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Vericiguat in patients with Heart failure and Reduced.pptx
- 1. Vericiguat in patients withHeart Failure and reduced Ejection Fraction Rephaim Mpofu Journal Club 16 March 2022
- 2. Failinghearts » Novel drugclasses have significantly improved management of HFrEF » Substantial cause of morbidity, mortality, and healthcare resource utilization » 50% mortality rate at 5 years post-diagnosis » Points towards the need for better, novel, pharmaceutical options 2
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- 5. Solubleguanylatecyclase:Weneedmore 5 "Please, sir, mayI have some more please?“ ~ Oliver Twist Armstrong, 2018
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- 10. Methods » Primary outcome:composite of death from cardiovascular causes or first hospitalization for heart failure. » Sample size calculation: 4872 participants – 782 events, 80% power, 11% event rate in placebo group » Hierarchical testing strategy for hypothesis testing » Time-to-event analysis with Cox regression model 10
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- 23. Treatmentimplications » Main effectdemonstrated in hospitalization reduction & composite endpoint • NNT = 24, but composite » No effect on mortality – high risk group • Annual mortality rate: 33% vs 11-20% in PARADIGM & DAPA-HF » Difference favoring vericiguat appeared promptly after initiation & persisted » More direct effect on sGC-cGMP pathway, does not induce tolerance with long-term administration 23
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- 25. Conclusion » Vericiguat reducedthe composite endpoint of cardiovascular mortality and hospitalisations in HFrEF patients. » Patients with advanced HFrEF with a recent history of acute decompensation despite optimal medical therapy are optimal candidates for starting treatment with vericiguat. » No effect on mortality, therefore likely limited role compared to some other agents, e.g. SGLT-2 inhibitors/ARNIs 25
Editor's Notes
- #2 Medical treatment of heart failure (HF) with reduced ejection fraction (HFrEF) has significantly advanced with an introduction of disease-modifying therapies with a proven benefit on survival, morbidity and functional limitations. Although advances in care have reduced mortality and morbidity, the prognosis for these patients remains poor. Average cost of hospital admission in one study in 2013 amounted to $10,000 It is estimated that only 50% of patients survive 5 years beyond their initial diagnosis. In SA, heart failure is most commonly diagnosed the third and fifth decades of life, with a varying sex distribution between studies, but a possible tendency towards increased risk for women based on a large SA cohort study Hospitalizations and the need for supplemental parenteral emergent therapy to treat exacerbations reduces quality of life and is a poor prognostic indicator prognosis. Points towards the need for better, novel, pharmaceutical options In a prospective cohort study of 11 000 patients that tracked the progression of heart failure on therapy, approximately 18.6% of patients were not on any of the 3 main drug classes, i.e. BB, RAS-inhibitors, or MRA, prior to worsening HF onset
- #3 HFrEF is a complex clinical syndrome, characterised by the compensatory activation of neurohormonal axes in response to the fall in cardiac output In the long-run neurohormonal activation leads to maladaptive changes in the heart, kidneys and the vasculature, which underly disease progression and contribute to end-organ damage. Shift in the major players Despite the use of these disease-modifying and life-prolonging interventions (mainly MRA, BB & RASI), many of the HFrEF patients still suffer a residual risk of mortality, HF hospitalisation and disease progression. Possibly due to progressoin, frailty, age, Aetiology, comorbidities, or inappropriate dosing of guideline directed medical therapies However, in the recent clinical trials of novel medications in HFrEF, the residual risk remained high despite optimal GDMT use. One important realization from recent therapeutic trials was that there are various novel pathways that go beyond neurohumoral blockade that can be manipulated
- #4 Numerous studies have demonstrated endothelium-dependent vasomotor abnormalities in HF, and impaired NO and cGMP signalling has been implicated in the pathogenesis of cardiovascular disease, including systemic arterial and pulmonary hypertension (PH), coronary artery disease, peripheral vascular disease and atherosclerosis The vascular endothelium normally generates nitric oxide, and that stimulates the soluble guanylate cyclase [SGC]-mediated cyclic GMP [guanosine monophosphate] production, or cGMP. Similarly, the endocardial endothelium is sensitive to nitric oxide and regulates contractility as well as diastolic function by raising that intracellular cGMP. In heart failure, this process becomes dysregulated, and there’s an insufficiency of cGMP and impairment of the diastolic relaxation and microvascular dysfunction. Reduced cGMP availability is associated with coronary microvascular dysfunction, cardiomyocyte stiffness, interstitial fibrosis, and ultimately, myocardial dysfunction has been suggested as a driving factor behind the progression of myocardial dysfunction in HF
- #5 Vericiguat is a soluble guanylate cyclase stimulator or agonist that acts by targeting endothelial dysfunction in patients with heart failure. The sGC is the intracellular receptor for its endogenous ligand nitric oxide (NO). NO is generated in endothelial cells upon physiologic stimuli such as laminar blood flow shear forces as well as within the endocardium. NO diffuses to neighboring tissues such as vascular or cardiac muscle cells and stimulates sGC to generate cyclic guanosine monophosphate (cGMP) in these cells By modulating the SGC, enhances the effect of nitric oxide, and overall increases cGMP. This has benefits that include vasodilation, direct antifibrotic effects, improvements in myocardial remodeling and, diastolic relaxation
