New Medications In the Field of Cardiology

Transcription

1 New Medications In the Field of Cardiology Hazal Babadagli, BScPharm, PharmD April 7, 2017

2 Outline Mechanism of action Evidence behind the medication Implications to disease management Contraindications Adverse effects and monitoring Availability and cost

3 ARNI (ENTRESTO ) Angiotensin II Receptor Blocker (Valsartan) + Neprilysin Inhibitor (Sacubitril)

4 Neprilysin Inhibitor MOA Heart failure -> release of endogenous vasoactive peptides (ANP, BNP) -> vasodilation, sodium and water elimination, reduction in hypertrophy/remodeling of the heart Neprilysin is an enzyme that inhibits vasoactive peptides Sacubitril inhibits neprilysin -> increased effects of ANP, BNP

5 ARB MOA Blocks angiotensin II receptors -> inhibits angiotensin II effects (RAAS system) -> prevents vasoconstriction and sodium and water reabsorption

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7 Why Combine with an ARB? Neprilysin inhibitor monotherapy activates RAAS system -> vasoconstriction, sodium and water re-absorption -> worsen heart failure Need to combine neprilysin with an agent that inhibits RAAS Combining with ACE-i led to increased risk of angioedema (since both ACE-i and neprilysin inhibitors prevent the breakdown of bradykinin) ARBs do not prevent breakdown of bradykinin (less risk of angioedema)

8 Paradigm-HF Trial Multicenter, randomized, double-blind, parallel-group, comparative trial 8,399 patients, duration of 27 months Patients: LVEF 40%, NYHA class II-IV, elevated BNP > 80% on beta blocker and ACE-i/ARB, ~ 55% on MRA Intervention: LCZ mg po BID versus enalapril 10mg po BID in addition to recommended therapy

9 Paradigm-HF Efficacy Outcomes Outcome LCZ696 Enalapril HR (95% CI) CV death or HF hospitalization (primary outcome) 21.8% 26.5% 0.80 ( ) (ARR: 4.7%, RRR: 17.7%, NNT: 22) CV death 13.3% 16.5% 0.80 ( ) HF hospitalization 12.8% 15.6% 0.79 ( ) Death from any cause 17% 19.8% 0.84 ( )

10 Paradigm-HF Safety Outcomes Outcome LCZ696 Enalapril P Value Symptomatic hypotension Symptomatic hypotension & SBP < 90 mm Hg 14.0% 9.2% < % 1.4% <0.001 SrCr 221 umol/l 3.3% 4.5% K + > 6.0 mmol/l 4.3% 5.6% Cough 11.3% 14.3% <0.001 Angioedema 0.44% 0.23% Not statistically significant

11 Implications of Paradigm-HF Trial New drug-class with mortality reduction Should be considered after standard triple therapy has been trialed (ACE-i/ARB, beta-blocker, MRA) CCS HF 2014 Guidelines: use in mild-moderate HF, at LVEF <40%, an elevated BNP level or hospitalization for HF in previous 12 months

12 CCS HF Guidelines 2015

13 Contraindications Symptomatic hypotension prior to initiation Concomitant use with ACE-inhibitors Wait at least 36 hours after last dose of ACE-i Known history of angioedema to ARBs or to ACE-i Pregnancy egfr< 30ml/min

14 Monitoring Symptomatic hypotension Hyperkalemia Avoid >5.2 mmol/l Serum Creatinine Avoid >30% increase Angioedema

15 Availability Tablet contains both sacubitril and valsartan (dose is sum of agents) 24 mg sacubitril/26 mg valsartan= 50mg 49 mg sacubitril/51 mg valsartan= 100mg 97 mg sacubitril/103 mg valsartan= 200mg Entresto valsartan 103mg = Diovan valsartan 160mg (different salts)

16 Availability and Cost Not formulary in AHS or Covenant Health yet Entresto 200mg po BID: $260/month Not covered by government insurance (seniors ABC, AISH) Coverage maybe provided depending on the private drug insurance plan Coverage cards are available through drug company

17 IVABRADINE (LANCORA ) I f current inhibitor

18 Heart Rate in Heart Failure Heart failure -> activation of sympathetic nervous system (compensatory) -> release of norepinephrine - > increased heart rate Elevated heart rate can increase myocardial energy demand and decrease in myocardial perfusion It has been associated with poor CV outcomes (increased CV death and HF hospitalizations)

