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  • For every 20 mm Hg systolic or 10 mm Hg diastolic increase in BP, there is a doubling of mortality from both ischemic heart disease and stroke.
    Data from observational studies involving more than 1million individuals have indicated that death from both ischemic heart disease and stroke increases progressively and linearly from BP levels as low as 115 mm Hg systolic and 75 mm Hg diastolic upward. The increased risks are present in all age groups ranging from 40 to 89 years old.
  • Systolic pressure differences seen in individual studies are shown in the above figure. Blood pressure after enrollment was reported at near mean or median follow-up in ten trials, at end of follow-up in four, and as average of whole follow-up in 13. In addition to ALLHAT, CAPPP, and NORDIL, differences in achieved systolic pressure, diastolic pressure, or both between study groups (reference minus experimental drug) were significant in hypertension trials that included less treated or untreated controls, and in MIDAS (difference 3·5 [systolic]/about 0 [diastolic] mm Hg), HOPE (3·3/1·0 mm Hg), PART2 (5/4 mm Hg), and SCAT (4/2 mm Hg). For MIDAS combined with NICS and VHAS, systolic/diastolic differences were 1·8/about 0 mm Hg. For PART2 combined with SCAT, these differences were 4·6/3·1 mm Hg.
  • Awareness, treatment, and control rates of hypertension (HTN) improved from the 1976 to 1980 Second National Health and Nutrition Examination Survey (NHANES II) to the 1988 to 1991 NHANES III, phase 1. Awareness increased from 51% to 73%, treatment rates from 31% to 55%, and control rates from 10% to 29%.
    However, from the first phase of NHANES III (1988-1991) to the second phase (1991-1994) there was a plateauing of awareness, treatment, and control rates. Awareness fell from 73% to 68%; treatment rates remained virtually unchanged, going from 55% to 54%; control rates dropped slightly from 29% to 27%.
    In the most recent NHANES survey (1999-2000), awareness was roughly the same (70%) as the 1991-1994 survey. Treatment increased to 59% from 54% and control increased from 27% to 34% in the 1991-1994 and 1999-2000 surveys, respectively.
    Definitions:
    HTN = systolic BP 140 or diastolic BP 90 mm Hg, or taking medication
    Aware HTN = With HTN and told by doctor
    Treated HTN = Take HTN medication
    Control HTN = Take HTN medication and systolic BP <140 and diastolic BP <90 mm Hg.
    Percentages are pts divided by total population with hypertension (denominator).
    Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension. 1995;25:305-313.
    The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Archives of Internal Medicine 1997;157:2413-2246
    Chobanian, A. V., G. L. Bakris, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6): 1206-52.
    Hajjar & Kotchen. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA 2003;290(2):199-206.
    Ong, K. L., B. M. Cheung, et al. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999-2004. Hypertension 2007;49(1): 69-75.
  • Key Points
    Rates of awareness, treatment, and control of blood pressure have increased substantially1,2 [Leenen, P1446, R Col, 2nd Para (13.7% unaware), Table 5]
    However, there continue to be at least 34% of patients with hypertension who are not reaching target blood pressures1 [Leenen, P1446, Table 5]
    Background
    1992 data are from the Canadian Heart Health Survey (CHHS)2 [Joffres P1102, Fig 4]
    2006 data are from the Ontario Survey on the Prevalence and Control of Hypertension1 [Leenen P1446, R Col, 2nd Para (13.7% unaware), Table 5]
    References
    1. Leenen FH, et al. Results of the Ontario survey on the prevalence and control of hypertension. CMAJ 2008;178:1441-9.
    2. Joffres MR, et al. Distribution of blood pressure and hypertension in Canada and the United States. Am J Hypertens 2001;14:1099-105
  • Key Points
    Rates of awareness, treatment, and control of blood pressure have increased substantially1,2 [Leenen, P1446, R Col, 2nd Para (13.7% unaware), table 5]
    However, there continue to be at least 34% of patients with hypertension who are not reaching target blood pressures1 [Leenen, P1446, Table 5]
    Background
    1992 data are from the Canadian Heart Health Survey (CHHS)2 [Joffres P1102, Fig 4]
    2006 data are from the Ontario Survey on the Prevalence and Control of Hypertension1 [Leenen, P1446, R Col, 2nd Para (13.7% unaware), Table 5]
    References
    1. Leenen FH, et al. Results of the Ontario survey on the prevalence and control of hypertension. CMAJ 2008;178:1441-9.
    2. Joffres MR, et al. Distribution of blood pressure and hypertension in Canada and the United States. Am J Hypertens 2001;14:1099-105
  • The BP control rate breakdown, country by country, shows that there is a need for improved BP control, whatever the countries or continents. Several explanations have been proposed, which include limited efficacy and poor compliance, as underlined by Prof P. Sever during the last ESC congress.
    A very recent paper published in the Journal of Hypertension in June 1998 shows that achievement of a BP level below 140/90 mm Hg can be as low as 6% in England.
    Data from this survey also provides some explanations for the reasons for the particularly poor control in England.
    Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI). Arch Intern Med. 1997;157:2413-2465.
    Chockalingham A, Fodor JG. Treatment of raised blood pressure in the population. The Canadian experience. Am J Hypertens. 1998;11:747-749.
    Colhoun HM, Dong W, Poulter NR. Blood pressure screening, management and control in England: results from the health survey for England 1994. J Hypertens. 1998;16:747-752.
  • Key Points
    Treatment inertia has been cited as an important factor contributing to inadequate BP control
    Treatment inertia can be defined as the failure to initiate or modify therapy in patients with uncontrolled blood pressure1 [Moser, P1, L Col, 2nd Para]
    Uncontrolled blood pressure is typically defined as being >140/90 mmHg or in patients with diabetes, renal issues, or coronary heart disease, >130/80 mmHg1 [Moser, P1, L Col, 2nd Para]
    When a fully compliant patient returns to the clinician and continue to fall short of blood pressure targets and no change in therapy takes place – this can be considered treatment inertia1 [Moser, P1, L Col, 2nd Para; R Col, 1st Para]
    Reference:
    1. Moser M. Physician or clinical inertia: what is it? Is it really a problem? And what can be done about it? J Clin Hypertens (Greenwich) 2009;11:1-4.
  • Key Points
    The DIOVANTAGE 4 study showed that therapeutic inertia is common in Canada [Tardif, Pe184, L Col, 1st Para]
    After 3 months of antihypertensive therapy, 41% of patients continued to have blood pressure above targets1 [Tardif, Pe184, L Col, 1st Para]
    Among patients not at target, antihypertensive therapy was changed in only 45% of cases1 [Tardif, Pe184, L Col, 1st Para]
    Background
    Observational study in 34,033 patients with hypertension taking either valsartan 80-160 mg monotherapy or valsartan 80-160 mg + hydrochlorothiazide 12.5-25 mg [Tardif, Pe179, R Col, 2nd Para; Pe180, L Col, 1st Para]
    3-month follow-up visit to assess response and the need for treatment modification [Tardif, Pe179, L Col, 2nd Para]
    Reference:
    1. Tardif JC, et al. Reaching the therapeutic goal in hypertension: results from the Canadian valsartan observational study (DIOVANTAGE 4). Can J Clin Pharmacol 2008;15:e177-87.
  • Key Points
    Possible barriers to effective management of blood pressure in patients with hypertension, include:1 [Moser, P2, R Col, 1st Para]
    Some physicians may not be as concerned about blood pressures that are only slightly above target
    A resistance to complex drug regimens and the corresponding monitoring burden
    Varying practice patterns or a lack of therapeutic alliance may be an issue
    A physician may fail to communicate to the patient the need for continued therapy in maintaining targets
    Hypertension, an asymptomatic condition, may become secondary when a patient presents with more symptomatic comorbidities
    Adverse effect profiles may be a concern
    Reference:
    1. Moser M. Physician or clinical inertia: what is it? Is it really a problem? And what can be done about it? J Clin Hypertens (Greenwich) 2009;11:1-4.
  • Key Points
    The UK Prospective Diabetes Study (UKPDS) showed the benefits of more intense blood pressure (BP) control in patients with type 2 diabetes [UKPDS, P707, Fig 4; P709, L Col, 3rd Para]
    There were significant relative risk reductions with tight vs. less tight BP control in diabetes related death (-32%, p=0.019), stroke (-44%, p=0.013), and microalbuminuria (-29%, p=0.009)1 [UKPDS, P707, Fig 4; P709, L Col, 3rd Para]
    Treatment inertia (less intensive therapy) appears to be associated with greater CV risk
    Background
    Randomized, controlled trial comparing tight blood pressure control (target: <150/85 mm Hg) vs. less tight control (target: <180/105 mmHg) in patients with hypertension and type 2 diabetes (n=1148). Trial had a median follow-up period of 8.4 years [UKPDS, P705, L Col, 1st Para; P706, R Col, 4th Para]
    Tight control treatments: captopril 25-50 mg/d or atenolol 50-100 mg/d [UKPDS, P705, L Col, 1st Para; 2nd Para]
    Less tight control treatments: avoidance of ACE-Is and beta-blockers [UKPDS, P705, L Col, 1st Para]
    Reference:
    1. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317:703-13.
