Are patients in heart failure trials representative of primary care populations? A systematic review

Nicholas D Gollop; John Ford; Pieter Mackeith; Caroline Thurlow; Rachel Wakelin; Nicholas Steel; Robert Fleetcroft

doi:10.3399/bjgpopen18X101337

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Figure 1. PRISMA diagram.

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Box 1. New York Heart Association classes of heart failure.⁴

Class	Patient symptoms
I	No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea (shortness of breath).
II	Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea (shortness of breath).
III	Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnoea.
IV	Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.

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Table 1 Example assessment of an extracted paper compared to the reference population

	Class I	Class II	Class III	Class IV
Reference population, %	47	36	7	10
Extracted study, %	10	25	40	25
Extracted study with 10% deviation, %	0–20	15–35	30–50	15–35
Closeness of match, %	>20	11–20	>20	11–20
Closeness of match, label	Poor	Fair	Poor	Fair

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Table 2 Characteristics of included studies

Study ID	Comparison	Number of participants	Primary outcome	Follow-up, months
AREA-CHF 2009 ²⁰	Canrenone Placebo	231 236	Change in LV diastolic volume	12
BEST 2003 ²¹	Bucindolol Placebo	114 112	Death and heart failure hospitalisation composite	19
Borghi 2013 ²²	Ramipril Zofenopril	73 102	Survival	73±14
CARNEBI 2013 ²³	Carvedilol Bisoprolol Nebivolol	61 crossover	NYHA class, biochemistry, and physiological testing	6 (2 x 3 crossover)
CELICARD 2000 ²⁴	Celiprolol Placebo	62 62	Functional score — Goldman score	12
CHARM Added 2003 ²⁵	Candesartan Placebo	1011 1014	Cardiovascular death or unplanned hospital admissions for worsening CHF	34
CHARM Alternative 2003 ²⁶	Candesartan Placebo	1273 1271	Cardiovascular death or unplanned hospital admissions for worsening CHF	41
CIBIS 1994 ²⁷	Bisoprolol Placebo	320 321	All-cause mortality	23
CIBIS 1999 ²⁸	Bisoprolol Placebo	1327 1320	All-cause mortality	16
Cicoira 2002 ²⁹	Spironolactone Placebo	54 52	Physiological or functional improvement	12
Cohn 2001 ³⁰	Valsartan Placebo	2511 2499	All-cause mortality, and combined mortality and morbidity	23
Colucci 1996 ³¹	Carvedilol Placebo	232 134	Disease progression and death composite	12
COMET 2003 ³²	Carvedilol Metoprolol	1511 1518	All-cause mortality	58
Dalla-Volta 1999 ³³	Delapril Enalapril	88 91	Physiological or functional improvement	12
ELITE II 2000 ³⁴	Losartan Captopril	1578 1574	All-cause mortality	18
Kum 2008 ³⁵	Add on Irbesartan Placebo	50 50	6MHW, Minnesota (QoL), peak exercise capacity on treadmill	12
Liu 2014 ³⁶	Metoprolol Conventional therapy	77 77	NYHA class, LVESD, LVEDD, LVEF, 6-min walking distance, medication safety	6
MAIN CHF II 2014 ³⁷	Bisoprolol Carvedilol	21 14	Clinical and functional status, mortality rate	8
MERIT-HF 1999 ⁴⁸	Metoprolol CR Placebo	1990 2001	All-cause mortality	12
Munich 1991 ³⁸	Captopril Placebo	83 87	Cardiovascular-cause mortality	33
Pitt 1999 ⁹	Spironolactone Placebo	822 841	All-cause mortality	24
Riegger 1999 ³⁹	Candesartan 4 mg Candesartan 8 mg Candesartan 16 mg Placebo	211 208 212 213	Increase in exercise tolerance, reduction in NYHA class	3
SENIORS 2005 ⁴⁰	Nevovitol Placebo	1067 1061	All-cause mortality and time to first CVD admission	21
SOLVD 1991 ⁴¹	Enalapril Placebo	1285 1284	Clinical and functional status, mortality rate	41.4
SOLVD 1992 ⁴²	Enalapril Placebo	2111 2117	Clinical and functional status, mortality rate	37.4
Sturm 2000 ⁴³	Atenolol Placebo	51 49	Worsening heart failure or death	24
US Carvedilol 2001 ⁴⁴	Carvedilol Placebo	Black: 127 Not Black: 569 Black: 90 Not Black: 308	Ethnicity (self-reported), ejection fraction, clinical status, and major clinical events	15
Yodfat 1991 ⁴⁵	Captopril Placebo	41 43	Functional status	3
Zannad 1998 ⁴⁶	Fosinopril Placebo	122 132	Cardiovascular mortality and event-free survival	12
Zannad 2011 ⁴⁷	Eplenerone Placebo	1364 1373	Cardiovascular mortality and event-free survival	21

