Replicating Randomized Trial Results with Observational Data Using the Parametric g-Formula: An Application to Intravenous Iron Treatment in Hemodialysis Patients

Figures & data

Table 1 Summary of PIVOTAL Trial¹⁵ Treatment Strategies Emulated in DOPPS

		Proactive High Dose			Reactive Low Dose
		TSAT (%)			TSAT (%)
Ferritin (ng/mL)		≤20	21–39	≥40	≤20	21–39	≥40
<100		400	400	0	400	400	0
100–200		400	400	0	200	200	0
201–700		400	400	0	100	0	0
>700		0	0	0	0	0	0

Notes: Intravenous (IV) iron dose administered in the following month (mg) based on most recent value of serum ferritin and transferrin saturation (TSAT) under the proactive high-dose vs reactive low-dose treatment strategy. Iron doses in both the PIVOTAL trial¹⁵ and this DOPPS analysis were completely determined by the most recent ferritin and TSAT value; Grey background highlights situations in which the IV iron dose administered differs between the 2 protocols.

Figure 1 Illustration of longitudinal data collection and hypothesized relationships.

Notes: Baseline characteristics captured at study enrollment. Laboratory values measured monthly. Updated prescriptions captured at the end of each month. Patients followed up continuously for mortality events.

Table 2 Summary of Step 1 Models and Covariates

Model	Variables	Regression Model When Used as Outcome	Functional Form When Used as Predictor
1	Hospitalization	Logistic	Binary (yes/no)
2	C-reactive protein	Linear (log-scale)	Log-linear
3	Serum albumin	Linear	Linear
4	Serum phosphorus	Linear (log-scale)	Categories (3.5, 5.5, 7.0 mg/dL)
5	Hemoglobin	Linear	Categories (9, 10, 11, 12, 13 g/dL)
6	Serum ferritin	Linear (log-scale)	Categories (100, 200, 400, 700, 1000 ng/mL)
7	TSAT	Linear (log-scale)	Categories (15, 20, 25, 30, 35, 40%)
8	Catheter use	Logistic	Binary (yes/no)
9	IV iron dose	Multinomial logistic	Categories (0, 35, 63 mg/week)
10+11	ESA dose	Logistic, linear (log-scale)	Categories (0, 3000, 6000, 9000, 15000 units/week)
12	Died next month	Logistic	N/A

Notes: Categories, indicates cut-points used; IV iron doses were largely discrete, and so the 3 non-zero categories of 1–35 (mostly 25), 35–63 (mostly 50 or 62.5), and >63 (mostly 100) mg/week generally correspond to 100, 200, and 400 mg/month, respectively; For ESA dose, separate models were used to first model use (yes/no), and then the dosage among the users; Died next month is an indicator for whether the patient died during the following (not current) month.

Figure 2 Flow diagram with PIVOTAL trial¹⁵ exclusion criteria.

Notes: PIVOTAL exclusion criteria derived from Table 2 in Macdougall et al¹⁹ and divided into 3 groups: (1) objective criteria we could implement directly in DOPPS; (2) criteria for which we did not capture enough information in DOPPS (living-donor transplant scheduled within 12 months; current active malignancy; chronic liver disease; pregnancy or breast feeding; history of acquired iron overload; previous severe hypersensitivity reactions to IV iron sucrose; compromised ability to give written informed consent and/or comply with study procedures); and (3) *Criteria that did not correspond directly with DOPPS data, but were estimated using available data as follows: (i) active infection: hospitalized with infection in previous month; (ii) advanced heart failure: hospitalized with heart failure in previous 2 months; (iii) life expectancy <12 months per judgement of the investigator: predicted death risk >5% (>96th percentile) in next month in Step 1 models. The first month that each patient met PIVOTAL eligibility criteria was selected as the new baseline for each eligible patient.

Table 3 Summary of Baseline Patient Characteristics in the DOPPS (by Type of Analysis) and the PIVOTAL Trial¹⁵ (by Treatment Group)

