Are There Any Dental Concerns Associated With One Baby Aspirin Each Day

Introduction

Clinical Perspective

What Is New?

Discontinuing long-term low-dose aspirin treatment in the absenteeism of major surgery or bleeding may be hazardous.
Nosotros investigated that question amidst 601 527 users of depression-dose aspirin for primary or secondary prevention identified in the Swedish drug prescription annals.
Patients who discontinued aspirin had a 37% higher rate of cardiovascular events than those who continued, respective to an additional cardiovascular outcome observed per twelvemonth in 1 of every 74 patients who discontinue aspirin.
The take chances increased shortly after discontinuation and did non appear to diminish over time.

What Are the Clinical Implications?

Adherence to low-dose aspirin handling in the absenteeism of major surgery or haemorrhage is likely an important treatment goal.
Millions of patients worldwide take aspirin on a daily basis and might consider stopping at some time during their lives.
This article may aid physicians and patients to make an informed decision on whether to stop aspirin use.

Low-dose aspirin has strong evidence for use in the secondary prevention of cardiovascular disease and is uniformly recommended in guidelines.^1–3 Its utility in primary prevention is under investigation.^iv–vi In patients with a recent myocardial infarction, 10% to 20% have been reported to discontinue aspirin use during the first 1^7–9 to three¹⁰ years subsequently the infarction. In broader patient settings, discontinuation rates of up to 30% take been reported, and poor aspirin compliance has been noted in upwardly to 50%.¹¹ The public health effects of discontinuing long-term aspirin handling may be substantial but are non well known.

Discontinuation of secondary prevention with aspirin has been associated with higher risk of cardiovascular events in some studies,^12,13 with indications of an increased gamble shortly after discontinuation.^14–18 Aspirin is ofttimes withdrawn considering of surgery^{14–17,nineteen} or haemorrhage,^{fourteen,xviii} factors that per se may stimulate platelet aggregation and increase the take a chance of cardiovascular events. Effects of discontinuation in settings other than surgery or bleeding are unknown.

Aspirin tin can be bought over the counter in many countries, and previous studies have typically relied on self-reported use data. Registers with consummate coverage in a country where low-dose aspirin is bachelor only past prescription have a unique potential to shed light on the issue.

We hypothesized that patients with aspirin handling gaps and those who discontinue long-term aspirin treatment in the absence of major surgery or bleeding are at higher take a chance of cardiovascular events than adherent patients without treatment gaps. We aimed to investigate the associations of aspirin treatment persistence patterns and aspirin discontinuation with risk of cardiovascular events using a large nationwide accomplice of patients on long-term low-dose aspirin therapy for main and secondary prevention.

Methods

Report Sample

Using the unique civil registration number allocated to all Swedish citizens, we linked the mandatory nationwide Swedish prescribed drug annals with the mandatory inpatient and cause-of-death registers with the help of the Swedish National Board of Health and Welfare. In Sweden, low-dose aspirin cannot exist purchased over the counter without a prescription.

For this study, we considered all individuals >40 years of age who had collected prescribed aspirin during the study period between July 1, 2005, and December 31, 2009, as identified in the prescribed drug annals by the detection of an aspirin dispense of 75 to 160 mg. We also included aspirin 75 to 160 mg dispensed as function of pharmacy-prepacked multidose prescriptions used for patients unable to safely self-administer their medication. Aspirin tablet strengths other than 75 or 160 mg are non available for prevention of cardiovascular events in Sweden; neither is carbasalate calcium (B01AC08). Nosotros considered all 889 655 aspirin-treated patients who were free from previous cancer (International Nomenclature of Diseases, 10th Revision codes C00–C99) at baseline. Nosotros were interested in handling breaks and permanent discontinuation after a stable (ane-year) period of continuous aspirin treatment. Therefore, we excluded 207 180 patients who had <292 divers daily doses of aspirin dispensed during the first year after their first aspirin prescription (which equals i year of aspirin handling with ≥eighty% adherence, or medication possession ratio, which is commonly viewed equally acceptable²⁰). Nosotros also excluded 80 621 patients who had a cardiovascular outcome (because our research question involved long-term utilize) or died during this beginning year of aspirin handling, equally well as 327 patients without any exposure fourth dimension subsequently the first year, rendering a final report sample of 601 527 long-term depression-dose aspirin users who entered the follow-up phase.

