The Prevalence, Healthcare Resource Utilization, and Clinical Characteristics of Individuals with Atherosclerotic Cardiovascular Disease in Manitoba

Abstract

Background

Many individuals with atherosclerotic cardiovascular disease (ASCVD) have elevated low-density lipoprotein cholesterol (LDL-C) levels, which increases the risk of adverse cardiovascular events such as stroke, myocardial infarction, and cardiovascular death. We conducted an observational study to report the point prevalence of ASCVD in Manitoba and to describe this population in terms of demographic, clinical characteristics, treatment received, and healthcare resource utilization.

Methods

Our retrospective cohort study linked population-level de-identified health administrative databases. We included adults (aged ≥ 18 years) with a diagnosis of ASCVD between April 1, 2006 and July 1, 2019. In a 1-year baseline period, we assessed LDL-C levels, lipid-lowering therapy (LLT) prescriptions, and cardiovascular events, along with their costs.

Results

A total of 112,601 individuals had ASCVD in Manitoba (point prevalence = 10.5%). The mean age was 68.6 ± 14.7 years, 60,353 (53.2%) were male, and 61,124 (54.3%) were being treated with LLT. In 19,046 individuals with an LDL-C at baseline, 7887 (41.4%) were meeting a target of < 1.8 mmol/L. A total of 4619 cardiovascular events occurred (rate = 41.28/1000 person-years [95% confidence interval: 39.98-42.63]), with a cumulative estimated hospitalization cost of $77.8 million.

Conclusions

The estimated prevalence of ASCVD among adults in Manitoba is 10.5%, and 45.7% of these individuals were not being treated with LLT. In individuals with an LDL-C measurement at baseline, 41.4% were meeting a target of < 1.8 mmol/L. These results may provide inputs to inform future cost-effectiveness analyses of incorporating smore novel LLT therapeutics to lower LDL-C levels in individuals with ASCVD.

Hypercholesterolemia is defined by elevated levels of low-density lipoprotein cholesterol (LDL-C) in the blood. Hypercholesterolemia can develop through lifestyle factors, such as poor diet and lack of exercise,¹ or can be inherited genetically (familial hypercholesterolemia [FH]).² Hypercholesterolemia is causal to atherosclerotic cardiovascular disease (ASCVD) and related morbidity and mortality.³ ASCVD includes coronary heart disease (CHD), cerebrovascular disease (CeVD), and peripheral arterial disease (PAD).⁴

Due in large part to a high risk of recurrent cardiovascular events, ASCVD remains a leading cause of mortality in Canada.^4,5 Although a well-established finding is that lipid-lowering therapies such as statins can reduce LDL-C levels and reduce mortality and morbidity associated with ASCVD,⁶ a treatment gap persists among Canadians with ASCVD.¹⁰ Indeed, recent studies have documented that approximately 40% of patients treated with statins do not reach recommended levels of LDL-C.⁷ A comprehensive assessment of patients with ASCVD is needed to better understand current treatment patterns and attained LDL-C levels.

We conducted a retrospective study using health administrative databases to report the point prevalence of ASCVD in Manitoba, Canada, and describe demographic and clinical characteristics, lipid-lowering treatments (LLTs), LDL-C levels, cardiovascular events, and healthcare resource utilization.

Materials and Methods

Our retrospective cohort study linked population-level de-identified health administrative databases from the province of Manitoba and received ethical approval from the University of Manitoba Health Research Ethics Board (File# HS24734).

Data sources

All databases required to conduct the study reside at the Manitoba Centre for Health Policy and consistently undergo quality assurance testing.⁸ The specific databases used for the study included the Canadian Institute for Health Information Hospital Discharge Abstracts Database (CIHI-DAD; inpatient hospital admissions and day surgeries), the Diabetes Education Resource for Children and Adolescents (DERCA; type of diabetes), the Drug Program Information Network (DPIN; complete record of all outpatient drug prescriptions in Manitoba), the Manitoba Health Insurance Registry (demographics and health coverage dates), and Medical Claims/Services (MHSC; physician claims), Shared Health Diagnostic Services (laboratory test results), and Vital Statistics (family history). Data from each source were linked to a unique record through a scrambled personal health identification number (PHIN).

Study design and population

The primary objective of the study was to determine the point prevalence of ASCVD in Manitoba (a Canadian province of ∼1.3 million people) as of July 1, 2019, which was defined as the index date. Secondary objectives of the study were to report baseline characteristics, describe adherence to LLTs, evaluate change in LDL-C level, express the proportion of patients achieving recommended LDL-C levels, determine the rate of cardiovascular events, and ascertain healthcare costs over a 1-year period prior to July 1, 2019 (Fig. 1). We also aimed to achieve these objectives for patients with FH, in an exploratory analysis.

