Evinacumab-dgnb (Evkeeza-REGN1500), A Novel Lipid-Lowering Therapy for Homozygous Familial Hypercholesterolemia.

Chronically elevated low-density lipoprotein (LDL) has harmful effects on the vasculature including increased vasoconstriction and the formation of plaques which may rupture, causing coronary heart disease and stroke. In patients with familial hypercholesterolemia, adequate reduction of LDL is especially challenging. Although HMG-CoA reductase inhibitors (statins) are the mainstays for LDL lowering, other treatments such as proprotein convertase subtilisin/kexin type 9 inhibitors, bempedoic acid, incliseran, lomitapide, and apheresis have been employed in an effort to achieve adequate LDL reduction in these patients. Despite these available therapies, many patients with familial hypercholesterolemia do not meet the LDL targets suggested in current guidelines. Evinacumab is a novel lipid-lowering therapy that exerts its LDL-lowering effect through inhibition of angiopoietin-like protein 3 (ANGPTL3). ANGPTL3 inhibits the breakdown of triglyceride-rich lipoproteins, such as very low-density lipoprotein and chylomicrons. By inhibiting ANGPTL3, evinacumab allows these lipoproteins to be degraded, ultimately leading to reductions in LDL, high-density lipoprotein, and triglycerides. Clinical trials have demonstrated evinacumab to be safe and effective in reducing LDL. However, data are lacking regarding its potential to reduce risk of atherosclerotic cardiovascular disease. Evinacumab is generally well tolerated with the primary adverse effects comprising infusion reactions, nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, and nausea. While evinacumab is an interesting therapy, until it is proven to reduce cardiovascular events, its high cost leaves its anticipated role in therapy somewhat ambiguous. In the meantime, it may be a useful therapy for those with homozygous familial hypercholesterolemia.

The Need for Competency-Based Education.

OBJECTIVES: While pharmacy education updates learning as new information arises, changes to learning experiences can trail behind current practices and technology. There have been multiple calls for radical changes in how health professions education is delivered to ensure patients are receiving high-quality care. Competency-based education has been one way discussed in the literature for how to handle this need to develop students who have a willingness to learn and can problem-solve. The goal of this review is to examine whether competency-based education is needed to drive the profession of pharmacy forward. FINDINGS: To address, we collaboratively identified stakeholder perspectives to evaluate the need. The following stakeholders achieved consensus among the committee members: patients/society, learners, workplace/profession, and academic institutions. SUMMARY: Based on those perspectives, needs, and gaps to address those needs were identified and are presented in this review.

Use of number needed to treat in cost-effectiveness analyses.

OBJECTIVE: To review the use of number needed to treat (NNT) and/or number needed to harm (NNH) values to determine their relevance in helping clinicians evaluate cost-effectiveness analyses (CEAs). DATA SOURCES: PubMed and EconLit were searched from 1966 to September 2012. STUDY SELECTION AND DATA EXTRACTION: Reviews, editorials, non-English-language articles, and articles that did not report NNT/NNH or cost-effectiveness ratios were excluded. CEA studies reporting cost per life-year gained, per quality-adjusted life-year (QALY), or other cost per effectiveness measure were included. Full texts of all included articles were reviewed for study information, including type of journal, impact factor of the journal, focus of study, data source, publication year, how NNT/NNH values were reported, and outcome measures. DATA SYNTHESIS: A total of 188 studies were initially identified, with 69 meeting our inclusion criteria. Most were published in clinician-practice-focused journals (78.3%) while 5.8% were in policy-focused journals, and 15.9% in health-economics-focused journals. The majority (72.4%) of the articles were published in high-impact journals (impact factor >3.0). Many articles focused on either disease treatment (40.5%) or disease prevention (40.5%). Forty-eight percent reported NNT as a part of the CEA ratio per event. Most (53.6%) articles used data from literature reviews, while 24.6% used data from randomized clinical trials, and 20.3% used data from observational studies. In addition, 10% of the studies implemented modeling to perform CEA. CONCLUSIONS: CEA studies sometimes include NNT ratios. Although it has several limitations, clinicians often use NNT for decision-making, so including NNT information alongside CEA findings may help clinicians better understand and apply CEA results. Further research is needed to assess how NNT/NNH might meaningfully be incorporated into CEA publications.

