Rapamycin (Sirolimus) for Feline Hypertrophic Cardiomyopathy: RAPACAT Trial, Evidence, and Safety

Bottom line

• As of July 2026, the RAPACAT trial — a double-blind, multicenter, NIH-funded, randomized, placebo-controlled clinical trial in 43 client-owned cats with subclinical non-obstructive HCM — is the first randomized evidence of a disease-modifying effect in feline HCM: maximum left ventricular (LV) myocardial wall thickness at Day 180 was significantly lower with low-dose delayed-release rapamycin than with placebo (P = 0.01).[1]
• Delayed-release rapamycin was well tolerated in RAPACAT, with no significant difference in adverse events versus placebo across the 6-month study.[1] A parallel hereditary-HCM colony pilot found dose-responsive transcriptomic suppression of the myocardial hypertrophy program and upregulation of autophagy — mechanistic support for a structural, not merely symptomatic, effect.[2]
• New ex vivo data (2026) show low-dose delayed-release rapamycin (LDDRR) impairs procoagulant platelet formation and reduces P-selectin expression in healthy cats while leaving classical agonist-induced aggregation largely intact — a hemostatically relevant nuance for a population already at risk of aortic thromboembolism (ATE/FATE).[3]
• Rapamycin (sirolimus) is not a fully FDA-approved feline drug and its use in cats remains off-label/investigational. The RAPACAT formulation (a proprietary delayed-release product) is not commercially available as a veterinary product; longer, larger, outcome-based confirmation is still required before this becomes standard of care. (A dispatch source reported a 2025 FDA conditional approval and target-animal-safety study for a sirolimus DR tablet in cats; that regulatory claim is uncited in the source material and is NOT independently confirmed here — see "Contraindications, precautions & PK.")

Drug facts

• Class: mTOR inhibitor (macrolide; immunosuppressant).
• Mechanism (MOA): Binds intracellular FK-binding protein 12 (FKBP12) → the complex inhibits mTORC1 (mechanistic target of rapamycin complex 1) → reduced mTOR-driven transcription of hypertrophic gene programs and de-repressed autophagy. Distinct from calcineurin inhibitors. In HCM, mTORC1 activation drives cardiomyocyte protein synthesis and hypertrophy; inhibition suppresses this program.[2]
• Dose / route / interval (as studied): Oral, delayed-release. RAPACAT used low- and high-dose delayed-release regimens dosed on an intermittent (weekly) schedule; the low-dose arm carried the more consistent efficacy signal.[1] The platelet study and the colony pilot both used LDDRR at 0.3 mg/kg PO once weekly.[2][3] No feline label dose is established outside investigational protocols.
• Indication: Not an approved veterinary indication. Investigated for subclinical, non-obstructive feline HCM. In humans, sirolimus (Rapamune) is FDA-approved for prophylaxis of organ transplant rejection.
• Approval status: No established full veterinary approval; use in cats is off-label extrapolation requiring owner informed consent. (Reported-but-unconfirmed 2025 FDA conditional approval / target-animal-safety study for a feline sirolimus DR tablet — treat as unverified; see below.)
• Contraindications (anticipated, no feline label): Caution in immunocompromised cats, active infection, or planned surgery, given mTOR effects on immune function and wound healing.
• Common AEs: No feline label AE profile. RAPACAT reported no significant AE difference vs placebo at the doses studied.[1] Class effects extrapolated from human use include hyperlipidemia, hyperglycemia at higher exposures, and hematologic changes (including effects on platelet counts).

Efficacy: does rapamycin modify feline HCM?

