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  • Increased blood pressure is the leading risk for death and disability globally according to the Global Burden of Disease Study published in 2012
  • Gold standard test for white coat
  • ACCOMPLISH (compared benazepril and amlodipine with benazepril and HCTZ
  • Studies—BP was reduced in resistant HTN with spironolactone, and was better than doxazosin

Current management of hypertension new Current management of hypertension new Presentation Transcript

  • EPIDEMIOLOGY  Worldwide prevalence is around 20% , and approximately 7.1 million deaths per year may be attributable to hypertension  The WHO reports that suboptimal BP (>115 mmHg SBP) is responsible for 62 percent of cerebrovascular disease and 49 percent of ischemic heart disease (IHD)  Suboptimal BP is top attributable risk factor for death throughout the world Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 19882000. JAMA 2003;290:199-206
  • Global Leading Risks for Death Systolic blood pressure > 115 mmHg Global Burden of Disease Study 2010 , Lancet 2012; 380: 2224–60
  • Attributable Risk 54% stroke 47% IHD 25% other CVD 13.5% Total mortality  Only half of the burden seen in people with hypertension (BP > 140 mmHg); remainder in prehypertensives (BP > 115mmHg)  > 80% of the burden seen in low-income and middle-income regions  Over half occurred in people aged 45-69 yrs Study by Int Society of hypertension; Lancet May 2008;371:1513-8
  • Impact of a 5 mmHg Reduction Overall Reduction Stroke 14% Coronary Heart Disease 9% All Cause Mortality 7% Hypertension 2003;289:2560-2572.
  • India- Soon Heading Towards Being Hypertension Capital No. of people with hypertension in India (millions) At least 1 out of every 5 adult Indians has hypertension 120 107.3 106.2 100 80 60.4 57.8 60 Hypertension is responsible for 57% of all stroke deaths 40 and 24% of all CHD deaths in India 20 0 2000 2025 Men Women Age > 20 yrs J Assoc Physicians India 2007;55:323-4 Lancet 2005;365:217-23; JHH 2004;18:73-8
  • The Natural History of Untreated Hypertension  Untreated hypertension is a self-accelerating condition Evolving arteriolar hypertrophy, and endothelial dysfunction facilitate the later increase of BP transition to higher stage  A summary of nearly all placebo- controlled early outcomes trials in hypertension indicated that  1493 of 13,342 (11.2%) subjects in the placebo groups progressed in stages of hypertension,  Compared with only 95 of 13,389 ( 0.7%) in the drug-treated groups Hansen TW, Staessen JA, Zhang H, et al. Cardiovascular outcome in relation to progression to hypertension in the Copenhagen MONICA cohort. Am J Hypertens. 2007;20: 483-491
  • MAP/PP  The BP can be divided into the steady [mean arterial pressure (MAP)] and the pulsatile [pulse pressure (PP)] components  The MAP is determined by cardiac output (CO) and vascular resistance and remain same throughout vascular tree  PP component is influenced by left ventricular ejection, large artery stiffness, pulse wave reflection, and heart rate and is an independent risk factor
  • Distribution of Hypertension Subtype in the untreated Hypertensive Population in NHANES III b Age ISH (SBP 140 mm Hg and DBP <90 mm Hg) SDH (SBP 140 mm Hg and DBP 90 mm Hg) IDH (SBP <140 mm Hg and DBP 90 mm Hg) 17% 16% <40 100 40-49 16% 20% 20% 11% 50-59 60-69 Age (y) 70-79 80+ 80 Frequency of hypertension 60 subtypes in all untreated 40 hypertensives (%) 20 0 Numbers at top of bars represent the overall percentage distribution of untreated hypertension by age. Franklin et al. Hypertension 2001;37: 869-874.
