Background
Methods
Study design and setting
Data collection
Data management
Statistical analysis
Patterns of malaria diagnosis and anti-malarial use
Identification of missed Day 1 dosing of anti-malarials
Results
Study population
Characteristic | Anti-malarial Use during the Current Hospitalization | ||
---|---|---|---|
Yes | No | Overall | |
Age, yearsa | 27 (21–35) | 30 (25–43) | 30 (24–42) |
Length of hospital stay, daysa | 4 (3–5) | 4 (3–6) | 4 (3–6) |
Patient-days of observation | 454 | 3287 | 3741 |
Extent of anti-malarial use | Anti-malarial Use during the Current Hospitalization, n (%) | ||
---|---|---|---|
Yes | No | Total | |
Pre-admission anti-malarials | 97 (13) | 665 (87) | 762 |
In-hospital anti-malarials | 100 (13) | 662 (87) | 762 |
Pre-admission anti-malarials | 38 (38) | 62 (62) | 100 |
Pre-/in-hospital co-trimoxazole | 15 (15) | 85 (85) | 100 |
In-hospital antibiotics | 61 (61) | 39 (39) | 100 |
In-hospital antiretrovirals | 14 (14) | 86 (86) | 100 |
Pre-/in-hospital anti-malarials | 159 (21) | 603 (79) | 762 |
Subgroup analyses on key variables | Anti-malarial Use, n (%) | Single factor analysis | ||||
---|---|---|---|---|---|---|
Yes | No | Total, [% col]b | ORc | 95% CId for OR | P-value | |
Gender | ||||||
Male | 20 ( 9) | 208 (91) | 228 [30] | 1.0 | ||
Female | 80 (15) | 454 (85) | 534 [70] | 1.8 | 1.09–3.07 | 0.022 |
Ward | ||||||
Gynaecological (GYN) | 25 (13) | 166 (87) | 191 [25] | 1.0 | ||
Infectious Diseases and Gastrointestinal Illnesses (IDGI) | 57 (18) | 263 (82) | 320 [42] | 1.4 | 0.87–2.39 | 0.161 |
Haematology, Neurology and Endocrinology (HNE) | 12 (10) | 105 (90) | 117 [15] | 0.8 | 0.37–1.58 | 0.459 |
Cardiovascular, Pulmonology and Nephrology (CPN) | 6 ( 4) | 128 (96) | 134 [18] | 0.3 | 0.12–0.78 | 0.013 |
Number of working diagnoses | ||||||
One | 21 (15) | 122 (85) | 143 [18] | 1.0 | ||
Two | 26 (13) | 177 (87) | 203 [27] | 0.9 | 0.46–1.59 | 0.616 |
Three | 28 (15) | 158 (85) | 186 [24] | 1.0 | 0.56–1.90 | 0.926 |
Four or more | 25 (11) | 205 (89) | 230 [30] | 0.7 | 0.38–1.32 | 0.277 |
Length of hospital stay, days | ||||||
Less than 5-days | 64 (15) | 368 (85) | 432 [57] | 1.0 | ||
Five days or more | 36 (11) | 294 (89) | 330 [43] | 0.7 | 0.46–1.09 | 0.115 |
HIV-serostatus | ||||||
Negative | 49 (14) | 291 (86) | 340 [45] | 1.0 | ||
Positive | 23 (10) | 209 (90) | 232 [30] | 0.7 | 0.39–1.11 | 0.113 |
Unknown | 28 (15) | 162 (85) | 190 [25] | 1.0 | 0.62–1.70 | 0.919 |
Hospitalization in past 3-months | ||||||
No | 75 (14) | 455 (86) | 532 [70] | 1.0 | ||
Yes | 25 (11) | 205 (89) | 230 [30] | 0.7 | 0.46–1.20 | 0.227 |
Charlson's co-morbidity index score | ||||||
Zero | 64 (16) | 329 (84) | 393 [52] | 1.0 | ||
One or more | 36 (10) | 333 (90) | 369 [48] | 0.6 | 0.36–0.86 | 0.008 |
Antiretroviral therapy use | ||||||
No | 86 (14) | 549 (86) | 635 [83] | 1.0 | ||
Yes | 14 (11) | 113 (89) | 127 [17] | 0.8 | 0.43–1.44 | 0.444 |
Microscopy—Malaria Parasitaemia Results Available | ||||||
No | 62 (62) | 616 (93) | 678 [89] | 1.0 | ||
