Recent News Articles of Big Study of Baby Aspirin and Its Value or Not?

Introduction

Clinical Perspective

What Is New?

Discontinuing long-term low-dose aspirin treatment in the absenteeism of major surgery or haemorrhage may be hazardous.
Nosotros investigated that question among 601 527 users of low-dose aspirin for primary or secondary prevention identified in the Swedish drug prescription register.
Patients who discontinued aspirin had a 37% higher charge per unit of cardiovascular events than those who continued, corresponding to an boosted cardiovascular event observed per twelvemonth in ane of every 74 patients who discontinue aspirin.
The risk increased shortly after discontinuation and did not announced 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 of import treatment goal.
Millions of patients worldwide accept aspirin on a daily basis and might consider stopping at some fourth dimension during their lives.
This article may help physicians and patients to make an informed decision on whether to stop aspirin use.

Depression-dose aspirin has potent evidence for use in the secondary prevention of cardiovascular disease and is uniformly recommended in guidelines.^one–3 Its utility in master prevention is under investigation.^{four–half-dozen} In patients with a recent myocardial infarction, 10% to 20% accept been reported to discontinue aspirin use during the showtime 1^7–9 to 3¹⁰ years after the infarction. In broader patient settings, discontinuation rates of up to thirty% have been reported, and poor aspirin compliance has been noted in up to 50%.^eleven The public health effects of discontinuing long-term aspirin treatment may be substantial but are not well known.

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with indications of an increased take a chance presently after discontinuation.^{fourteen–18} Aspirin is often withdrawn because of surgery^{14–17,nineteen} or bleeding,^14,18 factors that per se may stimulate platelet aggregation and increase the run a risk of cardiovascular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

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

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

Methods

Written report Sample

Using the unique ceremonious 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 assist of the Swedish National Lath of Health and Welfare. In Sweden, low-dose aspirin cannot be 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 menses between July 1, 2005, and December 31, 2009, equally identified in the prescribed drug annals past the detection of an aspirin dispense of 75 to 160 mg. We also included aspirin 75 to 160 mg dispensed as part of chemist's shop-prepacked multidose prescriptions used for patients unable to safely self-administer their medication. Aspirin tablet strengths other than 75 or 160 mg are not bachelor for prevention of cardiovascular events in Sweden; neither is carbasalate calcium (B01AC08). We considered all 889 655 aspirin-treated patients who were free from previous cancer (International Nomenclature of Diseases, 10th Revision codes C00–C99) at baseline. We were interested in treatment breaks and permanent discontinuation subsequently a stable (1-yr) menstruum of continuous aspirin treatment. Therefore, we excluded 207 180 patients who had <292 defined daily doses of aspirin dispensed during the first yr after their first aspirin prescription (which equals 1 yr of aspirin treatment with ≥fourscore% adherence, or medication possession ratio, which is commonly viewed equally adequate^twenty). Nosotros also excluded 80 621 patients who had a cardiovascular event (considering our research question involved long-term use) or died during this outset year of aspirin treatment, equally well as 327 patients without any exposure time after the starting time yr, rendering a last study sample of 601 527 long-term depression-dose aspirin users who entered the follow-up phase.

To report treatment patterns in aspirin-naïve patients, we also studied a sample of 227 135 patients who nerveless their first depression-dose aspirin dispense at least i year afterwards the beginning of the report period. This subsample was not subjected to the 1-twelvemonth definition of long-term users and was non used in any statistical modeling.

In a 2nd ready of analyses, the timing of cardiovascular events in people who discontinued aspirin was investigated. We defined inclusion criteria on the manipulate level and defined a timely dispense as i that was collected between 0 and x days earlier the end of the previous timely dispense, and it had to be the terminal in a chain of 4 consecutive timely dispenses (typically equal to one year of treatment, chosen to balance strictness of the inclusion criteria with statistical power). This strict definition, although rendering a pocket-sized sample of patients with presumed high adherence, was used to determine the time of discontinuation as precisely every bit possible and to avoid periods of accumulated medication during and after which drug use status is more than uncertain. This sample included the 38 736 patients who had iv sequent timely dispenses.

