Author + information
- Received August 18, 2017
- Revision received September 14, 2017
- Accepted September 19, 2017
- Published online January 30, 2018.
- Christian Madelaire, MDa,∗ (, )
- Gunnar Gislason, MD, PhDa,b,c,
- Søren L. Kristensen, MD, PhDd,
- Emil L. Fosbøl, MD, PhDe,
- Jenny Bjerre, MDa,
- Maria D’Souza, MDa,
- Finn Gustafsson, MD, PhD, DMSce,
- Lars Kober, MD, DMSce,
- Christian Torp-Pedersen, MD, DMScf,g and
- Morten Schou, MD, PhDa
- aDepartment of Cardiology, Cardiovascular Research Center, Gentofte and Herlev University Hospital, Hellerup, Denmark
- bNational Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark
- cCardiovascular Epidemiology and Outcomes Research, The Danish Heart Foundation, Copenhagen, Denmark
- dDepartment of Cardiology, Bispebjerg Hospital, Copenhagen, Denmark
- eDepartment of Cardiology, Rigshospitalet, Copenhagen, Denmark
- fDepartment of Health, Science, and Technology, Aalborg University, Aalborg, Denmark
- gDepartment of Cardiology and Epidemiology/Biostatistics, Aalborg University Hospital, Aalborg, Denmark
- ↵∗Address for correspondence:
Dr. Christian Madelaire, Department of Cardiology, Copenhagen University Hospital, Herlev and Gentofte Cardiovascular Research Unit 1–Post 635, Kildegårdsvej 28, DK-2900 Hellerup, Denmark.
Objectives This study sought to assess safety and effectiveness of low-dose aspirin in heart failure (HF) not complicated by atrial fibrillation.
Background Despite lack of evidence, low-dose aspirin is widely used in patients with HF and sinus rhythm with and without prior ischemic heart disease.
Methods The study included 12,277 patients with new-onset HF during 2007 to 2012 who had no history of atrial fibrillation. Of 5,450 patients using low-dose aspirin at baseline, 3,840 were propensity matched to non-aspirin users in a 1:1 ratio. Propensity-matched Cox models were calculated with respect to the primary composite outcome of all-cause mortality, myocardial infarction, and stroke and the secondary outcomes of bleeding and HF readmission.
Results The composite outcome occurred in 1,554 (40.5%) patients in the aspirin group and 1,604 (41.8%) patients in the non-aspirin group. Aspirin use was not associated with an altered risk of composite outcome (hazard ratio [HR]: 0.98; 95% confidence interval [CI]: 0.91 to 1.05), but it was associated with an increased risk of myocardial infarction (HR: 1.34; 95% CI: 1.08 to 1.67), whereas no differences were observed in all-cause mortality and stroke. An increased risk of HF readmission was observed in the aspirin group (HR: 1.25; 95% CI: 1.17 to 1.33). No difference in bleeding was observed. In subgroup analyses on the basis of a history of ischemic heart disease, the results were similar to the main result.
Conclusions No association was detected between low-dose aspirin use and the composite outcome of all-cause mortality, admission for myocardial infarction, and admission for stroke in patients with HF with no history of atrial fibrillation. Aspirin use was associated with an increased risk of readmission for HF.
Heart failure (HF) is considered to be a prothrombotic condition (1,2), and antithrombotic therapy, in particular with aspirin, is frequently used in ischemic HF and may also be used in nonischemic HF. The effect of aspirin taken for a short duration after an MI is well proven (3), whereas the effect of long-term use in ischemic heart disease (IHD) is undocumented (4). Similarly, the frequent use of aspirin in patients with HF is not backed by trial evidence and is thus controversial (5).
In clinical randomized trials, aspirin was tested against placebo, warfarin, and clopidogrel in 4,368 patients with HF with sinus rhythm (6–9). Only 1 study included a no-antithrombotic therapy arm (6). The study was underpowered and found no significant differences among aspirin, warfarin, and no antithrombotic therapy, although there was a trend toward an increased risk of the composite of all-cause mortality and cardiovascular hospitalization in the aspirin arm. In the 2 other studies, no significant differences in all-cause and cardiovascular events were found among aspirin, warfarin, and clopidogrel. The safety and efficacy of long-term use of low-dose aspirin in patients with HF are therefore unknown. In contrast to these clinical trials, in a more recent, relatively small (n = 1,476) retrospective cohort study of unselected patients with HF, low-dose aspirin (75 mg/day) was associated with a significantly reduced mortality risk (10). A larger number of patients is needed before any conclusions can be drawn with respect to major adverse events such as bleeding (11) and HF admissions for fluid retention induced by changes in renal function (12). An ongoing trial is comparing rivaroxaban to placebo in patients with HF and sinus rhythm and reduced ejection fraction (13). Ideally, the results will contribute to an understanding of whether antithrombotic therapy has a place in the treatment of HF.
