Epidemiology of heart failure and trends in diagnostic work-up: a retrospective, population-based cohort study in Sweden

Figures & data

Figure 1 (A) Study timelines (analysis and look-back periods) for cohort 1 (national cohort) and cohort 2 (counties of Uppsala and Västerbotten) and (B) patient flow for cohort 1 (national cohort) and cohort 2 (counties of Uppsala and Västerbotten).

Notes: ^aThe look-back for NPR data in cohort 2 extended from the same time points as for cohort 1 and ended on December 31, 2009; ^bLook-back period extended from January 1, 1997 for inpatient care and January 1, 2001 for outpatient care; ^cIncident HF patient population (prevalent HF population classified as those patients in whom HF was diagnosed during the look-back period and who survived into the analysis period). In cohort 1, data from 845,276 patients were extracted from the Swedish NPR on the basis of an observed HF diagnosis between 1997 and 2013, of which data for 174,537 patients met the inclusion criteria of at least two HF diagnoses in the analysis period (2005–2013) with no HF diagnosis in the look-back period (1997–2004). In cohort 2, data from 33,120 patients were extracted from the EMRs on the basis of an observed HF diagnosis between 1994 and 2015 (Uppsala County) and between 1992 and 2016 (Västerbotten County), of which data for 8,702 patients met the inclusion criteria of at least two HF diagnoses in the analysis period (2010–2015) and no HF diagnosis in the look-back period (NPR; 1997–2009, EMR; 1992–2009). The prevalent population (cohort 1, n=273,999; cohort 2, n=16,962) comprised those with a diagnosis of HF in the look-back period who were alive during the analysis period. The incident HF population comprised those with no HF diagnosis in the look-back periods.
Abbreviations: EMR, electronic medical record; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NPR, National Patient Register.

Table 1 Patient demographics and clinical characteristics at baseline for cohort 1 and cohort 2, overall and by HF phenotype (incident patient populations)

	Cohort 1	Cohort 2
	Total (N=174,537)	Total (N=8,702)	HFpEF (n=1,120)	HFrEF (n=2,047)	Unknown LVEF (n=5,535)
Mean age at HF diagnosis date, years (SD)	77.4 (12.0)	76.6 (12.6)	74.2 (12.6)	69.9 (13.7)	79.5 (11.0)
Age at HF diagnosis date, n (%)
18–54 years	9,041 (5.2)	539 (6.2)	84 (7.5)	273 (13.3)	182 (3.3)
55–64 years	17,281 (9.9)	859 (9.9)	136 (12.1)	370 (18.1)	353 (6.4)
65–74 years	34,159 (19.6)	1,951 (22.4)	298 (26.6)	613 (29.9)	1,040 (18.8)
75–84 years	62,859 (36.0)	2,944 (33.8)	384 (34.3)	543 (26.5)	2,017 (36.4)
≥85 years	51,197 (29.3)	2,409 (27.7)	218 (19.5)	248 (12.1)	1,943 (35.1)
Sex, n (%)
Men	92,740 (53.1)	4,695 (54.0)	547 (48.8)	1,379 (67.4)	2,769 (50.0)
Women	81,797 (46.9)	4,007 (46.0)	573 (51.2)	668 (32.6)	2,766 (50.0)
Mean CCI 0–5 years before diagnosisa (SD)	1.5 (2.0)	1.8 (2.2)	1.8 (2.3)	1.6 (2.1)	1.9 (2.3)
Common comorbidities and risk factors 0–5 years before diagnosis, n (%)b,c
Hypertension	63,361 (36.3)	4,501 (51.7)	599 (53.5)	866 (42.3)	3,036 (54.9)
Atrial fibrillation	45,556 (26.1)	2,609 (30.0)	347 (31.0)	429 (21.0)	1,833 (33.1)
Ischemic heart diseased	39,977 (22.9)	1,873 (21.5)	189 (16.9)	455 (22.2)	1,229 (22.2)
Diabetes mellitus	31,016 (17.8)	1,616 (18.6)	225 (20.1)	343 (16.8)	1,048 (18.9)
Cancer	28,580 (16.4)	1,280 (14.7)	190 (17.0)	252 (12.3)	838 (15.1)
Anemia	16,825 (9.6)	1,073 (12.3)	163 (14.6)	173 (8.5)	737 (13.3)
Cerebrovascular disease	19,425 (11.1)	1,043 (12.0)	103 (9.2)	192 (9.4)	748 (13.5)
Dyslipidemia	14,448 (8.3)	1,151 (13.2)	148 (13.2)	245 (12.0)	758 (13.7)
Aortic insufficiency/regurgitation	9,818 (5.6)	640 (7.4)	135 (12.1)	179 (8.7)	326 (5.9)
Setting of first HF diagnosis, n (%)
Hospital inpatient care	139,654 (80.0)	4,595 (52.8)	638 (57.0)	1,267 (61.9)	2,690 (48.6)
Hospital outpatient care	34,883 (20.0)	2,042 (23.5)	293 (26.2)	573 (28.0)	1,176 (21.2)
Primary care	NA	2,065 (23.7)	189 (16.9)	207 (10.1)	1,669 (30.2)

