First Last, Credentials

1. Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II Receptor Antagonists (ARBs), and Direct Renin Inhibitors for Treating Essential Hypertension: An Update First Last, Credentials

2. Accreditation Statement Physician Accreditation Statement PRIME Education, Inc. (PRIME®) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Professional Resources in Management Education, Inc. (PRIME®) designates this live activity for a maximum of.50AMA PRA Category 1 Credit™.Physicians should only claim credit commensurate with the extent of their participation in the activity. Physician Assistant Accreditation Statement AAPA accepts AMA Category 1 CME Credit™ for the PRA from organizations accredited by ACCME. Nurse Practitioner Accreditation Statement PRIME Education, Inc. (PRIME®) is accredited by the American Academy of Nurse Practitioners as an approved provider of nurse practitioner continuing education. Provider number: 060815. This program is accredited for .50 contact hour. Program ID# CER28. This program was planned in accordance with AANP CE Standards and Policies and AANP Commercial Support Standards. Nurse Accreditation Statement PRIME Education, Inc. (PRIME®) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. PRIME® designates this activity for .50 contact hour. California Nurse Accreditation Statement PRIME® designates this educational activity for .50 contact hour for California nurses. PRIME® is accredited as an approver of continuing education in nursing by the California Board of Registered Nursing.

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5. Learning Objectives • Compare the effectiveness of ACE inhibitors, ARBs, and direct renin inhibitors for controlling blood pressure and reducing risks of cardiovascular mortality and morbidity • Assess key differences in side-effect profiles, tolerability, and persistence outcomes associated with ACE inhibitors, ARBs, and direct renin inhibitors • Apply findings from the systematic review to guide decisions about appropriate patient-centered therapies for managing hypertension

6. Challenge of Managing Hypertension • Affects ~ 65 million American adults • 3rd decade ~30% • 5th decade ~50% • 7th decade ~70% • 8th decade ~ 80% • Leading risk factor for death worldwide • Adverse effects on many organs • Decreasing systolic BP by 10mm Hg reduces risk: • Of stroke by ~ 35% • Of ischemic heart disease events by ~ 25% • Among adults with hypertension • 25% unaware of their condition • 33% aware but not on treatment • 50% on treatment but above even modest BP goals • Hypertension is especially prevalent among African Americans and Hispanics • Responses to individual medications can vary widely across patients • Adverse effects may complicate treatment decisions Egan BM, et al. JAMA. 2010;303:2043-2050. Law, MR et al. BMJ. 2003;326:1427-1431.

7. Key Questions • Key Question 1. For adult patients with essential hypertension, how do ACEIs (angiotensin-converting enzyme inhibitors), ARBs (angiotensin II receptor antagonists), and direct renin inhibitors differ in blood pressure control, cardiovascular risk reduction, cardiovascular events, quality of life, and other outcomes? • Key Question 2. For adult patients with essential hypertension, how do ACEIs, ARBs, and direct renin inhibitors differ in safety, adverse events, tolerability, persistence with drug therapy, and treatment adherence? • Key Question 3. Are there subgroups of patients—based on demographic and other characteristics (i.e., age, race, ethnicity, sex, comorbidities, concurrent use of other medications)—for whom ACEIs, ARBs, or direct renin inhibitors are more effective, are associated with fewer adverse events, or are better tolerated?

8. Search Strategy for Systematic Review 2090 citations identified by literature search 1083 abstracts excluded 1007 passed abstract screening • 679 articles reviewed separately: • 276 review articles • 403 indirect comparator studies 328 direct comparator trials screened at full-text stage • 218 articles excluded: • 119 follow-up <12 weeks • 10 not essential hypertension • 26 no direct comparison of drugs • 11 no separate results for subgroup with hypertension • 52 other 110 direct comparator articles abstracted into evidence tables and included in review

9. Medications included in this report Sanders, GD et al. Rockville, MD: Agency for Healthcare Research and Quality. June 2011. http://www.effectivehealthcare.ahrq.gov/ehc/products/164/695/CER-34-ACEIs-ARBs_Executive-Summary_20110613.pdf

10. Grading the Strength of Evidence • Grading scheme similar to the “Grading of Recommendations Assessment, Development, and Evaluation” framework used in 2007 report • Considerations: number of studies, the size of the studies, strength of study design, and the quality of individual studies • Strength of evidence classified into 4 categories: e

11. Outcomes of Interest • Primary outcomes • Blood pressure control • Mortality • all-cause, cardiovascular disease-specific, cerebrovascular disease-specific • Morbidity • MI, stroke, and measures of quality of life • Safety • (serious AE rates, overall AE rates, withdrawal rates, switch rates) • Specific adverse effects • weight gain, impaired renal function, angioedema, cough, hyperkalemia • Persistence/adherence • Rate of use of a single medication for BP control • Secondary outcomes • Lipid levels (HDL, LDL, TC, TG) • Rates of progression to type 2 diabetes • Markers of carbohydrate metabolism/diabetes control • HbA1c, dosage of diabetes meds, fasting plasma glucose, aggregated measures of serial glucose measurements • Measures of left ventricular mass/function (LVMI and LVEF) • Measures of kidney disease • GFR, proteinuria

12. For adult patients with essential hypertension, how do ACEIs (angiotensin-converting enzyme inhibitors), ARBs (angiotensin II receptor antagonists), and direct renin inhibitors differ in blood pressure control, cardiovascular risk reduction, cardiovascular events, quality of life, and other outcomes? Key question 1: Blood Pressure Control Mortality and Major Cardiovascular Events Quality of Life Rate of use of a single antihypertensive medication Risk factor reduction and other intermediate outcomes

