Cardiac Drugs :The Latest and Greatest

Mir Varquez MD, FACC

Topics

u  Corlanor (Ivabradine)

u  Entresto (Sacubitril/Valsartan)

u  Brilinta (Tigagrelor)

u  Zontivity (Vorapaxar)

u  PCS K9 Inhibitors:

§  Praluent (Alirocumab)

§  Repatha (Evolocumab)

u  NOAC’S:

§  Xarelto, Eliquis, Pradaxa, Salaysa

Carlanor (Ivabradine)

Medication to reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with LVEF less than or equal to 35%, who are in sinus rhythm with resting HR greater than 70 BPM and either are on maximally tolerated doses of a BB or have a contraindication to BB use.

Contraindications

§  Acute decompensated heart failure

§  Blood pressure <90/50

§  Severe hepatic failure

§  Use of strong P450 3A4 inhibitors (CYP3A4)

§  Increased risk of atrial fibrillation

§  Renal toxicity

Mechanism of Action

§  Within SAN-blocks the HCN channel, inhibits If current, lowers HR hyperpolarization- activated cyclic nucleotide gated.

§  Has no effect on myocardial contractility (no negative inotropic effect)

§  No effect on ventricular repolarization

§  Reduction in HR with Corlanor is dose dependent and baseline heart rate dependent.

Adverse Drug Effects

u  Bradycardia

u  Hypertension

u  Atrial Fibrillation

u  Phosphenes- Translucently enhanced brightness in a limited area of visual field, usually triggered by variations in light intensity.Onset is generally within two months of treatment( usually mild to moderate) and led to discontinuation in less than 1% of patients. Most resolved during or after treatment.

SHIFT

u  Systolic Heart Failure Treatment with the If inhibitors Ivabradine Trial

u  Admission criteria:

§  Optimized and stable treatment ≥ 4 weeks.

§  Sinus rhythm with resting heart rate ≥70.

§  NHHA class II-IV

§  Reduced LVEF (≤35%)

§  Hospitalization for worsening HF within 12 months.

§  2.5-7.5 mg BID

§  Recommended starting dose 5mg BID, after 2 weeks increase by 2.5 mg 2x/day.

Goal

u  50-60 BMP

u  No dose adjustment is required for patients with moderate to severe renal impairment CRCL 15-60 ml/min.

u  Does not require routine lab monitoring.

Entresto (Sacubitril/Valsartan)

u  Sacubitril, a neprilysin inhibitor, and Valsartan (Angiotensin II receptor blocker) are indicated to reduce the risk of CV death and hospitalization for heart failure in patients with chronic HF (NYHA class II-IV) and reduced EF.

Dosage

u  Starting dose 49/51mg BID, increase after 2-4 weeks to target 97/103 mg.

u  Reduce starting dose 24/26 mg in severe renal impairment or moderate hepatic impairment.

Contraindications

u  Hypersensitivity

u  Angioedema to ACEI/ARB

u  Concurrent use of ACEI

u  Concurrent use of Aliskiren in patients with DM.

Paradigm HF

u  Multinational randomized double-blinded study comparing Entresto and Enalapril in 8442 with NHHA II-IV and systolic dysfunction ( EF≤ 40%).

u  Superior to Enalapril in reducing the risk of combined endpoint of CV mortality HF hospitalizations.

u  Improve overall survival.

Brilinta (Tigagrelor) P2Y12 Platelet inhibitor u  Indications: Reduce rate of CV death, MI and stroke in ACS

or Hx of MI, for at least 12 months following ACS.

u  Superior to Clopidogrel.

u  Reduces stent thrombosis in patients stented for ACS.

Dosing

u  Titrate with 180 mg load, 90 mg BID for 1 year, then 60 mg PO BID.

u  Maintenance doses of ASA above 100 mg reduces the effectiveness of Brilinta.

u  Do not start in patients undergoing urgent CABG.

u  In clinical trail 14% of pts. developed dyspnea. No adverse effects in pulmonary function, no specific treatment is required.

Contraindications

u  Avoid use in severe hepatic impairment, no dosage adjustment in renal impairment.

u  Drug interactions with CYP3A inducers and inhibitors.

u  No known treatment to reverse Brilinta ,and not dialyzable.

Zontivity

PCSK9

u  PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) is a critical regulator of cholesterol mechanism though its interactions with the hepatic LDL receptor (LDLR) PCSK9 is a kexin (endopeptidase) found in the kidneys, liver, and intestines.

u  Circulating PCSK9 binds to the extracellular EGFR-like domain of LDLR, followed by endocytosis and lysosomal degradation of the complex.

u  LDL-R upregulation by SREBP ( sterol regulatory element-binding protein).

u  Given SQ prefilled pen, or syringe (Alirocumab) or prefilled auto injector (Evolocumab) every 2 weeks or once a month.

Indications

u  Used with statins in CV disease and high risk of stroke or heart attack who do not reach goals with statins alone.

u  With side effects to statins

u  Familial hypercholesterolemia

Dosing

Repatha (Evolocumab)

u  140 mg every 2-4 weeks

Praluent (Alirocumab)

u  75-150 mg every 2 weeks

NOAC’s

Novel (or newer) oral anticoagulant

u  Minimal reaction with medications and foods, with no need for blood monitoring.

u  NOT approved for valvular heart disease.

u  All NOAC’s are associated with reduced rate of IC bleeding compared with Warfarin in treatment of AF.

Pradaxa (Dabigatran)

u  Pradaxa (Dabigatran) at 150 mg BID is superior to Warfarin for the reduction of ischemic strokes in nonvalvular AF (RE-LY).

u  Dabigatran 110 mg BID and Rivaroxaban 20 mg daily non-inferior to Warfarin in stroke reduction.

u  Eliquis (Apixaban) 5 mg associated with similar ischemic stroke risk, but superior to overall stroke.

u  Apixaban associated with overall reduction in mortality compared with Warfarin (ARISTOTLE)

Dosing

Eliquis (Apixaban)

u  DVT 10 mg BID X 7 days then 5 mg BID x 3 months.

u  Prevention of recurrent disease 2.5 mg BID following 6 months of 5 mg BID.

Pradaxa (Dabigatran)

u  150 mg BID preceded by 5 days with parenteral anticoagulant.

u  Consider 110 mg BID if > 80 years old, taking Verapamil, or renal impairment.

Dosing

Salaysa (Edoxaban)

u  60 mg daily with prior 5 day parenteral anticoagulant.

u  Lower dose to 30 mg daily in low body weight, or those taking P-gp inhibitors: Cyclosporin, Multaq, Ketoconazole, Erythromycin.

Xarelto (Rivaroxaban)

u  15 mg BID for 3 weeks then 20 mg daily.

References

u  Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2013 Dec 3. [Epub ahead of print]

u  Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

u  Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.

u  Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.

u  Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-2104.

u  Staritz P et al. (2008) Platelet reactivity and clopidogel resistance are associated with the H2 haplotype of the P2Y12-ADP receptor gene. Int J Cardiol [doi:10.1016/ j.ijcard.2007.12.118]