The prevalence of heart failure in Korea is steadily rising due to population aging.

According to Factsheet 2022, published by the Korean Society of Heart Failure, the prevalence rate in Korea increased significantly from 0.77 percent in 2002 to 2.58 percent in 2020. The number of hospitalizations for heart failure patients also increased from 743 in 2015 to 1,166 in 2020. Notably, the prognosis for heart failure is worse with repeated hospitalizations due to worsening symptoms. That explains why treatments for patients with heart failure with reduced ejection fraction (HFrEF) are aimed at reducing the risk of hospitalization.

Currently, four drugs—RAAS inhibitors (ACEIs, ARBs, and ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT-2 inhibitors—are the first-line treatment for HFrEF patients. Nevertheless, some patients experience worsening symptoms, requiring readmission or emergency outpatient care. Therefore, there has been a need for new treatment options for patients whose symptoms worsen despite the four-drug regimen.

It is against this backdrop that Verquvo (vericiguat) has emerged. This drug has a different mechanism than existing therapies and improves symptoms in patients with repeated heart failure exacerbations. In September last year, the drug began to be prescribed in earnest, starting with the application of health insurance benefits.

Korea Biomedical Review interviewed Dr. Hyun Jun-ho, professor of cardiology at Asan Medical Center, about the unmet needs of HFrEF patients who experience worsening symptoms despite first-line standard treatment, learning about the clinical value of Verquvo and Professor Hyun’s experience prescribing it.

Question: Heart failure is known for its poor prognosis. What is the current treatment landscape like?

Answer: Until the late 20th century, heart failure was thought of as a disease that would kill you. However, in the 1980s and 1990s, good heart failure medications became available. With the advent of beta-blockers, ACE inhibitors, ARBs, and MRAs, the survival of patients with heart failure increased with triple therapy. In 2014, ARNI's PARADIGM-HF study led to another paradigm shift and increased survival rates. In the 2020s, SGLT-2 inhibitors emerged and were approved as first-line agents, forming a four-drug regimen, the so-called "Fantastic Four." Survival rates for heart failure patients have since continued to increase. However, the burden for some heart failure patients remains high.

Q: Why does patients’ burden remain despite four agents becoming the first-line standard of care?

A: It is clear that first-line agents have improved outcomes. Still, there has been unmet need. Some patients deteriorate despite optimal use of all four agents. In recent SGLT-2 inhibitor studies, one in seven patients still experience heart failure exacerbations. Second-line treatment options are limited for patients whose symptoms worsen despite first-line standard therapy. Based on the 2016 European Heart Failure Guidelines, ivabradine or CRT (cardiac resynchronization therapy) are the only options. The problem is that patients who experience worsening are more likely to have another worsening, and mortality rates continue to increase with repeated worsening.

The financial burden of hospitalization for patients with heart failure exacerbations is also significant. Hospitalization is not just a matter of adjusting medications. Many additional tests are required, and hospitalizations take a long time. According to National Health Insurance Service data, insurance claims for inpatients are overwhelmingly higher than for outpatients.

Q: Last year, the second-line drug Verquvo entered the formulary as it was covered by health insurance. How will heart failure patients benefit from this treatment?

A: The indication criteria are easy to fulfill. For example, regarding renal function alone, most MRAs, ARNIs, sacubitril-valsartan (Entresto), and ACE inhibitors require an eGFR of at least 30 mL/min/1.73 ml2. Still, many patients do not meet this criterion. In contrast, Verquvo can be used with an eGFR of 15 mL/min/1.73 ml2 or higher.

There are also benefits in terms of blood pressure management. With traditional first-line agents, blood pressure usually drops. The degree of reduction varies depending on the agent. However, as you increase the dose, the blood pressure gets lower and lower, so less than half of patients reach the recommended target dose. Verquvo is on the lower end of the spectrum, with a prescription starting point of 100 mm Hg or higher. If you don't have significant hypotension, you can try it. The data also show that there is not much concern about blood pressure lowering. In the phase 3 VICTORIA study, systolic blood pressure was only 0.3 mm Hg lower in patients on Verquvo compared to those not on Verquvo.

Another advantage is its broader coverage. The reimbursement threshold for conventional drugs is a left ventricular ejection fraction of less than 40 percent, whereas Verquvo is based on less than 45 percent. For example, if you have an ejection fraction of 41 percent to 42 percent, Entresto is not covered. This suggests that Verquvo covers a patient population not covered by existing drugs.

Q: How do the results of the VICTORIA study, which supported Verquvo's approval and reimbursement, compare to clinical studies of existing drugs?

A: The relative risk reduction (RRR) is not as high as expected. SGLT-2 inhibitors had a relative risk reduction of about 20 percent, and Entresto also had a relative risk reduction of about 20 percent. In comparison, Verquvo had a relative risk reduction of about 10 percent, but the absolute risk reduction (ARR) was about the same or even higher at 4.2 percent.

The reason is that the patient populations are completely different. The SGLT-2 inhibitor and Entresto studies were conducted in stable, ambulatory patients. On the other hand, the VICTORIA study looked at high-risk patients who had experienced heart failure exacerbations, so the relative risk reduction may be lower, but the absolute patient improvement was higher. The VICTORIA study also had many patients who needed to be treated (NNT) to reduce one event.

Q: We would also like to ask about tolerability. What is the safety profile of Verquvo?

A: Based on the VICTORIA study, the tolerability profile is very good. When we look at the tolerability profile of heart failure drugs, the main things we look at are hypotension-related symptoms, such as dizziness or orthostatic hypotension, decreased renal function, electrolyte abnormalities, and hyperkalemia. Verquvo's safety profile is similar to that of placebos in most important respects. We started using Verquvo in clinical practice after it was reimbursed in Korea in September last year. When we prescribed Verquvo to hospitalized patients, blood pressure did not drop as much as expected, and patients tolerated it well.

Q: What caution should be taken when prescribing Verquvo?

A: It is important to ensure that fluid levels are adequately maintained. Hospitalized patients are often in a state of fluid overload, and diuretics can be used to relieve symptoms before adding Verquvo. Adding Verquvo after too much fluid has been removed can cause a lot of dizziness. One of the caveats with Verquvo is that it works through the nitric oxide-soluble guanylyl cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) pathway and should not be used in combination with PDE-5 inhibitors. This is because they can cause a decrease in blood pressure. A case in point is sildenafil.

Q: Can you share your experience prescribing Verquvo in clinical practice?

A: It's too early to tell because it's only been four or five months since the domestic reimbursement was implemented, but I've heard from patients with heart failure who have experienced exacerbations that they are doing better after using Verquvo than before. I've had patients who have had significant drops in NT-proBNP levels, and I've had patients who have been discharged from the hospital after being prescribed Verquvo and are almost symptom-free.

Q: With the advent of new second-line agents, what must be done to prevent deterioration and increase treatment effectiveness when treating high-risk heart failure patients?

A: High-risk patients need to be clearly defined and identified quickly. Patients are very diverse. Some patients respond very well to first-line medications, while others respond moderately well and have not too bad symptoms. However, some patients continue to worsen. It is important to define these high-risk patients well.

The definition of a high-risk patient is one whose BNP, NT-proBNP, or NT-proBNP levels are elevated, persistently elevated, and severely symptomatic. Most importantly, high-risk patients are hospitalized repeatedly and visit the emergency department frequently. Such patients show a poor prognosis. These high-risk patients need to be intervened and treated quickly. First-line agents should be tried first, and second-line agents should be used quickly if they worsen despite first-line agents or if they worsen despite reaching the target dose.