The direct oral anticoagulants (DOACs) have gained popularity recently among both patients and providers for their comparable or better efficacy and safety profiles compared with warfarin and the lack of need for routine monitoring of anticoagulant effect. One obstacle for the more widespread use of the DOACs in clinical practice has been the lack of a reversal agent. Most DOACs act by directly binding to and inhibiting the effects of factor Xa. Andexanet alfa (Andexxa, Portola Pharmaceuticals, San Francisco, CA) is a modified form of factor Xa that acts as a decoy binding entity for DOACs, thereby allowing endogenous factor Xa to perform its normal clotting functions. Andexanet has proven efficacious in clinical trials for reversing the anticoagulant effects of apixaban, edoxaban, and rivaroxaban, although its impact on clinical outcomes has not been adequately studied. Andexanet has a boxed warning for thromboembolic risks, ischemic risks, cardiac arrest, and sudden death, with these adverse events occurring in up to 18% of patients in clinical trials. However, the occurrence of these adverse events needs to be considered in relation to the fragile nature of patients who receive this agent. Because the duration of the DOACs is much less than that of warfarin, it is unclear how many patients would actually need andexanet in clinical practice, because cessation of the DOAC may be all that is needed to effectively manage bleeding. Nonetheless, having andexanet available in cases of DOAC-associated severe or life-threatening bleeding represents a therapeutic advance and should provide an added level of comfort with the clinical use of DOACs.
Antiplatelet therapy with a P2Y12 inhibitor is a key component of treatment for patients with acute coronary syndromes undergoing percutaneous coronary intervention. Before the development of cangrelor (Kengreal, The Medicines Company, Parsippany, NJ), only oral P2Y12 inhibitors were available. Cangrelor is a reversible P2Y12 inhibitor that is administered as an intravenous infusion, and its quick onset and offset make it an appealing option for antiplatelet therapy, particularly for patients who are unable to take oral medications. Although cangrelor struggled to show benefit in early trials, the positive results of the CHAMPION PHOENIX trial led to its approval for use as an adjunct to percutaneous coronary intervention to reduce the risk of periprocedural myocardial infarction, repeat coronary revascularization, and stent thrombosis in patients who have not been treated with another P2Y12 inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor. Cangrelor has also been evaluated as an option for bridging therapy in patients who must discontinue their oral P2Y12 inhibitor before coronary artery bypass grafting. This review of cangrelor will discuss its mechanism of action, its pharmacodynamics and pharmacokinetics, the clinical trial experience, and its potential place in therapy.
Sacubitril/valsartan [LCZ696 (Entresto), Novartis Pharmaceuticals Corp.] is the first in a new class of drugs that combines neprilysin inhibition with angiotensin II receptor antagonism, the combination of which acts to increase endogenous natriuretic peptides while inhibiting the renin-angiotensin-aldosterone system. Sacubitril/valsartan has been studied in the treatment of hypertension, heart failure with reduced ejection fraction (HFrEF), and heart failure with preserved ejection fraction (HFpEF) and has demonstrated clinical efficacy in blood pressure reduction in hypertensive patients with and without HFpEF and a reduction in hospitalizations and mortality for patients with HFrEF. Research to evaluate clinical outcomes in HFpEF is ongoing. Sacubitril/valsartan is approved to reduce hospitalization and risk of cardiovascular death for patients with HFrEF in New York Heart Association (NYHA) functional class II-IV. The product is as well tolerated as an angiotensin-converting enzyme inhibitor, with the most common side effect being hypotension. Expectedly, it is much more costly than generic angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, which will be a factor in determining how widespread the use of this agent will be. In summary, although the number of published studies evaluating its use is limited, sacubitril/valsartan represents a promising new treatment option for patients with HFrEF. Ongoing studies will continue to refine the role of this agent in clinical practice.
Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are novel agents indicated for the treatment of hyperlipidemia. Inhibition of PCSK9 produces an increase in surface low-density lipoprotein (LDL) receptors and increases removal of LDL from the circulation. Alirocumab (Praluent; Sanofi/Regeneron, Bridgewater, NJ) and evolocumab (Repatha; Amgen, Thousand Oaks, CA) are currently available and approved for use in patients with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, and clinical atherosclerotic cardiovascular disease. Bococizumab (RN316; Pfizer, New York, NY) is currently being studied in similar indications, with an estimated approval date in late 2016. The pharmacodynamic effects of PCSK9 inhibitors have been extensively studied in various patient populations. They have been shown to produce significant reductions in LDL and are well tolerated in clinical studies, but they are very costly when compared with statins, the current mainstay of hyperlipidemia treatment. Clinical outcome studies are underway, but not yet available; however, meta-analyses have pointed to a reduction in cardiovascular death and cardiovascular events with the use of PCSK9 inhibitors. This review will discuss the novel mechanism of action of PCSK9 inhibitors, the results of clinical studies, and the clinical considerations of these agents in current therapy.
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