Kohonneen verenpaineen hoidon tavoite ja lääkehoidon aiheet

Kohonneen verenpaineen hoidon tavoite ja lääkehoidon aiheet 19.9.2013 Jyväskylä Teemu Ahola, LT kardiologian ja sisätautien erikoislääkäri TYKS sydänkeskus

Kuva modifioitu artikkeleista: Kastarinen J Hypertens 2006;24:829-36 ja Kastarinen J Hypertens 2009;27:1552-9 ESIINTYVYYS TIETOISUUS LÄÄKEHOITO HOITOISUUS

Verenpaineen luokittelu Luokka Systolinen (mmhg) Diastolinen (mmhg) Optimaalinen <120 ja <80 Normaali 120-129 ja/tai 80-84 Tyydyttävä (korkea normaali) 130-139 ja/tai 85-89 Lievästi kohonnut (Gr. I) 140-159 ja/tai 90-99 Kohtalaisesti kohonnut (Gr. II) 160-179 ja/tai 100-109 Huomattavasti kohonnut (Gr. III) 180 ja/tai 110 Isoloitu systolinen hypertensio 140 ja <90

Lähde: Ahola T., Antihypertensive Drug Therapy in Finland THL Research 2013 (väitöskirja), www.julkari.fi Table 1. BP thresholds for drug therapy according to guidelines from 1994 to 2009 Uncomplicated Guideline Year General population DM CHD hypertension Remarks FHA w.g. 1994 DBP 120 for few days not specified not specified not specified start earlier with DBP 110-119 if organ damages 180/110-119 for ~ 1 month start in 3(4) months if organ damages 160-179/100-109 for 3-6 monhts start in 4-6 months with DBP 100 without organ damages DBP 90-99 for 6-12 months if organ damages, diabetic nephropathy or other CV risk factors JNC6 1997 160/100 130-139/85-89 130-139/85-89 160/100 140-159/90-99 * 140-159/90-99 * *after 12 months if non-pharmacologic therapy inssufficient WHO-ISH 1999 150/95 * 140/90 140/90 150/95 * * after 6-12 months if low-risk patient (CV event risk <15%/10y) if medium risk patient (CV event risk 20-30%/10y) BHS 1999 160/100 140/90 140/90 not specified * if target organ damage present 140-159/90-99 * FCCH 2002 160/100 * 140/90 140/90 not specified *in repeated measurements; consider drug therapy after lifestyle interventions 140-159/90-99 130-139/85-89 if CHV risk 20% /10year; consider treatment if DM1 or kidney failure; ESH 2003 180/110 for few days * 130/85 130/85 not specified * immediately; promptly if high risk patient, 140-179/90-109 within 3 monts if moderate risk patient and consider 130-139/85-89 drug therapy if low risk patient; if high risk patient JNC7 2003 140-159/90-99 130/80 not specified not specified * start with 2-drug combination 160/100 * BHS 2004 160/100 140/90 140/90 not specified 140-159/90-99 * *if CV complications or TOD or DM or CV-risk 20% per 10y FCCH 2005 160/100 * 140/90 140/90 not specified * in repeated measurements; consider drug therapy if risk of CV death after 140-159/90-99 130-139/85-89 lifestyle interventions 5% / 10y; mediation of lifestyle changes and other risk factors; consider treatment if DM1 or kidney failure; ESH/ESC 2007 180/110 * 130/85 130/85 180/110 * *promptly; after several weeks; # after several months 140-179/90-109 (120/80) 160-179/100-109 promptly if CV risk high or very high; after several weeks if CV 140-159/90-99 140-159/90-99 # risk mod.; after several months if no other RF; sometimes ESH 2009 160/100 * 140/90 140/90 not specified *promptly; after a suitable period with with lifestyle changes if low or 140-159/90-99 130-139/85-89 moderate CV risk; promptly if CV risk high; unsupported by prospective trial evidence, unless if microalbuminuria or proteinuria; controversial evidence FCCH 2009 160/100 140/90 140/90 not specified * if DM, renal disease, TOD, clinically significant cardiovascular disease; 140/90* 130-139/85-89 consider therapy after non-pharmacologic treatment if >140 and risk of 140/90 CV death >5% / 10y; consider treatment if DM1 or kidney failure

