Renin-angiotensin-aldosterone system (RAAS) blockers, consisting primarily of Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin II Receptor Blockers (ARBs), are among the most widely prescribed cardiovascular therapies in the world. Used by tens of millions of patients to manage hypertension, chronic kidney disease (CKD), and heart failure, these classes have established safety profiles documented over decades of clinical use. However, the sheer volume of exposure means that postmarketing surveillance data capture a substantial safety footprint. In 2025 alone, the FDA Adverse Event Reporting System (FAERS) received approximately 46,056 individual safety reports naming either an ACE inhibitor or an ARB, highlighting the steady stream of safety signals monitored by pharmacovigilance, medical-affairs, and drug-safety teams.
Quick answer
What is the scenario question? Our drug-safety and medical-affairs teams need a defensible quantitative baseline for ACE-inhibitor and ARB adverse-event reporting. How many FAERS reports name these drugs, and what are the real signals?
Direct Answer: In 2025 the FDA FAERS database carried about 46,056 reports naming an ACE inhibitor or an ARB, of which roughly 30,776 were serious, 3,371 fatal, and 14,430 involved hospitalization, per the public openFDA FAERS extract (export dated June 10, 2026). Reporting peaked at about 65,466 named reports in 2021 and has declined since. The recurring signals are angioedema (about 495 named-set mentions in 2025), acute kidney injury and renal failure (about 1,770), cough (about 1,273), and hyperkalemia (about 487), with an ACE-inhibitor-versus-ARB suspect split (19,161 ACE-inhibitor versus 26,603 ARB suspect reports in 2025) and an angioedema mention rate that runs higher for ACE inhibitors. These are reporting frequencies, not incidence, and cannot by themselves establish causality.
| Metric | 2021 | 2022 | 2023 | 2024 | 2025 | 2026 (Partial)* |
|---|---|---|---|---|---|---|
| Total Named Reports | 65,466 | 66,329 | 60,633 | 46,223 | 46,056 | 10,688 |
| Serious Reports | 44,225 | 41,130 | 39,850 | 32,496 | 30,776 | 7,212 |
| Fatal Reports | 6,301 | 5,616 | 5,369 | 3,747 | 3,371 | 925 |
| Hospitalizations | 20,589 | 19,307 | 17,441 | 15,288 | 14,430 | 3,283 |
| Angioedema Mentions | 659 | 718 | 851 | 648 | 495 | 125 |
| Hyperkalemia Mentions | 513 | 461 | 561 | 502 | 487 | 137 |
| Cough Mentions | 2,969 | 3,364 | 2,776 | 1,444 | 1,273 | 242 |
| Renal Impairment Mentions | 2,451 | 2,370 | 2,138 | 1,930 | 1,770 | 438 |
*Note: 2026 data are partial, reflecting reporting processed through the June 10, 2026 snapshot. These figures must not be annualized.
Who this is for
- Pharmacovigilance and Signal-Detection Teams: Establishing a quantitative reporting baseline to differentiate true safety alerts from background noise.
- Medical Affairs and Medical Information Specialists: Preparing dossiers, safety summaries, and clinical responses regarding class-wide vs. drug-specific risks.
- Hypertension Formulary and PBM Managers: Structuring step-therapy protocols and assessing drug-safety inputs for cardiovascular drug classes.
- Clinical Safety Directors at Biopharma Developers: Reviewing the established safety footprints of competitor molecules and standard-of-care agents.
Methodology, in one paragraph
The statistics presented in this analysis are computed directly from the public openFDA FAERS extract (export dated June 10, 2026), which aggregates millions of individual case safety reports (ICSRs) filed by clinicians, manufacturers, and consumers. An individual report is attributed to the ACE inhibitor and ARB class when the drug substance name matches a predefined regex pattern containing generic identifiers for the primary marketed agents in the class: lisinopril, enalapril, ramipril, benazepril, fosinopril, quinapril, moexipril, perindopril, trandolapril, captopril, losartan, valsartan, irbesartan, candesartan, telmisartan, olmesartan, eprosartan, azilsartan, and the direct renin inhibitor aliskiren. Reports are normalized by unique safety report IDs to prevent duplicate counting. Seriousness categories (serious, fatal, hospitalization) are based on the FDA’s standardized classification. Adverse event reactions are mapped to MedDRA Preferred Terms (PTs) within the dataset. Because FAERS is a spontaneous-reporting database, these figures represent raw reporting frequencies rather than incidence rates. They lack an exposure denominator (total patient-years), are prone to reporting bias (e.g., stimulated by recalls or media coverage), and do not prove direct clinical causality. For the broader database context and methodology, see our companion analysis of 20 million FAERS reports; for comparative chronic-drug baselines, see our statin safety numbers analysis.