RAPACAT — randomized evidence in client-owned cats. Kaplan et al. (2023, J Am Vet Med Assoc) randomized 43 client-owned cats with subclinical, non-obstructive HCM to low-dose delayed-release rapamycin, high-dose delayed-release rapamycin, or placebo, with echocardiography, hematology, biochemistry, urinalysis, NT-proBNP, and cardiac troponin I at baseline and Days 60, 120, and 180. The primary outcome — maximum LV myocardial wall thickness at any location — was significantly lower in the low-dose group vs placebo at Day 180 (P = 0.01). The high-dose arm did not reach statistical significance, a finding the authors flagged for further investigation. Baseline echocardiographic and clinicopathologic values did not differ between groups, confirming successful randomization. The clinical-relevance statement: delayed-release rapamycin may prevent or delay progressive LV hypertrophy in subclinical HCM, with low-dose showing the more consistent signal.[1]

Mechanistic corroboration. Rivas et al. (2023, Animals (Basel)) studied a naturally occurring hereditary-HCM research colony (n = 9) given once-weekly delayed-release oral rapamycin at low and high doses for 8 weeks, with tissue transcriptomics plus tissue/urine/plasma proteomics. Transcriptomic differences between dose groups supported dose-responsive suppression of the myocardial hypertrophy program and stimulation of autophagy; the proteome showed changes consistent with anti-coagulant/anti-thrombotic effects, cellular remodeling, and altered metabolism — closely recapitulating the human rapamycin literature. Rapamycin was safe and well tolerated at both doses. The nine-cat design limits power but provides hypothesis-generating mechanistic context for the clinical signal.[2]

Note on attribution: both the RAPACAT RCT and the multi-omic pilot were circulated in earlier dispatches under inconsistent author/journal labels. The verified primary sources are Kaplan JL et al., JAVMA 2023 (RAPACAT, PMID 37495229)[1] and Rivas VN et al., Animals (Basel) 2023 (pilot, PMID 37893908)[2]; those are carried here.

Comparators and the therapeutic gap

Feline HCM is the most common cardiomyopathy in cats, with prevalence reported as high as ~15% in some populations.[2] Established pharmacotherapy — atenolol, diltiazem, clopidogrel — is symptomatic or aimed at complications (arrhythmia, thromboembolism), not at the hypertrophic process itself. Prior to RAPACAT, no drug had shown disease-modifying effects on feline myocardial hypertrophy. The mechanistic rationale for rapamycin comes from rodent models (mTOR inhibition prevents/reverses cardiac hypertrophy) and human transplant medicine (sirolimus-based immunosuppression associated with reduced cardiac wall thickness in renal-allograft recipients). Rapamycin has not been compared head-to-head against atenolol, diltiazem, or clopidogrel in cats, and has not been tested in symptomatic/overt HCM; for cats with clinical CHF, dynamic LVOTO, or atrial thrombus, standard-of-care management remains first-line.

Safety and adverse effects: cardiac tolerability and the platelet signal

Overall tolerability. In both the RAPACAT RCT and the colony pilot, delayed-release rapamycin was well tolerated with no significant AE excess at the doses studied.[1][2] Because mTOR regulates immune function, wound healing, cell proliferation, and (at higher exposures) lipid/glucose metabolism, monitoring for infectious complications, hematologic change, and metabolic effects is prudent in any clinical use; cats with concurrent systemic disease, active infection, or planned surgery are higher-risk candidates.

Platelet function — new ex vivo data (2026). Shaverdian et al. (2026, Scientific Reports) gave healthy client-owned cats LDDRR 0.3 mg/kg PO once weekly for 4 weeks, sampling platelet function (light transmission aggregometry + flow cytometry) at 3, 24, and 48 h after the final dose.[3] Findings:

• Aggregation largely preserved: LDDRR did not significantly impair agonist-induced platelet aggregation — the classical aggregation pathway remained largely intact.
• Reduced activation: LDDRR significantly decreased P-selectin expression (a marker of platelet activation / alpha-granule release) at 3 h with thrombin + collagen stimulation and at 24 and 48 h with ADP stimulation.
• Impaired procoagulant phenotype: Most notably, LDDRR significantly impaired procoagulant platelet formation — the maximally activated subset that externalizes phosphatidylserine and supports thrombin generation — apparently by preventing mitochondrial membrane-potential loss, a key step in procoagulant commitment.

