Abstract
Background
In March and April 2020, medical societies published statements recommending continued use of renin–angiotensin system (RAS) inhibitors despite theoretical concerns that these medications could increase COVID-19 severity. Determining if patients discontinued RAS inhibitors during the COVID-19 pandemic could inform responses to future public health emergencies.
Methods
We analyzed claims data from US adults with health insurance in the Marketscan database. We identified patients who filled a RAS inhibitor and were persistent, defined by not having a ≥30-day gap without medication available, and high adherence, defined by having medication available on ≥80% of days, from March 2019 to February 2020. Among these patients, we estimated the proportion who discontinued their RAS inhibitor (i.e., had ≥30 consecutive days without a RAS inhibitor available to take) between March and August 2020. For comparison, we estimated the proportion of patients that discontinued a RAS inhibitor between March and August 2019 after being persistent with high adherence from March 2018 to February 2019.
Results
Among 816,380 adults who were persistent and adherent to a RAS inhibitor from March 2019 to February 2020, 10.8% discontinued this medication between March and August 2020. Among 822,873 adults who were persistent and adherent to a RAS inhibitor from March 2018 to February 2019, 11.7% discontinued this medication between March and August 2019. The multivariable-adjusted relative risk for RAS inhibitor discontinuation in 2020 vs. 2019 was 0.94 (95% CI 0.93–0.95).
Conclusions
There was no evidence of an increase in RAS inhibitor discontinuation during the early stage of the COVID-19 pandemic.
Keywords: blood pressure, COVID, 19, hypertension, renin, angiotensin system inhibitors, treatment discontinuation
In March 2020, there was concern raised that renin–angiotensin system (RAS) inhibitors, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptors blockers (ARBs), increased the risk of SARS-CoV-2 infection and the severity from COVID-19.1 This concern may have arisen from several studies showing SARS-CoV-2 bound to ACE2, which served as an entry of SARS-CoV-2 into cells.2–4 Also, some animal models showed that RAS inhibition upregulates the expression of ACE2.5,6 The upregulation of ACE2 by RAS inhibition in humans would have widespread implications, since ACE inhibitors and ARBs are among the most commonly prescribed medications in the United States and they substantially reduce the risk for cardiovascular events and kidney disease progression.7–10 The concern that patients would discontinue these medications prompted the American College of Cardiology, American Heart Association, Heart Failure Society of America, and many other groups to issue position statements, press releases, and editorials stating that RAS inhibitors have substantial risk reduction benefits, and there was no evidence warranting changes to standard clinical practice.11–14
Determining if a high percentage of patients discontinued taking a RAS inhibitor despite the recommendations from leading medical groups can inform the response to future public health emergencies. The goal of this study was to evaluate whether a higher than expected percentage of patients discontinued their RAS inhibitor during the early stage of the COVID-19 pandemic. To accomplish this goal, we estimated the proportion of people who had been persistent and adherent to a RAS inhibitor in the year prior to COVID-19 being declared a public health emergency in the United States, March 2019 to February 2020, that discontinued treatment during the first 6 months of the pandemic in the United States. For comparison, we assessed the proportion of patients who had been persistent and adherent to a RAS inhibitor from March 2018 to February 2019 that discontinued this medication over the next 6 months. Additionally, we calculated the proportion of patients that discontinued 2 other classes of antihypertensive medication during these periods, calcium channel blockers and thiazide diuretics. To evaluate the degree to which patients who discontinued treatment may be under-treated, we estimated the percentage of patients who discontinued each drug class that initiated and did not initiate a new antihypertensive medication class.