Lähde: Ahola T., Antihypertensive Drug Therapy in Finland THL Research 2013 (väitöskirja), www.julkari.fi Table 2. Description of major clinical trials of primary hypertensives Trial Publ. Population Study design STOP 1991 HBP; 70-84y Active treatment (BBs and D) vs. plasebo SHEP 1991 ISH ; 60y Active treatment (THZ,BB) vs. plasebo MRC 1992 HBP; 65-74y Diuretic vs. plasebo, BB vs. plasebo SYST-EUR 1997 ISH ; 60y Active treatment (Nitrendine-based) vs. plasebo VHAS 1997 HBP Verapamil vs. chlorthalidone HOT 1998 HBP DBP 80 vs 85 vs 90 mmhg UKPDS 38 1998 HBP+DM DBP <85 vs. < 105mmHg UKPDS 39 1998 HBP+DM Captopril vs. atenolol CAPPP 1999 HBP; 25-66y Captopril-based vs. conventional (D and/or BB) NORDIL 2000 DBP 100; 50-74y Diltiazem-based vs. D and/or BB INSIGHT 2000 HBP; 55-80y Long-acting nifedipine vs. HCTZ+amiloride LIFE 2002 ISH+LVH Losartan-based vs atenolol-based ALLHAT 2002 HBP+ 1RF Amlodipin vs. lisinopril vs. chlothalidone ELSA 2002 HBP Lacidipine vs. atenolol ANBP2 2003 HBP; 65-84y Enalapril vs HCTZ (as add-on therapy) SCOPE 2003 HBP; 70-89y Candesartan-based vs. plasebo ALPINE 2003 HBP; (newly detected) Candesartan±felodipine vs. HCTZ±atenolol VALUE 2004 HBP+high CV risk;>50y Valsartan vs. amlodipin FEVER 2005 HBP+1-2RF HCTZ+felodipin vs. HCTZ+plasebo ASCOT 2005 HBP+ 3RF; 40-79y CCB+ACE vs. BB+D CAFE 2006 HBP+ 3RF; 40-79y BB±D-based vs. CCB±ACE-based HYVET 2008 SBP 160 and 80y Indapamide (±perindopril) vs. plasebo ACCOMPLISH 2008 HBP+high CV risk ACE+CCB vs. ACE+D ONTARGET 2008 CVD or high risk DM;(69%HT) Ramipril vs. telmisartan vs. both

Lähde: Ahola T., Antihypertensive Drug Therapy in Finland THL Research 2013 (väitöskirja), www.julkari.fi Table 2 (continued) Trial Primary message briefly Secondary message friefly STOP Active treatment reduced fatal or nonfatal strokes, MI and CV deaths High BP in elderly should be treated with antihypertensive drugs SHEP Low-dose chlorthalidone reduced incidence of stroke by 36% Major CV event reduced, with 5y absolute benefit of 55 events per 1000 MRC Diur. reduced risk of stroke by 31%, CV events by 44% and all CV events by 35% BB showed no significant reductions in these endpoints SYST-EUR Nitrendipine reduces the rate of cardiovascular complications VHAS Similar antihypertensive efficacies and cardiovascular event rates More hyperuricemia and hypokalemia with chlorthalidone HOT Intensive lowering of BP to 82.6mmHg associated with a low rate of CV events 80 vs 90: 51% reduction in major CV events with diabetics UKPDS 38 Tight BP control reduces risk of death and complications related to diabetes UKPDS 39 Similarly effective in reducing the incidence of diabetic complications BP reduction in itself may be more important than the treatment used CAPPP ACE as effective as conventional treatment (D/ BB or both) Incidence of DM2 lower in captopril group NORDIL CCB as effective as treatment based on Ds, BBs, or both in preventing CV events In both arms drugs were equally tolerated INSIGHT Both equally effective in preventing CV or cerebrovascular events Choice of drug can be decided by tolerability and BP response LIFE ARB prevents more CV morbidity and mortality, especially stroke and CV death New-onset diabetes was less frequent with losartan ALLHAT No difference in prim. outcomes; in secondary outcomes diur better than ACE RRR of developing DM2 highest with lisinopril ELSA No significant difference between treatments was found in any CV events Clinic BP reductions were identical with both treatments ANBP2 ACE-based therapy superior in older men BP reduction similar in both arms SCOPE Market reduction of non-fatal strokes with candesartan No signific. difference in MI, CV mortality, MMSE or cognitive function ALPINE Diuretic-based treatment was associated with an aggravated metabolic profile ARB-based group had less adverse events but no metabol. adverse effect VALUE No significant difference in main outcomes of cardiac disease Emphasize the importance of prompt BP control FEVER Felodipin group superior in preventing CV morbidity and mortality SBP <140mmHg superior to that of >140mmHg in preventing CV outcomes ASCOT CCB+ACE combination superior in reducing CV events CCB+ACE combination induced less diabetes CAFE BB±D-based therapy less effective than CCB±ACE at lowering central BP For the same brachial BP, central BP may be higher with BBs HYVET Active treatment reduced fatal or nonfatal strokes by 30% in elderly ACCOMPLISH ACE+CCB combination superior in reducing CV events ONTARGET ACEs and ARBs have similar outcome benefits Combination had more adverse events without an increase in benefit

