Joseph E. Cruz, Pharm.D., BCPS is Clinical Assistant Professor at Rutgers University, and The State University of New Jersey Clinical Coordinator - Internal Medicine Englewood Hospital and Medical Center.

Joseph E. Cruz, Pharm.D., BCPS

	Cangrelor (Kengreal) is the first and currently only, FDA-approved injectable P2Y

â inhibitor available for use in the United States. Cangrelor exerts its effect on platelets by directly and reversibly blocking ADP-mediated activation, aggregation, and subsequent downstream signaling. This drug is indicated for patients undergoing percutaneous coronary intervention (PCI) who have not been treated with an alternative P2Y

 inhibitor or a glycoprotein IIb/IIIa inhibitor, such as eptifibatide or tirofiban.

	
	The pivotal CHAMPION PHOENIX trial found that IV cangrelor significantly reduced the composite of all-cause mortality, myocardial infarction, revascularization due to ischemia, and stent thrombosis as compared to oral clopidogrel therapy when given at the time of PC12.

	
	Conventional dosing of cangrelor is 30 mcg/kg administered as a bolus injection followed by a continuous infusion of 4 mcg/kg/min for 2 hours or for the duration of the procedure-whichever is longer. A loading dose of an oral P2Y

 inhibitor should be given  upon discontinuation of the infusion. If ticagrelor is chosen, however, the oral dose may be given at any point during the infusion.

	
	Off-label uses of cangrelor have begun to make their way into hospitals around the country following the drug’s approval. One such off-label indication that has modest clinical trial data to support its use is “bridge” therapy prior to non-emergent coronary artery bypass graft (CABG) surgery. In the cangrelor BRIDGE study (not to be confused with the recently published Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation study), patients taking oral antiplatelet agents were transitioned to either a prespecified low-dose continuous infusion of cangrelor (0.75 mcg/kg/min) or placebo.

 The primary goal of the BRIDGE trial was to determine if adequate platelet inhibition was maintained while the infusion was administered before surgery. Additionally, patients were assessed for the main safety endpoint of surgery-related bleeding.

	
	A larger percentage of patients treated with cangrelor maintained suppressed platelet activity during the infusion as compared to placebo (98.8% vs. 19.0%; p < 0.001). Rates of surgery-related bleeding did not differ significantly between patients treated with cangrelor  or placebo (11.8% vs. 10.4%; p = 0.76) and all other adverse event rates were similar between the two groups.

	
	There is a concern that ischemic events may occur following the discontinuation of oral antiplatelet therapies before non-emergent cardiothoracic surgery. Conversely, if antiplatelet agents are not discontinued with enough time for platelets to recover prior to surgery, then patients could be at an increased risk of bleeding during surgery. Cangrelor offers a theoretical advantage as a bridging therapy compared to traditionally used oral thienopyridines due its short pharmacokinetic (t1/2 = 3 to 6 minutes) and pharmacodynamic half-life (platelet recovery ~ 1 hour).1 The BRIDGE study provides a rationale for use of cangrelor in this clinical setting, though the use of a surrogate efficacy marker as a primary outcome limits the widespread generalizability of the results to practice.

	References
	1. The Medicines Company. Kengreal® Package Insert. Parsippany, NJ; 2016, May.
	2. Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368(14):1303-13.
	3. Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA. 2012 Jan 18;307(3):265-74.
	 

Articles

Cangrealor is the first FDA-approved P2Y12 inhibitor.

Cardiac Matters

	The first of their kind, evolocumab and alirocumab belong to a new class of cholesterol
	lowering agents: proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

	These human monoclonal antibodies both exert their lipid-lowering effect by binding to PCSK9 and preventing LDL receptors from being degraded in the liver. By inhibiting the destruction of LDL receptors, PCSK9 inhibitors promote the removal of LDL cholesterol (LDL-C) from the circulation, thus lowering levels of LDL-C in the blood.

	The labeling for both PCSK9 inhibitors includes indications for patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease (ASCVD) who need further LDL-C reductions despite concomitant diet control and statin pharmacotherapy. Evolocumab also has an indication as an adjunct therapy for patients with homozygous familial hypercholesterolemia.

	The LDL-C lowering effects observed in clinical trials for both drugs were significant, especially considering these studies evaluated patients on high-dose statin therapy. In a large open-label follow-up of the phase 3 clinical trials evaluating evolocumab, patients treated with the PCSK9 inhibitor in addition to standard lipid-lowering therapy saw a 61% reduction in LDL-C as compared to those treated with standard therapy alone. The combined OSLER-1 and OSLER-2 trials demonstrated the significant LDL-C lowering effect of evolocumab: patients with a median baseline LDL-C level of 120 mg/dL achieved an LDL-C of 48 mg/dL after 12 weeks of therapy.

 Likewise, alirocumab was evaluated against placebo in a large phase 3 trial in which all patients were given statins +/- other lipid lowering therapy. In the ODYSSEY LONG TERM trial, patients treated with alirocumab experienced a 61% reduction in LDL-C by week 24– reduction in mean LDL-C from 122.7 mg/dL to 48 mg/dL. 

