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. Author manuscript; available in PMC: 2025 Jul 2.
Published in final edited form as: Drugs Aging. 2024 Jul 2;41(7):583–600. doi: 10.1007/s40266-024-01121-0

Table 3.

Pharmacoepidemiologic Studies Evaluating Treatment Effect by Different Levels of Patient Frailtya

First Author (Year) Data Source and Study Design Primary Outcome Event Rate Effect Estimate
Intervention Comparison
Cardiovascular Medications
Kim
(2021)[81]

  • Data: Medicare claims, United States

  • Population: Beneficiaries ≥ 65 years old, AF, no prior use of oral anticoagulants

  • Exposure: dabigatran, rivaroxaban, warfarin, apixaban

  • Outcome: Composite of death, stroke, or major bleeding

  • Frailty measure: Kim index

 Composite clinical events
 Robust
 Pre-frail
 Frail
Composite clinical events
 Robust
 Pre-frail
 Frail
Composite clinical events
 Robust
 Pre-frail
 Frail		 Dabigatran
(Per 1000 PY)
25.4
62.1
170.0
Rivaroxaban
(Per 1000 PY)
31.6
76.5
200.8
Apixaban
(Per 1000 PY)
21.9
54.2
157.6		 Warfarin
(Per 1000 PY)
31.4
64.1
160.2
Warfarin
(Per 1000 PY)
37.2
76.7
219.8
Warfarin
(Per 1000 PY)
37.6
86.0
226.2		 HR (95% CI)
0.91 (0.68, 0.97)
0.98 (0.90, 1.08)
1.09 (0.96, 1.23)
HR (95% CI)
0.88 (0.77, 0.99)
1.04 (0.98, 1.10)
0.96 (0.89, 1.04)
HR (95% CI)
0.61 (0.52, 0.71)
0.66 (0.61, 0.70)
0.73 (0.67, 0.80)
Lin
(2023)[82]

  • Data: Medicare claims, United States

  • Population: Beneficiaries ≥ 65 years old, AF, no prior use of oral anticoagulants

  • Exposure: rivaroxaban, warfarin, apixaban

  • Outcome: Loss of days at home 14 days or more in 1 year

  • Frailty measure: Kim index

 1-Yr home time loss ≥ 14 d
 Robust
 Pre-frail
 Frail
1-Yr home time loss ≥ 14 d
 Robust
 Pre-frail
 Frail		 Rivaroxaban
(Per 100)
6.9
17.1
46.0
Warfarin
(Per 100)
7.7
18.9
46.9		 Apixaban
(Per 100)
6.0
16.0
43.4
Apixaban
(Per 100)
6.0
16.0
43.4		 RD (95% CI)
0.8 (0.5, 1.2)
1.1 (0.7, 1.4)
2.7 (1.9, 3.4)
RD (95% CI)
1.7 (1.2, 2.2)
2.9 (2.5, 3.2)
3.6 (2.8, 4.3)
Anderson
(2023)[83]

  • Data: Veterans Affairs and Medicare claims, United States

  • Population: Veterans ≥ 65 years old who were hospitalized for non-cardiovascular reasons and had elevated blood pressure readings

  • Exposure: Intensification of antihypertensive regimen during hospitalization

  • Outcome: Inpatient mortality, ICU transfer, stroke, acute kidney injury, BNP elevation, and troponin elevation

  • Frailty measure: Orkaby index (Veterans Affairs Frailty Index)

 Adverse inpatient events
 Non-frail
 Frail		 Intensive
(Per 100)
NR
NR		 Non-intensive
(Per 100)
NR
NR		 OR (95% CI)
1.26 (1.13, 1.41)
1.29 (1.15, 1.45)
Orkaby
(2023)[84]

  • Data: Veterans Affairs and Medicare claims, United States

  • Population: Veterans ≥ 65 years old, no prior CVD, no prior statin use

  • Exposure: statins

  • Outcome: Death, MACE

  • Frailty measure: Orkaby index (Veterans Affairs Frailty Index)

 Death
 Non-frail
 Frail
MACE
 Non-frail
 Frail		 Statin
(Per 1000 PY)
48.6
90.4
(Per 1000 PY)
51.7
88.2		 No statin
(Per 1000 PY)
72.6
130.4
(Per 1000 PY)
60.8
102.0		 HR (95% CI)
0.61 (0.61, 0.62)
0.63 (0.62, 0.64)
HR (95% CI)
0.87 (0.86, 0.88)
0.90 (0.88, 0.92)
Sheppard
(2023)[85]

  • Data: The Clinical Practice Research Datalink, England

  • Population: Patients ≥ 40 years old, hypertension, no prior antihypertensive treatment

  • Exposure: Antihypertensive treatment

  • Outcome: Serious falls (fall-related hospitalization or death) in 10 years

  • Frailty measure: Clegg index (electronic Frailty Index)