  • Key Points
    The Steno-2 study showed the benefit of more intensive multifactorial intervention in patients with type 2 diabetes1 [Gaede, P383, 3rd Para; P388, Table 3]
    Intensive treatment resulted in significantly greater decrease in BP 14/12 mm Hg compared to usual treatment 3/8 mm Hg1 [Gaede, P388, Table 3]
    Significantly greater reductions in cardiovascular events (RR=0.47, p=0.008), nephropathy (RR=0.39, p=0.003), retinopathy (RR=0.42, p=0.02), and autonomic neuropathy (RR=0.37, p=0.002) were seen with intensive treatment1 [Gaede, P383, 3rd Para]
    Treatment inertia (less intensive therapy) appears to be associated with greater CV risk
    Background
    Randomized, open, parallel trial in patients with type 2 diabetes and microalbuminuria (n=160) comparing conventional treatment vs. intensive treatment (behaviour modification and pharmacologic therapy to target hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, plus aspirin for CVD secondary prevention) [Gaede, P383, 2nd Para; P384, R Col, 2nd Para]
    Reference:
    1. Gaede P, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93.
  • Certainly, efficacy is one parameter which influences BP control, however in addition to efficacy, compliance can also influence BP control. Therefore an ideal antihypertensive agent which is both effective in BP lowering as well as being convenient in terms of dosing regimen and has a favorable side effect profile may increase the number patients with hypertension getting to goal.
  • Key Points
    Combination therapy can provide greater efficacy with fewer side effects than monotherapy1 [Neutel, P1471, R Col, 1st Para]
    As shown in the graph, with combination therapy, efficacy and safety are both going in the same direction, providing a more ideal antihypertensive therapy1 [Neutel, P1472, Fig 6]
    Several studies have shown that antihypertensives given in low-dose combinations result in substantially greater BP reduction, with fewer or similar side effects compared to monotherapy
    This is because some combinations have complementary effects1 [Neutel, P1471, R Col, 1st Para]
    For example, the metabolic effects of diuretics are significantly attenuated when given with an ACE inhibitor or an ARB1 [Neutel, P1471, R Col, 1st Para]
    Reference:
    1. Neutel JM. The role of combination therapy in the management of hypertension. Nephrol Dial Transplant 2006;21:1469-73.
  • Awareness, treatment, and control rates of hypertension (HTN) improved from the 1976 to 1980 Second National Health and Nutrition Examination Survey (NHANES II) to the 1988 to 1991 NHANES III, phase 1. Awareness increased from 51% to 73%, treatment rates from 31% to 55%, and control rates from 10% to 29%.
    However, from the first phase of NHANES III (1988-1991) to the second phase (1991-1994) there was a plateauing of awareness, treatment, and control rates. Awareness fell from 73% to 68%; treatment rates remained virtually unchanged, going from 55% to 54%; control rates dropped slightly from 29% to 27%.
    In the most recent NHANES survey (1999-2000), awareness was roughly the same (70%) as the 1991-1994 survey. Treatment increased to 59% from 54% and control increased from 27% to 34% in the 1991-1994 and 1999-2000 surveys, respectively.
    Definitions:
    HTN = systolic BP 140 or diastolic BP 90 mm Hg, or taking medication
    Aware HTN = With HTN and told by doctor
    Treated HTN = Take HTN medication
    Control HTN = Take HTN medication and systolic BP <140 and diastolic BP <90 mm Hg.
    Percentages are pts divided by total population with hypertension (denominator).
    Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension. 1995;25:305-313.
    The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Archives of Internal Medicine 1997;157:2413-2246
    Chobanian, A. V., G. L. Bakris, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6): 1206-52.
    Hajjar & Kotchen. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA 2003;290(2):199-206.
    Ong, K. L., B. M. Cheung, et al. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999-2004. Hypertension 2007;49(1): 69-75.
  • This slide shows the percentage of patients meeting systolic, diastolic, and overall BP goals at baseline, 6 months, and every year through 5 years of follow-up, along with the number of drugs. As shown, mean BP decreased from 145/83 mm Hg at baseline to 135/75 mm Hg at 5 years. BP control rates increased from 27.4% at baseline to 65.6% at 5 years. Systolic control rates increased from 30.9% to 67.1%, whereas diastolic control rates went from 68.1% to 92.4%. The mean number of drugs increased over the course of the study from 1.3 at 6 months to 2 at 5 years.
  • Key Points
    The Steno-2 study showed the benefit of more intensive multifactorial intervention in patients with type 2 diabetes1 [Gaede, P383, 3rd Para; P388, Table 3]
    Intensive treatment resulted in significantly greater decrease in BP 14/12 mm Hg compared to usual treatment 3/8 mm Hg1 [Gaede, P388, Table 3]
    Significantly greater reductions in cardiovascular events (RR=0.47, p=0.008), nephropathy (RR=0.39, p=0.003), retinopathy (RR=0.42, p=0.02), and autonomic neuropathy (RR=0.37, p=0.002) were seen with intensive treatment1 [Gaede, P383, 3rd Para]
    Treatment inertia (less intensive therapy) appears to be associated with greater CV risk
    Background
    Randomized, open, parallel trial in patients with type 2 diabetes and microalbuminuria (n=160) comparing conventional treatment vs. intensive treatment (behaviour modification and pharmacologic therapy to target hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, plus aspirin for CVD secondary prevention) [Gaede, P383, 2nd Para; P384, R Col, 2nd Para]
    Reference:
    1. Gaede P, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93.
  • The following hypothesis is based on computational models as well as in vitro and in vivo studies. The clinical significance of this hypothesis has not been established.
    Olmesartan medoxomil is a prodrug. Following oral administration, it is rapidly and completely hydrolyzed to its active metabolite, olmesartan, by de-esterification in the intestinal wall [Schwocho et al, 2001]. After the conversion of olmesartan medoxomil to olmesartan, olmesartan is not metabolized further. Olmesartan is the only compound detected in urine and feces.
    Structure activity relationships (SARs) for the imidazole based antagonists (ARBs) have been reported and show key elements required for effective antagonism. A number of different features come into play when examining the binding affinity of an ARB with the AT1 receptor. Weak binding forces such as hydrophobic interactions and hydrogen bonding are involved as well as acid-base interactions between acidic portions of the ARB and basic sites on the receptor.
    Lipophilic substitutents such as a biphenylmethyl group at the imidazole 1-position and a linear alkyl group at the imidazole 2-position associate with lipophilic pockets on the AT1 receptor. The nitrogen atom at the 3-position of the imidazole ring provides a point for hydrogen bonding with the receptor. An acidic group (tetrazole or carboxylic acid (COOH)) at the 2’-position of the biphenyl portion of the molecule provides a binding position with a basic group on the AT1 receptor, presumably arginine 167 on transmembrane region IV. Similarly, an acidic group at the 5-position of the imidazole ring provides another acidic point of attachment to the AT1 receptor (believed to be lysine 199 on transmembrane region V).
    Summary of key structural features
    Biphenylmethyl group at the imidazole 1-position and linear alkyl group at the imidazole 2-position
    - Associates with hydrophobic pockets on AT1 receptor
    Nitrogen atom at the imidazole 3-position
    - Provides site for hydrogen bonding with AT1 receptor
    Acidic substituent at the biphenyl 2'-position
    - Tetrazole or carboxylic acid will bind with basic position on AT1 receptor
    Substituents at the imidazole 4- and 5-positions
    - Key elements in differences between ARBs
    A wide variety of imidazole 4-substituents were examined to determine the effect on binding. When looking at alkyl and alkenyl substituents, bulkier groups decreased the binding affinity. However, when changing from alkyl/alkenyl groups to hydroxy containing substituents, binding affinities increased [Yanagisawa et al, 1996]. Additionally, a medium sized alkyl substituent aids in binding through lipophilic interaction, perhaps mimicking the isopropyl side chain of the Ile fragment in Ang II. Thus, the C(CH3)2OH substituent at the imidazole 4-position, which provided moderate bulk and hydrogen bonding capability, was chosen for olmesartan.
    The end result is that a hydroxy group on the substituent at the imidazole 4-position is important for high binding affinity.
  • Key Points
    A randomized controlled trial in 588 patients with hypertension compared the effects of four ARBs: olmesartan, irbesartan, losartan, and valsartan1,2 [Oparil 2005, P290, L Col, 2nd Para; Oparil 2001, P286, L Col, 2nd Para]
    A secondary analysis of the data showed that the percentage of patients achieving blood pressure targets (<140/90 mmHg) was greater with olmesartan 20 mg (32.4%) than irbesartan 150 mg (25.9%) and significantly greater than losartan 50 mg (16.1%) and valsartan 80 mg (14.5%) (both p<0.001)1 [Oparil 2005, P291, Fig 2a]
    Background
    Randomized, double-blind, multicenter, 8-week clinical trial with a 4-week placebo run-in phase in patients with hypertension (n=588) [Oparil 2005, P290, L Col, 2nd Para; Oparil 2001, P284, L Col, 3rd Para]
    Study medications included: olmesartan 20 mg, losartan 50 mg, valsartan 80 mg, or irbesartan 150 mg [Oparil 2005, P290, L Col, 2nd Para]
    References:
    1. Oparil S, et al. Role of angiotensin receptor blockers as monotherapy in reaching blood pressure goals. Am J Hypertens 2005;18:287-94.
    2. Oparil S, et al. Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension. J Clin Hypertens (Greenwich) 2001;3:283-91, 318.
  • Q25
    Another reason for the poor control of HTN and dyslipidemia, is patient adherence.
    The graph shows what happens over time to adherence when more than one therapy is taken.
    On the y-axis we have the % of initially treated patients maintaining adequate therapy.
    On the x-axis we have time from start of Rx
    We can see that patients are treated for both conditions with multiple pills, that far fewer will maintain adequate therapy
    Perhaps this is one of the ways that DT can add value to patients? We would like to believe that it lies in the “15% adherence gap.”
  • Key Points
    The Canadian Hypertension Education Program (CHEP) recommendations for the treatment of patients with systolic-diastolic hypertension (≥140/90 mm Hg) without other compelling indications, include:1 [CHEP treatment deck, Slide 51]
    BP target <140/90 mmHg
    Lifestyle modification is recommended as the first step, followed by initiation of pharmacotherapy (monotherapy is recommended, however a combination may be considered if initial blood pressure is ≥20/10 mmHg above targets)
    If a patient remains above targets after initial therapy a dual combination is recommended after careful consideration of any possible impeding factors such as nonadherence, secondary hypertension, interference from other medications, or a white coat effect
    Continual therapy modification is recommended in patients still above targets
    Reference:
    1. Canadian Hypertension Education Program. Part 2: Recommendations for hypertension treatment. Available at: http://www.hypertension.ca/chep/. Accessed Oct 22, 2009.