19 Ivabradine MOA Inhibits If current (positively charged ions) through the HCN channel in the SA node -> decreased firing in SA node -> reduction in heart rate Unlike beta-blockers or non-dihydropyridine CCB, does not reduce contractility

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21 SHIFT Trial Multicenter, randomized, double-blind, placebocontrolled 6,558 patients, duration of 23 months Patients: LVEF 35%, NYHA class II-IV, stable chronic HF, sinus rhythm, resting HR 70bpm, maximally tolerated HF meds > 80% on ACE-i/ARB, 90% beta blocker, ~ 60% on MRA Intervention: ivabradine mg po BID versus placebo

22 SHIFT Trial Efficacy Outcome Outcome Ivabradine Placebo HR (95% CI) CV death or HF hospitalization (primary outcome) 24% 29% 0.82 ( ) (ARR: 5%, RRR: 17.2%, NNT: 20) CV death 14% 15% Not statistically significant HF hospitalization 16% 21% 0.74 ( ) Death from HF 3% 5% 0.74 ( )

23 SHIFT Trial Criticism Only 26% of patients were at target dose of beta blockers Only 56% were at half or more of target dose of beta blockers Thus, average dose of beta blocker therapy was lower than doses used in previous HF trials Subgroup Analysis: patients receiving 50% of target dose beta blocker had no benefit of primary outcome? Underuse of beta blocker therapy may have overestimated benefit of ivabradine

24 SHIFT Trial Safety Outcome Outcome Ivabradine Placebo P value Symptomatic bradycardia Asymptomatic bradycardia 5% 1% < % 1% < Phosphenes 3% 1% < Blurred Vision 1% <1% Atrial Fibrillation 9% 8% 0.012

25 Implications of SHIFT Trial New drug-class for heart failure Patients should be titrated on max tolerated beta blocker therapy in addition to ACE-i/ARB, MRA before considering ivabradine If patients still symptomatic, with HR 70bpm, in SR, not pacemaker-dependent, can add ivabradine How many patients have HR 70bpm when they are on max tolerated beta blocker therapy?

26 CCS HF Guidelines 2015

27 Contraindications Resting HR < 70 bpm Unstable or acute HF Recent acute myocardial infarction BP < 90/50 mm Hg Sick sinus syndrome Sino-atrial block Third degree atrioventricular block Pacemaker dependence Severe hepatic impairment Concomitant use of mod-strong CYP-3A4 inhibitors (i.e. fluconazole, diltiazem, grapefruit) Pregnant or lactating women

28 Monitoring Bradycardia Hypertension Heart Block Atrial Fibrillation Visual effects (phosphenes and blurred vision)

29 Availability and Cost Not formulary in AHS or Covenant Health Ivabradine 7.5mg po BID: $120/month Not covered by government insurance (seniors ABC, AISH) Coverage maybe provided depending on the private drug insurance plan Coverage cards are available through drug company for patients in USA

30 IDARUCIZUMAB (PRAXBIND ) Dabigatran Antidote

31 MOA Dabigatran Directly inhibits thrombin -> prevents thrombin-mediated clotting effects (conversion of fibrinogen to fibrin, activation of factors V, VII, XI, XIII) -> prevents formation of blood clot Idarucizumab Humanized monoclonal antibody fragment that attaches to dabigatran -> forms a complex and prevents dabigatran from binding to thrombin -> thrombin is free to mediate clotting

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33 RE-VERSE AD Trial Multicenter, open-label, cohort case-series study (i.e. no control group) 494 patients followed for 3 months (preliminary report published for 90 patients) Ongoing study (full trial results will be based on 503 patients)

34 RE-VERSE AD Trial Patients: median age 78, dabigatran treated Group A (n=298): uncontrolled bleeding 97 intracranial, 135 GI, 87 other Group B (n=196) : emergency surgery/procedure (within 8 h) 23% abdomen, 15% bone fracture, 5% pacemaker implant Intervention: 5g IV idarucizumab (given as 2 back-toback bolus injections) Dilute thrombin time (dtt) was measured pre and post to idarucizumab to determine effects