 Serious falls
 Fit
 Mild frailty
 Moderate frailty
 Severe frailty		 Anti-hypertensive
(per 100)
2.1
6.6
12.2
16.6		 No anti-hypertensive
(per 100)
1.2
5.3
8.8
11.5
 HR (95% CI)
1.22 (1.18, 1.25)
1.10 (1.06, 1.14)
1.16 (1.07, 1.26)
1.31 (1.09, 1.58)
Diabetes Medications
Dave
(2019)[86]

  • Data: Commercial insurance claims, United States

  • Population: Adults ≥ 18 years old, type 2 diabetes, no prior use of the study drugs

  • Exposure: SGLT2i, GLP1RA, DPP4i

  • Outcome: Severe UTI

  • Frailty measure: Kim index

 Severe UTI
 Robust
 Pre-frail
 Frail
Severe UTI
 Robust
 Pre-frail
 Frail		 SGLT2i
(Per 1000 PY)
NR
NR
NR
SGLT2i
(Per 1000 PY)
NR
NR
NR		 DPP4i
(Per 1000 PY)
NR
NR
NR
GLP1RA
(Per 1000 PY)
NR
NR
NR		 HR (95% CI)
1.00 (0.46, 2.15)
0.60 (0.33, 1.09)
0.84 (0.49, 1.43)
HR (95% CI)
1.12 (0.58, 2.16)
0.59 (0.31, 1.10)
0.64 (0.40, 1.02)
Zhuo
(2021)[87]

  • Data: Medicare claims, United States

  • Population: Beneficiaries ≥ 65 years old, type 2 diabetes, no prior use of the study drugs

  • Exposure: SGLT2i, GLP1RA, DPP4i

  • Outcome: Fractures

  • Frailty measure: Kim index

 Fractures
 Robust
 Pre-frail
 Frail
Fractures
 Robust
 Pre-frail
 Frail		 SGLT2i
(Per 1000 PY)
2.9
4.5
10.0
SGLT2i
(Per 1000 PY)
2.9
4.5
10.0		 DPP4i
(Per 1000 PY)
2.2
5.9
10.7
GLP1RA
(Per 1000 PY)
2.2
4.3
9.2		 HR (95% CI)
1.28 (0.73, 2.25)
0.77 (0.59, 1.01)
0.93 (0.62, 1.41)
HR (95% CI)
1.33 (0.74, 2.39)
1.02 (0.75, 1.38)
1.09 (0.69, 1.70)
Htoo
(2023)[88]

  • Data: Medicare claims, United States

  • Population: Beneficiaries ≥ 65 years old, type 2 diabetes, no prior use of the study drugs

  • Exposure: SGLT2i, GLP1RA, DPP4i

  • Outcome: Severe hypoglycemia

  • Frailty measure: Kim index

 Severe hypoglycemia
 Robust
 Pre-frail
 Frail
Severe hypoglycemia
 Robust
 Pre-frail
 Frail		 SGLT2i
(Per 1000 PY)
4.1
9.8
28.8
SGLT2i
(Per 1000 PY)
5.3
10.6
28.6		 DPP4i
(Per 1000 PY)
5.2
13.5
34.6
GLP1RA
(Per 1000 PY)
5.1
12.1
32.8		 HR (95% CI)
0.78 (0.59, 1.03)
0.73 (0.64, 0.83)
0.83 (0.69, 1.00)
HR (95% CI)
1.03 (0.79, 1.35)
0.88 (0.77, 0.99)
0.87 (0.74, 1.04)
Kutz
(2023)[89]

  • Data: Medicare claims, United States

  • Population: Beneficiaries ≥ 65 years old, type 2 diabetes, no prior use of the study drugs

  • Exposure: SGLT2i, GLP1RA, DPP4i

  • Outcome: Death, MACE, diabetes drug-related safety events (lower-limb amputation, fracture, hypoglycemia, acute kidney injury, diabetic ketoacidosis, severe genital infection, severe UTI, acute pancreatitis, or non-malignant biliary event)

  • Frailty measure: Kim index

 Death or MACE
 Robust
 Pre-frail
 Frail
Composite safety events
 Robust
 Pre-frail
 Frail
Death or MACE
 Robust
 Pre-frail
 Frail
Composite safety events
 Robust
 Pre-frail
 Frail		 SGLT2i
(Per 1000 PY)
18.7
42.5
109.9
(Per 1000 PY)
21.1
45.0
109.0
GLP1RA
(Per 1000 PY)
20.5
49.4
130.3
(Per 1000 PY)
26.2
58.5
141.9		 DPP4i
(Per 1000 PY)
25.5
59.1
137.1
(Per 1000 PY)
26.4
55.3
120.6
DPP4i
(Per 1000 PY)
27.5
67.9
156.2
(Per 1000 PY)
29.4
65.7
138.4		 HR (95% CI)
0.74 (0.68, 0.81)
0.72 (0.69, 0.76)
0.79 (0.70, 0.89)
HR (95% CI)
0.90 (0.74, 0.87)
0.91 (0.77, 0.86)
0.89 (0.78, 1.01)
HR (95% CI)
0.75 (0.68, 0.82)
0.73 (0.70, 0.77)
0.83 (0.76, 0.91)
HR (95% CI)
0.89 (0.82, 0.97)
0.89 (0.85, 0.93)
1.01 (0.92, 1.10)
Anti-Neoplastic Agents
DuMontier
(2023)[90]

