GDMT for Everyone

Medications:

ACEI: angiotensin converting enzyme inhibitor
AKI: acute kidney injury
ARB: angiotensin receptor blocker
ARNI: angiotensin receptor blocker & neprilysin inhibitor
BB: beta blocker
ESKD: end-stage kidney disease
HCTZ: hydrochlorothiazide
IKi: funny current channel inhibitor
MRA: mineralocorticoid receptor antagonist
PCB: placebo
sGC stimulator: soluble guanylate cyclase stimulator
SGLT2i: sodium glucose co-transporter inhibitor

Outcomes:

ACH: all-cause hospitalization
ACM: all-cause mortality
CVH: cardiovascular hospitalization
CVM: cardiovascular mortality
HFH: heart failure hospitalization
HFM: heart failure mortality
RMI: recurrent MI
SCD: sudden cardiac death

Excluded population of trial

Included population of trial

Statin Intensity

First, let's take a look at which statins are high, moderate, and low intensity. Notice that rosuvastatin and atorvastatin are the only two ones with high intensity doses.

Statins that can't reach high intensity						Statins that can reach high intensity
	5	10	20	40		ROSUVAstatin
		10	20	40	80	ATORVAstatin
SIMVAstatin		10	20	40
PRAVAstatin		10	20	40	80
FLUVAstatin			20	40	80
LOVAstatin			20	40

What does high, moderate, and low intensity mean?

Low-intensity	30%	Moderate-intensity	50%	High-intensity
Lowers LDL by < 30%	30%	Lowers LDL by 30-50%	50%	Lowers LDL by >50%

Who qualifies for a statin?

The two situations that bypass the table below are:

If LDL ≥ 190: Go straight to a high-intensity statin, regardless of age
If clinical ASCVD: Go straight to a high-intensity statin, unless >75yo, then moderate-intensity statin
Other than ACS and stable ischemic heart disease, conditions included in ASCVD are stroke, transient ischemic attack, prior coronary revascularization, prior other arterial revascularization, and peripheral artery disease

Among individuals with LDL 70-189:

20-39 yo	40-75 yo						> 75 yo
	No diabetes				Has diabetes
	10y risk < 5% ("low risk")	10y risk 5-7.5% ("borderline risk")	10y risk 7.5-20% ("intermediate risk")	10y risk >20% ("high risk")	10y risk < 7.5%	10y risk ≥ 7.5%
If LDL ≥ 160 & FHx of premature ASCVD, then moderate statin. Else, lifestyle	Lifestyle changes	Moderate statin if risk factors	Moderate statin	High statin	Moderate statin	High statin	Discuss since elderly

Please click on the appropriate boxes to the right of the drug name to see information about use of this drug at different stages of kidney disease.

Please note that the above dosing of the drug for HFrEF/CAD/HLD is not generalizable to dosing of the drug for other disease states.

CKD 1-2

Patients with "eGFR >60 ml/min/1.73 m2 (and no history of kidney transplantation) may be treated with any statin regimen that is approved for use in the general population" (KDIGO)

CKD 3

No contraindications or dose adjustments needed.

CKD 4-5

In the general KDIGO CKD guideline, it was specified: "No increase in toxicity for simvastatin dosed at 20 mg per day or simvastatin 20 mg /ezetimide 10 mg combinations per day in people with GFR < 30 ml/min/1.73 m2 or on dialysis" (KDIGO)

Subsequently, in the KDIGO lipids guideline, it was specified that simvastatin "40 mg/day" is acceptable in patients with "eGFR G3a-G5, including patients on dialysis or with a kidney transplant" (KDIGO)

ESKD

Regarding the question of simvastatin dosing, in the general KDIGO CKD guideline, it was specified: "No increase in toxicity for simvastatin dosed at 20 mg per day or simvastatin 20 mg /ezetimide 10 mg combinations per day in people with GFR < 30 ml/min/1.73 m2 or on dialysis" (KDIGO)

Regarding the question of whether or not a statin should be used in ESKD: "In adults with dialysis-dependent CKD, we suggest that statins or statin/ezetimibe combination not be initiated." (KDIGO, Class II)

"However, patients might reasonably choose statin treatment if they are interested in a relatively small, uncertain reduction in cardiovascular events. Since very high LDL-C might increase the likelihood of benefit from statin in a dialysis patient, patients who meet this criterion may be more inclined to receive a statin, recognizing that the benefit remains uncertain. Other factors that might influence a patient’s decision to receive statin could include recent MI or greater life expectancy (both favoring treatment), and more severe comorbidity or higher current pill burden (both favoring non-treatment)." (KDIGO)

"In patients already receiving statins or statin/ezetimibe combination at the time of dialysis initiation, we suggest that these agents be continued." (KDIGO, Class II)