Yes | 38 (38) | 46 ( 7) | 84 [11] | 8.2 | 4.81–14.0 | < 0.001 |
Major admission diagnosis | ||||||
Malaria | ||||||
No | 17 ( 3) | 604 (97) | 621 [81] | 1.0 | ||
Yes | 83 (59) | 58 (41) | 141 [19] | 50 | 28.3–91.5 | < 0.001 |
Immunosuppressed syndrome (ISS) or HIV/AIDSe | ||||||
No | 86 (14) | 524 (86) | 610 [80] | 1.0 | ||
Yes | 14 ( 9) | 14 (91) | 152 [20] | 0.6 | 0.34–1.12 | 0.113 |
Tuberculosis (TB) | ||||||
No | 92 (14) | 548 (86) | 640 [84] | 1.0 | ||
Yes | 8 ( 7) | 114 (93) | 122 [16] | 0.4 | 0.20–0.88 | 0.023 |
Sepsis-related working diagnosis | ||||||
No | 81 (12) | 597 (88) | 678 [89] | 1.0 | ||
Yes | 19 (23) | 65 (77) | 84 [11] | 2.2 | 1.23–3.78 | 0.007 |
Respiratory Conditions except TB | ||||||
No | 85 (13) | 547 (87) | 632 [83] | 1.0 | ||
Yes | 15 (12) | 115 (88) | 130 [17] | 0.8 | 0.47–1.51 | 0.557 |
Miscellaneous infections | ||||||
No | 78 (12) | 571 (88) | 649 [85] | 1.0 | ||
Yes | 22 (19) | 91 (81) | 113 [15] | 1.8 | 1.05–2.98 | 0.032 |
Malaria suspected at admission (n = 141) ~ | Malaria not suspected at admission (n = 621) | ||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Malaria at discharge (n = 83) | No malaria at discharge (n = 58) | Malaria at discharge (n = 5) | No malaria at discharge (n = 616) | ||||||||||||||||||||||||||||
Microscopy requested, n (%) ¥ | |||||||||||||||||||||||||||||||
Yes | No | Yes | No | Yes | No | Yes | No | ||||||||||||||||||||||||
Returned Positive | Returned Negative | Not Returned | Not Requested | Returned Positive | Returned Negative | Not Returned | Not Requested | Returned Positive | Returned Negative | Not Returned | Not Requested | Returned Positive | Returned Negative | Not Returned | Not Requested | ||||||||||||||||
21 (25) | 13 (16) | 31 (37) | 18 (22) | 0 (0) | 16 (28) | 27 (47) | 15 (26) | 1 (20) | 0 (0) | 1 (20) | 3 (60) | 3 (0) | 30 (5) | 58 (9) | 525 (85) | ||||||||||||||||
In-hospital administration of anti-malarials, n (%) | |||||||||||||||||||||||||||||||
Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No |
20 (95) | 1 (5) | 11 (85) | 2 (15) | 26 (84) | 5 (16) | 15 (83) | 3 (17) | 0 (0) | 0 (0) | 5 (31) | 11 (69) | 3 (11) | 24 (89) | 3 (20) | 12 (80) | 1 (100) | 0 (0) | 0 (0) | 0 (0) | 1 (100) | 0 (0) | 1 (33) | 2 (67) | 0 (0) | 3 (100) | 1 (3) | 29 (97) | 4 (7) | 54 (93) | 9 (2) | 516 (98) |
Single admission diagnosis of malaria, n (%) | |||||||||||||||||||||||||||||||
Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No |
5 (24) | 16 (76) | 0 (0) | 13 (100) | 5 (16) | 26 (84) | 4 (22) | 14 (78) | 0 (0) | 0 (0) | 1 (6) | 15 (94) | 1 (4) | 26 (96) | 0 (0) | 15 (100) | 0 (0) | 1 (100) | 0 (0) | 0 (0) | 0 (0) | 1 (100) | 0 (0) | 3 (100) | 0 (0) | 3 (100) | 0 (0) | 30 (100) | 0 (0) | 58 (100) | 0 (0) | 525 (100) |
Received anti-malarials during the 4-weeks preadmission, n (%) | |||||||||||||||||||||||||||||||
Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No |