Notes:

Data are either number (n) and percentage (%) or mean (SD).

a Includes patients with a CCI of 0 (ie, no comorbidities).

b Index (HF diagnosis) date for cohort 1 is based on NPR and for cohort 2 on EMR.

c Comorbidities occurring in ≥10% of patients in any group are included.

d Angina or myocardial infarction.

Abbreviations: CCI, Charlson comorbidity index; EMR, electronic medical record; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NA, not applicable; NPR, National Patient Register.

Figure 2 Annual incidence per 1,000 inhabitants and prevalence of HF during 2010–2014 in Sweden (cohort 1) and in the counties of Uppsala and Västerbotten (cohort 2).

Notes: (A) Total age-adjusted; and (B) crude incidence and prevalence by age group. Estimates are based on data from the NPR (cohorts 1 and 2) and from primary and secondary care EMRs (cohort 2) for the period 2010–2014. Age-adjusted incidence and prevalence calculated using population weights based on the Swedish population in 2015.^{16 a}Second HF diagnosis used as the index date.
Abbreviations: EMRs, electronic medical records; HF, heart failure; NPr, National Patient Register.

Table 2 Key laboratory measures at baseline for cohort 2, overall and by HF phenotype (incident patient population)

Laboratory parameter	Total (N=8,702)	HFpEF (n=1,120)	HFrEF (n=2,047)	Unknown LVEF (n=5,535)
LVEF, n (%)a
Missing	5,535	0	0	5,535
<0.45	1,663 (52.5)	0 (0.0)	1,663 (81.2)	0 (0.0)
0.45–0.50	384 (12.1)	0 (0.0)	384 (18.8)	0 (0.0)
>0.50	1,120 (35.4)	1,120 (100.0)	0 (0.0)	0 (0.0)
NT-proBNP, pg/mL	n=7,264	n=1,032	n=1,830	n=4,402
	4,989.6 (8,243.3)	4,173.7 (6,697.1)	6,470.3 (10,042.0)	4,565.3 (7,647.0)
Systolic/diastolic BP, mmHg	n=8,412/8,399	n=1,088/1,088	n=1,976/1,973	n=5,348/5,338
	138.5 (25.4)/78.6 (15.0)	140.0 (26.1)/76.7 (14.0)	134.2 (24.1)/79.6 (15.3)	139.7 (25.5)/78.6 (15.1)
eGFR, mL/min/1.73 m^2	n=4,093	n=766	n=1,404	n=1,923
	54.1 (26.5)	52.4 (26.5)	60.9 (27.9)	49.8 (24.3)
Hemoglobin, g/L	n=8,577	n=1,114	n=2,040	n=5,423
	129.5 (19.2)	125.0 (19.8)	133.5 (19.1)	129.0 (18.9)
Pulse rate, bpm	n=5,105	n=885	n=1,435	n=2,785
	84.3 (20.4)	82.1 (19.8)	87.0 (21.3)	83.6 (20.0)
Potassium, mmol/L	n=8,563	n=1,107	n=2,028	n=5,428
	4.1 (0.6)	4.1 (0.6)	4.1 (0.5)	4.1 (0.6)
Sodium, mmol/L	n=8,404	n=1,100	n=2,023	n=5,281
	139.3 (4.0)	139.1 (4.2)	139.2 (3.9)	139.4 (4.1)
Creatinine, µmol/L	n=8,622	n=1,116	n=2,047	n=5,459
	103.1 (66.5)	105.0 (79.5)	101.8 (65.4)	103.2 (63.9)
Ferritin, µg/L	n=1,374	n=329	n=403	n=642
	325.4 (1,188.8)	356.2 (935.6)	365.0 (1,743.0)	284.7 (819.1)

Notes: Data are mean (SD) unless specified. n=number of patients with measurement.

a LVEF strata based on data available in the Uppsala County cohort, combining intervals <0.45. Data from Västerbotten County were processed from a mixture of interval data and exact values to fit data from Uppsala County.

Abbreviations: BP, blood pressure; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; bpm, beats per minute; eGFR, estimated glomerular filtration rate.

Figure 3 Diagnostic work-up of patients in cohort 2 in the 6 months before and after the year of first HF diagnosis: (A) by index year and (B) according to setting of HF diagnosis.