Interpreting the platelet signal (contested clinical direction). HCM cats are already prone to spontaneous platelet activation and thrombus formation (disturbed intracardiac flow, endothelial activation, hypercoagulable milieu). Rapamycin's reduction of procoagulant potential could theoretically be protective against ATE — or could modulate hemostasis in more complex ways, particularly if a treated cat sustains vascular injury. These are ex vivo findings in healthy cats; whether they translate to altered in vivo thrombosis risk in HCM patients is unproven and requires prospective evaluation.[3] The 2024 ACVIM consensus on immune thrombocytopenia (ITP) in dogs and cats separately lists sirolimus as an emerging option for refractory ITP, weighing its mTOR-mediated immunosuppressive and potential platelet-modulating properties against adverse effects including hyperlipidemia and hematologic change.[4]

Special populations and multimodal use

• Concurrent antithrombotics (clopidogrel, aspirin). Combining sirolimus with clopidogrel or aspirin in HCM cats is a live question: additive inhibition of procoagulant platelet function may further lower thrombotic risk, but could also impair hemostasis after vascular injury. There is no outcome evidence to adjudicate this; individualize and monitor.[3]
• Pre-existing thrombocytopenia. Where available, baseline platelet-function assessment (optical or impedance aggregometry) is reasonable before initiating sirolimus, especially with pre-existing thrombocytopenia or concurrent antithrombotic therapy.[3] Because aggregation may be relatively preserved while procoagulant capacity is impaired, platelet count and platelet function can diverge — factor this into interpretation.[3]
• Cats that develop thrombocytopenia on therapy. Dose reduction or a drug holiday should be considered; serial platelet-count monitoring is already standard given the human mTOR-inhibitor class effect on platelet counts.[3][4]
• Symptomatic/overt HCM. Not tested; rapamycin's benefit in symptomatic disease (CHF, dynamic LVOTO, atrial thrombus) is unknown — do not substitute it for standard-of-care management of clinical disease.[1]

Contraindications, precautions & PK

• Regulatory status (read carefully). Rapamycin/sirolimus is not established as a fully FDA-approved feline product; use in cats is off-label/investigational and warrants owner informed consent. One 2026 dispatch source asserted that sirolimus "received FDA conditional approval for this indication in 2025" and referenced a 2025 FDA target-animal-safety study for a sirolimus DR tablet in cats (stated approval date March 14, 2025). That regulatory claim is uncited in the source material and could not be independently verified for this hub; do not represent it to owners as an established approval. Confirm current status directly against FDA/manufacturer labeling before relying on it.
• Formulation. RAPACAT used a proprietary delayed-release formulation not commercially available as a veterinary product; general-practice formulation, dosing, and monitoring may not replicate the trial and should not be assumed equivalent to human immediate-release sirolimus.[1]
• PK / exposure context. Studied feline dosing is intermittent (weekly) delayed-release — 0.3 mg/kg PO once weekly in the pilot and platelet studies — rather than the daily trough-targeted regimens used in human transplant.[2][3] Human class effects that scale with exposure (hyperlipidemia, hyperglycemia, hematologic change, impaired wound healing, immunosuppression) inform monitoring even though feline exposure targets are not label-defined.
• Immunosuppression precautions. Anticipate caution in immunocompromised cats, active infection, or the perioperative period, given mTOR effects on immunity and wound healing.

Practical decision support

• Best current framing: an evidence-supported investigational option for subclinical, non-obstructive HCM — not standard of care. The RAPACAT signal is a genuine advance, but small n (43), a non-significant high-dose arm, a proprietary formulation, and 6-month follow-up without CHF/AF/survival outcomes mean confirmation trials are still needed.[1]
• If considering off-label use: obtain informed owner consent; document baseline and periodic echocardiography plus clinicopathologic monitoring (CBC with platelet count, biochemistry incl. lipids/glucose, urinalysis); prefer enrollment in or proximity to ongoing research.[1]
• Baseline before starting (where available): platelet-function assessment, particularly with pre-existing thrombocytopenia or concurrent clopidogrel/aspirin.[3]
• On therapy: serial platelet counts; watch for infection, hyperlipidemia/hyperglycemia; consider dose reduction or drug holiday if thrombocytopenia develops; remember count and function may diverge.[3][4]
• Do not use as a substitute for standard management of overt/symptomatic HCM (CHF, LVOTO, atrial thrombus).[1]
• Verify regulatory status against current FDA/manufacturer labeling before making approval-based representations; treat the reported 2025 conditional approval as unconfirmed until you check.