  • Blood Pressure Classification JNC 7 BP Classification Normal SBP mmHg* <120 DBP mmHg Lifestyle Modification Drug Therapy** and <80 Encourage No Prehypertension 120-139 or 80-89 Yes No Stage 1 Hypertension 140-159 or 90-99 Yes Single Agent Yes Combo Stage 2 Hypertension ≥ 160 or ≥ 100 *Treatment determined by highest BP category; **Consider treatment for compelling indications regardless of BP JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314
  • Prehypertension  SBP 120–139 or DBP 80–89  CV risk increases progressively from levels as low as 115 mmHg SBP  54% of stroke and 46% of ischemic heart disease events occurring in persons with blood pressures in this range Lawes CM, Vander Hoorn S, Rodgers A; International Society of Hypertension. Global burden of blood pressure- related disease, 2001. Lancet. 2008
  • Progress to HTN  Among patients > 35 yr or more than 17% of those with normal BP and 37% of those with BP in the prehypertensive range progress to overt hypertension within 4 years without changes in lifestyle or pharmacological intervention  Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of frequency of progression to hypertension in nonhypertensive participants in the Framingham Heart Study: a cohort study. Lancet. 2001; 358(9294):1682-1686
  • TROPHY  Trial of treatment with candesartan 16 mg once daily pre hypertensive subjects  During the 2 years, hypertension developed in 154 /381 (40%) participants in the placebo group and  53/391(13.5%) of those in the candesartan group  Relative risk reduction 66.3% P<0.001  The PHARAO study with ramipril have similar findings  Julius S, Nesbitt SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensinreceptor blocker. N Engl J Med 2006
  • Proposed New Definition of Hypertension  Current guidelines define HTN according to measured BP  Blood pressure serves as a biomarker for the disease hypertension.  Some patients may have elevated BP in the absence of hypertension.  Patients with the same levels of BP might be in different hypertension stages  So BP should be evaluated in the context of other cardiovascular risk factors and disease markers Expanding the Definition and Classification of Hypertension THE JOURNAL OF CLINICAL HYPERTENSION(WG-ASH) VOL. 7 NO. 9 SEPTEMBER 2005
  • Writing Group of the American Society of Hypertension (WG-ASH)
  • EVIDENCE OF TARGET ORGAN DAMAGE AND CARDIOVASCULAR DISEASE  Cardiac  LVH (moderate to severe) Systolic or diastolic dysfunction Ischemic heart disease  Vasculature Peripheral arterial disease Carotid arterial disease Aortic aneurysm  Renal  Albuminuria (urinary albumin >300 mg/day) CKD (estimated GFR <60 mL/min) or  Cerebrovascular  Stroke /Transient ischemic attack
  • Writing Group of the American Society of Hypertension (WG-ASH)
  • JNC 7 VS WG- ASH  Many individuals designated as having pre-hypertension by JNC 7 will be classified as normal in this system  Because occasional BP elevation without presence of cardiovascular risk factors/ disease markers is not hypertension
  • Stratification of total CV risk in HTN patients ESC 2013
  • Patient Evaluation 1. Two consecutive blood pressure measurements 2. Assess lifestyle and identify other CV risk factors or concomitant disorders that affects prognosis and guides treatment 3. Reveal identifiable causes of high BP 4. Assess the presence or absence of target organ damage and CVD; Accessed October 20, 2003; 8:15AM
  • ABPM  To collect information on BP during usual daytime activities and during sleep  Help in timing of drug therapy  Help in correct prognosis of patients  Latest NICE guidelines of hypertension management recommend ABPM in every patient with clinic blood pressure is >140/90
  • Indications Pre hypertension ii. Variable clinic blood pressure iii. White coat hypertension iv. Masked hypertension v. Resistant hypertension vi. Hypertension in elderly patients vii. Postural hypotension viii. BP evaluation in patients with the suspected or confirmed autonomic dysfunction ix. As an overall guide to hypertension treatment x. As a prognostic cardiovascular tool i.
  • How valid are office BP measurements?
  • ABPM – Diagnostic Thresholds Category 24hr systolic/diastoli c (mm Hg) Daytime (mm Hg) Nighttime (mm Hg) Optimal 115/75 120/80 100/65 Normal 125/75 130/85 110/70 HTN 130/80 140/85 120/70
  • SEARCH FOR CAUSE  Sleep apnea  Drug-induced or related causes  Chronic kidney disease  Primary aldosteronism  Renovascular disease  Chronic steroid therapy and Cushing’s syndrome  Pheochromocytoma  Coarctation of the aorta  Thyroid or parathyroid disease
  • Most Common Causes of Secondary Hypertension by Age* Am Fam Physician 2010 Dec 15;82(12):1471-8.