METHODS
The Marketscan database contains claims data for US adults enrolled in employer-sponsored healthcare plans and Medicare supplemental plans.15 We created 6 cohorts of patients. The first 3 cohorts evaluated discontinuation of RAS inhibitors (cohort 1), calcium channel blockers (cohort 2), and thiazide diuretics (cohort 3) from 1 March to 31 August 2020 while the second 3 cohorts evaluated discontinuation of RAS inhibitors (cohort 4), calcium channel blockers (cohort 5), and thiazide diuretics (cohort 6) from 1 March to 31 August 2019. For cohorts 1, 2, and 3, we included adults ≥20 years of age who filled a RAS inhibitor, calcium channel blocker, or thiazide diuretic, respectively, between 1 January and 31 March 2019 and excluded those not living in the United States and who did not have health insurance from 182 days before their first RAS inhibitor, calcium channel blocker, or thiazide diuretic in 2019 through 31 August 2020. As many people discontinue antihypertensive medication in the first year following treatment initiation, we restricted the analyses to patients who were persistent and had high adherence from their first medication fill in 2019 through 29 February 2020.16,17 For cohorts 4, 5, and 6, we included adults ≥20 years of age who filled an RAS inhibitor, calcium channel blocker, or thiazide diuretic, respectively, between 1 January and 31 March 2018. For each of these cohorts, we excluded individuals not living in the United States and who did not have health insurance from 182 days before their first RAS inhibitor, calcium channel blocker, or thiazide diuretic in 2018 through 31 August 2019. To create comparable cohorts, we further restricted the analyses for cohorts 4, 5, and 6 to patients with persistence and high adherence from their first fill of these medications in 2018 through 28 February 2019.
Definitions of treatment discontinuation and low adherence
All outpatient antihypertensive medication fills were identified using pharmacy claims in the Marketscan database. The primary outcome was discontinuation of RAS inhibitors (cohorts 1 and 4), calcium channel blockers (cohorts 2 and 5), and thiazide diuretics (cohorts 3 and 6) during the outcome assessment periods: between 1 March 2020 and 31 August 2020 for cohorts 1, 2, and 3 and between 1 March 2019 and 31 August 2019 for cohorts 4, 5, and 6 (Figure 1). Discontinuation was defined as having ≥30 consecutive days without the antihypertensive medication class being evaluated available to take during the outcome assessment periods.18,19 For a secondary outcome, we evaluated discontinuation or low adherence to RAS inhibitors (cohorts 1 and 4), calcium channel blockers (cohorts 2 and 5), and thiazide diuretics (cohorts 3 and 6). We used the interval-based proportion of days covered (PDC) method to estimate medication adherence.20 The PDC was calculated using the number of days for which a class of antihypertensive medication was available to take during the outcome assessment period as the numerator and the number of days in the outcome assessment period not in the hospital as the denominator. We defined low adherence as a PDC <80.16,17,20 A PDC <80% has been associated with an increased risk for cardiovascular disease (CVD) events.21
Figure 1.
Schematic of criteria used to define study eligibility and the outcome assessment.
Independent variables
The main independent variable was the calendar year during which discontinuation, as the primary outcome, and discontinuation or low adherence, as the secondary outcome, were assessed, 2020 for cohorts 1, 2, and 3 vs. 2019 for cohorts 4, 5, and 6. Age and sex were obtained from administrative data for the health insurance plans. Race/ethnicity is not available in the Marketscan database. Taking additional antihypertensive medication classes beyond the one being evaluated for discontinuation was estimated based on prescription fills in the 90 days prior to the start of the outcome assessment period. In addition to RAS inhibitors, calcium channel blockers, and thiazide diuretics, classes of antihypertensive medication included beta blockers, loop diuretics, potassium sparing diuretics, vasodilators, direct renin inhibitors, centrally acting agents, alpha blockers, and aldosterone agonists. Pharmacy type, mail order vs. other, and number of days of supply for a medication fill, having a 90-day prescription, were based on the last pharmacy fill for a RAS inhibitor (cohorts 1 and 4), calcium channel blocker (cohorts 2 and 5), and thiazide diuretic (cohorts 3 and 6) prior to the outcome assessment period. We used all health insurance claims from any time before the outcome assessment period and previously published algorithms to define diabetes, CVD, heart failure, chronic kidney disease, depression, and a serious fall injury.22,23 Polypharmacy was defined by filling prescriptions for 10 or more distinct classes of medications in the 90 days prior to the outcome assessment period.
