Λεωνίδας E. Πουληµένος, FESC Επιµελητής Α Ε.Σ.Υ.

Transcription

1 Νεότερη προσέγγιση στη θεραπευτική αντιµετώπιση της Σταθερής Στηθάγχης Από τη Βέλτιστη Φαρµακευτική Αντιµετώπιση στη Βέλτιστη Θεραπευτική Προσέγγιση για τον Εκάστοτε Ασθενή: Μια καινοτόµος Προσέγγιση Λεωνίδας E. Πουληµένος, FESC Επιµελητής Α Ε.Σ.Υ. Καρδιολογικό Τµήµα Γ.Ν. «Ασκληπιείο» Βούλας Διευθ: Καθ. Αθ. Ι. Μανώλης

2 Conflict of Interest (Honoraria and/or Advisory Boards) Astra Zeneca Bayer Menarini MSD Sanofi

3 Stable CAD: Multiple Treatment Options Lifestyle intervention PCI Reduce symptoms Treat underlying disease CABG Medical therapy

4 Repeat revascularization is common post-pci/cabg N = 18,240 who underwent elective PCI or CABG Patients (%) nd revascularization Kempf J et al. Presented at ESC

5 Despite Optimal Medical Therapy, Symptomatic CAD is Here to Stay The Heart and Soul Study: 937 outpatients treated for stable CAD, 3.9 years of follow-up CAD without angina or ischemia Symptomatic CAD Angina alone Ischemia alone (ETT) Angina + ischemia Gehi AK et al. Arch Intern Med. 2008;168(13):

6 Predictors of Physician Under-recognition of Angina in Outpatients with SCHD: APPEAR Study 1257 pts with SCHD Use Seattle Angina Questionnaire 411 reported experiencing angina during the last month 173 (42%) had their angina under recognized by their physician Predictors of under recognition: heart failure OR 3.06 angina OR 1.56 less frequent Arnold SV et al. Circ Cardiovasc Qual Outcomes August 19, 2016

7 Montalescot G, Sechtem U, et al. EHJ 2013;34(38): Medical Management of Patients with SCAD

8 Baseline Results from the STABILITY Study White HD,.Manolis AJ et al. N Engl J Med 2014;370:1702

9 Montalescot G, Sechtem U, et al. EHJ 2013;34(38): Medical Management of Patients with SCAD

10 Montalescot G, Sechtem U, et al. EHJ 2013;34(38): Medical Management of Patients with SCAD

11 Trimetazidine and Cardioprotection: Facts and Perspectives According to the published literature, there is sufficient evidence to support the addition of this agent in the treatment of symptomatic patients with stable angina. Tsioufis K, Manolis AJ Angiology 2014

12 Montalescot G, Sechtem U, et al. EHJ 2013;34(38): Medical Management of Patients with SCAD

13 Ivabradine Improves Exercise Capacity in Patients Already on β-blockers n=889 Change in ETT criteria (s) Ivabradine 7.5mg + atenolol 50mg Placebo + atenolol 50mg p<0.001 p<0.001 p< Total exercise duration Time to angina onset Time to limiting angina Tardif JC, et al. Eur Heart J. 2009; 29 (suppl) 386.

14 Primary Composite End Point Ivabradine n=654 (3.03% PY) Placebo n=611 (2.82% PY) HR = 1.08 [95% CI ] P= Patients with event (%) Ivabradine Placebo , ,5 42 Numbers at risk , ,5 42 Time from randomization (months) Ivabradine Placebo Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. N Eng J Med August 31. DOI: /NEJMoa

15 Components of Primary Composite End Point (angina population: CCS class II, n=12 049) Cardiovascular death Nonfatal myocardial infarction 10 Ivabradine n=245 (1.76% PY) Placebo n=210 (1.51% PY) HR = 1.16 [95% CI ] P= Ivabradine n=235 (1.72% PY) Placebo n=200 (1.47% PY) HR = 1.18 [95% CI ] P= Patients with event (%) , ,5 42 Numbers at risk Time from randomization (months) Ivabradine Placebo Ivabradine , ,5 42 Time from randomization (months) Placebo Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. N Eng J Med August 31. DOI: /NEJMoa

