Hydralazine + isosorbide dinitrate (H-ISDN)
AMT in HFrEF · Class IIa (self-identified Black patients, LVEF ≤40%, on optimal FMT); IIb (cannot tolerate ACE-I/ARNI/ARB)Removal by dialysis
What each drug's prescribing information says about removal by (haemo)dialysis. Where the label is silent, this page says so rather than inferring from protein binding.
- Hydralazine / isosorbide dinitratePartly or possibly removed
Hydralazine's dialysability has not been determined; dialysis does not remove isosorbide dinitrate or its mononitrate metabolite.
“Dialyzability of hydralazine has not been determined. Dialysis is not an effective method for removing isosorbide dinitrate or its metabolite isosorbide-5-mononitrate from the body.”
Drugs and doses
| Drug | Brands | Start | Target | Kidney dosing |
|---|---|---|---|---|
| Isosorbide dinitrate/hydralazine fixed-dose combination | BiDil | 1 tablet (ISDN 20 mg/hydralazine 37.5 mg) t.i.d. | 2 tablets (ISDN 40 mg/hydralazine 75 mg) t.i.d. | No dose adjustment in renal impairment per BiDil label (hydralazine dose was similar at CrCl 5-28 vs >100 mL/min). The generic hydralazine label says to use with caution in advanced renal damage. Hydralazine dialyzability is undetermined, and ISDN is not effectively removed by dialysis. |
| Hydralazine + isosorbide dinitrate (separate tablets) | generic hydralazine, Isordil | Hydralazine 25-50 mg + ISDN 20-30 mg 3-4 times daily | Hydralazine 300 mg/day + ISDN 120 mg/day in divided doses (ESC: 75 mg/40 mg t.i.d.) | Same as the fixed-dose combination. The generic hydralazine label (indicated for hypertension only) advises caution in advanced renal damage. |
Status by kidney stage
| Stage | Initiate | Continue |
|---|---|---|
| G1 | Recommended Class IIa (ESC 2026) in self-identified Black patients with symptomatic HFrEF on optimal FMT; Class IIb as an alternative when ACE-I/ARNI/ARB cannot be tolerated. No kidney restriction at this stage. | Recommended Continue; no kidney-related reason to stop at this stage. |
| G2 | Recommended Same as G1: IIa in self-identified Black patients; IIb when ACE-I/ARNI/ARB are not tolerated. | Recommended Continue. |
| G3a | Recommended ESC CVD-CKD 2026 gives a IIa recommendation for self-identified Black patients with HFrEF and CKD with eGFR ≥30. In A-HeFT the effect was not modified by CKD (eGFR above or below 60). No dose adjustment is needed. | Recommended Continue; the label requires no dose adjustment. |
| G3b | Recommended IIa in self-identified Black patients with eGFR ≥30 (ESC CVD-CKD 2026). AHA 2022 and ACC 2024 name it as the alternative when ACE-I/ARNI/ARB cannot be used because of renal insufficiency. | Recommended Continue; no dose adjustment. |
| G4 | Use with caution No formal recommendation below eGFR 30 (A-HeFT excluded severe kidney disease). It remains the RAAS-free option when ACE-I/ARNI/ARB are contraindicated, and KDIGO 2026 lists hydralazine/nitrates for advanced CKD. The BiDil label requires no dose adjustment; the generic hydralazine label advises caution in advanced renal damage. | Use with caution Continue with caution (hypotension, volume status); no dose adjustment per BiDil label. |
| G5 | Use with caution Allowed with caution. It is one of the few HFrEF drugs KDIGO 2026 lists for eGFR <15, but there are no trial data. Hydralazine is cleared mainly by metabolism and the BiDil label requires no dose adjustment. | Use with caution Continue with caution; monitor BP and volume status. |
| dialysis | Use with caution No randomized outcome data. A USRDS cohort (n=6306 users) found lower adjusted mortality with H-ISDN, and the HIDE pilot RCT (17 HD patients) found it tolerated but with more adverse events. Dialyzability of hydralazine is unknown and ISDN is not effectively removed (label). | Use with caution Continue with caution (intradialytic hypotension); no dose adjustment by label. |
| aki | Use with caution No source makes H-ISDN-specific AKI statements. ESC 2026 does not list it among the drugs to pause in AKI, but the label warns of hypotension when patients are volume or salt depleted, which must be corrected before starting. | Use with caution Usually continue unless hypotensive or volume depleted. In AKI from hypoperfusion, hold or reduce for hypotension. |
