Impact of poor medication adherence on clinical outcomes and health resource utilization in patients with hypertension and/or dyslipidemia: systematic review

Figures & data

Figure 1. PRISMA flow diagram.

Table 1. Number of patients with controlled or uncontrolled BP by adherence treated with antihypertensives.

			Good adherence group*				Poor adherence group*
Author (year)	Adherence measurement tool	Criteria for controlled BP	Controlled BP % (n/N)		Uncontrolled BP % (n/N)		Controlled BP % (n/N)		Uncontrolled BP % (n/N)
Bramlage (2014)	MMAS-8	SBP/DBP <140/90 mmHg	65.3% to 67.7%		NR		55.3%		NR
Kebede (2021)	MMAS-8	SBP/DBP <140/90 mmHg for <60 yrs, or 150/90 mmHg for ≥60 yrs	48.7% (93/191)		51.3% (98/191)		82 patients (unknown N)		137 patients (unknown N)
Wu (2009)	PDC	SBP/DBP <140/90 mmHg	60% (N = 25,376)		40% (N = 25,376)		55.8% (N = 4,309)		44.2% (N = 4,309)
Bhagavathula (2021)	PDC	SBP/DBP ≤130/80 mmHg	53.1% (34/64)		46.9% (30/64)		27.2% (34/125)		72.8% (91/125)
		SBP/DBP ≤140/80 mmHg	81.2% (52/64)		18.8% (12/64)		53.6% (67/125)		46.4% (58/125)
Hedna (2015)	PDC (adherence to any AHM 30 days prior)	SBP/DBP <140/90 mmHg or <130/80 mmHg if patient has diabetes	NR		NR		NR		65.2% (15/23)
	PDC (adherence to all AHM 30 days prior)		NR		NR		NR		45.9% (50/109)
	PDC (long-term adherence to any AHM)		NR		NR		NR		46.8% (22/47)
	PDC (long-term adherence to all AHM)		NR		NR		NR		43.5% (67/154)
Hamdidouche (2017)	Urine drug monitoring	Office SBP/DBP <140/90 mmHg	NR		22% (35/159)		NR		53% (8/15)
		Home SBP/DBP <135/85 mmHg	NR		32% (37/159)		NR		64% (9/15)
Overgaauw (2019)	Plasma/serum drug monitoring	NR	63% (19/30)		20% (6/30)		36% (4/11)		64% (7/11)
Kim (2017)	MPR	SBP <140 mmHg or DBP <90mmHg	MPR ≥97%: 82.6%(138/167); MPR 95–97%: 82.3% (139/169)		MPR ≥97%: 17.4% (29/167); MPR 95–97%: 17.8% (30/169)		MPR 89–95%: 70.8%(119/168); MPR <89%: 66.7% (112/168)		MPR 89–95%: 29.2%(49/168); MPR <89%: 33.3%(56/168)

Values in bold indicate statistically significant differences (p < 0.05) between good vs. poor adherence groups.

*Good adherence: MMAS-8 score = 6–8, PDC ≥ 80%, plasma/urine drug detection = 100%; poor adherence: MMAS-8 score < 6, PDC < 80%, plasma/urine drug detection < 100%. When three adherence groups were reported, data from two of them were grouped following the specified cutoffs for each adherence tool and shown as ranges in this table. ^†Good adherence in this study was defined as MPR = 100%.

Abbreviations: AHM: antihypertensive medication; BP: blood pressure; DBP; diastolic blood pressure; MMAS-8: 8-item Morisky Medication Adherence Scale; MPR: medication possession ratio; NR: not reported; PDC: proportion of days covered; SBP: systolic blood pressure; yrs: years.

Table 2. Incidence and risk of CVD events by adherence in patients on antihypertensives.