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18 Clinical Development Studies of Ranolazine in Patients with CAD 4 Key Randomized, Placebo-Controlled Trials MARISA = monotherapy (X-over) (n=191) CARISA = combination (parallel) (n=823) ERICA = comb. max dose (parallel) (n=565) MERLIN-TIMI 36 = acute-to-chronic Rx in pts with high-risk NSTE ACS (n=6,550) Pooled data comprise 8,129 patients more extensively studied than any agent in stable CAD

19 Unique Therapeutic and Pharmacology of Ranolazine A. Heart Rate B. Arterial Blood Pressure Beats/min mm Hg Systolic Diastolic 0 Placebo 2.7 ± ± ± Placebo 2.7 ± ± ± 0.4 Ranolazine Concentration (µm) Ranolazine Concentration (µm) Therapeutic concentrations are ~750-4,000 ng/ml (~2 to 8 µm)

20 Clinical Studies of Ranolazine in SCHD MARISA CARISA ERICA

21 Anti-ischaemic and Anti-anginal Effects of Ranolazine: A Comparison with Atenolol Exercise duration Rate-Pressure Product (mmhg min -1 ± SE) 40,000 30,000 20,000 10,000 * * ranolazine placebo atenolol (100mg) * * * * p <0.001 vs placebo p < p = p < Minutes on treadmill Placebo Ranolazine IR 400 mg tid (1741 ± 1026 ng base/ml) Atenolol 100 mg qd Rousseau MF, et al. Am J Cardiol 2005;95(3):311-6 All patients analysis, N = 154.

22 UA/NSTEMI CP < 48h, ST-Dep or +ctn, or DM, or TRS 3 Standard Therapy N = sites 17 Countries Ranolazine IV to PO (1000 mg BID) RANDOMIZE (1:1) Double-blind Placebo Matched IV/PO Holter at enrollment x 7d Duration Event-driven Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Segment Acute Coronary Syndromes Follow-up Visits: Q4 Months ETT at M8 or Final Final Visit (Median 348 Days) Primary End Point Cardiovascular death, MI or recurrent ischaemia Morrow DA et al. JAMA 2007;297:

23 Results Primary end point CV Death, MI, or Recurrent Ischaemia (% at 12M) Placebo 23.5% (N=3,281) Ranolazine 21.8% (N=3,279) HR 0.92 (95% CI 0.83 to 1.02) P= Days from Randomization Morrow DA et al. JAMA. 2007;297:

24 RESULTS - Primary End Point (CV death, MI or Recurrent Ischemia) Placebo (n = 1,776) Ranolazine (n = 1,789) i.v. 1,000 mg b.i.d. p.o. Percentage (%) P = Among patient with prior angina Wilson S.R. et al.: J Am Coll Cardiol 2009; 53 (17):

25 MERLIN-TIMI 36: Reduction in VT lasting 8 beats % 8 RR 0.65 P < Placebo Incidence (%) 6 4 RR 0.67 P = Ranolazine 5.3% 2 RR 0.63 ( ) P < Hours from randomization Scirica BM et al. Circulation. 2007;116.

