PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension

PATENT PLUS evaluated the safety and efficacy of riociguat in combination with sildenafil in pulmonary arterial hypertension patients.Patients receiving sildenafil (20 mg three times daily) were randomised to placebo or riociguat (up to 2.5 mg three times daily) for 12 weeks. The primary outcome was maximum change in supine systolic blood pressure (SBP) from baseline within 4 h of dosing. Secondary objectives comprised additional blood pressure, heart rate and exploratory efficacy variables, and safety. Patients could enter a long-term extension (LTE), where all patients received riociguat plus sildenafil.There was no difference in maximum change in supine SBP from baseline within 4 h between the riociguat (n=12) (mean±sd baseline: –20.2±15.3 mmHg; week 12: –20.7±18.0 mmHg) and placebo groups (n=6) (–7.6±3.9 and –20.2±12.9 mmHg, respectively). Changes in standing SBP and supine or standing diastolic blood pressure were also not different. Combination therapy showed no favourable effects on exploratory clinical parameters, including haemodynamics and exercise capacity. In the LTE, there were high rates of discontinuation due to hypotension and three (18%) deaths (not considered study drug-related by the investigator).There were potentially unfavourable safety signals with sildenafil plus riociguat and no evidence of a positive benefit/risk ratio. Concomitant use of riociguat with phosphodiesterase-5 inhibitors is therefore contraindicated.

Abstract 234: Plasma Renin-Independent Generation of Angiotensin II and its Role in the Supine Hypertension of Autonomic Failure

At least 50% of primary autonomic failure [AF] patients exhibit supine hypertension, despite profound impairments in sympathetic activity. Plasma renin activity is often undetectable in AF suggesting renin mechanisms are not involved in the hypertension. However, since aldosterone levels are preserved we examined the status and contribution of the renin-angiotensin [Ang] system in AF. Supine plasma Ang peptide levels were measured in hypertensive AF patients [AF-HT, n=18], normotensive patients [AF-NT, n=11] and matched healthy subjects [n=10]. Despite suppressed renin activity, total renin concentration was intact in AF [16 ± 5 AF-HT vs 11 ± 4 AF-NT vs 7 ± 1 pg/mL healthy; p=0.29] and plasma prorenin was selectively elevated in hypertensive patients [2.0 ± 0.5 AF-HT vs 0.7 ± 0.1 AF-NT vs 0.6 ± 0.1 ng/mL healthy; p < 0.05]. While levels of Ang I were similar among groups, Ang II was paradoxically elevated [39 ± 4 AF-HT vs 42 ± 6 AF-NT vs 27 ± 4 pg/mL healthy; p<0.05] in AF. In contrast, Ang-(1-7) was suppressed in AF patients [7 ± 1 AF-HT vs 4 ± 1 AF-NT vs 22 ± 6 pg/mL healthy; p<0.05]. Plasma aldosterone was preserved in AF and did not correlate with Ang II levels, suggesting Ang II-independent regulation. The Ang II AT 1 receptor antagonist losartan [50mg, PO] significantly reduced supine systolic blood pressure [25 ± 15 mmHg at 6 hrs after administration; p<0.05] in 9 AF-HT patients, indicating that elevated Ang II contributes to hypertension in AF. These findings suggest an imbalance in Ang II and Ang-(1-7) activity in AF independent of hypertensive status, which may reflect differences in ACE and ACE2 enzyme activity. The source of Ang II in these patients, in the absence of plasma renin activity, is still under investigation. The loss of renin activity is not due to reduced renin content, but may result from low substrate availability or defective enzyme activation. Regardless, Ang II appears to contribute to the supine hypertension of AF. Further, prorenin levels are elevated in hypertensive patients which could provide a stimulus for Ang II generation and actions. Collectively, these patients offer a unique model to study cardiovascular regulation and Ang II production in the absence of autonomic and traditional renin influences.

Nadolol and Propranolol in the Treatment of Hypertension: A Double-Blind Comparison

Nadolol and propranolol were compared in seventy-five hypertensive patients in a double-blind randomized study conducted at Ain-Shams Hospital. After an initial wash-out period of 5 weeks, including 3 weeks of placebo administration, forty-five patients were given nadolol once daily and thirty patients received propranolol four times per day for 12 weeks, followed by a tapering-off period of 2 weeks. Both beta-blocking agents were effective in controlling hypertension with final daily doses ranging from 80 to 320 mg. Of statistical significance, however, were the better responses of supine systolic blood pressure elicited by nadolol. The only adverse reactions that occurred in this series were slight weight gains in two patients treated with nadolol and moderate dizziness in one patient treated with propranolol. Nadolol was proved to be a safe antihypertensive drug, at least comparable to propranolol in efficacy, with the advantages of a once-daily dose and a lack of direct depressant action on the heart.

Comparison of Metoprolol and Propranolol in Modification of Haemodynamic and Renin-Aldosterone Responses to Tilting in Humans

1. Acute oral administration of metoprolol and propranolol to ten normal males resulted in equal reduction in heart rate both supine and after passive tilting to 60°. 2. Tilted systolic blood pressure was reduced by both agents but metoprolol alone reduced supine systolic blood pressure. 3. Tilted but not supine diastolic blood pressure was reduced by both agents. 4. Metoprolol and propranolol both reduced the rise in plasma renin activity induced by tilting. 5. No effect of tilting was observed on plasma aldosterone.

Adjuvant Effect of Bendrofluazide on Propranolol in Hypertension

A double-blind trial was undertaken to assess the effect of bendro-fluazide in lowering the blood pressure in patients with essential hypertension controlled on propranolol. An increased hypotensive effect was found and the greatest fall occurred in the supine systolic blood pressure. Side-effects were mild and transient and did not interfere with treatment.