The construction of the samples is displayed in Figure 1.

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

Clinical Characteristics

All definitions are described in Table I in the online-only Data Supplement. Age, sex, and diabetes mellitus were determined at the inclusion date—that is, the first day of the get-go stable i-yr menses of continuous aspirin treatment. Apply of nonsteroidal anti-inflammatory drugs, oral steroids, and antiplatelet (other than aspirin) or oral anticoagulant drugs was divers every bit the fraction of an aspirin treatment menstruum covered by the corresponding drug and was time updated during follow-up. Concomitant cardiovascular disease was defined as a prior hospitalization for myocardial infarction (International Classification of Diseases, 10th Revision codes I21 and I22) or stroke (International Nomenclature of Diseases, tenth Revision codes I63 and I64). Patients with concomitant cardiovascular disease were defined every bit users of aspirin for secondary prevention. Patients without concomitant cardiovascular were presumed to use their aspirin for primary prevention. Major bleeding was defined as a hospital admission caused by gastrointestinal bleeding, intracranial bleeding, hemopericardium, postoperative bleeding, bleeding from venous varices, bleeding events in the respiratory system, hematuria, and other signs of blood loss. Nosotros determined the occurrence of surgery equally all surgical procedures except small diagnostic procedures such every bit gastroscopy and coronary angiography.

Exposures

We investigated two sets of exposures. In the first set of comparisons, we synthetic groups based on time-updated aspirin treatment persistence patterns. In the 2nd gear up, we constructed groups that were on aspirin versus those that had only discontinued aspirin treatment. For both exposures, time spent in the hospital for diagnoses other than the outcome was added to the fourth dimension at adventure for the particular exposure group at the time of admission considering patients are provided all in-hospital medications free of accuse and hence practice non use their dispensed prescribed medications during hospitalization. Nosotros were well equipped to study persistence (staying on a drug long term or discontinuing) but non adherence (taking the prescribed number of pills).

Aspirin Treatment Persistence Patterns

To tape time on aspirin and off aspirin equally accurately as possible, accounting for the fact that the verbal time of discontinuation is uncertain, we synthetic 4 time-updated aspirin persistence groups, between which patients could motion freely over time during follow-upward:

On aspirin: the nominal duration of each aspirin manipulate.
Accumulated flow: the time after the nominal duration of each aspirin dispense when the patient has tablets left over from previous dispenses in a consecutively dispensed menstruum.
Grace period: from the end of the accumulated period plus 25% of the total duration on aspirin in the last consecutively dispensed period plus 20 days. This corresponds to 80% adherence with upward to a week's gap between dispenses.
Off aspirin: from the end of the grace period.

Although the hypothesis is answered with the use of groups 1 and 4, the other ii 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 set of analyses, we sought to determine the adventure of cardiovascular events in relation to the fourth dimension of the aspirin discontinuation amongst patients who nerveless their dispenses in a timely manner (as defined in a higher place). Nosotros compared patients who collected a timely fifth dispense with patients who did not after a series of 4 timely dispenses. A patient could contribute several times at risk to these analyses.

Follow-Upwardly and Outcomes

Outcomes were defined with the Swedish inpatient and cause-of-decease registers, which include all hospitalizations and deaths, respectively, classified with the International Classification of Diseases (codes in Table I in the online-but Information Supplement). The effect investigated was a first incidence of cardiovascular affliction after the first of follow-upwardly, defined as a hospitalization for myocardial infarction, stroke, or cardiovascular death. Only the principal diagnoses in the discharge letter or death certificates were used for classification of the issue. The accuracy in the Swedish registers is loftier for the diagnoses examined in this study (positive predictive values, 98%–100% for myocardial infarction and 69%–98% for stroke).²¹

Because there may be a risk of opposite causation (aspirin withdrawn from people near to die), nosotros also investigated a secondary nonfatal cardiovascular events outcome similar to the principal outcome merely without cardiovascular death. A similar bias may ascend if patients discontinue aspirin because they offset using an oral anticoagulant as a result of change to a higher adventure stratum; we therefore also investigated models censoring participants at the time of start of oral anticoagulant treatment.

