Newer drugs aliskerin and ivabradine


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Newer drugs aliskerin and ivabradine

  1. 1. NEWER DRUGS IVABRADINE AND ALISKIREN Dr. Puneet Chuchra Junior Resident Medicine Unit 1 GNDH Amritsar
  3. 3. Heart Rate and Heart disease
  4. 4. Atherosclerosis Endothelial dysfunction↑ Oxidative stress↑ Plaque stability↓ Arterial stiffness↑ Ischemia Oxygen consumption↑ Duration of diastole↓ Coronary perfusion↓ Remodeling Cardiac hypertrophy↑ Chronic heart failure Oxygen demand↑ Ventricular efficiency ↓ Ventricular relaxation↑ Elevated heart rate + + + + The role of heart rate in cardiovascular disease
  5. 5. If Current  The funny current a inward mixed sodium potassium current is highly expressed in : 1. SA node 2. AV node 3. Purkinje fibres  These are activated at voltages of diastolic range.  At the end of a sinoatrial action potential the membrane repolarizes below the If threshold (about -40/-50 mV), the funny current is activated and supplies inward current, which is responsible for starting the diastolic depolarization phase (DD);
  6. 6. Ivabradine  Binds the Funny channel Reduces the slope for diastolic depolarization Prolongs diastolic duration
  7. 7.  It dose not alter: 1. Ventricular repolarisation 2. Myocardial Contractility 3. Blood Pressure.  B-Blockers may not be tolerated in high doses to attain heart rate of 70.  In acute settings the negative inotropic effect could be deleterious. Advantages over B-Blockers
  8. 8. Pharmacokinetics  Route: Oral  Bioavailability: 40%  Protein Binding: 70%  Metabolism: Hepatic ( First- Pass) more than 50% CYP 3A4 mediated  Elimination: Renal and Fecal  Half Life: 2 hours.
  9. 9. Clinical Uses:  Chronic Stable Angina in patients with sinus rhytm who cannot take B-blocker.  In combination with B-blockers when heart rate is poorly controlled with b-blockers.  Off-label in treatment of inappropriate sinus tachycardia.  Heart failure
  10. 10. Clinical Trials: Beautiful Shift Signify Vivify Clarify
  11. 11.  Morbidity-mortality Evaluation of The If inhibitor Ivabradine in patients with coronary disease and left ventricular dysfunction. Beautiful
  12. 12.  Clinical objective To examine the effects of elevated HR (>70 bpm) on cardiovascular events in these coronary patients  Pathophysiological objective To examine the effects of ivabradine on cardiovascular events in coronary patients with left ventricular dysfunction
  13. 13. Results
  14. 14. Heart rate above 70 bpm increases risk of MI by 46%  Prospective data from the BEAUTIFUL placebo arm Years P=0.0066 Hazard ratio = 1.46 (1.11 – 1.91) 0 0.5 1 1.5 2 0 Heart rate <70 bpm Heart rate ≥70 bpm 8 %withhospitalizationfor fatalandnonfatalMI 0 4 6 2
  15. 15. Ivabradine reduces fatal and nonfatal myocardial infarction (HR ≥70 bpm) Hospitalizationfor fatalornonfatalMI(%) Placebo (HR >70 bpm) Ivabradine P=0.001 Hazard ratio = 0.64 (0.49 – 0.84) Years 0 0.5 1 1.5 2 0 4 8 RRR 36% RRR: relative risk reduction Fox K et al. Lancet. 2008;372:807-816.
  16. 16. Summary of observed cardiovascular risk reduction in angina patients 24%0.76Primary composite end point 12%0.88CV death 42%0.58 16%0.84Hospitalization for HF 13%0.87All-cause mortality Risk reduction Hazard ratio Predefined end point 30%0.70Coronary revascularization Hospitalization for MI (n=1507) Fox K, Ford I, et al; BEAUTIFUL Investigators. Effect of ivabradine on cardiovascular outcomes in patients with stable coronary artery diseaseand left-ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur heart Jour On line.
  17. 17. SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial)  In HF in sinus rhythm with HR ≥75 bpm heart rate reduction with ivabradine improves outcomes, including all-cause death and cardiovascular death reduces .  Ivabradine-associated risk reductions are related to both HR achieved and magnitude of HR reduction.  Patients achieving <60 bpm or with >10 bpm reduction have the best prognosis.