| transplant | No data No transplant-specific statement found in labels, ESC 2026, ESC CVD-CKD 2026, AHA 2022, KDIGO 2024 or the literature search. Apply the rules for the eGFR stage. | No data No transplant-specific statement; use the eGFR stage. |
Cutoffs recorded from the sources
- egfr < 30 mL/min/1.73m2 → caution (initiate; isdn-hydralazine-fdc, hydralazine-plus-isdn)“Treatment with a combination of hydralazine-isosorbide dinitrate should be considered in self-identified Black patients with HFrEF and CKD with an eGFR ≥30 mL/min/1.73 m2 and dilated left ventricle in combination with LVEF <45%, or LVEF ≤35%,” — esc2026-ckd, p. 39
- other <= 40 % LVEF → recommended (initiate; isdn-hydralazine-fdc, hydralazine-plus-isdn)“Hydralazine and isosorbide dinitrate should be considered in self-identified black patients with symptomatic HFrEF with LVEF ≤40% on top of optimal FMT to reduce the risk of HFH and death.” — esc2026, p. 38
- other <= 35 % LVEF (or <45% with LV dilatation) → recommended (initiate; isdn-hydralazine-fdc)“Patients were required to have LVEF ≤ 35% or left ventricular internal diastolic dimension > 2.9 cm/m2 plus LVEF < 45%.” — fda-bidil, Section 14 Clinical Studies
- other = 0 concomitant PDE5 inhibitor or riociguat (boolean) → contraindicated (initiate; isdn-hydralazine-fdc, hydralazine-plus-isdn)“Do not use BiDil in patients who are taking PDE-5 inhibitors, such as avanafil, sildenafil, tadalafil, or vardenafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia [see Drug Interactions (7.1)].” — fda-bidil, Section 4 Contraindications
Trial evidence (informational)
- A-HeFT · 1050 self-identified Black patients, NYHA III-IV, LVEF ≤35% or <45% with LV dilatation, on standard therapy (severe kidney disease excluded)All-cause mortality: 6.2% vs 10.2%; HR 0.57 (95% CI 0.37-0.89)“All-cause mortality | 6.2% | 10.2% | 0.57 (0.37, 0.89) | 0.012 |” — fda-bidil, Section 14 Clinical Studies, Table 2
- A-HeFT · as aboveFirst HF hospitalization: 16.4% vs 24.4%; HR 0.61 (95% CI 0.46-0.80)“Hospitalization for heart failure | 16.4% | 24.4% | 0.61 (0.46, 0.80) | <0.001 |” — fda-bidil, Section 14 Clinical Studies, Table 2
- A-HeFT (primary publication) · as aboveAll-cause mortality (trial stopped early): 10.2% vs 6.2%, P=0.02“The study was terminated early owing to a significantly higher mortality rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine (10.2 percent vs. 6.2 percent, P=0.02).” — taylor2004, Abstract (Results)
- V-HeFT I · 642 men on digoxin + diuretic (no ACE-I)2-year mortality: 34% risk reduction (P<0.028) vs placebo“For mortality by two years, a major end point specified in the protocol, the risk reduction among patients treated with both hydralazine and isosorbide dinitrate was 34 percent (P less than 0.028).” — cohn1986, Abstract
- V-HeFT II · 804 men on digoxin + diuretic2-year mortality vs enalapril: 25% H-ISDN vs 18% enalapril (P=0.016); H-ISDN inferior“Mortality after two years was significantly lower in the enalapril arm (18 percent) than in the hydralazine-isosorbide dinitrate arm (25 percent) (P = 0.016; reduction in mortality, 28.0 percent), and overall mortality tended to be lower (P = 0.08).” — cohn1991, Abstract (Results)
- USRDS dialysis cohort (Mavrakanas 2022) · Maintenance dialysis patients with HFAll-cause mortality (observational, IPW): HR 0.48 (95% CI 0.43-0.54)“H-ISDN use was independently associated with lower mortality: hazard ratio (HR) 0.48 (95% CI 0.43–0.54).” — mavrakanas2022, Abstract (Results)
Acute kidney injury
No H-ISDN-specific AKI guidance. ESC 2026 lists MRA/ARNI/ACE-I/ARB/SGLT2-I (not H-ISDN) for temporary discontinuation in AKI. The BiDil label warns that hypotension is most likely when patients are volume or salt depleted.
“However, temporary discontinuation of MRAs/ARNIs/ACE-Is/ARBs and SGLT2-Is may be needed in cases with acute kidney injury and eGFR <15 mL/min/1.73 m2.”
