Valsartan Amlodipine HCT Combination: Control To Goal Dr. Sameh Shaheen M.B.B.Ch, MSc, MD, FESC, FSCAI Prof of cardiology Ain Shams University Sonesta Hotel Cairo Egypt December 4 th 5 th ; 213 Hypertension Prevalence Overall the prevalence of hypertension appears to be around 3 45% of the general population, with a steep increase with ageing. 213 ESH/ESC Guidelines for the management of arterial hypertension 1
Hypertension is the Number One Risk Factor for Global Mortality Developing region Developed region 1 2 3 4 5 6 7 8 Attributable mortality in millions (total: 55,861,) Adapted from Ezzati et al. Lancet 22;36:1347 6 More Recent Data: In 212, the three leading risk factors for global disease burden were: 1. high blood pressure 2. tobacco smoking 3. and alcohol use. Lim SS, et al. Lancet. 212 Dec 15;38(9859):2224-6. 2
YLDs (thousands) Chronic kidney disease due to hypertension YLDs (thousands) due to Hypertensive heart disease All ages deaths related to Chronic kidney disease due to hypertension All ages deaths due to Hypertensive heart disease Mortality related o hypertension is increasing by : 2 +91.5% 1 +47 8% 15 8 1 6 4 5 2 199 21 199 21 Adapted from: Lozano R, et al. Lancet. 212 15;38(9859):295-128 YLDs related o hypertension is increasing by : 1 58.4% 5 +57 4% 8 4 6 3 4 2 2 1 Years lived with disability (YLDs) 199 21 199 21 Adapted from: Vos T, et al. Lancet. 212 15;38(9859):2163-96. 3
Controlling blood pressure with medication is unquestionably one of the most cost-effective methods of reducing premature CV morbidity and mortality Elliott. J Clin Hypertens 23;5(Suppl. 2):3 13 Suboptimal control of blood pressure in Egyptian Hypertensive patients predisposing to higher risk of Cardio-Vascular events Awareness Treatment Control 37.5% 23.9% 8% Awareness Treatment Control Adapted From: Ibrahim MM and Damasceno A. Hypertension in developing countries. Lancet. 212;38:611-619 4
Choice of Combination is Based on: Maximum CV Protection Maximum BP Control BP Cardiac output = = X Total peripheral resistance Heart rate X Stroke volume Arterial pressure Venous pressure Diuretics CCBs ARBs Different, but complementary mechanism of action ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin Type II receptor blocker; CCB = calcium channel blocker Beevers, et al. BMJ 21;322:912 6; McGhee, et al. Crit Care Nurse 22;22:6 4; Goodman & Gilman s Pharmacological Basis of Therapeutics. 9 th ed. 1995. 5
Addition of a RAAS Blocker Can Offset the Dose-limiting Effects of Other Antihypertensive Agents Thiazide diuretic Lowers BP Reduces antihypertensive effect CCB Natriuresis Activates RAAS & SNS RAAS Blocker RAAS = renin-angiotensin-aldosterone system SNS = sympathetic nervous system ESC/ESH 213, Recommendations for Combinations ESC/ESH stressed on the role of the combination therapy. However, Beta Blockers based combination is not among the preferred combination preferred combinations useful combination (with some limitations); possible but less well tested combinations; not recommended combination. 213 ESH/ESC Guidelines for the management of arterial hypertension 6