Follow-upwards started afterward ane year of aspirin treatment with loftier adherence, as divers above. Patients were followed up until the kickoff instance of the cardiovascular outcome, a new diagnosis of cancer, noncardiovascular death, or the end of follow-up on December 31, 2009. In the timing of events after aspirin discontinuation analyses, patients were also censored after 100 days because that is the maximum elapsing of the 5th dispense. Patients were followed up from the mean solar day later on dispense (or start of a gap) until a cardiovascular disease event or censoring, whichever came first.

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

Statistical Analysis

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

Cox proportional hazards models were used to investigate associations of the 4 aspirin persistence groups with risk of cardiovascular events. Models for minimizing bias were identified with directed acyclic graphs (Figure I in the online-simply Data Supplement).²² All models were adjusted for age, sexual activity, previous cardiovascular illness, diabetes mellitus, antiplatelet or oral anticoagulant drugs, nonsteroidal anti-inflammatory drugs, and oral steroids. Interactions in the form of deviation from multiplicativity were investigated between the aspirin persistence groups and age, sexual activity, prior cardiovascular affliction, diabetes mellitus, nonsteroidal anti-inflammatory drugs, oral steroids, other antiplatelet or oral anticoagulant drugs, aspirin-naïve/not-naïve, previous major bleeding, and pharmacy-prepacked multidose dispenses. Because of potential interaction signals, the chief 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 chance function associated with aspirin discontinuation may initially exist nonmonotonic and because nosotros 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 criterion and was used, with results displayed graphically and presented in the accelerated failure time metric. This analysis was adjusted for the same covariates equally the Cox models, and the aforementioned gear up of covariates was time updated at each dispense.

Considering this study used only official registers mandatory for all citizens, we causeless that no data were missing. The information were managed and analyzed at both an independent statistical contract company (Statisticon) and Uppsala University, and all authors had full admission to the information. The statistical packages R version 3.0.ane and Stata version 14 were used.

Results

Clinical characteristics of the aspirin handling persistence groups are displayed in Tabular array 1. Notably, one-half of the sample were female, the mean age 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 iii.0 years of follow-up (range, 0.002–three.5 years), respective to 1 491 369 person-years at gamble, 62 690 cardiovascular events occurred (incidence charge per unit, 42.0 per 1000 person-years at take a chance; divide outcomes presented in Table II in the online-only Data Supplement). A total of 73 636 people died during this time; xix 978 person-years were excluded from the analyses because of surgical procedures and major bleeding events as defined above.

**Table i.** Clinical Characteristics past Aspirin Persistence Patterns
	On Aspirin (n=577 578)	Accumulated (n=521 799)	Grace Period (n=492 074)	Off Aspirin (n=179 548)
Age, y	72.7 (11.5)	72.vii (eleven.v)	72.7 (11.three)	72.6 (xi.four)
Women, n (%)	311 844 (52)	308 576 (52)	279 886 (52)	266 479 (52)
Index twelvemonth, 2005/2006/2007/2008, %	70/12/9/nine	71/12/9/8	74/12/nine/five	75/12/9/5
Diabetes mellitus, northward (%)	95 768 (16)	94 982 (xvi)	89 974 (17)	83 893 (16)
Prior CVD, n (%)	329 941 (55)	327 258 (55)	301 675 (56)	281 388 (55)
Major bleeding, n (%)	fifteen 644 (iii)	15 313 (3)	14 774 (3)	14 336 (3)
Other antiplatelets, n (%)	23 111 (four)	23 698 (4)	9582 (ii)	9992 (2)
Oral anticoagulants, n (%)	1200 (0)	1127 (0)	1462 (0)	1656 (0)
NSAIDs, north (%)	35 870 (6)	37 544 (six)	23 184 (4)	22 992 (v)
Oral steroids, due north (%)	fourteen 191 (ii)	14 659 (2)	9286 (2)	10 626 (2)