Recommendations and Next Steps For Competency-Based Pharmacy Education.

In July 2021, the chairs of the American Association of Colleges of Pharmacy Council of Deans, Council of Faculties, and Council of Sections developed a task force to discuss potential ways to improve pharmacy education. The Competency-Based Education (CBE) Joint Task Force was created to explore the pros and cons of advancing a competency-based approach to pharmacy education (CBPE) and to determine ways to create more flexibility within pharmacy curricula to enable CBE. To achieve these goals, the Task Force systematically reviewed available resources and outlined the pros and cons of CBPE, best practices for implementation, strategies to minimize barriers, and recommendations on whether CBE should be implemented in pharmacy education. This commentary summarizes the Task Force's findings regarding whether CBPE is a suitable approach for pharmacy education and the next steps if implemented.

Blood pressure monitoring technique impacts hypertension treatment.

BACKGROUND: In 2005 the American Heart Association (AHA) released updated recommendations for blood pressure (BP) monitoring in order to ensure accurate BP measurements. OBJECTIVE: To determine if current methods of BP assessment in an ambulatory clinic result in significantly different BP measurements than those obtained by following the AHA recommendations and if these BP differences impact treatment decisions. RESEARCH DESIGN: Randomized prospective analysis. SETTING: University of New Mexico Hospital Adult Internal Medicine clinic. PATIENTS: Forty adults with hypertension METHODS: Patient BPs were measured using both the traditional triage method and the AHA-recommended method in cross-over fashion in random order. Two complete medical profile summaries were then constructed for each patient: one for each BP measurement obtained by each technique. These profiles were then reviewed by a panel of providers who provided hypothetical hypertension treatment recommendations. RESULTS: Individual BP results varied greatly between the two methods. SBP readings differed by ≥5 mmHg in either direction for 68% of patients while 78% of patient's DBP readings differed by ≥2 mmHg in either direction. Overall, 93% of patients had a BP difference of either ≥5 mmHg systolic or ≥2 mmHg diastolic. Five patients were determined to be at goal with the triage method, but were higher than their goal BP with the AHA method Significant differences were also seen in treatment recommendations for a given patient based on the differences seen between the two obtained BP readings. The number of patients with treatment variations between their two profiles ranged from 13% to 23% depending on the reviewing provider (p < 0.01 for all providers). CONCLUSION: Inaccurate BP assessment is common and may impact hypertension treatment decisions.

Tafamidis: A Novel Treatment for Transthyretin Amyloid Cardiomyopathy.

Transthyretin (TTR) amyloid cardiomyopathy is a life-threatening condition in which amyloid fibrils accumulate in the heart, eventually leading to cardiac symptomatology and death. To date, treatment of this condition has been directed at symptom relief due to a lack of effective treatment options which target the cause of the disease. The discovery that amyloid deposition was a result of dissociation of the TTR protein structure allowed for the development of tafamidis, which acts by stabilizing the TTR tetramer. Due to the rare nature of the disease, there is limited clinical trial data with tafamidis, with the largest clinical trial enrolling only 441 patients. Nonetheless, that trial demonstrated tafamidis to reduce all-cause mortality as well as cardiovascular hospitalizations compared to placebo with a comparable adverse effect profile, although not all subgroups of patients received benefit. The United States Food and Drug Administration subsequently granted Fast Track review status to tafamidis, leading to its approval in May 2019. Important questions still remain, however, such as which patient groups will receive the most benefit with this drug, how the exceptionally high cost of the drug will be handled by third-party payers, and how the therapeutic role of tafamidis will evolve as competing or perhaps complementary medications complete their ongoing clinical trials and move into the marketplace.

Nitrosamine Impurities in Angiotensin Receptor Blockers.

Nitrosamines are known carcinogens which have been recently discovered in several angiotensin receptor blockers (ARBs). This led to the recall of valsartan in the United States in 2018, and afterward, the recall of other ARBs as well as unrelated medications (e.g., ranitidine). The presence of nitrosamine in ARBs was likely a result of changes in the manufacturing process, although nitrosamine contamination is believed to occur by different mechanisms with other medications. The United States Food and Drug Administration has since taken steps to identify products affected by nitrosamine contamination and mitigate this concern going forward. Despite the contamination of some drug products, studies estimate that the overall risk to patients is low enough to not necessitate changes in prescribing patterns at this time.