35 RE-VERSE AD Trial Outcomes dtt normalized within 4 hours in 98.7% of group A and 98.6% of group B

36 RE-VERSE AD Trial Outcomes Group A: median time to bleed cessation For 97 GI bleeds: 3.5 hours For 61 non-gi, non-ich bleeds: 4.5 hours Group B: intraoperative hemostasis 93% normal, 5% mildly abnormal, 2% moderately abnormal No specific idarucizumab related AE s reported

37 Implications of RE-VERSE AD Trial Health Canada issued conditional approval for patients on dabigatran who require rapid reversal for: life-threatening or uncontrolled bleeding OR emergency surgery/urgent procedures Additional Provincial Requirement in Hospitals: for patients requiring reversal prior to urgent surgery/procedure, need to confirm elevation of thrombin time before administration of idarucizumab Not to be used for elective surgery/procedure or to reverse other anticoagulants

38 Idarucizumab Dosing 2 consecutive 2.5g IV doses over 5-10 minutes each (second vial no later than 15 minutes) Administer as undiluted solution Direct IV (syringe) or Intermittent IV infusion (hanging the vial) Dabigatran maybe restarted as early as 24 hours after idarucizumab if appropriate Limited data for administration of additional 5g dose

39 AE s and Monitoring Previous trials in healthy volunteers show similar frequency of AEs vs placebo: hypokalemia (7%) delirium (7%) constipation (7%) pyrexia (6%) pneumonia (6%) Symptoms of potential hypersensitivity: rash, pyrexia, pruritus, bronchospasm and hyperventilation (contraindication)

40 Monitoring Signs and symptoms of bleeding Signs of thromboembolic events If confirmation of reversal needed, consider following parameters: Dilute thrombin time or thrombin time aptt, ECT

41 Availability and Storage Each vial contains 2.5 g of idarucizumab Single use vial (no preservatives) Store in refrigerator (2 8 C), protect from light Unopened vials can be kept in room temperature for up to 48 hours Opened vials can be kept in room temp (up to 25 C) up to 1 hour

42 Availability and Cost Restricted formulary in Alberta hospitals (only to be used for the two approved indications) Provincially mandated audit form must be completed by prescriber and returned by fax to pharmacy Idarucizumab 2.5g X 2 doses: $2, Not covered by government insurance in Alberta

43 References McMurray JJ, Packer M, Desai AS, et al; PARADIGM HF Investigators and Committees. Angiotensin neprilysin inhibition versus enalapril in heart failure. N Engl J Med Sep 11;371(11): Moe G, Ezekowitz J, O Meara E, et al. The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: Anemia, Biomarkers & Recent Therapeutic Trial Implications. Canadian Journal of Cardiology 2015; 31:3 16. Vardeny O, Miller R, Solomon SD. Combined Neprilysin and Renin-Angiotensin System Inhibition for the Treatment of Heart Failure. JACC Heart Fail Dec;2(6): Packer M, Califf RM, Konstam MA, et al; Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation Aug 20;106(8): The Howlett, JG, Chan M, Ezekowitz JA. The Canadian Cardiovascular Society of Heart Failure Companion: Bridging Guidelines to Your Practice. Can J Cardiol Mar;32(3): ENTRESTO (valsartan/sacubitril). Product Monograph. Novartis Pharmaceuticals Canada Inc. March 26, Wilhelmsen L, Berglund G, Elmfeldt D, et al. The multifactor primary prevention trial in Göteborg, Sweden. Eur Heart J 1986; 7: Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R on behalf of the BEAUTIFUL investigators. Heart rate as a prognostic risk factor in patients with coronary artery disease and leftventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 2008; 372: Swedberg K, Komaida M, Bohm M et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebocontrolled study. Lancet Sep 11;376(9744): LANCORA (ivabradine) Product Monograph. Servier Canads Inc. March 29, Available from: Pollack CV Jr, Reilly PA, Eikelboom J. Idarucizumab for Dabigatran Reversal. N Engl J Med Aug 6;373(6): Pollack CV. Idarucizumab for Dabigatran Reversal: Updated Results of the RE-VERSE AD Study. Presented at 2016 American Heart Association Scientific Sessions 2016; New Orleans, Louisiana. PRAXBIND (idarucizumab) Product Monograph. Boehringer Ingelheim. March 27, Available from:

44 Questions?