant AHM Indication Placebo Tadalafil Placebo Tadalafil Alla ED as-needed All placebo-controlled, no. = 31 1512 3290 553 1228 6499 All studiesb, no. = 50 11 980 4648 16 628 ED once-daily All placebo-controlled, no. = 10 673 1484 405 832 3394 All studiesb, no. = 12 2314 1355 3669 BPH once-daily All placebo-controlled, no. = 13 1465 2065 717 1028 5275 All studiesb, no. = 13 2195 1114 3309 All ED/BPH All placebo-controlled, no. = 53 3552 6839 1635 3088 15 030 All studiesb, no. = 72 15 957 6868 22 825 Abbreviations: AHM, antihypertensive medication; BPH, benign prostatic hyperplasia; ED, erectile dysfunction; no., number of studies. TABLE 2. Demographic characteristics and treatment exposure by concomitant use of AHM and study category All placebo-controlled studies All studies Indication Without concomitant AHM With concomitant AHM Without concomitant AHM With concomitant AHM ED As-Needed Placebo (no. = 1512) Tadalafil (no. = 3290) Placebo (no. = 553) Tadalafil (no. = 1228) Tadalafil (no. = 11 980) Tadalafil (no. = 4648) Age (years), mean (SD) 53.32 (10.91) 52.56 (11.46) 59.60 (8.32) 59.47 (8.50) 52.39 (11.27) 59.03 (8.64) Age group 45 to < 65 years, no. (%) 1008 (66.7) 2034 (61.8) 373 (67.5) 822 (66.9) 7536 (63.0) 3201 (68.9) White, no. (%) 1092 (72.2) 2357 (71.6) 417 (75.4) 903 (73.5) 9108 (76.1) 3628 (78.1) BMI (kg/m2), mean (SD) 26.76 (3.89) 26.83 (4.11) 28.70 (4.79) 28.79 (4.54) 26.79 (4.27) 28.91 (4.51) Exposure, patient years 354.8 764.2 130.3 288.7 4632.5 1923.9 Duration of study treatment, days Median 87.0 90.0 85.0 89.0 101.0 101.0 Min : Max 1 : 358 1 : 311 1 : 291 1 : 295 0 : 961 0 : 893 Comorbidities, no./No. (%) Cardiovascular disordera 219/1512 (14.5) 412/3290 (12.5) 504/553 (91.1) 1117/1228 (91.0) 1335/11618 (11.5) 4106/4488 (91.5) Hypertension 71/1512 (4.7) 125/3290 (3.8) 464/553 (83.9) 1054/1228 (85.8) 446/11980 (3.7) 3922/4648 (84.4) Baseline IIEF-EF severity, severe, no./No. (%) 507/1393 (36.4) 1023/3022 (33.9) 242/525 (46.1) 493/1142 (43.2) 2580/8245 (31.3) 1303/3297 (39.5) ED Once-Daily Placebo (no. = 673) Tadalafil (no. = 1484) Placebo (no. = 405) Tadalafil (no. = 832) Tadalafil (no. = 2314) Tadalafil (no. = 1355) Age (years), mean (SD) 55.79 (10.13) 55.14 (10.32) 60.60 (8.71) 60.42 (9.10) 54.46 (10.51) 60.02 (8.96) Age group 45 to < 65 years, no. (%) 481 (71.5) 1011 (68.1) 258 (63.7) 519 (62.4) 1575 (68.1) 879 (64.9) White, no. (%) 586 (87.1) 1287 (86.8) 359 (88.6) 710 (85.3) 1994 (86.3) 1168 (86.3) BMI (Kg/m2), mean (SD) 28.02 (4.71) 27.61 (4.11) 29.95 (4.66) 29.92 (4.97) 27.61 (4.17) 29.69 (4.77) Exposure, patient years 183.9 342.5 103.5 202.5 848.8 510.9 Duration