  • For every 20 mm Hg systolic or 10 mm Hg diastolic increase in BP, there is a doubling of mortality from both ischemic heart disease and stroke.
    Data from observational studies involving more than 1million individuals have indicated that death from both ischemic heart disease and stroke increases progressively and linearly from BP levels as low as 115 mm Hg systolic and 75 mm Hg diastolic upward. The increased risks are present in all age groups ranging from 40 to 89 years old.
  • This graph summarizes the change in systolic blood pressure from baseline to the last visit for placebo, olmesartan 10 mg BID and olmesartan 20 mg QD as measured by 24 hour ambulatory monitoring. Over the 24 hour period, both doses of olmesartan medoxomil lowered the systolic blood pressure as compared to placebo. Moreover there was no appreciable difference between QD and BID dosing of olmesartan in terms of SBP lowering.
    These data taken in concert suggest that olmesartan can be conveniently dosed once per day instead of twice daily without loss of blood pressure-lowering efficacy which could ultimately contribute to an increase in compliance.
  • Slide Summary
    In 6 large double-blind, placebo-controlled studies, more than one agent was required to achieve desired target blood pressure (BP) goals.
    Background
    This slide shows evidence from 6 large placebo-controlled trials [1-6] demonstrating that when target BP values were set for subjects, 2 or more agents were required to achieve these goals [7].
    In the Hypertension Optimal Treatment (HOT) study, for example, 68% of subjects required more than one agent [4]. 41% of subjects were taking felodipine plus an ACE inhibitor, and 28% were taking felodipine plus a beta blocker.
    In the United Kingdom Prospective Diabetes Study (UKPDS) [1], 29% of subjects required 3 or more agents to achieve a BP of <150/85 mm Hg at 9 years after randomization.
    1. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-713.
    2. Estacio RO, Schrier RW. Antihypertensive therapy in type 2 diabetes: implications of the Appropriate Blood pressure Control in Diabetes (ABCD) trial. Am J Cardiol. 1998;82(9B):9R-14R.
    3. Lazarus JM, Bourgoignie JJ, Buckalew VM, et al, for the Modification of Diet in Renal Disease Study Group. Achievement and safety of a low blood pressure goal in chronic renal disease. Hypertension. 1997;29:641-650.
    4. Hansson L, Zanchetti A, Carruthers SG, et al, for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755-1762.
    5. Kusek JW, Lee JY, Smith DE, et al. Effect of blood pressure control and antihypertensive drug regimen on quality of life: the African American Study of Kidney Disease and Hypertension (AASK) Pilot Study. Control Clin Trials. 1996;16(suppl 4):40S-46S.
    6. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860.
    7. Bakris GL, Williams M, Dworkin L, et al, for the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000;36:646-661.
  • Many trials have been completed and many more have been initiated evaluating the effects of angiotensin II receptor blockers (ARBs) in various cardiac and renal diseases. Inhibition of the renin-angiotensin-aldosterone system with ARBs is clearly beneficial in patients at risk for progressive cardiac and renal disease.
    ARBs have been proven to reduce morbidity and mortality in patients with heart failure, left ventricular hypertrophy due to hypertension, and diabetic renal disease.
    Future studies will demonstrate the effects of ARBs in patients post myocardial infarction, in patients with heart failure due to diastolic dysfunction, and in patients at high risk for cardiovascular events.
  • Background
    Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial: ONTARGET
    Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease: TRANSCEND
    Talking Points
    ONTARGET/TRANSCEND are parallel trials designed to assess the protective effects of the ARB MICARDIS when used alone or in combination with the ACE inhibitor ramipril in high risk individuals with normal blood pressure at baseline. The studies will include patients with CAD, PVD, cerebrovascular disease or high-risk diabetes with end-organ damage.
    Primary objectives of ONTARGET: to determine if
    whether MICARDIS 80 mg daily alone is at least as effective as ramipril 10 mg alone daily
    the combination of MICARDIS 80 mg daily and ramipril 10 mg daily is more effective in reducing the composite of CV death, MI, stroke, or hospitalization for CHF than ramipril 10 mg alone, and
    Secondary and other outcomes to be measured in ONTARGET/TRANSCEND are newly diagnosed CHF, revascularization procedures, newly diagnosed diabetes, development of dementia/cognitive declines, nephropathy, newly diagnosed atrial fibrillation, all-cause mortality, Non-CV death, angina, TIAs, development of LVH, microvascular complications of diabetes, changes in BP/ankle-arm BP ratio, and malignancy.
    1. The ONTARGET/TRANSCEND Investigators. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J. 2004;148:52-61.
  • Weeks 0–12
    Medication titrated to the next level in patients with SeSBP ≥120 mm Hg and/or SeDBP ≥70 mm Hg
    If patients had SeSBP <120 mm Hg and SeDBP <70 mm Hg, and did not have symptomatic hypotension, patients entered maintenance phase on current dose
    If patients became uncontrolled on maintenance dose (SeSBP ≥130 mm Hg and/or SeDBP ≥80 mm Hg) then they were up-titrated to the next dose
    Weeks 12–18
    Medication titrated to the next level in patients with SeSBP ≥130 mm Hg
    If SeSBP was <130 mm Hg and ≥120 mm Hg, patients underwent orthostatic BP and heart rate assessments
    If SeSBP was <120 mm Hg, patients entered maintenance phase on current dose
    If patients became uncontrolled on maintenance dose (SeSBP ≥130 mm Hg and/or SeDBP ≥80 mm Hg [but not SeSBP <120 mm Hg]) then they were up-titrated to the next dose
    Patients meeting the screening inclusion criteria entered the placebo run-in phase and were dispensed placebo medication 2 weeks prior to active treatment. Patients were assessed at 1-week intervals during the placebo run-in period, and then those meeting inclusion criteria at Day –1 underwent ABPM to confirm the presence of hypertension. Those who met the ABPM criteria were dispensed the study medication (Day 0) and the 18-week active treatment phase began. Patients underwent a second ABPM procedure at Week 12. As described earlier, titration to the next level of the regimen could occur at any of the titration steps at Weeks 3, 6, 9, 12, and 15.
    Additional safety assessments:
    For subjects who qualified for initiation or increase of a dose of HCTZ, the following additional requirements were applied:
    If SeSBP was ≥130 mm Hg, patients received HCTZ dose up-titration.
    Patients with 120 mm Hg ≤MSBP <130 mm Hg had orthostatic assessments of blood pressure and heart rate.
    − If orthostatic drop in SBP was >10 mm Hg, there was no up-titration
    − If orthostatic drop in SBP was >10 mm Hg and taking HCTZ 12.5 mg, patients were withdrawn from the study
    − If orthostatic drop in SBP was ≤10 mm Hg, patients were up-titrated and returned for an interim safety visit
    Patients were required to exit the study if they met the following criteria:
    Mean office SBP ≥200 mm Hg or DBP ≥115 mm Hg
    SBP <120 mm Hg or DBP <70 mm Hg with symptomatic hypotension at any visit
    Patients taking HCTZ 12.5 mg or HCTZ 25 mg with an orthostatic drop in SBP of >10 mm Hg, symptomatic or asymptomatic, as measured at either Week 13, 15, or 16
  • This slide shows the additional incremental reductions in SeBP resulting collectively from the addition of HCTZ at either dose level to the various AML/OM regimens.
  • This slide shows the additional incremental reductions in SeBP as a result of titration from AML 5 mg to AML/OM 5/20 mg; from AML/OM 5/20 mg to AML/OM 5/40 mg; from AML/OM 5/40 mg to AML/OM 10/40 mg; from AML/OM 10/40 mg to AML/OM +HCTZ 10/40 + 12.5 mg; and from AML/OM +HCTZ 10/40 + 12.5 mg to AML/OM +HCTZ 10/40 + 25 mg.
  • Based on the American Society of Hypertension Position Paper on Home and Ambulatory Blood Pressure Monitoring, the normal limit for average-risk patients using 24-hour ABPM is 130/80 mm Hg.1
    Generally, 24-hour ambulatory BP values are approximately 10 mm Hg lower than cuff BP measurements.
    Reference:
    1. Pickering TG, White WB; American Society of Hypertension Writing Group. ASH Position Paper: Home and ambulatory blood pressure monitoring. When and how to use self (home) and ambulatory blood pressure monitoring. J Clin Hypertens (Greenwich). 2008;10(11):850-855.
  • Based on the American Society of Hypertension Position Paper on Home and Ambulatory
    Blood Pressure Monitoring, the normal limit for average-risk patients using ABPM while
    awake is 135/85 mm Hg.1
    The American Heart Association Council on High Blood Pressure Research has suggested
    120/70 mm Hg to be the upper limit of normal ambulatory BP during the nighttime (not
    specifically in patients with diabetes).2
    References:
    Pickering TG, White WB; American Society of Hypertension Writing Group. ASH Position Paper: Home and ambulatory blood pressure monitoring. When and how to use self (home) and ambulatory blood pressure monitoring. J Clin Hypertens (Greenwich). 2008;10(11):850-855.
    Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps SG, Roccella EJ; Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005;45(1):142-161.
  • This slide shows the primary endpoint, mean change in SBP, and one of the secondary endpoints, mean change in DBP, both assessed by 24-hour ABPM. SBP and DBP were significantly decreased by 20.4 and 11.1 mm Hg, respectively, in the overall cohort (P < 0.0001 to baseline). The majority of patients (81.4%) were titrated to olmesartan medoxomil plus HCTZ. There were significant decreases in both SBP and DBP in the patients who received HCTZ. The P-values are from one sample T-test.