How many FAERS reports name ACE inhibitors and ARBs, and is reporting rising or falling?
To evaluate the postmarketing safety profile of RAAS blockers, we analyzed reporting trends from 2021 through the first half of 2026. The overall volume of reports naming an ACE inhibitor or ARB in any role (primary suspect, secondary suspect, concomitant, or interacting) has experienced a steady downward trajectory after peaking in the early 2020s.
In 2021, the class accumulated 65,466 named reports. This volume rose slightly in 2022 to 66,329, before falling to 60,633 in 2023, 46,223 in 2024, and stabilizing at 46,056 in 2025. The partial 2026 data show 10,688 reports processed through June 10, indicating a continuation of this stable baseline.
This multi-year decline is primarily attributed to several converging factors:
- Recall Normalization: The massive wave of reporting associated with the sartan nitrosamine contamination recalls of 2018–2021 began to subside, removing a large volume of "stimulated" reports from the database. In the early phases of these recalls, pharmacy-led notifications and class-action lawsuits drove thousands of asymptomatic patients to file reports, creating an artificial bulge in the data.
- Prescribing Stabilization: The prescribing volume for both classes has reached a mature plateau in the US, with minor year-over-year fluctuations as older patients remain stabilized on generic therapy. The therapeutic algorithms for primary hypertension are well-entrenched, leaving little room for sudden surges in new patient starts.
- Database Maturation: The FDA's data ingestion and deduplication processes have become more sophisticated, reducing the duplicate submission rate that historically inflated raw counts in spontaneous surveillance systems.
Despite the drop in total named reports, the proportion of reports classified as "serious" has remained high. In 2021, serious reports accounted for 67.6% of the class total (44,225 reports). By 2025, serious reports still represented 66.8% (30,776 reports). This high proportion does not indicate that these drugs are highly toxic; rather, it reflects a well-known feature of spontaneous reporting systems, where mild, non-serious events are underreported, and reporting is heavily skewed toward events resulting in death, hospitalization, disability, or medical intervention.
How serious is the reported burden (fatal and hospitalization counts)?
The absolute numbers of severe outcomes in reports naming an ACE inhibitor or ARB are substantial. Over the 2021–2025 period, the database recorded:
- Fatal Outcomes: A total of 24,404 reports with a death flag (averaging over 4,800 deaths per year). In 2025, there were 3,371 fatal reports, representing 7.3% of all reports naming these drugs.
- Hospitalizations: A total of 87,055 reports documented a serious outcome of hospitalization or prolonged hospitalization. In 2025, hospitalizations were noted in 14,430 reports, representing 31.3% of the class total.
When pharmacovigilance teams encounter these numbers, they must apply critical epidemiologic caveats to avoid drawing incorrect conclusions:
- Polypharmacy and Multimorbidity: ACE inhibitors and ARBs are prescribed to patients with advanced cardiovascular disease, diabetes, and chronic kidney disease. These patients have high baseline mortality and hospitalization rates due to stroke, myocardial infarction, and end-stage renal disease, independent of drug therapy.
- Lack of Denominator: Because these drugs are taken by tens of millions of patients daily, a fatal reporting rate of ~3,300 cases per year represents an extremely small fraction of total exposed patient-years.
- Concomitant Biologics and High-Risk Therapies: Many cardiovascular patients are simultaneously taking high-risk drugs (such as oral anticoagulants or insulin). The adverse event may be attributed to a concomitant drug, yet the report still matches the search query because the ACE inhibitor or ARB was recorded in the patient's medication list.
- Reporting Bias: Highly publicized safety debates (such as the early-pandemic speculation regarding RAAS blockers and COVID-19 receptor vulnerability) transiently increased both patient and provider reporting behavior.
