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

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4. Disclosure Information Prime, Inc. Program Disclosure Information Advisory Board ConsultantGrants/ Research Salary/ Contractual Supported Promotional Education Stock/Share holder Other Financial Support Mori Krantz, MD, FACC Planner None GSK Lovaza Study None Carolyn LePage, PhD, ARNP Planner None Barry University None Heidi Wynn Maloni, PhD, ANP-BC Planner Sanofi- Aventis None Sherman Podolsky, MD Reviewer None Joyce M Knestrick, PhD, CRNP, FAANP Reviewer None Kathleen A Jarvis, MS, RN Reviewer None Chris R Prostko, PhD Scientific Program Director None PRIMENone Lynn S Goldenberg, RN, BSN Director of Accreditation & Compliance None PRIMENone AHRQ Contracted Faculty Program Disclosure Information Advisory Board ConsultantGrants/ Research Salary/ Contractual Supported Promotional Education Stock/Share holder Other Financial Support First, Last, Credentials Speaker None

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 – 3 rd decade ~30% – 5 th decade ~50% – 7 th decade ~70% – 8 th 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% Egan BM, et al. JAMA. 2010;303:2043-2050. Law, MR et al. BMJ. 2003;326:1427-1431. 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

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 1007 passed abstract screening 328 direct comparator trials screened at full-text stage 110 direct comparator articles abstracted into evidence tables and included in review 1083 abstracts excluded 679 articles reviewed separately: 276 review articles 403 indirect comparator studies 679 articles reviewed separately: 276 review articles 403 indirect comparator studies 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 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

9. Medications included in this report Angiotensin Converting Enzyme Inhibitor (Trade Name) Angiotensin Receptor Blocker (Trade Name) Direct Renin Inhibitor (Trade Name) Benazepril (Lotensin)Candesartan cilexetil (Atacand)Aliskiren (Tekturna) Captopril (Capoten)Eprosartan (Teveten) Enalapril (Vasotec)Irbesartan (Avapro) Fosinopril (Monopril)Losartan (Cozaar) Lisinopril (Prinivil; Zestril)Olmesartan medoxomil (Benicar) Moexipril (Univasc)Telmisartan (Micardis) Perindopril (Aceon)Valsartan (Diovan) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) 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 High High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect. Moderate Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate. Low Low confidence that the evidence reflects the true effect. Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate. Insufficient Evidence is either unavailable or does not permit estimation of an effect.

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. 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 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?

13. Overview of BP Reduction ComparisonOutcomeStrength of Evidence ACEI vs. ARB 70 RCTs N=26,170 ACEIs and ARBs appear to have similar long-term effects on BP No difference: 57 studies ACEI favored: 2 studies ARBs favored 11 studies High DRI vs. ACEI or ARB 3 Studies DRIs appear to have a greater reduction in blood pressure compared to the ACEI ramipril (2 studies) and no significant difference compared to the ARB losartan (1 study). Low 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 ComparisonOutcomeStrength of Evidence ACEI vs. ARB 21 Studies N=38,589 No discernable differences for these critical outcomes Low DRI vs. ACEI or ARB 3 Studies N=2,049 No discernable differences for these critical outcomes Insufficient ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor 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 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 ComparisonOutcomeStrength of Evidence ACEI vs. ARB 4 Studies No differences were found in measures of general quality of life 2 studies did not provide quantitative data Low DRI vs. ACEI or ARB No Studies No study evaluated the comparative effectiveness of direct renin inhibitors for quality-of-life outcomes. Insufficient 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 ComparisonOutcomeStrength of Evidence ACEI vs. ARB 26 Studies 23 RCTs, 3 Observational No statistically evident difference in the rate of treatment success based on use of a single antihypertensive for ARBs compared to ACEIs High DRI vs. ACEI or ARB No Studies No relevant studies evaluating direct renin inhibitors Insufficient 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 ComparisonOutcome: Lipid levels, markers of carbohydrate metabolism/ diabetes control, progression of renal disease: Strength of Evidence ACEI vs. ARB No consistent differential effects on several clinical outcomes, including lipid levels and markers of carbohydrate metabolism/diabetes control Small difference (but likely not clinically meaningful in change in renal function between ACEIs and ARBs (favoring ACEIs) Moderate DRI vs. ACEI or ARBThere were no studies that evaluated these outcomes in direct renin inhibitors. Insufficient 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 ComparisonOutcome: (this summary applies to both comparison groups) Progression to type 2 diabetes and LV mass/ function: Strength of Evidence ACEI vs. ARB No evidence for an impact of ACEIs, ARBs, or direct renin inhibitors on glucose or A1c and no included studies evaluated rates of progression to type 2 diabetes mellitus. 13 studies of LV mass/ function, but most were poor-quality studies with small sample sizes, and only one study included evaluation of a direct renin inhibitor Low DRI vs. ACEI or ARB Insufficient 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. KEY QUESTION 2 Withdrawals due to adverse events Angioedema Persistence with drug therapy/treatment adherence 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?

