Hypertension mechanisms

Transcription

1 הטיפול בלחץ דם בעזרת תרופות מישלב

2 Hypertension mechanisms ESH Task Force Document. J Hypertens 2009

3 The history of development of antihypertensive drugs ESH Task Force Document. J Hypertens 2009

4 הטיפול ביתר לחץ דם STROKE = 40% CHD = 15-20% CHF = 50%

5 ? כיצד להוריד לחץ דם

6 Monotherapy versus combination strategies Mild BP elevation Low/moderate CV risk Conventional BP target Choose between Marked BP elevation High/very CV high risk Lower BP target Single agent at low dose Two drug combination at low dose If goal BP not achieved Previous agent at Switch to different Previous combination at Add a third drug at lld full dose agent at low dose full dose low dose If goal BP not achieved Two to three drug Full dose Two three drug combination at Two to three drug combination at full dose monotherapy full doses

7 Current Guidelines Acknowledge that Combination Therapy is Required by the Majority of Patients to Reach BP Goal JNC 7 guidelines state 1 : Although effective BP control can be achieved in most patients who are hypertensive, the majority will require two or more antihypertensive drugs. ESH/ESC guidelines state 2 : Evidence has continued to grow that t in the vast majority of hypertensive patients, effective BP control can only be achieved by combination of at least two antihypertensive drugs. Whenever possible, use of fixed dose (or single pill) combinations should be preferred, because simplification of treatment carries advantages for compliance to treatment. ESH = European Society of Hypertension ESC = European Society of Cardiology JNC = Joint National Committee 1 Chobanian et al. Hypertension 2003;42: Mancia et al. Blood Pressure 2009;18:

8 ACCOMPLISH: Trial Design Prospective, randomized, double-blind, event-driven trial Target BP <140/90 mmhg; <130/80 mmhg in patients with diabetes or renal insufficiency Screening Random mization 11,506 patients Benazepril 20 mg + Amlodipine 5 mg Benazepril 20 mg + HCTZ 12.5 mg Forced titration Benazepril 40 mg + Amlodipine 5 mg Benazepril 40 mg + HCTZ 12.5 mg Benazepril 40 mg + Amlodipine 10 mg Benazepril 40 mg + HCTZ 25 mg Free add-on* Free add-on* 2 Weeks Day 1 Month 1 Month 2 Month 3 Year 5 8 *Beta blockers; alpha blockers; clonidine; loop diuretics; HCTZ = hydrochlorothiazide Follow up at 6 months and every 6 months thereafter Jamerson K, et al. J Clin Hypertens 2003;5(4 Suppl 3):29 35 Jamerson K, et al. Am J Hypertens 2004;17: Jamerson K, et al. Blood Press 2007;16:80 6

9 FIXED COMBINATION ACHIEVEMENTS ACCOMPLISH STUDY n engl j med 359; BP 131 2/73 4 mmhg

10 ACCOMPLISH: Primary Endpoint 0.16 Benazepril/amlodipine (552 patients with events: 9.6%) Benazepril/HCTZ (679 patients with events: 11.8%) rate Cumula ative event HR 0.80 (95%CI ); p< % relative risk reduction ,096 1,277 Time to first CV mortality/morbidity (days) Months Patients at risk (N) Benazepril/amlodipine l i 5, ,317 5,141 4,959 4,739 2,826 1,447 Benazepril/HCTZ 5,483 5,274 5,082 4,892 4,655 2,749 1, Jamerson K, et al. N Engl J Med 2008;359:

11 ACCOMPLISH: Conclusion The ACCOMPLISH trial demonstrates that excellent BP control rates can be achieved with RAS blocker-based single-pill combination therapies The combination of a RAS blocker (benazepril) + CCB (amlodipine) reduced the risk of CV morbidity and mortality more than a RAS blocker (benazepril) + diuretic (HCTZ) combination in high-risk hypertensive patients These findings support the use of a RAS blocker + CCB single-pill combination when combination therapy is required in high-risk hypertensive patients 11 Jamerson K, et al. N Engl J Med 2008;359:

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13 ACCOMPLISH: Conclusion The ACCOMPLISH trial demonstrates that excellent BP control rates can be achieved with RAS blocker-based single-pill combination therapies The combination of a RAS blocker (benazepril) + CCB (amlodipine) reduced the risk of CV morbidity and mortality more than a RAS blocker (benazepril) + diuretic (HCTZ) combination in high-risk hypertensive patients These findings support the use of a RAS blocker + CCB single-pill combination when combination therapy is required in high-risk hypertensive patients 13 Jamerson K, et al. N Engl J Med 2008;359:

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17 Aortic Stiffening and Early Wave Reflection Diastole Young compliant arteries : Normal PW velocity (8 m/sec) (1) Ventricular-Vascular coupling (2) coronary blood flow Systole Elderly stiff arteries with ISH : Increased PW velocity (12 m/sec) (1) Ventricular-vascular mismatch (2) The reflected wave increases or augments central SBP during late systole:

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20 Meta-analysis analysis of placebo-controlled controlled trials of monotherapy: 1- in unselected hypertensives,6 reports average (placebo corrected) showed blood pressure responses to single agents of: 9.1 mmhg for systolic blood pressure 5.5 mmhg for diastolic blood pressure.