What are the dominant signals: angioedema, hyperkalemia, renal effects, cough?
When we filter the MedDRA Preferred Terms in reports naming an ACE inhibitor or ARB, the clinical signature of RAAS blockade becomes clear. Four primary adverse event categories dominate the safety profile:
1. Renal Impairment (Acute Kidney Injury and Renal Failure)
Renal effects represent the single largest clinical signal in the dataset. In 2025, there were 1,770 reports containing acute kidney injury (AKI) or renal failure terms, down from a peak of 2,451 in 2021.
The physiological basis is well-understood: RAAS blockers dilate the efferent arteriole in the glomerulus, reducing intraglomerular pressure. While this effect is protective over the long term (slowing the progression of CKD), it can cause a transient increase in serum creatinine and acute decompensation in patients with severe bilateral renal artery stenosis, severe heart failure, or volume depletion. When combined with NSAIDs and diuretics (the "triple whammy"), this risk is compounded, frequently resulting in emergency admissions.
2. Cough
Cough accounted for 1,273 reports in 2025, down from a peak of 3,364 in 2022. Cough is a classic class-effect warning, particularly for ACE inhibitors, where it is estimated to affect 5% to 20% of treated patients. The dry, hacking cough is mediated by the accumulation of bradykinin and substance P in the respiratory tract, as ACE is responsible for breaking down these inflammatory peptides.
3. Angioedema
Angioedema represents a critical, high-risk safety gate. In 2025, the database recorded 495 reports mentioning angioedema. While less frequent than cough or renal impairment, angioedema is clinically serious due to the risk of upper airway obstruction, which can be fatal if not managed immediately.
The mechanism is identical to that of cough: bradykinin-mediated vasodilation. However, while cough is a minor nuisance, angioedema involves rapid, localized swelling of the dermis, subcutaneous tissue, and submucosal tissues. In severe cases, the swelling affects the tongue, glottis, or larynx, leading to acute asphyxiation. Unlike histamine-mediated allergic angioedema, bradykinin-mediated angioedema does not respond to epinephrine, antihistamines, or corticosteroids, requiring specialized airway management or the use of specific bradykinin-pathway inhibitors (such as icatibant or ecallantide) in emergency settings.
4. Hyperkalemia
Hyperkalemia (elevated potassium) was noted in 487 reports in 2025. Because RAAS blockade reduces aldosterone secretion, potassium excretion in the distal tubule is impaired. This signal is particularly relevant for patients with pre-existing renal impairment or those taking concomitant potassium-sparing diuretics or potassium supplements, as detailed in our hypertension therapy landscape clinical briefs.
How do ACE inhibitors and ARBs differ in suspect reporting and angioedema mentions?
One of the most important comparative clinical questions is how the safety profile shifts when a patient is prescribed an ACE inhibitor versus an ARB. In clinical practice, ARBs are frequently prescribed as alternatives for patients who cannot tolerate ACE inhibitors due to cough or mild angioedema.
To evaluate this contrast, we partitioned the 2025 FAERS suspect reports (where the drug was coded as the primary or secondary suspect, rather than a concomitant medication) into two distinct groups:
- ACE Inhibitor Suspects: 19,161 reports
- ARB Suspects: 26,603 reports
Comparative Suspect Safety Split (2025 Suspect Set)
| Parameter | ACE Inhibitor Suspects | ARB Suspects | Clinical & Physiological Rationale |
|---|---|---|---|
| Total Suspect Reports | 19,161 | 26,603 | ARBs account for a larger share of suspect reports in 2025. |
| Angioedema Mentions | 331 (1.73%) | 147 (0.55%) | ACE inhibitors show a 3.1-fold higher rate of angioedema mentions per suspect report compared to ARBs (1.73% vs. 0.55%). This aligns with bradykinin-mediated pathophysiology. |
| Cough Mentions | 468 (2.44%) | 808 (3.04%) | ARBs show a slightly higher proportion of cough suspect reports in this slice. This is likely a reporting artifact: patients who develop a cough on an ACE inhibitor are switched to an ARB, and if the cough persists or is reported during the transition, the ARB is listed as a suspect drug. |
This suspect split provides quantitative support for the bradykinin hypothesis. Because ARBs block the angiotensin II type 1 (AT1) receptor directly without inhibiting the enzyme kininase II (which is identical to ACE), they do not prevent the degradation of bradykinin. Consequently, ARB-induced angioedema is rare, typically occurring at a rate of less than 0.1% in clinical trials.
