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Most likely diagnosis: Anemia secondary to gastrointestinal bleeding; other considerations should include new-onset angina, congestive heart failure, and atrial fibrillation.

Next diagnostic step: A complete blood count (CBC) to evaluate for the anemia. To evaluate for the other conditions on your differential diagnosis list, you should perform an electrocardiogram (ECG) and cardiac enzymes. A prothrombin time (PT) and partial thromboplastin time (PTT) to look for coagulation abnormalities would be helpful as well.

Next step in therapy: Further workup, including blood transfusion (if needed), completion of two more sets of cardiac enzymes, and ECGs. A gastroenterology consult for esophagogastroduodenoscopy (EGD) and colonoscopy is appropriate because of the positive guaiac findings.

Assuming that the initial workup for cardiac and pulmonary causes is negative and that the hemoglobin and hematocrit levels are low, a thorough evaluation for the cause of the anemia is necessary. A CBC with peripheral smear, reticulocyte count, iron studies, vitamin B12, and folic acid levels would provide clues to the type of anemia that this patient has. A gastroenterology consult for possible EGD and colonoscopy to further investigate the source of gastrointestinal bleeding should be considered. The presence of epigastric and LUQ pain, along with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs), should also raise a flag for testing to rule out a bleeding ulcer.

The presence of other findings may direct your workup toward other diagnoses. If this patient was from a developing country, the possibility of intestinal parasites would need to be considered. If the PT and PTT were abnormal, gastrointestinal (GI) bleeding from a coagulopathy or liver disease would be possibilities. Weight loss, lymphadenopathy, and coagulopathy may warrant evaluation for nongastrointestinal malignancies, such as leukemias or lymphomas. In younger patients, sickle cell disease, thalassemias, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and other inherited causes of anemia would be on the differential diagnosis list. These are unlikely to manifest as an initial diagnosis at the age of 65.