Prof. Richard Češka, MD, PhD

Prof. Richard Češka, MD, PhD Head of the Center of Preventive Cardiology President of the Czech Society of Internal Medicine President of the Czech Atherosclerosis Society, member of EAS, IAS chair IAS Federation for Europe Focuses on internal medicine, preventive cardiology, lipidology and metabolism

ANTIHYPERTENSIVES & STATINS IN CV RISK PREVENTION: from guidelines to clinical practice Richard CESKA Centre for Preventive Cardiology University Hospital, Prague, Czech Republic

HLP Others HT CVD Smo king DM2T

How to influence it??? What is the priority???

Lifestyle changes, Lifestyle changes, Lifestyle changes, Lifestyle changes, Lifestyle changes, Lifestyle changes, Lifestyle changes, Lifestyle changes, lifestyle changes,

BUT!!!???

Complex treatment of the patient with CARDIOMETABOLIC RISK ACE-I ARBs CCBs Metformin Sulfonylurea Inzulin Statins Resins,eze,niacin CMR Glitazones Gliptines.. Niacin Fenofibrate Anti-Thrombotic Agents??? Diet & Physical Activity

Dyslipidemia Management Part of the complex approach to decrease CV RISK Influence all lipid parameters LDL-C The first target HDL-C,TGs, apob To lower MACROvascular risk To lower MICROvascular risk To lower CV morbidity and mortality

Treatment of Hyperlipidemia LDL-C Therapeutic Lifestyle Change Drug Therapy Therapy of Choice: Statin Alternative/combo: Ezetimibe,resin or niacin Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

Statins for everyone!!! Should we add statins to drinking water?

Association between preadmission statin use and death within 30 and 90 days /pneumonie/ Risk factor 0 30 d after hospital admission Patients (n) Deaths (n) Mortality (%) Odds ratio (95% CI) No statin use 28 538 4489 15.7 Reference Statin use 1372 141 10.3 0.69 (0.58 0.82) 0 90 d after hospital admission No statin use 28 538 6381 22.4 Reference Statin use 1372 230 16.8 0.75 (0.65 0.86) Thomsen R et al. Arch Intern Med 2008; 168:

Odds ratio (95% CI) for in-hospital onset of shock in patients with ACS without cardiogenic shock on admission Parameter OR (95% CI)* p ST-segment-elevation ACS 2.89 (1.97 4.22) <0.001 Age (per-y increase) 1.03 (1.02 1.05) <0.001 Primary PCI 0.59 (0.39 0.89) <0.012 Lipid-lowering drugs 0.52 (0.37 0.73) <0.001 *Adjusted for age, sex, cardiovascular diagnoses, diabetes, smoking status, electrocardiographic type of ACS, symptom-to-admission interval, whether cardioversion or cardiopulmonary resuscitation was administered, atrial fibrillation, heart rate, blood pressure, body-mass index, comorbidities, cardiovascular medications, and whether PCI, CABG, or intra-aortic balloon pump was used Jeger RV et al. Ann Intern Med 2008; 149:618-

Statin therapy postdischarge on stroke recurrence and mortality risk Statin therapy postdischarge Hazard ratio (95% CI) 1-y stroke recurrence 0.61 (0.35 0.92) Mortality 0.22 (0.12 0.40) Milionis HJ et al. Neurology 2009; 72:1816-1822.

Sattar N et al. Lancet 2010; available at: http://www.lancet.com. Association between statins and development of diabetes Statin Odds ratio (95% CI) Overall (n=91 140) 1.09 (1.02 1.17) Atorvastatin only (n=7773) 1.14 (0.89 1.46) Simvastatin only (n=18 815) 1.11 (0.97 1.26) Rosuvastatin only (n=24 714) 1.18 (1.04 1.33) Pravastatin (n=33 627) 1.03 (0.90 1.19) Lovastatin (n=6211) 0.98 (0.70 1.38)

