Heart Failure in Women: Key Differences and Clinical Tips

This transcript has been edited for clarity.

Hi. I'm Dr Eileen Hsich. I'm the medical director for heart transplantation at the Cleveland Clinic, and my specialty is sex differences in heart failure. I'm excited to talk to you about heart failure treatment in women, addressing the differences in managing heart failure in women as well as practical tips for clinicians. You think that I'm going to be starting off by telling you about the differences in how we're going to manage the patients, but I'm not. The reason I'm not going to do that is because our national guidelines are not sex specific.

What I'm really going to discuss with you today are the data so that you can decide for yourself what we should do and whether there really are differences. As we begin, I always think about the prevalence of the disease. Currently, there are 6.7 million Americans with heart failure, and approximately 45% of them are women. Globally, our best research shows that there are over 56 million people living with heart failure, and half of them are women.

We also know that there are different underlying causes in women and men. For women, the four risk factors are hypertension, diabetes, atrial fibrillation (AFib), and left bundle branch block. I know you knew about hypertension. Diabetes may not have been right up there in your mind. You see many women with AFib, so I know that you were thinking about it. We're going to come back to left bundle branch block; it really is very interesting.

For men, it is the risk for heart failure development after a myocardial infarction. Men are more likely to have an ischemic cardiomyopathy. It is also important to state that when women have heart failure, it is often with more preserved ejection fraction. We know that heart failure with preserved ejection fraction (HFpEF) is more common in women and heart failure with reduced ejection fraction (HFrEF) is more common in men.

Now we're going to talk about the four pillars in medical management, and we're going to start out with the easy medications that show no sex differences in benefit. The mineralocorticoid receptor antagonists (MRAs) show that there are no sex differences in regard to benefit. Women benefit as much as men, based on two of the largest studies, which were the RALES study, which studied heart failure that was ischemic and nonischemic, and then the EPHESUS study, which was specific to patients who had myocardial infarction. There was a mortality benefit in the women.

The next set of drugs that we're going to mention are the sodium-glucose cotransporter 2 (SGLT2) inhibitors. The combined endpoint for women and men was a combined endpoint of death and heart failure hospitalization. No matter what the ejection fraction was, women benefited like men for this drug.

The third class of agents that I want to discuss is the beta-blockers, which are really very interesting because they're so powerful. The studies for these drugs were stopped prematurely. When you take into consideration that women are underenrolled in clinical trials, remember that the studies for these drugs were stopped, so there weren't that many women. The fact that we showed a mortality benefit is really important.

The first drug that we're going to refer to is bisoprolol because CIBIS II was the first trial for this drug to demonstrate a mortality benefit in women and men. The second drug that I want to mention is metoprolol XL, which did not demonstrate a mortality benefit in the MERIT-HF study, but did demonstrate a benefit in reduced heart failure hospitalizations, which is also very important.

The third drug is carvedilol, which had been shown to reduce a combined endpoint of mortality and heart failure hospitalizations for patients with moderate symptoms. When I talk about these studies, they have anywhere from 250 to 1000 women enrolled, so these are relatively small studies and they still did demonstrate a benefit.

When we talk about angiotensin receptor-neprilysin inhibitors (ARNI), I think that's when it gets a little complex. The data are not very clear because ARNI is a combination pill — sacubitril combined with valsartan. When you have an ideal control for a study and you want to know what your magic ingredient is, which is the sacubitril, you really want to compare valsartan with ARNI so that you can find out what your magic little ingredient is doing.

When we had the PARAGON-HF study, which was for HFpEF patients who had an ejection fraction greater than 45%, there was a benefit in the women and not in the men, and that really was in the women with the lower ejection fractions. That's very interesting because the control was valsartan.

When we had the PARADIGM-HF study, that was more complex. The control was an angiotensin-converting enzyme (ACE) inhibitor, which is not an ideal control for women since, even in a meta-analysis that had over 1000 women, there has not been a proven benefit. The confidence intervals remain wide. Therefore, it's not quite a fair comparison to randomize women to ARNI versus an ACE inhibitor. Comparing ARNI to valsartan would be better in order to determine the additional benefit of sacubitril since valsartan alone has already been shown, in the Val-HeFT study, to reduce heart failure hospitalizations in women — although not mortality. There was a benefit.