Figure 1.

Study design scheme. ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol.

For our primary and secondary objectives, we included all adults in Manitoba (age ≥ 18 years) with a diagnosis of ASCVD between April 1, 2006 and July 1, 2019; we excluded those individuals who had a missing date of birth or sex, were < 18 years of age, died, or had < 365 days of observation time prior to the index date (ie, new residents of Manitoba). ASCVD was defined according to the Canadian Cardiovascular Society (CCS) dyslipidemia guidelines—that is, as any of coronary heart disease (CHD), cerebrovascular disease (CeVD), or peripheral arterial disease (PAD).⁹

We used International Classification of Diseases, 9th revision, Clinical Modification (ICD-9 CM) and ICD, 10th revision, Canada (ICD-10 CA) codes to identify the appropriate diagnoses and hospitalizations (Supplemental Appendix S1). The definition of CHD included acute coronary syndrome (ACS), myocardial infarction (MI), stable or unstable angina, coronary artery bypass graft (CABG), or percutaneous coronary intervention (PCI).¹⁰ The definition of CeVD included stroke, transient ischemic attack (TIA), or documented carotid disesase.¹¹ The definition of PAD included a documented diagnosis of PAD, abdominal aortic aneurysm, or femoral popliteal bypass graft surgery.¹² For our exploratory objective, individuals were classified as having FH if they had 1 or more hospitalizations, or if they met criteria published by Ruel et al.¹³

Outcomes

Our primary outcome was the point prevalence of ASCVD in Manitoba. The prevalence of ASCVD (and FH for exploratory analyses) was expressed as a percentage of the population of Manitoba, with the numerator defined as the number of individuals who met each case definition, and the denominator as the estimated number of adult residents of Manitoba from the Manitoba Health Insurance Registry. Both the numerator and denominator were assessed as of the index date.

In the ASCVD population, baseline characteristics described included demographic characteristics, clinical characteristics, concomitant medications, and laboratory test results. Demographic data were obtained through the Manitoba Health Insurance Registry, and they included age, sex, and geographic location (urban/rural). Manitobans residing in Winnipeg or Brandon were classified as urban; all others were classified as rural. Selected comorbidities and medications were used as clinical characteristics and are listed in Supplemental Table S1 along with concomitant medications.

The following laboratory tests were reported: high-density lipoprotein cholesterol (HDL-C), hemoglobin A1C (HbA1C), LDL-C, serum albumin, serum potassium, total cholesterol, triglycerides, uric acid, troponin, urine albumin-to-creatinine ratio, estimated glomerular filtration rate (eGFR), apolipoprotein b, non-HDL-C, and lipoprotein a [Lp(a)]. The amount of missing data for each laboratory test was also reported.

Adherence to LLTs was estimated using the DPIN database and via calculation of the medication possession ratio (MPR), which is expressed as the ratio of the number of total days' supply of a medication divided by the duration of therapy within the baseline period.¹⁴ LLTs were stratified as high-intensity statins,¹⁵ medium-intensity statins, low-intensity statins, ezetimibe, PSCK9 inhibitors, and all combinations thereof. Decreases and increases in daily doses also were captured.

Longitudinal changes in LDL-C were assessed by documenting measurements of LDL-C during the baseline period (July 1, 2018-July 1, 2019) and presented for the following time intervals: at index (0 months), 6 months, and 12 months prior to index. For the index measurement, the closest measurement prior to or on July 1, 2019 was used and could be no earlier than April 1, 2019. The 6-month measurement was the closest measurement to January 1, 2019 and needed to occur between October 1, 2018 and April 1, 2019. The 12-month measurement was the closest measurement to July 1, 2018 and needed to occur between July 1, 2018 and January 1, 2019. The 3 measurements used in the longitudinal change analysis had to be ≥ 90 days apart. Individuals missing an LDL-C measurement did not have their data imputed. A complete case analysis was performed.

The most recent LDL-C measurement on or before the index date (within 12 months) was used to determine the percentage of individuals with ASCVD who met LDL-C targets of < 1.8 mmol/L, < 2.0 mmol/L, or < 2.5 mmol/L at baseline. The target of 2.0 mmol/L was the CCS standard at the time of the study,¹⁶ whereas the threshold of 1.8 mmol/L was introduced as the recommended CCS target guideline in 2021.⁹ The 2.5 mmol/L cutoff was based on targets for those with FH.^9,16 As a complete case analysis was conducted, the denominator was the number of all individuals in the cohort who had an LDL-C measurement within the necessary time frame.

