Vericiguat

Mechanism of Action

There are two forms of guanylate cyclase; one is a transmembrane receptor for natriuretic peptides, and the other is a soluble guanylate cyclase (sGC), a receptor for nitric oxide. Nitric oxide and natriuretic peptides indirectly increase phosphokinase G (PKG) levels through sGC by activating guanosine triphosphate to cyclic guanosine monophosphate (cGMP). The phosphokinase G causes cellular hyperpolarization and cardiac muscle relaxation. In patients with cardiovascular risk factors, the endothelium-generated reactive oxygen species decrease the nitric oxide levels and inactivate the sGC by removing the heme group from sGC leading to decreased PKG and impaired muscle relaxation resulting in stiffness. The transforming growth factor-beta produced by monocytes led to the conversion of fibroblasts into myofibroblasts, ultimately leading to collagen formation and stiffening of cardiac muscle.[1][8]

The treatment of heart failure with nitric oxide generators is shown to have clinical benefits but is limited by the development of tolerance. Also, the reactive oxygen species decreases the sensitivity of soluble guanylate cyclase to nitric oxide. The soluble guanylate cyclase stimulators act by nitric oxide independent enhancement of soluble guanylate cyclase activity along with increased sensitivity of sGC to endogenous nitric oxide.

Vericiguat stimulates soluble guanylate cyclase that activates the cGMP pathway independent of nitric oxide involvement. It also sensitizes soluble guanylate cyclase to nitric oxide by stabilizing nitric oxide binding to the binding site. In other words, vericiguat restores the cyclic guanosine monophosphate under low nitric oxide conditions and oxidative stress.[2][9][10] Compared to other nitro-vasodilators, vericiguat does not induce tolerance on long-term administrations.[7] An increase in cardiac output and cardiac index and a decrease in systemic vascular resistance has been noted with vericiguat at a 5.0 mg or higher dose.[11][12]

Pharmacokinetics

Absorption: The bioavailability of vericiguat is 93% when taken with food. Food increases AUC (area under the curve-  total drug exposure across time) of vericiguat. 

Distribution: Vericiguat has high plasma protein binding (98%) and is primarily bound to albumin. The average volume of distribution(Vd) is approximately 44 Liters. 

Metabolism: Vericiguat is metabolized primarily by glucuronidation via UGT1A9(uridine diphosphate-glucuronosyltransferase) and UGT1A1 to form an inactive metabolite. The Cytochrome P450 system is responsible for <5% metabolism of vericiguat.

Excretion: The half-life is 30 hours in patients with heart failure. Clearance is approximately 1.6 L/h. Vericiguat is excreted primarily in urine as an inactive metabolite(53%). Vericiguat is also excreted as an unchanged drug in feces(43%).[9]

Administration

An increase in cardiac output, an increase in heart rate of 4 to 10 beats per minute, and an increase in the cardiac index are observed in patients who received a single dose of 5 to 15 mg per oral (PO). In addition, systemic vascular resistance has decreased from the baseline, thereby reducing blood pressure. However, the effect was inconsistent and not dose-dependent.

The immediate-release form of the vericiguat showed a mean half-life (t1/2) of about 18 to 22 hours. There were no significant differences between single and multiple doses regarding bioavailability, the area under the curve (AUC), and Cmax (maximum concentration). Absorption through percutaneous endoscopic gastrostomy (PEG) is reported to be faster when compared to oral administration. As discussed above, food increases the bioavailability of vericiguat and reduces the variability in the postprandial/fed state; hence medication should be administered with food. A single oral dose of 10 mg was well tolerated by healthy Japanese, Chinese and European subjects.[1][11]

According to phase III of the VICTORIA Heart Failure with Reduced Ejection Fraction study, the dose of vericiguat can be increased from 2.5 mg to 10 mg depending on patient response. Phase II of the VITALITY Heart Failure with Preserved Ejection Fraction study reported that the dose could be titrated up to 15 mg.[9]

Use in Specific Patient Population

Patients with Hepatic Impairment: No dosage adjustment of vericiguat is advised in patients with mild hepatic impairment(Child-Pugh A) or moderate hepatic impairment (Child-Pugh B). Use of vericiguat should be avoided in severe hepatic impairment(Child-Pugh C) as there are no studies conducted in these patient populations.

Patients with Renal Impairment: No dosage adjustment of vericiguat is suggested in patients with eGFR ≥15 mL/min/1.73m2. However, the use of vericiguat has not been investigated in patients with eGFR <15 mL/min/1.73m2 or on dialysis.[13]

Breastfeeding Considerations: Vericiguat has the potential cause for serious adverse reactions in breastfed infants. Hence, breastfeeding is not recommended during treatment with vericiguat. 