With all study results taken together, the role of aspirin in patients with HF remains unclear in terms of both benefit and safety. The aim of the present study was to evaluate the association between the long-term use of aspirin (75 mg/day) and the risk of the composite endpoint of death, myocardial infarction (MI), and stroke, as well as the risk of hospital admission for bleeding or admission for HF in a large, real-life unselected population of patients with HF with no history of atrial fibrillation (AF).
This was a retrospective, registry-based cohort study using nationwide Danish registries. In Denmark, all citizens are provided with a personal registration number at birth or immigration, and this number allows us to follow a person among different registries. In the present study data were obtained from the National Patient Registry (14), the Danish Registry of Medicinal Product Statistics (the National Prescription Registry) (15), and the Danish Civil Registry (16).
Although low-dose aspirin can be bought in Denmark without a prescription, the proportion sold by prescription in the general population has increased over the years. Since 2007, the percentage has been 90% or more (17).
The study cohort consisted of all Danish residents >18 years of age who were admitted to a hospital in the period 2007 to 2012 with a first diagnosis of HF (International Classification of Diseases-10th Revision [ICD-10] codes I50, I42, I110, J819) and no history of AF, who were still alive at the study’s start, 90 days after discharge. We identified all discharged patients who claimed a prescription for low-dose (75/150 mg/day) aspirin (Anatomical Therapeutic Chemical [ATC] code B01AC06) before the study’s start, whether or not these patients had a history of previous aspirin use. Starting the study 90 days (3 months) after discharge was considered optimal because aspirin was typically prescribed in packages of 100 pills. By doing this, it avoided the possibility that some members of the study population, taking aspirin, could carry a prescription from before the initial admission over into the study period and accidentally appear as non-aspirin users. Severity of HF was estimated on the basis of daily dosage of loop diuretic, as described previously (18). Comorbidities of interest were IHD, cerebrovascular disease, chronic renal failure, chronic obstructive pulmonary disease, and gastric ulcer, which were identified from ICD diagnoses, and diabetes, which was identified from ATC codes for antidiabetic medications. Comorbidities were considered to be present if a patient had at least 1 hospital or outpatient contact (or drug prescription for diabetes) in the past 5 years before the index hospitalization. Baseline medical therapy was defined as collected prescriptions in the past 6 months before the index hospitalization. All ICD-10 and ATC codes used are listed in the Online Tables 1 and 2.
History of AF was defined as an AF diagnosis (ICD-10 code I48) or other cardiac dysrhythmia (ICD-10 codes I46, I49). Thus, patients with diagnosed AF and/or other cardiac dysrhythmias and patients who had a permanent pacemaker implanted before or during the initial hospital admission were excluded; patients treated with amiodarone, class 1c antiarrhythmic drugs, and sotalol were also excluded. Further, we excluded all patients receiving warfarin because they could be misclassified as non-AF patients if they received warfarin as thrombus prophylaxis for AF but without an AF diagnosis. Patients with prosthetic heart valves and patients using other anticoagulant agents or antithrombotic treatment were excluded.
Follow-up and study outcomes
The primary outcome was the composite of all-cause mortality, admission for MI, or admission for stroke, whichever came first. Secondary outcomes were the individual components of the primary composite outcome, hospital admissions for bleeding events, and hospital readmission for HF. The study population was followed until death, emigration, or the end of study, whichever came first.
Differences in baseline characteristics were tested with chi-square and Kruskal-Wallis tests for categorical and continuous variables, respectively. Cox proportional hazard models were used to model time to event for each outcome. Interaction analyses were conducted considering age, sex, year of inclusion, HF severity, comorbidities, and concomitant medical treatment at baseline.
The models fulfilled the proportional hazard assumption and linearity of continuous variables. All p values reported were 2-sided, and p < 0.05 was considered statistically significant. The p values on cumulative incidences with competing risk calculations were calculated using the Fine and Gray method. Statistical calculations were performed with SAS software version 9.4 (SAS Institute, Inc., Cary, North Carolina) and RStudio version 00.99.903 (R Foundation, Vienna, Austria).