Statistical analysis
The age distribution and other characteristics were estimated as percentages for patients in each of the 6 cohorts including those taking RAS inhibitors, calcium channel blockers, and thiazide diuretics in 2020 and 2019, separately. For patients in each cohort, we estimated the percentage who discontinued treatment during the outcome assessment period: 1 March through 31 August 2020 for cohorts 1, 2, and 3 and 1 March through 31 August 2019 for cohorts 4, 5, and 6. We used Poisson regression models with robust variance estimators to estimate the relative risk for treatment discontinuation in 2020 vs. 2019 for patients in the RAS inhibitor, calcium channel blocker, and thiazide diuretic cohorts, separately. The robust variance estimators accounted for repeated measures in the regression models as some patients were taking a RAS inhibitor, calcium channel blocker and a thiazide diuretic in 2019 and 2020. Two levels of adjustment were conducted. First, we adjusted for age and sex. Second, we conducted full multivariable adjustment which included age, sex, number of antihypertensive medication classes being taken, number of days’ supply in the index prescription, pharmacy type, comorbidities (diabetes, CVD, heart failure, chronic kidney disease, depression, serious injurious falls), and polypharmacy. After pooling data from all 6 cohorts, we used Poisson regression with robust variance estimators to estimate relative risks for treatment discontinuation associated with calendar year, 2020 vs. 2019, calcium channel blockers and thiazide diuretics vs. RAS inhibitors, and patient factors. These models were conducted with age–sex and full multivariable adjustment as described above. Among patients who discontinued their RAS inhibitor (cohorts 1 and 4), calcium channel blocker (cohorts 2 and 5), and thiazide diuretic (cohorts 3 and 6), we estimated the proportion that initiated a new class of antihypertensive medication, 2 or more classes of antihypertensive medication and the individual classes initiated. In a secondary analysis, the proportion of patients who discontinued or had low adherence to RAS inhibitors, calcium channel blockers and thiazide diuretics in 2019 and 2020 was estimated. We used Poisson regression models with robust variance estimators and 2 levels of adjustment as described above to estimate the relative risk for treatment discontinuation or low adherence in 2020 vs. 2019 for patients in the RAS inhibitor, calcium channel blocker, and thiazide diuretic cohorts, separately. All analyses were conducted using SAS Version 9.4 (SAS Institute, Cary, NC).
RESULTS
After excluding patients who were not persistent or with low adherence in the prior year, in 2019 and 2020, there were 822,873 and 816,380 patients taking a RAS inhibitor, respectively, 331,329 and 333,800 patients taking a calcium channel blocker, respectively, and 420,745 and 408,926 patients taking a thiazide diuretic, respectively (Table 1). Between 60% and 75% of patients in 2019 and 2020 taking each medication were 45–64 years of age, between 40% and 55% were women and >50% of patients were taking 1 or 2 antihypertensive medication classes. Between 65% and 75% of patients in each group had filled antihypertensive medication prescriptions with 90 days of supply, and between 15% and 20% were using mail order to receive their medication. Diabetes and depression were the most common comorbidities.
Table 1.
Characteristics of patients taking renin–angiotensin system inhibitors, calcium channel blockers, and thiazide diuretics in 2019 and 2020
| 2019 | 2020 | |||||
|---|---|---|---|---|---|---|
| RAS (n = 822,873) |
CCB (n = 331,329) |
Thiazide diuretic (n = 420,745) |
RAS (n = 816,380) |
CCB (n = 333,800) |
Thiazide diuretic (n = 408,926) |
|
| Age, y | ||||||
| 20–44 | 68,244 (8.3%) | 24,384 (7.4%) | 34,977 (8.3%) | 67,293 (8.2%) | 24,602 (7.4%) | 33,681 (8.2%) |