Chloroquine or Hydroxychloroquine for Management of Coronavirus Disease 2019: Friend or Foe?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a threat to the health of many humans across the world as they confront coronavirus disease 2019 (COVID-19). Previous promising in vitro data that emerged after the SARS-CoV outbreak in 2003, along with the emergent need for pharmacologic management strategies in the fight against COVID-19, prompted interest in the use of chloroquine and hydroxychloroquine across the globe. Unfortunately, the in vitro activity of these drugs did not necessarily correlate with most in vivo studies, which showed no consistent efficacy. Safety is also a major concern, with these agents having a known risk of QT prolongation and proarrhythmic effects. In addition, clinical practice guidelines provide no clear consensus on the role of chloroquine or hydroxychloroquine for the management of COVID-19. The United States Food and Drug Administration has declared that the potential benefits of these agents no longer outweigh the possible risks, and unless new emerging information suggests a more favorable risk:benefit ratio, neither chloroquine nor hydroxychloroquine should be recommended for COVID-19 treatment or prevention at this time.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Patients With Coronavirus Disease 2019: Friend or Foe?

When the coronavirus disease 2019 (COVID-19) wreaked an unprecedented havoc of an escalating number of deaths and hospitalization in the United States, clinicians were faced with a myriad of unanswered questions, one of the them being the implication of the renin-angiotensin-aldosterone system in patients with COVID-19. Animal data and human studies have shown that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) increase the expression of ACE2. ACE2 is an enzyme found in the heart, kidney, gastrointestinal tract, and lung and is a coreceptor for severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV2), the virus responsible for COVID-19. Therefore, one can speculate that discontinuing ACE inhibitor or ARB therapy may lead to decreased ACE2 expression, thereby attenuating the infectivity of SARS-CoV-2, and mitigating the disease progression of COVID-19. However, several studies have also shown that ACE2 exhibits reno- and cardioprotection and preserves lung function in acute respiratory distress syndrome, which would favor ACE inhibitor or ARB therapy. This article is to examine and summarize the 2 opposing viewpoints and provide guideline recommendations to support the use or discontinuation of ACE inhibitors and ARBs in patients with COVID-19.

Andexanet Alfa for Reversing Factor Xa Inhibition.

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.

Impact of Department of Veterans Affairs Cooperative Studies Program clinical trials on practice guidelines for high blood pressure management.

Knowing the extent to which a clinical trial's findings translate into clinical practice can be challenging. One practical approach to estimating a trial's influence on clinical practice can be achieved by assessing how the trial informed relevant clinical practice guidelines (CPGs). Accordingly, the objectives of this study were to provide an overview of all the clinical trials involving the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) that aimed at informing or resulted in informing the management of high blood pressure and to identify and describe the extent to which these trials informed CPGs for the management of high blood pressure. A total of 26 clinical trials involving the VA CSP were identified. Using bibliographic information, 21 CPGs for the management of hypertension representing over 40 years of treatment recommendations from eight collectives were evaluated to determine how they were informed by trials involving the VA CSP. From 1977 to 2018, 13 of the 26 trials (50.0%) were found to have informed 19 of the 21 CPGs (90.5%) a total of 54 times (mean = 2.6 trial citations per CPG, SD ±â€¯1.8). Clinical trials involving the VA CSP have informed a sizeable proportion of CPGs for the management of high blood pressure over the past 40 years. Because of this impact on the CPGs, these trials are also likely to have had at least moderate influence on clinical practice.

Switching From Ticagrelor or Prasugrel to Clopidogrel.

