AMLODIPINE BESYLATE + OLMESARTAN MEDOXOMIL Dihydropyridine Ca channel blocker [Dhp-CCB] + Angiotensin II receptor blockage [ARB]
ESH/ESC HT MANAGEMENT GUIDELINE 2013
DIAGNOSIS
TARGET BP
TARGET BP CONTROL < 140/90 mmhg CVD [IHD,MI,stroke,TIA] CKD [GFR<60 ml/min/1.73m 2 ] DM <140/85[130-139 / 80-85] mmhg Elderly < 80yrs Start treatment if SBP >160 mmhg,target140-150 ก target < 140 mmhg Elderly >80 yrs target 140-150 mmhg ก DBP 80-85 mmhg, safe and well tolerated
ANTIHYPERTENSIVE DRUG
ANTIHYPERTENSIVE DRUG Drug 5 group: ACEI: Enalapril,Captopril ARB: Losartan, Varsatan Beta Blocker: Atenolol, propanolol, metoprolol CCB: Amlodipine, nifedipine, verapamil, Diltiazem Thiazide diuretic Other: Alpha-blocker, methydopa, hydralazine ACEI ก ARB [ 2combination of RAAS] : renal complication, hyperkalemia BB ก thiazide IGT, IFG or metabolic syndrome ก BB carvedilol or nebivolol
ก ก ACEI,ARB DM LVH, MI, IHD, CHF, Cardiomyopathy, AF Macro/ Micro Protinuria, CKD, ESRD Atherosclerosis: Stroke, Metabolic syndrome Beta blocker MI, angina, IHD, CHF[metoprolol] AF Aortic aneurysm CCBs DHP[Amlodipine]: Isolated systolic HT Non DHP[Verapamil,Diltiazem]: SVT, AF, angina Pregnancy: Methydopa, CCBs, BBs [propanolol, metoprolol] ACEI, ARB
Edema, constipation HypoNa
JNC 8
JNC 8
JNC 8
NORMETEC R AMLODIPINE BESYLATE + OLMESARTAN MEDOXOMIL COMBINATION THERAPY MANAGING THE HYPERTENSION CHALLENGE
BLOOD PRESSURE REDUCTION IS CRITICAL: THE LOWER, THE BETTER Meta-analysis of 61 prospective, observational studies 1 million adults 12.7 million person-years 2 mm Hg decrease in mean SBP 7% reduction in risk of ischemic heart disease 10% reduction in risk of stroke mortality *Epidemiologic studies, not clinical trials of hypertension agents. Lewington S et al. Lancet. 2002;360:1903-1913.
BP Control Usually Requires Combination Therapy Copley JB, Rosario R. Dis Mon. 2005;51:548-614; Dahlof B et al. Lancet. 2005;366:895-906.
Regimen Complexity: A Major Reason for Failure to Adhere to Medication LLT=lipid-lowering therapy; MCO=managed care organization. Retrospective cohort study of MCO population. N=8406 patients with hypertension who added antihypertensive therapy and LLT to existing Rx medications within a 90-day period.adherence to concomitant therapy: sufficient AH and LL Rx medications to cover 80% of days per 91-day period.chapman RH et al. Arch Intern Med. 2005;165:1147-1152.
Rationale for Use of FDC Therapy (1/2) Efficacy - 2 or more different and complementary pathways of BP control are blocked/interfered withfdc therapy often results in BP reductions that are additive Tolerability - Low doses of 2 agents often result in fewer adverse events than high doses of 1 agent Sica DA. Drugs. 2002;62:443-462.Quan A et al. Am J Cardiovasc Drugs. 2006;6:103-113.
Rationale for Use of FDC Therapy (2/2) Persistence and compliance - Lower pill burden likely to improve compliance and persistence with antihypertensive medications compared with agents given as separate pills Overcomes a major barrier to effective BP control A single, once-daily medication or FDC agent simplifies the treatment regimen Neutel J. Combination antihypertensive therapy. In: Oparil S, Weber MA, eds. Hypertension. Companion to Brenner and Rector s The Kidney. 2nd ed. Philadelphia, Pa: Elsevier Saunders; 2005:522-529.
RECOMMENDATIONS FOR COMBINATION THERAPY Most Patients Require 2 Antihypertensives to Reach BP Goal 1,2 Use agents with complementary mechanisms of action 1-3 RAAS blocker plus diuretic or CCB combinations are effective and widely used 1,2 CCB=calcium channel blocker; RAAS=renin-angiotensin-aldosterone system. 1. Chobanian AV, et al. JAMA. 2003;289(19):2560-2572. 2. Mancia G, et al. J of Hypertens. 2007;25:1105-1187. 3. Chrysant SG. Arch Fam Med. 1998;7:370-376. 26 26
ANTIHYPERTENSIVE DRUG
CCB+ARB: Complementary Mechanisms of Action Smith D. Am J Hypertens. 2002; 15:108S-114S.Raspa R. Am Fam Physician. 1993;48:461-470.
Proposed Effect of CCB/ARB Therapy on Peripheral Edema Sica DA. J Clin Hypertens. 2003;5:291-294,297.