Cardiovascular (CV) events during the baseline period were obtained using only the primary diagnosis code of an inpatient hospital admission using ICD-10 codes (Supplemental Table S2). A composite of all combined CV events also was counted. Each event was mutually exclusive except a coronary revascularization, which could be paired with another event if the former occurred during the same hospital stay.

Additionally, a 10-year risk of CV event recurrence was obtained using risk categories from the Secondary Manifestations of ARTerial disease (SMART) model derived by van't Klooster et al.¹⁷ Given data constraints, modifications to the SMART model were required and included: A systolic blood pressure of 140 mm Hg when hypertension was present was used, and 120 mm Hg was used when hypertension was not present; chronic obstructive pulmonary disease (COPD) was used as a proxy for smoking status. SMART risk was reported by 10-point strata (≤ 10%, 10%-20%, 20%-30%, 30%-40%, > 40%) and was possible only for patients with cholesterol measurements during the baseline period. The ASCVD population was additionally stratified by categorical LDL-C levels (< 1.8, 1.8-<2.0, 2.0-<2.6, 2.6-<3.5, 3.5-<5.0, ≥ 5.0 mmol/L).

The costs of hospitalizations related to the CV events described above were estimated using cost methodology described by the Canadian Institute for Health Information.¹⁸ Resource intensity weights estimate the human and capital resource costs of each hospital visit. The resource intensity weight is then multiplied by the cost of a standard hospital stay for that year. We also assessed direct costs of physician visits and the cost borne by Manitoba Pharmacare of any new prescription drugs that took place after the CV event. Physician visit costs are based on billing tariff codes and are obtained through the medical claims database. The cost of prescription drugs and dispensing fees paid by the province were obtained via DPIN. Only the concomitant medications that were assessed in the baseline period were included in the cost estimates. The physician visit costs assessed needed a diagnosis code to match their CV event. All costs were presented in 2020 Canadian dollars.

Statistical analysis

All analyses were descriptive in nature. Continuous variables were expressed as mean and standard deviation or median and interquartile range (IQR), depending on data distribution. Categorical variables were expressed as frequencies and percentages. Empty negative binomial regression models were used to ascertain CV event rates during the baseline period, both separate as components and as a composite outcome. Rates were presented as number of events per 1000 person-years at risk with 95% confidence interval (CI). We used SAS version 9.4 (SAS Institute, Cary, NC) to perform all statistical analyses.

Subgroup analysis

We identified a subgroup of individuals who filled at least one prescription for a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (evolocumab or alirocumab) within 365 days of the index date. In that subgroup, we reported demographic characteristics (age and sex), subtype of ASCVD (% of those with CHD, CeVD, PAD), and frequency of type 2 diabetes and polyvascular disease (defined as at least 2 types of ASCVD). We also ascertained the most recent LDL-C value prior to the PCSK9 inhibitor prescription date and reported the mean, standard deviation, median, interquartile range (IQR), and frequency and percentage of LDL-C > 1.8 mmol/L. Additionally, we reported statistics on the frequency and percentage of concomitant statins stratified by intensity and looked backwards from the PCSK9 inhibitor prescription date until the beginning of the study period to obtain the first prescription of other LLTs (statin or ezetimibe) and reported the mean, standard deviation, median, and IQR of the number of days between the PCSK9 inhibitor prescription date and the first LLT prescription date.

Results

Point prevalence and baseline characteristics

Between April 1, 2006 and July 1, 2019, a total of 112,601 active cases of ASCVD were present in Manitoba among 1,070,807 adults, corresponding to a point prevalence of 10.5%. The mean age was 68.6 ± 14.7 years. A majority were male (53.2%) and lived in an urban area (62.4%). The most common ASCVD subtype was CHD (58.2%), followed by PAD (38.2%) and/or CeVD (29.2%).

Of the concomitant medications assessed, the most common were statins, with 60,345 (53.6%) being prescribed a statin at some point during the baseline period. Of these patients, the vast majority were on a high-intensity (47.6%) or moderate-intensity (48.1%) regimen. Of the concomitant medications that were not LLTs, the most common were beta adrenergic antagonists (38.2%). A total of 19,046 individuals with ASCVD (16.9%) had at least one cholesterol test documented during the baseline period. The mean LDL-C level was 2.15 ± 0.99 mmol/L; mean HDL-C level was 1.25 ± 0.40 mmol/L; mean triglyceride levels were 1.64 ± 0.80 mmol/L; and mean total cholesterol level was 4.15 ± 1.16 mmol/L. Only 615 individuals (0.1%) had an apolipoprotein B test, and none had Lp(a) determinations.