We carried out a propensity-matched analysis, using the Greedy Match Macro (Mayo Clinic, Rochester, Minnesota) to match the patients in the aspirin group with non-users on the basis of propensity score. We calculated the propensity of receiving aspirin before 90 days after discharge from hospital (study start), considering sex, age, calendar year, HF severity, comorbidities, and concomitant medical treatment as listed in Table 1, but not previous use of aspirin. The propensity score was calculated using logistic regression, and matching was carried out in subgroups on the basis of IHD and age groups, with a maximum distance equivalent to one-fourth standard deviation. After merging subgroups, 3,840 patients using aspirin were matched to 1 control each. The distribution of propensity score was equal in the aspirin and non-aspirin groups (Kruskal-Wallis, p = 0.87). The patients in the propensity-matched population were older than the overall study population, and IHD- and HF-related medications were slightly more frequent. The matched aspirin and non-aspirin groups appeared to be similar in terms of sex, comorbidities, and concomitant medical therapy after propensity matching, thereby supporting the matching being successful.
From 2007 through 2012, 59,838 patients (≥18 years of age) had a diagnosis of HF during a hospital admission. During the initial hospital stay, 5,701 patients died. After excluding 34,902 patients because of a history of arrhythmia and/or anticoagulant therapy, 7,277 patients had an event before inclusion, 90 days subsequent to discharge. Among those events were 2,929 primary composite outcomes, including 2,616 deaths, 4,627 HF readmissions, and 126 bleeding events. A total of 12,277 patients met the inclusion criteria, and 5,450 of those patients were treated with aspirin at baseline, as shown in Figure 1.
Previous use of aspirin was common and was much more frequent in the aspirin group (72%) than in the non-aspirin group (21%). The propensity-matched analyses comprised 7,680 patients, as described earlier. The patients were followed for a median of 1.7 years. Baseline characteristics are presented in Table 1.
Study outcomes, unmatched population
A total of 4,817 patients (39.2%) met the composite outcome of all-cause mortality, MI, or stroke during follow-up. Of these patients, 2,160 were using aspirin, thereby yielding an unadjusted hazard ratio (HR) of 1.03 with a 95% confidence interval (CI) of 0.97 to 1.09.
The components all-cause mortality and stroke appeared neutral, whereas aspirin use was associated with an increased risk of MI (HR: 1.82; 95% CI: 1.52 to 2.19). A total of 3,582 patients had at least 1 HF readmission (HR for aspirin use vs. nonuse: 1.25; 95% CI: 1.17 to 1.33), and 750 patients had a bleeding event (HR for aspirin use vs. nonuse: 1.18; 95% CI: 1.02 to 1.36). Primary and secondary outcomes are listed in detail in Table 2.
Study outcomes, propensity-matched analyses
In the propensity-matched population, 3,158 patients (41.1%) met the composite outcome of all-cause mortality, MI, or stroke (HR: 0.98; 95% CI: 0.91 to 1.05). We observed no significant differences for the individual components all-cause mortality and stroke. However, we observed an association between aspirin use and increased risk of MI (HR: 1.34; 95% CI: 1.08 to 1.67). Of the 321 MI events, only 44 (13.7%) were described as ST-segment elevation MI, whereas 170 (53.0%) were described as non-ST-segment elevation. However, 107 (33.3%) were unspecified. The primary outcomes are shown in Table 2 and Figure 2.
We observed a significantly increased risk of HF readmission in the aspirin-treated group (HR: 1.10; 95% CI: 1.01 to 1.19). When considering death as a competing risk, the 5-year cumulative incidence of HF readmissions was 41.3% in the aspirin group and 35.1% in the non-aspirin group (p = 0.024). No association between aspirin and an altered risk of bleeding was observed. The results of the propensity-matched analyses are shown in Table 2 and Figure 3.
Subgroup analyses, propensity-matched analyses
Subgroup analyses were conducted for the primary composite outcome considering age, sex, IHD, and diabetes. The results were similar to the main results in all subgroups. In patients with history of IHD, the risk of the composite outcome was an HR of 0.91 with a 95% CI of 0.79 to 1.04, using nonusers as reference. The tendency in this subgroup was toward a lower risk (or greater benefit) associated with aspirin use, although it was not significant. The results of the subgroup analyses are illustrated in Figure 4.
