1. Initial Combination Treatment in Hypertension: Who Are the Candidates George Bakris, MD, F.A.S.H., F.A.S.N. Professor of Medicine Director, Hypertensive Disease Unit University of Chicago, Pritzker School of Medicine Chicago, IL

2. Monotherapy for Hypertension Is Inadequate in ~40% to 50% of Patients *Response = DBP <90 mm Hg at the end of titration period and having maintained a DBP of <95 mm Hg for 1 year without drug tolerance. Mean baseline BP = 152/99 mm Hg. Adapted from Materson BJ et al. Am J Hypertens. 1995;6:189-192. 50% response Patients With Response* (%) CCB (dilitiazem) α 2 Agonist (clonidine) β-blocker (atenolol) Diuretic (HCTZ) α 1 Antagonist (prazosin) ACEI (captopril) Placebo

3. Rationale for Fixed-Dose Combination Therapy: Background Traditional antihypertensive therapy yields goal BP in <60% of treated hypertensive patients 1-3 Switching from one monotherapy to another is effective in only about 50% of patients 1 Most patients will require at least two drugs to attain goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic renal disease) 4-6 BP = blood pressure 1.Materson BJ et al. J Hum Hypertens. 1995;9(10):791-796. 2.Messerli FH. J Hum Hypertens. 1992;6 Suppl. 2:S19-S21. 3.Ram CV. J Clin Hypertens (Greenwich). 2004;6(10):569-577. 4.Chobanian AV, et al. JAMA. 2003;289(19):2560-2572. 5.Guidelines Committee. J Hypertens. 2003;21:1011-1053. 6.American Diabetes Association. Diabetes Care. 2002;25(Suppl.1):S71-S73.

4. Monotherapy Fixed-Dose Combination 89.3% 10.7% 88.6% 11.4% 88.0% 12.0% 87.6% 12.4% Growth of Fixed-Dose Combinations IMS National Prescription Audit (NPA)

5. 0.19 Incremental SBP reduction ratio of observed to expected additive effects Thiazide Wald DS et al. Am J Med. 2009;122:290-300. Beta blocker Calcium channel blocker Adding a drug from another class (on average standard doses) Doubling dose of same drug (from standard dose to twice standard) 1.04 1.00 1.16 0.89 1.01 0.2 0.23 0.37 ACE inhibitor All classes 0.22 Ratio of Observed to Expected Incremental BP-Lowering Effects of Adding a Drug or Doubling the Dose According to Drug Class 1.00 0.60 0.40 0.20 0 1.40 0.80 1.20

6. SBP=systolic blood pressure. *Target blood pressure control groups in ACCORD defined as <120 mm Hg (intensive) and <140 mm Hg (standard). Updated from Bakris G et.al Am J Kidney Dis 2000. The ACCORD Study Group. N Engl J Med. 2010 Mar 14. [Epub ahead of print] ACCOMPLISH 131 ALLHAT138 HOT138 ACCORD (intensive)* 119 ACCORD (standard)* 133 INVEST133 IDNT138 RENAAL141 ABCD132 UKPDS144 MDRD132 AASK128 Multiple Medications Are Required to Achieve BP Control in Clinical Trials Hyper- tension Diabetes Kidney disease No. of BP medications 1234 SBP achieved (mm Hg) Trial

7. Adherence and Pill Burden Odds of Being Adherent to Both Lipid- and BP-Lowering Rx 1.0 0–12–38+4–7 Odds Ratio Chapman RH et al. Circulation. 2003;108(17 suppl IV):IV-756-757. Number of Medications in Addition to Lipid- and BP-Lowering Rx

8. Improved Adherence With Fixed-Dose Combination Therapy Compared With Free-Combination Therapy *P<.0001. MPR = number of days of therapy for medication dispensed 365 days of study follow-up. Gerbino PP, Shoheiber O. Am J Health-Syst Pharm. 2007;64:1279-1283. Because this was a retrospective analysis of administrative claims data, patients were not randomly assigned and could not be matched by any empirical methods. Although we know the prescriptions were filled based on these claims data, it is unknown if patients specifically took the medication as prescribed. Levels of disease severity as defined by clinical measurements were not available within the design of the study. Analyses of concomitant drug classes were used to estimate disease severity, as polypharmacy may affect adherence. Other factors may exist that might have influenced selection or use of antihypertensive agents, which could not be captured or assessed in the study. Fixed-Dose Combination (ACEI/CCB) Free Combination (ACEI+CCB) (n=2839) (n=3367) * Medication Possession Ratio (MPR) 88 69 020406080100

9. Compliance Gap Between Fixed-dose Combination and Dual Agent Regardless of Concomitant Medications Medication-possession ratio (MPR) Number of concomitant drugs * * * * * *p=<0.0001 * * US pharmacy claims data (n=6,206) Wanovich. Am J Hypertens 2004;17:223A

10. Adherence With Fixed-Dose Combinations Compared With Free-Drug Combinations Bangalore S et al. Am J Med. 2007;120:713-719. Risk Ratio 0.1 1 10 Risk Ratio (95% CI) % Weight 0.89 (0.51,1.57) 0.6 0.88 (0.55,1.42) 1.1 0.78 (0.55,1.11) 1.5 0.74 (0.67,0.81) 25.3 0.74 (0.65,0.84) 12.9 0.81 (0.77,0.86) 43.2 0.71 (0.62,0.80) 11.7 0.50 (0.35,0.71) 3.1 0.47 (0.22,1.01) 0.6 0.76 (0.73,0.79) Study Su WJ et al Geiter LJ et al Eron JJ et al Taylor AA et al Dezii CM et al NDC Dataset Dezii CM et al Melikian C et al Overall (95% CI)

