Combination therapy in the treatment of arterial hypertension. Franco Veglio SIIIA. UNIVERSITA degli STUDI di TORINO

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2 SIIIA UNIVERSITA degli STUDI di TORINO FACOLTA DI MEDICINA E CHIRURGIA DIPARTIMENTO DI MEDICINA ED ONCOLOGIA SPERIMENTALE SCU MEDICINA INTERNA CENTRO IPERTENSIONE ARTERIOSA AOU S.GIOVANNI BATTISTA TORINO Combination therapy in the treatment of arterial hypertension Franco Veglio Torino, November 20 th 2008

3 TIMELINE COMBINATION THERAPY 1950 s 1960 s 1970 s 1980 s 1990 s- 2000s 2007 Ser-Ap-Es (reserpine/hydralazine/ hydrochlorothiazide) Methyldopa/thiazide ACE inhibitor/thiazide Direct renin inhibitor Butiserpine (reserpine/butalbital) Hyphex (hexamethonium/hydralazine) Hypotensin A, B, & C (pentolinium/hydralazine/resperine) Renir (reserpine/ephedrine) Verapene (rauwolfia/veratrum) Thiazide/K + -sparing diuretic b blocker/thiazide Clonidine/thiazide ACE inhibitor/ccb ARB/thiazide ARB/ACE inhibitor ARB/CCB

4 Percent response Morgan, J Hypertens 2001 MONOTHERAPY IS INADEQUATE IN 40% 60% OF HYPERTENSIVE PATIENTS % response Calcium antagonist Alpha 2 agonist Betablocker Diuretic Alpha 1 antagonist ACEI Placebo

5 COMBINATION THERAPY IN TRIALS Struijker-Boudier, Int J Clin Pract, 2007

6 2007 ESH/ESC Guidelines Main Requirements for Combination of Two or More Antihypertensive Drugs BP by combination greater than that of combination components Different / complementary mechanisms of action Favourable tolerance profile, i.e. minimization of side effects of combination components

7 Advantages of fixed versus free-drug combination Simple therapy Compliance Efficacy Tolerability Cost Flexibility Fixed Free-drug + + Neutel, Hypertension, 2005

8 Effect of fixed-dose combination vs free-drug combination the risk of medication non-compliance in cohort with hypertension. Bangalore, Am J Med 2007

9 Cumulative Incidence of Modification of Initial Monotherapy (Lombardia Data-base; n = ) Corrao, J Hypert 2008

10 HOT study % Patients in combination therapy 100 Effetti collaterali Side effects 17 % 2 % baseline end Hansson, Lancet 1998

11 TREND OF COMBINATION THERAPY IN ITALY Pts= Mazzaglia, J Hypertension 2005

12 COMBINATION THERAPY 6261 pazienti (3343 femmine, 2918 maschi) % 4.0% 7.2% 6.4% 12.4% 11.7% ACE-I + DHP b-blocker ACE-I + TZD + DHP diuretics 17.2% DHP ACE-I + TDZ ACE-I 4.2% 3.3% 3.2% 13.2% ACE-I 10.9% 8.9% DHP ACE-I + diuretic 8.0% b-blocker ACE-I + DHP diuretic ACE-I + diuretic + DHP 0% 5% 10% 15% 20% 6261 patients (3343 females, 2918 males) 0% 5% 10% 15% 20% 6.5% 6.3% 5.2% 3.7% 3.6% 9.0% 12.6% ACE-I b-blockers ACE-I + diuretic ACE-I+ DHP ARB ARB+ diuretic ACE-I + ß-blocker % 5% 10% 15% 20% Veglio, J Human Hypert 2007

13 POOR OR TROUBLE COMBINATION THERAPY Israili, Am J Ther, 2007

14 Recommendations for combination therapy in special populations Khanna, Current Opinion in Nephrology and Hypertension, 2008

15 2007 ESH/ESC Guidelines Monotherapy versus Combination Therapy 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 full dose Switch to different agent at low dose Previous combination at full dose Add a third drug at low dose If goal BP not achieved Two-to-three drug combination at full dose Full dose monotherapy Two-three drug combination at full doses

16 2007 ESH/ESC Guidelines Combinations between Some Classes of Antihypertensive Drugs Thiazide diuretics ß-blockers AT 1 -receptor antagonists α-blockers Calcium antagonists ACE inhibitors The preferred combinations in the general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to beneficial in controlled intervention trials.

