Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

1. Management of the Patient with Stable Ischemic Heart Disease and Preserved Left Ventricular Systolic Function Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

2. Case Overview • Patient is a 55-year old male with a history of stable ischemic heart disease. • He S/P: percutaneous coronary intervention (PCI) with a stent to the left anterior descending (LAD) coronary artery six months ago. • His past medical history is significant for hypertension. • His current medication regimen includes: • Aspirin 81 mg po daily • Simvastatin 80 mg po daily • Clopidogrel 75 mg po daily • Metoprolol 50 mg po daily • ROS: He is currently without chest pain, dyspnea at rest or with exertion, or any anginal equivalents.

3. Physical Examination • Initial exam: • BP is 138/85 mm Hg. • HR 65 bpm. • Lungs are clear to auscultation. • Heart exam reveals: • A normal S1 and S2. • No S3 or S4 gallop present. • A 1/6 early systolic ejection murmur present in the right upper sterna border. • Lab results: • Echocardiogram (2 months ago): • Obtained for auscultation of a systolic murmur revealed mild aortic sclerosis but no significant valvular pathology. • Ejection fraction of 50-55% with mild hypokinesis of the distal anterior wall. • LDL-C was 65 mg/dl, Cr 1.1 mg/dl, and potassium 4.2 mmol/L.

4. Considering that the patient’s history of stable ischemic heart disease puts him at risk for future recurrent cardiac events and after considering current evidence and guidelines, is it reasonable to consider adding an ACEI to this patient's standard medical therapy? • Yes • No

5. Pharmacologic Effects of Antagonists on the Renin-Angiotensin-Aldosterone System Angiotensinogen Kininogen Kallikrein Renin Vasodilation Angiotensin I Bradykinin Angiotensin-converting enzyme inhibitor Angiotensin-converting enzyme Kininase II Angiotensin II Inactive Decreased peripheralvascular resistance Angiotensin II-receptor blocker Angiotensin II Type I Receptors LEGEND Stimulatory signal Reaction Aldosterone secretion Vasoconstriction Inhibitory pharmacologic effect Ceconi C, et al. Cardiovasc Res 2007;73:237-46; Faxon DP, et al. Circulation 2004;109:2617-2625; Schmidt-Ott KM, et al. RegulPept 2000; 93:65-77; Song JC, White CM. Pharmacotherapy 2000;20:130-9; Song JC, White CM. ClinPharmacokinet2002;41:207-24; Coleman CI, et al. AHRQ Comparative Effectiveness Review No. 18. October 2009. Increased Na+ and H2O reabsorption Increased peripheral vascular resistance

6. Through the stimulation of angiotensin II type-1 receptors, angiotensin II may have several potentially harmful activities including: • Induction of aldosterone production, which can cause sodium retention and increased fluid retention that, in turn, leads to an increase in blood pressure. • Increased aldosterone production, which can possibly lead to promotion of pathogenic remodeling (i.e., atherosclerosis and fibrosis). • Constriction of blood vessels, which can lead to increased blood pressure. • Potential reduction in the availability of nitric oxide through the production of free radicals and the induction of endothelial dysfunction. • All the above.

7. Patient Discussion • You suggest to this patient that they discuss the possibility of adding an ACEI to his current medications. • In order to do this, you review with him a patient guide titled, Choosing Medicines for Stable Coronary Heart Disease A Guide for Patients and Caregivers, from the Effective Health Care Program website at: http://effectivehealthcare.ahrq.gov. • You explain to him that the guide is based on a review of multiple studies about specific medications for patients with stable ischemic heart disease.

8. To help the patient make an informed decision about adding an ACEI or an ARB, you: • Tell the patient about the evidence of the benefits and harms for ACEI , or of ARBs if you suspect he is intolerant to ACEI. • Discuss the evidence in light of the patient’s personal medical history, current lab results, and examination findings. • Discuss the impact that adding an additional medication would have on the patient’s lifestyle, ensuring that the patient would adhere to the regimen. • Discuss the cost of the medication and the impact the additional cost might have on the patient, ensuring that the cost of the medication might not impact adherence. • Discuss the likelihood of benefits and adverse effects, if they are known, and incorporate his personal preferences into weighing the individual benefits and risks when agreeing on a course of action. • All of the above.

9. You explain that current research shows there is good evidence that adding an ACEI to his usual care may offer him: • Reduced risk of mortality. • Reduced risk of nonfatal myocardial infarction. • Reduced risk of heart failure-related hospitalizations. • All the above.

10. In explaining the evidence of benefits, the patient asks, “If I take this, I won’t have another heart attack?” You: • Agree with him and write the prescription. • Caution him that the studies are generalized and that the evidence may not apply to his specific case. • Show him the pictograph in the consumer guide titled, Choosing Medicines for Stable Coronary Heart Disease A Guide for Patients and Caregivers, of the evidence concerning the modest likelihood of benefit so that he can see the probability of facing a fatal heart attack with or without the medicine. Review the likelihood of the other benefits using the same pictograph as a model. • Explain to him that the likelihood of benefit is minimal, and that taking an ACEI may not make that much of a difference.

