Keith C. Ferdinand, MD, FACC, FAHA, FASPC, FNLA, professor of medicine and the Gerald S. Berenson Endowed Chair in Preventative Cardiology, Tulane University School of Medicine, discusses the results of the recently halted FRESH trial, why there is such a great need for new antihypertensive agents, and possible contributory factors to outcome disparities between Black and White patients.
The most powerful and prevalent risk factor for cardiovascular disease—including heart attacks, stroke, chronic kidney disease, and heart failure—is hypertension; the condition is poorly controlled across all populations, but there are higher levels among the non-Hispanic Black or African American patient populations. Reasons for this include social determinants of health and lack of adequate insurance coverage, explained Keith C. Ferdinand, MD, FACC, FAHA, FASPC, FNLA, professor of medicine and the Gerald S. Berenson Endowed Chair in Preventative Cardiology, Tulane University School of Medicine discusses the results of the recently halted FRESH trial.
Ferdinand is just one of the authors for, “Top-Line Results of The First-in-Class Aminopeptidase-A Inhibitor Firibastat in Treatment-Resistant Hypertension (FRESH) Study,” presented today at the American Heart Association’s Scientific Sessions in the annual meeting’s final late-breaking science presentation.
This transcript has been edited lightly for clarity.
What were you hoping to see from the FRESH trial of firibistat vs what did the results actually show?
The FRESH trial was a placebo-controlled trial with a new agent, firibistat, not yet approved by the FDA, to see if this particular agent would lower blood pressure. It works through a novel mechanism of inhibiting aminopeptidase-A, which converts angiotensin II to angiotensin III in the brain. What we know so far is that it was a negative trial and that there was not statistically significant lowering of blood pressure with this new agent.
How great is the need for a new class of antihypertensive agents, especially in addressing hypertension health disparities and increasing life expectancy?
Hypertension is the most powerful and prevalent risk factor for cardiovascular disease, including heart attacks, stroke, chronic kidney disease, and heart failure. Unfortunately, it's much higher in the African American population. Non-Hispanic Blacks get more severe hypertension, and it starts earlier in life. Furthermore, across all populations, hypertension is poorly controlled. Resistant hypertension—that is, patients who have elevated blood pressure despite being on 3 or more medications, one of which is a maximum-tolerated diuretic—is becoming increasingly recognized as a public health crisis. So hopefully, these new medicines which are being studied may add to our armamentarium so that we can control the scourge.
Can you discuss why Black patients and women have a higher risk of hypertension?
Hypertension, to some extent, is part of the aging process. Our vessels become more stiff, less compliant. So with the systolic blood pressure, it starts to elevate as we age. Let's look for instance at women. Early in life, women tend to have less high blood pressures than men. About 5 to 6 years post menopause, when some of the estrogen effects have been lost, the rates of hypertension increase in women such that by the time a woman is in her mid 60s, her risk of hypertension is equal to or greater than that of a man. In fact, they're more older women than older men in the United States. Therefore, looking at age as a risk factor, there are more women who have hypertension than men.
In the non-Hispanic Black community or African American community, the reason for elevated blood pressure is unclear. It's related to a multitude of factors. One is the social determinants of health, not having an identifiable source of primary care, not having access to medications. And another reason, of course, is lifestyle: physical inactivity, excess increase in sodium, increasing obesity, and psychosocial stress. These factors are hard to measure. But we know when we look across populations, especially in the Southeast, there are higher levels of blood pressure in the non-Hispanic Black population than in other populations. One of the reasons may be the so-called Southern diet—you know it when you see it. It's high in sodium, high in saturated fat. In the REGARDS trial, looking at thousands of patients across the Southeast, White vs Black patients, it appears that the Southern diet is one of the markers for the increase in blood pressure.
What role does masked hypertension play in disease progression?
Self-monitored blood pressure—checking the blood pressure out of the office—has now increasingly been recognized as the best way to appropriately diagnose hypertension. About 15% to 20% of persons have elevated blood pressures in the clinic, but not outside of the clinic and at home. That's called white coat hypertension. On the other hand, there are some people in whom the clinic is a safe place and their blood pressures may actually be lower in the clinic than at home. That's called masked hypertension.
In order to effectively diagnose hypertension on a regular basis, we need to embrace self-monitored blood pressure out of the office. That way, we can see which patients may have masked hypertension, which is hidden from the clinician at the time of the practice. What are some of the reasons why that happens? It's unclear, but it's how people respond to stress and the environment within the clinic, whether they have white coat hypertension or masked hypertension. Self-monitored blood pressure, checking the blood pressure outside of the clinic, therefore will give us a better window of actually diagnosing hypertension persistently. What was your next up question? It was related to that, yes,
How does inadequate insurance coverage influence short- and long-term patient outcomes for those with the condition?
So if you look at persons who have elevated blood pressure, and also are uncontrolled, their various markers, now Black vs White patients is one of the markers. But a strong measure of poorly controlled blood pressure is not having insurance. Patients who don't have insurance tend not to get their blood pressures treated earlier. As the blood pressure elevates, the arterioles become thickened, the heart becomes hypertrophyied, and the kidneys start to lose function. Patients who have uninsured status and don't have a primary source of medical care tend to have more poorly controlled hypertension and more complications of hypertension once it's diagnosed.
What are the next steps in investigating novel antihypertensive agents now that firibistat is not moving forward with trials?
Unfortunately, we have a negative trial. But there are other types of interventions, including renal nerve innervation, and other medications, such as endothelial antagonists, which are being investigated. We need all the tools we can to control blood pressure. Elevated blood pressure is the most potent and prevalent risk factor, and I think it's the main reason for what I call the White-Black mortality gap. When you look at life expectancy and life itself, Black adults in the United States have a shorter life expectancy. It’s driven mainly by cardiovascular disease, and the number one risk factor for that disparity in cardiovascular disease is uncontrolled hypertension.
So we need newer therapies if they're going to be well tolerated and effective to help lower blood pressure. At the same time, we know that many patients already have generic medicines that don't cost a lot, that are readily available, but [they] still don't take medicines. So we have to ensure that patients have what's called shared decision-making. They know they have a condition, they understand the risk, and they share in the therapy to control that risk.