Potentially inappropriate medications based on TIME criteria and risk of in-hospital mortality in COVID-19 patients

Durmuş, Nurdan Şentürk; Tufan, Aslı; Can, Büşra; Olgun, Şehnaz; Kocakaya, Derya; İlhan, Birkan; Bahat, Gülistan

doi:10.1590/1806-9282.20220907

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Revista da Associação Médica Brasileira

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Original Article • Rev. Assoc. Med. Bras. 68 (12) • 2022 • https://doi.org/10.1590/1806-9282.20220907 copy

Potentially inappropriate medications based on TIME criteria and risk of in-hospital mortality in COVID-19 patients

Authorship SCIMAGO INSTITUTIONS RANKINGS

SUMMARY

OBJECTIVE:

This study aimed to evaluate the relationship between hospital admission potentially inappropriate medications use (PIM) and in-hospital mortality of COVID-19, considering other possible factors related to mortality.

METHODS:

The Turkish inappropriate medication use in the elderly (TIME) criteria were used to define PIM. The primary outcome of this study was in-hospital mortality.

RESULTS:

We included 201 older adults (mean age 73.1±9.4, 48.9% females). The in-hospital mortality rate and prevalence of PIM were 18.9% (n=38) and 96% (n=193), respectively. The most common PIM according to TIME to START was insufficient vitamin D and/or calcium intake per day. Proton-pump inhibitor use for multiple drug indications was the most prevalent PIM based on TIME to STOP findings. Mortality was related to PIM in univariate analysis (p=0.005) but not in multivariate analysis (p=0.599). Older age (hazards ratio (HR): 1.08; 95% confidence interval (CI): 1.02–1.13; p=0.005) and higher Nutritional Risk Screening 2002 (NRS-2002) scores were correlated with in-hospital mortality (HR: 1.29; 95%CI 1.00–1.65; p=0.042).

CONCLUSION:

Mortality was not associated with PIM. Older age and malnutrition were related to in-hospital mortality in COVID-19.