Ticagrelor and prasugrel are newer antiplatelet drugs which, like clopidogrel, block the P2Y12 platelet receptor to inhibit platelet aggregation. Compared with clopidogrel, both ticagrelor and prasugrel have greater clinical efficacy but also have a higher risk of bleeding and are much more costly. Therefore, some institutions and providers switch patients from ticagrelor or prasugrel to clopidogrel in an effort to lower bleeding risk, stem costs, or otherwise ensure that patients can safely adhere to long-term P2Y12 inhibitor therapy. From a pharmacodynamic perspective, switching patients from ticagrelor or prasugrel to clopidogrel comes at a cost of less antiplatelet efficacy. However, it is unclear if antiplatelet efficacy is diminished enough to affect clinical outcomes. This is because clinical trial data investigating such a switch is scant, leaving the clinician unsure as to the acceptability of this practice. Current clinical trial data have thus far not shown any clinical detriment from switching from ticagrelor or prasugrel to clopidogrel, but there are many limitations to these investigations. So although a large-scale switch of patients from ticagrelor or prasugrel to clopidogrel is not recommended, if the patient is unable to adhere to long-term ticagrelor or prasugrel therapy, switching him/her to clopidogrel seems to be a reasonable practice to maintain chronic suppression of platelet aggregation and minimize the risk of ischemic events.

Are Shorter Durations of Dual Antiplatelet Therapy Acceptable Following Percutaneous Coronary Intervention?

Much debate has centered on whether or not the standard 12-month duration of dual antiplatelet therapy (DAPT) is still necessary postpercutaneous coronary intervention, given recent improvements in stent technology. The benefits of shorter (3-6 months) durations of DAPT include a potential lower risk for bleeding and less patient drug cost and pill burden. Although randomized clinical trials have shown noninferiority for shorter versus longer DAPT regimens in many regards, some endpoints (e.g., myocardial infarction) may still occur less frequently with longer DAPT regimens, particularly in higher risk populations (e.g., acute coronary syndromes). Bleeding risk is either comparable or less with shorter versus longer DAPT regimens. Given the lack of unequivocal data regarding the equality of shorter versus longer DAPT regimens in all patients, there is a growing consensus that an individualized approach is advisable for determining DAPT duration postpercutaneous coronary intervention. Clinical decision aids and updated clinical practice guidelines are available that consider risk:benefit ratios and clinical trial data to assist the clinician in developing a personalized DAPT regimen.

Open-Label Study of the Stability of Sublingual Nitroglycerin Tablets in Simulated Real-Life Conditions.

Contemporary practice favors refilling sublingual nitroglycerin (SL NTG) every 3 to 6 months. This recommendation is based on antiquated data that does not consider the reformulated tablet and the improved manufacturing process. Our objective was to investigate the stability of SL NTG over time using simulated real-life scenarios in comparison to controlled storage conditions. This was an open-label study of 100- and 25-count commercial SL NTG bottles stored in either controlled temperature and relative humidity conditions, or carried in a pocket or purse. SL NTG potency (chemical stability) was assessed using high performance liquid chromatography and physical stability was assessed by changes in tablet weights over time through the labeled expiration date. Both chemical and physical stability of SL NTG were affected by environmental and physical factors. High temperature storage resulted in the most rapid loss of potency. Tablets carried in a pant pocket lost potency faster than those carried in a purse. Potency was also dependent on headspace of the bottle. Tablets stored in the original bottle in a temperate environment could be expected to maintained potency for more than 2 years when carried in a purse, irrespective of package size. When carried in a pant pocket, potency of a 25-count bottle was maintained for 2 years, whereas potency of a 100-count bottle fell below acceptable limits at 12 months. In conclusion, since potency is dependent on temperature, headspace, and carrying practices, frequency of SL NTG refills should be based on individual patient behavior.

Cangrelor: A New Route for P2Y12 Inhibition.

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.

Celiprolol: A Unique Selective Adrenoceptor Modulator.

Celiprolol is a ß-blocker with a unique pharmacologic profile: it is a ß1-andrenoceptor antagonist with partial ß2 agonist activity. Given this combination of effects, celiprolol may be better described as a selective adrenoreceptor modulator. It has antihypertensive and antianginal properties and is indicated for those uses in various countries around the world. In the United States, however, the proposed indication for this drug will be for the treatment of vascular type Ehlers-Danlos syndrome, a rare connective tissue disorder characterized by fragile arterial structure and an increased risk of life-threatening vascular complications. By reducing heart rate and pulsatile pressure, celiprolol may reduce the mechanical stress on collagen fibers within the arterial wall and be of benefit in patients with vascular type Ehlers-Danlos syndrome. The largest investigation of celiprolol in vascular Ehlers-Danlos syndrome was prematurely terminated due to significant benefit with celiprolol in reducing arterial events in patients with this condition. Celiprolol, therefore, represents a ß-blocker that is unique from others in its class in both its pharmacology and clinical applications.

