Treatment Strategies in Hypertension and the Role of Single Pill Combination,Yuqing Zhang Division of Hypertension, Fu Wai Hospital, CAMS & PUMC,Issues to Adress,Antihypertensive treatment strategies: general considerations Importance of drug combinations vs strategies based on monotherapies Advantages of single pill combinations Adherence to treatment as a key factor for CV protection,Choice of antihypertensive drugs,Current Guidelines reconfirm that the following drug classes are all suitable for initiation and maintenance of antihypertensive treatment either as monotherapy or in some combination with each other (IA) Diuretics (thiazides / chlorthalidone / indapamide) Beta-blockers Calcium antagonists ACE-inhibitors Angiotensin receptor blockers,2013 ESH/ESC Hypertension Guidelines,Relative Risk (RR) of CV Events in Trials Comparing Drug vs Control Group,Law et al., BMJ 2009; 339: b1665,Thiazides -blockers ACEI ARB CA-channel blockers,Specified drug better,CHD RR (95% CI),Control better,1.0,2.0,0.5,Control better,1.0,2.0,0.5,Stroke RR (95% CI),CHF RR (95% CI),Control better,1.0,2.0,0.5,Trials Events,64 9031,64 10096,39 4256,Specified drug better,Specified drug better,Average BP over 24 Hours (Peak and Trough) from 357 Randomized Trials (n = 40000 Treated and 16000 Placebo Patients),Law MR et al., Brit Med J 2003; 326: 1427, SBP (mmHg), DBP (mmHg),Adverse Effects of Drugs in 357 Randomized Trials (n = 40000 Treated and 16000 Placebo Patients),Law MR et al., Brit Med J 2003; 326: 1427,%,Which strategy to adopt if initial Monotherapy at standard dose Fails？,Percentage of Patients Reaching a Target SBP140 mmHg with Different Classes of Antihypertensive Agents,Morgan et al., J Hypertens 2001; 14: 241-247,Placebo,ACEI,Beta- blockers,Calcium channel blockers,Diuretics,Ratio of observed to expected incremental blood pressure-lowering effects* of adding a drug or doubling the dose according to the class of drug,Wald DS et al., Am J Med 2009; 122: 290,* The expected incremental effect is the incremental blood pressure reduction of the added (or doubled drug), assuming an additive effect and allowing for the smaller reduction from 1 drug (or dose of 1 drug) given the lower pretreatment blood pressure because of the other,Greater BP Reductions by Combination Treatment,Several interactive factors are usually responsible for a BP elevation BP is a multiregulated variable, the involved factors enhancing or opposing each other The greater the number of BP lowering mechanisms recruited by treatment the better,UKPDS = United Kingdom Prospective Diabetes Study; MDRD = Modification of Diet in Renal Disease; HOT = Hypertension Optimal Treatment; AASK = African American Study of Kidney Disease; RENAAL = Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; IDNT = Irbesartan Diabetic Nephropathy Trial,Average Number of Antihypertensive Agents Needed per Patient to Achieve Target BP Goals,Average no. of antihypertensive medications,2,3,4,Trial (SBP achieved),1,Updated from Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661; Arch Int med 2003525-41,Combination Treatment,No matter which drug is employed, monotherapy can effectively reduce BP in only a limited number of hypertensive patientsMost patients require the combination of at least two drugs to achieve BP control,2013 ESH/ESC Hypertension Guidelines,Possible combinations of antihypertensive drug classes,Only dihydropyridines to be combined with -blockers (except for verapamil or diltiazem for rate control in AF) Thiazides + -blockers increase risk of new onset DM ACEI + ARB combination discouraged (IIIA),Green/continuous: preferred Green/dashed: useful (with some limitations) Black/dashed: possible but less well tested Red/continuous: not recommended,2013 ESH/ESC Hypertension Guidelines,Preferred combinations,PROGRESS ADVANCE HYVET CAPPP LIFE SCOPE,Diuretics*,ARBs,ACEIs,Syst-Eur Syst-China NORDIL INVEST ACCOMPLISH ASCOT,ARBs,ACEIs,ELSA FEVER CONVINCE VALUE,Diuretics*,CCBs,CCBs,* Including thiazides/chlorthalidone/indapamide,2013 ESH/ESC Hypertension Guidelines,17089 M,Which two-drug combination is preferable ? RAS Blocker+CCB or RAS Blocker+Diuretic?,Major drug combinations used in trials of antihypertensive treatment in a step-up approach or as a randomized combination,Hazard Ratios for Primary and Secondary Endpoints (olmesartan + CCB or D; n = 5658),Ogihara T et al., J Hypertens 2014; 32: 2054-2063,OutcomePrimary endpoint: Composite of CV events Sudden death Stroke (F and NF) Cardiac events (F and NF) Renal events Secondary endpoints All-cause mortality Composite of hard endpoints Cardiovascular death NF stroke NFmyocardial infarction Atrial fibrillation New-onset diabetes,Olmesartan plus CCB (n = 2568)116 (4.5) 6 (0.2) 63 (2.5) 37 (1.4) 14 (0.6)64 (2.5) 72 (2.8) 13 (0.5) 60 (2.3) 9 (0.4) 43 (1.7) 10 (0.4),Olmesartan plus diuretic (n = 2573) 135 (5.3) 11 (0.4) 66 (2.6) 47 (1.8) 14 (0.5)76 (3.0) 88 (3.4) 18 (0.7) 62 (2.4) 16 (0.6) 32 (1.2) 15 (0.6),