Pregnancy Considerations: Due to concerns for embryo-fetal toxicity and substantial fetal harm to the fetus, vericiguat should not be administered to pregnant women or currently planning for pregnancy.[6]

Adverse Effects

The most common adverse drug reactions of vericiguat include hypotension, syncope, and anemia.[2] Headache and postural dizziness reportedly could be due to vasodilation mediated by vericiguat. Diarrhea, nausea, and abdominal discomfort have been postulated due to smooth muscle relaxation.[11] Symptomatic hypotension, orthostatic hypotension, syncope, and anemia are some of the known side effects of vericiguat.[1] A mild increase in heart rate was observed, which researchers considered the compensatory baroreflex due to vasodilation and blood pressure reduction.[12][7]

Few subjects developed proteinuria, influenza, and nasopharyngitis during the drug trial, but no severe adverse event or death has been reported. Changes in vasoactive hormones for cGMP, plasma renin activity, and noradrenaline have been noted, but no changes in aldosterone activity, urine or serum electrolytes have been observed. Limited but consistent decrease in creatinine, urea, and uric acid was reported.[11] 

In contrast, one study reported no significant difference in worsening renal function between vericiguat or placebo use. Therefore, Vericiguat might be beneficial in patients with severe heart failure and does not require decreasing or stopping the dose of vericiguat in patients with a mild increase in serum creatinine or potassium levels.[13] Vericiguat would be potentially useful to treat heart failure with reduced ejection fraction and improve the patient's quality of life.[14][15]

Drug-Drug Interactions

Administration of omeprazole with vericiguat reduced the absorption of vericiguat. Magnesium hydroxide and aluminum hydroxide also decreased the absorption of vericiguat. Drug-drug interaction study indicates that vericiguat is a suitable drug for managing patients with heart failure with multiple comorbidities requiring polypharmacy.[9]

Contraindications

Vericiguat should be avoided in patients taking long-acting nitrates, soluble guanylate cyclase stimulators (e.g., riociguat), or phosphodiesterase type 5 (PDE-5) inhibitors concerning hypotension and syncope. Clinicians should also avoid using the drug in patients with severe anemia because of concerns of a decrease in hemoglobin level with vericiguat.[2][10]

Boxed Warning: Embryo-Fetal Toxicity: Animal reproduction studies suggest that vericiguat may cause fetal harm to a pregnant woman. Suggest females of reproductive age of the potential hazard to a fetus. Clinicians should order pregnancy tests before treatment with vericiguat. Advise females to use contraception during treatment and at least one month after the final dose of vericiguat.

Monitoring

The clinical team should monitor blood pressure, heart rate, and hemoglobin are advised in patients treated with vericiguat.[1][2][10]

Monitor BNP or NT-proBNP levels to assess response to the therapy to vericiguat. Monitor fluid intake and output, body weight, and clinical signs and symptoms of congestion and hypoperfusion in patients with heart failure.[6]

Toxicity

Limited information is available about toxicity in human patients treated with vericiguat. In the clinical trial, doses up to 10 mg have been investigated. In a study of patients with HFpEF, multiple doses of vericiguat 15 mg were investigated without toxicity. However, in the event of an overdose, hypotension may occur. There is no specific antidote for vericiguat toxicity. Symptomatic treatment should be provided. Vericiguat is not removed by hemodialysis due to the high plasma protein binding(98%).[9]

Enhancing Healthcare Team Outcomes

Heart failure remains a major burden in the US, with multiple patients at risk of death or recurrent hospitalization. An estimated 8 million people in the US will have heart failure by 2030.[16] Hence it is important to optimize heart failure therapy. GDMT (goal-directed medical therapy) for HFrEF includes beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter inhibitors. According to ACC/AHA 2022 guidelines, in high-risk patients with HFrEF (Stage C) and recent worsening of HF already on GDMT, vericiguat has an important role in reducing HF hospitalization and cardiovascular death.[6] VICTORIA trial has proven the efficacy and safety of vericiguat in patients with HFrEF. However, in the VITALITY-HFpEF trial, treatment with vericiguat did not improve the physical limitation score of the Kansas City Cardiomyopathy Questionnaire (KCCQ).[10]

Vericiguat is typically prescribed by clinicians (MD, DO, NP, PA) as part of the interprofessional healthcare team. The clinician plays the most crucial role in the overall care of heart failure patients with multiple comorbidities. Consultation with a cardiologist or heart failure specialist is highly recommended for high-risk patient populations for treatment optimization. Pharmacists have an important role in medication reconciliation and adverse drug reaction counseling. Specialist nurses play an important role in monitoring fluid status for patients with heart failure and reporting any adverse effects of vericiguat therapy to clinicians. Critical care physicians and HF specialists are crucial in stabilizing patients with acute decompensated heart failure requiring vasopressors and inotropes. Early hospital readmission in patients with heart failure is quite common. In the United States, approximately 30% of patients are re-hospitalized within 90 days of discharge. Hence optimization of heart failure treatment is crucial at discharge, where HF specialists and pharmacists can play a crucial role.[17] In summary, healthcare professionals have an essential role in educating patients regarding the importance of treatment of heart failure with GDMT, the role of vericiguat, and its adverse drug reactions. All interprofessional healthcare team members must have open lines of communication with the rest of the team to communicate any patient status changes and arrange for therapy adjustments when needed.

A systemic review and meta-analysis involving 19 randomized controlled trials showed that a multidisciplinary, interprofessional approach between primary care physicians, specialists, nurses, social workers, cardiologists, and pharmacist is crucial. Meta-analysis results indicated a significant reduction in mortality, heart failure readmissions, and all-cause readmissions involving the primary care provider model.[18] [Level 1]