All baseline characteristics are presented in Table 1, Table 2, Table 3.

Table 1.

Demographics and clinical conditions

Variable	N = 112,601
ASCVD presentation
CHD∗	65,540 (58.2)
Myocardial infarction	22,463 (20.0)
Stable angina	13,780 (12.2)
Unstable angina	13,907 (12.4)
Acute coronary syndrome	3391 (3.0)
CHD documented by procedures	36,023 (32.0)
Cerebrovascular disease†	32,858 (29.2)
Transient ischemic attack	9578 (8.5)
Ischemic stroke	12,553 (11.1)
Hemorrhagic stroke	3164 (2.9)
Documented carotid disease	2604 (2.3)
Peripheral arterial disease	42,985 (38.2)
Cardiovascular risk factors and comorbidities
Age, Y	68.6 ± 14.7
Sex (% female)	52,248 (46.4)
Geographic location (% urban)	70,214 (62.4)
Atrial fibrillation	24,563 (21.8)
Chronic kidney disease	18,539 (16.5)
Chronic obstructive pulmonary disease	16,735 (14.9)
Heart failure	17,761 (15.8)
Hypertension	87,952 (78.1)
Type 2 diabetes	34,530 (30.7)
Abdominal aortic aneurysm	2148 (1.9)

Values are n (%), or mean ± standard deviation.

ASCVD, atherosclerotic cardiovascular disease; CHD, coronary heart disease.

^∗Subcategories may not add up to 100%. CHD is defined as the presence of International Classification of Diseases, 9th revision—Clinical Modification codes 410-414 or International Classification of Diseases, 10th revision-Canada codes I21, I22, I24, I25. Each individual may have none or > 1 of: myocardial infarction, stable angina, unstable agina, acute coronary syndrome.

^†Subcategories may not add up to 100%. Cerebrovascular disease is defined as the presence of International Classification of Diseases, 9th revision—Clinical Modification codes 430-438, or International Classification of Diseases, 10th revision—Canada codes I60-I69. Each individual may have none or > 1 of: transient ischemic attack, stroke, documented carotid disease, or other cerebrovascular disease.

Table 2.

Concomitant medications

Variable	N = 112,601
Lipid-lowering therapies
Statins∗	60,345 (53.6)
High-intensity regimen	28,703 (47.6)
Moderate-intensity regimen	29,012 (48.1)
Low-intensity regimen	1516 (2.5)
Undefined regimen	1114 (1.8)
Ezetimibe	3344 (3.0)
PCSK9 inhibitors	80 (0.1)
Other concomitant medications
ASA†	20,987 (18.6)
Aldosterone antagonists	3634 (3.2)
ACE inhibitors	34,370 (30.5)
ARBs	4317 (3.8)
Anticoagulants	15,794 (14.0)
Anti-platelets	31,232 (27.7)
Beta adrenergic antagonists	42,969 (38.2)
Calcium-channel blockers	30,378 (27.0)
Bile acid sequestrants	395 (0.4)
Niacin	39 (0.03)
Digoxin	2372 (2.1)
GLP-1 receptor agonists	420 (0.4)
Loop diuretics	17,329 (15.4)
Potassium sparing diuretics	197 (0.2)
SGLT-2 inhibitors	3874 (3.4)
Thiazide diuretics	11,120 (9.9)
Fibrates	1934 (1.7)
Icosapent ehtyl	< 6

Values are n (%).

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ASA, acetylsalicylic acide; GLP-1, glucagon-like peptide 1; PCSK9, proprotein convertase subtilisin/kexin type 9; SGLT-2, sodium glucose transport 2.

^∗Percentages based on a denominator of 60,345.

^†Prescription ASA only. Does not account for over-the-counter purchases.

Table 3.

Baseline laboratory tests

Variable	Valid test, n (%)	Mean ± SD	Median (IQR)
HDL-C, mmol/L	19,046 (16.9)	1.25 ± 0.40	1.20 (1.00, 1.50)
LDL-C, mmol/L	19,046 (16.9)	2.15 ± 0.99	2.01 (1.44, 2.76)
Triglycerides, mmol/L	19,046 (16.9)	1.64 ± 0.80	1.46 (1.08, 2.00)
Total cholesterol, mmol/L	19,046 (16.9)	4.15 ± 1.16	4.00 (3.30, 4.90)
Non-HDL-C, mmol/L	19,046 (16.9)	2.90 ± 1.08	2.73 (2.10, 3.54)
Serum albumin, g/L	36,472 (32.4)	36.7 ± 5.74	37.2 (33.1, 41.0)
Serum potassium, mmol/L	55,703 (49.5)	4.25 ± 0.47	4.20 (3.90, 4.50)
eGFR, mL/min per 1.73 m2	57,189 (50.8)	71.2 ± 24.7	74.0 (55.0, 89.0)
Urine ACR, mg/mmol	28,293 (25.1)	20.7 ± 72.6	1.47 (0.50, 6.74)
HbA1C, %	28,896 (25.7)	6.72 ± 1.65	6.10 (5.70, 7.30)
Uric acid, μmol/L	13,200 (11.7)	356.6 ± 111.8	345.4 (283.0, 416.5)
Apolipoprotein B, g/L	615 (0.1)	0.98 ± 0.34	0.92 (0.75, 1.17)