    Data for SBP from Table 13, page 3/3. Also in Table 21.
    Data for DBP from Table 14, page 3/3. Also in Table 24.
  • This slide shows the primary endpoint, mean change in SBP, and one of the secondary endpoints, mean change in DBP, by treatment regimen at the end of study, both assessed by 24-hour ABPM. SBP and DBP were significantly decreased from baseline (P <0.0001) in patients that were titrated to OM+HCTZ. The majority of patients (81.4%) were titrated to olmesartan medoxomil plus HCTZ. There were significant decreases in both SBP and DBP in the patients who received HCTZ. The P-values are from one sample T-test.
    Data for SBP from Table 13, page 3/3. Also in Table 21.
    Data for DBP from Table 14, page 3/3. Also in Table 24.
  • This slide shows the hourly mean SBP at baseline and end of study, assessed by ABPM. Before administration of OM with or without HCTZ, patients did not achieve SBP goal of <130 mm Hg at any time throughout the day. After administration of OM ± HCTZ, patients were below the recommended SBP goal of <130 mm Hg (represented by the dotted line) for 18 out of 24 hours (75% of the time), including the crucial last 4 hours of the dose interval, and ≤130 mm Hg for 20 out of 24 hours (83.3% of the time). The decrease in SBP from baseline to the end of the study ranged from 13.7 mm Hg at hour 9 to 26.3 mm Hg at hour 14. Overall, the mean 24-h SBP was decreased from 146.3 mm Hg at baseline to 126.0 mm Hg at end of the study and 61.6% of patients (106/172) achieved recommended SBP goal of <130 mm Hg.
    Data from ABPM Hourly, received 05-14-08.
    Data for mean 24-h SBP: Table 13, p 1/3 and 2/3.
    Data for BP goal: Table 35, p 1
  • This slide shows the hourly mean DBP at baseline and end of study, assessed by ABPM. Before administration of OM ± HCTZ, patients were below recommended DBP goal of <80 mm Hg (represented by the dotted line) for 8 out of 24 hours (33.3% of the time). After administration of OM ± HCTZ, patients were below the recommended DBP goal of <80 mm Hg for 22 out of 24 hours or 91.6% of the time, including the crucial last 4 hours of the dose interval. The decrease in DBP from baseline to the end of the study ranged from 6.7 mm Hg at hour 9 to 13.9 mm Hg at hour 14. Overall, the mean 24-h DBP was decreased from 83.3 mm Hg at baseline to 72.2 mm Hg at end of the study and 86.6% of patients (149/172) achieved recommended DBP goal of <80 mm Hg.
    Data from ABPM Hourly, received 05-14-08.
    Mean 24-h DBP data from Table 14, p 1/3 and 2/3
    24-h goal DBP data from Table 35 p 2/3
  • This slide shows the secondary endpoint of mean change in seated SBP (SeSBP) and seated DBP (SeDBP), assessed in the office using an automated OMRON BP cuff measurement device. SeSBP and SeDBP were significantly decreased (P < 0.0001) from baseline in all treatment regimens.
    Data are from all patients who were exposed to a particular treatment regimen throughout the duration of the study, regardless of whether they remained on the regimen or were titrated to another. When the end of study value was missing, the last observation after the individual treatment baseline was carried forward. Values for each individual represented the mean of 3 consecutive readings at each visit. The P-values are from one sample T-test.
    Data for SeSBP from Table 15, page 2/2. Also in Table 26-27
    Data for SeDBP from Table 17, page 2/2. Also in Table 28-29
  • This slide shows the secondary endpoint of mean change in seated SBP (SeSBP) and seated DBP (SeDBP), assessed in the office using an automated OMRON BP cuff measurement device. SeSBP and SeDBP were significantly decreased (P < 0.0001) from baseline in all treatment regimens.
    Data are from all patients who were exposed to a particular treatment regimen throughout the duration of the study, regardless of whether they remained on the regimen or were titrated to another. When the end of study value was missing, the last observation after the individual treatment baseline was carried forward. Values for each individual represented the mean of 3 consecutive readings at each visit. The P-values are from one sample T-test.
    Data for SeSBP from Table 15, page 2/2. Also in Table 26-27
    Data for SeDBP from Table 17, page 2/2. Also in Table 28-29
  • This slide shows the overall achievement of BP goals, broken down by whether they were measured by 24-hour ABPM or in the office (cuff BP using OMRON automated BP machine). The ABPM measurements are calculated for those patients who had both baseline and end of study 24-hour ABPM (N = 172). The cuff BP measurements are calculated using the total number of subjects in the treatment cohort (N = 192), and the last observation was carried forward for patients who did not have a measurement at end of study. Assessed by 24-hour ABPM, a majority of the patients (61.6%) achieved the American Diabetes Association and JNC 7 recommended BP treatment goal for patients with diabetes, which is < 130/80 mm Hg [1] (green box).
    From Table 35, page 3/3. (24-h ABPM) and Table 34 page 2/2 (cuff BP).
    References:
    1. Chabobian, et al. Hypertension 2003; 42:1206-1252.
  • This slide shows the cumulative achievement of BP goals, assessed by cuff BP measurement and treatment regimen. The green box highlights goal achievement at the recommended BP goal of <130/80 mm Hg. The cuff BP measurements are calculated using the total number of subjects in the treatment cohort (N = 192), and the last observation was carried forward for patients who did not have a measurement at the end of the study. A larger percentage of patients achieved BP goals when they were up-titrated to combinations of olmesartan medoxomil plus HCTZ.
    Data from Table 34, page 2/2.

Transcript

  • 1. Treatment Inertia 1
  • 2. Are you guilty of Treatment Inertia in the Management of Hypertension 2
  • 3. Hypertension awareness, treatment and control: US 1976 to 2004 ACEIs introduced Adults (%) 73% 51% 55% ARBs introduced 71% 68% 70% 54% 59% 60% 34% 33% 31% 29% 27% 10% JNC IV JNC V JNC VI NHANES II NHANES III NHANES III NHANES 1976–1980 (Phase 1) (Phase 2) 1999–2000 1988–1991 1991–1994 76% 65% 37% Awareness Treatment Control JNC VII NHANES NHANES 2001–2002 2003–2004 Burt et al. Hypertension 1995;25:305–13; The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Int Med 1997;157:2413–46; Hajjar & Kotchen. JAMA 2003;290(2):199–206; Chobanian et al. Hypertension 2003;42(6):1206–52; Ong et al. Hypertension 2007;49(1):69–75
  • 4. Hypertensives on Treatment 5 out of 10 Treated Hypertensive Patients are not at Goal BP Controlled 53% Uncontrolled 47% 69% of hypertensive Americans are aware of their disease 58% of hypertensive Americans are receiving treatment for their disease Hajjar I, Kotchen TA. JAMA. 2003;290:199-206. Burt et al. Hypertention. 1995;25:305-313; Hyman et al. N Engl J Med. 2001;345:479-486; .