However, the presence of 147 angioedema mentions in the ARB suspect set highlights a critical clinical watch point: there is a small degree of cross-reactivity. Clinical safety guidelines advise caution when initiating an ARB in a patient with a history of severe ACE-inhibitor-induced angioedema, as some patients may have a baseline predisposition to angioedema that can be triggered by other physiological pathways.
How does the sartan nitrosamine recall history show up in the data?
A unique feature of the FAERS database is that it captures administrative, product-quality, and recall-related events in addition to purely clinical adverse drug reactions. This is highly visible when analyzing the top reaction terms for suspect ACE inhibitor and ARB reports.
In 2025, we tokenized and ranked the reaction terms reported for the suspect set. Strikingly, the single highest-frequency reaction term combination was:
- "no adverse event|recalled product administered" (or similar product-quality terms), appearing 932 times.
This administrative reporting volume represents the long tail of the sartan nitrosamine contamination recalls. Beginning in July 2018, the FDA and global regulators issued alerts for multiple generic valsartan, losartan, and irbesartan products after finding trace amounts of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA)—classified as probable human carcinogens—introduced during the chemical synthesis of the active pharmaceutical ingredient (API).
The Chemistry of Nitrosamine Contamination
Nitrosamines form when secondary or tertiary amines react with nitrosating agents (such as nitrites) under acidic conditions. During the manufacture of the tetrazole ring structure that characterizes sartans, dimethylformamide (DMF) or other amine solvents were used alongside sodium nitrite reagents. Under certain reaction parameters, DMF degraded into dimethylamine, which subsequently reacted with nitrous acid to yield NDMA.
Because many generic drug manufacturers sourced their APIs from a small number of global suppliers (such as Zhejiang Huahai Pharmaceutical), a single contaminated batch cascaded across dozens of finished product manufacturers, leading to global stockouts and an unprecedented regulatory enforcement campaign, as discussed in our drug recall analysis.
For pharmacovigilance teams, this is a classic example of "database noise." If a signal-detection algorithm simply counts reports naming valsartan, it would register a massive spike in the late 2010s and early 2020s. Without filtering out the "recalled product administered / no adverse event" reports, a team might conclude that valsartan had suddenly become clinically unsafe, when in reality the reporting spike was driven by administrative product-quality notifications, not clinical toxicity.
How should clinicians and pharmacists manage the transition from an ACE inhibitor to an ARB?
When a patient develops a persistent, dry cough on an ACE inhibitor, clinical guidelines recommend switching to an ARB to maintain RAAS blockade. While this transition is routine, access and clinical teams must follow a structured workflow to ensure safety and coverage:
- Document the Intolerance: Clear documentation of "ACE-inhibitor-induced cough" or "non-life-threatening angioedema" is required in the electronic health record to support future prior-authorization or step-therapy exceptions.
- Washout Period: While not strictly necessary for cough, a washout period is highly recommended when switching a patient who experienced mild ACE-inhibitor-induced angioedema to an ARB. Although ARBs have a low rate of cross-reactivity, allowing bradykinin levels to fully normalize before initiating ARB therapy reduces the risk of recurrent swelling.
- Payer step-therapy validation: Most commercial payers structure their hypertension step therapy to require trial of a generic ACE inhibitor or generic ARB first. Access teams must ensure the switch is processed as a clinical exception rather than a brand-tier start, utilizing generic sartans (losartan, valsartan) as the primary therapeutic alternatives.
- Monitor for Cross-Reactivity: Instruct the patient to seek immediate emergency care if they experience swelling of the lips, tongue, or throat, as the low rate of ARB cross-reactivity (estimated at 2% to 10% of patients with a history of ACE angioedema) remains a clinical possibility.
What this means for pharmacovigilance, medical-affairs, and access teams
- Establish a Clean Clinical Baseline: Signal-detection teams must exclude product-quality and recall-related MedDRA terms (such as "product quality issue" or "recalled product administered") when running disproportionality analyses for ARBs. Failure to do so will result in false-positive signals driven by nitrosamine recall reports rather than true clinical events.
