P-225: Effective blood-pressure control with valsartan/HCTZ combination therapy in patients with moderate to severe systolic hypertension: The valor trial

Increasing evidence shows that combination therapy with at least two antihypertensive agents is needed to achieve appropriate blood-pressure (BP) control in a large part of the hypertensive population. One of the most appealing combinations is that of adding a diuretic to an angiotensin-receptor blocker (ARB). We studied the effects on sitting systolic BP of the combinations valsartan (V; an ARB) 160 mg + HCTZ 12.5 mg and V160 mg + HCTZ 25 mg od, compared with monotherapy V160 mg od. Treatment-naive and previously treated patients (N=767) with moderate to severe systolic hypertension (SBP ≥160 mm Hg and ≤200 mmHg) and with or without co-morbidities, were randomised (after a 2-week washout if previously treated and a 2 week placebo run-in period) to either V80 od (monotherapy group) or V160 od (combination groups) for 4 weeks, with force-tration to V160 mg, V160/HCTZ 12.5 od or V160/HCTZ 25 od for an additional 4 weeks. Endpoints were change in SBP between V160 and V160/HCTZ 25 and between V160/HCTZ 12.5 and V160; changes in DBP between groups, response rates and tolerability. As shown in the Table, all treatments were highly effective and there were additional SBP and DBP reductions in the combination groups. Responder rates were above 50% in all groups and reached 75% in the V160/HCTZ 25 group. Rates of adverse events did not differ significantly between monotherapy and combination therapies. Table 1 V160 V160/HCTZ12.5 V160/HCTZ25 N 261 254 252 Male/female 130/131 141/113 140/112 Mean age 60.4 (10.6) 60.8 (11.5) 60.7 (11.6) Baseline mean SBP/DBP 167.9 (8.0)/93.2 (8.9) 167.4 (8.3)/93.4 (9.6) 167.2 (7.9)/93.7 (8.8) Mean change SBP/DBP −20.7 (15.7)/−6.6 (8.9) −27.9 (13.8) *−10.2 (7.7)* −28.3 (13.1) *−10.1 (7.8)* Response rate¥ 56.9% 74.4% * 75% * Any AE (monotherapy phase/combination phase) 37.3%/27.5% 32.1%/28.6% 32.8%/34.0% Values in brackets are ± SD. *P < 0.05 vs V160; ¥SBP < 140 or decrease in SBP ≥20 mmHg and/or DBP<90 mmHg. V160 mg od is safe and effective in patients with moderate to severe systolic hypertension. Adding HCTZ 12.5 or 25 mg provides significant additional reductions in systolic and diastolic BP and increases responder rates compared with V160 mg monotherapy, with maintained excellent tolerabilit

P-181: Fixed-dose valsartan + hydrochlorothiazide combination therapy compared with amlodipine monotherapy in hypertensive patients with additional cardiovascular risk factors: The vast study

Objectives: To determine whether the combination of valsartan 160 mg and hydrochlorothiazide (HCTZ) 25 mg once-daily (od) is more effective than amlodipine 10 mg od in reducing systolic blood pressure (BP) in patients suffering from moderate hypertension combined with at least one other cardiovascular risk factor or concomitant condition. Further, to study the effects of treatment on vascular markers. Methods: A multicenter, randomized, double-blind, active-controlled, three-arm study over 24 weeks. After a two-week single-blind placebo run-in period, 1088 stage-II hypertensive patients with additional risk factors were randomized to three groups, two receiving valsartan 160 mg od and one group receiving amlodipine 5 mg od. At Week 4, HCTZ 12.5 mg and 25 mg respectively, were added to the valsartan groups and the amlodipine dose was force-titrated to 10 mg od. Patients were followed-up for a total of 24 weeks. Results: The combination of valsartan 160 mg+HCTZ 25 mg reduced systolic BP significantly (p<0.05) more than amlodipine monotherapy (least-squares mean changes from baseline 29.7±0.7 mmHg and 27.6± 0.7 mmHg, respectively). For diastolic BP the values were 11.1±0.4 mmHg and 10.8±0.4 mmHg, respectively (differences not significant). Levels of IL-6, t-PA antigen and hs-CRP were reduced with both combination therapies at week 12 (figure). Significantly more patients discontinued because of adverse events in the amlodipine group (18.2%) than in the combination-therapy groups (4.2% and 3.5%) over the 6 months treatment period. Conclusions: Valsartan 160 mg+HCTZ 25 mg is an effective and well-tolerated therapy in this patient population with possible beneficial effects on vascular marker

P-182: 24-hour ambulatory blood-pressure effects of valsartan + hydrochlorothiazide combinations compared with amlodipine in hypertensive patients at increased cardiovascular risk