To study handling patterns in aspirin-naïve patients, nosotros likewise studied a sample of 227 135 patients who collected their outset low-dose aspirin dispense at least one yr after the first of the written report period. This subsample was non subjected to the 1-year definition of long-term users and was not used in whatsoever statistical modeling.

In a second set of analyses, the timing of cardiovascular events in people who discontinued aspirin was investigated. Nosotros defined inclusion criteria on the manipulate level and defined a timely dispense as i that was nerveless between 0 and ten days before the end of the previous timely dispense, and it had to exist the last in a chain of 4 consecutive timely dispenses (typically equal to 1 year of handling, called to residuum strictness of the inclusion criteria with statistical power). This strict definition, although rendering a minor sample of patients with presumed high adherence, was used to determine the time of discontinuation equally precisely as possible and to avert periods of accumulated medication during and later which drug use status is more uncertain. This sample included the 38 736 patients who had 4 sequent timely dispenses.

The construction of the samples is displayed in Figure 1.

Ethics approval was obtained from the Ethics Review Board in Uppsala, Sweden. No informed consent was required.

Clinical Characteristics

All definitions are described in Tabular array I in the online-just Data Supplement. Age, sex, and diabetes mellitus were determined at the inclusion engagement—that is, the first twenty-four hour period of the showtime stable 1-year menses of continuous aspirin treatment. Use of nonsteroidal anti-inflammatory drugs, oral steroids, and antiplatelet (other than aspirin) or oral anticoagulant drugs was defined as the fraction of an aspirin treatment menstruum covered past the respective drug and was time updated during follow-upwardly. Concomitant cardiovascular disease was defined as a prior hospitalization for myocardial infarction (International Classification of Diseases, tenth Revision codes I21 and I22) or stroke (International Classification of Diseases, tenth Revision codes I63 and I64). Patients with concomitant cardiovascular disease were divers as users of aspirin for secondary prevention. Patients without concomitant cardiovascular were presumed to employ their aspirin for principal prevention. Major haemorrhage was defined as a hospital admission caused by gastrointestinal bleeding, intracranial bleeding, hemopericardium, postoperative bleeding, bleeding from venous varices, haemorrhage events in the respiratory organization, hematuria, and other signs of blood loss. Nosotros determined the occurrence of surgery as all surgical procedures except small diagnostic procedures such as gastroscopy and coronary angiography.

Exposures

We investigated two sets of exposures. In the get-go fix of comparisons, we constructed groups based on time-updated aspirin treatment persistence patterns. In the 2d set, nosotros constructed groups that were on aspirin versus those that had just discontinued aspirin treatment. For both exposures, fourth dimension spent in the hospital for diagnoses other than the outcome was added to the time at risk for the particular exposure group at the fourth dimension of admission because patients are provided all in-hospital medications free of charge and hence do not use their dispensed prescribed medications during hospitalization. Nosotros were well equipped to study persistence (staying on a drug long term or discontinuing) just not adherence (taking the prescribed number of pills).

Aspirin Handling Persistence Patterns

To record time on aspirin and off aspirin equally accurately as possible, accounting for the fact that the verbal time of discontinuation is uncertain, we constructed iv time-updated aspirin persistence groups, between which patients could motility freely over time during follow-up:

On aspirin: the nominal duration of each aspirin dispense.
Accumulated period: the fourth dimension after the nominal duration of each aspirin dispense when the patient has tablets left over from previous dispenses in a consecutively dispensed catamenia.
Grace period: from the end of the accumulated period plus 25% of the total duration on aspirin in the final consecutively dispensed period plus 20 days. This corresponds to 80% adherence with up to a week's gap betwixt dispenses.
Off aspirin: from the terminate of the grace catamenia.

Although the hypothesis is answered with the use of groups 1 and iv, the other 2 groups are included for transparency. Persistence patterns were described for both aspirin-naïve patients and long-term aspirin users.

Timing of Events Later on Aspirin Discontinuation

For this ready of analyses, nosotros sought to determine the run a risk of cardiovascular events in relation to the time of the aspirin discontinuation among patients who nerveless their dispenses in a timely style (every bit defined above). We compared patients who collected a timely fifth dispense with patients who did non subsequently a series of 4 timely dispenses. A patient could contribute several times at adventure to these analyses.