- Quantify the Angioedema Differential: Medical affairs teams can utilize the 3.1-fold difference in angioedema reporting rates between ACE inhibitor suspects and ARB suspects to support medical information responses. While the risk of angioedema on ARBs is not zero, the spontaneous reporting rate is significantly lower than that of ACE inhibitors.
- Differentiate AKI Reporting: When analyzing renal safety, signal-detection teams must adjust for patient age and concomitant use of diuretics and NSAIDs (the "triple whammy" of acute kidney injury). Raw FAERS counts for AKI (1,770 in 2025) are heavily confounded by these patient-risk factors.
- Structure Formulary Steps Wisely: PBM and formulary managers can justify step-therapy designs that place generic ARBs alongside or immediately after ACE inhibitors, as the lower rate of bradykinin-mediated side effects (cough and angioedema) in ARBs improves long-term patient adherence.
FAQs
Do FAERS counts for ACE inhibitors and ARBs prove these drugs caused the adverse events?
No. FAERS counts are spontaneous reports of adverse events that occurred while a patient was taking a medication, but they do not prove that the drug caused the event. Spontaneous reports are subject to major limitations, including incomplete data, variable reporter training, and duplicate submissions.
Crucially, FAERS lacks a control group and a prescribing denominator (total exposed patients), meaning it is impossible to calculate the absolute risk or incidence of an event from FAERS data alone. Reports frequently list multiple suspect and concomitant drugs, making direct causal attribution difficult without clinical study.
Why do ACE inhibitors show a higher angioedema mention rate than ARBs in FAERS?
The higher angioedema rate for ACE inhibitors (1.73% of suspect reports vs. 0.55% for ARBs in 2025) is driven by their mechanism of action. ACE (angiotensin-converting enzyme) is identical to the enzyme kininase II, which degrades bradykinin, a potent vasodilator and inflammatory peptide.
By inhibiting this enzyme, ACE inhibitors allow bradykinin to accumulate in tissue, which can trigger localized vasodilation and increased vascular permeability, leading to angioedema. Because ARBs block the angiotensin receptor directly and do not inhibit the breakdown of bradykinin, their rate of angioedema is significantly lower.
How does the sartan nitrosamine recall affect the FAERS numbers?
The sartan nitrosamine recalls, which began in 2018 due to trace impurities of NDMA and NDEA in generic valsartan, losartan, and irbesartan products, led to a major wave of administrative reporting. Many patients and pharmacists submitted reports stating that a recalled product had been administered, even when the patient experienced no clinical symptoms.
In 2025, the term combination "recalled product administered / no adverse event" appeared 932 times in the suspect set, demonstrating that recall-related administrative noise continues to affect the database years after the initial recall alerts.
Sources
- US FDA. openFDA FAERS (Adverse Event Reporting System) extract, export dated June 10, 2026. Per-drug, class-union, suspect-split, and reaction aggregates computed by PharmaDossier from the public FAERS extract. openFDA Data
- U.S. National Library of Medicine. "ACE Inhibitors." StatPearls. NCBI Bookshelf. Last updated January 2026. NCBI Bookshelf
- National Kidney Foundation. "ACE Inhibitors and ARBs: Protecting Kidney Function and Managing Potassium." CKD Education Portal. Accessed July 1, 2026. National Kidney Foundation
- Toh S, Reichman ME, Houstoun M, et al. "Comparative Risk for Angioedema Associated with the Use of Drugs That Inhibit the Renin-Angiotensin System." JAMA Internal Medicine. 2012;172(20):1582-1589. JAMA Network
- Palmer BF. "Managing potassium and renal function in patients taking ACE inhibitors and ARBs." Cleveland Clinic Journal of Medicine. 2019;86(9):601-610. CCJM
- New Zealand Medicines and Medical Devices Safety Authority (Medsafe). "Reminder: ACE inhibitor-induced angioedema can be fatal." Prescriber Update. June 2023. Medsafe Article
- US FDA. "FDA Alerts Health Care Professionals and Patients to Recalls of Valsartan, Losartan, and Irbesartan." FDA Drug Safety Communications. Updated 2025. FDA Recalls Portal
