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Despite a higher incidence of dyspnea among patients with acute coronary syndromes (ACS) on ticagrelor compared with clopidogrel, the side effect is usually not serious and resolves spontaneously or after stopping the newer antiplatelet. Just as important, dyspnea does not attenuate the mortality advantage of ticagrelor, according to a subanalysis of the PLATO trial published online July 30, 2011, ahead of print in the European Heart Journal.

The subanalysis’ core findings were first presented in August 2010 at the European Society of Cardiology Congress in Stockholm, Sweden. 

In the main PLATO (Study of PLATelet Inhibition and Patient Outcomes) trial, 18,624 ACS patients were randomized to clopidogrel (300-600 loading dose plus 75 mg daily) or ticagrelor (10 mg loading dose and 90 mg twice a day) for up to 12 months. At 1 year, the primary endpoint of death from vascular causes, MI, or stroke had occurred in significantly fewer patients in the ticagrelor group compared with the clopidogrel group (9.8% vs. 11.7%; P < 0.001).

For the current study, investigators led by Robert F. Storey, MD, of the University of Sheffield (Sheffield, United Kingdom), characterized the dyspnea reported in the original trial and investigated its effect on clinical outcomes. A total of 18,421 (98.9%) patients received at least 1 dose of their assigned drug (n = 9,235 for ticagrelor; n = 9,186 for clopidogrel) and were considered for the analysis.

Patients with Baseline Dyspnea Included

At enrollment, about 20% of patients in both treatment arms had a history of dyspnea; nearly 14% continued to experience the condition, with heart failure the most common suspected cause, followed by COPD and asthma.

Over 1-year follow-up, 14.5% of ticagrelor-treated patients and 8.7% of clopidogrel-treated patients developed dyspnea. However, only 0.4% and 0.3% of cases, respectively, were judged by the investigators to be severe.

A greater proportion of dyspnea events in the ticagrelor group than in the clopidogrel group were considered to be of unexplained or unknown etiology (27.3% vs. 20.1%) and a smaller proportion were thought to be due to cardiac-related heart failure (23.7% vs. 30.8%).

Overall, patients with dyspnea were older and more likely to have diabetes or chronic renal disease. Not surprisingly, patients in both treatment groups who had dyspnea during follow-up were more likely to have experienced the condition prior to enrollment, often associated with heart failure, COPD, and/or asthma. However, the excess dyspnea in the ticagrelor group compared with the clopidogrel group was consistent whether patients did (20.2% vs. 14.7%) or did not (13.1% vs. 7.1%) have a history of the condition.

Another difference between the treatment arms is that ticagrelor patients were more likely than clopidogrel patients to develop dyspnea within 7 days of drug initiation. Moreover, 15% of cases in the ticagrelor group were categorized by the trial investigators as causally related to the study medication compared with 6.9% of cases in the clopidogrel group (P < 0.0001).

Among those who experienced dyspnea, 26.2% of ticagrelor patients and 22.3% of clopidogrel patients prematurely discontinued their medication (P = 0.043), with the excess in the ticagrelor group being specifically attributable to dyspnea (5.9% vs. 1.6%; P < 0.0001). The dyspnea-specific discontinuation rates represent 0.9% and 0.1% of the respective overall treatment groups.

About 30 days after discontinuation of the study medications, 5.0% of ticagrelor patients and 3.1% of clopidogrel patients had ongoing dyspnea (P < 0.0001).

Ticagrelor’s Efficacy Preserved

By 1 year, the primary endpoint occurred more often among patients with vs. without dyspnea in both the ticagrelor (11.9% vs. 9.4%; P < 0.001) and clopidogrel groups (15.7% vs. 11.2%; P = 0.008), in part due to a higher incidence of MI. However, after excluding patients whose dyspnea developed in the wake of an MI and possible heart failure, Kaplan-Meier analysis showed a trend toward reduced total mortality as well as numerically lower rates of the primary endpoint, MI, and cardiovascular death in the ticagrelor arm, in line with the overall trial results (table 1).