  18. 18.  Reduction in the total hospitalizations for worsening HF  Reduction in the incidence of recurrent HF hospitalizations  Increase in time to first and subsequent hospitalizations
  19. 19. Secondary endpoint: change in LVEDVI from baseline to 8 months 0 75 100 95 90 85 80 mL/m2 93.9 32.8 85.9 30.9 90.8 33.1 89.0 31.6 -7.9 18.9 -1.8 19.0 Ivabradine (n=204) Placebo (n=199) Baseline 8 months Baseline 8 months ∆ -5.5, P=0.0019 Left ventricular end-diastolic volume index
  20. 20. Baseline Baseline M008 M008 Secondary endpoint: change in LVEF from baseline to 8 months 65.2 29.1 0 5 10 15 20 25 30 35 40 % 32.3±9.1 34.7±10.2 31.6 ±9.3 31.5±10.0 2.4 7.7 - 0.1 8.0 Ivabradine (n=204) Placebo (n=199) Baseline 8 months Baseline 8 months ∆ + 2.7, P=0.0003 Left ventricular ejection fraction
  21. 21. Other ongoing trials:  SIGNIFY in patients with coronary artery disease without heart failure – results are expected in 2013.  VIVIFY 1st trial assessing safety of intravenous ivabradine in patients with ST- segment elevation myocardial infarction.  Clarify : International Registry.
  22. 22.  The new ESC guidelines emphasize the goals when treating patients with established heart failure “to relieve symptoms and signs (e.g. oedema), prevent hospital admission, and improve survival”.  Also Resting heart rate is established as a routine parameter guiding the choice of therapy. Hence guidelines recommend the addition of ivabradine in patients with heart failure in sinus rhythm who have a HR ≥70 bpm and an ejection fraction ≤35%, and who are already treated with β- blockers, ACEIs, and MRAs (mineralocorticoid receptor antagonists).
  23. 23. Dose  5mg twice daily and may be increased upto 7.5mg twice daily Dose may be increased or decreased according to heart rate If bradycardia persists then it may be stopped
  24. 24. Adverse Effects:  Luminous Phenomenon (Enhanced brightness in a fully maintained visual field).  Bradycardia  Headaches  First DegreeAV block,Ventricular extra systoles  Dizziness and/ or blurred vision
  25. 25. Contraindications  Sick Sinus Syndrome  Hypersenstivity  Cardiogenic shock  Severe hypotension  Pacemaker dependent  H R <60 prior to treatment  Acute myocardial infarction  Sino atrial block  Unstable or acute heart failure Concomitantly with inhibitors of CYP3A 4 such as azole antifungals (ketoconazole), macrolide antibiotics, nefazodone and the anti-HIV drugs nelfinavir and ritonavir.
  26. 26. Take home message Ivabradine should used in all cases of heart failure and coronary artery disease rate with heart rate more than 75.
  27. 27. ALISKIREN
  28. 28. Effects of renin angiotensin system on various organs
  29. 29. RENIN AND HYPERTENSION Overactivity of the RAAS with high renin, Angiotensin, and aldosterone levels causes fatal malignant hypertension and renovascular hypertension, whereas overactivity of the RAAS with milder elevations of renin levels has been associated with up to 70% of cases of essential hypertension.
  30. 30. Why Direct Renin Inhibitors?
  31. 31.  Inhibition of Ang II formation or action via ACEIs or ARBs leads to compensatory increase in renin .  Ang II can also be formed using pathways that do not involveACE.  Circulating renin can be taken up by cardiac and coronary tissues, leading to the long-lasting generation of Ang II via ACE and non-ACE activity that is only partially suppressed by an ACEI.  Therefore Inhibition of renin would favor more complete blockade of the system.
  32. 32. Direct Renin Inhibitors  Aliskiren is the first of these new nonpeptide DRIs to be approved by the FDA for the treatment of hypertension. It is administered once daily per orally, either as monotherapy or in combination with other antihyper- tensive agents also in Europe, aliskiren received approval for the treatment of hypertension.
  33. 33. Aliskiren:Mechanism  Aliskiren is a highly potent inhibitor of renin with a high affinity for renin and a high species specificity for primate renin.  It binds to S3bp binding site of renin essential for its activity.  Binding to this pocket prevents the conversion of angiotensinogen to angiotensin1.
  34. 34. Aliskiren Pharmacokinetics  Peak plasma concentration – 1- 2 hrs  Steady state after –5-8 days .  Pathway of elimination:- 1. Mainly via biliary excretion as unmetabolised drug 2. Less than 1% of an orally administered dose is excreted in urine.  Aliskiren is not metabolized by, and does not induce or inhibit, cytochrome P450 enzymes and shows no clinically relevant pharmaco- kinetic interactions.
  35. 35. Aliskiren dosage  DOSE-  150 mg once daily  May increse upto 300mg if B P is not controlled after two weeks .  Dose more than 300 did not provide additional blood pressure control rather causes diarrhea.