  • 5. Increasing Awareness and Treatment of Hypertension in Canada Adults with hypertension (%) Percentage of adults with hypertension who are aware, treated and controlled 100 86% 82% 60 Treated 66% 80 Aware Controlled 56% 40 34% 20 13% 0 1992 Leenen et al. CMAJ 2008;178:1441-9; Joffres et al. Am J Hypertens 2001;14:1099-105 2006 7
  • 6. Increasing Rates of Treatment and Control of Hypertension in Canada 1992 2006 Canadian Heart Health Survey: Canada Ontario Survey on the Prevention and Control of Hypertension 21% 13% 15% 22% 66% 6% 14% 43% Treated and controlled Treated and not controlled Aware, untreated Unaware, untreated Joffres et al. Am J Hypertens 2001;14:1099-105; Leenen et al. CMAJ 2008;178:1441-9 Treated and controlled Treated and not controlled Aware, untreated Unaware, untreated 8
  • 7. Worldwide blood pressure control in treated hypertensive patients Canada 66.0 USA 63.1 Mexico 21.8 Turkey 19.8 Germany 33.6 England 29.2 Greece 49.5 Japan 55.7 China 28.8 Spain 38.8 Taiwan 18.0 Egypt 33.5 South Africa 47.6 Italy 37.5 Updated from Kearney et al. J Hypertens 2004;22:11–9
  • 8. Treatment Inertia: Definition Failure to initiate, intensify or change therapy in patients with uncontrolled BP • >140/90 mm Hg • or >130/80 mm Hg in patients with diabetes, renal or coronary heart disease Situations in which patients return for visits having taken their medication but have not had therapy changed despite higher than guideline recommended BP levels Moser. J Clin Hypertens 2009;11:1-4 10
  • 9. Percentage of Patients Achieving Adequate Blood Pressure Control On or below Target DBP 37% Over target DBP 63% ● Target BP set by physician ● Study includes ● 11, 613 patients from France, Germany, Italy, Spain, and United Kingdom Taylor Nielson Healthcare, Epson, Surry, England-Cardiomonitor 2007
  • 10. Action Taken In Those Patients Not At Their Target BP Dose Titration Alternative Drug Additional Drug 18% 82% No Action Taken
  • 11. Therapeutic Inertia: Action Taken In Patients Not At Target BP Proportion of patients not meeting targets and medication changes in DIOVANTAGE 4 observational study across Canada (n=34,033) Total patients 59% Achieved target 41% Did not achieve target Treatment recommendation in patients not meeting targets 55.1% 44.9% change of medication Medication change NO • Over half of the 41% of patients not achieving BP targets did not receive any modification of their current therapy after 3 months Tardif et al. Can J Clin Pharmacol 2008;15:e177-87 13
  • 12. Barriers to Effective Management of Uncontrolled Hypertension • Lack of concern for higher than ideal but ‘not very high’ BPs • Complexity of prescribing or monitoring drug regimens • Practice patterns • Lack of physician-patient rapport • Failure to communicate the importance of continuing therapy • Lack of ongoing attention to asymptomatic diseases (HTN) in patients with symptomatic comorbidities • Concern regarding adverse effects Moser. J Clin Hypertens 2009;11:1-4 14
  • 13. UKPDS mean blood pressures Baseline (mmHg) Mean BP over 9 years (mmHg) Less tight control 160/94 154/87 Tight control 161/94 144/82 Difference 1/0 10/5 p-value n.s. p<0.0001 UKPDS(38). BMJ 1998;17:703–13
  • 14. UKPDS: Significant Benefits with Tight vs. Less Tight BP Control in Patients with Diabetes Relative risk reduction with tight vs. less tight BP control (10/5 mm Hg) (n=1148) Diabetesrelated death All cause mortality MI Stroke Microalbuminuria P=0.019 P=0.17 P=0.13 P=0.013 P=0.009 0 Patients (%) -10 -20 -18% -21% -30 -29% -32% -40 -44% -50 UKPDS 38. BMJ 1998;317:703-13 16
  • 15. Primary End Point: Nonfatal MI and Fatal CHD Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 36% reduction HR = 0.64 (0.50-0.83) Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58 p=0.0005
  • 16. Steno-2 Study: Significant Benefits with Intensive Treatment in Patients with Diabetes Macro and microvascular complications in type 2 diabetes BP (mmHg) Usual treatment Intensive treatment SBP initial 149 ± 19 146 ± 20 SBP final 146 132 Reduction -3 ± 3 -14 ± 2 DBP initial 86 ± 11 85 ± 10 DBP final 78 73 Reduction -8 ± 2 -12 ± 2 Intensive Usual better better STENO-2 (n=160); age 55.1 years; follow-up 7.8 years Gaede et al. N Engl J Med 2003;348:383-93 Cardiovascular events RR=0.47 P=0.008 Nephropathy RR=0.39 P=0.003 Retinopathy RR=0.42 P=0.02 Autonomic neuropathy RR=0.37 P=0.002 0 0.25 0.50 0.75 1 RR (95% CI) 18
  • 17. PROGRESS Study Lowering of BP and Secondary Prevention of Stroke Stroke Prevention Treat Placebo Favours Favours RR (CI 95%) (n= 2051) (n= 3054) treat placebo reduction 150 Combination 157 Monotherapy 163 Hypertensive Non-Hypertensive144 307 Total 255 165 235 185 420 BP reduction vs placebo: Monotherapy: 4.9/2.8 mmHg Combination: 12.3/5.0 mmHg 43% (30 - 54) 5% (-19 - 23) 32% (17 - 44) 27% (8 - 42) 28% (17 - 38) 0.5 1.0 2.0 PROGRESS. Lancet 2001; 358: 1033-1041
  • 18. Failure of the Stepped Care Approach 4 JNC Reports Between 1988 and 2000 11/09/13 Control Rate in the USA BP goal 140/90 mm HG 34% Control Rate (%) Why Has the Stepped Care Approach to the Management of Hypertension Failed? 29% NHANES 1988-91 27% NHANES 1991-94 NHANES 1991-2000 20
  • 19. Physician Considerations in the Selection of Anti-hypertensive Agents 1 Efficacy 2 Side Effects 3 Outcome Studies Neutel 2005
  • 20. The New Therapeutic Window in Hypertension 100 ideal Ideal Efficacy 80 80 60 60 Traditional 40 20 40 Efficacy Side Effects 0 20 0 Dose Man Int Veld AJ, Journal of Hypertens 1997;15 (suppl 7): S27-S33 Freedom from side effects 100
  • 21. Titration vs. Combination Frishman WH et al,Arch Intern Med 1994;154, 1461-1468
  • 22. Efficacy: Up-titration vs Combination Change in SBP (mm Hg) T40 T80 T40 T40 HCT12.5 V80 V160 V80 V80 HCT12.5 Ol20 Ol40 O20 Ol20 HCT12.5
  • 23. Adverse Events Placebo Bisoprolol/HCTZ 2.5-10mg N BP Reduction (mmHg) 144 2.9/3.9 221 15.8/12.6 Adverse Event (%) Bradycardia Peripheral Ischemia Bronchospasm Cough Fatigue Dizziness Headache Insomnia Somnolence Loss of Libido Impotence 0.7 0.9 0.0 0.7 1.7 1.8 2.7 2.0 0.7 1.2 0.7 0.9 0.4 0.0 1.5 3.0 3.2 0.4 1.2 0.9 0.4 1.1
  • 24. Tolerability of ARB Combination Therapy and Components 40 35 34.1 Placebo (n=44) 30 HCTZ monotherapy (n=123) 25 ARB monotherapy (n=126) Patients 20 (%) 15 10 ARB/HCTZ (n=390) 14.6 10.5 8.7 9.5 6.8 6.5 5 5.6 6.9 4.8 4.5 2.4 4.5 4.1 4.1 2.3 1.6 2.3 0 Headache Dizziness Fatigue Cough 3.8 0 Discontinuations due to adverse events
  • 25. Advantages of Combination Therapy 120 Ideal 100 Percent 80 60 40 Freedom from side effects Efficacy 20 0 Dose Neutel. Nephrol Dial Transplant 2006;21:1469-73. 27
  • 26. Hypertension awareness, treatment and control: US 1976 to 2004 ACEIs introduced Adults (%) 73% 51% 55% ARBs introduced 71% 68% 70% 54% 59% 60% 34% 33% 31% 29% 27% 10% JNC IV JNC V JNC VI NHANES II NHANES III NHANES III NHANES 1976–1980 (Phase 1) (Phase 2) 1999–2000 1988–1991 1991–1994 76% 65% 37% Awareness Treatment Control JNC VII NHANES NHANES 2001–2002 2003–2004 Burt et al. Hypertension 1995;25:305–13; The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Int Med 1997;157:2413–46; Hajjar & Kotchen. JAMA 2003;290(2):199–206; Chobanian et al. Hypertension 2003;42(6):1206–52; Ong et al. Hypertension 2007;49(1):69–75
  • 27. Prevalence of controlled BP in CONVINCE Fraction with controlled BP (%) SBP ≤140 mmHg DBP ≤90 mmHg 100 94 85 80 90 91 90 84 71 60 SBP ≤140 mmHg and DBP ≤90 mmHg 70 68 66 67 66 52 40 23 20 0 20 Baseline EOT 12 months 24 months 36 months (n=16,469) (n=15,314) (n=13,853) (n=6364) (n=773) Duration of study treatment Black et al. Am J Hypertens 2000;13(part 2):61A
  • 28. BP control in ALLHAT participants: Percentage meeting goal by year of follow-up SBP <140 mmHg DBP <90 mmHg Patients meeting goal (%) BP <140/90 mmHg Mean BP 145/83 140/81 138/79 137/78 136/77 135/76 135/75 No drugs - 1.3 1.4 1.6 1.7 1.8 2.0 Cushman et al. J Clin Hypertens 2002;4:393–404
  • 29. Steno-2 Study: Significant Benefits with Intensive Treatment in Patients with Diabetes Macro and microvascular complications in type 2 diabetes BP (mmHg) Usual treatment Intensive treatment SBP initial 149 ± 19 146 ± 20 SBP final 146 132 Reduction -3 ± 3 -14 ± 2 DBP initial 86 ± 11 85 ± 10 DBP final 78 73 Reduction -8 ± 2 -12 ± 2 Intensive Usual better better STENO-2 (n=160); age 55.1 years; follow-up 7.8 years Gaede et al. N Engl J Med 2003;348:383-93 Cardiovascular events RR=0.47 P=0.008 Nephropathy RR=0.39 P=0.003 Retinopathy RR=0.42 P=0.02 Autonomic neuropathy RR=0.37 P=0.002 0 0.25 0.50 0.75 1 RR (95% CI) 31
