Abstract
Lipoprotein (a) [Lp(a)] is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). As directed therapy for Lp(a) emerges, it is important to understand patterns of Lp(a) testing in routine clinical practice. We set out to characterize Lp(a) testing across a large academic health system. Using electronic health record (EHR) data from 2014 to 2019, we compared patients who underwent Lp(a) testing to date-matched peers who had low density lipoprotein (LDL-C) assessment alone. We analyzed ordering provider characteristics and rates of initiation of new lipid lowering therapy (LLT) within 12 months after testing. Of 1,296 adults with Lp(a) test results, 629 (48.5%) had prior history of ASCVD and 667 (51.4%) did not. Compared with those with LDL-C testing alone, individuals who underwent Lp(a) testing were more like to have a myocardial infarction or ischemic stroke at a young age and multiple prior cardiovascular events. Though the majority of Lp(a) tests were ordered in outpatient encounters, a higher proportion of Lp (a) tests compared with LDL-C tests were performed in the inpatient setting. Neurology and psychiatry were the most common specialty to order Lp(a) tests in our cohort. There was a significantly increased initiation of LLT after Lp(a) testing compared with LDL-C testing across all medication types. Consistent with guidelines, Lp(a) testing is used in those with early onset ASCVD, and among those with multiple cardiovascular events. Lp (a) testing is associated with more aggressive LLT in following year. Further research is needed to characterize Lp(a) testing across larger populations.
Lipoprotein (a) [Lp(a)] is a type of low density lipoprotein (LDL), with an additional apolipoprotein (Apo(a)) attached to the primary apolipoprotein (ApoB),1 Elevated Lp(a) has been linked to increased risk of atherosclerotic cardiovascular disease (ASCVD), including coronary disease2,3 and ischemic stroke.4 Though the exact mechanism remains unknown, Lp(a) may promote atherosclerosis by inhibiting fibrinolysis,5 disrupting endothelial function 6, and increasing LDL oxidation.7 While elevated Lp(a) is a known risk factor for ASCVD, it is not yet clear to what degree lowering Lp(a) improves cardiovascular outcomes.8,9 As several directed therapies for elevated Lp(a) are currently under evaluation, it is important to understand the landscape of Lp(a) testing in clinical practice.10 As such, we set out to characterize Lp(a) testing across a large health system in order to understand which patients undergo Lp(a) testing, which providers are testing for Lp(a), and how Lp(a) testing is associated with downstream changes in lipid lowering therapy (LLT).
Methods
We extracted data from Duke University Healthcare System (DUHS) electronic health record (EHR). DUHS includes three hospitals and a network of outpatient clinics that have been integrated on an EHR system since 2014. This study received approval from the Duke Institutional Review Board.
Patients included in this study had at least one Lp(a) test between January 1, 2014 and October 10, 2019 (hereto referred to as Lp(a) cohort). A 4:1 date-matched control group included patients who had a calculated low density lipoprotein (LDL-C) test, but not an Lp(a) test, on the same day (referred to as LDL-C cohort). Eligible individuals were over 20 years of age at the time of Lp(a) or LDL-C test and had to have at least 2 encounters of any type within DUHS in the 2 years prior to test date. Patients were included in the longitudinal outcome analysis if their Lp(a) or LDL-C test occurred between January 1, 2014 and October 10, 2018, to allow for adequate follow-up time. In the provider study, we included all providers who had ordered Lp(a) tests between January 1, 2014 and December 10, 2019, to include all available data, on patients at least 18 years old at the time of specimen collection.
