Alan Agins

Dr. Alan P. Agins is president of PRN Associates (Continuing Education in Pharmacology) in Tucson, AZ. He holds an MS and PhD in pharmacology. More »He has held faculty appointments at Northeastern University School of Pharmacy, University of Virginia School of Nursing and Brown Medical School where he was the recipient of the Dean's Teaching Excellence Award for five consecutive years. He has also taught pharmacology courses at a number of nursing schools around the country. Beyond academia, over the past 18 years, Dr. Agins has presented continuing education seminars and lectures to more than 70,000 advanced practice clinicians nationally, including nurses, NPs, PAs, physicians, pharmacists and other allied healthcare professionals. He has authored two books, produced an educational DVD and workbook, co-authored and served as a consultant and reviewer for numerous journals, continuing education monographs, textbook chapters and newsletters. He currently presents CE webinars regularly for pharmacists through RxSchool.com. His primary interest continues to be making pharmacology education understandable, interesting and fun.

News from the World of Pharmacology

An Explosion of New Anticoagulants

There has been a lot of activity in the anticoagulant arena over the past year. Dabigatran (Pradaxa®), approved in October 2010, became the first orally available anticoagulant contender to compete with age-old warfarin, at least in the atrial fibrillation market. While dabigatran, a direct thrombin inhibitor, offers some advantages over warfarin, such as more predictable pharmacology (ie., minimal potential for pharmacokinetic, life style or dietary interactions or genetic variability), easier dosing options and little or no need for monitoring in most patients, it is still far from the perfect oral anticoagulant. Stomach upset and the requirement for b.i.d dosing threaten compliance and, in this case, poor compliance can result in treatment failure and thrombotic events. Conversely, in the case where the anticoagulant causes hemorrhage, as all anticoagulants can do, there is no antidote to turn to, like vitamin K (warfarin) or protamine (heparin).

Enter Xarelto® (rivaroxaban), an oral Factor Xa inhibitor approved in July 2011 for prevention of DVT following orthopedic surgery. Much like Pradaxa, Xarelto has more predictable pharmacology than warfarin and no requirement for monitoring. One potential advantage it offers over Pradaxa is once daily dosing. It is also less likely to cause GI distress; that's a big plus for compliance. So far, so good, right? Not so fast. Xarelto, unlike Pradaxa, is cleared through the cytochrome P450 system (CYP3A4) and, therefore, the possibility for drug interactions could complicate therapy. There is also no specific antidote if hemorrhage occurs.

Both drugs are actively looking to compete with each other's currently approved indication: Pradaxa is looking for approval for prevention of DVT following orthopedic surgery (RE-NOVATE, RE-MODEL) and, just this week, Xarelto got a favorable nod from an FDA advisory committee for approval in the atrial fibrillation arena (ROCKET-AF). Of course, both would like to get approval across the board for everything thrombosis.

Look for the new (Factor Xa inhibitor) kid on the block to show up sometime soon. Apixaban (Eliquis®) is currently in the final stages of phase 3 trials (ARISTOTLE) evaluating it for the prevention of stroke or systemic embolism in patients with atrial fibrillation and at least one risk factor for stroke, compared to warfarin. Study data look promising. If approved (and that's likely), the upside, compared to Xarelto (rivaroxaban), is no cytochrome P450 interaction issues. The potential downside? That nagging b.i.d. dosing thing.

Without rehashing the well known clinical issues associated with the use of vitamin K antagonists, as a group, the drugs contending to replace warfarin certainly do offer some advantages (as mentioned above). In the end, however, it will still come down to evaluation and analysis of all the letters in the "STEPS" mnemonic: Safety, Tolerability, Efficacy, Price, Simplicity. By the sheer act of approval, the FDA pretty much sanctions the Safety (relative) and Efficacy (superiority or non-inferiority) pieces. It's those others that require the test of time, larger patient numbers and clinical observation by providers: Tolerability, Price and Simplicity (daily vs. b.i.d). We'll see.