6MHW = 6-minute hall walk. CHF = congestive heart failure. CVD = cardiovascular disease. LV = left ventricular. LVEDD = left ventricular end-diastolic diameter. LVEF = left ventricular ejection fraction. LVESD = left ventricular end-systolic diameter. NYHA = New York Heart Association. QOL = quality of life.

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Table 3 Summary of the ejection fraction <40% cohort for the reference population

Characteristic	Total (n = 72), n (%)
Mean age, years (SD)	69 (9)
Female	14 (19)
Male	58 (81)
Ever smoked	50 (69)
Non-white	2 (3)
Any electrocardiogram abnormality	2 (3)
Mean height, metres (SD)	1.71 (0.09)
Mean weight, kg (SD)	80.8 (14.6)
Mean heart rate, beats per min (SD)	77.3 (17.8)
Mean forced expiratory volume at 1 second, litres (SD)	2.11 (0.76)
Mean forced vital capacity, litres (SD)	2.55 (0.85)
Mean systolic blood pressure, mmHg (SD)	148.4 (21.1)
Mean diastolic blood pressure, mmHg (SD)	87.1 (12.3)
New York Heart Association class
I	34 (47)
II	26 (36)
III	5 (7)
IV	7 (10)
History
Myocardial ischaemia	38 (53)
Angina	26 (36)
Hypertension	28 (39)
Diabetes	11 (15)
Family myocardial ischaemia (age <65 years)	25 (35)
Medication taken
ACE inhibitors	19 (26)
Diuretics	26 (36)
Beta-blockers	9 (13)
Calcium antagonists	15 (21)
Aspirin	38 (53)
Digoxin	5 (7)

SD = standard deviation.

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Table 4. NYHA classification in heart failure RCTs compared to the reference population.

		NYHA class ⁵
Heart failure RCTs	N	I^a, %	II^b, %	III^c, %	IV^d, %
SOLVD 1992	4228	11–20	<10	<10	<10
Munich 1991	170	11–20	11–20	11–20	<10
Borghi 2013	175	11–20	11–20	11–20	<10
US Carvedilol 1996	1094	>20	<10	>20	<10
Liu 2014	154	>20	<10	>20	<10
CHARM Added 2003	2548	>20	<10	>20	<10
MERIT-HF 1999	3991	>20	<10	>20	<10
Zannad 1998	254	>20	>20	<10	<10
CELICARD 2000	124	>20	11–20	>20	<10
CHARM Alternative 2003	2028	>20	11–20	>20	<10
SENIORS 2005	2128	>20	11–20	>20	<10
SOLVD 1991	2569	>20	11–20	>20	<10
COMET 2003	3029	>20	11–20	>20	<10
Cicoira 2002	106	^e	^e	^e	^e
CARNEBI 2013	183	>20	>20	<10	>20
MAIN CHF II 2014	59	>20	>20	<10	>20
Colucci 1996	366	>20	>20	<10	>20
Zannad 2011	2737	>20	>20	>20	<10
Sturm 2000	100	>20	>20	>20	<10
Cohn 2001	5010	>20	>20	>20	<10
CIBIS 1994	641	>20	>20	>20	<10
CIBIS 1999	2647	>20	>20	>20	<10
ELITE II 2000	3152	>20	11–20	>20	>20
Kum 2008	100	>20	11–20	>20	>20
Rieger 1999	844	>20	>20	11–20	>20
BEST 2003	226	>20	>20	>20	>20
Dalla-Volta 1999	179	>20	>20	>20	>20
AREA-CHF 2009	382	>20	>20	>20	>20
Pitt 1999	1663	>20	>20	>20	>20
Yodfat 1991	84	^e	^e	^e	^e

^a47% of reference population. ^b36% of reference poulation. ^c7% of reference population. ^d10% of reference population. ^eInsufficient information to calculate deviation. RCT = randomised controlled trial. NYHA = New York Heart Association.