21 Monotherapy vs Combination therapy, Wald et al, AJM 2009

22 Ratio of observed to expected incremental blood pressure-lowering effects of adding a drug or doubling the dose according to the class of drug (Wald et al, AJM 2009)

23 Treatment of Systolic/Diastolic Hypertension Without Other Compelling Indications

24 CBPM 140/90 mmhg & ABPM/HBPM 135/85 mmhg Stage 1 hypertension CBPM 160/100 mmhg & ABPM/HBPM 150/95 mmhg Stage 2 hypertension Care pathway 2011 If target organ damage present or 10- year cardiovascular risk > 20% Offer antihypertensive drug treatment If younger than 40 years Consider specialist referral Offer lifestyle interventions Offer patient education and interventions to support adherence to treatment Offer annual review of care to monitor blood pressure, provide support and discuss lifestyle, symptoms and medication

25 Aged under 55 years Aged over 55 years or black person of African or Caribbean family origin of any age C 2 A Step 1 Summary of antihypertensive drug treatment A + C 2 Step 2 A + C + D Step 3 Resistant hypertension A + C + D + consider further diuretic 3, 4 or alpha- or beta-blockerblocker 5 Consider seeking expert advice Step 4 Key A ACE inhibitor or low-cost angiotensin II receptor blocker (ARB) 1 C Calcium-channel blocker (CCB) D Thiazide-like diuretic See slide notes for details of footnotes 1-5

26 ESH/ESC guidelines state 2011 Use of fixed combinations of two drugs can directly follow initial monotherapy when addition of a second drug is required to control blood pressure, or be the first treatment step when a high C.V. risk makes easy control desirable New evidence favours, whenever possible, the use of fixed combinations of two drugs in a single tablet because of the advantage of simplification of the treatment regimen

27 drug combinations for hypertension treatment in patients without specific compelling indications Preferred combinations Renin angiotensin aldosterone system inhibitors [ARB/ACEi] and calcium channel blockers Renin angiotensin aldosterone system inhibitors [ARB/ACEi] and diuretics Acceptable combinations Beta-blocker/diuretic CCB (dihydropyridine)/beta-blocker CCB/diuretic Renin inhibitor/diuretic Renin inhibitor/ccb Dihydopyridine CCB/non-dihydropyridine CCB Beta blockers and Alpha Blockers [personal opinion, only for patients with high degree of anxiety] Unacceptable/ineffective combinations Dual renin angiotensin aldosterone system blockade Renin angiotensin aldosterone system blocker and beta-blockers Beta-blockers and antiadrenergic drugs [normopresan]

28 Renin angiotensin aldosterone system inhibitors [ARB/ACEi] and calcium channel blockers in Israel 1 Exforge (Amlodipine+Valsartan) 2 Vasodip Combo (lercanidipine+enalapril)

29 Amlodipine/Valsartan: BP Lowering Across All Grades of Hypertension Mean change in mean sitting systolic BP from baseline (mmhg) 0 10 Mild HTN 1 Moderate HTN 1 Severe HTN mmhg 2 Systolic BP n=69 n=140 n=64 n= Diastolic BP reduction (mmhg) Data from Smith et al. J Clin Hypertens 2007;9: (Dose 10/160 mg) 2 Data from Poldermans et al. Clin Ther 2007;29: (Dose 5 10/160 mg)

30 Amlodipine/valsartan ABPM (1) Blood Pressure Monitoring 2011, 16:87 95

31 BP reduction- baseline Vs. end of treatment VASODIP COMBO 10/20

32 Significant reduction of ABPM values 24-hour SPB 24-hour DPB Piug JG et al. J Hum Hypertens. 2007; 21:

33 ACEI Vs ARB

34 Vol. 17, No. 8 October 2011 JMCP Supplement to Journal of Managed Care Pharmacy

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36 Discussion written by the authors it should be emphasized that we did not design this meta-analysis to make a head-to-head comparison between ACE inhibitors and ARBs. The finding that the beneficial effect is seen in the ACE inhibitor population as opposed to the ARB population should be considered a post hoc observation. Given the nature of meta-analyses, which are per definition data-driven, driven, the differential effect between ACE inhibitors and ARBs should be interpreted with caution to avoid overstating this subgroup finding vis-a`-vis the a priori hypothesis. In this respect it should also be noted that the difference in effect on cardiovascular mortality between ACE inhibitors and ARBs was not statistically significant

