The Evolution To Treatment Of Hypertension With Advanced Formulation

The Evolution To Treatment Of Hypertension With Advanced Formulation Dr. Donald Ang MBChB (UK) FRCP (Edin) MD (UK) CCST Cardiology (UK) FESC (Europe) Consultant Cardiologist Island Hospital Penang

High Blood Pressure, High Blood Cholesterol and CV Diseases CVD Burden Systolic blood pressure over 115 mm Hg 50% Blood Pressure Cholesterol Overall, 61% of cardiovascular disease is due to high blood pressure and/or cholesterol WHO Global Programme on Evidence for Health Policy

Major Public Health Issue: The rate of Hypertension is Increasing 26.4% In 2000, > quarter of the global population had hypertension 2000 1500 1000 Population (in millions) with hypertension globally 1,2 Predicted increase 60% 1 500 0 Yr 1980 Yr 2000 Yr 2008 Yr 2025 1. Kearney et al. Lancet 2005;365:217-223 2. WHO 2011. Global Atlas on Cardiovascular Disease Prevention and Control 3

Stroke and Ischemic Heart Disease Mortality Linked to SBP Levels Stroke Ischemic Heart Disease Lewington et al. Lancet 2002;360:1903-1913 4

Even Small Increases in BP Increases Risk for CVD Each 2 mmhg rise in mean SBP 7% 10% Risk of mortality from ischemic heart disease Risk of mortality from stroke Therefore, reducing BP prevents CV outcomes in patients with hypertension National Institute for Health and Clinical Excellence (NICE). Hypertension Clinical Guideline 127: http://www.nice.org.uk/guidance/cg127

Increased 24-hour BPV has been associated with CV risk Incidence of mortality and cardiovascular events by fifths of the distributions of the systolic average real variability in 8,938 patients Hansen TW, et al. Hypertension 2010;55:1049-1057. BPV, blood pressure variability; CV, cardiovascular; NCV, non CV.

Different types of BPV, their determinants, and prognostic relevance Pronounced fluctuations in BP can occur over short- and long-term observation periods Parati G, et al. Nat Rev Cardiol 2013;10:143-155. AHT, antihypertensive treatment; BP, blood pressure; BPV, BP variability; egfr, estimated glomerular filtration rate.

Guidelines on BPV NICE 2011 1 Variability in SBP when measured visit-to-visit is a strong predictor of stroke, independent of mean SBP Whatever the underlying mechanisms, SBP variability appears to be an important independent predictor of clinical outcomes Updated guidance recommends the best available evidence-based treatment options to suppress BPV in people with hypertension ESC/ESH guidelines 2013 2 Consideration should be given to the evidence that visit-to-visit BPV may be a determinant of CV risk, independently of the mean BP levels achieved during long-term treatment, and that, thus, CV protection may be greater in patients with consistent BP control throughout visits The target for management of hypertension should be BPV control BP, blood pressure; CV, cardiovascular; BPV, BP variability; SBP, systolic BP. 1. National Institute for Health and Clinical Excellence (NICE) Clinical Guideline 127. Available at: http://www.nice.org.uk/nicemedia/live/13561/56007/56007.pdf. 2. Mancia G, et al. Eur Heart J 2013;34:2159-2219.

Association between CV events and early morning period 18:00 0:00 6:00 12:00 Time of day 1. Muller JE, et al. N Engl J Med 1985;313:1315 1322. 2. Marler JR, et al. Stroke 1989;20:473 476. CV, cardiovascular risk; EMBPS, early morning blood pressure surge.

Pooled increase in coefficient of variation (%) Pooled variance ratio CCBs reduce systolic BPV more than other antihypertensive agents: Meta-analysis data 1.50 In a meta-analysis of 389 clinical trials, group systolic BPV was significantly reduced following treatment with CCBs Pooled VR = 0.89; 95% CI, 0.82-0.97; P = 0.0062 There was an increase in group systolic BPV with most other drug classes 1 0.75 50 40 30 20 10 0 CCB CCBND DD ARB ACEI BB AB Placebo Treatment allocation AB, alpha-1 blocker; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; BPV, blood pressure variability; CCB, calcium channel blocker; CCBND, non-dihydropyridine CCB; CI, confidence interval; DD, non-loop diuretic drugs. Webb AJ, et al. Lancet 2010;375:906-915.

CCBs reduce inter-individual systolic BPV more than most other antihypertensives Antihypertensive Class Meta-analysis of 389 trials Effect of Treatment on Inter-individual Systolic BPV Agent class versus all other antihypertensive agent classes Variance Ratio (95% CI) P-value CCB 0.81 (0.76-0.86) <0.0001 Non-loop diuretic 0.87 (0.79-0.96) 0.007 ACEI 1.08 (1.02-1.15) 0.008 ARB 1.16 (1.07-1.25) 0.0002 BB 1.17 (1.07-1.28) 0.0007 CCB versus placebo 0.76 (0.67-0.85) <0.0001 Webb AJ, et al. Lancet 2010;375:906-915. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; BP, blood pressure; BPV, BP variability; CCB, calcium channel blocker; CI, confidence interval.