Author (year)	Type of CVD event	Adherence group	Incidence rate	HR/OR (95% CI)
Incidence rate (per 1,000 person years)
Yang (2017)	Overall CVD	PDC <40% (N = 13,899)	98.1	Ref
		PDC 40–79% (N = 47,081)	93.9	1.00 (0.97–1.03)
		PDC ≥80% (N = 94,617)	40.1	0.44 (0.42–0.45)
	Heart failure	PDC <40% (N = 13,899)	17.6	Ref
		PDC 40–79% (N = 47,081)	15.4	0.99 (0.92–1.05)
		PDC ≥80% (N = 94,617)	8.1	0.57 (0.54–0.61)
	Ischemic heart disease	PDC <40% (N = 13,899)	49.9	Ref
		PDC 40–79% (N = 47,081)	49.4	1.01 (0.97–1.06)
		PDC ≥80% (N = 94,617)	20.8	0.44 (0.42–0.46)
	Stroke/transient ischemic attack	PDC <40% (N = 13,899)	13.2	Ref
		PDC 40–79% (N = 47,081)	11.0	0.84 (0.79–0.89)
		PDC ≥80% (N = 94,617)	5.1	0.40 (0.38–0.43)
Mazzaglia (2019)	Acute CVD	PDC <40% (N = 9,666)	7.4	Ref
		PDC 40–79% (N = 7,624)	8.4	0.87 (0.73–1.03)
		PDC ≥80% (N = 1,516)	7.5	0.50 (0.35–0.69)
Degli Esposti (2011)	Composite outcome of all-cause death, stroke, or acute myocardial infarction	PDC ≤40% (N = 8,038)	29.5	Ref
		PDC 41–60% (N = 4,640)	24.8	0.87 (0.74–1.03)
		PDC 61–80% (N = 5,651)	19.6	0.69 (0.58–0.81)
		PDC >80% (N = 12,977)	16.1	0.53 (0.46–0.61)
Kim (2018)	Composite risk of recurrent stroke, myocardial infarction, or all-cause death	PDC <40% (N = 534)	NR	1.80 (1.49–2.16)
		PDC 40–80% (N = 412)	NR	1.56 (1.27–1.93)
		PDC >80% (N = 926)	NR	Ref
Incidence rate (% of patients)
Dragomir (2010)	Coronary arterial disease	MPR <80% (N = 18,679)	12.8	1.07 (1.00–1.13)
		MPR ≥80% (N = 38,217)	13.8	Ref
	Chronic heart failure	MPR <80% (N = 18,679)	4.7	1.42 (1.27–1.58)
		MPR ≥80% (N = 38,217)	4.1	Ref
	Cerebrovascular disease	MPR <80% (N = 18,679)	4.7	1.13 (1.03–1.25)
		MPR ≥80% (N = 6,150)	4.5	Ref
	1 or more CVD (hospitalized patients)	MPR <80% (N = 11,838)	71	NR
		MPR ≥80% (N = 38,217)	67	NR

Values in bold indicate statistically significant differences (p < 0.05/p-trend <0.05) between good vs. poor adherence groups or compared to the reference group.

Abbreviations: CI: confidence interval; CVD: cardiovascular disease; HR: hazard ratio; MPR: medication possession ratio; NR: not reported; OR: odds ratio; PDC: proportion of days covered; Ref: reference.

Table 3. Mortality data by adherence in patients on antihypertensives.