20. Overview of Cough ComparisonOutcome:Strength of Evidence ACEI vs. ARB 40 Studies N=68,875 ACEIs consistently associated with greater risk of cough than ARBs (odds ratio 0.211; 95% CI 0.159 to 0.281) For RCTs, this translates to a difference in rates of cough of 7.8 percent For cohort studies with lower rates of cough, this translates to a difference of 1.2 percent High DRI vs. ACEI or ARB 2 Studies N=1,743 (aliskiren vs ramipril) These 2 studies gave an estimated odds ratio of 0.333 (95% CI 0.2241 to 0.4933). Insufficient 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 ComparisonOutcome:Strength of Evidence ACEI vs. ARB 41 Studies N=13,286 Withdrawal rates were significantly lower for ARBs vs. ACEIs Total withdrawal rates ranged 1% – 20% Mean withdrawal rates: 3% for ARBs and 5% ACEI High DRI vs. ACEI or ARB 2 Studies N=1,743 (aliskiren vs ramipril) DRI trials did not find a statistically significant difference (odds ratio 0.886; 95% CI 0.458 to 1.714) when compared with the withdrawal rate associated with ACEIs Low 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 ComparisonOutcome: (this summary applies to both comparison groups) Strength of Evidence ACEI vs. ARB The event rates were very low or zero for all studies limiting ability to accurately characterize the frequency of angioedema Only 6 cases in 4 studies it was observed only in patients treated with an ACEI (4 for lisinopril and 1 for enalapril in three studies) or a direct renin inhibitor (1patient in 1 study) Low DRI vs. ACEI or ARBInsufficient ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor Conclusion: Due to insufficient evidence, no clinically relevant conclusions could be reached 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 ComparisonOutcome:Strength of Evidence ACEI vs. ARB Adherence rates: No differences between patients treated with ARBs vs ACEIs Persistence rates: Slightly greater persistence among patients treated with ARBs vs ACEIs Moderate DRI vs. ACEI or ARB Adherence rates: No differences between patients treated with ARBs vs ACEIs or DRI Persistence was not evaluated in any of the studies including direct renin inhibitors. Insufficient ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker DRI = direct renin inhibitor Adherence = Number of pills taken Persistence = Number of patients remaining on therapy

24. 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?

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 ACEIs vs ARBsDRI vs ACEIDRI vs ARB Key Question 1: Benefits Blood pressure control ND ●●● Favors DRI ● ND ● Mortality and CV events ND ● IE Quality of life ND ● NE Success on monotherapy ND ●●● NE Lipids, markers of diabetes and renal disease ND ●● NE Key Question 2: Risks Cough Favors ARBs ●●● IENE Withdrawal due to adverse events Favors ARBs ●●● ND ● NE Angioedema IE Adherence ND ●● IE Persistence Favors ARBs ●● IENE 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. Limitations of AHRQ Review 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 Future Research Remaining Issues

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