  • 30. Management Principle Study protocol requires you to follow a prescribed drug algorithm
  • 31. Opportunities for accepting inadequate BP control Patient Persistent attempts at nonpharmacologic dx Cost Perception that drug is not working Education (HTN is curable) Concerns over polypharmacy Side effects Change in lifestyle Missed visits Diagnosis Physician Confirming diagnosis Inappropriate nonpharmacologic Rx Formulary guidelines Patient pressure Reluctance to titrate or add drug Cost Uneducated on BP goal Change in HMO plan Home BP measurements BP Control Concern over AEs Concern over metabolic effects Patient Pressure
  • 32. SBP control in three large trials CONVINCE @ 12 mo 71 (n=13,853) ALLHAT @ 12 mo 53* (n=14,722) LIFE @ 12 mo (n=9,194) 0 10 20 26† 30 40 50 60 70 80 Subjects with SBP <140 mmHg (%) *Cushman et al. Am J Hypertens 1998;11(part 2):17A †Dahlöf et al. Am J Hypertens 1999;12(part 2):142A
  • 33. Management Principle A well established blood pressure goal results in clinicians being more aggressive in their management of BP
  • 34. Goal Rates Drug Algorithm + BP Goal Neutel, Smith, Weber, Wang, Masonson. J Clin Hypertens 2004;6:168–74
  • 35. Management Principle Combination always more effective than Titration
  • 36. Treatment algorithm OLM 40mg/day + HCTZ 25mg/day + AMLO 10mg/day Target BP: <130/85 mmHg <140/90 mmHg OLM 40mg/day + HCTZ 25mg/day + AMLO 5mg/day OLM 40mg/day + HCTZ 25mg/day n=201 OLM 40mg/day + HCTZ 12.5mg/day OLM 40mg/day OLM 20mg/day Step 1 week 4 Step 2 week 8 Step 3 week 12 OLM: olmesartan; HCTZ: hydrochlorothiazide; AMLO: amlodipine Step 4 week 16 Step 5 week 20 Step 6 week 24 Neutel et al. J Clin Hypertens 2004;6:168–74
  • 37. Olmesartan: ARB/receptor interactions HO O N O VI III V IV N Binding Sites N N AT1 Receptor (transmembrane regions 3–6) N N Olmesartan Yanagisawa et al. J Med Chem 1996;39:323–38
  • 38. Proportion of Patients Achieving Treatment Goal with Various ARBs Proportion of patients achieving BP goal (<140/90 mmHg), retrospective analysis of RCT (n=588) 60 Patients (%) 50 *p<0.01 vs. olmesartan 40 32.4 30 25.9 20 16.1* 14.5* Losartan 50 mg Valsartan 80 mg 10 0 Olmesartan 20 mg Irbesartan 150 mg Oparil et al. Am J Hypertens 2005;18:287-94; Oparil et al. J Clin Hypertens 2001;3:283-91, 318 40
  • 39. Treat to goal study: Baseline demographics for efficacy cohort (n=197) Age (years) 53 Gender (% male) 65 Race (%) - Caucasian 74 - Black 16 - Asian 2 - Hispanic 7 Mean SBP (mmHg) 161.2 Mean DBP (mmHg) 96.6 Neutel et al. J Clin Hypertens 2004;6:168–74
  • 40. Hypertension management with an olmesartan-based algorithm Week 8 Week 16 Week 24 Patients achieving BP goal (%) 100 83.2 80 69.3 58.7 60 40 35.2 20 ≤130/ 85 ≤140/ 90 ≤130/ 85 ≤140/ 90 ≤130/ 85 ≤140/ 90 DBP SBP DBP SBP DBP SBP 0 Change in BP (mmHg) 87.7 N=198 93.3 -10 -20 BP goal -10.7 -17.7 -30 -16.1 -18.2 -29.3 -33.7 -40 OLM + HCTZ + AML OLM + HCTZ OLM Neutel et al. J Clin Hypertens 2004;6:168–74
  • 41. Baseline characteristics Stage 1 (n=85) Age (years) Stage 2 (n=113) 49.4 (28–80) 55.3 (35–80) 69.4 61.9 - Caucasian 70.6 76.1 - Black 18.8 14.2 6.8 9.4 Prior antihypertensives (%) 70.6 78.8 Baseline SBP/DBP (mmHg) 149.7/94.7 169.8/98.1 Gender (% male) Race (%) Duration of hypertension (years) Neutel et al. J Hum Hypertens 2006;20:255–62
  • 42. The majority of patients achieved BP goal with an olmesartan-based algorithm Patients achieving BP goal at week 24 (%) <140/90 mmHg Total Cohort Stage 1 93.3% 97.5% 87.7% 96.2% Stage 2 90% <130/85 mmHg Total Cohort: 179 patients; mean baseline BP = 161/97 mmHg Stage 1: 79 patients; mean baseline BP = 150/95 mmHg Stage 2: 100 patients; mean baseline BP = 170/98 mmHg 81% Neutel et al. J Clin Hypertens 2004;6:168–74 Neutel et al. J Human Hypertens 2006;20:255–62
  • 43. BP CRUSH: Study Design Open-label, titration study AML/OM 5/20 mg AML/OM 5/40 mg AML/OM 10/40 mg AML/OM AML/OM 10/40 mg + 10/40 mg + HCTZ 12.5 mg HCTZ 25 mg Visit 1 Screening (within 7 days ±6 of Visit 2) Visit 2 Day 1 Visit 2A Day 2 Visit 3 Week 4 Visit 4 Week 8 Visit 5 Week 12 Visit 5A Week 12 + 1 day Visit 6 Week 16 Visit 7 Visit 8 Week 20 Week 22 Visit 7A Week 20 + 1 day • Uptitrated if mean SeSBP was ≥120 and <200 mm Hg and/or mean SeDBP was ≥70 and <115 mm Hg. • Maintained on current dosage if SeSBP <120 mm Hg and SeDBP <70 mm Hg • Patients on maintenance therapy uptitrated to the next dosing level if mean SeSBP was ≥130 and <200 mm Hg and/or mean SeDBP was ≥80 and <115 mm Hg
  • 44. Secondary Endpoint: Proportions of Patients Achieving Cumulative SeBP Goals by Titration Dose Patients Achieving SeBP Goal (%) 86.7 90 77.1 80 70 63.8 60 50 49.5 40 30 20 10 0 AM L/OM 5/20 mg AML/OM 5/40 mg AML/OM 10/40 mg 90 80 70 63.8 60 56.2 50 44.3 40 31.8 30 20 18.2 10 0 AML/OM AM L/OM 10/40 + HCTZ 10/40 + HCTZ 12.5 mg 25 mg AM L/OM 5/20 mg AM L/OM 5/40 mg <120/80 mm Hg 100 Patients Achieving SeBP Goal (%) <130/80 mm Hg 100 90.3 Patients Achieving SeBP Goal (%) <140/90 mm Hg 100 90 80 70 60 50 43.4 37.1 40 30 20 10 0 25.2 8.5 AM L/OM 5/20 mg 15.7 AML/OM 5/40 mg Source: Study 8663-404 Data Table 7.10 (18 January 2010) AM L/OM AML/OM AM L/OM 10/40 mg 10/40 + HCTZ 10/40 + HCTZ 12.5 mg 25 mg AM L/OM 10/40 mg AML/OM AM L/OM 10/40 + HCTZ 10/40 + HCTZ 12.5 mg 25 mg
  • 45. Percentage Compliance in the Treatment of Hypertension During, Vetter German Survey Number of Tablets
  • 46. Two HTN Agents in One Pill Enhances Adherence Lisinopril/HCTZ combination pill (n=1644) 100% Lisinopril and diuretic in separate pills (n=624) % Persistence 90% 80% 70% 69% 11%* 60% 58% 50% 0 1 2 3 4 5 6 7 Months *p<0.05 vs fixed-dose combination Source: Dezii C. Managed Care. 2000;9:S2. 8 9 10 11 12
  • 47. Patient Compliance Δ of Medication in 1st 6 months 1 Compliance 2nd 6 months 93% 2 75% *P=< 0.05 vs. patient without Δ of medication Caro JJ, et al. CMAJ. 1999;160:41. V072004
  • 48. CHEP: Treatment of Systolic-Diastolic Hypertension without Other Compelling Indications Threshold ≥140/90 mmHg and TARGET <140/90 mmHg Lifestyle modification A combination of 2 first line drugs may be considered as initial therapy if the blood pressure is ≥20 mmHg systolic or ≥10 mmHg diastolic above target Initial therapy Thiazide diuretic ACEI ARB CONSIDER • Nonadherence • Secondary HTN • Interfering drugs or lifestyle • White coat effect Long-acting CCB Betablocker* Dual combination Triple or quadruple therapy *not indicated as first line therapy over 60 y ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blockers; CCB: calcium channel blocker 2009 CHEP Recommendations. www.hypertension.ca/chep 50
  • 49. Percentage of Total Events Occurring Between 6am and 12noon 80 70 68 60 49 50 45 38 40 29 30 20 10 0 Symptomatic Angina Pectoris MI Stroke 1998;23:992 Lancet 1999 ;353:643 Am J Cardiol 1999;83:507 Lancet 1998:2:755 Stroke Sudden Death Aortic Aneurysm Rupture
  • 50. Losartan Once-a-Day vs. Twice-a-Day Dosing Reductions from Baseline in Ambulatory DBP at Week 4 5 ∆ mmHg 0 -5 -10 Placebo (n = 26) Losartan 100 mg qd (n = 28) Losartan 50 mg bid (n = 30) -15 0 4 8 12 16 Hours Postdose Weber, et al. J Hum Hypertens. 1995;9(suppl):S29. 20 24 28
  • 51. Olmesartan Medoxomil 24 Hour ABPM – BID vs. QD Dosing Mean Change in SBP From Baseline at Last Visit 30 Placebo ∆ SBP (mm Hg) 20 Olmesartan medoxomil 10 mg BID 10 Olmesartan medoxomil 20 mg QD 0 -10 -20 -30 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Hours Since Treatment Average hourly difference in Systolic BP using 7-Term Fourier series smoothing Data compiled from non-black, randomized patients Data on file, Sankyo Pharma
  • 52. Multiple Antihypertensive Agents Are Needed to Achieve Target BP Trial Target BP (mm Hg) 1 UKPDS DBP <85 ABCD DBP <75 MDRD MAP <92 HOT DBP <80 AASK No. of antihypertensive agents 2 3 MAP <92 IDNT SBP <135/DBP <85 ALLHAT SBP <140/DBP <90 DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. Lewis EJ et al. N Engl J Med. 2001;345:851-860. Cushman WC et al. J Clin Hypertens. 2002;4:393-404. 4
  • 53. ARB Trials 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Heart failure ELITE II Val-HeFT CHARM I-Preserve OPTIMAAL VALIANT Post-MI LIFE SCOPE VALUE CV ONTARGET TRANSCEND Renal IDNT RENAAL IRMA 2 MARVAL ARB, angiotensin II receptor blocker.
