Journal Club - MyCred



Journal Club Cole SmithArmstrong PW, Pieske B, Oconnor CM. Effects of vericiguat in heart failure with reduced ejection fraction. NEJM. 2020;Background and OverviewBackground/Introduction~1 minVericiguat is a medication that stimulates guanylate cyclase and it has been studied for use as an add-on therapy for heart failure patients to help decrease hospitalization and mortality. Heart failure is a very common condition with more than 650,000 new patients diagnosed annually. 5-year absolute mortality rates for diagnosis of heart failure are roughly 50% which makes this a disease state requiring further research in order to improve survival rates. Currently there are 2 types of heart failure, diastolic or preserved ejection fraction, and systolic or reduced ejection fraction heart failure. The majority of guideline suggested therapy is targeted at systolic heart failure utilizing agents such as beta-blockers, ACE inhibitors, angiotensin receptor blockers, ANRIs, and loop diuretics. A combination of these agents is commonly utilized to help preserve heart function and decrease mortality risk, while also treating symptoms of heart failure such as pulmonary edema. The article being reviewed looks at the potential benefit of adding an additional medication for the treatment of heart failure, Vericiguat, a guanylate cyclase stimulator.1,2Objectives~30 secPrimaryTo see if adding guanylate cyclase stimulators (specifically Vericiguat) to current guideline directed therapy for heart failure with reduced ejection fraction (HFrEF) would be beneficial.SecondaryTo see if adding Vericiguat to therapy posed any safety risks to patients with HFrEF.MethodsStudy design~30 secThe study design was a prospective, parallel, experimental multi-national, multi-centered, randomized, double-blind, placebo-controlled trial utilizing intention to treat protocol.Inclusion &Exclusion~30 secEligible patients were at least 18 years of age and had chronic heart failure NYHA class II, III, or IV, a reduced left ventricular ejection fraction of less than 45% within 12 months before randomization, and an elevated natriuretic peptide level (300pg/mL BNP, or 1000pg/mL NT-proBNP or 500 and 1600 respectively if they had AF),within 30 days before randomization. They also had to have worsening HF as described as hospitalization or IV diuretic therapy. Exclusion criteria included things like: SBP of less than 100, concurrent use of nitrates, other guanylate cyclase stimulators, PDE5 inhibitors, or use of IV inotropes or implantable ventricular assist devices.Interventions & Comparators~30 secIntervention being studied: Vericiguat (slowly titrated up to 10mg PO QD).Comparator: inactive placeboEndpoints/OutcomesPrimary~15 secThe primary outcome or endpoint for this study was a composite of death from cardiovascular causes, OR, first hospitalization for HF. This is a great clinical endpoint to look at because it can show the effects of Vericiguat on mortality of patients diagnosed with HF and also can show decreases in hospitalization.Secondary~15 secThe secondary outcome measures for this study were components of the primary outcome, first and subsequent hospitalizations for HF, a composite of death from any cause or first hospitalization for heart failure, and death from any cause. There were also some safety outcomes which looked at the rates of syncope, and hypotension associated with Vericiguat. These secondary outcome measures are important for making sure overall mortality benefit is achieved. For example, its possible more deaths could occur from something non-cardiovascular related which would not be seen in the primary outcome measures. Sample Size The type of variable studied in this trial was survival data. The sample size needed to reach 80% power was 4872 patients with 782 events. 6857 patients underwent screening with 5050 undergoing randomizations. There were 897 primary outcome events in the vericiguat group and 972 in the placebo group meaning that this study was more than adequately powered beyond 80%. The study had an alpha value of 0.05 with a 95% CI. The statistical tests used were Cox regression model, and log-rank tests which utilized time to event analysis. This makes sense considering we are dealing with survival data such as time to first hospitalization and cardiovascular death. Statistical Analysis~1.5 minResults# Patients~30 secOf the 6857 patients that underwent screening for this trial, roughly 1800 were excluded for not meeting eligibility criteria. Of the 5050 that underwent randomization, 610 of the vericiguat group discontinued the trial with 177 lost due to adverse events, 195 decided to discontinue therapy, and 173 patient’s physicians discontinued therapy. In the placebo group 565 discontinued the trial with 159 leaving because of adverse events, 190 deciding to discontinue therapy, and 154 with patient’s physicians discontinuing the trial regimen. Comparing loss between the 2 groups they were fairly evenly distributed and there was no significant difference in patients lost during the trial.Primary Endpoints & Secondary Endpoints~2 minDeath from cardiovascular causes or first hospitalization for heart failure (the primary outcome) occurred in 897 patients (35.5%) in the vericiguat group and in 972 patients (38.5%) in the placebo group (a difference of 3%) (hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P = 0.02. This is statistically significant because our P value is less than our alpha of 0.05. The NNT is 24. This means that for every 24 people with HFrEF that we treat with Vericiguat, we prevent 1 primary outcome measure from occurring (HF hospitalization or cardiovascular death). The hazard ratio of 0.9 indicates that that 10% less patients treated with vericiguat will experience a primary outcome measure when compared to those on placebo.Clinical Relevance, Evaluation, & Conclusion ~3.5 minStrengths: The study met power, was double-blinded, multi-centered, and placebo-controlled and assessed a variety of patients in different stages of HF who could potentially benefit from this medication. Their inclusion and exclusion criteria made sense considering the different factors that could influence a patient’s risk of death or medication efficacy.Weaknesses: This trial specifically included only patients with “worsening heart failure” which means that the mortality benefit can really only be applied to those who are already on guideline directed therapy for HF who are experiencing increased heart failure burden. The owners of Vericiguat (Bayer and Merk) were co-sponsors for this trial and analyses were conducted by the sponsors. This however isn’t too bad because they were also analyzed independently by the duke clinical research institute. This study also did not include very many black individuals and a large majority of HF patients are black. Lastly there were not very many patients with class IV HF that were included in this study and so the effects of Vericiguat may not be applicable to this population. Internal Validity: The internal validity of the trial was great. As I said previously, the trial was double-blinded, multi-centered, occurred in multiple different countries, and was approved by all IRBs involved. It was also an experimental trial and therefore we can infer causation from it.External Validity: The study could probably be more externally valid by including patients who do not have worsening heart failure, more black individuals, and more individuals with class IV HF. Overall the external validity was good in terms of making sure the two arms of the trial were evenly balanced for males vs. females etc.In conclusion I think that this trial has some real clinical relevance. For patients with worsening heart failure, we can decrease their risk of hospitalization, and cardiovascular death. I think a NNT of 24 is fairly low and with a hazard ratio of 0.9 this seems clinically significant to me. Something that will definitely affect the clinical use of this medication is the price. Currently, I’m not sure if the price of this medication will deter its use in the future. I can definitely see this trial being pivotal in changing the HF guidelines in future updates and we may see more of this drug class used in the future treatment of HF.Overall, I would recommend the use of this medication in patients with worsening HFrEF that are already on guideline directed therapy. References:Gupta A, Ghimire G, Hage FG. Guidelines in review: 2013 ACCF/AHA Guideline for the Management of Heart Failure. Journal of Nuclear Cardiology. 2013;21(2):397–9.Armstrong PW, Pieske B, Oconnor CM. Effects of vericiguat in heart failure with reduced ejection fraction NEJM. 2020;Yancy CW, Jessup M, Bozkurt B. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. Journal of Cardiac Failure. 2017;23(8):628–51.What is Heart Failure? [Internet]. . [cited 2020Jul27]. Available from: ................
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