But wait! There's another drug that's been recently approved for the other side of the coagulation cascade - the platelet side...

Brilinta™ (ticagrelor) is a platelet aggregation blocker approved this past month (August 2011) for reducing the rate of thrombotic cardiovascular events in patients with acute coronary syndrome.

Like its thienopyridine predecessors ticlopidine, clopidogrel and prasugrel, ticagrelor blocks the P2Y12  ADP receptors on platelets, which prevents them from activation (from ADP). However, unlike the other antiplatelet drugs which bind covalently and permanently to the receptor, ticagrelor's blockade of the receptor is reversible. Furthermore, it is not a pro-drug like the thienopyridines, which require cytochrome P450 activation to become active. In that regard, it might have better efficacy than clopidogrel in patients with genetic variants regarding the CYP2C19 isoform of cytochrome P450.

The PLATO clinical trial reported ticagrelor had more favorable mortality rates than clopidogrel (9.8% vs. 11.7%) in treating patients with acute coronary syndrome (ACS). Patients given ticagrelor were less likely to die from vascular causes, heart attacks or strokes, but had greater chances of non-lethal bleeding (16.1% vs. 14.6%). In these trials, all patients also received acetylsalicylic acid (aspirin) at a dose of 75 to 100 mg daily unless they could not tolerate the drug. Aside from bleeding, dyspnea was reported in 14% of patients treated with ticagrelor and in 8% of patients taking clopidogrel.

Ticagrelor, because it does not require metabolic activation, has a faster onset than clopidogrel. And, because it is a reversible inhibitor, ticagrelor has a shorter duration of action than clopidogrel. The downside of the latter is that it has to be taken twice daily (vs. daily for clopidogrel), again getting into that issue of compliance. Conversely, its reversibility and shorter duration means less time for the drug (or drug's actions) to be cleared if serious side effects develop.

Finally, although it doesn't require cytochrome P450 for activation, ticagrelor does get metabolized and cleared by that hepatic enzyme system, in particular the CYP3A4. Inhibitors like the macrolide antibiotics, the azole antifungals, protease inhibitors, verapamil and possibly grapefruit juice, can raise plasma levels of the drug and consequently increase risk of bleeding and other adverse effects. Conversely, it appears that ticagrelor may slow the clearance of other drugs that are also metabolized by CYP3A4: for example, lovastatin or simvastatin, PDE5 inhibitors and others, which can increase the risk of their respective side effects.

So, how does ticagrelor (Brilinta) fair in the STEPS mneumonic compared to, say, clopidogrel (which is the leader right now)?

We'll see.

Influenza 2011-12 Update

The 2011-12 vaccine is shipping, flu clinics are gearing up, people are rolling up their sleeves and, well, it's that time of year. Alas, it is the same vaccine as last year's. The same three viral strains were chosen: A/California/7/09 (H1N1)-like virus, A/Perth /16/2009 (H3N2)-like virus and B/Brisbane/60/2008-like virus.

Here are a few questions that you may get about this year's vaccine:

If I got vaccinated last year and it's the same vaccine this year, do I need to get the shot again?

That's an obvious question that patients (and myself) will be asking. Well, according to the CDC, it is advisable. They cite studies that demonstrate that post-vaccination antibody titers do decline over the course of a year and to an even greater extent by three to four years post vaccination. They recommend annual vaccination for optimal protection against influenza.

Who should get the 2011-12 influenza vaccine and when?

In keeping with their recommendation from last year, ACIP and CDC state that routine annual influenza vaccination is recommended for all persons aged ≥ 6 months (not just pediatric, geriatric or other at-risk patients).

To allow time for production of protective antibody levels, they also recommend vaccination should optimally occur before onset of influenza activity in the community and that providers offer vaccination as soon as vaccine is available. Furthermore, vaccination should continue to be offered throughout the influenza season (remember, it only takes about two weeks for full immune response in adults).