17 The BHS guideline working party and the BHS Executive recommends that UK practitioners continue to use the current NICE/BHS guidance. GUIDELINES 2006

18 Effects of anti-renin drugs on BP and PRA in untreated Hypertensive Patients V-type / R-type Drugs V Drugs R Anti-Na+-Volume V Drugs: Thiazides-Loop Diuretics CCBs - -Blockers SARAs Anti-renin angiotensin R Drugs: ACEI / AIIRA b-blockers 2 -Central Blockers Laragh, Am J Hyperten 2001

19 Efficacy of antihypertensive treatment based on plasma renin activity * Pts= 200 * p<0.05 Veglio, Am J Hypertens, 2008 in press

20 2007 ESH/ESC Guidelines Combinations between Some Classes of Antihypertensive Drugs Thiazide diuretics ß-blockers AT 1 -receptor antagonists α-blockers Calcium antagonists ACE inhibitors

21 Rationale for combining thiazide diuretics and agents that block the renin-angiotensin system (RAS) Nash, Southern Medical J, 2007

22 Improved persistence and adherence to diuretic fixed-dose combination therapy compared to diuretic monotherapy 48,212 patients Patel, BMC Family Practice 2008

23 Irbesartan/HCTZ Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) Venkata, The American Journal of Medicine, 2008

24 2007 ESH/ESC Guidelines Combinations between Some Classes of Antihypertensive Drugs Thiazide diuretics ß-blockers AT 1 -receptor antagonists α-blockers Calcium antagonists ACE inhibitors The preferred combinations in the general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to beneficial in controlled intervention trials.

25 M-FACT STUDY vs vs p value Pts =1087 Frishman, Am J Hypert 2006

26 2007 ESH/ESC Guidelines Combinations between Some Classes of Antihypertensive Drugs Thiazide diuretics ß-blockers AT 1 -receptor antagonists α-blockers Calcium antagonists ACE inhibitors The preferred combinations in the general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to beneficial in controlled intervention trials.

27 Rationale for the combined use of calcium channel blocker (CCB) and renin angiotensin system (RAS) inhibitors Mizuno, Am J Hyperten, 2008

28 Biologic or pleiotropic actions independent of their interaction with the calcium channel Mizuno, Am J Hyperten, 2008

29 NICE-Combi Study Pts=331. Nifedipine CR + Candesartan Candesartan Hasebe, J Hypertension 2005

30 THERAPY COST COMBINATION NICE-Comby STUDY Fushigawa, Hyper Res 2005

31 Combination Therapy of Amlodipine/Ramipril (ATAR) Study Miranda, Clinical Therap, 2008

32 LOTHAR STUDY Pts=198 Kohlmann, Arch Br Cardiol, 2006

33 LOTHAR STUDY

34 The ACCOMPLISH Study patients Kjeldsen, Blood Press 2008

35 Cumulative event rate Primary Endpoint- ACCOMPLISH ACEI / HCTZ CCB / ACEI 20% Risk Reduction p = Time to 1 st CV morbidity/mortality (days) HR (95% CI): 0.80 (0.72, 0.90)

36 Amlodipine 5-10 mg add Perindopril 4-8 mg Atenolol mg add Bendroflumethiazide-K mg add Doxazosin GITS 4-8 mg add additional drugs, eg, Moxonidine/Spironolactone Lancet, 2005; 366,

37 Rate of Mono / Combination Therapy in ASCOT % Monotherapy Combination therapy Atenolol 14.6 Amlodipine

38 Summary of all end points Primary Non-fatal MI (incl silent) + fatal CHD Secondary Non-fatal MI (exc. Silent) +fatal CHD Total coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure Tertiary Silent MI Unstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke Amlodipine perindopril better Atenolol thiazide better 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 ( )

39 Effects in patients with type 2 diabetes Cumulative incidence total card events and procedures O Stergren, J Hypertens, 2008

40 2007 ESH/ESC Guidelines Combinations between Some Classes of Antihypertensive Drugs Thiazide diuretics ß-blockers AT 1 -receptor antagonists α-blockers Calcium antagonists ACE inhibitors The preferred combinations in the general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to beneficial in controlled intervention trials.

41 mm Hg POST HOC ANALYSIS ASCOT STUDY DOXAZOSIN GITS EFFECTS ON BP ,7 SBP Mean difference 11,7 Doxazosin GITS 4-8mg Pts=2987 (30%) ,0 120 p< ,1 DBP Mean difference 6, ,3 Baseline. Add Doxa-GITS Median Time ( 1,28 years) Last visit Unpublished data, B. Williams, 2006

42 Usefulness of the α1 - Blocker Doxazosin as a Third-Line Antihypertensive Drug OHTA, Hypertens Res 2007

43 ASOCIA STUDY Pts= 3200 * p< vs baseline * p< vs placebo Doxazosin GITS De Alvaro, J Cardiol Pharmacol 2006

44 2007 ESH/ESC Guidelines Combinations between Some Classes of Antihypertensive Drugs Thiazide diuretics ß-blockers AT 1 -receptor antagonists α-blockers Calcium antagonists ACE inhibitors

45 Systematic Review of Combined ACEI & ARBS in Hypertension ARBs+ACEIs vs ACEIs Δ BP: -4.7/-3.8 mmhg ARBs+ACEIs vs ARBs Δ BP: -3.8/-3.7 mmhg Doulton, Hypertension. 2005;45:

46 ONTARGET Screening/enrolment Double-blind treatment Telmisartan 80 mg/day (8542 pazienti) Ramipril 10 mg/day (8576 pazienti) Telmisartan 80 mg/day + ramipril 10 mg/day (8502 pazienti) 5 years ONTARGET, N Engl J Med 2008

47 ONTARGET Ramipril Telmisartan Combination Systolic BP Diastolic BP

48 End-point primario # at risk 1 Yr 2 Yr 3 Yr 4 Yr R R+T Telmisartan + Ramipril Ramipril Years follow-up ONTARGET, N Engl J Med 2008

49 T+R vs R: PRIMARY COMPOSITE ONTARGET, N Engl J Med 2008 Primary Composite Hx of CVD No Hx of CVD SBP <= < SBP <= 150 SBP > 150 Diabetes No Diabetes HOPE Low Risk Score HOPE Medium Risk Score HOPE High Risk Score Age < <= Age < 75 Age >= 75 No. of Patients Incidence of Primary Outcome in Ramipril Group Male Female Ramipril & Telmisartan better Ramipril better

50 ONTARGET - renal outcomes Mann, Lancet 2008;

51 ONTARGET Changes in log urine albumin to creatinine ratio Mann, Lancet 2008

52 Combination Therapy with Inhibitors of the Renin Angiotensin System on Proteinuria in Renal Disease Kunz, Ann Intern Med, 2008

53 Effect of pharmacologic agents on the renin angiotensin system β 1 receptors β Blockers Van Tassell, Ann Pharmacother, 2007

54 Aliskiren binds to the active site of renin Renin Aliskiren Angiotensinogen Azizi, J Hypertension, 2006 Adapted from Wood JM, et al. 2003

55 Combinations between Some Classes of Antihypertensive Drugs Thiazide diuretics ß-blockers AT 1 -receptor antagonists RENIN INHIBITORS α-blockers Calcium antagonists ACE inhibitors

56 Mean change from baseline in SBP (mmhg) ALISKIREN COMBINATION THERAPY 0 HCTZ 25 mg n=176 Aliskiren 300 mg + HCTZ 25 mg n=173 Ramipril 10 mg n=275 Aliskiren 300 mg + Ram 10 mg n=274 Amlodipine Aliskiren 150 mg 5 mg 10 mg + Amlo 5 mg n=177 n=177 n=187 Valsartan Aliskiren 300 mg 320 mg + Val 320 mg n=455 n= * * * 17.2 Schmieder J Clin Hypertens, 2007; 9 Suppl A(5): A182 P-436 Uresin, J Hypertens, 2006; 24(Suppl 4): S82 P-269 Drummond, J Clin Hypertens, 2007; 9: Oparil, Lancet, 2007; 370: *P<0.001; P<0.05

57 ALLAY Aliskiren/losartan combination therapy Aliskiren 300 mg Losartan 100 mg Aliskiren/losartan 300/100 mg n n = = n = n n = = * 6 5.4* 7 6.4* Mean change from baseline in LVMI after 36 weeks treatment (%) Baseline LVMI = 77.6, 79.4 and 78.4 g/m 2 in the aliskiren, losartan and aliskiren/losartan groups, respectively Aliskiren monotherapy was non-inferior to losartan monotherapy in reducing LVMI Aliskiren/losartan combination therapy showed similar tolerability to monotherapy, with no significant differences between treatment groups in the incidence of adverse events or laboratory abnormalities *p < vs baseline; p < for non-inferiority vs losartan 100 mg; p = 0.52 vs losartan 100 mg. Between-treatment analyses based on least-squares mean data Solomon et al

58 Effects of the direct renin inhibitor aliskiren and atenolol alone or in combination in patients with hypertension Dietz, J Renin Angiotensin Aldosterone Syst 2008

59 Molecular structure of SARAs (Facultative Diuretics) eplerenone

60 Combinations between Some Classes of Antihypertensive Drugs Thiazide diuretics ß-blockers AT 1 -receptor antagonists SARAs α-blockers Calcium antagonists ACE inhibitors

61 Treatment of low-renin essential hypertension Mulatero & Veglio, Clinical Endocrinology 2007

62 POST HOC ANALYSIS ASCOT SPIRONOLACTONE EFFECT ON BLOOD PRESSURE Chapman N, Hypertension 2007

63 Sharabi, Am J Hypertens 2006 Efficacy of Add-On Aldosterone Receptor Blocker in Uncontrolled Hypertension 340 patients

64 Efficacy of Add-On Aldosterone Receptor Blocker in Uncontrolled Hypertension Sharabi, Am J Hypertens 2006

65 Combined Selective Mineralocorticoid Receptor Blockade and Angiotensin-Converting Enzyme Inhibition for Vascular Protection Bauersachs, Hypertension 2008

66 Dihydropyridine Calcium Channel Blockers Have Mineralocorticoid Receptor Antagonist Activity Dietz, Hypertension 2008

67 Thanks