Treatment patterns are displayed in Figure ii and Figure Ii in the online-simply Data Supplement. Among the long-term depression-dose aspirin users (Figure two), persistence gradually but slowly tapered off; iii years after inclusion, 3 of 4 patients collected their aspirin dispenses before the expiration of the previous dispense, and iv of five had access to accumulated aspirin. Approximately 15% were off long-term aspirin treatment later on 3 years. Among the 227 135 aspirin-naïve patients, ≈xx% did non collect a second aspirin prescription (Figure 2 in the online-merely Data Supplement). Later on the first yr of inconsistent prescription collections, those who remained on treatment had approximately the aforementioned persistence pattern as those treated with long-term aspirin.

**Figure 2.** **Persistence patterns in patients on stable long-term aspirin treatment (n=601527).** *On aspirin* is the nominal duration of each aspirin dispense. *Accumulated* is the time after the nominal duration of each aspirin manipulate when the patient has tablets left over from previous dispenses in a consecutively dispensed period. *Grace period* is from the cease of the accumulated period plus 25% of the total duration on aspirin in the last consecutively dispensed period plus 20 days. This corresponds to 80% adherence with upward to a week's gap between dispenses. *Off aspirin* is from the end of the grace menstruum.

Adapted cumulative incidence of cardiovascular events according to aspirin treatment persistence groups is presented in Effigy 3. Patients on persistent aspirin treatment had the lowest incidence of cardiovascular events. Patients who had discontinued aspirin had a 37% college rate of cardiovascular events (Table 2), corresponding to an accented risk increase of 13.5 events per one thousand person-years at risk. Put another way, on average, ane of every 74 patients who discontinued aspirin had an boosted cardiovascular event in 1 yr.

**Tabular array 2.** Take chances of Cardiovascular Events past Aspirin Persistence Patterns
	Cardiovascular Events, n	Time at Gamble, y	Run a risk Ratio	95% Confidence Interval
Total sample
On aspirin	49 521	i 209 905	i
Accumulated	3957	94 643	1.xvi	1.12–1.20
Grace period	3667	84 932	1.xiv	1.10–ane.18
Off aspirin	5545	101 889	1.37	1.34–1.41
Master prevention
On aspirin	14 730	564 408	one
Accumulated	1202	44 966	1.13	1.07–1.20
Grace menses	1170	41 920	ane.13	1.07–1.20
Off aspirin	1885	57 194	1.28	1.22–1.34
Secondary prevention
On aspirin	34 791	645 498	1
Accumulated	2755	49 677	1.17	1.12–ane.21
Grace period	2497	43 012	1.fifteen	one.10–1.20
Off aspirin	3660	44 695	1.46	1.41–i.51

Figure 3. — **Figure iii.** **Adjusted cumulative incidence of cardiovascular events.** Adapted for the baseline variables of age, sexual practice, and diabetes mellitus and the time-updated variables of previous cardiovascular disease, antiplatelet or oral anticoagulant drugs, nonsteroidal anti-inflammatory drugs, and oral steroids. *On aspirin* is the nominal duration of each aspirin dispense. *Accumulated* is the time after the nominal duration of each aspirin dispense when the patient has tablets left over from previous dispenses in a consecutively dispensed flow. *Grace flow* is from the finish of accumulated flow plus 25% of the total elapsing on aspirin in the last consecutively dispensed menstruum plus 20 days. This corresponds to lxxx% adherence with upwardly to a week'south gap between dispenses. *Off aspirin* is from the terminate of the grace period.