7 (33) | 14 (67) | 5 (38) | 8 (62) | 8 (26) | 23 (74) | 7 (39) | 11 (61) | 0 (0) | 0 (0) | 5 (31) | 11 (69) | 8 (30) | 19 (70) | 3 (20) | 12 (80) | 0 (0) | 1 (100) | 0 (0) | 0 (0) | 1 (100) | 0 (0) | 1 (33) | 2 (67) | 0 (0) | 3 (100) | 10 (33) | 20 (67) | 5 (9) | 53 (91) | 37 (7) | 488 (93) |
Single discharge diagnosis of malaria, n (%) | |||||||||||||||||||||||||||||||
Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | Yes | No |
9 (43) | 12 (57) | 3 (23) | 10 (77) | 16 (52) | 15 (48) | 11 (61) | 7 (39) | 0 (0) | 0 (0) | 0 (0) | 16 (100) | 0 (0) | 27 (100) | 0 (100) | 15 (0) | 0 (0) | 1 (100) | 0 (0) | 0 (0) | 0 (0) | 1 (100) | 0 (0) | 3 (100) | 0 (0) | 3 (100) | 0 (0) | 30 (100) | 0 (0) | 58 (100) | 0 (0) | 525 (100) |
Laboratory diagnosis of malaria
Extent of anti-malarial use
Missed opportunity for hospital-initiated anti-malarials
Particulars | Clinical notes |
---|---|
Patient 1 | A 60-year-old female with unknown HIV-status, 6-year history of hypertension and type 2 diabetes mellitus (DM) presented with poorly controlled DM having defaulted on DM treatment for 8-months. Microscopy for malaria parasites was requested on the day of admission (Day 1). Results were returned on Day 1 with confirmed malaria parasitaemia. AL and paracetamol were prescribed on Day 2 but not dispensed. The patient was discharged on Day 3 without anti-malarial treatment |
Patient 2 | A 24-year-old female with unknown HIV-status was referred from a clinic where she had been treated for suspected malaria and typhoid with no improvement. She presented with poorly treated malaria and microscopy for malaria parasites was requested on Day 1. Results were returned on Day 2 with confirmed malaria parasitaemia. AL and paracetamol were prescribed on Day 2 but not dispensed and the patient was discharged on Day 2 without anti-malarial treatment |
Patient 3 | A 44-year-old HIV-negative male was transferred from a referral hospital. He presented with an admission diagnosis of chronic lymphocytic leukaemia and confirmed malaria parasitaemia by microscopy. No fresh request for malaria microscopy was made during the current admission. The patient did not receive any anti-malarial treatment prescription and/or administration both prior to admission and throughout the current hospitalization. He was transferred to Uganda Cancer Institute on Day 3 |
Patient 4 | A 43-year-old HIV-positive female with history of DM who was receiving second-line antiretroviral therapy (tenofovir, lamivudine, lopinavir/ritonavir) and co-trimoxazole presented with an admission diagnosis of colon cancer. Microscopy for malaria parasites was requested on Day 2 and results were returned the same day with confirmed malaria parasitaemia. No anti-malarial treatment was prescribed, dispensed or administered during hospitalization. The patient continued to receive her antiretrovirals and co-trimoxazole; and was transferred to Uganda Cancer Institute on Day 17 |
Frequency of administered anti-malarials
Anti-malarial | Number | n, % |
---|---|---|
Patient-level | ||
Pre-admission, n = 97 | ||
Artemether-Lumefantrine only | 50 | 52 |