Analyses assessing interactions with the propensity-matched results were carried out for the primary composite outcome with respect to age, sex, calendar year, diabetes, IHD, and HF severity, estimated by loop diuretic dosages, and all drugs listed in Table 1. We observed a significant interaction between previous aspirin use and the primary outcome (p = 0.04), with a significantly reduced risk in the aspirin group compared with the control subjects among the patients who were aspirin naïve at baseline. However, the age distributions in the 2 aspirin-naïve groups were uneven. To address this issue, we conducted a matched sensitivity analysis (see later). We further observed a significant interaction with HF severity (p = 0.03) because patients who received ≤40 mg/day loop diuretics had a reduced risk of the primary outcome if they were in the aspirin group (HR: 0.78; 95% CI: 0.64 to 0.94), driven by a significantly reduced risk of stroke (HR: 0.56; 95% CI: 0.35 to 0.89). We observed a significant interaction with beta-blockers (BB) and statins, meaning that patients using these drugs had a reduced risk of reaching the primary composite outcome if they were in the aspirin group. This was driven by reduced risk of all-cause mortality and stroke, whereas the risk of MI remained significantly higher among the aspirin users. Drug-drug interactions with the primary outcome are illustrated in Figure 5A, whereas interactions with the secondary outcome HF readmissions are illustrated in Figure 5B.
Because a significant interaction with previous aspirin use was observed, we conducted a propensity-matched sensitivity analysis only including naïve users of aspirin. This analysis comprised 1,373 patients who started using aspirin at baseline and 1,373 matched control subjects, with an even age distribution in the 2 groups. HR for the primary composite outcome was 1.08 with a 95% CI of 0.96 to 1.22, and in general the results for the primary and secondary outcomes were neutral and similar to those of the primary study population.
We conducted a per protocol–type analysis in which patients from the aspirin group were excluded if they stopped therapy and patients from the control group were excluded if they started using aspirin. The results were similar to the overall results, so even though a relatively large proportion of the patients in the non-aspirin group crossed over, it had no effect on the main results.
Finally, a propensity-matched analysis with inclusion 7 days after primary hospital discharge was conducted. It comprised 3,163 cases and 3,163 non-aspirin control subjects. No difference in the risk of reaching the primary composite outcome was observed (HR: 0.92; 95% CI: 0.85 to 1.01). The same applied for the risk of all-cause mortality and MI. However, the risk of admission for stroke was reduced in the aspirin group (HR: 0.75; 95% CI: 0.57 to 0.98). As in the main analyses, the risk of having an HF readmission was slightly increased in the aspirin group (HR: 1.13; 95% CI: 1.01 to 1.25), whereas no difference in the risk of bleeding was observed. Among the control subjects, 890 (28%) were included as aspirin users in the main analysis. Of those aspirin users, 86% used aspirin before the primary hospital admission.
Our results differ from those presented by Bermingham et al. (10), who reported that low-dose aspirin was associated with a significantly reduced risk of death and HF readmission. The study included AF, which was shown to be overrepresented in the non-aspirin group. Naturally, the frequency of warfarin use was also considerably higher in this group—in fact, higher than the frequency of AF. The propensity model considered age, sex, IHD, AF, diabetes, hypertension, and dyslipidemia, whereas factors such as concomitant medical therapy and severity of HF were left out. This may have influenced the results, and other factors such as younger age, fewer patients, and number of events may explain the difference between their results and ours.
The results of the present study are in accord with the results of WASH (Warfarin/Aspirin Study in Heart failure) (6), in which aspirin was tested against warfarin and no antithrombotic treatment. The trial was underpowered, and the primary purpose was to examine whether it would be feasible to conduct a larger trial. The trends, however, were that there were no significant differences among the 3 groups with respect to the primary composite outcome of all-cause mortality, nonfatal MI, and nonfatal stroke. In a larger trial, WATCH (Warfarin and Antiplatelet Therapy in Chronic Heart Failure) (7), aspirin was compared with warfarin without a no-antithrombotic therapy arm. The study was terminated prematurely because of slow enrollment. However, the investigators concluded that no significant differences between aspirin and warfarin treatment were found in terms of safety or effectiveness. The same results were found in WARCEF (Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction) (8), which is the largest trial conducted to address the issue until now, including only patients with sinus rhythm. None of the trials included a placebo arm, although there was a no-antithrombotic therapy arm in WASH. All these trials comprised patients 60 to 65 years of age, mostly male, and with a reduced ejection fraction, features that stand in contrast to our real-life cohort of older patients with HF with a high proportion of female patients. The event rates in the present study were higher than in the studies mentioned earlier (e.g., 16.78 deaths per 100 patient-years in the present study compared with 6.57 deaths per 100 patient-years in WARCEF, most likely because of the age differences). In light of the low probability that an adequately powered trial evaluating long-term use of aspirin in HF will ever be conducted, our analyses add knowledge and cast further doubt on whether aspirin is useful in HF, even in the presence of IHD.