26 Pleiotropic Effects and Advantages of Ranolazine Heart Failure with Preserved Ejection Fraction Microcirculation and Women Diabetes Mellitus and Cardiometabolic Risk Factors Arrhythmias Coronary Artery Disease Heart Rate and Blood Pressure

27 Medical treatment of stable angina: A tailored therapeutic approach Manolis AJ, Poulimenos L, Ambrosio G, Kallistratos M, Lopez-Sendon J, Dechend R, Mancia G, Camm J Current ESC guidelines suggest an algorithm for the medical treatment of stable angina categorizing antianginal drugs as first- or second-line therapy, and then providing no further suggestions to guide choice within each step. However, several questions emerge: Is there evidence for such an approach? Is there a true difference between first and second-line drugs in terms of prognosis and symptom relief? Do we have to individualize patients and tailor treatment according to their comorbidities or risk factors? Manolis AJ, Poulimenos L. Ambrosio G, et al. Int J Cardiol 2016;220:

28 First and Second Line Drug Treatment for the Management of SCHD: An Alternative Therapeutic Approach Second line drugs have been introduced much more recently and they have been tested according to much more stringent protocols and we have data on much larger size, with longer follow-up, and safety data. Trial Aspirin Statin Beta blocker RAS blocker Nitrates?????????????????????? SIGNIFY 91.7% 92.3% 83.1% 83% 40.5% MERLIN TIMI-36 95% 83% 89% 79% 40%

29 β-blockers and/or CCB s in SCHD Where is the Evidence?

30 β-blockers Use and Clinical Outcomes in Stable Outpatients with and without CHD Known prior MI: Known CHD, no MI: CHD risk factors: Mean follow-up: 44 mos Bangalore S, et al. JAMA 2012; 308:

31 N =26,793 J Am Coll Cardiol 2014;64(3):247 52

32 Recommended Management of Stable Angina: b-blockers and/or CCB s: Where is the Evidence? ESC Guidelines: b-blockers it has been extrapolated from the post-mi trials that beta-blockers may be cardioprotective also in patients with CHD. However, this has not been proven in a placebo-controlled trial. The beta-blockers trials post-mi were performed before the implementation of other secondary preventive therapy, such as treatment with statins and ACE-I s, which leaves some uncertainty regarding their efficacy on top of a modern treatment strategy. A recent retrospective analysis of the REACH registry suggested that in pts with either CAD RF only, known prior MI, or known CAD without MI, the use of b-blockers was not associated with lower risk of CV events ESC Guidelines: calcium channel blockers heart rate lowering CCB s may improve the prognosis of post-mi patients prognostic documentation in stable CHD has not been available for dihydropyridine CCB s until recently

33 First Step Treatment and Recent Published ESC Guidelines for SCHD Year No of pts Follow up Endpoint Nitrates h ED,ON-AN,ET wks ED, ON-AN days ED B-bl vs CCB s wks Holter ST, ED, LVEF wks ED,ON-AN, ST changes wks ED, ischemia wks EP mos EP wks Symptoms, EP wks Symptoms, EP wks Symptoms, EP wks ST changes

34 First Step Treatment and Recent Published ESC Guidelines for SCHD Trial Year No pts Follow up Treatment Endpoint p APSIS yrs Met vs Ver Death, MI, QOL NS INVEST (HTN and CHD) mos Ver vs Aten Death, MI, Angina NS INVEST mos Ver vs Aten Depression NS

35 Reference on β-blockers in the American Guidelines Review paper n=140; 2 arms of treament; 42 days on treatment; mins on stress test n=92; 2 arms of treatment; 70 days on treatment; mins on stress test n=112; 2 arms of treatment; 56 days on treatment; QoL n=114; 2 arms of treatment; 56 days on treatment; mins on stress test n=173; 2 arms of treatment; 1 years on treatment; QoL n=212; 2 arms of treatment; 84 days on treatment; mins on stress test; Holter n=17; 1 arm of treatment; 56 days on treatment; clinical and haemodynamic response

36 Reference on CCB s in the American Guidelines Review Review n=103; 2 arms of treatment; 77 days on treatment. Holter n=41; 2 arms of treatment;? Days on treatment. Holter, QoL Review n=207; 2 arms of treatment; 70 days on treatment. Holter

37 First and Second Line Treatment for SCHD Mortality Symptoms Relief b-blockers DHP s Non-DHP s LAN Ivabradine Ranolazine Nicorandil Trimetazidine No No No No No No No No