STATIN VS CONTROL Proportional effects on MAJOR VASCULAR EVENTS per mmol/l LDL-C No. of events reduction (% pa) Statin Control Relative risk (CI) per mmol/l LDL-C reduction Nonfatal MI CHD death Any major coronary event 2310 (0.9%) 1242 (0.5%) 3380 (1.3%) 3213 (1.2%) 1587 (0.6%) 4539 (1.7%) 0.74 (0.69-0.78) 0.80 (0.73-0.86) 0.76 (0.73-0.79) CABG PTCA Unspecified 816 (0.3%) 601 (0.2%) 1686 (0.6%) 1126 (0.4%) 775 (0.3%) 2165 (0.8%) 0.76 (0.69-0.83) 0.78 (0.69-0.89) 0.76 (0.70-0.83) Any coronary revascularisation 3103 (1.2%) 4066 (1.6%) 0.76 (0.73-0.80) Ischaemic stroke Haemorrhagic stroke 987 (0.4%) 188 (0.1%) 1225 (0.5%) 163 (0.1%) 0.80 (0.73-0.88) 1.10 (0.86-1.42) Unknown stroke Any stroke 555 (0.2%) 1730 (0.7%) 629 (0.2%) 2017 (0.8%) 0.88 (0.76-1.02) 0.85 (0.80-0.90) Any major vascular event 7136 (2.8%) 8934 (3.6%) 0.79 (0.77-0.81) 99% or 95% CI 0.4 0.6 0.8 1 1.2 1.4 Statin better Control better 18

MORE VS LESS STATIN Proportional effects on MAJOR VASCULAR EVENTS per mmol/l LDL-C reduction No. of events (% pa) More statin Less statin Relative risk (CI) per mmol/l LDL-C reduction Nonfatal MI 1175 (1.3%) 1380 (1.5%) 0.71 (0.58-0.87) CHD death Any major coronary event 645 (0.7%) 1725 (1.9%) 694 (0.7%) 1973 (2.2%) 0.85 (0.63-1.15) 0.74 (0.65-0.85) CABG 637 (0.7%) 731 (0.9%) 0.72 (0.55-0.95) PTCA Unspecified 1166 (1.3%) 447 (0.5%) 1508 (1.8%) 502 (0.6%) 0.60 (0.50-0.71) 0.78 (0.58-1.04) Any coronary revascularisation 2250 (2.6%) 2741 (3.2%) 0.66 (0.60-0.73) Ischaemic stroke Haemorrhagic stroke 440 (0.5%) 69 (0.1%) 526 (0.6%) 57 (0.1%) 0.69 (0.50-0.95) 1.39 (0.57-3.39) Unknown stroke Any stroke 63 (0.1%) 572 (0.6%) 80 (0.1%) 663 (0.7%) 0.63 (0.24-1.66) 0.74 (0.59-0.92) Any major vascular event 3837 (4.5%) 4416 (5.3%) 0.72 (0.66-0.78) 99% or 95% CI 0.4 0.6 0.8 1 1.2 1.4 More statin better Less statin better 19

Cochrane review: CVD risk in low risk population treated with statins Risk ratio (95% CI) Total mortality 0.83 (0.73 0.95) Fatal and non-fatal CHD 0.72 (0.65 0.79) Fatal and non-fatal stroke 0.78 (0.65 0.94)

GREACE study Treatment with atorvastatin to the National Cholesterol Educational Program goal versus usual care in secondary coronary heart disease prevention: the GREek Atorvastatin and Coronary- heart-disease Evaluation (GREACE) Study. The Lower The Better

Be carefull!!! Statins and increased risk of DM2T

Statins and increased risk of DM2T Increased risk of DM2T by 9% In patients over 60 years only Risk/benefit ratio 1 : 9 Risk of DM2T is dependent on LDL lowering potency

Effects on MAJOR VASCULAR EVENTS, per mmol/l reduction in LDL cholesterol, among participants with diabetes Major vascular event and prior diabetes Events (%) Treatment Control RR (CI) Major coronary event Diabetes 776 (8 3) 979 (10 5) No diabetes 2561 (7 2) 3441 (9 6) Any major coronary event 3337 (7 4) 4420 (9 8) 0 78 (0 69-0 87) 0 77 (0 73-0 81) 0 77 (0 74-0 80) Coronary revascularization Diabetes 491 (5 2) 627 (6 7) No diabetes 2129 (6 0) 2807 (7 9) Any coronary revascularization 2620 (5 8) 3434 (7 6) Stroke Diabetes 407 (4 4) 501 (5 4) No diabetes 933 (2 7) 1116 (3 2) Any stroke 1340 (3 0) 1617 (3 7) Major vascular event Diabetes 1465 (15 6) 1782 (19 2) No diabetes 4889 (13 7) 6212 (17 4) Any major vascular event 6354 (14 1) 7994 (17 8) 0 5 1 0 1 5 0 75 (0 64-0 88) 0 76 (0 72-0 81) 0 76 (0 73-0 80) 0 79 (0 67-0 93) 0 84 (0 76-0 93) 0 83 (0 77-0 88) 0 79 (0 72-0 86) 0 79 (0 76-0 82) 0 79 (0 77-0 81) RR (99% CI) RR (95% CI)