We observed a significant interaction with BB. In the subgroup of patients using BB, aspirin was associated with a slightly reduced risk of meeting the primary composite outcome, driven by all-cause mortality and stroke. Considering international guidelines, BB users from our cohort could have been more likely to have reduced ejection fraction than patients who were not receiving BB therapy, and this finding may indicate that there could be a slight positive effect in this subgroup of patients with HF. However, because we did not have access to information about left ventricular ejection fraction, further investigation was not possible in this study.
In the unmatched population of the present study, the patients using aspirin were slightly older than the non-aspirin control subjects. The frequency of IHD was higher and the frequency of HF-associated medication use, including loop diuretics, was higher. The mean dosage of loop diuretics did not differ. Because low-dose aspirin is indicated in patients with IHD, we were surprised that only 65% of the patients with known IHD were using aspirin at baseline.
There was, as expected, an overweight of previous aspirin use in the aspirin group. Previous use of aspirin was not included in the propensity score calculation, although this probably could have contributed to reduce the risk of confounding by indication (i.e., patients given aspirin were more likely to have ischemia even though they did not have a diagnosis of ischemia). Conversely, patients with a history of ischemia but who were not given aspirin could represent a population that does not tolerate aspirin very well. However, it seems likely that it would have introduced further selection bias and a smaller population. Furthermore, because there is no solid evidence to support or reject aspirin use in HF, we would expect that if aspirin is prescribed once, it is likely that the treatment will be continued if the patient is admitted to hospital, without further consideration about indication. All considered, we believe that we chose the lesser of 2 evils.
We observed a significantly increased risk of HF readmission in the aspirin group. This could be partly explained by impaired renal function caused by aspirin (12), which subsequently could contribute to salt and water retention and worsened HF. It has previously been suggested that aspirin could reduce the effect of angiotensin-converting enzyme inhibitors when these drugs are used simultaneously (5,19). In the present study, we did not observe a significant interaction with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, but we observed a trend to no risk difference between the aspirin and non-aspirin groups among patients not using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (Figure 5B). The increased risk is in accord with the trends found in the WASH trial (6). Although our results could be affected by residual confounding, it seems biologically plausible that aspirin could increase the risk of HF readmission. If so, on the basis of the event rates for HF readmission (1,181 [30.8%] in the aspirin group and 1,103 [28.7%] in the non-aspirin group), the number needed to harm was 1/(0.308 − 0.287) = 48.
We observed a significantly increased risk of admission for MI in the aspirin group, although relatively few events occurred. A biologically plausible explanation could be that aspirin may contribute to hemorrhage in existing plaques and thus contribute to progression and instability of the plaque, which increases the risk of MI. However, at this extent, it is difficult to reject that some level of confounding by indication and misclassification could contribute to the observation (i.e., patients prescribed aspirin for some reason have a higher frequency of undiagnosed or unregistered IHD). Moreover, it is not unlikely that some patients with a history of IHD or known aspirin use are more likely to have a diagnosis of MI when they are admitted to the hospital with dyspnea and increased troponin than are patients with no history of IHD and/or no known aspirin use. In the IHD subgroup, comprising 2,094 patients, there was still a tendency toward an increased risk of MI, although it was not significant (Figure 4).
We observed more bleeding events in the aspirin group compared with the control group (n = 252 [6.6%] vs. n = 224 [5.8%]), but the difference was not significant. However, for the safety outcome of bleeding, we considered only hospital admissions, and therefore, minor bleeding events treated at home, in general practice, or in the emergency department were not encountered. Thus, the actual event rate was most likely higher.