Author (year)	Adherence group	Per 100,000 PYs	Percentage of patients	Hazard ratio (95% CI)
All-cause mortality
Lee (2019)	MPR <50% (N = 560,941)	1,076.4	NR	1.66 (1.63–1.68)
	MPR 50–80% (N = 348,236)	866.5	NR	1.30 (1.28–1.33)
	MPR >80% (N = 742,387)	683.6	NR	Ref
Wong (2013)	PDC <40% (N = 71,734)	NR	14	Ref
	PDC ≥40% (N = 146,312)	NR	16	0.91 (0.89–0.93)
Degli Esposti (2011)	PDC ≤40% (N = 8,038)	NR	NR	Ref
	PDC 41–60% (N = 4,640)	NR	NR	0.81 (0.66–0.99)
	PDC 61–80% (N = 5,651)	NR	NR	0.59 (0.48–0.72)
	PDC >80% (N = 12,977)	NR	NR	0.37 (0.31–0.45)
Tsoi (2014)	PDC <40% (N = 3,577)	NR	19	NR
	PDC 40–69% (N = 4,525)	NR	11	NR
	PDC ≥70% (N = 7,520)	NR	29	NR
Kim (2016)*	PDC <50% (N = 10,844)	NR	NR	1.75 (1.58–1.93)
	PDC 50–80% (N = 10,568)	NR	NR	1.39 (1.26–1.53)
	PDC ≥80% (N = 12,316)	NR	NR	Ref
CVD-related mortality
Lee (2019)	MPR <50% (N = 560,941)	222.7	NR	1.88 (1.81–1.95)
	MPR 50–80% (N = 348,236)	174.9	NR	1.41 (1.34–1.47)
	MPR >80% (N = 742,387)	129.6	NR	Ref
Wong (2013)	PDC <40% (N = 71,734)	NR	1.8	Ref
	PDC 40–79% (N = 26,478)	NR	1.2	0.46 (0.41–0.52)
	PDC ≥80% (N = 119,834)	NR	1.8	0.91 (0.85–0.98)
Tsoi (2014)	PDC <40% (N = 3,577)	NR	4	NR
	PDC 40–69% (N = 4,525)	NR	2	NR
	PDC ≥70% (N = 7,520)	NR	7	NR

Values in bold indicate statistically significant differences (p < 0.05/p-trend <0.05) between good vs. poor adherence groups or compared to the reference group.

*Kim et al. (2016) reported also the rate of CVD-related mortality due to different CV conditions: significantly (p < 0.05) lower rate of CV-related mortality due to stroke, ischemic heart disease, cerebral hemorrhage, and cerebral infarction was found in the good adherence group (PDC ≥80%) compared to moderate (PDC 50–80%) or poor adherence (PDC <50%); whereas the mortality due to acute myocardial infarction was relatively similar across the three adherence groups (p-value not significant).

Abbreviations: CI: confidence interval; CV: cardiovascular; CVD: cardiovascular disease; MPR: medication possession ratio; NR: not reported; PDC: proportion of days covered; PY: person-year; Ref: reference.

Table 4. Health resource utilization and costs by adherence in patients on antihypertensives.