| 45–64 | 587,008 (71.3%) | 219,364 (66.2%) | 310,866 (73.9%) | 569,496 (69.8%) | 215,457 (64.5%) | 295,112 (72.2%) |
| 65–79 | 123,676 (15.0%) | 59,205 (17.9%) | 57,542 (13.7%) | 133,582 (16.4%) | 64,530 (19.3%) | 62,120 (15.2%) |
| ≥80 | 43,945 (5.3%) | 28,376 (8.6%) | 17,360 (4.1%) | 46,009 (5.6%) | 29,211 (8.8%) | 18,013 (4.4%) |
| Female sex | 354,627 (43.1%) | 144,347 (43.6%) | 226,561 (53.8%) | 352,272 (43.2%) | 146,696 (43.9%) | 219,851 (53.8%) |
| Number of antihypertensive classesa | ||||||
| 1 | 286,418 (34.8%) | 75,656 (22.8%) | 47,391 (11.3%) | 287,553 (35.2%) | 76,930 (23.0%) | 46,295 (11.3%) |
| 2 | 326,411 (39.7%) | 113,441 (34.2%) | 212,323 (50.5%) | 323,033 (39.6%) | 115,176 (34.5%) | 207,069 (50.6%) |
| ≥3 | 210,044 (25.5%) | 142,232 (42.9%) | 161,031 (38.3%) | 205,794 (25.2%) | 141,694 (42.4%) | 155,562 (38.0%) |
| Filled a 90-day prescription | 578,794 (70.3%) | 230,158 (69.5%) | 291,951 (69.4%) | 554,595 (67.9%) | 221,689 (66.4%) | 274,527 (67.1%) |
| Mail order fill | 164,799 (20.0%) | 62,982 (19.0%) | 82,919 (19.7%) | 150,021 (18.4%) | 60,443 (18.1%) | 72,875 (17.8%) |
| Prevalent conditions | ||||||
| Diabetes | 286,206 (34.8%) | 102,901 (31.1%) | 127,340 (30.3%) | 285,833 (35.0%) | 104,290 (31.2%) | 125,665 (30.7%) |
| Cardiovascular disease | 155,836 (18.9%) | 71,379 (21.5%) | 55,214 (13.1%) | 158,158 (19.4%) | 73,204 (21.9%) | 55,644 (13.6%) |
| Heart failure | 35,873 (4.4%) | 16,781 (5.1%) | 8,590 (2.0%) | 37,945 (4.6%) | 18,041 (5.4%) | 8,934 (2.2%) |
| Chronic kidney disease | 124,789 (15.2%) | 65,211 (19.7%) | 50,793 (12.1%) | 130,799 (16.0%) | 68,840 (20.6%) | 52,733 (12.9%) |
| Depression | 264,681 (32.2%) | 106,918 (32.3%) | 140,330 (33.4%) | 270,025 (33.1%) | 111,202 (33.3%) | 139,848 (34.2%) |
| Serious fall injury | 38,328 (4.7%) | 18,378 (5.5%) | 17,287 (4.1%) | 40,551 (5.0%) | 19,849 (5.9%) | 17,795 (4.4%) |
| Polypharmacy | 102,375 (12.4%) | 52,032 (15.7%) | 50,346 (12.0%) | 103,900 (12.7%) | 52,667 (15.8%) | 50,959 (12.5%) |
Abbreviations: CCB, calcium channel blocker; RAS, renin–angiotensin system inhibitor.
aIncludes the drug class being evaluated for discontinuation.
In 2019 and 2020, the percentage of patients who discontinued their medication was 11.7% and 10.8% for those taking a RAS inhibitor, respectively, 14.5% and 10.7% for those taking a calcium channel blocker, respectively, and 13.5% and 12.0% for those taking a thiazide diuretic, respectively (Table 2). After multivariable adjustment, the relative risk for treatment discontinuation in 2020 compared with 2019 was 0.94 (95% CI 0.93–0.95) for those taking RAS inhibitors, 0.72 (95% CI 0.71–0.73) for those taking calcium channel blockers, and 0.88 (95% CI 0.87–0.89) for those taking a thiazide diuretic.
Table 2.
Percentage of Marketscan beneficiaries who were persistent and had high adherence in the previous year that discontinued renin–angiotensin system inhibitors, calcium channel blockers, and thiazide diuretics in March through August 2019 and 2020
| Discontinuation, % | 2020 vs. 2019 relative risk (95% CI) for discontinuation | ||||||
|---|---|---|---|---|---|---|---|
| 2019 | 2020 | P value | Age and sex adjusted | P value | Multivariable adjusted | P value | |
| Drug class | |||||||
| RAS inhibitor | 11.7% | 10.8% | <0.001 | 0.92 (0.92–0.93) | <0.001 | 0.94 (0.93–0.95) | <0.001 |
| Calcium channel blocker | 14.5% | 10.7% | <0.001 | 0.74 (0.73–0.75) | <0.001 | 0.72 (0.71–0.73) | <0.001 |
| Thiazide diuretic | 13.5% | 12.0% | <0.001 | 0.89 (0.88–0.90) | <0.001 | 0.88 (0.87–0.89) | <0.001 |
Abbreviation: RAS, renin–angiotensin system inhibitor. Multivariable adjustment includes age, sex, number of antihypertensive classes, filled a 90-day prescription, mail order fill, diabetes, cardiovascular disease, heart failure, chronic kidney disease, depression, serious fall injury, and polypharmacy.