MacMahon Lancet 1990: - Alueella DBP 70-110mmHg riski ilman selvää kynnysarvoa jos lasketaan diastolista painetta Collins Lancet 1990: - DBP 5-6 mmhg => stroke 42%, CHD 14% Vasan NEJM 2001: - RR 130-139/85-89mmHg (high normal) assosioituu suurentuneeseen CVsairastavuuteen (HR 2.5, HR 1.6 ) Lewington Lancet 2002: - 20/10mmHg => aivohalv. ja sydäninfarkti kuolleisuus x 2 - RR assosioituu kuolleisuuteen ilman kynnysarvoa aina niin alas kuin 115/75mmHg Law BMJ2009: - Verenpaineen alentaminen 10/5 mmhg vähentää aivohalvauksia keskimäärin kolmanneksen ja iskeemisiä sydäntapahtumia keskimäärin neljänneksen

Sepelvaltimotauti- ja aivohalvauskuolleisuus kaksinkertaistuvat verenpaineen kohotessa 20/10 mmhg kuva mukailtu: Lewington et al. Lancet 2002;360:1903-13

STOP: - Aktiivinen hoito vähentää päätetapahtumia; iäkkäiden korkeaa verenpainetta tulisi hoitaa RR-lääkkein MRC: - Diureetti vähensi 31% aivohalv., 44% CV-tapahtumia SHEP: - pieniannoksinen tiatsididiureetti aivohalv. 36% (CV tapaht. 55/1000 per 5v.) HOT: - DBP 80 vs. 85 vs. 90 mmhg ( ad 82.6mmHg => CV tapaht. ) Syst-Eur trial: - Nitrendipine CV-komplikaatioita VALUE: - Valsartan vs. Amlodipin: ei eroa => korostaa RR laskun merkitystä FEVER: - SBP < 140mmHg parempi kuin >140mmHg

ESH/ESC 2007 <140/90 * <130/80 <130/80 *<140/90 and to lower values if tolerated, for all; <130/80 in high or very high risk patients (MI, renal dysfuntion, proteinuria, stroke) ESH 2009 130-139/80-85* SBP<130 SBP 130-139 * 130-139/80-85 (incl. high risk patients) may be prudent. Evidence missing in elderly; SBP<130/80 in diabetics and SBP<130 in patients with high CV risk is not consistently supported by trial evidence FCCH 2009 <140/85 <130/80 * <130/80 *<130/80 if kidney disease; <125/75 if proteinuria (diabetic or non-diabetic) >1g/day; <150/85 if >80 years of age; only for those suffered from MI or stroke Lähde: Ahola T., Antihypertensive Drug Therapy in Finland THL Research 2013 (väitöskirja), www.julkari.fi Table 5. Target of clinical BP according to guidelines from 1994 to 2009 Guideline Year General population DM CHD Remarks FHA w.g. 1994 <160/90 * not specified DBP<90 *desirable BP in all <130/85 not consistently DBP< 85 JNC6 1997 <140/90 <130/85 <140/90 * *<140/90 and even lower if angina persists WHO-ISH 1999 <140/90 <130/85 not specified <130/85 desirable in young, middle aged or diabetics BHS 1999 140/85 140/80 * not specified *<140/80 (DM1 and DM2) or lower if proteinuria present (DM1) FCCH 2002 <140/85 * <140/80 * not specified *<130/80 if renal disease or significant proteinuria ESH 2003 <140/90 * <130/80 not specified *<140/90 and definitely lower values if tolerated, for all; home BP 5/5 mmhg lower JNC7 2003 <140/90 <130/80 * not specified *<130/80 also if HT and renal disease BHS 2004 <140/85 * <130/80 * not specified *<140/80 minimum acceptable BP; < 125/75 if proteinuria 1g/day FCCH 2005 <140/85 * <140/80 * not specified *<130/80 if diabetic nephropathy, microalbuminuria, non-diabetic kidney disease, or significant proteinuria