Quinine only | 22 | 23 |
Sulfadoxine-Pyrimethamine only | 9 | 9 |
Artesunate only | 5 | 5 |
Coartem + Quinine only | 4 | 4 |
Duocotecxin only | 2 | 2 |
Artemether only | 1 | 1 |
Artesunate + Duocotexcin only | 1 | 1 |
P-alaxin + Quinine only | 1 | 1 |
Artemether + Quinine + Doxycycline only | 1 | 1 |
Dihydroartemisinin-Piperaquine only | 1 | 1 |
In-hospital, n = 100* | ||
Artesunate only± | 47 | 47 |
Quinine only~ | 23 | 23 |
Artemether-Lumefantrine only | 15 | 15 |
Artesunate + Artemether-Lumefantrine only | ||
Quinine + Artemether/Lumefantrine only | 3 | 3 |
Sulfadoxine-Pyrimethamine only | 2 | 2 |
Artesunate + Quinine only | 2 | 2 |
Drug-level | ||
Pre-admission, n = 105 | ||
Artemether-Lumefantrine | 54 | 51 |
Quinine | 28 | 27 |
Sulfadoxine-Pyrimethamine | 9 | 9 |
Artesunate | 6 | 6 |
Duocotexcin | 3 | 3 |
Artemether | 2 | 2 |
Dihydroartemisinin-Piperaquine | 2 | 2 |
Doxycycline | 1 | 1 |
In-hospital, n = 113 | ||
Artesunate | 57 | 50 |
Quinine | 28 | 25 |
Artemether-Lumefantrine | 26 | 23 |
Sulfadoxine-Pyrimethamine | 2 | 2 |
Medication-use-cycle
Overview of prescription, dispensing and administration of anti-malarials
Incomplete dosing of in-hospital anti-malarials
Missed Day 1 dosing of hospital-prescribed anti-malarials
Length of stay, days | Preadmission anti-malarial use | Admission Malaria Diagnosis | Discharge Malaria Diagnosis | AL co-prescribed | Switched to AL | AS Doses Prescribed | AS Doses Received | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 | Day 6 | Day 7 | Day 8 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
3 | No | Yes | No | No | No | 3 | 1 | 1 dose | |||||||
3 | No | Yes | Yes | Yes | No | 2 | 3 | 1 dose | 2 doses | ||||||
4 | No | Yes | Yes | No | No | 6 | 2 | 1 dose | 1 dose | ||||||
5 | No | Yes | Yes | Yes | No | 3 | 3 | 1 dose | 1 dose | 1 dose | |||||
2 | No | Yes | Yes | Yes | No | 2 | 1 | 1 dose | |||||||
4 | Yes | Yes | Yes | Yes | No | 10 | 3 | 1 dose | 1 dose | 1 dose | |||||
5 | No | No | No | No | No | 3 | 2 | 2 doses | |||||||
2 | No | Yes | Yes | Yes | Yes | 3 | 2 | 2 doses | |||||||
4 | No | Yes | No | Yes | Yes | 3 | 2 | 1 dose | 1 dose | ||||||
5 | Yes | Yes | Yes | Yes | Yes | 3 | 1 | 1 dose | |||||||
4 | No | Yes | Yes | Yes | No | 3 | 2 | 1 dose | 1 dose | ||||||
5 | No | Yes | Yes | No | No | 3 | 4 | 1 dose | 2 doses | 1 dose | |||||
5 | No | Yes | Yes | No | No | 3 | 3 | 1 dose | 1 dose | 1 dose | |||||
5 | No | Yes | No | No | No | 3 | 3 | 1 dose | 1 dose | 1 dose | |||||
10 | Yes | Yes | No | No | No | 3 | 2 | 1 dose | 1 dose | ||||||
3 | Yes | No | No | No | No | 2 | 3 | 1 dose | 2 doses | ||||||
5 | Yes | Yes | Yes | Yes | No | 2 | 2 | 1 dose | 1 dose | ||||||
2 | No | Yes | Yes | Yes | No | 3 | 2 | 1 dose | 1 dose | ||||||
3 | No | Yes | Yes | Yes | No | 2 | 3 | 2 doses | 1 dose | ||||||
10 | No | No | No | No | No | 3 | 4 | 1 dose | 1 dose | 2 doses | |||||
3 | No | Yes | Yes | Yes | No | 3 | 2 | 2 doses | |||||||
5 | No | No | Yes | Yes | No | 2 | 3 | 1 dose | 1 dose | 1 dose | |||||