Keywords
COVID; Older adult; Potentially inappropriate medication use; Criteria

	All participants (total n=201) n (%)	Survivors (total n=163) n (%)	Nonsurvivors (total n=38) n (%)	p-value
Sex
Female	97 (48.3%)	81 (49.7)	16 (42.1)	0.399
Male	104 (51.7%)	82 (50.3)	22 (57.9)	0.399
Age*	73.0 (60–96)	70.0 (60–95)	80.5 (61–96)	<0.001 ^†
BMI*	27.5 (16.3–44.1)	27.8 (16.3–44.8)	26.9 (18.4–40.0)	0.109
Smoking	62 (30.8%)	53 (32.5)	9 (23.7)	0.279
HT	131 (65.2%)	107 (65.6)	24 (63.2)	0.772
DM	87 (43.3%)	71 (43.6)	16 (42.19)	0.871
CAD	54 (26.9%)	44 (27)	10 (26.3)	0.932
COPD	36 (17.9%)	28 (17.2)	8 (21.1)	0.581
Malignancy	25 (12.4%)	23 (14.1)	2 (5.3)	0.105
CKD	24 (11.9%)	17 (10.4)	7 (18.4)	0.193
Dementia	22 (10.9%)	14 (8.6)	8 (21.1)	0.040 ^†
CHF	19 (9.5%)	8 (4.9)	11 (28.9)	<0.001 ^†
COVID severity
Mild	9 (4.5%)	9 (5.5)	0 (0.0)	0.077
Moderate	48 (23.9%)	39 (23.9)	9 (23.7)
Severe	135 (67.2%)	110 (67.5)	25 (65.8)
Critical	9 (4.5%)	5 (3.1)	4 (10.5)
COVID severity
Mild+moderate	57 (28.4)	48 (29.4)	9 (23.7)	0.478
Severe+critical	144 (71.6)	115 (70.6)	29 (76.3)	0.478
Number of chronic diseases*	3.0±1.5 (1–7)	2.9±1.5 (1–7)	3.4±1.7 (1–7)	0.174
Number of drugs*	4.0 (1–11)	4.0 (1–11)	4.0 (1–10)	0.663
Polypharmacy	76 (37.8%)	63 (38.7)	15 (39.5)	0.814
Number of PIM*^,†	2.0 (1–6)	2.0 (1–6)	2.5 (1–6)	0.005 ^†
PIM^†	193 (96)	155 (95.1)	38 (100)	0.064
TIME to START	180 (89.6)	142 (91.6)	38 (100)	0.015 ^†
TIME to STOP	59 (29.4)	47 (30.5)	12 (31.6)	0.549
Length of hospital stay (days)*	14.0 (3–68)	13.0 (3–68)	22.0 (4–67)	0.026 ^†
ICU stay	47 (23.4%)	19 (11.7)	28 (73.7)	<0.001 ^†
ICU stay (days)*	5.0 (1–28)	5.0 (2–27)	6.0 (1–28)	0.924
Score of NRS-2002*	3.4±1.5 (0–7)	3.2±1.5 (0–7)	4.3±1.2 (2–7)	<0.001 ^†
NRS-2002
Nonmalnutrition	62 (30.8%)	60 (36.8)	2 (5.3)	<0.001 ^†
Malnutrition risk	139 (69.2%)	103 (63.2)	36 (94.7)	<0.001 ^†
White blood cell (×10³/μL)*	7.2 (1.4–23.7)	7.1 (1.4–23.7)	7.3 (1.6–17.8)	0.856
Lymphocyte (×10³/μL)*	1.1 (0.1–11.0)	1.1 (0.1–3.9)	1.0 (0.2–11.0)	0.445
Neutrophil (×10³/μL)*	5.5 (0.7–23)	5.5 (0.7–23.0)	5.6 (0.2–13.2)	0.924
Hemoglobin (g/dL)	12.5 (4.1–16.9)	12.5 (4.1–16.9)	12.1 (8–16.6)	0.600
Thrombocyte (x10³/μL)*	201 (27–588)	204.0 (35–538)	162.0 (27–414)	0.007
LDH (U/L)*	383.0 (105–1329)	474.0 (149–1192)	425.0 (105–1329)	0.315
Glucose (mg/dL)*	127.0 (59–538)	128.0 (59–538)	108.5 (76–303)	0.042 ^†
GFR (mL/m)*	72.1 (4.2–159.6)	76.8 (4.2–159.6)	48.8 (11.7–112)	<0.001 ^†
C-reactive protein (mg/L)*	85.0 (0.6–342.0)	81.4 (0.6–342.0)	102.5 (3.3–300)	0.242
Prothrombin time (s)*	14.6 (10.6–85.2)	14.5 (10.6–47.1)	15.4 (11.6–85.2)	0.071
INR*	1.1 (0.9–6.9)	1.1 (1.02–1.21)	1.2 (0.94–6.94)	0.090
aPTT (s)*	30.6 (19.9–75.1)	30.4 (0.9–3.7)	31.8 (21.8–74.1)	0.049 ^†
Fibrinogen (mg/dL)*	544.0 (198–999)	547 (19.8–75.1)	533.5 (198–792)	0.376
D-dimer (mg/dL)*	0.99 (0.05–20)	0.91 (0.1–20.0)	1.5 (0.05–5.3)	0.230
Ferritin (μg/L)*	413.0 (14–3484)	397 (29.0–3484.0)	441.0 (14.0–1754.0)	0.946
Procalcitonin (μg/L)*	0.14 (0.02–31.4)	0.1 (0.1–29.9)	0.3 (0.1–31.4)	<0.001 ^†