ACR, albumin-to-creatinine ratio; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation.

Adherence to LLTs

In total, 61,124 individuals (54.3%) were receiving an LLT during the baseline period. The majority were on statins only (94.5%); the average adherence to LLT during the baseline period was 81%, and the median was 91% (mean MPR = 0.81 ± 0.23, median MPR = 0.91 [0.76, 0.96]). Adherence was highest in patients using a combination of statins and PCSK9 inhibitors (mean MPR = 0.92 ± 0.19, median MPR = 0.98 (0.94, 1.00)) and lowest in those using PCSK9 inhibitors alone (mean MPR = 0.73 ± 0.25; median MPR = 0.84 [0.59, 0.93]). An important point is that the sample size was low (n = 12-38) for each group with monotherapy or combination therapy with a PCSK9 inhibitor.

During the baseline period, 6.3% and 5.0% of individuals with ASCVD on LLT monotherapy had an increase and a decrease of medication dose, respectively, which was mostly driven by statins. Patients on ezetimibe were less likely to have dose adjustments in either direction (1.6% increase, 1.6% decrease), and patients on PCSK9 inhibitors were more likely to have a dose adjusted in either direction (8.8% increase, 12.5% decrease), compared to those on statins.

All statistics on LLT adherence are presented in Table 4 and Figure 2.

Table 4.

Lipid-lowering therapy (LLT) adherence

Variable	On LLT, n (%)	Mean ± SD	Median (IQR)
Overall	61,124 (54.3)	0.81 ± 0.23	0.91 (0.76, 0.96)
Statins only	57,750 (51.29)	0.81 ± 0.23	0.91 (0.76, 0.96)
Statins + ezetimibe	2,542 (2.26)	0.89 ± 0.16	0.95 (0.87, 0.98)
Statins + PCSK9 inhibitor	15 (0.01)	0.92 ± 0.19	0.98 (0.94, 1.00)
Ezetimibe only	752 (0.67)	0.79 ± 0.25	0.90 (0.73, 0.96)
Ezetimibe + PCSK9 inhibitor	12 (0.01)	0.90 ± 0.11	0.92 (0.83, 0.99)
PCSK9 inhibitor only	15 (0.01)	0.73 ± 0.25	0.84 (0.59, 0.93)
Statin + ezetimibe + PCSK9 inhibitor	38 (0.03)	0.96 ± 0.08	0.99 (0.95, 1.00)

Table represents a subgroup of individuals with a prescription for LLT at baseline.

IQR, interquartile range; PCSK9, proprotein convertase subtilisin/kexin type 9; SD, standard deviation.

Figure 2.

Lipid-lowering therapy dose adjustments. PCSK9, proprotein convertase subtilisin/kexin type 9.

Longitudinal changes in LDL-C

A total of 246 individuals with ASCVD had LDL-C measurements at the index date, 6 months prior to the index date, and 12 months prior to index the date (± 90 days). Mean LDL-C levels were 2.09 ± 1.05 mmol/L, 2.04 ± 1.02 mmol/L, during the 12- and 6-month periods prior to the index date, and 1.91 ± 0.91 mmol/L on the index date, corresponding to a mean decrease of 0.18 mmol/L during the 1-year baseline period.

Proportion of patients achieving recommended LDL-C levels

Of the 19,046 patients with ASCVD with an LDL-C test during the baseline period, 12,848 (67.5%) had an LDL-C level < 2.5 mmol/L; 9444 (49.6%) had an LDL-C level < 2.0 mmol/L; and 7887 (41.4%) had an LDL-C level < 1.8 mmol/L. Of those not meeting the 1.8-mmol/L target, nearly half (49.3%) were on a high- or moderate-intensity statin regimen.