MSSBP (mmhg) Amlodipine/Valsartan/HCTZ Therapy Study design: 8 week, multicentre, randomized trial in patients with moderate-to-severe hypertension (MSDBP 1 <12 mmhg; MSSBP 145 < 2 mmhg) Primary objective: to investigate whether triple combination therapy is superior to respective dualcombinations at lowering either MSDBP or MSSBP Randomization HCTZ/amlodipine 12.5/5 mg HCTZ/amlodipine 25/1 mg Single-blind placebo run-in Valsartan/HCTZ 16/12.5 mg Amlodipine/Valsartan 5/16 mg Valsartan/HCTZ 32/25 mg Amlodipine/Valsartan 1/32 mg Valsartan/HCTZ 16/12.5 mg Amlodipine/Valsartan/ HCTZ 5/16/12.5 mg Amlodipine/Valsartan/HCTZ 1/32/25 mg 4 weeks 1 week 1 week 6 weeks HCTZ = hydrochlorothiazide MSSBP = mean sitting systolic BP MSDBP = mean sitting diastolic BP Calhoun et al. Hypertension 29;54:32 9 Superior reduction in systolic BP after 2 weeks of treatment and at study end with Triple Therapy *P<.1 vs. triple therapy; BL 17.7 169.5 169.8 169.9 Aml/HCTZ Val/HCTZ Aml/Val Aml/Val/HCTZ -5-1 -15-2 -25-3 -35-4 -45-23.6-24.6-31.5-32 MSSBP=mean sitting systolic blood pressure; BL: baseline ; Aml=amlodipine; HCTZ=hydrochlorothiazide; Val=valsartan. * * After 2 weeks -26.3 * * -33.5 * * End of study -29.6-39.7 14.1 13.1 Calhoun et al Adv Ther (29) 26(11):112-123. 7
MSSBP (mmhg) Triple Therapy reduces SBP up to 5mmHg in severe HTN patients BL 188.1 187.1 187.4 187.6 Aml/HCTZ Val/HCTZ Aml/Val Aml/Val/HCTZ -1-2 -3-4 -5-6 -32.6-31.4 * -39.9-42.5 * * *P<.1 vs. triple therapy; P<.1vs. triple therapy MSSBP=mean sitting systolic blood pressure; BL: baseline ; Aml=amlodipine; HCTZ=hydrochlorothiazide; Val=valsartan. After 2 weeks -35.3-38 -43.6-49.6 148.9 End of study 137.3 Calhoun et al Adv Ther (29) 26(11):112-123. Triple Combination Therapy with Amlodipine/Valsartan/HCTZ: Reaching the Full BP Lowering Effect after 2 Weeks Week 2 of Treatment Calhoun et al. Hypertension 29;54:32 39 8
ASBP (mm Hg) Triple Combination Therapy with Amlodipine/Valsartan/HCTZ: Get 9 out of 1 Patients to BP Goal 15% 85% Patients to BP Goal Patients not to BP Goal Calhoun et al. Adv Ther (29) 26(11):112-123. Triple Combination Therapy with Amlodipine/Valsartan/HCTZ Provides Powerful BP Reductions Over 24 Hours 17 16 15 14 13 12 11 Baseline data 24-hour treatment data 1 Aml/Val/HCTZ 1/32/25 mg Val/HCTZ 32/25 mg Aml/Val 1/32 mg Aml/HCTZ 1/25 mg ASBP = ambulatory systolic blood pressure N=283 patients MSSBP/MSDBP=165/15 4 8 12 16 2 24 Hours after dosing MABP with triple combination was reduced by 3/2 mmhg MABP=15/95 Lacourcière et al. Poster presented at 19 th Scientific Meeting of the European Society of Hypertension, June 29, Milan, Italy 9
There was a low incidence of AEs related to, or potentially related to, low BP across treatment groups, eg, hypotension (1.5) % Calhoun et al. Hypertension 29;54:32 9 Choice of Combination is Based on: Maximum CV Protection Maximum BP Control 1
Valsartan has a Wealth of Cardiovascular Outcomes Data VALUE 1 VALIANT 2 Val-HeFT 3 5 DROP 7 1 Julius et al. Lancet 24;363:222 31; 2 Pfeffer et al. N Engl J Med 23;349:1893 96; 3 Maggioni et al. Am Heart J 25;149:548 57; 4 Wong et al. J Am Coll Cardiol 22;4:97 5; 5 Cohn et al. N Engl J Med 21;345:1667 7; 6 Hollenberg NK et al. J Hypertens 27;25:1921 6 Amlodipine has a Wealth of Cardiovascular Outcomes Data PREVENT 1 CAMELOT 2 ASCOT- BPLA/CAFE 3,4 ALLHAT 5 1 Pitt et al. Circulation 2;12:153 1; 2 Nissen et al. JAMA 24;292:2217 26; 3 Dahlof et al. Lancet 25;366:895 96; 4 Williams et al. Circulation 26;113:1213 25; 5 Leenen et al. Hypertension 26;48:374 84 11