Systolic BPV and risk of stroke lower with CCBs vs other antihypertensives despite similar mean BP Stroke risk Randomized trials with CCBs versus BBs, ACEIs, or ARBs with stroke risk and systolic BPV (SD) reported Events/patients CCB Drug B NORDIL (vs BB/D) 159/5410 196/5471 ASCOT (vs BB) 327/9639 422/9618 VALUE (vs ARB) 281/7596 322/7649 INVEST (vs BB) 176/11,267 201/11,309 ALLHAT (vs ACE) 377/9048 457/9054 CAMELOT (vs ACE) 6/663 8/673 Total 1326/43,623 1606/43,774 SBP at follow-up Mean (SD) CCB Drug B Mean SBP difference (95% CI) NORDIL (vs BB/D) 155.2 (16.3) 151.5 (17.4) 3.70 (3.07 to 4.33) ASCOT (vs BB) 138.4 (14.8) 140.3 (17.8) 1.90 ( 2.36 to 1.44) VALUE (vs ARB) 138.2 (13.8) 140.0 (16.2) 1.80 ( 4.92 to 1.32) INVEST (vs BB) 131.0 (11.0) 131.0 (10.0) 0.00 ( 0.27 to 0.27) ALLHAT (vs ACE) 137.1 (15.0) 138.4 (17.9) 1.30 ( 1.78 to 0.82) CAMELOT (vs ACE) 124.5 (15.5) 123.6 (18.0) 0.60 ( 1.20 to 2.40) Total 0.21 ( 0.41 to 0.01) 0.5 1.5 Odds ratio (95% CI) 0.81 (0.66 to 0.01) 0.77 (0.66 to 0.89) 0.87 (0.74 to 1.03) 0.88 (0.72 to 1.08) 0.82 (0.71 to 0.94) 0.76 (0.26 to 2.20) 0.82 (0.76 to 0.88) Variance ratio (95% CI) 0.88 (0.83 to 0.93) 0.69 (0.67 to 0.72) 0.73 (0.68 to 0.77) 0.83 (0.80 to 0.86) 0.70 (0.67 to 0.73) 0.74 (0.64 to 0.86) 0.76 (0.74 to 0.77) 0.5 1.5 ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BB, beta-blocker; BP, blood pressure; BPV, BP variability; CCB, calcium channel blocker; CI, confidence interval; D, diuretic; SBP, systolic BP; SD, standard deviation. Rothwell PM. Lancet 2010;375:938-948.

Managing white-coat effect and masked hypertension White-coat effect: A discrepancy of more than 20/10 mmhg between clinic and average daytime ambulatory BP monitoring (ABPM) or average home BP monitoring (HBPM) at the time of diagnosis Masked hypertension: The converse of white-coat hypertension. A subject with masked hypertension has normal BP measurements in the office or clinic but may experience episodes of elevated BP outside of the medical environment For people identified as having a white-coat effect or masked hypertension consider daytime ABPM or HBPM as an adjunct to clinic BP measurements to monitor response to treatment National Institute for Health and Clinical Excellence (NICE). Hypertension Clinical Guideline 127: http://www.nice.org.uk/guidance/cg127 13

2013 European hypertension guidelines: ESH/ESC emphasize out-of-office BP measurement Values Separating from medical environment better reflects true BP condition than office BP Use out-of-office BP for risk stratification: Patients with high office BP but normal out-of-office BP (white-coat hypertension) have lower CV risk than patients with sustained hypertension; the patients with normal office BP but elevated out-of-office BP (masked hypertension) is frequently associated with CV risk factors and has increased risk of CV events Close association with hypertension induced organ damage, especially left ventricular hypertrophy Better prediction of CV morbidity and mortality than office BP Mancia et al. J Hypertens 2013;31:1281-1357 14

2013 ESH/ESC hypertension guidelines: Self-monitoring of BP is a key component of comprehensive BP management Subject Phenomena Recommended improvements Discontinue Irregular therapy Self-monitoring of BP Self-management by simple patient guidance system Patients Establish patient population Strategic information Comprehensive intervention: Including message, reminder, BP self-monitoring, telephone follow-up, or working environment or pharmacy-based projects Comprehensive BP management focusing on patients and combining doctors and communities Poor compliance is a global problem o One-third of patients will discontinue the initial therapy within 6 months after treatment, and only one half of patients will continue treatment after 1 year o Self-monitoring of BP is an important means of improving adherence Mancia et al. J Hypertension 2013;31:1281-1357 15