11. You then discuss the possible risks of adverse effects from taking an ACEI, so that the patient can weigh the benefits and harms with you to determine an appropriate decision. You explain that research has found that he may experience: • Nothing. • Hypotension.  • Hypertension. • Need for future revascularizations.  • Syncope, cough, and hyperkalemia.

12. In reviewing the decision with the patient to add an ACEI to their standard therapy, you: • Discuss the likelihood of benefit this medication would have for this patient. • Discuss the likelihood of adverse events this medication might have for this patient. • Discuss the impact that adding an additional medication would have on the patient’s lifestyle, ensuring that the patient would adhere to the regimen. • Discuss the cost of the medication and the impact the additional cost might have on the patient, ensuring that the cost of the medication might not impact adherence. • All of the above.

13. Patient Discussion • At this point in the discussion you explain to him that this medication is being given in order to reduce the risk of future cardiac events even further than if he was only taking his usual medication. • You counsel the patient to call you immediately if he experiences any of the adverse effects such as swelling of the lips or mouth area, which could indicate the patient has developed angioedema. • You give him his own copy of the consumer guide titled, Choosing Medicines for Stable Coronary Heart Disease A Guide for Patients and Caregivers, to take home with him to review and keep these important adverse effects in mind.

14. The patient points out that the guide refers to drugs called ARBs as well as ACEIs. He mentions that if taking an ACEI is good, why are you not prescribing an ARB as well as an ACEI? • You realize he is correct and add an ARB to his prescription.  • Because ACEI have been proven to be significantly better than ARBs.  • The risks of taking a combination of ACEI/ARB outweigh the benefits for patients with stable ischemic heart disease and preserved LVSF.  • None of the above.

15. Patient Discussion • The patient asks about the source of the information that you have given him, and you explain it is a summary of a large analysis done at a university that included many studies on the benefits and harms of adding an ACEI and/or ARB to standard therapies for patients with stable ischemic heart disease and preserved LVSF. • This information was summarized in a way that would allow patients to make decisions with their doctors regarding their course of treatment. • You counsel him to take this guide (Choosing Medicines for Stable Coronary Heart Disease A Guide for Patients and Caregivers) home to share with his family, refer to it from time to time to remind him why he's taking the drugs, and refer to it for descriptions of the adverse effects. • After this discussion, you and your patient determine that the decreased risk of nonfatal heart attack, stroke, and death are worth the risk of possibly getting a cough, high levels of potassium, or suddenly fainting

16. Considering the patient’s values and his decision that the benefits outweigh the risk of harms in his situation, what do you decide to start him on? • ACE Inhibitor. • Alpha-blocker. • Telmisartan. • ACE Inhibitor + ARB.

17. Adverse Events from ACEIs • This patient is sent home with his medications and the consumer summary guide (Choosing Medicines for Stable Coronary Heart Disease A Guide for Patients and Caregivers), which he can continue to refer to in the event of questions. • In six weeks, he returns to your office with a dry persistent cough that keeps him up at night. • He has been referring to the consumer summary guide and wonders if there are any other drugs he can take to help him.

18. After reviewing the evidence presented in the Clinician's Guide titled, Adding ACEIs and/or ARBs to Standard Therapy for Stable Ischemic Heart Disease: Benefits and Harms, which medication is an acceptable alternative for a patient with stable ischemic heart disease with preserved left ventricular systolic function who is intolerant to an ACEI? • Beta-blockers.  • ARB.  • Aspirin. • Alpha-blocker.

19. Upon further review of the consumer guide with the patient, you discuss with him the potential benefits of taking an ARB which are: • Decreased risk of one or more of the following: cardiovascular mortality, nonfatal myocardial infarction, or stroke.  • Decreased rate of angina-related hospitalizations. • Decreased risk of blood dyscrasias. • Decreased risk of new atrial fibrillation.

20. He asks you about the adverse effects of taking an ARB. After reviewing the clinician guide, you inform him that there is only low level evidence available about patients such as himself who are taking an ARB due to intolerable adverse effects from ACEIs. Taking an ARB may increase his risk of what? • Hyperkalemia.   • Cough. • Cardiovascular-related mortality. • Revascularization.

21. Closing Remarks • After discussing the potential benefits and the small risk of adverse effects, and considering his experience with the ACEI, you decide to start him on the ARB and schedule him a followup visit. • After reviewing the consumer summary guide again with him, you remind him of the benefits and potential harms of taking an ARB. • Once he is comfortable with this decision, you remind him to refer to the guide he has when he has questions regarding his treatment. • In his next regularly scheduled visit, you will review his medications and ask him about any symptoms and any further questions he may have.