HCTZ Has Been Widely Studied in Hypertension For patients with uncomplicated hypertension, thiazide diuretics are the first-line recommendation in the JNC-7 guidelines 1 Diuretics are also widely used for enhancing hypertensive efficacy in multi-drug regimens, including in combination with ARBs and CCBs 1 HCTZ has been shown to enhance antihypertensive efficacy when combined with valsartan in numerous controlled clinical trials 3 More than 4, patients have been included in the valsartan/hctz groups 3 HCTZ resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressure when combined with valsartan 3 ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; HCTZ = hydrochlorothiazide; JNC = Joint National Committee 1 Chobanian et al. JAMA 23;289:256 72 3 DIOVAN HCT prescribing information. Novartis July 28 Low- Dose Diuretics Reduce Cardiovascular Disease Events Outcome Relative Risk (95% CI) P Value Favors Low- Dose Diuretics Favors Placebo CHD.79 (.69-.92).2 CHF.51 (.42-.62) <.1 Stroke.71 (.63-.81) <.1 CVD Events CVD Mortality Total Mortality.76 (.69-.83) <.1.81 (.73-.92).1.9 (.84-.96).2 CHD = coronary heart disease CHF = congestive heart failure CI = confidence interval CVD = cardiovascular disease.4.6.8 1. 1.2 1.4 Relative Risk Psaty BM, et al. JAMA. 23;289:2534-2544. 12
213 Conclusion: As typically prescribed, chlorthalidone in older adults was not associated with fewer adverse cardiovascular events or deaths than hydrochlorothiazide. However, it was associated with a greater incidence of electrolyte abnormalities, particularly hypokalemia. Dhalla, et al. Ann Intern Med. 213;158:447-455. Maximum Protection HCTz VALUE 1 VALIANT 2 PREVENT 1 CAMELOT 2 Val- HeFT 3 5 DROP 7 ASCOT- BPLA/CAF E 3,4 ALLHAT 5 Well Established 13
Influence of LVH on Cardiovascular Events Risk of acute myocardial infarction (MI) Promotes potentially lethal arrhythmias Development of LVH associated with myocardial fibrosis (MF) MF leads to diastolic dysfunction Coronary reserve in LVH heart LVH: Left Ventricular Hypertrophy Kahan T. J Hypertens 1998; 16:S23-S29. LVH is an independent risk factor for reducing survival The more decrease in Left Ventricular Mass Index, The more protection LVH: Left Ventricular Hypertrophy Adapted From: Devereux R, et al. JAMA. 24;292:235-2356. 14
R. Fogari et al Expert Opin. Pharmacotherapy. (212) 13(8):191-199 Triple therapy in hypertensive, diabetic patients with LVH over one year + Valsartan16 mg + Valsartan32 mg Amlodipine 1 mg + HCTZ 12.5 mg placebo + Ramipril 5 mg + Ramipril 1 mg -2 4 8 56 Novartis is not recommending indications outside the approved BPI in Egypt R. Fogari et al Expert Opin. Pharmacotherapy. (212) 13(8):191-199 15
Survival (all-cause mortality) LVMI (g/m2) The reduction in LVH as demonstrated by the decrease in LVMI was significantly greater in the Valsartan than in the Ramipril group over one year 16 14 12 1 8 6 4 2 149.3 148.5 119.2 p<.5 127.6 Val/Aml/HCTZ (n = 9) Ram/Aml/HCTZ (n = 88) Before After LVMI= left ventricular mass index R. Fogari et al Expert Opin. Pharmacotherapy. (212) 13(8):191-199 Novartis is not recommending indications outside the approved BPI in Proteinuria is an independent risk factor for mortality in type 2 diabetes 1..9.8.7.6 Normoalbuminuria (n=191) Microalbuminuria (n=86) Macroalbuminuria (n=51).5 1 2 3 4 5 6 Years The more decrease in albumin excretion, The more protection P<.1 normo vs. micro- and macroalbuminuria P<.5 micro vs. macroalbuminuria Gall, MA et al. Diabetes 1995;44:133 16