Diabetes mellitus

Table 3. Major clinical trials concerning HT and diabetes Trial Publ. Population Study design Lähde: Ahola T., Antihypertensive Drug Therapy in Finland THL Research 2013 (väitöskirja), www.julkari.fi Lewis et al. 1993 IDDM+nephropathy Captopril vs. placebo SHEP 1996 ISH+(NIDDM vs. non-dm ; 60y Low-dose THZ (±BB or reserpine) vs. placebo(±other) HOT 1998 HBP (8% had DM) DBP 80 vs 85 vs 90 mmhg UKPDS 38 1998 HBP+DM DBP <85 vs. < 105 mmhg UKPDS 39 1998 HBP+DM Captopril vs. atenolol ABCD-HT 1998 HBP+NIDDM (DBP 75 vs. 80-89); enalapril vs. nisoldipine FACET 1998 HBP+NIDDM Fosinopril vs. amlodipine SystEur (post hoc) 1999 ISH+DM; 60y SBP 20 + 150mmHg (Active treatment vs. plasebo) CAPPP 1999 HBP; 25-66y Captopril-based vs. conventional (D and/or BB) STOP-2 1999 HBP+DM; 70-84y Old vs. new anti-ht drugs ABCD 2000 HBP+NIDDM DBP 75 vs. 80-89 mmhg; micro-hope 2000 DM+ 1RF (58%HBP) Ramipril vs. placebo NORDIL 2000 DBP 100; (7% DM); 50-74y Diltiazem-based vs. D and/or BB IDNT 2001 HBP+DM+nephropathy Irbesartan vs. amlodipine vs. placebo RENAAL 2001 DM+nephropathy Losartan vs placebo ABCD-NT 2002 DM (normotensive) DBP 10 below baseline vs. 80-89 mmhg ALLHAT 2002 HBP+ 1RF (36% had DM) Amlodipin vs. lisinopril vs. chlorthalidone LIFE 2002 HBP+LVH; 55-80y Losartan-based vs atenolol-based LIFE 2002 HBP+DM+LVH; 55-80y Losartan-based vs atenolol-based IRMA-2 2003 HBP+DM2+U-µAlb Irbesartan 150mg/300mg vs. placebo HOT (post hoc) 2003 HBP+ medium CV risk DBP 80 vs 85 vs 90 mmhg BENEDICT 2004 HBP+DM2 Trandolapril+verapamil vs. both alone vs. placebo FEVER 2005 HBP+1-2RF (>10%DM) HCTZ+felodipin vs. HCTZ+placebo ASCOT 2005 HBP+ 3RF (27% DM); 40-79y CCB+ACE vs. BB+D CAFE 2006 HBP+ 3RF; 40-79y BB±D-based vs. CCB±ACE-based ADVANCE 2007 DM2 (~17%HBP) Perindopril and indapamide vs. placebo ACCOMPLISH 2008 HBP+high CV risk (27% had DM) ACE+CCB vs. ACE+D ONTARGET 2008 CVD or high risk DM Ramipril vs. telmisartan vs. both TRANSCEND 2008 High risk (75%CHD,36%DM) Telmisartan vs. placebo (as add-on therapy) ACCORD 2010 DM2 SBP<120 vs. <140 mmhg

Lähde: Ahola T., Antihypertensive Drug Therapy in Finland THL Research 2013 (väitöskirja), www.julkari.fi Table 3 (continued) Trial Primary message briefly Secondary message briefly Lewis et al. Captopril protects against deterioration in renal function The protection is significantly more effective than BP control alone SHEP Low-dose chlorthalidone effective in preventing major CV events Absolute risk reduction with active treatment twice as great for DM than non-dm HOT Intensive lowering of BP down to 82.6mmHg associated with a low rate of CV events 80 vs 90: 51% reduction in major CV events with diabetics UKPDS 38 Tight BP control reduces risk of death and complications related to diabetes UKPDS 39 Similarly effective in reducing the incidence of diabetic complications BP reduction in itself may be more important than the treatment used ABCD-HT ACE superior in preventing fatal and non-fatal MI FACET Fosinopril superior in preventing major vascular events Both had similar effects on biochemical measures SystEur (p.h.) Active treatment particularly beneficial in older patients with DM and ISH Does not support that CCB harmful for diabetics CAPPP ACE as effective as conventional treatment (D/ BB or both) Incidence of DM2 lower in captopril group STOP-2 Old and new: similar in prevention of cardiovascular mortality or major events Decrease in BP is most important in preventing CV events ABCD More intensive BP control decreased all-cause mortality No difference on the incidence and progression of microalbuminuria micro-hope Ramipril has beneficial vasculoprotective and renoprotective effects The benefit exceeded that attributable to changes in BP NORDIL Diltiazem as effective as treatment based on Ds, BBs, or both in preventing CV events Both arms were equally well tolerated IDNT Irbesartan superior in protecting the progression of diabetic nephropathy This protection is independent of the reduction in BP RENAAL Losartan conferred significant renal benefits (but no effect on the rate of death) The benefit exceeded that attributable to changes in BP ABCD-NT More intensive control decreased development and progression of nephropathy More intensive: decreased incidence of stroke and the progression of retinopathy ALLHAT No difference in prim. outcomes; in secondary outcomes diur better than ACE RRR of developing DM2 highest with lisinopril LIFE Losartan prevents more CV morbidity and death (for a similar BP reduction) New-onset diabetes was less frequent with losartan which was better tolerated LIFE Losartan superior in reducing CV morbidity and mortality and death for all cause Losartan seems to have benefits beyond BP reduction IRMA-2 Irbesartan significantly reduced proteinuria Reduction was dose-dependent but independent of the reduction in BP HOT (p.h.) Aggressive therapy most beneficial in diabetics BENEDICT ACE+verapamil as efective as ACE alone in preventing microalbuminuria FEVER Felodipin group superior in preventing CV morbidity and mortality SBP <140mmHg superior to that of >140mmHg in preventing CV outcomes ASCOT CCB+ACE combination superior in reducing CV events CCB+ACE combination induced less diabetes CAFE BB±D-based therapy less effective than CCB±ACE at lowering central BP For the same brachial BP, central BP may be higher with BBs ADVANCE Combination reduced the risks of major vascular events, including death Benefit seen irrespective of initial BP level ACCOMPLISH ACE+CCB combination superior in reducing CV events ONTARGET ACEs and ARBs have similar outcome benefits Combination had more adverse events without an increase in benefit TRANSCEND Telmisartan had no significant effect on primary outcome ARB modestly reduced risk of composite outcome of CV death, MI, or stroke ACCORD Tight BP control did not reduce fatal or non-fatal CV events