The primary exposure was the presence of an Lp(a) or LDL-C test. The index date was defined by the first Lp(a) test between January 1, 2014 and October 10, 2019 where the patient met all inclusion criteria. The index date for the LDL-C cohort was defined as the first LDL-C test, matching an Lp(a) test on date, where the patient met all inclusion criteria. Lp(a) and LDL-C values were reported in mass units (mg/dL), as this was the most common institutional practice. Lp(a) values reported in molar units (nmol/L) were converted to mass units using a conversion factor of 2.4 nmol/L to 1 mg/dL.11
Patient demographic data were collected from the index lab testing encounter. Comorbid diagnoses were extracted using International Disease Classifications (ICD)-9 and 10 codes from all dates available in the EHR prior to the index date. Vital signs and lab data were recorded from index date or, if not collected at that time, recorded from the closest prior encounter within 2 years. Atherosclerotic cardiovascular disease (ASCVD) risk score for 10 year risk from the pooled cohort equation was calculated from these lab values 12. Medication history for relevant cardiac medications was assessed from the 2 years prior to, and including, the index lab date. Provider specialty, trainee or advance practitioner status, and encounter type, were also extracted from each associated Lp(a) testing encounter. We assessed initiation of LLT, specifically statin, ezetimibe, niacin and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), within 12 months after Lp(a) or LDL-C testing.
We summarized characteristics of the Lp(a) and LDL-C cohorts using descriptive statistics (median and interquartile range (IQR) for continuous variables, frequencies and percentages for binary and categorical variables). We stratified the Lp(a) cohort based on Lp(a) level (normal Lp(a) < 60mg/dL, intermediate 60-100mg/dL, and high > 100 mg/ dL) and prior history of ASCVD.13 We compared characteristics between groups using the Wilcoxon rank-sum tests for continuous variables and Pearson chi-square or Fisher’s exact tests for categorical variables. To assess the association between Lp(a) levels and initiation of new LLT within 12 months of index date, we performed logistic regression modeling and adjusted for age, sex, race, prior ASCVD status and LDL-C value.
Results
Between January 1, 2014 and October 10, 2019, there were 2,088 Lp(a) lab tests results within DUHS on 1,926 individual patients. Among these, 1,296 patients had 2 prior encounters in the previous year to be included in the final analysis (Figure 1A). The LDL-C cohort was formed of 5,185 date-matched individuals (Figure 1B). The median Lp(a) value within the LP(a) cohort was 31mg/dL (Q1, Q3: 11, 78 mg/dL) (Figure 2).
Figure 1.
(A)Patient Flow for Lp(a) Cohort. (B)Patient Flow for LDL-C Cohort.
Abbreviations: Lipoprotein (a), Lp(a)
Abbreviations: Calculated Low Density Lipoprotein, LDL-C
Figure 2.
Range of Lp(a) Values by ASCVD status
*ASCVD includes prior history of coronary artery disease, myocardial infarction, coronary artery bypass, percutaneous coronary intervention, peripheral artery disease, lower extremity amputation, claudication, carotid artery stenosis, peripheral revascularization, cerebrovascular accident or ischemic stroke
Compared with date-matched controls with LDL-C but not Lp(a) testing, individuals with Lp(a) testing were younger (57 vs 59 years, p ≤0.001), less frequently female (50.1% vs. 55%, p≤0.001) and more commonly had private insurance (35.2% vs. 30.6%, p≤0.001) (Table 1). Traditional cardiovascular risk factors were less common in the Lp(a) group compared with the LDL-C group (hypertension 56.7% vs. 62.7%, p ≤0.001; diabetes 24.1% vs. 27.9%, p≤0.006) with the exception of hyperlipidemia which was more common in the Lp(a) group (72.4% vs. 64.5%, p ≤0.001). A higher proportion of patients with Lp(a) testing had prior ASCVD (49% vs 26%, p≤0.001) and, in particular, prior history of ischemic stroke (23% vs 5.9%, p≤0.001) compared with those with LDL-C testing alone. In addition, individuals with Lp(a) testing more frequently had myocardial infarction (MI) at a young age (6.4% vs. 1.7%, p ≤0.001), ischemic stroke at a young age (11.5% vs. 1.5%, p ≤0.001) and multiple prior cardiovascular events (27.0% vs. 8.1%, p ≤0.001). Baseline therapies were also different, as patients with Lp(a) testing were more frequently treated with statins (59.8% vs. 41.1%, p ≤0.001), ezetimibe (8.8% vs. 2.1%, p ≤0.001), and niacin (5.2% vs. 0.9%, p ≤0.001) (Table 1). Baseline characteristics of patients with Lp(a) testing by Lp(a) level and prior history of ASCVD are presented in Supplemental Table 1.