In a randomised, double-blind trial, the effects on 24-hr ABP of the combination valsartan 160 mg od and hydrochlorothiazide (HCTZ) 25 or 12.5 mg during 24 weeks of therapy were compared with the effects of amlodipine 10 mg monotherapy (group A10) in 474 stage-II hypertensive patients with additional cardiovascular risk factors. After a two-week single-blind placebo run-in period, patients were randomised to receive valsartan 160 mg od or amlodipine 5 mg od. At Week 4, HCTZ 12.5 mg (group V160/HCTZ12.5) and 25 mg (group V160/HCTZ25) were added to the valsartan groups and in the A10 patients the amlodipine dose was force-titrated to 10 mg od. All treatments reduced BP as well as night-time and daytime BP levels from baseline. 24-hr SBP was reduced by 15.9 ±1.0 mmHg (least-squares mean change ±SE), 19.3 ±1.0 mmHg and 16.1 ±1.1 mmHg in the V160/HCTZ12.5, V160/HCTZ25 and A10 groups, respectively and 24-hr DBP was reduced by 9.3 ±0.6 mmHg, 11.4 ±0.6 mmHg and 9.6 ±0.7 mmHg in the three groups. The differences between the V160/HCTZ25 group and the A10 group were significant (p<0.05) for the changes in 24-hr systolic BP as well as for changes in daytime systolic BP and night-time diastolic BP. Control rates defined as ABPM ≤130/80 mmHg were: 48.4%, 60.8% and 50.9% in the V160/HCTZ12.5, V160/25 and A10 groups, respectively; the differences between the V160/HCTZ25 group and the other two treatment groups were significant at p<0.05. (See Figure) In conclusion, the fixed-dose combination of valsartan 160 mg + HCTZ 25 mg od is an attractive therapeutic option measured on the effects on 24-hr ABPM, night-time and daytime BP reduction and control rates in hypertensive patients at additional cardiovascular ris

The effect of sacubitril/valsartan compared to olmesartan on cardiovascular remodelling in subjects with essential hypertension: the results of a randomized, double-blind, active-controlled study

Aims: Progressive aortic stiffening eventually leads to left ventricular (LV) hypertrophy and heart failure if left untreated. Anti-hypertensive agents have been shown to reverse this to some extent. The effects of sacubitril/valsartan (LCZ696), a dual-action angiotensin receptor blocker (ARB), and neprilysin inhibitor, on arterial stiffness and LV remodelling have not been investigated. Methods and results: This was a randomized, multi-centre, double-blind, double-dummy, active-controlled, parallel group, study to compare the effects on cardiovascular remodelling of sacubitril/valsartan with those of olmesartan in patients with hypertension and elevated pulse pressure. Magnetic resonance imaging scans were used to assess LV mass and local aortic distensibility, at baseline and at 12 and 52 weeks after initiation of treatment. Central pulse and systolic pressure were determined using a SphymoCor® XCEL device at each time point. A total of 114 patients were included, with 57 in each treatment group. The mean age was 59.8 years, and 67.5% were male. Demographic characteristics did not vary between the two sets of patients. Left ventricular mass index decreased to a greater extent in the sacubitril/valsartan group compared to the olmesartan group from baseline to 12 weeks (−6.36 vs. −2.32 g/m2; P = 0.039) and from baseline to 52 weeks (−6.83 vs. −3.55 g/m2; P = 0.029). These differences remained significant after adjustment for systolic blood pressure (SBP) at follow-up (P = 0.036 and 0.019 at 12 and 52 weeks, respectively) and similar signals (though formally non-significant) were observed after adjusting for changes in SBP (P = 0.0612 and P = 0.0529, respectively). There were no significant differences in local distensibility changes from baseline to 12 or 52 weeks between the two groups; however, there was a larger reduction in central pulse pressure for the sacubitril/valsartan group compared to the olmesartan group (P = 0.010). Conclusion: Since LV mass change correlates with cardiovascular prognosis, the greater reductions in LV mass indicate valuable advantages of sacubitril/valsartan compared to olmesartan. The finding that LV mass index decrease might be to some extent independent of SBP suggests that the effect of the dual-acting agent may go beyond those due to its BP-lowering ability

Sacubitril/valsartan (LCZ696) in heart failure

It has been known since the 1990s that long-term morbidity and mortality is improved in patients with heart failure with reduced ejection fraction (HFrEF) by treatments that target the renin–angiotensin–aldosterone system (RAAS). It has also long been thought that enhancement of the activity of natriuretic peptides (NPs) could potentially benefit patients with HFrEF, but multiple attempts to realize this benefit had failed over the years – until 2014, when a large, phase III, randomized, controlled clinical trial (PARADIGM-HF) was completed comparing sacubitril/valsartan with enalapril, a well-established treatment for HFrEF. Sacubitril/valsartan (formerly known as LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that simultaneously suppresses RAAS activation through blockade of angiotensin II type 1 receptors and enhances vasoactive peptides including NPs through inhibition of neprilysin, the enzyme responsible for their degradation. In PARADIGM-HF, patients with HFrEF treated with sacubitril/valsartan had 20% less risk for cardiovascular death or hospitalization for heart failure (the primary endpoint), 20% less risk for cardiovascular death, 21% less risk for first hospitalization for heart failure, and 16% less risk for death from any cause, compared with enalapril (all p &lt; 0.001). Concerning tolerability, the sacubitril/valsartan group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough, compared with the enalapril group. The use of sacubitril/valsartan has been endorsed by the latest heart failure treatment guidelines in Europe and the USA. This chapter reviews the discoveries, scientific reasoning, and clinical evidence that led to the development of sacubitril/valsartan, the first novel therapy in a new drug class to improve survival in HFrEF in the last 15 years

Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial

After an acute coronary syndrome, patients remain at risk of recurrent ischaemic events, despite contemporary treatment, including aspirin and clopidogrel. We evaluated the safety and indicators of efficacy of the novel oral direct thrombin inhibitor dabigatran. In this double-blind, placebo-controlled, dose-escalation trial, 1861 patients (99.2% on dual antiplatelet treatment) in 161 centres were enrolled at mean 7.5 days (SD 3.8) after an ST-elevation (60%) or non-ST-elevation (40%) myocardial infarction and randomized to twice daily treatment with dabigatran 50 mg (n = 369), 75 mg (n = 368), 110 mg (n = 406), 150 mg (n = 347), or placebo (n = 371). Primary outcome was the composite of major or clinically relevant minor bleeding during the 6-month treatment period. There were 96 primary outcome events and, compared with placebo, a dose-dependent increase with dabigatran, hazard ratio (HR) 1.77 (95% confidence intervals 0.70, 4.50) for 50 mg; HR 2.17 (0.88, 5.31) for 75 mg; HR 3.92 (1.72, 8.95) for 110 mg; and HR 4.27 (1.86, 9.81) for 150 mg. Compared with placebo, D-dimer concentrations were reduced in all dabigatran dose groups by an average of 37 and 45% at weeks 1 and 4, respectively (P <0.001). Fourteen (3.8%) patients died, had a myocardial infarction or stroke in the placebo group compared with 17 (4.6%) in 50 mg, 18 (4.9%) in 75 mg, 12 (3.0%) in 110 mg, and 12 (3.5%) in the 150 mg dabigatran groups. Dabigatran, in addition to dual antiplatelet therapy, was associated with a dose-dependent increase in bleeding events and significantly reduced coagulation activity in patients with a recent myocardial infarctio

Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study

Purpose: Some targeted anticancer agents are associated with serious ventricular tachyarrhythmias, which may be predicted by electrocardiographic evaluation of drug-related QT prolongation. We studied the effects of nintedanib (BIBF 1120; an oral, triple angiokinase inhibitor targeting vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors) on the QT interval in patients with renal cell carcinoma (RCC) participating in an open-label phase II trial. Methods: Treatment-naïve, adult patients with unresectable/metastatic, clear cell RCC received nintedanib 200 mg twice daily. QT intervals were evaluated at baseline (day −1), on day 1 (after the first dose), and on day 15 (steady state) by 12-lead electrocardiograms (ECGs) performed in triplicate. Pharmacokinetic sampling was also undertaken. Results: Among 64 evaluable patients, the upper limits of the 2-sided 90 % confidence intervals for the adjusted mean time-matched changes in QTcF interval (corrected for heart rate by Fridericia’s method) from baseline to day 1 and 15 (primary ECG endpoint) were well below the regulatory threshold of 10 ms at all times. No relationship between nintedanib exposure and change from baseline in QTcF was seen. Nintedanib was generally well tolerated with no drug-related cardiovascular adverse events. Conclusion: Nintedanib administered at 200 mg twice daily was not associated with clinically relevant QT prolongation

Dabigatran versus warfarin in patients with mechanical heart valves

Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves. In this phase 2 dose-validation study, we studied two populations of patients: those who had undergone aortic- or mitral-valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier. Patients were randomly assigned in a 2:1 ratio to receive either dabigatran or warfarin. The selection of the initial dabigatran dose (150, 220, or 300 mg twice daily) was based on kidney function. Doses were adjusted to obtain a trough plasma level of at least 50 ng per milliliter. The warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk. The primary end point was the trough plasma level of dabigatran. The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding. The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.

MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans

A large unmet medical need exists for safer antithrombotic drugs because all currently approved anticoagulant agents interfere with hemostasis, leading to an increased risk of bleeding. Genetic and pharmacologic evidence in humans and animals suggests that reducing factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with a minimal risk of bleeding. We generated a fully human antibody (MAA868) that binds the catalytic domain of both FXI (zymogen) and activated FXI. Our structural studies show that MAA868 traps FXI and activated FXI in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process, revealing a particularly attractive anticoagulant profile of the antibody. MAA868 exhibited favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a ferric chloride-induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by activated partial thromboplastin time without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects and showed that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in dose- and time-dependent robust and sustained prolongation of activated partial thromboplastin time and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as a potential once-monthly subcutaneous anticoagulant therapy