Case No: Familial hypercholesterolemia 12 years 2005

Statins in clinical studies in childern Study statin year No Weeks TC % LDL % HDL % De Jongh simva 2002 173 48-31 -41 3-9 Wiegman prava 2004 214 104-19 -24 6-17 Knipscheer prava 1996 72 52-18 -23 4 2 Lambert lova 1996 69 8-17 -21 3-9 Stein lova 1999 132 52-13 -17 4 4 Clauss lova 2005 54 104-22 -27-23 3 Mc Crindle atorva 2003 187 26-30 -40 6 13 Avis rosuva 2010 177 12-50 TG %

LDL-C Killer No.1 The most important risk factor for CVD The first target for lipid lowering treatment

The Lower = The Better for LDL-C lowering For clinical outcomes reduction

What is an appropriate therapeutic target for LDL-C?

The human evolution What was the LDL-C of our ancestry?

What is desirable LDL- C? Hunter-Gatherer humans Newborn Primates Domestic animals 1,3-1,9 50-75 0,8-1,8 30-70 1,0-2,1 40-80 > 2,1 >80 Adult Euro/American (probable physiologic level) 1,3-1,8 50-70 Desirable

TNT: The Lower the Better -22% Intensive lipid-lowering therapy with atorvastatin 80 mg/day in patie CHD provides significant clinical benefit beyond that provided by at J. C. LaRosa et al. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease. // N Engl J Med 2005;352:1425-35.

TNT pts after CABG n = 4,654 MACE -27%

High dose atorvastatin after stroke or transient ischaemic attack SPARCL -16% P. Amarenco et al. High-Dose Atorvastatin after Stroke or Transient Ischemic Attack.// N Engl J Med 2006;355:549-59.

The Longer The Better for appropriate treatment duration for longer life (without MI,ACS, stroke )

PCSK9 (proprotein convertase subtilisin/kexin type 9) Enzyme - associated with plasma levels of LDL C (expressed in the liver, intestine and kidney) Overexpression of gene for PCSK9 more PCSK9 enzyme LDL receptors reduction (LDL-Receptor enable removal of LDL-C from the plasma) increase in circulating LDL-C High levels of PCSK9 = high LDL-C levels Conversely, lacking Pcsk9 leads to increased levels of hepatic LDL receptors,and they remove LDL from the plasma at an accelerated rate) Low levels of PCSK9 = low LDL- C levels 1.Brown, M.S.,Science, Vol 311, March 24, 2006 2. Cohen J.C. et al.,new England Journal of Medicine, Volume 354, 2006 Number 12

Cohen et al. studied patients with lifelong low LDL-C levels, due to loss of- function mutations in the gene encoding PCSK9 = they have low level of PCSK9 = low level of LDL-C Severe mutation: LDL-C was reduced by 1 mmol/l (38 mg/dl) 88%. prevalence of CHD declined by a remarkable Less severe mut.:ldl-c was reduced by only 0,52 mmol/l (21 mg/dl) CHD incidence declined by 47%. The Longer The Better Cohen et al., N Engl J Med 2006;354:1264-72. Brown, M.S.,Science, Vol 311, March 24, 2006

Cohen s study The Longer The Better Why does lowering of LDL-C concentration by 40 mg/dl by a PCSK9 mutation reduce CHD incidence by 88% whereas a 40-mg/dl lowering with a statin reduces CHD prevalence by only 23% on average??? Cohen et al., N Engl J Med 2006;354:1264-72. Brown, M.S.,Science, Vol 311, March 24, 2006

Cohens study The Longer The Better The most likely explanation is: DURATION Cohen et al., N Engl J Med 2006;354:1264-72. Brown, M.S.,Science, Vol 311, March 24, 2006

Cohens study The Longer The Better People with mutations in PCSK9 likely have maintained relatively low LDL levels throughout their lives. People in statin trials have had their LDL levels lowered for only 5 years. Atherosclerosis is a chronic disease that begins in the teenage years Cohen et al., N Engl J Med 2006;354:1264-72. Brown, M.S.,Science, Vol 311, March 24, 2006