Follow-Up and Outcomes

Outcomes were defined with the Swedish inpatient and cause-of-death registers, which include all hospitalizations and deaths, respectively, classified with the International Classification of Diseases (codes in Tabular array I in the online-only Information Supplement). The consequence investigated was a first incidence of cardiovascular disease after the start of follow-upwardly, divers as a hospitalization for myocardial infarction, stroke, or cardiovascular death. Just the chief diagnoses in the discharge letter or decease certificates were used for nomenclature of the outcome. The accuracy in the Swedish registers is high for the diagnoses examined in this study (positive predictive values, 98%–100% for myocardial infarction and 69%–98% for stroke).²¹

Because there may exist a risk of reverse causation (aspirin withdrawn from people nigh to die), we also investigated a secondary nonfatal cardiovascular events outcome similar to the master event but without cardiovascular decease. A similar bias may ascend if patients discontinue aspirin because they starting time using an oral anticoagulant as a event of change to a higher risk stratum; we therefore too investigated models censoring participants at the time of start of oral anticoagulant treatment.

Follow-upwards started later 1 twelvemonth of aspirin treatment with loftier adherence, as defined above. Patients were followed up until the first example of the cardiovascular event, a new diagnosis of cancer, noncardiovascular death, or the end of follow-upward on December 31, 2009. In the timing of events later on aspirin discontinuation analyses, patients were as well censored after 100 days considering that is the maximum duration of the fifth manipulate. Patients were followed up from the day after manipulate (or commencement of a gap) until a cardiovascular illness event or censoring, whichever came starting time.

Major bleeding and surgical procedures may impact thrombogenicity, cause aspirin discontinuation, and exist related to cardiovascular affliction incidence for an unknown duration of time that we assumed to be less than a few months. Therefore, in this study, a major bleeding or a surgical procedure during the study incurred a 3-calendar month refractory period from the time at risk, during which person-fourth dimension was not counted and outcomes were not considered.

Statistical Analysis

Baseline characteristics were presented per patient equally observed numbers (percentages) for categorical variables and every bit ways (SDs) for continuous variables. Accented risks of events were illustrated with Nelson-Aalen cumulative incidence plots, which were also used to assess proportionality of hazards.

Cox proportional hazards models were used to investigate associations of the four aspirin persistence groups with risk of cardiovascular events. Models for minimizing bias were identified with directed acyclic graphs (Figure I in the online-merely Data Supplement).²² All models were adjusted for historic period, sex activity, previous cardiovascular disease, diabetes mellitus, antiplatelet or oral anticoagulant drugs, nonsteroidal anti-inflammatory drugs, and oral steroids. Interactions in the form of difference from multiplicativity were investigated between the aspirin persistence groups and age, sexual activity, prior cardiovascular disease, diabetes mellitus, nonsteroidal anti-inflammatory drugs, oral steroids, other antiplatelet or oral anticoagulant drugs, aspirin-naïve/not-naïve, previous major haemorrhage, and chemist's shop-prepacked multidose dispenses. Considering of potential interaction signals, the main analyses were also performed in subgroups with and without prior cardiovascular illness.

For the timing of events later on aspirin discontinuation analysis to which patients could contribute >1 ascertainment period, a model with shared frailty for participant identity was used. Because we assumed a priori that the hazard function associated with aspirin discontinuation may initially be nonmonotonic and because we wanted to compute time quantiles, we investigated parametric regression models with exponential, Gompertz, Weibull, log logistic, and log normal parameterizations. The log normal distribution had the highest log likelihood and lowest Akaike information benchmark and was used, with results displayed graphically and presented in the accelerated failure fourth dimension metric. This assay was adjusted for the same covariates as the Cox models, and the same gear up of covariates was time updated at each dispense.

Because this written report used only official registers mandatory for all citizens, nosotros assumed that no data were missing. The data were managed and analyzed at both an independent statistical contract company (Statisticon) and Uppsala Academy, and all authors had full admission to the data. The statistical packages R version 3.0.1 and Stata version 14 were used.