		DOPPS Observational Data		PIVOTAL Trial Data
Patient Characteristics		Primary Analysis	PIVOTAL- Restricted	Proactive High-Dose Arm	Reactive Low-Dose Arm
N patients		6325	1508	1093	1048
Time-fixed variables
Age (years)		65.9 ± 15.1	66.0 ± 15.4	62.7 ± 14.9	62.9 ± 15.1
Sex (% male)		61%	62%	65%	66%
Time since HD start (months)		23.0 (6.1, 62.0)	4.1 (2.5, 6.5)	4.9 (2.8, 8.4)	4.8 (2.8, 8.1)
Weight (kg)		72.0 ± 16.8	75.3 ± 17.6	81.3 ± 21.0	82.9 ± 20.9
Anemia-related variables
Serum ferritin (ng/mL)		357 (183, 581)	179 (99, 276)	214 (132, 305)	217 (137, 301)
TSAT (%)		24 (18, 33)	19 (15, 24)	20 (16, 24)	20 (16, 24)
Hemoglobin (g/dL)		11.4 ± 1.4	11.2 ± 1.4	10.6 ± 1.4	10.5 ± 1.4
ESA use (%)		88%	100%	100%	100%
ESA dose (1000 units/week)		7.8 (4.8, 12.5)	8.6 (5.0, 13.0)	8.0 (5.0, 10.0)	8.0 (5.0, 12.0)
IV iron use (%)		70%	81%	–	–
IV iron dose (mg/month)		383 ± 232	439 ± 245	–	–
Other time-updated variables
Serum albumin (g/dL)		3.7 ± 0.5	3.7 ± 0.5	–	–
Serum phosphorus (mg/dL)		4.9 ± 1.6	5.1 ± 1.5	–	–
C-reactive protein (mg/L)		6.0 (2.9, 13.4)	5.0 (2.9, 10.5)	6.0 (3.3, 13.9)	7.0 (4.0, 15.0)
Hospitalized in last month (%)		10%	10%	–	–
Catheter use (%)		28%	35%	41%	41%
Comorbidity history (%)
Coronary artery disease		34%	33%	–	–
Heart failure		21%	21%	4%	4%
Cerebrovascular disease		16%	15%	–	–
Other cardiovascular disease		31%	28%	–	–
Cancer (non-skin)		17%	17%	–	–
Diabetes		36%	42%	45%	44%
Hepatitis B or C		5%	0%	0%	0%
Gastrointestinal bleeding		5%	6%	–	–
Hypertension		87%	89%	74%	72%
Lung disease		14%	14%	–	–
Neurologic disease		12%	11%	–	–
Psychiatric disorder		17%	14%	–	–
Peripheral vascular disease		30%	28%	8%	9%
Recurrent cellulitis, gangrene		9%	7%	–	–

Notes: Mean ± standard deviation, median (IQR), or % shown; Median ESA dose restricted to users; PIVOTAL trial data derived from Table 1 in Macdougall et al¹⁵ with variables shown as “–” if not reported; PIVOTAL-restricted DOPPS patients are a subset of the patients included in the primary analysis, but further restricted to emulate PIVOTAL exclusion criteria.

Abbreviations: HD, hemodialysis; TSAT, transferrin saturation; ESA, erythropoiesis-stimulating agent; IV, intravenous.

Figure 3 Comparison of proactive high-dose vs reactive low-dose IV iron treatment strategy over 12 months using the parametric g-formula. High-dose and low-dose strategies defined by PIVOTAL trial¹⁵ protocol as described in Table 1; Outcomes: (A) all-cause mortality, (B) hemoglobin, (C) serum ferritin, (D) TSAT, (E) ESA dose, (F) IV iron dose.

Abbreviations: RR, risk ratio; RD, risk difference.

Figure 4 Comparison of proactive high-dose vs reactive low-dose IV iron treatment strategy over 12 months using the parametric g-formula, restricted to PIVOTAL-like patients. High-dose and low-dose strategies defined by PIVOTAL trial¹⁵ protocol as described in Table 1; N=1508 PIVOTAL-like DOPPS patients restricted to emulate PIVOTAL exclusion criteria; Outcomes: (A) all-cause mortality, (B) hemoglobin, (C) serum ferritin, (D) TSAT, (E) ESA dose, (F) IV iron dose.

Abbreviations: RR, risk ratio; RD, risk difference.

Table 4 Summary of Findings: Comparing PIVOTAL Trial with DOPPS Simulation Using the Full Sample (Objective 1) and PIVOTAL-Like Restricted Subset

		PIVOTAL Trial: Randomized Results			DOPPS Simulation: Full Sample			DOPPS Simulation: PIVOTAL-Restricted
Outcomes		High Dose	Low Dose	Difference	High Dose	Low Dose	Difference	High-Dose	Low-Dose	Difference
N patients		1093	1048	–	6325	6325	–	1508	1508	–
Laboratory values at baseline
Mean hemoglobin (g/dL)		10.6	10.5	–	11.39	11.39	–	11.16	11.16	–
Median ferritin (ng/mL)		214	217	–	357	357	–	184	184	–
Median TSAT (%)		20.0	20.0	–	25.0	25.0	–	20.0	20.0	–
Laboratory values after 12 months^a
Mean hemoglobin (g/dL)		11.1	10.9	0.2	11.54	11.41	0.13	11.46	11.35	0.11
Median ferritin (ng/mL)		580	130	450	475	292	183	435	268	167
Median TSAT (%)		26	19	7	27.5	23.9	3.6	27.0	23.4	3.6
Cumulative dose through 12 months^a
Median ESA dose (100K units)		380	470	−90	342	364	−22	353	379	−26
Mean IV iron dose (mg)		3800	1800	2000	3166	981	2185	3460	1267	2193
All-cause mortality^a
1-year risk		0.08	0.08	0	0.120	0.101	0.019	0.098	0.083	0.015

Notes: PIVOTAL trial data derived from Macdougall et al¹⁵; ^aIndicates numbers were approximated from figures; PIVOTAL-restricted DOPPS patients are a subset of the patients included in the primary analysis, but further restricted to emulate PIVOTAL exclusion criteria.

Macdougall IC, White C, Anker SD, et al. Intravenous iron in patients undergoing maintenance hemodialysis. N Engl J Med. 2018;380(5):447–458. doi:10.1056/NEJMoa181074230365356

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Macdougall IC, White C, Anker SD, et al. Randomized trial comparing proactive, high-dose versus reactive, low-dose intravenous iron supplementation in hemodialysis (PIVOTAL): study design and baseline data. Am J Nephrol. 2018;48(4):260–268. doi:10.1159/00049355130304714

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