  • Search Target Organ Damage  Predict CV mortality independently Framingham risk score stratification of SCORE  Change drug treatment  Prevention of TOD reflect adequate management /
  • TOD  Heart • • • • Left ventricular hypertrophy Angina or prior myocardial infarction Prior coronary revascularization Heart failure  Brain • Stroke or transient ischemic attack, cognitive disturbances  Chronic kidney disease  Peripheral arterial disease  Retinopathy  PWV
  • IMPORTANCE  Adequate control of BP and other risk factors can facilitate the regression of TOD.  Preliminary data indicate that regression of albuminuria and of left ventricular hypertrophy are followed by a decrease in the number of cardiovascular events.  Increase in the urinary excretion of albumin predicts cardiovascular events or death.  Wachtell, K. et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive therapy and reduction in sudden cardiac death. Circulation
  • Urine Albumin Predicts CV and Non-CV Mortality in the General Population (Hillege et al Circ 2002; 106: 1777) 6 Cardiovascular 5 Hazard Ratio for Death 4 Noncardiovascular 3 2 1 0 10 100 Urinary Albumin (mg/L) 1000
  • Microalbuminuria and CHD risk in Hypertension (Borch-Johnsen et al AJH 1999;19:92) Relative risk of CHD 6 4 Hi 2 Nl 0 Low <140 140-160 Systolic Pressure >160 High Urine albumin
  • Benefits of Therapy  Reductions in (1) stroke incidence- 35–40 % (2) Myocardial infarction (MI)- 20–25 % (3) HF averaging >40 % Blood Pressure Lowering Treatment Trialists' Collaboration. Lancet 2000
  • Benefits of Therapy .Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension 45:907, 2005
  • What are the goals of therapy?  <140/90 for patients without diabetes or renal disease  Most patients who achieve their systolic goal will also achieve their diastolic goal  <130/80 for patients with diabetes or renal disease JNC 7
  • HOW LOW TO GO  Data from observational studies have indicated that death from CV diseases increases progressively from levels as low as 115 mmHg SBP and 75 mmHg DBP upward in patients free from CV disease  For every 20 mmHg systolic or 10 mmHg diastolic increase in BP, there is a doubling of mortality from both IHD and stroke Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: A metaanalysis of individual data for one million adults in 61 prospective studies. Prospective Studies Collaboration. Lancet 2002;360:190313
  • J- curve  The “J-curve” describes the shape of the relationship between BP and the cardiovascular risk  Whether this J-curve exists in the range of BP at which patients might be exposed to further BP lowering by treatment is unknown  Various studies showed that J-curve exists for DBP for patients with coronary artery disease (CAD) not for renal disease or stroke prevention
  • Does J- curve exist for DBP??  Data showing associations between low in-trial DBP and risk do not prove that the lowering of DBP caused that risk  low baseline DBP would automatically identify a cohort of patients at high cardiovascular disease risk  The cohort of patients with low in-trial DBP are most likely to be older and have diabetes and more likely to have coronary heart disease and a Stiff aorta and higher SBP and pulse pressure  Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med 2006;144:884–93
  • Goal in Coronary Artery Disease and “High Risk” Groups  AHA/ACC Guidelines say: Treat to <130/80  High risk includes any vascular disease, Framingham risk score >10%  Evidence Level 5 (Expert Opinion)
  • Goal in Coronary Artery Disease and “High Risk” Groups  Lower Achieved BP has been associated with no benefit or worsened outcomes in post hoc analysis of trials  INVEST DM and CAD  ONTARGET Vascular disease or DM  ACCORD DM with high CV risk JAMA July 7,2010;304(1)61-68, N Engl J Med 2008;359:2456–67 NEJM 358:1547-1559
  • ACCORD Study Design • Randomized multi-center clinical trial • BP question: does a therapeutic strategy targeting SBP <120 mmHg reduce CVD events compared to a strategy targeting SBP <140 mmHg in patients with type 2 diabetes at high risk for CVD events?