	Evolocumab and alirocumab are both administered via subcutaneous injection. Evolocumab is available as a 140 mg injection given every 2 weeks, or a 420 mg injection given monthly. Patients with homozygous familial hypercholesterolemia should only receive the 420 mg monthly dose.Alirocumab is available as 75 mg or 150 mg injections, which are given every 2 weeks. The 75 mg dose should be used initially, but can be increased to 150 mg if there is an inadequate response after 4 to 6 weeks. Contraindications  include history of hypersensitivity reactions to the respective drugs. Adverse effects of both drugs can include nasopharyngitis, injection site reactions, infection, and musculoskeletal pain.

	    Because these drugs are biologics, cost is definitely a concern and recent publications have called into question the cost-effectiveness of PCSK9 therapy at current market prices.

 Additionally, the most recent hyperlipidemia treatment guidelines from the American College of Cardiology and American Heart Association do not include specific recommendations about the use of PCSK9 inhibitors since these drugs were not FDA approved at the time of publication. The guidelines advise against routine use of non-statin therapies due to a lack of strong clinical trial evidence of their effects on cardiovascular outcomes.

  Note though that studies of both PCSK-9 inhibitors have seemingly addressed this issue by focusing on clinically meaningful outcomes rather than simply lowering LDL-C.

  Once published, these studies will help to determine the place of PCSK9 inhibitors in therapy moving forward. 

The first of their kind, evolocumab and alirocumab belong to a new class of cholesterol lowering agents.

PCSK9 Inhibitors: The First of Their Kind

Entresto® is a newly approved combination of sacubitril, a neprilysin inhibitor, and

 valsartan, an angiotensin II receptor blocker (ARB) for patients who have chronic heart failure

 NYHA Class II-IV and reduced ejection fraction.

	Sacubitril exerts its effect by inhibiting the metabolism of natriuretic peptides, thereby subsequently augmenting excretion of sodium in the urine. Valsartan selectively blocks angiotension II receptors which reduces angiotensin-mediated aldosterone release and decreases vasoconstriction caused by dysregulation of the renin-angiotensin aldosterone system.

	The American College of Cardiology, the American Heart Association and the Heart Failure Society of America published a consensus statement of the newest pharmacological recommendations in the management of heart failure based on the latest literature.

	This update includes recommendations for the angiotensin receptorneprilysin inhibitor (ARNI) in NYHA class II-IV heart failure with reduced ejection fraction. When ARNI therapy is combined with a recommended beta-blocker and aldosterone antagonist, the risk of morbidity and mortality is reduced.

	This is a class I-BR recommendation, a strong recommendation based on moderate quality of evidence from a randomized controlled trial. The PARADIGM- HF study was an RCT involving over 8,000 patients given either the ARNI or enalapril. The primary endpoint was a composite of cardiovascular-related deaths or first hospitalization.

	There was a 20% decrease in CV-related deaths (HR: 0.80 [95% CI: 0.71–0.89; p<0.001]) and a 21% decrease in first hospitalizations for heart failure (HR: 0.79 [(95% CI: 0.71– 0.89; p<0.001]), although there was an increase in the incidence of hypotension in the ARNI group (14% vs. 9.2%; p<0.001).

	Treatment-naïve patients, or those on a low dose ACE inhibitor or ARB therapy should be started on the sacubitril 24 mg/valsartan 26 mg strength, twice daily. The 49mg/51mg twice daily dose can be initiated in those switching from greater than 10 mg of enalapril or 160 mg or more of valsartan daily.

	The target dose should be 97mg/103mg as long as the patient can tolerate therapy without substantial side effects. A 36-hour washout period is warranted when switching to sacubitril/ valsartan from an ACE inhibitor.

	Of note, the valsartan component in Entresto® is more bioavailable than that of the single tablet formulations currently marketed; therefore, the valsartan dose differs from the traditional formulation in the Entresto® combination.

	Use the lower strength formulation when starting therapy in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or moderate hepatic impairment (Child Pugh B). Doses may be doubled every 2 to 4 weeks as tolerated up to sacubitril 97 mg/valsartan 103 mg twice daily. Use is not recommended in severe hepatic impairment.

	Side effects of sacubitril/valsartan may include: hypotension, increase in serum creatinine; anemia, cough, and hyperkalemia. Most of these can be attributed to the ARB in the combination.

	Contraindications to starting Entresto® are concomitant ACE inhibitor use, prior angioedemia from an ACE inhibitor or ARB, and concomitant use of the antihypertensive agent aliskiren in diabetic patients. Notable drug interactions may occur with potassium sparing diuretics, lithium, and NSAIDs.

Clinical Assistant Professor at Ernest Mario School of Pharmacy at Rutgers University, and Clinical Pharmacist at Monmouth Medical Center in Long Branch, New Jersey.

is Clinical Assistant Professor at Rutgers University, and The State University of New Jersey Clinical Coordinator - Internal Medicine Englewood Hospital and Medical Center.

	1. Entresto [product information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015

	2. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Focused Update update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. 

	3. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. 

Entresto® is a newly approved combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker (ARB) for patients who have chronic heart failure NYHA Class II-IV and reduced ejection fraction.