2 | No | Yes | Yes | Yes | No | 4 | 1 | 1 dose | |||||||
3 | Yes | Yes | Yes | Yes | No | 4 | 3 | 1 dose | 1 dose | 1 dose | |||||
3 | No | Yes | Yes | Yes | No | 3 | 3 | 1 dose | 2 doses | ||||||
3 | Yes | Yes | Yes | No | No | 3 | 3 | 1 dose | 1 dose | 1 dose | |||||
3 | Yes | Yes | Yes | Yes | No | 3 | 2 | 1 dose | 1 dose | ||||||
5 | Yes | Yes | Yes | Yes | No | 3 | 4 | 1 dose | 1 dose | 1 dose | 1 dose | ||||
4 | Yes | Yes | Yes | Yes | No | 3 | 3 | 1 dose | 1 dose | 1 dose | |||||
3 | Yes | Yes | Yes | Yes | No | 3 | 3 | 1 dose | 1 dose | 1 dose | |||||
5 | Yes | Yes | Yes | Yes | No | 3 | 3 | 1 dose | 1 dose | 1 dose | |||||
7 | Yes | Yes | Yes | Yes | Yes | 3 | 3 | 1 dose | 1 dose | 1 dose | |||||
5 | No | No | No | Yes | No | 3 | 3 | 1 dose | 1 dose | 1 dose | |||||
3 | Yes | Yes | Yes | Yes | No | 3 | 2 | 1 dose | 1 dose | ||||||
4 | No | Yes | Yes | No | No | 3 | 2 | 1 dose | 1 dose | ||||||
2 | No | Yes | Yes | Yes | No | 3 | 1 | 1 dose | |||||||
9 | No | Yes | Yes | No | No | 3 | 2 | 1 dose | 1 dose | ||||||
6 | No | Yes | Yes | No | No | 3 | 3 | 1 dose | 2 doses | ||||||
3 | Yes | No | No | Yes | No | 3 | 1 | 1 dose | |||||||
4 | No | Yes | Yes | Yes | No | 3 | 3 | 1 dose | 2 doses | ||||||
3 | Yes | Yes | No | Yes | No | 3 | 3 | 1 dose | 2 doses | ||||||
4 | No | Yes | Yes | No | No | 3 | 3 | 1 dose | 1 dose | 1 dose | |||||
3 | Yes | No | Yes | Yes | No | 3 | 3 | 1 dose | 2 doses | ||||||
4 | Yes | Yes | Yes | Yes | No | 3 | 3 | 1 dose | 2 doses | ||||||
9 | No | Yes | Yes | Yes | Yes | 4 | 3 | 1 dose | 1 dose | 1 dose | |||||
4 | Yes | Yes | No | Yes | Yes | 2 | 3 | 2 doses | 1 dose | ||||||
4 | No | Yes | Yes | Yes | No | 6 | 2 | 1 dose | 1 dose | ||||||
3 | No | Yes | Yes | Yes | Yes | 1 | 1 | 1 dose | |||||||
16 | Yes | Yes | No | No | No | 3 | 3 | 1 dose | 2 doses | ||||||
4 | No | Yes | Yes | No | No | 3 | 1 | 1 dose | |||||||
6 | No | Yes | No | No | No | 3 | 4 | 1 dose | 1 dose | 2 doses | |||||
5 | No | Yes | Yes | Yes | No | 3 | 3 | 2 doses | 1 dose | ||||||
3 | No | Yes | No | No | No | 1 | 1 | 1 dose | |||||||
3 | No | Yes | Yes | Yes | No | 3 | 1 | 1 dose | |||||||
4 | Yes | No | No | No | No | 2 | 2 | 1 dose | 1 dose | ||||||
15 | Yes | No | Yes | No | No | 3 | 8 | 1 dose | 2 doses | 1 dose | 2 doses | 2 doses | |||
1 | No | Yes | Yes | Yes | No | 2 | 2 | 1 dose | 1 dose | ||||||
Missed-dose day, n | 16 | 10 | 8 | 1 | 1 | ||||||||||
Dose-day data unavailable, n1 | 0 | 5 | 27 | 44 | 52 | ||||||||||
Dose-day data available, N* | 57 | 52 | 30 | 13 | 5 | ||||||||||
Proportion of in-patients with missed Day 1 data, n/N ~ | 28% |
Mortality among in-patients who received in-hospital anti-malarials
Particulars | Clinical notes |
---|---|
Quinine | One in-patient who received Q during admission died in hospital |
