Clinical Context

Angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) are both associated with improved hospitalization and mortality outcomes among patients with heart failure with reduced ejection fraction, and they are a cornerstone of therapy for many patients. However, clinicians must also weigh the risk for known adverse events when prescribing these drugs. For ACE inhibitors, one of the most dangerous, albeit rare, adverse events of therapy is angioedema.

Angioedema occurs in 0.2% to 1.0% of patients receiving ACE inhibitors, and the severity of angioedema in the setting of ACE inhibitor treatment can vary from bothersome to life-threatening. A buildup of bradykinin appears to be responsible for the angioedema associated with ACE inhibitors. However, because ARBs block the angiotensin II receptor directly, they do not result in an increase in bradykinin. A previous meta-analysis of antihypertensive drugs found weighted incidence rates of angioedema of 0.30% for ACE inhibitors, 0.11% for ARBs, and 0.07% with placebo. Another analysis found no difference in the rate of angioedema in comparing ARBs and placebo.

Study Synopsis and Perspective

New renin-angiotensin-system (RAS) inhibitor therapy using sacubitril-valsartan is no more likely to cause angioedema than starting out with an ACE inhibitor or ARB.

However, the risk climbs when such patients start on an ACE inhibitor or ARB and then switch to sacubitril-valsartan compared with those prescribed the newer drug, the only available ARNI, in the first place.

Those findings and others from a large database analysis, by researchers at the US Food and Drug Administration (FDA) and Harvard Medical School, may clarify and help alleviate a residual safety concern about the ARNI (that it might promote angioedema) that persists after the drug’s major HF trials.^[1,2]

The angioedema risk increased the most right after the switch to the ARNI from one of the older RAS inhibitors. For example, the overall risk doubled for patients who started with an ARB then switched to sacubitril-valsartan compared with those who started on the newer drug. But it went up about 2.5 times during the first 14 days after the switch.

A similar pattern emerged for ACE inhibitors, but the increased angioedema risk reached significance only within 2 weeks of the switch from an ACE inhibitor to sacubitril-valsartan compared with starting on the latter.

The analysis, based on data from the FDA’s Sentinel adverse event reporting system, was published January 23 in the Journal of the American College of Cardiology.^[3]

A Rare Complication, but...

Angioedema was rare overall in the study, with an unadjusted rate of about 6.75 per 1000 person-years for users of ACE inhibitors, less than half that rate for ARB users, and only one fifth that rate for sacubitril-valsartan recipients.

But even a rare complication can be a worry for drugs as widely used as RAS inhibitors. And it is not unusual for patients cautiously started on an ACE inhibitor or ARB to be switched to sacubitril-valsartan, which is only recently a core guideline-recommended therapy for heart failure (HF) with reduced ejection fraction.

Such patients transitioning to the ARNI, the current study suggests, should probably be watched closely for signs of angioedema for 2 weeks, but especially during the first few days. Indeed, the study’s event curves show most of the extra risk “popping up” right after the switch to sacubitril-valsartan, lead author Efe Eworuke, PhD, told theheart.org | Medscape Cardiology.

The ARNI’s labeling, which states that the drug should follow ACE inhibitors only after a 36-hour washout period, “has done justice to this issue,” she said. But “whether clinicians are adhering to that, we can’t tell.”

Potentially, patients who miss the 36-hour washout between ACE inhibitors or ARBs and sacubitril-valsartan may account for the excess angioedema risk seen in the analysis, said Dr Eworuke, who is with the FDA’s Center for Drug Evaluation and Research, Silver Spring, Maryland.

But the analysis does not nail down the window of excess risk to only 36 hours. It suggests that patients switching to the ARNI, even those pausing for 36 hours in between drugs, should probably be monitored “2 weeks or longer,” she said. “They could still have angioedema after the washout period.”

New RAS Inhibition With ARNI “Protective”

Compared with ARNI “new users” who had not received any RAS inhibitor in the prior 6 months, patients in the study who switched from an ACE inhibitor to ARNI showed a hazard ratio (HR) for angioedema of 1.62 (95% CI, 0.91-2.89), that is, only a “trend,” the report states.

But that trend became significant when the analysis considered only angioedema cases in the first 14 days after the drug switch (HR, 1.98; 95% CI, 1.11-3.53).

Those switching from an ARB to ARNI, compared with ARNI new users (37,893 matched pairs), showed a significant HR for angioedema of 2.03 (95% CI, 1.16-3.54). The effect was more pronounced when considering only angioedema arising in the first 2 weeks (HR, 2.45; 95% CI, 1.36-4.43).

Compared with new use of ACE inhibitors, new ARNI use (41,998 matched pairs) was “protective,” the report states, with an HR for angioedema of 0.18 (95% CI, 0.11-0.29). So was a switch from ACE inhibitors to the ARNI (69,639 matched pairs), with an HR of 0.31 (95% CI, 0.23-0.43).

However, compared with starting with an ARB, ARNI new use (43,755 matched pairs) had a null effect on angioedema risk (HR, 0.59; 95% CI, 0.35-1.01); as did switching from an ARB to ARNI (49,137 matched pairs; HR, 0.85 (95% CI, 0.58-1.26).

The analysis has limitations, Dr Eworuke acknowledged. The comparator groups probably differed in unknown ways, given the limits of propensity matching, for example, and because the FDA’s Sentinel System data can reflect only cases that are reported, the study probably underestimates the true prevalence of angioedema.

For example, a patient may see a clinician for a milder case that resolves without a significant intervention, she noted. But “those types of angioedema would not have been captured by our study.”

Dr Eworuke discloses that her comments reflect her views and not those of the US Food and Drug Administration; she and the other authors, have disclosed no relevant financial relationships.

J Am Coll Cardiol. Published January 23, 2023.

Clinical Implications

• Angioedema occurs in 0.2% to 1.0% of patients receiving an ACE inhibitor. A buildup of bradykinin appears to be responsible for the angioedema associated with ACE inhibitors. However, because ARBs block the angiotensin II receptor directly, they do not result in an increase in bradykinin. Previous research has found similar rates of angioedema in comparing ARBs and placebo.
• In the current study, treatment with sacubitril-valsartan for HF with reduced ejection fraction was associated with lower rates of angioedema vs treatment with an ACE inhibitor. Switching from an ACE inhibitor to ARNI was protective against angioedema. Rates of angioedema were similar in comparing treatment with ARB and ARNI.
• Implications for the healthcare team: Members of the healthcare team who are prescribers should consider first-line treatment with ARNI for HF with reduced ejection fraction vs an ACE inhibitor based on clinical trial data as well as a lower risk for angioedema.

Earn Credit