Author	Adherence group	Health resource utilization				Costs
		Outpatient visits mean (SD)	Inpatient visits mean (SD)	Hospitalization events/length of stay	Hospitalization risk HR/OR (95% CI)/probability (%)	Currency (year)	Total health-care costs mean	Medical costs mean	Medication cost mean (SD/95% CI)
Campbell (2021)	PDC >80%	13.0 (14.0)	0.2 (0.7)	NR	NR	US$ (2015)	13,231	Inpatient: 3,503 Outpatient: 6,309	3,420 (5,583)
	PDC <80%	15.0 (16.7)	0.4 (1.0)	NR	NR		16,976	Inpatient: 6,066 Outpatient: 8,063	2,847 (5,746)
Wu (2009)	PDC >80%	NR	NR	NR	Ref; 2.3%	NR	NR	NR	NR
	PDC <80%	NR	NR	NR	All-cause: 1.47 (1.21–1.78); 3.1% CVD-related: 1.43 (1.14–1.81)	NR	NR	NR	NR
Will (2016)	PDC <40%	NR	NR	2.5	NR	US$ (2012)	NR	NR	1.02 (1.01–1.03)*
	PDC 40–79%	NR	NR	2.5	NR				1.37 (1.36–1.38)*
	PDC ≥80%	NR	NR	2.3	NR				0.31 (0.31–0.32) (Ref)*
Yang (2016)	MPR 0–59%	NR	NR	NR	CVD-related: 1.78 (1.64–1.96) CVD-related: 52.2%	US$ (2011)	5,669	Inpatient: 4,149	All cause: 1,231 (1,489) Antihypertensive medication: 352 (733)
	MPR 60–79%	NR	NR	NR	CVD-related: 1.42 (1.30–1.57) CVD-related: 42.2%		4,978	Inpatient: 3,226	All cause: 1,538 (1,499) Antihypertensive medication: 566 (623)
	MPR ≥80%	NR	NR	NR	Ref CVD-related: 31.3%		5,221	Inpatient: 2,747	All cause: 2,295 (1,703) Antihypertensive medication: 735 (693)
Pittman (2010)	MPR <60%	NR	NR	NR	CVD-related: 1.11 (1.03–1.20) All-cause: 2.1%	US$ (2008)	7,370	Inpatient: 1,913 Outpatient: 3,776	1,509 (3,400)
	MPR 60–79%	NR	NR	NR	CVD-related: 1.04 (0.99–1.10) All-cause: 2.1%		7,530	Inpatient: 1,759 Outpatient: 3,705	1,932 (3,789)
	MPR >80%	NR	NR	NR	Ref All-cause: 1.8%		7,261	Inpatient: 1,386 Outpatient: 3,390	2,383 (3,817)
Dragomir (2010)	MPR <80%	NR	NR	16.0 days	1.17 (1.12–1.22)	CAD	NR	Inpatient: 3,995 Outpatient: 1,370	1,800
	MPR ≥80%	NR	NR	10.6 days	1		NR	Inpatient: 2,464 Outpatient: 1,346	2,848
Sokol (2005)	PDC 1–19%	NR	NR	NR	CVD-related: 44%	US$	9,747	All-cause: 8,831	916
	PDC 20–39%	NR	NR	NR	CVD-related: 39%		11,238	All-cause: 10,286	952
	PDC 40–59%	NR	NR	NR	CVD-related: 36%		9,491	All-cause: 8,368	1,123
	PDC 60–79%	NR	NR	NR	CVD-related: 30%		8,929	All-cause: 7,658	1,271
	PDC ≥80%	NR	NR	NR	CVD-related: 27%		8,386	All-cause: 6,570 (Ref)	1,817
Qiao (2020)	PDC <25%	NR	NR	NR	NR	US$	14,077	NR	NR
	PDC 25–50%	NR	NR	NR	NR		12,875	NR	NR
	PDC 50–75%	NR	NR	NR	NR		13,955	NR	NR
	PDC 75–80%	NR	NR	NR	NR		13,811	NR	NR
	PDC 80–85%	NR	NR	NR	NR		11,752	NR	NR
	PDC 85–90%	NR	NR	NR	NR		10,900	NR	NR
	PDC 90–95%	NR	NR	NR	NR		9,762	NR	NR
	PDC >95%	NR	NR	NR	NR		8,951	NR	NR
Roebuck (2011)	MPR ≥80% vs. <80%	NR	Length of stay: −3.14 days/year^†	NR	NR	US$	−3,908^†	−4,337^†	429^†

Values in bold indicate statistically significant differences (p < 0.05) between good vs. poor adherence groups or compared to the reference group.

*Will et al. (2016) reported medication costs in crude rate per person-years of follow-up. ^†Roebuck et al. (2011) reported the incremental differences induced by good adherence (i.e. HRU/costs of the good adherence group minus the HRU/costs of the poor adherence group). Negative values indicate that the good adherence group had lower HRU/costs than the poor adherence group.

Abbreviations: CAD: Canadian dollar; CI: confidence interval; CVD: cardiovascular disease; HR: hazard ratio; MPR: medication possession ratio; NR: not reported; OR: odds ratio; PDC: proportion of days covered; Ref: reference; SD: standard deviation; US: United States.

Table 5. Health resource utilization and costs by adherence in patients on lipid-lowering medications.