- #6 First evidence of the potential for sGC modulation as an MOA was noted in vericiguat’s cousin, riociguat, an sGC developed for pulmonary arterial hypertension. Vericiguat was a result of PK and drug design optimization as it has been shown to have improved PK allowing once daily dosing. This was taken further for assessment in heart failure The first two trials of Vericiguat included the Soluble Guanylate Cyclase Stimulator in Heart Failure with Reduced Ejection Fraction Study (SOCRATES-REDUCED) and Soluble Guanylate Cyclase Stimulator in Heart Failure with Preserved Ejection Fraction Study (SOCRATES-PRESERVED) trials These trials looked at the safety and tolerability of Vericiguat as well as its effect on N-terminal pro hormone B-type natriuretic peptide Neither trial found a significant reduction in NT-proBNP but both studies showed Vericiguat was well tolerated. A post-hoc analysis also showed revealed numerical trends in both cardiovascular (CV) death and HF hospitalization, as well as improved New York Heart Association (NYHA) functional class in the 2 highest dose groups along with concurrent improvement in left ventricular EF with the highest target vericiguat dose Overall, vericiguat was safe and well tolerated relative to placebo, except for treatment-emergent syncope and hypotension that was more common in the 10-mg group (although this tended to occur within the first 2 weeks of randomization while receiving the 2.5-mg dose). The SOCRATES PRESERVED trial demonstrated an improvement in quality of life in HFpEF patients, which prompted the Patient-reported Outcomes in Vericiguat-treated Patients with HFpEF (VITALITY HFpEF) trial.
- #8 multinational, DB, placebo controlled randomized trial All the patients provided informed consent and entered a screening period (0 to 30 days), without a run-in period, during which adherence to the entry criteria was confirmed. Patients were then randomly assigned, in a 1:1 ratio, to 2.5 mg of vericiguat or matching placebo, within six strata based on geographic region and, within North America, race. Doses were increased to 5 mg and ultimately to the target dose of 10 mg once daily in a blinded manner, as guided by evaluation of blood pressure and clinical symptoms Patients were evaluated at weeks 2 and 4, and every 4 months thereafter until the end of the trial. Trial sponsors: Merck, Bayer, & Canadian Vigour centre, which is an Academic Research Organization (ARO) committed to the enhancement of cardiovascular health Data Analyses were conducted by the sponsors and independently replicated at the Duke Clinical Research Institute (DCRI). An independent data and safety monitoring committee evaluated patient safety.
- #9 18 years or older with CHF NYHA II to IV, a EF < 45% within 12 months of randomization, elevated NP Patients excluded: hypotesnsive, concomitant use of nitrates, PDE5 inhibitors, IV inotrobes or other medication IMPORTANT, TERATOGENICITY!! They note restriction on enrolled population with ESKD – capped at 15%, but no details as to how they did that
- #10 primary outcome was a composite of death from cardiovascular causes or first hospitalization for heart failure. The secondary outcomes were the components of the primary outcome, first and subsequent hospitalizations for heart failure, a composite of death from any cause or first hospitalization for heart failure, and death from any cause Adjudication of deaths, hospitalizations, and CV events was blinded Prespecified safety outcomes of clinical interest included symptomatic hypotension and syncope. A hierarchical testing strategy was prespecified for the certain secondary outcomes Where the P values are reported for the primary outcome and for subsequent secondary outcomes until the first outcome with a P value of greater than 0.05. P values are not reported for the components of the primary outcome because these analyses were not controlled for multiple comparisons. Time-to-event analysis with Cox regression model
- #15 Death from the primary outcome which was cardiovascular causes or first hospitalization for heart failure occurred in 897 patients (35.5%) in the vericiguat group and in 972 patients (38.5%) in the placebo group (hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P = 0.02) Death from cardiovascular causes occurred in 414 patients (16.4%) in the vericiguat group and in 441 patients (17.5%) in the placebo group (hazard ratio, 0.93; 95% CI, 0.81 to 1.06)
- #16 Hospitalization for heart failure occurred in 691 patients (27.4%) in the vericiguat group and in 747 patients (29.6%) in the placebo group (hazard ratio, 0.90; 95% CI, 0.81 to 1.00) Rate of hospitalization lower in treatment group – 38 vs 42 events per 100 patient years, HR = 0.91
- #18 Death from any cause was not significantly different – HR = 0.95 (0.84-1.07)
- #20 Serious adverse events occurred in 32.8% of the patients in the vericiguat group and in 34.8% of the patients in the placebo group -> point out safety of renal events – possible advantage compared with other agents, e.g. SGLT2 inhibitors, ACE inhibitors Other adverse events occurred in approximately 80% of participants and were equally distributed between groups Anaemia – more common in vericiguat group, absolute difference of 2% (from 5.7%) – observed class effect. Relative reduction in Hb at week 16 = -0.24 g/dl
- #21 Symptomatic hypotension – 9% in vericiguat group and 8% in placebo group, p = 0.12 Syncope – 4% in both groups
- #23 Main effect demonstrated in hospitalization reduction & composite endpoint – Role as additional, advanced disease therapy? – potential reduced efficacy in patients with severe disease
- #24 ICER based on model of add on therapy to prior SOC