“Symptomatic hypotension, particularly with upright posture, may occur with even small doses of BiDil. Hypotension is most likely to occur in patients who have been volume or salt depleted; correct prior to initiation of BiDil [see Adverse Reactions (6.1)].”
Dialysis
Dialysis evidence is limited to observational data and a small pilot RCT. In a USRDS cohort, H-ISDN users had lower adjusted all-cause mortality (HR 0.48) but more HF admissions. In the HIDE pilot (17 HD patients) it was tolerated, with more adverse events. KDIGO 2026 lists hydralazine/nitrates among HFrEF options at eGFR <15 and calls GDMT in G5D a knowledge gap. Labels: hydralazine dialyzability undetermined; dialysis does not effectively remove ISDN.
Trials: HIDE (pilot RCT, 17 maintenance HD patients, cited in Mavrakanas 2022), USRDS cohort (Mavrakanas 2022, n=6306 H-ISDN users)
“H-ISDN use was independently associated with lower mortality: hazard ratio (HR) 0.48 (95% CI 0.43–0.54).”
Mavrakanas TA, Soomro QH, Charytan DM. Hydralazine-isosorbide dinitrate use in patients with end-stage kidney disease on dialysis. Kidney Int Rep 2022;7:1332-1340 (PMC9171697, full text) (2022)· Abstract (Results) Source“In contrast, HF admission and MI were more frequent in patients treated with H-ISDN (195.5 and 18.0 events/100-PY) compared with nonusers (73.4 and 10.2 events/100-PY).”
Mavrakanas TA, Soomro QH, Charytan DM. Hydralazine-isosorbide dinitrate use in patients with end-stage kidney disease on dialysis. Kidney Int Rep 2022;7:1332-1340 (PMC9171697, full text) (2022)· Abstract (Results) Source“Although the combination was well tolerated, adverse events were more frequent among H-ISDN patients than placebo-treated patients.”
Mavrakanas TA, Soomro QH, Charytan DM. Hydralazine-isosorbide dinitrate use in patients with end-stage kidney disease on dialysis. Kidney Int Rep 2022;7:1332-1340 (PMC9171697, full text) (2022)· Discussion Source“To our knowledge, there are minimal data on the use of nitrates, particularly the combination of isosorbide and hydralazine, in the setting of maintenance dialysis.”
Mavrakanas TA, Soomro QH, Charytan DM. Hydralazine-isosorbide dinitrate use in patients with end-stage kidney disease on dialysis. Kidney Int Rep 2022;7:1332-1340 (PMC9171697, full text) (2022)· Discussion Source“Dialyzability of hydralazine has not been determined. Dialysis is not an effective method for removing isosorbide dinitrate or its metabolite isosorbide-5-mononitrate from the body.”
“No experience has been reported with extracorporeal or peritoneal dialysis.”
Hydralazine hydrochloride tablets USP, prescribing information, Strides Pharma Science Ltd (generic manufacturer SPL) (2026)· Overdosage Source“However, in CKD G5D, the efficacy and safety of GDMT remain knowledge gaps.”
Lam CSP, Bozkurt B, Cherney DZI, et al. Kidney Disease and Heart Failure: Recent Advances and Current Challenges. Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. JACC: Heart Failure 2026 (KDIGO Executive Conclusions) (2026)· p. 9“provides a limited amount of information for patients with eGFR <60 mL/min/1.73 m2 (it excluded patients with ‘severe kidney disease’).”
2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease, in collaboration with the ERA (2026)· p. 37, Section 6.2.2.1.7 Source“Long-acting nitrates are hepatically metabolized; therefore, may be safely used in patients with CKD, including those on haemodialysis.”
2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease, in collaboration with the ERA (2026)· p. 49, Section 7.1.2.3 Anti-anginal medication Source
Kidney transplant
No transplant-specific statement found.
No verbatim statement found for this cell.
Albuminuria
No albuminuria-specific statement found. The hydralazine label notes drug-induced lupus that can include glomerulonephritis, which matters if new proteinuria/haematuria appears on therapy.
“In a few patients hydrALAZINE may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis.”
Hydralazine hydrochloride tablets USP, prescribing information, Strides Pharma Science Ltd (generic manufacturer SPL) (2026)· Warnings Source
Monitoring
Monitor BP and orthostatic symptoms during titration (titration can take 3-5 days). The generic hydralazine label calls for CBC and ANA before and periodically during prolonged therapy. Stop for drug-induced lupus. Add pyridoxine if peripheral neuritis develops.
