Presentation on theme: "How to maximize patient benefit"— Presentation transcript:
1 How to maximize patient benefit Protecting patients with hypertension How to maximize patient benefit ? Pr Roland AsmarHow to maximize patient benefit
2 Goals of Antihypertensive Treatment ESH/ESC 2007 < 140/90mmHgHypertensive patients< 130/80mmHgDiabetesPatient at high riskHow to maximize patient benefit
3 Worldwide Blood Pressure Control in Treated Hypertensive Patients Turkey19.8Canada41.0Germany33.6Japan55.7England29.2Greece49.5USA53.1China28.8Spain38.8Taiwan18.0Mexico21.8The 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:Chockalingham A, Fodor JG. Treatment of raised blood pressure in the population. The Canadian experience. Am J Hypertens. 1998;11:Colhoun HM, Dong W, Poulter NR. Blood pressure screening, management and control in England: results from the health survey for England J Hypertens. 1998;16:Egypt33.5South Africa47.6Italy37.5How to maximize patient benefitKearney et al. J Hypertens 2004; 22: 11
4 HOT: Need for Combination Therapy How to maximize patient benefitHansson et al., Lancet 1998, 351:
5 Percentage of Patients with Combination Treatment in Clinical Trials %How to maximize patient benefit
7 Pharmacological Rationale for Combination Therapy How to maximize patient benefit
8 Rationale for Combination Therapy Increase EfficacySynergistic & additive effects on BPEffects on several patho-physiological mechanisms of HTInhibition of the contra-regulation mechanismsDecrease Side effectsInhibition of the contra-regulationLow dose Decrease dose-dependent side effectsHow to maximize patient benefit
9 Advantages of Combination Therapy EfficacyCertainly, 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.How to maximize patient benefit
10 Rationale of Combination Therapy Pathogenetic Mechanisms in HypertensionPatient A Patient B Patient CSympathetic nervous systemRenin-angiotensin systemTotal body sodiumWaeber B. 2004
12 Titration vs. Combination Diastolic BP How to maximize patient benefitFrishman WH et al,Arch Intern Med 1994;154:1461
13 Efficacy: Up-titration vs Combination HCT12.5V80HCT12.5O20HCT12.5T40T80T40V80V160V80Ol20Ol40Ol20Change in SBP (mm Hg)How to maximize patient benefit
14 How to maximize patient benefit Value of combination treatment: analysis of 354 randomised placebo controlled trialsHow to maximize patient benefitLaw MR BMJ 2003
15 Advantages of Combination Therapy SideEffectsCertainly, 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.How to maximize patient benefit
16 Effect of ARB and HCTZ on Serum Potassium Adjusted mean D from baseline at 8 weeks (mEq/L)300100GLB.IRBIrbesartan/HCTZ combination therapy ameliorates the hypokalemic effects of HCTZ.1In this same trial, HCTZ decreased serum potassium levels in a dose-related manner. However, this effect was less pronounced with the addition of increasing doses of irbesartan. The 300 mg dose of irbesartan appears to provide the most benefit in reversing the hypokalemic effects of HCTZ. No clinically significant occurrences of electrolyte imbalance have been observed in trials with irbesartan/HCTZ combination therapy or with irbesartan monotherapy.ReferenceKochar M, et al. Matrix study of irbesartan with hydrochlorothiazide in mild-to-moderate hypertension. Am J Hypertens. 1999;12:797–805ARB dose (mg/d)37.56.2512.525HCTZ dose (mg/d)How to maximize patient benefitKochar M, et al. Am J Hypertens. 1999;12:797
17 Drug related symptoms: comparison between monotherapy & combination 50 trials testing drugs of two different categories separately and in combination,How to maximize patient benefitBMJ 2003;326:1427
18 Advantages of Combination Therapy ConvenienceCertainly, 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.How to maximize patient benefit
19 Fixed-dose Combination Therapy Increases Compliance to Treatment Persistence rates of one pill of lisinopril/HCTZ in fixed-combination vs two separate pills of lisinopril and HCTZ10095908580757065605550MonthsPersistence (%)68.757.818.8%Lisinopril/HCTZ (1 pill)Lisinopril and HCTZ (2 pills)Dezii CM. Manag Care 2000; 9 : s2