After age–sex and multivariable adjustment and across all 3 classes of BP medications, treatment discontinuation was less common in 2020 compared with 2019 (Table 3). After multivariable adjustment, treatment discontinuation was more common among patients taking calcium channel blockers and thiazide diuretics vs. RAS inhibitors, among women vs. men and for patients with vs. without diabetes, CVD, heart failure, chronic kidney disease, depression, a serious fall injury, and polypharmacy. After multivariable adjustment, treatment discontinuation was less common among patients who were 45–64, 65–79, and ≥80 vs. 20–44 years old, taking 2 or ≥3 vs. 1 class of antihypertensive medication, and who filled a 90-day prescription for antihypertensive medication and received antihypertensive medication through mail order.
Table 3.
Relative risk for antihypertensive medication discontinuation in March through August 2019 and 2020
| Relative risk (95% confidence interval) for discontinuation | ||||
|---|---|---|---|---|
| Age–sex adjusted | P value | Multivariable adjusted | P value | |
| Calendar year | ||||
| 2019 | 1 (ref) | 1 (ref) | ||
| 2020 | 0.87 (0.86–0.88) | <0.001 | 0.87 (0.86–0.88) | <0.001 |
| Drug class | ||||
| RAS inhibitor | 1 (ref) | 1 (ref) | ||
| Calcium channel blocker | 1.12 (1.12–1.13) | <0.001 | 1.14 (1.13–1.15) | <0.001 |
| Thiazide diuretic | 1.13 (1.13–1.14) | <0.001 | 1.19 (1.19–1.20) | <0.001 |
| Age, y | ||||
| 20–44 | 1 (ref) | 1 (ref) | ||
| 45–64 | 0.77 (0.77–0.78) | <0.001 | 0.78 (0.77–0.79) | <0.001 |
| 65–79 | 0.69 (0.68–0.70) | <0.001 | 0.63 (0.62–0.64) | <0.001 |
| ≥80 | 0.88 (0.87–0.90) | <0.001 | 0.76 (0.75–0.78) | <0.001 |
| Female sex | 1.06 (1.05–1.06) | <0.001 | 1.03 (1.02–1.04) | <0.001 |
| Number of antihypertensive classesa | ||||
| 1 | 1 (ref) | 1 (ref) | ||
| 2 | 0.76 (0.75–0.77) | <0.001 | 0.87 (0.86–0.88) | <0.001 |
| ≥3 | 0.75 (0.74–0.76) | <0.001 | 0.82 (0.81–0.83) | <0.001 |
| Filled a 90-day prescription | 0.55 (0.55–0.55) | <0.001 | 0.82 (0.81–0.83) | <0.001 |
| Mail order fill | 0.81 (0.80–0.82) | <0.001 | 0.86 (0.85–0.87) | <0.001 |
| Prevalent conditions | ||||
| Diabetes | 1.05 (1.04–1.06) | <0.001 | 1.02 (1.01–1.03) | <0.001 |
| Cardiovascular disease | 1.12 (1.11–1.13) | <0.001 | 1.06 (1.05–1.07) | <0.001 |
| Heart failure | 1.35 (1.33–1.37) | <0.001 | 1.25 (1.23–1.28) | <0.001 |
| Chronic kidney disease | 1.23 (1.22–1.24) | <0.001 | 1.17 (1.16–1.18) | <0.001 |
| Depression | 1.12 (1.11–1.13) | <0.001 | 1.10 (1.09–1.11) | <0.001 |
| Serious fall injury | 1.12 (1.10–1.14) | <0.001 | 1.08 (1.06–1.10) | <0.001 |
| Polypharmacy | 1.04 (1.03–1.05) | <0.001 | 1.04 (1.02–1.05) | <0.001 |
The study population included patients who were persistent and had high adherence in the preceding year. Multivariable adjustment included all variables listed in the table in a single model. Abbreviation: RAS, renin–angiotensin system inhibitor.
aIncludes the drug class being evaluated for discontinuation.