13. Overview of BP Reduction ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor Sanders, GD et al. Rockville, MD: Agency for Healthcare Research and Quality. June 2011. http://www.effectivehealthcare.ahrq.gov/ehc/products/164/695/CER-34-ACEIs-ARBs_Executive-Summary_20110613.pdf

14. Overview of Mortality and Major Cardiovascular Events • Low number of reported deaths (39) and strokes (13) • Study limitations • Most excluded patients with CV disease and other comorbidities • Short duration of follow-up ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor Sanders, GD et al. Rockville, MD: Agency for Healthcare Research and Quality. June 2011. http://www.effectivehealthcare.ahrq.gov/ehc/products/164/695/CER-34-ACEIs-ARBs_Executive-Summary_20110613.pdf

15. Overview of Quality of Life ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor Sanders, GD et al. Rockville, MD: Agency for Healthcare Research and Quality. June 2011. http://www.effectivehealthcare.ahrq.gov/ehc/products/164/695/CER-34-ACEIs-ARBs_Executive-Summary_20110613.pdf

16. Overview of Rate of Use of a Single Antihypertensive Medication ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor Sanders, GD et al. Rockville, MD: Agency for Healthcare Research and Quality. June 2011. http://www.effectivehealthcare.ahrq.gov/ehc/products/164/695/CER-34-ACEIs-ARBs_Executive-Summary_20110613.pdf

17. Overview of Risk Factor Reduction and Other Intermediate Outcomes ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor Sanders, GD et al. Rockville, MD: Agency for Healthcare Research and Quality. June 2011. http://www.effectivehealthcare.ahrq.gov/ehc/products/164/695/CER-34-ACEIs-ARBs_Executive-Summary_20110613.pdf

18. Overview of Risk Factor Reduction and Other Intermediate Outcomes ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor Sanders, GD et al. Rockville, MD: Agency for Healthcare Research and Quality. June 2011. http://www.effectivehealthcare.ahrq.gov/ehc/products/164/695/CER-34-ACEIs-ARBs_Executive-Summary_20110613.pdf

19. For adult patients with essential hypertension, how do ACEIs, ARBs, and direct renin inhibitors differ in safety, adverse events, tolerability, persistence with drug therapy, and treatment adherence? Key question 2 Withdrawals due to adverse events Angioedema Persistence with drug therapy/treatment adherence

20. Overview of Cough ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor Sanders, GD et al. Rockville, MD: Agency for Healthcare Research and Quality. June 2011. http://www.effectivehealthcare.ahrq.gov/ehc/products/164/695/CER-34-ACEIs-ARBs_Executive-Summary_20110613.pdf

21. Overview of Withdrawals Due to Adverse Events ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor Sanders, GD et al. Rockville, MD: Agency for Healthcare Research and Quality. June 2011. http://www.effectivehealthcare.ahrq.gov/ehc/products/164/695/CER-34-ACEIs-ARBs_Executive-Summary_20110613.pdf

22. Overview of Angioedema Conclusion: Due to insufficient evidence, no clinically relevant conclusions could be reached ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor Sanders, GD et al. Rockville, MD: Agency for Healthcare Research and Quality. June 2011. http://www.effectivehealthcare.ahrq.gov/ehc/products/164/695/CER-34-ACEIs-ARBs_Executive-Summary_20110613.pdf

23. Overview of Persistence with Drug Therapy / Treatment Adherence Adherence = Number of pills taken Persistence = Number of patients remaining on therapy ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor

24. Are there subgroups of patients— based on demographic and other characteristics (i.e., age, race, ethnicity, sex, comorbidities, concurrent use of other medications)—for whom ACEIs, ARBs, or direct renin inhibitors are more effective, are associated with fewer adverse events, or are better tolerated? Key question 3

25. Overview of Subgroup Analysis • Few studies were designed to assess treatment-related differences within patient subgroups • For BP reduction, most studies revealed no significant differences in efficacy between ACEIs, ARBs, and aliskiren within subgroups studied • Women, African Americans, older adults • For all other outcomes, the evidence was insufficient to reach conclusions Sanders, GD et al. Rockville, MD: Agency for Healthcare Research and Quality. June 2011. http://www.effectivehealthcare.ahrq.gov/ehc/products/164/695/CER-34-ACEIs-ARBs_Executive-Summary_20110613.pdf

26. Clinical Bottom Line

27. Clinical Bottom Line ND = No difference; NE = No evidence; IE = Insufficient evidence; ● = Low strength of evidence; ●● = Moderate strength of evidence; ●●● = High strength of evidence

28. Remaining Issues Gaps in Knowledge

29. Remaining Issues Limitations of AHRQ Review Future Research • Lack of quality RCTs /observational studies • Limited number of long-term clinical outcomes studies • Poor controls for dose escalation and added therapies • Inconsistent adverse events reporting • Few studies on the effects of DRIs vs. ACEIs or ARBs • Insufficient evidence for patient subgroups • Broader representation of patient subgroups • Subgroup analyses of patients with essential hypertension and various comorbid conditions • Studies focusing on treatment consistent with typical clinical practice • Assessment of long-term clinical outcomes • Long-term comparisons of DRIs with ACEIs and ARBs • Evaluation of therapies within a class

30. Thank you for the opportunity to share this information with you • For CE/CME: • ce.effectivehealthcare.ahrq.gov/credit • Enter code: CER28 • For electronic copies of the clinician guide, the consumer guide, and the full systematic review • www.ahrq.gov • For free print copies • AHRQ Publications Clearinghouse (800) 358-9295 We encourage you to visit AHRQ’s continuing education website regularly to participate in future programs.