Definitions of hypertension by office and out-of-office blood pressure levels (mmhg) Category Systolic Diastolic Office BP 140 and/or 90 Ambulatory BP Daytime (or awake) 135 and/or 85 Nighttime (or asleep) 120 and/or 70 24-h 130 and/or 80 Home BP 135 and/or 85 Mancia et al. J Hypertension 2013;31:1281-1357 16

Out-of-office BP Methodologic aspects ABPM Measurement extended to 24 25 hours (includes the night) Difference from operator-measured BP to be checked Diary on events potentially influencing BP useful Measurements to be made at same frequency (eg, every 20 min) during day and night Excessive intervals to be avoided Recording satisfactory if 70% of values available HOME BP To be measured on at least 3 4 days (preferably 7 days) Morning/evening values (quiet environment) Values to be reported in standardized logbook but storage in memory equipped device useful Possible advantage of telemonitoring Data interpretation always by physician Mancia et al. J Hypertension 2013;31:1281-1357 17

HBP telemonitoring improves hypertension control in general practice Adapted from Parati G et al. J Hypertens 2009;27:198 203. A sample of 391 patents with uncontrolled hypertension (80% treated) randomized to usual care (office BP) or to integrated care teletransmitted HBP (TELEHBPM) Key Findings o The percentage of daytime BP normalization was higher in the TELEHBPM group (62%) than in control (50%) (P<0.05) o There were less frequent treatment changes in TELEHBPM than in control group (8.7% vs. 13.5%, P<0.05) Parati G et al. J Hypertens 2009;27:198 203. 18

The many causes of uncontrolled BP Diverse pathogenesis and etiology RAAS Salt-sensitive, volume of body fluid Sympathetic nerve activity Sleep apnea syndrome Secondary forms Poor adherence with AHTs Reduced self-cv perception Forget Adverse drug reactions Poor therapeutic effects Uncontrolled BP BP types Excessive BP variability Non-dipper/reversed dipper (nighttime) hypertension Morning surge Low renin activity Lifestyle (sodium intake) Interfering substances (eg, NSAIDs) Fail to adjust drug species or dosage timely Improper therapeutic regimens Mancia. J Hypertens 2013;31:1281-1357 White. J Manag Care Pharm 2007;13(suppl S-b):S34-S39 19

Patient Compliance is still LOW Adherence rate is only 53.4% in hypertensive patients In other studies looking in to adherence rates to antihypertensive medication, it shows: Only 46% of newly diagnosed patients remain compliant to their medication after 4 years After the first year of medication, there is a drop in compliance in about 50% of the population in the following 2 years.

How does compliance affect blood pressure control? Uncontrolled Blood Pressure 50.3% 36.4% Adherers Non adherers Ramli, A. et al. Medication adherence among hypertensive patients of primary health clinics in Malaysia. Patient Preference and Adherence. 2012;6

% Non Adherers How number of drugs affect compliance 80 70 60 50 40 30 20 10 0 1 2 3 >3 Number of Drugs Taken Ramli, A. et al. Medication adherence among hypertensive patients of primary health clinics in Malaysia. Patient Preference and Adherence. 2012;6

% non adherers Compliance remains a problem in all age group especially younger patients 60 50 40 30 20 10 0 30-49 50-59 60-69 70 Age Group Ramli, A. et al. Medication adherence among hypertensive patients of primary health clinics in Malaysia. Patient Preference and Adherence. 2012;6

Cardiovascular Event Rates: Controlled and Uncontrolled Hypertension Kaplan-Meier estimates of cardiovascular event rates in men and women with controlled (<140/90 mmhg) and uncontrolled blood pressure in the Brisighella Heart Study. Adapted from: Borghi C, et al. J Hypertens. 2004;22:1707 1716. 24

Dysphagia Dysphagia varies depending on the disorder1: 29% to 64% - stroke patients 24% to 34% - patients with multiple sclerosis 81% - patients with Parkinson's disease 30% patients with GERD (gastroesophageal reflux) Common complaints in difficulty in swallowing tablets are 2: Size Surface Form Taste of tablets 25 25

Oral dispersible tablet (ODT) A solid dosage form containing medicinal substances (or) active ingredient which disintegrates rapidly usually within a matter of seconds when placed upon a tongue (FDA) - United States of America food and drug administration

Norvasc ODT Norvasc is the first antihypertensive drug in it s class in Malaysia to have ODT formulation Malaysia is the first country in the SEA region to have launched this formulation. Formulated to increase usability and further enhance medication adherence Once put on the tongue, it disintegrates within seconds Ability to take it without water. The minty taste that Norvasc ODT has will make the medication palatable as well. 27 27

Summary Control of BP remains sub-optimal in many patients Factors that define appropriate BP management/control is more complex than initially understood Roles of home BP monitoring and ABPM in the management of hypertension should be emphasised