Table 1.
Baseline characteristics of the Lp(a) Cohort and LDL-C Cohort*
| Characteristic | Lp(a) Cohort (N=1296) | LDL-C Cohort (N=5184) |
|---|---|---|
| Age (years) | 57.0 (46.0-67.0) | 59.0 (48.0-70.0) |
| Women | 649 (50.1%) | 2853 (55.0%) |
| Hispanic | 16 (1.2%) | 103 (2.0%) |
| Non Hispanic Black | 254 (19.6%) | 1350 (26.0%) |
| Non Hispanic White | 930 (71.8%) | 3394 (65.5%) |
| Non Hispanic Other | 73 (5.6%) | 245 (4.7%) |
| Unknown/Not Reported | 23 (1.8%) | 92 (1.8%) |
| Insurance | ||
| Private | 382/1084 (35.2%) | 1473/4809 (30.6%) |
| Public | 357/1084 (32.9%) | 2042/4809 (42.5%) |
| Self-Pay | 10/1084 (0.9%) | 97/4809 (2.0%) |
| Other | 335/1084 (30.9%) | 1197/4809 (24.9%) |
| ASCVD Risk Score (n) | 364 | 2747 |
| Median 10 year Risk (Q1, Q3) | 0.06 (0.03-0.12) | 0.08 (0.03-0.16) |
| Prior ASCVD‡ | 629/1296 (48.5%) | 1338/5181 (25.8%) |
| Hypertension | 735/1296 (56.7%) | 3246/5181 (62.7%) |
| Hyperlipidemia | 938/1296 (72.4%) | 3341/5181 (64.5%) |
| Diabetes mellitus | 312/1296 (24.1%) | 1443/5181 (27.9%) |
| MI | 142/1296 (11.0%) | 281/5181 (5.4%) |
| MI within 12 months of index | 92/1296 (7.1%) | 112/5181 (2.2%) |
| Coronary Revascularization | 183/1296 (14.1%) | 382/5181 (7.4%) |
| CAD | 341/1296 (26.3%) | 830/5181 (16.0%) |
| Ischemic Stroke | 302/1296 (23.3%) | 308/5181 (5.9%) |
| PAD | 169/1296 (13.0%) | 462/5181 (8.9%) |
| CKD, Stage 3 or 4 | 217/1296 (16.7%) | 999/5184 (19.3%) |
| Dialysis | 19/1296 (1.5%) | 83/5181 (1.6%) |
| MI at a young age† | 83/1296 (6.4%) | 88/5181 (1.7%) |
| Coronary Revascularization at a young age† | 87/1296 (6.7%) | 103/5181 (2.0%) |
| IS at a young age† | 149/1296 (11.5%) | 80/5181 (1.5%) |
| Multiple prior CV events | 350/1296 (27.0%) | 421/5181 (8.1%) |
| Cancer | 29/1296 (2.2%) | 122/5181 (2.4%) |
| Labs and Vitals | ||
| Systolic blood pressure (mmHg) | 126.0 (115.0-140.0) | 124.0 (114.0-136.0) |
| Diastolic blood pressure (mmHg) | 76.0 (69.0-83.0) | 74.0 (68.0-80.0) |
| EGFR | 57.0 (50.0-78.0) | 57.0 (49.0-78.0) |
| Total Cholesterol (mg/dL) | 185 (149-229) | 180 (153-211) |
| HDL-C (mg/dL) | 47 (38.0-57.0) | 48 (39-60) |
| LDL-C (mg/dL) | 110 (79-146) | 103 (79-128) |
| Triglycerides (mg/dL) | 109 (76-165) | 113 (78-165) |
| Medications | ||
| Statin | 775 (59.8%) | 2129 (41.1%) |