With respect to pediatric patients, as with last year, it is recommended that children between 6 months and 8 years of age receive 2 doses of influenza vaccine (administered a minimum of 4 weeks apart) during their first season of vaccination to optimize immune response.

Are there any new recommendations specifically for 2011-12 vaccine?

There are a few - for example, because the 2011-12 vaccine is unchanged from last year, children in the 6 month to 8 years of age group who received at least 1 dose of the 2010-11 seasonal vaccine will require only 1 dose of this year's vaccine (instead of two). Conversely, children in this age group who did not receive at least 1 dose of last year's vaccine, or for whom it is not certain whether the 2010-11 seasonal vaccine was received, should receive 2 doses of the 2011-12 seasonal influenza vaccine.

What about the issue of egg allergy?

Several recent studies have documented safe receipt of TIV in persons with egg allergy. In fact, there have been recent revisions of some TIV package inserts noting that only severe allergic reaction (e.g., anaphylaxis) to egg protein is a contraindication.

Each of the following ACIP recommendations applies when considering influenza vaccination of persons who have or report a history of egg allergy. Patients who have experienced only hives following exposure to egg should receive influenza vaccine with the following additional measures:

Do the 2011-2012 seasonal flu vaccines contain thimerosal?

Multi-dose vials do contain thimerosal to safeguard against possible contamination of the vial once it is opened. Single dose units are made without thimerosal as a preservative because they are intended to be opened and used only once. Additionally, the live-attenuated version of the vaccine (FluMist®) is produced in single dose units and does not contain thimerosal.

Is thimerosal in vaccines safe?

There is a large body of scientific evidence on the safety of thimerosal. CDC, FDA and NIH have reviewed the published research on thimerosal and found it to be a safe product to use in vaccines.

With respect to autism, numerous studies have found no association between thimerosal exposure and autism. In Feb 2010, The Lancet retracted a 1998 research paper that started the scare. Despite the research dispelling the connection, there are still parents who are fearful for their children (incidentally, influenza vaccine is the only remaining vaccine used in pediatric patients that contains thimerosal). Work-arounds include single-dose syringes or vials or LAIV (FluMist). Remember also, influenza vaccine is a choice and, although highly recommended, is not a required childhood vaccine.

Any new products available this year?

An intradermal vaccine (Fluzone® Intradermal) was licensed in May 2011 in the U.S. It is approved for persons aged 18 - 64 years. The trivalent vaccine, which comes in single-dose, prefilled microinjection syringes, contains less antigen than intramuscular TIV preparations (9 vs 15 µg of each strain per dose) and comes in a smaller volume (0.1mL vs 0.5 mL) and with a smaller needle. The preferred site for administration is over the deltoid muscle.

In clinical trials, the intradermal vaccine produced immune responses at rates similar to vaccine administered IM.

As for tolerability, injection-site reactions were more frequent with intradermal vaccine compared to the IM vaccine and local reactions, if they occur, are more likely to be visible. Despite the smaller needle, smaller volume and smaller amount of protein, the experience of injection pain was similar for both intradermal and IM vaccines.

Any other thoughts or insights about this year's flu vaccine?

Yes, I think it's important to reiterate something we learned in the 2009 -10 season regarding the routine use of acetaminophen to prevent post-vaccination fevers in children. It had become commonplace for parents to give their children prophylactic acetaminophen in anticipation of fever and/or pain from the vaccine. However, we learned from studies that antibody response following vaccine in children using prophylactic acetaminophen was less than optimal (and this is a population that generally has a low immune response to vaccine to begin with). People forget that low grade fever is part of the normal inflammatory / immune response and that slightly elevated body temperature actually can enhance immune cell proliferation, activation and antibody production. So, the recommendations now are not to routinely pre-treat children with acetaminophen prior to influenza vaccine (or any vaccine). Reserve acetaminophen for post-vaccination significant fevers, or if child is at risk for fever and febrile seizures.

Educate those parents, please. Be pro-active.

Last year seemed to be a relatively mild flu season. Will this year be the same?

We'll see.