Results

Clinical characteristics of the aspirin treatment persistence groups are displayed in Table i. Notably, one-half of the sample were female, the hateful historic period was 73 years, 16% had diabetes mellitus, and half of the sample were on long-term aspirin treatment without having had a prior hospitalization for cardiovascular disease. During a median of 3.0 years of follow-up (range, 0.002–iii.5 years), corresponding to 1 491 369 person-years at risk, 62 690 cardiovascular events occurred (incidence rate, 42.0 per thou person-years at hazard; separate outcomes presented in Tabular array 2 in the online-only Data Supplement). A total of 73 636 people died during this time; nineteen 978 person-years were excluded from the analyses considering of surgical procedures and major haemorrhage events as defined above.

**Table 1.** Clinical Characteristics by Aspirin Persistence Patterns
	On Aspirin (due north=577 578)	Accumulated (n=521 799)	Grace Period (north=492 074)	Off Aspirin (n=179 548)
Historic period, y	72.7 (11.v)	72.7 (11.5)	72.seven (eleven.3)	72.6 (11.iv)
Women, n (%)	311 844 (52)	308 576 (52)	279 886 (52)	266 479 (52)
Index yr, 2005/2006/2007/2008, %	70/12/9/9	71/12/9/eight	74/12/9/five	75/12/ix/5
Diabetes mellitus, n (%)	95 768 (16)	94 982 (sixteen)	89 974 (17)	83 893 (16)
Prior CVD, n (%)	329 941 (55)	327 258 (55)	301 675 (56)	281 388 (55)
Major haemorrhage, north (%)	15 644 (iii)	15 313 (iii)	14 774 (3)	14 336 (3)
Other antiplatelets, n (%)	23 111 (4)	23 698 (4)	9582 (2)	9992 (ii)
Oral anticoagulants, north (%)	1200 (0)	1127 (0)	1462 (0)	1656 (0)
NSAIDs, n (%)	35 870 (half-dozen)	37 544 (6)	23 184 (4)	22 992 (5)
Oral steroids, n (%)	14 191 (2)	14 659 (2)	9286 (2)	10 626 (2)

Treatment patterns are displayed in Figure 2 and Figure II in the online-just Data Supplement. Amongst the long-term low-dose aspirin users (Effigy 2), persistence gradually only slowly tapered off; 3 years after inclusion, 3 of 4 patients collected their aspirin dispenses earlier the expiration of the previous dispense, and iv of 5 had access to accumulated aspirin. Approximately 15% were off long-term aspirin treatment afterwards iii years. Amid the 227 135 aspirin-naïve patients, ≈20% did not collect a 2nd aspirin prescription (Figure Ii in the online-simply Data Supplement). After the offset yr of inconsistent prescription collections, those who remained on treatment had approximately the same persistence pattern as those treated with long-term aspirin.

Adjusted cumulative incidence of cardiovascular events according to aspirin treatment persistence groups is presented in Figure 3. Patients on persistent aspirin treatment had the lowest incidence of cardiovascular events. Patients who had discontinued aspirin had a 37% higher rate of cardiovascular events (Table 2), respective to an accented risk increase of 13.5 events per 1000 person-years at risk. Put another mode, on average, 1 of every 74 patients who discontinued aspirin had an additional cardiovascular upshot in 1 year.

**Table 2.** Risk of Cardiovascular Events by Aspirin Persistence Patterns
	Cardiovascular Events, northward	Time at Adventure, y	Run a risk Ratio	95% Confidence Interval
Total sample
On aspirin	49 521	1 209 905	ane
Accumulated	3957	94 643	1.xvi	ane.12–1.20
Grace period	3667	84 932	one.14	i.10–1.18
Off aspirin	5545	101 889	1.37	one.34–1.41
Primary prevention
On aspirin	14 730	564 408	1
Accumulated	1202	44 966	1.13	i.07–1.20
Grace menstruation	1170	41 920	1.13	1.07–ane.20
Off aspirin	1885	57 194	1.28	1.22–i.34
Secondary prevention
On aspirin	34 791	645 498	1
Accumulated	2755	49 677	ane.17	1.12–1.21
Grace menstruation	2497	43 012	1.15	i.10–i.xx
Off aspirin	3660	44 695	1.46	1.41–1.51