| Statin+Ezetimibe combo | 90 (6.9%) | 82 (1.6%) |
| Ezetimibe monotherapy | 114 (8.8%) | 111 (2.1%) |
| PCSK9i | 16 (1.2%) | 8 (0.2%) |
| Niacin | 67 (5.2%) | 48 (0.9%) |
| ACEi/ARB | 607 (46.8%) | 2363 (45.6%) |
| Beta Blocker | 482 (37.2%) | 1483 (28.6%) |
| Aspirin | 635 (49.0%) | 1167 (22.5%) |
| No Lipid Lowering Therapy | 476 (36.7%) | 3010 (58.1%) |
| Encounter Type | ||
| Outpatient | 1015/1290 (78.7%) | 4758/5169 (92.0%) |
| Inpatient or ED | 275/1290 (21.3%) | 411/5169 (8.0%) |
Continuous variables reported as median and interquartile range (IQR), binary and categorical variables reported as frequencies and percentages.
Myocardial infarction, ischemic stroke and coronary revascularization were defined as occurring “at a young age” if the corresponding ICD codes were present in a male under 55 years or a female under 65 years.
Prior ASCVD includes: prior history of coronary artery disease, myocardial infarction, coronary artery bypass, percutaneous coronary intervention, peripheral artery disease, lower extremity amputation, claudication, carotid artery stenosis, peripheral revascularization, cerebrovascular accident or ischemic stroke
Abbreviations: ASCVD, atherosclerotic cardiovascular disease; MI, myocardial infarction; CAD, coronary artery disease; PAD, peripheral artery disease; CKD, chronic kidney disease; IS, ischemic stroke; CV, cardiovascular; EGFR, estimated glomerular filtration rate; LDL-C, calculated low density lipoprotein; HDL-C, calculated high density lipoprotein; PCSK9i, proprotein convertase subtilisin 9 inhibitor; ACE, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ED, emergency department
The majority of Lp(a) tests were ordered in outpatient encounters (77% outpatient, 18% inpatient, and 4% emergency department) (Table 2). However, a higher proportion of Lp(a) tests (21%) compared with LDL-C tests (8%) were performed in the inpatient setting (p≤0.01). There were 1,937 Lp(a) tests ordered by 322 providers between January 1, 2014 and December 10, 2019 (Table 2). Within DUHS, providers specializing in neurology/psychiatry (a combined category with the DUHS EHR) accounted for the most Lp (a) tests (19.4%), followed by endocrinology (17.6%), internal medicine (16.8%) and cardiology (12.9%).
Table 2.