Cardiovascular events

A total of 4619 CV events were counted in 4208 individuals with ASCVD (4.0%) during the 1-year outcome ascertainment period. The event rate was 41.28 per 1000 person-years (95% confidence interval [CI]: 39.98-42.63). The most common event was myocardial infarction, with 2099 events, corresponding to a rate of 18.67 events per 1000 person-years (95% CI: 17.85-19.53).

Strokes and coronary revascularizations had the highest cost per event at $22,275.15 CAD and $22,346.30 CAD, respectively. The total cost for all 4619 CV events was $77,755,922.67 CAD. The total downstream prescription costs borne by Manitoba Pharmacare 1 year after the CV event was $462,249.30 CAD ($109.85 CAD per person and $100.08 CAD per event). The total downstream physician visit cost paid by the provincial government 1 year after the CV event was $1,098,158.32 CAD ($260.97 CAD per person and $237.74 CAD per event).

CV event rates and costs are presented in Table 5.

Table 5.

Cardiovascular event rates and costs

Cardiovascular event	Number of events	Rate per 1000 PY (95% CI)	Cost per event, $ CAD	Total cost, $ CAD
Myocardial infarction	2099	18.67 (17.85–19.53)	9978.51	20,944,892.49
Stroke	1146	10.24 (9.61–10.91)	22,275.15	25,527,321.90
Peripheral arterial disease	375	3.34 (2.99–3.73)	21,044.90	7,891,837.50
Angina	429	3.81 (3.45–4.22)	5495.74	2,357,672.46
Coronary revascularization	1528	13.57 (12.90–14.28)	22,346.30	34,145,146.40
Combined	4619	41.28 (39.98–42.63)	16,833.93	77,755,922.67

CI, confidence interval; PY, person-year.

Cardiovascular risk

We were able to generate a SMART risk score for 18,331 patients with ASCVD (16.3%). The mean score was 43.3% ± 14.4%. A majority of patients (52.2%) had a > 40% risk for a recurrent CV event within 10 years, whereas 0 patients had a ≤ 10% risk. Additionally, 1694 patients (8.9%) had an LDL-C level of 3.5-5.0 mmol/L, and 150 (0.8%) had an LDL-C level ≥ 5.0 mmol/L.

Cardiovascular risk by SMART score and LDL-C level are presented in Table 6.

Table 6.

Cardiovascular event risk by SMART and low-density lipoprotein cholesterol (LDL-C) risk group

SMART risk group, %	N = 18,331, n (%)	LDL risk group, mmol?L	N = 19,046, n (%)
> 40	9576 (52.2)	< 1.8	7887 (41.4)
30–40	5374 (29.3)	1.8–2.0	1557 (8.2)
20–30	2943 (16.1)	2.0–2.6	4000 (21.0)
10–20	438 (2.4)	2.6–3.5	3758 (19.7)
≤ 10	0 (0)	3.5–5.0	1694 (8.9)
		≥ 5.0	150 (0.8)

Table represents a subgroup of individuals with measured LDL-C during the baseline period, or an LDL-C measurement plus an estimated glomerular filtration rate for calculation of SMART risk.

SMART, Secondary Manifestations of ARTerial disease.

Familial hypercholesterolemia

There were 0 occurrences of 1 or more hospitalizations of FH prior to the index date. There were 62,512 adult Manitobans with at least 1 LDL-C measurement. Of those, 833 had an LDL-C level ≥ 5.0 mmol/L, and 72 had an LDL-C level ≥ 4.5 mmol/L and were between the ages of 18 and 39 years.

Within those 905 individuals, 24 had an LDL-C level ≥ 8.5 mmol/L (definite FH); 61 had ASCVD and were either a male patients aged < 55 years or a female patient aged < 65 years; 17 had a first degree relative with ASCVD who was a male individual aged < 55 years or a female individual aged < 65 years; and none had a first-degree relative with an LDL level ≥ 8.5 mmol/L. Therefore, the total number of individuals with definite FH was 24, and the total with probable FH was 78. Given the small sample size, we determined that additional analyses would not be meaningful in the FH population.