“Although titration of BiDil can be rapid (3-5 days), some patients may experience side effects and may take longer to reach their maximum tolerated dose.”
BIDIL (isosorbide dinitrate/hydralazine) PI, Azurity (2026)· Section 2 Dosage and Administration Source“Complete blood counts and antinuclear antibody titer determinations are indicated before and periodically during prolonged therapy with hydrALAZINE even though the patient is asymptomatic.”
Hydralazine hydrochloride tablets USP, prescribing information, Strides Pharma Science Ltd (generic manufacturer SPL) (2026)· Precautions, Laboratory Tests Source“Hydralazine hydrochloride has been reported to cause a drug-induced systemic lupus erythematosus (SLE) syndrome. Symptoms and signs usually regress when hydralazine hydrochloride is discontinued.”
BIDIL (isosorbide dinitrate/hydralazine) PI, Azurity (2026)· Section 5.2 Systemic Lupus Erythematosus Source“Symptomatic hypotension, particularly with upright posture, may occur with even small doses of BiDil. Hypotension is most likely to occur in patients who have been volume or salt depleted; correct prior to initiation of BiDil [see Adverse Reactions (6.1)].”
In-hospital initiation
No source gives in-hospital initiation rules. Correct volume or salt depletion before starting because of hypotension risk. It is commonly used when ACE-I/ARNI/ARB are held for kidney dysfunction or hyperkalaemia.
“Symptomatic hypotension, particularly with upright posture, may occur with even small doses of BiDil. Hypotension is most likely to occur in patients who have been volume or salt depleted; correct prior to initiation of BiDil [see Adverse Reactions (6.1)].”
“In patients with current or previous symptomatic HFrEF who cannot be given first-line agents, such as ARNi, ACEi, or ARB, because of drug intolerance or renal insufficiency, a combination of hydralazine and isosorbide dinitrate might be considered to reduce morbidity and mortality (4,5).”
Outpatient
Start at 1 tablet t.i.d. and titrate to 2 tablets t.i.d. as tolerated. Headache and dizziness are the most common adverse effects.
“BiDil should be initiated at a dose of one BiDil Tablet, three times a day. Titrate to a maximum of two tablets three times daily, if tolerated.”
BIDIL (isosorbide dinitrate/hydralazine) PI, Azurity (2026)· Section 2 Dosage and Administration Source“Although titration of BiDil can be rapid (3-5 days), some patients may experience side effects and may take longer to reach their maximum tolerated dose.”
BIDIL (isosorbide dinitrate/hydralazine) PI, Azurity (2026)· Section 2 Dosage and Administration Source
Where sources disagree
Dose adjustment / caution in advanced kidney disease
“There are no studies of renal impairment using BiDil. No dose adjustment is required for hydralazine or isosorbide dinitrite [see Clinical Pharmacology (12.3)].”
“In a study with 49 hypertensive patients on chronic therapy with hydralazine in daily doses of 25-200 mg, the daily dose of hydralazine in 19 subjects with severely impaired renal function (creatinine clearance 5-28 mL/min) and in 17 subjects with normal renal function (creatinine clearance >100 mL/min) using a population PK approach was not different, suggesting no need for dose adjustment in patients with renal impairment.”
BIDIL (isosorbide dinitrate/hydralazine) PI, Azurity (2026)· Section 12.3 Pharmacokinetics (Renal Impairment) Source“However, as with any antihypertensive agent, hydrALAZINE should be used with caution in patients with advanced renal damage.”
Hydralazine hydrochloride tablets USP, prescribing information, Strides Pharma Science Ltd (generic manufacturer SPL) (2026)· Precautions, General Source
Tool uses fda-bidil: BiDil (the HF-indicated product, newer label with PK data down to CrCl 5 mL/min) requires no dose adjustment. Following the owner's conservative rule, G4/G5/dialysis are still shown as 'caution' because of the generic hydralazine label wording and the lack of trial data below eGFR 30.
Whether H-ISDN is recommended below eGFR 30
“Treatment with a combination of hydralazine-isosorbide dinitrate should be considered in self-identified Black patients with HFrEF and CKD with an eGFR ≥30 mL/min/1.73 m2 and dilated left ventricle in combination with LVEF <45%, or LVEF ≤35%,”
2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease, in collaboration with the ERA (2026)· p. 39 Source“The placebo-controlled African-American Heart Failure Trial (A-HEFT) trial was stopped early due to mortality benefit (HR 0.57, 95% CI 0.37–0.89) and provides a limited amount of information for patients with eGFR <60 mL/min/1.73 m2 (it excluded patients with ‘severe kidney disease’).”