Subgroup analyses farther revealed that patients with higher age and prior cardiovascular disease were at higher run a risk increase for cardiovascular events when off aspirin, whereas treatment with oral anticoagulant or other antiplatelet drugs was associated with lower take chances increase for cardiovascular events when off aspirin (Effigy 4). The majority (54%) of the report sample used aspirin for secondary prevention. Among those, discontinuing aspirin was associated with a 46% college charge per unit of cardiovascular events than continuing on aspirin (Tabular array two), corresponding to an absolute take chances increase of 28.0 per grand person-years at risk or an additional cardiovascular event per year in ane of every 36 patients who discontinued aspirin. Among the 46% who probably used aspirin as office of primary prevention, discontinuing aspirin was associated with a 28% college rate of cardiovascular events than standing on aspirin (Table 2), an absolute risk increase of half dozen.9 per 1000 person-years at risk or an additional cardiovascular consequence per year in 1 of every 146 patients who discontinued aspirin.

Figure 4. — **Figure four.** **Run a risk of cardiovascular events by aspirin persistence patterns in subgroups.** P values are for multiplicative interactions of the subgroup cistron with aspirin persistence blueprint. CI indicates confidence interval; CVD, cardiovascular disease; and NSAID, nonsteroidal anti-inflammatory drug.

Aspirin discontinuation was also associated with nonfatal cardiovascular events, with a 10% higher gamble of nonfatal cardiovascular events among people off versus on aspirin (Table Iii in the online-but Data Supplement). Censoring participants at the start of oral anticoagulant therapy produced results very similar to those of the master models, with a 43% higher risk of cardiovascular events if discontinuing rather than continuing on aspirin (Table IV 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 after a menstruation of 4 timely dispenses had an early adventure increase for cardiovascular events compared with those who collected their 5th timely dispense (Effigy 5). The median time to the first cardiovascular outcome in those who did not collect their 5th manipulate on schedule was 1-third the time of those who collected their manipulate on schedule (fourth dimension ratio, 0.31; 95% confidence interval, 0.22–0.43).

Figure 5. — **Figure five.** **Timing of cardiovascular events after aspirin discontinuation in patients who stopped (red line) vs continued (greenish line) taking aspirin after 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, sexual practice, and diabetes mellitus and the time-updated variables of previous cardiovascular affliction, antiplatelet or oral anticoagulant drugs, nonsteroidal anti-inflammatory drugs, and oral steroids.

Discussion

In this large nationwide patient cohort, discontinuation of long-term low-dose aspirin was associated with a >30% higher risk of cardiovascular events, corresponding to an additional cardiovascular event observed per year in one of every 74 patients who discontinue aspirin. The risk appeared to increment every bit soon as the patients discontinued aspirin, with no condom interval. In this sample, but half of the depression-dose aspirin users had been hospitalized for cardiovascular affliction before baseline; most of the remaining one-half were presumably treated, for example, for angina pectoris or stroke prevention in atrial fibrillation or treated as function of primary prevention. Aspirin discontinuation appeared specially perilous amidst patients with previous cardiovascular affliction, with an additional cardiovascular event per year in 1 of every 36 secondary prevention patients who discontinued aspirin compared with an additional cardiovascular issue per year in 1 of every 146 primary prevention patients who discontinued aspirin.

We confirm a high initial discontinuation rate, as seen in prior studies^7–11: 1 of 5 aspirin-naïve patients did not collect the 2nd aspirin dispense, and the master persistence drop was during the showtime year afterwards aspirin initiation. In contrast, those who picked up their second prescription had a modest discontinuation rate 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.^1,5 However, the timing of cardiovascular events after aspirin discontinuation remains uncertain. Although those analyses were based on a small-scale number of events, the risk in this study appeared to increment before long afterwards discontinuation. An acutely increased risk of cerebrovascular events,^14,fifteen ischemic events,^fifteen–17 and bloodshed^sixteen has been observed in example-control studies,^14,16 in perioperative studies,^fifteen,17 and in individuals with bleeding ulcers.^xviii In those studies, the main reasons for aspirin withdrawal were surgery^xiv–17 or bleeding,^14,18 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 inside 24 hours earlier the surgery in that study. Notably, the present study investigated aspirin discontinuation that was unrelated to surgery or bleeding events.