20 Advantages of Combination Therapy Equal efficacy?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.How to maximize patient benefit
21 Hypertension in special patient populations – ARBs-FDC Hypertension in special patient populations – ARBs-FDCBlood pressure control with ARBs and in Fixed Dose CombinationProtocolEndpointsWeber M. Journal of Hypertension 2003; 21 Suppl 6:S37-46Primary endpointChanges from baseline in SBP during last 6 hours of dosing interval using ABPMSecondary endpointsChanges from:Baseline in DBP during the last 6 hours of dosing intervalBaseline in pulse pressure during the last 6 hours of dosing intervalBaseline in the 24-hour mean SBP and DBPn=294n=160n=297Patients are randomised to starting dose Telmisartan (40 mg/day) or Losartan (50 mg/day), respectively or to high dose Telmisartan (80 mg/day), all in a fixed-dose combination with 12.5 mg/day Hydrochlorothiazide. The endpoints focus on parameters of blood pressure control derived from 24-hour ambulatory blood pressure measurements.Secondary Endpoints in detail:Reductions in blood pressure and responder rates for patients treated with Telmisartan combined with Hydrochlorothiazide compared to patients treated with Losartan combined with Hydrochlorothiazide at the end of a 6-week treatment phase as measured by:Change from baseline in the ABPM mean SBP during the last 6 hours of the 24-hour dosing interval.Changes from baseline in the 24-hour ABPM mean DBP and SBP.Changes from baseline in the ABPM mean DBP and SBP during other periods (i.e. morning, daytime,and nighttime) of the 24-hour dosing interval.Changes from baseline in mean seated trough DBP and SBP using manual cuff sphygmomanometer.Percentage of patients responding as determined by both ABPM and manual in-clinic blood pressures.Weber M. The Telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) programme. Journal of Hypertension 2003; 21 Suppl 6:S37-46Neutel JM, et al. Hypertens Res 2005;28:555
22 Telmisartan HCTZ & Losartan HCTZ ABPM Comparison ofTelmisartan HCTZ & Losartan HCTZParallel Group Comparison after 6 weeks TherapyTime after dosing (h)Time after dosing (h)-8-6Systolic BPDiastolic BPTelmisartan 80mg + HCTZ 12.5mg-8Telmisartan 40mg + HCTZ 12.5mg-12Losartan 50mg + HCTZ 12.5mg-10Change from baseline (mmHg)-16-12-20-14-24-16How to maximize patient benefitNeutel et al. Hypertens Res. 2005;28:555
23 Study of telMisartan On Obese/overweight Type2 diabetics with HypertensionProtocolEndpointsWeber M. Journal of Hypertension 2003; 21 Suppl 6:S37-46Primary endpointChanges from baseline in SBP during last 6 hours of dosing interval using ABPMSecondary endpointsChanges in other ABPM-derived parametersChanges in trough cuff SBP and DBPMetabolic blood markers (e.g.cholesterol)Urine markers (e.g. proteinuria)ObjectiveTo compare telmisartan with valsartan in a fixed-dose combination with a thiazide type diuretic in obese type 2 diabetics with hypertension.Patients receive Telmisartan (80 mg/day) and Valsartan (160 mg/day) as antihypertensive treatment in fixed-dose combination with Hydrochlorothiazide. The study is not powered to detect differences in prognosis but focuses on parameters of blood pressure control derived from ABPM and surrogate endpoints like changes in metabolic and urinary parameters.Secondary Endpoints in detail: Statistically greater reductions in ambulatory blood pressure for patients treated with Telmisartan/HCT compared to patients treated with Valsartan/HCT at the end of the 10-week study as measured by:Changes from baseline in the last 6 hours of the 24-hour dosing interval for pulse pressureChanges from baseline in the 24-hour ABPM mean (relative to dosetime) for SBP, DBP, and pulse pressureChanges from baseline in the ABPM mean SBP, DBP, and pulse pressure (relative to clocktime) during other periods (i.e. morning, daytime, nighttime) of the 24-hour dosing intervalChange from baseline in systolic and diastolic blood pressure