  • Data: Veterans Affairs and Medicare claims, United States

  • Population: Veterans with new multiple myeloma diagnosis who did not receive bone marrow transplant

  • Exposure: triplet therapy (bortezomib-lenalidomide-dexamethasone), doublet therapy (lenalidomide-dexamethasone)

  • Outcome: Overall survival

  • Frailty measure: Orkaby index (Veterans Affairs Frailty Index)

 Overall survival
 Non-frail
 Mildly frail
 Moderate-to-severely frail		 Triplet
(Per 100 PY)
NR
NR
NR		 Doublet
(Per 100 PY)
NR
NR
NR		 HR (95% CI)
0.86 (0.67, 1.10)
0.80 (0.61, 1.05)
0.74 (0.56, 0.97)
Deol
(2023)[91]

  • Data: Veterans Affairs and Medicare claims, United States

  • Population: Veterans with metastatic castration-resistant prostate cancer

  • Exposure: enzalutamide, abiraterone

  • Outcome: Overall survival

  • Frailty measure: Orkaby index (Veterans Affairs Frailty Index)

 Overall survival
 Non-frail
 Frail		 Enzalutamide (median)
27.7 months
20.6 months
 Abiraterone
(median)
26.1 months
17.1 months		 HR (95% CI)
0.93 (0.86, 1.01)
0.85 (0.77, 0.93)
Antipsychotic Medications
Maxwell
(2018)[92]

  • Data: Administrative health and clinical database of Ontario, Canada

  • Population: Home care clients ≥ 65 years with dementia or significant cognitive impairment

  • Exposure: antipsychotics

  • Outcome: Death

  • Frailty measure: 72-item frailty index from home care clinical database

 Death
 Robust
 Frail		 Anti-psychotics
(Per 100 PM)
2.0
3.8		 No anti-psychotics
(Per 100 PM)
0.8
2.6		 HR (95% CI)
At 1 month
3.72 (2.45–5.66)
1.74 (1.40–2.17)
At 6 months
1.83 (1.18–2.83)
1.02 (0.75–1.38)
Vaccines
Harris
(2023)[93]

  • Data: Medicare claims linked to customer data from national pharmacy companies, United States

  • Population: Beneficiaries ≥ 66 years old in the community, no COVID-19 in the past 4 weeks

  • Exposure: mRNA COVID-19 vaccine mRNA-1273, BNT162b2

  • Outcome: Vaccine-related adverse clinical events and COVID-19 diagnosis

  • Frailty measure: Kim index

 Facial nerve palsy
 Robust
 Pre-frail
 Frail
Thrombocytopenic purpura
 Robust
 Pre-frail
 Frail
Pulmonary embolism
 Robust
 Pre-frail
 Frail
Myocarditis/pericarditis
 Robust
 Pre-frail
 Frail
COVID-19 diagnosis
 Robust
 Pre-frail
 Frail		 mRNA-1273
(Per 100000)
NR
NR
NR
(Per 100000)
NR
NR
NR
(Per 100000)
NR
NR
NR
(Per 100000)
NR
NR
NR
(Per 100000)
NR
NR
NR		 BNT162b2
(Per 100000)
NR
NR
NR
(Per 100000)
NR
NR
NR
(Per 100000)
NR
NR
NR
(Per 100000)
NR
NR
NR
(Per 100000)
NR
NR
NR		 RR (95% CI)
0.86 (0.75, 0.99)
1.04 (0.93, 1.16)
1.14 (0.89, 1.45)
RR (95% CI)
0.89 (0.80, 0.99)
1.03 (0.94, 1.14)
0.96 (0.77, 1.20)
RR (95% CI)
0.94 (0.88, 1.00)
0.97 (0.93, 1.01)
1.00 (0.92, 1.08)
RR (95% CI)
0.76 (0.56, 1.03)
0.94 (0.77, 1.16)
0.96 (0.58, 1.61)
RR (95% CI)
0.85 (0.82, 0.88)
0.83 (0.81, 0.86)
0.94 (0.89, 0.99)

Abbreviations: AF, atrial fibrillation; BNP, B-type natriuretic peptide; CI, confidence interval; CVD, cardiovascular disease; d, days; DPP4i, dipeptidyl peptidase-4 inhibitor; GLP1RA, glucagon-like peptide-1 receptor agonist; HR, hazard ratio; ICU, intensive care unit; MACE, major adverse cardiovascular event; NR, not reported; OR, odds ratio; PM, person-months; PY, person-years; RD, risk difference; RR, risk ratio; SGLT2i, sodium-glucose cotransporter-2 inhibitor; UTI, urinary tract infection; Yr, year.

a

See Table 2 for the cutpoint to define frailty levels.