Peterson Annals Intern Med 1995: - Matala RR vähentää proteinuriaa - Korkeammalla paineella GFR huononi nopeammin - Jos proteinuria 1g/vrk => RR tavoite <125/75mmHg - Jos proteinuria 0.25-1g/vrk => RR tavoite ~ 130/80mmHg Curb Jama 1996: - SHEP:n alatutkimus (ISH), NIDDM ja non-niddm: - Aktiivinen hoito pieniannoksisella tiatsidilla vähensi päätetapahtumia - Riskin vähenemä suurempi diabeetikoilla

UKPDS 38: - DBP<85 vs. < 105mmHg; intensiivinen hoito kuolleisuutta ja DM-komplikaatioita UKPDS39: - Captopril vs. Atenolol; CV tapaht. samanlaista => korostaa RR-laskun merkitystä Syst-Eur (post hoc): - (<150mmHg ja vähint. 20mmHg) - Aktiivihoito erityisen hyödyllistä jos DM ja ISH ABCD: - DBP <75 vs. 80-89mmHg; intensiivinen hoito fataaleja ja ei fataaleja sydäninfarkeja ABCD-NT: - 10mmHg alle baseline vs. 80-89mmHg; intensiivisempi hoito nefropatian progressiota ja aivohalvauksia HOT (post hoc): - Aktiivinen hoito hyödyllisintä diabeetikoilla ADVANCE: - Perindopril + Indapamide vs. plasebo; yhdistelmähoito CV-tapahtumia ja kuolemia (ei riipu RR:sta)

Cooper Dehoff Jama 2010: - (DM ja CHD); SBP<130 vs. 130-139 vs. 140mmHg - Tiukka hoitotavoite ei tuonut lisähyötyä päätetapahtumiin tavanomaiseen hoitotavoitteeseen verrattuna Cederholm J Hypertens 2010: - (Swedish diabetes recister); SBP 110-129 vs. 130-139 vs. >140mmHg - >140 huono mutta 130-139 ~ sama kuin 110-129mmHg ACCORD 2010: - SBP <120 vs. <140mmHg - Päätetapahtumissa ei eroa, mutta haittavaikutuksia enemmän intensiivisemmässä hoidossa (3,3% vs. 1,3%)