Note: ^aFirst HF diagnosis used as the index date.
Abbreviations: Echo, echocardiography; HF, heart failure; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Table 3 COX and Fine and Gray regression analyses of 1-year all-cause and CVD-related mortality with Kaplan–Meier and cumulative incidence function estimates for 1-year mortality (cohort 1, incident HF population)

		1-year All-cause mortalitya		1-year CVD-related mortalityb
	n (N=174,537)	Mortality (95% CI)c	HR (95% CI)c–e	Mortality (95% CI)f	SHR (95% CI)e–g
Age, years
18–54	9,041	5.5% (5.0%, 5.9%)	1 (reference)	2.3% (2.0%, 2.6%)	1 (reference)
55–64	17,281	9.8% (9.3%, 10.2%)	1.82 (1.65, 2.01)	5.0% (4.7%, 5.3%)	2.25 (1.93, 2.62)
65–74	34,159	16.1% (15.7%, 16.5%)	3.14 (2.86, 3.44)	8.3% (8.0%, 8.6%)	3.82 (3.32, 4.40)
75–84	62,859	29.1% (28.7%, 29.5%)	6.18 (5.65, 6.76)	16.2% (15.9%, 16.5%)	7.81 (6.80, 8.97)
≥85	51,197	46.4% (46.0%, 46.8%)	11.38 (10.41, 12.44)	28.3% (27.9%, 28.6%)	14.89 (12.97, 17.09)
Sex
Women	81,797	30.9% (30.6%, 31.2%)	1 (reference)	18.1% (17.9%, 18.4%)	1 (reference)
Men	92,740	26.4% (26.1%, 26.6%)	1.07 (1.06, 1.09)	14.8% (14.6%, 15.0%)	1.04 (1.02, 1.07)
Year of HF diagnosis
2005	10,737	29.7% (28.8%, 30.5%)	1 (reference)	17.9% (17.1%, 18.6%)	1 (reference)
2006	15,749	28.6% (27.9%, 29.3%)	0.93 (0.88, 0.97)	17.4% (16.9%, 18.0%)	0.95 (0.89, 1.00)
2007	18,359	28.6% (28.0%, 29.3%)	0.92 (0.88, 0.96)	17.2% (16.6%, 17.7%)	0.92 (0.86, 0.97)
2008	19,950	28.7% (28.1%, 29.4%)	0.91 (0.87, 0.95)	16.8% (16.3%, 17.3%)	0.88 (0.83, 0.93)
2009	21,017	28.3% (27.7%, 28.9%)	0.88 (0.84, 0.92)	16.1% (15.6%, 16.6%)	0.83 (0.79, 0.88)
2010	21,633	28.3% (27.7%, 28.9%)	0.88 (0.84, 0.92)	16.3% (15.9%, 16.8%)	0.84 (0.80, 0.89)
2011	22,485	28.3% (27.7%, 28.9%)	0.88 (0.84, 0.92)	15.9% (15.5%, 16.4%)	0.82 (0.78, 0.87)
2012	22,594	28.3% (27.7%, 28.9%)	0.88 (0.85, 0.92)	15.6% (15.1%, 16.1%)	0.80 (0.76, 0.85)
2013	22,013	28.2% (27.6%, 28.8%)	0.88 (0.84, 0.92)	15.3% (14.8%, 15.8%)	0.79 (0.74, 0.83)

Notes:

a Patients are censored at emigration (loss to follow-up) and at end of follow-up (December 31, 2014).

b Patients are censored at emigration, at death due to non-CVD causes and at end of follow-up (December 31, 2014).

c Kaplan–Meier estimates of mortality (1–survival).

d Cox Multivariate HR, adjusted for age group, sex and year of HF diagnosis.

e End of follow-up restricted to 1 year after second observed HF diagnosis.

f Cumulative incidence function estimates of mortality (1–survival).

g Subdistribution HR, adjusted for age group, sex and year of HF diagnosis.

Abbreviations: CVD, cardiovascular disease; HF, heart failure; HR, hazard ratio; SHR, sub-distribution hazard ratio.

Figure 4 Trends in the most common causes of death for the prevalent HF population (cohort 1) between 2005 and 2013.

Notes: The percentages are relative to the number of all-cause deaths. “n” represents the number of prevalent patients at each year. Trends were significant (P<0.0001, Cochran–Armitage test) for chronic IHD, MI, HF, AF, and flutter over time.
Abbreviations: AF, atrial fibrillation; HF, heart failure; IHD, ischemic heart disease; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction.