In 2019 and 2020, 8.9% and 7.2% of patients who discontinued a RAS inhibitor, 11.6% and 10.7% of patients who discontinued a calcium channel blocker, and 8.4% and 9.7% of patients who discontinued a thiazide diuretic initiated a new class of antihypertensive medication (Figure 2). In each of these groups, over 75% of patients initiated a single drug class. Among patients who discontinued a RAS inhibitor or thiazide diuretic, calcium channel blockers were the most commonly initiated antihypertensive medication class (Supplementary Table S1 online). Among patients who discontinued a calcium channel blocker, RAS inhibitors were the most commonly initiated antihypertensive medication class. Additionally, beta blockers were initiated by greater than 20% of patients who discontinued a RAS inhibitor, calcium channel blocker, and thiazide diuretic.
Figure 2.
Percentage of patients who discontinued a renin–angiotensin system inhibitor (left panel), calcium channel blocker (middle panel), and thiazide diuretic (right panel) that initiated a new antihypertensive medication class in 2019 and 2020. The difference in the percentage of patients initiating a new drug class was statistically significantly lower in 2020 compared with 2019 for renin–angiotensin system inhibitors and calcium channel blockers and statistically significantly higher in 2020 vs. 2019 for thiazide diuretics (P value <0.001 for each comparison).
Secondary analysis—discontinuation or low adherence
In 2019 and 2020, the percentage of patients that discontinued treatment or had low adherence was 12.7% and 11.6% for those taking a RAS inhibitor, respectively, 15.5% and 11.5% for those taking a calcium channel blocker, respectively, and 14.6% and 12.8% for those taking a thiazide diuretic, respectively (Supplementary Table S2 online). After multivariable adjustment, the relative risk for discontinuation or low adherence in 2020 compared with 2019 was 0.92 (95% CI 0.91–0.93) for those taking RAS inhibitors, 0.72 (95% CI 0.71–0.73) for those taking calcium channel blockers, and 0.87 (95% CI 0.86–0.88) for those taking a thiazide diuretic. Less than 2% of patients taking RAS inhibitors, calcium channel blockers, and thiazide diuretics in each year did not discontinue treatment and had low adherence or discontinued treatment and had high adherence (Supplementary Table S3 online).
DISCUSSION
In the current study of US adults with health insurance, there was no evidence of an increase in the discontinuation of RAS inhibitors during the early stage of the COVID-19 pandemic compared with the previous year. After multivariable adjustment, the likelihood of patients taking RAS inhibitors discontinuing treatment was lower between March and August 2020 compared with the same period in 2019. A decline in treatment discontinuation also occurred in 2020 vs. 2019 among patients taking calcium channel blockers and thiazide diuretics. In 2019 and 2020, patients taking calcium channel blockers and thiazide diuretics were more likely to discontinue these medications compared with patients taking RAS inhibitors.