Subgroup analysis

There were 80 individuals (0.1%) with ASCVD who filled at least one prescription for a PCSK9 inhibitor during the baseline period. Their mean age was 62.6 ± 9.8 years, and 53 (66.3%) were male. The most common subtype of ASCVD was CHD (92.5%), followed by PAD (33.8%), and CeVD (13.8%). A total of 17 (21.3%) of these individuals had type 2 diabetes, and 28 (35%) had polyvascular disease. Among the 58 individuals for whom an LDL-C measurement was available, 47 (81.0%) had an LDL-C level > 1.8 mmol/L prior to initiation of their PCSK9 inhibitor (mean LDL-C level = 3.04 ± 1.45 mmol/L; median LDL-C level = 3.04 mmol/L (IQR: 2.19-3.60)). There were 53 individuals with PCSK9 inhibitors who were on concomitant statin therapy during the baseline period. Of those, 35 (66.0%) had a high-intensity statin regimen, 10 (18.9%) had a moderate-intensity regimen, and 8 (15.1%) had a low- or undefined-intensity regimen. The mean number of days between the initial LLT and the PCSK9 inhibitor was 3304 ± 1213 (median = 3773 days [IQR: 2449-4306]). Characteristics of individuals receiving PCSK9 inhibitors are presented in Table 7. Given the small sample size, these results should not be overinterpreted.

Table 7.

Characteristics of individuals receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors

Variable	N = 80
Age, Y, mean ± SD	62.6 ± 9.8
Age, Y, median (IQR)	63.5 (57.5–68.0)
Sex (female)	27 (33.8)
Subtype of ASCVD∗
Coronary heart disease	74 (92.5)
Cerebrovascular disease	11 (13.8)
Peripheral arterial disease	27 (33.8)
Polyvascular disease†	28 (35.0)
Type 2 diabetes	17 (21.3)
LDL-C at time of PCSK9 inhibitor prescription‡
Mean ± SD, mmol/L	3.04 ± 1.45
Median (IQR), mmol/L	3.04 (2.19–3.60)
> 1.8 mmol/L	47 (81.0)
Statins§
High-intensity regimen	35 (66.0)
Moderate-intensity regimen	10 (18.9)
Low- or undefined-intensity regimen	8 (15.1)
Time from first lipid-lowering therapy to PCSK9 inhibitor
Mean ± SD, d	3305 ± 1213
Median (IQR), d	3773 (2449–4306)

Values are n (%), unless otherwise indicated.

ASCVD, atherosclerotic cardiovascular disease; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation.

^∗These data are not mutually exclusive. Individuals may appear in more than 1 subtype.

^†Polyvascular disease is defined as 2 or more subtypes of ASCVD.

^‡A total of 58 individuals had an LDL-C measurement during the baseline period prior to the PCSK9 inhibitor prescription.

^§A total of 53 individuals had a concomitant statin prescription during the baseline period.

Discussion

In this observational study, we found that the prevalence of ASCVD among adults in Manitoba is estimated to be 10.5%, with 112,601 Manitobans affected. More than half of these individuals (54.3%) were being treated with LLT (mostly statins) within the previous year, and less than half (41.4%) of individuals with a known LDL-C measurement were meeting a target of < 1.8 mmol/L. Additionally, 4.0% of patients with ASCVD had at least one hospitalization for a CV event in the previous year, at a cost of over $80 million. It was estimated that more than half (52.2%) had a > 40% probability of experiencing a CV event within 10 years. These results show that many adults with ASCVD in Manitoba are not being treated with LLT, are not meeting LDL-C targets, and are at a high risk for a hospitalization for a CV event.

A previous population-level retrospective cohort study of adults with ASCVD has been conducted in the province of Alberta.¹⁹ Overall, the ASCVD case definition was consistent between the 2 studies, and findings reported for the Alberta ASCVD cohort were consistent with our analysis. In a 5-year period between 2012 and 2016, they found the 5-year period prevalence of ASCVD to be 8.99%, which is slightly lower than the 10.5% we found in Manitoba. However, our ascertainment period for ASCVD cases was 13 years rather than 5 years, and the Alberta study used period prevalence, which is a different estimate than point prevalence. Other notable differences include that the mean age in the Alberta ASCVD cohort was 5 years younger, 3 percentage points more were male patients, and 5 percentage points were less likely to have received statin treatment, compared to the Manitoba cohort. The difference in statin use at baseline also may have differed as they assessed statin treatment within a 6-month window from the ASCVD index date, as compared to our 1-year window.

The results of the analysis have several implications. Although CCS guidelines recommend that all patients with ASCVD be treated with statins,⁹ only slightly more than half of patients with prevalent ASCVD in Manitoba have filled a prescription for a statin within the previous year. Only 16.9% of individuals with ASCVD had an LDL-C measurement with Shared Health Diagnostic Services in the 1-year period, which may indicate a low rate of LDL-C testing province-wide. When LDL-C level is not known, it may be a barrier to treatment.²⁰ In addition, among those who are undergoing treatment with statins, only 47.6% had a statin treatment regimen that was high-intensity, despite evidence that this has more efficacy than moderate dosing.²¹ Additionally, very few patients with ASCVD in Manitoba were using other LLT in combination with, or apart from, statins. Lack of adherence to statins has been shown previously, as the majority of patients with ASCVD do not remain on a high-intensity statin regimen after 1 year.22, 23, 24 This may be due in part to medication intolerance, which can affect up to 15% of people using statins, with side effects that include muscle aches, pains, weakness, and cramps.²⁵ Additionally, a focus on improving adherence to statins alone would not be a complete strategy to achieve optimal LDL-C levels for all individuals with ASCVD, as some do not show a sufficient response to maximally tolerated statin doses.²⁶