load during the 24-hour dosing intervalPercentage of patients responding to treatment based on the 24-hour ABPM mean SBP and DBP (relative to dosetime).Changes from baseline in metabolic markers using laboratory assay for serum: triglycerides, low density lipoprotein cholesterol, high density lipoprotein cholesterol, total cholesterol, potassium, fasting glucose and HbA1c, and for urine: sodium, potassium, chloride, proteinuria (as measured by spot urine for protein:creatinine ratio).Weber M. The Telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) programme. Journal of Hypertension 2003; 21 Suppl 6:S37-46Sharma AM, et al. Cardiovascular Diabetology. 2007;6:28
24 Telmisartan + HCTZ vsValsartan + HCTZ Powerful 24 hr SBP reductions ***SBP change from baseline (mmHg)***p < T + H vs V + H 24-hour and last 6-hour mean SBPHow to maximize patient benefitSharma et al. Hypertension 2005;46:898
25 Telmisartan 80mg/HCTZ 12.5 mg vs Olmesartan 20mg/HCTZ12.5 mg Systolic BPDiastolic BPHow to maximize patient benefitFogari & al Current Therapeutic Research; 2008; 69
26 A comparison of Telmisartan plus HCTZ with amlodipine plus HCTZ in Older patients with predominantly Systolic hypertensionProtocolEndpointsWeber M. Journal of Hypertension 2003; 21 Suppl 6:S37-46Primary endpointChanges from baseline in SBP during last 6 hours of dosing interval using ABPMSecondary endpointsChanges from:Baseline in DBP during the last 6 hours of dosing intervalBaseline in pulse pressure during the last 6 hours of dosing intervalBaseline in the 24-hour mean SBP and DBPn=497n=503ObjectiveTo compare the effect of telmisartan with the calcium channel blocker amlodipine in a fixed dose combination with HCTZ in elderly patients with ISHWeber M. The Telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) programme. Journal of Hypertension 2003; 21 Suppl 6:S37-46Franklin SS et al. Hemodynamic Patterns of Age-Related Changes in Blood Pressure: The Framingham Heart Study Circulation 1997; 96(1):Neldam S, et al. AJGC 2006;15:
27 How to maximize patient benefit Neldam S, et al. AJGC 2006;15:
28 Telmisartan in combination HCTZ 25 mg How to maximize patient benefit
29 Comparison of Telmisartan HCTZ & Valsartan HCTZ Change in clinic trough BP from baseline after 8 weeks therapySystolic BPDiastolic BP-5-10Change from baseline (mmHg)-15-20-1.8 (-3.0, - 0.6) p<0.02Telmisartan-HCTZ 80/25mg (n=467)Valsartan-HCTZ 160/25mg (n=479)-25Placebo (n=120)-2.8 (-4.6, -1.0) p<0.004How to maximize patient benefitWhite et al. J Hypertens Suppl. 2003;21:S9-15.
30 Comparison of Telmisartan HCTZ & Valsartan HCTZ Change in clinic trough BP from baseline after 8 weeks therapyHow to maximize patient benefitWhite W & al BP Monitoring 2008, 13:21
31 How to maximize patient benefit AIIA + CCBHow to maximize patient benefit
32 How to maximize patient benefit Composed end-point comparing a fixed combination of a CCB +ACEI vs a thiazide+ACEIACCOMPLISH TrialHR: 0,80; IC 95%: 0,72 – 0,90Incidence of eventosEl estudio ACCOMPLISH se realizó para comprobar si la combinación a dosis fijas de amlodipino y un inhibidor del Sistema Renina Angiotensina (SRA) proporciona mayores beneficios en cuanto a reducción de la morbimortalidad por eventos cardiovasculares en una población hipertensa de alto riesgo, en comparación con una combinación tradicional con el mismo inhibidor del SRAEs el primer estudio en comparar dos combinaciones fijas de antihipertensivos en la reducción del riesgo CV.El estudio se interrumpió de forma prematura cuando el efecto positivo del brazo con amlodipino superó los límites de significación estadística marcados previamente: una reducción del riesgo de evento CV de aproximadamente el 20% en comparación con la combinación fija tradicional.Time for eventsHow to maximize patient benefitJamerson K et al. NEJM; 2008; 359:2417