AKI

Any data? Jiawei you wrote "no data to suggest harm. AKI may be from statin-induced rhabdomyolysis" in the excel sheet but I don't think there was an attached reference for that cell

Outcomes of HFrEF GDMT Trials
with serum creatinine-based renal exclusion criteria

Class	Medication	Dialysis	Cr 3.0-3.5	Cr 2.5-3.0	Cr 2.0-2.5	Cr 1.0-2.0
ACEI	Enalapril	Excluded	CONSENSUS (1987): Enalapril vs PCB: ↓ACM Excluded: Cr>3.4 mg/dL
	Enalapril	Excluded				SOLVD (1991): Enalapril vs PCB: ↓ACM, ↓CVM, ↓HFH Excluded: Cr>2.0 mg/dL
	Captopril	Excluded			SAVE (1992): Captopril vs PCB: ↓ACM, ↓CVM, ↓RMI Excluded: Cr>2.5 mg/dL
	Lisinopril	Excluded			ATLAS (1999): Lisinopril 35mg vs 2.5-5mg: ↓ACH, ↓HFH Excluded: Cr>2.5 mg/dL
ARB	Valsartan	Excluded			Val-HeFT (2001): Valsartan vs PCB: ↓HFH Excluded: Cr>2.5 mg/dL
	Candesartan	Excluded		CHARM Alt (2003): Candesartan vs PCB: ↓CVM, ↓HFH Excluded: Cr>3.0 mg/dL
	Losartan	Excluded			HEAAL (2009): Losartan 150mg vs 50mg: ↓ACM, ↓HFH Excluded: Cr>2.5 mg/dL
BB	Bisoprolol	Excluded	CIBIS (1994): Bisoprolol vs PCB: ↓HFH Excluded: Cr>3.4 mg/dL
	Bisoprolol	Excluded	CIBIS II (1999): Bisoprolol vs PCB: ↓ACM, ↓HFH Excluded: Cr>3.4 mg/dL
	Metoprolol	MERIT-HF (1999): Metoprolol vs PCB: ↓ACM, ↓CVM, ↓HFH, ↓SCD No renal exclusion
	Carvedilol	Excluded		COPERNICUS (2009): carvedilol vs PCB: ↓ACM, ↓HFH Excluded: Cr>2.8 mg/dL
	Carvedilol	COMET (2003): Carvedilol vs metoprolol low-dose: ↓ACM No renal exclusion
MRA	Enalapril	Excluded		RALES (1999): Spironolactone vs PCB: ↓ACM, ↓HFM, ↓SCD Excluded: Cr>2.5 mg/dL
Class	Medication	Dialysis	Cr 3.0-3.5	Cr 2.5-3.0	Cr 2.0-2.5	Cr 1.0-2.0

Outcomes of HFrEF GDMT Trials
with eGFR-based renal exclusion criteria

Class	Medication	Dialysis	eGFR 0-15	eGFR 15-30	eGFR 30-45	eGFR 45-60	eGFR>60
ARNI	Sacubitril-valsartan	Excluded			PARADIGM-HF (2014): sacubitril-valsartan vs enalapril: ↓CVM, ↓ACM, ↓HFH Excluded: eGFR < 30
MRA	Eplerenone	Excluded			EMPHASIS-HF (2001): Eplerenone vs PCB: ↓CVM, ↓HFH Excluded: eGFR < 30
SGLT2i	dapagliflozin	Excluded			DAPA-HF (2019): dapagliflozin vs PCB: ↓CVM, ↓ACM, ↓HFH Excluded: eGFR < 30
SGLT2i	empgaliflozin	Excluded		EMPEROR-Reduced (2020): empagliflozin vs PCB: ↓HFH Excluded: eGFR < 20
sGC stimulator	Vericiguat	Excluded		VICTORIA (2020): vericiguat vs PCB: ↓CVM, ↓HFH Excluded: eGFR < 15
Myosin activators	omecantiv/mecarbil	Excluded		GALACTIC-HF (2021): omecantiv/mecarbil vs PCB: ↓CVM, ↓HFH Excluded: eGFR < 15
Class	Medication	Dialysis	eGFR 0-15	eGFR 15-30	eGFR 30-45	eGFR 45-60	eGFR>60

Outcomes of HFrEF GDMT Trials
that excluded renal patients on miscellaneous criteria

Class	Medication	"Kidney disease"	"No kidney disease"
BB	Carvedilol	Excluded	US Carvedilol (1996): carvedilol vs PCB: ↓CVH, ↓HFM Excluded: "clinical important renal disease"
BB	Carvedilol	Excluded	CAPRICORN (2001): carvedilol vs PCB: ↓CVM, ↓ACM Excluded: "renal impairment"
IKi	Ivabradine	Excluded	SHIFT (2012): ivabradine vs PCB: ↓CVM, ↓HFH Excluded: "severe renal disease"
Class	Medication	"Kidney disease"	"No kidney disease"