Cohens et al. study The lesson of PCSK9 case is clear: The longer The better These data indicate that moderate lifelong reduction in the plasma level of LDL-C is associated with a substantial reduction in the incidence of coronary events Cohen et al., N Engl J Med 2006;354:1264-72. Brown, M.S.,Science, Vol 311, March 24, 2006

% reduction in CHD risk Reduction of CHD treatment duration (trial results are standardised to a LDL-C reduction of 1 mmol/l) According Years of treatment Statins life long treatment 2 need to encourage patients treatment persistence 2 2. Mantel:Heart 2004,90:1065-1066

What is the reason?

30% of adults in CZ: Metabolic Syndrome

RFs in abdominal obesity (104 cm) (1.8 mmol/l) (0.9 mmol/l) Patients with abdominal obesity (high waist circumference) often present with one or more additional CV risk factors (6.0 mmol/l)

Intra-abdominal (visceral) fat examination The dangerous inner fat! Front Visceral AT Subcutaneous AT Back

Intra-abdominal fat examination

Cardiometabolic risk in MS patient Hypertriglyceridemia Low HDL-C Elevated apolipoprotein B Small, dense LDL particles Postprandial hyperlipidaemia Hyperinsulinemia Glucose intolerance Insulin resistance Impaired fibrinolysis Endothelial dysfunction Hypertension Central obesity Smoking, Depression

TGs, (HDL-C) Fibrates (niacin) Statin + Fibrate (niacin) COMBO

HDL-C (LDL,TG) Niacin Statin + Niacin (laropiprant)

Complex approach to the patients ACE-inhibitors ARBs Ca antagonists Metformin Sulfonylurea Statins ezetimibe Fibrate Niacin KV Risk Anti-Thrombotic Agents Pioglitazon, Insulin Anti-obesity, Stop smoking drugs

RR reduction (%) HOPE - Heart Outcomes Prevention Evaluation 5 0-5 -10-15 -20-25 -30-35 -22 n = 9 297-26 -20-32 3-26 Yusuf et al., N Engl J Med 2000

Treatment of hypertension (RAS infl.drugs,bb,diuretics,ca antagonists) 70% combination!!! What antihypertensive drugs should we use? What combinations should be used?

Risk reduction (%) Atorva + AMLO/PERINDO lowers CV risk more than Atorva + BB/diuretics 0% -16% -20% (NS) -40% -36% (p=0,0005) -53% -60% ASCOT-LLA celkem (p<0,0001) Amlodipin+At vs Amlodipin Atenolol+At vs Atenolol Primary endpoint (fatal CHD, nonfatal MI) Sever PS, Dahlof B, Poulter NP, Wedel H. Anglo-Scandinavian Cardiac Outcomes Trial: Lipid Lowering Arm (ASCOT LLA) revisited: interaction of antihypertensive and lipid lowering therapy. Circulation. 2005;112(17 Suppl):II-134. Abstract 730.

ACCOMPLISH: Primary and secondary end points End point Hazard ratio (95% CI) Cardiovascular morbidity/mortality* 0.80 (0.72 0.90) Individual components Cardiovascular mortality 0.80 (0.62 1.03) Fatal and nonfatal MI 0.78 (0.62 0.99) Fatal and nonfatal stroke 0.84 (0.65 1.08) Hospitalization for unstable angina 0.75 (0.50 1.10) Coronary revascularization 0.86 (0.74 1.00) Resuscitation after sudden cardiac arrest 1.75 (0.73 4.17) *Primary end point Jamerson K et al. N Engl J Med 2008; 359: 2417-2428.

Primary outcome (%) Adjusted HR J-Curve in TNT Trial in Patients with CAD (n = 10,001) 35 Nadir = 79.2 mmhg 5 30 25 20 15 10 5 4 3 2 1 0 60 61-70 71-80 81-90 91-100 > 100 Diastolic blood pressure (mmhg) 0 Bangalore et al., 2009

Play with the scale What a game!!!