2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease, in collaboration with the ERA (2026)· p. 37 Source“<15 15–29 30–59 ≥60 • ß-blocker • Hydralazine/ nitrates • ß-blocker • SGLT2i if eGFR >20 • Vericiguat”
Lam CSP, Bozkurt B, Cherney DZI, et al. Kidney Disease and Heart Failure: Recent Advances and Current Challenges. Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. JACC: Heart Failure 2026 (KDIGO Executive Conclusions) (2026)· p. 11“In patients with current or previous symptomatic HFrEF who cannot be given first-line agents, such as ARNi, ACEi, or ARB, because of drug intolerance or renal insufficiency, a combination of hydralazine and isosorbide dinitrate might be considered to reduce morbidity and mortality (4,5).”
Tool uses esc2026-ckd: ESC CVD-CKD restricts the IIa recommendation to eGFR ≥30. KDIGO 2026 and AHA 2022 support use as the RAAS-free alternative in advanced CKD/renal insufficiency, so the proposal is 'caution' (not 'not-recommended') below 30.
Removal of isosorbide dinitrate by dialysis
“Dialyzability of hydralazine has not been determined. Dialysis is not an effective method for removing isosorbide dinitrate or its metabolite isosorbide-5-mononitrate from the body.”
“Similarly, it is not known which, if any, of these substances can usefully be removed from the body by hemodialysis.”
Isosorbide dinitrate tablets USP, prescribing information, Hikma Pharmaceuticals USA (generic manufacturer SPL) (2025)· Overdosage Source“ISDN also undergoes hepatic metabolism, but it does not have extensive protein binding and can be removed during dialysis.”
Mavrakanas TA, Soomro QH, Charytan DM. Hydralazine-isosorbide dinitrate use in patients with end-stage kidney disease on dialysis. Kidney Int Rep 2022;7:1332-1340 (PMC9171697, full text) (2022)· Introduction Source
Tool uses fda-bidil: FDA label > review; BiDil label states dialysis is not effective at removing ISDN or its 5-mononitrate. Clinically this matters little because no dose adjustment is proposed either way.
Coronary artery disease as a contraindication
“Hypersensitivity to hydrALAZINE; coronary artery disease; mitral valvular rheumatic heart disease.”
Hydralazine hydrochloride tablets USP, prescribing information, Strides Pharma Science Ltd (generic manufacturer SPL) (2026)· Contraindications Source“Do not use BiDil in patients who are taking PDE-5 inhibitors, such as avanafil, sildenafil, tadalafil, or vardenafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia [see Drug Interactions (7.1)].”
Tool uses fda-bidil: The old generic hydralazine (hypertension) label lists coronary artery disease as a contraindication. BiDil lists only nitrate allergy and PDE5i/riociguat, with a warning (5.3) about ischaemia. Use the BiDil label for HF. This does not affect kidney cells.
Population and background therapy
“Hydralazine and isosorbide dinitrate should be considered in self-identified black patients with symptomatic HFrEF with LVEF ≤40% on top of optimal FMT to reduce the risk of HFH and death.”
“For patients self-identified as African American with NYHA class III-IV HFrEF who are receiving optimal medical therapy, the combination of hydralazine and isosorbide dinitrate is recommended to improve symptoms and reduce morbidity and mortality (1,2).”
“There are insufficient data for concomitant use with ARNi.”
“It is unclear if a benefit of hydralazine and isosorbide dinitrate exists for non-black patients with HFrEF.”
Tool uses esc2026: ESC 2026 is primary (IIa, LVEF ≤40%, on optimal FMT, which includes ARNI). AHA 2022 (Class 1 for NYHA III-IV) notes insufficient data alongside ARNi. Show both views.
Open questions
- Matrix status for the general (non-Black) HFrEF population: ESC gives IIb when ACE-I/ARNI/ARB are not tolerated or contraindicated. Should the matrix show population-specific statuses (IIa self-identified Black vs IIb others), or one status with a note?
- G4/G5/dialysis set to 'caution' (conservative). The BiDil label alone would support 'allowed'. Owner to confirm.
- BiDil contraindicates riociguat (sGC stimulator). Vericiguat is also an sGC stimulator and is not named in the BiDil label. Cross-check the vericiguat label for nitrate co-use before the tool flags the H-ISDN + vericiguat combination.
- Wording around race-based prescribing (ESC/AHA/FDA use 'self-identified black/African American') needs an owner decision for UI text.