of study treatment, days Median 86.0 86.0 86.0 86.0 86.0 86.0 Min : Max 2 : 358 1 : 576 5 : 291 3 : 380 1 : 1009 3 : 935 Comorbidities, no./No. (%) Cardiovascular disordera 108/673 (16.0) 209/1484 (14.1) 386/405 (95.3) 762/832 (91.6) 312/2314 (13.5) 1258/1355 (92.8) Hypertension 59/673 (8.8) 97/1484 (6.5) 363/405 (89.6) 724/832 (87.0) 152/2314 (6.6) 1194/1355 (88.1) Baseline IIEF-EF severity, severe, no./No. (%) 211/668 (31.6) 401/1478 (27.1) 184/405 (45.4) 327/830 (39.4) 696/2305 (30.2) 541/1351 (40.0) BPH once-daily Placebo (no. = 1465) Tadalafil (no. = 2065) Placebo (no. = 717) Tadalafil (no. = 1028) Tadalafil (no. = 2195) Tadalafil (no. = 1114) Age (years), mean (SD) 61.07 (8.11) 61.33 (7.93) 65.54 (7.90) 65.41 (7.51) 61.44 (7.95) 65.56 (7.46) Age group 45 to < 65 years, no. (%) 993 (67.8) 1356 (65.7) 322 (44.9) 484 (47.1) 1426 (65.0) 510 (45.8) White, no. (%) 593 (40.5) 915 (44.3) 387 (54.0) 591 (57.5) 958 (43.6) 625 (56.1) BMI (Kg/m2), mean (SD) 25.86 (3.83) 25.73 (3.87) 27.59 (4.44) 27.63 (4.41) 25.67 (3.87) 27.57 (4.45) Exposure, patient years 430.7 569.4 210.6 279.6 947.1 525.1 Duration of study treatment, days Median 86.0 85.0 86.0 85.0 90.0 92.5 Min : Max 1 : 252 1 : 267 7 : 274 1 : 295 1 : 541 1 : 490 Comorbidities, no./No. (%) Cardiovascular disordera 181/1465 (12.4) 230/2065 (11.1) 650/717 (90.7) 943/1028 (91.7) 240/2195 (10.9) 1021/1114 (91.7) Hypertension 104/1465 (7.1) 118/2065 (5.7) 628/717 (87.6) 904/1028 (87.9) 120/2195 (5.5) 978/1114 (87.8) Baseline IIEF-EF severity, severe, no./No (%) – – – – – – All ED/BPH Placebo (no. = 3552) Tadalafil (no. = 6839) Placebo (no. = 1635) Tadalafil (no. = 3088) Tadalafil (no. = 15 957) Tadalafil (no. = 6868) Age (years), mean (SD) 56.88 (10.44) 55.77 (10.94) 62.50 (8.72) 61.70 (8.76) 53.90 (11.22) 60.32 (8.87) Age group 45 to < 65 years, no. (%) 2393 (67.4) 4401 (64.4) 915 (56.0) 1825 (59.1) 10175 (63.8) 4404 (64.1) White, no. (%) 2176 (61.3) 4559 (66.7) 1123 (68.7) 2204 (71.4) 11608 (72.8) 5210 (75.9) BMI (Kg/m2), mean (SD) 26.63 (4.13) 26.67 (4.10) 28.53 (4.74) 28.71 (4.70) 26.75 (4.25) 28.85 (4.63) Exposure, patient years 903.9 1676.1 420.1 770.8 6421.7 2964.4 Duration of study treatment, days Median 86.0 87.0 85.0 86.0 101.0 102.0 Min : Max 1 : 358 1 : 576 1 : 291 1 : 380 0 : 1009 0 : 935 Comorbidities, no./No. (%) Cardiovascular disordera 497/3552 (14.0) 851/6839 (12.4) 1500/1635 (91.7) 2822/3088 (91.4) 1850/15611 (11.9) 6168/6716 (91.8) Hypertension 230/3552 (6.5) 340/6839 (5.0) 1416/1635 (86.6) 2682/3088 (86.9) 704/15957 (4.4) 5885/6868 (85.7) Baseline IIEF-EF severity, severe, no./No. (%) 819/2767 (29.6) 1660/5610 (29.6)