Abstract
Objective
This study aimed to define the association between altitude and ticagrelor-associated dyspnea in patients with acute coronary syndrome (ACS).
Methods
We studied consecutive patients with de novo ACS who were admitted to two centers at a low altitude (18 and 25 m, n = 65) and two centers at a high altitude (1313 and 1041 m, n = 136). We managed them with ticagrelor between May 2017 and September 2017. Patients with ACS underwent an interventional procedure within <90 minutes in those with ST elevation and within <3 hours in those without ST elevation. We recorded the incidence of dyspnea in patients with ACS receiving ticagrelor therapy.
Results
The mean age was 59.5 ± 10 years, and the mean ejection fraction was 43% ± 18%. A total of 110 (56.7%) patients had ST elevation and 84 (43.3%) did not. There were no significant differences in cardiac risk factors, concurrent medications, or procedural variables between the two groups. Dyspnea developed during hospitalization in 53 (38%) patients from high-altitude centers and in 13 (20%) patients from low-altitude centers (66 patients represented 32% of the total ACS cohort).
Conclusions
Dyspnea is a common multifactorial symptom in patients following development of ACS. Ticagrelor-induced dyspnea appears to be associated with altitude.
Introduction
P2Y12 receptor inhibitors are one of the most critical agents in the treatment of patients with acute coronary syndrome (ACS). Ticagrelor is a P2Y12 receptor inhibitor and it induces dyspnea. 1 Currently, the association between ACS and dyspnea has become more challenging with the increasing use of ticagrelor. 2 The PLATO study showed a 6% increases in the rate of dyspnea in ticagrelor-treated patients compared with patients treated with clopidogrel. 3 Giannoni et al. showed that drug-related sensitization of the chemoreflex may be the cause of ventilatory instability and breathlessness in patients treated with ticagrelor. 4 The sole mechanism for this side effect is relatively unknown, although preliminary data indicate that ticagrelor has an off-target effect on adenosine reuptake. 5 Additionally, intravenous adenosine infusion can cause transient dyspnea in the absence of bronchoconstriction. 6 Conte et al. suggested the use of aminophylline as a potential reversal agent of ticagrelor-induced arrhythmia and dyspnea, especially in patients with congestive heart failure. 7 In addition to dyspnea, sleep apnea can also be increased with ticagrelor therapy. 8 Lamberts et al. suggested that dyspnea occurring after ticagrelor treatment should prompt active research of Cheyne–Stokes respiration. 9
The aim of this study was to determine the relationship between dyspnea due to ticagrelor and altitude.
Methods
Patients
We studied consecutive patients with de novo ACS who were admitted to two centers at a low altitude (Mersin University, Marmara University) and two centers at a high altitude (Fırat University, Cumhuriyet University). These patients were managed with ticagrelor, as suggested by guidelines, between May 2017 and September 2017. The medical treatment of every patient was performed in accordance with the American College of Cardiology/American Heart Association guidelines10,11 and the 2018 European Society of Cardiology/European Association for Cardiothoracic Surgery Guidelines on myocardial revascularization. 12 Aspirin and statin treatments were not administered to patients with an aspirin allergy or to those who were intolerant of statins (severely impaired liver function tests and high creatine kinase concentrations). Patients with ACS underwent an interventional procedure within <90 minutes in those with ST elevation and within <3 hours in those without ST elevation. Study approval was obtained from the ethics committee of Fırat University Faculty of Medicine. All patients provided written informed consent.
The inclusion criteria were as follows: patients with ACS for the first time; those who decided to be treated with ticagrelor by their primary physicians (interventional cardiologist); and those who were citizens of either high- or low-altitude cities. Exclusion criteria were as follows: treatment with fibrinolytic agents; patients with second- or third-degree atrioventricular block; patients with a history of intracranial hemorrhage; those with a prior history of dyspnea before index admission; concomitant medication that might induce dyspnea; those with chronic obstructive pulmonary disease requiring continuous use of long-acting beta-agonists or long-acting muscarinic antagonists; those with history of asthma; those with signs and/or symptoms of active infection; those traveling between high- and low-altitude cities, irrespective of the reason; those with prior exposure to ticagrelor; those with previous revascularization; and those with a history of heart failure. Echocardiography was performed with color Doppler imaging. All patients were evaluated with contrast echo with vagal maneuvers. Patients who were transferred to using agitated saline were not included in the study.