Lähde: Ahola T., Antihypertensive Drug Therapy in Finland THL Research 2013 (väitöskirja), www.julkari.fi Table 4. Major clinical trials concerning HT and CHD Trial Publ. Population Study design HOPE 2000 (CHD/CVD/DM) + RF Ramipril vs. placebo PART-2 2000 HCD/TIA/intermitt.claudication Ramipril vs. placebo DAVIT I+II,MDPIT 2001 HBP+ post-mi Diltiazem/Verapamil vs. placebo QUIET 2001 CHD+LVEF 40% Quinapril vs. placebo ALLHAT 2002 HBP+ 1RF Amlodipin vs. lisinopril vs. chlothalidone ELSA 2002 HBP Lacidipine vs. atenolol OPTIMAAL 2002 CHD+MI+CHF Losartan vs. Captopril INVEST 2003 HBP+CHD; >50y Verapamil+ACE-based vs. BB+HCTZ-based EUROPA 2003 CHD (27%HBP) Perindopril vs. placebo (after wash-out) VALIANT 2003 MI+(LVEF<35%/CHF/both) add-on: (valsart. vs. valsart.+captopr. vs. captopr.) PEACE 2004 CHD+LVEF>40% (Trandolapril vs. placebo)+ other drugs JMIC-B 2004 HBP+ CHD;<75y Nifedipine vs. ACE CAMELOT 2004 CHD+NBP Amlodipin vs. enalapril vs. placebo VALUE 2004 HBP+high CV risk;>50y Valsartan vs. amlodipin ACTION 2005 HBP+stable angina Nifedipine vs. placebo in NT- vs. HT-patients FEVER 2005 HBP+1-2RF (>10%CHD) HCTZ+felodipin vs. HCTZ+placebo JIKEI Heart 2007 HBP+CVD (Valsartan vs. non-arb therapy)+other drugs ACCOMPLISH 2008 HBP+high CV risk ACE+CCB vs. ACE+D ONTARGET 2008 CVD or high risk DM Ramipril vs. telmisartan vs. both INVEST substudy 2008 HBP+CHD+MI; >50y Verapamil-sustained release vs. atenol-based TRANSCEND 2008 High risk (75%CHD,36%DM) Telmisartan vs. placebo (as add-on therapy) Cooper-DeHoff et al. 2010 HBP+CHD+DM SBP<130 vs. 130-139 vs. 140 mmhg

Lähde: Ahola T., Antihypertensive Drug Therapy in Finland THL Research 2013 (väitöskirja), www.julkari.fi Table 4 (continued) Trial Primary message briefly Secondary message briefly HOPE Ramipril reduces rates of death, MI, and stroke PART-2 ACE inhibitor showed no benefits on major CV events ACE reduced signific. more BP and LV mass in nonhypertensive patients DAVIT I+II,MDPIT HR lowering CCB decrease event rates (without pulmonary congestion) With pulmonary congestion, event rates were increased QUIET NS difference in clin. outcomes or progression of coronary atheroscler. ACE was well tolerated ALLHAT NS difference in prim. outcomes; in sec. outcomes D better than ACE RRR of developing DM2 highest with lisinopril ELSA NS difference between treatments was found in any CV events Clinic BP reductions were identical with both treatments OPTIMAAL NS difference in total mortality Losartan better tolerated, however, ACE should remain first-choice after MI INVEST CCB+ACE-based as clinically efective as BB+HCTZ-based BP control 71.7% and 70.7% EUROPA Perindopril significantly improves outcome On top of other prevent. medications, should be consid. to all CHD patients VALIANT Valsartan as effective as captopril Combination increased adverse events without improving survival PEACE No CV benefit from the addition of ACE inhibitor JMIC-B No difference in reducing cardiac events and mortality CAMELOT Amlodipin reduced adverse CV events For amlodipine, IVUS showed slowing of atherosclerosis progression VALUE No significant difference in main outcomes of cardiac disease Emphasize the importance of prompt BP control ACTION Nifedip. effective in controlling high BP and reducing major vasc. events Supports the emphasis of BP control FEVER Felodipin group superior in preventing CV morbidity and mortality SBP <140mmHg superior to that of >140mmHg in preventing CV outcomes JIKEI Heart Valsartan+convent. therapy prevented more CV events than convent.therapy Mortality and tolerability did not differ ACCOMPLISH ACE+CCB combination superior in reducing CV events ONTARGET ACEs and ARBs have similar outcome benefits Combination had more adverse events without an increase in benefit INVEST substudy Verapamil-SR-based equival. to BB-based for BP control and prevent. CV events Verapam. group had greated subj. feeling of well-being than BB-based group TRANSCEND Telmisartan had no significant effect on primary outcome ARB modestly reduced risk of composite outcome of cv death, MI, or stroke Cooper-DeHoff Tight BP control not superior to usual control in preventing CV outcomes Tight BP control superior to uncontrolled in preventing CV outcomes