  36. 36. INDICATIONS AND USAGE Hypertension •Aliskiren is indicated for the treatment of hypertension. • Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. •There are no controlled trials demonstrating risk reduction with Aliskiren.
  37. 37. Containdications: 1) Pregnancy  Pregnancy: Category D  Reduces fetal renal function and increases fetal and neonatal morbidity and death.  Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria,hypotension, renal failure, and death.  When pregnancy is detected, discontinue it as soon as possible
  38. 38. 2)Diabetic receiving ARBs or ACEIs (GFR<60ml/min) Because of the increased risk of  Renal impairment  hyperkalemia  hypotension
  39. 39. 3) Anaphylactic Reactions and Head and Neck Angioedema  Hypersensitivity reactions such as anaphylactic reactions and angioedema of the face, extremities, lips, tongue, glottis.  DiscontinueAliskiren immediately in patients who develop anaphylactic reactions or angioedema, and do not readminister.
  40. 40. 4) Hypotension  In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients symptomatic hypotension may occur after initiation of treatment with Aliskiren.  This condition should be corrected prior to administration of Aliskiren, or the treatment should start under close medical supervision.  A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
  41. 41. 5) Impaired Renal Function  Monitor renal function periodically in patients treated with Aliskiren whose renal function may depend in part on the activity of the renin- angiotensin system (e.g., patients with renal artery stenosis, severe heart failure, postmyocardial infarction or volume depletion) or patients receiving ARB,ACEI or non-steroidal anti-inflammatory (NSAID).
  42. 42. 6)Hyperkalemia  Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, combination use with ARBs or ACEIs NSAIDs, or potassium supplements or potassium sparing diuretics. 7) Cyclosporine or Itraconazole  When aliskiren was given with cyclosporine or itraconazole, the blood concentrations of aliskiren were significantly increased. Avoid concomitant use of aliskiren with cyclosporine or itraconazole .
  43. 43. Adverse Effects  Angioedema  Hyerkalemia ( Particularly when used with ACE inhibitors in diabetic patients)  Hypotension (Particularly in volume depleted persons)  Diarrhoea and other GI symptoms.  Headache  Dizziness  Cough  Rash  Elevated uric acid, gout and renal stones.
  44. 44.  OVERDOSAGE  Limited data are available related to overdosage in humans.The most likely manifestation of overdosage would be hypotension. If symptomatic hypotension occurs, supportive treatment should be initiated.  Aliskiren is poorly dialyzed.Therefore, hemodialysis is not adequate to treat aliskiren overexposure .
  45. 45. Clinical Trials
  46. 46. As Monotherapy  The antihypertensive effects of Aliskiren have been demonstrated in six randomized, double- blind, placebo-controlled 8-week clinical trials in patients with mild-to-moderate hypertension.  A substantial proportion (85%-90%) of the blood pressure lowering effect was observed within 2 weeks of treatment .With cessationof treatment, blood pressure gradually returned toward baseline levels over a period of several weeks.  There was no evidence of rebound hypertension after abrupt cessation of therapy.
  47. 47. In Combinations:  With Hydrochlorthiazide : Additive  WithValsartan: Additive  With Amlodipine: Additive
  48. 48. Aliskiren in Patients with Diabetes treated with ARB or ACEI (ALTITUDE study)  Patients with diabetes with renal disease (defined either by the presence of albuminuria or reduced GFR) were randomized to aliskiren 300 mg daily and placebo . All patients were receiving background therapy with an ARB or ACEI.Trial was halted due to increased incidence of nonfatal stroke, renal complications, Hyperkalemia and hypotension in patients with diabetes and renal impairment.
  49. 49. Relating to cardiac diseases  ALLAY and ASPIRE trials show that there is no positive impact on LV hypertrophy or LV remodeling with combined 1. Aliskiren and ARB or 2. Aliskiren and ACE inhibitor therapy.
  50. 50. ALOFT Trial  Addition of Aliskiren in heart failure patients shows reduction of neurohumoral activation –(BNP and NT-pro-BNP which were previously linked to adverse outcome in patients with heart failure) .  These data are encouraging but not definitive.
  51. 51.  Results of two trials ATMOSPHERE and ASTRONAUT regarding its beneficial role in heart failure patients are underway.  Finally the Aliskiren in Prevention of Later Life Outcomes (APOLLO) trial will address elderly patients with a systolic BP 130 to 159 mm Hg, no overt cardiovascular disease, and a high cardiovascular risk profile, in order to test the efficacy of the drug in reducing the risk of major cardiovascular end points.
  52. 52. Take Home Message 1. Can be used as alternative to various antihypertensive as monotherapy or as combination therapy . 2. Regarding beneficial role in cardiovascular diseases and renal diseases ?