Angiotensin Receptor Blockers 1st Generation: Losartan 2nd Generation: Valsartan 3rd Generation: Irbesartan, Telmisartan, Candesartan, Olmesartan, etc.
ARB Pharmacokinetic Parameters ARB Half-Life (Hours) Affinity for AT 1 vs AT 2 receptor Time to Maximum BP Effect * (Weeks) Olmesartan medoxomil 1 13 >12,500 fold 2 Irbesartan 2 11-15 >8,500 fold 2 Losartan potassium 3 6-9 Approx. 1,000 fold 3-6 Telmisartan 4 24 >3,000 fold 4 Valsartan 5 6 Approx. 20,000 fold 4 *From clinical trials. The clinical significance of pharmacokinetic data is unknown. These data are not based on head-to-head studies. 1. Benicar [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc.; 2007. 2. Avapro [package insert]. New York, NY: Bristol-Myers Squibb Sanofi-Synthelabo Partnership; 2007. 3. Cozaar [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2005. 4. Micardis [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2008. 5. Diovan [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2007.
Calcium Channel Blockers Chemical Class First Generation IIa Dihydropyridine Nifedipine Nifedipine GITS Felodipine ER Nicardipine SR Benzothiazepine Diltiazem Diltiazem SR Second Generation IIb Felodipine Nimodipine Benidipine Isradipine Manidipine Nicardipine Nilvadipine Nisoldipine Nitrendipine Third Generation Amlodipine Phenylalkylamine Verapamil Verapamil SR Adapted from Toyo-Oka T., et al., BP (1996)
CCB Pharmacokinetic Parameters CCB Amlodipine besilate Half-Life (hours) Time to Peak plasma concentration (hours) 35-50 6-12 Felodipine ER 16-22 3-7 Lacidipine 3-8 1-3 Nifedipine GITS 12-18 5-10
AMLODIPINE BESYLATE + OLMESARTAN MEDOXOMIL The new power combination in blood pressure control beyond convenience
COACH STUDY: AMLODIPINE + OLMESARTAN COMBINATION MORE EFFECTIVE THAN MONOTHERAPY IN LOWERING SBP AFTER 8 WEEKS Dose (mg) 0 Placebo Olmesartan 10 20 40 Amlodipine 5 10 Amlodipine 5 + Olm Olm Olm 10 20 40 Amlodipine 10 + Olm Olm Olm 10 20 40-5 -4.8 Mean in SBP (mmhg) -10-15 -20-25 -11.5-13.8-16.1-14.9-19.7-24.2-23.6-25.4-25.3-30 -29.2-30.1-35 P<.001 (Hommel s multiple comparison for combinations vs monotherapy components). P<.0001 (for all active treatment groups from ANCOVA vs baseline). OLM = olmesartan. Chrysant SG et al. Presentation at: ASH Annual Meeting 2007. May 19-22; Chicago, Ill.
COACH STUDY: AMLODIPINE + OLMESARTAN COMBINATION MORE EFFECTIVE THAN MONOTHERAPY IN LOWERING DBP AFTER 8 WEEKS Dose (mg) 0 Placebo Olmesartan 10 20 40 Amlodipine 5 10 Amlodipine 5 + Olm Olm Olm 10 20 40 Amlodipine 10 + Olm Olm Olm 10 20 40 Mean in DBP (mm Hg) -2-4 -6-8 -10-12 -14-16 -18-3.1-8.3-9.2-10.2-9.4-12.7-13.8-14.0-15.5-16.0-17.0-20 -19.0 P<.001 (Hommel s multiple comparison for combinations vs monotherapy components). P<.0001 (for all active treatment groups from ANCOVA vs baseline). OLM = olmesartan. Chrysant SG et al. Presentation at: ASH Annual Meeting 2007. May 19-22; Chicago, Ill.
ADDING OLMESARTAN 40MG TO AMLODIPINE 10MG GIVES A LARGE REDUCTION IN OEDEMA FREQUENCY. Amlodipine 10 mg Azoren 40/10 mg Data on file. Sankyo Pharma Development Clinical Trial reportc58663-a-u301
COACH Study: Edema Tolerability Data With Normetec(amlodipine and olmesartan medoxomil): Proactive Evaluation in the Overall Population The incidence of edema was significantly reduced when 20 or 40 mg of olmesartan medoxomil was added to the 10-mg amlodipine dose A reduction in the incidence of edema was not observed with AZOR 5/20 mg or 5/40 mg compared with amlodipine 5 mg monotherapy Edema is a known, dose-dependent adverse event of amlodipine but not of olmesartan medoxomil Chrysant SG, et al. Clin Ther. 2008;30:587-604
ก ก ก ACS,Stroke,AKI, PAD ก ก ก ก
SUMMARY CONTROL BP<140/90 mmhg in General, CVD,CKD BP<140/85 mmhg DM 140-150/ < 90 in elderly HbA1C <6.5% HbA1C < 7, 7-8% ก CVD ก hypoglycemia LDL <100mg%, <70mg% in CVD, T2DM T1DM with DN, CKD