Data from early during the pandemic indicated that individuals with hypertension experienced more severe COVID-19 compared with their counterparts without hypertension.24–26 Reasons underlying the increased risk for adverse outcomes for individuals with vs. without hypertension began to focus on RAS inhibitors based on hypothesized mechanisms and animal studies.2 ACE2 had been previously identified as the receptor for SARS-CoV-2 and some experimental animal studies had reported that RAS inhibitors increased ACE2 levels.2,27 Although there were no data from human studies showing that RAS inhibitors increased ACE2 production, levels or activity, it was hypothesized that RAS inhibitors increased expression of ACE2 in the respiratory tract and this facilitated infection with SARS-CoV-2.28
Several observational studies and randomized trials were launched early during the COVID-19 pandemic to evaluate the potential risks of RAS inhibitors and benefits of discontinuing RAS inhibitors on COVID-19 infection and severity and death among patients with COVID-19. Among 824,650 patients with hypertension in the Kaiser Permanente Southern California health system, RAS inhibitors were not associated with an increased risk of COVID-19 infection vs. calcium channel blockers or beta blockers (adjusted odds ratio 1.06, 95% CI 0.90–1.25).29 In a case–control study of 1,139 patients hospitalized for COVID matched to 11,390 patients hospitalized in 2018, RAS inhibitors were not associated with hospital admission for COVID (odds ratio 0.94, 95% CI 0.77–1.15).30 Additionally, in a trial of 659 patients hospitalized with mild or moderate COVID-19 taking RAS inhibitors, there was no evidence of a difference in days spent in the hospital, COVID-19 progression or death between those randomized to discontinuation vs. continuation of treatment.31 These and other studies provided important data in humans on the safety of RAS inhibitors on COVID infection and severity but they were not completed until months into the COVID-19 pandemic.32,33
Based on the lack of human studies relating RAS inhibitors to COVID-19 severity or death and the substantial CVD risk reduction benefit of these medications, a number of professional medical societies published position statements in March 2020 with the strong recommendation that patients prescribed RAS inhibitors should continue taking these medications. Ultimately, patients who have medications must decide whether to take them or not. However, healthcare providers and professional medical societies can provide medical guidance based on the best available evidence. It is unknown whether position statements led healthcare providers to discuss the importance of remaining on RAS inhibitors with their patients or directly influenced patients’ decisions to continue their treatment. A formal evaluation of the impact that position statements and press releases have are needed to inform approaches to communicate evidence-based treatment for future epidemics.
There was no evidence of an increase in the discontinuation of any of the 3 drug classes that we studied in 2020 compared with 2019. Additionally, when we considered discontinuation or low adherence, this composite outcome was not substantially different in March to August 2020 vs. March to August 2019. This suggests the pandemic did not appear to disrupt antihypertensive medication refill patterns in this commercially insured patient population. However, in both 2019 and 2020, only a small percentage of patients who discontinued treatment initiated a new class of antihypertensive medication. This suggests that patients who discontinued antihypertensive medication may have been left under-treated.
Prior studies have reported that approximately 50% of patients discontinue antihypertensive medication in the first year following treatment initiation.16,17 In the current study, only 10%–15% of patients discontinued a RAS inhibitor, calcium channel blocker, or thiazide diuretic. The low percentage of patients discontinuing treatment likely reflects the requirement that patients had health insurance and took antihypertensive medication for at least 1 year without discontinuing treatment or having low adherence prior to be included in this study. These data suggest that discontinuation and low adherence to antihypertensive medication may not be common once a stable pattern of medication use is obtained.
Strengths of the current analysis include the use of a very large sample size of US adults that provided precise statistical estimates, longitudinal data that allowed the assessment of RAS inhibitor discontinuation following a period of persistence and high adherence, and the availability of individuals taking calcium channel blockers and thiazide diuretics to serve as control groups. However, the results should be interpreted in the context of known and potential limitations. We were not able to collect data on the reasons that people discontinued their antihypertensive medication. The direct impact of press releases or other interventions on continued RAS inhibitor use could not be evaluated. Blood pressure values are not available in the Marketscan database and it is possible that some patients discontinued antihypertensive medication due to low blood pressure. We only had data on whether a prescription was filled and not whether the patient actually took the medication. The Marketscan database only has information on patients in the United States with health insurance and the results may not be generalizable to individuals from other countries or US adults without health insurance.
In the current study, the percentage of patients who discontinued a RAS inhibitor was lower in 2020 compared with 2019. Additionally, patients taking RAS inhibitors were less likely to discontinue treatment when compared with their counterparts who were taking a calcium channel blocker or thiazide diuretic. In conclusion, there was no evidence in the current study of an increase in RAS inhibitor discontinuation during the early stage of the COVID-19 pandemic.
Supplementary Material
Contributor Information
Paul Muntner, Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Kathryn Foti, Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Zhixin Wang, Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Chibuike J Alanaeme, Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Eunhee Choi, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.
Adam P Bress, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA.
Daichi Shimbo, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.
Ian Kronish, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.
FUNDING
Dr. Kronish received support from the National Heart, Lung, and Blood Institute (R01 HL152699) and the National Institute on Minority Health and Health Disparities (P50 MD017341).
DISCLOSURE
The authors declared no conflict of interest.
This manuscript was sent to Guest Editor, Hillel W. Cohen, MPH, DrPH for editorial handling and final disposition.
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