  • ACCORD BP Trial Eligibility • Stable Type 2 Diabetes >3 months • HbA1c 7.5% to 11% (or <9% if on more meds) • High CVD risk = clinical or subclinical disease or ≥2 risk factors • Age (limited to <80 years) ≥ 40 yrs with history of clinical CVD (secondary prevention) ≥ 55 yrs otherwise • Urine protein <1.0 gm/24 hours or equivalent • Serum Creatinine ≤1.5 mg/dl
  • Outcomes Intensive Standard Events (%/yr) Events (%/yr) Primary HR (95% CI) P 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20 Total Mortality 150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55 Cardiovascular Deaths 60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74 Nonfatal MI 126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25 Nonfatal Stroke 34 (0.30) 55 (0.47) 0.63 (0.41-0.96) 0.03 Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01
  • Serious AE Hypotension Syncope Bradycardia or Arrhythmia Hyperkalemia Renal Failure eGFR ever <30 mL/min/1.73m2 Any Dialysis or ESRD Dizziness on Standing† Intensive Standard N (%) N (%) 77 (3.3) 30 (1.3) 17 (0.7) 1 (0.04) 12 (0.5) 5 (0.2) P <0.0001 <0.0001 0.10 12 (0.5) 3 (0.1) 0.02 9 (0.4) 5 (0.2) 1 (0.04) 1 (0.04) 0.01 0.12 99 (4.2) 52 (2.2) <0.001 59 (2.5) 217 (44) 58 (2.4) 188 (40) 0.93 0.36 † Symptom experienced over past 30 days from HRQL sample of N=969 participants assessed at 12, 36, and 48 months post-randomization
  • Conclusions  No conclusive evidence that the intensive BP control strategy reduces the rate of a composite of major CVD events  Assuming that this finding related to stroke were real, the number needed to treat to the lower SBP level to prevent one stroke over 5 years was 89.
  • INVEST Study International Verapamil-Trandolapril Study  Diabetic Subgroup 6400, all with CAD Achieved SBP <130, 130-139, 140+ OUTCOME TIGHT CONTROL USUAL CONTROL UNCONTROLLED 12.7 12.6 19.8 * % Death, MI, Stroke CI 1.01-1.31 11.0 Mortality JAMA July 7,2010;304(1)61-68 10.2 15.4
  • RESULTS  In the high-CV-risk patients of ONTARGET, it appears that this may have beneficial effects for stroke, renal , but not for myocardial infarction, heart failure, or overall CV events.  This suggests that protection against stroke is generally governed by the lower the BP, the better rule. This rule also appears to apply to renal protection
  • IMPLICATION  More aggressive BP lowering might be justified when the risk of stroke clearly exceeds that of a cardiac event.  In Asian countries where stroke accounts for 80% of the overall CV events  Aggressive BP control may also be considered in individuals with severe hypertension because the relative contribution of stroke to the overall incidence of CV events may be greater
  • Hypertension in CKD  Guidelines say: Treat to <130/80  Relevant clinical trials: AASK 2002  RCT 1094 African American patients with hypertensive nephropathy assigned to MAP<93 vs 102-107  Achieved BP 130/78 vs 141/86  4 year result no benefit  10 year Cohort follow up: No benefit overall  Proteinuria subgroup 27% reduction in doubling of GFR at 10 years
  •  Three trials with a total of 2272 participants were included  Analysis did not show that a BP target of less than 125/75 to 130/80 mm Hg is more beneficial than a target of less than 140/90 mm Hg.  low target may be beneficial in subgroups with proteinuria greater than 300 to 1000 mg/d. Ann Intern Med. 2011;154:541-548.
  • Hypertension in CKD  Guidelines say: Treat to <130/80  Evidence says: No renal or cardiovascular benefit in this overall group  Long term renal benefit in patients with proteinuria (>300mg/dl)  New ESC guideline: <140/90, consider <130/80 in patients with proteinuria
  • Evidence Based Goals JNC 8??  <140/90 for almost everybody  Perhaps <130/80 in patients with Proteinuric renal disease at risk for ESRD 2. Patients with recurrent stroke  perhaps a bit higher (<150 systolic) in older patients with isolated systolic HTN 1.
  • ESC 2013
  • ESC 2013  In summary, the goal BP <130/80 mmHg has been discarded for two reasons: 1. Because no concluding evidence exists that would support it 2. Goal BP <130/80 mmHg can be accompanied by an increased risk of cardiac events in patients with established CAD and in whose with diabetes.