Change from baseline in UACR (%) Amlodipine/Valsartan Reduces Urinary Albumin Excretion Compared with Amlodipine in Black Patients with Stage 2 Hypertension: EX-STAND Study 15 1 Amlodipine/Valsartan 1/16 mg Amlodipine 1 mg 1 5 N=16 5 N=157 1 15 2 25 3 35 3* *p=.3; UACR = urinary albumin-to-creatinine ratio 12 weeks. Novartis is not recommending indications outside the approved BPI in Egypt Flack et al. J Hum Hypertens 29;23:479 89 212 KDIGO : Pharmacological treatments for lowering blood pressure in CKD Non dialysis patients CKD ND Non dialysis-dependent CKD of any stage KDIGO BP Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney inter., Suppl. 212; 2: 337 414. 17
Factors May Affect Compliance and Treatment Adherence Tolerability Complexity Multiple Doses Cost Compliance Decreases as the Number of Medications Increases Number of pre-existing prescription medications 1 2 3 5 Unadjusted odds ratio for compliance (>8%) to both antihypertensive therapy and LLT (95% CI; p value) 1.73 (1.56 1.9; p<.1) 1.25 (1.13 1.39; p<.1).96 (.86 1.6; p=.41).87 (.79.94; p<.1) 6.65 (.59.71; p<.1).5 1 1.5 2 2.5 Decreased Increased compliance compliance Retrospective cohort study of MCO population. N=8,46 patients with hypertension who added antihypertensive therapy and LLT to existing prescription medications within a 9-day period. Compliance to concomitant therapy: sufficient antihypertensive and LL prescription medications to cover 8% of days per 91- day period CI=confidence interval; LLT = lipid-lowering therapy Chapman et al. Arch Intern Med 25;165:1147 52 18
A prospective, open-label, observational, multicenter study.7,181 Patients were enrolled in 95 practices in Germany.. Taking several pills per day is a strongly agreed real burden for 6%patients. This was also seen as a potential reason for medication errors. Approximately half of the patients would be willing to make an out-of-pocket payment for reducing the number of pills to half. Hagendorff, et al. Adv Ther (213) 3(4):46 19. The Time of: Single Pill Combination 19
Healthcare costs (US $) Patients (%) Compliance with Antihypertensive Therapy Results in More Patients Achieving (BP) Goal (<14/9 mmhg) Observational, cross-sectional study (n=1,) 8 7 6 5 4 3 2 1 >7% Compliant p<.5 Non-compliant Yiannakopoulou EC, et al. Eur J Cardiovasc Prev Rehabil 25;12:243 9 Patients Treated with Fixed-dose Combinations Use Less Resource 1, 8, 8,547 Fixed-dose combination (n=3,375) Component therapy (n=1,12) 6, 4,747 4, 2, 2,544 2,441 1,621 1,881 2,359 81 Total Ambulatory Drug Hospital Dickson and Plauschinat. J Manag Care Pharm. Accepted for publication 2
Valsartan based therapy has the lowest risk of non-persistence (the highest persistence) 1.2 Relative risk (RR) of non-persistence to initial therapy, 1.8.6.4 1.596*.714**.911.94.833.2 Losartan Valsartan Telmisartan Irbesartan Eprosartan Candesartan Costa et al, High Blood Press Cardiovasc Prev 29; 16 (4): 167-176 Relative risk (RR) of non-persistence to initial therapy, *if 12 months after the beginning of treatment they were still taking a regular therapy (same drug = same therapy users, added one or more drugs = add-on therapy users, different drug = switchers ) Adherence to antihypertensive management can be improved by a multi-pronged approach-ii Simplify medication regimens using longacting once-daily dosing Utilize fixed-dose combination pills Utilize unit-of-use packaging e.g. blister packaging Replacing multiple pill antihypertensive combinations with single pill combinations 213 21
For patients uncontrolled on Any Dual Therapy VAL/AML/HCT in single pill combination provides: Maximum CV Protection Maximum BP Control Thank You 22