  • 54. Diabetic Nephropathy Classification for ARB Renal Outcome Trials Stage 1 Pre-Mild Stage 2 Mild Stage 3 Moderate Normal Microalbuminuria Proteinuria ROADMAP (olmesartan) Stage 4 Severe Proteinuria ORIENT (olmesartan) RENAAL (losartan) IRMA II (irbesartan) IDNT (irbesartan) AMADEO/VIVALDI (telmisartan) MARVAL (valsartan) Stage 5 Dialysis ESRD
  • 55. ROADMAP Study Design Patients with type 2 diabetes and normoalbuminuria with at least a risk factor for cardiorenal disease, i.e., lipid disorders, smoking, obesity, hypertension; Median 5 years based on a cumulative number of 325 primary endpoint events; 4400 randomized patients (2200 in each group) Olmesartan medoxomil 40 mg/d Placebo (i.e., conventional anti-HTN Rx except ARBs and ACE-I ) Primary Outcome: Time to onset of microalbuminuria Secondary Outcomes: Cardiovascular events, Changes in creatinine clearance, Laser therapy for retinopathy Secondary Objectives: Composite cardiovascular endpoints (cardiovascular morbidity and mortality), Composite renal endpoints (increase of serum creatinine, decrease of GFR), Microangiopathy retinopathy (laser treatment)
  • 56. ORIENT Study Design Patients with type 2 diabetes, overt proteinuria, and diagnosed diabetic nephropathy; Treatment period of 3 – 5 years; 500 patients targeted for randomization Olmesartan medoxomil 10*, 20, or 40 mg/d (in an unforced titration fashion) in addition to background therapy with ACE-I** and/or other antihypertensive treatment Primary Outcome: Placebo in addition to background therapy with ACE-I** and/or other antihypertensive treatment Composite renal endpoints of: (1) Doubling of serum creatinine level, (2) Onset of ESRD (as defined by serum creatinine ≥ 5 mg/dL, or the necessity for hemodialysis or kidney transplantation) and, (3) Death * The recommended starting dose for olmesartan medoxomil in the U.S. is 20 mg once-daily ** Background therapy with an ACE-I is acceptable under the condition that the same dosage/administration regimen as given prior to the study treatment is used
  • 57. ONTARGET:Trial Design Study design Study population Double-blind, randomized, parallel-group study involving 25,620 patients in 40 countries ≥55 years with history of coronary artery disease, PAD, cerebrovascular disease, disease, or diabetes with end-organ damage MICARDIS 80 mg/day, ramipril 10 mg/day, or MICARDIS 80 mg/day + ramipril 10 mg/day Primary endpoint Composite endpoint of CV mortality, nonfatal stroke, acute MI, and hospitalization for CHF Secondary endpoint Newly diagnosed CHF, DM or atrial fibrillation, Revascularization procedures, development of dementia/cognitive declines, and neuropathy Treatment duration Results expected by 2007 Study drugs The ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
  • 58. A Prospective, Open-label, Dosetitration Study to Evaluate the Efficacy and Safety of an Olmesartan– and Amlodipine– based Treatment Regimen in Subjects With Hypertension and Type 2 Diabetes Study CS-8663-403 Study funded by Daiichi Sankyo, Inc.
  • 59. Azor® CS-8663-403 Study Design ABPM ABPM Screening (within 3–14 days of Week –2) Week –2 Placebo run-in phase (2-3 weeks) Week –1 Day –1 (Day –1) Day 0 AML 5 mg AML/OM 5/20 mg Week 3 AML/OM 5/40 mg Week 6 AML/OM 10/40 mg Week 9 AML/OM 10/40 mg + HCTZ 12.5 mg Week 12/ (+1 day) Week 13 Interim safety visit AML/OM 10/40 mg + HCTZ 25 mg Week 15 Follow-up Week 18 Week 20 Week 16 Interim safety visit CS-8663-403 Protocol Version 3.0. 22 April 2009
  • 60. Change From Baseline in Mean 24-hour Ambulatory SBP (± SEM; Primary Endpoint) and DBP (± SEM) at Week 12 Change From Baseline in Ambulatory BP (mm Hg) 0 144.3 N = 165 81.6 Baseline BP (mm Hg) -5 -10 –11.2 -15 ‡ -20 –19.9 -25 ‡ P < 0.0001 vs baseline. SBP DBP ‡ Source: Study 8663-403 Data Table D7.1 (4 August 2009).
  • 61. Mean hourly ambulatory SBP (mm Hg) Hourly Mean Ambulatory SBP at Baseline and Week 12 160 Baseline Week 12 150 Mean 24-hour SBP 144.3 mm Hg 140 130 120 110 100 Mean 24-hour SBP 124.3 mm Hg Dosing 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Clock hour Source: Study 8663-403 Data Table D7.8 (28 July 2009).
  • 62. Mean hourly ambulatory DBP (mm Hg) Hourly Mean Ambulatory DBP at Baseline and Week 12 95 Baseline Week 12 90 85 80 Mean 24-hour DBP 81.6 mm Hg 75 70 Mean 24-hour DBP 70.4 mm Hg 65 60 55 Dosing 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Clock hour Source: Study 8663-403 Data Table D7.8 (28 July 2009).
  • 63. Secondary Endpoints: Changes From Baseline in Mean Ambulatory SBP and DBP (± SEM) During Daytime, Nighttime, and Last 6, 4, and 2 Hours of Dosing Interval at Week 12 N = 165 Daytime Change From Baseline in Ambulatory BP (mm Hg) 0 149.1 85.7 134.7 74.7 139.5 78.9 142.6 81.4 147.5 85.1 Baseline BP (mm Hg) -5 -10 –10.4 –11.7 -15 –10.9 –11.1 ‡ ‡ ‡ ‡ -20 -25 –11.5 ‡ –18.5 –20.8 –18.9 –19.1 –19.5 ‡ ‡ ‡ SBP DBP ‡ ‡ P < 0.0001 vs baseline. ‡ Nighttime Last 6 hours Last 4 hours Last 2 hours Source: Study 8663-403 Data Table D7.1 (4 August 2009).
  • 64. Secondary Endpoint: Change From Baseline in Mean SeBP (± SEM) During Each Titration Period, by Titration Dose AML 5 mg N=200 Change From Baseline in BP (mm Hg) 0 158.8 89.0 -5 158.8 89.0 AML/OM 5/40 mg N=176 AML/OM 10/40 mg N=163 159.2 89.6 159.4 89.5 AML/OM + AML/OM + HCTZ 10/40 HCTZ 10/40 + 12.5 mg + 25 mg N=144 N=100 159.5 89.7 160.3 89.8 Baseline BP (mm Hg) –4.1 ‡ –8.2 ‡ -10 –10.4 ‡ –9.2 ‡ –10.4 ‡ -15 -20 -25 -30 P < 0.0001 vs baseline. ‡ AML/OM 5/20 mg N=188 –14.0 ‡ –18.0 ‡ –13.7 ‡ –19.3 ‡ –22.6 ‡ –27.6 ‡ –28.0 ‡ SBP DBP Source: Study 8663-403 Data Tables D8.1 & D8.2 (4 August 2009).
  • 65. Change From Baseline in BP (mm Hg) Secondary Endpoint: Change From Baseline in Mean SeBP (± SEM) During Each Titration Period, by Titration Drug 0 AML N = 200 158.8 89.0 -5 AML/OM N = 190 158.8 89.1 AML/OM + HCTZ N = 144 159.5 89.7 Baseline BP (mm Hg) –4.1 -10 ‡ –10.4 –10.8 -15 ‡ –14.9 ‡ -20 -25 -30 ‡ –23.0 SBP DBP ‡ –30.1 -35 ‡ ‡ P < 0.0001 vs baseline. Source: Study 8663-403 Data Tables D8.1 & D8.2 (4 August 2009).
  • 66. Mean Titration Effects (± SEM) in SeBP, by Titration Drug 0 AML to AML/OM N = 189 AML/OM to AML/OM + HCTZ N = 144 Change in BP (mm Hg) -2 -4 -6 –4.81 -8 ‡ -10 -12 -14 ‡ –6.70 –8.52 ‡ –12.53 SBP DBP ‡ P < 0.0001 for the change from previous treatment. ‡ Source: Study 8663-403 Data Table D8.3 (3 August 2009).
  • 67. Titration Effects in Mean SeBP (± SEM), by Titration Dose 0 5 mg to 5/20 mg N = 188 5/20 mg to 5/40 mg N = 174 5/40 mg to 10/40 mg N = 162 10/40 mg to 10/40 + 12.5 mg N = 144 10/40 + 12.5 mg to 10/40 + 25 mg N = 100 -1 Change in BP (mm Hg) -2 –1.42 -3 –2.05 –1.59 † # –1.33 NS ¶ -4 –4.05 –3.70 –3.89 ‡ -5 ‡ ‡ † -6 -7 –5.94 ‡ -8 –3.71 SBP DBP –7.29 -9 ‡ P < 0.0001, †P < 0.005, #P < 0.01, ¶P < 0.05, NSnot significant for the change from previous treatment. ‡ Source: Study 8663-403 Data Table D8.3 (19 October 2009).
  • 68. Secondary Endpoint: Proportions of Patients Achieving Mean 24-hour Ambulatory BP Targets at Week 12 Patients Achieving Ambulatory BP Target (%; N = 165*) 80 70 70.3 60 50 46.1 40 35.8 30 20 10 0 <130/80 mm Hg <125/75 mm Hg *Calculated using the total number of subjects having both baseline and end of study ABPM (N = 165) as the denominator. <120/80 mm Hg Source: Study 8663-403 Data Table D7.4 (28 July 2009).
  • 69. Patients Achieving Ambulatory BP Target (%; N = 165*) Secondary Endpoint: Proportions of Patients Achieving Daytime and Nighttime Ambulatory BP Targets at Week 12 90 83.0 80 72.1 70 67.9 60 50 50.3 40 29.1 30 25.5 20 10 0 <130/80 <125/75 <120/80 <130/80 Daytime <125/75 <120/80 Nighttime Target (mm Hg) Source: Study 8663-403 *Calculated using the total number of subjects having both baseline and end of study ABPM (N = 165) as the denominator. Data Table D7.4 (28 July Daytime, 8 AM–4 PM; nighttime, midnight–6 AM. 2009).