Experimental studies have suggested a rebound issue later on aspirin discontinuation, involving increased thromboxane levels^23,24 perchance resulting from the prothrombotic effects of residual very low levels of aspirin.²⁵ The clinical importance of a rebound effect may be substantial because of the big number of aspirin patients and the high discontinuation rates. For patients undergoing planned surgery or other procedures, it is unknown whether handling gaps >vii days or <24 hours before the process are rubber.^xix For patients discontinuing aspirin therapy, information technology is unknown whether or when the rebound upshot happens. In addition, for patients with poor adherence, any rebound effects may be in play more or less continuously. The possibility of such mechanisms is supported by the ascertainment in this study that aspirin discontinuation was not associated with cardiovascular events in patients protected by other antiplatelet or oral anticoagulant drugs (Effigy four), although those patients were likely at higher absolute risk of such events.

Some limitations of this study are worth mentioning. Most important, at that place is a take chances of confounding, every bit in all observational studies. We did not have access to data on socioeconomic status; physical examinations, including blood pressures and lipids; or lifestyle measures such as smoking. However, nosotros used directed acyclic graphs to place bias-minimized models and included merely people who had qualified every bit long-term users of aspirin. Furthermore, any misreckoning by indication would bias toward a goose egg result, assuming that people with the highest risk of cardiovascular events would be the ones least likely to discontinue aspirin treatment. In that location is also 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 consequence were similar but weaker, which may signify some reverse causation, a protective outcome of aspirin against fatal events, or lower statistical power in those analyses. Models censoring at the time of first of oral anticoagulant treatment produced results like to the principal results, indicating low risk of opposite causation by patients discontinuing aspirin treatment because of moving to a higher risk stratum and switching to oral anticoagulant therapy. An important limitation is the imprecision in determining the exposure condition, which besides would bias the results toward the nothing hypothesis. This is confirmed by the results among people with prepacked dispenses, for which we accept proficient precision in the exposure. These patients appear to be at conspicuously higher risk of aspirin discontinuation than those who collect dispenses themselves. Thus, the true outcome is likely higher than the chief observed effect. Another limitation is the end of follow-upwards in 2009, which implies lack of information on more recent handling patterns just, on the other hand, avoids accomplice event bias because aspirin guidelines were stable during the report menstruation.

Strengths include the large contemporary sample rendering >threescore 000 cardiovascular events, universal coverage of the prescription annals 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 >30% increased risk of cardiovascular events. The gamble increased before long after discontinuation. These findings can help policymakers focus on simple measures to ensure handling persistence with a cheap medication similar aspirin with substantial public health gains.

Acknowledgments

Editorial help was provided by Dr Ebba Bergman and Dr Vendela Roos, Uppsala Clinical Enquiry Eye, Sweden.

Sources of Funding

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

Disclosures

Drs Sundström, Hedberg, and Oldgren have served on an advisory lath for AstraZeneca. P. Aarskog is a current employee and G.Chiliad. 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

