What is the most likely cause of new intermittent dyspnea in a adult patient with non-ST elevation myocardial infarction (NSTEMI) started on aspirin and ticagrelor (antiplatelet agent), with normal chest X-ray (CXR), normal oxygen saturation, and no wheeze or crackles?

Ticagrelor-Induced Dyspnea

The new intermittent dyspnea in this patient is most consistent with ticagrelor-induced dyspnea, a well-recognized adverse effect that occurs in 10-15% of patients, typically within the first week of treatment, and is characterized by normal oxygen saturation, normal chest X-ray, and absence of pulmonary findings. 1

Clinical Presentation and Mechanism

Ticagrelor causes dyspnea through inhibition of adenosine reuptake by erythrocytes, leading to increased circulating adenosine levels. 2 This adverse effect presents with the following characteristic features:

• Onset within the first week of treatment (most commonly within 24 hours to 1 week) 3
• Normal oxygen saturation and normal chest X-ray 3
• No wheezing or crackles on examination 3
• Intermittent nature with episodes that are typically mild 1
• No associated cardiac or pulmonary dysfunction on objective testing 3

Incidence and Severity

The incidence of ticagrelor-induced dyspnea is substantially higher than with comparator agents:

• 13.8-38.6% of patients on ticagrelor experience dyspnea 1, 3
• Only 7.8-9.3% on clopidogrel report dyspnea 1, 3
• Most cases are mild and self-limited, lasting less than 24 hours 3
• Only 3-7.4% of patients discontinue ticagrelor due to dyspnea 1

Diagnostic Approach

In this clinical scenario, the key diagnostic features that point to ticagrelor-induced dyspnea include:

• Temporal relationship: Onset 2 days after starting ticagrelor 3
• Normal objective findings: Normal CXR, normal oxygen saturation, no adventitial sounds 3
• Exclusion of cardiac causes: No evidence of heart failure (no crackles), normal N-terminal pro-BNP if measured 3
• Exclusion of pulmonary causes: No bronchospasm (no wheeze), normal pulmonary function if tested 3

Management Algorithm

For mild to moderate dyspnea (as in this case), continue ticagrelor therapy as the cardiovascular benefits outweigh the discomfort. 1, 2 The specific approach is:

Continue Ticagrelor If:

• Dyspnea is mild to moderate in severity 2
• Patient can tolerate symptoms with reassurance 2
• No objective evidence of cardiopulmonary dysfunction 3

Switch to Alternative P2Y12 Inhibitor If:

• Dyspnea is severe or persistent 2
• Patient cannot tolerate symptoms despite reassurance 1
• Dyspnea leads to medication non-adherence 4

Switching Strategy:

• To clopidogrel: 600 mg loading dose, then 75 mg daily (note: less potent antiplatelet effect, potentially higher cardiovascular risk) 2
• To prasugrel: Only if patient underwent PCI; contraindicated if history of stroke/TIA 1, 2

Critical Pitfalls to Avoid

Do not prematurely discontinue ticagrelor for mild dyspnea, as this increases cardiovascular event risk and negates the mortality benefit demonstrated in clinical trials. 2, 4 The PLATO trial showed ticagrelor reduced all-cause mortality by 22% compared to clopidogrel (4.5% vs 5.9%, HR 0.78), and premature discontinuation eliminates this benefit. 1

Do not attribute all dyspnea to ticagrelor without excluding other causes, particularly acute heart failure, pulmonary embolism, or progression of coronary ischemia, though the normal examination and imaging in this case make ticagrelor the most likely etiology. 2

Do not use higher aspirin maintenance doses (>100 mg daily) with ticagrelor, as this reduces ticagrelor's effectiveness. 1 The FDA specifically warns that aspirin doses above 100 mg daily decrease ticagrelor efficacy. 1

Additional Ticagrelor Adverse Effects to Monitor

Beyond dyspnea, be aware of other ticagrelor-specific adverse effects:

• Ventricular pauses ≥3 seconds (5.8% vs 3.6% with clopidogrel), though rarely requiring pacemaker 1
• Modest increases in serum creatinine and uric acid 1, 5
• Non-CABG major bleeding (4.5% vs 3.8% with clopidogrel) 1