11. Adapted from Mancia et al. 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension. J Hypertension 2007; 25(9): 1751-62 Diuretics ACE inhibitors Calcium antagonists AT 1 -receptor blockers  -blockers  -blockers Preferred Combinations Concomitant Use of Antihypertensive Drugs Controversial Combinations

12. *Beta- or alpha- blockers, clonidine, loop diuretics 14 Days Day 1 Month 1 Month 2 Year 5 Screening Amlodipine 5 mg + benazepril 20 mg Randomization Benazepril 40 mg + HCTZ 12.5 mg Benazepril 40 mg + HCTZ 25 mg Free add-on antihypertensive agents* Month 3 Free add-on antihypertensive agents* Amlodipine 5 mg + benazepril 40 mg Amlodipine 10 mg + benazepril 40 mg Benazepril 20 mg + HCTZ 12.5 mg Titrated to achieve BP <140/90 mmHg or <130/80 mmHg with diabetes/renal insufficiency ACCOMPLISH: Design N = 11,462 with systolic hypertension and CV or renal disease or target organ damage Jamerson KA et al. Am J Hypertens. 2004;17:793-801; Presented at: ACC 2008 Chicago; ClinicalTrialResults.org.

13. mm Hg Month 57575408522250334825429925291042 57405404517850104866429828041074 Patients ACEI / HCTZ N=5733 CCB / ACEI N=5713 131.6 mmHg 132.5 mmHg Difference of 0.9 mmHg p<0.001 DBP: 73.3DBP: 74.4 ACCOMPLISH – Blood Pressure Results Jamerson et al. NEJM. 2008; 359(23); 2417-2428.

14. Cumulative event rate HR (95% CI): 0.80 (0.72, 0.90) 20% Risk Reduction Time to 1 st CV morbidity/mortality (days) p = 0 ACEI / HCTZ CCB / ACEI 679 552.001 ACCOMPLISH – Primary Endpoint Jamerson et al. NEJM. 2008; 359(23); 2417-2428.

15. STITCH: Objective and Study Design 2104 patients from 45 Primary Care Practices in Southern Ontario Primary endpoint: Proportion of patients reaching BP target (practice-level) at 6 months STITCH-Care Algorithm (18 Practices) STITCH-Care Algorithm (18 Practices) Guideline-Care Algorithm (27 Practices) Guideline-Care Algorithm (27 Practices) Objective : To assess if the use of a fixed-dose combination (FDC) as initial treatment of hypertension will improve the proportion of patients reaching goal BP as compared to the use of the Canadian Hypertension Education Program (CHEP) algorithm Design: Feldman RD et al. Hypertension. 2009;53:646-653.

16. STITCH: Study Design (cont’d) CHEP Guidelines: Treatment of hypertension without other compelling indications Target: SBP <140 DBP <90 mm Hg STITCH –Care Algorithm BP controlled? NoYes Initial therapy with a low dose ACE-diuretic or ARB/diuretic combination Continue with current therapy Up-titrate combination therapy successively to the highest dose Add calcium channel blocker and up-titrate Continue with current therapy Add alpha blocker, beta-blocker or spironolactone Yes No Feldman RD et al. Hypertension. 2009;53:646-653. Lifestyle Modification Therapy Thiazide Diuretic ACE-IACE-IARBARB Long- acting CCB Beta- blocker Dual Combination Triple or Quadruple Therapy

17. VariableUsual CareSTITCHP value N1246802 Baseline SBP (mm Hg) DBP (mm Hg) Diabetic (%) FDC (%) BP control (%) 153.4 87.7 15.9 9.3 0 155.1 88.1 15.1 11.2 0 NS Final visit  SBP (mm Hg)  DBP (mm Hg) FDC (%) Med titration (%) BP control (%) -17.5 -8.2 15 69.6 52.7 -22.6 -10.4 85 82.6 64.7 <0.005 <0.05 <0.001 <0.01 <0.05 STITCH: Main Results Feldman RD et al. Hypertension. 2009;53:646-653.

18. STITCH: Predictors of Achieving BP Target *The analysis was conducted using a modified Poisson regression model that evaluated patient-level data. † P values were derived by adjustment for clustering in the model. Feldman RD et al. Hypertension. 2009;53:646-653. Univariate AnalysesMultivariate Model Determinant Risk Ratio95% CIP*†P*† Risk Ratio95% CIP* † STITCH-care 1.21.02 to 1.400.031.21.0 to 1.40.03 Age (per 10 yr increase) 1.00.97 to 1.060.48 Female1.00.86 to 1.030.22 Not diabetic2.52.02 to 3.05<0.0012.52.0 to 3.1<0.001 Physician before 1984 1.10.88 to 1.260.63

19. Conclusions Monotherapy is the standard initial treatment for reducing BP, with stepwise increases in dose if the desired decrease in BP is not achieved Combining drugs from different classes is approximately 5 times more effective in lowering BP than increasing the dose of 1 drug Combination therapy is the preferred initial strategy in the treatment of high BP

20. Gradman AH et al. J Am Soc Hypertens 4:42-50, 2010. DRUG COMBINATIONS IN HYPERTENSION: RECOMMENDATIONS Preferred  ACE inhibitor/diuretic*  ARB/diuretic*  ACE inhibitor/CCB*  ARB/CCB* Acceptable  Beta blocker/diuretic*  CCB (dihydropyridine)/β-blocker  CCB/diuretic  Renin inhibitor/diuretic*  Renin inhibitor/ARB*  Thiazide diuretics/K+ sparing diuretics* Unacceptable  ACE inhibitor/ARB  ACE inhibitor/β-blocker  ARB/β-blocker  CCB (nondihydropyridine)/β-blocker  Centrally acting agent/β-blocker *SPC available in the US