Treatment of Stable Coronary Artery Disease Pharmacotherapy

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1 Treatment of Stable Coronary Artery Disease Pharmacotherapy José López-Sendón Hospital Universitario La Paz. Madrid. Spain Conflict of interest: I will discuss off label use and/or investigational use in my presentation Consultant for: Boeringher, Medtronic, Menarini, Lilly, Servier Research support from: Bayer, BMS, Boeringher, GKS, Medtronic, Menarini, Lilly, Roche, Sanophy-Aventis, Servier

2 Clinical spectrum of chronic ischaemic heart disease Uncertain diagnosis Impressionist diagnosis Chronic ischaemic heart disease certain No ischaemia Silent ischaemia Single episodes of angina Stable chronic angina Refractory angina Episodes of ACS. Complications of ischemic heart disease

3 Angina Free % Stable CAD. Pharmacotherapy

4 Optimal Medical Treatment NEJM 2007;356:1506

5 Ischaemic Heart Disease: Therapeutic objectives Delay progression of disease. Improve outcome Control symptoms Control ischaemia Treat complications

6 Chronic ischemic heart disease 1 Identify & treat HT, arrhythmias, anaemia 2 Control risk factors 3 Lifestyle 4 Pharmacological treatment Risk stratification 5 Revascularisation (selected patients) ESC Stable Angina Guidelines Eur Heart J 2006;27:1341

7 Treatments aimed at Improving Prognosis Aspirin mg od Contraindications Clopidogrel Statin Intolerant / contraindications Lower dose / alternative agent ACEI in proven CVD β-blocker in post MI ESC Guidelines Stable Angina Eur Heart J. 2006; 27:1341

8 Upgrade? Treatments aimed at Improving Prognosis Aspirin mg od Ticagrelor?, Prasugrel? Anti Xa? Statin Add a new lipid drug? Contraindications Clopidogrel Intolerant / contraindications Lower dose / alternative agent ACEI in proven CVD Only if LVD / HF? β-blocker in post MI Only if HF, HTA, arrythmias, Tachic? ESC Guidelines Stable Angina Eur Heart J. 2006; 27:1341

9 Treatments aimed at Symptom Relief β-blockers Intolerant or contraindication Symptoms not controlled after dose optimisation Add calcium antagonist or long-acting nitrate Intolerant Calcium antagonist or longacting nitrate or K channel opener or I f inhibitor Symptoms not controlled after dose optimisation Symptoms not controlled after dose optimisation Consider suitability for revascularization Either substitute alternative subclass of calcium antagonist or longacting nitrate Combination of nitrate and Ca antagonist or K- channel opener ESC Guidelines Stable Angina Eur Heart J. 2006; 27:1341 Symptoms not controlled on 2 drugs after dose optimization

10 Beta-blockers Chronic Heart Failure AMI (oral) Post AMI Chronic, stable ischaemia Hypertension Non cardiac surgery Aortic dissection Arrhythmias (SV / V) Sudden death prevention Class Recommend. I I I I I I I I / IIa, b I / IIa, b Level Evidence A A A A A A C A-C A-C

11 BB vs CC Blockers in Chronic Angina 1.0 Event Free Survival Bisoprolol p = Nifedipine sr 0.5 n = 316 Total Ischemic Burden Bisoprolol Study JACC 1996;28: Days

12 Event free survival in stable angina and HT treated with Betablockers 100 All-cause death (p=0.4) Primary endpoint for efficacy (death, MI, RA, HF, CVA, PREV) p=0.5 nifedipine placebo Primary endpoint for safety (death, MI, CVA, p=0.9) RA = refractory angina PREV = peripheral revascularisation ACTION Lancet 2004;364, 849 Years N=6779

13 Discontinuation of treatment Statin ACE-i Beta-blocker n= Gislason G. Eur Heart J. 2006;27:

14 Ivabradine in combination with Beta-Blockers New indication HR > 60 lpm Ivabradine is indicated: - in patients unable to tolerate or with a contraindication to beta-blockers - or in combination with beta-blockers in patients inadequately controlled with an optimal dose and whose heart rate is > 60

15 Ivabradine associated with beta-blockers P<0.001 Heart Rate > 60 bpm (Basal Heart Rate 67 bpm) Ivabradine + atenolol Placebo + atenolol P<0.001 P<0.001 P< Total Exercise Time Time to Limiting Angina Time to Angina Onset Time to 1 mm ST depression Tardif, et al. Eur Heart J 2009;30:540

16 Event rate (%) Tasa de eventos (%) Stable CAD. Pharmacotherapy Ivabradine in pacients with angina (FC>60 lpm) CV Death, hospitalization for MI or heart failure HR (95% CI), 0.76 ( ), P= Placebo 24% Procoralan Ivabradine Años Fox K, et al. Eur Heart J. 2009;30:2337

17 Authorisation valid through the European Union 9 July, Ranolazine Na channel inhibitor 4.1 Therapeutic indications Ranexa is indicated as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to firstline antianginal therapies (such as betablockers and/or calcium antagonists).

18 Chaitman BR, et al. JAMA. 2004;291:309 Stone PH, et al. JACC. 2006;48:566 Morrow DA, et al. JAMA. 2007;297:1775 JACC 2004;43:1375 Stable CAD. Pharmacotherapy Ranolazine: Key Clinical Trials Total patients enrolled = 8,139 Ranolazine vs placebo and on top of standard therapy improve exercise capacity in chronic angina MARISA CARISA ERICA Ranolazine improves outcomes in patiens with ACS and a history of angina MERLIN

19 Percentage (%) Stable CAD. Pharmacotherapy Merlin: Patients with prior angina CV death, MI or recurrent Ischemia Placebo (n = 1,776) Ranolazine (n = 1,789) i.v. 1,000 mg b.i.d. p.o P = Wilson S.R. et al. JACC 2009;53:1510

20 Mean Change From Baseline in HbA1c (%) Stable CAD. Pharmacotherapy Ranolazine in Patients With Diabetes and CAD Absolute Reduction in HbA1c From Baseline to Week 12 CARISA Placebo (n = 37) -0.02% Ranolazine 750 mg b.i.d. (n = 47) Baseline, mean HbA1c Ranolazine 7.9% Placebo 7.5% p = % Timmis AD, et al. Eur Heart J. 2006;27:42

21 Upgrade? Treatments aimed at Symptom Relief Betablockers, 1 st line treatment Insuficient control of angina / ischaemia Contraindication or intolerant Add Other option Ca antagonists: Amlodipine: Low heart rate, HT Diltiacem, verapamil: Tach, HT Ivabradine: Nitrate / Nicorandil: Ranolazine: if Heart rate > 60 b/m General option General option, better in diabetes

22 Future expectations 1- Better implementation of guidelines 2- New therapies - New antithrombotics: Anti Xa, Anti thrombin - New Lipid lowering drugs - Gene therapy?

23 Conclusions 1- Confirm diagnosis of ischemic heart disease! 2- Evaluate individual risk 3- Follow guidelines for optimal treatment 4- Follow-up and education of the patient 5- Room for improvement. Consider new therapies

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