Table 4 COX and Fine and Gray regression analyses of 1-year all-cause and CVD-related mortality with Kaplan–Meier and cumulative incidence function estimates for 1-year mortality (cohort 2, incident HF population)

	n (N=6,522)	1-Year all-cause mortalitya		1-Year CVD-related mortalityb
		Mortality (95% CI)c	HR (95% CI)c–e	Mortality (95% CI)f	SHR (95% CI)e–g
Age, years
18–54	395	5.8% (3.5%, 8.1%)	1 (reference)	1.8% (0.8%, 3.5%)	1 (reference)
55–64	652	9.6% (7.3%, 11.8%)	1.33 (0.81, 2.18)	3.4% (2.2%, 5.0%)	1.69 (0.71, 4.02)
65–74	1,460	10.7% (9.1%, 12.3%)	1.49 (0.95, 2.34)	4.1% (3.1%, 5.2%)	1.84 (0.82, 4.10)
75–84	2,228	16.6% (15.0%, 18.1%)	2.46 (1.60, 3.79)	6.9% (5.9%, 8.0%)	3.35 (1.55, 7.25)
≥85	1,787	30.5% (28.3%, 32.7%)	4.58 (2.98, 7.04)	16.8% (15.1%, 18.6%)	8.86 (4.12, 19.04)
Sex
Women	3,024	19.8% (18.3%, 21.2%)	1 (reference)	9.8% (8.8%, 10.9%)	1 (reference)
Men	3,498	15.6% (14.4%, 16.8%)	0.96 (0.84, 1.10)	7.0% (6.1%, 7.8%)	0.88 (0.72, 1.07)
HF diagnosis setting
Primary	1,558	9.1% (7.6%, 10.6%)	1 (reference)	4.8% (3.8%, 6.0%)	1 (reference)
Secondary	4,964	20.1% (19.0%, 21.3%)	2.30 (1.88, 2.80)	9.4% (8.6%, 10.2%)	2.04 (1.56, 2.68)
HF phenotype
HFpEF	826	19.3% (16.6%, 22.0%)	1 (reference)	7.4% (5.8%, 9.3%)	1 (reference)
HFrEF	1,536	14.3% (12.5%, 16.1%)	0.77 (0.62, 0.96)	7.0% (5.8%, 8.3%)	1.05 (0.75, 1.46)
Unknown	4,160	18.4% (17.2%, 19.6%)	0.85 (0.70, 1.02)	8.9% (8.1%, 9.8%)	1.06 (0.79, 1.41)
NT-proBNP level, pg/mL
0–300	369	6.5% (4.0%, 9.1%)	1 (reference)	3.5% (2.0%, 5.8%)	1 (reference)
301–1,000	946	11.6% (9.5%, 13.6%)	1.45 (0.93, 2.26)	5.8% (4.4%, 7.4%)	1.17 (0.63, 2.16)
1,001–3,000	1,813	12.9% (11.4%, 14.5%)	1.49 (0.97, 2.27)	6.1% (5.1%, 7.3%)	1.09 (0.60, 1.95)
>3,000	2,253	24.8% (23.0%, 26.6%)	2.75 (1.82, 4.17)	11.9% (10.6%, 13.3%)	1.90 (1.07, 3.38)
Year of HF diagnosis
2010	1,392	18.5% (16.4%, 20.5%)	1 (reference)	8.5% (7.1%, 10.0%)	1 (reference)
2011	1,644	17.0% (15.2%, 18.9%)	1.04 (0.86, 1.27)	8.2% (6.9%, 9.6%)	1.06 (0.81, 1.40)
2012	1,661	16.6% (14.8%, 18.4%)	1.02 (0.83, 1.24)	7.6% (6.4%, 8.9%)	0.90 (0.68, 1.19)
2013	1,825	18.2% (16.4%, 20.0%)	1.13 (0.94, 1.36)	8.9% (7.6%, 10.2%)	1.11 (0.86, 1.45)

Notes:

a Patients are censored at emigration (loss to follow-up) and at end of follow-up (December 31, 2014).

b Patients are censored at emigration, at death due to non-CVD causes and at end of follow-up (December 31, 2014).

c Kaplan–Meier estimates of mortality (1–survival).

d Cox Multivariate HR, adjusted for age group, sex, and year of HF diagnosis, as well as setting of HF diagnosis, HF phenotype, and NT-proBNP level.

e End of follow-up restricted to 1 year after second observed HF diagnosis. The end of follow-up is equivalent between cohort 1 and cohort 2 (Uppsala and Västerbotten counties).

f cumulative incidence function estimates of mortality (1–survival).

g Sub-distribution HR, adjusted for age group, sex, and year of HF diagnosis, as well as setting of HF diagnosis, HF phenotype, and NT-proBNP level.

Abbreviations: CVD, cardiovascular disease; HF, heart failure; HR, hazard ratio, NT-proBNP, N-terminal pro-B-type natriuretic peptide; SHR, sub-distribution hazard ratio.

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Data availability

Major findings from the study will be published in scientific manuscripts only. The data will not be made available in any other format in order to preserve the privacy of the patients in compliance with local laws and regulation.