Measurements
The complete blood count was obtained before the initiation of ticagrelor therapy in all patients as part of the routine care, and it was repeated at the first presentation of ticagrelor-induced dyspnea. Arterial blood gases in each patient were measured after percutaneous coronary intervention in ambient air. All patients underwent an echocardiographic evaluation within the first 24 hours of hospitalization by a standard protocol. The left ventricular diameter, ejection fraction (EF), valvular and septal anatomy, and pulmonary pressure were assessed. A respiratory function test was performed on the fourth day after percutaneous coronary intervention. High altitude was defined as at least 1000 m above sea level, and low altitude was defined as ≤100 m above sea level or being at the seaside (Sivas altitude: 1313 m, Elazig altitude: 1041 m, Mersin altitude: 18 m, Istanbul altitude: 25 m). Dyspnea was assessed using the Medical Research Council dyspnea scale. We scaled the symptoms from grade 1 (absence of dyspnea) to grade 4 (presence of severe dyspnea before the day of discharge).
Statistical analysis
All variables are presented as mean ± standard deviation, and skewed data are reported as the median (interquartile range). The chi-square or Fisher’s exact test was used for the comparison of categorical variables between groups, while the Mann–Whitney U test or unpaired Student t test was used for continuous variables, as appropriate. A p value <0.05 were considered statistically significant. As a result of our case–control study, propensity score analysis was performed to minimize the selection bias resulting from differences in clinical characteristics between the groups. Statistical analyses were performed using IBM SPSS for Windows (version 22.0; IBM Corp., Armonk, NY, USA).
Results
Baseline and procedural characteristics of the study sample are shown in Table 1. The mean age was 59.5 ± 10 years, and the mean ejection fraction was 43% ± 18%. There were 194 patients enrolled in our study, with 129 from high-altitude centers and 65 from low-altitude centers. Sixty-six (32.8%) patients had ticagrelor-associated dyspnea (grades 1–4) (Table 1).There was a significantly higher rate of ticagrelor-associated dyspnea in high-altitude centers compared with that in low-altitude centers (38% vs 20%, p = 0.005, Table 1).
Baseline and procedural characteristics of high versus low altitude.
Values are number, number (%), mean ± standard deviation, or median (interquartile range).
STEMI, ST-segment elevation myocardial infarction, NSTEMI, non-ST-segment elevation myocardial infarction; CRP, C-reactive protein; ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; PCO2, partial pressure of carbon dioxide; PO2, partial pressure of oxygen; SO2, oxygen saturation; FO2Hb, fraction of hemoglobin bound to oxygen; FCOHb, fraction of carboxyhemoglobin; FHHb, fraction of deoxygenated hemoglobin; FmetHb, fraction of methemoglobin; NT-proBNP, N-terminal probrain natriuretic peptide.
The EF was significantly higher in patients in high-altitude centers than that in patients in low-altitude centers (p < 0.001, Table 1). There were no significant differences in cardiac risk factors, concurrent medications, or procedural variables between patients in high-altitude centers and those in low-altitude centers. Respiratory function tests were performed in all patients. No pulmonary pathology or chronic obstructive pulmonary disease was detected. Arterial oxygen saturation levels were significantly higher in patients in low-altitude centers than in those in high-altitude centers (p < 0.001). The fraction of hemoglobin bound to oxygen was also higher in patients in low-altitude centers than in those in high-altitude centers (p < 0.001). Furthermore, the fraction of methemoglobin (FMetHb) was higher and the partial pressure of oxygen (PO2) was lower in patients in high-altitude centers than in patients in low-altitude centers (both p < 0.001). There were no correlations between dyspnea and other factors (Table 2).
Spearman’s correlation coefficients between dyspnea and the studied variables.