  • Lifestyle Modification Modification Weight reduction Approximate SBP Reduction (range) 5-20 mmHg/ 10 kg weight loss Adopt DASH eating plan 8-14 mmHg Dietary sodium reduction 2-8 mmHg Physical activity 4-9 mmHg Moderation of alcohol consumption 2-4 mmHg JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314
  • The Salt Controversy and Hypertension  The WHO recommends a sodium intake of less than 2 g per day, based on projections made from small clinical trials in primary prevention populations  Recent studies suggest that both low and high sodium intake are harmful and salt intake should be limited to 4 g ⁄d to 5 g⁄d  Stolarz-Skrzypek K, Kuznetsova T, Thijs L, et al; European Project on Genes in Hypertension (EPOGH) Investigators. Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion. JAMA. 2011
  • OPTIMAL SODIUM INTAKE IN HIGH RISK PATIENTS  A recent publication in high CV risk patients demonstrated the association between urinary sodium excretion and CV events may be J-shaped, based on data from ONTARGET and TRANSCEND studies O’Donnell MJ, Yusuf S, Mente A, et al. Urinary sodium and potassium excretion and risk of cardiovascular events. JAMA. 2011;306:2229–2238
  • Reasons proposed  Increase in sympathetic nervous system activation  Decreased insulin sensitivity,  Activation of the renin-angiotensin-aldosterone system
  •  Salt reduction is associated with a small physiological increase in plasma renin activity, aldosterone, and noradrenaline and no significant change in lipid concentrations  Their results showed larger reductions in salt intake will lead to larger falls in systolic blood pressure  Further Reduction to 3 g/day will have a greater effect and should become the long term target for population salt intake
  • CONCLUSION  Slow reduction in salt intake, as currently recommended, has a significant effect on blood pressure both in individuals with raised blood pressure and in those with normal blood pressure  Measurement error in assessing daily salt intake, Sudden reduction in salt intake with neuro harmonal activation and Reverse causality may be responsible for J curve
  • AHA 2013
  • Compelling Indications for Individual Drug Classes  Coronary artery disease/Post MI: BB, ACEI  Systolic heart failure: ACEI or ARB, BB, ALDO ANTAG,  thiazide Diastolic heart failure: ACEI or ARB, BB, thiazide Diabetes: ACEI or ARB, thiazide, BB, CCB Kidney disease: ACEI or ARB Stroke or TIA: Thiazide, ACEI  Hypertension. published online November 15, 2013   
  • Should therapy be given to a patient with CAD and ISH with low DBP  Concerns about the impact of further DBP lowering on coronary perfusion  With aging, the predominant effect of treatment is to lower SBP, because the ratio of DBP/SBP lowering with therapy progressively declines with age and low baseline DBP Wang J-G, Staessen JA, Franklin SS, Fagard R, Gueyffier F. Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension 2005
  • • Meta analysis that tested antihypertensive treatment against placebo or no treatment in 18500 patients across a spectrum of age and baseline DBP  Antihypertensive treatment reduced SBP/DBP by 8.3/4.6 mm Hg in young patients (30-59) II. By 10.7/4.2 mm Hg in old patients (60-79) III. By 9.4/3.2 mm Hg in very old patients ( >80) IV. Ratios of DBP to SBP lowering of 0.55, 0.39, and 0.32, respectively I.
  • Contd..  In spite of the differential lowering of SBP and DBP, treatment reduced the risk of all cardiovascular events to a similar extent.  Absolute benefit increased with age and with lower ratio of DBP to SBP lowering.  Suggests that antihypertensive drug treatment improves outcome mainly through lowering of SBP irrespective of the decrease in DBP or the achieved DBP.  These findings remained consistent if the achieved DBP averaged < 70 mm Hg.
  • What to choose first?  Initial antihypertensive therapy without compelling indications • JNC 6: Diuretic or a beta-blocker • JNC 7: Thiazide-type diuretics  Most outcome trials base antihypertensive therapy on thiazides JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314
  • Comparing NICE with JNC 7 First Medication Therapy Used.  NICE:  < 55 years: ACE inhibitor or ARB  > 55 years: Calcium Channel Blocker  If CCB not tolerated or contraindicated, use diuretic.  JNC 7:  Thiazide diuretic for most  Unless diuretic cannot be used or if compelling indication requires use of another class of antihypertensive.