37 RAAS inh & diuretics

38 Obesity paradox observed with hydrochlorothiazide, not amlodipine: ACCOMPLISH (ASH 2012) A single tablet benazepril/amlodipine p combination reduced the risk of morbidity and mortality by 20% /Stratifying patients in the entire cohort by BMI, the primary end point (CV, death, MI, and stroke) occurred in the 24.7% of patients with iha normal BMI, 20.5% of patients considered overweight (BMI 25 30), and in 17.2% of patients considered obese (BMI>30) >30). In a head to head comparison of the amlodipine treated patients with those treated withhydrochlorothiazide, hydrochlorothiazide, there was no difference in the primary end point in the obese patients. In the overweight and normal BMI cohorts, treatment favored amlodipine, Hypertension in obese patients is associated with excess volume, and a number of people have shown this, so thiazide therapy, as well as calcium channel blocker l therapy, is appropriate in those patients,"

39 Treatment of Hypertension in Patients 80 Years of Age or Older (N Engl J Med 2008;358)

40 ESH/ESC guidelines state 2011 Use of fixed combinations of two drugs can directly follow initial monotherapy when addition of a second drug is required to control blood pressure, or be the first treatment step when a high C.V. risk makes easy control desirable New evidence favours, whenever possible, the use of fixed combinations of two drugs in a single tablet because of the advantage of simplification of the treatment regimen

41 אז, אפשר להפסיק את הטיפול, דוקטור? לחץ דם שלך התאזן, מר לוי מצב מוכר

42 Canadian Recommendations 2011

43 Medication Persistence Beyond One Year is Even lower 39% used anti-hypertensive medications continuously over 10-years 39% discontinued permanently 22% discontinued temporarily Van Wijk BL et al. J Hypertens. 2005; 23:

44 Improved compliance with single-pill combination therapy compared with free-combination therapy P< Defined as the total number of days of therapy for medication dispensed/365 days of study follow-up Gerbino & Shoheiber Am J Health System Pharm 2007; 64:

45 Blood Pressure Reduction of 2 mmhg Decreases the Risk of Cardiovascular Events by 7 10% Meta-analysis of 61 prospective, observational studies 1 million adults 12.7 million person-years 2 mmhg decrease in mean SBP 7% reduction in risk of ischaemic heart disease mortality 10% reduction in risk of stroke mortality Lewington et al. Lancet 2002;360:

46 Prevalence and Correlates of Low Medication Adherence in Apparent Treatment-Resistant Hypertension, The Journal of Clinical Hypertension Vol 14 No 10 October 2012

47 Uncontrolled hypertension carries the same CV risk as untreated hypertension Third National Health and Nutrition Examination Survey (NHANES III) Not treated BP uncontrolled 48% (n = 2,458) Both are at equally increased risk compared with controlled BP (p>0.05) 35% (n = 1,756) BP controlled 17% (n = 872) Gu Q, et al. Am J Hypertens 2009; doi: /ajh

48 Adherence to antihypertensive medications and cardiovascular morbidity among newly diagnosed hypertensive patients Multivariable analysis of the association of patients characteristics with first-ever acute cardiovascular event estimated by Cox proportional-hazards models Adherence within 6 mo after diagnosis HR* (95% Cl) P Model 1 Low (PDC <40%) 1.00 < Intermediate (PDC, 40% to 79%) 0.87( ) Model 2 High (PDC 80%) 0.50 ( ) < Low (PDC <40%) 1.00 < Intermediate (PDC, 40% to 79%) 0.86( ) High (PDC 80%) 0.62 ( ) Circulation. 2009; 120:

49 Patients Taking FDCs (Fixed Dose Combinations) Use Fewer Healthcare Resources than Patients on Free Combinations In three one-year retrospective ti 7000 studies, total annual healthcare cost per patient was significantly less with 6000 an FDC (amlodipine/benazepril) 5000 compared with an equivalent free combination (DHP-CCB + ACEI) Reduced costs were linked to: fewer outpatient visits lower drug costs lower hospitalization costs r patient (US S$/yr) Total healthc care cost pe *** * * One pill* ** Two pills* ** * *One pill: combination of amlodipine and benazepril; two pills: combination of dihydropyridine CCB and ACEI. ACEI: angiotensin-converting genzyme inhibitor; DHP-CCB: dihydropyridine calcium channel blocker; FDC: fixed-dose combination 1. Dickson M, Plauschinat CA. J Manag Care Pharm; Am. J Cardiovasc drugs Taylor AA, Shoheiber O. Congest Heart Fail. 2003;9: Ngan GC et al. J Clin Hypertens. 2006;8(5, Suppl A):S >6 Charlson co-morbidity index *p<0.05; **p<0.01; ***p<0.001 two pills vs. one pill Graph based on ref. 2

50 לא לשכוח Disadvantages of a Fixed Dose Combination as Antihypertensive Therapy Loss of dose flexibility Fixed dose combinations may not contain appropriate doses when treating hypertension and a comorbid condition

51 לזכור אבל Advantages of a Fixed Dose Combination as Antihypertensive Therapy All of the advantages of giving 2 3 drugs individually, plus: Simplification of the regimen Improved adherence Reduced pill burden Potential for reduced cost

52 Combinations of More than Two Drugs No less than 15% 20% of the patients need more than two antihypertensive drugs to achieve an effective BP reduction The combination of a RAS blocker, a CA and a thiazide is a rational three drug combination. It will arrive to Israel in the 21th century

53 תודה רבה