Table 1. One-Year Outcomes in Patients with Dyspnea

Moreover, a landmark analysis showed that patients who reported dyspnea within the first 30 days continued to experience substantially lower cardiovascular and total mortality rates with ticagrelor from 31 days onward.

In PLATO, Holter monitoring in a subset of patients during the first week of treatment revealed a higher incidence of ventricular pauses longer than 3 seconds in the ticagrelor compared with the clopidogrel group. In this analysis, such pauses were not more common among ticagrelor patients with vs. without dyspnea.

As a whole, the current findings “at least provide reassurance that there does not appear to be any loss of treatment effect in those ticagrelor-treated patients who develop dyspnea as a side effect,” Dr. Storey and colleagues conclude. “It is particularly encouraging that the ticagrelor-treated patients with dyspnea had similar mortality rates to those without dyspnea despite having overall higher risk characteristics including greater mean age and higher incidence of diabetes mellitus and chronic renal disease.”

The finding from the ONSET/OFFSET trial (Storey RF, et al. J Am Coll Cardiol. 2010;56:185-193) that ticagrelor-related dyspnea was not associated with increases in serum NT-pro-BNP level or changes in left ventricular systolic function was replicated in this analysis, the investigators say. “This suggests that measurement of serum NT-pro-BNP may help differentiate ticagrelor-related dyspnea from a sign of heart failure and thus avoid unnecessary prescription of loop diuretics for heart failure,” they observe.

Safe But Not Necessarily Prudent

These data support the safety of giving ticagrelor to ACS patients who have COPD or heart failure, at least in the context of a carefully monitored clinical trial, said Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), in a telephone interview with TCTMD. But, he added, “physicians will need some hands-on experience to see how this plays out in real life.”

The concern is that if patients experience dyspnea, they will discontinue the medication on their own, he noted, adding, “I wouldn’t just say to a patient, ‘It’s not a big deal,’ because if a patient feels breathless, that’s a big deal for them and they’re not necessarily going to know that this is probably just a relatively benign side effect.

“Once ticagrelor is actually available, my first use will likely not be in a patient who has baseline dyspnea,” Dr. Bhatt said. “I would want first to become familiar with [the drug] in patients who are likely to tolerate it well. That’s not because I think there’s a safety issue, but for practical reasons. In real life, if a patient is dyspneic and becomes more dyspneic, evaluating that can get tricky. It requires a thorough evaluation.”

When dyspnea is caused by ticagrelor, it appears to manifest earlier rather than later. That pattern could be useful in differentiating the etiology, Dr. Bhatt said, though he cautioned that it is “not ironclad.”

According to Dr. Bhatt, ticagrelor is a major advance in the treatment of ACS, but he stressed, “I don’t think it makes sense to push a patient with dyspnea too hard and risk him getting no antiplatelet therapy. I would switch him to clopidogrel or, if it were a stented patient with a low bleeding risk, to prasugrel.”

Despite its apparently benign nature, this side effect adds to the complexity of managing patients on antiplatelet therapy because now both doctors and patients need education not only about bleeding but also the potential for dyspnea, Dr. Bhatt said. “We have to make sure that if patients develop any new symptom like dyspnea or bleeding, they give their cardiologist a call,” he added.

Better to ‘Work Through’ Dyspnea?

In a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), noted, “Perhaps the most important message of the study is that dyspnea is not a sign of abnormal response to ticagrelor but rather just a side effect.”

But unlike Dr. Bhatt, Dr. Brener said he would not hesitate to prescribe ticagrelor to patients with COPD or heart failure. “It is a lot like beta blockers for COPD. We try it and a small percentage of people don’t tolerate it so we take them off,” he said, characterizing the 0.9% discontinuation rate of ticagrelor as “nothing.”

If a patient does develop dyspnea while on ticagrelor, it is clearly important to determine whether or not the condition is due to heart failure, Dr. Brener said. “But if the patient does not have heart failure, I wouldn’t be in a hurry to take them off the drug,” he added. “I would first try to get them to work through [the dyspnea].”

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