  • Is it appropriate to start 2 agents?  Additional data from other trials suggest that delays of 3 months to 2 years in starting antihypertensive therapy can increase the risk of certain cardiovascular end points, particularly stroke.  Current data support more aggressive treatment to get patients to BP goal faster. Not slow uptritation of single agent as recommended in previous guidelines  So in addition to adequate BP control , prompt BP control is an additional goal
  • Benefits of antihypertensive therapy with early onset of effect  Various trials suggest that the risk of vascular events is significantly influenced by the time it takes to achieve BP control  The VALUE trial, which compared BP-lowering and clinical event rates between patients who achieved immediate vs delayed BP control provides the Evidence evidence of this to date  The combination treatment is more likely to achieve early BP control 1. 2. 3. VALUE:The Lancet, 2004; 363: 2022–2031 The study on cognition and prognosis in the elderly (SCOPE) . J Hypertension 2003 Staessen JA, et al. Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial. J Hypertens 2004; 22: 847–857
  • How to start treatment  Starting with at least two drugs from the start of treatment is recommended in the guidelines particularly in patients in whom actual BP and target BP differ by >20 mmHg  Patients with DM or CKD require even more intensive treatment to achieve a recommended BP goal  Contributes to the maintenance of adequate long-term BP control, as shown in the ACCOMPLISH study
  • Step 2 Treatment  ACE inhibitor/ARB + Calcium Channel Blocker  For those intolerant to CCBs or at high risk of heart failure: ACE inhibitor/ARB + Thiazide-like diuretic.  ACCOMPLISH trial and updated cost-effectiveness analysis both favored CCB
  • Step 3 Treatment  ACEi/ARB + CCB + Thiazide-like diuretic  Based on the recommendations and analyses performed in the first two steps.  Thiazide diuretic examples: chlorthalidone (Hygroton), indapamide (Lozol), hydrochlorothiazide (Hydrodiuril), metolazone (Zaroxolyn)
  • Step 4  Addition of low-dose Spironolactone  Considered when potassium level is <4.5 mmol/L  Higher-dose thiazide-like diuretic treatment  Considered when potassium level is >4.5 mmol/L  Other options for add-on therapy: alpha blockers or beta blockers
  • Combinations
  • ACCOMPLISH Hypothesis  ACCOMPLISH tested a new strategy for the treatment of hypertension –  Assigned 11,506 patients with hypertension  Evidence of cardiovascular or renal disease or target organ damage  Either benazepril hydrochlorothiazide plus amlodipine or benazepril plus
  • RESULTS  Absolute risk reduction of 2.2% with amlodipine- benazepril combination
  • ACEI/ARBs: One or the other, not both The ONTARGET Study  RCCT N=17,118 high risk patients with DM or vascular disease  Ramipril, Telmisartan or both for 56 months  No additional benefit in combined vascular events  Combination therapy caused higher rate of adverse events 1. Hypotensive symptoms (4.8% vs. 1.7%, P<0.001), 2. Syncope (0.3% vs. 0.2%, P=0.03) 3. Renal dysfunction (13.5% vs. 10.2%, P<0.001) NEJMVolume 358:15471559, April 10, 2008
  • Chronotherapy  Chronotherapy means changing the time of medicine administration  In a study - 52 patients >65 years with resistant HT and non-dipper circadian pattern taking 4 or more anti-HT drugs in the morning were included  All drugs were given at night for a 24-week period  After 24 weeks, control of the ambulatory BP was achieved in 22 patients (42.3%) and circadian variability reversed to a dipper pattern in 30 patients (57.7%) Journal of Hypertension : June 2010 - Volume 28 - Issue - p e264
  • Chronotherapy…  Another cross-sectional study investigated the impact of treatment time on the BP pattern in 700 patients with resistant HT.  Percentage of patients with controlled ambulatory BP was double in patients taking 1 drug at bedtime compared with those taking all medication on awakening.  Also, prevalence of non-dipping reduced from 82% to 57% when patients received 1 drug at bedtime Hermida RC et al. : Hypertension. 2005;46:1053–1059.
  • HYPOTHESIS  Prospective MAPEC study was designed to test the hypothesis that 1. Bed time chronotherapy with ≥1 hypertension medications exerts better BP control and 2. CVD risk reduction than conventional therapy, i.e., all medications ingested in the morning
  • METHODS  A total of 2156 hypertensive subjects were randomized to     ingest all their antihypertensive drugs Upon awakening or ≥1 of them at bedtime No differences in ambulatory BP between groups at baseline Sleep-time relative BP decline (an index of BP dipping) (Awake BP mean −Asleep BP mean)/Awake BP mean Patient was defined as dipper if the sleep-time relative SBP decline was ≥10%, and as non-dipper otherwise
  • RESULTS  Patients ingesting medication at bedtime showed Significantly lower mean sleep-time BP 2. Reduced prevalence of non-dipping (34% versus 62%; p < .001) 3. higher prevalence of controlled ambulatory BP (62% versus 53%; p < .001). 1.