Discussion
In this study, there were no significant differences in cardiac risk factors, concurrent medications, or procedural variables between patients in high-altitude centers and those in low-altitude centers. Additionally, no pulmonary pathology or chronic obstructive pulmonary disease was detected. Among ticagrelor-administered patients, we found that dyspnea was more frequent in those in high-altitude centers compared with those in low-altitude centers in patients with de novo ACS. We believe that this finding might be due to the difference in FMetHb values between high- and low-altitude centers. The reason for FMetHb values being different between the groups of patients is unclear, but it may have been due to the amount of local anesthetic (e.g., procaine) used. The difference in the FmetHb might be explained by hypoxia, and it may affect ventilation and the chemoreflex. Because of the difference in the FmetHb, patients might have had depressed ventilation at baseline with reduced saturation due to hypoxia and increased end-tidal carbon dioxide pressure. This difference could also be attributable to acclimatization to a high altitude.13,14
The PO2 is only approximately 70% at sea level, and at 5000 m, this value falls to 50%. Ainslie et al. provided an overview of the physiological basis for the complexity in chemoreflex testing at altitude. 15 With increasing altitude, the oxygen saturation is initially well maintained compared with the PO2 because of the relatively flat component of the upper portion of the oxygen–hemoglobin dissociation curve. At a high altitude, the body responds to hypoxia by hyperventilation. This response has individual and genetic components. High altitude adaptation is an interesting phenomenon that regularly applies to individuals living at a high altitude for long periods, but it is not usual for those visiting a high altitude. However, an understanding of the principles of tissue oxygen delivery is useful when considering the effects and adaptations of those coming from a higher barometric pressure to a lower pressure of high elevation. The concentration of oxygen in 1 L of air at sea level is 21%. This concentration is the same at 4000 m (approximately 13,200 feet). However, because of the decreased barometric pressure at this altitude, only 63% of the number of available oxygen molecules remain compared with at sea level. Therefore, to adequately deliver oxygen to the tissues, especially those most in need of oxygen for aerobic metabolism (brain, heart, lungs, and kidneys), particular adaptations must occur. The FmetHb is increased at a high altitude, although the mechanism is not clear. This finding in combination with ticagrelor-induced chemoreflex sensitivity might account for a higher rate of dyspnea at a high altitude.
Although the EF in patients at high-altitude centers was higher than that in those at low-altitude centers, the incidence of dyspnea was significantly more frequent in patients at high-altitude centers. Additionally, the rate of dyspnea increased with decreasing PO2 values. None of the patients included in this study had a history of dyspnea, and they did not live in an area other than their residential area and did not leave their residential area during the study after ticagrelor treatment. Therefore, the development of ticagrelor-induced dyspnea was not due to a decrease in PO2 levels. Our study is the first case–control, multicenter study to assess the relation of altitude with ticagrelor-associated dyspnea in a real-world patient population. Our results might be easily extrapolated to the general population to determine the severity and pattern of ticagrelor-associated dyspnea. Because our study excluded patients with comorbidities, such as respiratory diseases, we consider that we were able to determine the incidence and severity of ticagrelor-associated dyspnea in each patient as accurately as possible.15,16
A previous study investigated the prevalence of dyspnea and several covariates, and found associations between some demographic characteristics. 17 The oldest age group had an increased prevalence of dyspnea. Additionally, the overall prevalence of dyspnea was greater in women than in men. Obesity was associated with a 2.5-fold increased risk of dyspnea. Participants with self-reported disease, such as diabetes, atrial fibrillation, angina pectoris, heart attack, asthma, and bronchitis, were associated with an increased prevalence of dyspnea. However, in multivariable analysis, diabetes was not significantly associated with dyspnea and dyspnea. There were no relationships between atrial fibrillation, the ejection fraction, body mass index, chronic kidney disease, and dyspnea. This lack of finding may have been due to the small number of patients in this previous study.
There are some limitations to the current study. First, dyspnea might be associated with differences in temperature, which were not evaluated in this analysis. Therefore, data in winter, during which temperature differences might have affected the incidence of dyspnea to a large extent, were excluded, and patients were enrolled during the spring to summer season. Second, the groups were not well matched with regard to the ejection fraction. Notably, a lower ejection fraction, which might be associated with a higher frequency of dyspnea, was more frequent in the low-altitude centers. Therefore, a potentially large effect appeared to have been diluted. Third, the lack of a control group using other antiaggregant agents is another limitation to our study.
In conclusion, our study suggests that the incidence of ticagrelor-associated dyspnea becomes more frequent with an increase in altitude. Therefore, physicians should consider this difference when attempting to treat dyspnea in patients with ACS. In future studies, different altitude levels need to be evaluated, and the precise altitude where ticagrelor-induced dyspnea develops needs to be determined.