HOPE: - Ramipril vs. plasebo; Lääkehoito vähensi kuolleisuutta, sydäninfarkteja ja aivohalvauksia EUROPA: - Perindopril vs. plasebo; Lääkehoito huomattavasti parempi => ACEi tulisi suositella kaikilla sepelvaltimotautipotilaille CAMELOT: - Amlodipin vs. Enalapril vs. plasebo; Amlodipin vähensi päätetapahtumia ACTION: - Päätetapahtumissa ei eroa, mutta haittavaikutuksia enemmän intensiivisemmässä hoidossa (3,3% vs. 1,3%) ONTARGET: - ACEi vs. ATR:n salpaaja; hyödyt samankaltaisia, yhdistelmällä sivuvaikutukset

INVEST secondary analysis: - J-käyrän muotoinen yhteys diastolisella paineella ja päätetapahtumilla (nadir 119/84mmHg) - Matala diastolinen paine => koronaariperfuusio - Matalilla diastolisilla arvoilla AMI/stroke suhde kasvoi Tulisi välttää liian malataa diastolista painetta sepelvaltimotautipotilailla TNT: - Nadir 146.3/81.4mmHg ( eli RR kynnysarvo jossa tapahtumariski pienin) - Jos RR<110-120/<60-70mmHg => CV-tapahtumien riski

Stratification of total CV risk in categories of low, moderate, high and very high risk according to SBP and DBP and prevalence of RFs, asymptomatic OD, diabetes, CKD stage or symptomatic CVD. Subjects with a high normal office but a raised out-of-office BP (masked hypertension) have a CV risk in the hypertension range. Authors/Task Force Members et al. Eur Heart J 2013;34:2159-2219 The European Society of Hypertension (ESH) and European Society of Cardiology (ESC) 2013. All rights reserved. For permissions please email: journals.permissions@oup.com

Riskitekijät

Lääkehoidon aloitus milloin? Authors/Task Force Members et al. Eur Heart J 2013;34:2159-2219 In patients with diabetes, the optimal DBP target is between 80 and 85 mmhg. In the high normal BP range, drug treatment should be considered in the presence of a raised out-of-office BP (masked hypertension). The European Society of Hypertension (ESH) and European Society of Cardiology (ESC) 2013. All rights reserved. For permissions please email: journals.permissions@oup.com

Lääkehoidon aloitus milloin? Grade 1 HT, Grade 2 HT ja Grade 1 HT -high risk: hyvä tutkimusnäyttö lääkehoidon puolesta - Collins (meta-analyysi) 1994 - Law (meta-analyysi) BMJ 2009 Authors/Task Force Members et al. Eur Heart J 2013;34:2159-2219 In patients with diabetes, the optimal DBP target is between 80 and 85 mmhg. In the high normal BP range, drug treatment should be considered in the presence of a raised out-of-office BP (masked hypertension). The European Society of Hypertension (ESH) and European Society of Cardiology (ESC) 2013. All rights reserved. For permissions please email: journals.permissions@oup.com

Lääkehoidon aloitus milloin? Tutkimusnäyttö niukkaa Osa kuulunut high risk ryhmään FEVER alaryhmäanalyysi Eur Heart J 2011; 32:1500-1508 Poistettu DM + CHD- potilaat Näyttöä intensiivisen lääkehoidon puolesta MRC BMJ 1985; 291:97-104 AUSTRALIAN Lancet 1980; 1:1261-1267 HDFD NEJM 1982; 307:976-980 Authors/Task Force Members et al. Eur Heart J 2013;34:2159-2219 In patients with diabetes, the optimal DBP target is between 80 and 85 mmhg. In the high normal BP range, drug treatment should be considered in the presence of a raised out-of-office BP (masked hypertension). The European Society of Hypertension (ESH) and European Society of Cardiology (ESC) 2013. All rights reserved. For permissions please email: journals.permissions@oup.com

Lääkehoidon aloitus milloin? ESH 2007 jos high tai very high risk (DM, CHD, kidney disease) => lääkehoito ESH 2009 otti takapakkia kyseenalaisen/ niukan näytön vuoksi ESH 2013 - Tutkimusnäyttö vaihtelevaa Kriittisen tarkastelun jälkeen ei kiistatonta/vakuuttavaa tutkimusnäyttöä lääkehoidon eduista jos RR 130-139/85-89 Authors/Task Force Members et al. Eur Heart J 2013;34:2159-2219 The European Society of Hypertension (ESH) and European Society of Cardiology (ESC) 2013. All rights reserved. For permissions please email: journals.permissions@oup.com In patients with diabetes, the optimal DBP target is between 80 and 85 mmhg. In the high normal BP range, drug treatment should be considered in the presence of a raised out-of-office BP (masked hypertension).