  • Relative risks (with 95% confidence intervals) of CVD events
  • BETA BLOCKERS  Beta blockers are not recommended as initial treatment of uncomplicated hypertension  beta-blockers had a reduced ability to protect against stroke, though being equally effective for protection from coronary events and mortality  Administration of beta-blockers is beneficial in patients with angina pectoris, heart failure and a recent myocardial infarction
  • •Double-blind, randomized trial •Losartan (upto 100mg od) Vs atenolol(upto 100mg od) on cardiovascular morbidity and mortality • 9,193 patients (55 to 80 years old) – previously treated or untreated essential hypertension (systolic BP 160–200 mmHg or diastolic BP 95–115 mmHg) – ECG LVH •1,195 patients (13%) had diabetes at baseline •BP CHANGE:- -30/16(LOSARTAN) Vs -29/17(ATEN.) Dahlof B, et al. Lancet. 2002;359:995-1003.
  • LIFE: Primary Composite Endpoint Composite of CV Death / MI / Stroke P=0.021 15% 12.8% 11.0% 10% 5% 0% Rate 23.8/1,000 patient yrs Adjuste d Hazard Ratio = 0.87 Rate 27.9/1,000 patient yrs n=508 n=588 Losartan Atenolol
  • LIFE: Individual Endpoint Results Cardiovascular Death P=0.206 8% 6% Myocardial Infarction P=0.001 P=0.491 8% Adjuste d HR 0.89 Stroke 8% Adjusted HR 1.07 5.1% 6% 4.4% 6% 4.3% Adjuste d HR 0.75 6.7% 5.0% 4.1% 4% 4% 4% 2% 2% 2% 0% 0% 0% Losartan Atenolol Losartan Atenolol Losartan Atenolol
  • LIFE: New-onset diabetes P=0.001 10% 8% 6% 4% 5.2% Rate 13.0/1,000 patient yrs Adjuste d Hazard Ratio = 0.75 7.0% Rate 17.4/1,000 patient yrs 2% 0% n=241 n=319 Losartan Atenolol
  • ASCOT-BPLA: Additional reductions in group receiving the amlodipine-based regimen Amlodipine-based* (n = 9639) Atenolol-based (n = 9618) Rate/1000 patient years † Rate/1000 patient years Amlodipine-based better Secondary endpoints Nonfatal MI (excluding silent) + fatal CHD Total coronary endpoint Total CV events and procedures All-cause mortality CV mortality Fatal/nonfatal stroke Fatal/nonfatal HF 7.4 8.5 14.6 27.4 13.9 4.9 6.2 2.5 16.8 32.8 15.5 6.5 8.1 3.0 Tertiary endpoints Development of diabetes Development of renal impairment 11.0 7.7 Atenolol-based better 15.9 9.1 0.50 *Amlodipine 5–10 mg ± perindopril 4–8 mg prn †Atenolol 50–100 mg ± bendroflumethiazide 1.25–2.5 mg/potassium prn Unadjusted risk reduction P <0.05 <0.01 <0.0001 <0.05 0.001 <0.001 NS <0.0001 <0.05 0.70 1.00 1.45 2.00 Dahlöf B et al; ASCOT Investigators. Lancet. 2005;366:895-906.
  • ASCOT-BPLA: Summary • Amlodipine perindopril showed reductions in: – Major CV events 16% – New-onset diabetes 30% – Stroke 23% – Mortality 11% • Improved BP control* with amlodipine perindopril may explain some, but not all, of the benefit Dahlöf B et al. Lancet. 2005;366:895-906. Poulter NR et al. Lancet. 2005;366:907-13.