Frequently Asked Questions

What is the RAPACAT trial and what did it find? RAPACAT was a double-blind, multicenter, NIH-funded, randomized, placebo-controlled trial in 43 client-owned cats with subclinical non-obstructive HCM. Maximum LV myocardial wall thickness at Day 180 was significantly lower with low-dose delayed-release rapamycin than placebo (P = 0.01); the high-dose arm was not statistically significant.[1]

Is sirolimus (rapamycin) FDA-approved for cats with HCM? It is not established as a fully approved feline drug; use in cats is off-label/investigational. Sirolimus is FDA-approved in humans for transplant-rejection prophylaxis. A 2026 dispatch reported a 2025 FDA conditional approval and target-animal-safety study for a feline sirolimus DR tablet, but that claim is uncited and not independently verified here — confirm current FDA/manufacturer labeling directly.

How does rapamycin work in feline HCM? It binds FKBP12 and inhibits mTORC1, reducing the mTOR-driven hypertrophic gene program and de-repressing autophagy. The RAPACAT colony pilot confirmed dose-responsive transcriptomic suppression of myocardial hypertrophy and autophagy stimulation in HCM-affected cats.[2]

What dose of rapamycin was used in cats? RAPACAT compared low- and high-dose delayed-release regimens (low dose carried the more consistent efficacy signal).[1] The colony pilot and the platelet study both used low-dose delayed-release rapamycin at 0.3 mg/kg PO once weekly.[2][3] No feline label dose exists outside investigational protocols.

Does rapamycin affect clotting or thromboembolism risk in cats? Ex vivo (2026), low-dose delayed-release rapamycin left classical platelet aggregation largely intact but reduced P-selectin expression and significantly impaired procoagulant platelet formation in healthy cats.[3] Whether this lowers real-world ATE/FATE risk in HCM patients is unproven and needs prospective study.

How should I monitor a cat on sirolimus? Baseline and periodic echocardiography plus clinicopathology (CBC with platelet count, biochemistry including lipids/glucose, urinalysis); where available, baseline platelet-function testing (especially with thrombocytopenia or concurrent clopidogrel/aspirin); watch for infection and metabolic effects; consider dose reduction or drug holiday if thrombocytopenia develops.[1][3][4]

Can rapamycin be combined with clopidogrel or aspirin? There is no outcome evidence. Additive inhibition of procoagulant platelet function could theoretically reduce thrombotic risk but might impair hemostasis after vascular injury — individualize and monitor rather than assume benefit.[3]

Should clinicians offer rapamycin to cats with subclinical HCM now? The evidence is scientifically important but not sufficient to make it standard of care. Off-label use should follow informed owner consent, baseline and periodic echocardiographic/clinicopathologic monitoring, and ideally research enrollment; overt/symptomatic HCM should still receive standard-of-care management.[1]

Changelog

• 2026-07-06: Consolidated the sirolimus-feline-HCM cluster into this evergreen hub. Folded in the RAPACAT evidence dispatch (update-2026-06-14) and the platelet-safety dispatch (update-2026-06-09). Deduplicated the RAPACAT RCT and the multi-omic pilot to single canonical entries and corrected inconsistent author/journal attributions to the verified primary sources (Kaplan JL et al., JAVMA 2023; Rivas VN et al., Animals (Basel) 2023). Added the ex vivo platelet-function evidence (Shaverdian et al., Sci Rep 2026) and the 2024 ACVIM ITP consensus context. Presented the reported 2025 FDA conditional-approval claim as unverified rather than asserting it.
• 2026-06-08: Hub first published (RAPACAT trial and evidence).