References

1. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high gamble patients. BMJ . 2002; 324:71–86.CrossrefMedlineGoogle Scholar
2. Smith SC, Allen J, Blair SN, Bonow RO, Contumely LM, Fonarow GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca Fifty, Pasternak RC, Pearson T, Pfeffer MA, Taubert KA; AHA/ACC; National Heart, Lung, and Claret Establish. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Eye, Lung, and Blood Plant. Circulation . 2006; 113:2363–2372. doi: 10.1161/CIRCULATIONAHA.106.174516.LinkGoogle Scholar
iii. Graham I, Atar D, Borch-Johnsen K, Boysen M, Burell Chiliad, Cifkova R, Dallongeville J, De Backer G, Ebrahim South, Gjelsvik B, Herrmann-Lingen C, Hoes A, Humphries S, Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z, Ruilope 50, Sans-Menendez South, Scholte op Reimer Due west, Weissberg P, Wood D, Yarnell J, Zamorano JL, Walma E, Fitzgerald T, Cooney MT, Dudina A; European Lodge of Cardiology (ESC) Committee for Do Guidelines (CPG). European guidelines on cardiovascular disease prevention in clinical practice: executive summary: 4th Joint Task Force of the European Gild of Cardiology and Other Societies on Cardiovascular Affliction Prevention in Clinical Practice (constituted by representatives of nine societies and past invited experts). Eur Heart J . 2007; 28:2375–2414. doi: 10.1093/eurheartj/ehm316.CrossrefMedlineGoogle Scholar
4. Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Erqou Due south, Sattar N, Ray KK. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med . 2012; 172:209–216. doi: 10.1001/archinternmed.2011.628.CrossrefMedlineGoogle Scholar
v. Antithrombotic Trialists' Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. Aspirin in the master and secondary prevention of vascular illness: collaborative meta-analysis of individual participant data from randomised trials. Lancet . 2009; 373:1849–1860.CrossrefMedlineGoogle Scholar
six. Ikeda Y, Shimada K, Teramoto T, Uchiyama S, Yamazaki T, Oikawa Southward, Sugawara M, Ando K, Murata One thousand, Yokoyama M, Ishizuka N. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic gamble factors: a randomized clinical trial. JAMA . 2014; 312:2510–2520. doi: 10.1001/jama.2014.15690.CrossrefMedlineGoogle Scholar
7. Eagle KA, Kline-Rogers East, Goodman SG, Gurfinkel EP, Avezum A, Flather Md, Granger CB, Erickson S, White K, Steg PG. Adherence to prove-based therapies after belch for acute coronary syndromes: an ongoing prospective, observational study. Am J Med . 2004; 117:73–81. doi: x.1016/j.amjmed.2003.12.041.CrossrefMedlineGoogle Scholar
8. Sud A, Kline-Rogers EM, Eagle KA, Fang J, Armstrong DF, Rangarajan One thousand, Otten RF, Stafkey-Mailey DR, Taylor SD, Erickson SR. Adherence to medications past patients afterward acute coronary syndromes. Ann Pharmacother . 2005; 39:1792–1797. doi: x.1345/aph.1G249.CrossrefMedlineGoogle Scholar
ix. Kulkarni SP, Alexander KP, Lytle B, Heiss G, Peterson ED. Long-term adherence with cardiovascular drug regimens. Am Middle J . 2006; 151:185–191.CrossrefMedlineGoogle Scholar
ten. Mostaza JM, Lahoz C, Martín-Jadraque R, Sanmartín MA, Vicente I, Tranche S, Taboada M, Mantilla T, Monteiro B, Sanchez-Zamorano MA; PRESENAP Report. Factors associated with the discontinuation of evidence-based cardiovascular therapies in patients with stable coronary artery disease: a chief care perspective. Eur J Cardiovasc Prev Rehabil . 2009; xvi:34–38. doi: 10.1097/HJR.0b013e32831a47f3.CrossrefMedlineGoogle Scholar
11. Herlitz J, Tóth PP, Naesdal J. Depression-dose aspirin therapy for cardiovascular prevention: quantification and consequences of poor compliance or discontinuation. Am J Cardiovasc Drugs . 2010; 10:125–141. doi: 10.2165/11318440-000000000-00000.CrossrefMedlineGoogle Scholar