When you look at the PARADIGM-HF study, which was for HFrEF patients, and you see that there is a benefit in the women, where the combined endpoint was heart failure hospitalization and mortality, you then see that there's a figure that shows what happens when we look at mortality alone. The benefit is not driven by mortality; it's driven by heart failure hospitalizations for the women, for which valsartan already had been shown to do this. Therefore, I don't know if sacubitril/valsartan is more powerful because we didn't have the right control in studies. From my standpoint, the data really are not there. We can all have our own biased opinions.

When we talk about devices, that gets really interesting because it goes back to those risk factors. We're going to start with implantable cardioverter defibrillators (ICDs). We have shown in many ICD trials that women and men had similar survival. There were very few women in these device trials. If you think the medical trials had only a few women, just imagine what the ICD trials had.

Santangeli and colleagues hypothesized that an ICD only saves you from sudden death. It doesn't really save you from anything else. In heart failure, women do live longer than men. Is this device really saving you? They weren't interested in all-cause mortality; they were interested in whether the device fired appropriately for ventricular tachycardia or ventricular fibrillation. They demonstrated in that meta-analysis that it was not very clear that women had the benefit. The rationale behind that comes from the MADIT studies that showed that men were more likely than women to have ventricular arrhythmias.

This is also true based on the Seattle Heart Failure Model. The derivation cohort had very few ICDs at that time, and women were less likely than men to have ventricular arrhythmias as the cause of death. It's not that we shouldn't put them in — I very strongly believe that we should — but we don't have that data.

In fact, in the Santangeli and colleagues study, women were more likely to have inappropriate firing for AFib. Remember that we talked about how one of the risk factors for heart failure was AFib. Women are more likely to have AFib and the ICD firing for AFib and not ventricular arrhythmias. This may be dependent on the type of cardiomyopathy.

Next, we're going to talk about biventricular pacemakers. Women tend to benefit more so that there is an improvement in symptoms and survival. What is fascinating is that left bundle branch block is a risk factor for the development of heart failure in women, which makes this next statement even more fascinating.

The FDA does their own analysis when they are reviewing devices and everything else, and they published one of them in JAMA Internal Medicine, taking three studies and seeing the benefit in women and men. They found that everybody benefits when the left bundle branch block has a QRS greater than 150 milliseconds. But with a QRS between 130 and 149 milliseconds, only the women benefited. That's fascinating because that is a risk factor — the development of the left bundle branch block causing heart failure in women. It makes you wonder whether you are correcting something that actually was responsible for their heart failure.

In advanced heart failure, we have left ventricular assist devices (LVADs) and heart transplantation. For years, we couldn't get LVADs small enough to fit in women. When they were larger, there were complications that were more common in women, such as stroke. With the newer devices — the HeartMate 3 is small, for instance — complications for everyone are very infrequent, and women and men benefit. I'm going to encourage clinicians to use them.

For heart transplantation, as I mentioned before, women tend to get HFpEF. I didn't mention that they get heart failure when they're older, for the most part. There are fewer women who are transplanted than men and eligible at younger ages. What we had for decades was that women were dying while they were on the waitlist for heart transplantation at a faster rate than men but living longer after transplantation. As LVADs became more appropriately sized for women, the complication rates went down; and we did see an improvement on the waitlist mortality rate before we changed the allocation system. But it really wasn't until after we changed the allocation system in 2018 that we saw great success. Now, women have similar survival while on the waitlist. They're transplanted at a faster rate despite the fact that they're less likely to receive the temporary mechanical support, and they tend to still do very well.

I'll leave you with the thought that women and men are different. We have different underlying diseases, different onset for the development of heart failure, and different ejection fractions in instances when heart failure develops. We have some differences in therapy response. Thank you.