Because we ended up including only 12,277 patients of the 59,838 diagnosed with HF, it may be argued that the study population was selected and that the study has limited generalizability. However, the focus of the study was on patients with sinus rhythm and no concomitant anticoagulant or antithrombotic therapy, and that focus cost the study 34,902 patients. As described earlier, to keep misclassification at a minimum, we had to postpone inclusion to 3 months after the index hospitalization. Unfortunately, this cost an additional 8,338 patients because they met an outcome within this period. It is likely that these patients were among the frailest, and thus we may have introduced some survival or selection bias. However, this was thought to be equal in both groups, which a sensitivity analysis further supported.
Strengths of this study are the sample size and the completeness of data, with a nationwide unselected cohort of patients with HF. In Denmark, all residents, regardless of socioeconomic status, health insurance, and geography, are covered by a public health care system, ensuring complete registration of outpatient contacts and hospital admissions. The registries used in the present study have previously been validated as tools for epidemiological research (14–16). Identifying patients with HF in the National Patient Registry has been shown to have a very high specificity of 99%, although sensitivity was lower (20). Because part of the drug expenses in Denmark are reimbursed by the government-financed health care system, all Danish pharmacies are required to register each dispensed prescription in the National Prescription Registry, which ensures complete and precise registration. The diagnoses of interest, MI and stroke, have previously been found to have high positive predictive values in the National Patient Registry (21,22).
A noticeable limitation of the study is the sparse clinical data provided by the registries. This limitation introduces potential misclassification and unmeasured and residual confounding. It was not possible to assess information about ejection fraction or New York Heart Association functional classification. This was partially compensated for by collecting the dosages of loop diuretics and thereby determining relative HF severity (18). Fifty percent of the patients were female, and we may therefore have a relatively high percentage of patients with HF with preserved ejection fraction. In a Danish registry including patients with HF with both sinus rhythm and AF (23), 40.4% of the patients had preserved ejection fraction, and this is also likely to be the case in the present study. Lacking electrocardiography data, sinus rhythm was defined as the absence of admissions or outpatient contact for AF or other arrhythmic diseases, as well as the absence of relevant treatment (warfarin). The AF diagnosis has previously been validated with a high positive predictive value in the Danish registries (24). Finally, it may be argued that the increased risk of an HF admission is the result of confounding by indication, a concept supported by our observation of an increased risk of MI in the aspirin-treated group. However, the 2 groups of patients had the same mortality risk and the same degree of severity of HF evaluated by doses of loop diuretics, and the observed association between low-dose aspirin and the risk of an HF admission is biologically plausible.
In the present study, an association between low-dose aspirin and a reduced risk of the composite endpoint of death, MI, and stroke was not found, nor was an increased risk of bleeding observed. However, in these older adult patients with HF, a slightly increased risk of HF readmission was detected. The findings cast further doubt on the benefit associated with the use of aspirin in patients with HF. A prospective, randomized clinical trial could be relevant.
COMPETENCY IN MEDICAL KNOWLEDGE: Use of daily low-dose aspirin in patients with HF and no history of AF and no other antiplatelet or anticoagulant therapy was not associated with reduced risk of death, MI, or stroke.
TRANSLATIONAL OUTLOOK: Because low-dose aspirin is widely used in patients with HF regardless of known AF or IHD and without solid evidence supporting this use, a randomized, blinded clinical trial is needed.
Dr. Torp-Pedersen has received grants and speaker honoraria from Bayer. Dr. D’Souza has received grants from the Danish Heart Foundation and the VELUX Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- atrial fibrillation
- Anatomical Therapeutic Chemical
- confidence interval
- heart failure
- hazard ratio
- International Classification of Diseases
- International Classification of Diseases-10th Revision
- ischemic heart disease
- myocardial infarction
- Received August 18, 2017.
- Revision received September 14, 2017.
- Accepted September 19, 2017.
- 2018 American College of Cardiology Foundation
- Palka I.,
- Nessler J.,
- Nessler B.,
- Piwowarska W.,
- Tracz W.,
- Undas A.
- Gurbel P.A.,
- Tantry U.S.
- Massie B.M.,
- Collins J.F.,
- Ammon S.E.,
- et al.,
- WATCH trial investigators
- Bermingham M.,
- Shanahan M.K.,
- O’Connell E.,
- et al.
- Derry S.,
- Loke Y.K.
- Zannad F.,
- Greenberg B.,
- Cleland J.G.,
- et al.
- Schmidt M.,
- Schmidt S.A.,
- Sandegaard J.L.,
- Ehrenstein V.,
- Pedersen L.,
- Sørensen H.T.
- Schmidt M.,
- Hallas J.,
- Friis S.