ISOLOITU SYSTOLINEN HYPERTENSIO (ISH) nuoret potilaat - Monilla nuorilla miehillä RRs >140mmHg ja RRd <90mmHg: - Joskus heillä sentraalinen RR normaali - Ei näyttöä lääkehoidon hyödystä => hoitona elintapamuutokset ja huolellinen seuranta GRADE 1 HT iäkkäät potilaat - ESH 2007 suositteli Gr 1 HT:n hoitoa iästä riippumatta - 10 tutkimusta iäkkäillä (mm. STOP, SHEP, Syst-Eur, Syst-China, MRC elderly); kaikki olleet SBP 160mmHg (=Gr 2 ja 3) => näyttö Gr 1 puutteellinen

Hoidon tavoite eli kuinka matalaksi RR tulisi hoitaa? (lähtökohtana mikä on CV-riski!!) A. Matalan- kohtalaisen riskin potilaat: FEVER alaryhmäanalyysi (ei DM/ CHD) Eur Heart J 2011;32:1500-1508 - 137mmHg vs. 142 mmhg => intensiiv. hoito CV-tapahtumia => Tavoite : <140/90mmHg (DM: DBP<85mmHg) B. Korkean riskin potilaat: DM/ kardiovaskulaaritauti/munuaissairaus : - RR laskeminen <130/80mmHg ; Ei RCT näyttöä

B. Korkean riskin potilaat Diabeetikot - Vahva näyttö: RR lasku hyödyllistä=> CV-tapahtumat - DBP 80-85mmHg => saavutetaan hyötyä (näyttö: HOT, UKPDS38) - SBP <130mmHg (ei näyttöä, ainoastaan ABCD-NT, joka pieni tutkimus) - Huom! ACCORD (~ 119mmHg vs. ~133mmHg ) - Päätetapahtumissa ei eroa, mutta haittavaikutuksia enemmän intensiivisemmässä hoidossa (3,3% vs. 1,3%) => Tavoite : SBP<140mmHg, DBP 80-85mmHg

B. Korkean riskin potilaat Anamneesissa TIA/aivohalvaus (PATS, PROGRESS intens. verenpaineen hoito) - SBP <130mmHg ei saavutettu (PATS:ssa vain 16% normotensiivisia) => ei näyttöä - Yusuf NEJM 2008: SBP 136 vs. 140mmHg ; ei eroa päätetapahtumissa => Tavoite : RR<140/90mmHg Anamneesissa koronaaritapahtuma - SBP <130mmHg (saavutettu 5 tutkimuksessa; tulokset ristiriitaisia) - EUROPA pos., CAMELOT pos./neg., PREVENT neg., ACTION neg., PEACE neg. => Tavoite : RR<140/90mmHg

B. Korkean riskin potilaat Anamneesissa munuaissairaus SBP 125-130mmHg vs. <140 mmhg; 3 tutkimusta (CKD lähes kokonaan ilman DM) - ei eroa ESRD:n / kuolleisuuden osalta Huom! IDNT ja RENAAL (DM + nefropatia): RR laskettiin intensiivisemminkin hoidetussa ryhmässä vain ad ~ 140mmHg (IDNT) ja ~143mmHg (RENAAL) Huom! ACCORD: intensiivisempi hoito (119/67mmHg vs. 134/73mmHg) lähes 2 kertaisti potilaat, joilla egfr <30 Upadhyay (meta-analyysi) Ann Intern Med 2011;154:541-548: - RR tavoite 125-130/75-80 mmhg vs. <140/90mmHg; intensiivisemmästä hoidosta ei hyötyä - Intensiivisemmästä hoidosta mahdollisesti hyötyä, jos proteinuria 0.3-1g/vrk mutta toisaalta haittavaikutukset => Tavoite : RR<140/90mmHg (DM: DBP<85mmHg)

Mitä matalampi verenpaine sitä parempi vai J-käyrä? Verenpaineen laskiessa tietyn tason alapuolelle (RR raja-arvo?) ennuste huononee - Kynnysarvo jolla elinten verenkierron autoregulaatio toimii, vaihtelee - koronaariperfuusio; diastolinen verenpaine - vaskulaarisairaudet raja-arvoa - J-käyrän raja-arvon arviointi hankalaa (paljon sekoittavia tekijöitä) - tutkimuksia J-käyrän puolesta (4) ja vastaan (3) - SBP ja DBP nadir vaihtelee tutkimuksissa huomattavasti vaikka CV-riski baselinessa samanlainen - Viitettä, että J-käyrä olemassa koronaaritapahtumille mutta ei aivohalvaukselle (ONTARGET) - Hyvin suunniteltuja tutkimuksia tarvitaan

Lääkehoidon aloitus - yhteenveto

Hoidon tavoite - yhteenveto

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