33 ASCOT - Summary of all end points Unadjusted Hazard ratio (95% CI)0.90 ( )0.87 ( )0.87 ( )0.84 ( )0.89 ( )0.76 ( )0.77 ( )0.84 ( )1.27 ( )0.68 ( )0.98 ( )0.65 ( )1.07 ( )0.70 ( )0.85 ( )0.86 ( )0.84 ( )Primary Non-fatal MI (incl silent) + fatal CHDSecondary Non-fatal MI (exc. Silent) +fatal CHDTotal coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failureTertiary Silent MIUnstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairmentPost hocPrimary end point + coronary revasc procsCV death + MI + stroke0.500.701.001.452.00Amlodipine perindopril betterAtenolol thiazide betterThe area of the blue square is proportional to the amount of statistical informationHow to maximize patient benefit
34 How to maximize patient benefit Chemical structuresTelmisartan and other angiotensin II antagonistsLosartan (active form)ValsartanIrbesartanCandesartan (active form)Olmesartan (active form)ONNHNCOOHCOHCH3H3CNHNCO2HCINHNOCO2HNHNOCH2CH3NHCOOHTelmisartanNCH3OOHTelmisartan, a potent and highly selective AT1 receptor antagonist, displays a novel bis-benzimidazole structure. This unique feature of telmisartan accounts for both its high receptor affinity and its excellent pharmacokinetic properties.1This slide shows the active metabolites of losartan, candesartan and olmesartan.The chemical structures of valsartan, irbesartan and eprosartan are also shown.Ries UJ, et al. 6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure–activity relationships. J Med Chem 1993;36:4040–4051.Telmisartan是一種強效且具有高度選擇性的AT1受體拮抗劑，具有全新的bis-benzimidazole構造。Telmisartan的這個特徵是其同時具備高的受體親合力與優越的藥物動力學性質的主要原因。1這張投影片是losartan的活性代謝物candesartan與olmesartan。同時顯示的是valsartan、irbesartan、與eprosartan的化學構造。How to maximize patient benefit
35 Dissociation Half-Lives of ARB’s from Human AT1 Receptors Telmisartanminminmin60-83 min73-91 min60-77 minOlmesartanCandesartanValsartanLosartanTelmisartan : the strongest binding affinity to human AT1 receptors of all ARBsEXP317450100150200250Dissociation half-life (min)How to maximize patient benefitKakuta et al. Int J Clin Pharmacol Res. 2005;25:41-6.
37 Difference between Thiazolodinediones & ARBs in the Interaction with PPARg Receptor15010050Full AgonistsFold ActivationPartial AgonistPPARg activation was evaluated in a heterologous transactivation assay in CV1 cell lines (eliminating interference from endogenous nuclear receptors).Cells treated with thiazolodinediones & ARB’s at a concentration of 40 mmol/lrosiglitazonepioglitazonetelmisartanirbesartaneprosartanHow to maximize patient benefitBenson et al. Hypertension. 2004;43:993
38 Activation of PPARg by ARB’s 2520Telmisartan was the only ARB that activated PPARg at concentrations (1-5 mmol/l) attained in plasma with conventional oral dosing15Fold Activation10PPARg activation was evaluated in a heterologous transactivation assay in CV1 cell lines (eliminating interference from endogenous nuclear receptors).Cells were treated with ARB’s added at a concentration of 10 mmol/l5TelmisartanCandesartanOlmesartanEXP 3174IrbesartanValsartanEprosartanHow to maximize patient benefitBenson et al. Hypertension. 2004;43:993.
39 Effects of Telmisartan & Losartan in Patients with metabolic syndrome FPGFPIHOMA IRHbA1c-10-20-30P<0.05P<0.05P<0.06Change from baseline (%)Double-Blind Parallel Group Comparison of 3 Months Therapy with Telmisartan 80mg and Losartan 50mgDaytime ABPM ReductionsTelmisartan 13.5 / 8.9 mmHgLosartan 10.0 / 5.6 mmHgNight-time ABPM ReductionsTelmisartan 8.7 / 7.8 mmHgLosartan 7.8 / 4.7 mmHgTelmisartan (n=20)Losartan (n=20)P<0.05How to maximize patient benefitVitale et al. Cardiovasc Diabetol. 2005;15:6.
40 How to maximize patient benefit Effects of Telmisartan and Amlodipine on Metabolic Parameters in Type 2 Diabetic HypertensivesFPGHbA1cTGHOMA IRAdiponectinFPI*-16-14-12-10-8-6-4-2-60-40-2020406080100120TelmisartanAmlodipine% change from baseline% change from baseline40 diabetic hypertensive subjects were randomly assigned to 4 months treatment 4mg + Amlodipine 10mg. All patients were already treated with metformin, but not with antihypertensive drugs with either rosiglitazone 4mg + Telmisartan 80mg or rosiglitazonen.s.n.s.***** p<0.05 & ** p<0.01 vs amlodipineHow to maximize patient benefitNegro et al. JRAA 2006:243-6.