Participants with PIM n (%)	TIME to START n (%)	TIME to STOP n (%)
Participants with PIM n (%)	193 (96.0)	59 (37.6)
1	E1. n=170 (84.6%) Vitamin D if vitamin D intake <800–1000 IU per day and/or calcium if elementary calcium intake <1000–1200 mg per day	C4. n=10 (6.4%) PPIs for multiple drug use indication (no benefit, potential harm)
2	I1. n=127 (63.2%) ONS with MN or MNR if nutritional counseling/ dietary supplementation are not sufficient to achieve nutritional goals	C2. n=10 (6.4%) Aspirin, clopidogrel, NSAIDs or corticosteroids in patients with peptic ulcer history/dyspepsia-gastroesophageal reflux symptoms or with concurrent antiplatelet/anticoagulant/corticosteroid treatment(s) without PPI prophylaxis
3	A2. n=29 (14.4%) Statin therapy for secondary prevention in patients with documented atherosclerotic coronary artery disease (previous acute coronary syndrome/coronary artery angioplasty or stenting/coronary artery bypass grafting/abdominal aortic aneurysm), documented atherosclerotic cerebrovascular disease (presence of ischemic stroke/ TIA/previous carotid endarterectomy or stenting) or peripheral arterial disease	H1. n=9 (5.7%) High potency anticholinergic drugs [e.g. tricyclic antidepressants, chlorpromazine, thioridazine, clozapine, olanzapine, hyoscine, oral oxybutynin, first generation antihistamines (pheniramine, chlorpheniramine, hydroxyzine, cyproheptadine, dimenhydrinate, diphenhydramine, meclizine, etc.), paroxetine] in patients with falls/constipation/narrow angle glaucoma/delirium/dementia/urinary retention/obstructive LUTS symptoms/concurrent use of anticholinergic drugs
4	A1. n=21 (10.4%) Antiplatelet therapy (aspirin or clopidogrel) for secondary prevention in patients with documented atherosclerotic coronary artery disease (previous acute coronary syndrome/coronary artery angioplasty or stenting/coronary artery bypass grafting/abdominal aortic aneurysm), documented atherosclerotic cerebrovascular disease (presence of ischemic stroke (TIA/previous carotid endarterectomy or stenting) or symptomatic lower extremity artery disease	E1. n=7 (4.5%) Long-term use of NSAIDs (>3 months) in the presence of alternative treatment
5	A6. n=20 (10.0%) Beta-blocker with ischemic heart disease (antianginal effect in chronic ischemic heart disease/mortality reduction effect in post-MI era) or systolic heart failure (EF≤40%) (bisoprolol/prolonged release metoprolol succinate/carvedilol/nebivolol in systolic heart failure; any beta blocker in ischemic heart disease)	B18. n=7 (4.5%) Piracetam except for myoclonic convulsion therapy (with no proven clinical efficacy, cost burden, and side effect potential)

	Model 1		Model 2		Model 3		Model 4
	HR (95%CI)	p-value	HR (95%CI)	p-value	HR (95%CI)	p-value	HR (95%CI)	p-value
Age	1.07 (1.03–1.11)	<0.001 ^†	1.07 (1.03–1.12)	0.001 ^†	1.07 (1.03–1.12)	0.001 ^†	1.07 (1.02–1.13)	0.005 ^†
Sex: male	1.40 (0.71–2.76)	0.329	1.28 (0.64–2.56)	0.483	1.46 (0.72–2.98)	0.293	1.32 (0.67–2.85)	0.383
Number of PIM*	1.02 (0.79–1.32)	0.869	0.99 (0.75–1.30)	0.914	0.91 (0.67–1.23)	0.543	0.92 (0.68–1.25)	0.929
CHF			0.47 (0.21–1.08)	0.074	0.51 (0.22–1.19)	0.118	0.46 (0.17–1.20)	0.112
Dementia			1.05 (0.42–2.61)	0.922	1.23 (0.48–3.12)	0.669	1.11 (0.42–2.92)	0.834
Score of NRS-2002					1.26 (0.99–1.60)	0.056	1.20 (1.011–1.68)	0.045 ^†
Glucose (mg/dL)							1.00 (0.99–1.01)	0.895
Procalcitonin (μg/L)							1.04 (0.97–1.11)	0.294
GFR (mL/m)							1.01 (0.99–1.02)	0.487
aPTT (s)							1.02 (0.98–1.06)	0.375

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[1] *Corresponding author: nurdansenturkdurmus@hotmail.com