Subgroup analyses further revealed that patients with higher historic period and prior cardiovascular illness were at college risk increase for cardiovascular events when off aspirin, whereas treatment with oral anticoagulant or other antiplatelet drugs was associated with lower risk increase for cardiovascular events when off aspirin (Figure four). The majority (54%) of the report sample used aspirin for secondary prevention. Among those, discontinuing aspirin was associated with a 46% higher rate of cardiovascular events than continuing on aspirin (Table ii), corresponding to an absolute adventure increase of 28.0 per yard person-years at gamble or an additional cardiovascular result per year in 1 of every 36 patients who discontinued aspirin. Among the 46% who probably used aspirin every bit part of chief prevention, discontinuing aspirin was associated with a 28% higher rate of cardiovascular events than standing on aspirin (Tabular array 2), an accented risk increase of 6.9 per 1000 person-years at risk or an boosted cardiovascular outcome per year in 1 of every 146 patients who discontinued aspirin.

Figure 4. — **Figure iv.** **Gamble of cardiovascular events by aspirin persistence patterns in subgroups.** P values are for multiplicative interactions of the subgroup factor with aspirin persistence pattern. CI indicates confidence interval; CVD, cardiovascular affliction; and NSAID, nonsteroidal anti-inflammatory drug.

Aspirin discontinuation was too associated with nonfatal cardiovascular events, with a 10% higher risk of nonfatal cardiovascular events amongst people off versus on aspirin (Table III in the online-only Information Supplement). Censoring participants at the start of oral anticoagulant therapy produced results very similar to those of the primary models, with a 43% higher risk of cardiovascular events if discontinuing rather than continuing on aspirin (Table 4 in the online-only Data Supplement).

The timing of events later on aspirin discontinuation analyses included 38 736 patients with 40 355 times at risk during which 216 cardiovascular events occurred. Patients who stopped taking aspirin later on a period of 4 timely dispenses had an early risk increase for cardiovascular events compared with those who nerveless their 5th timely dispense (Figure 5). The median fourth dimension to the first cardiovascular event in those who did non collect their 5th manipulate on schedule was i-third the time of those who collected their manipulate on schedule (time ratio, 0.31; 95% confidence interval, 0.22–0.43).

**Figure 5.** **Timing of cardiovascular events later on aspirin discontinuation in patients who stopped (cherry line) vs continued (green line) taking aspirin subsequently four timely aspirin dispenses.** Parametric regression models with log normal parameterization and shared frailty on the patient level. Models adjusted for the baseline variables of historic period, sex, and diabetes mellitus and the time-updated variables of previous cardiovascular disease, antiplatelet or oral anticoagulant drugs, nonsteroidal anti-inflammatory drugs, and oral steroids.

Give-and-take

In this large nationwide patient cohort, discontinuation of long-term low-dose aspirin was associated with a >30% college risk of cardiovascular events, corresponding to an additional cardiovascular event observed per year in 1 of every 74 patients who discontinue aspirin. The take a chance appeared to increment as soon every bit the patients discontinued aspirin, with no safe interval. In this sample, only half of the low-dose aspirin users had been hospitalized for cardiovascular disease before baseline; most of the remaining half were presumably treated, for example, for angina pectoris or stroke prevention in atrial fibrillation or treated every bit role of primary prevention. Aspirin discontinuation appeared especially perilous amongst patients with previous cardiovascular disease, with an boosted cardiovascular effect per year in 1 of every 36 secondary prevention patients who discontinued aspirin compared with an additional cardiovascular event per yr in i of every 146 primary prevention patients who discontinued aspirin.

We ostend a high initial discontinuation rate, as seen in prior studies^7–11: 1 of five aspirin-naïve patients did not collect the 2d aspirin dispense, and the primary persistence drop was during the first twelvemonth after aspirin initiation. In dissimilarity, those who picked up their 2nd prescription had a modest discontinuation charge per unit over time.

Our observations of the risks associated with low-dose aspirin discontinuation are of a magnitude very similar to those of previous randomized trials of aspirin initiation.^1,v However, the timing of cardiovascular events after aspirin discontinuation remains uncertain. Although those analyses were based on a modest number of events, the chance in this report appeared to increase shortly subsequently discontinuation. An acutely increased risk of cerebrovascular events,^14,15 ischemic events,^15–17 and mortality¹⁶ has been observed in case-control studies,^fourteen,16 in perioperative studies,^15,17 and in individuals with bleeding ulcers.¹⁸ In those studies, the principal reasons for aspirin withdrawal were surgery^14–17 or bleeding,^fourteen,18 which per se may stimulate platelet aggregation. No increase in cardiovascular events was observed in a recent perioperative aspirin discontinuation trial,¹⁹ although aspirin was stopped within 24 hours before the surgery in that study. Notably, the present written report investigated aspirin discontinuation that was unrelated to surgery or bleeding events.