The paclitaxel-eluting stent in percutaneous coronary intervention: Part II. Comparison with the sirolimus-eluting stent, economics, and unanswered questions.

The paclitaxel- and sirolimus-eluting stents are currently the only drug-eluting stents approved for use in the United States. These 2 stents differ in terms of mechanism of drug action, the construct of the stent itself, and the drug delivery polymer. Clinical trials have demonstrated superiority of both paclitaxel- and sirolimus-eluting stents when compared with bare-metal stents in terms of reducing restenosis and the need for target vessel revascularization. Recently published head-to-head trials have not conclusively shown 1 drug-eluting stent to be superior to the other, but have demonstrated more favorable angiographic results with the sirolimus-eluting stent compared with the paclitaxel-eluting stent; however, no significant difference has been demonstrated in clinical outcomes such as myocardial infarction or death. In terms of economics, the paclitaxel-eluting stent is substantially more expensive than the bare-metal stent. However, by significantly reducing the risk of restenosis and need for repeat revascularization, the higher direct cost of the paclitaxel-eluting stent may in theory be offset by lower overall healthcare costs, although economic analyses have yet to definitively establish that the paclitaxel-eluting stent is truly cost-effective. There is still much to be discovered regarding the paclitaxel-eluting stent, specifically the optimal stent design and drug release mechanism, the relative safety and efficacy of the paclitaxel-eluting stent compared with other drug-eluting stents, the long-term effects of the paclitaxel-eluting stent, the ideal antiplatelet regimen to use in patients with a paclitaxel-eluting stent, the safety and efficacy of the paclitaxel-eluting stent in various high-risk patient groups, and the ultimate cost-effectiveness of this device.

The paclitaxel-eluting stent in percutaneous coronary intervention: part I: background and clinical comparison to bare metal stents.

The development of coronary artery stents that release (elute) a drug locally into the diseased vasculature has revolutionized the practice of interventional cardiology. These devices were designed to minimize the incidence of in-stent restenosis that may occur with bare metal stents. The paclitaxel-eluting stent is the most recent drug-eluting stent approved for use in the United States and is a bare metal stent coated with paclitaxel that is gradually released from the stent into the vessel wall with undetectable systemic concentrations of the drug. Paclitaxel functions to stabilize the assembly of microtubules, thereby interfering with cell division, motility, and shape, and ultimately inhibiting smooth muscle cell proliferation and migration, key processes in the development of neointimal hyperplasia during in-stent restenosis. Clinical trials have repeatedly demonstrated the superiority of the paclitaxel-eluting stent over the bare metal stent in terms of reducing restenosis rates and percent stenosis diameter as well as other angiographic end points. Although the rates of major adverse cardiac events are reduced with the paclitaxel-eluting stent compared with the bare metal stent, this is primarily the result of a reduction in the need for target vessel revascularization, whereas rates of myocardial infarction and death have not been shown to be significantly affected.

Treating Diuretic Resistance: An Overview.

Loop diuretics are central to the management of fluid overload in acute decompensated heart failure. However, a variance in the response to loop diuretics can alter a patient's clinical course and has an adverse effect on clinical outcomes. Thus, a diminished response to loop diuretics is an important clinical issue. Factors thought to contribute to diuretic resistance include erratic oral absorption in congested states and postdiuretic sodium retention. Further contributing to diuretic resistance in patients with advanced heart failure are decreases in renal perfusion and alterations in sodium handling that occur in an attempt to maintain circulatory homeostasis. Several pharmacologic interventions have been used to improve diuretic response. Intravenous diuretic administration, increasing diuretic doses, or changing diuretic agents can potentially overcome pharmacokinetic obstacles which contribute to drug resistance. Combination diuretic therapy may be useful to overcome increased sodium retention, dopamine may improve renal perfusion, and hypertonic saline may transiently increase intravascular volume and improve sodium delivery to the tubules of the nephron. Despite the prevalence of diuretic resistance, there remains a paucity of clinical trial evidence to help guide therapy in these patients.

PCSK9 Inhibitors: An Innovative Approach to Treating Hyperlipidemia.

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.