12. Rodríguez LA, Cea-Soriano L, Martín-Merino E, Johansson Due south. Discontinuation of depression dose aspirin and take chances of myocardial infarction: case-control written report in UK primary intendance. BMJ . 2011; 343:d4094.CrossrefMedlineGoogle Scholar
thirteen. García Rodríguez LA, Cea Soriano L, Hill C, Johansson Due south. Increased risk of stroke subsequently discontinuation of acetylsalicylic acid: a Britain primary care study. Neurology . 2011; 76:740–746. doi: 10.1212/WNL.0b013e31820d62b5.CrossrefMedlineGoogle Scholar
14. Maulaz AB, Bezerra DC, Michel P, Bogousslavsky J. Effect of discontinuing aspirin therapy on the risk of brain ischemic stroke. Arch Neurol . 2005; 62:1217–1220. doi: 10.1001/archneur.62.8.1217.CrossrefMedlineGoogle Scholar
fifteen. Burger W, Chemnitius JM, Kneissl GD, Rücker Yard. Low-dose aspirin for secondary cardiovascular prevention: cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation: review and meta-analysis. J Intern Med . 2005; 257:399–414. doi: 10.1111/j.1365-2796.2005.01477.ten.CrossrefMedlineGoogle Scholar
16. Collet JP, Montalescot Grand, Blanchet B, Tanguy ML, Golmard JL, Choussat R, Beygui F, Payot Fifty, Vignolles North, Metzger JP, Thomas D. Bear upon of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation . 2004; 110:2361–2367. doi: 10.1161/01.CIR.0000145171.89690.B4.LinkGoogle Scholar
17. Oscarsson A, Gupta A, Fredrikson M, Järhult J, Nyström M, Pettersson Due east, Darvish B, Krook H, Swahn Eastward, Eintrei C. To continue or discontinue aspirin in the perioperative period: a randomized, controlled clinical trial. Br J Anaesth . 2010; 104:305–312. doi: ten.1093/bja/aeq003.CrossrefMedlineGoogle Scholar
18. Sung JJ, Lau JY, Ching JY, Wu JC, Lee YT, Chiu Prisoner of war, Leung VK, Wong VW, Chan FK. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann Intern Med . 2010; 152:1–9. doi: x.7326/0003-4819-152-i-201001050-00179.CrossrefMedlineGoogle Scholar
19. Devereaux PJ, Mrkobrada M, Sessler DI, Leslie K, Alonso-Coello P, Kurz A, Villar JC, Sigamani A, Biccard BM, Meyhoff CS, Parlow JL, Guyatt Thousand, Robinson A, Garg AX, Rodseth RN, Botto F, Lurati Buse M, Xavier D, Chan MT, Tiboni M, Cook D, Kumar PA, Forget P, Malaga G, Fleischmann E, Amir Chiliad, Eikelboom J, Mizera R, Torres D, Wang CY, VanHelder T, Paniagua P, Berwanger O, Srinathan S, Graham M, Pasin L, Le Manach Y, Gao P, Pogue J, Whitlock R, Lamy A, Kearon C, Baigent C, Chow C, Pettit S, Chrolavicius Due south, Yusuf South; POISE-2 Investigators. Aspirin in patients undergoing noncardiac surgery. Due north Engl J Med . 2014; 370:1494–1503. doi: x.1056/NEJMoa1401105.CrossrefMedlineGoogle Scholar
20. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med . 2005; 353:487–497. doi: 10.1056/NEJMra050100.CrossrefMedlineGoogle Scholar
21. Ludvigsson JF, Andersson Eastward, Ekbom A, Feychting Yard, Kim JL, Reuterwall C, Heurgren M, Olausson PO. External review and validation of the Swedish national inpatient register. BMC Public Health . 2011; 11:450. doi: ten.1186/1471-2458-xi-450.CrossrefMedlineGoogle Scholar
22. Shrier I, Platt RW. Reducing bias through directed acyclic graphs. BMC Med Res Methodol . 2008; viii:70. doi: 10.1186/1471-2288-eight-lxx.CrossrefMedlineGoogle Scholar
23. McDonald JW, Ali Grand. Recovery of cyclooxygenase activeness after aspirin in populations of platelets separated on stractan density gradients. Prostaglandins Leukot Med . 1983; 12:245–252.CrossrefMedlineGoogle Scholar
24. Vial JH, McLeod LJ, Roberts MS. Rebound elevation in urinary thromboxane B2 and 6-keto-PGF1 alpha excretion afterward aspirin withdrawal. Adv Prostaglandin Thromboxane Leukot Res . 1991; 21A:157–160.MedlineGoogle Scholar
25. Doutremepuich C, Aguejouf O, Desplat V, Eizayaga FX. Paradoxical thrombotic effects of aspirin: experimental study on 1000 animals. Cardiovasc Hematol Disord Drug Targets . 2010; x:103–110.CrossrefMedlineGoogle Scholar

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