  • 70. Secondary Endpoint: Cumulative SeBP Goal (<130/80 mm Hg) Achievement by Titration Dose Patients Achieving SeBP Goal (%) 70 61.7 60 55.2 50 42.8 40 31.8 30 21.0 20 10 0 5.0 AML 5 mg N = 200 AML/OM 5/20 mg N = 200 AML/OM 5/40 mg N = 201 AML/OM 10/40 mg N = 201 AML/OM + HCTZ 10/40 + 12.5 mg N = 201 AML/OM + HCTZ 10/40 + 25 mg N = 201 Source: Study 8663-403 Data Table D8.7 (3 August 2009).
  • 71. Subgroup Analysis – Metabolic Syndrome Changes From Baseline in Mean 24-hour Ambulatory SBP and DBP (± SEM) at Week 12 Metabolic Syndrome N = 131 Change From Baseline in Ambulatory BP (mm Hg) 0 144.0 81.8 Total ABPM Cohort N = 165 144.3 81.6 Baseline BP (mm Hg) -5 -10 –11.2 –11.2 -15 ‡ ‡ -20 –19.7 -25 ‡ P< 0.0001 vs baseline. ‡ –19.9 SBP DBP ‡ Source: Study 8663-403 Data Tables D7.1 & D7.1s (4 August 2009).
  • 72. Subgroup Analysis – Metabolic Syndrome Mean 24-hour Ambulatory BP Target Achievement at Week 12 Patients Achieving Ambulatory BP Target (%) 80 70 71.8 70.3 60 50 46.6 40 46.1 35.9 35.8 30 20 10 0 <130/80 <125/75 <120/80 Metabolic Syndrome N = 131 <130/80 <125/75 <120/80 Total ABPM Cohort N = 165 Target (mm Hg) Source: Study 8663-403 Data Tables D7.4 & D7.4s (29 July 2009).
  • 73. Subgroup Analysis – Obesity Changes From Baseline in Mean 24-hour Ambulatory SBP and DBP (± SEM) at Week 12 BMI ≥ 30 kg/m N = 110 Change From Baseline in Ambulatory BP (mm Hg) 0 144.5 2 81.7 2 BMI <30 kg/m N = 55 144.0 81.5 Baseline BP (mm Hg) -5 -10 –11.0 -15 -20 -25 –11.8 ‡ ‡ SBP DBP –19.4 ‡ –21.1 ‡ ‡ P < 0.0001 vs baseline. BMI, body mass index. Source: Study 8663-403 Data Table D7.1s (4 August 2009).
  • 74. Subgroup Analysis – Obesity Mean 24-hour Ambulatory BP Target Achievement at Week 12 Patients Achieving Ambulatory BP Target (%) 80 70 72.7 69.1 60 50.9 50 43.6 40 41.8 32.7 30 20 10 0 <130/80 <125/75 <120/80 <130/80 2 BMI ≥30 kg/m N = 110 Target (mm Hg) <125/75 <120/80 2 BMI <30 kg/m N = 55 Source: Study 8663-403 Data Table D7.4s (29 July 2009).
  • 75. Subgroup Analysis – Race Changes From Baseline in Mean 24-hour Ambulatory SBP and DBP (± SEM) at Week 12 Black N = 28 Change From Baseline in Ambulatory BP (mm Hg) 0 149.1 Non-Black N = 137 87.7 143.3 80.4 Baseline BP (mm Hg) -5 -10 –11.1 –12.1 -15 ‡ ‡ -20 –19.7 -25 P < 0.0001 vs baseline. ‡ –20.0 ‡ SBP DBP ‡ Source: Study 8663-403 Data Table D7.1s (4 August 2009).
  • 76. Subgroup Analysis – Race Mean 24-hour Ambulatory BP Target Achievement at Week 12 Patients Achieving Ambulatory BP Target (%) 80 75.2 70 60 50 50.4 46.4 38.0 40 30 25.0 25.0 20 10 0 <130/80 <125/75 <120/80 Black N = 28 <130/80 Target (mm Hg) <125/75 <120/80 Non-Black N = 137 Source: Study 8663-403 Data Table D7.4s (29 July 2009).
  • 77. Subgroup Analysis – Hypertension Stage Changes From Baseline in Mean 24-hour Ambulatory SBP and DBP (± SEM) at Week 12 Change From Baseline in Ambulatory BP (mm Hg) 0 Stage 1 N = 94 139.5 79.9 Stage 2 N = 71 150.7 83.9 Baseline BP (mm Hg) -5 -10 –10.4 -15 -20 –12.4 ‡ ‡ SBP DBP –17.9 ‡ -25 –22.7 ‡ ‡ P < 0.0001 vs baseline. Source: Study 8663-403 Data Table D7.1s (4 August 2009).
  • 78. Subgroup Analysis – Hypertension Stage Mean 24-hour Ambulatory BP Target Achievement at Week 12 90 Patients Achieving Ambulatory BP Target (%) 80 81.9 70 60 55.3 50 54.9 44.7 40 33.8 30 23.9 20 10 0 <130/80 <125/75 <120/80 Stage 1 N = 94 <130/80 Target (mm Hg) <125/75 <120/80 Stage 2 N = 71 Source: Study 8663-403 Data Table D7.4s (29 July 2009).
  • 79. The Safety and Efficacy of Olmesartan Medoxomil ± HCTZ in Patients with Type 2 Diabetes and Hypertension Results of an open-label, multi-center, dosetitrated, single arm ABPM study (866-449) Study funded by Daiichi Sankyo, Inc.
  • 80. Mean Change in 24-hour ABPM SBP and DBP at End of Study Mean change in BP (mm Hg) 0 Total Cohort n=172 -5 -10 -11.1 -15 -20 -20.4 -25 SBP DBP Baseline mean 24-h ABPM: 146.3/83.3 mm Hg *P < 0.0001 to baseline
  • 81. Mean Change in 24-hour ABPM SBP and DBP by Treatment Regimen at End of Study Mean change in BP (mm Hg) 0.0 OM 20 mg n=3 OM 40 mg n=4 OM/HCTZ 40/12.5 mg n=25 OM/HCTZ 40/25 mg n=140 -5.0 -6.8 -10.0 -10.5 -15.0 -9.8 -10.8* -12.6 -13.5* -20.0 -20.2* -25.0 -23.7* SBP DBP Baseline mean 24-h ABPM: 146.3/83.3 mm Hg *P < 0.0001 to baseline
  • 82. Hourly Mean ABPM SBP at Baseline and End of Study Mean SBP (mm Hg) 160 Mean 24-h SBP: 146.3 mm Hg 150 Baseline 140 Mean 24-h SBP: 126.0 mm Hg 130 End of Study 120 110 0 4 8 12 16 20 24 Time (h) Overall, 61.6% of patients achieved mean 24-h ABPM SBP goal of <130 mm Hg
  • 83. Mean DBP (mm Hg) Hourly Mean ABPM DBP at Baseline and End of Study 90 Baseline 80 End of Study 70 60 Mean 24-h DBP: 83.3 mm Hg 0 4 8 12 16 20 Mean 24-h DBP: 72.2 mm Hg 24 Time (h) Overall, 86.6% of patients achieved mean 24-h ABPM DBP goal of <80 mm Hg
  • 84. Mean Change from Baseline in Cuff SeSBP and SeDBP Throughout the Study, by Treatment Regimen Mean change in SeBP (mm Hg) 0 Total Cohort n=192 -5 -10 -9.8 -15 -20 -21.3 -25 SeSBP Values are from treatment exposure throughout the study, regardless of whether patient remained on treatment regimen or were titrated to a different SeDBP Baseline mean Cuff BP: 158.1/90.0 mm Hg All data P < 0.0001 to baseline.
  • 85. Mean Change from Baseline in Cuff SeSBP and SeDBP Throughout the Study, by Treatment Regimen Mean change in SeBP (mm Hg) 0.0 OM 20 mg n=192 -5.0 OM 40 mg n=182 OM/HCTZ 40/12.5 mg n=171 OM/HCTZ 40/25 mg n=141 -4.0 -5.5 -10.0 -9.5 -8.7 -9.9 -10.4 -15.0 -20.0 -18.7 -21.8 -25.0 SeSBP Values are from treatment exposure throughout the study, regardless of whether patient remained on treatment regimen or were titrated to a different SeDBP Baseline mean Cuff BP: 158.1/90.0 mm Hg All data P < 0.0001 to baseline.
  • 86. Achievement of BP Goals at End of Study 100 BP Goal Achievement (%) Assessed by 24-h ABPM, N = 172 80 79.7 Assessed by Cuff BP measurement, N = 192 70.9 61.6 60 57.3 45.9 40.7 40 35.4 26.6 20 0 15.1 <140/90 mm Hg <135/85 mm Hg <130/80 mm Hg <120/80 mm Hg <125/75 mm Hg Baseline mean 24-h ABPM BP: 146.3/83.3 mm Hg Baseline mean Cuff BP: 158.1/90.0 mm Hg
  • 87. Achievement of BP Goals through the Duration of the Study using Cuff BP Measurement, by Treatment Regimen 100 BP Goal Achievement (%) OM 20 mg OM 40 mg OM/HCTZ 40/12.5 mg 80 OM/HCTZ 40/25 mg 71.4 64.6 60 51.0 44.8 40 41.1 39.6 31.3 29.7 24.0 23.4 20 13.5 17.7 17.2 10.4 5.2 8.3 0 <140/90 mm Hg <135/85 mm Hg Cumulative percents are calculated using the total number of subjects in the treatment cohort (N=192) as the denominator. <130/80 mm Hg <120/80 mm Hg Baseline mean Cuff BP: 158.1/90.0 mm Hg