From systemic and pulmonary hypertension to heart failure: novel drugs and devices

Hypertension remains one of the most important cardiovascular risk factors for stroke, peripheral vascular disease, and heart failure,1 and to a lesser degree than lipids for myocardial infarction. Although an array of effective and safe drugs have been developed over the last decades, many patients remain poorly controlled and do not reach ESC/ESH Guideline-recommended target values2 or those discussed after the publication of SPRINT.3,4 The reasons for this failure are multiple, but patient compliance plays a major role. Thus, interventional procedures that provide sustained blood pressure lowering independent of patient compliance have attracted a lot of interest. In their clinical review article entitled ‘Interventional procedures and future drug therapy for hypertension’, Melvin David Lobo and colleagues from the Barts Health Trust in London5 remind us that more effective antihypertensive drugs are required, drugs that have excellent tolerability and safety profiles in addition to being efficacious. For those patients who either do not tolerate or wish to take medication for hypertension, or in whom blood pressure control is not attained despite multiple antihypertensives, a novel class of interventional procedures to manage hypertension has emerged.6,7 While most of these target various aspects of the regulation of blood pressure by the sympathetic nervous system (and hence do not work in those with pure systolic hypertension8), an additional procedure is now available which addresses mechanical aspects of the circulation.9 Most of these new devices are supported by early and encouraging evidence for both safety and efficacy, although more rigorous randomized controlled trials will be essential before any of the technologies can be adopted as a standard of care. Although blood pressure is commonly measured at surgery and used as a basis for the management of hypertension, some patients may present with unusually high blood pressure, e.g. so-called white coat hypertension,10 while others may have paradoxically low values when seen by a physician. Of note, masked hypertension, which is present when in-office normotension translates to out-of-office hypertension, is present in a surprisingly high percentage of untreated persons and an even higher percentage of patients after beginning antihypertensive medication, as outlined in a review entitled ‘Masked hypertension: understanding its complexity’, authored by Stanley S. Franklin and colleagues from the University of California at Irvine, USA.11 The authors mention that persons with pre-hypertension are not only more likely to have masked hypertension than those with optimal blood pressure, but also frequently develop target organ damage prior to transitioning to sustained hypertension. Furthermore, the frequency of masked hypertension is high in individuals of African inheritance and in the presence of increased cardiovascular risk factors and disease states, such as diabetes and chronic renal failure. Nocturnal hypertension and non-dipping may be early markers of masked hypertension. Twenty-four hour ambulatory blood pressure monitoring, which can detect night-time and 24-h elevated blood pressure, remains the gold standard for diagnosing masked hypertension. Almost one-third of treated patients with masked hypertension remain as ‘masked uncontrolled hypertension’, and it becomes important, therefore, to use ambulatory blood pressure monitoring (and supplemental home blood pressure monitoring) for the effective diagnosis and control of hypertension. As again outlined by the most recent ESC Guidelines,12 a common consequence of hypertension is left ventricular hypertrophy, a condition often leading to symptoms of heart failure even in the presence of preserved ejection fraction, so-called HFpEF.13 Heart failure is characterized by increased peripheral vascular resistance due to neurohumoral activation. An important regulator of vascular tone is the l-arginine/nitric oxide pathway14 which eventually activates soluble guanylate cyclase and increases cyclic guanosine monophosphate or cGMP, a pathway that is altered by oxidative stress in heart failure.15 cGMP is impaired in patients with heart failure and preserved ejection fraction and may contribute to symptoms. In a FAST TRACK entitled ‘Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED)study’, Burkert Pieske and colleagues from the Charite Universitatsmedizin Berlin in Germany hypothesized that soluble guanylate cyclase stimulators may be beneficial in patients with heart failure and preserved ejection fraction by enhancing cGMP generation.16 SOCRATES-PRESERVED is a placebo-controlled dose-finding study to characterize the safety, tolerability, and pharmacological effects of vericiguat in heart failure and preserved ejection fraction. A total of 477 patients (with chronic heart failure and ejection fraction of ≥45%) were randomized within 4 weeks after heart failure hospitalization or outpatient treatment with intravenous diuretics for heart failure to vericiguat once daily fixed dose of 1.25 or 2.5 mg, or 5 or 10 mg titrated from 2.5 mg starting dose, or placebo for 12 weeks. The two primary endpoints were change from baseline in log-transformed N-terminal pro brain natriuretic peptide or NT-proBNP and left atrial volume at 12 weeks. Baseline median NT-proBNP was 1174 pg/mL and mean left atrial volume 86.3 mL. The change in logNT-proBNP in the pooled three highest dose arms was not different from placebo and there was no evidence of a dose–response relationship. Similarly, the decrease in left atrial volume in the pooled three highest dose arms by 1.7 ± 12.8 mL was not different from placebo. Vericiguat was well