Patient 1-Q | An 88-year-old female of unknown HIV-status presented with a single admission diagnosis of severe malaria which manifested with fever, chills and unconsciousness. She was referred from a clinic for further management after receiving an initial intramuscular dose of quinine (23 h prior to the current admission). Her vitals on admission were: pulse rate (98 beats per minute); blood pressure (116/63 mmHg); temperature (35.9 °C). Microscopy for malaria parasites was requested on admission (Day 1) but the results were not returned by Day 2. She received 2-doses of Q which were administered 11 h apart, the first dose being 2 h after admission on Day 1. The patient died on Day 2 of hospitalization |
Artesunate | Two in-patients who received AS during admission died in hospital. None of the two in-patients presented with either an admission or a definitive malaria diagnosis: |
Patient 1-AS | A 20-year-old female of unknown HIV-status was admitted with suspected severe sepsis of chest focus, bacterial pneumonia, urinary tract infection (UTI), salmonellosis and acute gastroenteritis. Microscopy for malaria parasites was requested on Day 1 but the results were not returned. She missed Day 1 dosing of AS and subsequently received 4 doses of AS. Her definitive diagnoses were UTI, pneumonia and salmonellosis. She died on Day 4 of hospitalization |
Patient 2-AS | A 24-year-old HIV-positive female presented with severe immunosuppression, sepsis, disseminated tuberculosis and/or tuberculous meningitis, atypical measles syndrome and toxoplasmosis. Microscopy for malaria parasites was not requested on admission. She received 2 doses of AS and never missed Day 1 dosing. Her definitive diagnosis was severe immunosuppression. She died on Day 10 of hospitalization |
Artemether + Lumefantrine | One in-patient who received AL in hospital died |
Patient 1-AL | A 23-year-old HIV-positive female presented with working diagnoses of immunosuppression, malaria, septicaemia, urinary tract infection and anaemia. Microscopy for malaria parasites was requested on admission (Day 1) but the results were not returned. Duocotexcin (DP) was prescribed on Day 1 but was neither dispensed nor administered. One dose of AL was administered on Day 3. Her definitive diagnoses were immunosuppression and malaria. She died on Day 6 of hospitalization |
Patient-level risk-factors for missed Day 1 dosing of anti-malarials
Missed Day 1 dosing of anti-malarials by calendar-day, n (%); (N = 83) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Factor | Missed Calendar-Day 1 dosing | Crude Analysis | Adjusted Analysis | |||||||||
Yes | No | Total, [% col]a | ORb | 95% for CIc | P-value | aORb | 95% for CIc | P-value | ||||
Antiretroviral therapy use | ||||||||||||
No | 15 (20) | 59 (80) | 74 [89] | 1.0 | 1.0 | |||||||
Yes | 5 (56) | 4 (44) | 9 [11] | 4.9 | 1.17–20.6 | 0.029 | 4.9 | 0.90–26.1 | 0.066 | |||
Malaria microscopy test results available | ||||||||||||
No | 8 (17) | 39 (83) | 47 [57] | 1.0 | 1.0 | |||||||
Yes | 12 (33) | 24 (67) | 36 [43] | 2.4 | 0.87–6.82 | 0.090 | 2.4 | 0.70–8.40 | 0.165 | |||
Linear on number of working | ||||||||||||
Diagnoses | 20 | 63 | 83 | 2.6 | 1.56–4.35 | < 0.001 | 2.6 | 1.52–4.56 | 0.001 |