Experimental studies have suggested a rebound effect subsequently aspirin discontinuation, involving increased thromboxane levels^23,24 mayhap resulting from the prothrombotic effects of residuum very low levels of aspirin.²⁵ The clinical importance of a rebound effect may exist substantial because of the large number of aspirin patients and the loftier discontinuation rates. For patients undergoing planned surgery or other procedures, it is unknown whether treatment gaps >seven days or <24 hours before the procedure are safe.¹⁹ For patients discontinuing aspirin therapy, it is unknown whether or when the rebound effect happens. In addition, for patients with poor adherence, any rebound effects may be in play more than or less continuously. The possibility of such mechanisms is supported by the observation in this report that aspirin discontinuation was non associated with cardiovascular events in patients protected past other antiplatelet or oral anticoagulant drugs (Figure 4), although those patients were likely at higher absolute risk of such events.

Some limitations of this study are worth mentioning. Nearly important, in that location is a hazard of confounding, equally in all observational studies. We did not have access to information on socioeconomic status; concrete examinations, including claret pressures and lipids; or lifestyle measures such equally smoking. However, nosotros used directed acyclic graphs to place bias-minimized models and included just people who had qualified as long-term users of aspirin. Furthermore, any confounding by indication would bias toward a zero issue, assuming that people with the highest run a risk of cardiovascular events would be the ones to the lowest degree likely to discontinue aspirin treatment. In that location is likewise a gamble of contrary causation—that is, patients about to die stop taking aspirin and then die anyway. Associations of aspirin discontinuation with the secondary nonfatal cardiovascular events outcome were similar but weaker, which may signify some reverse causation, a protective effect of aspirin confronting fatal events, or lower statistical power in those analyses. Models censoring at the time of kickoff of oral anticoagulant treatment produced results similar to the principal results, indicating low risk of opposite causation by patients discontinuing aspirin handling because of moving to a college adventure stratum and switching to oral anticoagulant therapy. An of import limitation is the imprecision in determining the exposure status, which also would bias the results toward the naught hypothesis. This is confirmed past the results among people with prepacked dispenses, for which we have practiced precision in the exposure. These patients appear to exist at clearly higher risk of aspirin discontinuation than those who collect dispenses themselves. Thus, the true result is likely higher than the master observed issue. Another limitation is the finish of follow-upwardly in 2009, which implies lack of data on more than recent treatment patterns simply, on the other mitt, avoids cohort effect bias because aspirin guidelines were stable during the study period.

Strengths include the large contemporary sample rendering >60 000 cardiovascular events, universal coverage of the prescription register and hence inclusion of all long-term low-dose aspirin users nationwide, the universal coverage of the high-precision²¹ registers for determining the outcomes, and minimal loss to follow-up.

Conclusions

Among long-term users of low-dose aspirin, discontinuation of aspirin in the absence of major surgery or bleeding was associated with a >thirty% increased risk of cardiovascular events. The chance increased soon after discontinuation. These findings tin help policymakers focus on simple measures to ensure treatment persistence with a cheap medication similar aspirin with substantial public health gains.

Acknowledgments

Editorial assistance was provided by Dr Ebba Bergman and Dr Vendela Roos, Uppsala Clinical Research Center, Sweden.

Sources of Funding

This written report was partly funded past AstraZeneca by funds to Statisticon for the statistical analyses.

Disclosures

Drs Sundström, Hedberg, and Oldgren take served on an informational lath for AstraZeneca. P. Aarskog is a current employee and K.M. Johannesen is a former employee of AstraZeneca. Dr Thuresson is employed by Statisticon, of which AstraZeneca is a client. Dr Sundström is on an advisory board for Itrim. Dr Oldgren has received consultancy and lecture fees from Bayer, Boehringer-Ingelheim, BristolMyers Squibb and Pfizer, outside the submitted work.

Footnotes

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Source: https://www.ahajournals.org/doi/10.1161/circulationaha.117.028321