Úmrtí na IM (na 1000 osoboroků) DTK (mmhg) Lancet 1987; i(8533):581-584

Úmrtí na IM (na 1000 osoboroků) DTK (mmhg)

Incidence (%) of Primary Outcome Incidence of Primary Outcome by SBP Strata 60 50 40 30 20 10 0 110 >110 to 120 >120 to 130 >130 to 140 >140 to 150 >150 to 160 >160 SBP (mm Hg) Patients with primary outcome (n) Total patients (n) 45 234 196 1709 493 6859 596 7216 437 3737 253 1663 248 1 157 Mean DBP (mm Hg) Patients with primary outcome Patients without primary outcome 65.7 67.9 70.8 73.5 74.4 76.7 76.8 78.9 79.6 81.3 81.7 84.6 89.1 90.4 Messerli FH, et al. Ann Int Med. 2006;144:884-893

Incidence (%) of Primary Outcome Incidence of Primary Outcome by DBP Strata 60 50 40 30 20 10 0 60 >60 to 70 >70 to 80 >80 to 90 >90 to 100 >100 to 110 >110 DBP (mm Hg) Patients with primary outcome (n) Total patients (n) 56 176 389 2239 1003 1 1306 596 7376 174 1230 33 202 17 46 Mean SBP (mm Hg) Patients with primary outcome Patients without primary outcome 124.3 127.0 131.7 129.1 135.1 131.0 143.7 138.8 160.2 154.2 171.6 169.4 186.0 187.5 Messerli FH, et al. Ann Int Med. 2006;144:884-893

Experience from ATRACTIV project

ATRACTIV project 1. Identification of CVD risk factors 2. Evaluation of the effects of implementation of new guidelines and results of new clinical trials into everyday practice 3. Evaluation of possibilites of CVD risk reduction using combination of modern, evidence based treatment strategies in everyday practice in the Czech Republic

Duration ATRACTIV - Design 12 months Participating physicians: All 464 General Practice 453 Specialized Centers 11 Patients: All 4427 Men 2372 / Women 2055 Intervention: lifestyle counseling + pharmacotherapy: DLP: atorvastatin HT: amlodipin +/- ramipril or perindopril or losartan DM2T: metformin

Average ATRACTIV participant Age (years) 63 BMI (kg/m 2 ) 29,9 SBP (mmhg) 153 DBP (mmhg) 90 HR (bpm) 77 Men (%) 47,2 Women (%) 52,8

Average ATRACTIV participant Variable Value Glycemia 6,3 (mmol/l) Total cholesterol (mmol/l) 6,6 LDL cholesterol 4,0 (mmol/l) HDL cholesterol (mmol/l) 1,4 Triglycerides 2,5 (mmol/l)

Sever P et al. Lancet 2003; 361: 1149 58. Vrablík M et al. Vnitr Lek 2008; 54 (12): 1131-9. ATRACTIV and ASCOT Basic characteristics of participants

Sever P et al. Lancet 2003; 361: 1149 58. Vrablík M et al. Vnitr Lek 2008; 54 (12): 1131-9. ATRACTIV and ASCOT Selected biochemical variables

mmhg ATRACTIV - results Blood pressure 132,5 152,5 80,2 90,5 P < 0,001

ATRACTIV - results Total and LDL cholesterol 23% 24% 28% 29% P < 0,001

ATRACTIV - results HDL cholesterol and triglycerides 26% 21% P < 0,001

ATRACTIV - results BMI.55 kg/m 2.65 kg/m 2 P < 0,001

ATRACTIV - results Waist circumference 3 cm 2 cm P < 0,001

ATRACTIV - results Glycaemia P < 0,001

ATRACTIV: change of the calculated CVD risk -48% P < 0,001

Results of ATRACTIV project Intesified treatment combining lifestyle changes, antihypertensive and lipid lowering therapy results in: Significant BP lowering Significant improvement of dyslipidemia Weigt loss and significant reduction of waist circumference Decreased glycaemia Minimum side effects Reduction of global risk of cardiovascular events

Do NOT treat LIPIDS!

Do NOT treat BP!!!

Do NOT treat Blood sugar!!!

TREAT THE PATIENT!!!

Stroke risk according to the number of RFs controlled n Hazard ratio 95% CI 1 0.98 0.76 1.27 2 0.78 0.61 0.99 3 0.62 0.46 0.84 4 0.35 0.13 0.96 Amarenco P. American Academy of Neurology 2009 Annual Meeting; April 29, 2009; Seattle WA.

What is the beauty? An indeal is changing. What is the best treatment of CV risk? Yesterday, today and tomorrow