Provider specialty and Lp(a) encounter type
| Year | Total (N= 1937) | Outpatient (N=1497) | Inpatient (N= 343) | ED* (N= 86) | Missing (N= 11) |
|---|---|---|---|---|---|
| Provider Type | |||||
| Internal Medicine | 325 (16.8%) | 208 (13.9%) | 69 (20.1%) | 48 (55.8%) | 0 (0.0%) |
| Cardiology | 249 (12.9%) | 226 (15.1%) | 20 (5.8%) | 3 (3.5%) | 0 (0.0%) |
| Endocrinology | 340 (17.6%) | 340 (22.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Other Medicine Subspecialties | 98 (5.1%) | 74 (4.9%) | 23 (6.7%) | 1 (1.2%) | 0 (0.0%) |
| Trainees or APPs* | 109 (5.6%) | 106(7.1%) | 3 (0.9%) | 0 (0.0%) | 0 (0.0%) |
| Pediatrics | 17 (0.9%) | 11 (0.7%) | 5 (1.5%) | 1 (1.2%) | 0 (0.0%) |
| Surgery | 33 (1.7%) | 3 (0.2%) | 28 (8.2%) | 2 (2.3%) | 0 (0.0%) |
| Anesthesiology | 6 (0.3%) | 0 (0.0%) | 6 (1.7%) | 0 (0.0%) | 0 (0.0%) |
| Neurology and Psychiatry | 375 (19.4%) | 189 (12.6%) | 176 (51.3%) | 10 (11.6%) | 0 (0.0%) |
| Missing | 385 (19.9%) | 340 (22.7%) | 13 (3.8%) | 21 (24.4%) | 11 (100.0%) |
APP = advanced practice provider, ED = emergency department
There was increased initiation of LLT after Lp(a) testing compared with LDL-C testing for all medication classes (Table 3). There was increased statin initiation [OR (95% CI): 2.36 (1.72, 3.24), p ≤0.001], ezetimibe initiation [OR (95% CI): 6.65 (3.92, 11.26), p ≤0.001] and niacin initiation [OR (95% CI): 26.42 (13.87, 50.31), p ≤0.001] which persisted with adjustment. There was also an increase in PCSK9i initiation, though total numbers were relatively small precluding further adjustment [OR (95% CI): 14.26 (4.68, 43.42), p ≤0.001]. While statin initiation did not differ significantly based on Lp(a) result, those with Lp(a) 60-100mg/dL were significantly more likely to initiate ezetimibe [adjusted OR (95% CI): 2.72 (1.30-5.67)] or niacin [adjusted OR (95% CI): 2.73 (1.45-5.15)] compared with those with Lp(a)<60 mg/dL.
Table 3.
New medications in the 12 months following the index visit
| Characteristic | Lp(a) Cohort n= 1033 | LDL-C Cohort N=4132 | Unadjusted OR* | Adjusted OR* |
|---|---|---|---|---|
| Statin | 97/414 (23.4%) | 273/2374 (11.5%) | 2.35 (1.82, 3.05) | 2.36 (1.72, 3.24) |
| Ezetimibe | 56/942 (5.9%) | 26/4043 (0.6%) | 9.77 (6.10, 15.64) | 6.65 (3.92, 11.26) |
| Niacin | 95/977 (9.7%) | 12/4094 (0.3%) | 36.63 (20.01, 67.06) | 26.42 (13.87, 50.31) |
| PCSK9 inhibitors | 14/1026 (1.4%) | 4/4128 (0.1%) | 14.26 (4.68, 43.42) | ** |
Denominators only include patients not previously on medication.
Adjusted: age, sex, race, prior ASCVD, LDL-C.
p < 0.001.
Adjusted model not presented due to too few events.
Abbreviations: ASCVD, atherosclerotic cardiovascular disease; Lp(a), lipoprotein (a); LDL-C, calculated low density lipoprotein; PCSK9, proprotein convertase subtilisin 9 inhibitor.
Discussion
To our knowledge, this is the first study to characterize Lp(a) testing patterns in a real-world setting. We found that within a large academic health system, patients who underwent Lp(a) testing more frequently had a history of ASCVD, especially at younger ages, compared to those with LDL-C testing alone. Lp(a) was ordered by a variety of provider types, but the type with the highest proportion was neurology and psychiatry (a combined provider category within DUHS EHR). Those with Lp(a) testing were more likely to have initiation of new LLT in the subsequent 12 months compared to those with LDL-C testing alone, with significantly increased statin, niacin, ezetimibe, and PSCK9i prescriptions.