38 First and Second Line Treatment for SCHD Mortality Symptoms Relief Symptoms ESC ACC/ b-blockers No Yes IA AHA IB DHP s No Yes IA IB Non-DHP s No Yes IA IIaB LAN No Yes IIaB IB Ivabradine No Yes IIaB - Ranolazine No Yes IIaB IIa Nicorandil No Yes IIaB - Trimetazidine No Yes IIbB -

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40 Cardiology 2014;129:

41 The J Curve in Hypertension: Fact or Fallacy? INVEST (CAD pts) 30 ONTARGET (high risk pts, mainly with CAD) 3 CV events (%) CV events (%) Adjusted HR >110 to 120 to > to > to > to > >160 On-treatment SBP (mmhg) On-treatment SBP (mmhg) 0 Cardiac events (%) VALUE (High risk pts) < 120 >120 to 130 >130 to 140 >140 to 150 >150 to 160 >160 to 170 >170 to On-treatment SBP (mmhg) CV events (%) TNT (CAD pts) > 100 On-treatment DBP (mmhg) Tsika E, Poulimenos L, Boudoulas KD, Manolis AJ et al. Cardiology 2014;129: Adjusted HR

42 Cardiovascular death, myocardial infarction, or st N= The Lancet 2016

43 Indications and Contraindications Preferred Contraindication/Caution b-blockers Non-DHP s High HR CHF AF (in Rate Control) High HR High BP AF (in Rate Control) DHP s High BP Severe AoS Low BP HOCM Low HR Low BP SSS COPD (non Cardioselective) Asthma MetS (non Vasodilating) Severe PAD (non Vasodilating) AV conduction abnormalities Low HR Low BP CHF AV conduction abnormalities Severe AoS SSS Constipation

44 Indications and Contraindications LA Nitrates Ivabradine Ranolazine Trimetazidine Preferred High BP Possibly in low HR Possibly in HF High HR CHF Low BP Low HR and BP AF Diabetes Mellitus Low HR Low BP NIcorandil Low HR CHF Low BP Contraindication/Caution HOCM PDE-5 Inhibitors AF Low HR Severe Hepatic Disease Patients on Non DHP s Cirrhosis Liver disease Renal impairment Class 1-3 amntiatythmics Parkinson s Disease Severe CKD

45 Preferred Drugs (listed alphabetically) Intolerance to BB / non-dhp CCB Significant AV conduction abnormalities Low HR Low BP AF CHF Microvascular ischemia Diabetes Mellitus COPD DHP s, Ivabradine, LA Nitrates, Nicorandil, Ranolazine, Trimetazidine. DHP s, Ivabradine, LA Nitrates, Nicorandil, Ranolazine, Trimetazidine, DHP s, LA Nitrates, Nicorandil, Ranolazine, Trimetazidine Ivabradine, Ranolazine, Trimetazidine b-blockers (Rate control), Non-DHP s (Rate Control), Ranolazine b-blockers, Ivabradine, Possibly Nitrates b-blocker, DHP, Nicorandil, Ranolazine Ranolazine, Trimetazidine, Vasodilating, b- blockers, b-blockers (cardio-selective), DHP s, Ivabradine, LA Nitrates, Nicorandil, Ranolazine, Trimetazidine

46 Heart Rate >60 bpm 60 bpm BP BP SBP 120 SBP <120 SBP 120 SBP <120 BB or Non-DHP CCB* Ranolazine Ivabradine** DHP Ranolazine DHP Ranolazine Ivabradine** Ranolazine First-line Second-line Third-line LA nitrates Nicorandil Trimetazidine Trimetazidine LA nitrates Nicorandil Trimetazidine Trimetazidine * normal ejection fraction; ** heart rate > 70 bpm BB = beta blocker; CCB = calcium channel blocker; DHP = dihydropyridine; SBP = systolic blood