  • Journal of Hypertension 2006, 24:2131–2141
  • CONCLUSION  Beta-blockers are inferior to CCBs and to RAS inhibitors and RAS inhibitors for reducing several important hard end points.  Hence beta-blockers are generally suboptimal first-line antihypertensive drugs
  • EXPLANATION ?  ASCOT trial Suggested that BP in the central aorta might be an explanation for increase stroke in beta blocker group  In this trial atenolol based regimen was less efficacious in reducing central aortic pressure than amlodipine based regimen  Williams Bet al: differential impact of blood pressure lowering drugs on central aortic pressure and clinicaL outcomes CAFÉ study . CIRCULATION 113:1213,2006
  • CAFE-Heart Rate  The difference in central aortic pressure is largely explained by heart rate lowering effect of beta blockers  Slowing heart rate will increase central augmentation index and in turn diminish central BP lowering effect of beta blockers  Williams B, Lacy PS. Impact of heart rate on central aortic pressures and hemodynamics: analysis from the CAFE (Conduit Artery Function Evaluation) study: CAFE-Heart Rate. J Am Coll Cardiol 2009;54:705–713.
  • NEW BETA BLOCKERS  These findings cannot be directly extrapolated to other β-blockers, such as nebivolol and carvedilol  They have vasodilating effect in the peripheral circulation and less heart-rate–slowing effect in the heart  They reduces central pulse pressure and aortic stiffness better than atenolol or metoprolol metoprolol  and affect insulin sensitivity less than Impact of Heart Rate on Central Hemodynamics and Stroke: A Meta-Analysis of β-Blocker Trials Feng-Hua Ding1, Yan Li1, Li-Hua Li1, Ji-Guang Wang1 American Journal of Hypertension 26(1) January 2013
  • JNC 8 WHAT IS EXPECTED  BP goal in all patients with hypertension should be 140/80 except: very elderly  < 150 Significant proteinuria  <130/80  In addition to good BP control prompt BP control should be the goal  One drug at bed time can be considered in patients with hypertension especially in non dippers  ACE inhibitors and ARB combination is not useful
  • JNC 8 WHAT IS EXPECTED  Chlorthalidone or indapamide should be highlighted as the evidence-based thiazide-type diuretic of choice  Reduced role for Beta-Blockers as initial therapy  Recommendation for low dose aldosterone antagonist as add-on therapy in resistant HTN.  Delineation of role for ambulatory/home BP monitoring
  • hypertension in the elderly  PREVELENCE
  • PATHOPHYSIOLOGY  Increased arterial stiffness (reduction of elasticity), with the resultant increase in PWV and alteration in wave reflection, is largely responsible for the age-related rise in the prevalence of hypertension Y O
  • Evaluation  Polypharmacy, OSA, ARAS, CKD very common  Exclude pseudohypertension  Postural hypotension very common because of increased stiffness of the carotid arteries leads to blunting of the carotid baroreflex  Postprandial hypotension, defined as a decrease in systolic BP of ≥20 mmHg within 2 h after a meal, is a common and often unrecognized cause of syncope among the elderly  Rx- Avoid diuretics/ alpha glucosidase inhibitors
  • GOAL  Less then 80 years- 140/80 with Close watch on adverse responses  More then 80 years, the target systolic BP should be <150 mmHg which reflects the findings of the Hypertension in the Very Elderly Trial (HYVET)  HYVET was the first prospective trial in patients with hypertension who were >80 years of age
  •  Randomly assigned 3845 ,>80 years of age  Had a sustained SBP of 160 mm Hg or more  Receive either the diuretic indapamide +-prindopril added if necessary to achieve the target blood pressure of 150/80  The primary end point was fatal or nonfatal stroke
  • RESULTS HR 95% CI All Stroke 0.70 S(0.49, 1.01) Stroke Death 0.61 (0.38, 0.99) All cause mortality 0.79 (0.65, 0.95) NCV/Unknown death 0.81 (0.62, 1.06) CV Death 0.77 (0.60, 1.01) Cardiac Death 0.71 (0.42, 1.19) Heart Failure 0.36 S(0.22, 0.58) CV events 0.66 S(0.53, 0.82) 0.1 0.2 0.5 0 2
  • Conclusions  Antihypertensive treatment based on indapamide (SR) 1.5mg ( perindopril) reduced  stroke mortality and total mortality in a very elderly cohort  Large and significant benefit in reduction of heart failure  NNT (2 years) = 94 for stroke and 40 for mortality
  • DRUG THERAPY IN ELDERLY  No specific drug by JNC7/ESC 2013  NICE guidelines CCBs or (for those intolerant of CCBs) thiazide-like diuretics preferred as initial therapy for patients aged >55 years,  Also recommend that more-potent and longer-acting thiazide-like diuretics (chlorthalidone/ indapamide ) should be be used in preference to HCZ