These results should be interpreted within the context of the current guidelines around Lp(a) testing and management. Elevated Lp(a) is considered a risk-enhancing factor by the ACC/AHA guidelines, and can be used to refine risk estimates in certain individuals, specifically those with premature ASCVD or a significant family history.9,14,15 This is consistent with the population who underwent Lp(a) testing in our study, as we found increased rates of cardiovascular disease and increased history of early ASCVD in the Lp(a) cohort. Of note, 88 (1.7%) patients in the LDL-C testing group had a history of early MI, 80 (1.5%) had early stroke, and 421 (8.1%) had a history of multiple CVD events, and yet Lp(a) was not checked in these individuals. Given that this population would meet guideline criteria for Lp(a) evaluation, this may represent an opportunity to improve care in a high-risk subset of the population.
Lp(a) testing was more often performed in non-Hispanic white patients and those with private insurance, which may indicate barriers in access to care. Although Lp(a) testing can provide useful clinical information with only one measurement, it may not be considered as frequently in groups with limited access.16 Further, there remains some controversy surrounding the appropriate cutoffs and the degree of Lp(a)-mediated cardiovascular risk among ethnic groups, which may complicate its use in minority populations.16–18
In our healthcare setting, neurology and psychiatry providers ordered Lp(a) testing more frequently than internal medicine, cardiology, or endocrinology clinicians, accounting for more than half of inpatient Lp(a) tests. We suspect this practice pattern is an institutional one, related to the standard work-up of ischemic stroke by the neurology department. This also explains the higher rates of prior stroke in the Lp(a) compared with LDL-C tested cohort. This practice pattern is based on The American Heart Association/American Stroke Association guidelines, as well as several observational and Mendelian randomization studies which have shown elevated Lp(a) to be associated with a modestly increased stroke risk.19–22
We found significantly increased initiation of lipid lowering therapies in the year following Lp(a) testing compared to LDL-C testing. This escalation may be prompted by Lp(a) results, may reflect changes following a clinical event, or may represent patient and provider engagement in risk assessment and risk reduction. As there is no randomized trial evidence yet to support Lp(a) as a target of therapy, guidelines recommend aggressive control of LDL-C levels with statins, ezetimibe or PSCK9 inhibitors.9,14,23 This is consistent with our findings in these medication classes. Although neither statin nor ezetimibe directly lower Lp(a), in fact statin may cause approximately a 10-20% increase in Lp (a) levels,24 these medications are used to address overall cardiovascular risk. PSCK9 inhibitors have been shown to reduce Lp(a) levels by up to 27%;25 however, the clinical impact of this is not fully understood.26,27
We also found significantly increased use of niacin in the year following Lp(a) testing. Niacin has been shown to reduce Lp(a) levels by 20% to 30%.28 However, treatment with niacin in two large clinical trials did not improve ASCVD outcomes among those already on statin therapy.29,30 Given this lack of evidence, guidelines generally do not recommend niacin for cardiovascular risk reduction.9,14 In the absence of other targeted Lp(a) therapy, it continues to be used in clinical practice, as evidenced by our study and others.9,16
The results of this study should be interpreted with several caveats. First, our study reflects Lp(a) testing at a single academic center, and therefore may not be generalizable to other populations or other institutions. Second, given the nature of observational EHR data, we cannot determine why a certain test was ordered or why a medication change was made. Finally, as with all EHR analyses, it is possible that medication changes were made outside of our institution, which would not be captured in our analysis. We attempted to mitigate this risk, however, by requiring that each patient had at least 2 encounters in the previous 2 years, making it more likely that they received the majority of their care from our institution.
As targeted Lp(a) therapies emerge, we sought to understand the landscape of Lp(a) testing in a real world setting. We found that Lp(a) testing often occurs in those with prior history of ASCVD, particularly those with early onset disease, and seem to prompt initiation of LLT compared with LDL testing alone.
Supplementary Material
Disclosures/Acknowledgements:
This study was supported by a grant from Amgen, Inc. MDK is supported by a National Institute of Health (NIH) training grant (NIH 5T32HL069749-17).
Disclosures
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Neha Pagidipati reports financial support was provided by Amgen, INC.
Footnotes
Supplementary materials
Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j.amjcard.2021.05.018.
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