A population-level health intervention strategy with a focus on lowering LDL-C level in patients with ASCVD would potentially reduce the risk of CV events, thereby improving quality of life and lowering healthcare expenditures for Manitobans. According to a meta-analysis by the Cholesterol Treatment Trialists’ Collaboration, a reduction of 1.0 mmol/L in LDL-C achieved through LLT is associated with an ∼20% risk reduction in a major vascular event of a coronary death, nonfatal myocardial infarction, coronary revascularisation, or stroke in patients with CHD (risk ratio [RR] 0.79, 95% CI: 0.76-0.82) and patients with other vascular diseases such as CeVD and PAD (RR 0.81, 95% CI: 0.71-0.92).²⁷ Given that the yearly cost of CV event hospitalizations was estimated at over $77 million in our study, further lowering of LDL-C levels by just 1.0 mmol/L could potentially save hundreds of hospital admissions per year and millions of dollars in healthcare costs in Manitoba for the ASCVD population alone.

Recent developments in the LLT milieu may help achieve these outcomes. Inclisiran is a novel (small interfering RNA) cholesterol-lowering agent approved for use in Canada in 2021 and therefore not included in this study. It is administered by a healthcare professional twice per year (after 2 initial doses) via subcutaneous injection as an add-on to maximally tolerated doses of statins. In phase III clinical trials, when inclisiran was added to statin therapy for patients with ASCVD and an LDL-C level > 1.8 mmol/L, LDL-C levels were reduced by 50%, compared to statin and placebo.²⁸ Unlike other subcutaneous medications that are administered monthly or biweekly, inclisiran is only required twice per year (after an initial and 3-month dose), which may improve adherence in patients who may be hesitant to use injectable therapies requiring more frequent administration.

The strength of this project was the robustness and completeness of the datasets. Because the databases are population-wide, we produced the largest possible sample size within Manitoba. Due to our single payer health insurance system, all Manitobans have identical coverage, and they all have personal health identification numbers that can be linked across administrative health databases. Nonetheless, the project has limitations. First, not all cholesterol tests in Manitoba could be included in the study, as only public laboratory tests through Shared Health Diagnostic Services were available. Therefore, we could not incorporate cholesterol tests conducted through private laboratories for this study. This may have had the effect of underestimating the proportion of Manitobans with ASCVD who were not meeting LDL-C targets. Shared Health Diagnostic Services laboratories are typically located in an outpatient setting at hospitals and are more likely to have patients referred for laboratory testing by specialists (and therefore a higher burden of illness) compared to the private laboratories, which are more likely to have referred for laboratory testing by general practitioners. Given this, patients with more recent presentation of ASCVD, higher burden of risk factors, or difficulties with lipid management may be overrepresented among those who tested for LDL-C with Shared Health Diagnostic Services. Additionally, they are often the only laboratory option that serves rural areas in the province.

Second, we could not capture an exact 10-year SMART risk score due to the unavailability of systolic blood pressure and smoking status, and we were limited to calculating the modified SMART risk score in a subgroup of patients due to the requirement of LDL-C and estimated glomerular filtration rate. However, despite these limitations, the SMART risk score findings appeared to be consistent with observed CV events, as 4.0% of the cohort experienced an event in 1 year, compared with a mean SMART risk probability of 43.3% for an individual to experience an event in a 10-year period. Finally, we may have underestimated the healthcare resource utilization costs that are direct results of the CV hospitalizations, as we were not able to capture the costs of emergency department visits, laboratory tests, or cardiac rehabilitation.

In conclusion, we estimate that the prevalence of ASCVD among adults in Manitoba is 10.5%. Many individuals with ASCVD in Manitoba are currently not being treated with LLT or meeting important LDL-C level targets, which may increase their risk of CV event hospitalizations. The actual proportion of individuals with ASCVD who are not achieving a target LDL-C level may be significantly higher or lower than estimated, as it was extrapolated from a subgroup representing 16.9% of the cohort. The data observed from this study may provide inputs to inform future cost-effectiveness analyses of a population health approach to further lowering LDL-C levels in the ASCVD population by incorporating more novel LLT therapeutics.