		Health resource utilization					Costs
Author (year)	Adherence group	Outpatient visits mean (SD)	Inpatient visits mean (SD)		Hospitalization events/length of stay	Hospitalization risk HR/OR (95% CI)/probability (%)	Currency (year)	Total health-care costs mean (SD/SE)	Medical costs mean (SD/SE)	Medication costs mean (SD/SE)
Campbell (2021)	PDC <80% (N = 480,346)	19.0 (18.0)	0.3 (0.9)		NR	NR	US$ (2015)	15,631 (35,303)	Outpatient: 7,465 (17,222) Inpatient: 5,298 (25,302)	2,867 (5,227)
	PDC >80% (N = 1,433,959)	17.9 (16.2)	0.2 (0.7)		NR	NR		13,722 (26,672)	Outpatient: 6,448 (14,790) Inpatient: 3,687 (17,526)	3,586 (5,491)
Pittman (2011)	MPR <60% (N = 57,614)	NR	NR		CVD-related: 7.0% patients	CVD-related: 1.26 (1.21–1.31)	US$	11,102 (84)	All cause: 7,708 (82) CV: 2,689 (44)	Statin: 488 (2) Other: 2,906 (15)
	MPR 60–79% (N = 65,795)	NR	NR		CVD-related: 6.7% patients	CVD-related: 1.12 (1.08–1.16)		10,609 (78)	All cause: 7,261 (76) CV: 2,583 (40)	Statin: 664 (2) Other: 2,684 (14)
	MPR ≥80% (N = 258,013)	NR	NR		CVD-related: 6.7% patients	Ref		10,198 (39)	All cause: 6,709 (38) CV: 2,395 (21)	Statin: 838 (1) Other: 2,651 (7)
Roebuck (2011)	MPR ≥80% vs. <80%	NR	NR		Length of stay: −1.18 days/year*	NR	US$	−1,258*	601*	−1,860*
Sokol (2005) Sokol (2005)	PDC-like 1–19%(N = 167)	NR	NR		NR	All-cause: 26% Disease-related: 15%	US$ US$	All-cause: 10916 Disease-related: 6,888	All-cause: 9,849 Disease-related: 6,810	All-cause: 1,067 Disease-related: 78
	PDC-like 20–39% (N = 216)	NR	NR		NR	All-cause: 18% Disease-related: 13%		All-cause: 7,982 Disease-related: 4,999	All-cause: 6,830 Disease-related: 4,786	All-cause: 1,152 Disease-related: 213
	PDC-like 40–59%(N = 324)	NR	NR		NR	All-cause: 20% Disease-related: 15%		All-cause: 6,756 Disease-related: 3,825	All-cause: 5,509 Disease-related: 3,452	All-cause: 1,247 Disease-related: 373
	PDC-like 60–79%(N = 520)	NR	NR		NR	All-cause: 21% Disease-related: 14%		All-cause: 8,412 Disease-related: 5,541	All-cause: 6,676 Disease-related: 4,938	All-cause: 1,736 Disease-related: 603
	PDC-like ≥80%(N = 1,754)	NR	NR		NR	All-cause: 16% (Ref) Disease-related: 12% (Ref)		All-cause: 6,752 Disease-related: 3,924	All-cause: 4,780 (Ref) Disease-related: 3,124 (Ref)	All-cause: 1,972 Disease-related: 801

Values in bold indicate statistically significant differences (p < 0.05) between good vs. poor adherence groups or compared to the reference group.

*Roebuck et al. (2011) reported the incremental differences induced by good adherence (i.e. HRU/costs of the good adherence group minus the HRU/costs of the poor adherence group). Negative values indicate that the good adherence group had lower HRU/costs than the poor adherence group.

Abbreviations: CI: confidence interval; CV: cardiovascular; CVD: cardiovascular disease; HR: hazard ratio; HRU: health resource utilization; MPR: medication possession ratio; NR: not reported; OR: odds ratio; PDC: proportion of days covered; Ref: reference; SD: standard deviation; SE: standard error; US: United States.