41 Change in the Visceral Fat Area (VFA) Change in waist circumference Effects of telmisartan on fat distribution in individuals with metabolic syndromeChange in the Visceral Fat Area (VFA)Change in waist circumference300100+10%p=0.046-12%p=0.008-5%+3%2509820096VFA cm²Waist circumference (cm)15094100BACKGROUND: Visceral fat obesity plays an essential role in the clustering of atherosclerotic multiple risk factors in the metabolic syndrome. Telmisartan, an angiotensin II type 1 receptor blocker, has partial agonistic properties for peroxisome proliferator-activated receptor gamma, which is a key regulator of adipocyte differentiation and function. METHODS: This study aimed to clarify the impact of telmisartan on fat distribution and insulin sensitivity in the metabolic syndrome. In this open-label, prospective, randomized study, patients with the metabolic syndrome (waist circumference: men >or= 85 cm, women >or= 90 cm) were treated either with amlodipine (n = 26) or with telmisartan (n = 27) for 24 weeks, and fat distribution and insulin sensitivity were determined. RESULTS: Systolic and diastolic blood pressure were decreased in both groups to a comparable level. However, insulin and glucose levels during an oral 75 g glucose loading were decreased only in the telmisartan group. The visceral fat area, determined by abdominal computed tomography scan, was reduced in the telmisartan group after 24 weeks' treatment, but the subcutaneous fat area did not change in either group. CONCLUSION: The results imply that telmisartan could treat both the hemodynamic and metabolic aberrations seen in patients with the metabolic syndrome, improving insulin resistance and glucose intolerance at least partly through visceral fat remodeling.925090AmlodipineTelmisartanAmlodipineTelmisartanBaseline24 wks treatmentHow to maximize patient benefitShimabukuro, J Hypertens 2007;25:84141
43 ConclusionsUse of more than one agent is necessary to achieve target BP in the majority of patients.Combination therapy is related with a higher BP reduction and CV protectionFixed combinations of two drugs can simplify treatment schedule and improve compliance and tolerability.A combination of two drugs should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very highAre all the combination therapies equipotent
44 How to maximize patient benefit BackupHow to maximize patient benefit
46 CV Risk Reduction in Diabetics The HOT Study:CV Risk Reduction in Diabetics25p < for trend (n = 1501)2015major CV events/1000 patient.y105Target Achieved< 90 mmHg 85 mmHg< 85 mmHg 83 mmHg< 80 mmHg 81 mmHgHow to maximize patient benefitHansson L, et al. Lancet 1998;351:1755–62.
47 Management of BP for adults- JNC VII BP classificationSBP* mmHgDBPmmHgLifestyle modificationInitial drug therapyWithout compelling indicationWith compelling indicationsNormal<120and <80EncouragePrehypertension120–139or 80–89YesNo antihypertensive drug indicated.Drug(s) for compelling indications. ‡Stage 1 Hypertension140–159or 90–99Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.Drug(s) for the compelling indications.‡Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.Stage 2 Hypertension>160or >100Two-drug combination for most† (usually thiazide-type diuretic and ACEI or ARB or BB or CCB).†Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.‡Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.How to maximize patient benefit
48 Adverse Events: HCTZ 25 mg vs ARB + HCTZ 25 mg PotassiumInsulinGlucoseLipidsUric AcidAdverse eventsImpotenceHow to maximize patient benefit
49 Effect of Telmisartan HCTZ 25 mg Change in clinic trough BP from baseline after 8 weeks therapyHow to maximize patient benefitNeldam & al J Clin Hypertens 2008; 10:612
50 INVEST: Primary Composite Endpoint by Treatment Group Calcium Antagonist Strategy (CAS) (Verap + ACEI)Non-Calcium Antagonist Strategy (NCAS) (BB + HCTZ)RR = 0.98 (0.90 – 1.06)Cumulative %Log-Rank P=.57During follow-up evaluations over 60 months, the time to first primary composite endpoint (all-cause mortality, nonfatal MI, or nonfatal stroke) was the same for the CAS and NCAS treatment groups.6121824364854426030No. at Risk CAS NCASTime, mo35 33Pepine CJ, et al. JAMA. 2003;290:2805
51 ONTARGET – Combination ACEI + ARB vs ACE How to maximize patient benefitThe ONTARGET Investigators N EJM 2008;358:1547