tolerated without differences in adverse events compared with placebo and with low discontinuation rates. At 12 weeks of treatment, blood pressure did not change compared with placebo. Kansas City Cardiomyopathy Questionnaire Clinical Summary score, a pre-specified exploratory endpoint, improved in the 10 mg arm by 19.3 points from baseline. The authors conclude that vericiguat up to 10 mg was well tolerated in patients with heart failure and preserved ejection fraction. Although vericiguat did not change NT-proBNP or left atrial volume at 12 weeks compared with placebo, it was associated with improvements in quality of life. For further trials, longer duration and higher doses of vericiguat might be considered to study its clinical potential. These disappointing findings are discussed further in an Editorial by John G.F. Cleland from the Imperial College London in the UK.17 Kaplan Meier event curves for the primary endpoint <110 mmHg (A), 110-<120 mmHg (B), 120-<130 mmHg (C), 130-<140mmHg (D) and >140 mmHg (E) on enalapril and LCZ696. Cox regression p-values and the interaction p-value are given (from Böhm M, Young R, Jhund PS, Solomon SD, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Swedberg K, Zile MR, Packer M, and McMurray JJV. Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF. See Pages 1132–1143). Although left ventricular dysfunction is a major and most frequent cause of pulmonary arterial hypertension,20 increases in blood pressure in the pulmonary circulation also occur in the absence of heart failure for many reasons. In another research article entitled ‘SERAPHIN haemodynamic substudy:theeffect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters andN-terminal pro brain natriuretic peptidelevels and their association with disease progression in patients with pulmonary arterial hypertension’, Nazzareno Galiè and colleagues from the University of Bologna in Italy evaluated the effect of macitentan, an endothelin receptor antagonist, on haemodynamic parameters and NT-proBNP levels in patients with pulmonary arterial hypertension.21 Of the 742 patients, 187 with right heart catheterization at baseline and month 6 participated in a haemodynamic substudy. Pre-specified endpoints included change from baseline to month 6 in cardiac index, right atrial pressure, mean pulmonary arterial pressure, pulmonary vascular resistance, mixed venous oxygen saturation, and NT-proBNP. At 6 months, macitentan improved cardiac index, right atrial pressure, mean pulmonary arterial pressure, pulmonary vascular resistance, and NT-proBNP as compared with placebo. Absolute levels of cardiac index, right atrial pressure, and NT-proBNP at baseline and 6 months, but not their changes, were associated with morbidity and mortality. Patients with a cardiac index >2.5 L/min/m2, right atrial pressure <8 mmHg, or NT-proBNP levels <750 fmol/mL at month 6 had a lower risk of morbidity and mortality than those not meeting these thresholds. Thus, the authors conclude that for all treatment groups, baseline and month 6 absolute values of cardiac index, right atrial pressure, and NT-proBNP, but not their changes, were associated with morbidity and mortality, confirming their relevance in predicting disease progression in patients with pulmonary arterial hypertension. Macitentan increased the likelihood of reaching such threshold values that are associated with lower risk of morbidity and mortality. The clinical implications of these findings are further discussed in a thought-provoking Editorial by Erik R. Swenson from the University of Washington in the USA.22 This issue concludes with an article entitled ‘Effect of breathing oxygen-enriched air on exercise performance in patients with pre-capillary pulmonary hypertension:randomized, sham-controlled crossover trial’ by Silvia Ulrich and colleagues from the University Hospital of Zurich in Switzerland. The purpose of their trial was to test the hypothesis that breathing oxygen-enriched air increases exercise performance of patients with pulmonary arterial or chronic thrombo-embolic pulmonary hypertension and to investigate the mechanisms involved.23 In a randomized, sham-controlled, single-blind, crossover design, 22 patients with pulmonary arterial or chronic thrombo-embolic pulmonary hypertension with resting mean pulmonary arterial pressure of 35 mmHg and ambient air PaO2 >7.3 kPa, underwent four bicycle ergospirometries to exhaustion on different days, while breathing either oxygen-enriched (FiO2 0.50 or hyperoxia) or ambient air (FiO2 0.21 or normoxia) using progressively increased or constant load protocols. During ramp exercise, the maximal work rate significantly increased from 113 W with normoxia to 132 W with hyperoxia. Constant load exercise endurance also increased significantly from 571 s to 1242 s. With hyperoxia, PaO2 and PaCO2 increased at the end of exercise, and ventilatory equivalents for CO2 were reduced, while the physiological dead space over tidal volume ratio remained unchanged. Thus, it appears that in patients with pulmonary arterial or chronic thrombo-embolic pulmonary hypertension, breathing oxygen-enriched air provides major increases in exercise performance. This is related to an improved arterial oxygenation that promotes oxygen availability in muscles and brain and to a reduction of the excessive ventilatory response to exercise, thereby enhancing ventilatory efficiency. Such patients may therefore benefit from oxygen therapy during daily physical activities and training. The practical implications of these findings are discussed by Hans-Peter Brunner-La Rocca from the University Hospital in Maastricht, the Netherlands in his balanced Editorial.24 The editors hope that readers of this issue of the European Heart Journal will find it of interest.